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Abstract & Commentary
Synopsis: Pregabalin appears to be a safe and effective alternative for the treatment of painful diabetic polyneuropathy.
Source: Rosenstock J, et al. Pregabalin for the Treatment of Painful Diabetic Neuropathy: A Double-Blind, Placebo-Controlled Trial. Pain. 2004:110:628-638.
Consequent to being the most common form of neuropathy in the Western Hemisphere, diabetic polyneuropathy (DPN) treatment is pursued with determined relentlessness. Tricyclic antidepressants and anticonvulsants are the major classes of medication used, and greater numbers of drugs in each category are reported as beneficial. Pregabalin, a gamma-aminobutyric acid (GABA) analog with analgesic, anxiolytic, and anticonvulsant activity, is among the most recent additions to the list.
One hundred forty-six DPN patients, with 1-5 years of pain, were enrolled in a randomized, double-blind placebo-controlled, multicenter 8 week trial to determine the efficacy of pregabalin (300 mg/d) in providing relief of painful neuropathy. Pain had to measure at least 40 on the Short-Form McGill Pain Questionnaire (SF-MPQ) visual analog scale, and at least 4 on the average daily pain score (scale 0-10, from no pain to worst possible pain). Patients were at least 18 years of age, male or female, not pregnant or lactating, and otherwise free of psychiatric disorders, renal insufficiency, or other confounding conditions. Analgesic medications, other than aspirin, tylenol, or serotonin reuptake inhibitors, were prohibited during the trial. Mean pain score at end point was the primary efficacy parameter, defined as the mean of the last 7 daily diary entries by the patient, scored on a 0-10 scale. Six secondary end point measures were employed, including the SF-MPQ, daily sleep interference score, patient global impression of change, physician global impression of change, Short Form (SF-36) Health Survey, and profile of mood states. Statistical analysis was achieved by using an analysis of covariance model.
Mean pain scores, mean sleep interference scores, SF-MPQ scores, SF-36 Bodily Pain subscale, and Total Mood Disturbance and Tension-Anxiety components of profile of mood states significantly improved with pregabalin compared to placebo. Dizziness, somnolence, infection (colds or upper respiratory infections, likely due to the winter season of the study period, rather than medication), and peripheral edema were more common in pregabalin treated patients, but were mild or moderate. Eleven percent (n = 8) of pregabalin patients discontinued treatment due to adverse effects, compared to 3% (n = 2) in the placebo group. Diabetic control was unchanged. Pregabalin appears to be a safe and effective alternative for the treatment of painful diabetic polyneuropathy.
Another recent addition to the therapeutic armamentarium for painful diabetic neuropathy (PDN) is the serotonin-norepinephrine reuptake inhibitor venlafaxine (Effexor). Two hundred forty-four PDN patients were randomized in a 6-week, double-blind placebo-controlled trial to study the safety and efficacy of venlafaxine extended-release (V-ER), in doses up to 225 mg/d. Pain had to measure greater than 40 on the Visual Analog Scale-Pain Intensity (VAS-PI) for entry into the trial, and patients had to have at least a 3 month history of moderate severity diabetic neuropathy pain. Exclusionary criteria included depression, drug or alcohol abuse, renal or hepatic disease, and seizure disorder. Primary efficacy measures included VAS-PI and VAS-PR (Visual Analog Scale-Pain Relief), and secondary efficacy measures encompassed Clinical Global Impressions-Severity of Illness, Clinical Global Impressions-Improvement, and Patient Global Rating of Pain Relief. Statistical analysis comprised parametric analysis of covariance, pairwise Fisher protected F-test, and t-test.
Higher dose V-ER (150-225 mg/d) provided significantly more pain relief than either the lower dose of V-ER or placebo, as measured by VAS-PI and VAS-PR. Lower dose V-ER was no more efficacious than placebo. Secondary outcome measures were similarly improved on the higher, but not lower dose V-ER or placebo. Somnolence (15%), nausea, dyspepsia, insomnia, sweating (10% each), and flatulence and myalgia (7% each) were the most common reported adverse events on the higher dose V-ER and occurred more than twice as frequently compared to placebo. In the higher dose V-ER group, 6% (n = 7) demonstrated noteworthy EKG changes, including 10 A-V block, ventricular extrasystoles, and atrial fibrillation. Of these, 3 withdrew from the study. Venlafaxine extended-release in doses of 150-225 mg/d is safe and effective for the relief of painful diabetic neuropathy, comparable to gabapentin or tricyclic antidepressants. — Michael Rubin, MD
Dr. Rubin, Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus, is Assistant Editor of Neurology Alert.