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Flupirtine

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Flupirtine
BERJAYA
BERJAYA
Clinical data
Trade namesKatadolon, others
Other namesFlupertine
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral
Drug classAnalgesic; KCNQ potassium channel opener
ATC code
Pharmacokinetic data
Bioavailability90% (oral), 70% (rectal)[1]
MetabolismHepatic to 2-amino-3-acetylamino-6-(para-fluorobenzylamino) pyridine (which has 20-30% the analgesic potential of its parent compound), para-fluorohippuric acid[2] and a mercapturic acid metabolite, presumably formed from a glutathione adduct[3]
Elimination half-life6.5 hours (average), 11.2–16.8 hours (average 14 hours) (elderly), 8.7–10.9 hours (average 9.8 hours) (in those with moderate-level renal impairment)[1]
Excretion72% of flupirtine and its metabolites appear in urine and 18% appear in feces[4]
Identifiers
  • ethyl {2-amino-6-[(4-fluorobenzyl)amino]pyridin-3-yl}carbamate
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.054.986 Edit this at Wikidata
Chemical and physical data
FormulaC15H17FN4O2
Molar mass304.325 g·mol−1
3D model (JSmol)
  • Fc1ccc(cc1)CNc2nc(N)c(NC(=O)OCC)cc2
  • InChI=1S/C15H17FN4O2/c1-2-22-15(21)19-12-7-8-13(20-14(12)17)18-9-10-3-5-11(16)6-4-10/h3-8H,2,9H2,1H3,(H,19,21)(H3,17,18,20) X markN
  • Key:JUUFBMODXQKSTD-UHFFFAOYSA-N X markN
 X markNcheckY (what is this?)  (verify)

Flupirtine, sold under the brand name Katadolon, is an analgesic medication which was originally used to treat acute and chronic pain.[5] It acts as a selective neuronal KCNQ potassium channel opener.[6] The drug first became available in Europe in 1984 and after it went off patent many generic brands were introduced.[7][8] In 2013, due to issues with liver toxicity, the European Medicines Agency restricted its use to acute pain, for no more than two weeks, and only for people who cannot use other painkillers.[9] In March 2018, marketing authorisations for flupirtine were withdrawn following a European Medicines Agency recommendation based on the finding that the restrictions introduced in 2013 had not been sufficiently followed in clinical practice, and cases of serious liver injury still occurred including liver failure.[10]

Medical uses

[edit]

Flupirtine is used as an analgesic for acute pain, in moderate-to-severe cases.[5][11] Its muscle relaxant properties make it popular for back pain and other orthopaedic uses, but it is also used for migraines, in oncology, postoperative care, and gynaecology.

In 2013 due to issues with liver toxicity, the European Medicines Agency restricted its use to acute pain, for no more than two weeks, and only for people who cannot use other painkillers.[9]

Side effects

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The most serious side effect is frequent hepatotoxicity which prompted regulatory agencies to issue several warnings and restrictions.[12][13]

Flupirtine is devoid of negative psychological or motor function effects, or effects on reproductive function.[14][15]

Pharmacology

[edit]

Pharmacodynamics

[edit]

Flupirtine is a selective neuronal KCNQ (Kv7) potassium channel opener.[6] This action is thought to be primarily responsible for its effects.[6] The drug may also act as a GABAA receptor positive allosteric modulator and this action may be involved in its muscle relaxant effects.[6] The drug was long thought to act as an NMDA receptor antagonist, but it does not directly interact with NMDA receptors.[6] Instead, it has been elucidated that flupirtine indirectly inhibits NMDA receptors by opening KCNQ potassium channels.[6] As such, the drug has since been described as an indirect or "functional" NMDA receptor antagonist.[6][5] Flupirtine was the first KCNQ potassium channel opener to be introduced for medical use.[6]

Chemistry

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Analogues

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Retigabine is a bioisostere of flupirtine in which the pyridine ring has been replaced with a phenyl ring.[6] Azetukalner (encukalner), pynegabine, and fluoxakalner are also analogues of flupirtine and retigabine.

History

[edit]

Flupirtine was discovered and developed between the 1970s and the 1990s by Chemiewerk Homburg in Frankfurt am Main, Germany, which became Degussa Pharma Group and then through mergers, ASTA Pharma and Asta Medica.[6] Retigabine, a bioisostere of flupirtine, was discovered as part of the same program and has a similar mechanism of action.[6] Flupirtine was approved for the treatment of pain in 1984 in Europe[16] under the brand name Katadolon.[17]

As of 2013 it was used in 11 member countries: Bulgaria, Estonia, Germany, Hungary, Italy, Latvia, Lithuania, Poland, Portugal, Romania and Slovak Republic.[16] Many generics entered the European market around 2011.[18]

It was never introduced to the United States market for any indication but in 2008, Adeona Pharmaceuticals, Inc. (now called Synthetic Biologics, Inc.) obtained an option to license issued and patent pending applications relating to flupirtine's use in the treatment of ophthalmic indications, particularly retinitis pigmentosa.[19]

