The Diagnosis and Treatment of Breakthrough Pain PDF

O A P L
OX FO RD A M E R I C A N P A I N L I B R AR Y
The Diagnosis and

Treatment of
Breakthrough Pain
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O A P L
OXFOR D A MERIC A N P A I N L IB R A R Y
The Diagnosis and Treatment

of Breakthrough Pain
Perry G. Fine, MD
Professor of Anesthesiology
Pain Research Center
University of Utah School of Medicine
Salt Lake City, UT
With contributions by
Andrew N. Davies, FRCP

Consultant in Palliative Medicine
Royal Marsden Hospital, Surrey
Sutton, UK
Scott M. Fishman, MD
Chief, Division of Pain Medicine
University of California
Davis, CA
Executive Series Editor
Russell K. Portenoy, MD
Chairman of Pain Medicine & Palliative Care
Beth Israel Medical Center
New York, NY
2008
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Library of Congress Cataloging-in-Publication Data
Fine, P. G. (Perry G.)

The diagnosis and treatment of breakthrough pain / Perry G. Fine with Andrew N. Davies.
p. ; cm.—(Oxford American pain library)
Includes bibliographical references.
ISBN 978-0-19-536903-8 (alk. paper) 1. Pain–Diagnosis. 2. Pain–Treatment. I. Davies, Andrew,
1963– II. Title. III. Series.
[DNLM: 1. Pain–therapy–Handbooks. 2. Analgesics, Opioid–therapeutic use–Handbooks.
3. Pain–diagnosis–Handbooks. WL 39 F495d 2008]
RB127.F564 2008
616'.0472–dc22 2007040530
9 8 7 6 5 4 3 2 1
Printed in the United States of America
on acid-free paper
Acknowledgments
The authors extend their gratitude to Janet Marietta of the Pain Research
Center, University of Utah, for her very helpful administrative support, ensuring
the timely completion of this handbook
v
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Contents
1 Incidence, prevalence, and characteristics 10

2 Clinical features 22
3 Assessment 34
4 Principles of management 44
5 Oral opioid analgesics 46
6 Oral transmucosal opioid analgesics 64
7 Opioid analgesics via other routes 84
8 Nonopioid pharmacotherapy 94
9 Nonpharmacologic interventions 106
10 Risk assessment and management in long-term opioid therapy 120
Index 134
Chapter 1
Incidence, prevalence,
and characteristics
The term “breakthrough pain” began appearing in the medical literature in the
1980s on the heels of the increased attention, brought about by the World
Health Organization, to the global problem of undertreated cancer pain. During
that time, it became apparent that cancer patients commonly experience inter-
mittent exacerbations of severe pain against a background of continuous, or
baseline, pain. Episodic pains that would “break through” during the treatment
of background pain that was otherwise well controlled through the use of
around-the-clock opioid therapy were categorized by Portenoy and Hagen
(1990) in a seminal work titled “Breakthrough pain: Definition, prevalence and
characteristics.” The definition of breakthrough pain proffered in that article
took root and has been used in pain management parlance ever since (Box 1.1).
1
As opioid therapy has become more commonly used in the treatment of
chronic noncancer pain over the past decade, it has become equally apparent
that a similar pattern of supervening severe pain episodes can confound oth-
erwise well-managed chronic pain (Zeppetella et al., 2001). Recognizing the
similarities of symptoms, independent of underlying pathophysiology, a group
of pain management experts came together in 2006 to create a unifying defi-
nition, based on a review of all the literature on the subject in all populations
studied to date. The more generalized definition incorporates the additional
observation that breakthrough pain seriously disrupts the quality of patients’
lives (Fig. 1.1). Therefore, the term breakthrough pain is now categorically
determined to define the particular clinical circumstance wherein patients
who have controlled baseline pain experience severe episodes of pain that
breaks through the medical therapy (usually opioids) that has relieved the
baseline pain.
Box 1.1 Definitions of breakthrough pain

• A transitory exacerbation of pain that occurs on a background of otherwise stable pain
in a patient receiving chronic opioid therapy (Portenoy and Hagen, 1990).
• In patients with chronic baseline pain undergoing analgesic drug therapy on most days,
breakthrough pain is a transitory pain that lasts from seconds to hours, is more severe
than the background pain, and has a negative effect on function or quality of life (Fine and
Portenoy, 2007).
Although the term breakthrough pain is widely used among pain manage-
Incidence, prevalence, characteristics
ment specialists, other terms are also used in the medical literature to describe
the same phenomenon, including “episodic pain,” “exacerbation of pain,” “pain
flare,” “transient pain,” and “transitory pain” (Colleau, 1999). Nevertheless, it is
important to use terms precisely and unambiguously so that clinical syndromes
can be properly identified and distinguished, both to advance clinical science
through research and to treat patients most appropriately.
Classification
Breakthrough pain can be classified according to its relationship to specific
events or to analgesic dosing (Portenoy and Hagen, 1990; Davies, 2005; Portenoy
et al., 2006):
CHAPTER 1
• Spontaneous pain (also known as “idiopathic pain”): this type of pain occurs
unexpectedly and is unrelated to other known provoking causes.
• Incident pain (also known as “precipitated pain” or, when appropriate,
“movement-related pain”): this type of pain is related to specific events and
can be subclassified into three categories:
1. volitional—pain is precipitated by a voluntary act (e.g., walking);
2. nonvolitional—pain is precipitated by an involuntary act (e.g., coughing);
2
and
3. procedural—pain is related to a therapeutic intervention (e.g., dressing
change).
• End-of-dose failure—This type of pain is related to analgesic dosing (i.e., de-
clining analgesic blood levels).
As discussed earlier, the diagnosis of breakthrough pain relies on the coexis-
tence of “adequately controlled background pain” (Portenoy et al., 2004). Some
authors regard end-of-dose failure as an artifact of actual (rather than ideal)
medication duration of action rather than a subtype of breakthrough pain per
se, and this is remedied by increasing the usual analgesic dose or increasing the
number of dosages per day (e.g., from every 12 hours to every 8 hours for a
continuous-release formulation) (Simmonds, 1999). Nevertheless, convention
developed over the past 15 years categorizes end-of-dose failure as a subtype
of breakthrough pain. Table 1.1 shows the prevalence of breakthrough pain sub-
types in English-language studies applying standard criteria for breakthrough
pain (Portenoy and Hagen, 1990; Fine and Busch, 1998; Portenoy et al., 1999;
Zeppetella et al., 2000; Gomez-Batiste et al., 2002; Hwang et al., 2003).
Epidemiology
Cancer-related pain
Pain is a common problem in patients with cancer. Indeed, the prevalence of pain
has been reported to be 30% to 40% among patients with early disease (receiving
Table 1.1 Prevalence of breakthrough pain subtypes in studies using standard criteria for breakthrough pain
Study Breakthrough pain subtypes Comments
Spontaneous pain Incident pain End-of-dose failure
Portenoy and Hagen, 1990 27% 43% 18% 12% of pain types were “mixed” in nature
(incident and end-of-dose failure). Incident pain
precipitants: movement 22%; coughing 12%;
sitting 4%; touch 2%.
Fine and Busch, 1998 No data 50% No data No further details in paper.
Portenoy et al., 1999 38% 49% 13% Incident pain precipitants: movement 27.8%;
defecation 5.7%; urination 3.8%; coughing 3.7%;
sitting 3.7%; breathing 1.9%; eating/drinking 1.9%.
Zeppetella et al., 2000 59% 24% 17% No further details in paper.
Gomez-Batisteet al., 2002 32% 52% 15% Incident pain precipitants: movement 38%;
eating/drinking 3%; defecation 2%; coughing 2%.
Hwang et al., 2003 17% 64% 19% Data based on initial assessment of patient.
Incident precipitants: movement 44%; coughing
4%; eating/drinking 4%; defecation 2%; sitting 2%.
Portenoy et al., 2006 31% 69% 19% Incident pain precipitants: sitting, standing,
driving, cold weather, stress, eating.
Updated with permission from Davies, 2006.
anticancer therapy) and 70% to 90% among patients with advanced disease
(Foley, 2004).
Similarly, breakthrough pain is a common problem in patients with cancer.
The prevalence of breakthrough pain has been reported to be 19% to 95%
among various groups of patients (Zeppetella and Ribeiro, 2003). This disparity
reflects a number of factors, including differences in the definition used, in the
methods used, and in populations studied (Mercadante et al., 2002). Further-
more, the reporting of breakthrough pain across populations in international
studies is affected by certain language and geographical variables.
Many authors have adopted the diagnostic criteria for breakthrough pain
used by Portenoy and Hagen (1990). These criteria are (1) the presence of
stable analgesia in the previous 48 hours, (2) the presence of controlled back-
ground pain in the previous 24 hours (i.e., average pain intensity of none,
mild, or moderate for over half of the previous 24 hours), and (3) the pres-
CHAPTER 1
ence of “temporary flares of severe or excruciating pain” in the previous

24 hours.
Table 1.2 shows the prevalence of breakthrough pain in English-language
studies applying standard criteria for breakthrough pain (Portenoy and Hagen,
1990; Fine and Busch, 1998; Portenoy et al., 1999; Zeppetella et al., 2000;
Gomez-Batiste et al., 2002; Fortner et al., 2002, 2003; Hwang et al., 2003). It
should be noted that these figures represent the prevalence of breakthrough
4
pain in selected populations of cancer patients rather than the prevalence of

breakthrough pain in the general population of cancer patients.
Interestingly, the International Association for the Study of Pain (IASP) survey
of cancer pain characteristics and syndromes found that pain specialists from
English-speaking (United States, Canada, Australia) and northern/western Euro-
pean countries reported more breakthrough pain than pain specialists from
South American, Asian, and southern/eastern European countries (Caraceni
and Portenoy, 1999; Caraceni et al., 2004).
Breakthrough pain appears to be more common in patients with advanced
disease (Colleau, 2004), in patients with poor performance status (Caraceni et
al., 2004), in patients with pain originating from the vertebral column (and, to a
lesser extent, other weight-bearing bones/joints) (Caraceni et al., 2004), and in
patients with pain originating from the nerve plexuses (and, to a lesser extent,
nerve roots) (Caraceni et al., 2004).
Noncancer chronic pain

Although breakthrough pain is commonly spoken about, there are few studies
that explicate breakthrough pain, using similar criteria as in cancer pain studies,
in noncancer populations with chronic pain syndromes. The most detailed re-
port (Portenoy et al., 2006) characterized breakthrough pain in patients from
several pain programs around the United States. Of 228 patients recruited, 168
(74%) met criteria for breakthrough pain (using an assessment algorithm origi-
nally designed for cancer patients). The most common pain syndrome was low
back pain (52%), with other patients carrying diagnoses of abdominal or pelvic
Table 1.2 Prevalence of breakthrough pain in studies applying standard criteria for breakthrough pain
Study Type of population Prevalence of Comments
breakthrough pain
(see comments)
Portenoy and Hagen, 1990 Hospital inpatients (pain 63% Criteria for BTP outlined in this study.
team referrals) United States 90 patients assessed; 63 patients reported controlled
n = 90 background pain; 41 patients reported BTP.
Fine and Busch, 1998 Palliative care patients Only patients with pain eligible.
(home setting)—United States 86% 22 patients assessed; 22 patients reported
n = 22 background pain; 19 patients reported BTP.
Portenoy et al., 1999 Hospital inpatients—United States 51% Only patients on regular opioid analgesics
n = 178 eligible. 178 patients assessed; 164 patients reported
controlled background pain; 84 patients reported BTP.
Zeppetella et al., 2000 Hospice inpatients—United 89% 381 patients assessed (33 patients not
Kingdom assessable); 245 patients reported background pain;
n = 414 218 patients reported BTP.
Fortner et al., 2002 Cancer patients (home setting) 63% Telephone survey of cancer patients.
—United States 1000 patients assessed; 256 patients reported regular
n = 1000 analgesic usage; 160 patients reported BTP.
Gomez-Batiste et al., 2002 Palliative care patients 41% 397 patients assessed (10 patients not
(various settings)—Spain assessable); 163 patients reported BTP.
n = 407
Fortner et al., 2003 Cancer patients (outpatient 23% Nonspecific data relating to the patients’ pain
setting)—United States scores and pain medications were used to
n = 373 diagnose presence of BTP.
373 patients assessed; 144 patients reported background
pain; 33 patients were deemed to have BTP.
(continued)
Table 1.2 (Continued)
Study Type of population Prevalence of C omments
breakthrough pain
(see comments)
Hwang et al., 2003 VA hospital patients 70% Only patients with pain eligible.
(inpatient/outpatient setting) 74 patients assessed, 74 patients reported
—United States background pain; 52 patients reported BTP.
n = 74 After a week of treatment, BTP prevalence decreased
from 70% to 36%.
Portenoy et al., 2006 Chronic (noncancer) pain patients 74% Telephone survey employing assessment tool
patients (outpatient setting, designed for cancer patients. Inclusion criteria:
9 pain programs) patients with well-controlled baseline pain using
—United States stable opioid dose; episodic pains had to be in “severe”
n = 228 or “excruciating” range to qualify as BTP.
BTP: breakthrough pain; VA: Veterans Affairs.
pain, arthritis, neck pain, complex regional pain syndrome, fibromyalgia, headache,

and various neuropathies.
Etiology
The etiology of the breakthrough pain is often the same as that of the background
pain (Portenoy and Hagen, 1990; Portenoy et al., 1999; Portenoy et al., 2006).
Thus, breakthrough pain may be due to (a) a direct effect of the underlying dis-
ease, (b) an indirect effect of the underlying disease (i.e., secondary to disability or
deconditioning), (c) a direct or an indirect effect of the treatment, or (d) an effect
of a concomitant illness (Zeppetella and Ribeiro, 2003). Indeed, breakthrough
pain may be experienced by patients with all stages of cancer (at diagnosis, during
active treatment, during remission, during relapse/progression, following cure)
CHAPTER 1
(Portenoy and Hagen, 1990; Portenoy et al., 1999) and by patients with chronic
pain syndromes of varying duration (Portenoy et al., 2006). Table 1.3 shows the
etiology of breakthrough pain in relevant published studies (Portenoy and Hagen,
1990; Portenoy et al., 1999; Zeppetella et al., 2000; Portenoy et al., 2006).
Not surprisingly, the pathophysiology of the breakthrough pain is also often the
same as that of the background pain. Thus, breakthrough pain may be (a) nocicep-
tive, (b) neuropathic, or (c) mixed (nociceptive and neuropathic). Occasionally, the
7
cause may be undetermined, in which case the condition would best be described
as breakthrough pain of indeterminate pathophysiology. Table 1.3 shows the
pathophysiology of breakthrough pain in relevant published studies (Portenoy and
Hagen, 1990; Portenoy et al., 1999; Zeppetella et al., 2000; Portenoy et al, 2006).
Clinical features
Breakthrough pain is not a single entity but rather a spectrum of very different
entities. The clinical features vary from individual to individual, and may vary
within an individual over time (Portenoy, 1997). However, the clinical features
of the breakthrough pain are often related to the clinical features of the back-
ground pain (Portenoy et al., 1999).
There appears to be an association between the presence of breakthrough
pain and the intensity/frequency of the background pain; that is, patients with
breakthrough pain often have more severe or more frequent background pain
(Portenoy et al., 1999; Caraceni et al., 2004). Indeed, breakthrough pain is asso-
ciated with poor overall pain control (Mercadante et al., 1992; Bruera et al.,
1995) and, not surprisingly, decreased satisfaction with overall pain control
(Zeppetella et al., 2000). In patients with cancer, breakthrough pain is also a
marker of poor prognosis (Bruera et al., 1995), and its prevalence appears to in-
crease with progressive, far-advanced disease (Fine and Busch, 1998).
Breakthrough pain may result in a number of other physical, psychological,
and social problems (see Chapter 2). Indeed, the presence of breakthrough pain
Table 1.3 Etiology/pathophysiology of breakthrough pain
Study Etiology of breakthrough pain Pathophysiology of breakthro ugh pain
Primarily Caused by cancer Caused by Nociceptive Neuropathic Mixed pain
caused by treatment another disease pain pain
malignancy (chemotherapy or
radiation therapy;
surgery)
Portenoy and Hagen, 1990* 76% 20% 4% 53% 27% 20%
Portenoy et al., 1999* 65% 35% 0% 38% 10% 52%
Zeppetella et al., 2000* 71% 11% 19% 74% 9% 16%
Portenoy et al., 2006† 42% 18% 40%
* Cancer patients.
†
Noncancer patients.
can have a significant negative impact on quality of life (Portenoy et al., 1999;

Hwang et al., 2003; Taylor et al., 2007). The degree of interference seems to be
related to the characteristics of the breakthrough pain: patients with sponta-
neous pain (Portenoy et al., 1999) and patients with severe pain (Swanwick et
al., 2001) may experience particular problems.
Not surprisingly, breakthrough pain is associated with the increased use of
health-care services (i.e., increased outpatient visits, increased inpatient admis-
sions) (Fortner et al., 2002). The result of the increased use of health-care ser-
vices is an increase in direct costs (e.g., physician time and expense, prescription
costs) and in indirect costs (e.g., transportation costs, time away from work) for
all components of the health-care system (public and commercial insurance),
the patient, and caregivers (Fortner et al., 2003).
CHAPTER 1
Conclusion
Poorly controlled pain has serious consequences on peoples’ lives and is a ma-
jor public health problem. Breakthrough pain is a common occurrence in pa-
tients with chronic pain syndromes of various etiologies and must be evaluated
and treated concomitantly in order to mitigate against the myriad ill conse-
quences of inadequate pain management. The following quotes from patient in-
9
terviews capture the powerful impact of pain and its relief:
You can’t find it [inner peace] in that darkness of pain . . . I can’t emphasize
that the pain blinds you to all of that, blinds you to all that’s positive. I mean
the real bad pain . . . it just closes you down. You just can’t get through it . . .
it’s an iron door and it’s one thing you don’t wanna go through . . . you just
wanna, wanna stop.
Once the pain was relieved it was the most beautiful experience of my life,
to be able to participate and control the pain. (Coyle, 2004)
Later chapters will address issues of the assessment, the general principles of
management, and specific options for the management of breakthrough pain.
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Chapter 2
Clinical features
Breakthrough pain can have multiple causes with multiple pathophysiologies,
and it can present with numerous clinical features and complications. In most
patients, due to its severity (by definition) and impact on quality-of-life indica-
tors, breakthrough pain is a cause of significant morbidity. From a practical
standpoint, breakthrough pain is recognized, and most readily differentiated, by
its temporal pattern. This is best described visually (Fig. 2.1).
Classification
As discussed in Chapter 1, breakthrough pain can be classified according to its
relationship to specific events or to analgesic dosing (Davies, 2005):
• Spontaneous pain (also known as idiopathic pain): this type of pain occurs
13
unexpectedly and seems to be most commonly caused by underlying neuro-
logical pain-inducing disorders.
• Incident pain (also known as precipitated pain or, when appropriate,
movement-related pain): this type of pain is related to specific events and
can be subclassified into three categories:
1. volitional—pain is precipitated by a voluntary act (e.g., walking);
2. nonvolitional—pain is precipitated by an involuntary act (e.g., coughing);
and
3. procedural—pain is related to a therapeutic intervention (e.g., wound-
dressing change).
• End-of-dose failure: this type of pain is related to analgesic dosing (i.e., de-
clining, subtherapeutic analgesic blood levels).
To create a clinical context for the categorization of breakthrough pain sub-
types presented in Table 1.2, case histories from patients with the different
types of breakthrough pain are exemplified in Boxes 2.1–2.3.
Breakthrough pain can also be classified according to the underlying patho-
physiology of the pain:
• Nociceptive pain: this type of pain is triggered by activation of somatic or
visceral nociceptors (usually as a result of noxious mechanical, thermal, or
inflammatory stimuli) and can be subclassified into two categories:
1. somatic pain—pain originates from the cutaneous and musculoskeletal
tissues of the body; and
2. visceral pain—pain originates from the organs of the body.
Clinical features
A Breakthrough Uncontrolled Baseline Pain

Pain
Basal
Pain Intensity Analgesic
Pain Intensity
CHAPTER 2
B Breakthrough Intermittent Pain

Pain
Basal
Analgesic
Pain Intensity
Pain Intensity
14
C Rescue Dose
Around-the-Clock
Medication
“Breakthrough”
Pain Episode
Pain Intensity
Figure 2.1 Patterns of pain. (A) Control of baseline (basal persistent) pain reveals break-
through pain. (B) By definition, breakthrough pain requires the presence, and control, of base-
line (basal persistent) pain. Intermittent episodic acute pain requires diagnosis and treatment
but does not require around-the-clock (basal analgesic) opioid therapy. (C) Treating temporal
patterns of pain with pharmacokinetically matched analgesic therapies for optimal pain control.
• Neuropathic pain: this type of pain results from injury or pathological

changes in peripheral or central neural structures.
• Mixed pain: this refers to a combination of nociceptive and neuropathic pain.
Table 1.3 shows the breakdown of the different pathophysiologies of break-
through pain in studies that have applied standard criteria for diagnosing break-
through pain (Portenoy and Hagen, 1990; Portenoy et al., 1999; Zeppetella et
al., 2000; Hanks et al., 2004).
Box 2.1 Case history of patient with spontaneous-type
breakthrough pain
Mr. PW is a 50-year-old man with localized Ewing’s sarcoma of the sacrum. His chief
complaint was excruciating pain in the penis/scrotum that was determined to be referred
from tumor encroachment. This pain was intermittent in nature, occurring 3 to 4 times per
hour, and lasting <1 minute per episode. There were no precipitating or aggravating factors.
He also complained of moderate pain in the gluteal area and legs. This pain was persistent
in nature. The patient had been receiving acetaminophen and low doses of gabapentin for
the pain.
Tramadol 50 mg was added (one to two tablets up to four times per day), which
resulted in good control of the persistent pain without adverse effects, but there was no
improvement in spontaneous pains, then categorized as breakthrough pains. The gabapentin
was titrated upward to a total dose of 900 mg TID, which resulted in good control of the
spontaneous pain. During this period, the patient also received an epidural injection of ste-
roid (which had little effect on the pain) and a course of radical radiotherapy to the sacrum
(which initially aggravated the pain). In due course, following completion of his multimodal
oncological therapy, the patient was able to discontinue all of the aforementioned analgesics.
Reprinted with permission, Davies, 2006.
Box 2.2 Case history of patient with incident-type

breakthrough pain
Mr. ML was a 64-year-old man with advanced renal cell carcinoma. He had widespread
bone metastases, including disease in the thoracic spine, lumbar spine, and pelvis (particularly
the left acetabulum). He complained of low back and hip pains, which were present at rest
but were more severe on movement. As a result of the incident pain, he was rendered bed-
bound. Moreover, movement in the bed also resulted in significant pain. He was unable to
use NSAIDs due to a history of severe peptic ulcer disease.
He was started on immediate-release oxycodone tablets due to concern about
accumulation of toxic morphine metabolites in view of his reduced creatinine clearance, and
the dose was gradually titrated upward in an attempt to control the pain. The pain at rest was
well controlled, and he was able to sleep comfortably. However, the pain on transference
from bed to chair or during short walks continued to cause severe pain, and further upward
titration of the oxycodone dose resulted in the development of excessive sedation. A dose
of oxycodone continuous-release formulation (60 mg q12h) was well tolerated. Fentanyl
buccal tablet, starting at 100 µg and titrated to 200 µg, was used 15 minutes prior to the
patient’s getting out of bed and several times throughout the day to encourage and facilitate
ambulation. This provided satisfactory prevention and relief of his incident breakthrough pain.
Subsequently, following a course of palliative radiotherapy to the lumbar spine, the dose of
oxycodone was able to be reduced to 20 mg q12h, but he
continued to use FBT 200 µg up to QID for breakthrough pain.

Clinical features
Box 2.3 Case history of patient with end-of-dose failure

Mr. GT is a recently retired accountant with insulin-dependent diabetes who has
maintained fastidious control over his blood sugars for many years. Nevertheless, he has
developed painful peripheral neuropathy involving his feet that interferes with his daily
activities. Until recently he had been quite active, but he has had to curtail his long-standing
enjoyment of twice-weekly golf outings with his friends and evening walks with his wife due
to pain. His inability to exercise routinely has caused his blood sugar control to become
CHAPTER 2
more erratic, and he is feeling depressed. The pain was constant and was aggravated by
walking, and it persisted even after Mr. GT sat down. He was able to tolerate duloxetine
30 mg BID, and he then added sustained-release morphine 15 mg po q12h (after titration
with immediate-release hydrocodone/acetaminophen) to get baseline pain levels
throughout most of the day and night down from 6- to 8/10 to 2/10 in intensity. He used a
senna preparation to maintain satisfactory bowel function. With this, his mood and usual
daily activity regimen improved greatly, but he still felt “down” and “tired out” by a
recrudescence of severe pain toward the late afternoon and severe pain that would cause
early-morning awakening. His sustained-release morphine was increased to an every-8-
hours dosing schedule, eliminating the periods of end-of-dose-failure breakthrough pain.
General features
16
As a group, breakthrough pain is not a single entity but rather a spectrum of

very different entities. The clinical features vary from individual to individual and
may vary within an individual over time (Portenoy, 1997). However, the clinical
features of an individual’s breakthrough pain are often related to the clinical fea-
tures of the background pain (Portenoy et al., 1999). Table 2.1 shows some of
the characteristics of breakthrough pain described in English-language studies
that have applied standard criteria for diagnosing breakthrough pain (Portenoy
and Hagen, 1990; Fine and Busch, 1998; Portenoy et al., 1999 ; Zeppetella et al.,
2000; Gomez-Batiste et al., 2002; Hwang et al., 2003; Hanks et al, 2004).
The diagnosis of breakthrough pain depends on the presence of well-
controlled background pain, and so the initial presentation of the breakthrough
pain often coincides with the successful management of the background pain.
The differential diagnosis of breakthrough pain includes the progression of un-
derlying pathology or the development of new pathology (e.g., pathological
fracture in cancer patients, vertebral compression fracture in degenerative
spine disease patients) (Patt and Ellison, 1998; Hadjistavropoulos et al., 2007).
The development and progression of breakthrough pain also may signify prob-
lems related to the analgesic regimen (e.g., reduced duration of action or devel-
opment of tolerance) (Patt and Ellison, 1998; Fine and Herr, 2006).
In addition to these aforementioned causes, there appears to be an associa-
tion between the presence of breakthrough pain and the intensity of the back-
ground pain insofar as patients with breakthrough pain often have more severe
background pain (Portenoy et al., 1999; Caraceni et al., 2004). Indeed, break-
Table 2.1A Characteristics of breakthrough pain in studies applying standard criteria for breakthrough pain
Study BTP connected to Number of types Number of episodes of Comments
background pain of BTP BTP (episodes/day)
Portenoy and 96% 1 pain: 78% Median 4 The patient with 3600
Hagen, 1990 2 pains: 20% (range 1 to 3600) episodes/day had a
3 pains: 2% rib fracture and a
persistent cough.
Fine and — — Mean 2.9
Busch, 1998 (range 1 to 5.5)
Portenoy 100% 1 pain: 83.1% Median 6
et al., 1999 2 pains: 14.5% (range 1 to 60)
3 pains: 2.4%
Zeppetella 89% Mean 2 pains Mean 4
et al., 2000 (range 1 to 5) (range 1 to 14)
Gomez-Batiste — — Mean 1.5
et al., 2002 (range 0 to 5)
Hwang 75% 1 pain: 79% Median 5 Data based on initial
et al., 2003 ≥2 pains: 21% (range 1 to 50) assessment of patients.
Portenoy — — Mean 2.4 Chronic (noncancer)
et al., 2006 Median 2.0 pain patients; majority with
chronic low back pain
BTP: breakthrough pain. Updated with permission from Davies, 2006.
Table 2.1B Additional characteristics of breakthrough pain in studies applying standard criteria for breakthrough pain
Study Duration of BTP Characteristics of BTP Characteristics of Comments
(min) (temporal) BTP (intensity)
Portenoy and Hagen, 1990 Median duration: 30 Rapid onset: 43% Severe/excruciating: 100% Only patients with severe or
(range 1 to 240) Gradual onset: 57% excruciating pain classified
as having BTP
Fine and Busch, 1998 Mean duration: 52 — Mean intensity: 7/10 —
(range <1 to 240) (range 3/10 to 10/10)
Portenoy et al., 1999 — Median time to peak Severe/excruciating: 100% Only patients with severe or
intensity: 3 min excruciating pain classified
(range 1 s to 30 min) as having BTP
Zeppetella et al., 2000 73% episodes ≤ 30 Rapid onset: 49% Slight: 16% —
Gradual onset: 51% Moderate: 46%
Severe: 36%
Excruciating: 2%
Gomez-Batiste et al., 2002 Mean duration: 33.8 Rapid onset: 60% Median intensity: 8 /10 —
(range 1 to 180) Gradual onset: 39% (range 2/10 to 10/10)
(Not recorded: 1%)
Hwang et al., 2003 Median duration: 15 Rapid onset: 62% Severe/excruciating: 94% Only patients with severe or
(range 1 to 120) Gradual onset: 38% excruciating pain classified
as having BTP
Portenoy et al., 2006 Median duration: 60 Rapid onset: 55% Severe: 50% Chronic (noncancer) pain patients;
Mean duration: 107.4 Gradual onset: 45% Excruciating: 50% majority of patients with
(range 1 to 720) chronic low back pain
[33% episodes < 30 ]
BTP:breakthrough
BTP: breakthroughpain.
pain. Updated with permission from Davies, 2006.
through pain has been reported to be associated with poor overall pain control
Clinical features
(Mercadante et al., 1992; Bruera et al., 1995) and, not surprisingly, with de-
creased satisfaction with overall pain control (Zeppetella et al., 2000).
Early reports revealed no relationship among the various clinical features of
breakthrough pain and its different etiologies (i.e., spontaneous pain, incident
pain, end-of-dose failure) (Portenoy and Hagen, 1990). More recently, it has
been reported that incident pains tend to be more rapid in onset (incident pain:
CHAPTER 2
76%; spontaneous pain: 52%; end-of-dose failure: 24%) and tend to have a
shorter median duration of action (incident pain: 20 minutes; spontaneous pain:
30 minutes; end-of-dose failure: 30 minutes) (Gomez-Batiste et al., 2002). Simi-
larly, neuropathic breakthrough pains have a shorter duration of action (neuro-
pathic pain: 91% < 30 minutes; somatic: 69% < 30 minutes; visceral: 62% < 30
minutes) (Zeppetella et al., 2000). These temporal patterns and relationships
have important implications for prevention and effective treatment, which are
elaborated on in later chapters. It should be noted that patients with different
pain pathophysiologies tend to report similar pain qualities. For example, patients
with nociceptive causes for their pain report “burning,” “scalding,” “shooting,”
and “pricking” pains as much as patients with neuropathic pain, which can con-
found diagnosis and treatment (Rasmussen et al., 2004).
Other features
19
Chronobiology of breakthrough pain
It appears that there is a circadian variation in the intensity of background pain
in patients with cancer (Labrecque and Vanier, 1995). Studies have demon-
strated a reduction in the intensity of background pain during the night/early
morning (Wilder-Smith and Wilder-Smith, 1992; Wilder-Smith et al., 1992).
Similarly, there also appears to be circadian variation in the occurrence of
breakthrough pain in patients with cancer. For example, in a mixed population
of hospice patients (i.e., patients with end-stage, terminal diseases), 86% experi-
enced breakthrough pain during the day, but only 45% of patients experienced
breakthrough pain during the night (Fine and Busch, 1998). In addition, various
studies have demonstrated a reduction in the use of breakthrough-pain medica-
tion during the night and early morning (Bruera et al., 1992; Citron et al., 1992).
The reasons for the circadian variation in breakthrough pain have yet to be
elucidated, but because most people are generally less active during the night, it
is logical that patients whose breakthrough pain is precipitated by specific (e.g.,
weight-bearing) activities would be less likely to experience incident pain during
this time. Furthermore, there appears to be a circadian variation in the metabo-
lism of certain analgesics (e.g., morphine), which may be of significance with re-
gard to pain control (Gourlay et al., 1995).
Interestingly, delirium results in an alteration in the circadian variation in
breakthrough pain. In support of this, Gagnon et al. (2001) reported that pa-
tients without delirium used breakthrough medication more often during the
day, while patients with delirium used breakthrough medication more often
Clinical features
during the evening. It should be noted that patients with delirium are often
more active—or more restless—during the evening/night, and so more likely to
experience incident pain at these times. Also, their behaviors (e.g., crying out,
moaning) may be interpreted, accurately or inaccurately, as being precipitated
by pain (Hadjistavropoulos and Fine, 2007).
CHAPTER 2
Complications of breakthrough pain

