Publications > Journals > Journal of Exploratory Research in Pharmacology > Article Full Text


Flupirtine as a Potential Treatment for Fibromyalgia

  • Kim Lawson1,* ,
  • Attam Singh2,
  • Ilya Kantsedikas3,
  • Christopher Arthur Jenner2 and
  • Daniel Keith Austen2
 Author information
Journal of Exploratory Research in Pharmacology 2021;():-

DOI: 10.14218/JERP.2020.00043


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 this chronic condition. Pharmacological and non-pharmacological therapeutic approaches are often required as 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. Activation of Kv7 potassium channels and agonism at gamma-aminobutyric acid receptor A leading to indirect N-methyl-D-aspartate receptor antagonism is responsible for the analgesic effects of flupirtine and appears to be involved in other symptoms associated with fibromyalgia. Patients with fibromyalgia reported improved control of their symptoms without significant adverse effects in an observational audit in clinical practice. This article presents evidence that flupirtine, or related drugs, is a therapeutic option for the treatment of fibromyalgia. The pharmacology of flupirtine and mechanisms of action involved provide a spectrum of effects that would not only 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 would be of interest.


Widespread chronic pain, Fatigue, Fibromyalgia, Flupirtine maleate, Potassium channels


Chronic pain affects approximately 20% of the adult population in Europe, with up to two-thirds of patients reporting dissatisfaction with current therapies.1 Patients often receive complex treatment plans that combine pharmacological and non-pharmacological approaches. The limited understanding of basic underlying mechanisms and their complex interplay involved in the pathophysiology has led to chronic pain remaining a significant unmet medical need. Current therapeutic approaches for chronic pain often do not provide adequate relief and, because the central nervous system (CNS) is the location of many drug targets, various central side effects are often experienced by patients.2 As new ideas for analgesic drug design are urgently needed, the biological processes responsible for chronic pain have been the focus of preclinical research to identify potential targets for drug discovery.

Flupirtine, a selective neuronal potassium channel opener and non-opioid analgesic, has exhibited pain relieving activity in various animal models and humans without anti-inflammatory or antipyretic properties.35 Flupirtine was synthesized and first approved in Germany in the 1980s and is a triaminopyridine derivative with the chemical structure of 2-amino-3-ethoxy-carbonylamino-6-4-fluoro-benzylamino-pyridine. Flupirtine exhibits indirect N-methyl-D-aspartate (NMDA) receptor antagonism via activation of potassium channels, leading to the suppression of neuronal overexcitability.3,4 Thus, flupirtine has been used as an analgesic for the last 35 years in the management of pain and also exerts skeletal muscle relaxation and neuroprotection properties.35 Flupirtine is available as the maleate salt, a hydrophilic compound that is rapidly absorbed from the gastrointestinal tract with a bioavailability of 90%.6,7 The volume of distribution (Vd) of 100 mg of flupirtine is 154 L in healthy volunteers and is up to 84% bound to human albumin.6,7 The half-life of flupirtine depends on the route of administration, but is typically between 6.5–10.7 h. Following oral administration of 100 mg of flupirtine, clearance is 275 ml/min in healthy volunteers.6,7 Flupirtine is metabolized in the liver by peroxidase enzymes to the active N-acetylated analogue D13223 and 4-fluorohippuric, which are further oxidised and then conjugated to inactive metabolites. The most common adverse effects, which occurred within 6 months of treatment and are dose dependent, are dizziness, drowsiness, pruritis, dry mouth, gastric discomfort, nausea and muscle tremor.35

This article will consider the potential of flupirtine as a treatment for the chronic pain condition fibromyalgia. Relevant studies and publications have been identified using the search terms flupirtine and chronic pain in the literature databases MEDLINE, Web of Science, The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Methodology Register) and Google Scholar. In addition, evidence from a clinical observational audit is considered.


Chronic widespread pain is a primary characteristic of fibromyalgia, with the accompaniment of fatigue, disturbed sleep and cognitive issues.8,9 The four main types of pain are nociceptive, inflammatory, neuropathic and functional. Nociceptive pain is associated with tissue damage, whilst inflammatory pain is associated with an inflammatory response. Neuropathic pain is caused by nerve irritation or damage and functional pain is pain without an obvious cause. The pain experienced with fibromyalgia is characterized by reduced pressure pain thresholds with hyperalgesia and allodynia. Fibromyalgia has been classified by the American College of Rheumatology (ACR) 1990 criteria of widespread pain (for at least 3 months) in all four quadrants of the body and pain in 11 of 18 tender point sites.10 Revisions were introduced in 2010 to avoid reliance on use of tender points in assessment and to reflect the range of symptoms by including the assessment of somatic symptom severity (sleep disturbance, cognitive disturbance and fatigue) and widespread pain.11 The use of a fibromyalgia symptom scale to avoid potential misclassification of patients was the basis of further revision in the 2016 criteria.12 The prevalence of fibromyalgia is 0.4–8% of the worldwide population, with a greater incidence of diagnosis in females than males.9,13 The presence of co-morbidities exhibiting similar symptoms, e.g. chronic fatigue syndrome, often complicates the diagnosis of fibromyalgia.

Neuronal excitability due to amplified responses of the CNS to peripheral input has led to central sensitization (CS) being proposed to be involved in the pathophysiology of fibromyalgia (Fig. 1).9 Peripheral sensory generators, including nerve pathologies, neuro-inflammation, skeletal muscle abnormalities and ischaemia, evoke heightened activity of the CNS leading to the symptoms of fibromyalgia.14,15 Altered neurotransmitter functioning and possible neuroplasticity has been suggested to lead to the augmented sensory processing by the CNS.14 Further, systemic stress-related effects, such as alterations in the hypothalamic pituitary adrenal axis, the autonomic nervous system and cardiovascular system, are also proposed to contribute to the symptoms of fibromyalgia.9,14

Pathophysiology of fibromyalgia.
Fig. 1  Pathophysiology of fibromyalgia.

Amplified neuronal excitability within the central nervous system associated with activation of peripheral generators leads to central sensitization. Altered biochemistry and neurotransmitter levels are linked to the symptoms of fibromyalgia. Raised biochemical levels are indicated by an upward facing arrow and lowered biochemical are indicated by a downward facing arrow. CSF, cerebrospinal fluid.

