Nefopam

Introduction

Nefopam is a centrally acting, non-opioid, non-steroidal analgesic used for the management of moderate pain. Unlike classical NSAIDs, nefopam does not exert its effects through inhibition of cyclooxygenase (COX) enzymes and therefore does not possess anti-inflammatory or antipyretic properties. Instead, it acts through a central mechanism involving modulation of monoaminergic pathways and inhibition of glutamatergic transmission.

Originally developed in the 1960s, nefopam was introduced as an alternative to opioids and NSAIDs for pain management, particularly useful in patients where opioid-related respiratory depression or NSAID-induced gastrointestinal and renal complications pose significant risks. It is marketed in many countries in Europe and Asia, but not in the United States.

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Pharmacological Classification

• Class: Centrally acting non-opioid analgesic

• ATC code: N02BG06

• Formulations:

  • Oral tablets (30 mg)

  • Injectable solution for intramuscular or intravenous administration (20 mg/mL)

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Mechanism of Action

Nefopam’s analgesic action is multifactorial and not completely understood, but key mechanisms include:

1. Monoamine reuptake inhibition

   • Inhibits reuptake of serotonin, norepinephrine, and dopamine.

   • Enhances descending inhibitory pain pathways within the central nervous system.

2. Modulation of glutamatergic transmission

   • Inhibits NMDA receptor-mediated responses.

   • Reduces excitatory neurotransmission involved in central sensitization and neuropathic pain.

3. Sodium and calcium channel modulation

   • Blocks voltage-sensitive sodium and calcium channels, decreasing neuronal excitability.

Unlike opioids, nefopam does not bind to opioid receptors, and unlike NSAIDs, it does not inhibit COX enzymes.

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Pharmacokinetics

• Absorption: Rapid and well absorbed orally.

• Bioavailability: Approximately 36% due to first-pass hepatic metabolism.

• Distribution: Highly protein bound (~75%).

• Metabolism: Hepatic metabolism by hydroxylation and conjugation.

• Elimination: Primarily via urine as metabolites.

• Half-life: 3–5 hours (longer in renal or hepatic impairment).

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Clinical Indications

1. Moderate acute pain

   • Used when NSAIDs or opioids are contraindicated or not tolerated.

   • Effective in post-operative pain management (as monotherapy or in multimodal regimens).

2. Chronic and neuropathic pain (off-label in some countries)

   • Occasionally used in conditions like musculoskeletal pain, dental pain, or cancer-related pain.

3. Prevention of shivering during anesthesia recovery (off-label)

   • Shown to reduce post-anesthetic shivering, especially in the postoperative care setting.

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Contraindications

• Hypersensitivity to nefopam or excipients

• History of convulsive disorders (e.g., epilepsy) – nefopam lowers seizure threshold

• Severe coronary artery disease, recent myocardial infarction

• Angle-closure glaucoma (risk of precipitating acute attacks)

• Urinary retention (especially due to prostatic hypertrophy)

• Pregnancy and breastfeeding (safety not established)

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Precautions

• Elderly patients: More susceptible to confusion, agitation, and anticholinergic side effects.

• Renal or hepatic impairment: Reduced clearance, requires caution and dose adjustments.

• Concomitant serotonergic drugs: Risk of serotonin syndrome when combined with SSRIs, SNRIs, MAOIs, or tramadol.

• Seizure risk: Avoid in patients with epilepsy or those at increased risk of seizures.

• Driving and machinery use: May impair psychomotor function; caution patients accordingly.

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Adverse Effects

Common

• Nausea and vomiting

• Sweating

• Dizziness

• Insomnia or nervousness

• Dry mouth (anticholinergic effect)

Less Common

• Palpitations, tachycardia

• Blurred vision

• Confusion, hallucinations (particularly in elderly)

Rare but Serious

• Convulsions (dose-related or in predisposed patients)

• Severe allergic reactions (angioedema, anaphylaxis)

• Urinary retention

• Acute angle-closure glaucoma

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Drug Interactions

• MAO inhibitors: Contraindicated due to risk of severe hypertension and serotonin syndrome.

• SSRIs, SNRIs, TCAs, Tramadol: Increased risk of serotonin syndrome.

• Anticholinergic drugs (e.g., atropine, antihistamines): Additive anticholinergic burden.

• CNS depressants (e.g., benzodiazepines, alcohol, opioids): May enhance sedative and psychomotor impairment.

• Drugs lowering seizure threshold (e.g., bupropion, tramadol, antipsychotics): Increased risk of convulsions.

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Dosage

Adults (Oral)

• Standard dose: 30 mg three times daily.

• Maximum dose: 90 mg/day (some references allow up to 120 mg/day under close supervision).

Adults (Parenteral)

• Intramuscular/Intravenous: 20 mg up to three times daily.

• Administer slowly if given IV to avoid tachycardia or hypotension.

Elderly Patients

• Lower initial doses advised; increased susceptibility to confusion and hallucinations.

Pediatric Use

• Safety not well established; generally avoided in children.

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Clinical Efficacy

• Multiple clinical trials show nefopam provides analgesia comparable to NSAIDs and weak opioids in postoperative pain.

• Effective as part of multimodal analgesia, reducing opioid requirements and associated side effects.

• Less effective in severe pain compared to strong opioids, but useful in moderate pain control.

• Additional benefit in reducing shivering during recovery from anesthesia has been well documented.

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Patient Counseling Points

• Take exactly as prescribed; do not exceed maximum daily dose.

• May cause dizziness or drowsiness – avoid driving or operating machinery until response is known.

• Avoid alcohol and sedatives while on nefopam.

• Report any visual disturbances, hallucinations, seizures, or severe allergic reactions immediately.

• Do not combine with antidepressants or tramadol without medical supervision due to serotonin syndrome risk.