Opioid use disorder (OUD) is a chronic relapsing disorder that, whilst initially driven by activation of brain reward neurocircuits, increasingly engages anti-reward neurocircuits that drive adverse emotional states and relapse. However, successful recovery is possible with appropriate treatment, although with a persisting propensity to relapse. The individual and public health burdens of OUD are immense; 26.8 million people were estimated to be living with OUD globally in 2016, with >100,000 opioid overdose deaths annually, including >47,000 in the USA in 2017. Well-conducted trials have demonstrated that long-term opioid agonist therapy with methadone and buprenorphine have great efficacy for OUD treatment and can save lives. New forms of the opioid receptor antagonist naltrexone are also being studied. Some frequently used approaches have less scientifically robust evidence but are nevertheless considered important, including community preventive strategies, harm reduction interventions to reduce adverse sequelae from ongoing use and mutual aid groups. Other commonly used approaches, such as detoxification alone, lack scientific evidence. Delivery of effective prevention and treatment responses is often complicated by coexisting comorbidities and inadequate support, as well as by conflicting public and political opinions. Science has a crucial role to play in informing public attitudes and developing fuller evidence to understand OUD and its associated harms, as well as in obtaining the evidence today that will improve the prevention and treatment interventions of tomorrow.
Subscribe to Journal
Get full journal access for 1 year
only $65.00 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Blanco, C. & Volkow, N. D. Management of opioid use disorder in the USA: present status and future directions. Lancet 393, 1760–1772 (2019).
Strang, J. et al. Drug policy and the public good: evidence for effective interventions. Lancet 379, 71–83 (2012).
Babor, T. et al. Drug Policy and the Public Good 2nd edn (Oxford Univ. Press, 2018).
Marsden, J. et al. Efficacy and cost-effectiveness of an adjunctive personalised psychosocial intervention in treatment-resistant maintenance opioid agonist therapy: a pragmatic, open-label, randomised controlled trial. Lancet Psychiatry 6, 391–402 (2019).
Barocas, J. A. et al. Estimated prevalence of opioid use disorder in massachusetts, 2011-2015: a capture-recapture analysis. Am. J. Public Health 108, 1675–1681 (2018).
Bose, J., Hedden, S. L., Lipari, R. N. & Park-Lee, E. Key substance use and mental health indicators in the United States: results from the 2017 national survey on drug use and health (SAMHSA, 2017).
Degenhardt, L. et al. What data are available on the extent of illicit drug use and dependence globally? Results of four systematic reviews. Drug Alcohol Depend. 117, 85–101 (2011).
Vos, T. et al. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 390, 1211–1259 (2017).
Khademi, H. et al. Opium use and mortality in Golestan Cohort Study: prospective cohort study of 50 000 adults in Iran. BMJ 344, e2502 (2012).
Malekinejad, M. & Vazirian, M. Transition to injection amongst opioid users in Iran: Implications for harm reduction. Int. J. Drug. Policy 23, 333–337 (2012).
Razani, N. et al. HIV risk behavior among injection drug users in Tehran, Iran. Addiction 102, 1472–1482 (2007).
Frenk, S. M., Porter, K. S. & Paulozzi, L. J. Prescription opioid analgesic use among adults: United States, 1999-2012. NCHS Data Brief 189, 1–8 (2015).
Dart, R. C. et al. Trends in opioid analgesic abuse and mortality in the United States. N. Engl. J. Med. 372, 241–248 (2015).
Han, B. et al. Prescription opioid use, misuse, and use disorders in u.s. adults: 2015 national survey on drug use and health. Ann. Intern. Med. 167, 293–301 (2017).
Jones, C. M. Heroin use and heroin use risk behaviors among nonmedical users of prescription opioid pain relievers – United States, 2002–2004 and 2008–2010. Drug Alcohol Depend. 132, 95–100 (2013).
Martins, S. S. et al. Changes in US lifetime heroin use and heroin use disorder: prevalence from the 2001-2002 to 2012-2013 national epidemiologic survey on alcohol and related conditions. JAMA Psychiatry 74, 445–455 (2017).
Rubin, R. Illicit fentanyl driving opioid overdose deaths. JAMA 318, 2174–2174 (2017).
Nutt, D., King, L. A., Saulsbury, W. & Blakemore, C. Development of a rational scale to assess the harm of drugs of potential misuse. Lancet 369, 1047–1053 (2007).
Kreek, M. J. et al. Opiate addiction and cocaine addiction: underlying molecular neurobiology and genetics. J. Clin. Invest. 122, 3387–3393 (2012).
Zinberg, N. E. & Jacobson, R. C. The natural history of “chipping”. Am. J. Psychiatry 133, 37–40 (1976).
Hser, Y. I., Hoffman, V., Grella, C. E. & Anglin, M. D. A 33-year follow-up of narcotics addicts. Arch. Gen. Psychiatry 58, 503–508 (2001). This seminal natural history paper shows both the important contribution of longitudinal observational cohort studies and also the captures the scale of morbidity and mortality associated with opioid use.
Sordo, L. et al. Mortality risk during and after opioid substitution treatment: systematic review and meta-analysis of cohort studies. BMJ 357, j1550 (2017).
Merrall, E. L. et al. Meta-analysis of drug-related deaths soon after release from prison. Addiction 105, 1545–1554 (2010).
Kimber, J., Larney, S., Hickman, M., Randall, D. & Degenhardt, L. Mortality risk of opioid substitution therapy with methadone versus buprenorphine: a retrospective cohort study. Lancet Psychiatry 2, 901–908 (2015).
Sweeting, M. J., De Angelis, D., Ades, A. E. & Hickman, M. Estimating the prevalence of ex-injecting drug use in the population. Stat. Methods Med. Res. 18, 381–395 (2009).
De Angelis, D., Hickman, M. & Yang, S. Estimating long-term trends in the incidence and prevalence of opiate use/injecting drug use and the number of former users: back-calculation methods and opiate overdose deaths. Am. J. Epidemiol. 160, 994–1004 (2004).
Gfroerer, J. & Brodsky, M. The incidence of illicit drug use in the United States, 1962-1989. Br. J. Addict. 87, 1345–1351 (1992).
Termorshuizen, F. et al. Prediction of relapse to frequent heroin use and the role of methadone prescription: an analysis of the Amsterdam cohort study among drug users. Drug Alcohol Depend. 79, 231–240 (2005).
Shah, N. G., Galai, N., Celentano, D. D., Vlahov, D. & Strathdee, S. A. Longitudinal predictors of injection cessation and subsequent relapse among a cohort of injection drug users in Baltimore, MD, 1988-2000. Drug Alcohol Depend. 83, 147–156 (2006).
Kimber, J. et al. Survival and cessation in injecting drug users: prospective observational study of outcomes and effect of opiate substitution treatment. BMJ 341, c3172 (2010).
Mehta, S. H. et al. Factors associated with injection cessation, relapse and initiation in a community-based cohort of injection drug users in Chennai, India. Addiction 107, 349–358 (2012). This paper explores these important factors in OUD development and progression in different contexts from most published papers, and shows the importance of studying opioid users in countries outside historically wealthy countries – especially low and middleincome countries.
Hser, Y. I., Huang, D., Chou, C. P. & Anglin, M. D. Trajectories of heroin addiction: growth mixture modeling results based on a 33-year follow-up study. Eval. Rev. 31, 548–563 (2007).
Degenhardt, L. et al. Prevention of HIV infection for people who inject drugs: why individual, structural, and combination approaches are needed. Lancet 376, 285–301 (2010).
Saha, T. D. et al. Nonmedical prescription opioid use and DSM-5 nonmedical prescription opioid use disorder in the United States. J. Clin. Psychiatry 77, 772–780 (2016).
Nelson, E. C. et al. Association of OPRD1 polymorphisms with heroin dependence in a large case-control series. Addict. Biol. 19, 111–121 (2014).
Dowell, D., Haegerich, T. M. & Chou, R. CDC guideline for prescribing opioids for chronic pain – United States, 2016. MMWR Recomm. Rep. 65, 1–49 (2016).
Dowell, D., Haegerich, T. M. & Chou, R. CDC guideline for prescribing opioids for chronic pain – United States, 2016. JAMA 315, 1624–1645 (2016).
Degenhardt, L. et al. Global patterns of opioid use and dependence: harms to populations, interventions, and future action. Lancet 394, 1560–1579 (2019). This global review takes illustrative examples of three very different parts of the world and, starting with data from the Global Burden of Disease and then applying mathematic modelling, identifies the general benefit of provision of treatment and the particular effectiveness of OAT, and yet finding that the coverage of these interventions remains low, even in high-income countries.
Paulozzi, L. J., Mack, K. A. & Hockenberry, J. M. Vital signs: variation among states in prescribing of opioid pain relievers and benzodiazepines – United States, 2012. MMWR Morb. Mortal. Wkly Rep. 63, 563–568 (2014).
Kolodny, A. et al. The prescription opioid and heroin crisis: a public health approach to an epidemic of addiction. Annu. Rev. Public Health 36, 559–574 (2015).
Dowell, D., Haegerich, T. M. & Chou, R. CDC guideline for prescribing opioids for chronic pain. MMWR Morb. Mortal. Wkly Rep. 65, 1–49 (2016).
Hadland, S. E., Cerda, M., Li, Y., Krieger, M. S. & Marshall, B. D. L. Association of pharmaceutical industry marketing of opioid products to physicians with subsequent opioid prescribing. JAMA Intern. Med. 178, 861–863 (2018).
Hadland, S. E., Rivera-Aguirre, A., Marshall, B. D. L. & Cerda, M. Association of pharmaceutical industry marketing of opioid products with mortality from opioid-related overdoses. JAMA Netw. Open. 2, e186007 (2019).
