Pain
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The aims of this review were to systematically identify the current evidence base of placebo (or "sham") randomised controlled trials (RCTs) of spinal cord stimulation (SCS) for neuropathic pain and to undertake a meta-analysis to investigate the effectiveness of SCS when compared with a placebo comparator arm. Electronic databases were searched from inception until January 2019 for RCTs of SCS using a placebo/sham control. Searches identified 8 eligible placebo-controlled randomised trials of SCS for neuropathic pain. ⋯ Our analyses suggest that the magnitude of treatment effect varies across trials and, in part, depends on the quality of patient blinding and minimisation of carryover effects. Improved reporting and further methodological research is needed into placebo and blinding approaches in SCS trials. Furthermore, we introduce a differentiation between placebo and sham concepts that may be generalisable to trials evaluating surgical or medical procedures.
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Chemotherapy-induced neuropathic pain (CINP) in both sexes compromises many current chemotherapeutics and lacks an FDA-approved therapy. We recently identified the sphingosine-1-phosphate receptor subtype 1 (S1PR1) and A3 adenosine receptor subtype (A3AR) as novel targets for therapeutic intervention. Our work in male rodents using paclitaxel, oxaliplatin, and bortezomib showed robust inhibition of CINP with either S1PR1 antagonists or A3AR agonists. ⋯ Thus, alternative mechanisms beyond receptor expression may account for sex differences in response to S1PR1 antagonists. Morphine and duloxetine, both clinical analgesics, reversed BINP in female mice, demonstrating that the lack of response is specific to S1PR1 and A3AR agents. Our findings suggest that A3AR- and S1PR1-based therapies are not viable approaches in preventing and treating BINP in females and should inform future clinical trials of these drugs as adjuncts to chemotherapy.
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Recent research has highlighted a need for the psychometric evaluation of instruments targeting core domains of the pain experience in chronic pain populations. In this study, the measurement properties of Short Form-36 Health Survey (SF-36),EuroQol 5-dimensions (EQ-5D) and Hospital Anxiety and Depression Scale (HADS) were analyzed within the item response-theory framework based on data from 35,908 patients. To assess the structural validity of these instruments, the empirical representations of several conceptually substantiated latent structures were compared in a cross-validation procedure. ⋯ In support of convergent and discriminant validity, correlations between questionnaires showed that theoretically similar traits were highly associated, whereas unrelated traits were not. Our models can be applied to score SF-36 and HADS in chronic pain patients, but we recommend against using the EQ-5D model due to its low reliability. These results are useful for researchers and clinicians involved in chronic pain populations because questionnaires' properties determine their discriminating ability in patient status assessment.
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Randomized Controlled Trial
The metabotropic glutamate receptor 5 negative allosteric modulator fenobam: pharmacokinetics, side effects, and analgesic effects in healthy human subjects.
Metabotropic glutamate receptor 5 (mGlu5) has been shown to modulate nociception in animals, but no mGlu5 antagonists have been developed commercially as analgesics. The mGlu5 antagonist fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea] was originally evaluated for development as a nonbenzodiazepine anxiolytic. Fenobam is analgesic in numerous mouse pain models, acting exclusively through mGlu5 blockade. ⋯ Fenobam reduced sensitization vs placebo at a single timepoint (peak plasma concentration); we found no other difference between fenobam and placebo. Our results suggest highly variable fenobam disposition and minimal analgesic effects at the dose tested. We suggest that future studies testing analgesic effects of mGlu5 blockade are warranted, but such studies should use molecules with improved pharmacokinetic profiles.
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An imbalance between excitatory and inhibitory neurotransmission has been linked to fibromyalgia (FM). Magnetic resonance spectroscopy has shown increased levels of glutamate in the insula and posterior cingulate cortex in FM as well as reduced insular levels of gamma-aminobutyric acid (GABA). Both of these changes have been associated with increased pain sensitivity. ⋯ The changes were widespread and not restricted to pain-processing regions. These findings suggest that the GABAergic system is altered, possibly indicating an imbalance between excitatory and inhibitory neurotransmission. Future studies should try to understand the nature of the dysregulation of the GABAergic system in FM and in other pain syndromes.