Vol. 29 No. 3 March 2005
`
`Journal of Pain and Symptom Management 297
`
`Review Article
`
`Buprenorphine: Considerations
`for Pain Management
`Rolley E. Johnson, PharmD, Paul J. Fudala, PhD, and Richard Payne, MD
`Department of Psychiatry and Behavioral Sciences, Behavioral Pharmacology Research Unit (R.E.J.),
`Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Psychiatry
`(P.J.F.) and Behavioral Health Service (P.J.F.), University of Pennsylvania School of Medicine,
`VA Medical Center, Philadelphia, Pennsylvania; and Department of Neurology (R.P.), Memorial
`Sloan-Kettering Cancer Center, New York, New York, USA
`
`Abstract
`New effective analgesics are needed for the treatment of pain. Buprenorphine, a partial mu-
`opioid agonist which has been in clinical use for over 25 years, has been found to be
`amenable to new formulation technology based on its physiochemical and pharmacological
`profile. Buprenorphine is marketed as parenteral, sublingual, and transdermal
`formulations. Unlike full mu-opioid agonists, at higher doses, buprenorphine’s physiological
`and subjective effects, including euphoria, reach a plateau. This ceiling may limit the
`abuse potential and may result in a wider safety margin. Buprenorphine has been used for
`the treatment of acute and chronic pain, as a supplement to anesthesia, and for behavioral
`and psychiatric disorders including treatment for opioid addiction. Prolonged use of
`buprenorphine can result in physical dependence. However, withdrawal symptoms appear
`to be mild to moderate in intensity compared with those of full mu agonists. Overdoses
`have primarily involved buprenorphine taken in combination with other central nervous
`J Pain Symptom Manage 2005;29:297–326. 쑖 2005 U.S. Cancer
`system depressants.
`Pain Relief Committee. Published by Elsevier Inc. All rights reserved.
`
`Key Words
`Buprenorphine, pharmacology, pharmacodynamics, pharmacokinetics, pain management,
`partial agonists, formulations, opioids
`
`Introduction
`Buprenorphine has been available worldwide
`as a parenteral and sublingual analgesic since
`
`the 1970s. Parenteral buprenorphine has been
`approved for commercial marketing in the
`United States since December 1981. It is one of
`
`Address reprint requests to: Rolley E. Johnson, PharmD,
`Reckitt Benckiser Pharmaceuticals, Inc., 10710 Mid-
`lothian Pike, Suite 430, Richmond, VA 23235, USA.
`Accepted for publication: July 5, 2004.
`At the time this review was written, Dr. Johnson was
`Associate Professor, Department of Psychiatry and
`Behavioral Sciences,
`Johns Hopkins University
`School of Medicine. Currently, Dr. Johnson is Vice-
`
`President Clinical, Scientific and Regulatory Affairs,
`Reckitt Benckiser Pharmaceuticals and Adjunct Pro-
`fessor, Department of Psychiatry and Behavioral Sci-
`ences, Johns Hopkins University School of Medicine.
`Dr. Payne was Chief of the Pain and Palliative
`Care Service, Department of Neurology, Memorial
`Sloan-Kettering Cancer Center. Dr. Payne is now Di-
`rector, Institute on Care at the End of Life, Duke
`Divinity School, Duke University, Durham, NC.
`
`쑖 2005 U.S. Cancer Pain Relief Committee
`Published by Elsevier Inc. All rights reserved.
`
`0885-3924/05/$–see front matter
`doi:10.1016/j.jpainsymman.2004.07.005
`
`Page 1
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`BDSI v. RB PHARMACEUTICALS LTD
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`298
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`Johnson et al.
