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Objectives: Paclitaxel and docetaxel are two commonly used chemotherapeutic agents in the treatment of various types of cancers. However, debilitating taxane-induced arthralgia and myalgia are among the most common adverse reactions associated with taxanes, which has greatly influenced medical practitioners. Most of the mild and moderate analgesics were found to be less effective in the management of taxane induced pain. So we used flupirtine, a non-opioid analgesic, in the treatment of taxane-induced pain. Materials and Methods: In this study, we analysed the baseline pain score and follow-up data of 60 patients receiving a taxane-based chemotherapy regimen. Baseline data of these study populations experiencing significant taxane-induced pain were compared with follow-up data after treating them with analgesic flupirtine (200 mg/day). The baseline and follow-up data representing pain were assessed with the help of the Visual Analogue Scale (VAS), and the quality of life was determined using the Brief Pain Inventory (BPI) scale questionnaire. Results: The mean baseline and follow-up VAS score was compared using paired sample t-test, which showed a significant reduction in taxane-induced pain after treatment with flupirtine (P < 0.001). Similarly, the mean BPI score representing the quality of life before and after treatment with flupirtine was compared, and a notable improvement in quality of life was seen after treatment with flupirtine. The mean and follow-up data of aspartate aminotransferase and alanine aminotransferase levels of patients were also compared to assess the adverse drug reaction profile of the drug, and the analyzed data was found to be statistically insignificant (no significant liver toxicity) which indicates that drug can be used effectively for a period of Conclusion: We believe that flupirtine can be used as an effective analgesic in dire situations where patients require opioid analgesics for the management of taxane-induced pain, provided that the drug is given for

Preoperative anxiety is unpleasant sensation, due to parasympathetic, sympathetic and, endocrine stimuli, is often unspecific and unknown to the person and known to cause hemodynamic instability. It can also leads to various intraoperative and postoperative complications which are difficult to manage thus it must be considered one of the important factor to treat preoperatively. Flupirtine acts as antagonism of N-methyld- aspartate antagonism and stimulate neuronal kv7 channels causing analgesic action, better tolerability, preservation of respiratory functions, antiepileptic properties. Due to limited study of flupirtine as anxiolytic we conducted study to evaluate role of flupirtine in patients undergoing brain tumor surgeries. Materials and Methods: This study was done in 100 patients who were undergoing brain tumor surgery. All patients were randomly assigned in to two groups. One group received flupirtine 100 mg and other group received placebo. Before drug administration and 2 hours after drug regimen level of preoperative anxiety was noted in term of VAS score. Unpaired t-test was used for various aspects of two groups and paired t-test was used for within group comparison. Results: Compare to baseline, Reduction of VAS was seen in both groups. But reduction was significantly more in flupirtine group compare to placebo group without any side effects. Conclusion: Flupirtine is useful drug as anxiolytic in patients undergoing brain tumor surgery. Keywords: Anxiolytic, Preoperative Anxiety, Visual analog scale.

Objectives Acute drug-induced liver failure is a rare indication for liver transplant. There is only one case of flupirtine-induced liver failure requiring transplant in the literature. In February 2018, the European Medicines Agency issued a withdrawal of approval for flupirtine medication in European countries as a result of the risk of acute liver failure. Materials and methods The aim of this study was a German-wide collection of data regarding patients with liver transplant as a result of flupirtine-associated liver failure. Results A total of 9 patients received transplants. All patients were women with a mean age of 43 years. Indication for flupirtine medication was musculoskeletal symptoms and migraine headache. The medication was taken over a period of approximately 3 months. All patients developed progressive acute liver failure, and no patient had previous chronic liver disease or cirrhosis. The mean laboratory Model for End Stage Liver Disease score for the patients was 31 ± 7 at time of transplant. Eight of the 9 patients were listed as "high urgency" for transplant. After transplant, they had an uneventful course with a prolonged mean intensive care unit stay of 13 ± 8.7 days. The whole hospitalization time was 43 ± 21 days. Conclusions This is the largest published series of patients who received liver transplant after a drug-induced acute liver failure from flupirtine medication.

NSAIDs are the drugs most commonly used to alleviate pain. Despite being a heterogeneous group of compounds, all of them share a mechanism of action based on blockade of COXs enzymes, which confers them anti-inflammatory and analgesic properties. Diclofenac is a NSAID with preferred activity on COX-2 isozymes, but additionally, other targets may be implicated in its analgesic activity. Among them, diclofenac may facilitate the activity of Kv7 channels, that have been previously recognized as potential therapeutic targets in analgesia. In this study, the antinociceptive actions of diclofenac acting at the spinal level and the role of Kv7 channels in its effects were evaluated. Electrophysiological recordings of spinal reflexes and responses of dorsal horn neurons were obtained using in vitro spinal cord preparations from neonatal mice. Diclofenac, applied at clinically relevant concentrations to the entire preparation, depressed wind-up of spinal reflexes with a pattern similar to that of flupirtine, an analgesic with activity as Kv7 channel opener. Depressant actions of both compounds were strongly reduced after Kv7 channel blockade with XE-991, indicating the implication of these channels in the observed effects. Flupirtine, but not diclofenac, also reduced action potential firing of dorsal horn neurons in response to electrical activation of nociceptive afferents, suggesting differences in the actions of both compounds on Kv7 channel configurations present in sensory areas of the cord. Results demonstrate previously unknown central actions of diclofenac on Kv7 channels located in spinal circuits, expanding the knowledge about its pharmacological actions.

Background Hypoxia-ischemia (HI) is the most common cause of brain injury in newborns and the survivors often develop cognitive and sensorimotor disabilities that undermine the quality of life. In the current study, we examined the effectiveness of flupirtine, a potassium channel opener, shown previously in an animal model to have strong anti-neonatal-seizure efficacy, to provide neuroprotection and alleviate later-life disabilities caused by neonatal hypoxic-ischemic injury. Methods The rats were treated with a single dose of flupirtine for four days following HI induction in 7-day-old rats. The first dose of flupirtine was given after the induction of HI and during the reperfusion period. The effect of treatment was examined on acute and chronic brain injury, motor functions, and cognitive abilities. Results Flupirtine treatment significantly reduced HI-induced hippocampal and cortical tissue loss at acute time-point. Furthermore, at chronic time-point, flupirtine reduced contralateral hippocampal volume loss and partially reversed learning and memory impairments, but failed to improve motor deficits. Conclusion The flupirtine treatment regimen used in the current study significantly reduced brain injury at acute time-point in an animal model of neonatal hypoxic-ischemic encephalopathy. However, these neuroprotective effects were not persistent and only modest improvement in functional outcomes were observed at chronic time-points.