Breakthrough pain can result in a number of physical, psychological, and social
sequelae:
• Physical complications: Breakthrough pain may be associated with a vari-
ety of physical problems, particularly in patients with volitional (movement-
related) incident pain. Such patients have difficulty mobilizing, which may lead
to pain-related reduction in functional capacities (see next point) (Portenoy
et al., 1999; Hwang et al., 2003). Sleep and mood disorders commonly result
from poorly treated pain (Portenoy et al., 1999; Hwang et al., 2003).
• As a result of decreased mobility, patients may develop a range of other
physical problems, including muscle wasting, joint stiffness, pressure sores,
constipation, deep vein thrombosis, and pneumonia.
• Psychological complications: The presence of breakthrough pain has
20
been linked to the presence of mood disturbances (Hwang et al., 2003),

most notably anxiety and depression (Portenoy et al., 1999) (see Fig. 2.2). In-
adequately treated pain of any type may extend into the broader realm of
“suffering” due to its impact on personal integrity. The “meaning” of the pain
(i.e., its implications), the physical complications of pain, and its treatment-
related adverse effects (e.g., constipation, nausea, cognitive impairment, etc.),
combined with the social complications of chronic or ongoing pain (e.g.,
change in work status, identity, stigmatization, etc.), create complex psycho-
logical challenges that must be recognized by the practitioner in order to
optimize therapy.
• Social complications: Breakthrough pain may be associated with a variety
of social problems, particularly in patients with volitional (movement-
related) incident pain. Such patients may have difficulty undertaking essential
activities of daily living, which may necessitate increased caregiver support.
Moreover, patients may be unable to engage in their usual social and work-
related activities, which may result in financial hardship for them and their
dependents (Portenoy et al., 1999; Hwang et al., 2003).
• Societal complications: Indirect costs of breakthrough pain are difficult
to calculate, although medical expenses, including physician visits and hospi-
talizations, have been reported to be appreciably greater in patients experi-
encing breakthrough pain compared to those who are not (Fortner et al.,
2002) (see Table 2.2). One can extrapolate, then, from the evidence of
breakthrough pain leading to increased medical utilization and decreased pa-
tient satisfaction that indirect costs (costs to society) would likely increase.
Clinical features
Patients without BTP
40 34.2
Pain Interference Patients with BTP
30 24.8
16.7 18.2 17.9 16.7
20
CHAPTER 2
12.8 9.9
10
0
Total Score Beck Beck Background
Depression Anxiety Pain Intensity
Figure 2.2 Effect of breakthrough pain (BTP) on mood (cancer patients). Adapted from
Portenoy et al., 1999.
Table 2.2 Costs associated with breakthrough pain

Frequency of Cost of hospitalization
hospitalization (millions of dollars)
Patients with BTP* 36.9% 1.7
Patients without BTP 22.5% 0.192
21
BTP: breakthrough pain.
* Significant at the 0.02 level.
Extracted with permission from Fortner et al., 2002.
It can be concluded that the presence of breakthrough pain can have a sig-
nificant and negative impact on quality of life (Portenoy et al., 1999; Hwang et
al., 2003). The degree of interference seems to be related to the characteris-
tics of the breakthrough pain, with patients who experience spontaneous pain
(Portenoy et al., 1999) and patients with more severe pain (Swanwick et al.,
2000) being prone to more problems. In addition, the ability to cope with break-
through pain seems to be related to the underlying etiology of the breakthrough
pain. Patients with cancer-related pain (with all its associated implications) may
have more problems coping than do patients with cancer-treatment-related pain
(Foley, 1985).
References
Bruera E, Macmillan K, Kuehn N, Miller MJ. Circadian distribution of extra doses of nar-
cotic analgesics in patients with cancer pain: A preliminary report. Pain. 1992;
49:311–314.
Bruera E, Schoeller T, Wenk R, et al. A prospective multicenter assessment of the Ed-
monton Staging System for cancer pain. Journal of Pain and Symptom Management.
1995;10:348–355.
Caraceni A, Martini C, Zecca E, et al. Breakthrough pain characteristics and syndromes in
Clinical features
patients with cancer pain. An international survey. Palliative Medicine. 2004;18:177–183.

Citron ML, Kalra JM, Seltzer VL, Chen S, Hoffman M, Walczak MB. Patient-controlled
analgesia for cancer pain: A long term study of inpatient and outpatient use. Cancer In-
vestigation. 1992;10:335–341.
Davies A. Current thinking in cancer breakthrough pain management. European Journal of
Palliative Care. 2005;12(Suppl):4–6.
CHAPTER 2

2006.
Fine PG, Herr KA. Efficacy, safety and tolerability of pharmacotherapy for management of
persistent pain in older persons. Annals of Long-term Care: Clinical Care and Aging.
2006;14(3):25–33.
Foley KM. The treatment of cancer pain. New England Journal of Medicine. 1985;313:84–95.
Gagnon B, Lawlor PG, Mancini IL, Pereira JL, Hanson J, Bruera ED. The impact of delirium
on the circadian distribution of breakthrough analgesia in advanced cancer patients.
Journal of Pain and Symptom Management. 2001;22:826–833.
22

ment. 2002;24:45–52.
Gourlay GK, Plummer JL, Cherry DA. Chronopharmacokinetic variability in plasma mor-
phine concentrations following oral doses of morphine solution. Pain. 1995;61:
375–381.
Hadjistavropoulos T, Fine PG. Chronic pain in older persons: Prevalence, assessment, and
management. Reviews in Clinical Gerontology. 2007;16:1–11.
Hadjistavropoulos T, Herr K, Turk D, et al. An interdisciplinary expert consensus state-
ment on assessment of pain in older persons. Clinical Journal of Pain. 2007;23:S1–S43.
Labrecque G, Vanier MC. Biological rhythms in pain and in the effects of opioid analgesics.
Pharmacology and Therapeutics. 1995;68:129–147.
Mercadante S, Maddaloni S, Roccella S, Salvaggio L. Predictive factors in advanced cancer
pain treated only by analgesics. Pain. 1992;50:151–155.
Patt RB, Ellison NM. Breakthrough pain in cancer patients: Characteristics, prevalence,
and treatment. Oncology (Huntington). 1998;12:1035–1052.
cology. 1997;5(S16):7–12.
Hanks G, Portenoy RK, Forbes K. Difficult pain problems: An integrated approach. In
Doyle D, Hanks G, Cherny N, Calman K (eds.), Oxford Textbook of Palliative Medi-
cine (3rd ed., pp. 438–458). Oxford, UK: Oxford University Press, 2004.
Pain. 1990;41:273–281.
Clinical features
Rasmussen PV, Sindrup SH, Jensen TS, Bach FW. Symptoms and signs in patients with sus-
pected neuropathic pain. Pain. 2004;110:461–469.
CHAPTER 2
Wilder-Smith CH, Schimke J, Bettiga A. Circadian pain responses with tramadol (T), a
short-acting opioid and alpha-adrenergic agonist, and morphine (M) in cancer pain.
Presented at the 5th International Conference on Chronopharmacology, July 1992.
Wilder-Smith CH, Wilder-Smith OH. Diurnal patterns of pain in cancer patients during
treatment with long-acting opioid. Presented at the 5th International Conference on
Chronopharmacology, July 1992.
ment. 2000;20:87–92.
23
Chapter 3
Assessment
The successful management of breakthrough pain depends on adequate assess-
ment, appropriate treatment, and adequate reassessment (i.e., determination of
whether therapeutic goals have been reached without excessive adverse effects
from the treatment) (Davies, 2002). Inadequate assessment may lead to ineffec-
tive treatment, or even inappropriate treatment. Similarly, inadequate reassess-
ment may lead to continuance of ineffective or harmful treatment.
The objectives of assessment are to determine the etiology of the pain (e.g.,
cancer- related, non-cancer-related), the pathophysiology of the pain (i.e., noci-
ceptive, neuropathic, mixed), and factors that would support, or contraindicate,
particular treatment strategies. The assessment of breakthrough pain is similar
to the assessment of background pain, but the two must be differentiated.
25
Assessment procedure
The assessment of pain primarily depends on basic clinical skills (i.e., taking a
history and performing an examination) (Davies, 2002). It is important to take a
general history as well as a pain history. In particular, patients should be
screened for psychological, spiritual, and social factors that may be contributing
to their experience of pain (Dworkin et al., 2005). Similarly, it is important to
perform a general physical examination as well as a physical examination of the
painful area, including a “functional exam”—that is, one that either leads to the
symptoms elaborated in the history or demonstrates that the analgesic regimen
is adequate. Corroborating imaging studies (e.g., plain radiographs, MRI, bone
scans) can be extremely useful in the assessment of a pain complaint or a new
finding that evokes pain on clinical examination. However, caution must be ex-
ercised in not overinterpreting results, whether negative or positive, insofar as
imaging studies, especially of the spine, may correlate poorly with the presence
or absence of pain (Weiner et al., 1994).
A detailed pain history should be taken for all patients. The features of the
pain that need to be determined include the following (Foley, 2004):
• onset of pain
• temporal pattern of pain (see Fig. 2.1)
• site of pain
• radiation of pain
• quality (character) of pain
• intensity (severity) of pain
Assessment
• exacerbating factors (what makes the pain start or get worse?)

• relieving factors (what prevents the pain or makes it better?)
• response to analgesics (including attitudes and concerns about opioids)
CHAPTER 3
• response to other interventions (including use of “complementary and alter-

native” [CAM] medicines and therapies)
• associated physical symptoms (The presence of other symptoms may help to
determine the etiology of the pain. For example, the presence of neuro-
logical symptoms suggests an underlying neuropathic component to the pain
[e.g., sensory disturbance] [Bennett, 2001].)
• associated psychological symptoms
• interference with activities of daily living (It is important to ascertain the
global impact of the pain. Activities of daily living can be used as a surrogate
marker of the response to treatment.)
A thorough physical examination must be performed on all patients. The exam-
ination should include a neurological examination of the relevant area, because
the presence of neurological signs suggests an underlying neuropathic compo-
nent to the pain (Bennett, 2001). It can be useful to reproduce the patient’s pain
by using provocative maneuvers (e.g., palpation, passive movement, active func-
tional evaluation) (Hagen, 1999). However, it is important that the benefits of
26
such maneuvers (i.e., improved understanding of the pain) outweigh the costs
of these maneuvers (i.e., causation of the pain) incurred by the patient. To as-
sess for incident breakthrough pain, it may be illuminating both to reproduce an
activity that incites pain (e.g., weight-bearing or walking) and to determine the
effectiveness (pain reduction and tolerability) of a proposed treatment. To do
so, it is important to have the treatment ready for use by the patient in the clin-
ical setting. This may require preplanning, such as writing a prescription for the
patient in advance of the appointment.
It should be noted that many patients have more than one type of break-
through pain (Portenoy and Hagen, 1990; Portenoy et al., 1999). Each break-
through pain should be individually assessed, because each breakthrough pain
may require a different form or timing of treatment.
Reassessment procedure
The primary objective of reassessment is to determine the efficacy and tolera-
bility of any therapeutic intervention. A further objective of reassessment is the
identification of significant changes in the breakthrough pain. For example, in-
creasing pain in a bone may represent impending fracture of that bone, which
may necessitate a more intensive therapeutic intervention, such as surgical sta-
bilization.
Various outcome measures have been used to assess the efficacy of thera-
peutic interventions, including (a) intensity of pain, (b) distress of pain, (c) pain
relief, (d) satisfaction with treatment, (e) improvement in function, and (f )
Assessment
improvement in quality of life (Davies, 2002). The different outcome measures
relate to different aspects of the pain. Consequently, there is often a poor cor-
relation between the results obtained with different outcome measures. For ex-
ample, in one study involving cancer patients, the percentage of subjects who
CHAPTER 3
were “inadequately treated” varied from 16% to 91% depending on the specific
outcome measure used (deWit et al., 1999).
A Unidimensional Pain Assessment Scales

Visual Analog Scale
No pain Worst
possible pain
Verbal Pain Intensity Scale
No pain Mild pain Moderate pain Severe pain Very severe Worst
pain possible pain
0-10 Numeric Pain Intensity Scale
0 1 2 3 4 5 6 7 8 9 10
No pain Moderate Worst
pain possible pain
Pain Thermometer
27
Pain as bad as it could be Adult Pain Faces
Extreme pain
Moderate pain
Severe pain
Mild pain
Slight pain
No pain
B Multidimensional Pain
Assessment Instruments
• Brief Pain Inventory (BPI)
– Resource-intensive and time-consuming
– Evaluates effects on function and QoL
• Pain Diary
Daily Pain Log Daily Pain Chart
10 X X
9 XXXXX
XX XX
8 X
– Useful for both initial 7 X
X X X
6 X
XX X XX X
patient evaluation and 5 X X X X X X X XX XXX
X X X X X X X XXXXX X X X
4 X X X X X X X X
evaluating/modifying 3 X XX X
X X
1 X X
0 X X X X X X X X X X X X X X
– More reliable than
7
8
9
10
1
2
3
4
5
7
8
9
10
1
2
3
4
5
11
11
6 am
12 pm
6 pm
12 am
recall memory
– Requires significant Senna-S 1
1 Oxycodone 51R 15 0 0 5 5.5 15 5 5
2
time commitment 3
4
to interpret 5
X Leg Burning X Back X Knee XXXSSShhhoooooottitin
innggg&
&&LLLeeeggg
Figure 3.1 Example of pain measurement scales. (A) Adapted with permission from Elsevier
(Daut et al., 1983; Fishman et al., 1987; Bierri et al., 1990; Herr and Mobily, 1993; Collins and
McQuay, 1997). (B) Reproduced with permission (Herr and Mobily, 1993; Cleeland et al.,
1994).
All of the aforementioned outcome measures have limitations. For example,
Assessment
pain relief is related to the change in pain intensity over a period of time; that is,
it is dependent on the patient’s recollection of the baseline pain intensity. There
is little consensus on the specific outcome measure that should be used to as-
sess treatment response (deWit et al., 1999). Nevertheless, it is important that
CHAPTER 3
patient-appropriate outcome measure(s) be used to assess treatment responses

in all patients (Davies, 2002; Dworkin et al., 2005).
Outcome measures are most commonly obtained through verbal, numerical,
or visual analogue scales, with pictorial variations having been created and vali-
dated for patients unable to use these other tools (Fig. 3.1A). Studies have
shown good correlation between the results obtained with these different
scales (McQuay and Moore, 1998). Multidimensional scales (Fig. 3.1B) further
elucidate the impact of pain on activity, mood, and other quality-of-life indica-
tors, in addition to providing insight into sensory and temporal characteristics of
pain. Patients with advanced illness, severe frailty, or cognitive impairment may
have difficulty in completing assessment tools. For example, in one study in-
volving palliative care inpatients, 45% of the subjects were unable to complete
any of the outcome measures (mainly because of cognitive impairment) (Shan-
non et al., 1995). On the more sanguine side, in a mixed-diagnosis population of
hospice patients, the majority were able to complete a quality-of-life survey
tool that used a Likert scale within 2 weeks prior to their deaths (Fine and
28
Busch, 1998).
It should be noted that studies suggest that the formal measurement of pain
leads to the improved management of pain. For example, in one study involving
oncology outpatients, subjects whose outcome measures were reviewed were
more likely to have had an improvement in their background pain intensity at
follow-up than were subjects whose outcome measures were unavailable for
review (Trowbridge et al., 1997).
Assessment tools
A number of different tools have been developed for the assessment of cancer-
related and noncancer chronic pain (Melzack, 1987; Cleeland and Ryan, 1994;
Caraceni et al., 2002). However, these tools focus on the background pain
rather than on the presence or absence of breakthrough pain. Portenoy and
Hagen (1990) developed the Breakthrough Pain Questionnaire to specifically
assess breakthrough pain in cancer patients. In various forms, and with modifi-
cation over the years, this scale has been used in several clinical studies involv-
ing cancer and noncancer populations (Portenoy and Hagen, 1990; Portenoy et
al., 1999; Portenoy et al., 2006).
The Breakthrough Pain Questionnaire enables the health-care professional
to identify patients with breakthrough pain as well as collect information about
the nature of the breakthrough pain and of the background pain. The criteria for
diagnosing breakthrough pain are (a) the presence of background pain (i.e., the
Box 3.1 Breakthrough pain assessment algorithm
This algorithm is designed for patients with controlled, persistent baseline pain. The
nature of the baseline pain is assessed. Those with controlled baseline pain are then asked
about flares of breakthrough pain. The nature of the breakthrough pain is assessed. Note
that the definition of controlled baseline pain depends in part on whether patients are
taking opioids more than 12 hours per day (Scenario A) or less than 12 hours per day
(Scenario B). Opioid therapy will be known of prior to beginning the assessment, and it is
expected that most patients will be taking opioids more than 12 hours per day.
Determining the presence of persistent baseline pain (determined at screening)
1. Does your pain currently have a component you would describe as “constant” or
“almost constant”, or would it be constant or almost constant if not for the
treatment you are receiving?
0 = No 1 = Yes
a) If Yes, go to question #2A or #2B
b) If No, STOP. Patient does not have persistent baseline pain.
Scenario A: Patient taking opioids greater than or equal to 12 hours per day
(screening)
2A. Have you had any pain during the past week?
0 = No 1 = Yes
a) If Yes, go to question #3A.
b) If No, patient has controlled baseline pain; skip to question #5.
3A. How would you judge your baseline pain on average during the past week?
1 = Mild 2 = Moderate 3 = Severe 4 = Excruciating
a) If severe or excruciating, STOP. Patient has uncontrolled baseline pain.
b) If mild or moderate, patient has controlled baseline pain. Continue to question #5.
Scenario B: Patients taking opioid less than 12 hours per day (screening)
2B. Have you had any pain during the past week?
0 = No 1 = Yes
a) If Yes, go to question #3B
b) If No, STOP. Patient does not have baseline pain.
3B. Did you feel this pain for more than half the time that you were awake?
0 = No 1 = Yes
a) If Yes, go to question #4B
b) If No, STOP. Patient has transient pains.
4B. How would you judge your baseline pain on average during the past week?
1 = Mild 2 = Moderate 3 = Severe 4 = Excruciating
a) If severe or excruciating, STOP. Patient has uncontrolled baseline pain.
b) If mild or moderate, patient has controlled baseline pain. Continue to question #5.
5. Assessing the nature of the baseline pain.
a) Where is this pain? (indicate “right”, “left”, or “both” if appropriate).
1. head 2. face 3. neck 4. shoulder (R,L,B) 5. chest 6. arm (R,L,B)
7. abdomen 8. upper back 9. lower back 10. leg (R,L,B)
11. buttock (R,L,B) 12. pelvis (R,L,B) 13. anorectal area 14. genitalia
15. other:
b) How long have you experienced this pain? (in weeks)
Box 3.1 (Continued)
c) What does it feel like? (indicate one or more description):
1. sharp 2. aching 3. crampy 4. radiating or shooting
5. pressing, squeezing, or tight 6. burning 7. throbbing 8. stabbing
9. other (describe):
b) How long have you experienced this pain? (in weeks)
d) Does anything that you do reduce your pain?
0 = No 1 = Yes
e) If Yes, please describe what reduces your pain:
f ) Does anything that you do make your pain worse?

0 = No 1 = Yes
g) If Yes, please describe what makes your pain worse:
Question 6 probes for the presence of breakthrough pain and question 7

assesses the nature of the breakthrough pain.
6. Do you also experience temporary flares of severe or excruciating pain?
0 = No 1 = Yes
a) If Yes, patient has breakthrough pain. Continue with the remainder of the
questionnaire to characterize the breakthrough pain.
b) If No, STOP. Patient has controlled baseline pain without breakthrough pain.
7. Assessing the nature of the breakthrough pain.
a) How many different types of temporary flare-ups do you have?
If you had one kind of severe pain flare-up during the past 24 hours, the following
questions refer to the worst flare-up you have had during the past 24 hours.
Patients can then describe the second- and third-worst flare-ups.
b) Where is this pain? (indicate “right”, “left”, or “both” if appropriate).
1. head 2. face 3. neck 4. shoulder (R,L,B) 5. chest 6. arm (R,L,B)
7. abdomen 8. upper back 9. lower back 10. leg (R,L,B)
11. buttock (R,L,B) 12. pelvis (R,L,B) 13. anorectal area 14. genitalia
15. other:
d) When your pain flare becomes as bad as it gets, would you say it is:
1 = Severe 2 = Excruciating
e) From the time that you first feel this pain start to flare until it gets to be as bad
as it gets, how long does it take (in minutes)?
f ) When the pain flare comes on, does it start mildly and gradually get worse, or
does it immediately start out severe?
1 = Gradual 2 = Severe
g) If the pain flare starts slowly and gradually gets worse, how long does it take from
the time that you first start to feel the pain coming on until it goes away?
Assessment
Box 3.1 (Continued)
h) How many times a day do you get this specific kind of pain flare?
i) Does your pain flare usually come on within a certain amount of time after you
have taken your pain medication?
0 = No 1 = Yes
CHAPTER 3
Describe
j) Do you kow what causes your pain flare to come on?
0 = No 1 = Yes
k) If Yes, please describe what causes your pain flare:
l) How well can you predict when your pain flare will occur?
1 = Can never predict when it will occur
2 = Can sometimes predict when it will occur
3 = Can often predict when it will occur
4 = Can almost always predict when it will occur
5 = Can always predict when it will occur
m) Does anything help to lessen your painful episode?
0 = No 1 = Yes
n) If Yes, please describe what reduces your pain:
o) If you do know of something that lessens your pain, how sure are you that it will
work? Does it work successfully each time you try it?
31
0 = No 1 = Yes
Describe
Adapted with permission, Portenoy et al., 2006.
patient has pain that has been there for more than half of his or her waking time
during the previous week, or the patient has been taking regular opioid anal-
gesics to control persistent pain for more than half the days during the previous
week); (b) the presence of controlled background pain (i.e., the patient has pain
that has been rated as “absent,” “mild,” or “moderate” [but not “severe”] for
more than half the time); and (c) the occurrence of one or more “severe or ex-
cruciating episodes of pain” during the previous day (Portenoy et al., 1999). The
most recent version of the breakthrough pain assessment algorithm is shown in
Box 3.1 (Portenoy et al., 2006).
It should be noted that patients with no background (baseline, persistent)
pain but who have severe or excruciating episodes of pain are classified as
having “transitory pains” (Portenoy et al., 1999). Similarly, patients who have
poorly controlled background pain and who have severe or excruciating
episodes of pain are simply classified as having “uncontrolled pain” (Portenoy
et al., 1999).
Other investigators have also developed tools to specifically assess break-
through pain. For example, Zeppetella produced an episodic (breakthrough)
pain documentation sheet (Zeppetella and Ribeiro, 2002) (Fig. 3.2).
Assessment
Patient name: Date:
Each pain should be marked on a separate sheet
Location Severity
Mild [ ]
CHAPTER 3
Moderate []
Severe []
Excruciating [ ]
Type
A. No background pain [ ] 0. No scheduled analgesia [ ]
B. Controlled background pain [ ] 1. Insufficient scheduled analgesia [ ]
C. Uncontrolled background pain [ ] 2. Sufficient scheduled analgesia [ ]
Temporal characteristics
Daily frequency: Weekly frequency (if less than daily)
Onset: Gradual [ ] Sudden [ ]
Time course
Time to max intensity (minutes) Total duration (minutes)
Precipitating event Pathophysiology

None (spontaneous) [ ] Somatic [ ]
Incident [ ] Visceral [ ]
Non-volitional [ ] Neuropathic [ ]
Mixed [ ]
Unknown [ ]
32
Predictable Aetiology
Yes [ ] Disease related [ ]
No [ ] Treatment related [ ]
Unrelated to disease/treatment [ ]
Notes
Figure 3.2 Episodic pain documentation sheet. Reproduced with permission from Zeppetella
& Ribeiro, 2002.
References
Bennett M. The LANSS Pain Scale: The Leeds assessment of neuropathic symptoms and
signs. Pain. 2001;92:147–157.
Caraceni A, Cherny N, Fainsinger R, et al. Pain measurement tools and methods in clinical
research in palliative care: Recommendations of an Expert Working Group of the Eu-
ropean Association of Palliative Care. Journal of Pain and Symptom Management.
2002;23:239–255.
Cleeland CS, Ryan KM. Pain assessment: Global use of the Brief Pain Inventory. Annals of
the Academy of Medicine. 1994;23:129–138.
Davies A. The assessment and measurement of physical pain. In Hillier R, Finlay I, Miles A
(Eds.), The Effective Management of Cancer Pain (2nd ed., pp. 23–28). London: Aescu-
lapius Medical Press, 2002.
de Wit R, van Dam F, Abu-Saad HH, et al. Empirical comparison of commonly used mea-
Assessment
sures to evaluate pain treatment in cancer patients with chronic pain. Journal of Clini-
cal Oncology. 1999;17:1280–1287.
Dworkin RH, Turk DC, Farrar JT, et al. Core outcome domains for chronic pain clinical
trials: IMMPACT recommendations. Pain. 2005;113:9–19.
CHAPTER 3
Foley KM. Acute and chronic cancer pain syndromes. In Doyle D, Hanks G, Cherny N,
Calman K (Eds.), Oxford Textbook of Palliative Medicine (3rd ed., pp. 298–316). Ox-
ford: Oxford University Press, 2004.
Hagen NA. Reproducing a cancer patient’s pain on physical examination: Bedside
provocative maneuvers. Journal of Pain and Symptom Management. 1999;18:406–411.
Herr KA, Mobily PR. Comparison of selected pain assessment tools for use with the el-
derly. Applied Nursing Research. 1993;6:39–46.
McQuay HJ, Moore RA. An Evidence-Based Resource for Pain Relief. Oxford: Oxford
University Press, 1998.
Melzack R. The short-form McGill Pain Questionnaire. Pain. 1987;30:191–197.
Portenoy RK, Bennett DS, Rauck R, et al. Prevalence and characteristics of breakthrough
pain in opioid-treated patients with chronic noncancer pain. Journal of Pain.
2006;7:583–591.
33
Pain. 1990;41:273–281.
Rasmussen PV, Sindrup SH, Jensen TS, Bach FW. Symptoms and signs in patients with
suspected neuropathic pain. Pain. 2004;110:461–469.
Shannon MM, Ryan MA, D’Agostino N, Brescia FJ. Assessment of pain in advanced cancer
patients. Journal of Pain and Symptom Management. 1995;10:274–278.
Trowbridge R, Dugan W, Jay SJ, et al. Determining the effectiveness of a clinical-practice
intervention in improving the control of pain in outpatients with cancer. Academic
Medicine. 1997;72:798–800.
Weiner DK, Distell B, Studenski S, et al. Does radiographic osteoarthritis correlate with
flexibility of the lumbar spine? Journal of the American Geriatrics Society. 1994;
42:257–263.
Zeppetella G, Ribeiro MD. Episodic pain in patients with advanced cancer. American Jour-
nal of Hospice and Palliative Care. 2002;19:267–276.
Chapter 4
Principles of management
Breakthrough pain is not a single entity but rather a manifestation of myriad
pain-producing disorders. Therefore, the effective treatment of breakthrough
pain depends on a variety of factors that relate to the expression and experi-
ence of pain: biomedical, psychological, and social. From a medical perspective,
the etiology, pathophysiology, and characteristics of the pain will point the way
toward potentially beneficial therapeutic options. Moreover, treatment needs
to be informed by a variety of patient-specific factors, including the stage of the
disease and the performance status of the patient (Mercadante and Arcuri,
1998). Thus, treatment is highly individualized (Patt and Ellison, 1998).
The management of breakthrough pain involves (a) assessment, (b) treatment
of the cause of the pain, (c) treatment of the pain per se (symptomatic—or
palliative—treatment), and (d) reassessment. Chapter 3 described the assess-
ment of breakthrough pain in detail. This chapter discusses the general principles
35
of the treatment of breakthrough pain. Subsequent chapters describe specific ap-
proaches to the symptomatic treatment of breakthrough pain in detail.
Management strategies
The optimal treatment for all types of breakthrough pain is management of the
underlying disease and the underlying pathological processes that are causing
pain, whenever possible. Whereas disease-modifying interventions have been
shown to be very effective in managing background pain, breakthrough pain has
not been an outcome measure in studies evaluating the results of the use of ra-
diotherapy, chemotherapy, bisphosphonates, anti-inflammatory medications, in-
jection therapies, and so forth (Mercadante et al., 2002). Nevertheless, there is
anecdotal evidence and considerable practice experience that some of these in-
terventions may also be effective in managing some instances of breakthrough
pain (Mercadante et al., 2001).
The symptomatic management of breakthrough pain includes both pharmaco-
logical and nonpharmacological treatments.
Pharmacological treatment of pain

1. Modification of the background analgesic regimen
a) Increase dose of analgesic drugs
b) Addition of opioid analgesic drugs
c) Addition of nonopioid analgesics (e.g., NSAIDs, which some consider
to be co-analgesics, or anticonvulsants, which some consider to be ad-

juvant analgesics)
2. Use of breakthrough (“rescue”) analgesics
a) Nonopioid analgesics
b) Opioid analgesics
c) Other classes of pain-attenuating agents (e.g., nitrous oxide, subanes-
thetic ketamine, baclofen, clonazapam, propofol)
Nonpharmacological treatment of pain
CHAPTER 4
A variety of nonpharmacological methods may be useful in treating break-

through pain, such as rubbing/massage, application of heat (Fine and Busch,
1998; Swanwick et al., 2001), application of cold (Fine and Busch, 1998; Petzke
et al., 1999), transcutaneous nerve stimulation (TENS) (Zeppetella and Ribeiro,
2003), distraction techniques (Portenoy, 1997; Petzke et al., 1999), and relax-
ation techniques (Portenoy, 1997; Fine and Busch, 1998).
Table 4.1 shows the relieving factors reported by patients in studies apply-
ing standard criteria for the diagnosis of breakthrough pain (Portenoy and
Hagen, 1990; Portenoy et al., 1999; Hwang et al., 2003). In these surveys,
without specific attention to amelioration of breakthrough pain, it can be
seen that only 44% to 61% of patients reported that their medication relieved
36
breakthrough pain. With attention to breakthrough pain, Hwang et al. (2003)

have shown that alterations in medication can lead to dramatic improve-
ments. In their study, 54% of patients reported that their medication relieved
breakthrough pain at baseline, while 83% of patients reported that their
medication relieved breakthrough pain after 1 week of intervention. Similar
to the relief of persistent pain, multimodal approaches to the relief of break-
through pain, combining pharmacotherapy with nonpharmacological inter-
ventions, lead to improved outcomes (Portenoy and Hagen, 1990; Swanwick
et al., 2001).
Table 4.1 Relieving factors of breakthrough pain in studies applying

recognized criteria for breakthrough pain
Study Relieving factors Comments
Other No relieving
Medication strategies factors
Portenoy and 44% 44% 12% Some patients had more
Hagen, 1990 than one relieving factor.
Portenoy 61% 26% 13%
et al., 1999
Hwang 54% 26% 20% Data refer to initial
et al., 2003 assessment.
Reproduced with permission from Davies, 2006.
Management of spontaneous pain
The symptomatic management of spontaneous pain primarily involves modifica-
tion of the background analgesic regimen in order to reduce the frequency and
intensity of spontaneous pains. Use of breakthrough medication supplements
the “around-the-clock” regimen. The options for modification of the back-
ground analgesia are as follows:
• Increase the dose of the around-the-clock analgesic. This strategy can be
effective in reducing the frequency and/or severity of breakthrough pain,
CHAPTER 4
and it has been suggested that the dose be increased by 25% to 50% in or-
der to determine efficacy and tolerability (Portenoy, 1997). If dose-limiting
side effects predominate, a different strategy, such as the consideration of
an alternative around-the-clock analgesic, is recommended (Fine and
Portenoy, 2007).
One of the major restrictions to increasing the dose of opioid analgesics is
the development of opioid-related drowsiness. Bruera et al. (1992) reported
that this problem can be relieved by the concurrent use of a psychostimulant,
such as methylphenidate. An alternative strategy would be opioid switching
(also known as opioid rotation) (Cherny et al., 2001). It should be noted that
opioid switching may also be useful in managing other opioid-related side ef-
37
fects (Cherny et al., 2001).
• Addition of analgesic drugs. The rationale for this strategy is that the addi-
tion of another analgesic drug may result in a better effect/side-effect profile
than increasing the dose of the original analgesic drug.
O Short-acting opioids may be used to increase analgesic effects for a period
of time commensurate with the episode of breakthrough pain.
O Other drugs may be added that have either direct (independent analge-
sia) or indirect analgesic effects. This strategy utilizes drugs that may
be termed co-analgesics or adjuvants and can be effective in reducing
the frequency and/or severity of specific types of breakthrough pain.
Most commonly, spontaneous pains that derive from neuropathic dis-
orders may be eased in many cases by certain anticonvulsant or anti-
depressant drugs (Portenoy et al., 2004).
Management of incident pain

The management of incident pain includes both treatment of precipitants of the
pain and symptomatic treatment of the pain. The precipitants of incident pain are
extremely varied (Table 1.2), and only some of these precipitants are amenable
to specific treatment (e.g., opioids to suppress coughing) (Portenoy, 1997).
Movement-related (volitional incident) pain due to osteoarthritis, degenera-
tive spine disease, or metastatic bone disease is a common phenomenon with
these disorders. This can be a very refractory type of breakthrough pain to
manage (Hwang et al., 2003). In cases of malignancy where medical manage-
ment has not been effective, it may be possible to perform surgical stabilization
or use an orthotic device to stabilize the relevant tissues(s) (Mercadante et al.,
2002; Mercadante and Arcuri, 1998) (Figs. 4.1 and 4.2). In all cases where skele-
tal disease is the underlying cause of incident pain and where internal or exter-
nal prostheses or fixation/stabilization are not feasible, patients will benefit
from adaptive strategies, including assistive devices and environmental modifi-
cations. When feasible, the provision of additional practical support with activi-
ties of daily living through the use of home-care or hospice services is of great
value (Mercadante and Arcuri, 1998; Fine and Davis, 2006).
CHAPTER 4
• The symptomatic management of incident pain rarely involves modification

of the background (around-the-clock) opioid analgesic regimen because
this usually creates an excessive burden of opioid-related side effects dur-
ing the majority of the time when incident pain is absent. An exception to
this was found by Mercadante et al. (2004) in a study of patients with
metastatic bone pain. These investigators reported that increasing the
dose of regular opioid was effective in managing movement-related (voli-
tional incident) pain in a group of patients with bone metastases without
undue adverse effects.
When there is a pharmacological rationale for modifying underlying pathology
that leads to incident pain, then maximizing that analgesic regimen (e.g., anti-
38
(a) (b)
Figure 4.1 Radiographs demonstrating surgical stabilization of a lytic bone metastasis.

