Page 11 of 32
PH3.4 | PH3.4 | Opioid Analgesics and Safe Use Instructions — SDL Guide — SDL Guide (Part 2)
Major Opioid Analgesics — PK, PD, Uses, and ADRs
Morphine: the prototype full μ-opioid agonist. Oral and parenteral (IV/SC/IM/epidural). Good first-pass metabolism when oral (bioavailability ~25%) — oral dose is 2-3× the parenteral dose. Active metabolite: morphine-6-glucuronide (M6G) contributes to analgesia; accumulates in renal failure. Extensive clinical use in moderate-severe pain, cancer pain, pulmonary oedema (reduces cardiac preload + anxiety), and palliative care. ADRs: nausea/vomiting (direct CTZ stimulation), constipation (μ receptor in enteric nervous system — tolerance does not develop to this effect — always co-prescribe a stimulant laxative), respiratory depression, sedation, pruritus, urinary retention, miosis, euphoria/dysphoria, physical dependence.
Codeine: prodrug — converted to morphine by CYP2D6. Ultra-rapid metabolisers (genotype) produce excessive morphine → overdose risk; poor metabolisers get no analgesic effect. Mild-moderate pain, antitussive (cough suppression). Less abuse potential than morphine. ADRs: similar but milder than morphine; constipation prominent.
Fentanyl: full μ-agonist; 100× more potent than morphine. High lipophilicity → rapid IV onset (suitable for procedural analgesia, GA supplement, ICU analgesia); transdermal patch for chronic cancer pain (72-hour patch — stable steady state). Buccal/sublingual/intranasal formulations for breakthrough cancer pain. ADRs: same as morphine; IV bolus can cause chest wall rigidity ('wooden chest' phenomenon — reversed by naloxone or neuromuscular blocker).
Pethidine (meperidine): full μ-agonist. Active metabolite: norpethidine (t½ 14-21h) — accumulates in renal failure → seizures, tremors, myoclonus. CRITICAL INTERACTION: pethidine + MAOIs → hyperpyrexic excitatory crisis (serotonin syndrome) with hyperthermia, agitation, myoclonus, seizures, death; OR hypotensive depressive reaction. Avoid pethidine in renal failure and in patients on MAOIs. Limited modern use (obstetric analgesia in some settings).
Tramadol: weak μ-opioid agonist + inhibits serotonin and noradrenaline reuptake (dual mechanism). Used for moderate pain. ADRs: nausea, dizziness, risk of seizures (lower seizure threshold), serotonin syndrome when combined with SSRIs, SNRIs, or MAOIs. Not first-line in epilepsy.
Buprenorphine: partial μ-agonist + κ-antagonist. Very high receptor binding affinity. Sublingual (pain, opioid substitution), transdermal patch. Used in opioid use disorder (OUD) as buprenorphine/naloxone combination (Suboxone) — the naloxone component deters IV misuse. Respiratory depression ceiling makes it safer than full agonists in overdose, but naloxone reversal requires high doses.
Methadone: full μ-agonist; long and unpredictable half-life (15-60h) — makes titration hazardous; used in opioid use disorder (substitution therapy) and chronic cancer pain. ADR: QTc prolongation (torsades de pointes risk, especially with other QTc-prolonging drugs).
| Agent | Class | Potency (vs morphine) | Key Concern |
|---|---|---|---|
| Morphine | Full μ-agonist | 1× (reference) | M6G accumulates in renal failure |
| Codeine | Full μ-agonist (prodrug) | ~0.1× | CYP2D6 variability; ultra-rapid metaboliser risk |
| Fentanyl | Full μ-agonist | ~100× | Chest wall rigidity (IV bolus) |
| Pethidine | Full μ-agonist | ~0.1× | Norpethidine seizures in renal failure; MAOI crisis |
| Tramadol | Weak μ + SNRI | ~0.2× | Seizures; serotonin syndrome with SSRIs/MAOIs |
| Buprenorphine | Partial μ-agonist | ~30× (ceiling) | High receptor affinity; precipitates withdrawal |
| Methadone | Full μ-agonist | ~variable | Long t½, QTc prolongation |
| Naloxone | Antagonist | 0 | Short t½ — re-narcotisation risk |
Special Instructions for Safe Opioid Use
Safe opioid prescribing requires specific vigilance beyond general analgesic prescribing. The following instructions are pharmacologically grounded and clinically non-negotiable.
Recognising opioid overdose: the classic overdose triad is: coma (unresponsive) + pinpoint pupils (miosis) + respiratory depression (bradypnoea, or shallow breaths, or apnoea). Cyanosis and hypotension may accompany severe overdose. This triad distinguishes opioid overdose from most other causes of coma (except pontine haemorrhage, which also causes miosis but with absent opioid history).
Naloxone (reversal): Naloxone is a competitive antagonist at all opioid receptor types. IV/IM/intranasal (0.4-2 mg, repeat every 2-3 min until adequate ventilation restored). Critically: naloxone t½ (~1 hour) is shorter than most opioids — re-narcotisation occurs when naloxone wears off before the opioid is eliminated. Patients revived with naloxone must be monitored for re-sedation; repeat doses or infusion may be needed. Naloxone precipitates acute withdrawal in opioid-dependent patients — use the minimum dose needed to restore ventilation.
