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Modafinil

A Review of its Pharmacology and Clinical Efficacy in the Management of Narcolepsy

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An Erratum to this article was published on 01 July 1998

Summary

Synopsis

Modafinil promotes wakefulness through an as yet unknown mechanism of action. It significantly increases daytime sleep latency and reduces excessive daytime sleepiness (EDS) compared with placebo in patients with narcolepsy. However, the drug does not suppress cataplexy.

Although direct comparative data are lacking, modafinil offers advantages over amphetamines and methylphenidate in patients with narcolepsy because of its lack of rebound phenomena after treatment withdrawal and its low abuse potential.

Clinical trials have shown modafinil to be well tolerated in patients with narcolepsy. Except for headache, which was reported with a significantly greater frequency in modafinil recipients, the tolerability profile of modafinil 200 to 400 mg/day was similar to that of placebo in patients treated for 9 weeks. Preliminary data suggest that the tolerability of modafinil is maintained long term (40 weeks).

Thus, modafinil is effective in the treatment of EDS in patients with narcolepsy, although it is not effective against cataplexy. Preliminary findings indicate that, unlike other psychostimulants, the drug is unlikely to be abused and is not associated with withdrawal phenomena. Therefore, modafinil is likely to be an effective therapeutic option for the treatment of EDS in patients with narcolepsy.

Pharmacodynamic Properties

The mechanism of action of modafinil has not been clearly established. However, it may indirectly increase wakefulness, at least in part, through inhibition of cortical γ-aminobutyric acid (GABA) release via serotonergic mechanisms.

Modafinil induces wakefulness and increases locomotor activity in a variety of animal species without causing stereotyped behaviour. In rhesus monkeys, the effects of oral modafinil were not associated with changes in blood pressure or heart rate.

In contrast to dexamphetamine 20mg, single night-time doses of modafinil 100 or 200mg had no significant effects on objective sleep variables or sleep structure in young or elderly healthy volunteers. Modafinil reduced the impairment of cognitive performance induced by sleep deprivation in volunteers, suppressed microsleeps and reduced the length of recovery sleep required. However, volunteers treated with modafinil reported recovery sleep patterns which were similar to those of placebo recipients.

Studies in volunteers indicate that modafinil has less abuse potential than dexamphetamine or methylphenidate.

Pharmacokinetic Properties

Peak plasma concentrations of modafinil (mean 4.82 mg/L) were reached 2.3 hours after a single 200mg oral dose in healthy volunteers. Over the dose range 200 to 600mg, the pharmacokinetics of modafinil were linear and dose dependent. Orally administered modafinil is extensively biotransformed in the liver to the inactive metabolites modafinil acid and modafinil sulphone, before being eliminated primarily in the urine (elimination half-life 9 to 14 hours). The pharmacokinetics of modafinil are not affected to a clinically significant extent by volunteer age or food intake, but both the maximum plasma concentration and the elimination half-life of the drug are increased in patients with hepatic or renal impairment.

Clinical Efficacy

The efficacy of modafinil 200 or 400 mg/day was rated as good or excellent (using a 4-point scale) in 84 of 131 evaluable patients (64%) with excessive daytime sleepiness treated for 1 to 114 months in a noncomparative study. 53 patients withdrew from the study (43 because of loss of efficacy). In another study, 1 or 2 months’ treatment with modafinil reduced or eliminated symptoms of excessive daytime sleepiness in 17 of 24 patients with narcolepsy.

Modafinil 200 or 400 mg/day for 9 weeks significantly increased daytime sleep latency and reduced daytime sleepiness compared with placebo in patients with narcolepsy, but did not suppress cataplexy. It tended to improve psychomotor performance, although this effect was variable. Importantly, modafinil did not affect patients’ nocturnal sleep parameters, ability to nap when necessary or feelings on awakening. There was no evidence of a withdrawal phenomenon (e.g. fatigue, vivid or unpleasant dreams, insomnia or hypersomnia) after treatment cessation.

Clinical data comparing the efficacy of modafinil with that of other stimulants in patients with narcolepsy are limited.

Tolerability

Although tolerability data for modafinil are limited, the drug appears to be well tolerated in patients with narcolepsy.

