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The pathological basis of migraine is not fully understood. Familial hemiplegic migraines (FHM) are monogenic forms of severe migraine, caused by mutations in genes encoding various neuronal and/or astrocytic ion transporting proteins. The leading hypothesis regarding the mechanism underlying migraine in FHM is that enhanced electrical excitability leads to increased extracellular potassium levels with subsequent cortical spreading depression. In this short commentary we would like to propose an additional mechanism distinct from enhanced electrical excitability per se. Rather, we propose that FHM mutations cause substantially increased energy expenditure of neurons for re-establishing ion gradients and/or for increased synaptic activity, a mechanism we call neuronal fatigue. Such a metabolic mechanism had been proposed earlier for common migraine and has received recent experimental evidence in particular for the case of FHM3. The hypothesis could be tested in future studies of FHM related models that would need to take metabolic parameters into account.
Learn More >Pain alters motor function. This is supported by studies showing reduced corticomotor excitability in response to experimental pain lasting <90 minutes. Whether similar reductions in corticomotor excitability are present with pain of longer durations or whether alterations in corticomotor excitability are associated with pain severity is unknown. Here we evaluated the evidence for altered corticomotor excitability in response to experimental pain of differing durations in healthy individuals. Databases were systematically searched for eligible studies. Measures of corticomotor excitability and pain were extracted. Meta-analyses were performed to examine i) group-level effect of pain on corticomotor excitability and ii) individual-level associations between corticomotor excitability and pain severity. 49 studies were included. Corticomotor excitability was reduced when pain lasted milliseconds-seconds (hedges g's = -1.26 to -1.55) and minutes-hours (g's = -0.55 to -0.9). When pain lasted minutes-hours, a greater reduction in corticomotor excitability was associated with lower pain severity (g = -0.24). For pain lasting days-weeks, there were no group level effects (g = -0.03 to 0.27). However, a greater reduction in corticomotor excitability was associated with higher pain severity (g = 0.26). In otherwise healthy individuals, suppression of corticomotor excitability may be a beneficial short-term strategy with long-term consequences.
Learn More >To develop and assess new dosage forms for the alternative to existing oral medication for peripheral neuropathy, a hydrogel film in the skin patch formation containing tramadol hydrochloride (TRA), a water-soluble drug used as an analgesic, was prepared and evaluated. A hydrogel film composed of 20%(w/w) hydroxypropyl methylcellulose (HPMC) irradiated with electron beams had high transparency and elasticity similar to commercially available wound dressings and soft tissues, suggesting that it is a suitable substrate for TRA. The inclusion of TRA was enabled by immersing the HPMC hydrogel film in TRA aqueous solution. The release and skin permeation of TRA from TRA-containing hydrogel films differed depending on the electron beam dose. Moreover, the analgesic effects in mice were confirmed in a dose-dependent manner. This study demonstrated the usefulness of a hydrogel film containing TRA as a new dosage form alternative to the existing oral medication for peripheral neuropathy.
Learn More >Opioids are the gold standard for chronic and acute pain management however its consequence on gastric function is relatively understudied. Opioid users have a higher incidence of gastric dysfunction, worse quality of life, increased hospitalizations, and increased use of antiemetic and pain modulator medications. In the current study, we show that morphine treatment in the murine model results in greater disruption of gastric epithelial cell morphology, increased gastric cell apoptosis, elevated inflammatory cytokines and MMP-9 secretion. Morphine treatment also increases gastric acid secretion and causes delays in gastric emptying. Moreover, morphine treatment causes an increase in systemic IL-6 level, which plays an important role in morphine-induced delayed gastric emptying and gastric damage. IL-6KO mice show a significant level of reduction in morphine-induced gastric delaying, acid retention and gastric damage. Thus, morphine-mediated gastric damage is a consequence of the accumulation of acid in the stomach due to increased gastric acid secretion and delayed gastric emptying. Treatment with a proton pump inhibitor resulted in a significant reduction in morphine-induced gastric inflammation, gastric delaying and improved morphine tolerance. Hence, these studies attribute morphine-mediated induction in gastric acidity and inflammatory cytokines as drivers for morphine-associated gastric pathology and show the therapeutic use of proton pump inhibitors as an inexpensive approach for clinical management of morphine-associated pathophysiology and analgesic tolerance.
