3 Clinical psychopharmacology3.3 Pharmacodynamics

3.3.2.8 Opioids

2 min read2 figures

Written by Resident Doctor Committee · Published

Opioid receptors

Mu, kappa and delta receptors are G protein-coupled receptors that couple to Gi/o.

  • The mu receptor mediates most of the reinforcing and dependence-producing effects of opioids, as well as analgesia, respiratory depression, miosis and constipation.

  • Kappa receptors, activated by dynorphin, produce dysphoria and reduce accumbens dopamine.

How opioids reward

Mu receptors on gamma-aminobutyric acid (GABA) interneurones in the ventral tegmental area inhibit those interneurones. This disinhibits mesolimbic dopamine neurones and raises dopamine in the nucleus accumbens.

Mu receptor activation on the GABA interneurone lifts its brake on the ventral tegmental dopamine neurone, so dopamine rises in the nucleus accumbens; naltrexone blocks the receptor, so the brake stays on and the reward is blunted. Drawn for MRCPsychiatrist

The agonist spectrum

Drug

Action at mu

Use

Methadone

Full agonist

Maintenance

Buprenorphine

High-affinity partial agonist; kappa antagonist

Maintenance

Naloxone

Pure competitive antagonist

Overdose reversal

Naltrexone

Long-acting competitive antagonist

Relapse prevention

Buprenorphine

  • Buprenorphine binds mu with high affinity but low intrinsic efficacy, so its effects, including respiratory depression, reach a ceiling.

  • The ceiling reduces but does not remove overdose risk, which rises sharply with alcohol or benzodiazepines.

  • Precipitated withdrawal happens because its high affinity lets it displace heroin while its lower intrinsic activity gives less effect, so the first dose can bring on withdrawal.

  • The first dose therefore waits for objective signs of withdrawal.

The partial agonist's curve flattens at a lower plateau however high the dose, the ceiling that limits buprenorphine's effects, while the full agonist keeps rising and the antagonist produces no effect. Xx684xx, CC0, via Wikimedia Commons

Methadone

  • Methadone is a full mu agonist with a long, variable elimination half-life, which allows once-daily supervised dosing.

  • It accumulates before its full effect shows, so the dose is titrated slowly.

  • It has no ceiling on respiratory depression.

  • It prolongs the QT interval, so the corrected QT interval (QTc) needs monitoring.

  • It also blocks N-methyl-D-aspartate (NMDA) receptors, which may blunt tolerance and help neuropathic pain.

Naloxone

  • Naloxone is a high-affinity, pure competitive mu antagonist with no intrinsic activity, and it displaces full agonists and mixed agonist-antagonists.

  • Its half-life of about an hour is far shorter than methadone's, so sedation can return after reversal; patients need observation and repeat doses or an infusion.

  • It does not reverse non-opioid depressants, and airway and ventilation are supported first.

Naltrexone

  • Naltrexone acts for a long time: one dose occupies mu receptors for about a day, blocking opioid reward and analgesia to prevent relapse.

  • It can start only once the patient is opioid-free.

Tolerance and withdrawal

  • Tolerance to euphoria develops quickly, but tolerance to respiratory depression is incomplete and tolerance to constipation and miosis is limited.

  • Lost tolerance after prison, hospital or detoxification makes a previously taken dose dangerous.

  • Withdrawal involves noradrenergic rebound, which clonidine or lofexidine treat, and causes sweating, piloerection, lacrimation, rhinorrhoea, yawning and insomnia.

Revision material for the MRCPsych examinations. Not clinical guidance, and not for use in patient care.