Buprenorphine

Abstract

Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativedrugs.com. The series editors welcome feedback on the articles ([email protected]). Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativedrugs.com. The series editors welcome feedback on the articles ([email protected]). Off-label use Continuous intravenous infusion Continuous subcutaneous infusion Cytochrome P450 Gastrointestinal Intramuscular Intravenous Opioid-receptor-like-1 Package insert Per os, by mouth Pro re nata, as required Every 4 hours etc. QT interval corrected for heart rate Randomized controlled trial Subcutaneous Sublingual Transdermal Three times daily Time to peak plasma concentration For international educational and comparative purposes, this article also refers to formulations not available in the USA. Buprenorphine is experiencing a renaissance in the management of chronic cancer and non-cancer pain, and opioid dependence (high-dose SL formulation ± naloxone).1Resnick R.B. Food and Drug Administration approval of buprenorphine-naloxone for office treatment of addiction.Ann Intern Med. 2003; 138: 360Crossref PubMed Scopus (10) Google Scholar, 2Budd K. Raffa R. Buprenorphine - the unique opioid analgesic. Georg Thieme Verlag, Stuttgart, Germany2005: 134Google Scholar, 3Griessinger N. Sittl R. Likar R. Transdermal buprenorphine in clinical practice–a post-marketing surveillance study in 13,179 patients.Curr Med Res Opin. 2005; 21: 1147-1156Crossref PubMed Scopus (131) Google Scholar, 4Gowing L. Ali R. White J.M. Buprenorphine for the management of opioid withdrawal.Cochrane Database Syst Rev. 2006; 2: CD002025PubMed Google Scholar, 5Landau C.J. Carr W.D. Razzetti A.J. et al.Buprenorphine transdermal delivery system in adults with persistent noncancer-related pain syndromes who require opioid therapy: a multicenter, 5-week run-in and randomized, double-blind maintenance-of-analgesia study.Clin Ther. 2007; 29: 2179-2193Abstract Full Text PDF PubMed Scopus (51) Google Scholar, 6Kress H.G. Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine.Eur J Pain. 2009; 13: 219-230Crossref PubMed Scopus (180) Google Scholar, 7Przeklasa-Muszynska A. Dobrogowski J. Transdermal buprenorphine for the treatment of moderate to severe chronic pain: results from a large multicenter, non-interventional post-marketing study in Poland.Curr Med Res Opin. 2011; 27: 1109-1117Crossref PubMed Scopus (20) Google Scholar Preliminary data suggest that compared to morphine and other opioids, buprenorphine appears to cause less hyperalgesia and tolerance, and has less effect on the immune and endocrine systems. However, clinical trials are needed to find out if such differences represent real clinical advantages. Class: Opioid analgesic. In the USA, the injection (300microgram) and low-dose TD patches (5, 10, 20microgram/h) are approved for moderate–severe chronic pain. High-dose SL tablets (2mg, 8mg) and a SL film (2mg, 4mg, 8mg, 12mg) also containing naloxone are labeled for use as maintenance therapy in opioid addicts. In many other countries, in addition to the injection, low-dose SL tablets (200microgram, 400microgram) and high-dose TD patches (35, 52.5, 70microgram/h) are approved for moderate–severe chronic pain. Contraindications: Hypersensitivity to buprenorphine, significant respiratory depression, acute or severe asthma, known or suspected paralytic ileus. TD buprenorphine should not be used for acute (transient, intermittent, short-term) pain, e.g., postoperative, or when there is need for rapid dose titration for severe pain. Buprenorphine is a partial μ-opioid receptor and opioid-receptor-like (ORL-1) agonist and a κ- and δ-opioid receptor antagonist.8Rothman R. Buprenorphine: a review of the binding literature.in: Cowan A. Lewis J. Buprenorphine: combatting drug abuse with a unique opioid. Wiley-Liss, New York1995: 19-29Google Scholar, 9Zaki P.A. Keith Jr., D.E. Brine G.A. Carroll F.I. Evans C.J. Ligand-induced changes in surface mu-opioid receptor number: relationship to G protein activation?.J Pharmacol Exp Ther. 2000; 292: 1127-1134PubMed Google Scholar, 10Lewis J.W. Husbands S.M. The orvinols and related opioids–high affinity ligands with diverse efficacy profiles.Curr Pharm Des. 2004; 10: 717-732Crossref PubMed Scopus (76) Google Scholar It has high affinity at the μ-, κ- and δ-opioid receptors, but affinity at the ORL-1 receptor is 500 times less. It associates and dissociates slowly from receptors.11Greenwald M. Johanson C.E. Bueller J. et al.Buprenorphine duration of action: mu-opioid receptor availability and pharmacokinetic and behavioral indices.Biol Psychiatry. 