Medication Overview
Modafinil (Provigil®) is a wake-promoting agent that is pharmacologically distinct from traditional central nervous system stimulants such as amphetamine, dexamphetamine, and methylphenidate. It is classified as a Schedule IV controlled substance in the United States due to its potential for abuse or dependency, though this potential is considered low compared to traditional stimulants. 5, 2
FDA-Approved Indications
Modafinil is FDA-approved for the treatment of:
- Narcolepsy
- Obstructive sleep apnea/hypopnea syndrome (as adjunctive therapy)
- Shift work sleep disorder 5, 2
Mechanism of Action
While the precise biochemical mechanism of action has not been clearly defined, modafinil:
- Acts similarly to other stimulants with significant dopaminergic activity
- Enhances activity in the hypothalamic wakefulness center
- Activates tuberomammillary nucleus neurons that release histamine
- Activates hypothalamic neurons that release orexin/hypocretin 5, 6
Clinical Efficacy
Modafinil has demonstrated effectiveness in:
- Improving excessive daytime sleepiness in narcolepsy and sleep disorders
- Reducing Epworth Sleepiness Scale scores from mild excessive daytime sleepiness to no excessive daytime sleepiness 5
- Treating hypersomnia secondary to Parkinson's disease 5
In clinical studies, modafinil at doses of 100-200 mg in the morning has been shown to improve:
- Daytime alertness
- Behavioral issues
- Attention concerns 5
Important Considerations and Precautions
Dosing
- Starting dose typically 100 mg/day
- Maintenance dose usually 100-200 mg/day
- Higher doses (200-400 mg/day) may increase risk of anxiety and stress-related symptoms 5, 6
Safety Concerns
- Not approved for use in individuals less than 17 years of age
- May cause serious side effects, including life-threatening Stevens-Johnson syndrome
- May reduce the effectiveness of oral contraceptives
- May cause fetal harm based on animal data (human data insufficient to determine risk) 5
Common Side Effects
Special Populations
Pregnancy
Based on animal data, modafinil may cause fetal harm. A 2018 annual report of the ongoing armodafinil/modafinil pregnancy registry in the United States showed a higher rate of major congenital anomalies and other adverse reactions in children exposed to the drug in utero. 5
Off-Label Uses
While not FDA-approved for these conditions, modafinil has been studied for:
- Attention-deficit hyperactivity disorder
- Cancer-related fatigue
- Post-anesthetic sedation
- Cocaine dependence and withdrawal
- As an adjunct to antidepressants for depression 5, 3, 4
Monitoring
When prescribing modafinil, it is essential to monitor for:
- Development or worsening of anxiety
- Sleep disturbances
- Agitation
- Cardiovascular symptoms (blood pressure, heart rate)
- Psychological changes 6