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Ciguatera: A Treating Physician's Perspective on a Global Illness
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Ritchie C. Shoemaker, James C. Ryan
Ciguatoxins activate voltage-gated sodium channels and quickly depolarize neurons. At one time, only ciguatera was thought to induce reversal of hot/cold sensations. We now know that such unusual paresthesias and hot/cold reversals can also occur in acute Pfiesteria exposure, as well as in CIRS-WDB (R. Shoemaker, unpublished). The mechanism of “cold allodynia,” defined as exposure to cold (including mild cooling) creating severe burning pain, has been demonstrated by elegant studies done on ciguatoxin-exposed laboratory animals. Vetter (83) and Lewis produced cold allodynia in mice by injecting Pacific ciguatoxin into heels of subject animals. Ciguatoxin targeted both myelinated and nonmyelinated primary sensory neurons. Transient receptor potential ankyrin-1 (TRPA-1) expressing C-fibers, in the presence of sodium channel activation by ciguatoxin, drives calcium influx that causes the cold allodynia. Zimmerman (84), working with Vetter and Lewis, showed in animals that inhibitors of sodium channels, including flupirtine and lamotrigine, inhibited ciguatoxin-associated responses.
Facial pain
Published in Peter R Wilson, Paul J Watson, Jennifer A Haythornthwaite, Troels S Jensen, Clinical Pain Management, 2008
Peter Svensson, Lene Baad-Hansen
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen in combination with diazepam have been shown to provide significantly better pain relief compared to ibuprofen alone and placebo in myofascial TMD pain patients.54[II] However, naproxen (500 mg twice a day) is significantly better than celecoxib (100 mg twice a day) and placebo for the management of TMJ arthralgia.55[II] A short-acting benzodiazepine (triazolam) has also been shown to improve sleep but failed to provide significant pain relief in myofascial TMD patients.56[II] Cyclo-benzaprine (a muscle relaxant) has been shown to have a minor but significant effect on jaw-muscle pain upon awakening57[II] and it has been suggested that flupirtine (another muscle relaxant), with its additional effects on potassium channels and membrane-stabilizing actions, may be useful in management of myofascial TMD pain.58 [V] A combination of paracetamol, codeine, and doxylamine succinate (antihistamine) provided significantly greater pain relief than placebo in another study on mixed TMD patients.59[III] Also, low doses of tricyclic antidepressants (TCA) have been shown to provide significantly better pain relief than placebo.60[III] Open studies later supported the usefulness of TCAs in the management of persistent TMD pain.61[IV] Intra-articular morphine (0.1–1.0 mg) administered as a single dose has been shown to increase the pressure pain thresholds and mouth opening capacity and to reduce the visual analog scale (VAS) pain intensity. However, the clinical relevance of these findings was not impressive.62 [II] The use of botulinum toxin for myofascial TMD pain cannot be recommended at present due to inconclusive evidence.63, 64[II] Recently, evidence was presented in favor of gabapentin in the management of myofascial TMD pain and tenderness.65[II] There is clearly a need for more research before firm recommendations of specific pharmacological procedures in the management of TMD pain conditions can be given since there is only scattered, reliable information on the efficacy of most of the suggested drugs.66
Drug utilization patterns of flupirtine following implementation of risk minimization measures in Germany
Published in Current Medical Research and Opinion, 2019
Sigal Kaplan, Birgit Ehlken, Xenia Hamann
Consistent with results from previous replication studies8, these findings for a large prescription database support and strengthen the results of a previous analysis that was performed in a smaller electronic medical records database; that analysis characterized prescribing practices for flupirtine-containing medicinal products and assessed the effectiveness of all six RMM implemented in Germany4. That analysis and the current analysis were performed using the same study protocol and reported a comparable magnitude of change with RMM implementation in several measures. The previously reported study showed a considerable decrease in the number of patients prescribed flupirtine-containing products after RMM implementation of 34.4%4; similar to 41.0% in the current study. In addition, it demonstrated an increase in the proportion of patients prescribed flupirtine for short-term use (duration ≤14 days) of 16.5% from 74.8% to 91.3% for the pre- to post-implementation periods, respectively; similar to an increase of 22.7%, from 67.9% to 90.6%, in the current study. Moreover, similar to the previous study, the current study found that almost two-thirds of flupirtine prescriptions were not concomitantly prescribed with drugs known to have a potential hepatotoxic effect, suggesting that flupirtine was not the optimal drug of choice for more than a third of patients. Furthermore, in both studies, a large proportion of patients who were prescribed flupirtine had a drug therapy history that did not indicate any conditions contraindicated with the use of other analgesics.
Emerging drugs for focal epilepsy
Published in Expert Opinion on Emerging Drugs, 2018
Potassium channels are ubiquitous in neuronal and glial cell membranes and they are central to excitability [35]. Among all voltage-gated potassium currents, the M-current has been historically linked to epilepsy with the discovery of benign familial neonatal seizures, a rare autosomal dominant condition associated with mutations of KCNQ subfamily genes [36]. Retigabine is the prototype of potassium channels openers and represents the first in-class AED marketed so far. It is a structure analog of Flupirtine, a centrally acting nonopioid analgesic with also muscle relaxant and neuroprotective properties [37,38]. It was already known since the 1980s that Flupirtine had some anticonvulsant activity and its subsequent structure-activity optimization let to the development of Retigabine [39]. In 2013, shortly after having been marketed, GlaxoSmithKline (GSK) announced that there were safety issues with the drug as it could cause blue discoloration of the skin and eye abnormalities. As a consequence, GSK decided to discontinue the production of Retigabine in 2017. However, research on the potential role of potassium channel openers is epilepsy has progressed with the identification of other potential drugs like 1OP-2198.
Prescribers’ compliance is part of benefit-risk assessment of medicines and it can lead to failure of risk minimization measures and withdrawals of medicines
Published in Current Medical Research and Opinion, 2019
Flupirtine is an analgesic that was first approved in Germany in 1984. It is neither an opioid nor a non-steroidal anti-inflammatory drug (NSAID); acting as an opener of KCNQ (Kv7) potassium channels and blocker of glutamate N-methyl-D-aspartate receptor2,3. Therefore, flupirtine served as an alternative for other painkillers, primarily for treating pain associated with chronic musculoskeletal conditions. It was touted as an analgesic that has no cardiac, renal, or gastrointestinal adverse effects, and other complications that may limit therapeutic use of NSAIDs in the treatment of pain. Additionally, flupirtine was not associated with typical concerns associated with opioids, such as respiratory depression or constipation4.