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Combined withdrawal and early preventive medication was the most effective treatment for medication overuse headache (MOH) within the first 6 months in a previous study, but results from a longer follow-up period are lacking.
Learn More >To determine the efficacy and safety of fremanezumab administration in Japanese and Korean patients with chronic migraine (CM).
Learn More >Chronic pain is among the most prevalent burdensome disorders worldwide. The -methyl-d-aspartate (NMDA) receptor system plays a critical role in central sensitization, a primary feature of chronic pain. Despite the proven efficacy of exogenous ligands to this receptor system in preclinical studies, evidence for the clinical efficacy of NMDA antagonists for the treatment of chronic pain is weak. Researchers are studying alternate approaches, rather than direct inhibition of the NMDA receptors in pain processing neurons. This indirect approach utilizes the modulation of molecular switches that regulates the synthesis, maturation, and transport of receptors from cellular organelles to the synaptic membrane. Kinesins are nanomotors that anterogradely transport the cargo using microtubule tracks across the neurons. Various members of the kinesin family, including KIF17, KIF11, KIF5b, and KIF21a, regulate the intracellular transport of NMDA receptors. Pharmacological targeting of these ATP-driven nanomotors could be a useful tool for manipulating the NMDAR functioning. It could provide the potential for the development of a novel strategy for the management of chronic pain.
Learn More >To evaluate the efficacy and safety of two dosing regimens of fremanezumab in Japanese and Korean patients with episodic migraine.
Learn More >Somatosensory stimuli guide and shape behavior, from immediate protective reflexes to longer-term learning and higher-order processes related to pain and touch. However, somatosensory inputs are challenging to control in awake mammals due to the diversity and nature of contact stimuli. Application of cutaneous stimuli is currently limited to relatively imprecise methods as well as subjective behavioral measures. The strategy we present here overcomes these difficulties, achieving 'remote touch' with spatiotemporally precise and dynamic optogenetic stimulation by projecting light to a small defined area of skin. We mapped behavioral responses in freely behaving mice with specific nociceptor and low-threshold mechanoreceptor inputs. In nociceptors, sparse recruitment of single action potentials shapes rapid protective pain-related behaviors, including coordinated head orientation and body repositioning that depend on the initial body pose. In contrast, activation of low-threshold mechanoreceptors elicited slow-onset behaviors and more subtle whole-body behaviors. The strategy can be used to define specific behavioral repertoires, examine the timing and nature of reflexes, and dissect sensory, motor, cognitive and motivational processes guiding behavior.
Learn More >The incidence of chronic postoperative pain after total knee replacement (TKR) is approx. 20%, and hence preoperative risk factors are important to identify. Recent studies have indicated that preoperative inflammatory markers might hold prognostic information for the development of chronic postoperative pain. Long non-coding RNA (lncRNA) regulates the expression of genes related to e.g. inflammatory processes. The current study aimed to investigate the preoperative lncRNA signature as possible preoperative predictive markers for chronic postoperative pain following TKR.
Learn More >Human NaV1.9 (hNaV1.9), encoded by SCN11A, is preferentially expressed in nociceptors, and its mutations have been linked to pain disorders. NaV1.9 could be a promising drug target for pain relief. However, the modulation of NaV1.9 activity has remained elusive. Here, we identified a new candidate NaV1.9-interacting partner, protein arginine methyltransferase 7 (PRMT7). Whole-cell voltage clamp recordings showed that coelectroporation of human SCN11A and PRMT7 in dorsal root ganglia (DRG) neurons of Scn11a-/- mice increased the hNaV1.9 current density. In contrast, a Prmt7 inhibitor (DS-437) reduced mNaV1.9 currents in Scn11a+/+ mice. Using the reporter molecule CD4, we observed an increased distribution of hLoop1 on the cell surface of PRMT7-overexpressing HKE293T cells. Furthermore, we found that PRMT7 mainly binds to residues 563-566 within the first intracellular loop of hNaV1.9 (hLoop1) and methylates hLoop1 at arginine residue 519. Moreover, overexpression of Prmt7 increased the number of action potential fired in DRG neurons of Scn11a+/+ mice but not Scn11a-/- mice. However, DS-437 significantly inhibited the action potential frequency of DRG neurons and relieved pain hypersensitivity in Scn11aA796G/A796G mice. In summary, our observations revealed that PRMT7 modulates neuronal excitability by regulating NaV1.9 currents, which may provide a potential method for pain treatment.
Learn More >The existence of a trigeminocervical complex (TCC) has been suggested based on animal data, but only indirect evidence exists in humans. We investigated the functional relationship between the trigeminal and the occipital region by stimulating one region and measuring electrical pain thresholds (EPTs) of the corresponding opposite region. This study consists of two single-blinded, randomized protocols. 40 healthy participants were recruited in the propaedeutic Protocol I. EPTs were measured on the V1 and the greater occipital nerve (GON) dermatome bilaterally as well as on the left forearm longitudinally before and after application of topical capsaicin. Protocol II was then online pre-registered and, additionally, the ipsilateral trigeminal dermatomes V2 and V3 were tested. GON stimulation increased the EPT ipsilateral at V1 after 20 minutes (p=0.006) compared to baseline, whereas trigeminal stimulation increased the EPT at the ipsilateral (p=0.023) as well as the contralateral GON (p=0.001) following capsaicin application. Protocol II confirmed these results and additionally showed that GON stimulation with capsaicin increased EPTs ipsilateral at all three trigeminal dermatomes and that trigeminal stimulation on V1 led to an ipsilateral increase of EPTs at GON, V2 and V3. Our data suggest a strong functional interplay between the trigeminal and occipital system in humans. The fact that stimulation of one of these dermatomes increases the electrical pain threshold of the respective other nerve could be explained by segmental inhibition on brainstem level.
Learn More >Reports have emerged of abrupt tapering among recipients of long-term prescription opioids to conform to new prescribing guidelines. We conducted a population-based, repeated cross-sectional time-series study among very high-dose (≥200 MME) opioid recipients in Ontario, Canada, to examine changes in the monthly prevalence of rapid tapering from 2014 to 2018, defined as recipients experiencing either a ≥50% reduction in daily doses or abrupt discontinuation sustained for 30 days. Interventional autoregressive integrated moving average (ARIMA) models were used to test for significant changes following key guidelines, and drug policies and programs. A sensitivity analysis examined rapid tapering sustained for 90 days. The monthly prevalence of rapid tapering events was stable from January 2014 to September 2016 (average monthly prevalence: 1.4%), but increased from 1.4% in October 2016 to 1.8% in April 2017 (p=0.001), coincident with Ontario's Fentanyl Patch-for-Patch Return Program implementation. Transient spikes in the prevalence of rapid tapering also occurred two months following Ontario's delisting of publicly funded high-strength opioids and the release of updated Canadian Opioid Prescribing Guideline for Chronic Pain, reaching 2.3% in March 2017 and July 2017, respectively. However this prevalence decreased to 1.2% in December 2018 (p<.0001). Although the prevalence of abrupt opioid discontinuation was lower, similar trends were observed. Our sensitivity analysis examining longer-lasting rapid tapering found similar trends but lower prevalence, with no changes in complete discontinuation. These temporary increases in rapid tapering events highlight the need for improved communication and evidence-based resources for prescribers to minimize negative consequences of evolving policies and guidelines.
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