`
`Vol. 29 No. 3 March 2005
`
`a number of opioid partial agonists and mixed
`agonist-antagonists currently approved as anal-
`gesics by the Food and Drug Administration
`(Table 1).1
`Buprenorphine (Figure 1) is a derivative of
`the morphine alkaloid thebaine2,3 and is a
`member of
`the 6,14-endo-ethanotetrahydro-
`oripavine class of compounds that includes
`other potent analgesics such as diprenorphine
`and etorphine.4,5 Although buprenorphine has
`been shown to interact in vivo and in vitro with
`multiple opioid receptors, its primary activity
`in man is that of a partial agonist at the mu-
`opioid receptor and antagonist at the kappa
`receptor.6–10 The effects of binding at mu-
`opioid receptors include supraspinal analgesia,
`respiratory depression, and miosis. Buprenor-
`phine, being a partial mu-opioid agonist, may
`have a wider safety profile compared to full mu
`agonists, especially with regard to respiratory
`depression. Further, the slow dissociation of bu-
`prenorphine from the receptor may result in
`fewer signs and symptoms of opioid withdrawal
`upon termination of buprenorphine therapy
`than those which occur with full mu-opioid ago-
`nists, such as morphine, heroin, and metha-
`done. Buprenorphine’s antagonist effects at the
`kappa receptor are associated with limited
`spinal analgesia, and dysphoria and psychoto-
`mimetic effects.11
`Several delivery formulations of buprenor-
`phine have been investigated. Oral bioavailabil-
`ity of buprenorphine is low because of extensive
`first-pass hepatic metabolism.12,13 However, bu-
`prenorphine has certain physiochemical proper-
`ties (discussed later) that can allow for other drug
`delivery technologies to be utilized. The admin-
`istration of buprenorphine by the sublingual
`route allows for bypassing of the first-pass he-
`patic metabolism. Transdermal administration
`
`Fig. 1. Chemical structure of buprenorphine. The
`chemical name of buprenorphine is 6,14-ethenomor-
`phinan-7-methanol, 17-(cyclopropylmethyl)- α-(1,
`1-dimethylethyl)-4, 5-epoxy-18, 19-dihydro-3-hydroxy-
`6-methoxy-α-methyl-, [5α, 7α, (S)]. The structural
`formula is described in Reference 2.
`
`has proven clinical utility for numerous medica-
`tions and provides clinicians the opportunity to
`treat patients who cannot take oral medications,
`such as those with head, neck, mouth or bowel
`lesions, or persistent nausea and vomiting. Both
`the sublingual and transdermal analgesic
`dosage forms of buprenorphine are approved
`for use outside of the United States. In the
`United States, the sublingual formulation has
`been recently approved for the treatment of
`opioid addiction (but not as an analgesic)14 and
`a transdermal formulation is under develop-
`ment. Both are discussed in this review.
`The purpose of this review is to provide
`clinicians and researchers with information
`regarding the appropriate therapeutic use of
`buprenorphine for pain management, and an
`understanding of the mechanisms underlying
`its pharmacodynamic actions. Buprenorphine
`is approved for use as an analgesic for various
`
`Table 1
`Opioid Partial Agonist and Agonist/Antagonists Analgesics Commercially Available for
`Analgesia in the United States
`Activity at
`Dosage Forms
`Activity at
`Mu-opioid Receptor Kappa-opioid Receptor
`Available
`
`Usual Single
`Analgesic Dose (mg)
`
`Controlled Substances
`Act Schedule
`
`Medication
`
`Buprenorphine partial agonist
`Pentazocine
`partial agonist or
`weak antagonist
`partial agonist
`
`Butorphanol
`
`antagonist
`Nalbuphine
`Adapted from Gutstein and Akil.1
`
`antagonist
`agonist
`
`strong agonist
`
`agonist
`
`parenteral
`parenteral
`oral
`parenteral
`nasal
`parenteral
`
`0.3
`30
`50
`1–2
`1–2
`10
`
`III
`IV
`
`IV
`
`Unscheduled
`
`Page 2
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`Vol. 29 No. 3 March 2005
`
`Buprenorphine for Pain Management
`
`299
`
`types of pain (e.g., acute, chronic, and neuro-
`pathic pain). It has also been used for treating
`various behavioral and psychiatric disorders
`(e.g., depression and opioid dependence).
