Opioids

Core

Introduction

Opioids are the most powerful analgesics in routine clinical use, and one of the leading causes of preventable harm in modern UK practice. Around 250,000 hospital admissions per year involve opioids in some form, and the UK has seen a steady rise in opioid-related deaths over the past 20 years. Understanding the pharmacology is therefore as much about understanding the harms as the benefits.

This article assumes the basic neuroscience covered in Action Potentials and the receptor pharmacology in Pharmacodynamics.

Pain Pathway Recap

The distinction between nociception (the sensory neural traffic generated by tissue damage) and pain (the conscious, emotional experience that follows) is foundational. Drugs can act at any point along the pathway:

1. Nociceptors in skin, muscle and viscera are stimulated by tissue damage and inflammatory mediators (bradykinin, prostaglandins, histamine, hydrogen ions).
2. Nociceptors release substance P and glutamate; primary afferents carry the signal towards the spinal cord.
3. Afferent fibres are of two main types:
   • Aδ fibres: thinly myelinated, fast, carrying sharp, well-localised "first" pain.
   • C fibres: unmyelinated, slow, carrying dull, throbbing "second" pain.
4. Afferents synapse in the dorsal horn (substantia gelatinosa, lamina I and II) on second-order neurons.
5. Second-order neurons decussate (cross to the opposite side) at the spinal level and ascend in the spinothalamic tract.
6. The signal synapses again in the thalamus on third-order neurons.
7. Third-order neurons project to the somatosensory cortex (postcentral gyrus) for conscious perception, and to limbic regions for the emotional component.

Two key sites of endogenous modulation:

• The periaqueductal grey matter (PAG) in the midbrain projects descending inhibitory fibres to the dorsal horn, mediated by serotonin, noradrenaline and endogenous opioids. Opioid analgesics work in part by activating this descending inhibitory system.
• At the spinal level, the substantia gelatinosa contains interneurons that gate the transmission of pain signals (the basis of the "gate theory" of pain).

Endogenous Opioids and Their Receptors

The body produces three families of endogenous opioid peptides:

• β-endorphins: primarily MOP agonists; major analgesic role.
• Enkephalins: primarily DOP agonists.
• Dynorphins: primarily KOP agonists.

The corresponding opioid receptors are G-protein coupled, all coupled to G_i: activation reduces adenylate cyclase activity and intracellular cAMP. Downstream, K⁺ channels open and Ca²⁺ channels close, producing presynaptic and postsynaptic inhibition with reduced neurotransmitter release.

• MOP (μ, mu) receptor: the principal target for clinical analgesia. Mediates analgesia, respiratory depression, euphoria, miosis, constipation, and physical dependence. Where most opioid effects come from.
• DOP (δ, delta) receptor: analgesia, mood effects.
• KOP (κ, kappa) receptor: spinal analgesia, dysphoria, miosis, diuresis.
• NOP (nociceptin) receptor: the most recently discovered; complex modulatory role.

The WHO Analgesic Ladder

The WHO analgesic ladder remains the standard pre-clinical framework for choosing analgesic strength, originally devised for cancer pain but widely applied:

Step 1: Non-opioid: paracetamol ± NSAID
Step 2: Weak opioid: codeine, tramadol, dihydrocodeine, ± non-opioid
Step 3: Strong opioid: morphine, oxycodone, fentanyl, ± non-opioid
+ Adjuvants at any step (e.g. amitriptyline or gabapentin for neuropathic pain)

Modern practice often skips step 2 in cancer pain, going straight from paracetamol to low-dose strong opioid, and uses a more nuanced approach to chronic non-cancer pain that emphasises non-opioid options because of dependence concerns.

Diagram: The WHO analgesic ladder. Climb up if pain remains uncontrolled; combine with non-opioid analgesia and adjuvants at every step.

Specific Opioids

Morphine

The reference opioid against which others are compared. Morphine is a strong full agonist at the MOP receptor.

Pharmacokinetics:

• Oral bioavailability ~30% (extensive first-pass metabolism); IV gives 100%. The oral-to-IV conversion ratio is therefore approximately 3:1.
• Crosses the blood-brain barrier slowly (relatively hydrophilic); crosses the placenta and reaches breast milk.
• Metabolised hepatically by glucuronidation to morphine-3-glucuronide (M3G): neuroexcitatory, possibly responsible for myoclonus and hyperalgesia, and morphine-6-glucuronide (M6G): analgesic, more potent than morphine itself.
• Both metabolites are renally excreted, which is why morphine accumulates and toxicity can develop in renal impairment.

