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VOLUME 32 䡠 NUMBER 16 䡠 JUNE 1 2014

JOURNAL OF CLINICAL ONCOLOGY R E V I E W A R T I C L E

Principles of Opioid Use in Cancer Pain


Russell K. Portenoy and Ebtesam Ahmed
All authors: Beth Israel Medical Center,
New York, NY. A B S T R A C T

Published online ahead of print at The management of pain is an essential aspect of comprehensive cancer care. Positive
www.jco.org on May 5, 2014.
outcomes can be achieved in most patients with widely available therapies. There is a broad
Authors’ disclosures of potential con- consensus that opioid-based pharmacotherapy is the first-line strategy for the treatment of
flicts of interest and author contribu-
moderate or severe chronic pain in populations with active disease, and treatment guidelines
tions are found at the end of this
article.
have been developed from the known pharmacology of these drugs, extant data, and
extensive clinical experience. This article describes the major opioid analgesics available for
Corresponding author: Russell K.
the treatment of cancer-related pain and reviews the key elements for safe and effective
Portenoy, MD, Department of Pain
Medicine and Palliative Care, Beth
prescribing, including selection of the best drug and route, approaches to titration and
Israel Medical Center, First Avenue at long-term administration of baseline and supplemental doses, rotation from one drug to
16th St, New York, NY 10003; e-mail: another in poorly responsive patients, and management of opioid risks.
rporteno@chpnet.org.

© 2014 by American Society of Clinical J Clin Oncol 32:1662-1670. © 2014 by American Society of Clinical Oncology
Oncology

0732-183X/14/3216w-1662w/$20.00
INTRODUCTION OPIOID PHARMACOLOGY
DOI: 10.1200/JCO.2013.52.5188

The prevalence of chronic pain in populations Opioids act by binding to receptors in three families:
with solid tumors is 15% to 75%, depending on mu, kappa, and delta. The mu receptor family has
the extent of disease, type of cancer, treatment numerous subtypes related to splice variants and
setting, and other factors.1 When the etiology of alleles of the opioid receptor mu-1 (OPRM-1) gene.
pain is related to active cancer of any type, and its This genetic variation helps explain the large intra-
intensity is moderate or severe, there is consensus individual and interindividual variation in the re-
that opioid therapy is first-line therapy.2,3 Despite sponse to the different mu agonist opioids.9
limited high-quality evidence,4 this consensus has Most opioid drugs are mu agonists, which may
evolved as an international standard of care that be divided into the pure agonists and the agonist-
has endured since it was codified by the WHO antagonists; the latter category includes mixed
more than a quarter century ago.5 Unfortunately, agonist-antagonist drugs and partial agonist drugs
(Table 3). Although cancer pain management has
neither this consensus nor the publication of
historically relied on the long-term use of the pure
evidence-based guidelines2 has corrected the
mu agonist drugs (Table 4), both the partial agonist
problem of undertreatment, which continues to
buprenorphine and centrally acting drugs with
be driven by the need for professional education
mixed mechanisms, specifically tramadol and tap-
about best practices6,7 and limited access to opi-
entadol, are sometimes used.
oid drugs in many parts of the world.
The use of opioid therapy requires a com-
Pure Mu Agonists
prehensive assessment that characterizes the
With the exception of meperidine, which has
pain and provides the information necessary an active metabolite that increases the risk of
for a plan that targets pain while addressing long-term therapy, any of the pure mu agonist
other problems4 (Table 1). Pain assessment al- opioids may be used to treat cancer pain. Patients
lows treatment that is individualized and balances who are opioid naive or have limited opioid
the benefits and burdens of various therapies in exposure are usually managed initially with a
relation to the broader goals of care.3,8 The ap- short-acting drug, either an immediate-release,
proach to analgesia may involve consideration of single-entity formulation, such as morphine or
disease-modifying therapy or any of a variety of hydromorphone, or a combination product con-
specific therapies (Table 2). Unrelieved moderate taining a nonopioid (usually acetaminophen)
or severe pain suggests that a trial of opioid ther- plus an opioid such as oxycodone or hydro-
apy or an adjustment in the current opioid regi- codone. Drugs from other classes, typically one of
men is needed. the mixed-mechanism drugs, also may be used,

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Principles of Opioid Use in Cancer Pain