Davis, C. S. & Carr, D. H. Self-regulating profession? Administrative discipline of “pill mill” physicians in Florida. Subst. Abus. 38, 265–268 (2017).
Centers for Disease Control and Prevention. Multiple cause of death data (CDC, 2016).
US National Center for Health Statistics. United States, 2014: with special feature on adults aged 55–64 (CDC, 2015).
US National Center for Health Statistics. United States, 2015: in brief (CDC, 2016).
Compton, W. M. & Volkow, N. D. Abuse of prescription drugs and the risk of addiction. Drug Alcohol Depend. 83, S4–S7 (2006).
Amin-Esmaeili, M. et al. Epidemiology of illicit drug use disorders in Iran: prevalence, correlates, comorbidity and service utilization results from the Iranian mental health survey. Addiction 111, 1836–1847 (2016).
Ford, J. A. & Rigg, K. K. Racial/ethnic differences in factors that place adolescents at risk for prescription opioid misuse. Prev. Sci. 16, 633–641 (2015).
Lascala, E., Friesthler, B. & Gruenwald, P. J. in Preventing Harmful Substance Use: The Evidence Base for Policy and Practice (eds Stockwell, T., Gruenwald, P., Toumbourou, J. & Loxley, W.) (John Wiley & Sons, 2005).
Fergusson, D. M., Boden, J. M. & Horwood, L. J. The developmental antecedents of illicit drug use: evidence from a 25 year longitudinal study. Drug Alcohol Depend. 96, 167–177 (2008).
Hawkins, J., Catalano, R. & Miller, J. Risk and protective factors for alcohol and other drug problems in adolescence and early adulthood: implications for substance abuse prevention. Psychological Bull. 112, 64–105 (1992).
Daniel, J. Z. et al. Is socioeconomic status in early life associated with drug use? A systematic review of the evidence. Drug Alcohol Rev. 28, 142–153 (2009).
Cohen, D. A., Richardson, J. & LaBree, L. Parenting behaviors and the onset of smoking and alcohol use: a longitudinal study. Pediatrics 94, 368–375 (1994).
Fergusson, D. M., Horwood, L. J. & Lynskey, M. T. Parental separation, adolescent psychopathology, and problem behaviors. J. Am. Acad. Child Adolesc. Psychiatry 33, 1122–1131 (1994).
Conroy, E., Degenhardt, L., Mattick, R. P. & Nelson, E. C. Child maltreatment as a risk factor for opioid dependence: comparison of family characteristics and type and severity of child maltreatment with a matched control group. Child Abuse Negl. 33, 343–352 (2009).
Needle, R. H., Su, S. & Doherty, W. J. Divorce, remarriage, and adolescent drug involvement: a prospective longitudinal study. J. Marriage Family 52, 157–169 (1990).
Campbell, G. et al. Pharmaceutical opioid use and dependence among people living with chronic pain: associations observed within the pain and opioids in treatment (POINT) cohort. Pain. Med. 16, 1745–1758 (2015).
Lynskey, M. T. & Fergusson, D. M. Childhood conduct problems and attention deficit behaviors and adolescent alcohol, tobacco and illicit drug use. J. Abnorm. Child Psychol. 23, 281–302 (1995).
Townsend, L., Flisher, A. & King, G. A systematic review of the relationship between high school dropout and substance use. Clin. Child Family Psychol. Rev. 10, 295–317 (2007).
Katz, C., El-Gabalawy, R., Keyes, K. M., Martins, S. S. & Sareen, J. Risk factors for incident nonmedical prescription opioid use and abuse and dependence: results from a longitudinal nationally representative sample. Drug Alcohol Depend. 132, 107–113 (2013).
Sullivan, M. D. Who gets high-dose opioid therapy for chronic non-cancer pain? Pain 151, 567–568 (2010).
Institute of Medicine & Committee on Opportunities in Drug Abuse Research. Pathways of Addiction: Opportunities in Drug Abuse Research. (National Academy Press, 1996).
Academy Medical Sciences. Brain science, addiction and drugs (ed. Horn, G.) (Academy Medical Sciences, 2007).
Macleod, J. et al. Early life influences on the risk of injecting drug use: case control study based on the edinburgh addiction cohort. Addiction 108, 743–750 (2013).
Butt, S., Chou, S. & Browne, K. A rapid systematic review on the association between childhood physical and sexual abuse and illicit drug use among males. Child Abuse Rev. 20, 6–38 (2011).
Konkoly Thege, B. et al. Relationship between interpersonal trauma exposure and addictive behaviors: a systematic review. BMC Psychiatry 17, 164 (2017).
Darke, S., Torok, M. & Ross, J. Developmental trajectories to heroin dependence: theoretical and clinical issues. J. Appl. Soc. Psychol. 47, 165–171 (2017).
Darke, S. Pathways to heroin dependence: time to re-appraise self-medication. Addiction 108, 659–667 (2013).
Martins, S. S. et al. Mood and anxiety disorders and their association with non-medical prescription opioid use and prescription opioid-use disorder: longitudinal evidence from the national epidemiologic study on alcohol and related conditions. Psychol. Med. 42, 1261–1272 (2012).
Dasgupta, N., Beletsky, L. & Ciccarone, D. Opioid crisis: no easy fix to its social and economic determinants. Am. J. Public Health 108, 182–186 (2018).
Degenhardt, L. et al. Evaluating the drug use “gateway” theory using cross-national data: consistency and associations of the order of initiation of drug use among participants in the who world mental health surveys. Drug Alcohol Depend. 108, 84–97 (2010).
Rudd, R. A., Aleshire, N., Zibbell, J. E. & Matthew Gladden, R. Increases in drug and opioid overdose deaths — United States, 2000–2014. Am. J. Transplant. 16, 1323–1327 (2016).
O’Donnell, J., Halpin, J., Mattson, C. L., Goldberger, B. A. & Gladden, R. M. Deaths involving fentanyl, fentanyl analogs, and U-47700 — 10 states, July–December 2016. MMWR Morb. Mortal. Wkly Rep. 66, 1197–1202 (2017).
Gladden, R., 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. 65, 837–843 (2016).
Fischer, B., Russell, C., Murphy, Y. & Kurdyak, P. Prescription opioids, abuse and public health in Canada: is fentanyl the new centre of the opioid crisis? Pharmacoepidemiology Drug Saf. 24, 1334–1336 (2015).
Carroll, J. J., Marshall, B. D. L., Rich, J. D. & Green, T. C. Exposure to fentanyl-contaminated heroin and overdose risk among illicit opioid users in Rhode Island: a mixed methods study. Int. J. Drug Policy 46, 136–145 (2017).
Somerville, N. J. et al. Characteristics of fentanyl overdose — Massachusetts, 2014–2016. MMWR Morb. Mortal. Wkly Rep. 66, 382–386 (2017).
Centers for Disease Control and Prevention. Viral hepatitis surveillance United States, 2015 (CDC, 2016).
Suryaprasad, A. G. et al. Emerging epidemic of hepatitis C virus infections among young nonurban persons who inject drugs in the United States, 2006–2012. Clin. Infect. Dis. 59, 1411–1419 (2014).
Zibbell, J. E. et al. Increases in hepatitis C virus infection related to injection drug use among persons aged ≤30 years – Kentucky, Tennessee, Virginia, and West Virginia, 2006–2012. MMWR Morb. Mortal. Wkly Rep. 64, 453–458 (2015).
Volkow, N. D. Opioids in pregnancy. BMJ 352, i19 (2016).
Larney, S. et al All-cause and cause-specific mortality in people using extra-medical opioids: a systematic review and meta-analysis. JAMA Psychiatry (in the press).
Maloney, E., Degenhardt, L., Darke, S., Mattick, R. P. & Nelson, E. Suicidal behaviour and associated risk factors among opioid-dependent individuals: a case-control study. Addiction 102, 1933–1941 (2007).
Degenhardt, L. et al. Global prevalence of injecting drug use and sociodemographic characteristics and prevalence of HIV, HBV, and HCV in people who inject drugs: a multistage systematic review. Lancet Glob. Health 5, e1192–e1207 (2017).
Degenhardt, L. et al. Estimating the burden of disease attributable to injecting drug use as a risk factor for HIV, hepatitis C, and hepatitis B: findings from the global burden of disease study 2013. Lancet Infect. Dis. 16, 1385–1398 (2016).
Larney, S., Peacock, A., Mathers, B. M., Hickman, M. & Degenhardt, L. A systematic review of injecting-related injury and disease among people who inject drugs. Drug Alcohol Depend. 171, 39–49 (2017).
Goldstein, R. Z. & Volkow, N. D. Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am. J. Psychiatry 159, 1642–1652 (2002).
Koob, G. F. & Le Moal, M. Drug abuse: hedonic homeostatic dysregulation. Science 278, 52–58 (1997).
Mansour, A., Fox, C. A., Akil, H. & Watson, S. J. Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications. Trends Neurosci. 18, 22–29 (1995).
Lutz, P. E. & Kieffer, B. L. Opioid receptors: distinct roles in mood disorders. Trends Neurosci. 36, 195–206 (2013).
O’Briend, C. P. “Needle freaks”: Psychological Dependence on Shooting Up. in Medical World News, Psychiatry Annual (McGraw Hill, 1974).
Meyer, R. E., & Mirin, S. M. The Heroin Stimulus: Implications for a Theory of Addiction (Springer, 1979).
Chen, S. A. et al. Unlimited access to heroin self-administration: independent motivational markers of opiate dependence. Neuropsychopharmacology 31, 2692–2707 (2006).
Mucha, R. F., van der Kooy, D., O’Shaughnessy, M. & Bucenieks, P. Drug reinforcement studied by the use of place conditioning in rat. Brain Res. 243, 91–105 (1982).
Le Merrer, J., Becker, J. A., Befort, K. & Kieffer, B. L. Reward processing by the opioid system in the brain. Physiol. Rev. 89, 1379–1412 (2009).