Learn More >This study explores the biomechanics underlying the sit-to-stand (STS) functional maneuver in chronic LBP patients to understand how different spinal disorders and levels of pain severity relate to unique compensatory biomechanical behaviors. This work stands to further our understanding of the relationship between spinal loading and symptoms in LBP patients.
Learn More >To evaluate the effectiveness of the cold intervention on relieving migraine symptoms among adult patients with migraine.
Learn More >The aim of this systematic review was to assess the reproducibility of exercise therapy used in clinical trials for chronic neck pain (CNP) based on reported items from the Template for Intervention Description and Replication (TIDieR) and the Consensus on Exercise Reporting Template (CERT) checklists.
Learn More >Multisensory sensitivity (MSS) to non-painful stimuli has been identified as a risk factor for the presence of coexisting chronic pain conditions (COPCs). However, it remains unclear whether MSS can differentiate pain phenotypes involving different levels of central sensitivity. Both pain-free and those with chronic pain, particularly fibromyalgia (FM), migraine or low back pain (LBP) were recruited, with pain co-morbidities assessed. MSS was highest in FM, followed by migraine, then LBP, and lowest in pain-free individuals (adjusted between condition Cohen's d = 0.32 – 1.2, p ≤ 0.0007). However, when secondly grouping patients by total number of pain comorbidities reported, those with a single pain condition (but not FM) did not have significantly elevated MSS versus pain-free individuals (adj d= 0.17, p = 0.18). Elevated MSS scores produced increased odds of having 2 or more pain comorbidities; OR [95%CI] =2.0 [1.15, 3.42] without, and 5.6 [2.74, 11.28], with FM (p ≤ 0.0001). Further, those with low MSS levels were 55% – 87% less likely to have ≥ 2 pain comorbidities with or without FM (OR 0.45 [0.22, 0.88] to 0.13 [0.05, 0.39]; p ≤ 0.0001). Our findings support that MSS can differentiate between pain phenotypes with different degrees of expected central mechanism involvement, and also serves as a risk and resilience marker for total COPCs. This supports the use of MSS as a marker of heightened central nervous system processing, and thus may serve as a clinically feasible assessment to better profile pain phenotypes with the goal of improving personalized treatment.
Learn More >Neuropathic pain causes substantial morbidity and healthcare utilization. Monotherapy with antidepressants or anticonvulsants often fails to provide relief. Combining different drugs sometimes provides improved analgesia and/or tolerability. Over half of patients receive 2 or more analgesics and combination trials continue to emerge. This review comprehensively searched CENTRAL, MEDLINE, and EMBASE for relevant trials. Included studies are double-blind RCTs evaluating combinations of two or more drugs versus placebo and/or at least one monotherapy in adults with neuropathic pain. Outcomes included measures of efficacy and adverse effects, and risk-of-bias was assessed. Meta-analyses compared combination to monotherapy wherever two or more similar studies were available. Forty studies (4,741 participants) were included. Studies were heterogenous with respect to various characteristics including dose titration methods and administration (i.e. simultaneous versus sequential) of the combination. Few combinations involved a non-sedating drug and several methodological problems were identified. For opioid-antidepressant, opioid-gabapentinoid and gabapentinoid-antidepressant combinations, meta-analyses failed to demonstrate superiority over both monotherapies. In general, adverse event profiles were not substantially different for combination therapy compared to monotherapy. Despite widespread use and a growing number of trials, convincing evidence has not yet emerged to suggest superiority of any combination over its respective monotherapies. Therefore, implementing combination therapy – as second- or third-line treatment – in situations where monotherapy is insufficient should involve closely monitored individual dosing trials to confirm safety and overall added benefit. Further research is needed, including trials of combinations involving non-sedating agents, and to identify clinical settings and specific combinations that safely provided added benefit.
Learn More >Chronic pain and mental illness in youth and parents are poised to reach new heights amidst the societal and healthcare impacts of the COVID-19 pandemic. Evidence from natural disasters (i.e., hurricanes) suggests that a degree of personal impact and individual personality may moderate the effects of high stress events, such as the COVID-19 pandemic, on mental health.
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