Pharmacy & Therapeutics - March 2008 - (Page 172) CONTINUING EDUCATION CREDIT altering the pain pathway. The most common adverse effects associated with tramadol include dizziness, headache, somnolence, vertigo, constipation, and nausea. The tramadol dose for moderate-to-severe chronic pain is 50 to 100 mg every four to six hours, not to exceed 400 mg/day.21 Few studies of tramadol in DPN are available; however, it has been studied alone and in combination with acetaminophen (see Table 9).48,49 In the study examining the use of tramadol alone, patients who completed a six-week double-blind, placebo-controlled portion of the study were eligible to enroll in an open-extension period for up to six months. On the first day of the openextension period, the group previously treated with placebo had significantly higher pain scores than those previously treated with tramadol; however, by the 30th day, mean pain relief scores were similar between the two groups. These results continued throughout the rest of the study period. On the basis of these findings, the authors concluded that tramadol provided effective relief of DPN pain over a six-month period. When tramadol plus acetaminophen was compared with placebo, patients reported a significant reduction in average daily pain scores with the combination. The authors of this study concluded that tramadol plus acetaminophen was effective in producing significant pain relief in patients with DPN and was generally well tolerated. Studies that support these claims are not well designed. At this time, evidence for the use of Metanx in DPN does not support routine use. Topiramate Topiramate (Topamax, Ortho-McNeil) is an anticonvulsant with numerous possible mechanisms of action. It is believed to block voltage-dependent sodium channels, increase GABA activity, antagonize glutamate receptors, and inhibit carbonic anhydrase activity. Commonly associated adverse effects are dizziness, somnolence, fatigue, anorexia, paresthesia, and nystagmus.21 In addition to its use as an anticonvulsant agent, topiramate has been used for painful conditions such as migraine prophylaxis, cluster headaches, and neuropathic pain. Studies of DPN have produced conflicting results. A 12-week trial of 323 patients comparing topiramate (up to 40 mg/day) with placebo revealed that topiramate significantly reduced VAS scores and body weight in patients with DPN.54 Another trial of 205 patients also demonstrated positive results supporting the use of topiramate in DPN.55 However, pooled results from three other trials involving a total of 1,269 patients showed no significant difference between topiramate and placebo in treating painful DPN.56 Because of the availability of numerous agents with better efficacy profiles, topiramate should not be considered a first-line therapy for DPN. Agents with Limited Use Metanx Treatment Selection Recommendations for choosing a treatment are based on the Diabetic Peripheral Neuropathic Pain consensus Treatment Guidelines Advisory Board and are based on clinical trials and expert opinion (Table 10). First-line agents that have been evaluated in at least two randomized controlled trials for DPN include duloxetine, oxycodone CR, pregabalin, and the TCAs. Oxcarbazepine, gabapentin, lamotrigine, and venlafaxine are considered second-line agents and have been evaluated in at least one randomized controlled trial involving DPN patients. Topical agents, including capsaicin and lidocaine, may be used as adjuncts at any time during treatment. Agents that have limited use include topiramate, tramadol, and others, because trials specific to DPN are lacking. Metanx (Pamlab), a B-complex vitamin, does not carry the FDA indication for DPN, but it has been used anecdotally.50 This nutritional supplement is a prescription product. It is the metabolically active form of folic acid (methylfolate), vitamin B6 (pyridoxal), and vitamin B12 (methylcobalamin) and thus does not require enzymatic activation. Elevated total homocysteine concentrations exhibit toxic effects on vascular endothelial cells and are an independent risk factor for atherosclerotic disease. Deficiencies in folic acid, vitamin B6, and vitamin B12 are associated with elevated homocysteine levels.51–53 However, it is not well established that hyperhomocysteinemia is related to DPN. Subsequently, it is not confirmed that the use of a vitamin B supplement to decrease homocysteine levels is an effective therapy for DPN. Table 10 Recommendations for First-Tier and Second-Tier Agents for Diabetic Peripheral Neuropathic Pain (DPN) First-Tier Agent Why: ≥2 RCTs in DPN • Duloxetine • Oxycodone CR • Pregabalin • TCAs Second-Tier Agent Why: 1 RCT in DPN; ≥1 in other PN • Carbamazepine • Gabapentin • Lamotrigine • Tramadol • Venlafaxine ER Topical Agent Why: mechanism of action • Capsaicin • Lidocaine Other Why: ≥1 RCT in other PN or other evidence • Bupropion • Citalopram • Methadone • Paroxetine • Phenytoin • Topiramate PN = painful neuropathy; RCT = randomized controlled trial. Adapted with permission from Argoff CE, Backonja MM, Belgrade MJ, et al. Mayo Clinic Proceedings 2006;81(4 Suppl):S12–S25.6 172 P&T® • March 2008 • Vol. 33 No. 3
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