Treatment of Narcolepsy
with Modafinil
By: Shelley Kislashko
History of Treatment for
Narcolepsy
• 1st drug used to treat narcolepsy was ephedrine
in 1931. Followed by the amphetamines.
• In 1959, methylphenidate was introduced and
extensive use proceeded.
• Modafinil originated in the late 1970’s and
approved by the U.S. Food and Drug
administration in 1998 for administration.
• Modafinil is now one of the most widely used
treatment options for Narcolepsy.
Neurobiology of
Narcolepsy
• Genetic factors appear to play an important role in the
development of narcolepsy. These genetic factors also
appear to vary with ethnicity.
• More commonly narcolepsy is an acquired disease often
from various head trauma situations.
• Orexin plays a critical role in the neurobiology of
narcolepsy. Orexin-containing neurons are found only in
the posterior and lateral hypothalamus, but they project
widely throughout the CNS, innervating the aminergic
and cholinergic regions that promote wakefulness.
Currently, it is only partially known which regions are
necessary for the wake-promoting effects of orexin.
Neurobiology of
Narcolepsy ~ Cont’d
• Gradual failure to produce orexin has been discovered
and researches have proposed that an autoimmine or
neurodegerative process could cause the selective loss.
• Dopaminergic signaling also may promote wakefulness.
It has been researched that lesions of dopaminergic
cells in the ventral midbrain can reduce wakefulness.
Mechanism of Action for
Modafinil
• The precise mechanism through which modafinil promotes
wakefulness is unknown.
• Early work on modafinil suggested action through alphaadrenergic receptors, but modafinil does not bind to alphareceptors, or other receptors or reuptake site for
noradrenaline, GABA, benzodiazepines, or adenosine.
• Modafinil can reduce the extra cellular concentrations of
GABA, and this decrease in GABA may disinhibit specific
wake promoting systems.
• Modafinil may increase dopaminergic signaling by weakly
binding to the dopamine reuptake transporter.
Case Study
• “A randomized trail of the long-term,
continued efficacy and safety of
modafinil in narcolepsy”
– By: Moldofsky, Broughton and Hill
• Objective: To assess the continued efficacy of modafinil in
the treatment of narcolepsy.
• Method: 69 patients with narcolepsy continued on modafinil
for 16 weeks of open-label treatment. Followed by 2 weeks
where patients were randomly and blindly allocated to
continue modafinil at the same dose or placebo.
Case Study
• Results: Mean dose of 330 mg of modafinil continued to
produce a significant decrease in EDS as measured.
Modafinil had no significant effects on nocturnal sleep,
blood pressure, heart rate, the ECG, weight, or mood.
• Conclusions: Modafinil continues to be an effective and
well-tolerated drug after 16 weeks of treatment.
• Limitations: Small population size, of 69 only 63
completed the full 16 week study.
Pharmacokinetics
• Modafinil is a racemic compound whose enantiomers
do not interconvert. The effective elimination half-life
of modafinil is about 15 hours.
• Absorption of the tablet is rapid, with peak plasma
concentrations occurring at 2-4 hours.
• Food has no effect on overall bioavailability, however,
its absorption may be delayed approximately one
hour if taken with food.
• The major route of eliminations is metabolisms
(~90%), primarily by the liver, with subsequent renal
elimination of the metabolites.
• The recommended dose is 200 mg taken as a single
dose in the morning.
Drug Interactions
• Co-administration of modafinil with drugs such as
diazepam, phenytoin and propranolol may
increase the circulating levels of those
compounds and dose adjustments maybe
necessary.
• Co-administration of modafinil with other CNS
active drugs such as methylphenidate and
dextroamphetamine did not significantly alter the
pharmacokinetics of either drug.
Tolerability, Safety and
Abuse Potential
• Generally well tolerated with the commonest
symptoms occurring include headache, nausea,
hyperactivity, dry mouth, palpitations and
insomnia.
• Abuse potential: modafinil is listed in Schedule IV
of the Controlled Substances Act, stating that the
substance has low potential for abuse.
• Overdose may lead to experiences of excitation
or agitation, and insomnia.
• No specific withdrawal symptoms have been
recorded based on clinical trials although
sleepiness is returned in narcoleptic patients.
Comparison of
Amphetamines and
Modafinil
Advantages of
Treatment with Modafinil
• Modafinil increases wakefulness without causing
autonomic arousal and psychostimulant
agitations as sympathomimetic drugs do.
• Amphetamines cause the release of
noradrenaline, which leads to enhance
sympathetic activity that may cause intolerable
side effects.
• Amphetamines have a higher risk for abuse,
tolerance and unfavorable withdrawal symptoms,
unlike modafinil.
• The half like of methylphenidate is 3-4 hours as
compared to 15hours for modafinil.
Disadvantages for
Treatment with Modafinil
• Few long-term studies have been conducted on
modafinil but show inconsistency regarding
efficacy or possible unfavorable effects.
• Modafinil is not a cure for narcolepsy. Narcolepsy
is a chronic disorder lasting a lifetime, and
modafinil is required for long-term treatment.
• Modafinil is not applicable for treatment with
individuals under the age of 16 years.
Future Research
• Clinical trials are needed to compare
sympathomimetic drugs with modafinil, in patients
with narcolepsy, to determine efficaciousness in their
wakefulness promotion and enhancement of cognitive
function.
• Long-term safety profile is necessary.
• Continued research in the neurobiology of modafinil to
fully understand the exact mechanisms of the agent
as a wakefulness promoter.
• Continued clinical trials are required to understand
interactions with alcohol and other drugs.
Future Research
• Research has not been conducted to see if
modafinil has potential use applicable to
individuals under the age of 16 years.
• With the discovery of orexin deficiency as a
possible cause leading to narcolepsy, research is
required to understand the reason for this
depletion and the possible relationship with
modafinil.
Evaluation
I feel when considering the advantages and disadvantages
of modafinil in comparison to other treatment mechanisms,
such as psychostimulants, modafinil appears to be a safer
alternative route. There are less uncomfortable side affects;
lesser risk of tolerance, abuse or withdrawal symptoms and
thus this may provide greater reasons for patient
compliance and overall satisfaction with the drug treatment.
Modafinil achieves the same promising effects for treatment
as other psychostimulants, minus the more adverse side
effects. My concern towards the use of this drug treatment
for narcolepsy is in regards to how new this treatment is
and the lack of information on important on long-term use
for the potential problems that could arise in the future.
Since narcolepsy is a chronic illness modafinil would be
required as a treatment for the length of ones life and if it is
unknown whether serious side effects await a longtime
user, administration of this drug keeps me skeptical.