A study in 283 evaluable patients showed that 9 weeks’ treatment with modafinil 200 or 400 mg/day was as well tolerated as placebo, with only headache reported with significantly greater frequency (52 and 51 vs 36% of patients; p < 0.05). Nausea and nervousness also tended to occur more frequently in modafinil than in placebo recipients, but this difference did not reach statistical significance. The incidence or severity of adverse events associated with the use of modafinil did not appear to be dose related. Preliminary data showed that open-label modafinil was well tolerated for up to 40 weeks.

Dosage and Administration

The recommended dosage of modafinil is 200 or 400 mg/day, given once or twice daily (morning and midday) to patients with narcolepsy.

Modafinil is contraindicated in patients with moderate to severe hypertension and may reduce the efficacy of low dose oral contraceptives via enzymatic induction.

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References

  1. Tanganelli S, Fuxe K, Ferraro L, et al. Inhibitory effects of the psychoactive drug modafinil on γ-aminobutyric acid outflow from the cerebral cortex of the awake freely moving guinea-pig. Possible involvement of 5-hydroxytryptamine mechanisms. Naunyn Schmiedebergs Arch Pharmacol 1992 Apr; 345: 461–5

    Article  PubMed  CAS  Google Scholar 

  2. Tanganelli S, Pérez de la Mora M, Ferraro L, et al. Modafinil and cortical τ-aminobutyric acid outflow. Modulation by 5-hydroxytryptamine neurotoxins. Eur J Pharmacol 1995 Jan 24; 273: 63–71

    Article  PubMed  CAS  Google Scholar 

  3. Ferraro L, Tanganelli S, O’Connor WT, et al. The vigilance promoting drug modafinil increases dopamine release in the rat nucleus accumbens via the involvement of a local GABA-ergic mechanism. Eur J Pharmacol 1996 Jun 13; 306: 33–9

    Article  PubMed  CAS  Google Scholar 

  4. Ferraro L, Tanganelli S, O’Connor WT, et al. The vigilance promoting drug modafinil decreases GABA release in the medial preoptic area and in the posterior hypothalamus of the awake rat: possible involvement of the serotonergic 5-HT3 receptor. Neurosci Lett 1996 Dec 6; 220: 5–8

    Article  PubMed  CAS  Google Scholar 

  5. De Séréville JE, Boer C, Rambert FA, et al. Lack of pre-synaptic dopaminergic involvement in modafinil activity in anaesthetized mice: in vivo voltammetry studies. Neuropharmacology 1994 Jun; 33: 755–61

    Article  PubMed  Google Scholar 

  6. Duteil J, de Séréville J-E, Boer C, et al. Lack of dopaminergic involvement in modafinil, but not amphetamine and methylphenidate, activity in anaesthetized mice and rats: in vivo voltammetry studies [abstract]. Eur J Pharmacol 1990 Jul; 183: 1406–7

    Article  Google Scholar 

  7. Mignot E, Nishino S, Guilleminault C, et al. Modafinil binds to the dopamine uptake carrier site with low affinity. Sleep 1994 Aug; 17: 436–7

    PubMed  CAS  Google Scholar 

  8. Ferraro L, Antonelli T, O’Connor WT, et al. Modafinil: an anti-narcoleptic drug with a different neurochemical profile to d-amphetamine and dopamine uptake blockers. Biol Psychiatry 1997 Dec; 42: 1181–3

    Article  PubMed  CAS  Google Scholar 

  9. Lin J-S, Hou Y, Jouvet M. Potential brain neuronal targets for amphetamine-, methylphenidate-, and modafinil-induced wakefulness, evidenced by c-fos immunocytochemistry in the cat. Proc Natl Acad Sci U S A 1996 Nov 26; 93: 14128–33

    Article  PubMed  CAS  Google Scholar 

  10. Duteil J, Rambert FA, Pessonnier J, et al. Central α1-adrenergic stimulation in relation to the behaviour stimulating effect of modafinil; studies with experimental animals. Eur J Pharmacol 1990 May 3; 180: 49–58

    Article  PubMed  CAS  Google Scholar 

  11. Hermant J-F, Rambert FA, Duteil J. Awakening properties of modafinil: effect on nocturnal activity in monkeys (Macaca-mulatta) after acute and repeated administration. Psychopharmacology 1991; 103(1): 28–32

