Strategies for Optimizing Antiepileptic Drug Therapy in Elderly People

Thomas E. Lackner, Pharm.D., FASCP

Disclosures

Pharmacotherapy. 2002;22(3) 

In This Article

Neuropathic Pain

Neuropathic pain is often refractory to therapy with traditional analgesics, with tricyclic antidepressants usually regarded as either a first- or second-line therapy depending on pain severity. Less studied than tricyclics, AEDs have been used as a second-line monotherapy or adjunctive therapy for elderly people with refractory painful neuropathies.[158,159,160,161]

Although not FDA approved, carbamazepine is an effective analgesic for diabetic neuropathy in the elderly.[158,159,160,162] However, its use is limited by frequent adverse effects and many potential drug interactions.[158,161,163,164,165] The starting dosage is 100 mg twice/day, increasing as necessary to a maximum of 1200 mg/day.[166] The usual effective dosage varies from 100-400 mg 3-4 times/day, or twice/day for the extended-release formulation.[167] A lower dosage and/or longer dosing interval may be required as drug clearance may be 25-40% lower than in younger adults.[1,168]

The effectiveness of phenytoin for neuropathic pain in elderly people is less substantiated than carbamazepine and it is not FDA approved for this purpose.[160,169,170,171,172,173] In addition to an undesirable adverse effect profile, phenytoin is associated with many potential drug interactions, nonlinear pharmacokinetics that prevent simple proportional dosage adjustment, and susceptibility to changes in protein binding that can confound the usual correlation of SDC and clinical response. An appropriate starting dosage in elderly patients is 3 mg/kg/day with slow titration to 300-600 mg/day as tolerated.[166,170,174]

A controlled study of gabapentin monotherapy up to 3600 mg/day for peripheral diabetic neuropathic pain in 165 young and elderly adults (mean age 53 yrs) reported significant pain relief compared with placebo, and similar to that achieved with tricyclics in other studies.[175,176] The largest dosage was substantially higher than the labeled maximum dosage for seizures of 2400 mg/day. Gabapentin monotherapy has not been compared directly with tricyclics or evaluated as adjunctive therapy to tricyclics for this painful neuropathy and is not FDA approved as analgesia. Nevertheless, because of its similar efficacy and superior safety profile, if financial resources permit, it should be considered the preferred primary therapy and certainly an alternative to tricyclics for diabetic neuropathy.

Although no controlled studies are available, a few descriptive reports suggest that valproate is effective for diabetic neuropathy.[167,169,170,171] An appropriate starting dosage is 125 mg 3 times/day or 250 mg twice/day, slowly increased as necessary and tolerated up to 1000 mg 3 times/day.[167,170,171]

A controlled study of gabapentin monotherapy up to 3600 mg/day in 229 patients (median age 73 yrs) showed significant relief of pain related to postherpetic neuralgia compared with placebo.[177] The degree of relief was similar to that with tricyclics.[178] A combination of carbamazepine or valproate and a tricyclic antidepressant may be effective in the treatment of postherpetic neuralgia refractory to monotherapy.[179,180] In an open study, pain relief was achieved with carbamazepine monotherapy in 36 of 40 patients and with combined carbamazepine and phenytoin in 3 of 4 patients.[179] Twenty-two of 27 evaluable patients experienced long-term relief. The authors reported that previous treatment with phenytoin resulted in good pain relief in 13 of 24 patients and no relief in the remaining patients. Although controlled studies directly comparing these therapies specifically in the elderly are necessary, because of its favorable adverse effect profile, gabapentin monotherapy should be considered as a primary therapy and as an alternative in patients refractory or intolerant to other AEDs and tricyclic agents.

Carbamazepine is an FDA-approved first-line alternative to clonazepam in treating trigeminal neuralgia and is effective in 80% of patients.[161,181,182,183] The labeled starting dosage is 100 mg twice/day, increased in increments of 100 mg twice/day as required up to 200-800 mg/day or a maximum of 1200 mg/day as tolerated.[51] Phenytoin does not appear to be as effective as carbamazepine.[172,181] Preliminary evidence suggests that gabapentin may be effective; all five elderly patients in a case series experienced excellent pain relief.[157]

For central pain after stroke, carbamazepine and phenytoin in combination with tricyclic antidepressants and possibly lamotrigine and gabapentin monotherapy may be effective.[157,166,169,184,185,186,187] Controlled studies are lacking, however, and none of these agents is FDA approved for this indication. Therefore, these AEDs should be reserved for patients whose pain is refractory to traditional analgesics. Preliminary evidence suggests that valproate appears to be ineffective for central poststroke pain.[188]

A therapeutic SDC range for analgesia has not been established for any of these neuropathic conditions. However, the SDC at which an optimum response is achieved in an individual patient may serve as a benchmark to facilitate future therapy.

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