Guignard, B. et al. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology 93, 409–417 (2000).
Laulin, J. P., Celerier, E., Larcher, A., Le Moal, M. & Simonnet, G. Opiate tolerance to daily heroin administration: an apparent phenomenon associated with enhanced pain sensitivity. Neuroscience 89, 631–636 (1999).
Martin, W. R. et al. Methadone – a reevaluation. Arch. Gen. Psychiatry 28, 286–295 (1973).
Yaksh, T. & Wallace, M. in Goodman and Gilman’s Pharmacological Basis of Therapeutics Ch. 20 (McGraw-Hill Education, 2017).
Cahill, C. M. et al. Does the κ opioid receptor system contribute to pain aversion? Front. Pharmacol. 5, 253 (2014).
Gaspari, S. et al. Nucleus accumbens-specific interventions in RGS9-2 activity modulate responses to morphine. Neuropsychopharmacology 39, 1968–1977 (2014).
Fields, H. State-dependent opioid control of pain. Nat. Rev. Neurosci. 5, 565–575 (2004).
Raehal, K. M. & Bohn, L. M. β-arrestins: regulatory role and therapeutic potential in opioid and cannabinoid receptor-mediated analgesia. Handb. Exp. Pharmacol. 219, 427–443 (2014).
Bohn, L. M., Gainetdinov, R. R., Lin, F. T., Lefkowitz, R. J. & Caron, M. G. Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature 408, 720–723 (2000).
Schmid, C. L. et al. Bias factor and therapeutic window correlate to predict safer opioid analgesics. Cell 171, 1165–1175 (2017).
Volkow, N. D. & McLellan, A. T. Opioid abuse in chronic pain-misconceptions and mitigation strategies. N. Engl. J. Med. 374, 1253–1263 (2016). This paper reviews the pharmacological properties of opoids that underlie their analgesic and rewarding effects, and identifies the cellular and neurobiological processes that result in physical dependence and tolerance versus those responsibe for addiction in the context of their implications vis a vis treatment.
Latowsky, M. Improving detoxification outcomes from methadone maintenance treatment: the interrelationship of affective states and protracted withdrawal. J. Psychoact. Drugs 28, 251–257 (1996).
O’Brien, C. P., Testa, T., O’Brien, T. J., Brady, J. P. & Wells, B. Conditioned narcotic withdrawal in humans. Science 195, 1000–1002 (1977).
Heimer, L. & Alheid, G. F. Piecing together the puzzle of basal forebrain anatomy. Adv. Exp. Med. Biol. 295, 1–42 (1991).
Koob, G. F. The dark side of emotion: the addiction perspective. Eur. J. Pharmacol. 753, 73–87 (2015).
Pothos, E., Rada, P., Mark, G. P. & Hoebel, B. G. Dopamine microdialysis in the nucleus accumbens during acute and chronic morphine, naloxone-precipitated withdrawal and clonidine treatment. Brain Res. 566, 348–350 (1991).
Rossetti, Z. L., Hmaidan, Y. & Gessa, G. L. Marked inhibition of mesolimbic dopamine release: a common feature of ethanol, morphine, cocaine and amphetamine abstinence in rats. Eur. J. Pharmacol. 221, 227–234 (1992).
Wang, G. J. et al. Dopamine D2 receptor availability in opiate-dependent subjects before and after naloxone-precipitated withdrawal. Neuropsychopharmacology 16, 174–182 (1997).
Zijlstra, F., Veltman, D. J., Booij, J., van den Brink, W. & Franken, I. H. Neurobiological substrates of cue-elicited craving and anhedonia in recently abstinent opioid-dependent males. Drug Alcohol Depend. 99, 183–192 (2009).
Koob, G. F. & Bloom, F. E. Cellular and molecular mechanisms of drug dependence. Science 242, 715–723 (1988).
Greenwell, T. N. et al. Corticotropin-releasing factor-1 receptor antagonists decrease heroin self-administration in long- but not short-access rats. Addict. Biol. 14, 130–143 (2009).
Greenwell, T. N., Walker, B. M., Cottone, P., Zorrilla, E. P. & Koob, G. F. The α1 adrenergic receptor antagonist prazosin reduces heroin self-administration in rats with extended access to heroin administration. Pharmacol. Biochem. Behav. 91, 295–302 (2009).
Park, P. E. et al. Chronic CRF1 receptor blockade reduces heroin intake escalation and dependence-induced hyperalgesia. Addict. Biol. 20, 275–284 (2015).
Whitfield, T. W. Jr et al. κ opioid receptors in the nucleus accumbens shell mediate escalation of methamphetamine intake. J. Neurosci. 35, 4296–4305 (2015).
Chavkin, C. & Koob, G. F. Dynorphin, dysphoria, and dependence: the stress of addiction. Neuropsychopharmacology 41, 373–374 (2016).
Carlezon, W. A. Jr., Nestler, E. J. & Neve, R. L. Herpes simplex virus-mediated gene transfer as a tool for neuropsychiatric research. Crit. Rev. Neurobiol. 14, 47–67 (2000).
Volkow, N. D., Hampson, A. J. & Baler, R. D. Don’t worry, be happy: endocannabinoids and cannabis at the intersection of stress and reward. Annu. Rev. Pharmacol. Toxicol. 57, 285–308 (2017).
Volkow, N. D. et al. Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse 14, 169–177 (1993).
Pirastu, R. et al. Impaired decision-making in opiate-dependent subjects: effect of pharmacological therapies. Drug Alcohol Depend. 83, 163–168 (2006).
Stewart, J. & Wise, R. A. Reinstatement of heroin self-administration habits: morphine prompts and naltrexone discourages renewed responding after extinction. Psychopharmacology 108, 79–84 (1992).
Kalivas, P. W. The glutamate homeostasis hypothesis of addiction. Nat. Rev. Neurosci. 10, 561–572 (2009).
Bossert, J. M. et al. Role of projections from ventral subiculum to nucleus accumbens shell in context-induced reinstatement of heroin seeking in rats. Psychopharmacology 233, 1991–2004 (2016).
Bossert, J. M., Busch, R. F. & Gray, S. M. The novel mGluR2/3 agonist LY379268 attenuates cue-induced reinstatement of heroin seeking. Neuroreport 16, 1013–1016 (2005).
Shaham, Y., Erb, S. & Stewart, J. Stress-induced relapse to heroin and cocaine seeking in rats: a review. Brain Res. Rev. 33, 13–33 (2000).
Kreek, M. J. Opiates, opioids and addiction. Mol. Psychiatry 1, 232–254 (1996).
Kreek, M. J. Opioid receptors: some perspectives from early studies of their role in normal physiology, stress responsivity, and in specific addictive diseases. Neurochem. Res. 21, 1469–1488 (1996).
Stinus, L., Caille, S. & Koob, G. F. Opiate withdrawal-induced place aversion lasts for up to 16 weeks. Psychopharmacology 149, 115–120 (2000).
Gracy, K. N., Dankiewicz, L. A. & Koob, G. F. Opiate withdrawal-induced fos immunoreactivity in the rat extended amygdala parallels the development of conditioned place aversion. Neuropsychopharmacology 24, 152–160 (2001).
Kenny, P. J., Chen, S. A., Kitamura, O., Markou, A. & Koob, G. F. Conditioned withdrawal drives heroin consumption and decreases reward sensitivity. J. Neurosci. 26, 5894–5900 (2006).
Epstein, D. H. et al. Real-time electronic diary reports of cue exposure and mood in the hours before cocaine and heroin craving and use. Arch. Gen. Psychiatry 66, 88–94 (2009).
Chase, H. W., Eickhoff, S. B., Laird, A. R. & Hogarth, L. The neural basis of drug stimulus processing and craving: an activation likelihood estimation meta-analysis. Biol. Psychiatry 70, 785–793 (2011).
Kuhn, S. & Gallinat, J. Common biology of craving across legal and illegal drugs - a quantitative meta-analysis of cue-reactivity brain response. Eur. J. Neurosci. 33, 1318–1326 (2011).
Nestler, E. J. Under siege: the brain on opiates. Neuron 16, 897–900 (1996).
Collier, H. O. & Francis, D. L. Morphine abstinence is associated with increased brain cyclic AMP. Nature 255, 159–162 (1975).
Nestler, E. J. & Malenka, R. C. The addicted brain. Sci. Am. 290, 78–85 (2004). This paper provides an overview of the molecular mechanims responsible for the neuroplastic adaptations at the cellular and synaptic level and how there contribute to the long-lasting changes in behaviour from repeated drug use.
Goldman, D., Oroszi, G. & Ducci, F. The genetics of addictions: uncovering the genes. Nat. Rev. Genet. 6, 521–532 (2005).
Levran, O., Yuferov, V. & Kreek, M. J. The genetics of the opioid system and specific drug addictions. Hum. Genet. 131, 823–842 (2012).
Yiannakopoulou, E. Pharmacogenomics and opioid analgesics: clinical implications. Int. J. Genomics 2015, 368979 (2015).
Hancock, D. B. et al. Cis-expression quantitative trait loci mapping reveals replicable associations with heroin addiction in OPRM1. Biol. Psychiatry 78, 474–484 (2015).
Nielsen, L. M. et al. Association between human pain-related genotypes and variability in opioid analgesia: an updated review. Pain Pract. 15, 580–594 (2015).
Jensen, K. P. A review of genome-wide association studies of stimulant and opioid use disorders. Mol. Neuropsychiatry 2, 37–45 (2016).
Gelernter, J. et al. Genome-wide association study of opioid dependence: multiple associations mapped to calcium and potassium pathways. Biol. Psychiatry 76, 66–74 (2014).
Nelson, E. C. et al. Evidence of CNIH3 involvement in opioid dependence. Mol. Psychiatry 21, 608–614 (2016).