Introduction and Aim: Post-surgical pain treated with NSAIDs and opioids is associated with many adverse effects and poor patient satisfaction. Our aim was to study the effect of oral Flupirtine (200mg), as a pre-emptive analgesic in maxillo-facial surgeries. Materials and Methods: A total of 60 patients between 18-60 years, ASA I and II, scheduled for maxillo-facial surgeries were randomised to receive orally Flupirtine maleate capsule (200mg) or Vitamin B complex capsule 2 hrs prior to surgery under general anaesthesia. The severity grading of post operative pain and time taken for first analgesic dose requirement in the post operative period was measured using Visual Analogue Score (VAS) as the primary outcome. Sedation and adverse effects of Flupirtine, if any were studied as the secondary outcome. Results: Significant delay in demand for first postoperative analgesic dose was observed in the Flupirtine group. After the first four hours of postoperative period, we did not observe any difference in the analgesic demand between the two study groups. There was no significant sedation or adverse effects in the Flupirtine group. In addition, it was observed that hemodynamic response to intubation was significantly attenuated in the Flupirtine group. Conclusion: Oral Flupirtine maleate is a good pre-emptive analgesic devoid of any side-effects in maxillo-facial surgeries with significant attenuation of intubation response. Keywords: Flupirtine maleate, Maxillo-facial surgeries, Pre-emptive analgesia, Intubation response.

Objective: The objective of the study was to assess and compare the efficacy and tolerability of flupirtine versus tramadol in patients with chronic moderate low back pain (LBP). Materials and Methods: A prospective study was conducted in the outpatient department of orthopaedics at tertiary care hospital, Rajamahendravarm. After meeting the inclusion criteria, a total of 60 patients were randomly allocated to tablet flupirtine 100 mg in Group A and tablet tramadol 50 mg in Group B. The efficacy of the study drugs was assessed at baseline and the end of treatment by numerical rating scale11, visual analog scale-100 mm, physician’s, and patient’s global assessment. Statistical analysis was done using paired and unpaired t-test and data were presented as mean±standard deviation. Adverse drug reactions were monitored during the treatment. Results: The study results showed that 90% of the patients in Group A and 78% of the patients in Group B had shown a good response to their respective drugs. 30% of flupirtine group patients reported adverse drug reactions which were mild. Conclusion: Both the drugs are effective in the treatment of moderate chronic LBP, but the advantage of flupirtine was, the incidence of adverse drug reactions was less when compared to tramadol group.

Flupirtine is a non-opioid analgesic without antipyretic or antiphlogistic properties. Flupirtine is a centrally acting analgesic but the analgesic action of flupirtine does not depend on any central opioid effect. The fact behind this statement is that the pain-relieving property of flupirtine is not reduced by the opioid antagonistic drug naloxone. Flupirtine has been reported for its neuro-protective properties and possess a selective neuronal potassium channel opener that also has NMDA receptor antagonist properties. Flupertine is transformed into two primary derivatives, 4-fluoro-hippuric acid and the Nacetylated analogue D13223. Both derivatives of are flupirtine pharmacologically active with 30% of the analgesic potency of the parent drug and further oxidized and then conjugated with glycine to form inactive metabolites, Recently, Flupirtine maleate has been introduced in Indian market in oral, intravenous and rectal dosage forms. The half life of flupirtine following intravenous administration was 1.8 hours, while the plasma elimination half life in healthy young volunteers following single dose administration of flupirtine by the intravenous, oral and rectal routes was 8.5, 9.6 and 10.7 hours respectively. There is plenty of literature available on the effect of Flupirtine maleate on chronic and acute pain management. These preliminary finding require confirmation in further comparative studies. Keywords: Flupirtine maleate, Naloxone, Opioid, NMDA

The highly structurally similar drugs flupirtine and retigabine have been regarded as safe and effective for many years but lately they turned out to exert intolerable side effects. While the twin molecules share the mode of action, both stabilize the open state of voltage-gated potassium channels, the form and severity of adverse effects is different. The analgesic flupirtine caused drug-induced liver injury in rare but fatal cases, whereas prolonged use of the antiepileptic retigabine led to blue tissue discoloration. Because the adverse effects seem unrelated to the mode of action, it is likely, that both drugs that occupied important therapeutic niches, could be replaced. Reasons for the clinically relevant toxicity will be clarified and future substitutes for these drugs presented in this review.

Flupirtine is the first representative in a class of triaminopyridines that exhibits pharmacological properties leading to the suppression of over-excitability of neuronal and non-neuronal cells. Consequently, this drug has been used as a centrally acting analgesic in patients with a range of acute and persistent pain conditions without the adverse effects characteristic of opioids and non-steroidal anti-inflammatory drug and is well tolerated. The pharmacological profile exhibited involves actions on several cellular targets, including Kv7 channels, G-protein-regulated inwardly rectifying K channels and γ-aminobutyric acid type A receptors, but also there is evidence of additional as yet unidentified mechanisms of action involved in the effects of flupirtine. Flupirtine has exhibited effects in a range of cells and tissues related to the locations of these targets. In additional to analgesia, flupirtine has demonstrated pharmacological properties consistent with use as an anticonvulsant, a neuroprotectant, skeletal and smooth muscle relaxant, in treatment of auditory and visual disorders, and treatment of memory and cognitive impairment. Flupirtine is providing important information and clues regarding novel mechanistic approaches to the treatment of a range of clinical conditions involving hyper-excitability of cells. Identification of molecules exhibiting specificity for the pharmacological targets (e.g., Kv7 isoforms) involved in the actions of flupirtine will provide further insight into clinical applications. Whether the broad-spectrum pharmacology of flupirtine or target-specific actions is preferential to gain benefit, especially in complex clinical conditions, requires further investigation. This review will consider recent advancement in understanding of the pharmacological profile and related clinical applications of flupirtine.

