Skip to main content
SpringerLink
Log in

Flupirtine in Pain Management

Pharmacological Properties and Clinical Use

  • Review Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Flupirtine is a centrally acting, non-opioid analgesic that is available in a number of European countries for the treatment of a variety of pain states. The therapeutic benefits seen with flupirtine relate to its unique pharmacological properties. Flupirtine displays indirect NDMA receptor antagonism via activation of potassium channels and is the first representative of a pharmacological class denoted the ‘selective neuronal potassium channel openers’. The generation of the M-current is facilitated by flupirtine via the opening of neuronal Kv7 potassium channels. The opening of these channels inhibits exaggerated neuronal action potential generation and controls neuronal excitability. Neuronal hyperexcitability is a physiological component of many pain states such as chronic pain, migraine and neurogenic pain.

Although large-scale clinical trials are lacking, the clinical trial database available to date from smaller-scale studies, together with extensive clinical experience, indicate that flupirtine effectively reduces chronic musculoskeletal pain, migraine and neuralgias, amongst other types of pain. In addition, flupirtine produces, at recommended clinical doses, muscle-relaxing effects in the presence of abnormally increased muscle tension. Its analgesic and muscle-relaxant properties were comparable to tramadol and chlormezanone, respectively, in two prospective trials in patients with lower back pain.

Cytoprotective, anti-apoptotic and antioxidant properties have also been associated with flupirtine use in a small number of studies to date. When provided as combination therapy with morphine, flupirtine increases the antinociceptive activity of morphine 4-fold. Flupirtine displays superior tolerability when compared with tramadol and pentazocine. The most common adverse effects associated with flupirtine use are drowsiness, dizziness, heartburn, dry mouth, fatigue and nausea.p ]With respect to its molecular structure, mechanism of action and adverse event profile, flupirtine is a unique drug. Flupirtine is an analgesic with many potential therapeutic benefits that may prove useful in the treatment of many disease states

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II
Table III
Fig. 1
Table IV
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Friedel HA, Fitton A. Flupirtine: a review of its pharmacological properties, and therapeutic efficacy in pain states. Drugs 1993; 45(4): 548–69

    Article  PubMed  CAS  Google Scholar 

  2. Kornhuber J, Maler M, Wiltfang J, et al. Neuronal potassium channel opening with flupirtine. Fortschr Neurol Psychiatr 1999; 67(10): 466–75

    Article  PubMed  CAS  Google Scholar 

  3. Nickel B. The antinociceptive activity of flupirtine: a structurally new analgesic. Postgrad Med J 1987; 63 Suppl. 3: 19–28

    Google Scholar 

  4. Szelenyi I, Nickel B, Borbe HO, et al. Mode of antinociceptive action of flupirtine in the rat. Br J Pharmacol 1989; 97(3): 835–42

    Article  PubMed  CAS  Google Scholar 

  5. Darius H, Schror K. The action of flupirtine on prostaglandin formation and platelet aggregation in vitro. Arzneimittelforschung 1985; 35(1): 55–9

    PubMed  CAS  Google Scholar 

  6. Kornhuber J, Bleich S, Wiltfang J, et al. Flupirtine shows functional NMDA receptor antagonism by enhancing Mg2+ block via activation of voltage independent potassium channels: rapid communication. J Neural Transm 1999; 106(9-10): 857–67

    Article  PubMed  CAS  Google Scholar 

  7. Jakob R, Krieglstein J. Influence of flupirtine on a G-protein coupled inwardly rectifying potassium current in hippo-campal neurones. Br J Pharmacol 1997; 122(7): 1333–8

    Article  PubMed  CAS  Google Scholar 

  8. Methling K, Reszka P, Lalk M, et al. Investigation of the in vitro metabolism of the analgesic flupirtine. Drug Metab Dispos 2009 Mar; 37(3): 479–93

    Article  PubMed  CAS  Google Scholar 

  9. Miceli F, Soldovieri MV, Martire M, et al. Molecular pharmacology and therapeutic potential of neuronal Kv7-modulating drugs. Curr Opin Pharmacol 2008; 8(1): 65–74

    Article  PubMed  CAS  Google Scholar 

  10. Blackburn-Munro G, Dalby-Brown W, Mirza NR, et al. Retigabine: chemical synthesis to clinical application. CNS Drug Rev 2005; 11(1): 1–20

    Article  PubMed  CAS  Google Scholar 

  11. Szelenyi I, Nickel B. Putative site(s) and mechanism(s) of action of flupirtine, a novel analgesic compound. Postgrad Med J 1987; 63 Suppl. 3:57–60

    Article  PubMed  CAS  Google Scholar 

  12. Abrams SM, Baker LR, Crome P, et al. Pharmacokinetics of flupirtine in elderly volunteers and in patients with moderate renal impairment. Postgrad Med J 1988; 64(751): 361–3

    Article  PubMed  CAS  Google Scholar 

  13. Hlavica P, Niebch G. Pharmacokinetics and biotransformation of the analgesic flupirtine in humans. Arzneimittelforschung 1985; 35(1): 67–74