Lee, C. W. & Ho, I. K. Sex differences in opioid analgesia and addiction: interactions among opioid receptors and estrogen receptors. Mol. Pain 9, 45 (2013).
US Department of Health and Human Services. Substance abuse and mental health data archive (SAMHSA, 2018).
Brady, K. T. & Randall, C. L. Gender differences in substance use disorders. Psychiatr. Clin. North Am. 22, 241–252 (1999).
Chartoff, E. H. & Mavrikaki, M. Sex differences in kappa opioid receptor function and their potential impact on addiction. Front. Neurosci. 9, 466 (2015).
Wiesenfeld-Hallin, Z. Sex differences in pain perception. Gend. Med. 2, 137–145 (2005).
Zubieta, J. K., Dannals, R. F. & Frost, J. J. Gender and age influences on human brain mu-opioid receptor binding measured by PET. Am. J. Psychiatry 156, 842–848 (1999).
Zubieta, J. K. et al. µ-opioid receptor-mediated antinociceptive responses differ in men and women. J. Neurosci. 22, 5100–5107 (2002).
Vijay, A. et al. PET imaging reveals sex differences in κ opioid receptor availability in humans, in vivo. Am. J. Nucl. Med. Mol. Imaging 6, 205–214 (2016).
Simonnet, G. & Rivat, C. Opioid-induced hyperalgesia: abnormal or normal pain? Neuroreport 14, 1–7 (2003).
Compton, P., Athanasos, P. & Elashoff, D. Withdrawal hyperalgesia after acute opioid physical dependence in nonaddicted humans: a preliminary study. J. Pain 4, 511–519 (2003).
Doverty, M. et al. Hyperalgesic responses in methadone maintenance patients. Pain 90, 91–96 (2001).
Tsui, J. I. et al. Chronic pain, craving, and illicit opioid use among patients receiving opioid agonist therapy. Drug Alcohol Depend. 166, 26–31 (2016).
Ren, Y., Whittard, J., Higuera-Matas, A., Morris, C. V. & Hurd, Y. L. Cannabidiol, a nonpsychotropic component of cannabis, inhibits cue-induced heroin seeking and normalizes discrete mesolimbic neuronal disturbances. J. Neurosci. 29, 14764–14769 (2009).
Carcoba, L. M., Contreras, A. E., Cepeda-Benito, A. & Meagher, M. W. Negative affect heightens opiate withdrawal-induced hyperalgesia in heroin dependent individuals. J. Addict. Dis. 30, 258–270 (2011).
Laulin, J. P., Larcher, A., Celerier, E., Le Moal, M. & Simonnet, G. Long-lasting increased pain sensitivity in rat following exposure to heroin for the first time. Eur. J. Neurosci. 10, 782–785 (1998).
Fu, Y. & Neugebauer, V. Differential mechanisms of CRF1 and CRF2 receptor functions in the amygdala in pain-related synaptic facilitation and behavior. J. Neurosci. 28, 3861–3876 (2008).
Koob, G. F. & Volkow, N. D. Neurocircuitry of addiction. Neuropsychopharmacology 35, 217–238 (2010). This paper provides a model that integrates neuroscientific advances from preclinical studies and from neuroimaging studies in individuals who are addicted, and identifies the main neurocircuits and neurotransmitters implicated in the three phases of the addiction cycle.
Koob, G. F. & Le Moal, M. Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24, 97–129 (2001).
Shurman, J., Koob, G. F. & Gutstein, H. B. Opioids, pain, the brain, and hyperkatifeia: a framework for the rational use of opioids for pain. Pain Med. 11, 1092–1098 (2010).
Neugebauer, V. The amygdala: different pains, different mechanisms. Pain 127, 1–2 (2007).
Price, D. D. Psychological and neural mechanisms of the affective dimension of pain. Science 288, 1769–1772 (2000).
Bester, H., Menendez, L., Besson, J. M. & Bernard, J. F. Spino (trigemino) parabrachiohypothalamic pathway: electrophysiological evidence for an involvement in pain processes. J. Neurophysiol. 73, 568–585 (1995).
McNally, G. P. & Akil, H. Role of corticotropin-releasing hormone in the amygdala and bed nucleus of the stria terminalis in the behavioral, pain modulatory, and endocrine consequences of opiate withdrawal. Neuroscience 112, 605–617 (2002).
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5) 5th edn (APA, 2013).
Nelson, H. D., Matthews, A. M., Girard, D. E. & Bloom, J. D. Substance-impaired physicians probationary and voluntary treatment programs compared. West. J. Med. 165, 31–36 (1996).
White, J. M. & Irvine, R. J. Mechanisms of fatal opioid overdose. Addiction 94, 961–972 (1999).
Pierce, M., Bird, S. M., Hickman, M. & Millar, T. National record linkage study of mortality for a large cohort of opioid users ascertained by drug treatment or criminal justice sources in England, 2005–2009. Drug Alcohol Depend. 146, 17–23 (2015).
Gibson, A., Randall, D. & Degenhardt, L. The increasing mortality burden of liver disease among opioid-dependent people: cohort study. Addiction 106, 2186–2192 (2011).
Csete, J. et al. Public health and international drug policy. Lancet 387, 1427–1480 (2016).
Drucker, E. Population impact of mass incarceration under New York’s rockefeller drug laws: an analysis of years of life lost. J. Urban Health 79, 434–435 (2002).
Faggiano, F., Minozzi, S., Versino, E. & Buscemi, D. Universal school-based prevention for illicit drug use. Cochrane Database Syst. Rev. 12, CD003020 (2014).
Foxcroft, D. R. & Tsertsvadze, A. Universal alcohol misuse prevention programmes for children and adolescents: cochrane systematic reviews. Perspect. Public Health 132, 128–134 (2012).
Stockings, E. et al. Prevention, early intervention, harm reduction, and treatment of substance use in young people. Lancet Psychiatry https://doi.org/10.1016/S2215-0366(16)00002-X (2016).
Georgie, J. M., Sean, H., Deborah, M. C., Matthew, H. & Rona, C. Peer-led interventions to prevent tobacco, alcohol and/or drug use among young people aged 11-21 years: a systematic review and meta-analysis. Addiction 111, 391–407 (2016).
Reuter, P. & Kleiman, M. A. R. Risks and prices: an economic analysis of drug enforcement. Crime Justice 7, 289–340 (1986).
Jalal, H. et al. Changing dynamics of the drug overdose epidemic in the United States from 1979 through 2016. Science 361, eaau1184 (2018).
Day, C., Degenhardt, L. & Hall, W. Documenting the heroin shortage in New South Wales. Drug. Alcohol. Rev. 25, 297–305 (2006).
Day, C., Degenhardt, L. & Hall, W. Changes in the initiation of heroin use after a reduction in heroin supply. Drug. Alcohol. Rev. 25, 307–313 (2006).
Luchenski, S. et al. What works in inclusion health: overview of effective interventions for marginalised and excluded populations. Lancet 391, 266–280 (2018).
Berterame, S. et al. Use of and barriers to access to opioid analgesics: a worldwide, regional, and national study. Lancet 87, 1644–1656 (2016).
Ballantyne, J. C. & Mao, J. Opioid therapy for chronic pain. N. Engl. J. Med. 349, 1943–1953 (2003).
Krawczyk, N. et al. Predictors of overdose death among high-risk emergency department patients with substance-related encounters: a data linkage cohort study. Ann. Emerg. Med. https://doi.org/10.1016/j.annemergmed.2019.07.014 (2019).
Haffajee, R. L., Lin, L. A., Bohnert, A. S. B. & Goldstick, J. E. Characteristics of US counties with high opioid overdose mortality and low capacity to deliver medications for opioid use disorder. JAMA Netw. Open 2, e196373 (2019).
British Pain Society. Guidelines for pain management programmes for adults (British Pain Society, 2013).
Centers for Disease Control and Prevention. Guideline for prescribing opioids for chronic pain (CDC, 2016).
Busse, J. W. et al. Guideline for opioid therapy and chronic noncancer pain. CMAJ 189, E659–E666 (2017).
Al Achkar, M. et al. The effects of state rules on opioid prescribing in Indiana. BMC Health Serv. Res. 18, 29 (2018).
Moyo, P. et al. Impact of prescription drug monitoring programs (PDMPs) on opioid utilization among medicare beneficiaries in 10 US States. Addiction 112, 1784–1796 (2017).
Rhodes, E., Wilson, M., Robinson, A., Hayden, J. A. & Asbridge, M. The effectiveness of prescription drug monitoring programs at reducing opioid-related harms and consequences: a systematic review. BMC Health Serv. Res. 19, 784 (2019).
Haegerich, T. M., Jones, C. M., Cote, P. O., Robinson, A. & Ross, L. Evidence for state, community and systems-level prevention strategies to address the opioid crisis. Drug Alcohol Depend 204, 107563 (2019).
Lin, L. A. et al. Impact of the opioid safety initiative on opioid-related prescribing in veterans. Pain 158, 833–839 (2017).
Irvine, M. A. et al. Modelling the combined impact of interventions in averting deaths during a synthetic-opioid overdose epidemic. Addiction 114, 1602–1613 (2019).
Barnett, M. L., Gray, J., Zink, A. & Jena, A. B. Coupling policymaking with evaluation - the case of the opioid crisis. N. Engl. J. Med. 377, 2306–2309 (2017).
Kariisa, M., Scholl, L., Wilson, N., Seth, P. & Hoots, B. Drug overdose deaths involving cocaine and psychostimulants with abuse potential - united states, 2003-2017. MMWR Morb. Mortal. Wkly. Rep. 68, 388–395 (2019).
Kertesz, S. G. Turning the tide or riptide? The changing opioid epidemic. Subst. Abus. 38, 3–8 (2017).