BACKGROUND AND AIMS : Flupirtine is non-opioid, non- NSAID, centrally acting indirect NMDA receptor antagonist. Its analgesic effect is equivalent to NSAIDS and opioids with devoid of their side effects. Abdominal surgeries are the most painful surgeries amongst the surgical procedures. So we did a prospective randomised controlled study to evaluate the pre-emptive analgesic effect of flupirtine for postoperative pain relief in patients undergoing abdominal surgeries. MATERIALS AND METHODS : 60 patients of either sex posted for elective abdominal surgeries were included in this study. These patients were aged between 18 and 60 years with ASA physical status I and II. They were randomly divided into two groups, named group A and group B. Patients in group A received 2 oral placebo capsules and group B patients received 2 flupirtine 100mg capsules orally. Both drugs were administered two hours before the surgery. All patients underwent abdominal surgeries under general anaesthesia. In the postoperative period patients were assessed for intensity of pain using Numerical rating scale, Time to first rescue analgesia, Ramsey sedation score and side effects in the first 24 hours postoperative period. If NRS score ≥ 4, rescue analgesia tramadol 50mg iv was given at 4 hours interval. RESULTS : The mean NRS score was significantly (p = 0.00, p = 0.00) decreased in group B patients for the first 3 hours. The time to first rescue analgesia was significantly high (p=0.00) in flupirtine group patients. 60% of the patients in control group received rescue analgesia in the first hour of postoperative period. The mean RSS score was high in group B patients in the first 3 to 5 hours. Seven patients in flupirtine group were experienced side effects such as giddiness, nausea, vomiting and retrosternal discomfort. CONCLUSION : This study concludes that pre-emptive administration of oral flupirtine 200mg provides effective analgesia in the first 2 to 3 hours of postoperative period in patients undergoing abdominal surgeries with mild to moderate sedation.

Osteoarthritic pain has a strong impact on patients’ quality of life. Understanding the pathogenic mechanisms underlying osteoarthritic pain will likely lead to the development of more effective treatments. In the present study of osteoarthritic model rats, we observed a reduction of M-current density and a remarkable decrease in the levels of KCNQ2 and KCNQ3 proteins and mRNAs in dorsal root ganglia (DRG) neurons, which were associated with hyperalgesic behaviors. The activation of KCNQ/M channels with flupirtine significantly increased the mechanical threshold and prolonged the withdrawal latency of osteoarthritic model rats at 3–14 days after model induction, and all effects of flupirtine were blocked by KCNQ/M-channel antagonist, XE-991. Together, these results indicate that suppression of KCNQ/M channels in primary DRG neurons plays a crucial role in the development of osteoarthritic pain.

Aging is an independent risk factor for hypertension, cardiovascular morbidity, and mortality. However, detailed mechanisms linking aging to cardiovascular disease are unclear. We studied the aging effects on the role of perivascular adipose tissue and downstream vasoconstriction targets, voltage-dependent KV7 channels, and their pharmacological modulators (flupirtine, retigabine, QO58, QO58-lysine) in a murine model. We assessed vascular function of young and old mesenteric arteries in vitro using wire myography. We also performed bulk RNA sequencing and quantitative reverse transcription polymerase chain reaction tests in mesenteric arteries and perivascular adipose tissue to elucidate molecular underpinnings of age-related phenotypes. Results revealed impaired perivascular adipose tissue-mediated control of vascular tone particularly via KV7.3-5 channels with increased age through metabolic and inflammatory processes and release of perivascular adipose tissue-derived relaxation factors. Moreover, QO58 was identified as novel pharmacological vasodilator to activate XE991-sensitive KCNQ channels in old mesenteric arteries. Our data suggest that targeting inflammation and metabolism in perivascular adipose tissue could represent novel approaches to restore vascular function during aging. Furthermore, QO58 represents a novel tool for cardiovascular and hypertension research in aging.

Native M-current is a low-threshold, slowly activating potassium current that exerts an inhibitory control over neuronal excitability. The M-channel is primarily co-assembled by heterotetrameric Kv7.2/KCNQ2 and Kv7.3/KCNQ3 subunits that are specifically expressed in the brain and peripheral nociceptive and visceral sensory neurons in the spinal cord. Reduction of M-channel function leads to neuronal hyperexcitability that defines the fundamental mechanism of neurological disorders such as epilepsy and pain, indicating that pharmacological activation of Kv7/KCNQ/M-channels may serve the basis for the therapy. The well-known KCNQ opener retigabine (ezogabine or Potiga) was approved by FDA in 2011 as an anticonvulsant used for an adjunctive treatment of partial epilepsies. Unfortunately, retigabine was discontinued in 2017 due to its side effects of blue-colored appearance of the skin and eyes after prolonged intake. In addition, flupirtine, a structural derivative of retigabine and a centrally acting non-opioid analgesic, was also withdrawn in 2018 for liver toxicity. Fortunately, these side effects are compound-structures related and can be avoided. Thus, further identification and development of novel potent and selective Kv7 channel openers may lead to an effective therapy with improved safety window for anti-epilepsy and anti-nociception.

Acute intoxications are common causes of admission to the Emergency Department (ED). Flupirtine is a non-opioid analgesic, originally used for acute and chronic pain. Because of several reports of severe liver toxicity, its use was limited to acute pain in 2013 by the European Medicines Agency. Although withdrawn from the European market in March 2018, there are still flupirtine tablets in many households, and most people are unaware of the hazards they might be facing. A 58-year-old man was admitted to the ED after a suicide attempt with 1 g of flupirtine. He was lethargic and confused but presented no focal neurological deficits or other symptoms, and the rest of his clinical examination was unremarkable. His cerebral CAT and blood chemistry showed no alterations. The only remarkable feature was that he had green urine. After a careful literature search, a similar case was found caused by flupirtine intoxication. After 24 hours of vigilance in the ED, he improved his neurological status and his urine lost part of its greenish color. He was then transferred to the Psychiatric Department, where he presented a complete remission of the clinical alterations. A follow-up check-up showed no permanent deficits.

