Pethidine

Pethidine: A Comprehensive Pharmacological and Clinical Review

Pethidine (meperidine) is a synthetic opioid analgesic belonging to the phenylpiperidine class, primarily employed for the management of moderate to severe pain. Initially synthesised in the 1930s with the intention of developing an anticholinergic agent, its potent analgesic properties were subsequently identified, leading to its clinical application. Although its use has diminished with the advent of alternative opioids possessing superior safety and efficacy profiles, Pethidine retains a niche role in pain management, particularly within obstetric and perioperative settings. Its pharmacokinetic and pharmacodynamic characteristics distinguish it from other opioids, necessitating judicious prescribing to mitigate potential risks such as neurotoxicity, serotonergic interactions, and dependence.

Image source Google

Image source Google

Therapeutic Applications

Pethidine remains indicated for acute pain scenarios, including but not limited to:

• Obstetric analgesia during labour
• Postoperative analgesia
• Acute renal or biliary colic
• Severe musculoskeletal and traumatic pain
• Pain management for minor surgical and diagnostic procedures
• Short-term adjunctive therapy for acute exacerbations of chronic pain syndromes

Despite historical widespread usage, contemporary guidelines increasingly recommend against its routine use due to concerns regarding its unique toxic metabolite, norpethidine, and the associated risk of neuroexcitatory adverse effects.

Dosage and Administration

The administration of Pethidine varies depending on the clinical scenario and patient-specific factors:

• Oral: 50–150 mg every 4 hours as required
• Intramuscular (IM) or Subcutaneous (SC): 25–100 mg every 3–4 hours
• Intravenous (IV): 25–50 mg administered slowly, with dose titration based on analgesic response
• Epidural or Intrathecal: Occasionally used under strict specialist supervision

Due to its relatively short half-life and propensity for metabolite accumulation, repeated dosing should be carefully monitored to prevent toxicity.

Dose Modifications in Special Populations

Renal Impairment

Renal dysfunction significantly impacts Pethidine clearance, leading to the accumulation of norpethidine, a metabolite with potent neurotoxic effects, including tremors, myoclonus, and seizures. In patients with moderate to severe renal impairment (eGFR <30 mL/min), Pethidine is contraindicated, with alternative opioids such as fentanyl or hydromorphone being preferred due to their superior renal safety profile.

Hepatic Impairment

As Pethidine undergoes extensive hepatic metabolism via CYP450 enzymes, hepatic insufficiency results in delayed drug clearance and increased bioavailability. In patients with hepatic impairment, dose adjustments are essential, with extended dosing intervals to mitigate excessive drug accumulation. Severe hepatic dysfunction warrants the selection of alternative analgesics.

Elderly and Frail Patients

Geriatric populations exhibit heightened sensitivity to Pethidine, with an increased risk of sedation, cognitive dysfunction, respiratory depression, and falls. Dosage reductions and close monitoring are imperative to prevent iatrogenic harm.

Adverse Effects

The adverse effect profile of Pethidine is consistent with other opioids but includes distinct concerns related to norpethidine toxicity. Common and severe adverse effects include:

• Common: Nausea, vomiting, dizziness, sedation, constipation, dry mouth, urinary retention, hypotension, diaphoresis
• Serious: Respiratory depression, serotonin syndrome (when combined with serotonergic agents), seizures, delirium, dependence and withdrawal syndromes

Chronic administration is discouraged due to the progressive accumulation of norpethidine, which is not effectively reversed by naloxone.

Drug Interactions

Pethidine exhibits significant drug interactions, necessitating careful consideration in polypharmacy contexts:

• Monoamine Oxidase Inhibitors (MAOIs): Contraindicated due to the risk of fatal serotonin syndrome
• Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Increased risk of serotonin toxicity
• Benzodiazepines and Other CNS Depressants: Heightened risk of profound sedation and respiratory depression
• CYP3A4 Inhibitors (e.g., ketoconazole, ritonavir): Prolonged Pethidine half-life, increasing toxicity risk
• Alcohol: Exacerbation of CNS depression

Pharmacokinetics and Pharmacodynamics

• Absorption: Oral bioavailability is limited due to first-pass metabolism; parenteral administration ensures more predictable analgesic effects.
• Distribution: High lipid solubility results in rapid CNS penetration; volume of distribution is approximately 4.5 L/kg.
• Metabolism: Predominantly hepatic, via CYP2B6 and CYP3A4, forming norpethidine, which has an elimination half-life of 8–12 hours.
• Excretion: Renal clearance is the primary route; impaired renal function leads to metabolite accumulation and neurotoxicity.
• Mechanism of Action: Acts primarily as a mu-opioid receptor agonist, with additional effects on serotonin reuptake, contributing to its unique risk profile for serotonergic toxicity.

Comparative Analysis with Other Opioids

Drug	Potency	Half-Life	Neurotoxic Metabolite	Use in Renal Impairment
Pethidine	Low	2.5-4 hr	Norpethidine (high risk)	Contraindicated
Morphine	High	2-3 hr	Morphine-6-glucuronide (low risk)	Dose adjustment required
Fentanyl	Very High	3-4 hr	None	Preferred option
Oxycodone	High	3-5 hr	Noroxycodone (low risk)	Can be used with caution
Hydromorphone	Very High	2-3 hr	Hydromorphone-3-glucuronide (low risk)	Preferred in renal impairment

Toxicity and Overdose Management

Clinical Manifestations of Overdose

• Profound respiratory depression
• Severe hypotension
• CNS excitation (seizures due to norpethidine accumulation)
• Coma and potential fatality

Antidotal Therapy

• Naloxone remains the primary opioid antagonist for reversal of Pethidine-induced respiratory depression, though its efficacy in norpethidine toxicity is limited.
• Supportive care including airway management, mechanical ventilation if necessary, and benzodiazepines for seizure control.
• Haemodialysis may be considered in cases of severe norpethidine accumulation in renal failure.

2025 Guidelines and Clinical Recommendations

• WHO Pain Management Guidelines (2025): Strongly advise against the use of Pethidine for chronic pain management due to its adverse safety profile.
• NICE Guidelines (2025): Advocate for the phasing out of Pethidine in favour of fentanyl or hydromorphone for acute pain scenarios requiring opioid therapy.
• Obstetric Analgesia Protocols: While still used in certain labour analgesia settings, alternative agents such as remifentanil PCA are increasingly recommended.

Key Clinical Considerations

• Pethidine should not be used in patients with renal or hepatic impairment due to neurotoxic metabolite accumulation.
• Risk of serotonin syndrome necessitates caution when prescribing alongside serotonergic agents.
• Chronic use is discouraged due to the potential for tolerance, dependence, and neurotoxicity.
• Pethidine is no longer recommended as a first-line opioid in most clinical settings due to the availability of safer alternatives.

References

1. WHO 2025 Guidelines on Pain Management.
2. British National Formulary (BNF) – Pethidine Monograph.
3. National Institute for Health and Care Excellence (NICE) Guidelines.
4. Pain Management in Obstetrics – Royal College of Obstetricians and Gynaecologists.
5. European Journal of Pain – Advances in Opioid Analgesia.