Skip to main content
SpringerLink
Log in

Buprenorphine, Polydrug Use and Deaths

  • Living reference work entry
  • First Online:
Handbook of Substance Misuse and Addictions

  • 42 Accesses

Abstract

Buprenorphine is an opioid analgesic and a medication used for opioid agonist treatment. Being a partial mu-opioid receptor agonist, it has a greater margin of safety compared to full agonists. Despite the relative safety of buprenorphine, the concomitant use of central nervous system depressant drugs is associated with an increased risk of respiratory depression, intoxication, and death. Injection of buprenorphine and polydrug use are major mortality risk factors. Clonazepam, alprazolam, diazepam, pregabalin, and alcohol are particularly often associated with fatal poisonings. An established user does not favor buprenorphine because of its euphoric effect, but the drug is rather used to manage opioid withdrawal symptoms, while concomitant sedative-hypnotic or illicit drugs may be taken to obtain or augment the opioid high. Perceived underdosing of buprenorphine in opioid agonist treatment is one reason for polydrug use. Prevention measures include encouraging safer consumption habits such as avoiding injection, as well as efforts to reduce concomitant use of alcohol, sedative-hypnotic drugs, and illicit drugs among buprenorphine users.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

Similar content being viewed by others

Abbreviations

alpha-PVP:

alpha-pyrrolidinopentiophenone

CNS:

Central nervous system

GHB:

gamma-hydroxybutyric acid

MDMA:

3,4-methylenedioxymethamphetamine, ecstasy

OAT:

Opioid agonist treatment

SSRI:

Selective serotonin reuptake inhibitor

THC:

Tetrahydrocannabinol

References

  • Alhaddad H, Cisternino S, Decleves X et al (2012) Respiratory toxicity of buprenorphine results from the blockage of P-glycoprotein-mediated efflux of norbuprenorphine at the blood-brain barrier in mice. Crit Care Med 40:3215–3223

    CAS  PubMed  Google Scholar 

  • Alhaddad H, Cisternino S, Saubamea B et al (2013) Gender and strain contributions to the variability of buprenorphine-related respiratory toxicity in mice. Toxicology 305:99–108

    CAS  PubMed  Google Scholar 

  • Alho H, Sinclair D, Vuori E, Holopainen A (2007) Abuse liability of buprenorphine-naloxone tablets in untreated IV drug users. Drug Alcohol Depend 88(1):75–78

    CAS  PubMed  Google Scholar 

  • Auriacombe M, Fatseas M, Dubernet J et al (2004) French field experience with buprenorphine. Am J Addict 13(Suppl 1):S17–S28

    PubMed  Google Scholar 

  • Bardy G, Cathala P, Eiden C et al (2015) An unusual case of death probably triggered by the association of buprenorphine at therapeutic dose with ethanol and benzodiazepines and with very low norbuprenorphine level. J Forensic Sci 60(Suppl 1):S269–S271

    CAS  PubMed  Google Scholar 

  • Bickel WK, Stitzer ML, Bigelow GE et al (1988) Buprenorphine: dose-related blockade of opioid challenge effects in opioid dependent humans. J Pharmacol Exp Ther 247:47–53

    CAS  PubMed  Google Scholar 

  • Bishop-Freeman SC, Friederich LW, Feaster MS, Hudson JS (2021) Buprenorphine-related deaths in North Carolina from 2010–2018. J Anal Toxicol. https://doi.org/10.1093/jat/bkab073

  • Blom Y, Bondesson U, Anggard E (1985) Analysis of buprenorphine and its N-dealkylated metabolite in plasma and urine by selected-ion monitoring. J Chromatogr 338:89–98

    CAS  PubMed  Google Scholar 

  • Boas RA, Villiger JW (1985) Clinical actions of fentanyl and buprenorphine. The significance of receptor binding. Br J Anaesth 57:192–196

    CAS  PubMed  Google Scholar 

  • Brewster D, Humphrey MJ, McLeavy MA (1981) Biliary excretion, metabolism and enterohepatic circulation of buprenorphine. Xenobiotica 11:189–196

    CAS  PubMed  Google Scholar 

  • Brunt TM, Lefrançois E, Gunnar T et al (2021) Substances detected in used syringes of injecting drug users across 7 cities in Europe in 2017 and 2018: the European Syringe Collection and Analysis Project Enterprise (ESCAPE). Int J Drug Policy 95:103130. https://doi.org/10.1016/j.drugpo.2021.103130. Online ahead of print

