Valproate (sodium)
Class: anti-epileptic (muti-modal action)
Indications (NB some may be unlicensed): epilepsy, mania associated with bipolar disease, neuropathic pain; hyperactive delirium, intractable hiccup
Contraindications/cautions: liver dysfunction; renal impairment (may need to reduce dose)
Adverse reactions: common: GI upset, especially nausea, drowsiness, tremor; less common: thrombocytopenia, sedation, transient hair loss, hepatotoxicity
Metabolism/clearance: may be metabolised by CYP metabolising enzymes family mainly in the liver
Interactions:
- increased clinical effect/toxicity of some drugs (due to increased blood concentrations of them) may occur variably with valproate due to metabolising enzyme inhibition by valproate e.g. amitriptyline, carbamazepine, citalopram, NSAIDs (e.g. diclofenac), pantoprazole, phenobarbitone, phenytoin
- decreased clinical effect/toxicity of valproate (due to increased clearance leading to decreased blood concentrations) may occur with some CYP metabolism enzyme inducers e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin
| Dosing: | neuropathic pain |
|---|---|
| oral: | Start with 150 to 200 mg at night; increase by 150 mg-200 mg /24 hours every 2 to 3 days – give as bd dose. (max. 2,000 mg per day, start low) |
| subcut: | available in injectable form, not commonly used |
| rectal: | not available |
Syringe driver: available in 100 mg/mL injection – has been used in syringe driver in the UK (range 400 mg-1800 mg/24 hours) – WFI as diluent; Oral: subcut dose 1:1
Mechanism of action: Valproate is a sodium-channel blocker, an NMDA-receptor channel blocker, it increases potassium conductance, alters glutamate, GABA, dopamine and serotonin transmission. Role in pain
Bioavailability: 95% (oral)
Onset of action: within 24 hours for neuropathic pain
Peak effect: not known but peak concentrations reached in 4 to 8 hours
Duration of action: 12 to 24 hours
Notes:
- co-analgesic sometimes used with opioids in the treatment of neuropathic pain although gabapentin or pregabalin have become common alternatives
- valproate is not first line for neuropathic pain or hyperactive delirium
- may be used in neuropathic pain when tricyclic antidepressants have failed or in combination with tricyclic antidepressants
- when switching from carbamazepine to valproate watch for toxicity from other drugs as carbamazepine induces the metabolism of several drugs while valproate inhibits the metabolism of several drugs
- don’t discontinue abruptly as risk of rebound seizures
- therapeutic drug monitoring is usually available but is of limited value
- monitor LFTs