2007; 61: 101-110Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar Subjective and physiological effects are generally similar to morphine (μ-opioid receptor agonist). Studies in volunteers suggest that compared to morphine and other opioids, buprenorphine exerts a more prominent antihyperalgesic than analgesic effect;12Koppert W. Ihmsen H. Körber N. et al.Different profiles of buprenorphine-induced analgesia and antihyperalgesia in a human pain model.Pain. 2005; 118: 15-22Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 13Simonnet G. Opioids: from analgesia to anti-hyperalgesia?.Pain. 2005; 118: 8-9Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar however, this is not a consistent finding.14Ravn P. Secher E.L. Skram U. et al.Morphine- and buprenorphine-induced analgesia and antihyperalgesia in a human inflammatory pain model: a double-blind, randomized, placebo-controlled, five-arm crossover study.J Pain Res. 2013; 6: 23-38Crossref PubMed Scopus (22) Google Scholar Animal studies and case reports also suggest that buprenorphine may be of particular benefit in neuropathic pain,2Budd K. Raffa R. Buprenorphine - the unique opioid analgesic. Georg Thieme Verlag, Stuttgart, Germany2005: 134Google Scholar, 15Hans G. Buprenorphine–a review of its role in neuropathic pain.J Opioid Manag. 2007; 3: 195-206PubMed Google Scholar but controlled studies are needed to confirm this.6Kress H.G. Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine.Eur J Pain. 2009; 13: 219-230Crossref PubMed Scopus (180) Google Scholar, 16Sanchez-Blazquez P. Garzon J. Pertussis toxin differentially reduces the efficacy of opioids to produce supraspinal analgesia in the mouse.Eur J Pharmacol. 1988; 152: 357-361Crossref PubMed Scopus (59) Google Scholar, 17Likar R. Sittl R. Transdermal buprenorphine for treating nociceptive and neuropathic pain: four case studies.Anesth Analg. 2005; 100: 781-785Crossref PubMed Scopus (54) Google Scholar, 18Penza P. Campanella A. Martini A. et al.Short- and intermediate-term efficacy of buprenorphine TDS in chronic painful neuropathies.J Peripher Nerv Syst. 2008; 13: 283-288Crossref PubMed Scopus (15) Google Scholar The co-administration of an ultra-low dose of an opioid antagonist potentiated the analgesic effect of buprenorphine (as with other opioids) in healthy volunteers but not in patients.19Hay J.L. La Vincente S.F. Somogyi A.A. Chapleo C.B. White J.M. Potentiation of buprenorphine antinociception with ultra-low dose naltrexone in healthy subjects.Eur J Pain. 2011; 15: 293-298Crossref PubMed Scopus (14) Google Scholar, 20Ling W. Hillhouse M. Jenkins J. et al.Comparisons of analgesic potency and side effects of buprenorphine and buprenorphine with ultra-low-dose naloxone.J Addict Med. 2012; 6: 118-123Crossref PubMed Scopus (7) Google Scholar Antagonist effects at the κ-opioid receptor may limit spinal analgesia, sedation and psychotomimetic effects.21Johnson R.E. Fudala P.J. Payne R. Buprenorphine: considerations for pain management.J Pain Symptom Manage. 2005; 29: 297-326Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar In animal studies, buprenorphine shows a ceiling effect or a bell-shaped dose-response curve for analgesic (>1mg/kg) and respiratory effects (0.1mg/kg). This is thought to be due to its partial agonist effect at the μ-opioid receptor. An agonist effect at the pronociceptive supraspinal ORL-1 receptor also may contribute.22Lutfy K. Eitan S. Bryant C.D. et al.Buprenorphine-induced antinociception is mediated by mu-opioid receptors and compromised by concomitant activation of opioid receptor-like receptors.J Neurosci. 