    Article  PubMed  Google Scholar 

  • Chang Y, Moody DE, McCance-Katz EF (2006) Novel metabolites of buprenorphine detected in human liver microsomes and human urine. Drug Metab Dispos 34:440–448

    CAS  PubMed  Google Scholar 

  • Chilcoat HD, Amick HR, Sherwood MR, Dunn KE (2019) Buprenorphine in the United States: motives for abuse, misuse, and diversion. J Subst Abus Treat 104:148–157

    Google Scholar 

  • Cicero TJ, Ellis MS, Surratt HL, Kurtz SP (2014) Factors contributing to the rise of buprenorphine misuse: 2008–2013. Drug Alcohol Depend 142:98–104

    CAS  PubMed  Google Scholar 

  • Coe MA, Lofwall MR, Walsh SL (2019) Buprenorphine pharmacology review: update on transmucosal and long-acting formulations. J Addict Med 13:93–103

    PubMed  PubMed Central  Google Scholar 

  • Cone EJ, Gorodetzky CW, Yousefnejad D et al (1984) The metabolism and excretion of buprenorphine in humans. Drug Metab Dispos 12:577–581

    CAS  PubMed  Google Scholar 

  • Cowan A (2007) Buprenorphine: the basic pharmacology revisited. J Addict Med 1:68–72

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  • Darke S, Duflou J, Larance B et al (2021) Characteristics and circumstances of death related to buprenorphine toxicity in Australia. Drug Alcohol Depend. https://doi.org/10.1016/j.drugalcdep.2020.108360

  • Elkader A, Sproule B (2005) Buprenorphine: clinical pharmacokinetics in the treatment of opioid dependence. Clin Pharmacokinet 44:661–680

    CAS  PubMed  Google Scholar 

  • Gaulier JM, Marquet P, Lacassie E et al (2000) Fatal intoxication following self-administration of a massive dose of buprenorphine. J Forensic Sci 45:226–228

    CAS  PubMed  Google Scholar 

  • Greenwald M, Johanson CE, Bueller J et al (2007) Buprenorphine duration of action: mu-opioid receptor availability and pharmacokinetic and behavioral indices. Biol Psychiatry 61:101–110

    CAS  PubMed  Google Scholar 

  • Häkkinen M, Launiainen T, Vuori E, Ojanperä I (2012) Benzodiazepines and alcohol are associated with cases of fatal buprenorphine poisoning. Eur J Clin Pharmacol 68:301–309

    PubMed  Google Scholar 

  • Harris DS, Jones RT, Welm S et al (2000) Buprenorphine and naloxone co-administration in opiate-dependent patients stabilized on sublingual buprenorphine. Drug Alcohol Depend 61:85–94

    CAS  PubMed  Google Scholar 

  • Haukka J, Kriikku P, Mariottini C et al (2018) Non-medical use of psychoactive prescription drugs is associated with fatal poisoning. Addiction 113(3):464–472

    PubMed  Google Scholar 

  • Heikman PK, Muhonen LH, Ojanperä IA (2017) Polydrug abuse among opioid maintenance treatment patients is related to inadequate dose of maintenance treatment medicine. BMC Psychiatry 17(1):245

    PubMed  PubMed Central  Google Scholar 

  • Høiseth G, Middelkoop G, Mørland J, Gjerde H (2015) Has previous abuse of flunitrazepam been replaced by clonazepam? Eur Addict Res 21(4):217–221

    PubMed  Google Scholar 

  • Huang P, Kehner GB, Cowan A, Liu-Chen LY (2001) Comparison of pharmacological activities of buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioid agonist. J Pharmacol Exp Ther 297:688–695

    CAS  PubMed  Google Scholar 

  • Jasinski DR, Pevnick JS, Griffith JD (1978) Human pharmacology and abuse potential of the analgesic buprenorphine: a potential agent for treating narcotic addiction. Arch Gen Psychiatry 35:501–516

    CAS  PubMed  Google Scholar 

  • Jin H, Marshall BDL, Degenhardt L et al (2020) Global opioid agonist treatment: a review of clinical practices by country. Addiction 115(12):2243–2254

    PubMed  PubMed Central  Google Scholar 

  • Johnson RE, Fudala PJ, Payne R (2005) Buprenorphine: considerations for pain management. J Pain Symptom Manag 29:297–326

