To Compare the Efficacy of Pregabalin and Amitriptyline for Pain Relief in Patients with Diabetic Peripheral Neuropathy

World Health Organization (WHO) ranks Pakistan 7th on diabetes mellitus prevalence list with an estimated overall prevalence of diabetes at 11.45%. Diabetic neuropathy affects more than 50% of patients with diabetes of more than 25 years’ duration [1]. Painful neuropathy is present in up to 16.2% of diabetic patients and can profoundly undermine their quality of life [2]. Symptoms include paresthesia in feet (and rarely in hands), pain in lower limbs (dull, aching and/or lancinating, worse at night, and mainly felt on the anterior aspect of legs), burning sensations in soles of feet, cutaneous hyperesthesia and an abnormal gait (commonly wide-based), often associated with a sense of numbness in feet [3].

More importantly, however, is the pathogenic mechanism behind painful neuropathy, which is multifactorial and includes metabolic disturbances such as hyperglycemia, impaired glucose tolerance, dyslipidemia, oxidative and nitrosative stress, growth factor deficiencies, micro-vascular insufficiency and autoimmune damage to nerve fibers [4]. Current first-line therapies for painful diabetic peripheral neuropathy (DPN) are tricyclic antidepressants (TCA) such as Amitriptyline, SNRI such as Duloxetine or anticonvulsants such as Pregabalin or Gabapentin [5].

One limitation of evidence in the treatment of DPN is relative lack of comparative studies. Often, the treatment of DPN is not entirely satisfactory and the aim is to achieve 50% reduction in pain intensity [6]. NICE Guidelines recommend Duloxetine as first-line treatment for painful DPN, with Amitriptyline as alternative and Pregabalin as second-line agent [7]; whereas the American Academy of Neurology (AAN) considers Pregabalin as the first line and all other treatment options as second line [8]. Amitriptyline (25-75 mg) is effective in painful DPN and the dramatic response is seen within 48-72 hours. Drowsiness is its major concern which usually improves with time [9]. There are limited head-to-head studies comparing Pregabalin with Amitriptyline. In one study, good pain relief was seen in 48% of patients in Pregabalin group as compared to 34% in Amitriptyline group [10].

Both American Diabetic Association (ADA) and AAN guidelines recommend that Pregabalin should be used as a first-line drug (Level A evidence) for DPN, however, they also agree on the role of Amitriptyline in reducing pain associated with DPN (Level B evidence). Because of major cost difference between the two drugs and lack of evidence from local studies, we conducted this trial to examine the difference in DPN pain control between the two drugs.

This randomized non-blinded controlled trial was conducted at the Diabetic Clinic of Department of Medicine at Benazir Bhutto Hospital, Rawalpindi, Pakistan between January and August 2015. We enrolled patients between the ages of 18 and 60 with at least 5 years history of diabetes and symptoms of pain, numbness, paresthesia, tingling sensation, burning or hyperesthesia, symptoms consistent with diabetic neuropathy for at least 6 months. Patients had an average pain score of at least 4 or higher during a 7-day pre-enrollment period on a 10-point Likert scale. We excluded patients with peripheral neuropathy due to other causes, patients who were pregnant or were lactating, critically ill patients or those who were taking Amitriptyline or Pregabalin during the 3 months prior to the screening for study enrollment.

Study Protocol: Patients were randomly assigned to Pregabalin or Amitriptyline groups using the RandList 1.2 software. The study duration was 6 weeks. The starting dose was 75 mg twice daily for Pregabalin and 10 mg at bedtime for Amitriptyline. Doses were titrated upwards if needed at week 1 and week 3 follow-up visit to a maximum dose of 300 mg twice daily for Pregabalin and 75 mg at bedtime for Amitriptyline. We used a Likert Numeric Rating Scale (NRS) to assess the severity of pain at the time of enrollment in the study and six weeks later. The primary outcome was good pain relief which was defined as a decrease in NRS pain score of more than 50% at 6 weeks from baseline. Patient-reported adverse outcomes were recorded. Chi-square test was applied to compare pain relief amongst the two groups. SPSS 19 was used for the statistical analysis.

