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Treatment Options for Diabetic Peripheral Neuropathy

Neuropathy is a common complication of long standing diabetes that can affect many organ systems. Autonomic dysfunction may present as gastro-esophageal reflux, gastroparesis, erectile dysfunction, urinary retention, or postural hypo-tension. Paresthesia, allydonia and chronic pain are common and can be debilitating. Many drugs have been used to treat this pain, and two have gained FDA approval.

Duloxetine (Cymbalta) has been shown to treat diabetic neuropathic pain (DNP) at a recommended dose of 60 mg/day. In one trial, 457 patients with diabetes (types I and II) and neuropathic pain were randomly assigned to receive either placebo or treatment with 20, 60, or 120 mg of duloxetine once daily for twelve weeks. Beginning at week one and continuing throughout the study, patients receiving 60 or 120 mg of duloxetine showed significantly greater reductions in weekly mean pain scores. Duloxetine, 60 and 120 mg, also significantly improved night pain scores, brief pain inventory severity and interference scores. All doses of duloxetine were well tolerated. Common adverse events were somnolence and constipation with 60 mg daily, and nausea, somnolence, dizziness, constipation, dry mouth, sweating, increased appetite, anorexia, and weakness with 120 mg daily.

Pregabalin (Lyrica) is FDA approved for treatment of DNP and has been studied at dosages of 75, 150, 300, and 600 mg/day. Only the higher doses of 300 and 600 mg/day dosages showed good efficacy on pain and function measures.. Pregabalin 600 mg/day significantly decreased the mean pain score to 4.3 compared with 5.6 for placebo, and increased the proportion of patients who had a 50% or greater decrease from baseline pain. Pregabalin also reduced sleep interference, pain intensity, sensory and affective pain scores, and bodily pain. The most common adverse effect was dizziness.

Gabapentin (Neurontin) has been used effectively to treat several kinds of neuropathy. Two clinical trials demonstrated pain relief in patients with diabetic neuropathy, whereas a third trial did not. When compared head-to-head with amitriptyline, gabapentin had equal efficacy. Reduction in neuropathic pain required doses higher than 1600 mg/day; this is an important consideration, since many patients are under-dosed. The side-effect profile of gabapentin is more favorable than those of many other agents, but nearly twenty-five percent of patients report dizziness, and thirty percent report sedation.

Tricyclic antidepressants (TCAs) are commonly prescribed and are one of the most investigated classes of medications for the treatment of diabetic neuropathy. The analgesic effect of TCAs appears dependent on inhibition of the reuptake of norepinephrine and serotonin, which each agent does to various degrees. Desipramine (Norpramin), amitriptyline (Elavil), imipramine (Tofranil), and clomipramine (Anafranil) have demonstrated the best efficacy. One head-to-head comparison of desipramine with amitriptyline showed no difference in efficacy but suggested that desipramine was better tolerated. A second study comparing des-ipramine with placebo demonstrated improvement in a majority of patients who had previously failed to receive pain relief from amitriptyline or had dis-continued taking it due to bothersome adverse effects. Clomipramine exhibited efficacy com-parable to that of desipramine in a small crossover study.

The severity of adverse effects associated with TCAs is attributed to their relative affinities for muscarinic, histamine-1, and alpha-1 receptors. The anticholinergic adverse effects commonly associated with TCAs are xerostomia, constipation, dizziness, blurred vision, and urinary retention. Sedation and orthostatic hypotension are also common. TCAs should be used with extreme caution in the geriatric population.

Oxycodone CR (OxyContin) has shown efficacy in two randomized controlled trials for DNP. One trial randomly assigned patients to treatment with oxycodone CR (beginning at 10 mg every twelve hours to a maximum dose of 60 mg every twelve hours) or placebo for six weeks. The primary efficacy endpoint was reduction in average pain intensity, as recorded in a daily diary from days 28 to 42. At an average dosage of 37 mg/day, treatment with oxycodone CR significantly reduced average pain intensity, worst pain, and present pain compared with placebo. Adverse reactions seen with oxycodone were constipation, somnolence, nausea/vomiting, dizziness, pruritus, and dry mouth.

Venlafaxine ER (Effexor XR) at 75 mg/day or 150-225 mg/day has been compared with placebo for treatment of DNP. Patients with a three-month or longer history of painful DNP and without comorbid depression were randomly assigned to treatment with 75 mg/day or 150 to 225 mg/day of venlafaxine ER or placebo. Results for the primary end point of pain intensity on the 100-mm visual analog scale showed that at week six, the higher dose of venlafaxine ER significantly reduced pain intensity compared with placebo, and when compared with venlafaxine ER 75 mg/day. The most common adverse events in the venlafaxine groups were nausea and somnolence.

Data regarding the selective serotonin reuptake inhibitors (SSRIs) for the treatment of diabetic neuropathy are limited to studies of paroxetine (Paxil), fluoxetine (Prozac), and citalopram (Ce-lexa). Clinical trials of these agents suggest that their efficacy is lower than that of TCAs. Paroxetine reduces the pain of diabetic neuropathy better than placebo but was not as effective as imipramine in a head-to-head comparison. Citalopram diminishes neuropathic pain with an efficacy equal to that of paroxetine, whereas fluoxetine showed no benefit in diabetic neuropathy.

Carbamazepine (Tegretol) was one of the first anticonvulsants studied for treatment of DNP. It has been examined in several small clinical trials. Two small placebo-controlled studies found that carbam-azepine effectively reduced pain.

Several other agents have been evaluated for the treatment of DNP. A six-week trial compared tramado (Ultram) to placebo. At interim visits, patients reported less pain with tramadol, and the difference was significant by the final visit. Common adverse effects were nausea, constipation, headache, and somnolence.

Lamotrigine (Lamictal) was also studied versus placebo in a small controlled trial. A significant difference was seen in the numerical pain scale, but no difference was found on secondary measures. It appears to be effective at 200 to 400 mg/day. The most common adverse effects were nausea, epigastric pain, headache, drowsiness, and dizziness.

The lidocaine patche 5%, (Lidoderm) has been evaluated in an open label study. As measured by patient pain diaries, use of the lidocaine patch improved pain during the three-week study. Significant improvements in quality-of-life measures also were seen. Among patients who continued the therapy for five more weeks, some tapering of other analgesics was possible.

Topical capsaicin was effective when compared to placebo cream. Final analysis showed a significant difference in Physician's Global Evaluation and visual analogue scale. The burning sensation and frequent dosing make this agent problematic.

Phenytoin, intravenous lidocaine, mexiletine, acupuncture, and even dextromethorphan have all been investigated for DNP with varying degrees of success.

This is a brief review of the many agents available to treat diabetic neuropathic pain. DNP causes great morbidity in patients. Therapy should begin with proven agents, and adjunctive therapy can be added if needed. Duloxetine and pregabalin are great options, but cost may be an issue for some patients. Gabapentin is always an old favorite, but high doses are often needed to achieve success. Oxycodone CR is also a reasonable option, but must be weighed against the risks of opioid therapy. Low cost and reasonable efficacy have made TCA?s the "old school" drug of choice, but those pesky anticholinergic side effects can be detrimental to an elderly patient. Venlafaxine, tramadol, lamotrigine, or a lidocaine 5% patch can all be considered for adjuvant therapy.