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Amitriptyline vs Pregabalin for Painful Diabetic Neuropathy

Several effective treatments are available for painful diabetic neuropathy. The current study provides important insight into treatment choice by comparing two effective medications in patients with painful diabetic neuropathy. The results of this trial should help physicians tailor the best therapy for individual patients.

Neuropathy is one of the most common complications of diabetes mellitus, and its impact on patients can be severe. An analysis of a large managed care database in the United States yielded an estimated prevalence of painful neuropathy of 11% to 21% among patients with diabetes. This estimate is in line with an estimated prevalence of painful diabetic neuropathy of 16.2% in a community-based sample in the United Kingdom. The rate of painful diabetic neuropathy in the control group of people who had not been diagnosed with diabetes was 4.9%, meaning that a diagnosis of diabetes increased the risk for painful peripheral neuropathy more than threefold in this study.

The pain and comorbidity associated with diabetic neuropathy are significant. In an observational study of 140 patients with painful diabetic neuropathy, 57% reported moderate levels of pain, and one quarter of subjects had severe pain. Neuropathy was linked to worse functional status, and 35% of respondents described work disruption resulting from neuropathy symptoms. In addition, 43% of the cohort reported the use of prescription medication to treat concomitant anxiety, depression, or sleep disturbance.

Despite the significant morbidity associated with diabetic neuropathy, there is evidence that this condition remains undertreated This is all the more frustrating given the fairly wide range of available therapeutic options. Follow-up of the cohort from the United Kingdom found that only 65% of patients with painful diabetic neuropathy had received treatment for their symptoms, even though 96% of patients had reported symptoms to their physician. Among those who received treatment, antidepressants were the most common drug class used, followed by opiates, complementary therapies, and anticonvulsant drugs.

Clinical trials confirm the efficacy of both antidepressants and anticonvulsants for the treatment of painful diabetic neuropathy. In a randomized study comparing amitriptyline, desipramine, and fluoxetine among patients with painful diabetic neuropathy, amitriptyline improved pain in 74% of study participants, which was significantly more than the 48% of participants who improved with fluoxetine. In a randomized trial comparing gabapentin with placebo for painful diabetic neuropathy, the rates of at least moderate improvement in pain were 60% with gabapentin and 33% with placebo, a significant difference. Gabapentin was also significantly more effective than placebo in improving quality of life in this study cohort.

Moreover, a recent trial demonstrated that the combination of 2 established medications for painful neuropathy, gabapentin and nortriptyline, could be more effective in reducing pain compared with either treatment alone. Combination therapy was not associated with a higher rate of adverse events compared with treatment with either drug alone, and the anticholinergic effects of nortriptyline accounted for the majority of adverse events reported.

Comparative trials of medications proven to be effective for chronic conditions are rare and merit the attention of clinicians. The current study comparing amitriptyline and pregabalin is such a trial. Researchers recruited people between the ages of 18 and 75 years from one tertiary center to participate in the study. All participants had Type 2 diabetes and painful diabetic neuropathy for at least 1 month. Patients had to report neuropathy pain above 50% on a visual analog scale to be included in the research protocol.

All participants underwent a 1-week washout period without study medications. They then completed 2 randomized 5-week treatment periods with either amitriptyline or pregabalin in a crossover design. A 3-week washout period occurred between these active treatment periods.

Active treatments were titrated upward as necessary during weeks 1 and 3 of therapy. The initial doses of pregabalin and amitriptyline were 75 mg twice daily and 10 mg at bedtime, respectively. The maximum doses of pregabalin and amitriptyline were 300 mg twice daily and 50 mg at bedtime, respectively. There was no placebo treatment arm in the study, which lessens the impact of the findings.

The primary study outcome was participant pain, which was measured in several ways. Researchers also followed the subjects’ evaluations of depressive symptoms, sleep quality, and overall impressions of the study treatment. This was a double-blind study.

A total of 51 patients underwent randomization, and 44 of these individuals completed the study assessments. The researchers did not include the 7 study dropouts in intention-to-treat analysis because none of them received study treatment. This was another minor methodologic flaw in the study protocol.

The average age of participants was 54.5 years, and 57% of subjects were women. The average duration of diabetes was 5 years, and approximately half of participants had previously received treatment for painful neuropathy. The median pain intensity at baseline was rated as 70 out of a possible 100 points on a visual analog scale.

