2010 Pain Practice - Buprenorphine

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Current Knowledge of Buprenorphine and Its

Unique Pharmacological Profile
ARTICLE in PAIN PRACTICE MAY 2010
Impact Factor: 2.36 DOI: 10.1111/j.1533-2500.2010.00378.x Source: PubMed
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Joseph Pergolizzi
Anna Maria Aloisi
114 PUBLICATIONS 1,294 CITATIONS
Universit degli Studi di Siena
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Sebastiano Mercadante
Paola Sacerdote
La Maddalena Cancer Center
University of Milan
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Retrieved on: 10 February 2016
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REVIEW ARTICLE
Current Knowledge of
Buprenorphine and Its Unique
Pharmacological Profile
Joseph Pergolizzi, MD*; Anna Maria Aloisi, MD, PhD;
Albert Dahan, MD, PhD; Joerg Filitz, MD; Richard Langford, MD, PhD;
Rudolf Likar, MD, FRCA**; Sebastiano Mercadante, MD;
Bart Morlion, MD; Robert B. Raffa, PhD; Rainer Sabatowski, MD;
Paola Sacerdote, PhD***; Luis M. Torres, MD, PhD;
Avi A. Weinbroum, MD
*Johns Hopkins University, Baltimore, Maryland, U.S.A.; University of Siena, Siena, Italy;
Leiden University Medical Center, Department of Anesthesiology, Leiden, The Netherlands;
Department of Anesthesiology, University Hospital Erlangen, Erlangen, Germany; St

Bartholomews Hospital, London, U.K.; **Pain Clinic, General Hospital Klagenfurt,
Klagenfurt, Austria; La Maddalena Cancer Centre, Palermo, Sicily, Italy; University
Hospitals, Leuven, Belgium; School of Pharmacy and School of Medicine, Temple
University, Philadelphia, Pennsylvania, U.S.A.; Department of Anesthesiology and Intensive
Care, University Hospital Carl Gustav Carus, Dresden, Germany; ***Department of
Pharmacology, University of Milan, Milan, Italy; Anesthesiology, Intensive Care and Pain
Unit Department, University Hospital, Puerta del Mar, Cadiz, Spain; Post Anesthesia Care
Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
Abstract: Despite the increasing clinical use of transdermal buprenorphine, questions have persisted about the
possibility of a ceiling effect for analgesia, its combination
Address correspondence and reprint requests to: Joseph Pergolizzi,
MD, 4840 Sycamore Drive, Naples, FL 34119, U.S.A. E-mail: jpjmd@
msn.com.
Disclosure: Dr. Pergolizzi is a consultant for Grnenthal GmbH. There
was industry funding involved in the Expert meeting sponsored by Grnenthal GmbH, Aachen, Germany and editorial support.
Submitted: December 1, 2009; Revision accepted: February 7, 2010
DOI. 10.1111/j.1533-2500.2010.00378.x
2010 World Institute of Pain, 1530-7085/10/$15.00

Pain Practice, Volume 10, Issue 5, 2010 428450
with other m-opioid agonists, and the reversibility of side

effects. In October 2008, a consensus group of experts met
to review recent research into the pharmacology and clinical use of buprenorphine. The objective was to achieve consensus on the conclusions to be drawn from this work. It
was agreed that buprenorphine clearly behaves as a full
m-opioid agonist for analgesia in clinical practice, with no
ceiling effect, but that there is a ceiling effect for respiratory depression, reducing the likelihood of this potentially
fatal adverse event. This is entirely consistent with receptor
theory. In addition, the effects of buprenorphine can be
completely reversed by naloxone. No problems are encountered when switching to and from buprenorphine and
other opioids, or in combining them. Buprenorphine
Key Words: opioids, buprenorphine, analgesia, ceiling

effect, reversibility, safety, novel signaling mechanism,
antihyperalgesia, neuropathic pain
INTRODUCTION
The launch of the transdermal formulation in 2001 saw
a resurgence of interest in the use of buprenorphine to
treat chronic moderate to severe cancer pain and nonmalignant pain which does not respond to non-opioid
analgesics. However, questions persisted about its use in
clinical practice as a result of misinterpreted animal
data,1 particularly regarding the possibility of an analgesic ceiling effect, its combination with other m-opioid
agonists, and the reversibility of side effects. Open questions also remained about buprenorphines dose
response curve for other pharmacodynamic parameters,
its efficacy in neuropathic pain, equipotency ratios,
interaction with the immune and hormonal systems, and
suitability for patients with impaired renal function.
Scientific and clinical research has not only aimed to
increase knowledge about buprenorphine, but also to
confute lingering myths about the drug by providing
scientific data and statistical evidence. Open questions
have been systematically investigated by preclinical
experiments, volunteer studies, and clinical trials which
addressed the efficacy, safety and tolerability of the
compound. A strong body of evidence has now been
accumulated which supports its use. For example, the
original registration data included a meta-analysis of
three randomized, placebo-controlled, double-blind
studies in 435 patients, 55% with cancer pain.26 Over a
15- to 16-day period, a clear doseresponse effect was
observed, based on the reduction in pain intensity and
consumption of rescue medication. There were also
dose-dependent differences with respect to placebo,
both for the single studies and the pooled database.
Long-term data are essential to determine the performance of an analgesic in the management of chronic
pain. Therefore an open-label, uncontrolled, follow-up
study in patients from the the previous clinical trials was
Pain intensity
Pain intensity (NRS)
exhibits a pronounced antihyperalgesic effect that might

indicate potential advantages in the treatment of neuropathic pain. Other beneficial properties are the compounds
favorable safety profile, particularly in elderly patients and
those with renal impairment, and its lack of effect on sex
hormones and the immune system. The expert group
agreed that these properties, as well as proven efficacy in
severe pain and favorable tolerability, mean that buprenorphine can be considered a safe and effective option for
treating chronic cancer and noncancer pain.
10
3
2
1
1
14
Buprenorphine sl 0.2 mg (tab/d)
Current Knowledge of Buprenorphine 429
Use of co-medication
1.8
1.3
1.0
0.7
0.4
Treatment duration (days)

Buprenorphine TDS 70 g/h
Placebo
14
Treatment duration (days)

(n=94)
(n=94)
Figure 1. Pain intensity and rescue medication in patients with

severe cancer pain (Poulain et al.).8
undertaken, to obtain data on the efficacy and tolerability of long-term transdermal buprenorphine treatment
in patients with chronic persistent pain.7 The maximum
study participation was 3.4 years in cancer patients
(n = 134) and 5.75 years in noncancer patients
(n = 105). Pain relief was at least satisfactory in 90% of
the subjects, clearly demonstrating that transdermal
buprenorphine is effective against cancer and noncancer
pain.7 The buprenorphine patch was generally well tolerated; the most common systemic adverse drug reactions were nausea (9.2%) and dizziness (4.6%), whereas
the most common local reactions were erythema
(12.1%) and pruritis (10.5%).7
Strong opioids are recommended for treating severe
pain in the advanced stages of cancer. The efficacy
and safety of high-dose transdermal buprenorphine
(70 mg/h) has been compared with placebo in a randomized, double-blind, placebo-controlled, parallel group
study in patients with severe cancer pain.8 Opioidtolerant patients requiring strong opioids (90150 mg/
day oral morphine equivalents) were switched to
transdermal buprenorphine during a 2-week run-in
phase. Those who could be stabilized on this regime
were randomized to receive either a transdermal
buprenorphine or placebo patch for a 2-week maintenance phase. Rescue medication was allowed as necessary. Response was defined as a pain intensity of 24 on
an 11-point numerical rating scale (NRS) and a mean
daily buprenorphine sublingual tablet intake of 22
tablets. The proportion of responders was significantly
higher in the active treatment group (P = 0.0003) and
this was supported by a consistently lower pain intensity
and requirement for rescue medication in this group (see
Figure 1).8 The buprenorphine patch was well tolerated,
with a comparable incidence of adverse events in the
two groups, showing that it is safe as well as effective in
patients with severe cancer pain.8
430 pergolizzi et al.
A substantial body of evidence has also been collected on the efficacy and safety of transdermal
buprenorphine under routine clinical conditions.9 A
postmarketing surveillance survey gathered data on
13,179 patients who had been prescribed transdermal
buprenorphine in accordance with its Summary of
Product Characteristics, from hospitals, outpatient
clinics, and general practitioners in Germany. A total of
3,690 (28%) suffered from cancer pain and 9,489
(72%) from noncancer pain, most frequently musculoskeletal disorders and neuropathy. Buprenorphine
patches provided effective, sustained, and dosedependent analgesia in patients with both cancer and
noncancer pain, irrespective of their age or pain syndromes.9 Only 6% of patients rated their pain relief as
good or very good at the initial assessment; this
increased to 71% at the first follow-up visit and 80% at
the final assessment. Fewer than 5% of subjects discontinued treatment owing to unsatisfactory pain relief.
The tolerability profile was typical of an opioid and did
not vary with either the patients age or cause of pain
(cancer or noncancer).
No evidence emerged of any previously unknown
side effects and there was no clinically relevant development of tolerance.9
By October 2008 a wide range of projects had been
completed, and a multidisciplinary group of experts in
pharmacology, toxicology, pain management, and anaesthesia met in Berlin to review and critically evaluate
the outcomes, with the object of achieving consensus on
the conclusions to be drawn from this work.
PHARMACOLOGY
New Insights into the Pharmacology of Buprenorphine
The terminology used to characterize agonist action in
preclinical studies must be carefully applied according
to the fundamental concepts of receptor theory.10 The
terms intrinsic activity, efficacy, and full- or
partial- agonists are especially important; failure to
apply or interpret these terms correctly can lead to erroneous prediction or perception of a compounds clinical
utility. For example, buprenorphine has sometimes been
labeled a partial agonist based on the results of early
preclinical studies, but more recent work demonstrates
that it is inappropriate to regard buprenorphine as a
partial agonist on the basis of preclinical data, or to
predict a ceiling effect in the clinical setting.10
Affinity characterizes the interaction between drug
and receptor. Intrinsic activity involves the binding of
the drug to the receptor and the production of a second

