A patient on long-term opioid therapy for chronic cancer pain requires escalating doses to maintain the same level of pain relief. This phenomenon is best explained by:

• A Physical dependence leading to withdrawal symptoms on dose reduction
• B Opioid tolerance resulting from receptor downregulation and uncoupling of G-proteins ✓
• C Pseudo-addiction from under-treatment of pain
• D Opioid-induced hyperalgesia mediated by NMDA activation

Explanation

Opioid tolerance is the reduction in analgesic effect with repeated dosing, requiring dose escalation to maintain the same effect. At the cellular level, tolerance involves receptor desensitisation through phosphorylation, internalisation (downregulation) of mu-opioid receptors, and uncoupling from inhibitory G-proteins (Gi/Go), reducing downstream cAMP inhibition and potassium channel activation. Physical dependence (option A) refers to withdrawal symptoms on abrupt cessation, not reduced efficacy. Opioid-induced hyperalgesia (option D) is a distinct phenomenon of paradoxical increased pain sensitivity.

Reference: Morgan & Mikhail's Clinical Anesthesiology, 6th ed.

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