Open Access Open Access  Restricted Access Subscription or Fee Access

Emerging pharmacologic mechanisms of buprenorphine to explain experience of analgesia versus adverse effects

Jeffrey Bettinger, PharmD, Himayapsill Batista Quevedo, PharmD, Jacqueline Cleary, PharmD, BCACP

Abstract


Buprenorphine’s unique pharmacologic mechanisms of action lend itself to a higher level of complexity than its typical characterization as a partial agonist at μ-opioid receptors. It is well-documented that its additional activity at Δ- and κ-opioid receptors, and opioid receptor ligand 1 may be associated with varying degrees of analgesia and usual opioid-related adverse effects. However, novel downstream molecular and cellular mechanisms from μ-opioid receptor activation contain potential new insights into its overall unique effects. These include buprenorphine’s peculiar ability to induce analgesia at escalating doses, while exhibiting a plateaued effect on respiratory depression, euphoria, gastrointestinal (GI) motility, depression, anxiety, and addictive potential. Thus, this review aims to discuss several of these emerging mechanisms to gain a better understanding of these curious actions, as well as support much of this in vitro evidence with various human clinical trial data to further support buprenorphine’s place on the analgesic ladder.


Keywords


buprenorphine, G-protein-coupled opioid receptors, β-arrestin, respiratory depression, analgesia, euphoria

Full Text:

PDF

References


Olfson M, Zhang V, Schoenbaum M, et al.: Trends in buprenorphine treatment in the United States, 2009-2018. JAMA. 2020; 323(3): 276-277.

Rosen K, Gutierrez AM, Haller D, et al.: Sublingual buprenorphine for chronic pain: A survey of clinician prescribing practices. Clin J Pain. 2014; 30(4): 295-300.

Khroyan TV, Wu J, Polgar WE, et al.: BU08073 a buprenorphine analogue with partial agonist activity at mu-receptors in vitro but long-lasting opioid antagonist activity in vivo in mice. Br J Pharmacol. 2015; 172(2): 668-680.

Grinnell SG, Ansonoff M, Marrone GF, et al.: Mediation of buprenorphine analgesia by a combination of traditional and truncated mu opioid receptor splice variants. Synapse. 2016; 70(10): 395-407.

Gudin J, Fudin J: A narrative pharmacological review of buprenorphine: A unique opioid for the treatment of chronic pain. Pain Ther. 2020; 9(1): 41-54.

Yamamoto T, Shono K, Tanabe S: Buprenorphine activates mu and opioid receptor like-1 receptors simultaneously, but the analgesic effect is mainly mediated by mu receptor activation in the rat formalin test. J Pharmacol Exp Ther. 2006; 318(1): 206-213.

Webster L, Gudin J, Raffa R, et al.: Understanding buprenorphine for use in chronic pain: Expert opinion. Pain Med. 2020; 21(4): 714-723.

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

Maehle AH, Prull CR, Halliwell RF: The emergence of the drug receptor theory. Nat Rev Drug Discov. 2002; 1: 637-641.

Traynor J: mu-Opioid receptors and regulators of G protein signaling (RGS) proteins: From a symposium on new concepts in mu-opioid pharmacology. Drug Alcohol Depend. 2012; 121: 173-180.

Traynor JR: G-protein coupling and efficacy of mu-opioid agonists: Relationship to behavioral efficacy. Rev Analgesia. 2004; 8: 11-22.

Huang P, Kehner GB, Cowan A, et al.: Comparison of pharmacological activities of buprenorphine and norbuprenorphine: Norbuprenorphine is a potent opioid agonist. J Pharmacol Exp Ther. 2001; 297: 688-695.

Bidlack JM, Knapp BI, Deaver DR, et al.: In vitro pharmacological characterization of buprenorphine, samidorphan, and comintations being developed as an adjunctive treatment of major depressive disorder. J Pharmacol Exp Ther. 2018; 367(2): 267-281.

Masuho I, Ostrovskaya O, Kramer GM, et al.: Distinct profiles of functional discrimination among G proteins determine the actions of Gprotein-coupled receptors. Sci Signal. 2015; 8(405): ra123-ra123.

Al-Hasani R, Bruchas MR: Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology. 2011; 115(6): 1363-1381.

Smrcka AV: G protein βγ subunits: Central mediators of G protein-coupled receptor signaling. Cell Mol Life Sci. 2008; 65(14): 2191-2214.

Hubbard KB, Hepler JR: Cell signaling diversity of the G-alpha family of heterotrimeric G proteins. Cell Signal. 2006; 18(2): 135-150.

Winpenny D, Clark M, Cawkill D: Biased ligand quantification in drug discovery: From theory to high throughput screening to identify new biased mu-opioid receptor agonists. Br J Pharmacol. 2016; 173(8): 1393-1403.

Raehal KM, Walker JKL, Bohn LM: Morphine side effects in OE≤-arrestin 2 knockout mice. J Pharmacol Exp Ther. 2005; 314: 1195-1201.

Bohn LM, Lefkowitz RJ, Gainetdinov RR, et al.: Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science. 1999; 286: 2495-2498.

