Topiramate inhibits excitatory neurotransmission by enhancing the effects of gamma-aminobutyric acid, and also by blocking NMDA receptors. Topiramate is FDA-approved for seizures and migraine prophylaxis, and is used off-label for treating neuropathic pain. A 12-week trial of topiramate for diabetic neuropathy found significant analgesia in 50% of patients taking the drug, compared with 34% receiving placebo.18
Lamotrigine is approved for several types of seizures and maintenance of bipolar I disorder, and is used off-label for neuropathic pain. A recent Cochrane database review concluded that lamotrigine is ineffective for neuropathic pain14; however, some guidelines recommend using lamotrigine to treat neuropathies that do not respond to treatment with carbamazepine.19
Carbamazepine is a complex AED that is structurally similar to TCAs. It blocks sodium channels and has various pharmacologic properties, including anticholinergic, muscle relaxant, antidepressant, and sedative effects. Carbamazepine has analgesic effects through blockade of synaptic transmission in the trigeminal nucleus and is FDA-approved for seizures, bipolar disorder, neuropathic pain, and trigeminal neuralgia. In a systematic review of 12 trials of carbamazepine that included 4 placebo-controlled trials for trigeminal neuralgia, 2 studies showed a number needed to treat (NNT) of 1.8.20 For diabetic neuropathy, there was insufficient data to calculate NNT.
Oxcarbazepine, an analog of carbamazepine, also is FDA-approved for seizures and is used off-label for neuropathic pain. In the only double-blind trial with positive results, oxcarbazepine titrated to 1,800 mg/d reduced diabetic neuropathy pain scores on a visual analog scale by 24 points—roughly 25%.15
Table 3
Antiepileptic drugs for pain treatment
| Drug | Dosage range for pain | Comments |
|---|---|---|
| Carbamazepine | Starting dose: 100 mg twice a day, doses titrated to 400 to 800 mg/d usually are adequate. Maximum of 1,200 mg/d12 | Anticholinergic effects, blood dyscrasias, hyponatremia, increase in LFTs, ECG changes. CYP450 inducer, many DDIs |
| Gabapentin | Starting dose: 100 to 300 mg at bedtime or 100 to 300 mg 3 times a day, slow titration, maximum of 3,600 mg/d13 | Dizziness, sedation, weight gain, peripheral edema. Adjust dose in renal insufficiency |
| Lamotrigine | 200 to 400 mg/d14 | Sedation, headache, dizziness, ataxia, GI upset, blurred vision. Risk of life-threatening rash |
| Oxcarbazepine | Starting dose: 300 mg/d, then titrated as tolerated to a maximum of 1,800 mg/d15 | Adverse drug reactions similar to carbamazepine, less anticholinergic effects, more hyponatremia. Fewer DDIs than carbamazepine |
| Pregabalin | Starting dose: 50 mg 3 times a day or 75 mg twice a day, may increase every 3 to 7 days as tolerated, maximum of 600 mg/d13 | Same adverse drug reactions as gabapentin, less sedation. Adjust dose in renal insufficiency. More costly than gabapentin |
| Topiramate | Starting dose: 12.5 to 25 mg once or twice a day for 4 weeks; then double the dose every 4 weeks to reach a maximum dose of 100 to 200 mg/d in divided doses16 | Weight loss, anorexia, nephrolithiasis, cognitive impairment |
| CYP450: cytochrome P450; DDIs: drug-drug interactions; GI: gastrointestinal; LFTs: liver function tests | ||
Non-opioid analgesics
NSAIDs have antipyretic, analgesic, and anti-inflammatory effects and are used for fever, headache, mild-to-moderate pain, musculoskeletal pain, menstrual pain, and dental pain. They are particularly useful in treating acute pain, often in combination with opioid analgesics. NSAIDs exert their analgesic action through blockade of prostaglandin production via reversible inhibition of cyclooxygenase-1 and cyclooxygenase-2.
The most common side effects of NSAIDs are the result of gastrointestinal (GI) toxicity and include dyspepsia, heartburn, nausea, anorexia, and epigastric pain.21 GI ulceration and bleeding are rare but serious complications. To decrease these risks, tell patients to take NSAIDs with food. Add a GI protective agent, such as an H2 blocker or proton pump inhibitor, for patients at higher risk for GI complications.22
In addition, inhibition of renal prostaglandins by NSAIDs can cause renal toxicity, fluid retention, and edema, potentially exacerbating existing cardiovascular conditions such as hypertension and heart failure. NSAIDs may increase the risk of serious thrombotic events such as myocardial infarction and stroke. Use NSAIDs at the lowest effective dose for the shortest duration possible and generally avoid prescribing in patients at high risk for cardiovascular disease and pregnant women, especially those in their third trimester.23,24
NSAIDs may cause pharmacodynamic and pharmacokinetic drug-drug interactions. The risk of GI toxicity and bleeding increases when NSAIDs are administered with drugs that also irritate the gastric mucosa or have antiplatelet/anticoagulant effects.21 Plasma concentrations of drugs with a narrow therapeutic index that are renally eliminated, such as methotrexate and lithium, can increase to potentially toxic levels with concurrent NSAID use because NSAIDs decrease renal perfusion.21 Also, the therapeutic effects of antihypertensives may be attenuated because NSAIDs cause fluid retention.25