Evaluation of anti-hyperalgesic and analgesic effects of two benzodiazepines in human experimental pain: a randomized placebo-controlled study

Abstract

Background and aims: Compounds that act on GABA-receptors produce anti-hyperalgesia in animal models, but little is known on their effects in humans. The aim of this study was to explore the potential usefulness of GABA-agonism for the control of pain in humans. Two agonists at the benzodiazepine-binding site of GABAA-receptors (clobazam and clonazepam) were studied using multiple experimental pain tests. Positive results would support further investigation of GABA agonism for the control of clinical pain.

Methods: In a randomized double-blind crossover design, 16 healthy male volunteers received clobazam 20 mg, clonazepam 1 mg and tolterodine 1 mg (active placebo). The area of static hyperalgesia after intradermal capsaicin injection was the primary endpoint. Secondary endpoints were: area of dynamic hyperalgesia, response to von Frey hair stimulation, pressure pain thresholds, conditioned pain modulation, cutaneous and intramuscular electrical pain thresholds (1, 5 and 20 repeated stimulation), and pain during cuff algometry.

Results: For the primary endpoint, an increase in the area of static hyperalgesia was observed after administration of placebo (p<0.001), but not after clobazam and clonazepam. Results suggestive for an anti-hyperalgesic effect of the benzodiazepines were obtained with all three intramuscular pain models and with cuff algometry. No effect could be detected with the other pain models employed.

Conclusions: Collectively, the results are suggestive for a possible anti-hyperalgesic effect of drugs acting at the GABAA-receptors in humans, particularly in models of secondary hyperalgesia and deep pain. The findings are not conclusive, but support further clinical research on pain modulation by GABAergic drugs. Because of the partial results, future research should focus on compounds acting selectively on subunits of the GABA complex, which may allow the achievement of higher receptor occupancy than unselective drugs. Our data also provide information on the most suitable experimental models for future investigation of GABAergic compounds.

Trial registration: ClinicalTrials.gov NCT01011036.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Flowchart of the study.

Figure 2. Capsaicin model.

The dots represent the points where stimulation was applied. The circle in the center of the hectagon is the site of capsaicin injection.

Figure 3. Time plan of the experiment.

Horizontal arrow: Testing time; ZZ: Resting time; EX: Medical examination, installation of the testing equipment and training measures; CT: Measures on the area of capsaicin hyperalgesia; ET: Cutaneous electrical stimulation; ED: Intramuscular electrical stimulation, pressure stimulation, cold pressor test, conditioned pain modulation and cuff algometry; BT: Psychomotor performance test; b: Blood sample.

Figure 4. Static pinprick hyperalgesia after capsaicin.

The area of static hyperalgesia significantly increased with the active placebo tolterodine (p

Figure 5. Intramuscular repeated electrical stimulation (5 stimuli).

There was a statistically significant increase in the temporal summation thresholds for clonazepam (p = 0.021) and clobazam (p = 0.021) between baseline measures and 120 minutes, whereas no statistically significant change in threshold after the active placebo tolterodine was observed.