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German authorities reimburse migraine prevention with erenumab only in patients who previously did not have therapeutic success with at least five oral prophylactics or have contraindications to such. In this real-world analysis, we assessed treatment response to erenumab in patients with chronic migraine (CM) who failed five oral prophylactics and, in addition, onabotulinumtoxinA (BoNTA). We analyzed retrospective data of 139 CM patients with at least one injection of erenumab from two German headache centers. Patients previously did not respond sufficiently or had contraindications to β-blockers, flunarizine, topiramate, amitriptyline, valproate, and BoNTA. Primary endpoint of this analysis was the mean change in monthly headache days from the 4-weeks baseline period over the course of a 12-weeks erenumab therapy. Secondary endpoints were changes in monthly migraine days, days with severe headache, days with acute headache medication, and triptan intake in the treatment period. Erenumab (starting dose 70 mg) led to a reduction of -3.7 (95% CI 2.4-5.1) monthly headache days after the first treatment and -4.7 (95% CI 2.9-6.5) after three treatment cycles ( < 0.001 for both). All secondary endpoint parameters were reduced over time. Half of patients (51.11%) had a >30% reduction of monthly headache days in weeks 9-12. Only 4.3% of the patients terminated erenumab treatment due to side effects. In this treatment-refractory CM population, erenumab showed efficacy in a real-world setting similar to data from clinical trials. Tolerability was good, and no safety issues emerged. Erenumabis is a treatment option for CM patients who failed all first-line preventives in addition to BoNTA.
Learn More >Topical analgesics are an upcoming treatment option for neuropathic pain. In this observational study, we performed a double-blind placebo-controlled response test (DOBRET) in patients with polyneuropathy to determine the personalized analgesic effect of phenytoin 10% cream.
Learn More >Initially developed to generate new treatments for epilepsy, gabapentin, and pregabalin ("gabapentinoids") were engineered to mimic the action of GABA and to modulate GABA metabolism. Rather than their intended pharmacological action on GABA neurotransmission, instead, they exhibit a high affinity for the α2δ-1 and α2δ-2 subunits of voltage-activated calcium channels, wherein binding of gabapentinoids inhibits cellular calcium influx and attenuates neurotransmission. Despite a lack of activity on GABA levels, gabapentin and pregabalin are effective at suppressing seizures and subsequently approved as a new class of antiepileptic therapy for partial-onset epilepsy. Through the same hypothesized molecular mechanism and by controlling neuronal hyperexcitability, gabapentinoids demonstrate clear efficacy in pain management, which has arguably been their most extensively prescribed application to date. In this review, we focus on pregabalin as a second-generation gabapentinoid widely employed in the treatment of a variety of pain conditions. We also discuss the wider functional roles of α2δ subunits and the contributions that pregabalin might play in affecting physiological and pathophysiological processes.
Learn More >Opioids and non-steroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed for chronic musculoskeletal pain, despite limited evidence of effectiveness and well-documented adverse effects. We assessed the effects of participating in a structured, personalized self-experiment ("N-of-1 trial") on analgesic prescribing in patients with chronic musculoskeletal pain.
Learn More >The development of analgesic tolerance to opioids is an important limitation in the management of chronic pain. Spinal cord glial cell activation appears to play a pivotal role in the development and maintenance of opioid tolerance, indicating the presence of an opioid-induced neuronal-glial interaction; however, how opioids drive this cross-talk is still elusive. In search of treatments to attenuate morphine analgesic tolerance, our research focused on the role of Notch signaling pathway, one of the most important mechanisms of cell-to-cell interactions, in the spinal dorsal horn after morphine repeated exposure and whether Notch inhibition attenuates morphine analgesic tolerance. Double immunofluorescence experiments on spinal sections from morphine-tolerant mice showed a neuronal localization of Notch-1 receptor whereas the Notch ligand Jagged was localized on neighboring astrocytes. Morphine-induced μ opioid receptor (MOR) stimulation triggered Notch-1 signaling activation and this event was mediated by astrocyte JNK activation. Notch-1 activation selectively reduced the expression of histone deacetylase (HDAC)-1, resulting in an overphosphorylation of PKC and ERK, kinases involved in MOR phosphorylation and internalization after repeated morphine exposure. Notch-1 signaling inhibition, through intrathecal administration of the γ-secretase inhibitor, DAPT, counteracted PKC and ERK overphosphorylation, MOR internalization, and analgesic tolerance. Conversely, the HDAC-1 inhibitor, LG325, further aggravated MOR internalization, PKC overphosphorylation, and analgesic tolerance.Our findings implicate the MOR-triggered Notch-1 signaling in promoting MOR internalization and morphine analgesic tolerance by epigenetic regulation mechanisms. These data suggest that Notch-1 inhibitors could represent an innovative therapeutic perspective for the management of opioid tolerance in chronic pain therapy.
Learn More >To assess the efficacy of erenumab across the spectrum of response thresholds (≥50%, ≥75%, 100%) based on monthly migraine days (MMD) reduction in patients with chronic migraine from a 12-week, randomized study (NCT02066415).