    CAS  Google Scholar 

  • Jones JD, Mogali S, Comer SD (2012) Polydrug abuse: a review of opioid and benzodiazepine combination use. Drug Alcohol Depend 125(1–2):8–18

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kintz P (2001) Deaths involving buprenorphine: a compendium of French cases. Forensic Sci Int 121:65–69

    CAS  PubMed  Google Scholar 

  • Kintz P (2002) A new series of 13 buprenorphine-related deaths. Clin Biochem 35(7):513–516

    CAS  PubMed  Google Scholar 

  • Kosten TR, George TP (2002) The neurobiology of opioid dependence: implications for treatment. Sci Pract Perspect 1:13–20

    PubMed  PubMed Central  Google Scholar 

  • Kress HG (2009) Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine. Eur J Pain 13:219–230

    CAS  PubMed  Google Scholar 

  • Kriikku P, Häkkinen M, Ojanperä I (2018) High buprenorphine-related mortality is persistent in Finland. Forensic Sci Int 291:76–82

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Larance B, Lintzeris N, Ali R et al (2014) The diversion and injection of a buprenorphine-naloxone soluble film formulation. Drug Alcohol Depend 136:21–27

    CAS  PubMed  Google Scholar 

  • Lofwall MR, Walsh SL (2014) A review of buprenorphine diversion and misuse: the current evidence base and experiences from around the world. J Addict Med 8(5):315–326

    CAS  PubMed  PubMed Central  Google Scholar 

  • MacDonald K, Lamb K, Thomas ML, Khentigan W (2016) Buprenorphine maintenance treatment of opiate dependence: correlations between prescriber beliefs and practices. Subst Use Misuse 51:85–90

    PubMed  Google Scholar 

  • Macleod J, Steer C, Tilling K et al (2019) Prescription of benzodiazepines, z-drugs, and gabapentinoids and mortality risk in people receiving opioid agonist treatment: observational study based on the UK Clinical Practice Research Datalink and Office for National Statistics death records. PLoS Med. https://doi.org/10.1371/journal.pmed.1002965

  • Mahoney JJ, Winstanley EL, Lander LR et al (2021) High prevalence of co-occurring substance use in individuals with opioid use disorder. Addict Behav. https://doi.org/10.1016/j.addbeh.2020.106752

  • Mariottini C, Kriikku P, Ojanperä I (2021) Concomitant drugs with buprenorphine user deaths. Drug Alcohol Depend. https://doi.org/10.1016/j.drugalcdep.2020.108345

  • Mattick RP, Breen C, Kimber J, Davoli M (2014) Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD002207.pub4

  • Mégarbane B, Marie N, Pirnay S et al (2006) Buprenorphine is protective against the depressive effects of norbuprenorphine on ventilation. Toxicol Appl Pharmacol 212:256–267

    PubMed  Google Scholar 

  • Mégarbane B, Chevillard L, Vodovar D (2020) Naloxone should remain the appropriate antidote to treat opioid overdose. Crit Care 24(1):173

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Obadia Y, Perrin V, Feroni I et al (2001) Injecting misuse of buprenorphine among French drug users. Addiction 96:267–272

    CAS  PubMed  Google Scholar 

  • Ohtani M, Kotaki H, Uchino K et al (1994) Pharmacokinetic analysis of enterohepatic circulation of buprenorphine and its active metabolite, norbuprenorphine, in rats. Drug Metab Dispos 22:2–7

    CAS  PubMed  Google Scholar 

  • Ohtani M, Kotaki H, Sawada Y, Iga T (1995) Comparative analysis of buprenorphine- and norbuprenorphine-induced analgesic effects based on pharmacokinetic-pharmacodynamic modeling. J Pharmacol Exp Ther 272:505–510

    CAS  PubMed  Google Scholar 

  • Park TW, Larochelle MR, Saitz R et al (2020) Associations between prescribed benzodiazepines, overdose death and buprenorphine discontinuation among people receiving buprenorphine. Addiction 115(5):924–932

    PubMed  PubMed Central  Google Scholar 

  • Reynaud M, Petit G, Potard D, Courty P (1998) Six deaths linked to concomitant use of buprenorphine and benzodiazepines. Addiction 93:1385–1392