messenger (G-proteins in the case of opioids). In addition to the intrinsic activity, efficacy characterizes the
level of the effect, or endpoint. Efficacy is therefore a
property of the drug plus the specific system and may
vary according to the individual tissue, species or endpoint involved (eg, analgesia vs. respiratory depression).
Thus terms such as partial agonist are not a property
of the drug and only have validity as a functional
descriptor, which depends upon the conditions in which
the drug is being used.
Buprenorphine has a high affinity for the m-opioid
receptor11 and low intrinsic activity in test tube assays,12
and thus displays a ceiling effect in some animal models
of analgesia and in humans with respect to respiratory
depression. Owing to a misunderstanding of the fundamental difference between intrinsic activity and efficacy,
it was mistakenly extrapolated from these findings that
buprenorphine is a partial agonist that should display a
ceiling effect with respect to analgesia in humans.
However, receptor theory precludes such extrapolation
from one endpoint to another, and many studies indicate
that buprenorphine does not act as a partial agonist at
the m-opioid receptor. In animal models buprenorphine
has been shown to produce a full analgesic effect13 that
is dependent upon the intensity of the stimulus.10 In
addition, radio-labeling studies in humans have demonstrated that full analgesia is produced at less than 100%
occupancy of the m-opioid receptor14the definition of
a full agonist. As the presence or absence of a ceiling
effect depends upon the intensity of the stimulus and the
specific endpoint chosen, it is perfectly possible for one
endpoint (eg, respiratory depression) to exhibit this
effect, but not another (eg, analgesia).15
A recent study in opioid-nave male mice investigated
the action of buprenorphine at the level of both the
spinal cord and the brain in comparison with morphine
and fentanyl.16 The pain models chosen were the
acetylcholine-induced abdominal irritant test (MAIT)
described by Collier et al.17 and the water tailimmersion/flick test (TI) described by Janssen et al.18
When administered subcutaneously (s.c.), all three drugs
induced dose-related antinociception that reached
100% in both tests. The doseresponse curve of
buprenorphine was biphasic in the TI test, increasing
below 10 mg/kg and decreasing above 10 mg/kg10 but
not in the MAIT test.
Subcutaneous buprenorphine was antagonized by
intraperitoneal (i.p.) and spinal (intrathecal [i.t.]) naloxone, butunlike morphine and fentanylnot by
supraspinal (intracerebroventricular [i.c.v.]) naloxone.16

This indicates that there are both naloxone-sensitive and
naloxone-insensitive components to its action and, furthermore, implies that buprenorphine produces an
opioid effect at the level of the spinal cord but an additional effect in the brain. Pretreatment with pertussis
toxin antagonized buprenorphine, morphine and fentanyl when toxin was administered i.t. When toxin was
administered i.c.v., however, morphine and fentanyl
were antagonized but there was no significant effect on
buprenorphine.16 The nociceptin/orphanin-FQ (NOP)
receptor antagonist JTC-801 (1 mg/kg) potentiated both
a low dose (ie, on the ascending limb) and a high dose
(ie, on the descending limb) of the s.c. buprenorphine
doseresponse curve (1 and 30 mg/kg, i.p., respectively).
Nociceptin enhanced the antinociceptive effect of s.c.
buprenorphine when given i.t., but not when given i.c.v.,
whereas there was no effect on morphine and fentanyl
via either route.16 The analgesia produced by s.c.
buprenorphine was antagonized by Gz antisense i.c.v.,
but not when administered i.t. Morphine and fentanyl
were unaffected.16
These results suggest that buprenorphines opioid
action is mainly at the level of the spinal cordnot the
brainand is different from those of morphine and
fentanyl. Moreover, buprenorphine-induced antinociception in the brain is not mediated only via the usual
(naloxone- and pertussin toxin-sensitive) opioid receptors or by NOP receptors.16 To investigate this additional signaling pathway in the brain further, the effect
of the Ser/Thr protein phosphatase inhibitor okadaic
acid on the antinociceptive action of buprenorphine,
morphine, and fentanyl was compared. The i.c.v.
administration of okadaic acid had no effect on the
analgesia produced by s.c. morphine and fentanyl. In the
case of s.c. buprenorphine, however, low doses of i.c.v.
okadaic acid significantly (P < 0.05) decreased antinociception, but high doses significantly (P < 0.05) increased
it; ie, the effect was biphasic, with low dose attenuation
and high dose enhancement.16 This supports the idea
that there is a mechanistic difference between the
supraspinal signaling pathway of buprenorphine and
those of morphine and fentanyl.
These recent findings are consistent with previous
research. For example, the biphasic doseresponse curve
produced by buprenorphine in some antinociceptive
tests is compatible with the dominant spinal site/
mechanism of antinociception and less powerful brain
site/mechanism described here.16 The present study also
revealed that there is a naloxone-insensitive brain site/
mechanism which contributes to antinociception,

whereas opioid-induced respiratory depression is
known to be mediated via m-opioid receptors.19 The
clinical significance of these findings is that they could
explain why buprenorphine displays a ceiling effect for
respiratory depression but not for analgesia.20 In addition, the primarily spinal site of m-opioid agonism not
only accords with the clinical profile of buprenorphine,
but suggests that analgesia can be achieved with a
reduced effect on the brain, suggesting a lower abuse
potential than other opioids.
Buprenorphine and Hyperalgesia

Experimental models of pain in humans not only produce
pain and thermal hyperalgesia at the site of injury, but
also punctuate hyperalgesia and allodynia in the noninjured surrounding area.21 Similar patterns are observed in
neuropathic and postoperative pain, suggesting common
underlying mechanisms for their induction and maintenance.22 Pain reduction by opioids largely results from
the activation of opioid-receptors in the central nervous
system (CNS) at both spinal and supraspinal levels, but a
lack of antihyperalgesic properties in some clinical
studies suggests that opioids have only a limited ability to
prevent central sensitization of the pain pathway.23
Moreover, experimental studies and clinical observations
suggest that pure m-opioid receptor agonists may contribute to the induction of hyperalgesia.24 Therefore, different mechanisms have been proposed for opioid-induced
analgesia and antihyperalgesia, possibly with different
pharmacodynamics.24 In support of this hypothesis,
Koppert et al. have demonstrated differences between
the analgesic and antihyperalgesic effects of three agents:
alfentanil reduced pain and hyperalgesia during infusion;
ketamine produced brief but effective analgesia and more
prolonged antihyperalgesia; whereas the local anaesthetic lidocaine resulted in moderate analgesia but longlasting antihyperalgesia.22
The time course of analgesic and antihyperalgesic
effects of sublingual (s.l.) and intravenous (i.v.)
buprenorphine have been investigated in an experimental human model, using intradermal electrical stimulation to induce ongoing pain and secondary mechanical
hyperalgesia.25 In 15 volunteers, the current was gradually increased to produce a pain rating of 56 on an
11-point NRS (0 = no pain and 10 = maximum tolerable pain), and was then kept constant for the duration
of the experiment.25 This approach has been proved to
provoke stable areas of secondary hyperalgesia to punc-
Figure 2. (A) Analgesic and (B) antihyperalgesic effects after sublingual and
intravenous buprenorphine (Koppert
et al.).28
tate stimuli and touch, caused by the activation of primarily mechano-insensitive (silent) C-nociceptors.26
In this randomized, double-blind, placebocontrolled, cross-over study, pain intensity and the area
of secondary hyperalgesia were repeatedly assessed
before and up to 150 minutes after administration of
one of the following: 0.15 mg of i.v. buprenorphine and
s.l. placebo pill, 0.2 mg of s.l. buprenorphine and i.v.
saline 0.9%, or i.v. saline 0.9% and s.l. placebo pill as a
control.25 Three separate treatment trials, at least 2
weeks apart, were performed. For both routes of administration, antihyperalgesic effects were more pronounced than analgesic effects. The decreases in pain
ratings were 26 1 5% for i.v. and 10 1 6% for s.l.
administration. The corresponding reductions in hyperalgesic areas were 66 1 9% and 43 1 10%, respectively
(see Figure 2), and these lasted significantly longer.25
This is in direct contrast to the intravenous administration of pure m-opioid agonists in the same model, in
which analgesic effects were stronger than antihyperalgesic ones.22,27 In the placebo group, the intensity of pain
decreased to about 42% of the initial level after 3 hours.
This had been observed in previous studies and was
found to be reversed by naloxone, indicating that the
electrical stimulation induces a release of endogenous
opioids.28
The mechanism for the pronounced antihyperalgesic
effect of buprenorphine is not yet understood. Its receptor subtype selectivity, binding characteristics and coupling to G-proteins are quite different from typical
m-opioid agonists.2931 Systemic opioids increase the
spinal expression of dynorphin, an endogenous
k-receptor agonist which has been shown to promote
Figure 3. Possible antihyperalgesic mechanism of buprenorphine.
hyperalgesic pain states and antinociceptive tolerance.32

