The Diabetic Neuropathies

Practical and Rational Therapy

J. Robinson Singleton, M.D.; A. Gordon Smith, M.D.


Semin Neurol. 2012;32(3):196-203. 

In This Article

Treatment of Neuropathic Pain

A majority of DSP patients complain of neuropathic pain, making diabetes the single most common cause of neuropathy and neuropathic pain in industrialized countries. A cross-sectional study comparing 350 people with diabetes to 344 age- and sex-matched controls in Liverpool found chronic painful neuropathy in 16% of diabetic patients, but only 4% of controls. Evaluation of the same cohorts 5 years later found neuropathic pain continued for 77% of diabetic subjects, without significant improvement as measured by the Visual Analog Pain Scale despite multimodal pain treatment.[51] One-third had not received specific treatment despite requesting pain medication from their physician. This result mirrors the frustrating experience of many patients and physicians in treating established neuropathic pain in DSP.[52] A wide variety of antidepressants, antiepileptic drugs, opiates, and mixed serotonin/norepinephrine reuptake inhibitors have been shown to significantly reduce neuropathic pain compared with placebo in randomized controlled trials,[52] but pain relief is incomplete for most patients.

Tricyclic antidepressants (amitriptyline, nortriptyline, desipramine) have been mainstays of neuropathic pain treatment, with efficacy proven in several well-designed studies.[53] Tricyclic antidepressants are inexpensive, and because of their long half-life, dosing is simple. When administered 2 hours before bedtime, amitriptyline often aids in sleep initiation, even at low dose. This sedative effect is durable, and is of significant benefit for patients who report that neuropathic pain increases with rest, and makes it hard to fall asleep at night. A typical dose of amitriptyline is 50–200 mg, 2 hours before bedtime. To minimize side effects, patients should gradually increase their dose, beginning at 10 mg, and increasing by 10 mg increments every 5 days to an initial plateau dose of 50 mg nightly. Dosing increases can then proceed in 25 mg increments. Because of the risk for partial or complete heart block, older patients should have an electrocardiogram in evaluation of conduction defects. Orthostatic hypotension, urinary hesitancy, fatigue, somnolence, and confusion are also common dose-related side effects. Patients taking monoamine oxidase inhibitors should not take tricyclics.

Gabapentin is structurally related to the pain-modulating neurotransmitter, g-aminobutyric acid (GABA), although it acts neither as a GABA agonist or antagonist. Its mechanism is thought to be related to binding to the α 2 delta subunit of voltage gated Ca2+ channels. In several placebo controlled, randomized trials examining patients with painful neuropathies, gabapentin has been shown to significantly reduce neuropathic pain and improve sleep.[54] In the largest clinical trials, doses in excess of 1800 mg divided three times daily were often necessary for optimal pain relief. Dose escalation of gabapentin should begin at 300 mg taken 2 hours before bedtime, increasing in 300 mg increments every 3 to 7 days to 600 mg three times daily. This conservative escalation schedule minimizes side effects. A therapeutic trial should involve at least 4 weeks at a therapeutic dose, with some patients requiring 4800 mg daily in divided doses. Gabapentin is generally well tolerated, and renal excretion means there is no interaction with medications that undergo hepatic cytochrome p450 metabolism. Dizziness and somnolence are the only side effects reported to occur more frequently in patients taking gabapentin than in those receiving placebo.

Pregabalin (Lyrica®, Pfizer Pharmaceuticals, New York, NY) is structurally similar to gabapentin and offers a very similar pharmacokinetic, metabolic, and side-effect profile, with a somewhat faster onset of pain reduction. Pregabalin has been approved by the Food and Drug Administration (FDA) for treatment of neuropathic pain in diabetes, and for treatment of fibromyalgia.[55] Dose escalation of pregabalin can begin at 75 mg twice daily, and increase by 75 mg increments to 150 mg twice daily.

Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor FDA-indicated for neuropathic pain associated with diabetic DSP, as well as for depression, anxiety, pain associated with fibromyalgia, and chronic musculoskeletal pain. In two randomized controlled trials, diabetic subjects with painful DSP of less than 6 months duration showed statistically better cumulative pain relief over the 12-week trial period when administered duloxetine 60 mg daily compared with placebo.[56] This is the recommended dose. Common side effects include nausea, somnolence, dry mouth, and constipation. Appetite suppression is common, but is often regarded as a benefit of the drug.

