What are the mechanisms of action and recommended uses of Paracetamol (acetaminophen) compared to Morphine and Pethidine for pain management in adults?

Mechanisms of Action: Paracetamol vs Morphine and Pethidine

Paracetamol (Acetaminophen) Mechanism

Paracetamol works primarily through central nervous system inhibition of cyclooxygenase (COX) enzymes, though its exact mechanism remains incompletely understood despite over a century of clinical use. 1

• Central COX inhibition: Paracetamol selectively inhibits COX enzymes in the CNS, with evidence suggesting it may target a COX-1 variant enzyme to mediate analgesic and antipyretic effects 1
• Reducing agent activity: Works as a reducing agent to inhibit COX-2, though in vitro studies show low potency against both COX-1 and COX-2 1
• Serotonergic pathway: Potentiates the descending inhibitory serotonergic pathway for analgesia, though direct binding to serotonergic molecules has not been demonstrated 1
• Endocannabinoid system: The metabolite AM404 may activate endocannabinoid and TRPV1 systems, contributing to analgesic effects 1
• No peripheral anti-inflammatory action: Unlike NSAIDs, paracetamol lacks significant peripheral anti-inflammatory effects, explaining its superior gastrointestinal and cardiovascular safety profile 2

Morphine Mechanism

Morphine is a full mu-opioid receptor agonist that produces analgesia through direct action on CNS opioid receptors throughout the brain and spinal cord. 3

• Mu-opioid receptor binding: Morphine is relatively selective for mu-opioid receptors, though it can bind other opioid receptors at higher doses 3
• No ceiling effect: As a full agonist, morphine has no ceiling effect for analgesia—dosage is titrated to adequate pain relief and limited only by adverse effects 3
• CNS depression: Produces respiratory depression by direct action on brainstem respiratory centers, reducing responsiveness to CO2 tension 3
• Multiple system effects: Causes miosis, reduces GI motility, produces peripheral vasodilation, and affects endocrine function through inhibition of ACTH, cortisol, and LH secretion 3

Pethidine (Meperidine) Mechanism

Pethidine is a synthetic opioid agonist with similar mu-receptor binding properties to morphine, though the provided evidence does not contain specific mechanistic details for pethidine. Based on general medical knowledge, pethidine acts as a mu-opioid receptor agonist with additional anticholinergic and local anesthetic properties.

Clinical Positioning and Recommended Uses

Paracetamol: First-Line for Mild-to-Moderate Pain

Paracetamol is recommended as first-line therapy for mild-to-moderate pain across all major guidelines, with a maximum daily dose of 4g (or 3g for chronic use). 4

• Standard dosing: 650-1000mg every 4-6 hours, maximum 4g daily (3g daily for chronic use to minimize hepatotoxicity) 5
• WHO analgesic ladder: Serves as the mainstay of steps 1 and 2, though evidence supporting its efficacy is surprisingly limited 4
• Combination therapy: Can be combined with opioids at any step of the WHO ladder for additive analgesia 4
• Superior safety profile: Minimal gastrointestinal, cardiovascular, and renal toxicity at recommended doses compared to NSAIDs 6, 2
• Opioid-sparing effect: Demonstrated to reduce opioid consumption when used in multimodal analgesia 7

Morphine: Moderate-to-Severe Pain Requiring Opioid Therapy

Morphine is indicated for acute and chronic pain severe enough to require an opioid analgesic when alternative treatments (non-opioid analgesics or combination products) are inadequate. 3

• WHO step 3: Reserved for moderate-to-severe pain after failure of non-opioid and weak opioid options 4
• Titration required: Dosage must be individually titrated to balance adequate analgesia against adverse effects including respiratory depression 3
• Addiction risk: Reserved for cases where non-opioid alternatives have failed or are not expected to be tolerated due to risks of addiction, abuse, and misuse 3
• Cancer pain: Widely used for moderate-to-severe cancer pain, though some guidelines suggest eliminating weak opioids (step 2) and moving directly to low-dose morphine 4

Pethidine: Limited Modern Role

While pethidine was historically used for moderate-to-severe pain, modern guidelines do not prominently feature it. Based on general medical knowledge, pethidine has fallen out of favor due to:

• Accumulation of toxic metabolite normeperidine causing seizures
• Shorter duration of action than morphine
• No advantages over other opioids
• Higher risk of adverse effects, particularly in elderly and renally impaired patients

Practical Treatment Algorithm

Start with paracetamol 1000mg every 6 hours (maximum 4g daily) for any mild-to-moderate pain. 4

• If inadequate relief after 24-48 hours, add an NSAID (ibuprofen preferred) rather than exceeding paracetamol maximum dose 6
• If pain persists or is severe at presentation, consider weak opioids (tramadol, codeine) while continuing paracetamol 4
• For severe pain unresponsive to step 2 agents, initiate morphine at low doses while maintaining paracetamol for opioid-sparing effect 4
• In very severe pain, consider starting strong opioids (morphine) as first-line therapy rather than progressing through the WHO ladder 4

Critical Safety Considerations

Never exceed 4g daily paracetamol (3g for chronic use, elderly, or liver disease) to avoid hepatotoxicity. 5, 2

• Combination products: Explicitly counsel patients to avoid all other paracetamol-containing products including OTC cold remedies and opioid combinations 5
• Morphine monitoring: Monitor for respiratory depression, constipation, and endocrine effects (hypogonadism with chronic use) 3
• Elderly patients: Reduce paracetamol to maximum 3g daily; morphine requires careful titration due to increased sensitivity 5
• Liver disease: Limit paracetamol to 2-3g daily; morphine undergoes hepatic metabolism requiring dose adjustment 5
• Renal impairment: Paracetamol is safer than NSAIDs; morphine metabolites accumulate, requiring dose reduction 4

Common Pitfalls to Avoid

• Do not assume paracetamol is ineffective: Despite limited evidence in systematic reviews, it remains guideline-recommended first-line therapy with proven clinical utility 4
• Do not skip paracetamol when initiating opioids: Continue paracetamol for its opioid-sparing effect and multimodal analgesia benefits 7, 8
• Do not use pethidine as first-line opioid: Modern practice favors morphine, oxycodone, or other opioids over pethidine due to superior safety profiles
• Do not continue morphine indefinitely without reassessment: Regularly evaluate for addiction risk, tolerance, and alternative pain management strategies 3