Pharmacology chapters
Opioid analgesics
How opioids relieve pain: opioid receptors, morphine's effects and adverse effects, the other opioids (pethidine, fentanyl, codeine, tramadol, methadone, buprenorphine), opioid overdose and naloxone, tolerance, dependence and withdrawal, and dose conversion between opioids.
- Opioids act on μ (mu) receptors (also κ and δ), which are Gi-coupled: they close presynaptic calcium channels (less transmitter release) and open postsynaptic potassium channels (hyperpolarisation), reducing pain transmission in the spinal cord and brain.
- Morphine causes analgesia, euphoria, sedation, respiratory depression (the main cause of death), miosis, constipation, nausea and vomiting, cough suppression, histamine release (itch, bronchospasm) and biliary spasm; tolerance develops to most effects but not to miosis and constipation.
- Overdose triad: pinpoint pupils, respiratory depression, coma → IV naloxone (short-acting, so repeat or infuse); buprenorphine is a partial agonist; methadone (long-acting) is used for maintenance; pethidine's metabolite causes seizures and it can cause serotonin syndrome with MAOIs.
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Opioid receptors
Opioids include natural opiates from the poppy (morphine, codeine), semi-synthetic (diamorphine, oxycodone) and synthetic drugs (fentanyl, pethidine, methadone, tramadol). The body's own opioids are endorphins, enkephalins and dynorphins.
| Receptor | Effects |
|---|---|
| μ (mu) | Analgesia (spinal and supraspinal), euphoria, respiratory depression, miosis, constipation, dependence |
| κ (kappa) | Spinal analgesia, sedation, dysphoria, diuresis |
| δ (delta) | Analgesia, mood |
Mechanism: all are Gi protein-coupled. They close presynaptic voltage-gated calcium channels (less release of glutamate and substance P) and open postsynaptic potassium channels (hyperpolarisation), damping pain signals in the dorsal horn, brainstem and limbic system.
Morphine: effects
| System | Effect |
|---|---|
| CNS | Analgesia (especially for dull, continuous visceral pain), euphoria, sedation, respiratory depression (less response to CO₂; the main cause of death), cough suppression, nausea and vomiting (chemoreceptor trigger zone), miosis (Edinger-Westphal nucleus), muscle rigidity at high doses (fentanyl: chest wall) |
| Gut | Constipation (reduced peristalsis, increased tone); spasm of the sphincter of Oddi (biliary colic may worsen) |
| Cardiovascular | Vasodilation and postural hypotension (histamine release); useful in acute pulmonary oedema (less preload, less anxiety) |
| Urinary | Urinary retention (sphincter tone) |
| Skin | Itching, flushing (histamine release) |
| Endocrine | Less GnRH and CRH; more ADH and prolactin |
| Pregnancy and labour | Crosses placenta: neonatal respiratory depression |
Tolerance develops to analgesia, euphoria and respiratory depression, but not to miosis or constipation.
Pharmacokinetics: high first-pass metabolism (oral bioavailability is roughly a quarter to a third); metabolised by glucuronidation to morphine-6-glucuronide (active, accumulates in renal failure) and morphine-3-glucuronide.
Contraindications and cautions: respiratory depression, head injury (raised CO₂ raises intracranial pressure, and miosis hides pupil signs), acute severe asthma, biliary colic (relative), renal failure (accumulation), liver failure (encephalopathy), elderly, hypothyroidism, use with other CNS depressants, pregnancy near term.
Other opioids
| Drug | Key points |
|---|---|
| Diamorphine (heroin) | More lipid-soluble prodrug of morphine; faster onset |
| Codeine | Weak; prodrug converted to morphine by CYP2D6; poor metabolisers get little effect, ultra-rapid metabolisers risk toxicity (avoided in children under 12 and in breastfeeding); cough suppressant, mild pain, diarrhoea |
| Pethidine (meperidine) | Short-acting; anticholinergic (no miosis in some cases); toxic metabolite norpethidine → seizures (worse in renal failure); serotonin syndrome with MAOIs; less used now |
| Fentanyl | About 100 times as potent as morphine; very lipid-soluble; IV in anaesthesia, transdermal patches for chronic pain; chest-wall rigidity |
| Tramadol | Weak μ agonist plus serotonin and noradrenaline reuptake inhibition; lowers seizure threshold; serotonin syndrome risk with SSRIs and MAOIs |
| Methadone | Long half-life, oral; opioid substitution (maintenance) therapy; QT prolongation |
| Buprenorphine | Partial μ agonist, high affinity; ceiling effect on respiratory depression; maintenance therapy; can precipitate withdrawal in a person dependent on full agonists; only partly reversed by naloxone |
| Pentazocine, nalbuphine | Mixed agonist-antagonists (κ agonist, weak μ antagonist); dysphoria |
| Loperamide, diphenoxylate | Act on gut; antidiarrhoeal (loperamide hardly enters the brain) |
| Dextromethorphan | Cough suppressant (not analgesic) |
Opioid antagonists
- Naloxone: competitive antagonist at all opioid receptors; given IV (or IM, intranasal); acts in 1–2 minutes; short duration (about 30–90 minutes), shorter than most opioids, so patients can slip back into respiratory depression: repeat doses or infusion and observe. May precipitate acute withdrawal in dependent people.