As with many chronic pain conditions, pharmacological and non-pharmacological therapeutic approaches are often used in the treatment of fibromyalgia.8 The focus of drug therapies is often towards the treatment of pain by lowering levels of pro-nociceptive excitatory neurotransmission or/and increasing anti-nociceptive neuro-transmission rather than treating the overall condition.8 An altered biochemistry in fibromyalgia is consistent with the decreased activity of the descending serotonergic-noradrenergic efferent pathways responsible for an aberrant diffuse noxious inhibitory control (DNIC).9,14 Thus, current therapeutic options for fibromyalgia may modulate serotonin and noradrenaline levels, or act on voltage-gated calcium channel subunits.9 Although a few drugs have exhibited efficacy in the management of fibromyalgia symptoms, the outcomes are limited with only a proportion of patients experiencing a partial reduction of symptom severity, often only marginally better than placebo.16,17 The incidence of adverse effects leading many patients to discontinue use further limits the effectiveness of current medications.16,17 Thus, no definitive treatment or treatment algorithm exists with management guidelines indicating individualised approaches.12

Elevated glutamate, glutamine and glycine levels in pain-related brain regions, such as the posterior insula and cerebrospinal fluid, which correlate to the levels in pain in fibromyalgia, have been reported in brain spectroscopy studies.18,19 Thus, in this patient group, NMDA receptors in the spinal cord and brain are exposed to raised levels of glutamate. Several drugs that downregulate NMDA receptors, such as ketamine, dextromethorphan and memantine, reduce fibromyalgia-related symptoms.20 Drugs used in the management of fibromyalgia, such as gabapentin, pregabalin and certain antidepressants, reduce glutamate levels and may evoke an indirect effect on NMDA receptor activation.21,22

Flupirtine as a treatment of pain

Effective analgesia has been reported in a range of acute and chronic pain conditions, such as musculoskeletal pain, postoperative pain, migraine and neuralgia following treatment with flupirtine.5,23,24 Restoration of the normal sensitivity of over-excitable nociceptive pathways and inhibition of the stimulation of nociceptive neurons by factors such as inflammatory mediators (e.g. bradykinin) have been suggested to be responsible for the effects of flupirtine.25,26 In a post-marketing surveillance study of 7,806 patients, flupirtine (200–300 mg/day) exhibited effective analgesia after four weeks in more than 95% of patients with acute, subacute and chronic pain.27 Clinically relevant improvements in quality-of-life and sleep were also associated in addition to a direct effect on pain with flupirtine treatment, where the incidence of adverse effects was 0.9% with no serious events reported. Thus, flupirtine is well tolerated with mild and infrequent adverse effects.28 Flupirtine has been used extensively in clinical practice, as exemplified by 28.6 x 106 defined daily doses in Germany in 2010, supporting its use as a viable therapeutic treatment.2931

Short-term flupirtine, 100 mg twice daily, treatment in patients undergoing lower limb surgery and gynaecological ambulatory surgeries reduced pain levels comparable with, and gave patient satisfaction scores similar or superior to, the non-steroidal anti-inflammatory drugs (NSAID) piroxicam and ibuprofen.24,32 In both studies, there were no serious adverse effects reported with short-term (up to 5 days) flupirtine treatment. Flupirtine, at 100 mg, was reported to be preferable to pentazocine at 50 mg or tramadol at 50 mg for pain remission in controlled, double-blind clinical trials of patients with severe cancer pain.33,34 In an eight day, open-label study of palliative care patients with incurable cancer, flupirtine at 100 to 300 mg, four times daily, reduced pain scores and was associated with some reduction in opioid use.35 No serious adverse effects were observed and 80% of participants continued to take flupirtine after the trial with very good pain control until death. Flupirtine at 100 mg also evoked comparable efficacy to paracetamol at 1g in treating acute episodic tension-type headache or acute attacks of migraine.36,37

A meta-analysis of flupirtine in chronic pain showed that benefits were non-inferior to active comparators (e.g. tramadol, indomethacin, chlormezanone and pentazocine).38 Studies of flupirtine in chronic pain conditions are summarized in Table 1.3843 The conditions in which flupirtine was used varied significantly but were predominantly musculoskeletal in nature, of which lower back pain, a commonly associated symptom of patients with fibromyalgia, was the most studied chronic pain condition (67.2%). In patients with lower back pain, the efficacy of flupirtine was comparative with that of tramadol and superior to placebo, whilst the incident of treatment-emergent adverse effects and related study discontinuations was significantly lower in the flupirtine group relative to the tramadol group.39 The incidence of raised liver function tests (LFTs) was comparable in the flupirtine, tramadol and placebo groups. These observations are consistent with a previous lower back pain study where comparable efficacy for flupirtine and tramadol was observed but the incidence of adverse effects related to raised LFTs and number of discontinuation post treatment were significantly higher in the tramadol group (1% with flupirtine vs 15% with tramadol; p < 0.001).40 In an open-label study of osteoporosis-related pain (low back pain, neck pain, shoulder-arm pain), efficacy of flupirtine was also observed with low reporting of adverse effects (2.4% of patients) and withdrawal from the trial (1.4% of patients).41 The duration of treatment within these studies was short for chronic conditions and extrapolation of the data for a condition such as fibromyalgia may be limited. One long-term (12-month) treatment study investigated use of flupirtine in patients with chronic pain secondary to arthrosis or arthritis who had been treated with other analgesics (excluding NSAIDs).42 Most of the patients showed an improvement in pain intensity following flupirtine treatment despite a high drop-out rate, primarily due to ineffectiveness or adverse effects of which dizziness was the most common and, constipation and vomiting less frequent.