    CAS  PubMed  Google Scholar 

  • Santo T Jr, Clark B, Hickman M et al (2021) Association of opioid agonist treatment with all-cause mortality and specific causes of death among people with opioid dependence: a systematic review and meta-analysis. JAMA Psychiat 78(9):979–993

    Google Scholar 

  • Seldén T, Ahlner J, Druid H, Krostrand R (2012) Toxicological and pathological findings in a series of buprenorphine related deaths. Possible risk factors for fatal outcome. Forensic Sci Int 220(1–3):284–290

    PubMed  Google Scholar 

  • Shulman M, Wai JM, Nunes EV (2019) Buprenorphine treatment for opioid use disorder: an overview. CNS Drugs 33:567–580

    CAS  PubMed  PubMed Central  Google Scholar 

  • Simonsen KW, Kriikku P, Thelander G et al (2020) Fatal poisoning in drug addicts in the Nordic countries in 2017. Forensic Sci Int 313:110343. https://doi.org/10.1016/j.forsciint.2020.110343. Epub 2020 May 20

    Article  CAS  PubMed  Google Scholar 

  • Stein MD, Kanabar M, Anderson BJ et al (2016) Reasons for benzodiazepine use among persons seeking opioid detoxification. J Subst Abus Treat 68:57–61

    Google Scholar 

  • Stinchcomb AL, Paliwal A, Dua R et al (1996) Permeation of buprenorphine and its 3-alkyl-ester prodrugs through human skin. Pharm Res 13:1519–1523

    CAS  PubMed  Google Scholar 

  • Strain EC, Walsh SL, Bigelow GE (2002) Blockade of hydromorphone effects by buprenorphine/naloxone and buprenorphine. Psychopharmacology 159:161–166

    CAS  PubMed  Google Scholar 

  • Sun EC, Dixit A, Humphreys K et al (2017) Association between concurrent use of prescription opioids and benzodiazepines and overdose: retrospective analysis. BMJ 356:j760

    PubMed  PubMed Central  Google Scholar 

  • Tournier N, Chevillard L, Mégarbane B et al (2010) Interaction of drugs of abuse and maintenance treatments with human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2). Int J Neuropsychopharmacol 13:905–915

    CAS  PubMed  Google Scholar 

  • Tracqui A, Kintz P, Ludes B (1998) Buprenorphine-related deaths among drug addicts in France: a report on 20 fatalities. J Anal Toxicol 22:430–434

    CAS  PubMed  Google Scholar 

  • Vodovar D, Tournier N, Mégarbane B (2021) Ventilatory depression following oral buprenorphine exposure: insight into the involved mechanisms. Clin Toxicol (Phila) 59(7):677–679

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Walsh SL, Nuzzo PA, Babalonis S et al (2016) Intranasal buprenorphine alone and in combination with naloxone: abuse liability and reinforcing efficacy in physically dependent opioid abusers. Drug Alcohol Depend 162:190–198

    CAS  PubMed  PubMed Central  Google Scholar 

  • Welsh C, Valadez-Meltzer A (2005) Buprenorphine: a (relatively) new treatment for opioid dependence. Psychiatry (Edgmont) 2:29–39

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Forensic Medicine, University of Helsinki, Helsinki, Finland

    Ilkka Ojanperä, Claudia Mariottini & Pirkko Kriikku

  2. Forensic Toxicology Unit, Finnish Institute for Health and Welfare, Helsinki, Finland

    Ilkka Ojanperä, Claudia Mariottini & Pirkko Kriikku

Authors
  1. Ilkka Ojanperä
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Claudia Mariottini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pirkko Kriikku
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ilkka Ojanperä .

Editor information

Editors and Affiliations

  1. Department of Biomedical Sciences, University of Westminster, London, UK

    Vinood B. Patel

  2. Dept of Nutrition & Dietetics, King's College London, London, UK

    Victor R. Preedy

Rights and permissions

Reprints and permissions

Copyright information

© 2022 Springer Nature Switzerland AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Ojanperä, I., Mariottini, C., Kriikku, P. (2022). Buprenorphine, Polydrug Use and Deaths. In: Patel, V.B., Preedy, V.R. (eds) Handbook of Substance Misuse and Addictions. Springer, Cham. https://doi.org/10.1007/978-3-030-67928-6_156-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-67928-6_156-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-67928-6

  • Online ISBN: 978-3-030-67928-6

  • eBook Packages: Springer Reference MedicineReference Module Medicine

Publish with us

Policies and ethics

Search

Navigation