Buprenorphine might counter these mechanisms by its
k-receptor antagonist properties. It has also been postulated that its antihyperalgesic action is mediated via the
blockage of voltage-gated sodium channels, as shown in
Figure 3. The ability to block sodium channels, which is
the mechanism of action of local anesthetics such as
lidocaine, has also been demonstrated for sufentanil,
fentanyl and tramadol, but does not parallel the opioid
potency of the individual compounds.33
In the clinical situation, this particular property of
buprenorphine confers definite benefits. If a patient is
receiving a pure m-opioid agonist and pain control is
becoming less effective, it may be difficult to determine
whether this is caused by the development of tolerance,
requiring higher doses or opioid rotation, or to opioidinduced hyperalgesia, requiring the discontinuation of
opioids. Where the patient is receiving buprenorphine
the clinician does not face this dilemma, owing to its
intrinsic antihyperalgesic characteristics.
SAFETY PHARMACOLOGY
Buprenorphine-Induced Respiratory Depression
and Reversibility
Opioids are generally well-tolerated. However, the
development of respiratory depression is a particularly
important adverse event, because of the possibility of a
fatal outcome. Although all potent opioid analgesics act
via the m-opioid receptor system, they differ in how they
affect respiratory control.34 The analgesia and respiratory depression induced by fentanyl and buprenorphine
have been compared by a team based at Leiden University, in order to quantify the balance between efficacy
and safety. As part of this project, the ability of naloxone to reverse buprenorphine-induced respiratory
depression was measured.
Fentanyl is widely used for the treatment of chronic
pain. It is a full agonist at the m-opioid receptor, with
fast receptor association/dissociation kinetics and no
active metabolites. Buprenorphine has previously been
classified as a partial agonist at the m-opioid receptor
with slow receptor association/dissociation kinetics.
Approximately 10% is converted to the active metabolite norbuprenorphine, but this plays only a minor role
in buprenorphines respiratory effect, owing to its lower
potency and lower receptor affinity.35,36 Respiratory
depression and analgesia were recorded after the administration of these opioids in rats and human volunteers,
as there is evidence that the m-opioid receptor functions
almost identically in both species.37
In rats, both opioids were infused i.v. over 20

minutes, and the arterial partial pressure of carbon
dioxide (PCO2) was subsequently measured up to 20
minutes after the start of fentanyl infusion and up to
390 minutes after the start of buprenorphine infusion.38
Doses ranged up to 3,000 mg/kg of buprenorphine and
up to 90 mg/kg of fentanyl. The relationship between
PCO2 and dose was linear for fentanyl, with maximum
respiratory depression after 20 minutes (maximum
PCO2 = 8 kPa). By contrast, buprenorphine showed
a modest, nonlinear effect on PCO2 (maximum
value = 5.5 kPa) with a ceiling effect at doses above
1.4 mg/kg.38 In a randomized, double-blind, placebocontrolled study in healthy human volunteers, the
opioids were infused i.v. over 90 seconds at doses up to
7.1 mg/kg for fentanyl and 8.6 mg/kg for buprenorphine.
Minute ventilation was then recorded at a fixed endtidal PCO2 of 7 kPa for 7 hours. Fentanyl produced a
dose-dependent depression of minute ventilation with
apnoea at doses of 2.9 mg/kg and above, with a consistent time to peak effect of 4.8 minutes. The depression
of minute ventilation caused by buprenorphine levelled
off at doses of 3.0 mg/kg and above (see Figure 4). None
of the subjects receiving buprenorphine developed
apnoea and the dose-independent time to peak effect
averaged 117 minutes.38
Using the same methodology to measure respiratory
depression in healthy human volunteers, the effects of
two different doses of intravenous buprenorphine
(0.2 mg per 70 kg and 0.4 mg per 70 kg) on respiratory
Figure 4. Doseresponse relationships

for (A) fentanyl and (B) buprenorphine
(Dahan).34
Figure 5. Therapeutic utility of buprenorphine and fentanyl

(Yassen et al.).39
depression and analgesia were compared.20 Experimental pain was induced using transcutaneous electrical
stimulation and a gradually increasing current. Pain tolerance was measured at regular intervals before and up
to 8 hours after drug infusion. Ventilation showed a
rapid, dose-independent decline after drug infusion,
reaching a peak effect after 150180 minutes. The
0.2 mg dose produced a short-lived analgesic effect with
a maximum pain tolerance of 6.7 mA (29% above baseline current) after 75 minutes. By contrast, the longlasting analgesia produced by the 0.4 mg dose was
significantly higher, peaking at 23.8 mA (160% above
baseline current) after 130 minutes. The implication is
that buprenorphine displays a ceiling effect for respiratory depressionie, it acts as a partial agonist for this
endpointbut not for analgesia over the dose range
tested.20 The comparison between buprenorphine and
fentanyl, taking into account their analgesic and respiratory effects, can be expressed in terms of their therapeutic utility, as shown in Figure 5. This clearly shows
the greater safety margin offered by buprenorphine.39
It was originally believed that the strong affinity of
buprenorphine for the m-opioid receptor, and the slow
association/dissociation kinetics, would preclude its
effects being reversed by naloxone, but this has recently
been shown to be incorrect. In 21 opioid-nave volunteers, 0.2 mg/kg of buprenorphine was administered as
a continuous intravenous infusion for 1 hour.34 After 30
minutes from the start of infusion, naloxone (0.55 mg)
was infused for 30 minutes, and the effect on breathing
assessed for a further 30 minutes afterwards. Low-dose
naloxone (0.5 mg) had little discernible effect, but
2.0 mg produced a full reversal of respiratory depression, with ventilation returning to its baseline level.34
Thus full reversal can be achieved by a continuous infusion of sufficiently high dosages of naloxone.
Another study found that higher doses of naloxone
(5 mg7 mg) caused a decline in reversal activity, as the
naloxone/buprenorphine doseresponse relation is bellshaped.40 Taking this into account, an infusion scheme
consisting of a naloxone bolus of 2 to 3 mg, followed by
a continuous infusion of 4 mg/h, was developed. This
achieved full reversal of the respiratory depression
caused by 0.2 mg to 0.4 mg of buprenorphine within
4060 minutes.40 The high affinity of buprenorphine for
the m-opioid receptor explains why relatively high doses
of naloxone are needed before reversal occurs. A continuous infusion is then required to maintain the supply
of naloxone to opioid receptor sites in the brain; otherwise, the naloxone bolus is rapidly washed out and
eliminated from the body.40 Furthermore, to remove
higher doses of buprenorphine requires not higher doses
of naloxone but a longer period of infusion.40
The respiratory depression produced by buprenorphine, and its reversibility using naloxone, has also been
measured in a double blind, double dummy, randomized, placebo-controlled, parallel group study (data on
file, Langford). Patients (n = 84) under general anesthesia, breathing spontaneously, were randomized to
receive normal saline (5 mL), i.v. morphine (0.1 mg/kg),
i.v. buprenorphine (3 mg/kg) or i.m. buprenorphine
(0.85 mg/kg). Patients were connected to a wet wedge
spirometer.41 The threshold for respiratory depression
was a >33% decrease in respiration rate or an end tidal
CO2 increase of >1.5 kPa within the first 20 minutes.
Those patients who experienced respiratory depression
were further randomized to receive either naloxone
(2 mg followed by 1 mg in 50 mL of normal saline over
30 minutes) or placebo (data on file, Langford).
Figure 6 shows clearly that no respiratory depression
was seen in patients receiving either placebo or
0.85 mg/kg of i.m. buprenorphine. Plasma concentrations of i.m. buprenorphine, measured at 5, 10 and 15
minutes after administration, were broadly equivalent
to those produced by the 35 mg/h buprenorphine patch,
indicating that normal doses of transdermal buprenorphine do not produce clinically relevant respiratory
depression. Naloxone fully reversed the respiratory
depression induced in all the i.v. morphine patients (not
shown). In the i.v. buprenorphine patients, naloxone
produced a statistically significant improvement in
minute ventilation after 5 minutes (data on file, Lang-
Figure 6. Reversal of buprenorphine-induced respiratory depression by naloxone.
ford). Although the reversal of respiratory depression

was incomplete, it may be regarded as clinically meaningful and it supports the need for higher naloxone
doses.
The Influence of Buprenorphine on
Immune Parameters
The immunomodulatory effects of opioids are currently
generating considerable interest, because of concerns
that these may influence the outcome of surgery and
various disease processes, including bacterial and viral
infection and cancer.42,43 Morphine has been shown to
decrease interleukin-2 (IL-2)44 and interferon-g (IFNg)45,46 production, strongly inhibiting adaptive immunity, and also to down-regulate natural killer (NK)
cells47,48 and several macrophage functions.45,49 Both the
presence and regulated expression of opioid receptors
have been demonstrated in cells involved in host defence
and immunity,50,51 with the m-opioid receptor playing a
pivotal role.5254 Moreover, binding to m-opioid receptors in the brain activates the descending pathways of
the hypothalamo-pituitary-adrenal (HPA) axis, eliciting
the production of immunosuppressive glucocorticoids52,55 and the sympathetic nervous system, causing
the release of catecholamines in close proximity to
immune cells.56 There is general agreement that morphine suppresses the effector function of both innate
and adaptive immune functions, acting directly on
immune cells and also via activation of central receptors. Moreover, the intracellular pathways modulated
by morphine are currently being elucidated.43,45,46
However, it is becoming increasingly apparent that
not all opioid drugs have similar immunosuppressive
properties. This is clinically important because of the
potential consequences for patients, particularly those

