Imipramine and pregabalin combination for painful polyneuropathy

Abstract

Monotherapy with first-line drugs for neuropathic pain often fails to provide sufficient pain relief or has unacceptable side effects because of the need for high doses. The aim of this trial was to test whether the combination of imipramine and pregabalin in moderate doses would relieve pain more effectively than monotherapy with either of the drugs. This was a randomized, double-blind, placebo-controlled, crossover, multicenter trial consisting of four 5-week treatment periods in patients with painful polyneuropathy. Treatment arms were imipramine 75 mg/d vs pregabalin 300 mg/d vs combination therapy vs placebo. Patients with polyneuropathy and symptoms for more than 6 months, age 20 to 85 years, pain intensity ≥4 on a 0- to 10-point numeric rating scale (NRS) and pain at least 4 days a week were included in the trial. A total of 262 patients were screened for participation, 73 patients were randomized, and 69 patients were included in the data analysis. The effect on average pain in comparison with placebo was: combination (-1.67 NRS points, P < 0.001), imipramine (-1.08 NRS points, P < 0.001), and pregabalin (-0.48 NRS points, P = 0.03). The combination therapy had significantly lower pain scores than both monotherapies: combination vs imipramine (P = 0.009), combination vs pregabalin (P < 0.001). During combination therapy, the dropout rate was higher and the patients reported a higher rate and severity of side effects. Combination of moderate doses of the tricyclic antidepressant imipramine and pregabalin could be considered as an alternative to high-dosage monotherapy. However, the trial also emphasized that balance between efficacy and safety is an issue.

Combination treatment of neuropathic pain: Danish expert recommendations based on a Delphi process

“…Gilron et al10 (2400 mg gabapentin plus 50 mg TCA) and Holbech et al11 (300 mg pregabalin plus 75 mg TCA) studied this combination in RCTs in patients with peripheral NeP. Both studies showed a significant effect of the combination therapy over monotherapy.…”

A Systematic Review of Treatment of Painful Diabetic Neuropathy by Pain Phenotype versus Treatment Based on Medical Comorbidities

“…In the most recent randomized controlled trial (15), the authors found that the combination of moderate doses of imipramine (75 mg/daily) and pregabalin (300 mg/daily) was more effective in the symptomatic treatment of PDN than the monotherapy of one of these drugs, but at the expense of an increased dropout rate, associated with an increased severity and frequency of adverse events (AEs). In this trial, no impact of pain phenotype was registered in the response rates for any of the four groups (imipramine, pregabalin, the combination of both drugs, and the placebo).…”

Impact of etiology and duration of pain on pharmacological treatment effects in painful polyneuropathy

“…This was a retrospective analysis of data from four randomized, double-blind, placebo-controlled, crossover trials (Sindrup et al, 2003;Otto et al, 2008;Demant et al, 2014;Holbech et al, 2015) of almost similar design and in which there was a significant effect of the study drug. The trials were performed at Odense University Hospital, Aarhus University Hospital and Aalborg University Hospital from 1999 to 2014.…”

“…In three of the trials (Otto et al, 2008;Demant et al, 2014;Holbech et al, 2015), the patients had to have a median total pain rating of at least 4 on an 0-10-point numeric rating scale (0 = no pain, 10 = worst possible pain) (NRS) during 1 week without pain medication. Patients were male and female, aged > 18 years and had symptoms compatible with polyneuropathy for more than 6 months with distal symmetric pain localisation and sensory disturbance in the area of pain.…”

“…In painful polyneuropathy, the etiology could be a factor with for example pain in diabetic polyneuropathy being more responsive to treatment than neuropathies of other etiologies, as has been indicated in one of our previous trials (Sindrup et al, 2003). Based on these observations, we retrospectively searched for a possible influence of duration of pain and diabetes as the etiology for polyneuropathy on the treatment response to the major drug classes in peripheral neuropathic pain as determined in a series of previously conducted controlled clinical trials in painful polyneuropathy (Sindrup et al, 2003;Otto et al, 2008;Demant et al, 2014;Holbech et al, 2015). within a few weeks of pain (Moore et al, 2002).…”