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Benzodiazepines (BZDs), a class of sedative-hypnotic medications, generated concern as their popularity grew, with particular alarm regarding elevated rates of BZD use among chronic pain populations. Consistent with negative reinforcement/motivational models of substance use, desire for pain alleviation may motivate BZD use. Yet, little is known about relations between pain and addiction-relevant BZD use processes. This cross-sectional survey study aimed to: a) test associations between pain intensity and clinically relevant BZD use patterns, and b) examine the role of pain catastrophizing in hypothesized pain-BZD relations. Participants included 306 adults with chronic musculoskeletal pain and a current BZD prescription who completed an online survey study (M = 38.7, 38.9% female). Results indicated that pain intensity was positively associated with past-month BZD use frequency, BZD dependence severity, and likelihood of endorsing BZD misuse behaviors (ps < .05). Pain catastrophizing was positively associated with BZD dependence/likelihood of BZD misuse, covarying for pain intensity (p < .05). These findings build upon an emerging literature by highlighting positive covariation of pain intensity and pain catastrophizing with addiction-relevant BZD use behaviors. Results underscore the need to further investigate high-risk BZD use among individuals with chronic pain, with and without concurrent opioid use, to inform prevention/intervention efforts. PERSPECTIVE: : This article presents findings on cross-sectional associations of pain intensity and pain catastrophizing with clinically relevant benzodiazepine (BZD) use outcomes, including dependence and misuse, among individuals with chronic pain. Findings help elucidate the higher burden of BZD misuse/dependence in chronic pain populations and suggest that pain relief may be a common, yet underrecognized, self-reported motivation for taking BZDs.
Learn More >Fibroblast Growth Factor Homologous Factors (FHFs) are cytosolic members of the of the FGF proteins. Four members of this subfamily (FHF1-4) are differentially expressed in multiple tissues in an isoform-dependent manner. Mutations in FHF proteins have been associated with multiple neurological disorders. FHF proteins bind to the C-terminus of voltage-gated sodium (Nav) channels and regulate current amplitude and gating properties of these channels. FHF2, which is expressed in DRG neurons, has two main splicing isoforms, FHF2A and FHF2B, which differ in the length and sequence of their N-termini, have been shown to differentially regulate gating properties of Nav1.7, a channel that is a major driver of DRG neuron firing. FHF2 expression levels are downregulated following peripheral nerve axotomy, which suggests that they may regulate neuronal excitability via an action on Nav channels after injury. We have previously shown that knockdown of FHF2 leads to gain-of-function changes in Nav1.7 gating properties: enhanced repriming, increased current density and hyperpolarized activation. From this we posited that knockdown of FHF2 might also lead to DRG hyperexcitability. Here we show that knockdown of either FHF2A alone or all isoforms of FHF2 results in increased DRG neuron excitability. In addition, we demonstrate that supplementation of FHF2A and FHF2B reduces DRG neuron excitability. Overexpression of FHF2A or FHF2B also reduced excitability of DRG neurons treated with a cocktail of inflammatory mediators, a model of inflammatory pain. Our data suggest that increased neuronal excitability after nerve injury might be triggered, in part, via a loss of FHF2-Nav1.7 interaction.
Learn More >Transcatheter arterial embolization (TAE) is one of the first-line treatments for advanced hepatocellular cancer. The pain caused by TAE is a stark complication, which remains to be prevented by biomedical engineering methods.
Learn More >Sickle cell disease (SCD) is a heritable chronic health condition characterized by pain symptoms throughout the life course that are routinely treated with opioids.
Learn More >Cytochrome P450 2D (CYP2D) metabolises many centrally-acting substrates including opioids. Hydrocodone, an opioid and CYP2D substrate, is metabolised to hydromorphone, an active metabolite. CYP2D in the brain is active in vivo and can alter drug response however, it is unknown whether metabolism by CYP2D in the brain alters oral hydrocodone induced analgesia. Propranolol, a selective CYP2D mechanism-based inhibitor, or vehicle, was administered into the right cerebral ventricle of male rats, (HAN Wistars, Envigo), 24 hours before testing for analgesia from oral hydrocodone (or hydromorphone, a non-CYP2D substrate). Hydrocodone and its CYP2D-mediated metabolites were simultaneously quantified using a novel LC-MS/MS assay. After propranolol vs vehicle pretreatment, there was significantly higher analgesia from oral hydrocodone, and a significantly lower brain CYP2D metabolic ratio (an in vivo phenotype of brain CYP2D activity that was derived from the molar sum of hydromorphone and its metabolites divided by hydrocodone). The brain CYP2D metabolic ratio correlated significantly with analgesia. There was no pretreatment effect on plasma hydrocodone concentrations, elimination rates, or metabolic ratio (an in vivo phenotype for hepatic CYP2D activity). The liver CYP2D metabolic ratio did not correlate with analgesia. Propranolol pretreatment had no impact on analgesia from oral hydromorphone. These data suggest that inhibited CYP2D activity in brain, causing reduced metabolism of brain hydrocodone, resulted in higher analgesia from oral hydrocodone, despite hydrocodone having a lower μ-opioid receptor affinity than hydromorphone. Thus, variation in CYP2D in the brain may be an important source of interindividual differences in response to CYP2D substrates, including oral hydrocodone.
