Effect of single-dose imipramine on chronic low-back and experimental pain. A randomized controlled trial

Abstract

Antidepressants are frequently prescribed as co-analgesics in chronic pain. While their efficacy is well documented for neuropathic pain, the evidence is less clear in musculoskeletal pain conditions. The present study therefore evaluated the effect of the tricyclic antidepressant imipramine on chronic low-back pain in a randomized, double-blinded placebo-controlled design. To explore the mechanisms of action and the influence of drug metabolism, multimodal quantitative sensory tests (QST) and genotyping for cytochrome P450 2D6 (CYP2D6) were additionally performed. A single oral dose of imipramine 75 mg was compared to active placebo (tolterodine 1 mg) in 50 patients (32 females) with chronic non-specific low-back pain. Intensity of low-back pain was assessed on a 0-10 numeric rating scale at baseline and every 30 minutes after drug intake. Multimodal QST were performed at baseline and in hourly intervals for 2 hours. Pharmacogenetic influences of cytochrome P450 were addressed by CYP2D6 genotyping. No significant analgesic effect was detected neither on low-back pain nor on any of the sensory tests in the overall analyses. However, evidence for an interaction of the imipramine effect and CYP2D6 genotype was found for electrical and for pressure pain detection thresholds. Intermediate but not extensive metabolizers had a 1.20 times greater electrical pain threshold (95%-CI 1.10 to 1.31) and a 1.10 times greater pressure pain threshold (95%-CI 1.01 to 1.21) 60 minutes after imipramine than after placebo (p<0.001 and p = 0.034, respectively). The present study failed to demonstrate an immediate analgesic effect of imipramine on low-back pain. Anti-nociceptive effects as assessed by quantitative sensory tests may depend on CYP2D6 genotype, indicating that metabolizer status should be accounted for when future studies with tricyclic antidepressants are undertaken.

Fig 1. Patient flow-chart.

Flow-chart displaying study design and treatment allocation.

Fig 2. Effect of imipramine on quantitative sensory tests.

Imipramine effect on pressure pain detection (PPDT, a) and tolerance thresholds (PPTT, b), and on electrical single pain detection threshold (ESPT, c) and electrical repeated pain threshold (ERPT, d) in all patients (n = 50), independent of genotype. GMR = geometric mean ratio.

Fig 3. Interaction of drug effect and genotype.

Effect of imipramine (filled symbols) vs. placebo (open symbols) on electrical pain detection threshold with a single (ESPT) or repeated stimulus (ERPT), on pressure pain detection (PPDT) and tolerance thresholds (PPTT) for intermediate (squares) and extensive (circles) CYP2D6 metabolizers. The interaction between imipramine effect and CYP2D6 genotype is suggested by the diverging lines within the first 60 minutes in intermediate metabolizers (squares), whereas no such divergence is seen in extensive metabolizers (circles).