2010; 23: 10331-10337Google Scholar In humans, a ceiling effect has been shown for respiratory depression (∼200microgram/70kg IV)23Dahan A. Yassen A. Bijl H. et al.Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in humans and rats.Br J Anaesth. 2005; 94: 825-834Crossref PubMed Scopus (237) Google Scholar, 24Dahan A. Yassen A. Romberg R. et al.Buprenorphine induces ceiling in respiratory depression but not in analgesia.Br J Anaesth. 2006; 96: 627-632Crossref PubMed Scopus (260) Google Scholar and other effects, e.g., euphoria (4–8mg SL),25Budd K. Buprenorphine: a review.in: Evidence based medicine in practice. Hayward Medical Communications, Newmarket2002: 1-24Google Scholar, 26Walsh S.L. Preston K.L. Stitzer M.L. Cone E.J. Bigelow G.E. Clinical pharmacology of buprenorphine: ceiling effects at high doses.Clin Pharmacol Ther. 1994; 55: 569-580Crossref PubMed Scopus (644) Google Scholar but not for analgesia.24Dahan A. Yassen A. Romberg R. et al.Buprenorphine induces ceiling in respiratory depression but not in analgesia.Br J Anaesth. 2006; 96: 627-632Crossref PubMed Scopus (260) Google Scholar Total daily doses up to 24mg SL are reported to provide effective analgesia;27Malinoff H.L. Barkin R.L. Wilson G. Sublingual buprenorphine is effective in the treatment of chronic pain syndrome.Am J Ther. 2005; 12: 379-384Crossref PubMed Scopus (93) Google Scholar, 28Heit H.A. Gourlay D.L. Buprenorphine: new tricks with an old molecule for pain management.Clin J Pain. 2008; 24: 93-97Crossref PubMed Scopus (72) Google Scholar, 29Rosenblum A. Cruciani R.A. Strain E.C. et al.Sublingual buprenorphine/naloxone for chronic pain in at-risk patients: development and pilot test of a clinical protocol.J Opioid Manag. 2012; 8: 369-382Crossref PubMed Scopus (40) Google Scholar anecdotally, even higher doses have been used, with no upper dose limit clearly established (R. Portenoy, February 2013, personal communication). Thus, the ceiling dose for analgesia in humans is much higher than the “maximum” TD dose recommended in the UK, namely 3.36mg/day (70microgram/h patches x 2). Studies of buprenorphine TD or SL up to 1.6mg/day confirm that it is possible to use morphine (or other μ-opioid receptor agonist) for breakthrough (episodic) pain30Mercadante S. Villari P. Ferrera P. et al.Safety and effectiveness of intravenous morphine for episodic breakthrough pain in patients receiving transdermal buprenorphine.J Pain Symptom Manage. 2006; 32: 175-179Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar and to switch either way between buprenorphine and morphine (or other μ-opioid receptor agonists) without loss of analgesia.31Atkinson R.E. Schofield P. Mellor P. The efficacy in sequential use of buprenorphine and morphine in advanced cancer pain.in: Doyle D. Opioids in the treatment of cancer pain. Royal Society of Medicine Services, London1990: 81-87Google Scholar, 32Mercadante S. Porzio G. Fulfaro F. et al.Switching from transdermal drugs: an observational "N of 1" study of fentanyl and buprenorphine.J Pain Symptom Manage. 2007; 34: 532-538Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar However, greater difficulties are experienced when switching patients on higher doses of opioids, using larger doses of buprenorphine.29Rosenblum A. Cruciani R.A. Strain E.C. et al.Sublingual buprenorphine/naloxone for chronic pain in at-risk patients: development and pilot test of a clinical protocol.J Opioid Manag. 2012; 8: 369-382Crossref PubMed Scopus (40) Google Scholar When patients on various opioids (oral morphine equivalent 15–450mg/24h) were switched using doses of buprenorphine 2mg SL (resulting in maximum post-switch doses of 6–24mg/24h), over half experienced intolerable adverse effects and abandoned the switch. Generally, adverse effects related to opioid excess in patients receiving low doses of oral morphine equivalent (≤20mg/24h) and opioid withdrawal in those receiving high doses (>300mg/24h). This experience guided the development of a clinical protocol, although the modified dosing algorithm has not yet been tested formally.29Rosenblum A. Cruciani R.A. Strain E.C. et al.Sublingual buprenorphine/naloxone for chronic pain in at-risk patients: development and pilot test of a clinical protocol.J Opioid Manag. 