Clobazam is more effective than placebo in reducing low back pain, according to a randomized, placebo-controlled trial described in the European Journal of Pain.1
Benzodiazepines were initially used in the treatment of low back pain because of their muscle-relaxant effects. Rodent and human studies suggest that benzodiazepines also have analgesic effects, which were later attributed to benzodiazepines binding to GABA-A receptors in the dorsal horn of the spinal cord.2-4
“However, despite promising initial results, benzodiazepines have never gained as wide an acceptance in pain therapy as other drugs, likely due to their liability to addiction and tolerance development and their sedative side effects,” wrote the authors of the new study.
Based on more recent findings highlighting the role of GABAergic and glycinergic inhibition loss in neuropathic and inflammatory pain, there has been a renewed interest in spinal inhibitory pathways.5 “As benzodiazepines facilitate GABAergic inhibition through positive allosteric modulation of GABA-A receptors, they should be able to compensate for this loss of inhibition,” wrote the researchers. Rodent studies have also shown that benzodiazepines reverse hyperalgesia.6
The current cross-over study examined the analgesic and side effects of clobazam – found to be less sedating than commonly used benzodiazepines – in 49 adult patients with chronic low back pain. Tolterodine, an anticholinergic medication, was used as an active placebo. Because tolterodine does not exert analgesic effects but mimics certain sedative side effects of benzodiazepines, the use of this drug allowed for more rigorous blinding of both researchers and study participants.
The experiment was conducted over 2 sessions with a washout period of at least 1 week between sessions. Patients received either a single oral dose of 20 mg clobazam or 1 mg tolterodine. At baseline and every 30 minutes for 2 hours after drug administration, patients rated the intensity of their low back pain on a scale of 0 to 10. In addition, quantitative sensory testing was performed at baseline, at 60 and at 120 minutes.
Clobazam led to a greater reduction in pain intensity vs placebo in the supine position (60 min: 2.9 vs 3.5, P =.008; 90 min: 2.7 vs 3.3, P =.024; 120 min: 2.4 vs 3.1, P =.005), but not in the sitting position. At 2 hours, 62% of patients demonstrated a response to clobazam vs 43% for placebo (odds ratio [OR]: 2.17, 95% confidence interval [CI], 1.00–4.74, P =.051). None of the sensory tests revealed significant effects. Fatigue and dizziness occurred in 33 and 30 patients in the clobazam condition vs 22 and 8 in the placebo condition (P =.052 and P <.001, respectively), although intensity ratings were low.
While these findings support an antihyperalgesic effect of benzodiazepines, this conclusion is somewhat limited by their sedative and muscle relaxant properties. “A substance that enhances GABAergic inhibition without causing these side effects would offer the opportunity to study these mechanisms in more detail,” the authors stated. Although further investigation is required, these results “support the hypothesis that GABAergic modulation of nociceptive pathways may be effective for some chronic pain conditions,”they concluded.
Summary and Clinical Applicability
Clobazam more effectively reduced low back pain compared with tolterodine, although further research is needed before clear treatment implications can be inferred.
The more frequent occurrence of side effects with clobazam vs placebo suggests that tolterodine may not be an adequate placebo. The short observation period (2 hours) may represent another limitation of the study, considering the chronicity of low back pain.
- Schliessbach J, Vuilleumier PH, Siegenthaler A, et al. Analgesic effect of clobazam in chronic low-back pain but not in experimentally induced pain. Eur J Pain. 2017; doi:10.1002/ejp.1032
- Goodchild CS, Noble J. The effects of intrathecal midazolam on sympathetic nervous system reﬂexes in man–a pilot study. Br J Clin Pharmacol. 1987; 23(3):279–285.
- Goodchild CS, Serrao JM. Intrathecal midazolam in the rat: Evidence for spinally-mediated analgesia. Br J Anaesth. 1987; 59(12):1563– 1570.
- Edwards M, Serrao JM, Gent JP, Goodchild CS. On the mechanism by which midazolam causes spinally mediated analgesia. Anesthesiology. 1990; 73(7):273–277.
- Zeilhofer HU. Loss of glycinergic and GABAergic inhibition in chronic pain – Contributions of inﬂammation and microglia. Int Immunopharmacol. 2008; 8(2):182–187. doi:10.1016/j.intimp.2007.07.009
- Knabl J, Zeilhofer UB, Crestani F, Rudolph U, Zeilhofer HU. Genuine antihyperalgesia by systemic diazepam revealed by experiments in GABAA receptor point-mutated mice. Pain. 2009;141(3):233-238.