whose immune systems may already be impaired.
Early work performed in experimental animals and
humans indicated that, unlike morphine, tramadol did
not affect immune responses. It was preferable to morphine at equianalgesic doses as tramadol demonstrated
intrinsic immunostimulatory activity.57,58 The immunological profile of fentanyl appears similar to that of
morphine.43,59
Investigation of the immune effects of buprenorphine
reveals that these differ markedly from those of morphine and fentanyl.6064 Work in animal models suggests
a comprehensive safety profile for buprenorphine when
administered both acutely and chronically. Following
the acute injection of equianalgesic doses of buprenorphine and morphine into the mesencephalic periaqueductal gray matter of rats, buprenorphine did not
alter splenic NK cell activity or T-cell and macrophage
function, whereas morphine significantly suppressed
these parameters.61,63 Similar results have been obtained
in mice when the chronic administration of buprenorphine was compared with morphine and fentanyl.62,64
Continuous infusion of fentanyl has been shown to suppress NK activity, lymphoproliferation and cytokine
production in mice, whereas equianalgesic doses of
buprenorphine did not affect immune responses.64
The overall effect of opioid drugs on the immune
system depends not only on the intrinsic immunosuppressive properties of the specific agent, but also on the
prevention of pain and neuroendocrine activation. Pain
itself is a physical and psychological stressor that causes
activation of the HPA axis and the sympathetic nervous
system, leading to an alteration of immune responses. In
a rat model of peri-surgical pain, experimental surgery
significantly raised corticosterone levels, suppressed NK
activity and increased metastasis of the NK-sensitive
tumour MADB106.58,60 Morphine and fentanyl stimulated the HPA axis, decreased NK activity and did not
prevent surgery-induced metastasis. An equianalgesic
dose of buprenorphine did not possess immunosuppressive properties, so was able to prevent the neuroendocrine and immune system alterations and impair the
increase of tumor metastasis.60 This suggests that
adequate treatment of surgically-induced immunosuppression with an opioid devoid of immunosuppressive
effects may also play a protective role against the negative consequences of impaired immune response. Two
studies are now available on the effect of buprenorphine
on immunity in humans, involving drug abusers who
were chronically treated with the drug for opioid depen-
dence.65,66 Although the doses of buprenorphine were

extremely high, a significant amelioration of immune
parameters was observed, compared with the values
recorded before switching to the drug.
Thus morphine and fentanyl have a negative effect on
the immune system, tramadol has a positive effect, and
buprenorphine may be regarded as neutral. The mechanisms underlying these differing effects are not completely understood, but may result from the different G
proteins involved as second messengers; after binding
with identical opioid receptors, each opioid agonist
determines the specific class of G proteins to be activated, and these vary in their effects upon the HPA axis
and sympathetic nervous system. Like other side effects,
the impact upon the immune system tends to diminish
with chronic administration, owing to the development
of tolerance.49,64
The clinical importance of these differences is that in
vulnerable patients, such as children and the elderly, it
may be desirable to avoid the risk of immunosuppression. Patients experiencing psychosocial or surgical
stress may also have compromised immune systems,
indicating the use of an analgesic devoid of immunosuppressant activity that will therefore not increase the risk
of infection.43 Immunosuppression must be taken into
account in cancer pain patients, as a result of the underlying disease and concomitant treatment with other
potentially immunosuppressive drugs, such as glucocorticoids and chemotherapeutic agents. The immunosuppressive properties of individual agents may therefore be
an important consideration in peri-operative and cancer
patients needing opioid therapy.
Buprenorphine, Other Opioids, and the HPG Axis
The sex hormones testosterone and estradiol are strong
modulators of body functions. Both hormones are produced by the gonads and adrenal glands of both males
and females, but plasma levels differ markedly between
the sexes (normal testosterone levels 310 ng/mL for
men and 0.51 ng/mL for women, normal estradiol
levels <50 pg/mL for men and 20400 pg/mL for
women). Sex hormones can modulate pain, and testosterone in particular has repeatedly been shown to
have a possible protective function against chronic
pain67; men have higher endogenous levels of testosterone and a lower incidence of many chronic pain syndromes than women.68 Men who do suffer from chronic
pain conditions, such as cluster headaches, may have
lower than normal androgen levels.69 In experimental
animals testosterone has been shown to decrease
formalin-induced behavioral responses in rats, the

effects appearing to be different in males and females.70
Chronic opioid therapy with morphine may result in
clinically significant hypogonadism (testosterone plasma
levels <3 ng/mL in men) and sexual dysfunction, with
decreased libido, increased fatigue and generally poor
functioning.71,72 This condition in men is also associated
with physical symptoms such as osteoporosis, decreased
axillary and pubic hair, infertility, lower testicular
volume, gynecomastia, decreased strength and muscle
mass, and decreased bone marrow activity.73 Hypogonadism is also present in subjects receiving morphine via
the intrathecal route.71 To compare the effect of
buprenorphine on the hypothalamo-pituitary-gonadal
(HPG) axis with those of other opioids, equianalgesic
doses of morphine, buprenorphine, tramadol and fentanyl were administered to experimental animals.74
Male rats received a single subcutaneous injection of
morphine (10 mg/kg), fentanyl (0.1 mg/kg), tramadol
(40 mg/kg), buprenorphine (0.1 mg/kg) or saline
(0.7 mL/kg).74 Plasma and brain testosterone levels were
then measured by radioimmunoassay either 4 hours or
24 hours after treatment. In the animals studied after 4
hours, all the opioids, including buprenorphine,
decreased plasma testosterone compared with saline
control. At the same time point, testosterone concentration in the diencephalon was drastically reduced in all
opioid groups except buprenorphine, in which it
remained at control levels. Blood and brain testosterone
concentrations had all returned to control levels 24
hours after treatment. The fact that buprenorphine
unlike the other opioidsdid not affect brain levels of
testosterone must be emphasized, as it indicates that this
compound is the most suitable for prolonged use. Clinicians using this opioid to rescue addicts already
acknowledge these characteristics.75
Most of the available clinical and experimental data
in humans are obtained from male patients treated with
morphine. However, pain patients are predominantly
women. Therefore in a recent study the possible interactions between the long-term administration of
buprenorphine and the HPG axis were evaluated in both
women (of reproductive age or menopausal) and men
(younger or older than 55 years) (data on file, Aurilio).
Sixty patients suffering from chronic noncancer pain
were treated with transdermal buprenorphine at a dose
of 35 mg/h. Clinical evaluations were undertaken at the
beginning of treatment and again after 15 days, 13
months, and 6 months. At each visit, in addition to a
review of medical treatment and pain evaluation, a
1
Buprenorphine (ng/ml)
blood sample was taken to determine hormone levels.

Results showed good pain control (the mean score on
the 0100 mm visual analog scale [VAS] decreased from
>70 to <35 mm) with no significant differences between
groups. In addition, buprenorphineunlike other
opioidsdid not induce significant changes in the blood
levels of testosterone and cortisol in either male or
female patients.
In conclusion, human and animal data indicate that
buprenorphine does not produce the same effects as
other common opioids on gonadal hormones. Testosterone and its metabolites are well-known compounds
involved in the development and maintenance of all
body structures, including the brain. In the treatment of
pain therefore the choice of an opioid without detrimental effects on these functions may be preferred, to avoid
hormone replacement therapy having to be carried out.
0.5
Median
0.1
0.05
Before
hemodialysis
After
hemodialysis
Figure 7. Buprenorphine plasma concentrations before and

immediately after hemodialysis (Filitz et al.).36 Filled circles
represent samples in which detectable norbuprenorphine concentrations were determined. Median values are circled in red.
Buprenorphine and Impaired Renal Function

With most opioid analgesics in current use, there is a
risk of the parent compound or metabolites accumulating in patients who have impaired renal function. In
some cases this can lead to drug-related tolerability
problems, particularly in elderly patients or those with
co-morbidity. To investigate the impact of hemodialysis
on the plasma concentrations of buprenorphine and its
metabolite norbuprenorphine, and possible effects upon
the level of analgesia, a German study enrolled 10
patients who were dependent on intermittent hemodialysis and who also required pain therapy according to
step 3 of the WHO analgesic ladder.36 Patients had to
have received transdermal buprenorphine for at least
one week to ensure steady state conditions. The mean
age of the subjects was 63 years, the mean weight was
65 1 9 kg, and the average dose was 50.8 mg/h. Blood
samples, taken directly before and 1020 minutes after
standard hemodialysis, were analysed to establish the
plasma concentrations of buprenorphine and norbuprenorphine. Pain ratings taken before and after hemodialysis were also recorded.
The median buprenorphine plasma concentrations
were 0.16 ng/mL before and 0.23 ng/mL after hemodialysis (See Figure 7), so buprenorphine was not removed
by hemodialysis at the concentrations used in this study.
This is consistent with the finding that haemodialysis
had no impact on average pain ratings. A significant
correlation (P < 0.05) between the administered
buprenorphine doses and plasma concentrations
indicates that buprenorphine metabolism is largely
unaffected by renal insufficiency and there is no accu-
mulation of the compound. Norbuprenorphine is

mainly excreted via the urine, but in seven patients the
plasma concentrations of the metabolite were undetectable (<0.05 ng/mL), and in the other three patients they
were lower than the concentrations of the parent compound.36 These results suggest that, in the clinical
situation, no dose adjustment is necessary during intermittent hemodialysis in patients receiving transdermal
buprenorphine up to the highest dose tested (70 mg/h).
Moreover, the evidence from clinical practice indicates
that higher doses are equally safe.
Buprenorphine and Driving Ability
The ability to drive is an important aspect of selfdetermination. Opioids are associated with altered cognition and impaired psychomotor function, but the
initial side effects tend to decrease with long-term use,
so various studies have been undertaken to evaluate
these effects and their impact on driving ability.76,77 In a
prospective, non-inferiority trial, a group of chronic
noncancer pain patients, who had received a stable dose
of transdermal buprenorphine for at least 4 weeks
without a dose change in the previous 12 days, was
compared with a historical control group of healthy
volunteers, using the Vienna test system.78 The influence
of alcohol on complex psychomotor and cognitive performance was used as a standardized definition of a
clinically relevant driving impairment. The computerized test battery followed the German national recommendations for tests to determine driving ability and
included measurements of reaction time under pressure,