Compton, W. M., Jones, C. M. & Baldwin, G. T. Relationship between nonmedical prescription-opioid use and heroin use. N. Engl. J. Med. 374, 154–163 (2016).
European Monitoring Centre for Drugs and Drug Addiction. Harm reduction: evidence, impacts and challenges (EMCDDA, 2010).
World Health Organization. Harm reduction (WHO, 2019).
European Centre for Disease Prevention and Control & European Monitoring Centre for Drugs and Drug Addiction. Prevention and control of infectious diseases among people who inject drugs (EMCDDA, 2011).
Amato, L. et al. An overview of systematic reviews of the effectiveness of opiate maintenance therapies: available evidence to inform clinical practice and research. J. Subst. Abuse Treat. 28, 321–329 (2005). This review paper examines evidence from a set of five Cochrane reviews of different aspects of MOUD, comparing OAT with no treatment and with detoxification as well as with OAT utilizing different available medications, and integrates the evidence in a way that is designed to guide both clinical practice and associated research.
Mattick, R. P., Breen, C., Kimber, J. & Davoli, M. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst. Rev 8, CD002209 (2009).
Mathers, B. M. et al. Mortality among people who inject drugs: a systematic review and meta-analysis. Bull. World Health Organ. 91, 102–123 (2013).
MacArthur, G. J., Jacob, N., Pound, P., Hickman, M. & Campbell, R. Among friends: a qualitative exploration of the role of peers in young people’s alcohol use using Bourdieu’s concepts of habitus, field and capital. Sociol. Health Illn. 39, 30–46 (2017).
MacArthur, G. J. et al. Opiate substitution treatment and HIV transmission in people who inject drugs: systematic review and meta-analysis. BMJ 345, e5945 (2012).
Platt, L. et al. Needle syringe programmes and opioid substitution therapy for preventing HCV transmission among people who inject drugs: findings from a Cochrane Review and meta-analysis. Addiction 113, 545–563 (2018). This review paper draws on a Cochrane review of needle exchange and conducts metaanalysis to identify the extent to which both needle exchange and OAT protect against transmission of HCV infection: this review considers each of OAT and needle and syringe programmes separately, and also in combination.
Platt, L. et al. Needle syringe programmes and opioid substitution therapy for preventing hepatitis C transmission in people who inject drugs. Cochrane Database Syst. Rev. 9, CD012021 (2017).
Godfrey, C., Stewart, D. & Gossop, M. Economic analysis of costs and consequences of the treatment of drug misuse: 2-year outcome data from the national treatment outcome research study (NTORS). Addiction 99, 697–707 (2004).
Low, A. J. et al. Impact of opioid substitution therapy on antiretroviral therapy outcomes: a systematic review and meta-analysis. Clin. Infect. Dis. 63, 1094–1104 (2016).
Connock, M. et al. Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation. Health Technol. Assess. 11, 1–171 (2007).
Gisev, N. et al. A cost-effectiveness analysis of opioid substitution therapy upon prison release in reducing mortality among people with a history of opioid dependence. Addiction 110, 1975–1984 (2015).
Martin, N. K., Miners, A. & Vickerman, P. Assessing the cost-effectiveness of interventions aimed at promoting and offering hepatitis C testing to injecting drug users: an economic modelling report (NICE, 2012).
McLellan, A. T., Lewis, D. C., O’Brien, C. P. & Kleber, H. D. Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA 284, 1689–1695 (2000).
O’Brien, C. P. & McLellan, A. T. Myths about the treatment of addiction. Lancet 347, 237–240 (1996).
Marsden, J. et al. Does exposure to opioid substitution treatment in prison reduce the risk of death after release? A national prospective observational study in England. Addiction 112, 1408–1418 (2017). This large-scale observational study compares provision of OAT (versus non-provision) to prisoners during and after imprisonment: the study starts from the point of prior awareness of the considerable excess mortality of drug-using former prisoners during the first few weeks post-release, confirms this particular excess mortality in the first month, and also identifies the substantial protective effect of OAT.
Degenhardt, L. et al. The impact of opioid substitution therapy on mortality post-release from prison: retrospective data linkage study. Addiction 109, 1306–1017 (2014).
Fazel, S., Bains, P. & Doll, H. Substance abuse and dependence in prisoners: a systematic review. Addiction 101, 181–191 (2006).
Rich, J. D. et al. Methadone continuation versus forced withdrawal on incarceration in a combined US prison and jail: a randomised, open-label trial. Lancet 386, 350–359 (2015).
Larney, S. et al. Opioid substitution therapy as a strategy to reduce deaths in prison: retrospective cohort study. BMJ Open. 4, e004666 (2014).
Taylor, A. et al. Low incidence of hepatitis C virus amongst prisoners in Scotland. Addiction 108, 1296–1304 (2013).
Stone, J. et al. Modelling the impact of incarceration and prison-based hepatitis C virus (HCV) treatment on HCV transmission among people who inject drugs in Scotland. Addiction 112, 1302–1314 (2017).
Fraser, H. et al. Scaling up HCV prevention and treatment interventions in rural USA - model projections for tackling an increasing epidemic. Addiction 113, 173–182 (2018).
Cepeda, J. A. et al. Potential impact of implementing and scaling up harm reduction and antiretroviral therapy on HIV prevalence and mortality and overdose deaths among people who inject drugs in two Russian cities: a modelling study. Lancet HIV 5, e578–e587 (2018).
Cornish, R., Macleod, J., Strang, J., Vickerman, P. & Hickman, M. Risk of death during and after opiate substitution treatment in primary care: prospective observational study in UK general practice research database. BMJ 341, c5475 (2010).
Hickman, M. et al. The impact of buprenorphine and methadone on mortality: a primary care cohort study in the United Kingdom. Addiction 113, 1461–1476 (2018).
Martin, N. K. et al. Prioritization of HCV treatment in the direct-acting antiviral era: An economic evaluation. J. Hepatol. 65, 17–25 (2016).
Aspinall, E. J. et al. Are needle and syringe programmes associated with a reduction in HIV transmission among people who inject drugs: a systematic review and meta-analysis. Int. J. Epidemiol. 43, 235–248 (2014).
Strang, J. et al. Preventing opiate overdose fatalities with take-home naloxone: pre-launch study of possible impact and acceptability. Addiction 94, 199–204 (1999).
Strang, J. et al. Family carers and the prevention of heroin overdose deaths: unmet training need and overlooked intervention opportunity of resuscitation training and supply of naloxone. Drugs Educ. Prevent. Policy 15, 211–218 (2008).
McDonald, R., Campbell, N. D. & Strang, J. Twenty years of take-home naloxone for the prevention of overdose deaths from heroin and other opioids-conception and maturation. Drug Alcohol Depend. https://doi.org/10.1016/j.drugalcdep.2017.05.001 (2017).
McDonald, R. & Strang, J. Are take-home naloxone programmes effective? Systematic review utilizing application of the Bradford Hill criteria. Addiction 111, 1177–1187 (2016).
Irvine, M. A. et al. Distribution of take-home opioid antagonist kits during a synthetic opioid epidemic in British Columbia, Canada: a modelling study. Lancet Public Health 3, e218–e225 (2018).
Potier, C., Laprevote, V., Dubois-Arber, F., Cottencin, O. & Rolland, B. Supervised injection services: what has been demonstrated? A systematic literature review. Drug Alcohol Depend. 145, 48–68 (2014).
Milloy, M. J., Kerr, T., Tyndall, M., Montaner, J. & Wood, E. Estimated drug overdose deaths averted by North America’s first medically-supervised safer injection facility. PLOS ONE 3, e3351 (2008).
Petrar, S. et al. Injection drug users’ perceptions regarding use of a medically supervised safer injecting facility. Addict. Behav. 32, 1088–1093 (2007).
Wood, E., Tyndall, M. W., Montaner, J. S. & Kerr, T. Summary of findings from the evaluation of a pilot medically supervised safer injecting facility. CMAJ 175, 1399–1404 (2006).
Global Commission on Drug Policy. globalcommissionondrugs http://www.globalcommissionondrugs.org/ (2019).
Hughes, C. E. & Stevens, A. What can we learn from the Portuguese decriminalization of illicit drugs? Br. J. Criminol. 50, 999-1022 (2010).
Felix, S. & Portugal, P. Drug decriminalization and the price of illicit drugs. Int. J. Drug Policy 39, 121–129 (2017).
Goncalves, R., Lourenco, A. & Silva, S. N. A social cost perspective in the wake of the Portuguese strategy for the fight against drugs. Int. J. Drug Policy 26, 199–209 (2015).
National Institute of Drug Abuse. Principles of drug addiction treatment: a research-based guide (NIDA, 2018).
Rich, K. M., Bia, J., Altice, F. L. & Feinberg, J. Integrated models of care for individuals with opioid use disorder: how do we prevent HIV and HCV? Curr. HIV/AIDS Rep. 15, 266–275 (2018).
Nguyen Bich, D., Korthuis, P. T., Nguyen Thu, T., Van Dinh, H. & Le Minh, G. HIV patients’ preference for integrated models of addiction and HIV treatment in Vietnam. J. Subst. Abuse Treat. 69, 57–63 (2016).
Brooner, R. K., King, V. L., Kidorf, M., Schmidt, C. W. Jr & Bigelow, G. E. Psychiatric and substance use comorbidity among treatment-seeking opioid abusers. Arch. Gen. Psychiatry 54, 71–80 (1997).
Petry, N. M., Stinson, F. S. & Grant, B. F. Comorbidity of DSM-IV pathological gambling and other psychiatric disorders: results from the national epidemiologic survey on alcohol and related conditions. J. Clin. Psychiatry 66, 564–574 (2005).
Meier, A. et al. Co-occurring prescription opioid use problems and posttraumatic stress disorder symptom severity. Am. J. Drug Alcohol Abuse 40, 304–311 (2014).
