The effect of duloxetine on mechanistic pain profiles, cognitive factors and clinical pain in patients with painful knee osteoarthritis-A randomized, double-blind, placebo-controlled, crossover study

Abstract

Background: Duloxetine is indicated in the management of pain in osteoarthritis. Evidence suggests that duloxetine modulates central pain mechanisms and cognitive factors, and these factors are assumed contributing to the analgesic effect. This proof-of-mechanism, randomized, placebo-controlled, crossover, double-blinded trial evaluated the effect of duloxetine on quantitative sensory testing (QST), cognitive factors and clinical pain in patients with osteoarthritis and to predict the analgesic effect.

Methods: Twenty-five patients completed this cross-over study with either 18-week duloxetine (maximum 60 mg/daily) followed by placebo or vice-versa. Pressure pain thresholds, temporal summation of pain and conditioned pain modulation were assessed using cuff algometry. The Hospital Anxiety and Depression Scale and the Pain Catastrophizing Scale evaluated cognitive factors. Clinical pain was assessed using Brief Pain Inventory and Western Ontario and McMaster Universities Osteoarthritis Index. Linear regression models were used to predict the analgesic effect of duloxetine.

Results: Depending on the clinical pain outcome, 40%-68% of patients were classified as responders to duloxetine. Linear regression models predicted the analgesic effect (predictive value of 45%-75% depending on clinical pain outcome parameter) using a combination of pretreatment QST parameters, cognitive factors and clinical pain. No significant changes were found for QST, cognitive factors or clinical pain on a group level when comparing duloxetine to placebo.

Conclusion: A combination of pretreatment QST, cognitive factors and clinical pain was able to predict the analgesic response of duloxetine. However, in this relatively small study, duloxetine did not selectively modulate QST, cognitive factors or clinical pain intensity when compared with placebo.

Significance: Duloxetine is proposed as a treatment for chronic pain. Pre-clinical trials suggest that duloxetine provides analgesia through modulation of descending pain inhibitory pathways or through improvements in cognitive factors. The current study demonstrates that pretreatment mechanistic pain profiling, cognitive factors and clinical pain can predict the analgesic effect of duloxetine and that only a subset of patients might benefit from duloxetine treatment.

FIGURE 1

Patients with osteoarthritis were screened (visit 0) and randomized (visit 1) into 18 weeks of duloxetine followed by 18 weeks of placebo (sequence 1) or 18 weeks of placebo followed by 18 weeks of duloxetine (sequence 2). A 2‐week washout period was conducted between the two treatments. Patients were assessed before (visit 1 and 3) and after (visit 2 and 4) each treatment. Assessments were conducted at each of the four visits. HADS: Hospital anxiety and depression scale, BPI: Brief pain inventory, WOMAC: Western Ontario and McMaster universities osteoarthritis index.

FIGURE 2

CONSORT diagram of patient flow.

FIGURE 3

Quantitative sensory testing data before (dark blue) and after (light blue) 18 weeks' treatment with either placebo or duloxetine. QST was assessed using ipsilateral (a) and contralateral (b) cuff pain detection thresholds, ipsilateral (c) and contralateral (d) cuff pain tolerance thresholds, (e) temporal summation of pain and (f) conditioned pain modulation. The data presented illustrate means and standard deviations.

FIGURE 4

Cognitive factors assessed before (red) and after (pink) 18 weeks' treatment with either placebo or duloxetine. Cognitive factors assessed using (a) the hospital anxiety and depression score and (b) the pain catastrophizing scale. The data presented illustrate means and standard deviations.