Learn More >Lasmiditan, a highly selective 5-hydroxytryptamine receptor 1F (5-HT) agonist, is the first drug in its class and is lacking triptan-like vasoactive properties. The US Food and Drug Administration (FDA) has recently approved lasmiditan for the acute treatment of migraine in adults based on positive results of two pivotal phase III trials, which showed a significant difference to placebo in the proportion of patients achieving total migraine freedom within 2 h. More patients with lasmiditan achieved headache freedom and, in addition, freedom from the most bothersome symptom, that is, photophobia, than with placebo. Treatment-related side effects seem to be related to the rapid penetration of the drug into the brain and include dizziness, paresthesia and drowsiness, mostly of mild to moderate intensity. Interim results from an ongoing long-term phase III trial suggest a decrease in the frequency of adverse events after multiple lasmiditan use. Lasmiditan is a promising acute anti-migraine therapy, in particular for patients with cardiovascular risk factors, contraindications, or unwanted side effects to triptans.
Learn More >The earliest descriptions of botulism were in the early 19th century, and was reported by the German physician Justinus Kerner. The term "botulism" was derived from the Latin word botulus, indicating its original association with sausages. It took another 150 years or so to come into clinical use. The first clinical application was strabismus, and was developed by the American ophthalmologist Alan B. Scott, whose effort led to the pharmaceutical product known as onabotulinumtoxinA today. The therapeutic benefit in migraine was an incidental finding in a report by the American plastic surgeon William J. Binder, which inspired a series of clinical studies in headache disorders. The doses and injection techniques in the earlier reports were variable, so were the results. It was until the Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) 1 and 2 studies when its efficacy and safety, as well as the indication, i.e., chronic migraine (CM), were ascertained. Even though there were criticisms regarding the heterogeneities in the results between the PREEMPT 1 and 2 studies, the data on efficacy endpoints and safety were generally consistent, which were subsequently confirmed by the open-label extension of the PREEMPT 1 and 2 studies, and three open-label studies, namely the Chronic Migraine OnabotulinuMtoxinA Prolonged Efficacy open Label (COMPEL), the REal-life use of botulinum toxin for the symptomatic treatment of adults with chronic migraine, measuring healthcare resource utilization, and Patient-reported OutcomeS observed in practice (REPOSE) studies, and the CM Post-Authorization Safety Study (CM PASS) studies. On the other hand, the results were challenged by the Chronification and Reversibility of Migraine (CHARM) study, which involved CM patients with medication overuse. It was concluded that the clinical improvement was attributed to early withdrawal of the overused acute medications, rather than onabotulinumtoxinA injections. However, fundamental differences in the patient profile and methodology between the CHARM and PREEMPT studies existed, and cautious should be exercised when interpreting and comparing the results. According to the practical guidelines and reimbursement regulations in many countries, its use is limited to CM patients, and is reserved for those who fail at least 2-3 preventive medications, due to either lack of efficacy or intolerability. Cessation of treatment is recommended in patients who do not respond to 2-3 injection cycles, or in patients whose headache frequency has dropped to <10-15 days a month. Even in the era of calcitonin-gene-related peptide monoclonal antibodies, onabotulinumtoxinA injection remains a treatment option of reasonable cost-effectiveness in carefully selected patients.
Learn More >The "gepants" are a class of calcitonin gene-related peptide (CGRP) receptor antagonist molecules that have been developed for the prevention and treatment of migraine. Rimegepant is reported to act at the CGRP receptor, has good oral bioavailability, and has had positive clinical trial results. However, there is very little data available describing its receptor pharmacology. Importantly, rimegepant activity at the AMY receptor, a second potent CGRP receptor that is known to be expressed in the trigeminovascular system, has not been reported. The ability of rimegepant to antagonize activation of human CGRP, AMY, and related adrenomedullin receptors was determined in transfected in Cos7 cells. Rimegepant was an effective antagonist at both the CGRP and AMY receptor. The antagonism of both CGRP and AMY receptors may have implications for our understanding of the mechanism of action of rimegepant in the treatment of migraine.
Learn More >Interstitial cystitis/bladder pain syndrome (IC) is a debilitating condition of chronic pelvic pain with unknown etiology. Recently, we used a genetic approach in a murine model of IC to identify the lipase acyloxyacyl hydrolase (AOAH) as a modulator of pelvic pain. We found that AOAH-deficient mice have elevated pelvic pain responses, and AOAH immunoreactivity was detected along the bladder-brain axis. Lipidomic analyses identified arachidonic acid (AA) and its metabolite PGE2 as significantly elevated in the sacral spinal cord of AOAH-deficient mice, suggesting AA is a substrate for AOAH. Here, we quantified the effects of AOAH on phospholipids containing AA. Spinal cord lipidomics revealed increased AA-containing phosphatidylcholine in AOAH-deficient mice and concomitantly decreased AA-phosphatidylethanolamine, consistent with decreased CoA-independent transferase activity (CoIT). Overexpression of AOAH in cell cultures similarly altered distribution of AA in phospholipid pools, promoted AA incorporation, and resulted in decreased membrane fluidity. Finally, administration of a PGE2 receptor antagonist reduced pelvic pain in AOAH-deficient mice. Together, these findings suggest that AOAH represents a potential CoA-independent AA transferase that modulates CNS pain pathways at the level of phospholipid metabolism.
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