Diabetic Peripheral Neuropathic Pain

Diabetes mellitus (DM) has been a significant public health problem for many years. However, the number of cases is continuing to grow at such an alarming rate that some have suggested we are facing or are already experiencing a "diabetes epidemic." Since peripheral neuropathy is commonly associated with DM, occurring in at least 50% of patients,¹ there will no doubt be a rise in this problem as well. Although diabetic neuropathies can present in a variety of forms, including the loss of sensory and motor functions, pain is one of the more common symptoms. A recent study reported that neuropathy is a problem so commonly associated with DM that all patients with symptoms of peripheral neuropathies, including pain, should receive a 2-hour oral glucose tolerance test to rule out undetected DM.²

Diabetic peripheral neuropathic pain (DPNP) is most commonly described as a burning or electric shock-like sensation in the feet and lower extremities, although the hands can also be affected. Patients may also experience allodynia, in which normally nonpainful stimuli induce pain, or hyperalgesia (in which there is an increase in response to a painful stimuli). Curiously, even when patients are experiencing pain, they may complain of numbness over the affected area. Patients usually report that placing weight on their feet exacerbates the pain. DPNP frequently worsens at night, which can cause or increase sleep problems. Interestingly, insomnia has been reported to be associated with abnormal glucose tolerance test results and may precipitate DM.³

Although DPNP appears to be related to pathologic changes in the peripheral nerves, why some patients with peripheral neuropathy develop pain while others do not remains uncertain. Better glucose control appears to reduce the overall risk of developing diabetic peripheral neuropathy, but it is still unclear whether it specifically decreases the incidence of DPNP.

Neuropathic pain, including DPNP, is among the most difficult forms of pain to treat. Many medications have been tried and most have either been found to be ineffective or to have side effects that drastically limit their use. However, a number of medications have been consistently found to provide relief for DPNP. Two recent papers that examined the literature on neuropathic pain⁴ and, in DPNP specifically,⁵ provided guidance in choosing the most effective pharmacologic options.

Finnerup and colleagues⁴ recommended beginning treatment with a lidocaine patch (Lidoderm) with 5% lidocaine if the pain is localized. Although this medication is FDA-approved only for the treatment of postherpetic neuralgia (PHN) pain, there is research indicating that it is effective for DPNP also.⁶ A significant advantage of this medication is the limited potential for side effects because it is a topical medication.

The 2 review papers were essentially in agreement with regard to choosing oral medications for pain. Both found that the literature most strongly supported the use of the tricyclic antidepressants (TCAs), pregabalin (Lyrica) and duloxetine (Cymbalta) (the only 2 medications that are FDA-approved for the management of DPNP), and controlled-release oxycodone (OxyContin, others). The major factors to consider when choosing which medication to try first are the associated side effects and the presence of comorbid medical and psychiatric conditions.

Of all of the medications, the TCAs probably have been studied the most and have consistently demonstrated marked analgesia for neuropathic pain. They have the additional benefits of offering relief for depression, which is experienced by many patients with DPNP,⁷ and ameliorating insomnia through their sedative effects. Obviously, the drawback to their use is the side-effect profile, which includes anticholinergic and cardiotoxic effects.

Duloxetine is FDA-approved for the treatment of depression as well as for treatment of DPNP. Thus, it can provide the antidepressant benefits of the TCAs but with a much more benign side-effect profile. Unlike the TCAs, it is not a very sedating drug; therefore, if insomnia is a problem, an additional sleep medication may be required. It should be noted that the reviews indicated that venlafaxine (Effexor), a second-line drug for DPNP, should be considered if there is limited response to the first-line agents; venlafaxine shares the same advantages as duloxetine. TCAs, duloxetine, and venlafaxine are all primarily serotonin-norepinephrine reuptake inhibitors (SNRIs). Tramadol (Ultram)--which the reviews also considered a second-line medication for DPNP--shares the benefits of these drugs, and although it also contains an opioid, its analgesic effect appears to be predominantly associated with its actions as an SNRI.

Pregabalin is approved as an analgesic for both DPNP and PHN and as an anticonvulsant for seizures related to epilepsy. Many anticonvulsants have been found to be effective analgesics for neuropathic pain, but side effects have often limited their use. Pregabalin appears to be better tolerated than its predecessors. Its major side effects are dizziness and sedation in patients prone to falls or who have problems with balance, so this treatment should be prescribed with caution. Pregabalin does appear to be a less sedating medication than gabapentin (Gabarone), another anticonvulsant that is approved for use in PHN and is considered by the reviews to be a second-tier drug for treating DPNP.

Whether controlled-release oxycodone actually provides more analgesia for DPNP than the other long-acting opioids is open to question. There are many studies supporting its use in DPNP, which may be because of the fact that it is one of the newer opioid preparations. Certainly if the antidepressants and anticonvulsants described do not provide relief, its use should be considered. The use of any opioid is associated with certain risks--most notably abuse, physical and psychological dependence on the drug, and the potential for exacerbating depression.

Although combinations of medications are often used in clinical practice, there are few formal studies of them. If a combination is considered, medications with different mechanisms of action should be tried.

With regard to nonpharmacologic treatments, Argoff and coworkers⁵ noted that although there are limited studies on acupuncture, there is evidence to support its use, especially in light of the limited risk of side effects associated with it.

Dr King is clinical professor of psychiatry at the New York University School of Medicine, New York.

References:

References:

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