GABAergic modulation in central sensitization in humans

Abstract

Positive allosteric modulators of GABAA receptors (GAMs) acting at specific subtypes of GABAA receptors effectively restore compromised spinal pain control in rodents. Studies addressing a similar antihyperalgesic effect in humans are sparse and are hampered by sedative effects of nonselective GAMs available for use in humans. We present results from a randomized controlled double-blind crossover study in 25 healthy volunteers, which addressed potential antihyperalgesic actions of clobazam (CBZ) and clonazepam (CLN) at mildly sedating equianticonvulsive doses. Clobazam was chosen because of its relatively low sedative properties and CLN because of its use in neuropathic pain. Tolterodine (TLT) was used as an active placebo. The primary outcome parameter was a change in the area of cutaneous UVB irradiation-induced secondary hyperalgesia (ASH), which was monitored for 8 hours after drug application. Sedative effects were assessed in parallel to antihyperalgesia. Compared with TLT, recovery from hyperalgesia was significantly faster in the CBZ and CLN groups (P = 0.009). At the time point of maximum effect, the rate of recovery from hyperalgesia was accelerated by CBZ and CLN, relative to placebo by 15.7% (95% confidence interval [CI] 0.8-30.5), P = 0.040, and 28.6% (95% CI 4.5-52.6), P = 0.022, respectively. Active compounds induced stronger sedation than placebo, but these differences disappeared 8 hours after drug application. We demonstrate here that GAMs effectively reduce central sensitization in healthy volunteers. These results provide proof-of-principle evidence supporting efficacy of GAMs as antihyperalgesic agents in humans and should stimulate further research on compounds with improved subtype specificity.

New insights in the systemic and molecular underpinnings of general anesthetic actions mediated by γ-aminobutyric acid A receptors

“…When clonazepam and clobazam were tested at mildly sedating equiconvulsive dose in cutaneous UVB irradiation-induced secondary hyperalgesia in humans, these compounds accelerated recovery from hyperalgesia by 28.6% (CI 4.5–52.6] and 15.7% [CI 0.8–30.5], respectively. [19] These results provide the first proof-of-principle evidence supporting an antihyperalgesic action of GABA A receptor modulation in humans.…”

Refractory burning mouth syndrome: clinical and paraclinical evaluation, comorbidities, treatment and outcome

“…The drug binds to the peripheral GABA A receptors that have been identified within the tongue nerve fibers of rats [28] and enhances GABA inhibitory effects that may control pain pathways. Additionally, clonazepam promotes brain stem serotonergic descending pain inhibition by binding to the central GABA A receptors located within the brainstem [29]. Because of this dual-site action of clonazepam (peripheral and central) the drug was given both systematically and locally in our patients.…”

The clobazam metabolite N-desmethyl clobazam is an α2 preferring benzodiazepine with an improved therapeutic window for antihyperalgesia

“…Already 15 min after administration of CBZ, blood levels of NDMC exceed those of CBZ ( Besson et al., 2013 ) suggesting that NDMC would make a major contribution to any in vivo effect seen after CBZ administration. In humans, this conversion occurs much more slowly with blood concentrations of CBZ exceeding those of NDMC for more than 24 h after a single oral dose of 20 or 30 mg CBZ ( Besson et al., 2015 , Pullar et al., 1987 ). It is hence likely that, in humans, treatment with NDMC – instead of with the parent compound CBZ – would improve the therapeutic margin and result in less sedation at concentrations where antihyperalgesia is expected.…”

“…However, in the light of recent concerns raised about the predictive value of animal and, in particular, rodent models in pain research ( Tappe-Theodor and Kuner, 2014 ), it appears important to obtain proof-of-concept data on the translatability of these findings to humans. Classical BDZ site agonists such as clonazepam and CBZ exert weak analgesic effects when given at standard therapeutic doses ( Besson et al., 2015 , Vuilleumier et al., 2013 ). Our recent preclinical study ( Ralvenius et al., 2015 ) that compared antihyperalgesic and sedative effects of DZP in genetically modified mice suggests that the doses needed to achieve relevant analgesia can typically not be achieved in human patients because of dose limiting sedation.…”