Neuropathic Pain Medicines

Neuropathic pain medicines relieve pain caused by a lesion or disease of the somatosensory system, for example diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, HIV-associated neuropathy and spinal root injury. Paracetamol and NSAIDs are ineffective.

Classification. Tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors, alpha2delta ligands, topical agents (lidocaine, capsaicin), sodium channel blockers, and opioid-like agents (tramadol).

• Amitriptyline 10 to 25 mg at night, increased to 75 mg; maximum 150 mg. Nortriptyline 10 to 25 mg at night, increased to 75 to 100 mg.
• Duloxetine 30 mg daily, increased to 60 mg daily; maximum 120 mg.
• Pregabalin 75 mg twice daily, increased to 150 to 300 mg twice daily; maximum 600 mg daily.
• Gabapentin 300 mg on day 1, increased over 3 days to 900 to 3,600 mg daily in three doses.
• Lidocaine 5% plaster, up to 3 plasters for 12 hours in 24, for localised pain.
• Capsaicin 8% patch for 30 to 60 minutes, repeated every 3 months; capsaicin 0.075% cream four times daily.
• Carbamazepine for trigeminal neuralgia: 100 mg twice daily, increased to 200 mg three to four times daily.
• Tramadol 50 mg twice to four times daily; maximum 400 mg daily.

Differences. Tricyclic antidepressants have the strongest effect but the most adverse effects. Duloxetine and the gabapentinoids are better tolerated.

• Step 1: amitriptyline, duloxetine, pregabalin or gabapentin; choose by comorbidity (heart disease or glaucoma favour duloxetine or a gabapentinoid; depression and insomnia favour amitriptyline).
• Step 2: switch or combine drugs from different classes after a 4 to 6 week treatment period at the target dose.
• Localised pain: add lidocaine plaster or capsaicin patch.
• Postherpetic neuralgia prevention: aciclovir 800 mg five times daily or valaciclovir 1 g three times daily for 7 days started within 72 hours of the zoster rash.
• Tramadol: second-line for short-term rescue.
• Strong opioids: specialist use only.
• Regional: in HIV-associated neuropathy, stop neurotoxic antiretrovirals (stavudine, didanosine) and treat with a gabapentinoid or capsaicin 8% patch. Prevent isoniazid neuropathy with pyridoxine 10 to 25 mg daily.

Selection. Evaluate and treat the cause (glycaemic control, vitamin B12 deficiency, alcohol, drugs).

Contraindications. Tricyclic antidepressants in recent myocardial infarction, arrhythmia and glaucoma; duloxetine in severe liver disease and creatinine clearance under 30 mL/min.

Adverse effects. Tricyclics: dry mouth, constipation, urinary retention, sedation, orthostatic hypotension, QT prolongation, and fatal overdose. Duloxetine: nausea, hypertension, hyponatraemia, hepatotoxicity. Gabapentinoids: drowsiness, dizziness, oedema, misuse. Tramadol: seizures, serotonin syndrome, dependence.

Interactions. Serotonergic drugs (tramadol, duloxetine, tricyclics, SSRIs) risk serotonin syndrome. Carbamazepine lowers levels of tramadol and tricyclics. Opioids with gabapentinoids add respiratory depression.

Special groups.

• Pregnancy: avoid duloxetine and gabapentinoids unless essential; amitriptyline acceptable if needed.
• Breastfeeding: amitriptyline and gabapentin acceptable; avoid duloxetine.
• Older adults: avoid tricyclics over 65; use low-dose gabapentinoid or duloxetine.
• Kidney impairment: reduce gabapentin and pregabalin by creatinine clearance (for gabapentin, 400 to 1,400 mg daily at 30 to 59 mL/min).
• Liver impairment: avoid duloxetine.

Monitoring. Pain score and function, sedation, blood pressure, ECG for tricyclics in older adults or cardiac disease, sodium and liver enzymes for duloxetine.

Referral and escalation. Pain not controlled after 2 drug combinations, red flag signs (cauda equina, progressive weakness, cancer), or dependence concerns.