2012; 8: 369-382Crossref PubMed Scopus (40) Google Scholar The use of other μ-opioid receptor agonists for breakthrough (episodic) pain in patients on higher doses of buprenorphine also may be less straightforward (see SL opioid-maintenance therapy in addicts). Nonetheless, various μ-opioid receptor agonists have been used in patients on SL buprenorphine 2–32mg/24h, although higher doses than usual may be required.28Heit H.A. Gourlay D.L. Buprenorphine: new tricks with an old molecule for pain management.Clin J Pain. 2008; 24: 93-97Crossref PubMed Scopus (72) Google Scholar, 33Kornfield H. Manfredi L. Effectiveness of full agonist opioids in patients stablized on buprenorphine undergoing major surgery: a case series.Am J Ther. 2010; 17: 523-528Crossref PubMed Scopus (58) Google Scholar Unlike morphine, buprenorphine has little or no effect on pressure in biliary and pancreatic ducts.34Pausawasdi S. Kanjanapitak A. Kanjanapanjapol S. The effect of buprenorphine and morphine on intraluminal pressure of the common bile duct.J Med Assoc Thai. 1984; 67: 329-333PubMed Google Scholar, 35Staritz M. Poralla T. Manns M. Meyer Zum Büschenfelde K.H. Effect of modern analgesic drugs (tramadol, pentazocine, and buprenorphine) on the bile duct sphincter in man.Gut. 1986; 27: 567-569Crossref PubMed Scopus (84) Google Scholar Buprenorphine slows intestinal transit, but possibly less than morphine.36Robbie D.S. A trial of sublingual buprenorphine in cancer pain.Br J Clin Pharmacol. 1979; 7: S315-S317Crossref PubMed Scopus (42) Google Scholar, 37Bach V. Kamp-Jensen M. Jensen N.-H. et al.Buprenorphine and sustained-release morphine – effect and side-effects in chronic use.Pain Clinic. 1991; 4: 87-93Google Scholar Constipation may be less severe.38Pace M.C. Passavanti M.B. Grella E. et al.Buprenorphine in long-term control of chronic pain in cancer patients.Front Biosci. 2007; 12: 1291-1299Crossref PubMed Scopus (49) Google Scholar Compared with morphine and other opioids, buprenorphine appears less likely to suppress the gonadal axis or testosterone levels.39Hallinan R. Byrne A. Agho K. et al.Hypogonadism in men receiving methadone and buprenorphine maintenance treatment.Int J Androl. 2009; 32: 131-139Crossref PubMed Scopus (88) Google Scholar This may relate to its κ-opioid receptor antagonist effect.40Bliesener N. Albrecht S. Schwager A. et al.Plasma testosterone and sexual function in men receiving buprenorphine maintenance for opioid dependence.J Clin Endocrinol Metab. 2005; 90: 203-206Crossref PubMed Scopus (175) Google Scholar Because hypogonadism is associated with reduced sexual desire and function, mood disturbance, fatigue and other physiological effects (e.g., muscle wasting, osteoporosis), this may be an important consideration in patients requiring long-term opioid therapy.41Daniell H.W. Hypogonadism in men consuming sustained-action oral opioids.J Pain. 2002; 3: 377-384Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar, 42Rajagopal A. Vassilopoulou-Sellin R. Palmer J.L. Kaur G. Bruera E. Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids.Cancer. 2004; 100: 851-858Crossref PubMed Scopus (171) Google Scholar, 43Hallinan R. Byrne A. Agho K. et al.Erectile dysfunction in men receiving methadone and buprenorphine maintenance treatment.J Sex Med. 2008; 5: 684-692Crossref PubMed Scopus (122) Google Scholar Compared with morphine and other opioids, buprenorphine has little or no immunosuppressive effect.2Budd K. Raffa R. Buprenorphine - the unique opioid analgesic. Georg Thieme Verlag, Stuttgart, Germany2005: 134Google Scholar, 44Sacerdote P. Bianchi M. Gaspani L. et al.The effects of tramadol and morphine on immune responses and pain after surgery in cancer patients.Anesth Analg. 2000; 90: 1411-1414Crossref PubMed Scopus (294) Google Scholar, 45Budd K. Shipton E. Acute pain and the immune system and opioimmunosuppression.Acute Pain. 2004; 6: 123-135Abstract Full Text Full Text PDF Scopus (17) Google Scholar, 46Sacerdote P. Franchi S. Gerra G. et al.Buprenorphine and methadone maintenance treatment of heroin addicts preserves immune function.Brain Behav Immun. 