Conway, K. P., Compton, W., Stinson, F. S. & Grant, B. F. Lifetime comorbidity of DSM-IV mood and anxiety disorders and specific drug use disorders: results from the national epidemiologic survey on alcohol and related conditions. J. Clin. Psychiatry 67, 247–257 (2006).
Fiellin, D. A. et al. Primary care-based buprenorphine taper vs maintenance therapy for prescription opioid dependence: a randomized clinical trial. JAMA Intern. Med. 174, 1947–1954 (2014).
Kakko, J., Svanborg, K. D., Kreek, M. J. & Heilig, M. 1-year retention and social function after buprenorphine-assisted relapse prevention treatment for heroin dependence in Sweden: a randomised, placebo-controlled trial. Lancet 361, 662–668 (2003).
Newman, R. G. & Whitehill, W. B. Double-blind comparison of methadone and placebo maintenance treatments of narcotic addicts in Hong Kong. Lancet 2, 485–488 (1979).
Seaman, S. R., Brettle, R. P. & Gore, S. M. Mortality from overdose among injecting drug users recently released from prison: database linkage study. BMJ 316, 426–428 (1998).
Farrell, M. & Marsden, J. Acute risk of drug-related death among newly released prisoners in England and Wales. Addiction 103, 251–255 (2008).
Merrall, E. L., Bird, S. M. & Hutchinson, S. J. A record-linkage study of drug-related death and suicide after hospital discharge among drug-treatment clients in Scotland, 1996-2006. Addiction 108, 377–384 (2013).
Amato, L., Minozzi, S., Davoli, M. & Vecchi, S. Psychosocial and pharmacological treatments versus pharmacological treatments for opioid detoxification. Cochrane Database Syst. Rev. 9, CD005031 (2011).
Gossop, M. The development of a short opiate withdrawal scale (SOWS). Addictive Behav. 15, 487–490 (1990).
Wesson, D. R. & Ling, W. The clinical opiate withdrawal scale (COWS). J. Psychoact. Drugs 35, 253–259 (2003).
Himmelsbach, C. K. The morphine abstinence syndrome, its nature and treatment. Ann. Intern. Med. 15, 829–839 (1941).
Gossop, M., Johns, A. & Green, L. Opiate withdrawal: inpatient versus outpatient programmes and preferred versus random assignment to treatment. Br. Med. J. 293, 103–104 (1986).
Gowing, L., Farrell, M., Ali, R. & White, J. M. Alpha2-adrenergic agonists for the management of opioid withdrawal. Cochrane Database Syst. Rev. 3, CD002024 (2016).
Walsh, S. L., Strain, E. C. & Bigelow, G. E. Evaluation of the effects of lofexidine and clonidine on naloxone-precipitated withdrawal in opioid-dependent humans. Addiction 98, 427–439 (2003).
Ridge, G., Gossop, M., Lintzeris, N., Witton, J. & Strang, J. Factors associated with the prescribing of buprenorphine or methadone for treatment of opiate dependence. J. Subst. Abuse Treat. 37, 95–100 (2009).
Gold, M., Redmond, D. & Kleber, H. Clonidine in opiate withdrawal. Lancet 1, 929–930 (1978).
Sigmon, S. C. et al. A randomized, double-blind evaluation of buprenorphine taper duration in primary prescription opioid abusers. JAMA Psychiatry 70, 1347–1354 (2013).
World Health Organization. Essential medicines (WHO, 2017).
Bickel, W. K. et al. Buprenorphine: dose-related blockade of opioid challenge effects in opioid dependent humans. J. Pharmacol. Exp. Ther. 247, 47–53 (1988).
Donny, E. C., Walsh, S. L., Bigelow, G. E., Eissenberg, T. & Stitzer, M. L. High-dose methadone produces superior opioid blockade and comparable withdrawal suppression to lower doses in opioid-dependent humans. Psychopharmacology 161, 202–212 (2002).
Strain, E. C., Stitzer, M. L., Liebson, I. A. & Bigelow, G. E. Dose-response effects of methadone in the treatment of opioid dependence. Ann. Intern. Med. 119, 23–27 (1993).
Donny, E. C., Brasser, S. M., Bigelow, G. E., Stitzer, M. L. & Walsh, S. L. Methadone doses of 100 mg or greater are more effective than lower doses at suppressing heroin self-administration in opioid-dependent volunteers. Addiction 100, 1496–1509 (2005).
Feng, X. Q., Zhu, L. L. & Zhou, Q. Opioid analgesics-related pharmacokinetic drug interactions: from the perspectives of evidence based on randomized controlled trials and clinical risk management. J. Pain. Res. 10, 1225–1239 (2017).
Volpe, D. A., Xu, Y., Sahajwalla, C. G., Younis, I. R. & Patel, V. Methadone metabolism and drug-drug interactions: in vitro and in vivo literature review. J. Pharm. Sci. 107, 2983–2991 (2018).
Meemken, L., Hanhoff, N., Tseng, A., Christensen, S. & Gillessen, A. Drug-drug interactions with antiviral agents in people who inject drugs requiring substitution therapy. Ann. Pharmacother. 49, 796–807 (2015).
Stringer, J., Welsh, C. & Tommasello, A. Methadone-associated QT interval prolongation and torsades de pointes. Am. J. Health Syst. Pharm. 66, 825–833 (2009).
Jasinski, D. R., Pevnick, J. S. & Griffith, J. D. Human pharmacology and abuse potential of the analgesic buprenorphine: a potential agent for treating narcotic addiction. Arch. Gen. Psychiatry 35, 501–516 (1978).
Squeglia, L. M., Fadus, M. C., McClure, E. A., Tomko, R. L. & Gray, K. M. Pharmacological treatment of youth substance use disorders. J. Child Adolesc. Psychopharmacol. https://doi.org/10.1089/cap.2019.0009 (2019).
Walsh, S. L. et al. Effects of buprenorphine and methadone in methadone-maintained subjects. Psychopharmacology 119, 268–276 (1995).
Stoller, K., Bigelow, G. E., Walsh, S. L. & Strain, E. C. Effects of buprenorphine/naloxone in opioid-dependent humans. Psychopharmacology 154, 230–242 (2001).
Rosado, J., Walsh, S. L., Bigelow, G. E. & Strain, E. C. Sublingual buprenorphine/naloxone precipitated withdrawal in subjects maintained on 100 mg of daily methadone. Drug Alcohol Depend. 90, 261–269 (2007).
Johnson, R. E. et al. A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N. Engl. J. Med. 343, 1291–1297 (2000).
Hser, Y. I. et al. Long-term outcomes after randomization to buprenorphine/naloxone versus methadone in a multi-site trial. Addiction 111, 695–705 (2016).
Rosenthal, R. N. et al. Effect of buprenorphine implants on illicit opioid use among abstinent adults with opioid dependence treated with sublingual buprenorphine: a randomized clinical trial. JAMA 316, 282–290 (2016).
Nasser, A. F. et al. Sustained-release buprenorphine (RBP-6000) blocks the effects of opioid challenge with hydromorphone in subjects with opioid use disorder. J. Clin. Psychopharmacology 36, 18–26 (2016).
US Food and Drug Administration. Sublocade. FDA https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209819s000lbl.pdf (2017).
Lofwall, M. R. et al. Weekly and monthly subcutaneous buprenorphine depot formulations vs daily sublingual buprenorphine with naloxone for treatment of opioid use disorder: a randomized clinical trial. JAMA Intern. Med. 178, 764–773 (2018).
Eder, H. et al. Comparative study of the effectiveness of slow-release morphine and methadone for opioid maintenance therapy. Addiction 100, 1101–1109 (2005).
Beck, T. et al. Maintenance treatment for opioid dependence with slow-release oral morphine: a randomized cross-over, non-inferiority study versus methadone. Addiction 109, 617–626 (2014).
Meini, M. et al. Relationship between plasma concentrations of the l-enantiomer of methadone and response to methadone maintenance treatment. Eur. J. Pharmacol. https://doi.org/10.1016/j.ejphar.2015.03.081 (2015).
Verthein, U. et al. The effects of racemic D, L-methadone and L-methadone in substituted patients-a randomized controlled study. Drug Alcohol Depend. 80, 267–271 (2005).
Robertson, J. R. et al. Addressing the efficacy of dihydrocodeine versus methadone as an alternative maintenance treatment for opiate dependence: a randomized controlled trial. Addiction 101, 1752–1759 (2006).
van den Brink, W. et al. Medical prescription of heroin to treatment resistant heroin addicts: two randomised controlled trials. BMJ 327, 310 (2003).
Haasen, C. et al. Heroin-assisted treatment for opioid dependence: randomised controlled trial. Br. J. Psychiatry 191, 55–62 (2007).
Strang, J. et al. Supervised injectable heroin or injectable methadone versus optimised oral methadone as treatment for chronic heroin addicts in England after persistent failure in orthodox treatment (RIOTT): a randomised trial. Lancet 375, 1885–1895 (2010).
Oviedo-Joekes, E. et al. Diacetylmorphine versus methadone for the treatment of opioid addiction. N. Engl. J. Med. 361, 777–786 (2009).
Strang, J. et al. Heroin on trial: systematic review and meta-analysis of randomised trials of diamorphine-prescribing as treatment for refractory heroin addiction. Br. J. Psychiatry 207, 5–14 (2015).
Blanken, P., Hendriks, V. M., van Ree, J. M. & van den Brink, W. Outcome of long-term heroin-assisted treatment offered to chronic, treatment-resistant heroin addicts in the Netherlands. Addiction 105, 300–308 (2010).
Oviedo-Joekes, E. et al. Hydromorphone compared with diacetylmorphine for long-term opioid dependence: a randomized clinical trial. JAMA Psychiatry 73, 447–455 (2016).