Table 1. Key Objectives of the Pain Assessment in Populations With Table 2. Categories of Treatments for Pain Related to Cancer
Active Cancer
Category Type of Treatment
1. To characterize the multiple dimensions of the pain
Pharmacologic Opioid analgesics
Intensity
Nonopioid analgesics
Temporal features: onset, course, daily fluctuation, and breakthrough pains
Nontraditional analgesics (adjuvant analgesics)
Location and radiation
Interventional Injection therapies
Quality
Neural blockade
Provocative or relieving factors
Implant therapies
2. To formulate an understanding of the nature of the pain
Rehabilitative Modalities such as heat and cold
Etiology
Therapeutic exercise
Inferred pathophysiology
Occupational therapy
Pain syndrome
Hydrotherapy
3. To characterize the impact of the pain on quality-of-life domains
Therapies for specific disorders (eg,
Effect on physical functioning and well-being lymphedema)
Effect on mood, coping, and related aspects of psychological well-being Psychological Psychoeducational interventions
Effect on role functioning and social and familial relationships Cognitive-behavioral therapy
Effect on sleep, mood, vitality, sexual function Relaxation therapy, guided imagery, other
4. To clarify the extent of neoplastic disease, planned treatment, and types of stress management
prognosis Other forms of psychotherapy
5. To clarify the nature and quality of prior pain evaluation and treatments Neurostimulation Transcutaneous
6. To elucidate medical comorbidities Transcranial
7. To elucidate psychiatric comorbidities Percutaneous peripheral nerve and spinal
Substance use history cord/root stimulation
Depression and anxiety disorders Integrative (complementary Acupuncture
Personality disorders or alternative) Massage
8. To determine need for other palliative care interventions Movement therapies
Other symptoms Others
Distress related to psychosocial or spiritual concerns
Caregiver burden and concrete needs
Problems in communication, care coordination, and goals setting

Hydromorphone, oxymorphone, and oxycodone, like mor-


phine, are available in both immediate-release and modified-release
and some patients appear to benefit when a long-acting pure mu oral formulations. Oxycodone binds to both mu and kappa receptors,
agonist drug, such as modified-release morphine or transdermal but the clinical implications of this dual binding are uncertain. In
fentanyl, is used to initiate treatment.2 some countries, such as the United States, oxycodone has become the
The historical preference for codeine to initiate opioid therapy is largest contributor to a rising problem of prescription drug abuse.
waning, with new information about the risks associated with Although drug abuse is not prevalent among those with cancer pain, it
genomic variation in its metabolism.10 Codeine is a prodrug and has highlighted the need for appropriate risk management in all pop-
requires conversion to morphine via the CYP2D6 isoenzyme of the ulations and has led to the development of an abuse-deterrent formu-
P450 hepatic enzyme system. CYP2D6 is highly polymorphic, with lation that cannot easily be crushed or converted to an injectable.
more than 90 known allelic variants. Five percent to 10% of patients Other modified-release formulations are being developed or reformu-
inherit a slow metabolizer phenotype and may experience limited or lated with similar technology.
no therapeutic benefit from codeine. Patients who are ultrarapid me- Fentanyl is a highly lipophilic opioid and is used for cancer pain
tabolizers may develop a higher-than-expected morphine level, result- in transdermal and transmucosal immediate-release formulations.
ing in a potential overdose. The patch is indicated for chronic pain and the transmucosal formu-
Morphine is the prototypic opioid drug for severe cancer pain. lations are indicated for cancer-related breakthrough pain. Clinical
There is no evidence, however, that morphine offers superior safety or experience and limited data suggest that the transdermal formulation
efficacy when compared with any other pure mu agonist drug, and is preferred by some patients when pill burden is high, when a dosing
there is no way to predict whether a patient will have a more favorable frequency of 2 to 3 days would be beneficial, or when GI symptoms are
balance between analgesia and adverse effects with morphine or an- prominent.13,14 Comparative data from randomized trials are limited,
other opioid. Morphine is metabolized by the liver into two active however, and the superiority of this formulation has not been con-
metabolites, morphine-6-glucuronide (M6G) and morphine-3- firmed.15 The lowest dose patch is 12 ␮g/h and can be used in opioid-
glucuronide (M3G). M6G binds to the mu receptor and contributes to naive patients; titration can ensue by using larger doses and multiple
opioid effects during therapy; M3G is not an opioid and may cause patches. Specific risks of this formulation include increased drug ab-
toxicity, such as myoclonus and agitation.11 These metabolites are sorption when the patch is exposed to heat, either with fever or an
cleared by the kidneys, and in patients with kidney disease, metabolite external heating pad, and the possibility of local burns if the patch is
concentration may be high. If renal function is declining or fluctuat- worn during magnetic resonance imaging. It is prudent to remove the
ing, use of an opioid without active metabolites, such as fentanyl, or patch before the scan begins and replace it after.
one with lower concentration of renally cleared metabolites, such as Recent guidelines call for the use of methadone only by clinicians
hydromorphone, is preferable.12 who have acquired the skills for safe use of this opioid.2 This drug has