Since 1955, several alkyl-carbamates have been developed for the treatment of anxiety and epilepsy, including meprobamate, flupirtine, felbamate, retigabine, carisbamate, and cenobamate. They have each enjoyed varying levels of success as antiseizure drugs; however, they have all been plagued by the emergence of serious and sometimes life-threatening adverse events. In this review, we compare and contrast their predominant molecular mechanisms of action, their antiseizure profile, and where possible, their clinical efficacy. The preclinical, clinical, and mechanistic profile of the prototypical γ-aminobutyric acidergic (GABAergic) modulator phenobarbital is included for comparison. Like phenobarbital, all of the clinically approved alkyl-carbamates share an ability to enhance inhibitory neurotransmission through modulation of the GABAA receptor, although the specific mechanism of interaction differs among the different drugs discussed. In addition, several alkyl-carbamates have been shown to interact with voltage-gated ion channels. Flupirtine and retigabine share an ability to activate K+ currents mediated by KCNQ (Kv7) K+ channels, and felbamate, carisbamate, and cenobamate have been shown to block Na+ channels. In contrast to other alkyl-carbamates, cenobamate seems to be unique in its ability to preferentially attenuate the persistent rather than transient Na+ current. Results from recent randomized controlled clinical trials with cenobamate suggest that this newest antiseizure alkyl-carbamate possesses a degree of efficacy not witnessed since felbamate was approved in 1993. Given that ceno-bamate's mechanistic profile is unique among the alkyl-carbamates, it is not clear whether this impressive efficacy reflects an as yet undescribed mechanism of action or whether it possesses a unique synergy between its actions at the GABAA receptor and on persistent Na+ currents. The high efficacy of cenobamate is, however, tempered by the risk of serious rash and low tolerability at higher doses, meaning that further safety studies and clinical experience are needed to determine the true clinical value of cenobamate.

Sensory abnormalities generated by nerve injury, peripheral neuropathy or disease are often expressed as neuropathic pain. This type of pain is frequently resistant to therapeutic intervention and may be intractable. Numerous studies have revealed the importance of enduring increases in primary afferent excitability and persistent spontaneous activity in the onset and maintenance of peripherally-induced neuropathic pain. Much of this activity results from increased activity, modulation and /or expression of voltage-gated Na+ channels and hyperpolarization-activated cyclic nucleotide–gated (HCN) channels (particularly Nav1.3, 1.7, 1.8 and 1.9 and HCN2). Expression and/or function of K+ channels is reduced. This also increases excitability, alters axonal conduction and increases neurotransmitter release from primary afferent terminals in the spinal dorsal horn. The properties of nociceptive free nerve endings may also be affected. Although A-channels (Kv1.4, 3.3, 3.4, 4.1, 4.2 and 4.3), KCNQ or M-channels (Kv7.2, 7.3, 7.4 and 7.5) and ATP-sensitive channels (Kir6.2) have been extensively studied in this regard, less information is available for other K+ channel types particularly Ca2+-activated K+ channels (KCa1.1, 2.1, 2.2, 2.3 and 3.1), Na+-activated K+ channels (KCa4.1 and 4.2) and two pore domain leak channels (K2p; TWIK related channels). This review presents the distribution, physiological role and effect of injury on K+ channels in nociceptive and non-nociceptive primary afferents and how injury-induced changes might contribute to the onset and persistence of neuropathic pain. Whilst it is established that various mediators, including cytokines and growth factors bring about injury-induced changes in DRG function and excitability, evidence presently available points to a seminal role for interleukin 1 (IL-1) in control of K+ channel function. Despite the current state of knowledge, attempts to target K+ channels for therapeutic pain management have met with very limited success. Moreover, K+ channel activators such as pinacidil, retigabine, flupirtine and diazoxide which are approved for other therapeutic applications, have not gained widespread acceptance in the area of pain management. This situation may change with the advent of personalized medicine. Identification of specific sensory abnormalities and genetic profiling of individual patients may predict therapeutic benefit of K+ channel activators.

CLN3 disease is a fatal neurodegenerative disorder affecting children. Hallmarks include brain atrophy, accelerated neuronal apoptosis, and ceramide elevation. Treatment regimens are supportive, highlighting the importance of novel, disease-modifying drugs. Flupirtine and its new allyl carbamate derivative (compound 6) confer neuroprotective effects in CLN3-deficient cells. This study lays the groundwork for investigating beneficial effects in Cln3&Delta, ex7/8 mice. WT/Cln3&Delta, ex7/8 mice received flupirtine/compound 6/vehicle for 14 weeks. Short-term effect of flupirtine or compound 6 was tested using a battery of behavioral testing. For flupirtine, gene expression profiles, astrogliosis, and neuronal cell counts were determined. Flupirtine improved neurobehavioral parameters in open field, pole climbing, and Morris water maze tests in Cln3&Delta, ex7/8 mice. Several anti-apoptotic markers and ceramide synthesis/degradation enzymes expression was dysregulated in Cln3&Delta, ex7/8 mice. Flupirtine reduced astrogliosis in hippocampus and motor cortex of male and female Cln3&Delta, ex7/8 mice. Flupirtine increased neuronal cell counts in male mice. The newly synthesized compound 6 showed promising results in open field and pole climbing. In conclusion, flupirtine improved behavioral, neuropathological and biochemical parameters in Cln3&Delta, ex7/8 mice, paving the way for potential therapies for CLN3 disease.

Non-opioid analgesics are widely used for pain relief in palliative medicine. However, there is a lack of evidence-based recommendations addressing the efficacy, tolerability, and safety of non-opioids in this field. A comprehensive systematic review and meta-analysis on current evidence can provide a basis for sound recommendations in clinical practice. A database search for controlled trials on the use of non-opioids in adult palliative patients was performed in Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO, and EMBASE from inception to 18 February 2018. Endpoints were pain intensity, opioid-sparing effects, safety, and quality of life. Studies with similar patients, interventions, and outcomes were included in the meta-analyses. Our systematic search was able to only identify studies dealing with cancer pain. Of 5991 retrieved studies, 43 could be included (n = 2925 patients). There was no convincing evidence for satisfactory pain relief by acetaminophen alone or in combination with strong opioids. We found substantial evidence of moderate quality for a satisfactory pain relief in cancer by non-steroidal anti-inflammatory drugs (NSAIDs), flupirtine, and dipyrone compared with placebo or other analgesics. There was no evidence for a superiority of one specific non-opioid. There was moderate quality of evidence for a similar pain reduction by NSAIDs in the usual dosage range compared with up to 15 mg of morphine or opioids of equianalgesic potency. The combination of NSAID and step III opioids showed a beneficial effect, without a decreased tolerability. There is scarce evidence concerning the combination of NSAIDs with weak opioids. There are no randomized-controlled studies on the use of non-opioids in a wide range of end-stage diseases except for cancer. Non-steroidal anti-inflammatory drugs, flupirtine, and dipyrone can be recommended for the treatment of cancer pain either alone or in combination with strong opioids. The use of acetaminophen in the palliative setting cannot be recommended. Studies are not available for long-term use. There is a lack of evidence regarding pain treatment by non-opioids in specific cancer entities.