Minozzi, S. et al. Oral naltrexone maintenance treatment for opioid dependence. Cochrane Database Syst. Rev. 16, CD001333 (2011).
Dunn, K. E. et al. Employment-based reinforcement of adherence to oral naltrexone treatment in unemployed injection drug users. Exp. Clin. Psychopharmacol. 21, 74–83 (2013).
Krupitsky, E. et al. Injectable extended-release naltrexone for opioid dependence. Lancet 377, 1506–1513 (2011).
Krupitsky, E. et al. Randomized trial of long-acting sustained-release naltrexone implant vs oral naltrexone or placebo for preventing relapse to opioid dependence. Arch. Gen. Psychiatry 69, 973–981 (2012).
Lee, J. D. et al. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet 391, 309–318 (2018).
Larochelle, M. R. et al. Medication for opioid use disorder after nonfatal opioid overdose and association with mortality: a cohort study. Ann. Intern. Med. 169, 137–145 (2018).
Morgan, J. R., Schackman, B. R., Weinstein, Z. M., Walley, A. Y. & Linas, B. P. Overdose following initiation of naltrexone and buprenorphine medication treatment for opioid use disorder in a United States commercially insured cohort. Drug. Alcohol. Depend. 200, 34–39 (2019).
Substance Abuse and Mental Health Services Administration. Federal guidelines for opioid treatment programs (SAMHSA, 2015).
National Institute for Health & Clinical Excellence. Drug misuse – psychosocial interventions (NICE, 2007).
Clinical Guidelines on Drug Misuse and Dependence Update 2017 Independent Expert Working Group. Drug misuse and dependence: UK guidelines on clinical management (Global and Public Health, 2017).
Intstitute of Medicine. Psychosocial interventions for mental and substance use disorders: a framework for establishing evidence-based standards (National Academies Press, 2015).
Department of Health and Social Care. Drug misuse and dependence: UK guidelines on clinical management (Department of Health and Social Care, 2017).
Amato, L., Minozzi, S., Davoli, M. & Vecchi, S. Psychosocial combined with agonist maintenance treatments versus agonist maintenance treatments alone for treatment of opioid dependence. Cochrane Database Syst. Rev. 5, CD004147 (2011).
Weiss, R. D. et al. Adjunctive counseling during brief and extended buprenorphine-naloxone treatment for prescription opioid dependence: a 2-phase randomized controlled trial. Arch. Gen. Psychiatry https://doi.org/10.1001/archgenpsychiatry.2011.121 (2011).
Fiellin, D. A. et al. Counseling plus buprenorphine-naloxone maintenance therapy for opioid dependence. N. Engl. J. Med. 355, 365–374 (2006).
Sigmon, S. C. et al. Interim buprenorphine vs. waiting list for opioid dependence. N. Engl. J. Med. 375, 2504–2505 (2016).
Schwartz, R. P. et al. A randomized controlled trial of interim methadone maintenance. Arch. Gen. Psychiatry 63, 102–109 (2006).
Kelly, J. F. & Greene, M. C. The twelve promises of alcoholics anonymous: psychometric measure validation and mediational testing as a 12-step specific mechanism of behavior change. Drug Alcohol Depend 133, 633–640 (2013).
Humphreys, K. & Moos, R. H. Encouraging posttreatment self-help group involvement to reduce demand for continuing care services: two-year clinical and utilization outcomes. Alcohol Clin. Exp. Res. 31, 64–68 (2007).
Humphreys, K. Circles of Recovery: Self-help Organisations for Addictions (Cambridge Univ. Press, 2004).
White, W. L. Addiction recovery: its definition and conceptual boundaries. J. Subst. Abuse Treat. 33, 229–241 (2007).
White, W. L. Medication-assisted recovery from opioid addiction: historical and contemporary perspectives. J. Addict. Dis. 31, 199–206 (2012).
Betty Ford Institute Consensus Panel. What is recovery? A working definition from the Betty Ford institute. J. Subst. Abuse Treat. 33, 221–228 (2007).
Gilman, S. M., Galanter, M. & Dermatis, H. Methadone anonymous: a 12-step program for methadone maintained heroin addicts. Subst. Abus. 22, 247–256 (2001).
Kelly, J. F., Humphreys, K. & Ferri, M. Alcoholics Anonymous and other 12-step programs for alcohol use disorder. Cochrane Database Syst. Rev. 9, CD012880 (2019).
Melnick, G., De Leon, G., Thomas, G., Kressel, D. & Wexler, H. K. Treatment process in prison therapeutic communities: motivation, participation, and outcome. Am. J. Drug Alcohol Abuse 27, 633–650 (2001).
De Leon, G., Hawke, J., Jainchill, N. & Melnick, G. Therapeutic communities. Enhancing retention in treatment using “Senior professor” staff. J. Subst. Abuse Treat. 19, 375–382 (2000).
Strang, J. et al. Take-home naloxone for the emergency interim management of opioid overdose: the public health application of an emergency medicine. Drugs 79, 1395–1418 (2019). This overview paper describes the development and application of take-home naloxone as a public health strategy to reduce fatal outcome from opioid overdose by mobilizing and enabling civilian interim emergency care with the antidote naloxone: it also considers the concentrated naloxone nasal sprays which have recently been developed in addition to the long-established injectable form of naloxone.
Ravndal, E. & Amundsen, E. J. Mortality among drug users after discharge from inpatient treatment: an 8-year prospective study. Drug Alcohol Depend 108, 65–69 (2010).
Hawk, K. & D’Onofrio, G. Emergency department screening and interventions for substance use disorders. Addict. Sci. Clin. Pract. 13, 18 (2018).
Stewart, L. M., Henderson, C. J., Hobbs, M. S., Ridout, S. C. & Knuiman, M. W. Risk of death in prisoners after release from jail. Aust. N. Z. J. Public. Health 28, 32–36 (2004).
Lee, J. D. et al. Extended-release naltrexone to prevent opioid relapse in criminal justice offenders. N. Engl. J. Med. 374, 1232–1242 (2016).
Gordon, M. S. et al. A randomized controlled trial of prison-initiated buprenorphine: prison outcomes and community treatment entry. Drug Alcohol Depend. 142, 33–40 (2014).
Hser, Y. I., Anglin, M. D., Grella, C., Longshore, D. & Prendergast, M. Drug treatment careers. A conceptual framework and existing research findings. J.Subst. Abuse Treat. 14, 543–558 (1997).
Dennis, M. L., Scott, C. K., Funk, R. & Foss, M. A. The duration and correlates of addiction and treatment careers. J. Subst. Abuse Treat. 28 (Suppl. 1), S51–S62 (2005).
Simpson, D. D., Joe, G. W., Lehman, W. E. K. & Sells, S. B. Addiction careers: etiology, treatment, and 12-year follow-up outcomes. J. Drug. Issues 16, 107–122 (1986).
Krebs, E. et al. Estimating state transitions for opioid use disorders. Med. Decis. Mak. 37, 483–497 (2017).
Hser, Y. I., Evans, E., Grella, C., Ling, W. & Anglin, D. Long-term course of opioid addiction. Harv. Rev. Psychiatry 23, 76–89 (2015).
Scott, C. K., Foss, M. A. & Dennis, M. L. Pathways in the relapse-treatment-recovery cycle over 3 years. J. Subst. Abuse Treat. 28 (Suppl. 1), S63–S72 (2005).
Gjersing, L. & Bretteville-Jensen, A. L. Patterns of substance use and mortality risk in a cohort of ‘hard-to-reach’ polysubstance users. Addiction 113, 729–739 (2018).
Hser, Y. I. et al. High mortality among patients with opioid use disorder in a large healthcare system. J. Addict. Med. 11, 315–319 (2017).
Degenhardt, L., Larney, S., Randall, D., Burns, L. & Hall, W. Causes of death in a cohort treated for opioid dependence between 1985 and 2005. Addiction 109, 90–99 (2014).
Darke, S. et al. Patterns and correlates of sustained heroin abstinence: findings from the 11-year follow-up of the australian treatment outcome study. J. Stud. Alcohol. Drugs 76, 909–915 (2015).
Dowell, D. et al. Contribution of opioid-involved poisoning to the change in life expectancy in the United States, 2000-2015. JAMA. 318, 1065–1067 (2017).
Rudd, R. A., Seth, P., David, F. & Scholl, L. Increases in drug and opioid-involved overdose deaths - United States, 2010-2015. MMWR Morb. Mortal. Wkly. Rep. 65, 1445–1452 (2016).
Fischer, B., Pang, M. & Tyndall, M. The opioid death crisis in Canada: crucial lessons for public health. Lancet Public Health 4, e81–e82 (2019).
Roxburgh, A. et al. Trends in heroin and pharmaceutical opioid overdose deaths in Australia. Drug Alcohol Depend. 179, 291–298 (2017).
Kimber, J., Hickman, M., Strang, J., Thomas, K. & Hutchinson, S. Rising opioid-related deaths in England and Scotland must be recognised as a public health crisis. Lancet Psychiatry 6, 639–640 (2019).
Case, A. & Deaton, A. Mortality and morbidity in the 21(st) century. Brook. Pap. Econ. Act. 2017, 397–476 (2017).
Marsch, L. A. et al. Comparison of pharmacological treatments for opioid-dependent adolescents: a randomized controlled trial. Arch. Gen. Psychiatry 62, 1157–1164 (2005).
Ward, J., Hall, W. & Mattick, R. P. Role of maintenance treatment in opioid dependence. Lancet 353, 221–226 (1999).
Mitchell, S. G. et al. Changes in quality of life following buprenorphine treatment: relationship with treatment retention and illicit opioid use. J. Psychoact. Drugs 47, 149–157 (2015).
Nosyk, B. et al. Short term health-related quality of life improvement during opioid agonist treatment. Drug. Alcohol. Depend. 157, 121–128 (2015).