Reprinted with permission from Davies, 2006.
CHAPTER 4
Figure 4.2 Orthotic device (Polysling) for supporting/immobilizing upper arm. Reprinted with
permission from Davies, 2006.
inflammatory drugs) makes sense as long as adverse effects are monitored, man-
aged, and tolerated.
• Addition of other analgesic drugs—see “Management of spontaneous pain.”
In most cases, though, the effective pharmacological approach to incident pain
39
relies on the use of breakthrough medication. In those cases where pain is pre-
dictable, it is possible to take the breakthrough pain medication in advance. The
timing of preventative medication use must match the onset of the medication
and timing of the activity so there is overlap of peak medication effect and pain-
inducing events. For example, the time to onset of oral morphine is 20 to 30
minutes (Twycross et al., 1998), and the time to maximum effect is 60 minutes
(Mercadante et al., 2002). Thus oral morphine should be given at least 30 min-
utes, and probably 60 minutes, before the relevant activity. The same parame-
ters generally exist for most of the immediate-release opioid analgesics (e.g.,
tramadol, hydrocodone, hydromorphone, oxycodone, oxymorphone), al-
though there is considerable variability—and unpredictability—based upon
stomach contents and gastrointestinal absorption and transit time. The rapid-
onset formulations of buccal fentanyl (oral transmucosal fentanyl citrate
[OTFC; flavored lozenge on a stick]; fentanyl effervescent buccal tablet [FEBT])
have consistently meaningful onset of analgesic effects in 10 to 15 minutes (Fine
et al., 1991; Portenoy et al., 2006; Portenoy et al., 2007).
Management of end-of-dose failure

The management of end-of-dose failure involves modification of the back-
ground analgesic regimen (Mercadante et al., 2002). The options are as follows:
• Increase the dose of the analgesic. This strategy has been recommended as a
first-line approach for treating end-of-dose failure with most opioid analgesics
(Hanks et al., 2001). This strategy is invariably effective, although the increase
in dosage may lead to an increase in side effects that may not be tolerable
(Simmonds, 1999).
• Increase the frequency of the analgesic. This is a recommended strategy for
treating end-of-dose failure when dose increases are not tolerated or the
patient’s past experience with dose escalation suggests that adverse effects
will be problematic (Breitbart et al., 2000; Hanks et al., 2001).
Duration of action for all opioids—and notably the controlled-release
formulations—can vary enough from patient to patient that individualization of
the dosing interval should always be considered during the course of treatment.
CHAPTER 4
For instance, the fentanyl transdermal patch was designed and tested in clinical
trials for a 72-hour duration of action. Nevertheless, in up to 43% of patients
the duration of action of transdermal fentanyl is somewhere between 48 and 72
hours (Payne et al., 1995; Grond et al., 1997). It has been recommended that pa-
tients whose pain is controlled for 48 hours but who require breakthrough
medication at between 48 and 72 hours replace their patch every 48 hours
rather than every 72 hours instead of increasing the dose of the patch to obvi-
ate breakthrough pain (Breitbart et al., 2000).
• Provision of nonopioid analgesic drugs, opioid switching, or other pain relief
methods. In some cases, the aforementioned strategies are either not possible
or lead to intolerable side effects. In such cases, the provision of nonopioids (e.g.,
40
NSAIDs, corticosteroids, anticonvulsants, etc.), switching to a different opioid

(opioid rotation), or nonpharmacological pain relief methods are optimal for
controlling the background pain. If opioid rotation fits the clinical circumstances
as the most reasonable option, use of an established algorithm is recommended
(Indelicato and Portenoy, 2003) (Box 4.1). Note that particular care must be
taken when converting from an opioid to methadone; older dose- conversion
tables may be inaccurate and could lead to dangerous overdosing.
Box 4.1 Recommendations for opioid rotation

• Calculate the equianalgesic dose of the new opioid based on an accepted equianalgesic
table.
• If switching to any opioid other than methadone or fentanyl, decrease the equianalgesic
dose by 25% to 50%.
• If switching to methadone, reduce the dose by 75% to 90%.
• If switching to transdermal fentanyl, do not reduce the equianalgesic dose.
• Consider further changes in the adjusted equianalgesic dose based on medical condition
and pain. If the patient is elderly or has significant cardiopulmonary, hepatic, or renal
disease, consider further dose reduction. If the patient has severe pain, consider a lesser
dose reduction.
• Calculate a rescue dose as 5% to 15% of the total daily opioid dose and administer at an
appropriate interval.
• Reassess and titrate the new opioids.
Adapted with permission from ASCO (Indelicato and Portenoy, 2003).
Breakthrough (rescue/supplemental) medication
In theory, any fast-acting analgesic can be used to treat breakthrough pain (i.e.,
nonopioid analgesics, opioid analgesics, adjuvant analgesics) (Mercadante and
Arcuri, 1998). Due to their predictable analgesic effects, opioid preparations
have become the mainstay of the pharmacological management of breakthrough
pain. However, opioid preparations will only be effective if the breakthrough
pain is an opioid-responsive pain. Moreover, individual opioid preparations will
only be effective if the pharmacokinetic profile of the preparation mirrors the
CHAPTER 4
temporal pattern of the pain. It should be noted that effectiveness (efficacy, tol-
erability) to individual opioid preparations varies from person to person and
may vary over time within the same person.
The oral and transdermal routes are most commonly used for around-the-
clock opioid therapy in the management of chronic, continuous pain. These
routes pose problems in the treatment of breakthrough pain. The oral route is
associated with a delayed onset of action ( 20 to 30 minutes for oral mor-
phine) (Twycross et al., 1998), and a delayed peak effect ( 60 minutes for oral
morphine) (Mercadante et al., 2002), and there is not a transdermal system
available yet that allows for rescue dosing with an ample variety of doses. In an
attempt to overcome these issues, a variety of alternative routes have been uti-
41
lized, including the oral transmucosal (Gardner-Nix, 2001), intravenous (Mer-
cadante et al., 2004a), subcutaneous (Enting et al., 2005), intranasal (Pavis et al.,
2002), and intrapulmonary (Zeppetella, 2000) routes. All of these routes have
been shown to be very effective, but only the oral transmucosal (buccal) route
both has commercially available preparations for its use and is realistic for most
patients in an outpatient setting. Subsequent chapters describe these routes of
administration in more detail.
In the past, it has been recommended that the opioid used to treat break-
through pain should be the same as the opioid used to treat background pain
(Patt and Ellison, 1998). However, there are no data to support using the
same opioid, and the decision to use an opioid should be based primarily on
its pharmacokinetic profile, the prescriber’s knowledge and comfort with the
drug, and the patient’s past experience with the drug. Moreover, in the past,
it has been recommended that the dose of opioid to treat breakthrough pain
should be a fixed ratio of the daily dose of opioid being used to treat the
background pain (Patt and Ellison, 1998). However, the recommended ratio
has varied significantly among various guidelines (e.g., one-twenty-fourth to
one-sixth of the daily dose) (Cleary, 1997). Data from recent studies suggest
that there is no relationship between the dose of opioid required to control
breakthrough pain and the dose of opioid required to control background
pain (Coluzzi et al., 2001). Thus the dose of breakthrough medication should
be titrated in a manner that balances safety and efficacy (Mercadante et al.,
2002). For oral agents, a starting dose equivalent to 10% to 15% of the usual
24-hour total opioid dose is recommended; for buccal delivery systems, the
recommended starting dose of OTFC is 200 µg, and for FEBT it is 100 µg (Fine
and Portenoy, 2007).

The potential side effects associated with taking a breakthrough dose of opi-
oid are similar to those associated with taking any dose of opioid (e.g., somno-
lence, nausea, vomiting, dizziness, and respiratory depression) (Coluzzi et al.,
2001; Portenoy et al., 2006). Due to risks of sedation and somnolence, certain
guidelines on driving and opioid medication state that in view of the risk of
somnolence, “you must not drive on days where you have had to take extra
(breakthrough or rescue) doses of a strong painkiller” (Pease et al., 2004). Pre-
scribing clinicians need to determine what they believe is the best balance be-
CHAPTER 4
tween public safety and patients’ interests based on their assessment of drug
effects and the duration of action of breakthrough pain medications.
Other issues
Prescription of breakthrough medication
Studies suggest that patients are frequently not prescribed breakthrough med-
ication. For example, Ferrell et al. (1999) reported that 27% of patients with
chronic pain involved in their study had not been prescribed breakthrough
medication. Other authors have reported even higher levels of inattention to
42
breakthrough pain (38% to 57%) (Weber and Huber, 1999; Zeppetella et al.,
2000; Lawrie et al., 2003). Ferrell et al. (1999) also reported that patients in their
study who had been prescribed breakthrough medication had arbitrary limita-
tions imposed on the frequency of use of the breakthrough medication, regard-
less of frequency of breakthrough pain episodes or demonstrated effectiveness
of treatment.
Adherence to breakthrough medication recommendations
Nonadherence to prescribed medication instructions is common. For example,
Zeppetella et al. (1999) reported that 44% of home-care patients they ques-
tioned were not taking their medication as prescribed. In particular, patients
were not taking their analgesics as prescribed (i.e., nonopioids, opioids).
Similarly, Ferrell et al. (1999) reported that only 3% of patients they ques-
tioned were taking their breakthrough medication as prescribed. Overall, 96%
of patients were taking too low a dose, 3% were taking the prescribed dose, and
1% were taking too high a dose; the mean dose taken was only 21% of the dose
prescribed (Ferrell et al., 1999).
It is unclear what the reasons for this nonadherence were in the aforemen-
tioned studies, although other studies have reported that patients do not take
their medication because of lack of effect, adverse events, concerns about ad-
verse events, difficulty in taking the medication, and lack of knowledge about
the medication (Zeppetella, 1999).
Other authors have reported that the use of breakthrough medication de-
pends on the type of breakthrough pain, with patients experiencing incident pain
being less likely to use breakthrough medication than patients with spontaneous
pain or end-of-dose failure (Gomez-Batiste et al., 2002). One plausible reason for
this, although purely speculative, is that incident pain is perceived to be more
controllable by the patient (without requiring medication) than spontaneous
pain or end-of-dose failure. However, this may lead to unnecessary—and poten-
tially problematic—self-imposed restrictions in activities and functions.
Acceptability of breakthrough medication
One of the factors that may affect adherence is the acceptability of the break-
through medication. Table 4.2 shows the acceptability of various routes of ad-
CHAPTER 4
ministration to palliative care patients if their pain were rated as “severe”
(Walker et al., 2003). It should be noted that patients were informed that the
onset of pain relief was 5 minutes for the intravenous route; 10 minutes for the
nasal, sublingual, transmucosal, inhaled, subcutaneous, and intramuscular
Table 4.2 Acceptability of different routes of administration

of breakthrough medication for severe pain
Acceptability of route for severe pain Reasons for unacceptability
Route Yes (%) Possibly (%) No (%)
Oral 88 4 8 Slow onset of action
43
Rectal 48 10 42 Slow onset of action, dignity,
previous bad experience,
localized pain/disease, difficult
to administer,
unpleasant/uncomfortable
Nasal 68 14 18 Localized pain/disease,
difficult to administer, catches
in back of throat, fear of bad
taste/nausea, unfamiliar
with/dislike idea
Sublingual 75 11 14 Slow onset of action,
previous bad experience, fear
of bad taste/nausea, unfamiliar
with/dislike idea
Transmucosal 63 12 25 Localized pain/disease, fear of
bad taste/nausea, “childlike,”
unfamiliar with/dislike idea
Inhaled 75 9 16 Previous bad experience,
localized pain/disease, difficult
to administer, fear of bad
taste/nausea, unfamiliar
with/dislike idea
Subcutaneous 87 8 5 Dislike of injections
Intramuscular 76 12 12 Dislike of injections
Intravenous 83 8 9 Previous bad experience,
dislike of injections
Adapted from Walker et al., 2003.
routes; and 30 minutes for the oral and rectal routes. It can be seen that the
likelihood that the patient will accept an invasive route of administration is re-
lated to the severity of pain (Walker et al., 2003). The advent of potent, rapidly
acting opioid formulations that have the time-of-onset characteristics of invasive
therapies obviates the need for this exchange of burdens for benefits.
References
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fentanyl for cancer-related pain. Oncology (Huntington). 2000;14:695–705.
CHAPTER 4
Bruera E, Fainsinger R, MacEachern T, Hanson J. The use of methylphenidate in patients

with incident cancer pain receiving regular opiates. A preliminary report. Pain.
1992;50:75–77.
Cherny N, Ripamonti C, Pereira J, et al. Strategies to manage the adverse effects of oral
morphine: an evidence-based report. Journal of Clinical Oncology. 2001;19:2542–2554.
Cleary JF. Pharmacokinetic and pharmacodynamic issues in the treatment of breakthrough
pain. Seminars in Oncology. 1997;24(Suppl 16):13–19.
Coluzzi PH, Schwartzberg L, Conroy JD Jr, et al. Breakthrough cancer pain: A randomized
trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate imme-
diate release (MSIR). Pain. 2001;91:123–130.
Davies A. Cancer-Related Breakthrough Pain. Oxford, UK: Oxford University Press, 2006.
44
Enting RH, Mucchiano C, Oldenmenger WH, et al. The “Pain Pen” for breakthrough cancer
pain: A promising treatment. Journal of Pain and Symptom Management. 2005;29:213–217.
Ferrell BR, Juarez G, Borneman T. Use of routine and breakthrough analgesia in home
care. Oncology Nursing Forum. 1999;26:1655–1661.
Fine PG, Davis M. Hospice: Comprehensive care at the end of life. Anesthesiology Clinics.
2006;24:181–204.
Fine PG, Marcus M, DeBoer AJ, Van der Oord B. An open label study of oral transmu-
cosal fentanyl citrate (OTFC) for the treatment of breakthrough cancer pain. Pain.
1991;45:149–153.
dome, 2007.
Gardner-Nix J. Oral transmucosal fentanyl and sufentanil for incident pain. Journal of Pain
and Symptom Management. 2001;22:627–630.
ment. 2002;24:45–52.
Grond S, Zech D, Lehmann KA, Radbruch L, Breitenbach H, Hertel D. Transdermal fen-
tanyl in the long-term treatment of cancer pain: A prospective study of 50 patients
with advanced cancer of the gastrointestinal tract or the head and neck region. Pain.
1997;69:191–198.
Hanks GW, de Conno F, Cherny N, et al. Morphine and alternative opioids in cancer pain:
The EAPC recommendations. British Journal of Cancer. 2001;84:587–593.
Indelicato RA, Portenoy RK. Opioid rotation in the management of refractory cancer
pain. Journal of Clinical Oncology. 2003;21(Suppl):87s–91s.
Lawrie I, Lloyd-Williams M, Waterhouse E. Breakthrough strong opioid analgesia pre-
scription in patients using transdermal fentanyl admitted to a hospice. American Jour-
Mercadante S, Arcuri E. Breakthrough pain in cancer patients: Pathophysiology and treat-
ment. Cancer Treatment Reviews. 1998;24:425–432.
Mercadante S, Radbruch L, Caraceni A, et al. Episodic (breakthrough) pain. Consensus
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Mercadante S, Villari P, Ferrera P, Bianchi M, Casuccio A. Safety and effectiveness of
intravenous morphine for episodic (breakthrough) pain using a fixed ratio with
the oral daily morphine dose. Journal of Pain and Symptom Management. 2004a;
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venting incident pain associated with bone metastases. Journal of Pain and Symptom
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Mercadante S, Villari P, Ferrera P, Dabbene M. Pamidronate in incident pain due to bone
metastases. Journal of Pain and Symptom Management. 2001;22:630–631.
45
Pavis H, Wilcock A, Edgecombe J, et al. Pilot study of nasal morphine-chitosan for the re-
lief of breakthrough pain in patients with cancer. Journal of Pain and Symptom Man-
agement. 2002;24:598–602.
Payne R, Chandler S, Einhaus M. Guidelines for the clinical use of transdermal fentanyl.
Anti-Cancer Drugs. 1995;6(Suppl 3):50–53.
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cer pain: Transitory pains on admission to a multidisciplinary pain clinic. Journal of Pain
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fentanyl buccal tablet for breakthrough pain in opioid-treated patients with cancer.
Clinical Journal of Pain. 2006;22:805–811.
Portenoy RK, Messina J, Xie F, Peppin J. Fentanyl buccal tablet (FBT) for relief of break-
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CHAPTER 4
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2003;17:219–221.
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Zeppetella G. Nebulized and intranasal fentanyl in the management of cancer-related
breakthrough pain. Palliative Medicine. 2000;14:57–58.
ment. 2000;20:87–92.
46

Chapter 5
Oral opioid analgesics

Pain treatment guidelines recommend the least invasive route for opioid use in
the management of chronic pain, and this is usually the oral route (World
Health Organization [WHO], 1996; American Geriatrics Society [AGS], 2002;
British Pain Society [BPS], 2005; Miaskowski et al., 2005). However, although the
oral route is generally effective in the management of background pain, it is of-
ten less effective in the management of breakthrough pain. This is because oral
opioids have a relatively delayed and highly variable interindividual and intrain-
dividual onset of action and time to peak effect. These properties make them
less than ideal for the management of breakthrough pain. Nevertheless, due to
convenience, practice habits, and cost, oral opioids remain the cornerstone of
the symptomatic management of breakthrough pain. This chapter focuses on
those oral opioid preparations that are suitable for treating breakthrough pain
(so-called normal-release, immediate-release, or short-acting opioids).
47
This chapter concentrates on opioids for moderate to severe pain (formerly
“strong opioids”) (WHO, 1996; Fine, 2005). Nevertheless, combination opioid
products that are customarily used to treat mild to moderate pain (formerly
given the misnomer “weak opioids”) may be used to treat breakthrough pain,
but the dose is limited by the co-compounded analgesic (acetaminophen, as-
pirin, or ibuprofen). There are a number of different combination oral opioids
that are usually prescribed for acute pain. The relevant ones that are available in
the United States are shown in Table 5.1. In addition, some basic clinical and
pharmacokinetic data on these opioids are shown in Tables 5.2 and 5.3. For pa-
tients who require higher doses of around-the-clock opioids (i.e., more than 50
to 100 mg oral morphine equivalents per day), the maximum safe doses of
combination-product opioids may not provide sufficient analgesia to control
breakthrough pain. Also, routine use of acetaminophen, aspirin, or other
NSAIDs may be contraindicated in certain patients who require one or more
doses of a breakthrough pain analgesic per day (e.g., those with renal or hepatic
dysfunction, hypertension, heart failure, gastropathy, or peptic ulcer disease)
(AGS, 2002).
Route considerations
The advantages and disadvantages of the oral route for treating breakthrough
pain include the following (Patt and Ellison, 1998; Hanks et al., 2004):
Table 5.1 Combination oral opioids available in the United States
for the treatment of breakthrough pain

Generic name Opioid doses Comments
Hydrocodone + 5, 7.5, 10 mg In healthy adults, maximum daily
acetaminophen dose of acetaminophen is 4000 mg.
or ibuprofen In patients with liver disease or a history of
moderate or greater alcohol ingestion, or in
frail, elderly individuals, restrict maximum
acetaminophen doses to 1500 mg.
CHAPTER 5
Oxycodone + 5, 7.5, 10, 15 mg See above

acetaminophen
or aspirin
Tramadol + 37.5 mg See above
acetaminophen
Note: Codeine combination formulations are generally not recommended.
Adapted from Fine and Portenoy, 2007.
Table 5.2 Basic clinical data for combination opioids commonly

used for acute pain in the United States
Drug Onset of pain relief Peak pain relief Duration of pain relief
Hydrocodone 30 to 60 min 60 to 120 min 3 to 6 h
Oxycodone 30 min 60 to 120 min 3 to 6 h
48
Tramadol 30 min 180 min 4 to 6h

From Fine and Portenoy, 2007; Twycross et al., 2002; Grond and Sablotzki, 2004.
Table 5.3 Basic pharmacokinetic data for combination opioids

commonly used for acute pain in the United States
Drug Peak plasma level Half-life
Hydrocodone 1 to 2 h 2 to 3 h
Oxycodone 1 to 2 h 3 to 4 h
Tramadol 2h 6 h*
* Active metabolite has longer half-life (7.4 hours).
From Fine and Portenoy, 2007; Twycross, 2002.
• Advantages
1. Familiar/acceptable to patients (Walker et al., 2003)
2. Convenient for patients
3. Familiar/acceptable to health-care professionals
4. Convenient for health-care professionals
5. Large variety of oral opioid drugs available
6. Large variety of oral opioid formulations available
• Disadvantages
1. Not suitable for patients with dysphagia
2. Not suitable for patients with nausea and vomiting
3. Not suitable for patients with dysfunction of the upper gastrointestinal tract
4. Variation in oral bioavailability

5. Relatively slow onset of action
6. Relatively long duration of action
Drug considerations
Commonly used oral opioids
CHAPTER 5
There are a number of µ opioid agonists that are used for the treatment of
breakthrough pain. The relevant ones that are available in the United States are
shown in Table 5.4, along with some basic clinical and pharmacokinetic data
(Prommer, 2006; Fine and Portenoy, 2007). It should be noted that although
there is a significant amount of data about the pharmacokinetic profiles of these
opioids, there is a limited amount of data about their associated clinical effects
(e.g., time to onset of pain relief, time to maximum pain relief ) for the treat-
ment of breakthrough pain. This information needs to be extrapolated from
pharmacokinetic and acute pain studies.
By convention and convenience only, the opioid used for breakthrough pain
is usually the same as the opioid used for background pain (Mercadante et al.,
2002). However, an alternative opioid may be just as or more suitable for treat-
ing breakthrough pain. Furthermore, in certain circumstances, an alternative
49
opioid is the only option for treating breakthrough pain. For example, there is
no oral preparation of fentanyl to offer a patient being treated with transdermal
fentanyl for whom an oral opioid is preferred for breakthrough pain.
Drug formulation
The oral immediate-release opioids commonly used to treat breakthrough pain
(Table 5.4) are all available in tablet form. Morphine, oxycodone, and
methadone are commercially available in liquid form, and the other agents can
be extemporaneously prepared in a liquid form by a compounding pharmacy, if
needed. The choice of preparation depends on a number of patient-related fac-
Table 5.4 Basic clinical data for oral µ opioids that can be used for
breakthrough pain
Drug Onset of pain Peak pain Duration of Half-life
relief relief pain relief
Morphine 20 to 30 min 60 to 120 min 3 to 6 h 2 to 3 h
Hydromorphone 30 min 60 to 120 min 3 to 6 h 2 to 3 h
Methadone* 30 min 60 to 120 min 6 to 8 h 8 to 150 h
Oxycodone 20 to 30 min 60 to 120 min 3 to 6 h 2 to 3 h
Oxymorphone 20 to 30 min 30 to 60 min 4 to 6 h 8h
* Pharmacokinetics of methadone are complex due to a highly variable and long half-life; use for
breakthrough pain in addition to baseline pain control can lead to dose accumulation and potentially life-
threatening respiratory depression.
From Fine and Portenoy, 2007; Prommer, 2006.
25
Plasma concentration (ng/ml) 20 Oral tablet 20 mg

Oral solution 20 mg
15
10
CHAPTER 5
0
0 3 6 9 12
Time (hr)
Figure 5.1 Mean plasma morphine sulfate (ms) concentrations following oral administration
of 20 mg tablet of morphine and 20 mg oral solution of morphine (Napp Pharmaceuticals Ltd.,
data on file). Reprinted with permission from Davies, 2006.
tors (e.g., patient preference, presence of dysphagia, presence of enteral feeding

tube) and a number of drug-related factors (e.g., taste, alcohol content, sucrose
content). There is no evidence that the formulation of the opioid affects the
clinical/pharmacokinetic profile of the opioid (Collins et al., 1998) (Fig. 5.1).
50
Some commercial and extemporaneously compounded liquid preparations

contain alcohol, which makes them unsuitable for use in patients with certain
physiological contraindications or religious beliefs, so it is worthwhile to make
this determination prior to prescribing. Furthermore, some patients report that
the alcohol-containing preparations cause oral and/or esophageal discomfort
on ingestion. Similarly, if sucrose is used in oral solutions, diabetic patients must
be made aware of this.
Drug dose
The “correct” dose of breakthrough medication is the dose that provides maxi-
mal analgesia with minimal side effects (Zeppetella and Ribeiro, 2002). There is an
absence of scientific data supporting specific recommendations for a fixed ratio of
the baseline opioid dose. An Expert Working Group of the European Association
for Palliative Care has recommended using one-sixth of the daily dose of back-
ground opioid analgesia (Hanks et al., 2001). However, the same document stated
that “it may be that the optimal dose for breakthrough pain can only be deter-
mined by titration” (Hanks et al., 2001). Other authorities have recommended us-
ing between 5% and 15% of the daily dose of background opioid analgesia (Cherny
and Portenoy, 1993; Indelicato and Portenoy, 2003).
Coluzzi et al. (2001) examined the use of oral morphine for the treatment of
breakthrough pain within the context of a double-blind, randomized, controlled
trial of oral transmucosal fentanyl citrate. The trial showed that there was no
relationship between the dose of oral morphine (or oral transmucosal fentanyl
citrate) needed to control the breakthrough pain and the dose of opioid
60 60

45
Successful MSIR dose (mg)

45
Successful MSIR dose (mg)
30 30
15 15
CHAPTER 5
y = 0.03x + 28 y = 0.07x + 23
R2 = 0.084 R2 = 0.095
0 0
0 200 400 600 800 0 50 100 150 200 250 300
Fixed schedule oral opioid dose Transdermal fentanyl fixed
morphine equivalent (mg/day) schedule dose (g/hr)
Figure 5.2 Relationship between suc- Figure 5.3 Relationship between suc-
cessful dose of breakthrough oral mor-
cessful dose of breakthrough oral mor-
phine (MSIR) and background dose of
phine (MSIR) and background dose of
oral opioid. Reproduced with permis- transdermal fentanyl. Reproduced with
permission from Coluzzi et al., 2001.
sion from Coluzzi et al., 2001.
3
OTFC
51
MSIR *
*
2 *
Pain relief score
*p 0.009
0
0 15 30 45 60
Minutes
Figure 5.4 Timing of breakthrough pain
relief with oral morphine (MSIR) vs. oral
transmucosal fentanyl citrate (OTFC). Re-
produced with permission from Coluzzi et
al, 2001.
needed to control the background pain (Figs. 5.2 and 5.3). Furthermore, the
trial also confirmed that the time to maximum pain relief is at least 60 minutes
after oral administration of morphine (Fig. 5.4).
On the basis of the above, it would seem reasonable to initially prescribe
tablets (or liquid formulation) that is equivalent to 5% of the daily dose of back-
ground opioid analgesia, and then to titrate the dose upward according to the
response achieved. Obviously, if the pain is not relieved and side effects are
troublesome, then an alternative treatment should be prescribed.
Drug usage
The usefulness of oral opioids for treating breakthrough pain depends on a
number of factors:
CHAPTER 5
1. The pain must be opioid-responsive.

