Key Facts

Opioids are the most effective analgesics for moderate-to-severe acute pain and cancer pain. However, their potential for dependence, tolerance, and serious adverse effects mandates careful prescribing. Understanding receptor pharmacology and individual drug profiles is essential.

Epidemiology

Opioid prescribing has increased significantly in the UK over the past 20 years. Approximately 5-8% of the UK adult population receive a long-term opioid prescription. Opioid-related deaths in England and Wales have doubled since 2012, reaching approximately 4,900 per year. The UK uses approximately 33 million prescriptions for opioids annually.

Aetiology

Opioids mimic endogenous peptides (endorphins, enkephalins, dynorphins) that modulate pain transmission. They act at three main receptor types:

• Mu (µ): Supraspinal and spinal analgesia, respiratory depression, euphoria, miosis, constipation
• Kappa (κ): Spinal analgesia, sedation, dysphoria
• Delta (δ): Spinal analgesia, modulation of mu receptor activity

Pathophysiology

Mechanism of action:

• Opioid receptors are G-protein coupled receptors (GPCRs)
• Activation inhibits adenylyl cyclase → reduced cAMP → decreased neuronal excitability
• Pre-synaptic: Inhibits calcium channels → reduced neurotransmitter release
• Post-synaptic: Opens potassium channels → hyperpolarisation

Tolerance: Progressive reduction in response with repeated exposure — requires dose escalation for same effect. Develops fastest for euphoria and analgesia, slowest for constipation and miosis.

Physical dependence: Withdrawal symptoms (sweating, diarrhoea, tachycardia, agitation) on abrupt cessation.

Opioid-induced hyperalgesia (OIH): Paradoxical increased pain sensitivity — differs from tolerance; managed by opioid dose reduction, not increase.

Therapeutic Effects

• Analgesia (dose-dependent)
• Anxiolysis, sedation, euphoria
• Antitussive effect (codeine, dextromethorphan)

Adverse Effects

• Respiratory depression: Most dangerous — dose-dependent, CO2 response curve shifted right
• Nausea and vomiting: Stimulation of CTZ (chemoreceptor trigger zone)
• Constipation: Reduced peristalsis — does NOT develop tolerance
• Pruritus: Histamine release (morphine) or central mu receptor activation
• Urinary retention: Increased sphincter tone, reduced detrusor activity
• Miosis: Parasympathetic stimulation of Edinger-Westphal nucleus
• Rigidity: Chest wall rigidity with rapid IV bolus (especially fentanyl)

Opioid Toxicity/Overdose

• Pinpoint pupils, respiratory depression (RR <8), reduced GCS
• Cyanosis, hypotension, hypothermia

Red Flags

• Respiratory rate <8/min — administer naloxone 400mcg IV, repeat every 2-3 min
• Reduced consciousness with opioids in renal failure — M6G accumulation
• Codeine in breastfeeding — risk of neonatal toxicity in ultra-rapid CYP2D6 metabolisers
• Tramadol + SSRI — serotonin syndrome risk

Bedside

• Respiratory rate: Most important clinical monitor for opioid safety
• Sedation score: 0 (awake) to 3 (unrousable)
• Pain score: NRS to guide dosing
• Pupil size: Miosis suggests opioid effect

Bloods

• U&Es: Renal function — reduce dose and avoid morphine in severe renal impairment (use oxycodone or fentanyl)
• LFTs: Hepatic impairment reduces metabolism of most opioids
• CYP2D6 genotyping: Consider if codeine/tramadol response is unexpected (not routine)

Imaging

• Not specific to opioid pharmacology

Special Tests

• Urine drug screen: Detect opioid use/misuse
• ECG: If methadone prescribed — QT prolongation risk
• Serum opioid levels: Not routinely available or useful clinically

Non-pharmacological

• Education: Inform patients about side effects, storage, driving restrictions, and safe disposal
• Opioid stewardship: Prescribe lowest effective dose for shortest duration
• Review and taper: Regular review of ongoing need; gradual reduction (10-25% every 2-4 weeks)

Pharmacological

Acute pain prescribing:

• Morphine 5-10mg PO 4-hourly PRN (elderly: 2.5-5mg)
• Oxycodone 5mg PO 4-6 hourly PRN (renal impairment preferred)
• Fentanyl 25-100mcg IV titrated (anaesthesia/acute settings)
• PCA: Morphine 1mg bolus, 5-min lockout

Chronic pain (if opioids indicated):

• Start with lowest dose modified-release preparation
• Do not exceed 120mg oral morphine equivalent/day without specialist review
• Always co-prescribe laxative (lactulose 15mL BD + senna 15mg ON)
• Regular review with clear goals and exit strategy

Opioid reversal:

• Naloxone 400mcg IV — repeat every 2-3 min to effect (max 10mg); duration 20-90 min
• Infusion may be needed for long-acting opioids: 2mg in 500mL 0.9% saline at rate titrated to RR

Surgical/Interventional

• Not applicable (pharmacological topic)

Referral Criteria

• Chronic opioid use with dose escalation — pain specialist/addiction services
• Opioid use disorder — substance misuse team
• Cancer pain requiring dose optimisation — palliative care

• Acute use: Safe and effective when used appropriately with monitoring
• Chronic use >3 months: Associated with tolerance, dependence, hyperalgesia, endocrine dysfunction, immune suppression, increased mortality
• Opioid use disorder: Affects approximately 1-3% of chronic pain patients prescribed opioids
• Overdose mortality: Naloxone has dramatically reduced in-hospital opioid-related deaths
• Tapering: Most chronic pain patients can successfully reduce or stop opioids with appropriate support

Oral Morphine Equivalent Conversion Table

Opioid Receptor Summary

Special Populations