Most patients with diabetic peripheral neuropathic pain will experience significant relief and improved quality of life when treated with tricyclic antidepressants, duloxetine, controlled-release oxycodone, pregabalin, or a combination of these agents, according to new treatment guidelines issued by the American Society of Pain Educators.
Treatment strategies should begin with these drugs, which have already been proved effective in the disorder, and take into account physical and psychiatric comorbidities, adverse event profiles, and cost, according to the guidelines (Mayo Clin. Proc. 2006;81[4 Suppl]:S12–25).
Almost all patients with diabetic peripheral neuropathic pain (DPNP) will improve if they and their physicians are patient and persistent, said Dr. B. Eliot Cole, executive director of the American Society of Pain Educators and chairman of the panel that created the guidelines.
Problems arise when both parties become frustrated over nonresponsiveness to initial therapies, Dr. Cole said. Overcoming this attitude will go a long way toward improving treatment outcomes. Since the approval of several agents specifically for treatment of DPNP, and with the judicious use of older agents, DPNP is far from being the untreatable problem many believe it to be, he said in an interview.
If the first treatment doesn't work, another probably will. It is also important to instill realistic expectations, noted Dr. Cole. “Of course our goal is always 100% freedom from pain, but the reality is that most patients probably won't experience that. We can, however, put together plans that are easy to follow and have low side effects, which significantly increase compliance and the chances of pain control.”
Undertreatment is probably the biggest obstacle to success, he said. “The majority of diabetics with pain are taking over-the-counter nonsteroidal anti-inflammatories as their primary form of treatment. Many physicians might not know that those drugs are totally ineffective for DPNP.”
Even those who receive prescriptions appear to be undertreated, according to a 2004 study cited in the guidelines. Of 55,686 DPNP patients, 53% were getting only a short-acting opioid and 40% an NSAID. Other commonly prescribed drugs included benzodiazepines and SSRIs (J. Pain 2004;5:143–9), neither of which are effective for neuropathic pain, said Dr. Cole.
In constructing the guidelines, the committee reviewed 120 drug studies published in 1995–2005. The studies included those specific to DPNP as well as studies of other neuropathic pain conditions.
Duloxetine, controlled-release oxycodone, pregabalin, and tricyclic antidepressants, having the strongest evidence of efficacy, are the committee's first-tier drug treatment choices, each having more than two positive randomized, controlled trials specific for DPNP, according to the new guidelines.
Duloxetine and pregabalin are the only drugs approved for DPNP. With duloxetine, more than 50% of patients can expect at least a 50% decrease in pain. Its effects are rapid, usually occurring within 1 week. Advantages include once-daily dosing and antidepressant efficacy.
The guidelines go on to note that pregabalin, especially at its higher doses, can decrease pain by 70% or greater in at least 30% of patients, and by 50% in at least 50% of patients. Patients should notice its effects within 1 week. Side effects of somnolence and dizziness can be bothersome, however.
The tricyclics amitriptyline and desipramine are also effective, although they are not tolerated as well as duloxetine, according to the guidelines. In two DPNP trials, controlled-release oxycodone significantly reduced all measures of pain. However, it's important to evaluate each patient's potential for abuse before prescribing the drug.
Second-tier agents—with one randomized, controlled trial for DPNP and at least one trial in another painful neuropathy—include carbamazepine, gabapentin, lamotrigine, tramadol, and extended-release venlafaxine.
The guidelines committee also reviewed the evidence for topical treatments (capsaicin and lidocaine) and the evidence for bupropion, citalopram, methadone, paroxetine, phenytoin, and topiramate, none of which have been studied for treating DPNP. However, each has at least one randomized, controlled trial in other painful neuropathies.
To reap maximum benefit, first-tier agents should be aggressively dosed, but physicians shouldn't waste a lot of time waiting for results, according to the guidelines. “First-tier agents should be titrated to maximum tolerated dose. A reduction in pain of at least 50% from baseline should be expected if the agent is effective for that patient.” If there are no significant results by 3 weeks, a modification of therapy is warranted.
Once therapy is initiated, patients should undergo regular follow-up. “Patients must be asked at each visit whether their pain is improved and, if so, to what degree. … If they are not satisfied with the treatment effect, they should be offered the option to add therapy, along with an explanation that they may receive more relief at the expense of more potential adverse events,” according to the guidelines.