Pharmacy & Therapeutics - March 2008 - (Page 168) CONTINUING EDUCATION CREDIT concentrations of hemoglobin A1c, low-density lipoprotein, high-density lipoprotein, or triglycerides. Subsequent trials have helped to establish the efficacy and safety of duloxetine for the treatment of DPN. Patients can expect improvement after one week of treatment, but they may experience somnolence and constipation; these effects appear better tolerated at a dose of 60 mg/day. Patients with depression were typically excluded in the duloxetine trials, suggesting that analgesia was independent of antidepressant effects. The advantages of duloxetine include once-daily dosing and its efficacy for comorbid depression.6 Venlafaxine Anticonvulsant Agents Gabapentin Similar to duloxetine, venlafaxine (Effexor, Wyeth) is an antidepressant that inhibits the reuptake of the neurotransmitters 5-HT and NE. Common adverse effects associated with this agent include dizziness, somnolence, dry mouth, nausea, and sweating.21 Venlafaxine has been compared with placebo and imipramine in patients with DPN, with doses of 150 to 225 mg showing the greatest efficacy (Table 3).22,23 When it was compared with placebo, patients receiving extended-release (ER) venlafaxine reported significantly reduced pain intensity and greater pain relief. Common adverse events in these trials included nausea and somnolence; anorexia, dyspepsia, insomnia, sweating, and impotence were reported to a lesser extent. The trial that compared venlafaxine and imipramine showed no significant difference between the agents in terms of efficacy or tolerability. Patients reported more fatigue and nausea with venlafaxine and more dr y mouth and sweating with imipramine. Gabapentin (Neurontin, Pfizer) is an anticonvulsant agent with a structure similar to that of gamma-aminobutyric acid (GABA), but it does not interact with the GABA receptors. In fact, the true mechanism of action of gabapentin is unknown. Commonly associated adverse effects include somnolence, dizziness, ataxia, and fatigue. The recommended dosage range for gabapentin in the treatment of DPN is 1,800 to 3,600 mg/day.21 Gabapentin has been used to treat a variety of painful conditions. In the treatment of DPN, gabapentin has been compared with placebo as well as with amitriptyline (Table 4).24–27 When compared with placebo, gabapentin 900 to 3,600 mg/day was required to produce significant changes in pain scores. In comparative trials, gabapentin was at least equivalent to amitriptyline in treating pain associated with DPN. However, the cost of gabapentin, coupled with limited data on its efficacy, may preclude its use as a first-line agent. Pregabalin Pregabalin (Lyrica, Pfizer) is an anticonvulsant structurally similar to its predecessor drug, gabapentin. Although it is a structural analogue of GABA, it does not interact with GABA-A or GABA-B receptors, and it does not affect the uptake of GABA. Pregabalin is believed to exert its action by altering the presynaptic release of NE and glutamate. The most common adverse effects associated with pregabalin therapy include dizziness, somnolence, peripheral edema, headache, blurred vision, and constipation. The recommended dosage range for the treatment of diabetic neuropathy is 150 to Table 2 Clinical Trials of Duloxetine Reference Goldstein17 Raskin19 No. Design Treatment DUL 20 mg/day, DUL 60 mg/day, DUL 120 mg/day, or PBO DUL 60 mg/day, DUL 60 mg b.i.d., or PBO DUL 60 mg twice daily or routine care* Study Conclusions Improvement in pain with 60 and 120 mg; more constipation and somnolence in the 60-mg group Both DUL doses significantly improved pain beginning at week 1; more patient dropouts in the twice-daily group because of adverse events DUL was safe and well tolerated compared with routine care 457 R, DB, PC 348 R, DB, PC, P Raskin20 237 R, OL * Routine care consisted primarily of gabapentin, amitriptyline, or venlafaxine. b.i.d. = twice daily; DB = double-blind; DUL = duloxetine; OL = open-label; P = parallel; PBO = placebo; PC = placebo-controlled; R = randomized. Table 3 Clinical Trials of Venlafaxine Reference Rowbotham22 Sindrup23 No. Design Treatment VEN 75 mg /day,VEN 150–225 mg/day, or PBO VEN 225 mg/day, IMI 150 mg/day, or PBO Study Conclusions Significantly greater pain control with 150–225 mg; common adverse effects include nausea and somnolence Both VEN and IMI provided significant pain relief; no difference in efficacy or tolerability 244 R, DB, PC 40 R, DB, PC, CO CO = crossover; DB = double-blind; IMI = imipramine; PBO = placebo; PC = placebo-controlled; R = randomized; VEN = venlafaxine. 168 P&T® • March 2008 • Vol. 33 No. 3
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