3 Clinical psychopharmacology3.4 Therapeutics
3.4.6 Controlled substances and drugs used in addictions
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Written by Resident Doctor Committee · Published
Methadone
Methadone is a long-acting full mu opioid agonist whose effect keeps rising with dose, so unlike buprenorphine it has no ceiling on respiratory depression.
Its long, unpredictable half-life lets it accumulate over the first few days, so doses start at 10 to 30 mg and are raised slowly.
Methadone also blocks NMDA receptors, which may slow tolerance.
Methadone prolongs the QTc interval by blocking hERG potassium channels and can cause torsades de pointes, especially at high doses or with interacting drugs.
Buprenorphine
Property | Consequence |
|---|---|
Partial mu agonist | A ceiling on respiratory depression makes it safer than methadone, though not safe with sedatives |
High mu affinity | It displaces full agonists and can precipitate withdrawal |
Slow dissociation | It allows less frequent dosing |
Suboxone combines buprenorphine with naloxone to deter injecting and diversion; Subutex is buprenorphine alone.
Naloxone has negligible sublingual bioavailability, so it does nothing when the tablet is taken as prescribed but is fully active, precipitating withdrawal, if injected.
Opioid antagonists
Naltrexone is a long-acting, orally active antagonist used for relapse prevention; naloxone is short-acting and reserved for overdose reversal.
Naltrexone blocks opioids rather than replacing them, and it is used in both opioid and alcohol dependence.
Naltrexone can precipitate withdrawal, so it starts after an opioid-free interval of at least 7 to 10 days following short-acting opioids.
Tolerance falls during naltrexone treatment, so relapse after stopping can be fatal.
Alpha-2 agonists
Alpha-2 adrenergic agonists ease the autonomic symptoms of opioid withdrawal but provide no maintenance.
Drug | Points |
|---|---|
Lofexidine | No opioid receptor action; much less hypotension, so preferred when low blood pressure is a concern |
Clonidine | Commonly causes postural hypotension and syncope |
Xylazine | Adulterant in illicit opioids; naloxone does not reverse its sedation, bradycardia and hypotension |
Naloxone is still given when xylazine exposure comes with suspected opioid overdose.
Alcohol relapse prevention
Acamprosate
Acamprosate (calcium acetylhomotaurinate) is a synthetic analogue of the amino acid taurine.
It damps the glutamatergic hyperexcitability of early abstinence, mainly by functional antagonism at NMDA and metabotropic mGluR5 receptors, with a lesser GABA-A action.
Baclofen, not acamprosate, acts at GABA-B receptors.
Acamprosate supports abstinence but does not treat withdrawal.
The liver does not metabolise acamprosate, so renal impairment, not liver disease, limits its use.
Disulfiram
Disulfiram irreversibly inhibits aldehyde dehydrogenase, which converts acetaldehyde to acetate in the second step of ethanol oxidation.
When the person drinks, acetaldehyde accumulates and produces the aversive reaction.
Treatment starts at least 24 hours after the last drink, and the risk of a reaction lasts up to two weeks after stopping.
Effects without alcohol | Effects only with alcohol |
|---|---|
Metallic taste, halitosis, drowsiness, fatigue, headache, rash, neuropathy, liver injury | Flushing, tachycardia, hypotension, respiratory distress, vomiting, collapse |
Naltrexone and nalmefene
Naltrexone reduces opioid-mediated alcohol reward, but it also blocks opioid analgesia.
Nalmefene has a mixed opioid receptor profile and is licensed in the UK to cut drinking in alcohol-dependent adults with a high drinking risk level who do not need immediate detoxification.
People take nalmefene one to two hours before drinking on days of risk.
Smoking cessation
Drug | Action | Cautions |
|---|---|---|
Nicotine replacement therapy | Delivers nicotine more slowly than cigarettes, without smoke | A patch plus a short-acting form works better than either alone |
Varenicline | Nicotinic partial agonist | Reduce the dose in severe renal impairment |
Bupropion | Noradrenaline and dopamine reuptake inhibitor, nicotinic antagonist | Seizures; avoid in seizure disorder, eating disorders, alcohol or sedative withdrawal |
Varenicline
Varenicline is a selective partial agonist at alpha4beta2 nicotinic acetylcholine receptors.
It releases a modest amount of dopamine, which eases craving and withdrawal, while blunting the reward from any cigarette smoked.
It is licensed in the UK and recommended by the National Institute for Health and Care Excellence (NICE) among the drug options for adults who want to stop smoking.
Abnormal or vivid dreams and nasopharyngitis are very common adverse effects, affecting 1 in 10 or more, alongside nausea, insomnia and headache.
Neuropsychiatric reactions are uncommon, and the EAGLES trial found no significant rise in them, even in people with stable mental illness.
Smoking and clozapine
Hydrocarbons in smoke induce cytochrome P450 1A2, but nicotine does not, so stopping smoking raises clozapine and olanzapine levels even when nicotine replacement continues.
Image- and performance-enhancing drugs
Anabolic steroid users misuse anti-oestrogenic drugs, such as tamoxifen (a selective oestrogen receptor modulator) or an aromatase inhibitor, chiefly to prevent gynaecomastia.
Bodybuilders misuse insulin to build muscle because it drives glucose and amino acids into muscle; its main hazard is life-threatening hypoglycaemia.