Livia Puljak1,2 1Laboratory for Pain Research, University of Split School of Medicine, Split, Croatia; 2Department for Development, Research and Health Technology Assessment, Agency for Quality and Accreditation in Health Care and Social Welfare, Zagreb, CroatiaOn October 16, 2017 in the Journal of Pain Research, a randomized controlled trial (RCT) comparing efficacy and safety of flupirtine versus piroxicam in postoperative pain in patients undergoing lower limb surgery was published.1 However, this paper fails to report important information.Author’s replySowmya Chinnaiyan,1 Narayana Sarala,1 Heddur Shanthappa Arun21Department of Pharmacology, 2Department of Orthopedics, Sri Devaraj Urs Medical College, Sri Devaraj Urs Academy of Higher Education and Research, Kolar, Karnataka, IndiaWe thank Livia Puljak for the valuable insights on the article titled “A comparative study of efficacy and safety of flupirtine versus piroxicam in postoperative pain in patients undergoing lower limb surgery” published in the Journal of Pain Research. The concerns highlighted in the Letter to the Editor have been answered.View the original paper by Chinnaiyan and colleagues.&nbsp

In this review of the literature on modern drugs and techniques to ensure multicomponent analgesia in surgical wards is presents. The technique of pre-emptive analgesia, which reduces the intensity of postoperative pain and contributes to the prevention of chronic postoperative pain. Clear instructions on the use of pharmacological agents (non-steroidal inflammatory drugs, gabapentin, ketamine) and preventive epidural anaesthesia are given. The characteristic of narcotic and non-narcotic analgesics are available for use after surgery and alsonefopam, flupirtine and gabapentine. The results of the application of the prolonged epidural analgesia using microinfusion elastomeric pumps are presents.

Yanfang Liu, Hua Huo, Zhibo Zhao, Wenli Hu, Yujia Sun, Yunbiao Tang Technical Center for Clinical Pharmacy, Department of Drug Clinical Trail Management Agency, General Hospital of Shenyang Military Area Command, Shenyang, China Aim: This study developed a high-performance liquid chromatography–tandem mass spectrometry method to simultaneously determine the concentrations of flupirtine and its major active metabolite D-13223 in human plasma in order to assess the bioequivalence (BE) of two flupirtine maleate capsules among healthy male Chinese volunteers under fasting and fed conditions. Materials and methods: There were two single-center, randomized, single-dose, open-label, laboratory-blinded, two-period, cross-over studies which included 24 healthy male Chinese volunteers under fasting and fed conditions, respectively. Plasma samples were collected prior to and up to 48h after dosing. The concentrations of flupirtine and its major active metabolite D-13223 in plasma samples were determined by a validated method, that is, high-performance liquid chromatography coupled with a tandem mass spectrometry detector. Pharmacokinetic metrics of area from time zero to the last measurable concentration (AUC0-t), area under the plasma concentration–time curve from administration to infinite time (AUC0-∞), and Cmax were used for BE assessment. Results: Forty-eight healthy volunteers who met the criteria were enrolled and completed the study. According to the observation of vital signs and laboratory measurement, no volunteers had any adverse reactions. Under fasting condition, the geometric mean ratios (90% CI) of the test/reference drug for flupirtine were 103.0% (98.1%–108.2%) for AUC0-t, 102.9% (98.2%–107.9%) for AUC0-∞, and 97.0% (85.9%–109.5%) for Cmax. Under fed condition, the geometric mean ratios (90% CI) of the test/reference drug for flupirtine were 101.7% (98.4%–105.1%) for AUC0-t, 101.6% (98.5%–104.8%) for AUC0-∞, and 103.5% (94.7%–113.0%) for Cmax. The difference between test and reference formulations, Tmax, was not statistically significant. The 90% CIs of the test/reference AUC ratio and Cmax ratio of D-13223 were also within the acceptance range for BE both under fasting and fed conditions. Conclusion: The two formulations of flupirtine maleate capsule were bioequivalent (the test and the reference products) under fasting and fed conditions, and thus both can be used interchangeably in the clinical setting. Keywords: flupirtine, D-13223, LC–MS/MS

Objective Status epilepticus (SE) is a neurological emergency requiring rapid termination of seizures. New treatment choices are needed for benzodiazepine-refractory SE or established SE (ESE). Previous studies have demonstrated that the potassium-channel opener flupirtine terminates seizures in neonatal animals. However, its effectiveness in adult ESE has not been tested. We tested whether flupirtine alone or in combination with the benzodiazepine diazepam would terminate ESE in three animal models. Methods SE was induced by administration of lithium followed by pilocarpine, by electrical stimulation of the hippocampus or by diisopropylfluorophosphate (DFP) administration. Seizures were assessed by EEG recorded from the hippocampus and cortex. Results Flupirtine alone did not terminate ESE within 60 min of administration in any of the three models of ESE. A combination of flupirtine and diazepam terminated ESE within 60 min in all the three models. The drug combination shortened the duration of ESE in all three models. Drug responsiveness was distinct between each model. Conclusion A combination of the potassium channel opener flupirtine and diazepam is a potential therapy for ESE.