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Portenoy and Ahmed

Table 3. Classification of Opioid Drugs


Drug Type and Name Comment
Pure agonists
Codeine No clinically relevant ceiling effect to analgesia; as dose is raised, analgesia is achieved or dose-limiting side
Morphine effects supervene
Fentanyl Most commonly used for moderate to severe pain
Hydrocodone
Hydromorphone
Levorphanol
Meperidine
Methadone
Oxycodone
Oxymorphone
Agonist-antagonist
Mixed agonist-antagonists Ceiling effect for analgesia
Butorphanol
Pentazocine Some produce psychotomimetic side effects more readily than do pure agonist
Nalbuphine Potential to induce acute abstinence in patients with physical dependence to agonist opioids
Partial agonists
Buprenorphine Transdermal buprenorphine is available in a lower dose formulation in the United States and a higher dose
formulation in other countries and is used for cancer pain
Centrally acting drugs with opioid effects
Tramadol Analgesic mechanism is partially mu opioid and partially related to serotonergic and/or noradrenergic effects
Tapentadol Ceiling effect imposed by safe dosing; typically considered as an option for initial therapy in patients with
no prior opioid exposure
Pure antagonists
Methylnaltrexone Administered for prevention or reversal of opioid effects
Naloxone
Naltrexone
Alvimopan

been favored by some because of its low cost, potential for high reassessed, at minimum, early during dose titration and when the dose
efficacy, and perceived value in reducing the risk of abuse in patients exceeds 100 mg per day. Finally, methadone is a weak serotonin
predisposed to addiction. Unfortunately, increased use has become reuptake inhibitor and has a complex metabolism that involves both
associated with a high rate of serious adverse events, particularly in CYP3A4 and CYP2D6. As a result, drug-drug interactions are rela-
populations with noncancer pain. Safe administration of methadone tively likely,19 and dosing strategies to limit risk are particularly impor-
requires knowledge of its unique characteristics. tant when the patient is receiving other drugs.
Methadone pharmacokinetics are highly variable. The half-life
averages about 24 hours but ranges from less than 15 hours to more Partial Agonists
than 130 hours.16 Although the time to approach steady-state after Buprenorphine, a partial mu agonist with a high affinity for the
initiating or increasing the dose is 5 to 7 days in most patients, it can mu receptor, is available in some countries in sublingual formulations
extend to a few weeks in some. Plasma concentration slowly increases indicated for the treatment of opioid addiction and transdermal for-
until steady-state is approached, and monitoring after each dose ad- mulations indicated for chronic pain. Although experience with bu-
justment must be continued long enough to ensure that the patient prenorphine in the management of cancer pain is limited,15 there is
has stabilized on the higher dose. accumulating evidence that the transdermal formulation may be
Methadone potency can be much higher than anticipated in useful.20-22 The combination of convenient dosing (a 7-day patch)
patients already receiving a pure mu opioid agonist. This unantici- and some favorable pharmacologic characteristics, such as efficacy in
pated potency presumably is related to the D-isomer in the commer- the treatment of opioid addiction, a ceiling effect for respiratory de-
cially available racemate, which blocks the N-methyl-D-aspartate pression, and lesser effects on neuroendocrine function than pure mu
receptor and may have analgesic effects and reverse opioid tolerance. agonists, may support greater use in the cancer population.23
As a result of this potential for high potency, a switch to methadone In the United States, the transdermal formulation is available in
from another mu agonist drug requires a substantial reduction in doses of 5 ␮g/h, 10 ␮g/h, and 20 ␮g/h; higher doses, are available in
the calculated equianalgesic dose.17 Methadone also can prolong the other countries. As a partial agonist, administration of buprenorphine
heart-rate corrected QT (QTc) interval,18 and in most cases, a pre- to opioid-treated patients has the potential for inducing withdrawal if
treatment review of the electrocardiogram is needed to determine physical dependence is present; it is therefore prudent to limit treat-
whether there is a relative contraindication (QTc interval from 450 to ment to those who are opioid naive or are receiving a low-dose opioid
500 ms) or a strong contraindication (QTc interval ⬎ 500 ms) to regimen. Because of the high affinity of buprenorphine for the mu
treatment. Should therapy proceed, the electrocardiogram should be receptor, serious toxicity, should it occur, requires high and prolonged

