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Botulinum toxin A (BTA) is widely used as treatment of chronic migraine. Efficacy in studies, however, was only modest and likely influenced by unblinding due to BTA-induced removal of forehead wrinkles. Moreover, most study participants were overusing acute headache medications and might have benefitted from withdrawal. We assessed in a double blind, placebo-controlled, randomized clinical trial whether add-on therapy with BTA enhances efficacy of acute withdrawal. Participants were enrolled between December 2012 and February 2015, with follow-up to January 2016, in a single academic hospital in the Netherlands. A total of 179 participants, male and female, aged 18-65, diagnosed with chronic migraine and overuse of acute headache medication were included. All participants were instructed to withdraw acutely from all medication for a 12-week period, in an outpatient setting. In addition, they were randomly assigned (1:1) to 31 injections with BTA (155 units) or placebo (saline); to prevent unblinding, placebo-treated participants received low doses of BTA (17.5 units in total) in the forehead, along with saline injections outside the forehead region. Primary endpoint was percentage change in monthly headache days from baseline to the last 4 weeks of double-blind treatment (Weeks 9-12). Among 179 randomized patients, 90 received BTA and 89 received placebo, and 175 (98%) completed the double-blind phase. All 179 patients were included in the intention-to-treat analyses. BTA did not reduce monthly headache days versus placebo (-26.9% versus -20.5%; difference -6.4%; 95% confidence interval: -15.2 to 2.4; P = 0.15). Absolute changes in migraine days at 12 weeks for BTA versus placebo were -6.2 versus -7.0 (difference: 0.8; 95% confidence interval: -1.0 to 2.7; P = 0.38). Other secondary endpoints, including measures for disability and quality of life, did also not differ. Withdrawal was well tolerated and blinding was successful. Thus, in patients with chronic migraine and medication overuse, BTA does not afford any additional benefit over acute withdrawal alone. Acute withdrawal should be tried first before initiating more expensive treatment with BTA.
Learn More >The advent of anti-CGRP medications is an example of translational research made real. Pioneering research by Drs. Lars Edvinsson and Peter Goadsby has yielded the monoclonal antibody therapeutics and will likely also result in the gepants. The availability of MABs represents a watershed moment in the treatment of migraine. These medications have specificity, as they were designed for primary migraine prevention. They work across a group of wide therapeutic targets, episodic migraine, chronic migraine, medication-overuse headache, and episodic cluster headache. They separate from placebo within 1 week, and often show clinical effects within a month or less. They have tolerability similar to placebo. There has been no significant or worrisome safety signal thus far in their use. They manifest unprecedented responder rates at ≥ 75% and even 100%. They lower all acute medication use and can convert patients from chronic migraine to episodic migraine and from acute medication overuse to non-overuse. They work in patients who have already had lack of success with at least 2-4 previous preventive medications. Pent-up demand for designer, well-tolerated, and effective migraine preventive medication in the USA has resulted in more than 100,000 individual patients prescribed erenumab from May to December of 2018, and the numbers continue to increase. The preventive treatment of migraine in the USA has shifted dramatically, and is likely to do so in the rest of the world as well.
Learn More >Pain is one of the cardinal signs of inflammation and is present in many inflammatory conditions. Therefore, anti-inflammatory drugs such as NSAIDs also have analgesic properties. We previously showed that prostaglandin D-glycerol ester (PGD-G), endogenously produced by cyclooxygenase-2 from the endocannabinoid 2-arachidonoylglycerol, has anti-inflammatory effects in vitro and in vivo that are partly mediated by DP1 receptor activation. In this work, we investigated its effect in a model of carrageenan-induced inflammatory pain. PGD-G decreased hyperalgesia and edema, leading to a faster recovery. Moreover, PGD-G decreased carrageenan-induced inflammatory markers in the paw as well as inflammatory cell recruitment. The effects of PGD-G were independent from metabolite formation (PGD and 15d-PGJ-G) or DP1 receptor activation in this model. Indeed PGD delayed recovery from hyperalgesia while 15d-PGJ-G worsened the edema. However, while PGD-G decreased hyperalgesia in this model of inflammatory pain, it had no effect when tested in the capsaicin-induced pain model. While the targets mediating the effects of this bioactive lipid in inflammatory pain remain to be elucidated, our findings further support the interest of anti-inflammatory lipid mediators in the management of inflammatory pain.
Learn More >To assess efficacy and safety of lidocaine 700 mg medicated plaster (lidocaine plaster) compared to placebo in patients with moderate to severe chronic post-surgical neuropathic pain (PSNP).
Learn More >Selective N-methyl-d-aspartate receptor subunit 2B (NR2B) antagonists show potential as analgesic drugs, and do not cause side effects associated with non-selective N-methyl-d-aspartate (NMDA) antagonists. Using a scaffold-hopping approach, we previously identified isoxazole derivative 4 as a potent selective NR2B antagonist. In this study, further scaffold hopping of isoxazole derivative 4 and optimization of its pharmacokinetic profile led to the discovery of the orally bioavailable compound 6v. In a rat study of analgesia, 6v demonstrated analgesic effects against neuropathic pain.
Learn More >Does the GnRH antagonist, ASP1707, reduce endometriosis-associated pelvic pain?
Learn More >Neuropathic pain is often debilitating, severely limiting the daily lives of patients who are affected. Typically, neuropathic pain is difficult to manage and, as a result, leads to progression into a chronic condition that is, in many instances, refractory to medical management.
Learn More >GABA receptors containing the α6 subunit are located in trigeminal ganglia, and their reduction by small interfering RNA increases inflammatory temporomandibular and myofascial pain in rats. We thus hypothesized that enhancing their activity may help in neuropathic syndromes originating from the trigeminal system. Here, we performed a detailed electrophysiological and pharmacokinetic analysis of two recently developed deuterated structurally similar pyrazoloquinolinone compounds. DK-I-56-1 at concentrations below 1 μM enhanced GABA currents at recombinant rat α6β3γ2, α6β3δ and α6β3 receptors whereas it was inactive at most GABA receptor subtypes containing other α subunits. DK-I-87-1 at concentrations below 1 μM was inactive at α6-containing receptors and only weakly modulated other GABA receptors investigated. Both plasma and brain tissue kinetics of DK-I-56-1 were relatively slow, with half-lives of 6 h and 13 h, respectively, enabling the persistence of estimated free brain concentrations in the range 10-300 nM throughout a 24-h period. Results obtained in two protocols of chronic constriction injury of the infraorbital nerve in rats dosed intraperitoneally with DK-I-56-1 during 14 days after surgery, or with DK-I-56-1 or DK-I-87-1 during 14 days after trigeminal neuropathy was already established, demonstrated that DK-I-56-1 but not DK-I-87-1 significantly reduced the hypersensitivity response to von Frey filaments. This article is protected by copyright. All rights reserved.
Learn More >The association between chronic pain, depression and anxiety has gained particular attention due to high rates of comorbidity. Recent data demonstrated that the mesolimbic reward circuitry is involved in the pathology of chronic pain. Interestingly, the mesolimbic reward circuit participates both in pain perception and in pain relief. The endocannabinoid system (ECS) has emerged as a highly relevant player involved in both pain perception and reward processing. Targeting ECS could become a novel treatment strategy for chronic pain patients. However, little is known about the underlying mechanisms of action of cannabinoids at the intersection of neurochemical changes in reward circuits and chronic pain. Because understanding the benefits and risks of cannabinoids is paramount, the aim of this review is to evaluate the state-of-art knowledge about the involvement of the ECS in dopamine signalling within the reward circuits affected by chronic pain.
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