    PubMed  CAS  Google Scholar 

  14. Hummel T, Friedmann T, Pauli E, et al. Dose-related analgesic effects of flupirtine. Br J Clin Pharmacol 1991; 32(1): 69–76

    Article  PubMed  CAS  Google Scholar 

  15. Schuster M, Schwarz M, Block F, et al. Flupirtine: a review of its neuroprotective and behavioral properties. CNS Drug Rev 1998; 4(2): 149–64

    Article  CAS  Google Scholar 

  16. Metanor® [flupirtine maleate 100mg]: summary of product characteristics. Lisbon: Meda Pharmaceuticals, 2006

  17. Efiret® [flupirtine maleate 100mg capsule]: summary of product characteristics. Milan: Meda Pharmaceuticals, 2007

  18. Mueller-Schwefe G. Flupirtine in acute and chronic pain associated with muscle tenseness: results of a postmarket surveillance study. Fortschr Med Orig 2003; 121(1): 11–8

    PubMed  CAS  Google Scholar 

  19. Luben V, Muller H, Lobisch M, et al. Treatment of tumor pain with flupirtine: results of a double-blind study versus tramadol. Fortschr Med 1994; 112(19): 282–6

    PubMed  CAS  Google Scholar 

  20. Li C, Ni J, Wang Z, 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): 3523–30

    CAS  Google Scholar 

  21. Ringe JD, Miethe D, Pittrow D, et al. Analgesic efficacy of flupirtine in primary care of patients with osteoporosis related pain: a multivariate analysis. Arzneimittelforschung 2003; 53(7): 496–502

    PubMed  CAS  Google Scholar 

  22. Worz R, Bolten W, Heller B, et al. Flupirtine in comparison with chlormezanone in chronic musculoskeletal back pain: results of a multicenter randomized double-blind study. Fortschr Med 1996; 114(35-36): 500–4

    PubMed  CAS  Google Scholar 

  23. Worz R. Flupirtine in chronic myofascial pain conditions. Fortschr Med 1991; 109(6): 158–60

    PubMed  CAS  Google Scholar 

  24. Worz R, Lobisch M, Schwittmann B, et al. Effectiveness of flupirtine in chronic tension headache: results of a double-blind study versus placebo. Fortschr Med 1995; 113(32): 463–8

    PubMed  CAS  Google Scholar 

  25. Heusinger JH. Efficacy and tolerance of flupirtine and pentazocine in two multicentre trials. Postgrad Med J 1987; 63 Suppl. 3:71–9

    PubMed  Google Scholar 

  26. Goodchild CS, Kolosov A, Tucker AP, et al. Combination therapy with flupirtine and opioid: studies in rat pain models. Pain Med 2008; 9(7): 928–38

    Article  PubMed  Google Scholar 

  27. Nickel B, Jakovlev V, Szelenyi I. The effect of flupirtine, various analgesics and muscle relaxants on skeletal muscle tone in the conscious rat. Arzneimittelforschung 1990; 40(8): 909–11

    PubMed  CAS  Google Scholar 

  28. Sitzer G. Einfacblindstudie mit Flupirtin gegen Acetyl-salicylsaure bei Patienten mit spinalem Wurzelreizsyndrom. Orthopadie/Traumatologie 1991; 6: 37–42

    Google Scholar 

  29. Mastronardi P, D’Onofrio M, Scanni E, et al. Analgesic activity of flupirtine maleate: a controlled double-blind study with diclofenac sodium in orthopaedics. J Int Med Res 1988; 16(5): 338–48

    PubMed  CAS  Google Scholar 

  30. Marczyk LRS. Avaliacao comparativa do maleato de flupirtina versus diclofenaco potassico em afeccoes musculo-esqueleticas. Arq Bras Med 1992; 66(3): 269–75

    Google Scholar 

  31. Million R, Finlay BR, Whittington JR. Clinical trial of flupirtine maleate in patients with migraine. Curr Med Res Opin 1984; 9(3): 204–12

    Article  PubMed  CAS  Google Scholar 

  32. Muller-Schwefe GH, Uberall MA. Analgesic and muscle tonus normalizing effect of flupirtine retard in chronic back pain: results of a standardized therapeutic evaluation applying objective methods for measuring pain pressure threshold, pain pressure tolerance and muscle tension. MMW Fortschr Med 2008; 149 Suppl. 4: 153–61

    Google Scholar 

  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

    Google Scholar 

  34. Goodchild CS, Nelson J, Cooke I, et al. Combination therapy with flupirtine and opioid: open-label case series in the treatment of neuropathic pain associated with cancer. Pain Med 2008; 9(7): 939–49

    Article  PubMed  Google Scholar 

  35. Belgrade MJ. Following the clues to neuropathic pain: distribution and other leads reveal the cause and the treatment approach. Postgrad Med 1999; 106(6): 127–32, 135-40