attention, visual orientation, motor co-ordination and
vigilance.
Patients in the treatment group suffered predominantly from chronic lower back pain and neuropathic
pain. The mean duration of pain was more than 5 years,
the mean duration of transdermal buprenorphine treatment before testing was 52 days, and the mean dosage
was 45 mg/h. The primary endpoint was the sum score
of the reaction time, attention and visual orientation,
which comprised the cognitive elements of the test
battery. The researchers found that the driving ability
of patients receiving a stable dose of transdermal
buprenorphine was non-inferior when compared with
the healthy matched controls.78 However, because of the
individual variability of test results, the individual
assessment of patients is recommended.
CLINICAL DATA
Registration Studies
The key features of the three randomized, placebocontrolled, double-blind registration studies previously
mentioned are as follows. Study 1 evaluated the efficacy
and tolerability of three doses of transdermal buprenorphine in 151 patients (83 with cancer) suffering from
severe to very severe chronic pain.2 Patients who
obtained satisfactory pain relief during a 5-day run-in
phase with sublingual buprenorphine (0.81.2 mg/day)
were randomized to receive two consecutive patches of
transdermal buprenorphine (35, 52.5 or 70 mg/h) or
placebo. In study 2, a total of 157 patients (121 with
cancer) who reported inadequate pain relief from
weak opioids or morphine (30 mg) were randomized
to receive transdermal buprenorphine (35, 52.5 or
70 mg/h) or placebo.3 There was no run-in phase and
patients received five consecutive patches over 15 days.
In Study 3, 137 patients (45 with cancer) received sublingual buprenorphine (0.81.6 mg/day) as needed
during a 6-day run-in phase.6 Those who achieved satisfactory pain relief were randomized to receive three
consecutive patches (transdermal buprenorphine
35 mg/h or placebo). Sublingual buprenorphine tablets
(0.2 mg) were permitted as rescue medication for all
patients in all three studies.
The endpoints for assessment of efficacy included
pain intensity, pain relief, duration of sleep undisturbed
by pain and the consumption of rescue medication.
Patients were considered to be responders if they
reported at least satisfactory pain relief and needed no
more than one sublingual tablet per day. A metaanalysis of the three trials clearly shows that the percentage of responders increased with the dosage of
transdermal buprenorphine. Among cancer patients,
40% with the 70 mg/h patch, 42% with the 52.5 mg/h
patch and 36% with the 35 mg/h patch were responders.4 Patients receiving active treatment also had longer
sleep periods uninterrupted by pain than those treated
with placebo. A decline in the need for rescue medication was seen at all dose levels of transdermal buprenorphine.4 Tolerability was very good, with a favorable
side-effect profile that was generally benign. Adverse
events were typical of those associated with opioid
drugs and, notably, constipation was reported by only
5.3% of the patients who received the active drug in the
three trials.4
More than half the patients in the three trials participated in the open-label follow-up study, which used
only the 35 mg/h patch. On a 5-point verbal rating scale
(VRS), 42.3% of the patients reported good to complete
pain relief, and a further 47.7% rated their pain relief as
satisfactory.4 More than 50% required only one sublingual buprenorphine tablet (0.2 mg) per day or less to
keep their pain well controlled.4 The most frequently
reported adverse events were typical of those associated
with strong opioids.7 Constipation occurred in 3.8% of
patients, comparable with the incidence reported in
long-term studies of transdermal fentanyl and morphine, in which the prophylactic use of a laxative is
almost always necessary.7,79
Transdermal Buprenorphine in Elderly Patients
The proportion of the population aged over 65 years is
rising throughout the Western world and these people
present particular problems as patients. Multiple morbidity and polypharmacy are frequent, the latter often
complicated by altered pharmacodynamics and pharmacokinetics. Renal impairment is a common problem but
may remain undetected owing to the effect of decreasing
muscle mass on creatinine clearance. Adverse drug reactions are also common.
Buprenorphine has a favorable safety profile, producing limited respiratory depression38 and no immunosuppressive effects.64 Also, no dose adjustment is necessary
in patients with renal impairment who are receiving
doses up to 70 mg/h.35,36 However, questions remained
about the efficacy and safety of buprenorphine in geriatric patients and its metabolism in this age group, so a
recent study evaluated these properties in patients 365
years of age and <65 years who were treated with the
transdermal formulation.80 A second objective was to

establish the position of transdermal buprenorphine
in the treatment of elderly patients with chronic pain
conditions.
A total of 82 subjects were recruited (n = 30 365
years, mean age 74.3 years; n = 52 <65 years, mean age
51 years). At baseline, most patients (80.5%) suffered
from moderate or severe pain, measured on a VAS. After
28 days the percentages of patients with no and mild
pain had increased whereas the percentages with moderate and severe pain had decreased, with no statistically
significant difference between the two age groups. Clinically, no age-related differences in efficacy or safety were
observed.80 The plasma levels of buprenorphine and
norbuprenorphine were comparable in the two groups,
with no evidence of accumulation of either the parent
compound or its major metabolite. These results indicate that transdermal buprenorphine may be considered
suitable for use in elderly patients, not only because of
its ease of use and long duration of patch application,
but primarily for its unaltered profile in this age group.80
Transdermal Buprenorphine4-Day
Patch Application
When transdermal buprenorphine was introduced, it
was recommended that the patches be worn for 3 days
before replacement. An open-label, randomized, crossover Phase III study has compared the efficacy and
safety of a 4-day application period with the established
3-day application regimen.81 Subjects, with a variety of
pain conditions, had already responded to at least 4
weeks treatment with transdermal buprenorphine and
achieved steady state conditions for at least 2 weeks.
The primary endpoint was the patients rating of the
quality of treatment on a 5-point scalevery good,
good, satisfactory, poor and inadequateon completion of each treatment regimen. Also recorded were the
clinicians ratings of the quality of treatment, pain intensity on an 11-point NRS and the McGill Pain Questionnaire, health status and pain relief.81
Patients received a wide range of doses of transdermal buprenorphine, from 17.5 mg/h to 105 mg/h. The
proportion of patients rating the quality of treatment as
very good, good or satisfactory was exactly the same for
the 3-day and 4-day regimens, at 96.3%. The corresponding physicians ratings were 93.8% and 97% for
3-day and 4-day application, respectively. Dosages
remained constant over the total study period and the
prolongation of wearing time to 96 hours had no impact
on analgesic efficacy.81 The two treatment regimes did
not differ in the frequency or dosage of sublingual

buprenorphine required to relieve breakthrough pain.
Systemic and local tolerability was comparable for both
application times.81 Thus extension of the wearing time
to 4 days had no impact on the proven efficacy and
tolerability of the patch.
Equipotency with Other Opioids
Individuals vary greatly in their response to different
opioids,82 and opioid rotation may be required to identify the agent that produces the most favorable balance
between analgesia and adverse events.83 When switching
from one opioid to another, equipotency is defined as
the ratio of the doses of the two opioids that produce the
same analgesic effect.84 Oral morphine is the standard
comparator used when calculating equipotent doses.
A ratio of transdermal buprenorphine to oral morphine of 1:75 has been proposed, but has not been
confirmed in clinical studies. Much lower doses of
buprenorphine are used in clinical practice and there is
growing evidence that this conversion ratio may still be
too high.85 This is supported by a retrospective cohort
study which compared calculated equipotent oral morphine doses of transdermal fentanyl and transdermal
buprenorphine in 4,742 patients on the IMS Disease
Analyzer-Mediplus database. Equipotent doses were
estimated using ratios of 1:100 and 1:75 for fentanyl
and buprenorphine, respectively.86 The all-patients
groups consisted of 2,544 patients with cancer pain and
2,198 patients with noncancer pain. Identical cohort
sub-groups were also identified, who had received
similar analgesic medication for pain of similar intensity. The calculated equipotent doses of oral morphine
were significantly lower in patients receiving buprenorphine than those receiving fentanyl; in cancer patients
the ratios were 85.2 mg to 88.8 mg and 130.9 mg to
138.9 mg for buprenorphine and fentanyl, respectively.
The corresponding figures for noncancer patients were
80.2 mg to 80.9 mg and 117.0 mg to 118.3 mg, respectively.86 These results suggest that an equipotency ratio
of 1:1101:115 would be more appropriate than the
proposed ratio of 1:75.
Studies in Different Pain Indications
The Spanish Pain Society Study Group on Opioids has
carried out clinical trials on the use of buprenorphine
for treating nociceptive, neuropathic and cancer-related
pain,8789 as well as on combination treatment with
buprenorphine plus tramadol and buprenorphine plus
morphine. These were open-label, multi-centre studies,
Most frequent adverse events
20
18
16
16
14
14
% of patients
18
12
10
8
12
Baseline
10
W2
W4
W8
Nausea
Baseline
W1
W2
W3
W4
Vomiting
Dizziness
Constipation
W8
T. Lattinen
12.7
10
8.3
7.4
6.9
6.2
S.D
2.13
3.1
3.1
3.1
3.04
Baseline vs week 8: p<0.001
Figure 8. Lattinen test scores in patients with chronic nociceptive