2. The clinical and pharmacokinetic characteristics of the opioid need to
match the temporal characteristics of the pain.
3. The patient must be able to use the oral route (see earlier section).
Unfortunately, the clinical and pharmacokinetic characteristics of oral opioids
often do not match the temporal characteristics of a patient’s breakthrough
pain pattern. As evidenced by the various surveys evaluating onset times of
breakthrough pain, an appreciable number of these pains arise rapidly and last
less than 1 hour (Table 2.1B). As such, the oral agents peak too slowly and last
too long to meet the needs of many patients with breakthrough pain.
The role of oral opioids in treating breakthrough pain also depends on the
particular subtype of breakthrough pain:
52
• Spontaneous pain—oral opioids are taken at the first sign of pain. However,
once the pain has flared, it is usually too late for oral agents to work effectively.
• Incident pain—in cases of nonvolitional pain, oral opioids are given once the
pain has begun. However, in cases of volitional pain or procedural pain, oral
opioids can be given in advance of the precipitating event in order to try to
prevent or ameliorate the incident pain. It is important that the opioids are
given far enough in advance of the precipitating event. For example, in the case
of oral morphine, the dose needs to be given at least 30 minutes (time to on-
set of pain relief ), and probably 60 minutes (time to maximum pain relief ), in
advance of the precipitating event. Predictable (volitional) incident pain may be
the most appropriate application of the oral route of administration.
• End-of-dose failure—immediate-release oral opioids can be given to relieve
pain during the dose-titration phase of initiating around-the-clock opioid ther-
apy or prior to modification of an existing background analgesic regimen.
Other considerations
Drug acceptability
In a survey looking at the acceptability of different routes of administration for
breakthrough medication, 97% of patients stated that the oral route was accept-
able for “mild to moderate” pain, while 88% of patients stated that the oral route
was acceptable for “severe” pain (Walker et al., 2003) (see Tables 4.2 and 4.3).
The only concern about the oral route involved the time to onset of effect (i.e.,

30 minutes). The speed-of-onset factor seems to be significant insofar as in head-
to-head comparisons, it appears that patients prefer rapid-onset formulations
(OTFC, FEBT) of fentanyl over oral opioids (Coluzzi et al., 2001; Webster et al.,
2006).
Drug costs
The oral route is considered to be relatively cost effective (Patt and Ellison,
1998). However, although oral opioids are relatively inexpensive to pur-
CHAPTER 5
chase, they will only be truly cost effective if they actually relieve the break-
through pain. Unrelieved breakthrough pain is associated with an increased
use of health-care services (i.e., increased outpatient visits, increased inpa-
tient admissions) (Fortner et al., 2002). The impact of the increased use of
health-care services is an increase in direct (e.g., prescription costs, labora-
tory studies) and indirect (e.g., transportation costs, time off from work)
costs for patients and their caregivers, employers, and insurers (Fortner et
al., 2003).
References
American Geriatrics Society (AGS) Panel on Persistent Pain in Older Persons. The man-
53
agement of persistent pain in older persons. Journal of the American Geriatrics Soci-
ety. 2002;50:S205–S224.
British Pain Society (BPS). Recommendations for the Appropriate Use of Opioids for Per-
sistent Non-Cancer Pain. London: British Pain Society, 2005.
Cherny NI, Portenoy RK. Cancer pain management. Current strategy. Cancer. 1993;72(11
Suppl):3393–3415.
Collins SL, Faura CC, Moore A, McQuay HJ. Peak plasma concentrations after oral mor-
phine: A systematic review. Journal of Pain and Symptom Management. 1998;16:388–402.
2006.
Fine PG. The evolving and important role of anesthesiology in palliative care. Anesthesia
and Analgesia. 2005;100:183–188.
Fine PG, Portenoy RK. Clinical Guide to Opioid Analgesia (2nd ed.). New York: Ven-
dome, 2007.
Fortner BV, Demarco G, Irving G, et al. Description and predictors of direct and indirect
costs of pain reported by cancer patients. Journal of Pain and Symptom Management.
2003;25:9–18.
Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clinical Pharmacokinetics.
2004;43:879–923.
Hanks GW, de Conno F, Cherny N, et al. Morphine and alternative opioids in cancer pain:
The EAPC recommendations. British Journal of Cancer. 2001;84:587–593.

Hanks G, Roberts CJ, Davies AN. Principles of drug use in palliative medicine. In Doyle D,
Hanks G, Cherny N, Calman K (Eds.), Oxford Textbook of Palliative Medicine (3rd ed.,
pp. 213–225). Oxford: Oxford University Press, 2004.
Indelicato RA, Portenoy RK. Opioid rotation in the management of refractory cancer
pain. Journal of Clinical Oncology. 2003;21(Suppl):87s–91s.
Leow KP, Smith MT, Williams B, Cramond T. Single-dose and steady-state pharmacoki-
netics and pharmacodynamics of oxycodone in patients with cancer. Clinical Pharma-
CHAPTER 5
cology and Therapeutics. 1992;52:487–495.

Care. Cancer. 2002;94:832–839.
Miaskowski C, Cleary J, Burney R, et al. Guideline for the Management of Cancer Pain in
Adults and Children, APS Clinical Practice Guidelines Series, No. 3. Glenview, IL:
American Pain Society, 2005.
Prommer E. Oxymorphone: A review. Supportive Care in Cancer. 2006;14:109–115.
Twycross R, Wilcock A, Charlesworth S, Dickman A. Palliative Care Formulary (2nd ed.).
Abingdon: Radcliffe Medical Press, 2002.
54

2003;17:219–221.
Webster L, Taylor D, Peppin J, Niebler G. Open-label study of fentanyl effervescent buc-
cal tablets in patients with chronic noncancer pain and breakthrough pain: Patient
preference assessment. Journal of Pain (abstracts from the 2006 annual scientific con-
ference).
World Health Organization (WHO). Cancer Pain Relief (2nd ed.). Geneva: World Health
Organization, 1996.
Zeppetella G, Ribeiro MD. Episodic pain in patients with advanced cancer. American Jour-
Chapter 6
Oral transmucosal opioid

analgesics
The ideal treatment for breakthrough pain is an analgesic with good efficacy, a
rapid onset of action, a short duration of action, and minimal adverse effects. As
discussed in Chapter 5, the oral route may not be suitable for many patients
with breakthrough pain because the pharmacokinetic profile of orally delivered
drugs does not closely mirror the characteristics of breakthrough pain, resulting
in only partially effective treatment and/or troublesome adverse effects. In an
effort to deliver more effective treatment, various other routes of administra-
tion have been explored, including the transmucosal routes of administration.
The transmucosal routes include ocular, nasal, buccal, sublingual, pulmonary,
rectal, and vaginal. This chapter elaborates on the role of the oral transmucosal
routes (buccal, sublingual), and Chapter 7 outlines the role of certain other
55
transmucosal routes (nasal, pulmonary, rectal) in the management of break-
through pain.
Oral mucosa
The oral mucosa refers to the lining of the oral cavity. It is composed of an
outer layer of stratified squamous epithelium, below which lies the basement
membrane and then the lamina propria (connective tissue layer). The total sur-
face area of the oral mucosa is 200 cm2, which is relatively small compared
with the gastrointestinal tract ( 350,000 cm2) (Zhang et al., 2002). The lamina
propria is highly vascular tissue, so drugs diffusing into the oral mucosa have ac-
cess to the systemic circulation via its capillaries and venous drainage (internal
jugular vein). The rate of blood flow through the oral mucosa is substantial; it is
0.97 mL/min/cm2 in the sublingual mucosa and 2.4 mL/min/cm2 in the buccal mu-
cosa. The oral mucosa is covered by a layer of saliva, which is secreted by the
three pairs of major salivary glands (parotid, submandibular, sublingual) and the
hundreds of minor salivary glands distributed throughout the mouth.
The composition of the epithelium varies depending on the site in the oral
cavity. For example, the hard palate, the gingiva, and the dorsal surface of the
tongue are covered by a layer of keratinized cells, whereas the epithelium cov-
ering the soft palate, the buccal mucosa, and the sublingual mucosa is nonkera-
tinized. (Nonkeratinized epithelium is more permeable to water than keratinized
epithelium.) Similarly, the thickness of the epithelium varies according to the
Oral transmucosal opioid analgesics
site: for example, the buccal mucosa is approximately 3 times as thick as the
sublingual mucosa (500 to 600 µm versus 100 to 200 µm [Lee, 2001]). As a re-
sult of these characteristics, the permeability of the sublingual mucosa is greater
than that of the buccal mucosa, which is greater than that of the remainder of
the oral mucosa (Shojaei, 1998).
The absorption of drugs across the oral mucosa involves a process of passive
absorption and may involve either the transcellular route, the paracellular route
(via the intercellular spaces), or a combination of the two routes (Hao and
Hang, 2003). Lipophilic drugs are predominantly absorbed using the transcellu-
lar route, while hydrophilic drugs are predominantly absorbed using the para-
cellular route. It should be noted that lipophilic drugs also need a degree of
hydrophilicity in order to transverse the inner part of the cell (Zwang et al.,
CHAPTER 6
2002). Paracellular absorption is limited by the small surface area available for
this type of absorption (Hao and Hang, 2003).
A number of drug factors affect the absorption of drugs across the oral mu-
cosa, including the lipophilicity of the drug as described earlier, the nonionized
fraction of the drug (a property that is taken advantage of in the newer
modified-release-delivery fentanyl buccal tablet [FBT]), and the duration of con-
tact with the mucosa (Hao and Hang, 2003). Due to surface-area limitations, the
amount of drug that can be absorbed at any one time is relatively small com-
56
pared with oral ingestion, so only potent drugs are suitable for administration
via the oral transmucosal route (Zwang et al., 2002).
Patients with oral mucosal disease may have altered oral transmucosal ab-
sorption (Hao and Hang, 2003), and such patients may have either decreased
absorption of drugs (mucosal thickening) or increased absorption of drugs (mu-
cosal inflammation). Patients with salivary-gland dysfunction may also have al-
tered oral transmucosal absorption (Hao and Hang, 2003). Saliva is important in
maintaining the pH of the oral cavity, which can affect the ionized fraction of the
drug (Hao and Hang, 2003). Moreover, saliva may be necessary to dissolve the
drug formulation (tablets, lozenges).
Oral transmucosal administration

The oral transmucosal route offers several advantages over the gastrointestinal
tract and other alternative routes of administration (Zhang et al., 2002):
• Acceptable to patients (noninvasive) (Walker et al., 2003)
• Convenient for patients
• Convenient for health-care professionals
• Suitable for patients with dysphagia
• Suitable for patients with nausea and vomiting
• Suitable for patients with dysfunction of the upper gastrointestinal tract
• Potentially fast onset of action
• Avoidance of degradation by gastric acid/enzymes

• Avoidance of first-pass metabolism by liver enzymes
Oral transmucosal drug delivery does not require expertise, preparation,
technical equipment, or supervision of patients (except in circumstances where
dose initiation might best be monitored in particularly vulnerable patients).
Overall, oral transmucosal administration is convenient for patients and for
health-care professionals, and it is more cost effective than invasive (e.g., par-
enteral) routes of administration (Zhang et al., 2002). Furthermore, oral trans-
mucosal administration of certain drugs can provide patients with an onset of
action approaching that seen with intravenous administration.
The disadvantages of the oral transmucosal route include the following
(Zhang et al., 2002):
• Not suitable for patients with dryness of mouth
CHAPTER 6
• Not suitable for patients with pathology of the mouth
• Limited number of suitable drugs
• Limited number of suitable formulations
• Variation in oral transmucosal bioavailability
Opioids approved for oral transmucosal
57
administration
Many opioids have been subject to oral transmucosal administration. However,
most of these opioids are not very lipophilic and, therefore, not suited for buc-
cal or sublingual administration due to limited absorption across the oral mu-
cosa. Figure 6.1 shows the percentage absorption for selected opioids
administered via the sublingual route (Weinberg et al., 1988).
A number of pharmaceutical companies are developing oral transmucosal
preparations of fentanyl for the management of breakthrough pain, including
various sublingual sprays and buccal patches. In addition, several authors have
reported success with the sublingual administration of the parenteral prepara-
tion of fentanyl (Gardner-Nix, 2001; Zeppetella, 2001; Duncan, 2002). Cur-
rently, though, there are only two drugs for which applications have been
submitted and specifically approved by the U.S. Food and Drug Administration
(FDA) for the treatment of breakthrough pain: oral transmucosal fentanyl cit-
rate (OTFC) (Actiq) and FBT (Fentora). The current indications as set forth in
the FDA approvals—and thus the indications for which these drugs can be pro-
moted by the companies that make and market them—are limited to opioid-
tolerant patients with cancer-related breakthrough pain. These formulations
have been tested in randomized, controlled trials of patients experiencing
breakthrough pain from causes unrelated to cancer (e.g., chronic low back pain,
neuropathic pain syndromes), and their use has extended to these types of pa-
tients since the drugs have become commercially available (Portenoy et al.,
2007; Taylor et al., 2007).
60
50
Mean absorption (%)
40
30
20
10
0
CHAPTER 6
Opioid (dose)
Figure 6.1 Absorption of opioid analgesics after sublingual administration. Adapted from
Weinberg et al, 1988.
Fentanyl
58
Drug class and characteristics

Fentanyl is a synthetic opioid and a pure agonist at the µ opioid receptor. Com-
pared with morphine, it is relatively lipophilic and approximately 50 to 100
times more potent (Gauthier and Fine, 1997). In the United States, fentanyl is
available for intravenous administration (50 µg/mL); as a transdermal patch
(dose strengths of 12, 25, 50, 75, and 100 µg/h); as a lozenge (dose strengths of
200, 400, 600, 800, 1200, and 1600 µg); and as a buccal tablet (dose strengths of
100, 200, 400, 600, and 800 µg).
Transmucosal fentanyl: Commercially available products
Oral transmucosal fentanyl citrate
OTFC (Fig. 6.2A) consists of a hardened, sweetened, and flavored fentanyl-
impregnated lozenge on a plastic handle (Fig. 6.2). OTFC is rubbed against the
inside of the cheek, which allows the lozenge to be dissolved by the saliva and
the fentanyl to be absorbed through the buccal mucosa.
It takes about 15 minutes to dissolve the lozenge. However, dry-mouthed pa-
tients may take longer or be unable to dissolve the lozenge. It is recommended
that the lozenge be removed from the mouth if the pain is relieved before the
lozenge has completely dissolved, and the partly consumed lozenge should not
be recycled but should be dissolved under hot running water (Fine, 1997).
Fentanyl buccal tablet
The FBT formulation (Fig. 6.2B) uses OraVescent drug delivery technology to
produce an effervescent reaction that enhances the rate and extent of fentanyl
59 CHAPTER 6
Figure 6.2 (A) Oral transmucosal fentanyl citrate (Actiq). Reprinted with permission from
Davies, 2006. (B) Fentanyl buccal tablet (Fentora).
absorption (Fig. 6.3). FBT is placed next to the buccal mucosa between the up-
per third molar area and the cheek, in the oral buccal pouch. When it comes in
contact with saliva, a reaction takes place, resulting in transient changes in pH.
As the pH decreases, dissolution is facilitated. As CO2 is released, the pH rises,
enhancing the absorption of fentanyl through the mucosa by altering the ionic
charge and making it more lipophilic (Durfee et al., 2006). The pharmacokinet-
ics of FBT in human subjects can be seen in Table 6.1.
Pharmacokinetic Profile
Fentanyl is highly lipid soluble and is 80% nonionized, making it ideally suited for
transmucosal absorption. The bioavailability of OTFC is 47% to 50%: 25% is rap-
idly absorbed through the buccal mucosa, while 25% is more slowly absorbed
through the gastrointestinal mucosa as a result of swallowing the drug (Hanks,
2001; Darwish, 2007a). In comparison, the absolute biovailability of FBT is 65%:
Fentanyl buccal tablets are formulated to create
a reaction that releases carbon dioxide when
the tablet comes in contact with saliva
– Transient pH changes accompanying this reaction
are believed to optimize dissolution (at a lower
pH) and membrane permeation (at a higher pH)
Lower pH Higher pH
High pH High pH
Low pH Low pH
Enhancing Dissolution
When the tablet comes in contact with
saliva, a combination of acid and
bicarbonate forms carbonic acid
This drives down the pH and may enhance the

dissolution of ionized fentanyl
Enhancing Absorption
Carbonic acid dissociates into CO2 and H2O
– CO2 bubbles out of solution or is absorbed
across oral mucosa
H2CO3
carbonic acid
The loss of CO2 results in an increase in pH, which

may favor the absorption of nonionized fentanyl
Figure 6.3 OraVescent Drug Delivery Technology.
Table 6.1 Pharmacokinetic parameters of fentanyl buccal tablet

(FBT) obtained from studies in healthy volunteers*† ‡
Study Dose in µg (n) Tmax (min) Cmax (ng/mL) AUC0-Tmax’ AUC0-infinity
(ng• h/mL) (ng• h/mL)
Darwish FBT 200 (n = 25) 45.6 0.62 0.37 3.5
et al., 2005 FBT 500 (n = 26) 45.0 1.5 0.91 9.7
FBT 810 (n = 27) 59.4 2.3 1.4 15.0
FBT 1080 (n = 27) 45.0 2.7 1.6 19.0
Darwish FBT 100 (n = 31) 45.0 0.25 0.09 0.98
et al., 2006a FBT 200 (n = 31) 40.2 0.40 0.13 2.11
FBT 400 (n = 31) 34.8 0.97 0.34 4.72
FBT 800 (n = 31) 40.2 1.59 0.52 9.05
Darwish FBT 1080 (n = 40) 60 2.7 1.5 18.0
et al., 2006b OTFC 1600 (n = 40) 120 2.2 0.8 18.0
CHAPTER 6
Darwish FBT 400, one 45.0 0.94 0.34 6.15
et al., 2006c tablet (n = 27)
FBT 100, four 45.0 1.03 0.36 6.30
tablets (n = 27)
Darwish FBT 400 (n = 26) 46.8 1.02 0.40 6.48
et al., 2007a FBT 800, oral 90.1 0.98 0.11 6.60
(n = 26)
OTFC 800 (n = 26) 90.8 1.26 0.28 9.58
Fentanyl 400 IV NA 3.00 1.43 10.29
61
(n = 26)
Darwish FBT 400 single- 52.2 0.88 0.35 6.07
et al., 2007b dose (n = 21)
FBT 400 multiple 49.8 1.77 1.09 NR
doses (n = 21)
NA: not applicable; NR: not reported.
* All values are expressed as means, with the exception of Tmax (median).
† All studies were randomized and open-label and featured a crossover design.
‡ Numbers of patients evaluable for pharmacokinetic analysis may differ from total number of enrolled
patients reported in text.
48% is rapidly absorbed through the buccal mucosa while 17% is absorbed en-
terally (Darwish, 2007a).
Clinical Data: OTFC and FBT
OTFC can provide pain relief within 10 to 15 minutes, with the peak effect oc-
curring within 20 to 30 minutes (Hanks, 2001), whereas FBT has been shown to
provide meaningful pain relief in 5 to 10 minutes with similar time course for
peak effect (Darwish et al., 2007b; Slatkin et al., 2007) (Fig. 6.4). The duration of
analgesia is 2 hours for both formulations (Hanks, 2001; Portenoy et al.,
2006). The onset of action is dependent on the absorption of fentanyl through
the buccal mucosa because the drug rapidly crosses the blood–brain barrier
once it enters the systemic circulation. With OTFC, patients who suck the
lozenge, rather than rub the lozenge against the inside of the cheek, will experi-
ence a delayed and reduced effect.
There have been numerous studies of the use of OTFC in the management
of cancer-related breakthrough pain (Mystakidou et al., 2005). Table 6.2 shows

some data from the randomized trials of OTFC (Christie et al., 1998; Farrar et
al., 1998; Portenoy et al., 1999; Coluzzi et al., 2001). There have been more re-
cent trials of OTFC in non-cancer-related breakthrough pain (Taylor et al.,
2007) and with FBT in both cancer-related and non-cancer-related break-
through pain (Portenoy et al., 2006; Fine et al., 2007; Portenoy et al., 2007). Both
formulations of transmucosal fentanyl have been found to be effective in treat-
1.0
Mean Plasma Fentanyl
Concentration (ng/mL)
0.8
CHAPTER 6
0.6
0.4
0.2
FBT OTFC
median Tmax median Tmax
0
0 15 30 45 60 90 120
62
Time (min)
Figure 6.4 Oral transmucosal fentanyl citrate (OTFC) vs. fentanyl buccal tablet (FBT) mean
plasma concentrations. Adapted from Darwish, 2007.
OTFC
MSIR
Pain relief score
*p 0.009
Minutes
Figure 6.5 Pain relief scores with oral
transmucosal fentanyl citrate (OTFC) and
immediate-release oral morphine sulphate
(MSIR). Reproduced with permission from
Coluzzi et al., 2001.
Table 6.2A Randomized trials of oral transmucosal fentanyl citrate
Study Methodology Principal outcomes
Christie et al., 1998 Multicenter, double-blind, randomized • 76% of patients titrated to an effective dose of OTFC.
dose-titration study of OTFC • No relationship was found between the successful
dose of OTFC and the dose of background
transdermal fentanyl.
62 cancer patients using transdermal • OTFC produced significantly quicker/better pain
fentanyl for background analgesia relief than usual breakthrough analgesic.
• Global satisfaction significantly higher for OTFC than
usual breakthrough analgesic.
• The most common adverse effects of OTFC were somnolence,
nausea, dizziness, and vomiting.
Portenoy et al., 1999 Multicenter, double-blind, randomized • 74% of patients titrated to an effective dose of OTFC.
dose-titration study of OTFC • No relationship was found between the successful
dose of OTFC and the dose of background oral opioid.
65 cancer patients using oral opioids for • OTFC produced significantly quicker/better pain
background analgesia relief than usual breakthrough analgesic.
• Global satisfaction significantly higher for OTFC than
usual breakthrough analgesic.
• The most common adverse effects of OTFC
were somnolence, dizziness, nausea, and headache.
OTFC: oral transmucosal fentanyl citrate.
Table 6.2B Randomized trials of oral transmucosal fentanyl citrate
Study Methodology Principal outcomes
Farrar et al., 1998 Multicenter, double-blind, randomized, • OTFC produced significantly quicker/better pain relief
controlled crossover trial of OTFC vs. placebo than placebo.
• Global performance of OTFC better
than placebo.
92 cancer patients using oral opioids or • Patients required significantly less additional rescue
transdermal fentanyl for background analgesia medication when using OTFC.
Patients only eligible for main trial if • Most patients chose to continue with
they responded to OTFC OTFC following the trial.
• The most common adverse effects of OTFC
were dizziness, nausea, somnolence, constipation,
and asthenia.
Coluzzi et al., 2001 Multicenter, double-blind, randomized, • No relationship was found between the successful
controlled crossover trial of dose of OTFC and the dose of background
OTFC vs. oral morphine oral opioid or transdermal opioid (Figs. 6.5 and 6.6).
• OTFC produced significantly quicker/better
93 cancer patients using oral opioids or pain relief than oral morphine (Figs. 6.3 and 6.4).
transdermal opioid for background analgesia • Global performance of OTFC better than placebo.
• Most patients chose to continue with
Patients only eligible for main trial if they OTFC following the trial.
responded to OTFC • The most common adverse effects of OTFC were
somnolence, nausea, constipation, and dizziness.
OTFC: oral transmucosal fentanyl citrate.
Pain Intensity Response
50% Improvement
80
70
64†
60
Percentage of Distribution
51†
50
40
35
CHAPTER 6
30
24* 25
20 16
10 8 6
65
0
15 30 45 60
Time (min)
*P < 0.05
†P < 0.0001
Figure 6.6 Breakthrough pain intensity improvement by treatment episode. FBT: fentanyl
buccal tablet. Adapted with permission from Portenoy et al., 2006. FENTORA (package in-
sert). Frazer, PA: Cephalon, Inc., 2007.
ing these difficult-to-control, debilitating, episodic pains (Figs. 6.5 and 6.6) and
to be well tolerated.
Dose-finding studies have demonstrated that there is no correlation between
the dose of opioid needed to control the background pain and the dose of
OTFC or FBT needed to control the breakthrough pain (i.e., the dose requires
individual titration) (Christie et al., 1998; Portenoy et al., 1999; Coluzzi et al.,
2001; Portenoy et al., 2006) (Figs. 6.7, 6.8, and 6.9). Figure 6.10 shows a titration
schedule for FBT and OTFC that has been safe and effective (Fentora Package In-
sert, 2007; Zeppetella, 2005). More rapid titration schedules have been devel-
oped, but this is not advised unless performed under circumstances where
monitoring can detect and lead to immediate reversal of untoward adverse ef-
fects (e.g., respiratory depression) (Zeppetella, 2005; Fine and Portenoy, 2007).
The side effects of OTFC and FBT are similar to those of other opioid prepa-
rations and include somnolence, nausea, dizziness, and headache (Christie et al.,
1600
1400
Successful OTFC dose (µg)

1200
1000
800
600
400
200 y = 0.47x + 807
R2 = 0.024
0
0 200 400 600 800
Fixed schedule oral opioid dose
morphine equivalent (mg/day)
Figure 6.7 Relationship between suc-

cessful dose of oral transmucosal fen-
tanyl citrate (OTFC) and background
dose of oral opioid. Reproduced with
permission from Coluzzi et al., 2001.
Figure 6.8 Relationship between successful dose of oral transmucosal fentanyl citrate
(OTFC) and background dose of transdermal fentanyl. Reproduced with permission from
Coluzzi et al., 2001.
30%
25%
% of Patients
20%
15% 33%
10% 22% 20%
5% 13%
12%
0%
100 200 400 600 800
Figure 6.9 Titration of the fentanyl buccal tablet (FBT) Pivotal Cancer Trials. Distribution of
successful doses of FBT following titration (N = 167). Successful dose = dose strength that pro-
vided adequate analgesia (sufficient pain relief within 30 minutes after placing a single tablet of
that dose strength in the buccal cavity for each of two consecutive episodes of breakthrough
CHAPTER 6
pain (BTP) in cancer patients that occurred at least 4 hours apart) without unacceptable ad-
verse effects; no correlation was found between baseline opioid dose and BTP dose. Source:
Cephalon, Inc., Frazer, PA.
67
1998; Farrar et al., 1998; Portenoy et al., 1999; Coluzzi et al., 2001; Portenoy et
al., 2006). Respiratory depression is a potential hazard, but this has been a very
rare occurrence when these formulations have been titrated appropriately.
Limitations to the use of OTFC include patients who cannot actively rub the
preparation against the buccal membrane (e.g., patients who are severely dis-
abled, fatigued, or cognitively impaired.)
Dry mouth is one of the main reasons cited for not being able to use OTFC
or FBT. However, it is usually possible to treat the dry mouth in order to facil-
itate use of these formulations when deemed appropriate (Davies and Vriens,
2005). Severe oral pathology may alter absorption or result in painful applica-
tion, so these situations must be managed on a case-by-case basis. Unique to
FBT is the potential for application-site irritation from the effervescent reac-
tion. Similarly, there are anecdotal reports of dental caries from frequent
OTFC use.
Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoen-
zyme system (CYP3A4); thus, potential interactions may occur when it is given
concurrently with agents that affect CYP3A4 activity. Particular caution should
be exercised for patients receiving CYP3A4 inhibitors, and the lowest possible
dose of fentanyl-containing formulations should be used in these patients (e.g.,
dexamethasone, dextromethorphan, fluoxetine, paroxetine [weak inhibitor],
sertraline, venlafaxine) (Inturrisi, 2002). Patients receiving OTFC or FBT and
moderate or potent CYP3A4 inhibitors should be carefully monitored for an
extended period of time, and dosage increases should be conservative (Fine and
Portenoy, 2007).
Patients considered opioid-tolerant are those
who are taking:
– At least 60 mg of oral morphine daily
– At least 25 µg of transdermal fentanyl per
hour
– At least 30 mg of oxycodone daily
– At least 8 mg of oral hydromorphone daily
– An equianalgesic dose of another opioid
for 1 week or longer
FBT: Start dosing at 100 µg

OTFC: Start dosing at 200 µg
1. Patient waits 15 to 30 minutes after complete

dissolution of either drug formulation. If
inadequate analgesia results, patient
applies/consumes a second FBT/OTFC unit of
the same strength.
2. Patient tries this FBT/OTFC dose for
consecutive episodes of breakthrough pain.
With FBT, 100 µg tablets can be placed
concurrently on either side of the mouth to
use up the initial prescription.
Did patient achieve adequate pain relief with one

FBT/OTFC unit?
Yes No
Successful dose Increase dose to

determined next strength
Figure 6.10 Titration protocol for transmucosal formulations of fentanyl (fentanyl buccal
tablet [FBT] and oral transmucosal fentanyl citrate [OTFC]) in opioid-tolerant patients with
breakthrough pain. Adapted from Zeppetella, 2005, and Fentora package insert.
Other opioids for oral transmucosal

administration
Alfentanil
Alfentanil is a synthetic opioid analgesic that is chemically similar to fentanyl. It
is less lipophilic than fentanyl but has a more rapid onset of action and shorter
duration of action when given parenterally (Scholz et al., 1996). For example,
when given intravenously, the onset of action is < 2 minutes, and the duration of
action is 10 minutes (Twycross et al., 2002). These characteristics suggest that
alfentanil could be particularly helpful in the management of breakthrough pain.
A parenteral preparation of alfentanil was reported to be effective and well
tolerated when administered bucally/sublingually in a small case series of pa-
CHAPTER 6
tients with cancer-related breakthrough pain (Duncan, 2002). Interestingly, pa-
tients preferred buccal administration of the preparation. It should be noted
that the main reason for choosing alfentanil in this series was the availability of
a suitable (concentrated) preparation of alfentanil (i.e., only small volumes of
alfentanil were required to be administered).
Buprenorphine
Drug characteristics
69
Buprenorphine is a semisynthetic opioid and is a partial agonist at the µ receptor.
Product characteristics
Buprenorphine, an analgesic used primarily for addiction therapy in the United
States, has a very high affinity for the µ receptor. As a partial agonist, it can
compete for the receptor and has antagonist properties in opioid-sensitized in-
dividuals, and it also is difficult to displace from the receptor once bound. Oral
sublingual buprenorphine is now available in the United States for office-based
substitution treatment of opioid addiction, but it is also being studied for use in
chronic pain. A transdermal buprenorphine formulation is also being studied for
use in chronic pain (Fine and Portenoy, 2007).
Buprenorphine is available as a sublingual tablet and may become available in
the United States as a transdermal patch and a parenteral preparation, formula-
tions that are currently available in the United Kingdom. In the United Kingdom,
the sublingual tablet is licensed for the management of moderate to severe
pain; the sublingual tablet is primarily used in the management of background
pain but is also recommended for use in the management of breakthrough pain
in patients prescribed the transdermal patch (Anonymous, 2005).
Pharmacokinetic profile
Buprenorphine is highly lipophilic and is well absorbed across mucosal mem-
branes. The percentage absorption is 55% after sublingual administration (Wein-
berg et al., 1988) (Fig. 6.1), although it is somewhat less after buccal administration
(Davis, 2005). However, the rate of systemic absorption can be slow: peak plasma
concentrations occur 0.5 to 3 hours after sublingual administration (Davis, 2005).
Clinical data
The reported onset of action of sublingual buprenorphine is 15 to 30 minutes,
the peak analgesic effect is at 60 to 120 minutes, and the duration of action is
8 hours (Thompson, 1990). The delayed peak analgesic effect and the long
duration of action make this preparation of questionable value for the treat-
ment of breakthrough pain.
There have been numerous studies of the use of sublingual buprenorphine in
the management of cancer-related pain (Davis, 2005). The majority of these stud-
ies report its use for background pain, but some studies also report its use for
breakthrough pain, especially when used with the transdermal buprenorphine
CHAPTER 6
patch (Sittl et al., 2003; Sorge and Sittl, 2004). However, there are no studies
specifically designed to evaluate the effectiveness of sublingual buprenorphine in
the management of breakthrough pain.
The adverse effects encountered with buprenorphine are typical of those en-
countered with opioid analgesics. Buprenorphine is reported to cause more
dizziness, nausea, and vomiting than morphine. However, it is reported to cause
less respiratory depression and constipation than morphine (Davis, 2005). It
should be noted that the effects of buprenorphine are only partially reversed by
70
opioid antagonists (e.g., naloxone), an issue of particular concern should there

be accidental overdose (Anonymous, 2005).
Hydromorphone
Hydromorphone has a relatively low lipid solubility, which results in limited
transmucosal absorption (Weinberg et al., 1988) (see Fig. 6.1). The low bioavail-
ability and long duration of action of hydromorphone ( 4 hours) mean that
this drug is not suited for the treatment of breakthrough pain.
Methadone
Methadone is a lipophilic drug that is well absorbed across mucosal membranes.
The percentage absorption is 35% after sublingual administration (Weinberg et
al., 1988) (see Fig. 6.1). Sublingual methadone has been reported to be effective
in the management of pain in adults, and the sublingual bioavailability is reported
to be similar to the oral bioavailability, with the time to maximum peak concen-
tration reported to be similar for the two routes (McQuay et al., 1986).
In view of the comparable pharmacokinetic profiles of oral and sublingual
methadone, it would seem reasonable to suppose that the clinical profile is simi-
lar for sublingual and oral methadone. Oral methadone is reported to have an on-
set of action of 30 to 60 minutes, a peak analgesic effect at 30 to 120 minutes, and
a duration of action of 6 to 8 hours (Thompson, 1990). However, a recent study
of oral methadone for breakthrough pain stated that some patients reported an
analgesic effect at 10 minutes following ingestion of the oral methadone (Fisher
et al., 2004).
The fast onset of action and relatively low cost of sublingual methadone could

be viewed as advantageous. Nonetheless, the pharmacology of methadone has
been shown to differ so substantially from other opioids as to pose unique risks
related to its metabolism, protein binding, excretion, arrhythmogenesis, and un-
predictable eqianalgesic dosing (Fishman et al., 2002). Likewise, methadone has a
uniquely shorter analgesic half-life compared to its rather long plasma half-life
(8 to 150 hours), which potentially complicates its dosing. Overall, it can be con-
cluded that the risks of dose accumulation due to the very long half-life of
methadone simply outweigh any potential benefits for treatment of break-
through pain in most cases.
Morphine
Among opioids, morphine is relatively hydrophilic, and 90% of its molecules are
CHAPTER 6
ionized at the normal oral pH (Coluzzi, 1998). Thus the physicochemical prop-
erties of morphine are not favorable for oral transmucosal absorption (Wein-
berg et al., 1988) (see Fig. 6.1). In addition, the time to maximum peak
concentration and the maximum peak concentration are reported to be similar
for the sublingual and oral routes (McQuay et al., 1986).
A review of the literature on the use of sublingual morphine stated that “the
limited clinical data do not provide compelling evidence for the effectiveness of
sublingual morphine for the rapid relief of pain in cancer patients” (Coluzzi,
71
1998). Nothwithstanding these findings, oral morphine concentrate (20 mg/mL)
is commonly used for “rescue analgesia” or breakthrough pain in hospice and
palliative care settings. This is most likely a matter of convention, convenience,
and cost. There may be a desire to avoid invasive parenteral drug delivery de-
vices (e.g., patient-controlled analgesia pumps) or an inability to pay for the ap-
preciably higher cost of rapid-onset noninvasive drug delivery systems (i.e.,
OTFC or FBT) compared to oral morphine solution under the financial con-
straints of the Medicare Hospice Benefit (Fine and Davis, 2006).
Oxycodone
Oxycodone has a very low lipid solubility, which results in very limited trans-
mucosal absorption (Weinberg et al., 1988) (see Fig. 6.1). Again, the low bio-
availability and long duration of action of oxycodone ( 4 hours) mean that this
drug is not ideally suited for the treatment of breakthrough pain. Nevertheless,
there are reports of buccal administration of oxycodone in the management of
background pain (Parodi et al., 1997).
Sufentanil
Sufentanil is another synthetic opioid analgesic and is chemically similar to
fentanyl. It is more lipophilic and about 10 times more potent than fentanyl,
with a more rapid onset of action and shorter duration of action when given
parenterally (Scholz et al., 1996). Again, these characteristics suggest that
sufentanil could be particularly helpful in the management of breakthrough
pain.
There have been a number of published reports supporting the role of sub-
lingual sufentanil in the management of breakthrough pain (Kunz et al., 1993;

