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A history of opioid abuse: Why buprenorphine is superior for the management of opioid use disorder and pain

Michael D. Komrowski, MS, Nitin K. Sekhri, MD


Opioid abuse represents a public health crisis that has significant associated morbidity and mortality. Since beginning in the early 1990’s, the opioid abuse epidemic has been difficult to control due to regulatory, economic, and psychosocial factors that have perpetuated its existence. This era of opioid abuse has been punctuated by three distinct rises in mortality, precipitated by unique public health problems that needed to be addressed. Patients affected by opioid abuse have been historically treated with either methadone or naltrexone. While these agents have clinical utility supported by robust literature, we the authors posit that buprenorphine is a superior therapy for both opioid use disorder (OUD) as well as pain. This primacy is due to the pharmacological properties of buprenorphine which render it unique among other opioid medications. One such property is buprenorphine’s ceiling effect of respiratory depression, a common side effect and complicating factor in the administration of many classical opioid medications. This profile renders buprenorphine safer, while simultaneously retaining therapeutic utility in the medical practitioner’s pharmacopeia for the treatment of opioid use disorder and pain.


opioid-related overdose deaths (ORODs), opioid use disorder (OUD), medication-assisted treatment, μ opioid receptor (MOR), κ opioid receptor (KOR)

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Hagemeier NE: Introduction to the opioid epidemic: The economic burden on the healthcare system and impact on quality

of life. Am J Manag Care. 2018; 24(10 Suppl): S200-S206. 2. Underlying Cause of Death 1999-2019 on CDC WONDER Online Database. 57 vital statistics jurisdictions through the Vital Statistics Cooperative Program. National Center for Health Statistics; 2020. Available at Accessted November 12, 2020.

Leonard J, Paulozzi M, Jones CM, et al.: Vital signs: Overdoses of prescription opioid pain relievers—United States. MMRW Morb Mortal Wkly Rep. 2011; 60(43): 1487-1492.

Rudd RA, Paulozzi LJ, Bauer MJ, et al.: Increases in heroin overdose deaths—28 states, 2010 to 2012. MMWR Morb Mortal Wkly Rep. 2014; 63(39): 849.

Gladden RM, Martinez P, Seth P: Fentanyl law enforcement submissions and increases in synthetic opioid-involved overdose deaths—27 states, 2013–2014. MMWR Morb Mortal Wkly Rep. 2016; 65(33): 837-843.

O’Donnell JK, Gladden RM, Seth P: Trends in deaths involving heroin and synthetic opioids excluding methadone, and law enforcement drug product reports, by census region—United States, 2006–2015. MMWR Morb Mortal Wkly Rep. 2017; 66(34): 897-903.

O’Donnell JK, Halpin J, Mattson CL, et al.: Deaths involving fentanyl, fentanyl analogs, and U-47700—10 states, July–December 2016. MMWR Morb Mortal Wkly Rep. 2017; 66(43): 1197-1202.

Armenian P, Vo KT, Barr-Walker J, et al.: Fentanyl, fentanyl analogs and novel synthetic opioids: A comprehensive review. Neuropharmacology. 2018; 134(Pt A): 121-132.

Prekupec MP, Mansky PA, Baumann MH: Misuse of novel synthetic opioids: A deadly new trend. J Addict Med. 2017; 11(4): 256-265.

Gladden M, O’Donnell J, Mattson C, et al.: Changes in opioid-involved overdose deaths by opioid type and presence of benzodiazepines, cocaine, and methamphetamine—25 states, July-December 2017 to January-June 2018. MMWR Morb Mortal Wkly Rep. 2019; 68(34): 737-744.

Kariisa M, Scholl L, Wilson N, et al.: Drug overdose deaths involving cocaine and psychostimulants with abuse potential—United States, 2003-2017. MMWR Morb Mortal Wkly Rep. 2019; 68(17): 41-43.

Bershad AK, Miller MA, Norman GJ, et al.: Effects of opioid- and non-opioid analgesics on responses to psychosocial stress in humans. Horm Behav. 2018; 102: 41-47.

Krupitsky E, Nunes EV, Ling W, et al.: Injectable extended-release naltrexone for opioid dependence: A double-blind, placebo-controlled, multicentre randomised trial. Lancet. 2011; 377(9776): 1506-1513.