`
`Preclinical Pharmacology
`Receptor Binding/Interactions Studies
`In vitro studies have shown that buprenor-
`phine binds with high affinity to mu- and kappa-
`opioid receptors and relatively lower affinity
`to delta-opioid receptors.15,16 Although most
`in vitro studies have shown buprenorphine to be
`relatively non-selective for these receptors,
`others have shown a selective potency of the (-)
`enantiomer of buprenorphine for kappa1 ⫽
`mu ⬎ delta ⬎ kappa2a ⬎ kappa2b,17 with a slow
`dissociation from all receptors.18
`In vivo studies have shown that buprenor-
`phine binds at the mu-opioid receptor,19 where
`it is believed that analgesic and other effects
`(e.g.,
`supraspinal analgesia, respiratory de-
`pression, miosis, decreased gastrointestinal
`motility, and euphoria) are mediated. Bupren-
`orphine is an antagonist at the kappa-opioid
`receptor; agonist activity at the kappa-opioid re-
`ceptor is thought to be associated with spinal
`analgesia, sedation, miosis, and psychotomi-
`metic (i.e., dysphoric) effects. Although bu-
`prenorphine binds with high affinity to the
`delta opioid receptor (but still lower than to
`the mu or kappa1 receptor), the functional sig-
`nificance of this interaction has not been fully
`elucidated.1 More recently, it has been proposed
`that partial agonist activity at the opioid-receptor-
`like 1 (ORL-1) receptor, with its endogenous
`ligand nociceptin or orphanin FQ (N/OFQ),
`may contribute to the analgesic effect of
`buprenorphine.20
`
`Buprenorphine Effects in Pain Models
`Buprenorphine has been shown to increase
`the nociceptive threshold to electrical stimula-
`tion in the tooth pulp assay in dogs.21,22 The
`antinociceptive potency of buprenorphine in
`the rat and guinea pig paw pressure tests was
`noted to be greater than morphine,23 and bu-
`prenorphine was shown to be 10 times more
`potent than morphine in the formalin test (a
`model of post-injury pain).24
`In addition to the biphasic dose-response
`curve observed for buprenorphine with regards
`to effects on respiration in mice and intestinal
`
`motility in rats,25 a bell-shaped dose-response
`curve for the antinociceptive action of bupren-
`orphine has been observed in certain preclini-
`cal pain models (e.g., mouse and rat hot plate,
`rat and monkey tail dip, and rat electrical
`stimulation of the tail and formalin-induced
`flinching),26–31 whereas a linear dose-response
`relationship has been observed in others (e.g.,
`rodent writhing and tail pressure).26 A curvilin-
`ear dose response for antinociceptive effects
`was first observed by Cowan and coworkers in
`the rodent tail dip/flick test,26 and later by Dum
`and Herz27 in in vivo binding studies in the rat.
`Explanations for this bell-shaped curve include
`a 2-receptor model and noncompetitive autoin-
`hibition.7,17,19,26 The peak of the dose-response
`curve occurred at a dose of approximately
`1 mg/kg. The entire curve shifted to the right
`following pretreatment with the opioid anta-
`gonists naloxone32 or naltrexone.27 Although
`readily demonstrated in preclinical analgesic
`studies, the bell-shaped dose-response curve has
`not been observed in clinical analgesic trials that
`have utilized much lower doses of buprenor-
`phine. A study (not an analgesic trial) designed
`to find the peak of this dose-response curve in
`human subjects used a maximum single dose of
`32 mg administered as a sublingual solution.33 A
`plateau of subjective and respiratory depressive
`effects was observed, consistent with the partial
`agonist classification of buprenorphine (Figure
`2); however, the effects were not biphasic even
`in this dose range.
`
`Distinguishing (Discriminative) Stimulus
`Properties and Self-Administration
`In studies where animals were trained to dis-
`tinguish between an opioid (e.g., morphine)
`and no drug (e.g., saline), buprenorphine gen-
`eralized to medications such as morphine and
`fentanyl.34,35 These results indicated that the
`internal drug cues produced by buprenorphine
`are similar to those of the other opioids. Ani-
`mals that have previously been made depen-
`dent on morphine will acquire drug-taking
`behavior (i.e., self-administration by pressing a
`lever that activates administration) when ex-
`posed to morphine-like drugs. Albeit some-
`times weakly, buprenorphine has been shown
`to support intravenous self-administration in
`animals under various conditions of reinforce-
`ment.36–40 Both drug-naı¨ve and drug-experienced
`
`Page 3
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`300
`
`Johnson et al.
`
`Vol. 29 No. 3 March 2005
`
`precipitate an abstinence syndrome in rhesus
`monkeys maintained on morphine.43 In an-
`other study, no signs of opioid withdrawal were
`observed when saline was substituted for chroni-
`cally-administered buprenorphine in rhesus
`monkeys, and there were no signs of disrup-
`tions in other behaviors such as food intake.37
`Taken together, the ability of buprenorphine
`to generalize to morphine-like drugs along with
`its production of only relatively mild physical
`dependence indicates that buprenorphine’s
`potential for abuse is limited compared to many
`other opioids.