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Principles of Opioid Use in Cancer Pain

Table 4. Pure Mu Agonist Opioid Drugs Commonly Used in the Management of Cancer Pain
Equianalgesic Dose

Amount Method of Half-Life Duration


Drug (mg) Administration (hours) (hours) Comments
Codeine 200 PO 2-4 4-6 Sometimes used for moderate pain but not preferred because of
unpredictability introduced by genetic differences in conversion of
prodrug (codeine) to active metabolite (morphine)
Hydrocodone 30 PO 3-4 4-8 Used for moderate pain in a combination product containing a nonopioid
Morphine 10 IM/IV/SC 2-3 3-4 Standard for comparison for opioids; multiple routes available
30 PO 2-3 3-6
Modified-release morphine 30 PO 2-3 8-12
Sustained- release morphine 30 PO 2-3 12-24
Hydromorphone 1.5 IM/IV/SC 2-3 3-4 Potency and high solubility may be beneficial for patients requiring high
7.5 PO 2-3 3-6 opioid doses and for subcutaneous administration
Modified-release 7.5 PO 2-3 24
hydromorphone
Oxycodone 20 PO 2-3 3-6 Available as a single entity or combined with aspirin or acetaminophen
Modified-release oxycodone 20 PO N/A 8-12
Oxymorphone 1 IM/IV/SC — 3-6
10 PR — 4-6
15 PO
Modified-release 15 PO N/A 12
oxymorphone
Levorphanol 2 IM/IV/SC 12-15 3-6 With long half-life, accumulation possible after beginning or increasing
4 PO 12-15 3-6 dose
Methadone 10 IM/IV/SC ⬍ 75-⬎ 130 6-8 May be far more potent than indicated in the table, presumably because
20 PO potency of available racemate is due in part to the D-isomer, an
NMDA antagonist that may reverse tolerance and augment analgesia;
with highly variable half-life, patients require greater vigilance for
weeks, until steady state has definitely occurred; also can prolong the
QTc interval, and in most cases, baseline ECG, and repeat ECGs
during dose titration, should be checked
Fentanyl 50-100 ␮g IV/SC 7-12 1-2 Can be administered as a continuous IV or SC infusion
Fentanyl transdermal system — N/A 48-72 per Refer to package insert for oral and parenteral medication equianalgesic
patch dosing guidelines. Not usually recommended for opioid-naive patients
in currently available doses. Not recommended for acute pain
Transmucosal fentanyl citrate — 7-12 1-2 New formulations indicated for the treatment of breakthrough pain.
formulations Varied products, including intraoral, buccal tablet, buccal patch,
sublingual, and intranasal formulations. Not recommended for opioid-
naive patients. Initial dose should always be one of the lowest doses
available, even if the patient is receiving a relatively high dose of a
scheduled opioid

Abbreviations: ECG, electrocardiogram; IM, intramuscular; IV, intravenous; N/A, not applicable; NMDA, N-methyl-D-aspartate; PO, orally; PR, per rectum; SC,
subcutaneous.

antagonist doses (usually naloxone) to achieve reversal. Buprenor- agents, extensive clinical experience, and a slowly expanding evi-
phine can also prolong the QTc interval, but this effect is less than that dence base.2,3,8,28
produced by methadone.24
Selection of Drug and Route
Mixed-Mechanism Drugs Opioid therapy usually is initiated in opioid-naive patients who
Tramadol and tapentadol are centrally acting analgesics whose are able to use oral medications. As noted, conventional treatment
mechanism of action depends on both mu agonism and monoamine usually relies on a short-acting, single-entity opioid or combination
(serotonin and norepinephrine) reuptake inhibition. There is no evi- product. There is no evidence for drug-selective effects that would
dence that tramadol is superior to pure mu agonists for cancer uniformly justify the selection of one drug over another, and the drug
pain,25,26 but nonetheless, it is widely used in some countries, partic- chosen is typically based on the experience of the clinician, availability,
ularly in patients who are opioid naive or have limited opioid expo- cost, and prior patient experience. The starting opioid dose usually is
sure. Tapentadol is a relatively new drug, and there is little published roughly equivalent to 5 to 15 mg of oral morphine every 3 to 4 hours.
experience in cancer pain.27 Both of these drugs have a ceiling dose Initial as-needed dosing allows rapid titration of the dose through
imposed by the risks associated with the monoaminergic mechanism. frequent administration or, if necessary, rapid dose escalation by in-
crements of 33% to 50%.
PRINCIPLES OF PRESCRIBING If pain persists and multiple daily doses are required, it is com-
mon to transition the patient to a single-entity, long-acting opioid
Guidelines for optimizing the outcome of opioid therapy in popula- formulation (Table 4). This change can reduce pill burden, potentially
tions with active cancer derive from the known pharmacology of these enhance adherence, and may facilitate dose titration by distinguishing