As of 2016 it is marketed under many brand names, including Efiret, Flupigil, Flupirtin, Flupirtina, Flupirtine, Flupizen, Fluproxy, Katadolon, Metanor, Trancolong, and Zentiva.[7]

Society and culture

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Recreational use

[edit]

Although some studies have reported flupirtine has no addictive properties,[20][21] there was suggestion that it may possess some miuse potential and liability.[22] There were at least two registered cases of flupirtine misuse.[23] Drug tolerance does not develop in most cases, but has individually occurred.[23] Flupirtine was reported as a novel designer drug in 2025.[8] The effects of flupirtine have been said to be very difficult to describe.[8] They have been reported to include "strong helicopter-like effects at high doses" causing users to have to "walk leaning against a wall", dissociative effects, feelings of euphoria throughout the body, and a very light buzzing sensation.[8] Some have compared it to mephedrone, while others have described the physical bodily sensations as similar to those of MDMA and other entactogens.[8] The drug is said to be able to produce psychosis and mania as adverse effects and to do so more readily than cathinone stimulants.[8] The euphoria produced by flupirtine is said to last 40 to 60 minutes, whereas other effects last all day.[8] The effects are said to convert after 2 hours from stimulant or euphoriant effects into a kind of nootropic effect that affects thinking.[8] The drug is frequently used to enhance the effects of other recreational drugs.[8]

Research

[edit]

Flupirtine has been noted for its neuroprotective properties, and has been investigated for possible use in Creutzfeldt–Jakob disease, Alzheimer's disease, and multiple sclerosis.[24][25] It has also been proposed as a possible treatment for Batten disease.[26]

Flupirtine underwent a clinical trial as a treatment for multiple sclerosis[27] and fibromyalgia.[28] Flupirtine showed promise for fibromyalgia due to its different action than the three approved by U.S. FDA drugs: pregabalin, milnacipran, and duloxetine.[29] Additionally, there are case reports regarding flupirtine as a treatment for fibromyalgia.[30] Adeona Pharmaceuticals (now called Synthetic Biologics) sub-licensed its patents for using flupirtine for fibromyalgia to Meda AB in May 2010.[29]