McPherson J, Rivero G, Baptist M, et al.: Mu-opioid receptors; correlation of agonist efficacy for signaling with ability to activate internalization. Mol Pharmacol. 2010; 78: 756-766.

Chen XT, Pitis P, Liu G, et al.: Structure-activity relationships and discovery of a G protein biased mu opioid receptor ligand, [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl) -6-oxaspiro-[4.5]decan- 9-yl]ethyl})amine (TRV130), for the treatment of acute severe pain. J Med Chem. 2013; 56: 8019-8031.

Pan YX, Xu J, Mahurter L, et al.: Generation of the mu opioid receptor (MOR-1) protein by three new splice variants of the Oprm gene. Proc Natl Acad Sci U S A. 2001; 98(24): 14084-14089.

Majumdar S, Grinnell S, Le Rouzic V, et al.: Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects. Proc Natl Acad Sci U S A. 2011; 108(49): 19778-19783.

Pan YX, Xu J, Xu M, et al.: Involvement of exon 11-associated variants of the mu opioid receptor MOR-1 in heroin, but not morphine, actions. Proc Natl Acad Sci U S A. 2009; 106(12): 4917-4922.

Ding Z, Raffa RB: Identification of an additional supraspinal component to the analgesic mechanism of action of buprenorphine. Br J Pharmacol. 2009; 157: 831-843.

Dahan A, Schrier RV, Smith T: Averting opioid-induced respiratory depression without affecting analgesia. Anesthesiology. 2018; 128(5): 1027-1037.

Butrans (buprenorphine): Package insert [Internet]. Purdue Pharma L.P. 2014. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021306s015s019lbl.pdf. Accessed October 10, 2020.

Belbuca (buprenorphine): Package insert [Internet]. Endo Pharmaceuticals Inc. 2015. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207932s000lbl.pdf. Accessed October 10, 2020.

White LD, Hodge A, Vlok R, et al.: Efficacy and adverse effects of buprenorphine in acute pain management: Systematic review and meta-analysis of randomised controlled trials. Br J Anaesth. 2018; 120(4): 668-678.

Degnan M, Mousa SA: A narrative review of buprenorphine in adult cancer pain. Expert Rev Clin Pharmacol. 2020; 13: 1159-1167.

Aiyer R, Gulati A, Gungor S, et al.: Treatment of chronic pain with various buprenorphine formulations: A systematic review of clinical studies. Anesth Analg. 2018; 127(2): 529-538.

Neumann AM, Blondell RD, Jaanimagi U, et al.: A preliminary study comparing methadone and buprenorphine in patients with chronic pain and co-existent opioid addiction. J Addict Dis. 2013; 32(1): 68-78.

Mitra F, Chowdhury S, Shelley M, et al.: A feasibility study of transdermal buprenorphine versus transdermal fentanyl in the long-term management of persistent non-cancer pain. Pain Med. 2013; 14(1): 75-83.

Webster L, Gruener D, Kirby T, et al.: Evaluation of tolerability of switching patients on chronic full mu-opioid agonist therapy to buccal buprenorphine. Pain Med. 2016; 17(5): 899-907.

Nielsen S, Rivas C, Demirkol A, et al.: Effects of ascending buprenorphine doses on measures of experimental pain: A pilot study. J Subst Abuse Treat. 2019; 104: 128-134.

Dahan 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(6): 825-834.

Ciraulo DA, Hitzemann RJ, Somoza E, et al.: Pharmacokinetics and pharmacodynamics of multiple sublingual buprenorphine tablets in dose-escalation trials. J Clin Pharmacol. 2006; 46(2): 179-192.

Nielsen S, Dietze P, Lee N, et al.: Concurrent buprenorphine and benzodiazepines use and self-reported opioid toxicity in opioid substitution treatment. Addiction. 2007; 102(4): 616-622.

Dahan A, Aarts L, Smith TW: Incidence, reversal and prevention of opioid-induced respiratory depression. Anesthesiology. 2010; 112(1): 226-238.

Lintzeris N, Mitchell TB, Bond A, et al.: Interactions on mixing diazepam with methadone or buprenorphine in maintenance patients. J Clin Psychopharmacol. 2006; 26(3): 274-283.

Hakkinen M, Launiainen T, Vuori E, et al.: Benzodiazepines and alcohol are associated with cases of fatal buprenorphine poisoning. Eur J Clin Pharmacol. 2012; 68: 301-309.

Smith HS, Elliott JA: Opioid-induced androgen deficiency (OPIAD). Pain Phys. 2012; 15(3 Suppl.): ES145-ES156.

Daniell HW: DHEAS deficiency during consumption of sustained- action prescribed opioids: Evidence for opioid-induced inhibition of adrenal androgen production. J Pain. 2006; 7(12): 901-907. DOI: 10.1016/j.jpain.2006.04.011.