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Portenoy and Ahmed

between baseline pain and breakthrough pain. It simplifies the admin- There is no ceiling dose for the pure mu agonist opioids, and the
istration of a fixed scheduled (around-the-clock) regimen, which may dose may be increased until acceptable analgesia is produced or intol-
have the ability to prevent pain from occurring.29 erable and unmanageable adverse effects supervene. Most patients will
Although the choice of opioid usually is determined by expe- never require a daily dose higher than the equivalent of 300 mg of oral
rience, access, and cost, it may be reasonable to consider either morphine per day. It is therefore prudent to view the need for a dose
transdermal buprenorphine or methadone in those with a signifi- above this level as a signal to carefully reassess the causes of the pain
cant history of alcohol or drug abuse. The impact of doing so on and the possibility that other factors, such as comorbid psychiatric
adherence and other outcomes has not been evaluated in cancer disease or other sources of distress, are driving pain reports. This
populations, but the efficacy of these two drugs in the treatment of assessment may suggest that other types of interventions are needed.
opioid addiction offers at least theoretical reasons to offer one or If a favorable balance between analgesia and adverse effects is
the other to these patients. obtained, this is usually maintained for a prolonged time. If dose
Given the variation among patients, other strategies for drug escalation produces intolerable and unmanageable adverse effects,
selection are worthy of mention. Some patients do not prefer a switch however, the patient should be considered to be poorly responsive to
to a long-acting formulation. If the ability to exercise finer control over the current regimen. This outcome necessitates reassessment and a
dosing is valued by the patient, continuing treatment by using a change in the analgesic strategy. Common approaches include more
short-acting, single entity drug such as oral morphine should be con- aggressive adverse effect management, the addition of one or more of
sidered. Other patients who experience pain that is likely to persist and the adjuvant analgesics, and so-called opioid rotation.35
increase over time can be considered for initial treatment with a
long-acting, modified-release formulation.2 The challenge inherent in Opioid Rotation
rapidly titrating the dose of a drug that is administered once or twice The change from one opioid to which a patient is poorly respon-
daily can be overcome by concurrent prescription of a short-acting sive to another is usually accompanied by a better therapeutic
drug for breakthrough pain. outcome.36 The reasons for this phenomenon are unknown but pre-
Conventionally, the oral and transdermal routes are used for sumably relate to incomplete cross-tolerance between opioids that
chronic pain, and alternative routes are considered for specific rea- occurs at the multiple mu receptor subtypes possessed by each indi-
sons. The intramuscular route is not recommended because it is pain- vidual. A recent survey observed that 31% of ambulatory patients with
ful and provides no pharmacologic advantage, and the rectal route cancer pain underwent rotation, yielding benefit in more than
usually is considered only when the oral route is unavailable and two thirds.36
treatment duration will be limited. There is anecdotal experience with To switch from one opioid to another, the information contained
longer-term rectal treatment by using a modified-release oral formu- on a standard equianalgesic dose table must be consulted (Table 4).
lation.30 The potency of rectally administered opioids is believed to This information originates from a large number of relative potency
approximate oral dosing, but absorption is variable, and the relative studies that were well controlled but not representative of the usual
potency between oral and rectal doses may be higher or lower than situation encountered in practice.37 The patients in these studies typ-
expected. Accordingly, a switch from oral to rectal dosing is usually ically had little prior opioid exposure and evaluated outcomes after
accompanied by a reduction in the equivalent dose. single doses. These populations were not racially and ethnically di-
Intravenous and subcutaneous infusions are often used, particu- verse, and there are few data specific to the elderly or to children. Given
larly in the management of pain or dehydration in advanced illness. these differences between the study populations and patients, the
Patient-controlled analgesia can be accomplished with either. Contin- ratios in these tables must be adapted to ensure the safety of opioid
uous subcutaneous infusion usually involves insertion of a butterfly rotation. Consensus-based guidelines for opioid rotation incorporate
catheter under the skin of the chest wall or abdomen for a week or standard reductions in the equianalgesic doses and clinical judgment
more; any injectable drug or drug combination can be delivered in this (Table 5).38
way.31 Methadone is not preferred, however, because of the potential
for local skin reactions at the needle site. Hyaluronidase can be added Management of Breakthrough Pain
to the infusate to permit high-volume subcutaneous infusion for Breakthrough pain is a transitory severe acute pain that occurs on
hydration or to facilitate the delivery of relatively high drug doses.32-34 a background of chronic pain that is controlled by an opioid regimen.
Long-term intravenous therapy may be accomplished by using a pe- The phenomenon is highly prevalent and associated with adverse
ripherally inserted central catheter or an implanted central venous pain-related outcomes.39-41 The use of supplemental doses offered as
access device. needed in combination with a fixed scheduled opioid regimen, an
approach known as rescue dosing, has become a widely accepted
Dose Individualization strategy to manage breakthrough pain.
The success of opioid therapy requires individualization of the Guidelines for the treatment of breakthrough pain have been
dose by using a process of dose titration, by which safe increments in developed on the basis of expert opinion.42,43 Assessment of the break-
dose are undertaken to identify a stable dose associated with a favor- through pain itself is a key guideline and may suggest the value of a
able balance between analgesia and adverse effects. Titration is typi- primary therapy, such as radiation to bone metastases.
cally needed at the start of therapy and periodically thereafter. Rescue dosing is generally considered to be appropriate for
Conventionally, a dose increment is calculated as either 33% to 50% of most patients with chronic cancer pain who are receiving opioid
the average total daily dose during the prior few days or a daily amount therapy with a long-acting drug. The rescue dose may be a
equal to the average of the supplemental doses taken by the patient single-entity oral opioid formulation, such as immediate-
each day during the prior few days. release hydromorphone, morphine, oxycodone, oxymorphone,