2008; 22: 606-613Crossref PubMed Scopus (65) Google Scholar In an anecdotal report, 2 of 5 patients with cholestatic pruritus responded to buprenorphine.47Juby L.D. Wong V.S. Losowsky M.S. Buprenorphine and hepatic pruritus.Br J Clin Pract. 1994; 48: 331PubMed Google Scholar, 48Reddy L. Krajnik M. Zylicz Z. Transdermal buprenorphine may be effective in the treatment of pruritus in primary biliary cirrhosis.J Pain Symptom Manage. 2007; 34: 455-456Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar However, there are insufficient data at present to recommend its use for this. Compared with methadone, buprenorphine has less effect on the QT interval.49Wedam E.F. Bigelow G.E. Johnson R.E. Nuzzo P.A. Haigney M.C. QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial.Arch Intern Med. 2007; 167: 2469-2475Crossref PubMed Scopus (220) Google Scholar, 50Esses J.L. Rosman J. Do L.T. Schweitzer P. Hanon S. Successful transition to buprenorphine in a patient with methadone-induced torsades de pointes.J Interv Card Electrophysiol. 2008; 23: 117-119Crossref PubMed Scopus (20) Google Scholar Doses of TD buprenorphine up to 140microgram/h are approved in countries other than the USA but, because of QT prolongation in healthy volunteers with 40microgram/h, the maximum approved dose in the USA is only 20microgram/h. However, the mean increase in QTc was 9msec, well below the level generally considered to be of concern (20–60msec) or serious concern (>60msec).51Twycross R. Wilcock A. Prolongation of the QT interval in palliative care.in: Palliative care formulary. 4th ed. palliativedrugs.com Ltd., Nottingham, UK2011Google Scholar Such dose limitation seems excessively restrictive. Buprenorphine is highly lipid-soluble making it suitable for TD delivery. It is available in formulations delivering 5, 10 or 20microgram/h over 7 days (BuTrans®).52Steiner D.J. Sitar S. Wen W. et al.Efficacy and safety of the seven-day buprenorphine transdermal system in opioid-naive patients with moderate to severe chronic low back pain: an enriched, randomized, double-blind, placebo-controlled study.J Pain Symptom Manage. 2011; 42: 903-917Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 53Conaghan P.G. O'Brien C.M. Wilson M. Schofield J.P. Transdermal buprenorphine plus oral paracetamol vs an oral codeine-paracetamol combination for osteoarthritis of hip and/or knee: a randomised trial.Osteoarthritis Cartilage. 2011; 19: 930-938Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 54Steiner D. Munera C. Hale M. Ripa S. Landau C. Efficacy and safety of buprenorphine transdermal system (BTDS) for chronic moderate to severe low back pain: a randomized, double-blind study.J Pain. 2011; 12: 1163-1173Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar Outside the USA, formulations delivering 35, 52.5 or 70microgram/h over 4 days are also available (Transtec®).55Likar R. Lorenz V. Korak-Leiter M. Kager I. Sittl R. Transdermal buprenorphine patches applied in a 4-day regimen versus a 3-day regimen: a single-site, Phase III, randomized, open-label, crossover comparison.Clin Ther. 2007; 29: 1591-1606Abstract Full Text PDF PubMed Scopus (23) Google Scholar Like other strong opioids, buprenorphine is an alternative to both weak opioids and morphine.56Davis M.P. Buprenorphine in cancer pain.Support Care Cancer. 2005; 13: 878-887Crossref PubMed Scopus (51) Google Scholar Buprenorphine is evenly distributed in a drug-in-adhesive matrix. Its release is controlled by the physical characteristics of the matrix and is proportional to the surface area of the patch. Absorption of the buprenorphine through the skin and into the systemic circulation is influenced by the stratum corneum and blood flow. Thus, if the skin is warm and vasodilated, the rate of absorption increases. There are few practical differences in the use of the buprenorphine or fentanyl matrix patches, and similar safety considerations apply, e.g., not to expose the patch to