`Tolerance to the behavioral effects of bu-
`prenorphine has been reported in the rhesus
`monkey.38,44 Cross-tolerance of buprenorphine
`to morphine has been shown in the mouse25
`and rat.41
`
`Safety
`The LD50 values for buprenorphine, assessed
`in a number of animal species by various routes
`of administration, are shown in Table 2.45 Table
`3 shows the comparison of the ratio of the acute
`toxic doses to the antinociceptive doses yielding
`the therapeutic index for morphine and bu-
`prenorphine in rats. These data are consistent
`with a wide safety margin for buprenorphine.
`Studies in mice and rats have shown that bu-
`prenorphine is not a carcinogen at doses 1600
`times greater than the analgesic dose. From
`genetic toxicity studies, including the Ames test,
`the chromosomal aberration assay, and the
`mouse lymphoma forward mutation assay, it has
`been concluded that buprenorphine is not a
`mutagen and presents no genetic danger to
`man.
`
`Table 2
`Acute Toxicity (LD50) of Buprenorphine
`LD50 (mg/kg)
`Base
`HCI salt
`
`Route of Administration
`
`Species
`
`oral
`Mouse
`intravenous
`Mouse
`intramuscular
`Mouse
`intraperitoneal
`Mouse
`subcutaneous
`Mouse
`oral
`Rat
`intravenous
`Rat
`intramuscular
`Rat
`intraperitoneal
`Rat
`subcutaneous
`Rat
`intravenous
`Dog
`– -Data not available. Reference 45.
`
`260
`24
`–
`90
`–
`–
`31
`–
`197
`–
`–
`
`800
`72
`⬎600
`–
`⬎1000
`⬎1000
`62
`⬎600
`–
`⬎1000
`79
`
`Fig. 2. The effects of the partial-agonist buprenor-
`phine (closed circle) and the full-agonist methadone
`(open circle) on an opioid agonist scale. The scale
`contains 16 adjectives descriptive of opioid-like ago-
`nist effects rated on a 0–4 ordinal scale (maximum
`score ⫽ 64). Each vertical bar represents ⫾ 1 SEM.
`Reprinted from Walsh SL, Preston KL, Stitzer ML,
`Cone EJ, Bigelow GE, Clinical pharmacology of
`buprenorphine: ceiling effects at high doses. Clinical
`Pharmacology and Therapeutics, 1994, 55: 569–580,33
`with permission from the American Society for
`Clinical Pharmacology and Therapeutics.
`
`animals have been shown to self-administer
`buprenorphine.37,38
`
`Physical Dependence Liability
`Three primary preclinical experimental pro-
`cedures have been used to evaluate the mor-
`phine-like physical dependence potential of
`buprenorphine in animals. The first procedure
`is the substitution of buprenorphine for mor-
`phine in morphine-withdrawn animals. The
`second is the precipitation of an opioid absti-
`nence syndrome by buprenorphine in mor-
`phine-dependent animals. The third is the
`substitution of placebo (i.e., saline) to assess
`the presence of spontaneous withdrawal in bu-
`prenorphine-maintained animals.
`In studies of the above-described procedures,
`buprenorphine has been shown to produce
`either no, or a protracted but mild, opioid-
`like withdrawal syndrome in rats, dogs, and
`non-human primates.6,26,27,37,41,42 For example,
`Martin and coworkers showed that in dogs
`maintained on 125 mg/day morphine, at low
`doses, buprenorphine substituted for morphine
`(i.e., suppressed spontaneous withdrawal) and
`at higher doses, precipitated an abstinence syn-
`drome.6 Buprenorphine was also reported to
`
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`Vol. 29 No. 3 March 2005
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`Buprenorphine for Pain Management
`
`301
`
`Table 3
`Therapeutic Indices for Morphine
`and Buprenorphine
`ED50,
`LD50, Acute Tail Pressure
`(mg/kg)
`(mg/kg)
`
`Therapeutic
`Index
`LD50/ED50
`
`Opioid
`
`Morphine
`
`Buprenorphine
`
`306
`[237, 395]
`197
`[145, 277]
`
`0.66
`[0.26, 1.6]
`0.016
`[0.011, 0.024]
`
`464
`
`12,313
`
`References 25,26
`Numbers in brackets are 95% confidence limits.
