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Current status of opioid addiction treatment and related preclinical research

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Science Advances  02 Oct 2019:
Vol. 5, no. 10, eaax9140
DOI: 10.1126/sciadv.aax9140
  • Fig. 1 Chemical structures of the most commonly abused opioids.

    Structures of (A) morphine, (B) heroin, (C) oxycodone, and (D) fentanyl and of the opioidergic therapeutics methadone (E) and buprenorphine (F). In addition, shown are antagonists naltrexone (G) and nalmefene (H). The structurally similar morphinan derivatives (A, B, C, F, G, and H) derived from opium, or synthesized from thebaine obtained from opium, contrast sharply with the structures of the synthetic opioids methadone and fentanyl (E and D, respectively).

  • Fig. 2 Heroin addiction contrasted with methadone maintenance.

    (A) Difference in plasma protein binding and metabolism results in substantially different pharmacokinetic profiles and bioavailability for heroin versus methadone (55). (B) Prototypic administration pattern and subjective state for heroin versus methadone. Multiple doses of heroin are self-administered daily to achieve a state of “high” (euphoria) or, in cases with a depleted supply, to avoid a feeling of “sick” (withdrawal). Methadone, at steady state with single daily administration, leads neither to subjective states of high nor sick (43).

  • Fig. 3 Opioid overdose deaths in the United States, 1999–2017.

    Data from Centers for Disease Control and Prevention, 2018 Annual Surveillance Report of Drug-Related Risks and Outcomes. Asterisk indicates synthetic opioids other than methadone, e.g., prescribed or illicit fentanyl, fentanyl analogs, and tramadol. Number sign indicates natural or semisynthetic opioids other than heroin, e.g., morphine, oxycodone, and hydrocodone.

  • Fig. 4 Model of the progression from misuse of opioids toward moderate or severe OUD (i.e., opioid addiction).

  • Table 1 Epidemiology of drug use.

    Prevalence of specific drug abuse and vulnerability to develop addictions. SAMHSA National Survey on Drug Use and Health, 2017; others 2007–2018.

    National household survey and related surveys (2007–2016)
    Heroin use—ever~5.2 million
    Heroin addiction~652,000
    Illicit use of opiate medication—ever~37.1 million (i.e., 14.2% of the population 12 and over)
    Dependence on such medication use~2.1 million
    Opiate (heroin, fentanyl, and other) overdose deaths~72,3000 (in 2017)*
    Cocaine use—ever~40.5 million
    Cocaine addiction~966,000
    Alcohol use—ever~216 million
    Alcoholism~14.5 million
    Marijuana use—ever~123 million
    Marijuana daily use~4 million
    Development of addiction after self-exposure
    Opiate addiction~1 in 5 to 1 in 15 (20 to 6.5%)
    Alcoholism, marijuana, and cocaine dependency~1 in 8 to 1 in 15 (12.5 to 6.5%)

    *National Center for Health Statistics (U.S. Centers for Disease Control and Prevention), 2019.

    • Table 2 Status of methadone, buprenorphine, and extended-release naltrexone treatments for opioid addiction in the United States: Decrease and then increase in numbers in treatment 2015–2017 (SAMHSA, 2018).

      TreatmentU.S. patients in treatment
      201520162017
      Methadone
      maintenance
      356,843345,443
      (−11,400; −3.2%)
      382,867
      (+37,424; +10.8%)
      Buprenorphine
      maintenance
      75,72361,486
      (−14,237; −18.8%)
      112,223
      (+50,737; +82.5%)
      Extended-release
      naltrexone
      703510,128
      (+3093; +44.0%)
      23,065
      (+12,937; +128.7%)
    • Table 3 FDA-approved medications for OUD, with typical dosing paradigms for each of the approved formulations.

      FDA-approved medications for OUD, with typical dosing paradigms for each of the approved formulations.. PO, per os (oral); SL, subligual; BUC, buccal; SQ, subcutaneous; IM, intramuscular.

      TreatmentDose rangeConsiderations
      Methadone (PO)80–150 mg/day
      (typical range)
      Maintenance dosing
      is determined
      during the early
      weeks of treatment
      following upward
      titration. Individual
      genetic and drug
      history differences
      may lead to
      requirement of
      higher doses than
      the typical range.
      FDA approved in
      1972.
      Buprenorphine-
      naloxone (SL or BUC)
      8–24 mg/day
      buprenorphine
      (1–6 mg/day
      naltrexone)
      (typical range)
      4:1 ratio (w/w) of
      buprenorphine-
      naloxone. Because
      of partial agonist
      nature of
      buprenorphine, no
      further treatment
      effect to be gained
      by doses greater
      than 24 mg/day.
      FDA approved in
      2002.
      Buprenorphine
      extended-release
      formulation (SQ)
      80–300 mg/monthly
      injection
      Two formulations
      available. FDA
      approved in 2016
      and 2017.
      Naltrexone tablets
      (PO)/extended-
      release formulation
      (IM)
      50 or 100 mg/day
      orally; 380 mg/
      monthly IM
      injection
      Requires a patient
      to be opioid free for
      7–10 days before
      administration. FDA
      approved in 1984
      (tablets, no longer
      marketed); 2010
      (extended release).

    Supplementary Materials

    • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/5/10/eaax9140/DC1

      Table S1. Methadone maintenance treatment for opiate (heroin) addiction.

      Table S2. SNPs of genes related to endocrine stress responsivity that has been found to be associated with opioid addiction (101, 102, 116).

      Fig. S1. Model for the contribution of pain states and pain treatment to the development of OUD.

    • Supplementary Materials

      This PDF file includes:

      • Table S1. Methadone maintenance treatment for opiate (heroin) addiction.
      • Table S2. SNPs of genes related to endocrine stress responsivity that has been found to be associated with opioid addiction (101, 102, 116).
      • Fig. S1. Model for the contribution of pain states and pain treatment to the development of OUD.

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