external sources of heat. Compared with fentanyl, TD buprenorphine (as Transtec®) adheres better. However, after patch removal, it is associated with more persistent erythema (± localized pruritus), and sometimes a more definite dermatitis.57Schmid-Grendelmeier P. Pokorny R. Gasser U.E. Richarz U. A comparison of the skin irritation potential of transdermal fentanyl versus transdermal buprenorphine in middle-aged to elderly healthy volunteers.Curr Med Res Opin. 2006; 22: 501-509Crossref PubMed Scopus (21) Google Scholar This is generally caused by the adhesive, but occasionally buprenorphine itself causes a contact dermatitis ± more widespread skin rash.58Vander Hulst K. Parera Amer E. Jacobs C. et al.Allergic contact dermatitis from transdermal buprenorphine.Contact Dermatitis. 2008; 59: 366-369Crossref PubMed Scopus (28) Google Scholar Retrospective analysis suggests that, compared with TD fentanyl, patients receiving TD buprenorphine (as Transtec®) have a slower rate of dose increase and longer periods of dose stability.59Sittl R. Nuijten M. Nautrup B.P. Patterns of dosage changes with transdermal buprenorphine and transdermal fentanyl for the treatment of noncancer and cancer pain: a retrospective data analysis in Germany.Clin Ther. 2006; 28: 1144-1154Abstract Full Text PDF PubMed Scopus (34) Google Scholar This requires confirmation in a controlled study. Indeed, systematic reviews have highlighted a lack of high quality studies of TD buprenorphine.60Deandrea S. Corli O. Moschetti I. Apolone G. Managing severe cancer pain: the role of transdermal buprenorphine: a systematic review.Ther Clin Risk Manag. 2009; 5: 707-718PubMed Google Scholar, 61Tassinari D. Drudi F. Rosati M. Maltoni M. Transdermal opioids as front line treatment of moderate to severe cancer pain: a systemic review.Palliat Med. 2011; 25: 478-487Crossref PubMed Scopus (28) Google Scholar Buprenorphine binds to the μ-opioid receptor with a higher affinity than other μ-opioid agonists. Studies in addicts indicate that buprenorphine 16mg SL leads to 80% of the μ-opioid receptors in the brain being occupied which is sufficient to antagonize the subjective and respiratory depressant effects of hydromorphone, a μ-opioid receptor agonist.11Greenwald M. Johanson C.E. Bueller J. et al.Buprenorphine duration of action: mu-opioid receptor availability and pharmacokinetic and behavioral indices.Biol Psychiatry. 2007; 61: 101-110Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 62Greenwald M.K. Johanson C.E. Moody D.E. et al.Effects of buprenorphine maintenance dose on mu-opioid receptor availability, plasma concentrations, and antagonist blockade in heroin-dependent volunteers.Neuropsychopharmacology. 2003; 28: 2000-2009Crossref PubMed Scopus (227) Google Scholar This has implications for the management of acute pain in these patients, e.g., postoperative or traumatic pain (for an overview, see63Twycross R. Wilcock A. Management of postoperative pain in opioid-dependent patients.in: Palliative care formulary. 4th ed. palliativedrugs.com Ltd., Nottingham, UK2011Google Scholar) and potentially for patients on higher-dose buprenorphine for chronic pain (see above). Significant respiratory depression is rarely seen with clinically recommended doses. A lower risk of respiratory depression also may explain why buprenorphine (mainly SL ± naloxone) appears to have a better safety profile than methadone.64Dasgupta N. Bailey E.J. Cicero T. et al.Post-marketing surveillance of methadone and buprenorphine in the United States.Pain Med. 2010; 11: 1078-1091Crossref PubMed Scopus (69) Google Scholar However, serious or fatal respiratory depression has occurred in addicts misusing buprenorphine, generally in high-dose IV and in combination with benzodiazepines or other CNS depressants, e.g., alcohol.65Kintz P. Deaths involving buprenorphine: a compendium of French cases.Forensic Sci Int. 2001; 121: 65-69Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar, 66Häkkinen M. Launiainen T. Vuori E. Ojanperä I. Benzodiazepines and alcohol are associated with cases of fatal buprenorphine poisoning.Eur J Clin Pharmacol. 