`
`Although buprenorphine has been reported
`to be without teratogenic effects in rodents,46
`significant increases in skeletal abnormalities
`were noted in rats after subcutaneous admin-
`istration of 1 mg/kg/day and greater, but not
`at oral doses up to 160 mg/kg/day.14 Increases
`in skeletal abnormalities in rabbits after intra-
`muscular administration of 5 mg/kg/day, or
`1 mg/kg/day or more given orally were not
`statistically significant. Buprenorphine pro-
`duced statistically significant pre-implantation
`(oral doses of 1 mg/kg/day or more) and post-
`implantation (intravenous doses of 0.2 mg/kg/
`day) losses in rabbits.14
`Unlike effects observed from some other opi-
`oids, prenatal exposure in rats to buprenor-
`phine does not appear to affect activity, cycles of
`rest-activity, or developmental milestones.46–52
`The oral administration of buprenorphine to
`rats during gestation and lactation, at doses sev-
`eral hundred times greater than the analgesic
`dose, has been associated with delayed post-
`natal development of the righting reflex and
`startle response.14,53 It has been reported that
`buprenorphine reduces striatal nerve growth
`factor54 and produces toxic effects similar to
`methadone.52 Mixed effects of buprenorphine
`on maternal water intake, postnatal growth,
`maternal weight gain, frequency of resorption,
`or pup birth weights, number of stillbirths,
`and offspring mortality have also been re-
`ported.14,52,55–57 Physical dependence and toler-
`ance to the antinociceptive effects of morphine
`in pups exposed perinatally to buprenorphine
`and methadone have been demonstrated; gen-
`eralized neuromuscular development does not
`appear to be delayed by perinatal exposure to
`buprenorphine.57
`
`the mu-opioid receptor.18,58–60 This slow recep-
`tor dissociation has generally been regarded
`as
`the property responsible for buprenor-
`phine’s relatively long duration of action as an
`analgesic. Buprenorphine also has a high af-
`finity for the mu-opioid receptor, and is not
`displaced easily by antagonists, such as nalox-
`one, which have a lower receptor affinity.61
`The elimination half-life of buprenorphine
`in humans has been described as either bipha-
`sic62 or triphasic.63,64 Buprenorphine is highly
`bound (96%) to plasma proteins, primarily to
`α- and β-globulin fractions.65 Studies utilizing
`human liver microsomal preparations indicated
`that buprenorphine is demethylated to form
`norbuprenorphine, and is also metabolized
`to other compounds by cytochrome P-450
`3A4.66,67 Both buprenorphine and norbupren-
`orphine form conjugates with glucuronic
`acid.68,69 Studies in rats utilizing intraventricu-
`lar administration of norbuprenorphine and
`buprenorphine indicated that the intrinsic an-
`algesic activity of norbuprenorphine was 25%
`that of buprenorphine.70
`The oral bioavailability of buprenorphine
`is approximately 10%, secondary to extensive
`first-pass hepatic metabolism.12,71 Preclinical
`studies in rats indicate that buprenorphine
`distributes rapidly to the brain following intra-
`venous administration.70 Brain to plasma con-
`centration ratios of buprenorphine in rats
`following a single intravenous dose ranged from
`3.0 at 15 minutes to 10.5 at 6 hours post-drug
`administration.72 The more polar metabolite
`norbuprenorphine has an n-octanol:water par-
`tition coefficient about 10% that of bupren-
`orphine70 and penetrates
`into the central
`nervous system to a much lesser degree than
`the parent compound.73 In the rat, dog, monkey,
`and human, approximately 70% or more of an
`intravenous dose is recovered in the feces;74
`enterohepatic recycling is likely.75 A much
`lesser percentage of buprenorphine (10–30%)
`is found in the urine following administration
`by various other routes.65,75 Concentrations
`found in human red blood cells are comparable
`to those in the plasma.63
`
`Pharmacokinetics
`General Observations
`Buprenorphine is an extremely lipophilic
`compound58 that dissociates very slowly from
`
`Parenterally Administered Buprenorphine
`In the United States, buprenorphine, used
`as an analgesic, is only approved for parenteral
`administration, typically by the intramuscular
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`
`Johnson et al.