Table 1

Summary of chronic pain studies using flupirtine

ReferencesTypeSample size (n) and characteristicsMethodReported outcomesAdverse eventsDaily flupirtine dose, mgComparators
Ueberall et al.38Retrospective pooled analysis1,046 (efficacy)/1,096 (safety) patients with subacute and chronic musculoskeletal pain.Retrospective pooled analysis of individual patient data from 8 randomized controlled (by either placebo or other analgesic) Phase III–IV clinical trials. Efficacy evaluated using primary endpoints (pain scores) as defined in the original studies. Adverse events and treatment discontinuationsFor patients with subacute/chronic musculoskeletal pain, the efficacy of flupirtine was superior to placebo across its effective and approved dosage range. Flupirtine was non-inferior to the active comparatorsTEAE 28.6% vs 39.1% for comparators and 17.7% for placebo. Two most commonly reported TEAEs were nausea and vertigo. TEAE-related drug discontinuations 7.1% for flupirtine vs 11.7% for comparators.150–400Chlormezanone 200–800 mg; Indomethacin 75 mg; Pentazocine 150 mg; Tramadol 150 mg
Trials/case reports
Uberall et al.39Randomized, double-blind, active-/placebo-controlled double-dummy multicentre study363 patients with moderate-to-severe chronic low back pain (men and women 18–75-year old). Patients with organic causes of back pain and those with liver or renal impairment excluded.Patients randomised 1:1:1 to receive flupirtine MR 400 mg, tramadol ER 200 mg, or matching placebo (each given OD in the evening) over 4 weeks. Primary endpoint was change from baseline in the LBPIX (11–point NRS) at week 4; last observation carried forward was used to impute missing scores.Non-inferiority in LBPIX reduction compared to tramadol ER (mean ± SD: –2.23 ± 1.73 vs –1.92 ± 1.84, p < 0.001) and superiority to placebo (–1.81 ± 1.65, p = 0.003) on intention-to-treat analysis.TEAE 21.0%. TEAE-related study discontinuations 3.4%. AST and ALT; elevations were noted in 51% and 58.6% of flupirtine-treated patients. Similar rates of liver enzyme elevations were noted in the placebo group.400 (MR)Tramadol ER 200 mg; Placebo
Li et al.40Randomized, double-blind, parallel-group trial209 subacute low back pain patients (flupirtine group = 105, comparator group = 104; mostly Han Chinese, men and women aged 18–83 years).Patients orally treated with flupirtine vs tramadol for 5–7 days. Other analgesics and antidepressants were withdrawn. Outcome measures: patient assessment of pain intensity after 5–7 days (primary); physicians’ assessment of improvement in pain and functional capacity; adverse events.Flupirtine non-inferior to tramadol (pain relief rates of 57% (95% CI: 51–63%) and 56% (95% CI: 50–62%) respectively; p = 0.796).Adverse event rate in flupirtine group 33% vs 49% for tramadol. Most frequently events were vertigo, nausea and vomiting (tramadol) and vertigo and nausea (flupirtine). Transient changes in white cell count (4 in tramadol group, 2 in flupirtine group) and liver enzymes (1 in tramadol group, 3 in flupirtine) were observed, which resolved after end of treatment. Discontinuation rates: flupirtine 1% vs tramadol 15%.300 (100 TDS)Tramadol 50 mg TDS
Ringe et al.41Open-label, multicentre, prospective, observational study869 patients with osteoporosis-related pain (81% female, mean age 67 years). No exclusion criteria.Flupirtine up to 600 mg/day administered for an average duration of 3 (range 2–6) weeks. VAS for pain recorded. Multivariate analyses performed to determine factors associated with VAS pain reduction.Mean pain reduction at the end of flupirtine treatment: 43% for low back pain, 44% for neck pain, 40% for shoulder-arm pain and 40% for other pain (all reductions p < 0.05 vs baseline).2.4% reported adverse events (CNS side effects 1.3%, n = 11; GI side effects 1.1%, n = 10). 1.4% (n = 12) withdrew from trial. No serious adverse events were reported.270 (mean)None
Hermann et al.42Open-label, single-centre, prospective, observational study104 patients with chronic pain secondary to arthrosis or arthritis (preliminary report from a sample of 200). Mean age 61.59 years. Excluded patients on potent analgesics (excluding NSAIDs), those with decompensated cardiovascular, liver or renal diseases, pregnant and breast-feeding women, and women not practising contraception.12-month treatment with flupirtine followed by a 2-week period of placebo administration to assess withdrawal response. Withdrawal symptom scale completed monthly during the study then following the 2-week washout period.55 patients completed 12-month treatment with flupirtine. 49 dropouts 75% demonstrated a response to treatment. Degree of analgesic response and doses remained constant.The most frequent side effects were drowsiness (9% of patients), dizziness (11%), dry mouth (5%) and pruritus (9%). 49 patients dropped out: 15 due to side effects, 10 due to ineffectiveness, 7 due to side effects plus ineffectiveness, 3 due to side effects and other reasons, and 14 due to other or non-medical reasons. Lab abnormalities: transient rise in bilirubin or liver enzymes, returning to normal on study completion. Transient rise in creatinine and urea.300None
Stoll R.43Open-label case series4 fibromyalgia patients (aged 29–60, all female).Case series in which flupirtine was added to patient’s regular medications.Reduction of pain, sleep disturbance, fatigue and depressive symptomsDizziness, drowsiness, pruritus, dry mouth, nausea and headache.200 (100 BD) to 1,200 (300 QDS)N/A