    PubMed  CAS  Google Scholar 

  36. Gassen M, Pergande G, Youdim MB. Antioxidant properties of the triaminopyridine, flupirtine. Biochem Pharmacol 1998; 56(10): 1323–9

    Article  PubMed  CAS  Google Scholar 

  37. Osborne NN, Cazevieille C, Pergande G, et al. Induction of apoptosis in cultured human retinal pigment epithelial cells is counteracted by flupirtine. Invest Ophthalmol Vis Sci 1997; 38(7): 1390–400

    PubMed  CAS  Google Scholar 

  38. Wood JP, Pergande G, Osborne NN. Prevention of glutathi-one depletion-induced apoptosis in cultured human RPE cells by flupirtine. Restor Neurol Neurosci 1998; 12(2-3): 119–25

    PubMed  CAS  Google Scholar 

  39. Boscia F, Annunziato L, Taglialatela M. Retigabine and flupirtine exert neuroprotective actions in organotypic hippocampal cultures. Neuropharmacology 2006; 51(2): 283–94

    Article  PubMed  CAS  Google Scholar 

  40. Sattler MB, Williams SK, Neusch C, et al. Flupirtine as neuroprotective add-on therapy in autoimmune optic neuritis. Am J Pathol 2008; 173(5): 1496–507

    Article  PubMed  Google Scholar 

  41. Zimmer G, Balakirev M, Zwicker K, et al. Effect of the triaminopyridine flupirtine on calcium uptake, membrane potential and ATP synthesis in rat heart mitochondria. Br J Pharmacol 1998; 123(6): 1154–8

    Article  PubMed  CAS  Google Scholar 

  42. Stoll AL. Fibromyalgia symptoms relieved by flupirtine: an open-label case series. Psychosomatics 2000; 41(4): 371–2

    Article  PubMed  CAS  Google Scholar 

  43. US FDA. News release: FDA approves first drug for treating fibromyalgia [online]. Available from URL: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108936.htm [Accessed 2010 May 21]

  44. Eli Lilly. News release: FDA approves Cymbalta® for the management of fibromyalgia [online]. Available from URL: http://www2.prnewswire.com/cgi-bin/micro_stories.pl?ACCT=916306&TICK=LLY&STORY=/www/story/06-16-2008/0004832743&EDATE=Jun+16,+2008 [Accessed 2010 May 21]

  45. Forest Laboratories, Inc. News release: Forest and Cypress announce FDA approval of Savella™for the management of fibromyalgia [online]. Available from URL: http://www.frx.com/news/PressRelease.aspx?ID=1244788 [Accessed 2010 May 21]

  46. Herrmann WM, Hiersemenzel R, Aigner M, et al. Long-term tolerance of flupirtine: open multicenter study over one year. Fortschr Med 1993; 111(15): 266–70

    PubMed  CAS  Google Scholar 

  47. Herrmann WM, 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

    PubMed  Google Scholar 

  48. McMahon FG, Arndt Jr WF, Newton JJ, et al. Clinical experience with flupirtine in the U.S. Postgrad Med J 1987; 63 Suppl. 3: 81–5

    Article  PubMed  Google Scholar 

  49. Hirschowitz BI. Nonsteroidal antiinflammatory drugs and the gastrointestinal tract. Gastroenterologist 1994; 2(3): 207–23

    PubMed  CAS  Google Scholar 

  50. Theifin G, Flipo RM, Schaeverbeke T, et al. Upper gastrointestinal symptoms in patients treated with NSAIDs: evaluation of physician-patient agreement and impact in the COMPLAINS study. 14th United European Gastro-enterology Week; 2006 Oct 21–25; Berlin

  51. Laine L. Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient. Gastroenterology 2001; 120(3): 594–606

    Article  PubMed  CAS  Google Scholar 

  52. Schug SA, Zech D, Grond S. Adverse effects of systemic opioid analgesics. Drug Saf 1992; 7(3): 200–13

    Article  PubMed  CAS  Google Scholar 

  53. Powell-Jackson P, Williams R. Use of flupirtine maleate as an analgesic in patients with liver disease. Br J Clin Pract 1985; 39(2): 63–6

    PubMed  CAS  Google Scholar 

  54. Data on file, Degussa Pharma, 1987

Download references

Acknowledgements

Medical writing assistance for the preparation of this article was provided by Raelene Simpson of InScience Communications, a Wolters Kluwer business; technical assistance for revision of the manuscript after peer review was provided by Tracy Harrison of InScience Communications. This assistance was funded by Meda Pharmaceuticals. The author has no other conflicts of interest that are directly relevant to this review.

Author information

Authors and Affiliations

  1. Department of Anaesthesia, Section Pain Clinic, Ghent University Hospital, De Pintelaan 185, Ghent, 9000, Belgium

    Jacques Devulder

Authors
  1. Jacques Devulder
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jacques Devulder.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Devulder, J. Flupirtine in Pain Management. CNS Drugs 24, 867–881 (2010). https://doi.org/10.2165/11536230-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11536230-000000000-00000

Keywords

Search

Navigation