Learn More >Patients with chronic pain exhibit anxiety and deficits in memory. Additionally, α-adrenoceptors that are wildly expressed in the brain have an important role in modulating both pain and memory formation. In the present study, we investigated the interaction effects of crocin with central α-adrenoceptors on pain comorbidity and hippocampal synaptic plasticity changes following chronic constriction injury (CCI) of the sciatic nerve in rats. All the drugs (crocin, an antagonist (yohimbine) and agonist (clonidine) of α-adrenergic receptors) were injected (via intracerebroventricular injection) from the day of CCI operation (day 0) and continued daily (once per day) until the 14 day post-CCI. The effects of drugs on the cold allodynia (using acetone test) and anxiety-like behaviors (using elevated plus maze, EPM and open field tests) were assessed. Spatial memory (using Barnes maze) was assessed on day 14 post-CCI operation. Hippocampal synaptic plasticity (using in-vivo extracellular field potential recording) was performed on day 14 post-CCI operation. We observed that crocin induced analgesic, anxiolytic and memory enhancer action following CCI surgery. Furthermore, crocin significantly increased long-term potentiation (LTP) (increased fEPSP slope and population spike amplitude). Furthermore, the co-injection of yohimbine effectively decreased analgesic, anxiolytic and enhancer action of crocin on the LTP parameters (fEPSP slope and population spike amplitude). Our study provided information that protective effects of crocin on pain/anxiety responses and synaptic plasticity were possibly mediated by central α-adrenoceptor in the rats with chronic pain.
Learn More >Etrolizumab is a gut-targeted anti-β7 monoclonal antibody targeting α4β7 and αEβ7 integrins. We aimed to compare the safety and efficacy of two doses of etrolizumab with placebo in patients with Crohn's disease.
Learn More >Diabetes is associated with several complications, including neuropathic pain, which is difficult to manage with currently available drugs. Descending noradrenergic neurons possess antinociceptive activity; however, their involvement in diabetic neuropathic pain remains to be explored.
Learn More >This study investigated the usefulness of urinary biomarkers for assessing bladder condition and histopathology in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). We retrospectively enrolled 315 patients (267 women and 48 men) diagnosed with IC/BPS and 30 controls. Data on clinical and urodynamic characteristics (visual analog scale (VAS) score and bladder capacity) and cystoscopic hydrodistention findings (Hunner's lesion, glomerulation grade, and maximal bladder capacity (MBC)) were recorded. Urine samples were utilized to assay inflammatory, neurogenic, and oxidative stress biomarkers, including interleukin (IL)-8, C-X-C motif chemokine ligand 10 (CXCL10), monocyte chemoattractant protein-1 (MCP-1), brain-derived neurotrophic factor (BDNF), eotaxin, IL-6, macrophage inflammatory protein 1 beta (MIP-1β), regulated on activation, normal T cell expressed and secreted (RANTES), tumor necrosis factor-alpha (TNF-α), prostaglandin E2 (PGE2), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and 8-isoproatane, and total antioxidant capacity. Further, specific histopathological findings were identified via bladder biopsy. The associations between urinary biomarker levels and bladder conditions and histopathological findings were evaluated. The results reveal that patients with IC/BPS had significantly higher urinary MCP-1, eotaxin, TNF-α, PGE2, 8-OHdG, and 8-isoprostane levels than controls. Patients with Hunner's IC (HIC) had significantly higher IL-8, CXCL10, BDNF, eotaxin, IL-6, MIP-1β, and RANTES levels than those with non-Hunner's IC (NHIC). Patients with NHIC who had an MBC of ≤760 mL had significantly high urinary CXCL10, MCP-1, eotaxin, IL-6, MIP-1β, RANTES, PGE2, and 8-isoprostane levels and total antioxidant capacity. Patients with NHIC who had a higher glomerulation grade had significantly high urinary MCP-1, IL-6, RANTES, 8-OHdG, and 8-isoprostane levels. A significant association was observed between urinary biomarkers and glomerulation grade, MBC, VAS score, and bladder sensation. However, bladder-specific histopathological findings were not well correlated with urinary biomarker levels. The urinary biomarker levels can be useful for identifying HIC and different NHIC subtypes. Higher urinary inflammatory and oxidative stress biomarker levels are associated with IC/BPS. Most urinary biomarkers are not correlated with specific bladder histopathological findings; nevertheless, they are more important in the assessment of bladder condition than bladder histopathology.
Learn More >A qualitative interview study of GPs’ experiences of prescribing opioid medication for chronic pain.
Prescribing of opioid medication has increased over the last twenty years. Most occurs in primary care for chronic pain. There is little evidence that these drugs are effective for this indication and concerns about continuing prescribing, particularly in the long term and at high doses.
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