Gabapentin, pregabalin, and duloxetine are frequently offered in sequence to neuropathic pain patients, but have not been compared head-to-head in blinded or crossover trials. An open label trial in DSP patients who did not improve with gabapentin found no significant difference in efficacy between pregabalin and duloxetine.[57] Retrospective review suggested a statistical advantage for pain relief to pregabalin (33% responders) compared with duloxetine (21%).[58] Overall, none of these medications provides effective neuropathic pain control for the majority of DSP patients, and combination therapy has not been well evaluated.

Opiates have a defined role as adjunct treatment in poorly controlled neuropathic pain, but are often overlooked because of concerns for tolerance and addiction.[59] The oral opiate oxycodone improved pain and quality of life in a small diabetic neuropathy cohort,[60] and a larger study (338 subjects) found significantly enhanced pain relief when added in a randomized and double-blinded fashion to optimized gabapentin dosing.[61] However, in a recent study of 62 diabetic neuropathy subjects, randomized addition of low-dose oxycodone did not significantly improve the neuropathic pain effects of pregabalin.[62] The novel mu-opioid receptor binding agent tapentadol has recently been shown superior to placebo in reducing neuropathic pain in a randomized trial cohort of 395 subjects with diabetic neuropathy.[63]

In practice, a short-acting agent, such as hydrocodone or oxycodone, can be used to slowly titrate the dose to efficacy. Once an effective dose has been found, conversion to a long-acting ("time contingent") opiate such as extended release morphine (MS Contin) or oxycodone helps provide sustained pain relief with fewer side effects. A short-acting agent may be used for breakthrough pain or exacerbations. Ethanol and benzodiazepines synergize with opiates to cause respiratory depression and sedation. Patients should be counseled to avoid alcohol consumption. Constipation is the most common side effect of low-dose oral opiate use. Prophylactic institution of a bowel control regimen helps prevent constipation. Sedation and central respiratory depression are of concern at higher doses, and may be more dangerous in obese patients with obstructive sleep apnea.

Treating physicians are often reluctant to prescribe opiates due to concern for risk of addiction. Although physical dependence occurs in many patients, it is rarely a problem. A prospective study in patients with diabetes suggests that psychological dependence and addiction are rare when these agents are used for pain, even for long periods.[64] Patients should taper off of opiates rather than stopping them suddenly. Patients at higher risk of addiction, such as those with a history of drug or alcohol abuse, may require referral to a pain specialist.

Tramadol, an agent that binds to opiate receptors and blocks reuptake of serotonin and norepinephrine, was significantly more effective than placebo in treating neuropathic pain in a 42-day double-blind placebo controlled study of 131 diabetic subjects,[65] and in combination with acetaminophen was shown to be significantly more effective than placebo alone in a cohort of 160 subjects.[66] Long-term use of Tramadol in patients with diabetic neuropathy did not result in significant tolerance or dose escalation.[64]

Mexiletine is an orally active local anesthetic agent that showed statistically significant reduction in Visual Analog Pain Scale pain ratings for diabetic neuropathy patients in two small trials at doses of 225–675 mg day. Nausea and other gastrointestinal complaints were the most common side effects.[67]

Capsaicin cream is applied topically, and acts to reduce pain sensation by depleting substance P from proximal terminals of cutaneous nociceptive c-fibers. Its use is well validated in patients with herpes zoster. In a study of 13 patients with painful diabetic neuropathy, capsaicin reduced Visual Analog Pain Scale ratings while improving heat pain perception threshold.[68] Capsaicin is practical only for patients with small areas of neuropathic pain. Pragmatically, few patients tolerate capsaicin therapy: the cream must be applied three to four times daily using rubber gloves to avoid affecting nonpainful skin or mucosa. Failure to maintain treatment for even one dose allows substance-P regeneration and recrudescence of pain.

Several other anticonvulsants and antidepressants have been studied with mixed results. There are also several innovative and promising pain therapies in development (including the gene therapy approaches described above). The interested reader is referred to the review of neuropathic pain in this issue of Seminars in Neurology.