Pethidine contraindications: (1) Renal failure — norpethidine accumulates; (2) MAOI therapy — excitatory (serotonin) syndrome; avoid for ≥14 days after MAOI discontinuation.
Tramadol warnings: avoid with SSRIs, SNRIs, MAOIs (serotonin syndrome); avoid in patients with seizure disorders; use with caution in elderly (falls, delirium).
Opioid rotation: when a patient develops intolerable side-effects on one opioid, switching to an equianalgesic dose of another (opioid rotation) is rational — individual variation in opioid receptor genetics means responses differ between agents.
Controlled drug prescriptions: opioids are scheduled controlled substances. Prescriptions must include: full patient name and address, date, name and formulation, dose in words AND figures, total quantity, prescriber signature and registration number. Verbal/telephone prescriptions are illegal in most jurisdictions for Schedule I substances.
Monitoring: respiratory rate (target ≥10/min), sedation score, pain score, bowel function (co-prescribe laxative always), and naloxone availability on wards where opioids are used.
SELF-CHECK
A patient is brought to the emergency department unresponsive, with a respiratory rate of 4/min and bilateral pinpoint pupils. A syringe is found in their pocket. What is the immediate pharmacological treatment?
A. IV flumazenil — reverses CNS depression
B. IV naloxone — competitive antagonist at opioid receptors, reverses respiratory depression and coma
C. IV dextrose — hypoglycaemia causes coma and miosis
D. IV physostigmine — reverses cholinergic crisis causing miosis
Reveal Answer
Answer: B. IV naloxone — competitive antagonist at opioid receptors, reverses respiratory depression and coma
The triad of coma + pinpoint pupils (miosis) + respiratory depression (RR 4/min) in the context of parenteral drug use is classic opioid overdose. Naloxone (0.4-2 mg IV/IM, repeat every 2-3 min) is the immediate treatment — it is a competitive antagonist at all opioid receptors, reversing the respiratory depression rapidly. Flumazenil reverses BZDs (also cause coma) but does not cause miosis; BZD overdose is unlikely here. Blood glucose should also be checked (hypoglycaemia is a reversible cause of coma and must always be excluded), but pinpoint pupils point specifically to opioid toxicity.
SELF-CHECK
Which opioid analgesic is CONTRAINDICATED in a patient with moderate chronic renal failure, and why?
A. Morphine — causes acute kidney injury by reducing renal blood flow
B. Pethidine — its active metabolite norpethidine accumulates in renal failure, causing seizures and tremors
C. Codeine — CYP2D6 is inhibited in renal failure, preventing conversion to morphine
D. Fentanyl — excreted unchanged by the kidneys, leading to accumulation
Reveal Answer
Answer: B. Pethidine — its active metabolite norpethidine accumulates in renal failure, causing seizures and tremors
Pethidine is contraindicated in renal failure because its active metabolite, norpethidine (half-life 14-21 hours), accumulates when renal excretion is impaired. Norpethidine is a CNS excitant — it causes tremors, myoclonus, agitation, and seizures. Morphine also requires dose reduction in renal failure (morphine-6-glucuronide accumulates), but the specific seizure risk from accumulation is uniquely dangerous with pethidine. Fentanyl is actually relatively safe in renal failure (hepatic metabolism, no active metabolite). Codeine's CYP2D6 conversion is genetically variable but not renal-failure-dependent.
SELF-CHECK
What is the receptor classification of buprenorphine, and what clinical property results from its partial agonist activity at the mu-opioid receptor?
A. Full μ-agonist — same as morphine but with longer duration of action
B. Pure opioid antagonist — blocks all opioid effects, used only for overdose reversal
C. Partial μ-agonist + κ-antagonist — produces a ceiling effect on respiratory depression (and analgesia), and can precipitate withdrawal if given to a fully opioid-dependent patient
D. Mixed κ-agonist + partial μ-antagonist — causes dysphoria and should not be used for analgesia
Reveal Answer
Answer: C. Partial μ-agonist + κ-antagonist — produces a ceiling effect on respiratory depression (and analgesia), and can precipitate withdrawal if given to a fully opioid-dependent patient
Buprenorphine is a partial μ-opioid agonist plus κ-opioid antagonist. Its partial agonism at μ receptors means: (1) it has a ceiling effect on respiratory depression — making it safer than full agonists in overdose; (2) it has an analgesic ceiling — adequate for moderate pain but limited in severe pain; (3) its very high receptor affinity means it can displace full μ-agonists and precipitate acute withdrawal in opioid-dependent patients if given before adequate washout. These properties make it valuable for opioid use disorder treatment (buprenorphine/naloxone combination).
CLINICAL PEARL
Pethidine + MAOI = medical emergency. The combination produces one of two catastrophic reactions: (1) an excitatory (serotonin) syndrome — hyperthermia, agitation, tremor, myoclonus, hypertension, seizures, potentially fatal; or (2) a depressive reaction — profound hypotension, respiratory depression, coma. There is no safe dose of pethidine with an MAOI, and the interaction persists for 14 days after MAOI discontinuation (time required to re-synthesise MAO enzyme). Similarly: tramadol + SSRI/SNRI/MAOI risks serotonin syndrome. These interactions kill patients — they are not pharmacology trivia.