pain.
mostly of 8 weeks duration, to evaluate the titration,

efficacy and safety of the transdermal buprenorphine
patch or the combination treatment.
In 361 patients (average age 60.3 years) suffering
from chronic nociceptive pain who were treated with
transdermal buprenorphine, the mean pain intensity on
an 11-point NRS decreased from 7.7 at baseline to 3.4
in week 8.87 On the Lattinen Test, which quantifies the
five aspects of pain (intensity, frequency, use of analgesics, level of activity and rest at night) the mean score
declined from 12.7 at baseline to 6.2 in week 8 (see
Figure 8). Concomitantly, the proportion of patients
needing rescue medication dropped from 69% in week
153% in week 8. In approximately 60% of these
patients the rescue medication was tramadol; this
m-opioid agonist caused no problems when used in conjunction with the buprenorphine patch. The frequency
of local adverse events remained fairly constant
throughout the observation period at about 10%, but
the incidence of systemic adverse events decreased from
45.4% in week 116.7% in week 8. No severe systemic
adverse events occurred. It was concluded that transdermal buprenorphine is a safe and effective treatment for
chronic nociceptive pain.87 Also, that titration from a
low dose can be useful in opioid-nave patients to avoid
early opioid side effects, that the need for co-medication
is low, and that combination with tramadol as rescue
medication is both possible and effective.87
A total of 237 patients were enrolled for the study on
neuropathic pain, the average time since onset being 37
months.88 Pain was caused by a variety of conditions
and over 99% of the patients had previously been
treated unsuccessfully with one or more of the following: nonsteroidal anti-inflammatory drugs (NSAIDs;
Figure 9. Adverse events in neuropathic pain patients.
50.6%), antidepressants (64.6%), anticonvulsants

(75.5%) or other agents (32.9%). The mean prescribed
dose of buprenorphine was 30 mg/h, ie, less than the
smallest patch then available. Over the 8-week trial, the
mean NRS score decreased from 7.7 to 3.5, and
the Lattinen Test score decreased from 12.3 to 6.4. In
week 2, 63.3% of subjects required tramadol rescue
medication, but this had dropped to 46.2% by week 8.
Thus buprenorphine demonstrated good efficacy in
patients with neuropathic pain, even when other agents
had been ineffective.88 Combination with other centrally
acting drugs, such as tricyclic antidepressants or anticonvulsants, and with tramadol rescue medication, did
not cause any problems. The safety profile was very
good (see Figure 9), reflected by the fact that 59% of the
subjects asked to continue treatment with transdermal
buprenorphine after the study had been completed.88
Of the 164 subjects in the study of patients with
cancer-related pain (average age 64.3 years), previous
treatment had provided inadequate pain relief in 94%.89
The mean dose of transdermal buprenorphine was again
low, at 33 mg/h, but the mean NRS score declined significantly from 7.4 at baseline to 3.2 in week 8. Subjects
in this study also completed a quality of life test covering
seven aspects of daily living: physical fitness, feelings,
social activities, daily activities, change in health, overall
health and pain. In each category, a score of 5 is the
worst and 1 is the best. It can be seen from Figure 10
that the mean score improved from 4.62.8 over the
course of the study. The decrease in each of the seven
categories was statistically significant. Both local and
systemic adverse events decreased over the 8 weeks
(from 10.9% to 6.2% and 45.7% to 18.0%, respectively) and the need for rescue medication stabilized at
about 50%. Most patients achieved satisfactory pain
relief with low to medium patch strengths, showing
transdermal buprenorphine to be a highly effective analgesic for the treatment of cancer-related pain, with no
evidence of a ceiling effect for analgesia.89
their potential for worsening pain and biliary obstruction. However, investigations using endoscopic manometry have demonstrated that buprenorphine does not
induce SO spasm, but significantly decreases the amplitude of SO contraction waves without altering
other parameters.92,93 This suggests that buprenorphine
offers potential benefits for patients suffering from
pancreatitis.
Quality of life score

(Score 1-5)
5.0
4.5
4.0
3.5
3.0
2.5
Transdermal Buprenorphine and Cancer Pain
2.0
Baseline
Week 2
Week 4
Week 8
Figure 10. Quality of life score in cancer pain patients.
Another study of 297 patients with nociceptive, neuropathic or mixed pain of any aetiology evaluated the
efficacy and safety of transdermal buprenorphine and its
compatibility with tramadol as rescue medication.90
Pain had been present for an average of 49.7 months
and previous pain management had been unsatisfactory
in 96% of subjects. The mean NRS score decreased
from 7.7 to 3.6 over the 8-week observation period,
with a mean dose of 27.5 mg/h. The buprenorphine
patch was well tolerated and no problems were encountered in combining it with tramadol.90 Similar results
were obtained in 93 patients with chronic pain of any
type who were switched from morphine to the transdermal buprenorphine patch for basal analgesia and morphine as rescue medication.90
Collectively, these studies demonstrate that transdermal buprenorphine provided effective pain relief in
chronic nociceptive, neuropathic and cancer-related
pain in a total of 1,152 patients. Safety and tolerability
were good, with a reduction in opioid-induced adverse
events over the course of treatment, but dose titration is
very important in order to minimize side effects. No case
of respiratory depression was recorded in any of the
studies. Buprenorphine could be safely combined with
pure m-opioid receptor agonists like tramadol and morphine, whereas the convenience and compliance of the
patch delivery system was rated highly by both doctors
and patients.
Also, it should be noted that spasm of the sphincter
of Oddi (SO) is a well-recognized effect of narcotic
drugs (eg, morphine and pentazocine), which can occasionally cause debilitating pain.91 Consequently, many
clinicians are reluctant to prescribe strong opioids in
patients with acute or chronic pancreatitis, because of
Transdermal buprenorphine fits well on the World

Health Organizations (WHO) three-step ladder for
cancer pain relief, particularly on Step 2 and Step 3 in its
medium dose range of morphine equivalents.94 It provides the stable plasma levels required by WHO guidelines and also meets the recommendation that analgesics
used to treat chronic pain should be easy to selfadminister.94 An Italian group has investigated the efficacy and safety of combining buprenorphine with
morphine,95 the potential existence of a ceiling effect at
high doses,96 and the effects of switching between
buprenorphine and fentanyl.97
Supplemental dosing with an opioid is the main treatment suggested to manage breakthrough pain in cancer
patients. The first study95 was undertaken to verify the
safety and effectiveness of intravenous morphine for
treating episodic breakthrough pain in cancer patients
receiving transdermal buprenorphine. 29 consecutive
patients with advanced cancer who reported acceptable
basal analgesia with transdermal buprenorphine (mean
dose 44.5 mg/h), but who experienced breakthrough
pain, were selected for this open label study. Episodic
pain peaks were treated with an intravenous morphine
bolus, the dose being 1/5 of the morphine equivalent
daily dose of buprenorphine. For each episode, pain
intensity and opioid-related adverse effects were
recorded when severe pain occurred and again 15
minutes later. Of 106 episodes, 92% were successfully
treated and the mean pain intensity decreased from 7.3
to 2.9 on a 11-point NRS after 15 minutes.95 Adverse
events occurred in 18% of episodes after administration
of the morphine bolus. In this study intravenous morphine was as effective as in patients that received
chronic treatment with transdermal fentanyl or oral
morphine.98 Thus, the combination of immediate release
(IR) morphine and a basal analgesic regime of transdermal buprenorphine was both effective and safe. Clinically, there was evidence of an additive analgesic effect,
but not of any safety-relevant conflict.95
To explore the possibility of a ceiling effect at higher

than usual doses of transdermal buprenorphine, 10
cancer pain patients who were no longer responsive to
the 70 mg/h patch were enrolled in an open label trial.96
The dose of transdermal buprenorphine was increased
incrementally up to a maximum of 140 mg/h within 6
days, until a stable dose was achieved. Intravenous morphine was given as needed (a 7-mg bolus for each
70 mg/h patch). Where stable analgesia (<3 doses of
morphine per day) could not be achieved, patients were
switched to escalating doses of other opioids. In six
patients the rapid dose escalation above 70 mg/h
achieved stable pain control with no increase in adverse
events.96 Four patients were switched to other opioids
and achieved stabiliaation (oxycodone 320 and 400 mg/
day, methadone 120 mg/day, transdermal fentanyl
200 mg/h) at higher doses than those of transdermal
buprenorphine. This suggests that transdermal
buprenorphine at doses even higher than the 140 mg/h
maximum used in this study may be effective in cancer
pain. No evidence of a ceiling effect was observed
during the study and, as in the previous study, the combination with IR morphine was safe and effective.96
To confirm that the concomitant presence of fentanyl and buprenorphine is feasible without important
consequences, 22 cancer pain patients who obtained
adequate pain relief from either transdermal buprenorphine (35 or 70 mg/h) or transdermal fentanyl (25 or
50 mg/h) were switched from one opioid to the other
for 3 days, and then back again.97 The fentanyl : buprenorphine ratio used was 0.6:0.8. Pain intensity,
rescue medication and adverse events were recorded
on day 0, day 1 (after switch), day 3 (rotation to previous drug), day 4 (1 day after rotation), and day 6 (3
days after rotation). No significant changes were seen
in these parameters over the 6 days, indicating that
equianalgesia was maintained after each switch. Also,
no evidence of interference was seen during the first
day after switching, when both opioids were likely to
have significant blood concentrations.97
A continuing multicenter, open-label study is assessing the efficacy and safety of transdermal buprenorphine
in patients with severe cancer pain, after switching from
a stable dose of oral sustained release (SR) morphine
(data on file, Langford). The primary aim is to establish
a clinically meaningful equipotency ratio between them.
Subjects have to demonstrate satisfactory pain control
from a stable dose of SR morphine or equivalent strong
opioid over the previous 7 days, with no more than 25%
variation in the total morphine dose (SR + IR morphine
Table 1. Starting Doses of Transdermal Buprenorphine

Cohort
I
II
III
IV
Oral Daily Morphine

Equivalent Dose (mg/24 h)
Buprenorphine TDS
Starting Dose (mg/h)
3060
6190
91120
121150
151210
211240
241270
>270
17.5
35
52.5
70
rescue medication). Starting doses are shown in Table 1.

