Anticonvulsant Relieves Painful Diabetic Neuropathy
June 1, 1999 7 minutes read
Anticonvulsant Relieves Painful Diabetic Neuropathy
By Joan Unger, RN, MS, ARNP-C
Summary—One of the most common complications of diabetes mellitus is painful, debilitating peripheral neuropathy. Pain, one of the most difficult complications to control, negatively affects sleep, appetite, mobility, and quality of life. Gabapentin is an anticonvulsant that has shown promise in treating neuropathic pain in animal studies. A randomized, double-blind, placebo-controlled study evaluated the efficacy of gabapentin to control painful diabetic neuropathy. Investigators learned that approximately 60% of patients receiving gaba pentin reported at least moderate improvement vs. only 33% of the placebo patients. Study subjects in the gabapentin group also demonstrated improvement in sleep, mood, and quality of life measures.
About 16 million people in the United States have diabetes, and nearly half do not yet know it.1 Complications of diabetes, whether type 1 or 2, are common and often produce no symptoms until well advanced. Probably the most common complication of diabetes in the Western world is diabetic neuropathy.2,3 In a study of 4400 diabetic patients followed for 20-25 years, 45% developed neuropathy.4 The condition can be extremely painful, interfering with mood, sleep, appetite, mobility, and quality of life.
Previous studies in animal models have shown gabapentin is effective for chronic neuropathic pain. These findings, along with an established favorable safety profile, suggest gabapentin may be a promising treatment for diabetic neuropathic pain.
Study Methodology
The randomized, double-blind, placebo-controlled study was conducted in 20 outpatient sites. It consisted of two phases: a seven-day screening phase and an eight-week double-blind phase. The eight-week phase consisted of four weeks of dose titration followed by four weeks on a fixed-dose of gabapentin. Researchers recruited 165 patients who had a one- to five-year history of pain attributed to diabetic neuropathy and a minimum 40 mm pain score on the 100 mm visual analog scale (VAS) of the Short-Form McGill Pain Questionnaire (SF-MPQ).5 The study followed these criteria (in table 1):
| Table 1 |
| Diabetic Neuropathy Study Criteria |
Inclusion Criteria |
The study intervention was placebo or gabapentin gradually titrated to tolerability or to the study maximum of 3600 mg/d taken in three divided doses. Gabapentin was increased weekly during the first four-week period, beginning with 900 mg/d for week one, increasing to 1800 mg/d for week two, 2400 mg/d at week three, and 3600 mg/d at week four. If adverse reactions occurred to an intolerable level, the dosage was decreased by one step.
Medication dosages for diabetes control were unchanged during the study. Medications that might affect symptoms of painful diabetic neuropathy were prohibited, with the exception of acetaminophen (up to 3 mg/d) or aspirin (up to 325 mg/d for prophylaxis of myocardial infarction or transient ischemic attacks). Serotonin reuptake inhibitors also were permitted if there had been no dosage change within 30 days before or during the study. A number of other medications were prohibited within 30 days prior to randomization and throughout the study. (See table 2, p. 47.)
| Table 2 |
| Drugs Prohibited Before and During Study |
• tricyclic antidepressants |
The primary outcome measure was daily pain severity measured on an 11-point Likert scale (0 = no pain, 10 = worst possible pain). Secondary outcome measuring tools included weekly mean sleep interference score from the daily sleep diary; the VAS of the SF-MPQ);5 Patient Global Impression of Change (PGIC, completed by patient); Clinical Global Impression of Change (CGIC, completed by clinician); the Short Form-36 Quality of Life Questionnaire (SF-36 QOL);6 and the Profile of Mood States (POMS).7
Study Results
Of the 165 study patients randomized, 84 were randomized to gabapentin and 81 to placebo. Of the 84 patients who received gabapentin, 83% (70) completed the study, as did 80% (65) of the 81 placebo patients. Sixty-seven percent (56) of the gabapentin-treated patients achieved the maximum 3600 mg/d dosage. Patient demographics and baseline characteristics were similar between groups. Approximately 75% of patients in each group had type 2 diabetes. Almost 77% of all study patients had neuropathic pain involving the foot/toe and calf. The mean pain score at baseline was similar between the treatment groups. Pain descriptors on the SF-MPQ were similar between groups and between patients with type 1 and type 2 diabetes at baseline.
