The Pharmacological Treatment of Painful Diabetic Neuropathy
Zachary Simmons, MD, and Eva L. Feldman, MD, PhD
In managing diabetic neuropathy, a major goal of most patients and their physicians is control of pain. A large number of treatments have been studied in both uncontrolled and controlled clinical trials. Patients with symptoms of <6 months' duration associated with alterations in glycemic control have a good prognosis when compared to patients with chronic symptoms lasting longer than 6 months.
Nonsteroidal anti-inflammatory drugs have been shown to be effective. A placebo-controlled, single-blind, crossover study demonstrated both ibuprofen, 600 mg q.i.d., and sulindac, 200 mg b.i.d., to be more effective than placebo in relieving the pain of diabetic neuropathy. The response to sulindac was significantly better than the response to ibuprofen.1 Caution must be exercised when using nonsteroidal anti-inflammatory medications in patients with diabetes because of the risk of nephrotoxicity, although none was noted in the study above.
Tricyclic antidepressants have also been studied extensively. Amitriptyline, imipramine, and desipramine were all found to relieve pain in patients with diabetic neuropathy better than did placebo in double-blind, placebo-controlled trials. These compounds were effective in both depressed and nondepressed patients, and the efficacy appeared to be independent of any antidepressant effect.2-5 Additional support for the efficacy of tricyclic antidepressants was provided by a meta-analysis of 21 different clinical trials.6
Although nortriptyline as monotherapy would also be expected to be effective in treatment of painful diabetic neuropathy and is often used in this manner, there is no study to support its use. All of the tricyclic antidepressants may produce sedation, confusion, and anticholinergic side effects such as constipation, dry mouth, blurred vision, urinary hesitancy, and orthostatic dizziness. These agents are contraindicated in patients with a variety of heart diseases and must be used with great caution in patients with orthostatic hypotension or angle-closure glaucoma.
Arranged in order from most to least potent anticholinergic effects, the most commonly used agents are amitriptyline, imipramine, nortriptyline, and desipramine.7 Thus, for patients who do not tolerate amitriptyline, other tricyclic antidepressants, particularly despiramine, may represent useful alternatives. The usual dosage schedule is 1025 mg at bedtime initially, increasing as tolerated up to 100 or 150 mg as a single bedtime dose.
Serotonin reuptake inhibitors are another category of antidepressants that may have some efficacy, but the evidence for this is less convincing than that for tricyclic antidepressants. In a randomized, double-blind, crossover study, paroxetine, 40 mg per day, reduced symptoms significantly more than did placebo, although it was somewhat less effective than imipramine.8 Fluoxetine at a mean daily dose of 40 mg was shown to be no more effective than placebo except in patients who were depressed in a double-blind, placebo-controlled study.5 Open-label sertraline up to 150 mg/day was shown to lead to a reduction in pain from diabetic neuropathy in a small study of 8 patients, but a placebo-controlled study has not yet been carried out.9 Trazodone is often used empirically. Open-label use raises the possibility that it may have some efficacy in treating painful diabetic neuropathy, but there are no controlled studies.10
Another group of medications with utility in pain control is the anticonvulsants. Gabapentin has been shown to be more effective than placebo when used in doses ranging from 900 to 3,600 mg per day.11 The lower end of this dosage range may be relatively ineffective; another placebo-controlled study did not demonstrate efficacy at a dose of 900 mg per day.12 The main side effects of gabapentin are dizziness, somnolence, headache, diarrhea, confusion, and nausea. The dose is typically started at 300 mg per day or less, and increased very gradually, up to a maximum of 2,4003,600 mg per day if tolerated and as needed for control of pain.
Carbamazepine, 200 mg t.i.d., was more effective than placebo in a double-blind crossover trial.13 Side effects are somnolence, dizziness, unsteadiness, nausea, and vomiting. We suggest beginning at 100 mg b.i.d. or t.i.d., increasing gradually to 200 q.i.d. as tolerated and if needed for pain control. Because aplastic anemia and agranulocytosis may occur on rare occasions, patients should undergo hematologic monitoring at baseline and regularly while being treated.
Double-blind studies have not demonstrated efficacy of phenytoin in patients with diabetic neuropathy14,15
Several other oral agents have been used. Randomized, double-blind, placebo-controlled trials of the anti-arrythmic agent mexiletine have demonstrated efficacy in the treatment of painful diabetic neuropathy.16-18 Tramadol acts via low-affinity binding to micro-opioid receptors and weak inhibition of norepinephrine and serotonin reuptake.19 It was recently found to be effective in treatment of pain in diabetic neuropathy in a double-blind, placebo-controlled, randomized trial.20 It is often good treatment for breakthrough or refractory pain and can be given as 50100 mg every 46 h, up to 400 mg per day.
Narcotic analgesics are often used for severe, refractory pain but are controversial for treatment of this chronic condition, because of the habituation that typically occurs. Some experts use them at night for sleep, but patients must be cautioned not to escalate the dose.
Not all agents for pain control must be administered systemically. Topical capsaicin cream stimulates the release and subsequent depletion of substance P from sensory fibers. A placebo-controlled study21,22 demonstrated the superiority of capsaicin cream 0.075% to placebo in control of pain and improvement of daily activities, whereas another double-blind study found it to be overall as effective as amitriptyline.23 In contrast, a double-blind, placebo-controlled study of capsaicin cream in patients with chronic distal painful neuropathy of various causes demonstrated no benefit over placebo.24
Overall, capsaicin cream appears to be effective. A meta-analysis of four randomized, double-blind, placebo-controlled trials of capsaicin in diabetic neuropathy found capsaicin overall to be more effective than placebo.25 Poor compliance is common because of the need for frequent applications, an initial exacerbation of symptoms, and frequent burning and redness at application site.
Other nonsystemic treatments that have been studied include transcutaneous electrical nerve stimulation (TENS) units and acupuncture. In a controlled study, TENS was more effective than sham treatment in reducing pain in patients with diabetic neuropathy.26 Uncontrolled studies of TENS and of acupuncture have been reported to decrease pain in >75% of patients with diabetic neuropathy.27,28 However, the powerful effect of placebo treatment in diabetic neuropathy, documented in multiple studies, raises questions about the reliability of such uncontrolled trials.
In summary, nonsteroidal anti-inflammatory drugs can offer pain relief, especially in patients with musculoskeletal or joint abnormalities secondary to long-standing neuropathy. The tricyclic antidepressants remain the most commonly used drugs in the treatment of painful neuropathy. After 6 weeks of treatment, many patients report significant pain relief independent of mood but correlating with increasing drug dosage. The topical cream capsaicin may be added to the patient's therapeutic regimen if neuropathic pain persists in spite of treatment with maximally tolerated doses of antidepressant medication.
In an outpatient setting, approximately two-thirds of diabetic patients treated with a combination of antidepressant medication and capsaicin cream experience substantial relief of neuropathic pain. In patients who experience continued pain on combination therapy, an anticonvulsant can be added as a third drug. If neuropathic pain persists despite these treatments, referral to a specialist for consideration of the other treatments mentioned may be helpful, although the prognosis for pain relief in these patients is poor.
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This work was supported by National Institutes of Health grants NS36778 and NS38849 and grants from the Juvenile Diabetes Foundation and American Diabetes Association (E.L.F.).
Zachary Simmons, MD, is an associate professor of medicine (neurology) and of orthopedics and rehabilitation, at the Pennsylvania State University College of Medicine, in Hershey. Eva L. Feldman, MD, PhD, is an associate professor of neurology at the University of Michigan in Ann Arbor.
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