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Principles of Opioid Use in Cancer Pain

Table 5. Guidelines for Opioid Rotation38


Step 1
Select the new drug on the basis of prior experience, availability, cost, and other factors.
Calculate the equianalgesic dose from the equianalgesic dose table.
If switching to any opioid other than methadone or fentanyl, identify an automatic dose reduction window of 25%–50% less than the calculated
equianalgesic dose.
If switching to methadone, the automatic dose reduction window is 75%–90%, rarely converting to methadone at a dose higher than 40 mg per day.
If switching to transdermal fentanyl, do not do an automatic dose reduction; use the calculated equianalgesic dose included in the package insert.
Select a dose closer to the lower bound (25% reduction) or the upper bound (50% reduction) of the automatic dose reduction window on the basis of a
judgment that the equianalgesic dose table is relatively more or less applicable to the characteristics of the regimen or patient.
Select a dose closer to the upper bound if the patient is receiving a relatively high dose of the current opioid, is not white, or is elderly or medically frail.
Select a dose closer to the lower bound otherwise and particularly if being switched to a different route using the same drug.
Step 2
On the basis of assessment of pain severity and other medical or psychosocial characteristics, increase or decrease the calculated dose by 15%–30% to
enhance the likelihood that the initial dose will be effective, or conversely, unlikely to cause withdrawal or adverse effects.
Assess response and titrate the dose of the new opioid regimen to optimize outcomes.
If a supplemental dose as needed is used, calculate this at 5%-15% of the total daily opioid dose and administer at an appropriate interval; transmucosal
fentanyl formulations are exceptions and always should be initiated at one of the lower doses.