The first buprenorphine patch is applied on Day 7 and
SR morphine is discontinued on Day 8. During the
ensuing titration phase, if pain intensity increases above
4 on a 0 to 10 NRS, and/or more than four sublingual
buprenorphine tablets are taken for breakthrough pain,
the patch dose is increased. Once a stable dose has
produced adequate analgesia for 3 days the buprenorphine dose is fixed. Interim results have recently been
calculated, and suggest a morphine : buprenorphine
equipotency ratio of 139:1 (data on file, Langford). This
is higher than the figures that have recently been suggested.81,86
Another recent study evaluated the equipotency
ratios of transdermal buprenorphine with oral morphine and transdermal fentanyl.99 10 cancer patients
who had received a stable daily dose of 120240 mg of
oral morphine or 50 to 100 mg of transdermal fentanyl
for more than 6 days, and who required no more than
two doses of oral morphine per day for breakthrough
pain, were switched to transdermal buprenorphine.
Equipotency ratios of 70:1 with morphine and 0.6:0.8
with fentanyl were used. Opioid doses, pain and
symptom intensity, global satisfaction and the consumption of rescue medication were recorded before the
switch, and then 3 and 6 days afterwards. No significant
changes in pain intensity or breakthrough medication
were observed, but there were improvements in constipation (P = 0.014) and global satisfaction with analgesia. Thus the existing level of analgesia was maintained
after the switch at these ratios.99 However, it must be
emphasized that equipotency ratios are only a guideline
and individual titration is important.
Buprenorphine and Neuropathic Pain
Neuropathic pain, found in conditions such as diabetic
peripheral neuropathy and post-herpetic neuralgia,
arises as a direct consequence of a lesion or disease
Patient pain relief over time:

"moderate pain relief"
10
Number of patients
9
8
7
6
5
4
3
2
1
0
Visit 1
Visit 2
buprenorphine
Visit 3
Visit 4
gabapentine
Patient pain relief over time:

"a lot less pain"
6
Number of patients
affecting the somatosensory system. Various drugs are

currently used to treat neuropathic pain and a review of
105 high-quality, randomized, placebo-controlled clinical trials calculated the number needed to treat for many
of these agents; ie, the number of patients that must be
treated before at least one individual experiences pain
relief of 50% or more.100 Opioids were among the most
effective, better than gabapentin, pregabalin and
N-methyl-D-aspartate antagonists.100 Opioid analgesics
and tramadol are also recommended for the treatment
of neuropathic pain by international guidelines,100103
generally as second-line treatments that can be
considered for first-line use in particular clinical
circumstances.103
A body of evidence from preclinical and experimental
human studies supports the efficacy of buprenorphine in
managing neuropathic pain. In rats, buprenorphine
showed potent, dose-dependent inhibition of mechanical
allodynia in the spinal nerve ligation and streptozotozininduced diabetic pain models, and of cold allodynia in the
chronic constriction injury and vincristine-induced polyneuropathic pain models.13 A randomized, double-blind,
placebo-controlled, cross-over study in human volunteers demonstrated a pronounced antihyperalgesic effect,
in direct contrast to the intravenous administration of
pure m-opioid agonists in the same model.25 Also, various
reports of buprenorphine successfully treating cases of
neuropathic pain can be found in the literature, in conditions as diverse as trigeminal neuralgia,104 radicular
pain,104 post-herpetic neuralgia,105 phantom limb pain106
and post-thoracotomy pain.107
A prospective open, randomized, parallel-group trial
is currently comparing the efficacy and safety of transdermal buprenorphine and gabapentin in patients with
neuropathic pain syndromes. To be included, subjects
must have suffered from neuropathic pain of 33 months
duration, the intensity reaching at least 5 on an 11-point
NRS and at least 12 on the 7-element Leeds Assessment
of Neuropathic Symptoms and Signs (LANSS) pain scale.
The trial lasts 42 days: a 14-day titration period followed
by a 28-day maintenance period. No rescue medication is
allowed. To date 28 patients have been enrolled, 19 in the
buprenorphine group and nine in the gabapentin group.
Interim results, such as the proportion of patients achieving moderate pain relief and experiencing a lot less
pain (see Figure 11), indicate that the pain relief provided by the two agents is not dissimilar, although the
mechanisms of action are different. Indications are that
transdermal buprenorphine exhibits non-inferiority with
respect to gabapentin.
5
4
3
2
1
0
Visit 1
Visit 2
buprenorphine
Visit 3
Visit 4
gabapentine
Figure 11. Interim results of transdermal buprenorphine vs.

gabapentin.
Thus transdermal buprenorphine appears to be effective in different neuropathic pain indications, with
potent antihyperalgesic and antiallodynic effects. It alleviates typical neuropathic pain symptoms and retains its
analgesic properties with long-term administration.
Buprenorphine in Combination with Morphine
Pain after major abdominal surgery is intense in the first
few hours and requires large amounts of analgesics.
Intravenous opioids are most frequently used for early
postoperative pain control. Morphine is the reference
opioid, but is associated with adverse events, including
sedation, respiratory depression, pruritus, nausea, and
vomiting.108 The slow receptor kinetics and bell-shaped
doseresponse curve of buprenorphine had originally
raised fears of possible interaction with other m-opioid
agonists or antagonists, but recent preclinical data109
and human models110 suggest these fears are groundless.
In addition, the concomitant administration of mor-
phine and buprenorphine has been shown to produce a

prolonged antinociceptive state and lower incidence of
adverse events than the individual agents,111,112 although
large scale clinical comparisons are still lacking.
A recent Israeli study compared the efficacy, tolerability and safety of postoperative analgesia obtained
with either buprenorphine or morphine alone, and the
combination of the two opioids, in 120 patients undergoing major open abdominal surgery under standardized general anaesthesia.113 In this prospective,
randomized, double-blind study, postoperative patients
who were awake and coherent but rated their pain as
35 on a 0 to 10 VAS, were connected to an intravenous patient-controlled analgesia device (IV-PCA)
delivering one of four protocols (n = 30 per group).
The protocols were: (1) buprenorphine infusion
(0.4 mg/kg/h) + buprenorphine
bolus
(0.15 mg/kg/
bolus), (2) morphine infusion (10 mg/kg/h) + morphine
bolus (5 mg/kg/bolus), (3) buprenorphine infusion
(0.4 mg/kg/h) + morphine bolus (5 mg/kg/bolus), or (4)
morphine infusion (10 mg/kg/h) + buprenorphine bolus
(0.15 mg/kg/bolus). The treatment lasted 12 hours and
the bolus lock-out time was 7 minutes. Rescue medication consisted of intramuscular diclofenac (75 mg)
every 6 hours.113
Pain scores for the first 2 hours postoperatively were
similarly high among all groups. From 3 to 12 hours the
intensity of pain declined and during this period the VAS
scores of patients in Group 1 were lower than in the
other groups (P = 0.018). The correlation between the
average pain score and the log of the mean sum of the
delivered boluses was also better in Group 1 than in all
other groups.113
Drug requirements generally diminished during the
312 hour period, but the bolus demand/delivery ratio
was lower when buprenorphine was infused than when
morphine was infused, and lowest of all in Group 1
(P = 0.026). This may be the result of a better analgesic
effect at the given doses and buprenorphine : morphine
equipotency (1:32 overall). The requirements for rescue
medication were similar in all groups. None of the protocols had a negative effect on respiratory or hemodynamic parameters, sedation or the level of patient
satisfaction. Postoperative nausea and vomiting was
mild and similar in all groups.113
It can be concluded that a low dosage infusion and
boluses of buprenorphine, delivered via IV-PCA, effectively control early postoperative pain. Contrary to
earlier beliefs, buprenorphine is safe and effective when
administered alone and in combination with morphine,
a pure m-opioid receptor agonist,113 and no hint of

buprenorphine : morphine antagonism was observed.
A recent clinical trial in the U.K. investigated
whether buprenorphine antagonizes morphine in 18
patients with severe pain from osteoarthritis (data on
file, Langford). The double-blind, double-dummy,
cross-over design began with a run-in phase, during
which patients were treated with a 35 mg/h transdermal buprenorphine patch. This continued during the
first 2-week double-blind phase, when patients who
required rescue medication were randomized to receive
either IR morphine plus a placebo that mimicked sublingual s.l. buprenorphine, or s.l. buprenorphine plus a
placebo that mimicked IR morphine. Pain scores, pain
relief and the number of doses of rescue medication
per day were recorded over the 2 weeks. After a crossover period, the rescue regimens of the two groups
were switched for a further 2-week, double-blind
phase (data on file, Langford).
Analysis of the interim results shows that IR morphine and s.l. buprenorphine demonstrated comparable
efficacy in terms of average pain score, with a similar
number of doses of each rescue medication being
required. Both regimens were similar in terms of patient
satisfaction, but there was a trend to suggest better
ratings for the combination of transdermal buprenorphine and IR morphine. It can be concluded that full
m-opioid agonists are safe and effective in combination
with transdermal buprenorphine, and IR morphine is as
effective as s.l. buprenorphine for the treatment of
breakthrough pain in patients suffering from osteoarthritis (data on file, Langford).
Low-Dose Transdermal Buprenorphine
A low-dose transdermal buprenorphine patch, delivering 5 mg/h, 10 mg/h or 20 mg/h, has recently been introduced. The application period is 7 days and it is
indicated for the treatment of nonmalignant pain of
moderate intensity when an opioid is necessary for
obtaining adequate analgesia. The rationale underlying
development was that the low dose patch would be
given instead of WHO Step II opioids, not after them,
on the assumption that a low dose of a potent opioid
would have clinical advantagesespecially in terms of
tolerabilityover a high dose of a Step II opioid.
Phase III clinical trials included a randomized,
double-blind, parallel-group comparison between low
dose transdermal buprenorphine and s.l. buprenorphine, in 238 patients suffering from moderate to severe
osteoarthritis. The primary endpoint was pain intensity.
Secondary endpoints included the amount of rescue

