Drug Treatment Options    
By Dr. Steven J. Dolgoff

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Pharmacological Treatment Options

The classes of drugs with the best proven efficacy are anti- depressants, anticonvulsants, and opioids.10Duloxetine, a serotonin noradrenaline reuptake inhibitor (SNRI), and pre-gabalin are specifically approved by the U.S. Food and Drug Administration (FDA) for the treatment of painful DPN.All other agents must be considered “off-label,” although other considerations, including cost, intolerance of approved agents, comorbidities, and efficacy, may dictate their use.


Duloxetine has been studied in 2 randomized, double- blind, placebo-controlled trials for relief of pain in patients with painful diabetic neuropathy, and is approved by the FDA at total dosages of 60 mg/day.

The first study, published in 2005, was a 12-week, multi- center, double-blind study in which 457 patients experienc- ing pain due to polyneuropathy caused by type 1 or type 2 diabetes mellitus were randomly assigned to treatment with duloxetine 20 mg/day, 60 mg/day, or 60 mg BID or placebo. Duloxetine 60 and 120 mg/day demonstrated statistically significant greater improvement on the 24-hour average pain score compared to placebo. Duloxetine also proved more efficacious than placebo on almost all second- ary measures (ie, worst pain severity and mood). Patients in the 120-mg/day treatment arm experienced a statistically significant improvement in Short Form-36 mental (P ? 0.01) and general health perception domains (P ? 0.001) as well.

All doses of duloxetine were well tolerated, with no sig- nificant changes in concentrations of A1C, LDL-C, HDL-C, or triglycerides.54 Adverse events included somnolence and constipation with the 60-mg/day dose, and nausea, somno- lence, dizziness, constipation, dry mouth, sweating, decreased appetite, anorexia, and weakness with the 120-mg/day dose.

In another trial, patients with diabetic neuropathy were randomly assigned to receive either placebo (n = 116), duloxetine 60 mg/day (n = 116), or duloxetine 60 mg BID (n = 116).55 The patients treated with duloxetine 60 mg daily had marked improvements in 24-hour average pain score, 24-hour worst pain severity score, and night pain score (P < 0.001). Patients treated with duloxetine 60 mg BID also had improvements in 24-hour average pain score (P < 0.001), 24-hour worst pain severity score (P < 0.01), and night pain score (P < 0.001)

Another antidepressant, venlafaxine, has yielded efficacy in alleviating pain in diabetic neuropathy when used in higher doses (150-225 mg/day).57 In a randomized, placebo controlled trial, venlafaxine extended-release (ER) at 2 doses (75 mg/day or 150-225 mg/day) was compared to placebo for the treatment of painful diabetic neuropathy. Rowbotham and colleagues concluded that the higher dose of venlafaxine ER significantly reduced pain intensity compared to placebo and venlafaxine ER 75 mg/day at week 6.The most common adverse events in the venlafaxine groups were nausea (> 10%) and somnolence (> 10%). Dyspepsia, insomnia, and sweating also occurred in 10% of the patients treated with venlafaxine ER 150-225 mg/day. Impotence was reported in 6% of the men receiving venlafaxine ER 75 mg/day and in 5% of the men receiving venlafaxine ER 150-225 mg/day.

Tricyclic Antidepressants

Tricyclic antidepressants (TCAs) are widely used to treat neuropathic pain but are not FDA-approved for this purpose and have a significant adverse-effect profile. TCAs include amitriptyline, desipramine, clomipramine, and nortriptyline. TCAs have yielded significant pain relief in patients with DPN, although clinical trials of these agents have typically included small patient populations. Randomized, double- blind, crossover, placebo-controlled studies of amitriptyline and desipramine demonstrated that 67% of the patients receiving amitriptyline (P ? 0.001) experienced good to excellent pain relief, while 63% (P < 0.05) of the patients receiving desipramine experienced moderate or greater pain relief.

The side-effect profile of TCAs includes anticholinergic and muscarinic side effects, contraindicating all (especially amitriptyline) in the elderly and those with cardiovascularpathology. There is little efficacy difference between amitriptyline and desipramine (which has the lowest sideeffect profile in this group), as Max and colleagues demon- strated in a small crossover study in 20 patients. The lower cost and demonstrated efficacy must be weighed against the significant side-effect profile including sudden cardiac death at higher doses.


Pregabalin is FDA-approved for painful diabetic neuropathy and postherpetic neuralgia. As an anticonvulsant, it is approved for the treatment of partial seizures. It is a Schedule V controlled substance with a mild potential for abuse.

Studied in doses of 75, 150, 300, and 600 mg daily, pregabalin has yielded efficacy at the higher 2 doses in 3 random- ized, double-blind, placebo controlled studies. There may be a tendency for weight gain, especially at higher doses. Furthermore, a study conducted by Lesser et al reported significant incidences of dizziness, somnolence, and peripheral edema in both the 300- and 600-mg groups.

The efficacy of gabapentin is comparable to amitriptyline at doses of 1565 mg/day compared to 59 mg/day.

Lidocaine Patches

Lidocaine patches may be useful if the pain of diabetic neuropathy is very focal. One to 3 patches can be applied to intact skin over the painful area, 12 hours on and 12 hours off.

Capsaicin Cream

Capsaicin cream depletes substance P, the major neurotransmitter used in conveying messages about pain into the central nervous system. This can be applied over the painful area 3-4 times daily. Gloves should be worn if this is used, and care taken to avoid contact with the eyes. Clinicians should note that many patients are unable to tolerate the intense increase in pain that occurs over the first few days that capsaicin cream is applied (until substance P is depleted).

Education and Effective Patient-Clinician Communication Is Critical for Treatment Success

Therapeutic patient education is a patient-centered approach directed toward patient needs, resources, and values. Education enables patients to improve their knowledge and skills with both their illness and treatment. It brings a better QOL, a greater therapeutic compliance, and a reduction in complications.