References

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  1. 1 2 Abrams SM, Baker LR, Crome P, White AS, Johnston A, Ankier SI, et al. (May 1988). "Pharmacokinetics of flupirtine in elderly volunteers and in patients with moderate renal impairment". Postgraduate Medical Journal. 64 (751): 361–363. doi:10.1136/pgmj.64.751.361. PMC 2428663. PMID 3200777.
  2. ↑ Narang PK, Tourville JF, Chatterji DC, Gallelli JF (January 1984). "Quantitation of flupirtine and its active acetylated metabolite by reversed-phase high-performance liquid chromatography using fluorometric detection". Journal of Chromatography. 305 (1): 135–143. doi:10.1016/S0378-4347(00)83321-6. PMID 6707137.
  3. ↑ Methling K, Reszka P, Lalk M, Vrana O, Scheuch E, Siegmund W, et al. (March 2009). "Investigation of the in vitro metabolism of the analgesic flupirtine". Drug Metabolism and Disposition. 37 (3): 479–493. doi:10.1124/dmd.108.024364. PMID 19074524. S2CID 5661841.
  4. ↑ Blackburn-Munro G, Dalby-Brown W, Mirza NR, Mikkelsen JD, Blackburn-Munro RE (2005). "Retigabine: chemical synthesis to clinical application". CNS Drug Reviews. 11 (1): 1–20. doi:10.1111/j.1527-3458.2005.tb00033.x. PMC 6741764. PMID 15867950.
  5. 1 2 3 Harish S, Bhuvana K, Bengalorkar GM, Kumar T (April 2012). "Flupirtine: Clinical pharmacology". Journal of Anaesthesiology Clinical Pharmacology. 28 (2): 172–177. doi:10.4103/0970-9185.94833. PMC 3339720. PMID 22557738.
  6. 1 2 3 4 5 6 7 8 9 10 11 Szelenyi I (March 2013). "Flupirtine, a re-discovered drug, revisited". Inflamm Res. 62 (3): 251–258. doi:10.1007/s00011-013-0592-5. PMID 23322112.
  7. 1 2 Flupirtine Drugs.com. Accessed 30 August 2016
  8. 1 2 3 4 5 6 7 8 9 "Флупиртин (Flupirtine)". АИПСИН [Aipsin] (in Russian). Retrieved 1 January 2026.
  9. 1 2 "Flupirtine-containing medicines". European Medicines Agency. November 21, 2013. Archived from the original on December 18, 2014. Retrieved July 31, 2014.
  10. ↑ "European Medicines Agency - Human medicines - Flupirtine-containing medicinal products". www.ema.europa.eu. Archived from the original on 2022-01-21. Retrieved 2018-03-18.
  11. ↑ McMahon FG, Arndt WF, Newton JJ, Montgomery PA, Perhach JL (1987). "Clinical experience with flupirtine in the U.S". Postgraduate Medical Journal. 63 Suppl 3 (3): 81–85. PMID 3328854.
  12. ↑ "EMA information about flupirtine". Archived from the original on 2014-12-18. Retrieved 2014-07-31.
  13. ↑ "Flupirtin: EMA startet Risikobewertung wegen Leberrisiko". Deutsches Ärzteblatt. 15 March 2013.
  14. ↑ Singal R, Gupta P, Jain N, Gupta S (June 2012). "Role of flupirtine in the treatment of pain - chemistry and its effects" (PDF). Maedica. 7 (2): 163–166. PMC 3557425. PMID 23401726.
  15. ↑ "DRUGDEX Evaluations - Flupirtine". Retrieved 24 March 2013.
  16. 1 2 "Assessment report for flupirtine containing medicinal products" (PDF). EMA. June 24, 2013. Archived from the original (PDF) on September 15, 2016. Retrieved August 31, 2016.
  17. ↑ Allen RC (1986). "To Market, To Market - 1985". In Hesp B (ed.). Annual Reports in Medicinal Chemistry, Volume 21. Orlando: Academic Press. p. 328. ISBN 9780080583655.
  18. ↑ "Rationale for the triggering of procedure under Article 107i of Directive 2001/83/EC on flupirtine presented by the Federal Institute for Drugs and Medicinal Devices/BfArM, Germany" (PDF). EMA. March 8, 2013. Archived from the original (PDF) on September 15, 2016. Retrieved August 31, 2016.
  19. ↑ "Adeona Pharmaceuticals and National Neurovision Research Institute (NNRI) Collaborate to Test Flupirtine for Retinitis Pigmentosa". Ann Arbor, MI and Owings Mills, MD: Synthetic Biologics, Inc. December 2, 2008. Archived from the original on 6 June 2014. Retrieved 2 June 2014.
  20. ↑ Preston KL, Funderburk FR, Liebson IA, Bigelow GE (March 1991). "Evaluation of the abuse potential of the novel analgesic flupirtine maleate". Drug and Alcohol Dependence. 27 (2): 101–113. doi:10.1016/0376-8716(91)90027-v. PMID 2055157.
  21. ↑ Sofia RD, Diamantis W, Gordon R (1987). "Abuse potential and physical dependence liability studies with flupirtine maleate in laboratory animals". Postgraduate Medical Journal. 63 (Suppl 3): 35–40. PMID 3447127.
  22. ↑ Gahr M, Freudenmann RW, Connemann BJ, Hiemke C, Schönfeldt-Lecuona C (December 2013). "Abuse liability of flupirtine revisited: implications of spontaneous reports of adverse drug reactions". Journal of Clinical Pharmacology. 53 (12): 1328–1333. doi:10.1002/jcph.164. PMID 24037995. S2CID 35299692.
  23. 1 2 Stoessel C, Heberlein A, Hillemacher T, Bleich S, Kornhuber J (August 2010). "Positive reinforcing effects of flupirtine--two case reports". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 34 (6): 1120–1121. doi:10.1016/j.pnpbp.2010.03.031. PMID 20362025. S2CID 19710997.
  24. ↑ Klawe C, Maschke M (June 2009). "Flupirtine: pharmacology and clinical applications of a nonopioid analgesic and potentially neuroprotective compound". Expert Opinion on Pharmacotherapy. 10 (9): 1495–1500. doi:10.1517/14656560902988528. PMID 19505216. S2CID 11597721.
  25. ↑ Swedberg MD, Shannon HE, Nickel B, Goldberg SR (September 1988). "Pharmacological mechanisms of action of flupirtine: a novel, centrally acting, nonopioid analgesic evaluated by its discriminative effects in the rat". The Journal of Pharmacology and Experimental Therapeutics. 246 (3): 1067–1074. doi:10.1016/S0022-3565(25)22194-2. PMID 2901483.
  26. ↑ Dhar S, Bitting RL, Rylova SN, Jansen PJ, Lockhart E, Koeberl DD, et al. (April 2002). "Flupirtine blocks apoptosis in batten patient lymphoblasts and in human postmitotic CLN3- and CLN2-deficient neurons". Annals of Neurology. 51 (4): 448–466. doi:10.1002/ana.10143. PMID 11921051. S2CID 23653281.
  27. ↑ Flupirtine as Oral Treatment in Multiple Sclerosis (FLORIMS) Clinical Trials.gov Accessed 20 September 2011.
  28. ↑ Pipex Pharmaceuticals (PPXP)' Oral Flupirtine Receives IND With FDA for Phase II Clinical Trial for Fibromyalgia Archived 2017-08-30 at the Wayback Machine 4/21/2008
  29. 1 2 "Partnered Program. Effirma for Fibromyalgia". Synthetic Biologics, Inc. Archived from the original on 6 June 2014. Retrieved 2 June 2014.
  30. ↑ Stoll AL, Belmont MA. (2000) "Fibromyalgia Symptoms Relieved by Flupirtine: An Open-Label Case Series Archived 2010-09-02 at the Wayback Machine" Psychosomatics 41:371-372. Accessed 20 September 2011.
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