Abstract & Commentary
By Michael Rubin, MD, Professor of Clinical Neurology at Weill Cornell Medical College and Attending Neurologist at New York Presbyterian Hospital. Dr. Rubin does research for ASTA Medica and Eli Lilly.
Synopsis: Pregabalin appears to be a safe and effective alternative in the treatment of painful diabetic neuropathy.
Source: Richter RW, et al. Relief of Painful Diabetic Peripheral Neuropathy with Pregabalin: A Randomized, Placebo-Controlled Trial. J Pain. 2005;6:253-260.
In this latest quest for the panacea of painful diabetic neuropathy, diabetics with 1-5 years of painful neuropathy were recruited over a 1-year period to determine the efficacy and safety of 6 weeks of pregabalin, 150 mg or 600 mg/d orally, compared to placebo. Diagnosis of neuropathy was confirmed by history and physical examination. Inclusion criteria included hemoglobin A1c level < 11%, ongoing moderate-to-severe neuropathic pain, as measured by a visual analog scale score > 39 on the Short Form-McGill Pain Questionnaire, and a daily average score > 3 for 4 or more days during a 1-week baseline. Pregnant patients and those with other causes of peripheral neuropathy, serious medical disorders, other neurologic conditions, or recent enrollment in investigational drug trials were excluded. Concomitant pain medications, including tricyclic antidepressants, antiepileptic medication, opioids, capsaicin, and mexiletine were discontinued up to 30 days prior to study drug administration. Aspirin, acetaminophen, and serotonin reuptake inhibitors were permitted without change of dosage. Patients were randomized and, over 2 weeks, titrated upward from 25 mg/d to 150 mg/d (n = 79) or from 100 mg/d to 600 mg/d (n = 82), which they maintained for 4 weeks. Daily pain measurements were the primary end points, while secondary end points included pain characteristics, sleep interference, health status as measured by the 36-Item Short-form Health survey, psychologic state as measured by the Profile of Mood States, and global improvement as measured by the Clinician and Patient Global Impression of Change.
Compared to placebo, pregabalin 600 mg/d significantly lowered mean pain scores, visual analog scale scores, present pain intensity, and effective and total scores on the Short Form-McGill Pain Questionnaire. Sleep interference was significantly lowered and was associated with better Clinician and Patient Global Impression of Change evaluations. Pregabalin 150 mg/d was no more efficacious than placebo. Dizziness (37.8%), somnolence (22%), peripheral edema (17.1%), headache (15.9%), and asthenia (12.2%) were the most common adverse effects in the 600 mg/d group, but was usually graded no worse than mild-to-moderate in severity. Pregabalin appears to be a safe and effective alternative in the treatment of painful diabetic neuropathy.
n Commentary
Which oral medication is best for diabetic neuropathic pain with respect to safety and tolerability, the latter as assessed by the incidence of drug-related adverse events and study discontinuation resulting thereof? Review of English-language, placebo-controlled and direct-comparison studies of drug trials for painful diabetic neuropathy, published from 1990 to November 2203, was undertaken to answer this question (Diab Metab Res Rev. 2005;21;231-240). MEDLINE, EMBASE, and the Cochrane Controlled Trials registry library 2003 were utilized, and key search words included diabetic peripheral neuropathy and drug therapy. Topical treatments were excluded, as were studies involving other painful conditions such as post-herpetic neuralgia and cancer, and only randomized controlled trials were included.
Nineteen placebo-controlled and 5 comparative trials met the search criteria. Treatment duration ranged from 2-52 weeks, and enrollment ranged from 14-333 patients. End points varied and included pain scales (Likert, Gracely, visual analog) or questionnaires (Short Form-McGill Pain).
Tricyclic antidepressants were plagued by dose-limiting side effects, both annoying (dry mouth, constipation, sedation, weight gain) and potentially serious (urinary retention, orthostatic hypotension, cardiac conduction defects). Selective serotonin reuptake inhibitors (SSRIs) demonstrated only weak benefit. Tramadol and oxycodone similarly demonstrated side-effect limitations. Carbamazepine, lamotrigine, and sodium valproate are alternatives that would benefit from further study. Dilantin has no role in the treatment of diabetic neuropathy and may exacerbate glucose control due to its inhibitory effect on insulin secretion. Gabapentin was effective and well tolerated with little drug interaction and appears to be the preferred agent, particularly in the elderly. However, not surprisingly, more studies are needed.
Pregabalin appears to be a safe and effective alternative in the treatment of painful diabetic neuropathy.
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