Gardner-Nix, 2001). In the study by Gardner-Nix, the onset of action was re-
ported to be between 4 and 6 minutes, and the duration of action was 35 min-
utes (Gardner-Nix, 2001). In fact, in some patients the duration of action was so
brief that they required a combination of the short-acting sufentanil and a
longer-acting oral opioid (i.e., morphine or hydromorphone) to control some
longer episodes of breakthrough pain. Although sufentanil has a very suitable
profile for breakthrough pain, as of yet no commercially available transmucosal
formulations of sufentanil have been approved for this indication.
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Portenoy RK, Messina J, Xie F, Peppin F. Fentanyl buccal tablet (FBT) for relief of break-
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treatment of breakthrough pain in cancer patients: A controlled dose titration study.
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Shojaei AH. Buccal mucosa as a route for systemic drug delivery: A review. Journal of
Pharmacy and Pharmaceutical Sciences. 1998;1:15–30.
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Therapeutics. 2003;25:150–168.
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in opioid-tolerant patients with cancer-related chronic pain. Supportive Oncology.
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Chapter 7
Opioid analgesics via other

routes
Ideally, breakthrough pain should be treated with a self-manageable method
that consistently provides a rapid onset of action, a short duration of action,
good efficacy, and good tolerability. Furthermore, the method must be accept-
able and affordable. By convention and convenience, the majority of patients
with breakthrough pain are treated with oral opioids. However, as discussed in
Chapter 5, the oral route of administration is not ideally suited to the treatment
of breakthrough pain. Furthermore, there are a number of clinical conditions
that contraindicate the oral route of administration (e.g., dysphagia, nausea, and
vomiting).
Opioids can be delivered via a number of other routes, including the rectal,
intravenous, intramuscular, subcutaneous, transdermal, oral transmucosal, in-
75
tranasal, and intrapulmonary routes (Stevens and Ghazi, 2000). Some of these
routes have become more commonly used to manage breakthrough pain (e.g.,
subcutaneous, oral transmucosal), while others are still being investigated for
their utility (e.g., intranasal, intrapulmonary).
The suitability of different opioids for delivery via certain routes depends on
a number of physicochemical factors (i.e., drug-specific factors) and pharmaceu-
tical factors (i.e., product formulation factors). For example, methadone—
regardless of its long half-life and benefit-to-risk ratio as a breakthrough pain
drug—is not ideally suited to intranasal administration because it causes irri-
tation of the nasal mucosa (Dale et al., 2002b). On the other hand, fentanyl
and its congeners (e.g., sufentanil) have been tested via the intranasal route,
but no formulation has been submitted for U.S. Food and Drug Administra-
tion (FDA) approval, let alone made commercially available, for such use
(Duncan, 2002).
Enteral routes
Oral administration
A comprehensive discussion of oral administration is given in Chapter 5. How-
ever, some comparative aspects of oral versus other routes of administration
are shown in Table 7.1.
Table 7.1 Characteristics of different routes of administration
Characteristic Oral Rectal Intravenous Intramuscular Subcutaneous Transmucosal Intrapulmonary
route route route route route routes* route
First-pass metabolism ++ (+) − − − − −
Bioavailability Variable Variable Maximum High Medium to high Medium to high Medium to high
Onset of action >30 min >30 min 5 min 10 to 15 min 10 to 15 min 10 min 5 min
Invasive method − − + ++ + − −
Self-administered + + − ** − + + +
method
Duration of usage Unlimited Medium term Long term Short term Long term Unlimited Undetermined
* Oral transmucosal, intranasal
** Except for intravenous PCA (patient-controlled analgesia)
Rectal administration
Opioid analgesics via other routes

The rectum is 15 to 19 cm in length and has a surface area available for drug
absorption of 200 to 400 cm2. The upper part of the rectum drains into the
portal vein, while the lower part of the rectum drains into the inferior vena cava
(and thus circumvents first-pass metabolism through the liver). However, there
are anastomoses between the two venous systems (van Hoogdalem et al., 1991;
Warren, 1996).
Drug transport across the rectal mucosa occurs predominantly via passive dif-
fusion. Absorption is mostly dependent on the amount of surface area and dura-
tion of contact of the drug with the rectal mucosa. Stool in the rectum may
prevent the absorption of all or some portion of the drug. Furthermore, defeca-
tion will obviate the absorption of the drug, and reflex expulsion will occur if sig-
CHAPTER 7
nificant volumes of solubilized formulations of medications are inserted into the
rectum (i.e., 10 to 25 mL) (van Hoogdalem et al., 1991; Warren, 1996). Rapidity
and amount of drug absorption from the rectum also depend to a high degree
on the formulation used (e.g., liquid enemas tend to be more rapidly absorbed
than solid suppositories).
Rectal administration may result in a faster onset of action than oral adminis-
tration, due to the time taken for the drug to reach the site of absorption for
the oral route (i.e., the small bowel). For example, it has been shown in healthy
volunteers that there is more rapid uptake of methadone after rectal adminis-
77
tration (Dale et al., 2004). In addition, rectal administration of an opioid may re-
sult in a higher bioavailability than oral administration of the same drug for
those that undergo extensive first-pass metabolism (e.g. morphine, fentanyl).
However, rectal bioavailability can be extremely variable, for the reasons dis-
cussed earlier (Hanks et al., 2004).
Although the rectal route has been suggested as being potentially suitable for
the treatment of breakthrough pain, there are no specific studies of the use of
the rectal route for this purpose (Mercadante et al., 2002). Nonetheless, in
those rare cases where other routes are simply not acceptable or accessible,
rectal administration may be an option (Mercadante and Fulfaro, 1999).
The rectal route is simple, does not require any equipment, and can be used
by both patients and their nonprofessional caregivers (Hanks et al., 2004). How-
ever, the rectal route may be inappropriate in patients with local disease of the
rectum and may be difficult to use in patients who are not cooperative. In addi-
tion, many patients do not find the rectal route to be an acceptable route of ad-
ministration for drugs. For example, in a study by Walker et al. (2003), only 48%
or patients thought that rectal administration of analgesics was acceptable for
pain that was severe in nature. A variety of different reasons were given for re-
jecting this route (see Table 4.2).
Parenteral routes
Intravenous administration
The intravenous (IV) route is associated with a 100% bioavailability (by defini-
tion) and a very rapid onset of action ( 5 minutes).
Mercadante et al. (2004) reported on the use of IV morphine to treat break-
through pain episodes in patients receiving oral morphine. Intravenous morphine
was found to be effective, well tolerated, and safe (in the inpatient setting). In ad-
dition, other authors have reported on the use of IV morphine to treat break-
through pain episodes in patients receiving continuous infusions of morphine (i.e.,
IV patient-controlled analgesia [PCA]) (Swanson et al., 1989; Wagner et al., 1989).
The IV route requires appropriate venous access, some basic equipment (for
CHAPTER 7
bolus injections), and some training in performing the technique and caring for
the IV site. This route can be used in community settings, and the technique can
be taught to patients and their caregivers. However, in practice, this route is
generally restricted to inpatient settings (with the exception of home-based
post-acute care), palliative care, and hospice situations, where IV PCA has been
successfully used (Swanson et al., 1989; Wagner et al., 1989).
Intravenous administration has high acceptability when the pain is severe in
intensity (83% acceptability) (Walker et al., 2003) and there are no other rea-
78
sonable alternatives presented. The main objections to the use of this route are
its invasiveness and previous bad experiences with this route. In patients with-
out a permanent IV access device (e.g., Broviac catheter), it goes without saying
that in the vast majority of cases, use of this route is temporary and labile until
other modalities (e.g., oral transmucosal formulations) can take over.
Intramuscular administration
The intramuscular (IM) route of administration is not recommended for the treat-
ment of breakthrough pain because of the discomfort associated with IM injection
(Mercadante et al., 2002). Indeed, the IM route of administration is not acceptable
to many patients because of their dislike for injections (and particularly IM injec-
tions) (Walker et al., 2003). Nevertheless, in certain crisis circumstances, there
may be no alternative to the IM route of administration (Hanks et al., 2004).
Proper planning and anticipation of needs are the best means of preventing such
a crisis, obviating the need for unscheduled emergency/urgent care and prevent-
ing the suffering and costs associated with it (Ferrell and Griffith, 1994).
Subcutaneous administration
The subcutaneous (SC) route is the most commonly used parenteral route of
administration in palliative care (Hanks et al., 2004). The SC route is associated
with a relatively high bioavailability: for example, a pharmacokinetic study in
healthy volunteers showed that SC morphine has a bioavailability of 80% to
100% (higher for continuous infusion than for bolus doses) (Stuart-Harris et al.,
2000). The SC route is also associated with a relatively rapid onset of action
( 10 to 15 minutes) depending on site, state of hydration, peripheral perfusion,

and use of absorption-enhancing agents (e.g., hyaluronidase).
Subcutaneous administration of hydromorphone via a “pain pen”—an
adapted insulin injection pen—has been reported to treat breakthrough pain
(Enting et al., 2005). Other studies are being planned to confirm the efficacy,
tolerability, and safety of this approach. In addition, other authors have re-
ported on the use of SC morphine to treat breakthrough pain episodes in pa-
tients receiving continuous infusions of morphine (i.e., SC PCA) (Swanson et al.,
1989; Wagner et al., 1989).
The SC route requires some basic equipment for bolus injections or admin-
istration via PCA pump, as well as some training in performing the technique. It
is used successfully in community settings, and the technique can be taught rap-
idly to cooperative patients and responsible, capable caregivers (Swanson et al.,
CHAPTER 7
1989; Wagner et al., 1989).
Subcutaneous administration has high acceptability when pain is severe in in-
tensity (87% acceptability) (Walker et al., 2003). The main objection to the use
of this route was the dislike of injections. With the availability of rapid-onset
oral transmucosal opioid formulations, it is anticipated that this route will have
little long-term utility but may be useful in selected cases as a transition to less
invasive routes or when other routes are precluded by clinical circumstances.
79
Transdermal administration
Transdermal administration has had no role to play in the treatment of break-
through pain due to the very slow egress of drug through the skin. However,
new patch technology using iontophoresis may alter that rate-limiting barrier.
A fentanyl hydrochloride patient-activated transdermal system (Ionsys) has
recently been developed and FDA approved for the treatment of acute postop-
erative pain in hospitalized patients. The system uses a low-intensity direct cur-
rent to transport fentanyl from the reservoir in the patch into the SC tissues,
where it is then absorbed into the systemic circulation (Sinatra, 2005). The sys-
tem is patient activated, delivers a 40 µg bolus of fentanyl over 10 minutes, and
has a 10-minute “lock-out” period. Each patch is operational for 24 hours and
delivers a maximum of 80 boluses of fentanyl. The system compared favorably to
conventional PCA in recent studies of postoperative pain (Viscusi et al., 2004;
Viscusi et al., 2006). No studies as of yet have been designed to evaluate this sys-
tem for breakthrough pain, although the technology lends itself to this indication.
Other routes
Intranasal administration
Although the nose has a relatively small surface area for absorption ( 150 to
180 cm2), the nasal epithelium is very permeable and highly perfused with blood.
These factors help to facilitate the absorption of drugs. A special feature of the
nose is its close connection to the brain in the olfactory area (i.e., an absence of
the normal blood–brain barrier); this may enable a fraction of the drug to enter
the intrathecal space directly (Dale et al., 2002a).

The nose can accommodate only volumes of 150 to 200 µL in each nostril,
which restricts the opioid formulations suitable for intranasal administration. In
addition, there is a continuous turnover/flow of mucus within the nose, which
limits the time available for the drug to be absorbed ( 15 minutes). The phar-
macokinetics of relevant opioids following nasal administration have been stud-
ied in groups of healthy volunteers (Dale et al., 2002a).
The intranasal route of administration is well established in other areas of med-
icine (e.g., otolaryngology). In addition, several explorative studies have looked at
the use of intranasal opioids for the treatment of breakthrough pain (Zeppetella,
2000; Pavis et al., 2002; Fitzgibbon et al., 2003; Kendall et al., 2003). Morphine
(Pavis et al., 2002; Fitzgibbon et al., 2003), diamorphine (Kendall et al., 2003), fen-
CHAPTER 7
tanyl (Zeppetella, 2000; Duncan, 2002), and alfentanil (Duncan, 2002) have all
been reported to be useful for intranasal administration. Methadone has been re-
ported to be too irritating for intranasal administration (Dale et al., 2002b).
Zeppetella reported on a small, open-label, fixed-dose study of intranasal fen-
tanyl (Zeppetella, 2000). The patient population consisted of 12 hospice inpatients,
and the treatment regimen consisted of 20 µg of fentanyl citrate (administered as
0.2 mL solution to each nostril, using two separate nasal spray bottles). Eight (67%)
patients reported good or very good pain relief, and pain relief invariably occurred
80
within 5 to 10 minutes. Moreover, nine (75%) patients reported that the pain relief
with the intranasal fentanyl was greater than the pain relief with oral morphine.
Two patients reported nasal discomfort/nasal itching, which subsided with ongoing
use of the spray. No patients reported systemic opioid side effects, and no side ef-
fects were noted by the medical staff caring for the patients.
The intranasal route is simple, does not require particularly specialized
equipment, and can be used by patients alone or with assistance from their non-
professional caregivers. Opioids can be delivered by traditional nasal spray bot-
tles and by syringes fitted with atomizers (Fig. 7.1). Newer methods of delivery
include devices that increase the deposition of the spray in the deeper parts of
the nose and incorporate a lock-out function (Djupesland et al., 2004). The in-
tranasal route may be inappropriate for patients with local disease of the nose
and could be difficult to use in patients who are uncooperative.
A major limitation associated with the intranasal administration of opioids is
the small volume of drug that can be administered, making this approach most
suitable for potent, concentrated formulations. The addition of absorption-
facilitating agents may overcome this potential problem (Pavis et al., 2002).
Other problems relate to local side effects such as irritation (nose, pharynx) and
taste disturbance. It should be noted that little is known about the risks of long-
term adverse effects from repeated intranasal administration of opioids, such as
mucosal/septal erosion, polyp formation, or rhinorrea (Dale et al., 2002a).
Based on current literature and experience, it can be concluded that the in-
tranasal route is only moderately attractive for the treatment of breakthrough
pain, regardless of setting or clinical circumstances. Even though 68% of pallia-
CHAPTER 7
Figure 7.1 Atomization device (MAD™) for intranasal administration of drugs. Reprinted
with permission from Davies, 2006.
tive care patients surveyed thought that the route was acceptable for pain that
was severe in nature (Walker et al., 2003), this does not account for the host of
potential problems that could be associated with long-term use that have yet to
be fully appreciated. Even so, a number of different reasons were given for not
81
wanting to use the intranasal route (see Table 4.3).
Bronchopulmonary administration
The lungs have an extremely large surface area for absorption. Moreover, the
alveolar surface is highly permeable and highly perfused with blood. The lungs
are the most highly perfused organs in the body. All of these factors help to fa-
cilitate the absorption of drugs.
The inhalational route of administration is well established in other areas of
medicine (e.g., respiratory medicine, anesthetics, and, most recently, diabetes
with the advent of inhaled insulin). Furthermore, it has been used to deliver
opioids for the treatment of dyspnea in palliative care settings and to deliver
opioids for the treatment of pain in the postoperative setting (Thipphawong et
al., 2003). However, there are few data on the use of intrapulmonary opioids
for the treatment of breakthrough pain.
Zeppetella (2000) reported on a small case series involving intrapulmonary
fentanyl. The first patient was treated with 25 µg fentanyl, achieved good pain
control within 15 minutes, and did not develop any local or systemic adverse ef-
fects. The second patient was treated with 125 µg fentanyl (dose titrated), also
achieved good pain control within 15 minutes, and also did not develop any lo-
cal or systemic adverse effects. In both cases, treatment was continued until ei-
ther discharge (Patient 2) or death (Patient 1).
The intrapulmonary route is simple and does not require particularly special-
ized equipment, but it does require a relatively cooperative and capable patient.
Opioids can be delivered by traditional nebulizers; newer methods of delivery
include breath-activated delivery systems that produce small particle sizes,
deliver the particles to the distal parts of the lung, and incorporate a lock-out
function (Thipphawong et al., 2003). It should be noted that efficient delivery of
the drug requires that the particle sizes are of the order of 1 to 3 µm in diame-
ter. The intrapulmonary route may be inappropriate for patients with respira-
tory ailments or pulmonary disease.
The intrapulmonary route is reasonably attractive for the treatment of break-
through pain for chronic pain and palliative care patients. Use of inhalers of one
sort or another for self-treatment has become a familiar and acceptable prac-
tice in our society. In one survey, 75% of patients thought that the route was ac-
ceptable for pain that was severe in nature (Walker et al., 2003). As is the case
with all routes, there is a fraction of the population who finds this route to be
unacceptable (see Table 4.3). Given the diversity of patients and their individual
CHAPTER 7
circumstances—and thus the need to be able to tailor therapies—and the range

of routes by which opioids can be effectively administered and absorbed con-
cordant with the time frame necessary to prevent or treat breakthrough pain,
the future bodes well for imminent improvements in this area.
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82
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in adults. Acta Anaesthesiologica Scandinavica. 2002a;46:759–770.
Dale O, Hoffer C, Sheffels P, Kharasch ED. Disposition of nasal, intravenous, and oral
methadone in healthy volunteers. Clinical Pharmacology and Therapeutics.
2002b;72:536–545.
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subjects. British Journal of Clinical Pharmacology. 2004;58:156–162.
Djupesland PG, Skretting A, Windren M, Holand T. Bi-directional nasal delivery of
aerosols can prevent lung deposition. Journal of Aerosol Medicine. 2004;17:249–259.
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2002;16:550.
Enting RH, Mucchiano C, Oldenmenger, et al. The “pain pen” for breakthrough cancer pain:
A promising treatment. Journal of Pain and Symptom Management. 2005;29:213–217.
Ferrell BR, Griffith H. Cost issues related to pain management: Report from the Cancer
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Symptom Management. 1994;9(4):221–234.
Fitzgibbon D, Morgan D, Dockter D, Barry C, Kharasch ED. Initial pharmacokinetic, safety
and efficacy evaluation of nasal morphine gluconate for breakthrough pain in cancer
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Hanks G, Roberts CJ, Davies AN. Principles of drug use in palliative medicine. In Doyle D,
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Mercadante S, Villari P, Ferrera P, Bianchi M, Casuccio A. Safety and effectiveness of in-
travenous morphine for episodic (breakthrough) pain using a fixed ratio with the oral
daily morphine dose. Journal of Pain and Symptom Management. 2004;27:352–359.
Pavis H, Wilcock A, Edgecombe J, et al. Pilot study of nasal morphine-chitosan for the re-
lief of breakthrough pain in patients with cancer. Journal of Pain and Symptom Man-
agement. 2002;24:598–602.
Sinatra R. The fentanyl HCl patient-controlled transdermal system (PCTS): An alternative
to intravenous patient-controlled analgesia in the postoperative setting. Clinical Phar-
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macokinetics. 2005;44(Suppl 1):1–6.
Stevens RA, Ghazi SM. Routes of opioid analgesic therapy in the management of cancer
pain. Cancer Control. 2000;7:132–141.
Stuart-Harris R, Joel SP, McDonald P, Currow D, Slevin ML. The pharmacokinetics of
morphine and morphine glucuronide metabolites after subcutaneous bolus injection
and subcutaneous infusion of morphine. British Journal of Clinical Pharmacology.
2000;49:207–214.
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cology. 1989;7:1903–1908.
Thipphawong JB, Babul N, Morishige RJ, et al. Analgesic efficacy of inhaled morphine in pa-
tients after bunionectomy surgery. Anesthesiology. 2003;99:693–700.
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tion, Part I. General considerations and clinical applications of centrally acting drugs.
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Viscusi ER, Reynolds L, Chung F, Atkinson LE, Khanna S. Patient-controlled transdermal
fentanyl hydrochloride vs intravenous morphine pump for postoperative pain: A ran-
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Chapter 8
Nonopioid
pharmacotherapy
Breakthrough pains have diverse characteristics, as they span all pain-related eti-
ologies. This inherent diversity means that the management of breakthrough
pain can potentially involve every class of pain-modifying drug. In most cases,
the relevant drugs are analgesics in their own right, although their analgesic ac-
tivity may not be their primary indication (so-called adjuvant analgesics) (Lussier
and Portenoy, 2004). In other cases, the relevant drugs may not be analgesics at
all, in which case their analgesic activity is an indirect result of their primary
function (e.g., antibiotics may reduce pain by treating the underlying cause of in-
flammation) (Bruera and MacDonald, 1986).
This chapter focuses on prescribed nonopioid drugs that are commonly
used in the management of cancer and noncancer chronic pain. The first part
85
of the chapter examines the evidence for nonopioid drugs in the management
of relevant pain syndromes (i.e., neuropathic pain, bone pain), and the second
part of the chapter examines evidence for the use of specific nonopioid drugs
in the treatment of breakthrough pain episodes (e.g., benzodiazapines, nitrous
oxide).
Role of nonopioids
Nonopioids may improve pain via a variety of different mechanisms:
• Acting as independent analgesics. Nonopioid analgesics are crucial for treat-
ing pain that is poorly responsive to opioids.
• Supplementing opioid analgesic use. Nonopioid drugs can be used as an
opioid-sparing measure, thereby avoiding the need to increase the opioid
dose, and possibly even allowing a decrease in the opioid dose.
• Facilitating opioid analgesic use. Nonopioid drugs can be used to combat
opioid side effects, thereby avoiding the need to decrease the opioid dose,
and possibly even allowing an increase in the opioid dose (e.g., psychostimu-
lants for sedation).
In addition, nonopioid drugs may be used in a variety of different ways:
• Around-the-clock—the drugs are taken regularly, and their role is to treat
the underlying pathological process and so reduce the frequency/severity of
breakthrough pain episodes.
• As needed—the drugs are taken intermittently for breakthrough pain, and
Nonopioid pharmacotherapy
two distinct scenarios are applicable:

1. “Rescue” analgesia—the drugs are given once the breakthrough pain has
started, and their role is to minimize the breakthrough pain episode (i.e.,
spontaneous pain episodes, nonvolitional incident pain episodes).
2. “Anticipatory” analgesia—the drugs are given in advance of the precipitat-
ing event for the breakthrough pain, and their role is to prevent/ameliorate
the breakthrough pain episode (i.e., volitional incident pain episodes, proce-
dural pain).
CHAPTER 8
Nonopioid drugs for neuropathic pain

The standard treatment of neuropathic pain involves using evidence- and
consensus-based clinical guidelines (Dworkin et al., 2003). Studies suggest that
while many patients with neuropathic pain respond to conventional analgesics
(e.g., opioids), a significant number of patients also require the use of other anal-
gesics (often referred to as adjuvant analgesics) and/or the use of other inter-
ventions (e.g., anesthetic techniques) (Grond et al., 1999; Fine, 2001). A range of
nonopioid analgesics have been used in the treatment of neuropathic pain, in-
cluding corticosteroids, certain antidepressants, anticonvulsants, local anesthet-
86
ics, antiarrhythmic drugs, baclofen, clonidine, capsaicin, ketamine, and magnesium

sulfate (Lussier and Portenoy, 2004; Argoff et al., 2006). However, the most
commonly used drugs are antidepressants and anticonvulsants (Table 8.1).
Making a selection from the bewildering range of options available is difficult,
because of the limited data available on the effectiveness of individual drugs and
the even more limited data available on the relative effectiveness of different
drugs. Notwithstanding the need for head-to-head trials and more guiding data, it
is believed that most neuropathic analgesics share essentially the same efficacy
potential. In practice, the choice of a neuropathic analgesic is therefore not largely
made on the basis of efficacy but more on the basis of safety, tolerability, and ease
Table 8.1 Treatment guidelines for peripheral neuropathic pain

Agent type Reason for recommendation Agent names
First tier ≥2 RCTs in DPN Duloxetine, oxycodone CR, pregabalin,
TCAs
Second tier 1 RCT in DPN and ≥1 in Carbamazepine, gabapentin, lamotrigine,
other painful neuropathies tramadol, venlafaxine ER (Effexor)
Topical Mechanism of action Capsaicin, lidocaine
Other ≥1 RCTs in other painful Bupropion (Wellbutrin), citalopram
neuropathies or other (Celexa), methadone (Dolophine),
evidence paroxetine (Paxil), phenytoin (Dilantin),
topiramate (Topamax)
CR = controlled release; DPN = diabetic peripheral neuropathy; ER = extended release; RCT = randomized
controlled trial; TCAs = tricyclic antidepressants.
of use. For example, amitriptyline may be a good choice for a patient with insom-
nia, but it would not be a good choice for an older patient with balance problems,
risk of urinary retention, or cardiac arrhythmias. There is great interindividual vari-
ation in patient response to these medications in terms of both efficacy and ad-
verse effects, and a trial-and-error approach is often necessary.
Antidepressants
Tricyclic antidepressants
The tricyclic antidepressants (TCAs) are commonly used in the management of
neuropathic pain. Their analgesic effect has been considered to be a result of
the prevention of presynaptic reuptake of serotonin and norepinephrine, al-
CHAPTER 8
though other mechanisms (e.g., sodium channel–blocking effects) may be more
relevant (Twycross et al., 2002).
There is a reasonable amount of data on the use of TCAs, and particularly
on the use of amitriptyline, in the management of neuropathic pain. Most of
the data derive from studies of postherpetic neuralgia and diabetic neuropa-
thy, but extensive clinical experience supports its use in the management of
other neuropathic pain conditions, including those associated with malig-
nancy. This same experience also suggests that TCAs have a narrow window
of safety relating to their complex pharmacology that involves activity at mul-
tiple ion channel and receptor systems. Caution must therefore be used in
87
prescribing TCAs in susceptible populations (e.g., older patients and those
with cardiac conduction abnormalities). These provisos also apply to many of
the other adjuvant drugs used in the management of neuropathic pain, espe-
cially the anticonvulsants.
A systematic review of the literature calculated an overall number needed to
treat (NNT) of two for amitriptyline (Saarto and Wiffen, 2005). The NNT
refers to the number of patients who need to receive a drug for one patient to
achieve at least 50% relief of pain compared with placebo (Moore et al., 2003).
The NNT was lower for diabetic neuropathy (1.3) than for postherpetic neu-
ralgia (2.2), and amitriptyline did not appear to be effective in HIV-related neu-
ropathy (Saarto and Wiffen, 2005).
The number needed to harm (NNH) for minor adverse effects was 4.6, while
the NNH for major adverse effects (requiring withdrawal from the study) was 16
(Saarto and Wiffen, 2005). The side effects of amitriptyline mostly derive from its
multiplicity of receptor effects including anticholinergic, anti-α-adrenergic, and
antiserotonergic effects as well as sodium channel blockade. These effects often
lead to adverse effects such as drowsiness, dry mouth, blurred vision, constipa-
tion, urinary retention, heart block, and arrhythmias (Saarto and Wiffen, 2005).
Indeed, side effects are often the major barrier to the use of amitriptyline, if not
all TCAs, in the management of neuropathic pain.
Other tricyclic drugs have also been used in the management of neuro-
pathic pain (e.g., imipramine, desipramine, nortriptyline). The data on other
tricyclic drugs are much more limited, but the data that are available suggest
that they may have a similar efficacy to amitriptyline, although the secondary
amines (desipramine, nortriptyline) have fewer anticholinergic effects and
therefore may be better tolerated (Saarto and Wiffen, 2005) (Fig. 8.1).
Selective norepinephrine serotonin reuptake inhibitors
The selective norepinephrine-serotonin reuptake inhibitors (NSRIs) have also
been used in the management of neuropathic pain. Their analgesic effect is also
thought to be related to the combined prevention of presynaptic reuptake of
serotonin and norepinephrine (Terneus, 2007). Comparatively, the selective
serotonin reuptake inhibitors (SSRIs) have not been found to be particularly
beneficial in the treatment of neuropathic pain (Saarto and Wiffen, 2005) other
than as an adjuvant in treating related depressive illness.
CHAPTER 8
The data on NSRIs in the management of neuropathic pain are currently rel-
atively limited. Two drugs of this class, venlafaxine and duloxetine, are currently
available in the United States, and duloxetine is approved by the U.S. Food and
Drug Administration (FDA) for the treatment of peripheral diabetic neuropa-
thy. Duloxetine is formulated for once-daily dosing and is available in 20, 30, and
60 mg strengths.
It is contraindicated in patients with uncontrolled narrow-angle glaucoma
and patients taking monoamine oxidase inhibitors (MAOIs). Caution should be
exercised in the setting of alcoholism or preexisting liver disease. Common ad-
verse effects include nausea, diarrhea, constipation, dizziness, drowsiness, anxi-
88
ety, nervousness, and insomnia, but with slow titration, most patients are able
to find an acceptable dose (Fishbain et al., 2006). The mechanism of action for
the neuropathic analgesic properties of NSRIs is not known for certain. How-
ever, recent findings that suggest that analgesia is usually not achieved until
reaching higher dosages associated with predominance of norepinephrine reup-
take effects suggest that the mechanism is more related to presynaptic reuptake
of norepinephrine than serotonin. This would be consistent with the lack of in-
dependent analgesia seen with SSRIs as a drug class.
• Commonly reported AEs Fewest • Desipramine

(generally anticholinergic): AEs
– blurred vision • Nortriptyline
– cognitive changes
– constipation
• Imipramine
– dry mouth
– orthostatic hypotension
– sedation • Doxepin
– sexual dysfunction
– tachycardia • Amitriptyline
– urinary retention
Most
AEs
Figure 8.1 Tricyclic antidepressants and their adverse effects (AEs).