`
`Vol. 29 No. 3 March 2005
`
`or intravenous route. Peak plasma concentra-
`tions following intramuscular administration
`occurred, in general, 5 minutes after dosing,
`and in some patients, by 2 minutes.63 Mean
`plasma concentrations of buprenorphine in
`that study differed little after 5 minutes post-
`drug administration by either the intravenous
`or intramuscular routes; intramuscular bioavail-
`ability ranged from 40% to greater than 90%.
`The volume of distribution at steady state has
`usually been found to be between 200 and
`400 liters.76
`Following the administration of 0.3 mg of
`intravenous buprenorphine given intraopera-
`tively, the initial half-life was found to be about
`2 minutes,63 with a mean terminal half-life of 5
`hours.77 A study by Mendelson and coworkers78
`indicated that the mean terminal half-life of
`intravenously given buprenorphine (1 mg in-
`fused over 30 minutes) was about 6 hours.
`Kuhlman and colleagues79 reported a mean ter-
`minal half-life of 3.2 hours following single
`doses of 1.2 mg given intravenously.
`Buprenorphine clearance following intrave-
`nous administration has typically been reported
`to be between 70 and 80 liters/hour when doses
`in the analgesic range have been used.63,79 The
`clearance of buprenorphine in anesthetized
`patients was found to be lower than in the
`same individuals not under anesthesia secondary
`to reduced hepatic blood flow from the
`anesthetic.63
`
`Buprenorphine Sublingual Liquid/Buccal Strip
`The absorption of buprenorphine liquid
`from the sublingual mucosa is rapid, occurring
`within 5 minutes.80 In a study utilizing healthy
`volunteers,80,81 the bioavailability of buprenor-
`phine in a 30% ethanol solution administered
`sublingually was approximately 30%. Kuhlman
`and colleagues79 studied the pharmacokinetics
`of buprenorphine by various routes of admin-
`istration using a crossover design in healthy,
`non-dependent men who had a history of
`heroin abuse. Buprenorphine bioavailability by
`the sublingual and buccal routes was approxi-
`mately 51% and 28%, respectively, with much
`interindividual variability. The mean terminal
`half-lives were 28 hours following sublingual
`administration and 19 hours following buccal
`administration, compared with 3.2 hours
`following the intravenous route, perhaps re-
`lated to the sequestering of buprenorphine in
`
`the oral mucosa. Average clearances for the 3
`routes of administration were 210, 712, and 77
`liters/hour, respectively. In a study that evalu-
`ated sublingual dosages of buprenorphine up
`to 32 mg,33 peak plasma concentrations of bu-
`prenorphine were observed at 60 minutes fol-
`lowing doses of 2 and 4 mg, and at 30 minutes
`for doses of 8, 16, and 32 mg. Plasma concentra-
`tions after administration of the 32 mg dose
`were significantly elevated for up to 60 hours
`following medication administration. As noted
`previously, the oral bioavailability of buprenor-
`phine is very low (approximately 10%). Thus,
`the swallowing of buprenorphine that is not
`absorbed buccally or sublingually would con-
`tribute little to overall absorption.
`
`Buprenorphine Sublingual Tablets
`Following the sublingual administration of
`0.4 or 0.8 mg doses, there was no significant
`rise in buprenorphine plasma concentrations
`for 20 minutes; the time to maximum concen-
`tration was variable, ranging from 90 to 360
`minutes.76,77 The average systemic bioavailabil-
`ity was 55%, with large intersubject variability.
`A number of studies have assessed the phar-
`macokinetic profile of a buprenorphine tablet
`formulation. Bioavailability of the tablet was
`reported to be approximately 50–65% that
`of the sublingual solution, based on 48- and
`24-hour AUC measurements, respectively.82,83
`Results were generally comparable regardless
`of whether buprenorphine was administered
`as a single dose, or administered once daily
`over multiple days. When buprenorphine tab-
`lets were given over multiple days, average con-
`centrations peaked 2 hours after medication
`administration, in contrast to 1 hour as has
`been found for the solution.
