Table 2.

Available pharmacological medication-assisted therapies used for treatment of substance-use disorders

	Type of dependence	Mechanism of action	Pharmacological properties	Side-effects	Substance-use treatment outcomes	Effect on HIV	Other issues
Methadone	Opioid	Pure opioid μ-receptor agonist	Half-life 24–36 h; ingested orally as tablet or liquid; achieves steady state within 5 days	Tolerance to side-effects usually develops; diaphoresis, constipation, and amenorrhoea (menses usually return after 12–18 months); excessive dosing or when combined with alcohol might cause overdoses or death	Decreases relapse to illicit opioid use; decreases number of days using illlicit opioids; decreases opioid and cocaine use after release from prison; decreases criminal activity; increases employment; cost effective	Decreases injection and HIV transmission; increases retention in HIV care; effective supporter of DAART; increases effectiveness of ART	No euphoria felt after being on stable methadone dose; doses of 30–60 mg per day will block opioid withdrawal symptoms, but this dose seldom produces abstinence. Instead, higher doses in the 80–120 mg per day range are needed to decrease opioid craving and decrease illicit drug use. These higher doses are also associated with greater retention in treatment
Buprenorphine	Opioid	Partial opioid μ-receptor agonist and partial κ–receptor antagonist	Half-life 24–36 h; administered sublingually; slow dissociation from the μ-receptor allowing alternate-day dosing	Improved safety profile compared with methadone; unlikely to cause overdose or respiratory depression; higher binding affinity for the μ receptor than heroin or methadone, therefore precipitates withdrawal in person still with opioids in their system	Decreases relapse to illicit opioid use; decreases number of days using illlicit opioids; decreases opioid and cocaine use after release from prison; decreases criminal activity; increases employment; cost effective	Decreases injection and HIV transmission; increases retention in HIV care; effective supporter of DAART; increases effectiveness of ART; increases retention on ART after release from prison	Decreased likelihood for medication diversion; injection of buprenorphine in opioid-dependent individuals precipitates withdrawal symptoms
Buprenorphine-naloxone	Opioid	Partial opioid μ-receptor agonist and partial κ–receptor antagonist; naloxone is a shortacting μ-receptor but not orally bioavailable antagonist	Half-life 24–36 h; administered sublingually; slow dissociation from the μ receptor allowing alternate-day dosing	Same as for buprenorphine; naloxone used to reduce likelihood for diversion and injection	Compared with high dose methadone, retention in treatment is lower	Same as for buprenorphine; when injected, probably results in more frequent injecting and increased risk for HIV transmission	Used to decrease likelihood of illicit injection and injection frequency; however, might increase the frequency of injections
Naltrexone	Opioid	Pure μ-receptor opioid antagonist	Oral formulation dosing is daily or alternate-day dosing; injectable formulation given intramuscularly monthly (improves adherence)	Hepatoxicity possible; has been administered safely in HCV-infected patients	Retention in treatment is lower than for methadone or buprenorphine, but might be considered in highly motivated patients	··	Discourages opioid use by diminishing the pleasurable effect of and craving for opioids, and has shown efficacy in highly motivated populations
Naltrexone	Alcohol	Blocks the pleasant and reinforcing effects of alcohol by preventing the stimulation of opioid receptors and the reduction of dopamine release in the ventral tegmental area	Oral formulation dosing is daily or alternate-day dosing; injectable formulation given intramuscularly monthly (improves adherence7,8)	Hepatoxicity possible; has been administered safely in HCV-infected patients	Superior to behavioural counselling and acamprosate for treatment of alcohol-use diseases in HIV-uninfected individuals; increases time to relapse, decreases number of days of heavy drinking7,8	··	··
Acamprosate	Alcohol	Structural analogue of the γ-aminobutyric acid neurotransmitter; normalises glutamatergic neurotransmission; slow acting, can attenuate relapse in some	Orally dosed with two tablets three times per day; adherence might be problematic	Few side-effects	Increased abstinence confirmed in placebo-controlled trials, but no benefit in preventing relapse by itself or in combination with counselling	Not studied in HIV-infected patients	··
Disulfiram	Alcohol	Inhibits acetaldehyde dehydrogenase and causes accumulation of acetaldehyde when alcohol is consumed; leads to painful symptoms such as facial flushing, dypsnoea, nausea, vomiting, and headache, thereby discouraging relapse to alcohol consumption	Orally dosed, half-life 24 h; should not be combined with amprenavir (probable) or metronidazole (probable)	Nausea and vomiting if alcohol is ingested; hepatotoxicity	Not studied in HIV-infected individuals	Hepatotoxicity; causes profound nausea and vomiting when alcohol is ingested	Might be useful when combined with other interventions, including methadone when a patient is opioid-dependent
Varenicline	Tobacco	Binds with high affinity and selectivity at α4β2-neuronal nicotinic acetylcholine receptors and exerts its effect by producing agonist activity at a subtype of the α4β2-nicotinic receptor while also preventing nicotine binding to α4β2 receptors	Orally ingested, half-life 24 h and 92% renally cleared; no hepatic metabolism	Rare but serious neuropsychiatric events (eg, depression, suicidal ideation, suicide attempt, and completed suicide) have been reported	In meta-analysis, associated with the highest rates of abstinence and greatest reduction in smoking	Has not been systematically studied in HIV-infected individuals	··
Nicotine-replacement therapy	Tobacco	Competitive binding of α4β2-neuronal nicotinic acetylcholine receptors	Route of administration includes transdermal, orally ingested, sublingual or inhaled	Can rarely cause cardiac dysrhythmia, hypertension, or tachyarrhythmia; more commonly, causes nicotine withdrawal, dizziness, headache, insomnia	Is more effective than placebo or counselling, but results in greatest abstinence rates and reductions in tobacco smoking when combined with bupropion or with two forms of nicotine replacement9,10	Has not been systematically studied in HIV-infected individuals	··
Buproprion	Tobacco	Acts as a norepinephrine and dopamine reuptake inhibitor for treating depression, as well as α3β4-nicotinic receptor antagonist	Orally administered; half-life 24 h, efavirenz and lopinavir moderately decrease bupropion concentrations	Rare but serious neuropsychiatric events, including depression, suicidal ideation, suicide attempt, and completed suicide have been reported in patients with and without pre-existing psychiatric disease who were taking bupropion for smoking cessation; some had worsening of their psychiatric illnesses	Superior to placebo but most optimum outcomes associated with combination with nicotine replacement therapy in RCTs	Has not been systematically studied in HIV-infected individuals	··

DAART=directly administered antiretroviral therapy. ART=antiretroviral therapy. HCV=hepatitis C virus. RCTs=randomised controlled trials.