Used for moderate-to-severe acute pain, post-operative pain, cancer pain, and breathlessness in advanced palliative care.

Codeine and Dihydrocodeine

Codeine is a weak MOP agonist with around 1/10 the analgesic potency of morphine. It is a pro-drug requiring metabolism to morphine by hepatic CYP2D6; pharmacogenetic variability therefore strongly influences efficacy and toxicity.

• Poor metabolisers (around 7% of Caucasians) get little analgesia.
• Ultra-rapid metabolisers can develop morphine toxicity from standard doses; this prompted the MHRA to contraindicate codeine in breastfeeding mothers (after fatal infant cases) and in children under 12.
• Fluoxetine, paroxetine and other CYP2D6 inhibitors reduce codeine's analgesic effect.

Beyond the CYP2D6 warning, the MHRA also restricts codeine after tonsillectomy or adenoidectomy in any child under 18 with obstructive sleep apnoea (avoid entirely), and advises caution in 12-18-year-olds with any condition that compromises respiration.

Codeine is also used as an antitussive and antidiarrhoeal.

Dihydrocodeine has similar potency and a similar profile but does not require CYP2D6 activation.

Tramadol

Tramadol is an unusual drug with a dual mechanism:

• Weak MOP agonist (its main metabolite is more active than tramadol itself).
• Inhibitor of serotonin and noradrenaline reuptake: producing a non-opioid analgesic action via descending inhibitory pathways.

The serotonergic activity creates the risk of serotonin syndrome when combined with SSRIs, MAOIs, triptans or linezolid. Tramadol also lowers the seizure threshold; avoid in epilepsy.

Oxycodone

Oxycodone is a strong MOP agonist with similar effect profile to morphine but considered roughly twice as potent orally. Often used as the alternative when morphine is poorly tolerated, and is the standard strong opioid in some hospital pain regimens.

Fentanyl

Fentanyl is highly lipophilic, around 100 times more potent than morphine, and crosses the blood-brain barrier rapidly. Available as IV bolus, transdermal patch, sublingual lozenge, and buccal/intranasal preparations.

• Half-life when given IV is brief (a few minutes) because of rapid redistribution; longer with patches because release is rate-limited.
• Metabolised by CYP3A4; safer than morphine in renal impairment because it has no active renally cleared metabolite.
• Causes less histamine release than morphine, so less hypotension.

Standard uses: induction of anaesthesia, intra-operative analgesia, severe breakthrough pain, and chronic stable pain via patch (only after the patient is opioid-tolerant).

Methadone

Methadone is a synthetic full MOP agonist with a long and variable half-life (15-60 hours), oral bioavailability around 80%, and additional NMDA receptor antagonism. The prolonged half-life makes it useful in opioid substitution therapy for opioid use disorder, and a useful option in chronic cancer pain unresponsive to other opioids.

It also prolongs the QT interval at higher doses, which is a meaningful prescribing concern.

Buprenorphine

Buprenorphine is a partial agonist at the MOP receptor with very high affinity. As a result, its dose-response curve is sub-maximal; the ceiling on respiratory depression is lower than for full agonists, which is why it is preferred for community opioid-use disorder treatment. The high affinity also means it is hard to displace with naloxone.

Routes: sublingual (Subutex, Suboxone), transdermal patch (BuTrans), buccal. Long half-life (~30 hours).

Naloxone

Naloxone is a competitive opioid antagonist with high MOP affinity. Used to reverse opioid-induced respiratory depression in overdose. Given intravenously (or intramuscularly, or intranasally in community kits supplied to drug users and their families).

Its short half-life (30-90 minutes) is a critical prescribing point: if the offending opioid is long-acting (e.g. methadone) or sustained-release, naloxone must be given as a continuous infusion or repeated boluses, otherwise respiratory depression returns once the drug wears off.

Side Effects of Opioids

Predictable from MOP receptor distribution. The classical effects:

• Respiratory depression: reduced sensitivity of the medullary respiratory centre to CO₂. The cause of death in opioid overdose.
• Constipation: reduced gut motility, increased anal sphincter tone. Tolerance to this effect does not develop; every opioid prescription should be accompanied by laxatives. The pharmacology is the same as the antidiarrhoeal action of loperamide (covered in Antiemetics and Laxatives).
• Nausea and vomiting: CTZ stimulation; usually subsides over a few days. Co-prescribe an antiemetic.
• Sedation, particularly on initiation and dose increase.
• Miosis: pinpoint pupils on examination; useful diagnostic clue in overdose.
• Pruritus, particularly with morphine, due to histamine release.
• Hypotension and bradycardia: vagal stimulation and histamine release.
• Urinary retention.
• Tolerance, dependence and addiction: see below.
• Endocrine effects, with long-term use, hypogonadism (reduced LH/FSH/testosterone).
• Opioid-induced hyperalgesia: paradoxical increased pain sensitivity with prolonged high-dose use.