`
`Buprenorphine for Intranasal Administration
`The bioavailability of intranasal buprenor-
`phine has been assessed in humans84 and
`sheep85 using a polyethylene glycol 300 (PEG)
`and a 5% dextrose vehicle. The buprenorphine
`formulation in humans was found to be approx-
`imately 50% bioavailable, with a time to maxi-
`mum concentration of 30 minutes. In sheep,
`the bioavailability of buprenorphine in PEG
`and dextrose was 70% and 89%, respectively;
`time to maximum concentration was 10 mi-
`nutes. From these data, it appears that an intra-
`nasal
`formulation of buprenorphine would
`
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`

`Vol. 29 No. 3 March 2005
`
`Buprenorphine for Pain Management
`
`303
`
`Fig. 3. Approximate bioavailability of buprenorphine by route of administration. Reprinted from Methadone
`Treatment for Opioid Dependence [Figure 13.2 (c)]. Strain, Eric C., M.D., and Maxine L. Stitzer, Ph.D.,
`eds. The Johns Hopkins University Press. Baltimore, Maryland: The Johns Hopkins University Press, 1999: 300.
`Reprinted with permission from The Johns Hopkins University Press.
`
`provide a rapid onset of analgesic effect. The ap-
`proximate bioavailability of buprenorphine by vari-
`ous routes of administration is shown in Figure 3.
`Buprenorphine for Transdermal Administration
`The ideal medication for transdermal ad-
`ministration should be highly lipophilic and of
`low molecular weight (less than approximately
`1000) for ease of crossing the skin barrier.86 It
`should also be highly potent so that adequate
`doses could be delivered through the skin. Bu-
`prenorphine meets these requirements. It has
`an octanol-to-water partition coefficient of 1217
`(i.e., high lipophilicity),87 a molecular weight
`of 468, and is 25 to 50 times more potent as
`an analgesic, per mg, than morphine. Further,
`with a transdermal formulation, a therapeutic
`blood level could be maintained over an ex-
`tended period of time, thus improving compli-
`ance and effectiveness of the medication.
`Recently, a transdermal buprenorphine pro-
`duct has been approved and marketed in a
`number of European countries.88,89 This trans-
`dermal system is designed to continuously re-
`lease buprenorphine at one of three defined
`rates: 35, 52.5, or 70 µg/hr, corresponding to
`daily doses of 0.84, 1.26, and 1.68 mg/24 hr,
`respectively. Effective plasma levels are reached
`within 12 to 24 hours and are kept at a constant
`level for 72 hours. The buprenorphine is incor-
`porated into a polymer adhesive matrix.
`Three dosage strengths of a seven-day bu-
`prenorphine transdermal system are being de-
`veloped in the United States, which deliver 5,
`
`10, or 20 µg/hr buprenorphine, respectively.90
`The highest strength patch (20 µg/hr) will
`result in a dosage of 0.48 mg/day. Compared
`to the higher-strength European product de-
`scribed above, these three dosage strengths may
`be more useful for milder pain syndromes. The
`buprenorphine is dissolved in a polymer matrix
`and the rate of drug release is controlled by
`the diffusion of the buprenorphine in the adhe-
`sive matrix through the stratum corneum of
`the epidermis. The concentration of buprenor-
`phine mixed in the adhesive matrix is the same
`for each strength. After application of the trans-
`dermal system with release rates of 5, 10, and
`20 µg/hr to healthy subjects, mean (⫾SEM)
`peak buprenorphine plasma concentrations
`(Cmax) were 176 ⫾ 34, 191 ⫾ 19, and 471 ⫾
`77 pg/mL, respectively.90 The concentration of
`buprenorphine released from each system per
`hour is proportional to the surface area of the
`system. The time to reach steady-state plasma
`concentrations was approximately 24 to 48
`hours and the percentage of the total dose del-
`ivered in 7 days was 15%.90 Following system
`removal, concentrations decreased to about
`one-half in 12 hours, then declined more gradu-
`ally with an apparent
`terminal half-life of
`26 hours.90,91
`
`Special Considerations
`
`Buprenorphine in Renal Failure. The disposition
`of buprenorphine in patients with renal failure
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`Johnson et al.
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`Vol. 29 No. 3 March 2005
`
`was examined in studies utilizing both single-
`and multiple-dosing.92 In the single-dose study
`using balanced anesthesia, buprenorphine was
`given intravenously at a dose of 0.3 mg. In the
`multiple-dose study, a variable-rate infusion was
`utilized with controlled ventilation to provide
`analgesia in the intensive care unit (median
`infusion rate of 161 µg/hr for a median of 30
`hours). In the first study, there were no differ-
`ences
`in buprenorphine kinetics between
`healthy patients and those with renal failure
`(all dialysis-dependent with creatinine clear-
`ances less than 5 mL/min). Buprenorphine
`clearances and dose-corrected plasma concen-
`trations were similar in the 2 groups of patients.