BACKGROUND & AIMS The analgesic flupirtine has been linked to cases of severe idiosyncratic drug-induced liver injury (sFILI). We therefore examined whether N-acetylcysteine (NAC) and glucocorticoid therapy is effective in the management of sFILI. METHODS In a retrospective cohort study efficacy of NAC-infusion and oral prednisolone treatments on liver-function-tests (LFTs) and clinical outcome of 21 sFILI cases was evaluated by comparing it to an external cohort of 30 sFILI cases not receiving the antidote. LFTs were also assayed in human hepatocyte cultures treated with flupirtine for 96 hours. Additionally, modulation of glutathione stores in cultures of human hepatocytes treated with 80 drugs was investigated. RESULTS Upon admission, patients presented Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin elevations of up to 90-, 35- and 30-fold of upper limits of normal (ULN) respectively. The average INR was 2.2, and 50% of patients had a high Model for end-stage liver disease (MELD) score of ≥25 and included 5 cases of 28-32. The combined NAC/prednisolone treatment was well tolerated and led to significant ALT, AST and INR improvements within 2 weeks. However, the hyperbilirubinaemia resolved slowly. Two patients with late start of NAC/prednisolone treatment developed hepatic encephalopathy and required liver transplantation; the remaining patients recovered without long-term sequela. Based on serum biochemistries sFILI cases resolved more rapidly (P

We present the first case of fatality due to Flupirtine related acute liver failure from India. Flupirtine is an amino-pyridine with the centrally acting non-opioid analgesic property, used for acute and chronic pain. The drug is not used or approved in the United States and has restricted use status in the European Union due to severe hepatotoxicity and deaths or transplantation due to acute liver failure. Drug Council of India has not issued usage restriction or warnings regarding Flupirtine which is frequently used by physicians/orthopaedics and available over the counter. Unexpected and frequent hepatotoxicity of this drug, marketed for about 30 years needs caution, and safer analgesic use should be practiced.

Background Functional endoscopic sinus surgery (FESS) is the mainstay therapeutic management for nasal pathologies. We evaluated flupirtine, a centrally acting analgesic, for producing perfect perioperative conditions in FESS for adults in a day-care setting. Materials and methods Sixty-two patients (25-40 years) scheduled for FESS under general anesthesia were randomly divided into Group F (n = 31) receiving preoperative flupirtine (100 mg) and Group C (n = 31) receiving identical-looking placebo capsule per oral 60 min before induction of anesthesia. Perioperative Nasal bleeding and surgeon's satisfaction score during operation; amount and number of patients receiving fentanyl, propofol, and esmolol infusion for analgesia; maintenance of desired bispectral index (BIS) and deliberate hypotension, respectively. Postanesthesia Care Unit (PACU) and hospital stay, hemodynamic parameters, and side effects were all recorded for each patient. Results Significantly, less number of patients and less dosage of esmolol were required (P = 0.0040 and 0.0001, respectively) in Group F as compared to that in Group C. Again, number of patients requiring fentanyl and dosage of the same drug was significantly lower in Group F. Dose of propofol for the maintenance of BIS was significantly lower in Group F. However, the duration of controlled hypotension was almost similar in both groups. Group F patients suffered significantly less nasal bleeding and surgeon's satisfaction score was also high in this group. Discharge time from PACU and hospital was similar between two groups without any appreciable side effects. Conclusion Flupirtine as a premedication found to be providing more favorable perioperative hemodynamic conditions, analgesia and thus allowing less nasal bleeding as well as more surgeons' satisfaction score.

Background: Kv7 neuronal channels are recognized as a potential drug target for anxiolytic effects. We hypothesize that flupirtine as a potassium channel opener would effectively reduce the preoperative anxiety of patients undergoing craniotomy procedure. Methods: In prospective-double-blinded fashion, 124 counseled patients were randomized to receive 5 sequential doses of capsule flupirtine 100 mg (F Group) or physically similar starch capsules (C Group), at 12 h intervals during preoperative hospitalization. Primary outcome included various aspects of patient anxiety measured by visual analog scale (VAS) just before preoperative counseling and 2 h after the completion of drug regimen under trial. Statistical tool included Mann–Whitney U-test and Wilcoxon signed rank test. Results: Baseline VAS scores were higher for fear of surgical harm, being at the mercy of medical staff, and not awakening after surgery. A significant decline in VAS scores was observed after the completion of drug regime, but to a higher extent in flupirtine-treated patients; it achieved statistical significance in comparison to Group C. No side effects were observed in any patient. Conclusion: Flupirtine is a useful premedication in conjunction with behavioral therapy to alleviate patient anxiety during the preoperative period.

This review summarizes the efforts of our laboratories to develop a mechanism-based therapy for the treatment of organophosphate (OP) nerve agent-induced seizures. Organophosphate poisoning can occur during warfare and terrorist attacks and in the civilian sphere because of intentional or unintentional poisoning. Persons exposed to OPs experience seizures. We developed animal models of OP poisoning and then evaluated the effects of OP on excitatory α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated glutamatergic neurotransmission in the hippocampus using patch-clamp electrophysiology. Organophosphate agents enhance glutamatergic transmission by enhancing neurotransmitter release. M1 muscarinic receptors mediate this effect, at least in part. Muscarinic receptors exert this action by inhibiting specific KCNQ2/3 potassium channels, which mediate the M-current. Flupirtine, a drug that open channels, is effective against OP-induced seizures. This article is part of the Special Issue"Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".

Risk minimization measures (RMMs) were implemented to prevent or reduce the possibility of serious adverse reactions associated with exposure to a medicine, or to reduce their severity impact on th...

Introduction: Gout arthritis is an inflammatory disease characterized by severe acute pain. The goal of pharmacological gout arthritis treatments is to reduce pain, and thereby increase the patient’s quality of life. The Kv7/M channel activators retigabine and flupirtine show analgesic efficacy in animal models of osteoarthritic pain. We hypothesized that these drugs may also alleviate gout arthritis pain. Objective: To determine the effects of retigabine and flupirtine on pain behavior associated with monosodium urate (MSU)-induced gout arthritis. Methods: The gout arthritis model was established with an intra-articular injection of MSU into the right ankle joint, animals were treated with retigabine or flupirtine, and pain-related behaviors were assessed. Results: Retigabine and flupirtine significantly increased the mechanical threshold and prolonged the paw withdrawal latency in a rat model of gout arthritis pain in a dose-dependent manner. The antinociceptive effects of retigabine and flupirtine were fully antagonized by the Kv7/M channel blocker XE991. Conclusion: Retigabine and flupirtine showed antinociceptive effects for MSU-induced gout pain at different times during pain development.

Objectives: This report characterizes flupirtine prescribing patterns before and after the implementation of risk minimization measures (RMM) in Germany as a complementary analysis to suppo...