Flupirtine exerts analgesic properties by activation of voltage-gated potassium channels belonging to the KCNQ Kv7 subfamily evoking hyperpolarization and stabilization of neuronal membranes, which indirectly reduces NMDA receptor activity.5,44,45 NMDA receptors are a major target in the prevention and treatment of hyper-algesic pain states, thus supporting the use of flupirtine in the treatment of neuropathic pain conditions. Affinity to NMDA receptors by flupirtine has not been reported in binding studies, supporting an indirect action.46 Peripheral and central nociceptive pathways contain Kv7 channels with expression in central terminals of primary afferents and dorsal horn neurons within the spinal cord.28,4749 Key locations of Kv7 channel expression in the nociceptive pathway include the thalamus, cerebral cortex and spinal cord. After peripheral injury, a decrease in expression of Kv7 channels in the peripheral nervous system, such as Aδ and C fibres, contributes to increased sensory neuron excitability, which would be suppressed by activation of the remaining Kv7 channels.50,51 Thus, enhancing or recovering the activity of Kv7 channels would lead to suppression of aberrant neuronal activity as observed in persistent pain conditions. Flupirtine has also demonstrated agonist properties at the gamma-aminobutyric acid receptor A (GABAA), possibly via reinforcement of GABA binding.52 Studies have suggested that flupirtine prefers δ-subunit containing GABAA receptors over γ-containing GABAA receptors.53 The different subunit compositions define specific pharmacological characteristics such that γ2-subunit containing receptors are modulated by benzodiazepines, whereas δ-subunits are highly sensitive towards neurosteroids (brain-synthesized metabolites of ovarian and adrenal cortical steroid hormones).54 These findings suggest that the pharmacological properties of flupirtine at GABA receptors differ from those of benzodiazepines. Although agonism at GABAA receptors is associated with the induction of addictive behaviours in certain drugs, such properties have had limited anecdotal reporting for flupirtine.55 Analysis of the database of the German Federal Institute for Drugs and Medical Devices (BfArM) for the period 1991 to 2013 only revealed 48 reports of flupirtine abuse or dependence.56 Further, treatment with flupirtine and development of addictive behaviour being de facto causative or mere correlation could not be clarified.

Thus, the analgesic activity of flupirtine may be due to a combined action on Kv7 channels and GABAA receptors in pain neural circuits. Although flupirtine failed to exhibit affinity for α1- or α2-adrenoceptors, or serotonin 5HT1 or 5HT2 stimulation of inhibitory brainstem monoaminergic pathways which descend to the spinal dorsal horn associated with the diffuse noxious inhibitory control (DNIC) has been postulated as a contributory factor for the analgesic effects.28,56 Further, no affinity for dopamine, benzodiazepine, opiate, central muscarinic or nicotinic receptors that have clinical relevance have been reported with flupirtine consistent with the limited adverse effect profile.28

Flupirtine as a treatment of fibromyalgia

Evidence of effectiveness of flupirtine for the treatment of fibromyalgia is lacking with only one published open-label case study. A reduction of the symptoms of fibromyalgia following treatment with flupirtine was reported in the open-label case study,43 suggesting a viable therapeutic approach (Table 1).

Having used flupirtine as an adjunct for patients with fibromyalgia in our practice, an observational audit of 14 patients offered the medication as a treatment option is presented in Table 2. Fibromyalgia was the sole condition for flupirtine use and diagnosis was made by patients meeting the ACR Diagnostic Criteria for Fibromyalgia 2010 and the absence of a possible cause noted from blood results and radiological imaging. The assessment of effectiveness was based on the patient perspective identified on co-administration of flupirtine with their current therapies. Benefit was reported throughout the period of flupirtine treatment which was the only common medication administered to all the subjects. The mean age of the patients was 53 (range: 27–72) years, of which 11 were female and three were male. Treatment duration ranged between 210 and 1,626 days up to the implementation of the European Medicine Agency’s withdrawal of flupirtine-containing medications.28 Dosages of flupirtine were variable (200–600 mg/day), with 100 mg at four times daily a common regimen and 50% of patients prescribed up to 600 mg within 24 hours. All patients reported ‘improvement’ in their symptoms following flupirtine treatment. This was self-reported, and despite the lack of numerical quantification, their persistence (up to 1,626 days) in continuing flupirtine treatment was consistent with a benefit in symptoms being gained. Thirteen patients reported an improved control of their symptoms with 50% of the cohort reporting a ‘significant’ to ‘excellent’ improvement. No significant adverse effects were reported and raised LFTs were not observed, even though 12 patients used flupirtine for 750 days or greater and eight of those patients had received treatment for more than 1,000 days continuously. Although numbers of patients in this observational audit were low, considering the higher dosages administered to and the duration of use (2–4.5 years) by the majority of the patients, the complications (rare serious liver injury) concerning the European Medicine Agency’s withdrawal of flupirtine-containing products were not evident. These findings support a controlled study to evaluate flupirtine treatment in patients with fibromyalgia who are identified as flupirtine responders.

Table 2

Observational audit of flupirtine treatment in patients with fibromyalgia in our clinical practice