or a transmucosal immediate-release fentanyl formulation. Res- treatment-limiting adverse effects are constipation and mental cloud-
cue dosing during long-term parenteral infusion typically is ing or somnolence. Constipation is highly prevalent and presumably
provided via a patient-controlled analgesia system. multifactorial in most patients.46 Prophylactic treatment is indicated
The transmucosal immediate-release fentanyl formulations are in those with predisposing factors. Management may involve an in-
indicated for cancer-related breakthrough pain. In the United States, crease in dietary fiber and hydration if appropriate and a simple oral
six formulations have been approved, including a lozenge, a sublin- regimen by using a surfactant, such as docusate, and either an osmotic
gual tablet, a nasal spray, an effervescent buccal tablet, a buccal film, agent (eg, a poorly absorbed sugar such as sorbitol or lactulose, or
and sublingual spray. All of these products are required by the US polyethylene glycol) or a stimulant cathartic (eg, bisacodyl or senna).
Food and Drug Administration to participate in a risk evaluation and In some countries, including the United States, new drug therapies
mitigation strategy (REMS), the purpose of which is to reduce the risk approved for opioid-induced constipation include peripherally acting
of unintentional overdose and abuse. The REMS mandates an online opioid antagonists, such as methylnalthrexone, and lubiprostone. The
education program for prescribers and registration of the patient, evidence for the efficacy of opioid antagonists for this indication
physician, and the dispensing pharmacist. is strong.47,48
Studies of the transmucosal immediate-release fentanyl formu- The mental clouding and somnolence caused by opioids often
lations have demonstrated efficacy in cancer-related breakthrough wanes over a period of days to weeks but can be persistent, especially if
pain, with onset of effect that is faster than that expected with oral other factors augment the effect. Limited supporting data suggest
opioid formulations.44 These studies have generally failed to find dose benefit from the coadministration of a psychostimulant, such as
proportionality between the effective dose of the transmucosal prod- methylphenidate or modafinil, for patients with persistent symp-
uct and the dose of the baseline opioid regimen, which suggests that toms.49 Other opioid-related adverse effects that are less common but
treatment with a transmucosal fentanyl formulation should be initi- well recognized include nausea or pyrosis, dry mouth, urinary reten-
ated at one of the lower available doses, irrespective of the baseline tion, itch, and myoclonus. Treatment strategies for these problems
dose.44 In contrast, rescue dosing with oral drugs has conventionally are empirical.8
assumed dose proportionality, with the rescue dose 5% to 15% of the Opioids also are associated with risks that may be occult for some
daily dose. time, ultimately presenting when severe enough to pose substantial
Few studies have compared the transmucosal immediate-release concern. For example, opioid use may worsen sleep apnea of any type
fentanyl formulations with other drugs, but those extant suggest that or cause a syndrome of opioid-induced sleep-disordered breathing.50
they may be more efficacious than oral morphine for breakthrough Evaluation should be considered when the clinical scenario suggests
pain.45 Given the cost of these newer formulations, however, and that interventions may be appropriate for addressing disturbed sleep
concern about unintentional overdose, their positioning relative to or the risks associated with sleep apnea.
oral drugs remains ill-defined. It is reasonable to consider one of these Neuroendocrine effects represent a similar situation. Opioid-
drugs in those patients who have not experienced benefit from an oral induced hypogonadism is a common problem and raises concern
rescue dose as a result of a mismatch in the timing of the pain and the about the potential for sexual dysfunction, accelerated bone loss,
onset of drug effect, and perhaps in those patients who are unlikely to mood disturbance, and fatigue.51 Currently, there is no evidence to
benefit from an oral drug because of the rapidity with which break- guide treatment in the cancer population, but carefully selected pa-
through pain appears and worsens. tients may be considered for hormonal therapy if the long-term ben-
efits are likely to exceed the risks.
Management of Adverse Effects Opioid-induced hyperalgesia also may be considered an adverse
Adverse effect management should be considered a necessary effect of opioid therapy. This phenomenon has been clearly demon-
element in the clinical approach to opioid therapy. The most common strated in animal models and may explain the anecdotal occurrence of

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Portenoy and Ahmed

escalating pain in the absence of worsening pathology during opioid by loss of control, craving, compulsive use, and continued use despite
therapy.52,53 Clinical observations suggest that opioid-induced hyper- demonstrable harm from the drug. Addiction may or may not be
algesia is rarely the driver of clinical pain, particularly when pain is accompanied by physical dependence, which is defined solely by the
related to a progressive illness, but the possibility should be considered potential for an abstinence syndrome after abrupt dose reduction or
whenever pain is escalating in the absence of worsening pathology, the administration of an antagonist, or by tolerance, which is defined
and particularly when tremulousness, confusion, or skin sensitivity by a decline in drug effect over time. Addiction is also different from
occur simultaneously. If suspected, it is reasonable to rotate the opioid drug abuse, which refers to the use of any drug outside of social norms.
or encourage the use of nonopioid strategy for pain control. In the medical setting, abuse behaviors also may be characterized by
other descriptors, such as aberrant drug-related behavior or nonad-
Risk Management herence behavior.58 Finally, diversion is a legal concept, referring to
Nonadherence, drug abuse, addiction, unintentional overdose, the distribution of a drug into the illicit marketplace.
and diversion of drugs into the illicit marketplace are known risks of All prescribing of opioids to ambulatory patients should be in-
opioids and other controlled prescription drugs.54 To manage opioid formed by a universal precautions strategy (Table 6).8,58 Physicians are
therapy safely, clinicians must have a working knowledge of these required to stop prescribing when there is a strong likelihood that
problems. The increase in prescription drug abuse that has occurred in diversion of prescribed drugs is occurring, but other problematic
the United States during the past decade underscores the need for behaviors can be managed as medical issues, based on the evaluation
basic skills in risk assessment and management and has led the US of current risk and benefit. Appropriate consultation with a specialist
Food and Drug Administration to implement a voluntary REMS in addiction medicine, pain medicine, or palliative care is reasonable
program for extended-release opioids.55,56 when drug-related behavioral problems are complex.
Risk management requires an understanding of key phenom- In conclusion, the consensus that opioid-based pharmacother-
ena.57 Addiction is a disease with a strong genetic basis characterized apy is the mainstay approach for the long-term treatment of chronic