    Article  PubMed  CAS  Google Scholar 

  12. Lin JS, Roussel B, Akaoka H, et al. Role of catecholamines in the modafinil and amphetamine induced wakefulness, a comparative pharmacological study in the cat. Brain Res 1992 Sep 25; 591: 319–26

    Article  PubMed  CAS  Google Scholar 

  13. Rambert FA, Pessonnier J, Duteil J. Modafinil-, amphetamine- and methylphenidate-induced hyperactivities in mice involve different mechanisms. Eur J Pharmacol 1990; 183(2): 455–6

    Article  Google Scholar 

  14. Piérard C, Satabin P, Lagarde D, et al. Effects of a vigilance-enhancing drug, modafinil, on rat brain metabolism: a 2D COSY 1H-NMR study. Brain Res 1995 Sep 25; 693: 251–6

    Article  PubMed  Google Scholar 

  15. Ueki A, Rosén L, Andbjer B, et al. Evidence for a preventive action of the vigilance-promoting drug modafinil against striatal ischemic injury induced by endothelin-1 in the rat. Exp Brain Res 1993 Sep; 96: 89–99

    PubMed  CAS  Google Scholar 

  16. Fuxe K, Janson AM, Rosén L, et al. Evidence for a protective action of the vigilance promoting drug modafinil on the MPTP-induced degeneration of the nigrostriatal dopamine neurons in the black mouse: an immunocytochemical and biochemical analysis. Exp Brain Res 1992; 88: 117–30

    Article  PubMed  CAS  Google Scholar 

  17. Ueki A, Rosén L, Andbjer B, et al. The vigilance-promoting drug modafinil counteracts the reduction of tyrosine hydroxylase immunoreactivity and of dopamine stores in nigrostriatal dopamine neurons in the male rat after a partial transection of the dopamine pathway. Exp Brain Res 1993; 93: 259–70

    Article  PubMed  CAS  Google Scholar 

  18. Lagarde DPS, Anton G. Comparative study of stimulant effects of d-amphetamine sulfate and modafinil, an original psychostimulant [abstract]. Eur J Pharmacol 1990 Jul; 183: 1476

    Article  Google Scholar 

  19. Lagarde D. Effects of modafinil on the nocturnal activity and behavioural sleep of Rhesus monkeys (Maccaca mulatta). Med Sci Res 1990 May 16–31; 18: 397–9

    CAS  Google Scholar 

  20. Lagarde D, Milhaud C. Electroencephalographic effects of modafinil, an alpha-1-adrenergic psychostimulant, on the sleep of rhesus monkeys. Sleep 1990 Oct; 13: 441–8

    PubMed  CAS  Google Scholar 

  21. Touret M, Sallanon-Moulin M, Jouvet M. Awakening properties of modafinil without paradoxical sleep rebound: comparative study with amphetamine in the rat. Neurosci Lett 1995 Apr 7; 189: 43–6

    Article  PubMed  CAS  Google Scholar 

  22. Adrien J, Lebrand C, Maudhuit C. Effects of modafinil on wakefulness and sleep in the rat [abstract]. J Sleep Res 1994 Jun; 3Suppl. 1: 2

    Google Scholar 

  23. Edgar DM, Scidel WF, Contreras PC, et al. Modafinil promotes EEG wake without intensifying motor activity in the rat [abstract]. Can J Physiol Pharmacol 1994; 72Suppl. 1: 362

    Google Scholar 

  24. Edgar DM, Scidel WF. Modafinil induces wakefulness without intensifying motor activity or subsequent rebound hypersomnolence in the rat. J Pharmacol Exp Ther 1997 Nov; 283: 757–69

    PubMed  CAS  Google Scholar 

  25. Shelton J, Nishino S, Vaught J, et al. Comparative effects of modafinil and amphetamine on daytime sleepiness and cataplexy of narcoleptic dogs. Sleep 1995 Dec; 18: 817–26

    PubMed  CAS  Google Scholar 

  26. Panckeri KA, Schotland HM, Pack AI, et al. Modafinil decreases hypersomnolence in the English bulldog, a natural animal model of sleep-disordered breathing. Sleep 1996 Oct; 19: 626–31

    PubMed  CAS  Google Scholar 

  27. Rambert FA, Pessonnier J, Autran L, et al. Intracerebroventricular injected MODAFINIL (but not its main metabolites, acid and sulfone) induces hyperlocomotor activity in mice [abstract]. Neuropsychopharmacology 1994 May; 10 (3S/Pt 2): 169S