The average dose of pregabalin was 218 mg/day, and the average dose of amitriptyline was 16 mg/day. Only 5% of participants in each treatment group received the maximum dose of either pregabalin or amitriptyline.

There was no significant difference between pregabalin and amitriptyline in the main study outcome of pain relief. Overall response rates were 77% for pregabalin and 73% for amitriptyline. Good pain relief was reported among 48% and 34% of users of pregabalin and amitriptyline, respectively, and there was evidence that both study treatments reduced pain within 1 week of the initiation of therapy. Of note, nearly half of participants who had previously received amitriptyline or pregabalin for painful diabetic neuropathy responded to study treatment.

There was also no difference between study treatments in depression or sleep scores. Participants’ global assessments of efficacy were similar for pregabalin and amitriptyline, and there was no distinct patient preference for one medication over the other.

Of the 52 adverse events reported, 65.4% occurred with amitriptyline. The rates of treatment discontinuation because of adverse events were 38.6% and 13.6% in the amitriptyline and pregabalin groups, respectively. Drowsiness was the most common adverse event associated with both study treatments and was more common with amitriptyline vs pregabalin (43% vs 20% of subjects, respectively). No serious adverse events were associated with study therapies.

The results of the current trial echo those of a previous randomized study comparing amitriptyline with gabapentin in the treatment of painful diabetic neuropathy. This small trial compared 6 weeks of treatment with gabapentin at a mean dose of 1565 mg/day or amitriptyline at a mean dose of 59 mg/day. Moderate or greater pain relief was reported in 52% of participants receiving gabapentin and 67% of subjects receiving amitriptyline, with no significant difference in pain outcomes between randomized groups. Moreover, the overall rate of adverse events was similar in the amitriptyline and gabapentin groups.

The results of these studies can leave the clinician in a conundrum: what exactly is the best treatment for painful diabetic neuropathy? A systematic review and meta-analysis, sponsored by the manufacturers of duloxetine, attempted to answer this question, and the researchers found that the body of comparative research on treatment for painful diabetic neuropathy is sorely lacking. In indirect comparisons of 11 studies (none of which tested amitriptyline), the authors found that pregabalin, duloxetine, and gabapentin were all effective in improving pain. Duloxetine was associated with less dizziness compared with pregabalin, but not compared with gabapentin.

The clinician can thus conclude that multiple treatments are effective for the management of diabetic peripheral neuropathy, and therefore individual patient factors and preferences are critical in the decision of which treatment to choose. A major factor in this decision for many patients and insurance companies is the profound difference in price between medications such as pregabalin and amitriptyline. Given the average dosages used in the current study, treatment with pregabalin could cost greater than 20 times more than treatment with amitriptyline For example, the cost of generic amitriptyline can be as low as .09 per 10-mg pill compared to $2.41 for 75 mg of pregabalin at the same discount pharmacy.

However, the lower cost of amitriptyline must be weighed against its more significant profile of adverse events. Many younger patients could tolerate these bothersome symptoms, particularly when the dosage of amitriptyline is kept low. However, tricyclic antidepressants are associated with potentially disastrous adverse events, particularly among older adults. Such events include a higher risk of falling as well as life-threatening arrhythmias. These risks must be balanced against the potential benefits of tricyclic antidepressant therapy as well as the known side effect profiles of other medications used to treat painful diabetic neuropathy.

The current study is a good reminder that newer therapeutics are not necessarily more effective than established treatments. Because all medications used to treat painful diabetic neuropathy have their limitations, it is better to have a variety of medications from which to choose.

Clinical Pearls:

  • Painful neuropathy is a common condition in the population, and much of this neuropathy is secondary to diabetes.
  • Painful neuropathy is associated with significant levels of disability.
  • Multiple medications have proven effective in the management of painful diabetic neuropathy, but research comparing these treatments is lacking.
  • The current study finds that amitriptyline is as effective as pregabalin for the treatment of painful diabetic neuropathy, although amitriptyline was associated with a higher rate of adverse events.

Physicians can choose from a variety of medications to treat painful diabetic neuropathy. Patient preference, side effects, and cost of treatment will influence treatment choice.

Diabet Med. 2009;26:1019-1026.