Anticonvulsants
A variety of different drugs have been used to treat seizure disorders, and a few
of them have also been found to have some efficacy in the treatment of neuro-
pathic pain (Wiffen et al., 2005). The putative mechanism of action is via selec-
tive inhibition of sodium and voltage-gated calcium channels (Tremont-Lukats,
2000). There have been clinical trials, case reports, and conventional usage of
several agents (Backonja, 2002), but currently, only carbamazapine, gabapentin,
and pregabalin are FDA approved for neuropathic pain indications (Table 8.2).
Results of systematic reviews
CHAPTER 8
1. Carbamazepine
A systematic review of the use of carbamazepine in the management of neuro-
pathic pain calculated an NNT of 1.8 for trigeminal neuralgia but was unable to
calculate an NNT for other conditions because of lack of suitable data (Wiffen
et al., 2005c). The NNH for minor harm was 3.7, while the NNH for major
harm was not statistically different from that of a placebo (Wiffen et al., 2005c).
The side effects of carbamazepine include nausea, vomiting, dizziness, drowsi-
ness, headache, ataxia, confusion, agitation, and visual disturbances (e.g., double
vision), and serious, although rare, adverse effects include the syndrome of in-
appropriate antidiuretic hormone (SIADH), aplastic anemia, and liver failure.
89
2. Gabapentin
A further (related) systematic review of the use of gabapentin in the manage-
ment of neuropathic pain calculated a combined NNT of 4.3 (Wiffen et al.,
2005b). (The NNT was 2.9 for diabetic neuropathy and 3.9 for postherpetic
neuralgia.) The NNH for minor harm was 3.7, while the NNH for major harm
was not statistically different from that of a placebo (Wiffen et al., 2005b). The
undesirable effects of gabapentin include sedation and mental clouding, diar-
rhea, dry mouth, dyspepsia, nausea, and vomiting.
Table 8.2 Anticonvulsant drugs for neuropathic pain disorders

• Postherpetic neuralgia • HIV-associated neuropathy
– gabapentin* – lamotrigine
– pregabalin* • Trigeminal neuralgia
• Diabetic neuropathy – carbamazepine*
– carbamazepine – lamotrigine
– gabapentin – oxycarbazepine
– lamotrigine • Central poststroke pain
– phenytoin – lamotrigine
– pregabalin* • Cancer-related neuropathic pain disorders
– All of the above agents
*Approved by FDA for this use.
HIV = human immunodeficiency virus.
3. Other drugs
Other anticonvulsant drugs that are commonly used to treat neuropathic pain
include sodium valproate (limited evidence of efficacy), phenytoin (limited evi-
dence of efficacy), and pregabalin (increasing evidence of efficacy; Rosenstock
et al., 2004; Terneus, 2007).
Nonopioid drugs for bone pain

The standard treatment of bone pain associated with malignant diseases in-
CHAPTER 8
volves using the World Health Organization analgesic guidelines (WHO,

1996). A range of adjuvant analgesics have been used in the treatment of
cancer-related bone pain, including corticosteroids, bisphosphonates, calci-
tonin, and drugs for neuropathic pain (see earlier sections) (Lussier and
Portenoy, 2004).
Bisphosphonates
Bisphosphonates are indicated for the management of osteoporosis, Paget’s dis-
ease, bone metastases, and hypercalcemia (Anonymous, 2005). Bisphospho-
nates have a number of mechanisms of action, but their main mechanism of
90
action relates to inhibition of osteoclast activity (leading to inhibition of bone

resorption) (Fine and Bellamy, 2005).
A systematic review of the literature concluded that long-term (≥6 months)
bisphosphonate therapy reduces skeletal morbidity associated with cancer (i.e.,
reduces the need for radiotherapy, reduces the incidence of fractures, and re-
duces the incidence of hypercalcemia) (Ross et al., 2003). The evidence of ef-
fectiveness is so compelling that the authors concluded that bisphosphonate
therapy should commence as soon as bone metastases are diagnosed and con-
tinue until “it is no longer clinically relevant” (Ross et al., 2003).
A systematic review that focused on the pain literature concluded that bis-
phosphonate therapy provides analgesia in cancer-related bone pain (Wong
and Wiffen, 2002). The NNT was 11 at 4 weeks, improving to an NNT of 7
at 12 weeks. The NNH for major side effects (leading to discontinuation of
treatment) was 16. The authors stated that “there was insufficient evidence
to recommend bisphosphonates for immediate effect,” and “bisphospho-
nates should be considered where analgesics and/or radiotherapy are in-
adequate for the management of painful bone metastases” (Wong and
Wiffen, 2002).
On the basis of the data, it would seem reasonable to prescribe bisphospho-
nates to patients who have already experienced morbidity as a result of bone
metastases, with the primary aim of preventing further morbidity and the sec-
ondary aim (if relevant) of treating pain. As such, this class of drugs may have a
prophylactic effect against bone-related breakthrough pain, but there is no role
for bisphosphonates in the active treatment of breakthrough pain.
Other nonopioid drugs for breakthrough pain
Nonsteroidal anti-inflammatory drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) are approved for the treatment
of variety of painful conditions, including inflammatory diseases (e.g., rheumatoid
arthritis), degenerative conditions (e.g., osteoarthritis), other painful conditions
(e.g., dysmenorrhoea), and postoperative pain (Anonymous, 2005). Their anal-
gesic action appears to be related to inhibition of prostaglandin production both
at the site of injury/disease (reducing inflammation) and in the central nervous
system (reducing central sensitization) (Twycross et al., 2002).
CHAPTER 8
NSAIDs inhibit prostaglandin production by inhibiting the enzyme cyclooxy-
genase (COX). COX is present in a number of different forms (Dickman and
Ellershaw, 2004). Conventional NSAIDs are nonselective, inhibiting both COX-
1 and COX-2, while the newer class of NSAIDs, the coxibs, specifically inhibit
COX-2. It was thought that COX-2 was an inducible (by inflammation) enzyme
and that inhibition of COX-2 would be associated with minimal systemic ad-
verse events. However, it is now known that COX-2 is also a constitutive en-
zyme and that inhibition of COX-2 is associated with significant systemic
adverse events (discussed in a later section).
In chronic conditions, NSAIDs are generally used as around-the-clock med-
91
ications, although they may be used as supplemental medications when contin-
ual use is either not tolerated or excessively risky. In the management of acute
pain and in advanced medical illness, NSAIDs have an established role as an
opioid-sparing maneuver (Mercadante and Portenoy, 2001).
Systematic reviews of oral NSAIDs have confirmed benefits in cancer pain
(Eisenberg et al., 1994; McNichol et al., 2005). In the original systematic review,
NSAIDs were found to be more effective than placebo, and there appeared to
be no benefit to the combination of a NSAID and an opioid for mild to moder-
ate pain (Eisenberg et al., 1994). In the subsequent systematic review, NSAIDs
were again found to be more effective than placebo, and there appeared to be
a slight benefit to the combination of an NSAID and an opioid (McNichol et al.,
2005). However, the authors of this review were unable to comment on the
relative efficacy (i.e., calculate NNTs) or tolerability (i.e., calculate NNHs) of in-
dividual NSAIDs (McNicol et al., 2005).
Data from acute pain studies suggest NNTs of 2 to 3 for a single dose of the
common oral NSAIDs (e.g., diclofenac, ibuprofen) (Moore et al., 2003). It
should be noted that the NNTs for NSAIDs are lower than the NNTs for other
analgesic drugs (e.g., opioids for mild to moderate pain). Data from other stud-
ies suggest a combined NNT of 3.1 for topical NSAIDs (Moore et al., 1998).
The onset and duration of action of certain oral NSAIDs is shown in Table
8.3. There are a number of contraindications to the use of NSAIDs, including
hypersensitivity to aspirin/NSAIDs, coagulation defects, active peptic ulcer dis-
ease (all NSAIDs), previous peptic ulcer disease (conventional NSAIDs), is-
chemic heart disease (coxibs), cerebrovascular disease (coxibs), peripheral
arterial disease (coxibs), and moderate to severe heart failure (all NSAIDs). In
addition, there are a number of relative contraindications relating to the known

adverse effects of NSAIDs (see later sections).
Side effects are relatively common. The major side effects of conventional
NSAIDs are hypersensitivity reactions (e.g., bronchospasm), gastrointestinal
problems (e.g., peptic ulceration), renal problems (e.g., renal failure), and car-
diovascular problems (e.g., congestive cardiac failure). Gastrointestinal prob-
lems are a major cause of morbidity and/or mortality. However, gastrointestinal
problems may be reduced by prescribing proton pump inhibitors and address-
ing other risk factors (Dickman and Ellershaw, 2004). The major side effects of
coxibs are cardiovascular problems (e.g., ischemic heart disease), but if used
CHAPTER 8
chronically (e.g., more than several months), the adverse gastrointestinal effects
may also become problematic (Lebwohl and Neugut, 2007).
In summary, the NSAID class of analgesics is useful in the management of
acute pain and chronic painful conditions involving inflammation, although
risks—especially in older patients—become appreciable. The use of NSAIDs
for breakthrough pain has never been addressed in specific clinical trials, but
episodic use, especially for the control of incident nociceptive pain, may be ben-
eficial alone or in combination with immediate-release or rapid-onset opioid
analgesics.
92
Midazolam and other benzodiazapines

Midazolam is a benzodiazepine indicated for anxiolysis, sedation, premedication
for anesthesia, and induction of anesthesia (Reeves et al., 2000). Its mechanism
of action involves binding to the GABAA receptor, thereby enhancing the in-
hibitory effect of GABA (Twycross et al., 2002).
Table 8.3 Clinical features of specific nonsteroidal

anti-inflammatory drugs
Nonsteroidal anti- Onset of action Duration of action Comments
inflammatory drug (oral route) (oral route)
Ibuprofen 15 to 25 min 4 to 6 h Peak effect: 30 to 90 min
Long-acting preparations
available
Diclofenac 30 min 8h Long-acting preparations
available
Ketorolac 30 min 5 to 6 h Peak effect: 3 h
Onset of action intravenous/
intramuscular route: 30 min
Naproxen 30 to 60 min Up to 12 h —
Meloxicam 90 min — Given once a day
Onset of action intra-
muscular route: 80 min
Celcoxib 45 to 60 min 4 to 8 h Given once or twice a day
(single dose)
From Micromedex database; Twycross et al., 2002; reprinted with permission from Davies, 2006.
Midazolam is highly effective for sedation and amnesia. It is used to sedate pa-
tients prior to diagnostic and therapeutic procedures (e.g., endoscopy, dressing
changes). Its role in managing procedural pain has been endorsed in the European
Association for Palliative Care expert consensus document on breakthrough pain
(Mercadante et al., 2002). Apart from the use of benzodiazepines in combination
with opioids in procedural pain, there is little evidence to support a wider role in
the management of breakthrough pain. However, there has been a report of its
use in the treatment of refractory incident pain secondary to bone metastases
(del Rosario et al., 2001), and there is the potential for its use in the management
of breakthrough pain secondary to muscle spasm (Twycross et al., 2002).
Midazolam is available in parenteral and oral preparations in the United
CHAPTER 8
States. The parenteral preparation may be administered via enteral routes (buc-
cal, rectal) as well as via parenteral routes (intravenous, subcutaneous), similar
to lorazapam. Midazolam has the advantage of a short onset of action (intra-
venous—2 to 3 minutes; subcutaneous—5 to 10 minutes), but it has an inter-
mediate duration of action ( 4 hours) (Twycross et al., 2002), which can be
problematic for very brief episodes or events where sedation and analgesia are
required on a recurrent basis. Outside of highly circumscribed clinical situations
involving invasive procedures or in palliative care settings, use of the benzodi-
azepines either alone or as an adjunctive agent cannot be recommended for the
prevention or treatment of breakthrough pain.
93
Ketamine
Ketamine is a parenteral anesthetic agent and is approved for induction and main-
tenance of anesthesia (Reeves et al., 2000), but it is also used for treatment of
difficult-to-control pain (Fine, 1999). The analgesic effect of ketamine is thought to
be related to blockade of the N-methyl-D-aspartate receptor (and reduction of
central sensitization/“wind-up”), although it may be related to a number of other
actions, including an effect on descending inhibitory pathways (Meller, 1996).
Ketamine has been used effectively in subanesthetic doses in the management
of breakthrough pain (Carr et al., 2004) and in the management of certain types of
background pain (e.g., neuropathic pain) (Twycross et al., 2002). In general, keta-
mine is used in combination with opioids in the management of background pain.
Carr et al. (2004) reported a small, double-blind, randomized, controlled,
crossover trial of intranasal ketamine in the management of breakthrough pain.
The intranasal ketamine was found to be effective with an onset of pain relief
within 10 minutes, peak effect at 40 minutes, and duration of pain relief of at
least 60 minutes. The intranasal application of ketamine was also found to be
generally well tolerated; side effects included fatigue, dizziness, feeling of unre-
ality, and change in taste.
The literature contains a number of case reports, case series, and clinical trials
of the use of ketamine in the management of cancer pain. As discussed earlier,
ketamine is generally used in combination with opioids in the management of
background pain. It has been reported that ketamine can restore opioid re-
sponsiveness and prevent the development of opioid tolerance. However, a re-
cent systematic review of the literature concluded that the evidence was “insuf-
ficient to assess the benefits and harms of ketamine” (Bell et al., 2003).
Nitrous oxide
Nitrous oxide is an inhalational anesthetic used for maintenance of anesthesia
and management of pain (most commonly in dental care). Its mechanism of ac-
tion has not been completely elucidated; one hypothesis is that nitrous oxide
causes the release of opioid peptides in the periaqueductal gray area of the mid-
brain, which leads to activation of descending noradrenergic pathways, which
leads to modulation of pain impulses in the dorsal horn of the spinal cord
(Entonox Reference Guide).
CHAPTER 8
Apart from its use in procedural pain, there is mixed evidence justifying the use
of nitrous oxide in the management of breakthrough pain in palliative care and/or
cancer pain settings. Findings from a small case series (Keating and Kundrat, 1996)
and a small, double-blind, randomized, controlled, crossover trial (Parlow et al.,
2005) support the use of nitrous oxide in the management of breakthrough pain.
However, there is another small case series that does not support the use of ni-
trous oxide in the management of breakthrough pain (Enting et al., 2002).
Nitrous oxide is co-administered with oxygen (50:50 mixture for analgesia): it
comes in a portable gas cylinder with a breath-activated valve and may be used
with either a facemask or a mouthpiece. It has a short onset of action (<1 minute),
94
a quick time to peak effect (2 minutes), and a short duration of action (5 to 40

minutes: subjective measures–objective measures) (Entonox Reference Guide).
Contraindications to the use of nitrous oxide include the presence of a
pneumothorax—the nitrous oxide can diffuse into the pneumothorax, causing an
increase in the volume/pressure of the pneumothorax. The side effects of nitrous
oxide include sedation (7.6%), dizziness (10.3%), nausea (5.7%), excitation (3.7%),
and “numbness” (0.3%) (Entonox Reference Guide). Nitrous oxide can interfere
with vitamin B12, and chronic use may result in megaloblastic anemia and neuro-
logical problems (polyneuropathy, spinal cord degeneration) (Doran et al., 2004).
In addition, there is the potential to develop tolerance to the drug; this problem
may occur during acute administration of the drug (Ramsay et al., 2005).
In summary, nitrous oxide is a well-proven anesthetic and analgesic, but a trial of
nitrous oxide for the treatment of breakthrough pain should be limited to palliative
care settings only where other agents have proved ineffective or are contraindi-
cated. Dysphoric reactions may occur, so use under supervision of someone who
can quickly turn off the flow of the agent and calm the patient is important.
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Wiffen PJ, McQuay HJ, Edwards JE, Moore RA. Gabapentin for acute and chronic pain.
Cochrane Database of Systematic Reviews. 2005b;(3):CD005452.
Wiffen PJ, McQuay HJ, Moore RA. Carbamazepine for acute and chronic pain. Cochrane
Database of Systematic Reviews. 2005c;(3):CD005451.
Wong R, Wiffen PJ. Bisphosphonates for the relief of pain secondary to bone metastases.
Cochrane Database of Systematic Reviews. 2002;(2):CD002068.
Chapter 9
Nonpharmacologic
interventions
A wide variety of nonpharmacologic interventions have been used to treat

chronic pain syndromes (Doyle et al., 2004; Hadjistavropoulos and Fine, 2007).
This chapter focuses on anesthetic interventions used to treat difficult pain prob-
lems associated with breakthrough pain episodes. Anesthetic interventions are
usually intended to be an adjuvant to systemic analgesic treatment. Indeed, these
interventions have been proposed in a modification of the World Health Orga-
nization analgesic ladder (Miguel, 2000; Fine, 2005). In the management of cancer
pain, it has been estimated that between 5% and 15% of patients may benefit
from interventional therapies (Zech et al., 1995). There are no well-validated
studies that specify the percentage of patients with chronic noncancer pain syn-
97
dromes who might benefit from interventional therapies, but they are commonly
performed, again, with variable reported success (Bernstein et al., 2005).
General principles
The usual indications for anesthetic and related techniques (i.e., injections,
neuraxial drug delivery, or neurostimulation) include pain that is poorly re-
sponsive to systemic analgesics or the development of intolerable side effects
to systemic analgesics. Thus these techniques may allow patients to experi-
ence better pain relief from current drug doses or may allow patients to re-
duce drug doses, thereby reducing drug side effects. A patient with a short life
expectancy, and with limited time available for the safe titration of systemic
analgesics, may also be considered for anesthetic techniques (Hicks and Simp-
son, 2004).
Nerve blockade may be useful in patients with well-localized pain, and also in
patients with pain with a neuropathic element. Similarly, neuraxial analgesic de-
livery may be useful in patients with pain from spinal, thoracoabdominal, pelvic,
or lower extremity pain-producing disorders.
Under most circumstances, alternative options should have been considered
before an anesthetic intervention is undertaken (e.g., disease-modifying treat-
ments, alternative systemic analgesics). Furthermore, when an anesthetic inter-
vention is undertaken, initially the simplest and least invasive method should
be undertaken. For example, a temporary local anesthetic blockade should be
performed before a permanent neurolytic blockade or ablative procedure is
Nonpharmacologic interventions
performed in those situations where neurolysis is acceptable (e.g., pancreatic

malignancy; medial branch rhizotomy for facet disease).
As with any form of treatment, appropriate patient selection is necessary.
The assessment process involves taking a history, performing an examination,
and the utilization of relevant investigations. The history should include a de-
tailed assessment of the pain, and the examination should include a full neuro-
logical assessment (Bruera and Neumann, 2003). Laboratory investigations will
include a platelet count and a coagulation screen to identify potential bleeding
problems. Radiological investigations may include a computed tomography
(CT) scan or a magnetic resonance imaging (MRI) scan: these tests are neces-
sary to identify the potential cause of the pain and potential problems relating
CHAPTER 9
to planned procedure (e.g., anatomical distortion or variance) (Erdine, 2005).

Absolute contraindications to anesthetic interventions include patient re-
fusal, noncorrectable coagulopathy, and localized infection at the proposed site
of the anesthetic intervention.
The assessment for and use of complex interventions such as neuraxial anal-
gesia or dorsal column stimulation require a coordinated approach from a mul-
tidisciplinary pain management team, which will usually comprise pain medicine
specialists, nurses, physical and/or occupational therapists, and psychologists. It
requires appropriate resources to apply these techniques, including relevant
98
support services (e.g., laboratory service, radiology services, operating suite

with fluoroscopic imaging). It also requires appropriate resources to monitor
and provide follow-up on patients who have received these techniques. Fur-
thermore, it is important that there be effective communication with, and sup-
port for, others involved in the patient’s care (e.g., primary care/specialist
physicians, other health-care providers, case workers, third-party payers, etc.).
Peripheral procedures
Local anesthetic injections are probably the most common interventions prac-
ticed in pain management. Examples of useful techniques include myofascial
trigger point injections, sympathetic blocks (e.g., stellate ganglion block; lumbar
sympathetic block), intercostal nerve blockade for rib pain, suprascapular nerve
blockade for shoulder pain, plexus blockade (e.g., brachial plexus blockade for
upper extremity pain, celiac plexus blockade for pancreatic cancer, or superior
hypogastric blockade for pain from pelvic tumor), lateral femoral cutaneous
nerve block for meralgia parasthetica, and sciatic/femoral nerve blockade for
lower extremity pain. These procedures cause minimal patient discomfort and
carry a low incidence of serious adverse effects when performed by a skilled,
experienced expert.
Local anesthetic nerve blockade can produce anesthesia/analgesia lasting up
to 12 hours, although it has been observed that the analgesic effect may outlast
the anesthetic effect by days or weeks (Boys et al., 1993). Corticosteroids may
be combined with local anesthetics with the aim of providing additional and/or
longer-lasting analgesia if inflammation is a contributing factor (Twycross, 1994).
A modification of the “single-shot” technique involves the placement of a
catheter for the administration of repeated boluses, or continuous infusion, of
local anesthetic (Aguilar et al., 1995; Fisher et al., 1996).
To provide more prolonged analgesia, a temporary block using local anes-
thetic may be followed up by a more permanent block using a neurolytic agent.
Neurolytic agents include alcohol (3% to 100%), phenol (5% to 15%), and glyc-
erol. Neurolytic agents damage the nerves in different ways, but all have the po-
tential to be reversible, thereby causing the pain to return after a period of time
(weeks to months) (Williams, 2003).
One complication of neurolytic blockade is the development of postneuroly-
CHAPTER 9
sis deafferentiation neuralgia (neuropathic pain). When life expectancy is more
than a few months, nonchemical neurolytic blockade (e.g., radiofrequency abla-
tion, cryoablation) is preferable to chemical neurolytic blockade (e.g., alcohol,
phenol), as the incidence of neuropathic pain has been found to be reduced
with these techniques (Erdine, 2005).
It should be noted that a successful local anesthetic block does not guarantee
a successful neurolytic block, because there is no guarantee that the neurolytic
agent will be placed at precisely the same location as the local anesthetic or that
the neurolytic agent will act physiologically in the same manner as the local
99
anesthetic.
Neuraxial drug delivery

The epidural and intrathecal (subarachnoid) routes are the two main routes
used to deliver neuraxial blockade (Erdine, 2005). The epidural route remains
the preferred route of neuraxial analgesia for short-term therapy (Baker et al.,
2004). However, there is growing evidence to suggest that opioids delivered by
the intrathecal route may provide better analgesia, and may be even safer, than
opioids delivered by the epidural route (Gestin et al., 1997; Dahm et al., 1998).
As a result, the intrathecal route is being used increasingly and is being used ex-
clusively in some treatment centers (Baker et al., 2004).
In oncologic care, the epidural route should probably be avoided in patients
with known epidural disease, because this may interfere with the positioning of the
catheter and with the free flow of the analgesic agents. In addition, the epidural
route may not be suitable for long-term use because of the potential for develop-
ment of local fibrosis, which may also interfere with the flow of the analgesic
agents (Wagemans et al., 1997). Epidural opioids become absorbed into the sys-
temic circulation via Batson’s plexus, and because they also need to be given in
higher dosages than intrathecal opioids, epidural opioid delivery may be associated
with greater side effects compared with intrathecal opioid delivery.
Drug delivery is via a percutaneous catheter and external pump or via a to-
tally implantable drug delivery system. Percutaneous catheters may or may not
be tunneled under the skin (to exit at a distant site): tunneled catheters are more
robust and have a lower incidence of infection than nontunneled catheters (Arbit
and Pannullo, 2003). Implantable delivery systems are reserved for longer-term in-
trathecal therapy (i.e., for patients with a prolonged life expectancy). Implantable
delivery systems have a high initial cost but appear to be cost effective in the
longer term (several months to years) (Swarm et al., 2004).
Neuraxial analgesia is best established by a constant infusion (Baker et al., 2004),
as adverse events frequently relate to bolus delivery of the analgesic agents, partic-
ularly when treatment is first instituted. Large boluses have caused cardiorespira-
tory arrest (Piquet et al., 1998). The newer external pumps, and some implantable
delivery systems, offer the ability to deliver low-dose, patient-controlled boluses of
the analgesic agents, which may provide improved analgesia with less systemic side
CHAPTER 9
effects and may be applicable in the treatment of breakthrough pain.

A variety of opioids have been used for neuraxial analgesia, although mor-
phine has been the traditional opioid of choice (Hicks and Simpson, 2004). Mor-
phine is relatively hydrophilic, which results in a relatively slower onset of
action (epidural route) and longer duration of action compared with other opi-
oids (Hicks and Simpson, 2004). Morphine is also more likely to spread in a cra-
nial direction, which may extend the level of analgesia but also increases the risk
of respiratory depression. Other opioids that have been used for neuraxial anal-
gesia include hydromorphone, oxycodone, fentanyl, sufentanil, and methadone,
100
but only preservative-free morphine is currently approved for this indication in

the United States.
Neuraxial delivery of opioids produces inadequate analgesia in 10% to 30% of
patients (Malone, 1985). In these cases, the co-administration of a local anes-
thetic may provide additional analgesia (Du Pen et al., 1992). Indeed, there is a
growing trend to use combination treatment from the outset. Opioids and local
anesthetics may act synergistically, allowing lower doses of the individual drugs
to be used, which may limit the side effects of the individual drugs.
It should be noted that low-dose infusions of local anesthetics (e.g., bupiva-
caine, ropivacaine) can provide adequate analgesia without producing significant
sensory disturbance or motor impairment (Dahm et al., 2000). However, boluses
of local anesthetics can produce unpleasant paraesthesia and symptomatic hy-
potension. Other analgesic agents may also be delivered via the neuraxial route,
including clonidine, baclofen, midazolam, ketamine, and ziconotide (Swarm et al.,
2004). Clonidine, an α2 adrenoreceptor agonist, is a useful adjunct to spinal opi-
oids, particularly in patients with neuropathic pain (Eisenach et al., 1995).
The early complications of these techniques include catheter misplacement,
cerebrospinal fluid leak, bleeding, and infection. The later complications of
these techniques include catheter kinking, catheter displacement or catheter
obstruction by fibrosis (epidural catheters), or granuloma formation (intrathe-
cal catheters). Rarely, spinal cord compression is caused by hematomas, ab-
scesses, or granulomas (Cabbell et al., 1998). Other complications relate to the
analgesic agents that are used. Long-term intrathecal opioid infusion can lead to
tolerance or hyperalgesia (Osenbach and Harvey, 2001).
Neuromodulation
Transcutaneous electrical nerve stimulation
Transcutaneous electrical nerve stimulation (TENS) is a potent form of nerve
stimulation (Thompson, 1998). It acts by inhibiting transmission of pain impulses
from the periphery to the central nervous system, as a result of stimulating pe-
ripheral sensory nerve fibers (Bercovitch and Waller, 2004). Other mechanisms
may also be relevant, including activation of descending inhibitory pathways and
activation of the sympathetic nervous system (Bercovitch and Waller, 2004).
A basic TENS machine consists of a small, battery-operated electrical-pulse
generator and a set of electrodes (Fig. 9.1) (Bercovitch and Waller, 2004). Most
CHAPTER 9
machines have the ability to vary the intensity, frequency, pulse duration, and
type of output (i.e., continuous pulses, bursts of pulses, modulation/variation of
pulses). The optimal settings for obtaining pain relief vary from patient to pa-
tient and need to be determined by trial and error in each patient (Bercovitch
and Waller, 2004).
TENS is a well-established treatment of musculoskeletal pain syndromes.
However, there is relatively little evidence to support its use in the treatment of
cancer pain (Bercovitch and Waller, 2004). TENS has been used to treat back-
ground pain and episodes of breakthrough pain (Filshie and Thompson, 2000;
101
Zeppetella and Ribeiro, 2003). TENS is not used as often as perhaps it might,
partly because of doubts about effectiveness for pain disorders associated with
advanced medical illness and the time and effort needed to find the optimal
electrode placement and generator settings (Thompson, 1998).
TENS can be used to treat any localized pain of somatic or neuropathic ori-
gin, providing paresthesias can be generated in the region of the pain or within
Figure 9.1 Physio-Med TPN 200 PP TENS machine. Reprinted with permission from Davies, 2006.
the same or a closely related dermatome (Woolf and Thompson, 1994). It can
be difficult to predict the response to TENS; a therapeutic trial is the only way
to determine whether TENS will be successful ( Johnson et al., 1991).
Contraindications to TENS include skin inflammation, skin infection, and the
presence of a cardiac pacemaker (Bercovitch and Waller, 2004). TENS should
not be used over the anterior neck, as stimulation of the laryngeal nerves may
lead to laryngospasm and stimulation of the carotid sinus may lead to hypoten-
sion. Serious adverse effects are rare. Local adverse effects include skin irrita-
tion, skin burns, and allergy (to electrode gel and/or tape) (Bercovitch and
Waller, 2004).
Spinal cord stimulation

CHAPTER 9
The analgesic mechanism of spinal cord stimulation is not fully understood, but
it is thought to work by activating endogenous inhibitory systems within the
central nervous system (Swarm et al., 2004). Spinal cord stimulation involves
implanting electrodes in the epidural space at the spinal level corresponding to
the site of pain. The procedure is now performed percutaneously, and with the
patient awake, in order to ensure the safe and correct placement of the elec-
trodes (Stannard, 2003). Initially, a trial of spinal cord stimulation is undertaken
using a temporary external system. Subsequently, if this proves successful, the
temporary external system can be replaced by a fully implantable system.
102
Although numerous studies document the efficacy of spinal cord stimulation,

there are few data on the effectiveness of spinal cord stimulation in reducing
breakthrough pain associated with cancer and noncancer chronic pain condi-
tions. Older case series provided mixed conclusions; Meglio et al. (1989) con-
cluded that spinal cord stimulation was not useful for cancer pain, but the
results were equivocal in a preceding series (Krainick and Thouden, 1974).
The main complications of spinal cord stimulation are infection (<1%) and
technical failures such as migration of electrodes and breakage of electrodes. In
this author’s experience, most patients who benefit from spinal cord stimula-
tion still require intermittent analgesic therapy to treat breakthrough pain.
Neuroablation
Neuroablation (neurolytic blockade) is defined as the physical interruption or
destruction of neurons and pathways conducting pain impulses. It can be per-
formed chemically, thermally, or surgically.
Over the past two decades, there has been a diminishing role for neurolytic
blockade and an increasing role for neuraxial analgesic delivery. Nevertheless,
there remains a limited role for its use in patients with well-localized intractable
pain, and especially those with a relatively short life expectancy (Goh, 2005).
Peripheral neurolytic blockade