2012; 68: 301-309Crossref PubMed Scopus (95) Google Scholar Because buprenorphine has very strong receptor affinity (reflected in its high relative potency with morphine), naloxone in standard doses does not reverse the effects of buprenorphine and higher doses must be used (Box A).2Budd K. Raffa R. Buprenorphine - the unique opioid analgesic. Georg Thieme Verlag, Stuttgart, Germany2005: 134Google Scholar, 67Dahan A. Aarts L. Smith T.W. Incidence, reversal, and prevention of opioid-induced respiratory depression.Anesthesiology. 2010; 112: 226-238Crossref PubMed Scopus (428) Google Scholar The non-specific respiratory stimulant doxapram can also be used, 1–1.5mg/kg IV over 30sec, repeated if necessary at hourly intervals or 1.5–4mg/min CIVI.67Dahan A. Aarts L. Smith T.W. Incidence, reversal, and prevention of opioid-induced respiratory depression.Anesthesiology. 2010; 112: 226-238Crossref PubMed Scopus (428) Google Scholar, 68British National FormularySection 3.5.1 Respiratory stimulants.in: British National Formulary (No. 61). British Medical Association and Royal Pharmaceutical Society of Great Britain, London2013www.bnf.orgGoogle Scholar, 69Orwin J.M. The effect of doxapram on buprenorphine induced respiratory depression.Acta Anaesthesiol Belg. 1977; 28: 93-106PubMed Google ScholarBox AReversal of Buprenorphine-induced Respiratory Depression1.Discontinue buprenorphine (stop CSCI/CIVI, remove TD patch).2.Give oxygen by mask.3.Give IV naloxone 2mg stat over 90sec.4.Commence naloxone 4mg/h by CIVI.5.Continue CIVI until the patient’s condition is satisfactory (probably <90min).6.Monitor the patient frequently for the next 24h, and restart CIVI if respiratory depression recurs.7.If the patient’s condition remains satisfactory, restart buprenorphine at a reduced dose, e.g., half the previous dose. 1.Discontinue buprenorphine (stop CSCI/CIVI, remove TD patch).2.Give oxygen by mask.3.Give IV naloxone 2mg stat over 90sec.4.Commence naloxone 4mg/h by CIVI.5.Continue CIVI until the patient’s condition is satisfactory (probably <90min).6.Monitor the patient frequently for the next 24h, and restart CIVI if respiratory depression recurs.7.If the patient’s condition remains satisfactory, restart buprenorphine at a reduced dose, e.g., half the previous dose. Buprenorphine has a longer duration of action than morphine. In postoperative single-dose studies, buprenorphine provided analgesia for 6–7h compared with 4–5h with morphine.70Heel R.C. Brogden R.N. Speight T.M. Avery G.S. Buprenorphine: a review of its pharmacological properties and therapeutic efficiency.Drugs. 1979; 17: 81-110Crossref PubMed Scopus (340) Google Scholar This is reflected in the recommended dose frequency (q8h–q6h vs. q4h for morphine). However, the longer duration of action of buprenorphine almost certainly means that potency ratios based on single-dose studies will underestimate the potency of buprenorphine. Thus, the following ratios should be not be regarded as “cast iron.” They merely provide a rough guide for use when switching route or opioids (see also Opioid dose conversion ratios, in PCF):71Twycross R. Wilcock A. Opioid dose conversion ratios.in: Palliative care formulary. 4th ed. palliativedrugs.com Ltd., Nottingham, UK2011Google Scholar•SL buprenorphine is about half as potent as IV/IM/SC buprenorphine; thus, in round figures, 200microgram SL is equivalent to 100microgram by injection72Ellis R. Haines D. Shah R. Cotton B.R. Smith G. Pain relief after abdominal surgery–a comparison of i.m. morphine, sublingual buprenorphine and self-administered i.v. pethidine.Br J Anaesth. 1982; 54: 421-428Crossref PubMed Scopus (53) Google Scholar, 73Bullingham R.E. O'Sullivan G. McQuay H.J. et al.Mandatory sublingual buprenorphine for postoperative pain.Anaesthesia. 1984; 39: 329-334Crossref PubMed Scopus (12) Google Scholar•SL buprenorphine is about 80 times more potent than PO morphine31Atkinson R.E. Schofield P. Mellor P. The efficacy in sequential use of buprenorphine and morphine in advanced cancer pain.in: Doyle D. Opioids in the treatment of cancer pain. Royal Society of Medicine Services,