PharmacologyTier 1Medical Sciences concept

Anticonvulsant/neuropathic pain drug mechanisms (gabapentinoids, Na channel blockers)

Core concept

Neuropathic pain arises from ectopic, spontaneous firing and central sensitisation - the drugs that work reduce excitability or restore descending inhibition
Three mechanistic families
- 1. Voltage-gated calcium channel alpha-2-delta ligands - gabapentin, pregabalin
  - Bind the alpha-2-delta-1 auxiliary subunit -> reduce trafficking of the channel to the presynaptic terminal -> dec Ca2+ influx -> dec release of glutamate, substance P and CGRP
  - *Not GABAergic despite the name* - no action at GABA receptors
- 2. Voltage-gated sodium channel blockers - carbamazepine, oxcarbazepine, lacosamide, lignocaine, phenytoin
  - Use-dependent stabilisation of the inactivated state -> selectively silences high-frequency ectopic firing
- 3. Descending inhibition (monoamine reuptake) - amitriptyline (TCA), duloxetine (SNRI)
  - Noradrenaline reuptake block in the dorsal horn is the analgesic mechanism; serotonergic action alone is not analgesic - SSRIs do not work

Drug	Mechanism	Key problem
Pregabalin	alpha-2-delta	Linear kinetics, ~90% renal - dose by eGFR. PBS-listed for neuropathic pain in Australia; gabapentin is not
Gabapentin	alpha-2-delta	Saturable absorption -> non-linear kinetics; TDS dosing; renal
Amitriptyline	NA > 5HT reuptake, Na channel, antimuscarinic	Anticholinergic burden, orthostatic hypotension, QT - avoid in the elderly
Duloxetine	SNRI	First-line for painful diabetic neuropathy; nausea, hypertension
Carbamazepine	Na channel	*First-line for trigeminal neuralgia. HLA-B15:02 (SJS/TEN) and HLA-A31:01, hyponatraemia, potent CYP3A4 inducer + autoinducer*
Oxcarbazepine	Na channel	Fewer interactions; worse hyponatraemia
Lamotrigine	Na channel	Rash/SJS - titrate slowly; valproate doubles the level
Sodium valproate	Multiple	*Teratogen - avoid in anyone of childbearing potential*; hyperammonaemia, weight gain, hair loss
Levetiracetam	SV2A	Neuropsychiatric effects - irritability, low mood; no interactions, renal clearance
Topiramate	Multiple + carbonic anhydrase	Cognitive slowing, renal stones, weight loss, glaucoma

*Gabapentinoids: misuse and dependence are now well recognised, especially with opioids -> respiratory depression and overdose death*; sedation, ankle oedema, weight gain, withdrawal on abrupt cessation

First-line for neuropathic pain: amitriptyline, duloxetine, pregabalin or gabapentin - choose by comorbidity, not by hierarchy
- Trigeminal neuralgia is the exception - carbamazepine first
- Topical lignocaine 5% patch for localised post-herpetic neuralgia; capsaicin 8% patch specialist use
Titrate slowly, review at 4-6 weeks, and STOP if ineffective - number needed to treat ~4-8; number needed to harm is not much higher
*Opioids are not first-line and are largely ineffective for neuropathic pain - tramadol and tapentadol have weak evidence via noradrenaline reuptake*
Renal dosing of pregabalin/gabapentin - accumulation causes myoclonus, encephalopathy and falls in CKD and dialysis
Non-drug: exercise, CBT, treat the underlying cause (glycaemic control, B12, decompression)

Painful diabetic neuropathy, post-herpetic neuralgia, trigeminal neuralgia, chemotherapy-induced peripheral neuropathy, radiculopathy, post-stroke central pain, MS-related pain, phantom limb
Fibromyalgia - pregabalin, duloxetine, amitriptyline (a central sensitisation disorder, not neuropathic pain)
Restless legs syndrome - alpha-2-delta ligands are now preferred first-line over dopamine agonists (augmentation risk)
Carbamazepine interactions - warfarin, DOACs, oral contraceptive, tacrolimus, antiretrovirals
Nerve conduction studies are normal in small-fibre neuropathy - diagnosis is clinical +/- skin biopsy or QST
Anticholinergic burden and falls - the reason amitriptyline is a poor choice in a frail older patient

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