    Google Scholar 

  28. Simon P, Hémet C, Costentin J. Analysis of stimulant locomotor effects of modafinil in various strains of mice and rats. Fundam Clin Pharmacol 1996; 10(5): 431–5

    Article  PubMed  CAS  Google Scholar 

  29. Moachon G, Rambert FA, Matinier D, et al. Modafinil plasma levels are correlated to locomotor effect in mice [abstract]. Therapie 1990 Jan–Feb; 45: 79

    Google Scholar 

  30. Hermant JF, Rambert FA, Duteil J. Lack of cardiovascular effects after administration of modafinil in conscious monkeys [abstract]. Fundam Clin Pharmacol 1991; 5: 825

    Google Scholar 

  31. Saletu B, Frey R, Krupka M, et al. Differential effects of a new central adrenergic agonist —modafinil — and d-amphetamine on sleep and early morning behaviour in young healthy volunteers. Int J Clin Pharmacol Res 1989; 9(3): 183–95

    PubMed  CAS  Google Scholar 

  32. Saletu B, Frey R, Krupka M, et al. Differential effects of the new central adrenergic agonist modafinil and d-amphetamine on sleep and early morning behaviour in eiderlies. Arzneimittel Forshung 1989 Oct; 39: 1268–73

    CAS  Google Scholar 

  33. Baranski JV, Pigeau RA. Self-monitoring cognitive performance during sleep deprivation: effects of modafinil, d-amphetamine and placebo. J Sleep Res 1997; 6: 84–91

    Article  PubMed  CAS  Google Scholar 

  34. Pigeau R, Naitoh P, Buguet A, et al. Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. I. Effects on mood, fatigue, cognitive performance and body temperature. J Sleep Res 1995; 4(4): 212–28

    Article  PubMed  Google Scholar 

  35. Lagarde D, Batejat D, Van Beers P, et al. Interest of modafinil, a new psychostimulant, during a sixty-hour sleep deprivation experiment. Fundam Clin Pharmacol 1995; 9(3): 271–9

    Article  PubMed  CAS  Google Scholar 

  36. Bensimon G, Benoit D, Lacomblez L, et al. Antagonism by modafinil of the psychomotor and cognitive impairment induced by sleep-deprivation in 12 healthy volunteers. Eur Psychiatry 1991; 6(2): 93–7

    Google Scholar 

  37. Buguet A, Montmayeur A, Pigeau R, et al. Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. II. Effects on two nights of recovery sleep. J Sleep Res 1995; 4(4): 229–41

    Article  PubMed  Google Scholar 

  38. Gold LH, Balster RL. Evaluation of the cocaine-like discriminative stimulus effects and reinforcing effects of modafinil. Psychopharmacology 1996 Aug; 126: 286–92

    Article  PubMed  CAS  Google Scholar 

  39. Warot D, Corruble E, Payan C, et al. Subjective effects of modafinil, a new central adrenergic stimulant in healthy volunteers: a comparison with amphetamine, caffeine and placebo. Eur Psychiatry 1993; 8(4): 201–8

    Google Scholar 

  40. Jasinski DR. An evaluation of the abuse potential of modafinil using methylphenidate as a reference [poster]. CPDD: 1997 Jun; Nashville

  41. Moachon G, Kanmacher I, Clenet M, et al. Pharmacokinetic profile of modafinil. Drugs Today 1996 Jun; 32: 327–37

    CAS  Google Scholar 

  42. Civil RH, Gorman SH, Strong DB, et al. Safety, tolerance and pharmacokinetics of single doses of modafinil in healthy subjects [abstract]. 9th Annual Meeting Sleep Research Society: 1995 May 30; Nashville, 49

  43. Gorman SH, Neidlinger SK, Stong DB, et al. Pharmacokinetic profiles of modafinil and modafinil acid during a double-blind, ascending dose, seven-day administration of modafinil tablets in normal male subjects [abstract]. ISSX Proc 1994; 6: 75

    Google Scholar 

  44. Moachon G, Matinier D, Lubin S, et al. Pharmacokinetics of multiple doses of modafinil in hepatic insufficiency [abstract]. Can J Physiol Pharmacol 1994; 72Suppl. 1: 303