Wersocki E, Bedson J, Chen Y, et al.: Comprehensive systematic review of long-term opioids in women with chronic noncancer pain and associated reproductive dysfunction (hypothalamic- pituitary-gonadal axis disruption). Pain. 2017; 158(1): 8-16. DOI: 10.1097/j.pain.000000000000069.

Hallinan R, Byrne A, Agho K, et al.: Erectile dysfunction in men receiving methadone and buprenorphine maintenance treatment. J Sex Med. 2008; 5(3): 684-692. DOI: 10.1111/j.1743-6109.2007.00702.x.

Hallinan R, Byrne A, Agho K, et al.: Hypogonadism in men receiving methadone and buprenorphine maintenance treatment. Int J Androl. 2009; 32(2): 131-139. DOI: 10.1111/j.1365-2605.2007.00824.x.

Vallejo R, Barkin RL, Wang VC: Pharmacology of opioids in the treatment of chronic pain syndromes. Pain Physician. 2011; 14(4): E343-E360.

Comer SD, Sullivan MA, Whittington RA, et al.: Abuse liability of prescription opioids compared to heroin in morphine-maintained heroin abusers. Neuropsychopharmacology. 2008; 33(5): 1179-1191. DOI: 10.1038/sj.npp.1301479.

Pickworth WB, Johnson RE, Holicky BA, et al.: Subjective and physiologic effects of intravenous buprenorphine in humans. Clin Pharmacol Ther. 1993; 53(5): 570-576. DOI: 10.1038/clpt.1993.72.

Comer SD, Collins ED, Fischman MW: Intravenous buprenorphine self-administration by detoxified heroin abusers. J Pharmacol Exp Ther. 2002; 301(1): 266-276.

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

Tassinari D, Sartori S, Tamburini E, et al.: Adverse effects of transdermal opiates treating moderate-severe cancer pain in comparison to long-acting morphine: A meta-analysis and systematic review of the literature. J Palliat Med. 2008; (3): 492-501. DOI: 10.1089/jpm.2007.0200.

Likar R, Kayser H, Sittl R: Long-term management of chronic pain with transdermal buprenorphine: A multicenter, open-label, follow-up study in patients from three short-term clinical trials. Clin Ther. 2006; (6): 943-952. DOI: 10.1016/j.clinthera.2006.06.012.

Griessinger N, Sittl R, Likar R: Transdermal buprenorphine in clinical practice—A post-marketing surveillance study of 13,179 patients. Curr Med Res Opin. 2005; 21: 1147-1156.

Matsumoto AK, Babul N, Ahdieh H: Oxymorphone extended-release tablets relieve moderate to severe pain and improve physical function in osteoarthritis: Results of a randomized, double-blind, placebo-and active-controlled phase III trial. Pain Med. 2005; 6: 357-366.

Kalso E, Edwards JE, Moore RA, et al.: Opioids in chronic non-cancer pain: Systematic review of efficacy and safety. Pain. 2004; 112: 372-380.

Robb G, Loe E, Maharaj A, et al.: Medication-related patient harm in New Zealand hospitals. N Z Med J. 2017; 130(1460): 21-32.

Allen C, Zarowitz BJ, O'Shea T, et al.: Clinical and functional characteristics of nursing facility residents with opioid-induced constipation. Consult Pharm. 2017; 32(5): 285-298.

Alinejad S, Kazemi T, Zamani N, et al.: A systematic review of the cardiotoxicity of methadone. EXCLI J. 2015; 14: 577-600. DOI: 10.17179/excli2015-553.

Behzadi M, Joukar S, Beik A: Opioids and cardiac arrhythmia: A literature review. Med Princ Pract. 2018; 27(5): 401-414. DOI: 10.1159/000492616.

Harris SC, Morganroth J, Ripa SR, et al.: Effects of buprenorphine on QT intervals in healthy subjects: Results of 2 randomized positive- and placebo-controlled trials. Postgrad Med. 2017; 129(1): 69-80. DOI: 10.1080/00325481.2017.1270156.

Wedam EF, Bigelow GE, Johnson RE, et al.: QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial. Arch Intern Med. 2007; 167(22): 2469-2475.

Isbister GK, Brown AL, Gill A, et al.: QT interval prolongation in opioid agonist treatment: Analysis of continuous 12-lead electrocardiogram recordings. Br J Clin Pharmacol. 2017; 83(10): 2274-2282. DOI: 10.1111/bcp.13326.

Stallvik M, Nordstrand B, Oistein K, et al.: Corrected QT interval during treatment with methadone and buprenorphine—Relation to doses and serum concentrations. Drug Alcohol Depend. 2013; 129(1-2): 88-93.

Fareed A, Patil D, Scheinberg MD: Comparison of QTc interval prolongation for patients in methadone versus buprenorphine maintenance treatment: A 5-year follow-up. J Addict Dis. 2013; 32(3): 244-251.

Cowan A, Lewis JW, Macfarlane IR: Agonist and antagonist properties of buprenorphine, a new antinociceptive agent. Br J Pharmacol. 1977; 60(4): 537-545.




DOI: https://doi.org/10.5055/jom.2021.0639

Refbacks

  • There are currently no refbacks.