Differences between gabapentin and placebo were significant at end point for mean pain score, mean sleep interference score, and total pain, VAS, and PPI scores of the SF-MPQ. As measured by both PGIC and CGIC scales, patients treated with gabapentin had significantly (p= 0.001) greater improvement in pain than patients randomized to placebo. Approximately 60% of patients receiving gabapentin had at least moderate improvement on the PGIC scale, whereas only 33% of patients receiving placebo reported that degree of improvement. Gabapentin had a significant effect on four items of the POMS, compared with placebo: anger/hostility, vigor/activity, fatigue/inertia, and total mood disturbance. Gabapentin also had a positive effect on quality of life, bodily pain, mental health, vitality on the SF-36 QOL. The trend of all other items of the QOL was toward a positive effect of gabapentin; however, none was significantly different than placebo.
Adverse events included dizziness, somnolence, headache, diarrhea, confusion, and nausea. Several were significantly more frequent in the gabapentin group: dizziness 20 (24%) vs. four (4.9%) in control group (p = < 0.001), somnolence 19 (23% in gabapentin vs. five (6%) in control group (p = .004), and confusion seven (8%) in gabapentin vs. one (1.2%) in control (p = 0.06).
Researchers reanalyzed the efficacy data excluding data from patients reporting dizziness or somnolence to assess the effect on the primary efficacy variable. They found that including these patients had not changed the overall efficacy of the trial drug. Seven gabapentin patients and five placebo patients withdrew due to adverse events. Most adverse events were mild or moderate in intensity.
Investigators found no significant changes in hemoglobin A1c levels from baseline to the end of treatment in either group, indicating that subjects maintained glycemic control during the study. No difference between groups was found in the rate of disease progression or gait changes.
Study authors state "gabapentin monotherapy produced rapid onset of clinically meaningful pain relief with relatively minor and potentially avoidable adverse effects in this trial." Researchers concluded that gabapentin monotherapy appeared efficacious for treatment of pain and the accompanying sleep interference associated with diabetic peripheral neuropathy. They also found the drug showed positive effects on mood and quality of life and consider it "a promising new agent for use in patients with neuropathic pain when therapeutic options are limited and offers advantages over currently available treatments as a first-line agent."
Implications for Practice
The authors acknowledge that this was a large, simple clinical trial in which diagnosis was made clinically and did not depend on electrophysiological data. Such a trial is considered appropriate when treatment is designed to affect symptoms without altering the disease process. An earlier study demonstrated that a history and physical examination alone were adequate for diagnosis of neuropathy in the diabetic population.8
It is important for clinicians to remember that gabapentin is eliminated entirely by renal excretion, and its clearance is reduced in patients with renal insufficiency, especially those with a creatinine clearance of less than 60 mL/min.
Recently, a number of studies have demonstrated the usefulness and safety of gabapentin in disease conditions other than seizures. RN Advanced Practice Alert has reported on its efficacy in relieving the severe pain associated with post-herpetic neuralgia.9 A spokesperson for Parke-Davis reported that gabapentin has not been approved by the U.S. Food and Drug Administration for those uses, and the company has no plans to seek approval because "our patent runs out soon."
References
1. Margolis S, Saudek C. The Johns Hopkins White Papers: Diabetes Mellitus. New York City: Medletter Associates Inc.; 1999.
2. Backonja M, Beydoun A, Edwards K, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus. JAMA 1998;280: 1831-1836.
3. Huether S, Tomky D. Alterations of hormonal regulation In: Pathophysiology: The Biologic Basis for Disease in Adults and Children. 3rd ed. St. Louis: Mosby ;1998, p. 689.
4. Pirart J. Diabetes mellitus and its degenerative complications: a prospective study of 4400 patients observed between 1947 and 1973. Diabetes Care 1978;1:168-188, 252-263.
5. Melzack R. The Short-Form McGill Pain Question naire. Pain 1987; 30-191-197.
6. Ware JE Jr, Snow K, Konsinski M, Gandek B. SF-36 Health Survey: Manual and Interpretation Guide. Boston: The Health Institute, New England Medical Center; 1993.
7. McNair D, Lorr M, Droppleman L. Profile of Mood States: Manual. San Diego: Educational and Industrial Testing Service; 1981.
8. Feldman E, Steven M,Thomas P, et al. A practical two-step quantitative clinical and electrophysiolog ical assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care 1994;17:1281-1289.
9. Biedrzycki, Barbara. Post-herpetic neuralgia: New treatment option for a painful condition. RN Advanced Practice Alert 1999; 2:25-27.
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