Tolerance, Dependence and Addiction

Three concepts that are often confused:

• Tolerance: declining effect at the same dose over time, requiring dose escalation. Develops to most effects of opioids except constipation and miosis.
• Physical dependence: the body adapts to the presence of opioid, and abrupt cessation produces a withdrawal syndrome (anxiety, agitation, sweating, mydriasis, lacrimation, rhinorrhoea, yawning, abdominal cramping, diarrhoea, "gooseflesh"). Predictable physiology, not addiction.
• Addiction (opioid use disorder): a behavioural disorder defined by compulsive use despite harm, craving, and loss of control. A complication of opioid prescribing in around 5-10% of patients on long-term high-dose opioids for non-cancer pain.

Withdrawal is unpleasant but not life-threatening (unlike alcohol or benzodiazepine withdrawal). Treatment of dependence is generally with methadone or buprenorphine as substitution therapy, sometimes combined with naltrexone for relapse prevention after detoxification.

Opioid Overdose

The classic clinical triad is:

Opioid overdose triad
Pinpoint pupils (miosis) · Respiratory depression · Reduced consciousness

Management:

1. Airway, breathing, circulation. Bag-valve-mask ventilation if hypoventilation is severe.
2. Naloxone: 400 micrograms IV initially, repeated and titrated to respiratory rate (the aim is restoring adequate respiration, not full reversal, which can precipitate withdrawal in dependent patients).
3. If response is positive but the patient slips back, consider a naloxone infusion, particularly with long-acting opioids.
4. Transfer to a monitored area; check for co-ingestion (paracetamol, alcohol, benzodiazepines) and complications (aspiration pneumonitis, rhabdomyolysis).

Contraindications and cautions for therapeutic opioid prescribing include hepatic failure, head injury and raised intracranial pressure (opioids cause CO₂ retention and cerebral vasodilation), acute respiratory failure, and untreated paralytic ileus.

Prescribing Practicalities

UK prescribing rules for opioids (controlled drugs schedules 2 and 3) are covered in Safe Prescribing. A few additional pre-clinical points:

• For regular or strong opioids, co-prescribe a laxative as routine prophylaxis (some patients on short-course or weak opioids may not need it).
• Always co-prescribe an antiemetic for the first few days.
• For chronic regular dosing, prescribe a modified-release "background" dose with an immediate-release "breakthrough" dose equal to about 1/6 of the 24-hour total for as-needed use.
• If breakthrough doses are being used regularly, the background dose is too low.
• Convert between opioids using equivalence tables (e.g. oral morphine 30 mg = oral oxycodone 15 mg = subcutaneous morphine 15 mg = subcutaneous diamorphine 10 mg).
• Reduce dose by around 25-50% when switching opioid because of incomplete cross-tolerance between drugs.

Summary

• Opioids act predominantly at the MOP (μ) receptor, a G_i-coupled GPCR; they reduce neurotransmitter release in pain pathways.
• The WHO analgesic ladder is the standard escalation framework: paracetamol/NSAID → weak opioid (codeine, tramadol) → strong opioid (morphine, oxycodone, fentanyl).
• Codeine is a pro-drug activated by CYP2D6; contraindicated in breastfeeding and in children under 12 because of ultra-rapid metaboliser-related deaths.
• Morphine has active renally cleared metabolites (M3G, M6G) and accumulates in renal impairment; fentanyl and buprenorphine are safer in renal failure.
• Buprenorphine is a partial agonist with high MOP affinity; used in opioid use disorder.
• Naloxone reverses opioid overdose; short half-life (30-90 min) means infusion is often required for long-acting opioids.
• Predictable side effects: respiratory depression, constipation, nausea, sedation, miosis. The cause of death in overdose is respiratory depression.
• Tolerance, dependence and addiction are distinct concepts. Co-prescribe laxatives and antiemetics with regular opioids.

Drug Summary Table

Reviewed by: Dr. Marcus Judge

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