medication, sleep quality, pain at night and acceptance
of treatment. Patients were randomized to receive either
a transdermal buprenorphine patch plus placebo sublingual buprenorphine tablets, or sublingual buprenorphine tablets and a placebo patch. The dose was then
titrated over 21 days to give optimum pain control and
patients entered a 28-day assessment phase. Pain scores
on an 11-point NRS decreased between the start of the
study and week 7 of the assessment period in both
groups, demonstrating equivalent pain control. This
was accompanied by an improvement in sleep quality.
Mean night pain also decreased. The proportion of
patients who rated their treatment as good or very good
was 63.3% in those receiving transdermal buprenorphine, and 35.8% in those receiving sublingual
buprenorphine, which may be partially explained by the
higher rate of adverse events in the sublingual buprenorphine group.
Another randomized, double-blind, parallel-group
trial compared low dose transdermal buprenorphine
and hydrocodone/paracetamol in patients suffering
from low back pain (n = 270).114 After a 7-day run-in
period, during which all previous pain medication was
discontinued and 400 mg of ibuprofen was administered every 6 hours, patients were randomized to receive
either the low dose patch or a combination of hydrocodone and paracetamol every 6 hours. No rescue medication was allowed. Doses were titrated to achieve
optimum pain control over 21 days before commencing
the 35-day assessment period.115 The main endpoints
were the mean pain intensity and patient satisfaction
scores. Mean pain intensity scores were very similar for
the two regimens at baseline and during the maintenance phase. The proportion of patients with adequate
analgesia was almost identical, at 73.6% for transdermal buprenorphine and 73.7% for hydrocodone/
paracetamol, whereas drug-related adverse events were
comparable in the two groups.114
Many of the patients (n = 385) in these two trials
participated in a long-term follow-up study. Most
started with a 5 mg/h patch, the dose then being titrated
to obtain effective pain control. Some patients remained
on the low-dose transdermal buprenorphine patch for
more than 3 years but the average duration of treatment
was 7.6 months. The average buprenorphine dose
remained consistent up to 21 months of the study, as did
the maximum and minimum pain intensity and the pain
relief obtained. Thus there was no indication of the
development of tolerance. The most frequent adverse
events were constipation and nausea, cumulatively

affecting 34.6% and 32% of patients, respectively.
To give an idea of the considerable level of experience
already gained with low dose transdermal buprenorphine, data from more than 821,000 patient treatment
days is now available.
CONCLUSION
Opioids are the mainstay of treatment for chronic,
cancer and noncancer pain. Available research on the
pharmacology of buprenorphine suggests that it may
offer a number of advantages over other opioids, and
this is supported by the clinical experience gained to
date, although further studies are required to confirm
certain aspects of its therapeutic action. The introduction of a transdermal formulation has facilitated the
maintenance of constant plasma levels of the drug, and
significantly increased its clinical use.
Modern receptor theory makes it clear that the action
of a drug can vary according to the individual tissue,
species, or endpoint involved. Thus it is perfectly possible for the drug to be a partial agonist for one effect,
but a full agonist for another. Despite earlier misconceptions, buprenorphine has been shown to act as a full
m-agonist for analgesia with no ceiling effect in animal
and human pain models, and in cancer patients. Unlike
other opioids, it exhibits a ceiling effect for respiratory
depressionie, it acts as a partial agonist for this endpoint. The margin of safety for patients, in whom respiratory depression may be fatal, is thereby improved.
This property may be caused by a novel supraspinal
signaling pathway that is not mediated via opioid or
NOP receptors and which is not activated by, for
example, morphine, or fentanyl. Moreover, if buprenorphine does induce respiratory depression, it has been
demonstrated that the effect can be fully reversed by
naloxone.
Different mechanisms have been suggested for
opioid-induced analgesia and antihyperalgesia, with
some studies suggesting that pure m-opioid receptor agonists may contribute to the induction of hyperalgesia.
Thus, in a patient being treated with such an agent,
increasing pain intensity could be caused by either the
development of tolerance or opioid-induced hyperalgesia, posing a diagnostic dilemma. By contrast, buprenorphine has a pronounced antihyperalgesic effect, which
may be because of its k-receptor antagonism. Other
benefits include its lack of immunosuppressive properties, found in some opioids, which can compromise
treatment and hasten tumor metastasis. This is particu-
larly important in patients who may already be immunocompromised. Unlike other opioids it does not affect
the HPG axis, making buprenorphine suitable for longterm administration without the risk of hypogonadism,
and it has no significant effect on driving ability, an
important aspect of patients self-determination.
Elderly patients present particular problems, owing
to the prevalence of co-morbidity, polypharmacy, renal
impairment and their susceptibility to adverse drug reactions. The efficacy and safety of buprenorphine remain
unaltered in this age group, whereas the ease of use of
the transdermal patch and the long duration of application are especially suitable for these patients. In particular, buprenorphine metabolism is largely unaffected by
renal insufficiency, so that no dose adjustment is
required in patients with renal impairment, even in endstate renal failure requiring hemodialysis.
Further randomized, placebo-controlled clinical trials
are required to provide additional evidence, but transdermal buprenorphine has so far been shown to be
effective in chronic nociceptive, neuropathic and mixed
pain caused by a wide variety of conditions, including
cancer, osteoarthritis, low back pain, diabetic neuropathy, and post-herpetic neuralgia. In many cases the analgesia previously provided by other opioids had proved
inadequate. Where appropriate, transdermal buprenorphine can be combined with pure m-opioid agonists as
rescue medication, whereas switching from buprenorphine to other opioids and vice versa does not present any
problems. Given its favorable safety profile, buprenorphine can now be considered an effective and realistic
option for treating chronic cancer and noncancer pain.
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Current Knowledge of Buprenorphine and Its

Anna Maria Aloisi

114 PUBLICATIONS 1,294 CITATIONS

Universit degli Studi di Siena

121 PUBLICATIONS 2,779 CITATIONS

La Maddalena Cancer Center

401 PUBLICATIONS 10,206 CITATIONS

239 PUBLICATIONS 6,162 CITATIONS

Available from: Sebastiano Mercadante

Leiden University Medical Center, Department of Anesthesiology, Leiden, The Netherlands;

Department of Anesthesiology, University Hospital Erlangen, Erlangen, Germany; St

2010 World Institute of Pain, 1530-7085/10/$15.00

with other m-opioid agonists, and the reversibility of side

Key Words: opioids, buprenorphine, analgesia, ceiling

exhibits a pronounced antihyperalgesic effect that might

Buprenorphine sl 0.2 mg (tab/d)

Current Knowledge of Buprenorphine 429

Treatment duration (days)

Treatment duration (days)

Figure 1. Pain intensity and rescue medication in patients with

430 pergolizzi et al.

the drug to the receptor and the production of a second

Current Knowledge of Buprenorphine 431

supraspinal (intracerebroventricular [i.c.v.]) naloxone.16

mechanism which contributes to antinociception,

Buprenorphine and Hyperalgesia

432 pergolizzi et al.

Figure 3. Possible antihyperalgesic mechanism of buprenorphine.

hyperalgesic pain states and antinociceptive tolerance.32

Current Knowledge of Buprenorphine 433

In rats, both opioids were infused i.v. over 20

Figure 4. Doseresponse relationships

434 pergolizzi et al.

Figure 5. Therapeutic utility of buprenorphine and fentanyl

Current Knowledge of Buprenorphine 435

Figure 6. Reversal of buprenorphine-induced respiratory depression by naloxone.

ford). Although the reversal of respiratory depression

potential consequences for patients, particularly those

436 pergolizzi et al.

dence.65,66 Although the doses of buprenorphine were

formalin-induced behavioral responses in rats, the

Current Knowledge of Buprenorphine 437

blood sample was taken to determine hormone levels.

Figure 7. Buprenorphine plasma concentrations before and

Buprenorphine and Impaired Renal Function

mulation of the compound. Norbuprenorphine is

438 pergolizzi et al.

included measurements of reaction time under pressure,

Current Knowledge of Buprenorphine 439

transdermal formulation.80 A second objective was to

not differ in the frequency or dosage of sublingual

440 pergolizzi et al.

Most frequent adverse events

Baseline vs week 8: p<0.001

Figure 8. Lattinen test scores in patients with chronic nociceptive

mostly of 8 weeks duration, to evaluate the titration,

Figure 9. Adverse events in neuropathic pain patients.

50.6%), antidepressants (64.6%), anticonvulsants

Current Knowledge of Buprenorphine 441

Quality of life score

Transdermal Buprenorphine and Cancer Pain

Figure 10. Quality of life score in cancer pain patients.