See previous section.
Neurolytic blockade of the sympathetic nervous system
The sympathetic nervous system plays a role in the modulation of certain pain
impulses (Swarm et al., 2004). Moreover, the sympathetic chain and ganglia are
traversed by visceral nociceptive fibers. Consequently, blockade of the sympa-
thetic nervous system may be useful in certain types of pain (i.e., visceral pain,
neuropathic pain).
It has recently been suggested that neurolytic sympathetic blockade of the
celiac plexus, lumbar plexus, or superior hypogastric plexus be considered ear-
lier, rather than later, in the management of pain due to abdominal or pelvic
cancers (de Oliveira et al., 2004). A diagnostic block using local anesthetic is
sometimes used to establish the relative contribution of the sympathetic system
to the etiology of the pain.
CHAPTER 9
Celiac plexus blockade
Celiac plexus blockade is probably the most established and beneficial of all the
neurolytic procedures. It can be useful for visceral pain arising from the lower
half of the stomach through the hepatobiliary system, the pancreas, and mid-
transverse colon (Swarm et al., 2004).
Needle placement is performed using radiographic imaging such as fluo-
roscopy or CT in sedated or anesthetized patients. Endoscopic ultrasound
103
(EUS)–guided neurolytic celiac plexus blockade has recently been described
(Arcidiacono and Rossi, 2004).
A meta-analysis of relevant studies found that 89% of patients had good to
excellent pain relief during the first 2 weeks post-blockade, that ≈90% of pa-
tients had partial to complete pain relief at 3 months post-blockade, and that
70% to 90% of patients had partial to complete pain relief up until death (Eisen-
berg et al., 1995).
Certain adverse effects are common after celiac plexus block. These include
orthostatic hypotension (63%) and diarrhea (44%) (Swarm et al., 2004). These
effects are usually transient, are generally mild in nature, and require little or no
treatment. Other more serious, although uncommon, complications have also
been reported. These include paraplegia (<1%), aortic dissection, generalized
seizures, and circulatory arrest (Davies, 1993; Kaplan et al., 1995). Although
post-neurolysis breakthrough pain has not been studied specifically, in this au-
thor’s experience, most patients continue to require intermittent opioid anal-
gesics for breakthrough pain. This conclusion can be deduced from findings
from a comparative trial reported by Wong (2004), wherein he reported bene-
fits from neurolytic celiac plexus block but continued high rates of opioid use
for pain control.
Lumbar sympathetic blockade

Lumbar sympathetic blockade can be useful for neuropathic and ischemic pain
arising from the lower extremities and for visceral pain arising from lower ab-
dominal and pelvic structures (Brevik et al., 1998).
Superior hypogastric blockade
This type of blockade may be useful in patients with visceral pain from pelvic
structures (Swarm et al., 2004). This is usually reserved for terminal illness, usu-
ally related to tumors.
Ganglion impar (ganglion of Walther) blockade

This type of blockade may be useful in patients with perineal pain and/or rectal
pain (Swarm et al., 2004).
Benefits with regard to breakthrough pain have not been reported following
any of these techniques.
CHAPTER 9
Neurolytic blockade of the central nervous system

Intrathecal (subarachnoid) neurolysis
The aim of intrathecal neurolysis is to disrupt the anterolateral spinothalamic
tracts. These blocks can be effective for bilateral perineal pain (“saddle pain”)
and for unilateral torso pain (Patt and Cousins, 1998).
Cervical cordotomy
The aim of cervical cordotomy is to disrupt the spinothalamic tracts just below
104
the medulla oblongata. It is particularly helpful for unilateral pain from a

mesothelioma (Kanpolat et al., 2002) or a Pancoast’s tumor (Ischia et al., 1985)
that has failed to respond to other treatment. However, it may also be helpful
for other unilateral pains involving the chest, upper extremity, pelvis, and lower
extremity (Hassenbach and Cherny, 2004).
A variety of other neurolytic procedures have been reported, although many
of them are rarely used these days due to the increased safety and relative ease
of intrathecal drug delivery (Hassenbach and Cherny, 2004; Swarm et al., 2004).
Other interventions
Acupuncture
Acupuncture is an ancient and time-tested therapeutic modality. It is a form of sen-
sory stimulation that relies on Aδ nerve stimulation using percutaneous needles to
produce analgesia via neuromodulation of pain pathways and numerous endoge-
nous spinal and supraspinal analgesic mechanisms (Filshie and Thompson, 2004).
Acupuncture has been shown to raise the pain threshold (Brockhaus and El-
ger, 1990), as well as to reduce experimentally induced pain (White, 1999) and
acute pain (Kotani et al., 2001). It is regularly used to treat noncancer chronic
pain and cancer pain, although there is a lack of good evidence to support its
role in the treatment of cancer pain. One of the main reasons for the lack of
good evidence is the difficulty of undertaking controlled and/or blinded trials of
acupuncture (Filshie and Thompson, 2004).
Acupuncture can provide acute pain relief as well as more prolonged pain re-
lief (i.e., days to weeks) (Filshie and Thompson, 2004). It seems to be more
helpful in treating the underlying pain state than in treating actual breakthrough
pain episodes. Acupuncture is especially useful for pain of musculoskeletal ori-
gin (Baldry, 2004).
A variety of techniques may be used involving different acupuncture points,
different modes of stimulation (e.g., minimal stimulation, vigorous stimulation),
different durations of stimulation, and variable course lengths. A typical course
of acupuncture will involve weekly treatments for 6 weeks, followed by “top-
up” treatments every few weeks thereafter (Filshie and Thompson, 2004).
Contraindications to acupuncture have been described in patients with ad-
vanced medical illness and include thrombocytopenia, neutropenia, lymph-
CHAPTER 9
edema, local infection, and local tumor (Filshie, 2001). Furthermore, needling
should not be performed near an unstable spine, because any muscle relaxation
may worsen the spinal stability. Acupuncture has been shown to be safe in a
number of large prospective studies, with the common adverse effects being
post-treatment pain (≈1%), bleeding and/or bruising (≈3%), and somnolence
(MacPherson et al., 2001; White et al., 2001).
Miscellaneous interventions for bone pain

A variety of other interventional techniques have been reported to be useful in
105
treating pain secondary to bone disease, although most of them have not been
subjected to rigorous scientific investigation. These include the following: (1)
corticosteroid instillation (Rousseff and Simeonov, 2004), (2) alcohol instillation
(Gangi et al., 1996), (3) phenol instillation (Gangi et al., 1996), (4) cryoablation
(Callstrom et al., 2006), (5) radiofrequency ablation (Goetz et al., 2004), (6)
laser ablation (Callstrom et al., 2006), (7) cementoplasty/vertebroplasty (Gangi
et al., 2003) (this technique involves injecting methylmethacrylate cement into
the affected bone), and (8) balloon kyphoplasty (Fourney et al., 2003) (this tech-
nique is similar to vertebroplasty but involves initially inflating a balloon within
the affected bone to improve the alignment of the bone, and also to create a
cavity for the cement within the bone).
Miscellaneous interventions for breakthrough pain episodes

A variety of other nonpharmacological methods have also been reported to be
useful in treating actual breakthrough pain episodes, although most of them
have not been subjected to rigorous scientific investigation: (1) rubbing and/or
massage (Fine and Busch, 1998; Swanwick et al., 2001), (2) application of heat
(Fine and Busch, 1998; Swanwick et al., 2001), (3) application of cold (Fine and
Busch, 1998; Petzke et al., 1999), (4) distraction techniques (Portenoy, 1997;
Petzke et al., 1999), (5) relaxation techniques (Portenoy, 1997; Fine and Busch,
1998), and (6) hypnotherapy/hypnosis (Liossi, 2000; Wild and Espie, 2004).
The noninvasive, low-risk, and relatively inexpensive nature of these inter-
ventions means that it is usually worth a therapeutic trial of these modalities.
Furthermore, patients find these types of treatment highly acceptable for man-
aging their breakthrough pain, particularly as they have often used them for
managing other types of pain (e.g., benign musculoskeletal pain).

In summary, there are myriad nonpharmacologic techniques that are practiced
commonly for the control of pain, but there is only anecdotal evidence for the
reduction or relief of breakthrough pain per se. Clearly, this suggests that there
is a need to evaluate breakthrough pain as an independent outcome variable
when clinical trials are implemented. Methodology to discern breakthrough pain
and quality-of-life improvements related to breakthrough pain reduction re-
quires refinement in clinical trials involving these various techniques.
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110 CHAPTER 9
Chapter 10
Risk assessment and

management in long-term
opioid therapy
Regardless of medical diagnosis, the decision to proceed with long-term opioid

therapy requires serious initial consideration and reconsideration over time based
on meeting specific therapeutic goals and minimizing potential harms. Effective-
ness of therapy, which is a positive balance of therapeutic outcomes and adverse
effects, must be continually reassessed and documented. Because immediate-
release and rapid-onset opioids are a mainstay for breakthrough pain and their
use has the potential to create powerful positive conditioning for the brain’s “re-
ward center,” it must be ascertained over time that the use of these agents is
111
medically appropriate and beneficial (Ballentyne and LaForge, 2007; Fields, 2007).
Long-term management with opioids implies a life expectancy greater than
weeks to months. Unfortunately, there is an absence of prospective studies that
allow for accurate predictions of effectiveness in a given patient over such a pe-
riod of time. Therefore, in such cases, clinicians who prescribe opioid analgesics
for the treatment of chronic pain have an obligation to implement therapy ac-
cording to accepted principles of prescribing and to minimize the risk of misuse,
abuse, addiction, and diversion through individualized application of risk assess-
ment and management strategies (Fine and Portenoy, 2007). This requires physi-
cians to have the ability to evaluate for and recognize potential or ongoing
problematic drug-related behaviors, part and parcel of a basic skills set in addic-
tion medicine. This necessity is underscored by a documented increase in pre-
scription drug abuse in recent years, especially among teens and young adults, and
the strong call for “balance” by both pain specialists and those in the regulatory
and law enforcement communities (Birnbaum et al., 2006; Katz et al., 2007). Clin-
icians must understand the regulations and laws that govern the use of controlled
prescription drugs, assess and stratify risk in every case, and structure a prescrip-
tion regimen that is consistent with the perceived risk of abuse or addiction.
Laws and regulations

Uncertainty regarding regulatory issues and a fear of potential disciplinary action
may give physicians pause when considering whether to prescribe long-term
opioid therapy. Surveys have shown that physicians have a very real fear of dis-
Risk assessment and management
ciplinary action for prescribing controlled substances, particularly if the patient

has noncancer pain or a history of drug abuse. Even in populations with cancer
pain or HIV-related pain, for which there is wide acceptance of opioid therapy,
concerns about regulatory scrutiny are believed to be a significant cause of un-
dertreatment (Dahl et al., 2005).
The framework of laws and regulations governing the use of opioids and
other controlled substances has three tiers: (1) international laws and treaties,
(2) federal laws and regulations, and (3) state laws and regulations. National
governments are obligated to ensure the availability of opioid medications for
legitimate medical and scientific purposes. International treaties have been de-
signed to achieve a balance between ensuring the availability of controlled sub-
stances for medical purposes and preventing illegal diversion.
CHAPTER 10
International regulation
The International Narcotics Control Board was established in 1968 as an in-
dependent and quasi-judicial body empowered to implement the United Na-
tions drug conventions. It attempts to ensure that adequate supplies are
available for medical and scientific uses and that leakages from licit sources to
illicit traffic do not occur. To accomplish this, the board administers a system
for estimating and fulfilling the legitimate need for opioids and monitoring in-
112
ternational trade in drugs. It also monitors government control over the

chemicals used in the illicit manufacture of drugs and assists governments in
preventing diversion of these chemicals into illicit traffic. Finally, the board
also attempts to identify where weaknesses in the national and international
control systems exist.
Federal regulation
In the United States, two federal agencies, the Food and Drug Administration
(FDA) and the Drug Enforcement Administration (DEA), work together to reg-
ulate drugs and limit diversion and abuse. Before a pain medication can become
available to patients, the FDA must assess its efficacy and safety, including its
potential for abuse. If a product does not receive marketing approval (or an ex-
emption) from the agency, it cannot be legally produced or prescribed.
The Controlled Substances Act empowers the DEA to classify drugs into dif-
ferent schedules based on the risk of abuse and diversion, medical use, and
safety. Controlled substance schedules range from I to V. Schedule I drugs (e.g.,
heroin, LSD, marijuana) have a high potential for abuse, a lack of accepted
safety, and no current federally accepted medical use. Schedule II drugs (e.g.,
morphine, fentanyl, hydromorphone, levorphanol, methadone, oxycodone,
oxymorphone, methylphenidate, dextroamphetamine, dronabinol) have a high
potential for abuse, may produce severe psychological or physical dependence
liability, and have current accepted medical uses. Drugs classified into Schedules
III through V (e.g., hydrocodone [only available co-compounded with acetamin-
ophen or NSAID], codeine, diazepam) represent substances considered to
have progressively less abuse potential and relatively reduced psychological or

physical dependence (Portenoy et al., 2005).
The DEA enforces the Controlled Substances Act and the laws regulating the
manufacture, distribution, dispensing, and record-keeping requirements for
controlled substances. It also sets production quotas for controlled drugs,
which are intended to accommodate all legitimate medical and scientific uses of
scheduled drugs. According to the Controlled Substances Act, the use of a
scheduled drug is legal as long as it is prescribed and dispensed in the usual
course of professional practice and for a legitimate medical purpose (Gilson,
2002). This underscores the importance of documenting ongoing indications for
and outcomes of ongoing opioid therapy.
State regulation
CHAPTER 10
Each state works independently as well as with the federal government to over-
see the movement of controlled prescription drugs and minimize abuse and di-
version. Each also has sole responsibility for maintaining standards of health-care
practice through licensure of professionals. Law enforcement involvement oc-
curs at the local and the state level through numerous agencies. Medical practice
and licensure are governed through state medical boards, whereas law enforce-
ment under the Department of Justice in each state oversees criminal activities
that are deemed outside the bounds of medicine (Joranson et al., 2002b).
113
Historically, the policies, laws, and regulations that govern the use of con-
trolled prescription drugs in most states have been skewed toward enforce-
ment and not patient care. The principle of balance found in international and
federal law has not been central to the oversight efforts of the states (PPSG,
2006). During the past 5 years, however, many states have attempted to redress
the major concerns and explicitly recognize the need to protect clinical practice
while reducing opioid abuse and diversion. In the area of medical practice, for
example, the Federation of State Medical Boards, a national organization, has
drafted model policies for the medical use of controlled substances (“Model
Policy for the Use of Controlled Substances for the Treatment of Pain”), which
have now been adopted, at least in part, by almost half of the states. This model
policy is used by state boards to judge the appropriateness of a therapy and
should be considered by prescribers as the basic approach to the structuring
and documentation of opioid therapy (Table 10.1) (FSMB, 2007).
Although progress also has been made in establishing a dialogue with state
regulatory and law enforcement communities about the evolving role of opioid
analgesics in pain management, physicians continue to be concerned about in-
vestigation and potential sanctions. The number and complexity of the agencies
that can initiate an investigation after a complaint, the variation in laws and regu-
lations from jurisdiction to jurisdiction, the lack of certainty that local investiga-
tors follow the intentions of senior management in any agency, and the potential
to be duped by those who would divert drugs into the illicit market combine to
create, at very least, a perceived level of prescriber risk associated with prescrib-
ing controlled drugs. Anecdotal reports of physicians who have been investi-
Table 10.1 Key elements in the Model Policy for the Use of
Controlled Substances for the Treatment of Pain of the
Federation of State Medical Boards
Guideline Comment
Evaluation of the patient History and examination must be documented.
Pain history, comorbidities, and indication for
opioid should be documented.
Treatment plan Objectives used to determine success should be
noted. Treatment should be adjusted over time
to reflect changes; nonopioid therapies should be
prescribed if indicated.
Informed consent and Risks and benefits should be discussed.
agreement for treatment Prescriptions given by one physician and
pharmacy whenever possible. Consider written
agreement if patient is at high risk of abuse; if
used, agreement should outline patient
responsibilities, including drug screening when
requested, number and frequency of all
prescription refills, and reasons for which drug
may be discontinued.
Periodic review Continuation or modification of therapy should
depend on evaluation of progress toward
treatment objectives; satisfactory response may
be indicated by decreased pain, improved
function, or better quality of life. Objective
indicators of improvement should be monitored
and use of history from family or other caregivers
should be considered. If progress unsatisfactory,
therapy should be reconsidered.
Consultation There should be willingness to refer, particularly
if patient is at risk for misuse, abuse, or diversion;
consider consulting an expert if patient has a
history of substance abuse or a comorbid
psychiatric disorder that may require extra care.
Medical records Accurate and complete medical records should
include:
• the medical history and physical examination;
• diagnostic, therapeutic, and laboratory results;
• evaluations and consultations;
• treatment objectives;
• discussion of risks and benefits;
• informed consent;
• treatments;
• medications (including date, type, dosage, and
quantity prescribed);
• instructions and agreements; and
• periodic reviews.
Compliance with controlled Both federal and state laws and
substances laws and regulations regulations must be followed.
gated (a costly and highly stressful process, even if the outcome is favorable), dis-

ciplined by their licensing boards, or prosecuted by state authorities for alleged
criminal activities further lead to a high level of concern and may produce a chill-
ing effect that contributes to the undertreatment of pain (Gilson et al., 2004).
To minimize risk, prescribers must follow laws and regulations when pre-
scribing, and both prescribe and document in accordance with accepted med-
ical practice, as depicted in the Model Guideline (Table 10.1). A clinician who
recognizes the necessity of risk assessment and management is best able to
maintain the controls necessary to prescribe in a manner consistent with fed-
eral and state requirements.
Structuring therapy to reduce risk
CHAPTER 10
Risk assessment is key to the positioning of opioid therapy among the treat-
ments that may be offered for breakthrough pain. If the decision is made to
implement an opioid trial with the intention of continuing therapy, the treat-
ment must include strategies to minimize the risk of misuse, abuse, and addic-
tion. This is no less important than strategies to optimize drug administration
to achieve the best balance between analgesia and side effects (Fine and
Portenoy, 2007).
115
The creation of an individualized plan to minimize risk and maintain an ap-
propriate level of monitoring should be considered a part of the plan of care for
all patients, a concept that has been termed “universal precautions” (Gourlay et
al., 2005). As with universal precautions associated with infectious diseases, ap-
plying a set of criteria to every patient with chronic pain improves patient care,
reduces stigma, and minimizes overall risk (Box 10.1).
The initial assessment can be based on clinical findings or on the findings of a
validated instrument designed to predict risk (Webster and Webster, 2005; Ives
et al., 2006). The goal of the initial assessment is risk stratification. Empirically, it
is reasonable to stratify patients into lower and higher risk categories based on
the assessed level of risk. Although this process cannot yet be guided by scien-
tifically based principles, the clinical utility is clear. Decision making concerning
the need for consultation or referral can be based on risk strata, and if opioid
treatment proceeds, the therapy should be structured in a manner commensu-
rate with the perceived risk.
Proactive strategies should be adopted at the start of therapy to structure
the therapy based on risk in a manner that minimizes the potential for aberrant
drug-related behaviors and establishes appropriate monitoring (Box 10.2) (Fine
and Portenoy, 2007). If the risk is perceived to be very low (e.g., the opioid-
naïve elderly with no history of substance abuse and progressive pain from os-
teoarthritis), then minimal or no special strategies may be needed. If the risk is
relatively high (e.g., the work-injured, depressed man with a history of binge
drinking and a family history of alcoholism), then treatment might be initiated
with many of the strategies in place.
Box 10.1 The 10 steps of universal precautions in pain medicine

1. Make a diagnosis with appropriate differential
a. Identify treatable causes for pain and direct therapy to pain generator
b. In absence of specific objective findings, treat symptoms
c. Address any comorbid symptoms, including substance abuse and psychiatric illness
2. Psychological assessment including risk of addictive disorders
a. Inquiry into personal and family history of substance abuse
b. Perform patient-centered urine drug testing
3. Informed consent
4. Treatment agreement
a. Expectations and obligations of patient and practitioner should be understood
b. Forms basis of therapeutic trial
CHAPTER 10
5. Pre- and post-intervention assessment of pain level and function

6. Appropriate trial of opioid therapy with or without adjunctive medication
7. Reassessment of pain score and level of function
8. Regularly assess the “Four A’s” of pain medicine (analgesia, activity, adverse effects, and
aberrant behavior)
9. Periodically review pain diagnosis and comorbid conditions, including addictive disorders
10. Documentation
Adapted from Gourlay et al., 2005.
116
Managing aberrant drug-related behavior

As treatment proceeds, drug-related behaviors must be monitored. This can be
performed by regular clinical assessment. This assessment can be supplemented
by ancillary sources of information, such as drug screening, pill counts, inter-
views with family members (with patient approval in the case of adult patients),
and prescription monitoring programs where available (Joranson et al., 2002a).
The plan to acquire this type of information should be part of the plan when the
patient is assessed as relatively high risk, and the specifics should be explained
to the patient beforehand.
Ongoing assessment of drug-related behaviors has been incorporated into a
clinical tool developed for the purpose of monitoring and documenting the key
outcomes associated with long-term opioid therapy. The Pain Assessment and
Documentation Tool (PADT) assesses four types of outcomes: analgesia, activ-
ities of daily living, adverse events, and potential aberrant drug-related behavior
(known by the mnemonic “the 4 As”). It provides a checklist of problematic be-
haviors and, if used repeatedly, provides a means of documenting changes in
therapeutic adherence (Passik et al., 2004).
If problematic behavior is identified, a detailed reassessment is needed. The
purpose is to clarify the meaning of the behavior and to generate one or more
potential diagnoses (Box 10.3). The plan should be based on the diagnosis. For
Box 10.2 Proactive and reactive strategies to minimize risk of
abuse and enhance monitoring
Proactive strategies
• Written agreement after detailed consent discussion
• Prescribe long-acting drug without “rescue dose”
• Frequent visits and small quantities prescribed
• Urine drug screen at baseline and expressed intention to request occasional screens in the
future
• Requirement that only one pharmacy be used (with permission to contact)
• Instruction to bring pill bottle to appointment (for count)
• Instruction that there will be no early refills and no replacement of lost prescription
without a police report documenting loss
CHAPTER 10
• Requirement for nonopioid therapies, including psychotherapy
• Requirement for all prior records and permission to contact all other health-care
providers prior to prescribing
• Required referral to addiction medicine specialist for all at-risk patients
• Requirement that others (e.g., spouse) be allowed to give feedback to the physician
• In states with electronic prescription reporting/tracking, intention to query the database
initially and on a regular basis
Reactive strategies
117
• Written agreement that addresses specific behaviors and outlines consequences going
forward
• Discontinue rescue dose
• Frequent visits and small quantities prescribed
• Urine drug screen at baseline and expressed intention to request screens in the future
• Requirement that only one pharmacy be used (with permission to contact)
• Instruction to bring pill bottle to appointment (for count)
• Instruction that there will be no early refills and no replacement of lost prescription
without a police report documenting loss
• Requirement for nonopioid therapies, including psychotherapy
• Requirement that all other health-care providers be contacted
• Required referral to addiction medicine specialist, with follow-up treatment for aberrant
behaviors
• Requirement that others (e.g., spouse) be allowed to give feedback to the physician
• In states with electronic prescription reporting, intention to query the database on a
regular basis going forward
Adapted with permission, Fine and Portenoy, 2007.
example, in the extreme case of the patient who begins to grind and inject an
oral formulation, the diagnosis of abuse is certain and that of addiction usually
is clear. Subsequently, the abused pain therapy typically is suspended or greatly
altered as the patient is referred to a specialist in addiction medicine for pri-
mary follow-up. If the nature of the behavior is uncertain and the assessment
concludes that therapy can be continued, ample resources for assessing risk
Box 10.3 Differential diagnosis of aberrant drug-related behavior

Addiction: a primary, chronic, neurobiologic disease with genetic, psychosocial, and
environmental factors; characterized by impaired control over drug use, compulsive use,
continued used despite harm, and drug craving.
Undertreated pain (often called “pseudoaddiction”): aberrant drug-related behaviors
induced by desperation over unrelieved pain; may be driven by psychiatric disease or co-
exist with addiction.
Other psychiatric disorder:
Axis I disorder (e.g., anxiety disorders, major depression)
Axis II disorder (e.g., personality disorders such as borderline personality, sociopathic
personality)
Encephalopathy (e.g., associated with medication toxicity)
Other psychosocial/emotional issues (e.g., family discord, financial worries, work-related
CHAPTER 10
discontent, “rebellion”)
Recreational use (e.g., experimentation, pleasure, escape, peer pressure)
Criminal intent (e.g., selling drugs, falsifying prescriptions to procure more drug)
Consensus Document: The American Academy of Pain Medicine, The American Pain Society, The American
Society of Addiction Medicine, 2001.
and observing outcomes must be in place, as the diagnosis may become evi-
118
dent over time as the patient deals with a new structure for the therapy.
The restructuring of therapy may involve the addition of one or more reac-
tive strategies (see Box 10.2) (Fine and Portenoy, 2007). Like those imposed at
the start of therapy, these are intended to minimize future risk of abuse, addic-
tion, or diversion and increase the level of monitoring.
Whenever problematic drug-related behaviors occur, the clinician has cause
to decide about continuation of treatment and the possibility of referral. Pain
treatment may be continued with opioids (using a different structure for pre-
scribing) or continued without opioids, or the patient may be discharged from
the practice. The decision to continue treatment with the opioid should be
based on careful assessment of the severity and meaning of the problematic
behavior. There should be an explicit plan to change or discontinue the cur-
rent therapy (often called an “exit strategy”) unless (1) favorable outcomes
(pain relief, improved function, and/or improved quality of life) are manifest,
(2) there is a high likelihood that control over the therapy can be reacquired,
and (3) restructuring allows better monitoring of drug-related behavior. Dis-
charge from the practice may be warranted if the possibility of therapeutic
progress has been severely undermined by mistrust or the assessment reveals
that the patient lacks interest in treatments other than the opioid agent (Fine
and Portenoy, 2007).
When aberrant drug-related behavior of a significant enough magnitude or
frequency occurs, referral to a specialist in addiction medicine or an addiction
program also should be considered. Addiction is a chronic disease like any
other, and it is no more appropriate to neglect referral for this disorder once it
is suspected than it is to neglect referral for any other complex, potentially life-

threatening disease. The clinician also might consider referral to a pain special-
ist or to a mental health care provider (other than an addiction specialist),
depending on the needs identified.
If therapy must be restructured, it is important that documentation be com-
prehensive and complete. The medical record should reflect the thoughtful re-
assessment, and the written plan of care should be explicit. It may be useful to
provide the patient with a letter that clarifies the next steps, his or her obliga-
tions, and the consequences should problems recur.
Opioid agreements
CHAPTER 10
A formal written agreement between the patient and the physician at the start
of opioid therapy is a common tool for defining expectations and documenting
informed consent. Although these agreements have been called “contracts,”
they have no statutory force of law, and this term is not preferred because it
suggests a legal rather than therapeutic relationship between the physician (or
other prescriber) and the patient.
Pain specialists differ in their views of this approach (Fishman and Kreis,
2002). On the positive side, these agreements can be used as educational tools
119
that outline the clinician’s policy for providing controlled prescription drugs and
describe the consequences of problematic drug-related behavior. They can re-
inforce the idea that opioid medications must be used responsibly and can also
assure patients that medication will be prescribed as long as outcomes are pos-
itive and there is adherence to therapy.
On the negative side, these agreements can contribute to the stigmatization
of opioid therapy. If they are framed in a manner that the patient perceives as
threatening, they may contribute to assessment difficulties as the patient with-
holds or skews information in an effort to meet expectations. If they give a cli-
nician a false sense of security and thereby reduce the vigilance, monitoring, and
use of appropriate proactive and reactive strategies that are essential to risk
management, they could paradoxically increase risk. Finally, if the agreements
implicitly hold a clinician to a certain level of clinical performance, they could ul-
timately be used adversely in a medicolegal dispute.
Given these potential positives and negatives—and the lack of consensus
about the role of this approach—each clinician must decide whether the use
of an agreement is appropriate and likely to be beneficial. Use of opioid
agreements may be informed by a recent survey that identified the most
common elements used by 39 university-affiliated pain management centers
(Table 10.2). This work highlighted the necessity for careful consideration of
prohibitions endorsed in order to help patients normalize, rather than re-
strict, their activities. For example, rather than prohibiting patients from driv-
ing while using opioids for breakthrough pain, an admonition against driving
for the first hour or two after a rapid-onset agent (transmucosal opioid) or
for 3 to 4 hours after an immediate-release agent (oral opioid) would be sen-
sible. Likewise, rather than prohibiting pregnancy during treatment, the

agreement may outline the prescriber’s concerns about pregnancy and re-
quire notification should pregnancy occur or be anticipated, so that counsel-
ing and appropriate perinatal referral can be provided. In an effort to further
clarify the type of language that may be most appropriate for these agree-
ments, the American Academy of Pain Medicine developed a model approach
(Box 10.4).
Table 10.2 Statement groups found most often in opioid

agreements
CHAPTER 10
Statement category Contracts (%)

1. Avoid improper use of controlled substances (includes 95
overdosing, seeking medication elsewhere, selling medication,
stopping medication abruptly)
2. Terms of disciplinary termination (medication abuse, missed 92
appointments, contract violation, inappropriate behavior)
3. Limitations for replacing medication or changing prescriptions 85
4. Inform physician of relevant information (e.g., side effects, other 74
medications, changes in condition)
120
5. Submit to random drug screens 69