Age/sexFlupirtine dose (mg) treatment durationOther medicationsTherapeutic effectLFTs and adverse reactionsDiagnosis
52/F100 QDS then MR 400 OD (767 days)Pregabalin 200 mg OM/300 mg ON; Amitriptyline 50 mg ON; Codeine 15–30 mg QDS PRNBaseline “pain score” 16/18 “overall having a better time, there has been some improvement”ALT 39 03/18. Normal prior to that.Fibromyalgia
72/F100 up to 6 times/day; Then MR 400 + IR 100 BD PRN (1,626 days)Butrans buprenorphine transdermal patch 20 µg/hour 1 patch every 7 days; Nortriptyline 10 mg OD“Beneficial”, keeping well and active, and doing lots of walking and gardening. Forced to reduce dose to MR 200 mg (in 2015 difficulties funding the prescription)–return of symptoms. Improved once dose increased back to MR 400 mg.Normal LFTs throughout.Fibromyalgia; Low back pain; Osteoarthritis (knees)
53/F100 mg QDS (1,292 days)Pregabalin 100 mg BD; Tapentadol 12.5 mg lunch and afternoon; Tapentadol 50 mg ON; Diazepam 5 mg PRN; Versatis (lidocaine) 5% topical patch 12 hrs/day; Zomorph (morphine sulphate MR) 10 mg ONSuccessful in reducing the pregabalin and tapentadol dosages, in particular tapentadol. She has been reducing steadily over the last 3 years.Normal LFTsFibromyalgia CRPS (lower limb); Pigmented villonodular synovitis; Degenerative disc disease in the cervical and lumbar spine
48/F100 mg up to 6 times/day (751 days)Pregabalin 300 mg BD; Duloxetine 120 mg OD; Zopiclone 7.5 mg ON PRN; Metoclopramide 10 mg TDS PRN; Tapentadol 50 mg BDPain score pre-flupirtine 8/10; Pain is under better control and her mobility has improved (14/09/2016)Normal LFTsFibromyalgia; Chronic migraine
36/F100 mg TDS PRN (1,029 days)Duloxetine 50 mg OD (and weaning); Meds before established on flupirtine: Amitriptyline 20 mg ON; Duloxetine 120 mg OD; Tapentadol 50 mg PRN (up to 400 mg)“Excellent progress, pain & other symptoms from the fibromyalgia much improved. Recently completed a 2 hours bike ride.” Patient very disappointed to learn flupirtine was discontinued.Normal LFTs. Stomach pain, headaches, muscle twitches and trembling initially.Fibromyalgia
27F100 mg up to 6 times/day (449 days)Dihydrocodeine MR 90 mg BD; Fluoxetine 60 mg OD; Diazepam 5 mg TDS PRN; Morphine (Oramorph) 2.5–5 mL TDS PRN; Meds before established on flupirtine: Baclofen 10 mg up to 6 times/day; Dihydrocodeine MR 60 mg BD; Duloxetine 90 mg OD; Paracetamol 1 g QDS; Propranolol 40 mg TDS; Calceos 2 tabs OD“… found the flupirtine to be of significant benefit reducing her pain and fatigue by approximately 40–50%”Normal LFTsFibromyalgia; Hypermobility syndrome
54/M100 mg 6 times/day (to TDS at time of discontinuation) (1,598 days)Amitriptyline 120 mg ON; Naproxen 500 mg BD PRN; Omeprazole 20 mg OD; Pregabalin 150 mg BDRefractory fibromyalgia, eventually symptoms sufficiently controlled to allow return to work, light exercise.Normal LFTs; Sleepy and agitated for approximately an hour after 3rd doseFibromyalgia
66/F100 mg BD (1,304 days)Ibuprofen 200 mg PRN (1,200 mg max/24 hours)“Finding flupirtine to be of benefit … fibromyalgia symptoms seem to be under relatively good control … doing extremely well.”Normal LFTsFibromyalgia
52/F100 mg up to 6 times/day (1,360 days)Gabapentin 200 mg TDS“… small improvement, with the addition of flupirtine, of approximately 15–20%” – on initiation. “… has not had any pain for some time …” – after 3 years of treatment. Fibromyalgia pain recurred after discontinuing flupirtine.Normal LFTsFibromyalgia
64/F100 mg QDS (750 days)Zopiclone 3.75 mg OD PRN; Tapentadol 50 mg TDS–QDSSome improvement overall with starting the flupirtine, tapentadol requirements have reduced.Normal LFTsNeuropathic pelvic pain; ME
64/F100 mg QDS (1,565 days)Amitriptyline 10–20 mg ON; Diazepam 5 mg PRN; Ibuprofen 400 mg TDS PRN; Epilim (valproate) 400 mg BD; Amlodipine 5 mg OD; Zopiclone 10 mg OD PRN“Flupirtine does take the edge off her pain.”; Patient’s own words: “it is the only thing that gives me a little relief”; NB. Patient with complex chronic pain who experienced adverse effects with a number of medications.Normal LFTsFibromyalgia; Myofascial pain syndrome; CFS; TMJ; Epilepsy (controlled); IBS; Central hypersensitivity syndrome
59/F100 mg 4–5 times/day (896 days)Dihydrocodeine 15–30 mg QDS PRN“…treated with the medication flupirtine on which she was stable & doing extremely well in terms of efficacy & minimal adverse effects”Normal LFTsNo diagnosis recorded
53/M100 mg 4–5 times/day (1,418 days)Tramadol 50 QDS; Trazadone 100 mg ON; Cyclobenzaprine 2.5 mg ON; Zolpidem 10 mg ON“…pain is under good control, with over 90% pain relief.”Normal LFTsFibromyalgia
43/M100 mg 6 times/day (210 days)Low-dose naltrexone 3 mg OD“… overall pain score has dropped from approximately 7 out of 10 to approximately 2/3 out of 10.”Normal LFTsFibromyalgia

Relevance of flupirtine to fibromyalgia

Flupirtine controlling the symptoms of fibromyalgia, particularly pain, is suggested from the included observational audit which is consistent with the observations of Stoll.43 Thus, activation of Kv7 channels in nociceptive pathways by flupirtine evokes analgesic benefit to patients with fibromyalgia.57 Kv7 channels have also been identified in nodose ganglion cells where nerve fibres involved in visceral perception in the respiratory organs, gastrointestinal organs and heart originate.58 Thus, the action of flupirtine on Kv7 channels, which regulate the sensitivity of visceral sensory neurons to noxious chemical and mechanical stimuli in humans,59 represent an additional property for the management of pathologies which can occur as comorbidities in fibromyalgia. NMDA receptor-mediated spinal mono- and poly-synaptic reflexes were attenuated in humans by flupirtine being treated with a 400 mg oral dose, suppressing rigidity in skeletal muscle and subsequent akinesia.60,61 The skeletal muscle relaxant and analgesic properties of flupirtine are demonstrated in the same dose range, and thus would be applicable in the treatment of fibromyalgia.

Reductions in gray matter volume, particularly in the anterior cingulate cortex, the prefrontal cortex and the insula areas of the brain, are consistently observed in patients with fibromyalgia.62 The atrophy in pain-related brain areas in fibromyalgia has been suggested to contribute to some of the symptoms.63 Flupirtine has been reported to exhibit neuro-protective activity in a variety of neurodegenerative disease models due to indirect antagonism of NMDA receptors, upregulation of the anti-apoptotic protein B-cell lymphoma 2 (Bcl2) and antioxidant activity via increased glutathione levels.6467 These effects are suggested to be due to mechanisms such as prevention of intracellular calcium overload and oxidative stress reduction associated with the analgesic properties of flupirtine.