Table 6. Principles of Risk Management During Opioid Therapy for Pain


Principle Goals Strategies Comment
Stratify risk To clarify the likelihood of future Consider higher risk if: All patients should undergo risk assessment
aberrant drug-related behavior ● History of alcohol or drug abuse and stratification
● Family history of alcohol or drug abuse Although many questionnaires have been
● Major psychiatric disorder developed to predict aberrant behavior or
Other factors that suggest risk: addiction, the clinical assessment is
● Cancer associated with heavy alcohol use or generally used in practice
smoking
● Current heavy smoking
● Younger age
● History of automobile accidents, chronic
unemployment, limited support system
Factors that may mitigate risk:
● Poor performance status
● Limited prognosis
● Active recovery program
Structure therapy Practices to match monitoring Strategies include The decision to implement one or more of
commensurate with risk and, when needed, ● Use of urine drug screening these strategies is a matter of clinical
with risk help patients maintain control ● Small amounts prescribed judgment
● No use of short-acting drugs
● Use of one pharmacy
● Pill counts at time of visit
● Required consultations
Assess drug-related Track drug use in tandem with Monitor Broad monitoring of outcomes is consistent
behaviors over all relevant outcomes ● Drug-related behavior (eg, need for early refills, with integration of pain management into
time obtaining multiple prescriptions) a palliative care model
● Pain relief
● Adverse drug effects
● Effect of drug on other outcomes
Respond to Clinician compliance with laws If the patient engages in aberrant drug-related behavior: Even advanced illness does not free the
aberrant drug- and regulations ● Reassess and diagnose (addiction, other clinician from the requirement of
related Identification of patient needing psychiatric disorder, pseudoaddiction, family compliance with laws and regulations
behaviors additional management issues, criminal intent)
● Stop prescribing if diversion into the illicit
marketplace is discovered; otherwise, consider
restructuring therapy to improve control and obtain
consultative help as needed
Document and Risk assessment and Document It is also valuable to openly discuss the
communicate management should be ● Plan for monitoring and education of patient and need for universal risk management with
viewed as integral to safe family other clinicians to reduce the risk of
and effective prescribing ● Monitoring of drug-related behavior on a regular stigmatizing patients
basis
● Response should aberrant behavior occur

Adapted.8

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Principles of Opioid Use in Cancer Pain

pain in populations with active cancer drives an imperative to follow with a “C” were compensated. For a detailed description of the disclosure
best practices. These practices are widely accepted, notwithstanding categories, or for more information about ASCO’s conflict of interest policy,
the ongoing need for more research to provide comparative and please refer to the Author Disclosure Declaration and the Disclosures of
Potential Conflicts of Interest section in Information for Contributors.
long-term data pertinent to current therapies and novel treatment Employment or Leadership Position: None Consultant
strategies for refractory pain. or Advisory Role: None Stock Ownership: None Honoraria: Russell K.
Portenoy, Grupo Ferrer Pharmaceuticals Research Funding: None
Expert Testimony: None Patents, Royalties, and Licenses: None Other
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS Remuneration: None
OF INTEREST

Although all authors completed the disclosure declaration, the following AUTHOR CONTRIBUTIONS
author(s) and/or an author’s immediate family member(s) indicated a
financial or other interest that is relevant to the subject matter under Conception and design: Russell K. Portenoy
consideration in this article. Certain relationships marked with a “U” are Manuscript writing: All authors
those for which no compensation was received; those relationships marked Final approval of manuscript: All authors

15. Tassinari D, Drudi F, Rosati M, et al: Transder- Management. New York, NY, Cambridge University
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