Lee JD, Friedmann PD, Kinlock TW, et al.: Extended-release naltrexone to prevent opioid relapse in criminal justice offenders. N Engl J Med. 2016; 374(13): 1232-1242.

Mattick RP, Breen C, Kimber J, et al.: Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev. 2009; 2009(3): Cd002209.

Mattick RP, Kimber J, Breen C, et al.: Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev. 2004; 2(3): Cd002207.

Degenhardt L, Randall D, Hall W, et al.: Mortality among clients of a state-wide opioid pharmacotherapy program over 20 years: Risk factors and lives saved. Drug Alcohol Depend. 2009; 105(1-2): 9-15.

Gibson A, Degenhardt L, Mattick RP, et al.: Exposure to opioid maintenance treatment reduces long-term mortality. Addiction. 2008; 103(3): 462-468.

Schwartz RP, Gryczynski J, O'Grady KE, et al.: Opioid agonist treatments and heroin overdose deaths in Baltimore, Maryland, 1995-2009. Am J Public Health. 2013; 103(5): 917-922.

WHO Guidelines Approved by the Guidelines Review Committee: Guidelines for the Psychosocially Assisted Pharmacological Treatment of Opioid Dependence. Geneva: World Health Organization, 2009.

Services UDHaH: TIP 63: Medications for Opioid Use Disorder. Rockville, MD: HHS Publication, 2020: 63.

Johnson RE, Fudala PJ, Payne R: Buprenorphine: Considerations for pain management. J Pain Symptom Manag. 2005; 29(3): 297-326.

Bershad AK, Jaffe JH, Childs E, et al.: Opioid partial agonist buprenorphine dampens responses to psychosocial stress in humans. Psychoneuroendocrinology. 2015; 52: 281-288.

Raffa RB, Haidery M, Huang HM, et al.: The clinical analgesic efficacy of buprenorphine. J Clin Pharm Ther. 2014; 39(6): 577-583.

Dahan A, Yassen A, Romberg R, et al.: Buprenorphine induces ceiling in respiratory depression but not in analgesia. Br J Anaesth. 2006; 96(5): 627-632.

Khanna IK, Pillarisetti S: Buprenorphine—An attractive opioid with underutilized potential in treatment of chronic pain. J Pain Res. 2015; 8: 859-870. DOI:10.2147/JPR.S85951.

Goel A, Azargive S, Weissman JS, et al.: Perioperative Pain and Addiction Interdisciplinary Network (PAIN) clinical practice advisory for perioperative management of buprenorphine: Results of a modified Delphi process. Br J Anaesth. 2019; 123(2): e333-e342.

DailyMed Database: National Institutes of Health. 2020. Available at Accessed December 14, 2020.

Malinoff HL, Barkin RL, Wilson G: Sublingual buprenorphine is effective in the treatment of chronic pain syndrome. Am J Ther. 2005; 12(5): 379-384.

Elkader A, Sproule B: Buprenorphine. Clin Pharmacokinet. 2005; 44(7): 661-680.

Bullingham RE, McQuay HJ, Moore A, et al.: Buprenorphine kinetics. Clin Pharmacol Ther. 1980; 28(5): 667-672.

Lutfy K, Cowan A: Buprenorphine: A unique drug with complex pharmacology. Curr Neuropharmacol. 2004; 2(4): 395-402.

Waldhoer M, Bartlett SE, Whistler JL: Opioid receptors. Annu Rev Biochem. 2004; 73(1): 953-990.

Pradhan AA, Befort K, Nozaki C, et al.: The delta opioid receptor: An evolving target for the treatment of brain disorders. Trends Pharmacol Sci. 2011; 32(10): 581-590.

Pfeiffer A, Brantl V, Herz A, et al.: Psychotomimesis mediated by kappa opiate receptors. Science. 1986; 233(4765): 774-776.

Roth BL, Baner K, Westkaemper R, et al.: Salvinorin A: A potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proc Natl Acad Sci USA. 2002; 99(18): 11934-11939.