6. Terms regarding appointments (missing appointment, follow-up, 62
appearing without appointment)
7. Include additional health-care providers involved in care 59
(e.g., primary care physician, physical therapist, psychologist)
8. Limits on drug refills (telephone allowances, only in person, 56
call in advance, normal office hours)
9. Education about side effects (including withdrawal) 56
10. Terms of nondisciplinary termination (e.g., no improvement, 51
pregnancy, tolerance, toxicity)
11. Education on addiction risks and behaviors 49
12. Education on opioids and chronic pain 49
13. Health-care providers informed of prescription (e.g., primary 46
care physician, pharmacist)
14. Pharmacy issues included (use of only one pharmacy, use of 44
in-state pharmacy)
15. Goals (outline goals) 38
16. Additional risks discussed (e.g., other drug use, misuse, pregnancy) 38
17. Necessity of contract discussed (reasons why necessary, 36
including federal guidelines and abuse)
18. Legal considerations discussed 33
19. Single prescriber for all opioid prescriptions 33
20. Dosing limitation (how much, interval between prescriptions, 31
rescue dosing, as-needed use, dose escalation)
Adapted with permission, Fishman et al., 1999.
Box 10.4 Sample opioid agreement
SAMPLE FOR ADAPTATION AND REPRODUCTION ON PHYSICIAN
LETTERHEAD, PLEASE CONSULT WITH YOUR ATTORNEY.
Long-term controlled substances therapy for chronic pain
The purpose of this agreement is to protect your access to controlled substances and to
protect our ability to prescribe for you.
The long-term use of such substances as opioids (narcotic analgesics, benzodiazepine
tranquilizers, and barbiturate sedatives) is controversial because of uncertainty regarding the
extent to which they provide long-term benefit. There is also the risk of an addictive
disorder developing or of relapse occurring in a person with a prior addiction. The extent of
this risk is not certain.
Because these drugs have potential for abuse or diversion, strict accountability is necessary
when use is prolonged. For this reason the following policies are agreed to by you, the
patient, as consideration for, and a condition of, the willingness of the physician whose
signature appears below to consider the initial and/or continued prescription of controlled
substances to treat your chronic pain.
1. All controlled substances must come from the physician whose signature appears
below or, during his or her absence, by the covering physician, unless specific
authorization is obtained for an exception. (Multiple sources can lead to untoward
drug interactions or poor coordination of treatment.)
2. All controlled substances must be obtained at the same pharmacy, where possible.
Should the need arise to change pharmacies, our office must be informed.
The pharmacy that you have selected is: Phone:
3. You are expected to inform our office of any new medications or medical
conditions and of any adverse effects you experience from any of the medications
that you take.
4. The prescribing physician has permission to discuss all diagnostic and treatment
details with dispensing pharmacists or other professionals who provide your health
care, for purposes of maintaining accountability.
5. You may not share, sell, or otherwise permit others to have access to these
medications.
6. These drugs should not be stopped abruptly, as an abstinence syndrome will likely
develop.
7. Unannounced urine or serum toxicology screens may be requested, and your
cooperation is required. Presence of unauthorized substances may prompt referral
for assessment for addictive disorder.
8. Prescriptions and bottles of these medications may be sought by other individuals
with chemical dependency and should be closely safeguarded. It is expected that
you will take the highest possible degree of care with your medication and
prescription. They should not be left where others might see or otherwise have
access to them.
9. Original containers of medications should be brought in to each office visit.
10. Since the drugs may be hazardous or lethal to a person who is not tolerant to their
effects, especially a child, you must keep them out of reach of such people.
11. Medications may not be replaced if they are lost, get wet, are destroyed, are left
on an airplane, etc. If your medication has been stolen and you complete a police
report regarding the theft, an exception may be made.
12. Early refills will generally not be given.
13. Prescriptions may be issued early if the physician or patient will be out of town
when a refill is due. These prescriptions will contain instructions to the pharmacist
that they not be filled prior to the appropriate date.
14. If the responsible legal authorities have questions concerning your treatment, as
might occur, for example, if you were obtaining medications at several pharmacies,
Box 10.4 (Continued)

all confidentiality is waived and these authorities may be given full access to our rec-
ords of controlled substance administration.
15. It is understood that failure to adhere to these policies may result in cessation of
therapy with controlled substance prescribing by this physician or referral for further
specialty assessment.
16. Renewals are contingent on keeping scheduled appointments. Please do not phone
for prescriptions after hours or on weekends.
17. It should be understood that any medical treatment is initially a trial and that
continued prescription is contingent on evidence of benefit.
18. The risks and potential benefits of these therapies are explained elsewhere (and you
acknowledge that you have received such explanation).
19. You affirm that you have full right and power to sign and be bound by this
agreement and that you have read, understand, and accept all of its terms.
CHAPTER 10
Physician signature
Patient signature
Date
Patient name (printed)

122
Adapted from the American Academy of Pain Medicine, Glenview, IL.
Conclusion
In summary, risk management is an implicit part of all medical care, and of pre-
scribing of controlled substances in particular. Optimal treatment of break-
through pain requires skillful use of all available tools and methods in order to
allow patients to maintain the most functional life they can. Physicians must
become adept and skilled at integrating risk assessment and management tech-
niques into their day-to-day practices in order to meet their professional re-
sponsibilities to their patients and to the public health and to protect their
prescribing privileges.
References
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chronic pain. Pain. 2007;129:235–255.
Birnbaum HG, White AG, Reynolds SL, et al. Estimated costs of prescription opioid anal-
gesic abuse in the United States in 2001: A societal perspective. Clinical Journal of Pain.
2006;22:667–676.
Dahl JL. How to reduce fears of legal/regulatory scrutiny in managing pain in cancer pa-
tients. Journal of Supportive Oncology. 2005;3:384–388.
Federation of State Medical Boards, Inc. (FSMB). Model Policy for the Use of Controlled

Substances for the Treatment of Pain. 2007. Available at: http://www.fsmb.org/pdf/
2004_grpol_Controlled_Substances.pdf. Accessed August 1, 2007.
Fields HL. Should we be reluctant to prescribe opioids for chronic non-malignant pain?
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dome, 2007.
Fishman SM, Bandman T, Edwards A, et al. The opioid contract in the management of
chronic pain. Journal of Pain and Symptom Management. 1999;18:27–37.
Fishman SM, Kreis PG. The opioid contract. Clinical Journal of Pain. 2002;18:S70–S75.
Gilson AM, Joranson DE. US policies relevant to the prescribing of opioid analgesics for
the treatment of pain in patients with addictive disease. Clinical Journal of Pain.
2002;18:S91–S98.
CHAPTER 10
Gilson AM, Ryan KM, Joranson DE, Dahl JL. A reassessment of trends in the medical use
and abuse of opioid analgesics and implications for diversion control: 1997–2002. Jour-
nal of Pain and Symptom Management. 2004;28:176–188.
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proach to the treatment of chronic pain. Pain Medicine. 2005;6:107–112.
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Joranson DE, Carrow GM, Ryan KM, et al. Pain management and prescription monitoring.
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Katz NP, Adams EH, Benneyan JC, et al. Foundations of opioid risk management. Clinical
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report card. 2006. Available at: http://www.medsch.wisc.edu/painpolicy. Accessed Au-
gust 1, 2007.
Passik SD, Kirsh KL, Whitcomb L, et al. A new tool to assess and document pain out-
comes in chronic pain patients receiving opioid therapy. Clinical Therapeutics.
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Portenoy RK, Payne R, Passik S. Acute and chronic pain. In Lowinson JH, Ruiz P, Millman
RB (Eds.), Comprehensive Textbook of Substance Abuse (4th ed., pp. 863–903). Balti-
more: Williams and Wilkins, 2005.
Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated patients: A
preliminary validation of the Opioid Risk Tool. Pain Medicine. 2005;6:432–442.
Index
A Assessment, 25–32, 27f,

29f–31f, 32f, 116–19, 118f.
Breakthrough Pain
Questionnaire, 28–31,
Abdominal pain, 4 See also reassessment; 29f–31f
Aberrant (drug-related) risk assessment case histories, 15f–16f
behavior, 116–19, 118f Breakthrough Pain characteristics, 17t–18t
Acetaminophen, 15, 16f Questionnaire, 28–31, classification, 2, 13–14
Active functional 29f–31f complications, 20–21,
evaluation, 26 comorbid condition 21f, 21t
Acupuncture, 104–5 assessment, 116f definition, 1–2
Addiction, 115–16, 116f. Likert assessment scale, 28 demographics, 4
See also aberrant pain documentation sheet, etiology, 7, 8t
(drug-related) behavior; 3t, 31–32, 32f clinical features vs., 19
risk assessment public safety vs. patients’ European Association for
definition, 118f interests, 42 Palliative Care, 93
Adjuvant analgesics, 37, 85 risk, 111–22, 114t, 116f, general features of, 16
Agitation, 89. See also 117f, 118f, 120t, management strategies,
anxiety 121f–122f 41–42
Alcohol instillation, 105 tools for, 28–32, 29f–31f mixed, 8t
Alfentanil, 68 difficulty in using, 28 more than one type of, 26
Alternative medicine and Ataxia, 89 multimodal management
125
therapies, 26, 36, 36t, 40 Atomization device, 81 of, 36
American Academy of Pain neuropathic, 8t, 14, 16f,
Medicine, 120, 121f 19, 37
Amitriptyline, 88f
Analgesics, 15, 37. See also B treatment guidelines for
peripheral, 86t
specific types Background pain, 1, 14f. See patterns of, 14f, 25, 32f,
additional, 37, 85 also chronic pain; 50–52, 51f, 66f
basal, 1, 14f end-of-dose failure circadian variation, 19–20
increasing frequency of, 40 breakthrough dose vs. post-surgery, 8t
onset of action, 43t background dose for, prevalence, 1, 3, 3t, 5t–6t
oral transmucosal opioid 50–52, 51f, 66f Breakthrough pain:
analgesics, 55–71 multimodal management Definition, prevalence and
fentanyl, 58–68, 59f, of, 36 characteristics (Portenoy
60t, 61f, 62t–63t, 64f, poorly controlled, 14f, 31 and Hagen), 1, 3
65f, 66f, 67f Balloon kyphoplasty, 105 Breakthrough Pain
responsiveness to, 26, 52, 93 Basal analgesic, 1, 14f Questionnaire, 28–31,
rotation of, 37, 40, 40f Benzodiazepines, 92–93 29f–31f
timing for, 39 opioids in combination Bronchopulmonary route, 41,
World Health Organization with, 93 43t, 76t, 81–82
guidelines, 90 Bisphosphonates, 90 BTP. See breakthrough pain
Anesthesia induction, 92 Blood sugar control, 16f. See Buprenorphine, 58f,
Anticipatory analgesia, 86 also diabetes 68–69
Anticonvulsants, 37, 40, Bone metastases, 15f Bupropion (Wellbutrin), 86t
89–90, 89t Bone pain, nonopioid
Antidepressant drugs, 37, 86t, pharmacotherapy for, 90
87–88, 88f Bowel function, 16f
Anxiety, 20, 21f, 88f, 89. See constipation, 16f, 20, C
also nervousness 88f, 88t CAM. See complementary and
Anxiolysis, 92 diarrhea, 88f alternative medicine
Application-site irritation, 65 Breakthrough pain (BTP). See Cancer
Around-the-clock medication, also background pain; chronic pain from, 2–4, 3t,
14f, 41, 52 chronic pain; pain 5t–6t, 62t–63t
nonopioid, 85 background pain vs., 50–52, circadian variation vs.
starting dose for, 41–42 51f, 66f pain intensity, 19–20
INDEX
Cancer (continued ) antidepressants, 37, 86t, pharmacokinetic profile,

-related BTP, 93 87–80, 88f 60–61, 60t
mood disorders vs., Desipramine, 87, 88f sublingual absorption of, 58f
20–21, 21f Diabetes, 16f transdermal patch, 40, 40f,
OTFC and FBT for, 61–71 neuropathy, 89t 51f, 63t
-related neuropathic pain Diagnosis, 116f, 118f transmucosal route
disorders, 89t Diamorphine, 58f for, 58–68, 59f, 60t,
stages of, 7 Diarrhea, 88f 61f, 62t–63t, 64f, 65f,
Capsaicin, 86t Diclofenac, 92t 66f, 67f
Carbamazepine, 86t, 89, 89t Differential diagnosis, 118f Fentanyl buccal tablet (FBT),
Celecoxib, 92t Dilantin. See phenytoin 15f, 59f, 60t
Celexa. See citalopram Distraction techniques, 36, 105 absorption of, 58–60, 59f
Cementoplasty/vertebroplasty, Dizziness, 42, 62t, 88f clinical data, 61–68, 64f,
105 Documentation, 116f 66f, 67f
Chemotherapy, BTP pain documentation sheet, OTFC vs. FBT, 61f
from, 8t 3t, 31–32, 32f titration protocol, 66f, 67f
Chronic pain. See also Dolophine. See methadone modified-release, 56
background pain Doxepin, 88f opioid-tolerant patients, 67f
from cancer, 2–4, 3t, Drowsiness, 88f pharmacokinetic profile, 60t
5t–6t, 62t–63t Drugs. See also medication; Fentora. See fentanyl buccal
noncancer, 4–7, 6t side-effect; specific tablet (FBT)
Circadian variation, 19–20 medications Fibromyalgia, 7
Citalopram (Celexa), 86t accidental overdosing, 40 Food and Drug Administration
Co-analgesics, 37, 85 antidepressant, 37, 86t, (FDA) approval, 89
Cognitive impairment, 20, 87–80, 88f “Four A’s” of pain medicine,
88t, 89 Food and Drug 116f
difficulty in using Administration Functional capacities
assessment tools, 28 approval, 89 (patients’), 20, 26
Cold application, 36, 105 neuraxial drug delivery, analgesics timed for, 39
126
Comorbid condition 99–100 assessment of, 116f

assessment, 116f nonsteroidal environmental modification
Complementary and anti-inflammatory, for, 38
alternative medicine 40, 91–92, 92t evaluation of, 26
(CAM) and therapies, 26, OraVescent Drug Delivery
36, 36t, 40 Technology, 59f
Complex regional pain risk assessment, aberrant G
syndrome, 7 drug-related behavior,
Gabapentin, 15, 86t, 89, 89t
Concomitant disease, 116f 116–19, 118f
Gomez-Batiste, X., 3t
BTP from, 8t urine drug screen, 117f
Constipation, 16f, 20, Dry mouth, 65, 88t, 89
88f, 88t Duloxetine, 16f, 86t, 88
Controlled-release H
oxycodone, 86t Hagen, N. A., 1, 3
Controlled substances, E Headache, 7, 62t, 89
111–22, 114t, 116f, Heat application, 36, 105
Effexor. See venlafaxine,
117f, 118f, 120t, Herpetic neuralgia, 89t
extended release (Effexor)
121f–122f History of patient, 25–26
End-of-dose failure, 2, 3t, 13,
model policy for, 114t with analgesics, 26, 52, 93
16f, 19, 39–40, 40f. See also
sample agreement form, HIV-associated
rescue dose
121f–122f neuropathy, 89t
European Association for
Corticosteroids, 40 Home setting (palliative care)
Palliative Care, 93
instillation of, 105 patients, 5t, 15
Ewing’s sarcoma, 15
Cost effectiveness, 9, environmental modification
20–21, 21t, 53 for, 38
Coughing, 17t European Association for
Cryoablation, 105 F Palliative Care, 93
FBT. See fentanyl buccal tablet Hospice patients, 5t
FDA. See Food and Drug environmental modification
D Administration for, 38
Deep vein thrombosis, 20 Fentanyl, 56, 59t, 60t. See also Likert assessment scale used
Delirium, 19–20 fentanyl buccal tablet; by, 28
Dental caries, 65 morphine; oral transmucosal Hospital patients, 5t, 6t
Depression, 20, 21f fentanyl citrate costs vs. BTP, 21, 21t
INDEX
Hydrocodone, 16f, 39 Lidocaine, 86t Movement-related pain. See
Hydromorphone, 39, 41, 49t, Likert assessment scale, 28 incident pain
58f, 69 Lorazepam, 93 MSIR. See immediate-release
Hypnotherapy/hypnosis, 105 Low back pain, 4, 15f, 17t oral morphine sulphate
Multidimensional measure-
ment scales, 26–28, 27f
I M Muscle wasting, 20
IASP. See International MAD atomization device, 81f
Management strategies, 3
Association for the Study
of Pain 5–44. See also specific N
Ibuprofen, 92t medications Naproxen, 92t
Imaging studies, 25 breakthrough medication, Nasal route, 41, 43t, 76t,
Imipramine, 87, 88f 41–42 79–81, 81f, 93
Immediate-release opioids, incident pain, 37–39, 38f, 39f Nausea, 20, 42, 62t, 88f, 89.
39, 61f multimodal, 36 See also vomiting
Immediate-release oral nonpharmacological Nervousness, 88f. See also
morphine sulphate (MSIR), interventions, 36, anxiety
61f. See also morphine 36t, 97–106 Neuraxial drug delivery,
Incident pain, 3t, 13, 15f, 19, pain management vs. pain 99–100
20, 37–39, 38f, 39f measurement, 28 Neuroablation, 102–4
Informed consent, 116f pharmacological treatment, Neurological examination, 26.
Inhalation 35–36, 36t, 41–44, 43t See also neuropathic
(bronchopulmonary) route, spontaneous pain, 13, 15f, breakthrough pain;
41, 43t, 76t, 81–82 19, 21, 37 neuropathy
Injections, patients’ dislike for, surgical stabilization/orthotic Neuromodulation, 101–2, 101f
43t, 44 devices, 38, 38f Neuropathic breakthrough
Insomnia, 88f MAOIs. See monoamine pain, 8t, 14, 16f, 19, 37
Intensity of pain, 14f, 20, oxidase inhibitors treatment guidelines for
21f, 26 Massage, 36, 105 peripheral, 86t
127
circadian variation vs., 19–20 Medical records, 114t Neuropathy, 7
FBT vs., 64f Medication, 35–36, 36t, nonopioid pharmacotherapy
severe vs. moderate vs. 41–44, 43t. See also drugs; for, 86–90, 88f, 89t
slight, 18t specific medication; specific post-herpetic neuralgia, 89t
Intermittent pain, 14f type of pain trigeminal neuralgia, 89t
International Association for acceptability of, 43–44, 43f Nitrous oxide, 94
the Study of Pain (IASP), 4 accidental overdosing, 40 NNH. See number needed to
Intramuscular route, 43t, adherence to, 42–43 harm
76t, 78 around-the-clock, 14f, 41, 52 NNT. See number needed to
Intranasal route, 41, 76t, nonopioid, 85 treat
79–81, 81f, 93 starting dose for, 41–42 Nociceptive breakthrough
Intrapulmonary route, 41, 43t, effect/side-effect profile, pain, 8t, 13, 19
76t, 81–82 37, 40 Nonopioid pharmacotherapy
Intravenous route, 41, 43t, “Four A’s” of, 116f anticonvulsants, 37, 40,
76t, 78 peak effect of, 39, 41, 92t 89–90, 89t
prescription of, 42 antidepressants, 37, 86t,
Meloxicam, 92t 87–80, 88f
J Methadone (Dolophine), 40, benzodiazepines, 92–93
49t, 58f, 69–70, 86t bisphosphonates, 90
Joint stiffness, 20
Methylphenidate, 37 bone pain management, 90
Midazolam, 92–93 ketamine, 93–94
K Mixed breakthrough pain,
8t, 14
midazolam, 92–93
neuropathic pain
Ketamine, 93–94 Mobility, decreased, 20–21, 21f management, 86–90,
Ketorolac, 92t Monoamine oxidase inhibitors 88f, 89t
Kyphoplasty, balloon, 105 (MAOIs), 88 nitrous oxide, 94
Mood disorders, 20–21, 21f nonsteroidal anti-
Morphine, 41, 49t, 58f, 70. See inflammatory drugs, 40,
L also fentanyl; oral 91–92, 92t
Lamotrigine, 86t, 89t transmucosal opioid role of, 85–86
Laser ablation, 105 analgesics Nonpharmacological
Laws, controlled substance, immediate-release oral interventions, 36, 36t,
111–15, 114t. See also morphine sulphate, 61f 97–106
controlled substances plasma concentration of, 50f acupuncture, 104–5
INDEX
Nonpharmacological routes for administering, 41 Outcome measurement,

interventions (continued ) short-acting, 37 26–28, 27f
alcohol instillation, 105 Opioid therapy agreement, Overdosing, 40
balloon kyphoplasty, 105 117f, 119–22, 120t, Oxcarbazepine, 89t
cementoplasty/vertebroplast 121f–122f Oxycodone, 15f, 39, 49t,
y, 105 sample, 121f–122f 58f, 70, 86t
cold application, 36, 105 Opioid-tolerant patients, 67f controlled release, 86t
corticosteroid instillation, Oral mucosa, 55–56. See also Oxymorphone, 39, 49t
105 oral route
cryoablation, 105 Oral opioids, 48t, 47–53,
distraction techniques, 49–52, 49t, 50f, 51f. See P
36, 105 also opioid therapy; oral Pain. See also breakthrough
general principles, 97–98 transmucosal opioid pain; chronic pain; site
heat application, 36, 105 analgesics of pain
hypnotherapy/hypnosis, 105 acceptability to patient, American Academy of Pain
laser ablation, 105 52–53 Medicine, 120, 121f
massage, 105 background dose vs. background, 1, 14f, 31, 36,
neuraxial drug delivery, breakthrough dose, 50–52, 51f, 66f
99–100 50–52, 51f, 66f cancer-related, 2–4, 3t,
neuroablation, 102–4 combination products, 48t 5t–6t, 7, 19–20, 61–71,
neuromodulation, 101–2, cost effectiveness of, 53 62t–63t, 89t, 93
101f drug considerations, mood disorders vs.,
peripheral procedures, 98–99 49–52, 51f 20–21, 21f
phenol instillation, 105 pharmacokinetics vs. end-of-dose failure, 2, 3t,
radiofrequency ablation, 105 breakthrough pain 13, 16f, 19, 39–40, 40f
relaxation techniques, 105 pattern, 52 exacerbating vs. relieving
Nonsteroidal anti- plasma concentration of factors, 26
inflammatory drugs morphine sulfate, 50f function capacities vs., 116f
(NSAIDS), 40, 91–92, 92t route considerations, 47–49 incident, 3t, 13, 15f, 19, 20,
128
Nonvolitional pain, 2, 13 Oral route, 41–42, 43t. See 37–39, 38f, 39f
Norepinephrine serotonin also oral opioids; routes of management vs. measure-
reuptake inhibitors medication administration ment, 28
(NSRIs), 88 Oral transmucosal fentanyl mixed breakthrough, 8t, 14
Nortriptyline, 87, 88f citrate (OTFC), 39, 41 nonvolitional, 2, 13
NSAIDs. See nonsteroidal absorption of, 58, 58f, 59f opioid-responsive, 26, 52, 93
anti-inflammatory drugs clinical data, 61–68, paroxysmal, 3t
NSRIs. See norepinephrine 62t–63t, 65f, 66f, 67f post-stroke, 89t
serotonin reuptake MSIR vs. OTFC, 61f precipitants of, 3t, 32f
inhibitors OTFC vs. FBT, 61f procedural, 2, 13
Number needed to harm titration protocol, 66f, 67f quality of, 25
(NNH), 87, 89, 90 dry mouth from, 65 radiation of, 25, 26
Number needed to treat opioid-tolerant patients, 67f spontaneous, 13, 15f, 19,
(NNT), 87, 89, 90 pharmacokinetic 21, 37
profile, 60–61 temporal patterns of, 14f,
Oral transmucosal opioid 19–20, 25, 32f, 50–52,
O analgesics, 55–71. See also 51f, 66f
Onset of action morphine; oral opioids circadian variation, 19–20
(analgesia), 43t alfentanil, 68 transitory, 31
Onset of pain, 18t, 25 buprenorphine, 58f, 68–69 visceral, 13, 19
Opioid-responsive pain, 26, fentanyl, 58–68, 59f, Pain documentation sheet, 3t,
52, 93 60t, 61f, 62t–63t, 64f, 31–32, 32f
Opioid therapy. See also oral 65f, 66f, 67f Pain measurement scales,
opioids; oral transmucosal hydromorphone, 69 26–28, 27f
opioid analgesics methadone, 40, 49t, 58f, Palliative care patients, 5t, 15
dose increase, 38 69–70, 86t environmental modification
immediate-release, 39, 61f oxycodone, 70 for, 38
oral, 48t, 47–53, 49t, 50f, 51f sufentanil, 70–71 European Association for
patient’s responses to/ OraVescent Drug Delivery Palliative Care, 93
concerns about, 26, 52, 93 Technology, 59f Palpation, 26
risk assessment, 111–22, Orthostatic hypotension, 88t Paroxetine (Paxil), 86t
114t, 116f, 117f, 118f, Orthotic devices, 38, 39f Paroxysmal pain, 3t
120t, 121f–122f OTFC. See oral transmucosal Patient history, 25–26
rotation of, 37, 40, 40f fentanyl citrate with analgesics, 26, 52, 93
INDEX
Paxil. See paroxetine Rectal route of administration, SIADH. See syndrome of
Peak effect, 39, 41, 92t 43t, 76t, 77, 93 inappropriate antidiuretic
Pelvic pain, 4, 7 Regulatory issues (opioid hormone
Pharmacological treatment, therapy), 111–15, 114t Side-effect, 37, 42. See also
35–36, 36t, 41–44, 43t. See Relaxation techniques, 36, 105 drugs; specific medication;
also specific medications Relieving factors, 36t. See also specific side-effect
Pharmacy, 117f management strategies dental caries, 65
Phenol instillation, 105 Renal cell carcinoma, 15f dosage increase vs., 40
Phenytoin (Dilantin), 86t, 89t Rescue dose, 14f, 40f, 41–44, dry mouth, 65, 88t, 89
Physical exam, 25–26. See also 43t, 86. See also gabapentin, 89
history of patient end-of-dose failure intranasal route vs., 80
Pneumonia, 20 discontinuation of, 117f respiratory depression, 65
Polysling, 38, 39f Respiratory depression, 42, 65 tricyclic antidepressants, 88f
Portenoy, R. K., 1, 3 Responsiveness to analgesics, Site of pain, 25, 32f
Post-herpetic neuralgia, 89t 26, 52, 93 abdominal, 4
Precipitating event, 3t, 32f Risk assessment, 111–22, complex regional pain
Pregabalin, 86t, 89, 89t 114t, 116f, 117f, 118f, syndrome, 7
Pregnancy, 120 120t, 121f–122f. See also fibromyalgia, 7
Prescription, 42, 117f. See also assessment; reassessment headache, 7, 62t, 89
risk assessment procedure low back, 4, 15f, 17t
Pressure sores, 20 aberrant drug-related neuropathies, 7
Proactive vs. reactive behavior, 116–19, 118f neuropathy, 7, 86–90,
strategies (drug abuse opioid therapy, 111–22, 88f, 89t
risk), 117f 114t, 116f, 117f, 118f, pelvic, 4, 7
Procedural pain, 2, 13 120t, 121f–122f Sleep disorders, 20–21, 42, 62t
Prostheses, 38 agreement form, Sling, 38, 39f
Psychological assessment, 116f. 117f, 119–22, 120t, Social and societal
See also assessment 121f–122f complications, 20–21, 21f
Psychological complications, sedation, 42, 88t, 89 Somatic pain, 13, 19
129
20–21, 21f, 26 structuring therapy to Somnolence, 42, 62t
Psychotherapy, 117f reduce risk, 115–16, 116f Spontaneous pain, 13, 15f,
Public safety, side effects of Routes of medication 19, 21, 37
opioids vs., 42 administration, 41. See also Steroid. See also routes of
Pulmonary, intra-, route of specific medications medication administration
administration, 41, 43t, inhalation cortico-, 40, 105
76t, 81–82 (bronchopulmonary), 41, injection, 15
43t, 76t, 81–82 nonsteroidal anti-
muscular, 76t, 78 inflammatory drugs, 40,
Q nasal, 76t, 79–81 91–92, 92t
neuraxial drug delivery, Stigmatization, 20
Quality of life, 9, 20–21,
99–100 Stroke, pain from post-, 89t
21f, 25–26
oral transmucosal opioids, Subcutaneous route, 41, 43t,
after therapeutic
56–57, 58f 76t, 78–79
intervention, 27, 27f
patient’s acceptability Sublingual route, 43t
Quality of pain, 25. See
toward, 43t Sufentanil, 70–71
also pain
rectal, 43t, 76t, 77, 93 Supplemental medication,
subcutaneous, 41, 43t, 76t, 41–44, 43t
78–79 Surgery
R sublingual route, 43t BTP from, 8t
Radiation of pain, 25, 26 transdermal, 40, 40f, 51f, stabilization of tissues,
Radiation therapy, BTP 63t, 79 38, 38f
from, 8t venous, 76t, 78 Symptoms, 116f
Radiofrequency ablation, 105 Syndrome of inappropriate
Radiotherapy, 15 antidiuretic hormone
Reactive vs. proactive S (SIADH), 89
strategies (drug abuse Salivary-gland dysfunction, 56
risk), 117f Sedation risks, 42, 88t, 89
Reassessment procedure, Selective norepinephrine T
26–28, 27f, 116f. See also serotonin reuptake Tachycardia, 88t
assessment; risk inhibitors (NSRIs), 88 TCAs. See tricyclic
assessment Senna preparation, 16f. See antidepressants
recommendations for opioid also bowel function Temporal patterns of pain,
rotation, 37, 40, 40f Sexual dysfunction, 88t 14f, 25, 32f
INDEX
Temporal patterns of pain Transitory pains, 31 Volitional pain, 2, 13, 20

(continued ) Treatment agreement, 116f Vomiting, 42, 62t, 89. See also
breakthrough dose vs. Tricyclic antidepressants nausea
background dose, (TCAs), 37, 86t,
50–52, 51f, 66f 87–80, 88f
circadian variation, 19–20 Trigeminal neuralgia, 89t W
TENS. See transcutaneous Wellbutrin. See bupropion
nerve stimulation WHO analgesic guidelines.
Topamax. See topiramate U See World Health
Topiramate (Topamax), 86f Uncontrolled background Organization analgesic
Tramadol, 15, 86t pain, 14f, 31 guidelines
Transcutaneous nerve Urinary retention, 88t Work status, 20
stimulation (TENS), 36 Urine drug screen, 117f World Health Organization
Transdermal fentanyl patch, (WHO) analgesic
40, 40f, 63t guidelines, 90
background, vs. V
breakthrough oral Venlafaxine, extended release
morphine, 51f (Effexor), 86t Z
Transdermal route of Vertebroplasty, 105 Zeppetella, G., 3t, 32f
administration, 40, 40f, Visceral pain, 13, 19
51f, 63t, 79 Vision impairment, 88t, 89
130

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O A P L

The Diagnosis and

The Diagnosis and Treatment

Andrew N. Davies, FRCP

Executive Series Editor

Copyright © 2008 by Oxford University Press, Inc.

Published by Oxford University Press, Inc.

Library of Congress Cataloging-in-Publication Data

Fine, P. G. (Perry G.)

1 Incidence, prevalence, and characteristics 10

Box 1.1 Deﬁnitions of breakthrough pain

ence of “temporary ﬂares of severe or excruciating pain” in the previous

pain in selected populations of cancer patients rather than the prevalence of

Noncancer chronic pain

Incidence, prevalence, characteristics

Incidence, prevalence, characteristics

dome (in press).

Incidence, prevalence, characteristics

A Breakthrough Uncontrolled Baseline Pain

B Breakthrough Intermittent Pain

• Neuropathic pain: this type of pain results from injury or pathological

Reprinted with permission, Davies, 2006.

Box 2.2 Case history of patient with incident-type

Reprinted with permission, Davies, 2006.

Box 2.3 Case history of patient with end-of-dose failure

Reprinted with permission, Davies, 2006.

As a group, breakthrough pain is not a single entity but rather a spectrum of

Complications of breakthrough pain

been linked to the presence of mood disturbances (Hwang et al., 2003),

Table 2.2 Costs associated with breakthrough pain

patients with cancer pain. An international survey. Palliative Medicine. 2004;18:177–183.

Davies A. Cancer-Related Breakthrough Pain. Oxford, UK: Oxford University Press,

Gómez-Batiste X, Madrid F, Moreno F, et al. Breakthrough cancer pain: Prevalence and

• exacerbating factors (what makes the pain start or get worse?)

• response to other interventions (including use of “complementary and alter-

A Unidimensional Pain Assessment Scales

0-10 Numeric Pain Intensity Scale

patient-appropriate outcome measure(s) be used to assess treatment responses

f ) Does anything that you do make your pain worse?

Question 6 probes for the presence of breakthrough pain and question 7

Adapted with permission, Portenoy et al., 2006.

Patient name: Date:

Each pain should be marked on a separate sheet

Onset: Gradual [ ] Sudden [ ]

Precipitating event Pathophysiology

Pharmacological treatment of pain

to be co-analgesics, or anticonvulsants, which some consider to be ad-

A variety of nonpharmacological methods may be useful in treating break-

breakthrough pain. With attention to breakthrough pain, Hwang et al. (2003)

Table 4.1 Relieving factors of breakthrough pain in studies applying

Management of incident pain

• The symptomatic management of incident pain rarely involves modiﬁcation

Figure 4.1 Radiographs demonstrating surgical stabilization of a lytic bone metastasis.

Management of end-of-dose failure

NSAIDs, corticosteroids, anticonvulsants, etc.), switching to a different opioid

Box 4.1 Recommendations for opioid rotation

and Portenoy, 2007).

Table 4.2 Acceptability of different routes of administration

Bruera E, Fainsinger R, MacEachern T, Hanson J. The use of methylphenidate in patients

routes of administration of analgesia for breakthrough pain. Palliative Medicine.

Zeppetella G, Ribeiro MD. Pharmacotherapy of cancer-related episodic pain. Expert

Oral opioid analgesics

for the treatment of breakthrough pain