Potential limitations of flupirtine

Mild increases in liver enzymes, bilirubin and creatinine have been observed in some patients, but are usually not viewed significant enough to interrupt treatment.68 Flupirtine has however been associated with very rare cases of severe drug-induced liver injury due to hepatotoxic metabolites.69,70 The incidence of flupirtine-related hepatobiliary adverse events in the BfArM database was estimated to be about eight in 100,000 patients (>0.01%).71 The reactive metabolites responsible for liver injury are detoxified via glutathione and thus, sufficient cellular glutathione stores will limit hepatotoxicity.70

The European Medicines Agency’s Pharmacovigilance Risk Assessment committee recommended risk minimization measures (RMM) for flupirtine (use only after other analgesics were trialled, patients restricted to up to two week-long treatments, with weekly LFT) due to concern of rare serious liver injury associated with long-term use of flupirtine.28 Limited adherence to the RMM led to withdrawal of flupirtine-containing medications from the European market in 2018.28 Serious liver injury, however, was not seen as a complication in the studies discussed above.

Future directions

The complex heterogenous disorder fibromyalgia is currently medically unmet with limited benefit gained from available therapies. The diversity of the symptoms of fibromyalgia and the related physiology suggests that to achieve effective therapeutic control drug treatments need to target multiple events, which has led to combination therapy as a standard approach. Kv7 channel activation alone or in combination with other pharmacological mechanisms of action, as exemplified by flupirtine, appears to exhibit a spectrum of pharmacology beneficial to patients with fibromyalgia that responded to this treatment. Development of novel Kv7 channel activators has gained interest, which could offer additional approaches for the management of complex clinical conditions.72 Thus, investigation in patient responders of the efficacy of flupirtine, or related drugs exhibiting a similar pharmacology, as a treatment approach would be of interest.


Flupirtine, an indirect NMDA receptor antagonist due to Kv7 channel activation and GABAA receptor agonism, is a novel analgesic medication with utility in the treatment of patients with fibromyalgia who have often proven refractory to standard anti-neuropathic pain medications.



American College of Rheumatology


central nervous system


gamma-aminobutyric acid


voltage-gated potassium channels


liver function test








Conflict of interest

The authors have no conflicts of interest related to this publication.

Authors’ contributions

DKA and KL proposed the aim of the work; AS, IK and KL carried out the literature search; AS, IK and CAJ evaluated and assembled the contents of Tables 1 & 2; KL wrote a draft of the manuscript that all authors contributed comments to. All authors were involved in the manuscript preparation, and have read and approved the manuscript.