    Google Scholar 

  45. Broughton RJ, Fleming JAE, George CFP, et al. Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of excessive daytime sleepiness in narcolepsy. Neurology 1997 Aug; 49: 444–51

    Article  PubMed  CAS  Google Scholar 

  46. Besset A, Chetrit M, Carlander B, et al. Use of modafinil in the treatment of narcolepsy: a long term follow-up study. Neurophysiol Clin 1996; 26: 60–6

    Article  PubMed  CAS  Google Scholar 

  47. Billiard M, Besset A, Montplaisir J, et al. Modafinil: a double-blind multicentric study. Sleep 1994 Dec; 17 Suppl.: S107–12

    PubMed  CAS  Google Scholar 

  48. Boivin DB, Montplaisir J, Petit D, et al. Effects of modafinil on symptomatology of human narcolepsy. Clin Neuropharmacol 1993 Feb; 16: 46–53

    Article  PubMed  CAS  Google Scholar 

  49. Laffont F, Agar N, Mayer G, et al. Effect of modafinil in narcoleptic patients. Electrophysiologic and psychometric studies [in French]. Neurophysiol Clin 1995; 25: 84–95

    Article  PubMed  CAS  Google Scholar 

  50. Carpenter V, Barone Kribbs N, for the US Modafinil Multicenter Study Group. Self-reported and manifest sleepiness during blind withdrawal from modafinil in patients with narcolepsy [poster]. European Federation of Neurological Societies: 1997 Jun 4–8; Prague

  51. US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. Ann Neurol 1998; 43: 88–97

    Article  Google Scholar 

  52. Laffont F, Mayer G, Minz M. Modafinil in diurnal sleepiness. A study of 123 patients. Sleep 1994 Dec; 17(8 Suppl.): S113–5

    PubMed  CAS  Google Scholar 

  53. Bastuji H, Jouvet M. Successful treatment of idiopathic hypersomnia and narcolepsy with modafinil. Prog Neuropsychopharmacol Biol Psychiatry 1988; 12: 695–700

    Article  PubMed  CAS  Google Scholar 

  54. Laffont F, Agar N, Mayer G, et al. Modafinil in narcoleptic patients: electrophysiological and psychometric analysis [abstract]. J Sleep Res 1994 Jun; 3Suppl. 1: 135

    Google Scholar 

  55. Walsleben JA, Beusterien KM, Walls M, et al. Modafinil improves health-related quality of life (HQL) in narcolepsy [abstract]. British Sleep Society Meeting 1997

  56. Mitler MM, Hajdukovic R. Relative efficacy of drugs for the treatment of sleepiness in narcolepsy. Sleep 1991 Jun; 14: 218–20

    PubMed  CAS  Google Scholar 

  57. Laboratoire L. Lafon. Modafinil. Vidal. Paris: Editions du Vidal, 1997

    Google Scholar 

  58. Monthly Index of Medical Specialities (MIMS). Mar 1998 ed. London: Haymarket Medical Ltd, 1998

  59. Diagnostic Classification Steering Committee. Thorpy MJ (chairman). The International Classification of Sleep Disorders: diagnostic and coding manual. Rochester (MN): American Sleep Disorders Association, 1990

    Google Scholar 

  60. Hublin C, Kaprio J, Partinen M, et al. The prevalence of narcolepsy: an epidemiological study of the Finnish twin cohort. Ann Neurol 1994; 35: 709–16

    Article  PubMed  CAS  Google Scholar 

  61. Broughton WA, Broughton RJ. Psychosocial impact of narcolepsy. Sleep 1994 (17): S45-9

  62. Aldrich MS. Narcolepsy. Neurology 1992 Jul; 42Suppl. 6: 34–43

    PubMed  CAS  Google Scholar 

  63. Hublin C. Narcolepsy: current drug treatment options. CNS Drugs 1996; 5(6): 426–36

    Article  CAS  Google Scholar 

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Karen J. McClellan & Caroline M. Spencer

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  1. Karen J. McClellan
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Correspondence to Karen J. McClellan.

Additional information

An erratum to this article is available at http://dx.doi.org/10.1007/BF03256940.

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McClellan, K.J., Spencer, C.M. Modafinil. Mol Diag Ther 9, 311–324 (1998). https://doi.org/10.2165/00023210-199809040-00006

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