Out of the 320 patients, 46.6% (149) were male with a mean of 45.2±9.7 years of age. As expected secondary to randomization, both study groups were homogenous based on demographic characteristics and mean duration of diabetes. Fifty percent or greater improvement in NRS scores from baseline was noted in 180 (56.3%). Significantly higher number of patients in the Pregabalin group had pain relief than patients in the Amitriptyline group (104 vs 76; p= 0.002). Amitriptyline was associated with dry mouth, daytime somnolence and postural hypotension, whereas, the main side effects seen with Pregabalin were confusion and headache. Overall more patients in the Amitriptyline group reported adverse events than the Pregabalin group (256 vs 128; p= <0.001; Table 1).

In this randomized controlled trial of patients with DPN, we found Pregabalin to be significantly more effective than Amitriptyline in pain relief during the 6-week study period. Furthermore, we found a significantly higher risk of adverse events with Amitriptyline. DPN is a common complication of long-standing, poorly controlled diabetes and is associated with significant morbidity. The prevalence of DPN is about 30% in hospitalized patients and 20% in the community-dwelling with an annual incidence rate of 2% [11]. Painful DPN is marked by pain, paresthesia and sensory loss. The pathology of DPN involves oxidative stress, advanced glycation end products, polyol pathway flux and protein kinase C activation, all contributing to micro-vascular disease and nerve dysfunction [12]. For symptom management, current evidence from clinical trials support the use of Desipramine, Amitriptyline, Capsaicin, Gabapentin, Pregabalin, Bupropion and Venlafaxine as the preferred medications. Escitalopram, Non-steroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics may be used as adjuvant agents. Glycemic control remains the foundation and the prerequisite of prevention and adequate control.

A recent trial [13] did not find a significant difference between Pregabalin and Amitriptyline in the main study outcome of pain relief. The overall response rates in this study were 77% for Pregabalin and 73% for Amitriptyline. The discrepancy between results of our study and this study may stem from the difference in definition of outcomes. While we defined a 50% or greater reduction in pain as pain relief, this study defined pain relief as any reduction in pain from baseline.

Another study from a population similar to ours by Shabbir et al [14] showed that only 12.8% of the patients demonstrated better response with Pregabalin compared to Amitriptyline. The discrepancy might stem from the fact that our trial was non-blinded and the patients knew which drug they were taking which could have affected compliance and hence the results of our trial.

Pregabalin is approved by the Food and Drug Administration in the United States for management of DPN. The drug acts peripherally at GABA receptors to block the perception of pain. Pregabalin is relatively well tolerated and causes less sedation than Gabapentin, another drug that acts on GABA receptors. However, Pregabalin is associated with other adverse events including rhabdomyolysis, acute renal failure, central nervous system dysfunction, hyperthermia and secondary acute glaucoma. Patients on Pregabalin therapy must be monitored closely for myopathy and ocular complaints. Pregabalin is also associated with peripheral edema and weight gain; this adverse event is intensified when given with thiazolidinediones. Pregabalin should be avoided in patients with hypertension and congestive heart failure.

Our study has some limitations. First, it was a non-blinded, non-placebo, active-control, randomized trial so the elements of bias due to non-blinding cannot be eliminated. An alternative could have been the use of a crossover study design with a placebo washout period. The outcome was measured using an NRS which is a crude assessment of pain.

In conclusion, we found that Pregabalin is a more effective drug than Amitriptyline for improving symptoms of painful DPN over a 6-week period. Longer duration studies are needed to examine if the difference between the two drugs is sustained after 6 weeks of therapy. Furthermore, cost-effectiveness studies are needed to examine the cost of additional benefit obtained from Pregabalin

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