Flupirtine, a nonopioid analgesic drug, is effective in treating neonatal seizures. However, its brain delivery and pharmacokinetics are unknown in neonatal mammals. The purpose of this study was to determine the pharmacokinetics of flupirtine and the formation of its active metabolite D-13223 in various tissues such as brain in neonate animals. On postnatal day 7, rat pups received 25 mg/kg of flupirtine intraperitoneally. Liver, heart, kidney, lung, spleen, retina, serum, and brain regions hippocampus, cortex, and the remaining brain (devoid of cerebellum) were harvested up to 24-h postdosing. An LC-MS/MS assay was developed to quantify flupirtine and D-13223. Flupirtine was delivered to all tissues assessed, with the highest area under the concentration vs. time curve (AUC0&ndash, 24h) in liver (488 &micro, g&middot, h/g tissue) and the lowest in spleen (82 &micro, h/g tissue). Flupirtine reached the brain, including the hippocampus and cortex, within 1 h of dosing and persisted at 24 h. Flupirtine AUC in various brain regions was approximately 195 &micro, h/g tissue. The half-life of flupirtine in various tissues ranged from 3.1 to 5.2 h. D-13223 was formed in vivo and detected in all tissues assessed, with the concentrations being the highest in the liver. Incubation of isolated neonatal rat liver, heart, kidney, lung, spleen, whole eye, serum, or whole brain with flupirtine for 3 h at 37 &deg, C formed D-13223 in all tissues, except serum. D-13223 formation was the highest in isolated liver tissue. Tissue partition coefficients based on isolated tissue uptake correlated well with in vivo tissue:serum drug exposure ratios. Thus, flupirtine reaches the target brain tissues from the systemic route in neonatal rats, and brain tissue forms the active metabolite D-13223.

Fibromyalgia is a complex disorder characterised by chronic pain, fatigue, sleep disturbance and cognitive dysfunction with limited benefit gained with current therapies. The mean global prevalence of 2.7% is estimated for\ud this chronic condition. Pharmacological and non-pharmacological therapeutic approaches are often required as\ud treatments of the challenges associated with fibromyalgia. Flupirtine, a non-opioid drug, exhibits effective analgesia in a range of acute and persistent pain conditions, and evidence as treatment of fibromyalgia is considered.\ud Activation of Kv7 potassium channels and agonism at gamma-aminobutyric acid receptor A leading to indirect\ud N-methyl-D-aspartate receptor antagonism is responsible for the analgesic effects of flupirtine and appears to be\ud involved in other symptoms associated with fibromyalgia. Patients with fibromyalgia reported improved control\ud of their symptoms without significant adverse effects in an observational audit in clinical practice. This article\ud presents evidence that flupirtine, or related drugs, is a therapeutic option for the treatment of fibromyalgia. The\ud pharmacology of flupirtine and mechanisms of action involved provide a spectrum of effects that would not only\ud control the chronic pain characteristic of fibromyalgia but many of the other symptoms. Thus, further investigation of the efficacy of flupirtine or related drugs exhibiting a similar pharmacology as a treatment of fibromyalgia\ud would be of interest.

Objective Flupirtine is a nonopioid analgesic with regulatory approval in a number of European countries. Because of the risk of serious liver injury, its use is now limited to short-term pain management. We aimed to identify genetic risk factors for flupirtine-related drug-induced liver injury (DILI) as these are unknown. Materials and methods Six flupirtine-related DILI patients from Germany were included in a genome-wide association study (GWAS) involving a further 614 European cases of DILI because of other drugs and 10588 population controls. DILI was diagnosed by causality assessment and expert review. Human leucocyte antigen (HLA) and single nucleotide polymorphism genotypes were imputed from the GWAS data, with direct HLA typing performed on selected cases to validate HLA predictions. Four replication cases that were unavailable for the GWAS were genotyped by direct HLA typing, yielding an overall total of 10 flupirtine DILI cases. Results In the six flupirtine DILI cases included in the GWAS, we found a significant enrichment of the DRB1*16:01-DQB1*05:02 haplotype compared with the controls (minor allele frequency cases 0.25 and minor allele frequency controls 0.013; P=1.4x10(-5)). We estimated an odds ratio for haplotype carriers of 18.7 (95% confidence interval 2.5-140.5, P=0.002) using population-specific HLA control data. The result was replicated in four additional cases, also with a haplotype frequency of 0.25. In the combined cohort (six GWAS plus four replication cases), the haplotype was also significant (odds ratio 18.7, 95% confidence interval 4.31-81.42, P=6.7x10(-5)). Conclusion We identified a novel HLA class II association for DILI, confirming the important contribution of HLA genotype towards the risk of DILI generally. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved

Background: Flupirtine (FP) is found to antagonize both glutamate and N methyl, D aspartate (NMDA) and the current study was undertaken to elucidate a possible neuroprotective role of flupirtine against NMDA induced neurotoxicity in experimental rat model. Methods: Excitotoxicty was produced in rat and it is counteracted by flupirtine. The animals were grouped as Group 1 (vehicle treated), Group 2 (received NMDA+vehicle), Group 3 (received FP+NMDA only), and Group 4 (received FP+vehicle) and were observed of animal behavior and oxidative stress biomarkers and also mRNA expression using reverse transcriptase-polymerase chain reaction (PCR PCR) was performed to determine the level of mRNA expression of acetyl cholinesterase (AChE) and muscarinic cholinergic receptor (MChR) in brain samples (hippocampus) of experimental animals. Results: Depression effect induced by NMDA was reversed by flupirtine. Decrease in oxidative stress bio-markers associated with increase in the antioxidant enzyme activities in group 3 and 4 compared to group 1 and 2. Gene expression were up-regulated in group 2 compared to 1, 3 and 4. Flupritine treatment reversed these alterations. Conclusions: This study represents the neuroprotective characteristics of flupiritne against the excitotoxicity induced by NMDA in an in vivo rat models.

The efficacy of KCNQ2/3 channel agonists against drug reward has not been defined despite their ability to reduce locomotor-stimulant and dopamine-activating effects of psychostimulants. We tested the hypothesis that flupirtine (FLU) (2.5, 10, 20 mg/kg), a KCNQ2/3 agonist, reduces cocaine (15 mg/kg) conditioned place preference. FLU (20 mg/kg), injected concurrently with cocaine during conditioning, reduced the development of cocaine conditioned place preference. FLU (20 mg/kg) also reduced cocaine locomotor activation without affecting baseline activity. The disruption of cocaine place preference by FLU suggests that KCNQ2/3 channels influence cocaine's rewarding effects.