Sadeghi, N., Davaridolatabadi, E., Rahmani, A., Ghodousi, A. & Ziaeirad, M. Quality of life of adolescents and young people arrive at an addiction treatment centers upon their admission, and 1, 4 and 8 months after methadone maintenance therapy. J. Educ. Health Promot 6, 95 (2017).
Knudsen, H. K., Abraham, A. J. & Roman, P. M. Adoption and implementation of medications in addiction treatment programs. J. Addict. Med. 5, 21–27 (2011).
Mayet, S., Farrell, M., Ferri, M., Amato, L. & Davoli, M. Psychosocial treatment for opiate abuse and dependence. Cochrane Database Syst. Rev. 25, CD004330 (2005).
Zhang, Z., Friedmann, P. D. & Gerstein, D. R. Does retention matter? Treatment duration and improvement in drug use. Addiction 98, 673–684 (2003).
Levine, A. R. et al. Gender-specific predictors of retention and opioid abstinence during methadone maintenance treatment. J. Subst. Abuse Treat. 54, 37–43 (2015).
Hser, Y. I. et al. Treatment retention among patients randomized to buprenorphine/naloxone compared to methadone in a multi-site trial. Addiction 109, 79–87 (2014).
Matson, S. C., Hobson, G., Abdel-Rasoul, M. & Bonny, A. E. A retrospective study of retention of opioid-dependent adolescents and young adults in an outpatient buprenorphine/naloxone clinic. J. Addict. Med. 8, 176–182 (2014).
Burns, L. et al. A longitudinal comparison of retention in buprenorphine and methadone treatment for opioid dependence in New South Wales, Australia. Addiction 110, 646–655 (2015).
Cousins, S. J., Crevecoeur-MacPhail, D., Kim, T. & Rawson, R. A. The Los Angeles county hub-and-provider network for promoting the sustained use of extended-release naltrexone (XR-NTX) in los angeles county (2010-2015). J. Subst. Abuse Treat. 85, 78–83 (2018).
Kaskutas, L. A. et al. Elements that define recovery: the experiential perspective. J. Stud. Alcohol. Drugs 75, 999–1010 (2014).
White, W. L. Recovery. Alcohol. Treat. Q. 23, 3–15 (2005).
Humphreys, K. & Lembke, A. Recovery-oriented policy and care systems in the UK and USA. Drug Alcohol Rev. 33, 13–18 (2014).
Bray, J. W. et al. Quality of life as an outcome of opioid use disorder treatment: a systematic review. J. Substance Abuse Treat. 76, 88–93 (2017).
Garner, B. R., Scott, C. K., Dennis, M. L. & Funk, R. R. The relationship between recovery and health-related quality of life. J. Subst. Abuse Treat. 47, 293–298 (2014).
Feelemyer, J. P., Jarlais, D. C. D., Arasteh, K., Phillips, B. W. & Hagan, H. Changes in quality of life (WHOQOL-BREF) and addiction severity index (ASI) among participants in opioid substitution treatment (OST) in low and middle income countries: an international systematic review. Drug. Alcohol. Depend. 134, 251–258 (2014).
Laudet, A. B. The case for considering quality of life in addiction research and clinical practice. Addict. Sci. Clin. Pract. 6, 44–55 (2011).
Strada, L., Franke, G. H., Schulte, B., Reimer, J. & Verthein, U. Development of OSTQOL: a measure of quality of life for patients in opioid substitution treatment. Eur. Addict. Res. 23, 238–248 (2017).
[No authors listed]. Development of the World Health Organization WHOQOL-BREF quality of life assessment. The WHOQOL Group. Psychol. Med. 28, 551–558 (1998).
De Maeyer, J., Vanderplasschen, W. & Broekaert, E. Quality of life among opiate-dependent individuals: a review of the literature. Int. J. Drug. Policy 21, 364–380 (2010).
Neale, J. et al. Development and validation of ‘sure’: a patient reported outcome measure (prom) for recovery from drug and alcohol dependence. Drug Alcohol Depend 165, 159–167 (2016).
Neale, J. et al. Emerging consensus on measuring addiction recovery: findings from a multi-stakeholder consultation exercise. Drugs Educ. Prev. Policy 23, 31–40 (2015).
Hser, Y.-I., Grella, C., Chou, C.-P. & Douglas Anglin, M. Relationships between drug treatment careers and outcomes: findings from the national drug abuse treatment outcome study. Eval. Rev. 22, 496–519 (1998).
Flynn, P. M., Joe, G. W., Broome, K. M., Simpson, D. D. & Brown, B. S. Recovery from opioid addiction in DATOS. J. Subst. Abuse Treat. 25, 177–186 (2003).
Panebianco, D., Gallupe, O., Carrington, P. J. & Colozzi, I. Personal support networks, social capital, and risk of relapse among individuals treated for substance use issues. Int. J. Drug. Policy 27, 146–153 (2016).
Muller, A. E., Skurtveit, S. & Clausen, T. Building abstinent networks is an important resource in improving quality of life. Drug Alcohol Depend 180, 431–438 (2017).
Nestler, E. J. Is there a common molecular pathway for addiction? Nat. Neurosci. 8, 1445–1449 (2005).
Koob, G. F. Negative reinforcement in drug addiction: the darkness within. Curr. Opin. Neurobiol. 23, 559–563 (2013).
Martin, N. K. et al. Combination interventions to prevent HCV transmission among people who inject drugs: modeling the impact of antiviral treatment, needle and syringe programs, and opiate substitution therapy. Clin. Infect. Dis. 57 (Suppl. 2), S39–S45 (2013).
World Health Organization. ICD-10 classification of mental and behavioural disorders (WHO, 2016).
Koob, G. F., Everitt, B. J. & Robbins, T. W. in Fundamental Neuroscience 4th edn (eds Squire, L. R. et al.) 871–898 (Elsevier, 2013).
The authors acknowledge M. Bela at King’s College London for enduring patience with manuscript preparation and M. Krieger at Brown University for his research assistance. J.S. and M.H. acknowledge UK NIHR Senior Investigator grants. J.S. is supported by the NIHR Biomedical Research Centre for Mental Health at South London & Maudsley NHS Foundation Trust and King’s College London. B.D.L.M. is supported in part by the US National Institute of General Medical Sciences (P20GM125507).
J.S.’s employer (King’s College London) has received, connected to his work, project grant support and/or honoraria and/or consultancy payments from the UK Department of Health, Public Health England, and the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) as well as research grants from (past 3 years) the UK National Institute for Health Research (NIHR), the Medical Research Council and the Pilgrim Trust. J.S. has also worked with the EMCDDA, United Nations Office on Drugs and Crime, US FDA and US National Institute on Drug Abuse (NIDA), and WHO as well as with other international government agencies. King’s College London has registered intellectual property on a buccal naloxone with which J.S. is involved, and J.S. has been named in a patent registration by MundiPharma as inventor of a potential concentrated naloxone nasal spray. King’s College London has also received, connected to the work of J.S., research grant support and/or payment of honoraria, consultancy payments, and/or travelling, accommodation and/or conference expenses (past 3 years) from Braeburn, Camurus, Indivior, Molteni Farma and MundiPharma, and has received trial medication supplies from Braeburn and iGen related to medications and technologies potentially applicable in the treatment of addictions and related problems. J.S. has worked with and received grant support from the charity Action on Addiction and with the Pilgrim Trust and is a Patron of DrugFAM. L.D. has received investigator-initiated untied educational grants for studies of opioid medications in Australia from Indivior, MundiPharma and Seqirus. The Australian National Drug and Alcohol Research Centre of the University of New South Wales Sydney is supported by funding from the Australian Government Department of Health under the Drug and Alcohol Program. L.D. is supported by an Australian National Health and Medical Research Council Senior Principal Research Fellowship (#1041742, #1135991) and by US National Institutes of Health grant NIDA (R01DA1104470). M.H. has received unrestricted honoraria for presenting at scientific meetings within the past 2 years from Gilead and MSD, and acknowledges support from the NIHR Public Health and Prevention in Evaluation, NIHR School for Public Health Research and NIHR Biomedical Research Centre at Bristol. In the past year, K.J. has received funding from Johnson, Bassin and Shaw to conduct analysis of Medicare data for assessment of opioid use for a Medicare contractor. She has a subcontract to NIDA (grant no. DA035789) to write a paper on the results of a clinical trial on a mobile app to address substance use disorders. She has consulted several times for AlphaSights on opioid issues for their clients, who cannot be disclosed but are not pharmaceutical companies, pharmacies or other entities currently engaged in the industry. K.J. is the Executive Director of the International Consortium of Universities for Drug Demand Reduction, which is registered as a not-for-profit organization in the USA and is funded by the US Department of State. K.J. declares that, for the period prior, she was employed by the US government. S.L.W.’s employer, University of Kentucky, has received research support related to her work from the Braeburn Pharmaceuticals, US FDA and US NIDA (in the past 3 years). S.L.W. has worked with the FDA, NIDA, NIH and WHO on issues related to substance use disorders and opioid abuse liability; has served as a scientific advisory board member for the Addiction Policy Forum, the NIDA Scientific Advisory Council and Opiant Pharmaceuticals; and has received, connected to her work, research grant support and/or payment of honoraria, consultancy payments and/or travelling, accommodation and/or conference expenses from pharmaceutical/device companies (over the past 3 years) from Brainsway, Braeburn, Camurus, Eli Lilly and Co., Indivior, Neurocrine, Otsuka, Pfizer, Summit Biosciences, Trevi Pharmaceuticals and U.S. World Meds. All other authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Strang, J., Volkow, N.D., Degenhardt, L. et al. Opioid use disorder. Nat Rev Dis Primers 6, 3 (2020). https://doi.org/10.1038/s41572-019-0137-5