Simonin F, Valverde O, Smadja C, et al.: Disruption of the kappa-opioid receptor gene in mice enhances sensitivity to chemical visceral pain, impairs pharmacological actions of the selective kappa-agonist U-50,488H and attenuates morphine withdrawal. EMBO J. 1998; 17(4): 886-897.

Lalanne L, Ayranci G, Kieffer BL, et al.: The kappa opioid receptor: From addiction to depression, and back. Front Psychiatr. 2014; 5: 170. DOI:10.3389/fpsyt.2014.00170.

Carlezon WA Jr, Krystal AD: Kappa-opioid antagonists for psychiatric disorders: From bench to clinical trials. Depress Anxiety. 2016; 33(10): 895-906.

Kuhlman JJ Jr, Lalani S, Magluilo J Jr, et al.: Human pharmacokinetics of intravenous, sublingual, and buccal buprenorphine. J Anal Toxicol. 1996; 20(6): 369-378.

Brown Sarah M, Holtzman M, Kim T, et al.: Buprenorphine metabolites, buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, are biologically active. Anesthesiology. 2011; 115(6): 1251-1260.

Iribarne C, Picart D, Dréano Y, et al.: Involvement of cytochrome P450 3A4 in N-dealkylation of buprenorphine in human liver microsomes. Life Sci. 1997; 60(22): 1953-1964.

Kobayashi K, Yamamoto T, Chiba K, et al.: Human buprenorphine N-dealkylation is catalyzed by cytochrome P450 3A4. Drug Metab Dispos. 1998; 26(8): 818-821.

Holstege CP, Borek HA: Toxidromes. Crit Care Clin. 2012; 28(4): 479-498.

Boyer EW: Management of opioid analgesic overdose. N Engl J Med. 2012; 367(2): 146-155.

Barnwal P, Das S, Mondal S, et al.: Probuphine® (buprenorphine implant): A promising candidate in opioid dependence. Ther Adv Psychopharmacol. 2017; 7(3): 119-134.

Mendelson J, Upton RA, Everhart ET, et al.: Bioavailability of sublingual buprenorphine. J Clin Pharmacol. 1997; 37(1): 31-37.

Nath RP, Upton RA, Everhart ET, et al.: Buprenorphine pharmacokinetics: Relative bioavailability of sublingual tablet and liquid formulations. J Clin Pharmacol. 1999; 39(6): 619-623.

Gunderson EW, Hjelmström P, Sumner M: Effects of a higher-bioavailability buprenorphine/naloxone sublingual tablet versus buprenorphine/naloxone film for the treatment of opioid dependence during induction and stabilization: A multicenter, randomized trial. Clin Ther. 2015; 37(10): 2244-2255.

Greenwald MK, Johanson CE, Moody DE, et al.: Effects of buprenorphine maintenance dose on mu-opioid receptor availability, plasma concentrations, and antagonist blockade in heroin-dependent volunteers. Neuropsychopharmacology. 2003; 28(11): 2000-2009.

Zubieta J, Greenwald MK, Lombardi U, et al.: Buprenorphine-induced changes in mu-opioid receptor availability in male heroin-dependent volunteers: A preliminary study. Neuropsychopharmacology. 2000; 23(3): 326-334.

Walsh SL, Preston KL, Stitzer ML, et al.: Clinical pharmacology of buprenorphine: Ceiling effects at high doses. Clin Pharmacol Ther. 1994; 55(5): 569-580.

Walsh SL, Preston KL, Bigelow GE, et al.: Acute administration of buprenorphine in humans: Partial agonist and blockade effects. J Pharmacol Exp Ther. 1995; 274(1): 361-372.

Volpe DA, McMahon Tobin GA, Mellon RD, et al.: Uniform assessment and ranking of opioid μ receptor binding constants for selected opioid drugs. Regul Toxicol Pharmacol. 2011; 59(3): 385-390.

Yang PP, Yeh GC, Yeh TK, et al.: Activation of delta-opioid receptor contributes to the antinociceptive effect of oxycodone in mice. Pharmacol Res. 2016; 111: 867-876.

Cooney M, Quinlan-Colwell A: Assessment and Multimodal Management of Pain: An Integrative Approach. 1st ed. Amsterdam: Elsevier, 2020.



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