- Naltrexone: oral, long-acting; prevents relapse in opioid and alcohol dependence.
- Methylnaltrexone: does not enter the brain; treats opioid-induced constipation.
Give 400 micrograms (0.4 mg) IV
Repeat 400–800 micrograms every 2–3 minutes until breathing is adequate
Aim for breathing, not full wakefulness (avoid sudden withdrawal)
Very large or long-acting overdose (methadone): infusion
Rule of thumb: hourly infusion rate ≈ 2/3 of the dose that woke the patient
Woke after 1.2 mg total → infuse 2/3 × 1.2 = 0.8 mg per hou
Doses follow common emergency teaching; follow current local protocols.
Tolerance, dependence and withdrawal
- Tolerance: higher doses needed for the same effect (receptor desensitisation).
- Physical dependence: withdrawal syndrome when stopped.
- Withdrawal (the opposite of the drug's effects): craving, anxiety, yawning, lacrimation, rhinorrhoea, sweating, dilated pupils, piloerection ("cold turkey"), abdominal cramps, diarrhoea, vomiting, muscle aches, tachycardia. Unpleasant but rarely life-threatening in adults (neonatal withdrawal can be serious).
- Management: substitution with methadone or buprenorphine, then gradual reduction; clonidine or lofexidine eases autonomic symptoms.
Using opioids for pain
WHO analgesic ladder:
- Non-opioid (paracetamol, NSAIDs) ± adjuvant.
- Weak opioid (codeine, tramadol) + non-opioid ± adjuvant.
- Strong opioid (morphine, oxycodone, fentanyl) + non-opioid ± adjuvant.
Adjuvants: antidepressants and anticonvulsants for neuropathic pain, steroids, bisphosphonates for bone pain.
Always prescribe a laxative with regular opioids, and an antiemetic if needed.
Oral morphine : IV or SC morphine ≈ 2 : 1
Oral codeine 60 mg ≈ oral morphine 6 mg (codeine about 1/10 as potent)
Oral tramadol 100 mg ≈ oral morphine 10 mg (about 1/10)
Patient on oral morphine 60 mg per day → SC morphine per day:
60 ÷ 2 = 30 mg per day
For safety, many guides reduce by 25–50% when switching between different opioids.
Conversion ratios vary between references; check local palliative care guidance before switching.
Expect: opioid receptors and mechanism, effects of morphine, effects to which tolerance does not develop, causes of death in overdose, the overdose triad and naloxone (short duration, repeat doses), codeine and CYP2D6, pethidine problems, fentanyl potency, tramadol and serotonin syndrome, methadone and buprenorphine in maintenance, contraindications (head injury), withdrawal features, and the analgesic ladder.
Quick revision
- μ receptor, Gi: ↓ Ca²⁺ entry, ↑ K⁺ exit.
- Morphine: analgesia, euphoria, respiratory depression, miosis, constipation, nausea, itch.
- No tolerance to miosis or constipation.
- Overdose: pinpoint pupils, respiratory depression, coma → naloxone, repeat.
- Codeine needs CYP2D6. Pethidine: norpethidine seizures, MAOI interaction.
- Methadone and buprenorphine for maintenance; naltrexone prevents relapse.
- Withdrawal: dilated pupils, yawning, rhinorrhoea, diarrhoea, piloerection.
Written by The House Job from standard pharmacology references (Katzung's Basic and Clinical Pharmacology).
FAQ
What is the triad of opioid overdose?
Pinpoint pupils, respiratory depression and reduced consciousness (coma).
Why does naloxone often need to be repeated?
Its action lasts a shorter time than most opioids, so respiratory depression can return as it wears off.
To which effects of morphine does tolerance not develop?
Miosis and constipation.
Why is codeine risky in some people?
It must be turned into morphine by CYP2D6; ultra-rapid metabolisers make too much morphine and can develop toxicity, while poor metabolisers get little pain relief.