  1. van Hecke O, Torrance N, Smith BH. Chronic pain epidemiology and its clinical relevance. Br J Anaesth 2013;111(1):13-18 View Article
  2. Gilron I, Dickenson AH. Emerging drugs for neuropathic pain. Expert Opin Emerg Drugs 2014;19(3):329-341 View Article
  3. Devulder J. Flupirtine in Pain Management Pharmacological Properties and Clinical Use. CNS Drugs 2010;24(10):867-881 View Article
  4. Harish S, Bhuvana K, Bengalorkar GM, Kumar T. Flupirtine: Clinical pharmacology. J Anaesthesiol Clin Pharmacol 2012;28(2):172-177 View Article
  5. Szelenyi I. Flupirtine, a re-discovered drug, revisited. Inflamm Res 2013;62(3):251-258 View Article
  6. Hlavica P, Niebch G. Pharmacokinetics and biotransformation of the analgesic flupirtine in humans (in German). Arzneimittelforschung 1985;35(1):67-74
  7. Abrams SM, Baker LR, Crome P, White AS, Johnston A, Ankier SI, et al. Pharmacokinetics of flupirtine in elderly volunteers and in patients with moderate renal impairment. Postgrad Med J 1988;64(751):361-363 View Article
  8. Lawson K. Emerging pharmacological strategies for the treatment of fibromyalgia. World J Pharmacol 2017;6(1):1-10 View Article
  9. Borchers AT, Gershwin ME. Fibromyalgia: a critical and comprehensive review. Clinic Rev Allerg Immunol 2015;49(2):100-151 View Article
  10. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 1990;33(2):160-172 View Article
  11. Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Katz RS, Mease P, et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res (Hoboken) 2010;62(5):600-610 View Article
  12. Macfarlane GJ, Kronisch C, Dean LE, Atzeni F, Häuser W, Fluß E, et al. EULAR revised recommendations for the management of fibromyalgia. Ann Rheum Dis 2017;76(2):318-328 View Article
  13. Queiroz LP. Worldwide epidemiology of fibromyalgia. Curr Pain Headache Rep 2013;17(8):356 View Article
  14. Clauw DJ. Fibromyalgia: a clinical review. JAMA 2014;311(15):1547-1555 View Article
  15. Üçeyler N, Zeller D, Kahn AK, Kewenig S, Kittel-Schneider S, Schmid A, et al. Small fibre pathology in patients with fibromyalgia syndrome. Brain 2013;136(Pt 6):1857-1867 View Article
  16. Häuser W, Jung E, Erbslöh-Möller B, Gesmann M, Kühn-Becker H, Petermann F, et al. The German fibromyalgia consumer reports - a cross-sectional survey. BMC Musculoskelet Disord 2012;13:74 View Article
  17. Wolfe F, Walitt BT, Katz RS, Lee YC, Michaud KD, Häuser W. Longitudinal patterns of analgesic and central acting drug use and associated effectiveness in fibromyalgia. Eur J Pain 2013;17(4):581-586 View Article
  18. Fayed N, Garcia-Campayo J, Magallón R, Andrés-Bergareche H, Luciano JV, Andres E, et al. Localized 1H-NMR spectroscopy in patients with fibromyalgia: a controlled study of changes in cerebral glutamate/glutamine, inositol, choline, and N-acetylaspartate. Arthritis Res Ther 2010;12(4):R134 View Article
  19. Pyke TL, Osmotherly PG, Baines S. Measuring glutamate levels in the brains of fibromyalgia patients and a potential role for glutamate in the pathophysiology of fibromyalgia symptoms: a systematic review. Clin J Pain 2017;33(10):944-954 View Article
  20. Littlejohn G, Guymer E. Modulation of NMDA receptor activity in fibromyalgia. Biomedicines 2017;5(2):15 View Article
  21. Puiu T, Kairys AE, Pauer L, Schmidt-Wilcke T, Ichesco E, Hampson JP, et al. Association of alterations in gray matter volume with reduced evoked-pain connectivity following short-term administration of pregabalin in patients with fibromyalgia. Arthritis Rheumatol 2016;68(6):1511-1521 View Article
  22. Harris RE, Napadow V, Huggins JP, Pauer L, Kim J, Hampson J, et al. Pregabalin rectifies aberrant brain chemistry, connectivity, and functional response in chronic pain patients. Anesthesiology 2013;119(6):1453-1464 View Article
  23. Mastronardi P, D’Onofrio M, Scanni E, Pinto M, Frontespezi S, Ceccarelli MG, et al. Analgesic activity of flupirtine maleate: a controlled double-blind study with diclofenac sodium in orthopaedics. J Int Med Res 1988;16(5):338-348 View Article
  24. Chinnaiyan S, Sarala N, Arun HS. A comparative study of efficacy and safety of flupirtine versus piroxicam in postoperative pain in patients undergoing lower limb surgery. J Pain Res 2017;10:2471-2477 View Article
  25. Busserolles J, Tsantoulas C, Eschalier A, López García JA. Potassium channels in neuropathic pain: advances, challenges, and emerging ideas. Pain 2016;157(Suppl 1):S7-S14 View Article
  26. Du X, Gao H, Jaffe D, Zhang H, Gamper N. M-type K+ channels in peripheral nociceptive pathways. Br J Pharmacol 2018;175(12):2158-2172 View Article
  27. Mueller-Schwefe G. Flupirtine in acute and chronic pain associated with muscle tenseness. Results of a postmarket surveillance study (in German). Fortschr Med Orig 2003;121(1):11-18
  28. Lawson K. Pharmacology and clinical applications of flupirtine: current and future options. World J Pharmacol 2019;8(1):1-13 View Article
  29. Schwabe U, Paffrath D. . Arzneiverordnungs-Report 2011. Springer Medizin Verlag; 2012 View Article
  30. Treudler R, Pohle K, Simon JC. Flupirtine is a safe alternative drug in patients with hypersensitivity to NSAIDs. Eur J Clin Pharmacol 2011;67(9):961-963 View Article
  31. Siegmund W, Modess C, Scheuch E, Methling K, Keiser M, Nassif A, et al. Metabolic activation and analgesic effect of flupirtine in healthy subjects, influence of the polymorphic NAT2, UGT1A1 and GSTP1. Br J Clin Pharmacol 2015;79(3):501-513 View Article
  32. Ahuja V, Mitra S, Kazal S, Huria A. Comparison of analgesic efficacy of flupirtine maleate and ibuprofen in gynaecological ambulatory surgeries: a randomized controlled trial. Indian J Anaesth 2015;59(7):411-415 View Article
  33. Scheef W. Analgesic efficacy and safety of oral flupirtine in the treatment of cancer pain. Postgrad Med J 1987;63(Suppl 3):67-70
  34. Lüben V, Müller H, Lobisch M, Wörz R. Treatment of tumor pain with flupirtine. Results of a double-blind study versus tramadol (in German). Fortschr Med 1994;112(19):282-286
  35. Goodchild CS, Nelson J, Cooke I, Ashby M, Jackson K. Combination therapy with flupirtine and opioid: open-label case series in the treatment of neuropathic pain associated with cancer. Pain Med 2008;9(7):939-949 View Article
  36. Pothmann R, Lobisch M. Acute treatment of episodic childhood tension-type headache with flupirtine and paracetamol – a double-blind crossover-study (in German). Schmerz 2000;14(1):1-4 View Article
  37. Million R, Finlay BR, Whittington JR. Clinical trial of flupirtine maleate in patients with migraine. Curr Med Res Opin 1984;9(3):204-212 View Article
  38. Ueberall MA, Mueller-Schwefe GH, Terhaag B. Efficacy and tolerability of flupirtine in subacute/chronic musculoskeletal pain – results of a patient level, pooled re-analysis of randomized, double-blind, controlled trials. Int J Clin Pharmacol Ther 2011;49(11):637-647 View Article