`However, in patients with renal failure (plasma
`creatinine concentration greater than 140
`µmol/liter), plasma concentrations of nor-
`buprenorphine were increased by a median of
`4 times, and buprenorphine-3-glucuronide by
`a median of 15 times.
`Another study, which measured only bupren-
`orphine (not metabolites) over a 3-hour sam-
`pling period, reported that the disposition of
`buprenorphine was similar in patients with end-
`stage renal failure compared to healthy con-
`trols.93 The renal failure patients did not show
`clinical evidence of sedation or respiratory
`depression.
`
`Buprenorphine in Hepatic Failure. Few data are
`available with regard to the use of buprenor-
`phine in patients with hepatic failure. A recent
`study evaluated the pharmacokinetic profile of
`buprenorphine (0.3 mg given intravenously) in
`subjects with mild to moderate chronic hepatic
`impairment and in healthy controls matched
`for age, weight, and sex.94 No differences be-
`tween the groups were observed for most
`pharmacokinetic parameters (e.g., steady-state
`volume of distribution, total clearance). How-
`ever, the maximum plasma concentrations of
`buprenorphine and norbuprenorphine were
`50% and 30% lower, respectively, in individuals
`with hepatic impairment. These subjects also
`had less nausea and vomiting than the controls.
`The results did not indicate the need for a
`buprenorphine dosage adjustment in individu-
`als with mild to moderate chronic hepatic
`impairment.
`
`Buprenorphine in Children and Infants. When
`buprenorphine (3 µg/kg) was given intrave-
`nously as premedication to children aged 4 to
`
`7 years, mean clearance was 3.6 liters/hr/kg
`and steady state volume of distribution varied
`from 1.2 to 8.3 liters/kg.95 None of the kinetic
`parameters correlated with age, body weight,
`or body surface area. Because buprenorphine
`plasma concentrations declined rapidly, termi-
`nal elimination half-life could not be estimated
`reliably. In a study of the pharmacokinetics of
`a buprenorphine infusion in premature neo-
`nates,96 the clearance of buprenorphine was
`lower than values previously reported for
`adults and children, probably related to im-
`maturity of
`the glucuronidation metabolic
`pathway.
`
`Clinical Pharmacology
`Analgesia and Anesthesia
`
`Pain Assessment and Treatment. Pain may be de-
`scribed as an unpleasant sensory and emotional
`experience associated with actual or potential
`tissue damage, or described in terms of such
`damage. It is typically categorized broadly as
`being either acute or chronic. Whereas acute
`pain is often associated with a particular injury
`or procedure, chronic pain is pain that has been
`present for more than three months, and which
`may be persistent or intermittent. In addition,
`chronic pain may persist after the disease itself
`has been effectively treated.97
`As noted by Bonica,98 few basic and clinical
`scientists had devoted their efforts to pain re-
`search prior to the 1960s. Differences between
`acute and chronic pain were not appreciated,
`and animal models, particularly for chronic
`pain, were not being developed. More recently,
`preclinical and clinical research studies have
`elucidated multiple mechanisms and sites asso-
`ciated with the production of pain.99 Pain itself
`is subject to much inter-individual variability
`with regard to threshold and tolerance, and has
`expectational and emotional components.100
`Thus, all clinical practice guidelines emphasize
`the need to use patient self-report as the gold
`standard for assessing pain rather than observ-
`ers’ reports because pain is such a personal
`experience.
`Numerous opioids and opioid-like medica-
`tions have been used to treat both acute and
`chronic pain. Chronic pain may involve pain
`related to cancer, as well as noncancer pain due
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`Buprenorphine for Pain Management
`
`305
`
`to osteoarthritis, chronic back pain, and neural-
`gia. Although morphine is the prototypical
`agent, numerous other drugs such as hydroco-
`done, oxycodone, methadone, and others have
`been utilized effectively. The use of opioid anal-
`gesics for the treatment of chronic noncancer
`pain, however, still elicits controversy, much of
`it related to concerns regarding adverse effects
`and possible addiction.101 It is especially im-
`portant to differentiate between addiction to
`opioids and the a