Fibromyalgia is characterized by the primary symptoms of persistent diffuse pain, fatigue, sleep disturbance and cognitive dysfunction. Persistent pain conditions, such as fibromyalgia, are often refractory to current available therapies. An involvement of K+ channels in the pathophysiology of fibromyalgia is emerging and supported by drug treatments for this condition exhibiting action at these molecular processes. K+ channels constitute potential novel target candidates for pain therapy offering peripheral and/or central actions. The Kv7 channel activators, flupirtine and retigabine, have exhibited pharmacological profiles compatible to the requirements needed for use as a therapeutic approach to fibromyalgia. Clinical trials to address the multidimensional challenges of fibromyalgia with flupirtine and retigabine will provide important insight to the role of K+ channels in this condition.

Objective: In response to safety concerns, risk minimization measures (RMM) for flupirtine were implemented in Europe in 2013 to reduce hepatotoxicity risk. This study aims to characterize compliance and prescribing practices of flupirtine before and after RMM implementation. Research design and methods: A retrospective pre–post design cohort study was conducted in the outpatient setting using a longitudinal electronic medical record database in Germany. The study population included patients who initiated flupirtine. One-year pre- and post-implementation periods were assessed. Main outcome measures: Six RMM elements were evaluated, including indication of acute pain, use for maximum of 2 weeks, use when other analgesics are contraindicated, no pre-existing liver disease or alcohol abuse, no concomitant drug induced liver injury, and weekly liver function tests. Results: The number of flupirtine users decreased by 34.4% from 18,291 in the pre-implementation period (2012) to 12,000 in the post-implementation period (April 2015 to March 2016). Elements of RMM with substantial improvement included flupirtine prescription duration, where the proportion of patients with duration ≤14 days increased significantly by 16.5% from 74.8% to 91.3% in the pre- and post-implementation periods, respectively. RMM with a moderate-to-high degree of compliance during the post-implementation period, although with a very small or no change from the pre- implementation period, included restriction of flupirtine prescribing to patients with acute pain when other analgesics are contraindicated, and avoiding use in patients with either pre-existing liver disease or concomitant drugs known to have a potential hepatotoxic effect. Weekly liver function tests had a low degree of compliance. Conclusions: These findings demonstrate that, while physicians restricted flupirtine prescriptions to short-term use in the target population of acute pain, not all drug labeling elements were followed to the same extent in routine practice.

Flupirtine, an effective analgesic, but hepatotoxicity should limit its use. Flupirtine has indeed been shown in multiple studies to be an effective analgesic for acute pain. However, following this new evidence and EMA’s latest decision, it appears there may be a good reason that flupirtine should be neglected.

A patient is admitted with complaints of recent onset nausea, discomfort, jaundice and blood tests that reveal severe hepatitis. At the time, she had been taking medication with Hypericum perforatum (St John’s wort) for 6 months, and 6 weeks before this event, she took flupirtine maleate. A few days after being admitted, she developed encephalopathy progressing to acute liver failure (ALF) requiring unsuccessful liver transplantation. The patient was ultimately diagnosed with drug-induced liver injury (DILI). In this context, while H. perforatum could interfere with other medication or trigger DILI itself, flupirtine appears to have triggered the DILI, given its liver toxicity capacity. DILI is one of the major ALF causes and can jeopardise patient’s life. Accordingly, all efforts to reduce medication potentially hazardous to the liver are recommended.

Introduction: Many peripheral and central causes lead to neuropathic pain disorders. Effective treatment of neuropathic pain is not completely manageable and hence, it becomes necessary to evaluate the application of Zonisamide as a sodium channel and T-type calcium (Ca+) current inhibitors and Flupirtine by activation of potassium (K) channel through N-methyl-D-aspartate (NMDA) receptor inhibition in the treatment of neuropathic pain. Aim: To analyze the analgesic effect of Zonisamide and Flupirtine in paclitaxel induced neuropathic pain model in rats by hot plate and cold allodynia test. Materials and Methods: Total of six groups of animals, each with six rats were given with single intraperitoneal (i.p.) injection of 1 mg/kg of paclitaxel on four alternate days (day 0, 2, 4, and 6). Drugs Zonisamide (50 mg/kg daily for group 2, 100 mg/ kg daily for group 3, Flupirtine (10 mg/kg, daily for group 4, 20 mg/kg daily for group 5) and Gabapentin daily for group 6 were administered in the dosages per group from days 0 to 7. Nociceptive tests were done for all animals on days 0, 7, 14, 21, 28 to assess the pain threshold. Student's t-test was used to analyze the statistical significance. Results: In our study, on the 21st day of testing we observed that 100 mg/kg dosage of Zonisamide group has shown a significant increase in reaction time suggesting analgesic effect. Prominent increase in the reaction time was also observed that on day 14 of testing, both the Gabapentin and Flupirtine groups showed an earlier analgesic effects when compared with the Zonisamide group. Conclusion: Zonisamide and Flupirtine showed anti-nociceptive activity in the Paclitaxel model of peripheral neuropathy compared with the standard treatment of Gabapentin.

Combination therapy with two or more analgesics is widely used for conditions associated with moderate to severe pain. Combinations of diverse analgesics with different modes of action can improve the risk-benefit ratio of analgesic treatments. The aim of this study is to evaluate the antinociceptive effect of tapentadol (TAP) and flupirtine (FLP), when administered separately or in combination, as well as their synergistic interaction in the orofacial formalin test in rats. After i.p. injection of TAP at different doses (2, 5, 10 and 15 mg/kg), the biphasic nociceptive behavior was reduced in a dose-dependent manner in both phase I and II. Conversely, i.p. injection of FLP at different doses (0.6, 1.6, 3.3, 6.6, 16.6 and 22.2 mg/kg) induced a dose-dependent antinociceptive effect in phase II only. TAP was found to be more effective than FLP. The interaction between TAP and FLP was synergistic in phase II with an interaction index (γ) of 0.50±0.24. The data reported in this study indicate that FLP enhances the antinociceptive effect of TAP and this drug combination might be potentially useful in the treatment of chronic pain.