  39. Uberall MA, Mueller-Schwefe GH, Terhaag B. Efficacy and safety of flupirtine modified release for the management of moderate to severe chronic low back pain: results of SUPREME, a prospective randomized, double-blind, placebo- and active-controlled parallel-group phase IV study. Curr Med Res Opin 2012;28(10):1617-1634 View Article
  40. Li C, Ni J, Wang Z, Li M, Gasparic M, Terhaag B, et al. Analgesic efficacy and tolerability of flupirtine vs. tramadol in patients with subacute low back pain: a double-blind multicentre trial. Curr Med Res Opin 2008;24(12):3523-3530 View Article
  41. Ringe JD, Miethe D, Pittrow D, Wegscheider K. Analgesic efficacy of flupirtine in primary care of patients with osteoporosis related pain. A multivariate analysis. Arzneimittelforschung 2003;53(7):496-502 View Article
  42. Hermann KW, Kern U, Aigner M. On the adverse reactions and efficacy of long-term treatment with flupirtine: preliminary results of an ongoing twelve-month study with 200 patients suffering from chronic pain states in arthrosis or arthritis. Postgrad Med J 1987;63(Suppl 3):87-103
  43. Stoll AL. Fibromyalgia symptoms relieved by flupirtine: an open-label case series. Psychosomatics 2000;41(4):371-372 View Article
  44. Raffa RB, Pergolizzi JV. The evolving understanding of the analgesic mechanism of action of flupirtine. J Clin Pharm Ther 2012;37(1):4-6 View Article
  45. Rupalla K, Cao W, Krieglstein J. Flupirtine protects neurons against excitotoxic or ischemic damage and inhibits the increase in cytosolic Ca2+ concentration. Eur J Pharmacol 1995;294(2-3):469-473 View Article
  46. Osborne NN, Cazevieille C, Wood JP, Nash MS, Pergande G, Block F, et al. Flupirtine, a nonopioid centrally acting analgesic, acts as an NMDA antagonist. Gen Pharmacol 1998;30(3):255-263 View Article
  47. Passmore GM, Selyanko AA, Mistry M, Al-Qatari M, Marsh SJ, Matthews EA, et al. KCNQ/M currents in sensory neurons: significance for pain therapy. J Neurosci 2003;23(18):7227-7236 View Article
  48. Gribkoff VK. The therapeutic potential of neuronal Kv7 (KCNQ) channel modulators: an update. Expert Opin Ther Targets 2008;12(5):565-581 View Article
  49. Rivera-Arconada I, Roza C, Lopez-Garcia JA. Enhancing m currents: a way out for neuropathic pain?. Front Mol Neurosci 2009;2:10 View Article
  50. Linley JE, Rose K, Patil M, Robertson B, Akopian AN, Gamper N. Inhibition of M current in sensory neurons by exogenous proteases: a signaling pathway mediating inflammatory nociception. J Neurosci 2008;28(44):11240-11249 View Article
  51. Zheng Q, Fang D, Liu M, Cai J, Wan Y, Han JS, et al. Suppression of KCNQ/M (Kv7) potassium channels in dorsal root ganglion neurons contributes to the development of bone cancer pain in a rat model. Pain 2013;154(3):434-448 View Article
  52. Klinger F, Geier P, Dorostkar MM, Chandaka GK, Yousuf A, Salzer I, et al. Concomitant facilitation of GABAA receptors and Kv7 channels by the non-opioid analgesic flupirtine. Br J Pharmacol 2012;166(5):1631-1642 View Article
  53. Klinger F, Bajric M, Salzer I, Dorostkar MM, Khan D, Pollak DD, et al. δ-Subunit-containing GABAA receptors are preferred targets for the centrally acting analgesic flupirtine. Br J Pharmacol 2015;172(20):4946-4958 View Article
  54. Brickley SG, Mody I. Extrasynaptic GABA(A) receptors: their function in the CNS and implications for disease. Neuron 2012;73(1):23-34 View Article
  55. Szelenyi I, Nickel B, Borbe HO, Brune K. Mode of antinociceptive action of flupirtine in the rat. Br J Pharmacol 1989;97(3):835-842 View Article
  56. Gahr M, Freudenmann RW, Kölle MA, Schönfeldt-Lecuona C. Dependence on flupirtine. J Clin Pharmacol 2013;53(9):1003-1004 View Article
  57. Lawson K. Kv7 channels a potential therapeutic target in fibromyalgia: a hypothesis. World J Pharmacol 2018;7(1):1-9 View Article
  58. Wladyka CL, Kunze DL. KCNQ/M-currents contribute to the resting membrane potential in rat visceral sensory neurons. J Physiol 2006;575(Pt 1):175-189 View Article
  59. Peiris M, Hockley JR, Reed DE, Smith ESJ, Bulmer DC, Blackshaw LA. Peripheral KV7 channels regulate visceral sensory function in mouse and human colon. Mol Pain 2017;13:1744806917709371 View Article
  60. Schmidt WJ, Schuster G, Wacker E, Pergande G. Antiparkinsonian and other motor effects of flupirtine alone and in combination with dopaminergic drugs. Eur J Pharmacol 1997;327(1):1-9 View Article
  61. Schwarz M, Nolden-Koch M, Purr J, Pergande G, Block F. Antiparkinsonian effect of flupirtine in monoamine-depleted rats. J Neural Transm (Vienna) 1996;103(5):581-590 View Article
  62. Ceko M, Bushnell MC, Fitzcharles MA, Schweinhardt P. Fibromyalgia interacts with age to change the brain. Neuroimage Clin 2013;3:249-260 View Article
  63. Robinson ME, Craggs JG, Price DD, Perlstein WM, Staud R. Gray matter volumes of pain-related brain areas are decreased in fibromyalgia syndrome. J Pain 2011;12(4):436-443 View Article
  64. Gassen M, Pergande G, Youdim MB. Antioxidant properties of the triaminopyridine, flupirtine. Biochem Pharmacol 1998;56(10):1323-1329 View Article
  65. Perovic S, Schröder HC, Pergande G, Ushijima H, Müller WE. Effect of flupirtine on Bcl-2 and glutathione level in neuronal cells treated in vitro with the prion protein fragment (PrP106-126). Exp Neurol 1997;147(2):518-524 View Article
  66. Jaeger HM, Pehlke JR, Kaltwasser B, Kilic E, Bähr M, Hermann DM, Doeppner TR. The indirect NMDAR inhibitor flupirtine induces sustained post-ischemic recovery, neuroprotection and angioneurogenesis. Oncotarget 2015;6(16):14033-14044 View Article
  67. Kinarivala N, Patel R, Boustany RM, Al-Ahmad A, Trippier PC. Discovery of aromatic carbamates that confer neuroprotective activity by enhancing autophagy and inducing the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2). J Med Chem 2017;60(23):9739-9756 View Article
  68. Yadav G, Behera SS, Das SK, Jain G, Choupoo S, Raj J. Role of flupirtine as a preemptive analgesic in patients undergoing laparoscopic cholecystectomy. J Anaesthesiol Clin Pharmacol 2015;31(2):169-173 View Article
  69. Scheuch E, Methling K, Bednarski PJ, Oswald S, Siegmund W. Quantitative LC-MS/MS determination of flupirtine, its N-acetylated and two mercapturic acid derivatives in man. J Pharm Biomed Anal 2015;102:377-385 View Article
  70. Methling K, Reszka P, Lalk M, Vrana O, Scheuch E, Siegmund W, et al. Investigation of the in vitro metabolism of the analgesic flupirtine. Drug Metab Dispos 2009;37(3):479-493 View Article
  71. Anderson N, Borlak J. Correlation versus causation? Pharmacovigilance of the analgesic flupirtine exemplifies the need for refined spontaneous ADR reporting. PLoS One 2011;6(10):e25221 View Article
  72. Surur AS, Bock C, Beirow K, Wurm K, Schulig L, Kindermann MK, et al. Flurpirtine and retigabine as templates for ligand-based drug design of K(v)7.2/3 activators. Org Biomol Chem 2019;17(18):4512-4522 View Article
  • Journal of Exploratory Research in Pharmacology
  • eISSN 2572-5505

Flupirtine as a Potential Treatment for Fibromyalgia

Kim Lawson, Attam Singh, Ilya Kantsedikas, Christopher Arthur Jenner, Daniel Keith Austen
  • Reset Zoom
  • Download TIFF