Wakefulness agents compared: the efficacy evidence

This page is a reference summary of published evidence and regulatory documents. It is not a substitute for individual medical advice, and it is not a recommendation to take or avoid any medicine.

Medically reviewed by Dr. Sofia Lindqvist, · Last reviewed 11 August 2026

All four drugs on this page have randomised placebo controlled evidence behind them, and all four work. What the evidence does not support is putting them in order.

Why this is harder than it looks

There are five FDA approved drugs for excessive daytime sleepiness in narcolepsy, and almost no direct comparisons between them.

Each was tested against placebo, in its own trial population, using its own outcome measures, at a different point in time. Comparing an effect measured in one trial against an effect measured in another is unreliable, because the populations, baselines and measurement conditions differ.

This page sets out what each trial found. It does not rank the drugs, because the evidence does not support ranking them.

approved drugs for daytime sleepiness

25+

years of modafinil trial data

239

patients in the solriamfetol phase 3

261

patients across the pitolisant studies

The outcome measures

Two instruments recur, and understanding them is necessary to read any of this.

Instrument	Type	What it measures
Epworth Sleepiness Scale (ESS)	Subjective	How likely a person is to doze in eight everyday situations, scored out of 24. Higher scores indicate greater sleepiness. It measures reported experience.
Maintenance of Wakefulness Test (MWT)	Objective	Latency to sleep onset while sitting in a quiet, dim room and trying to stay awake. It measures capacity to remain awake under conditions designed to make that difficult.

A drug can move one and not the other. Both are relevant, and they answer different questions.

Modafinil and armodafinil

The largest evidence base by a wide margin, accumulated across more than twenty five years.

Randomised controlled trials support efficacy in reducing excessive daytime sleepiness in narcolepsy, in obstructive sleep apnea with residual sleepiness on CPAP, and in shift work disorder. A meta analysis by Sukhal and colleagues examined wakefulness promoting agents specifically in sleep apnea patients already treated with CPAP and found benefit on sleepiness measures.

For armodafinil against modafinil, the most cited comparative finding comes from shift work sleep disorder. A multicentre, randomised, double blind, parallel group study using comparative doses found armodafinil produced longer maintenance of wakefulness, with the modafinil group showing poorly sustained wakefulness in the final third of the night shift.

That result is what the pharmacokinetics predict, since the difference between the two drugs concentrates late in the dosing interval. It is reasonable evidence, and it is also the scenario most favourable to armodafinil.

Solriamfetol

Approval rested on a phase 3 trial randomising 239 narcolepsy patients to 75 mg, 150 mg, 300 mg or placebo once daily.

Patients on 150 mg showed statistically significant improvements on both the maintenance of wakefulness test and the Epworth Sleepiness Scale at week 12, with effects apparent from week 1 and consistent through to week 12. At week 12, 78.2 percent of patients on 150 mg reported improvement on the patient global impression of change scale, against 39.7 percent on placebo.

37.5 mg

4.5 min

ESS difference 1.9 points

75 mg

8.9 min

ESS difference 1.7 points

150 mg

10.7 min

ESS difference 4.5 points

Treatment effect differences against placebo on the Maintenance of Wakefulness Test, in minutes of additional sleep latency.

Two observations. The 300 mg arm was twice the maximum recommended daily dose, and the label subsequently noted that doses above 150 mg do not confer effectiveness sufficient to outweigh dose related adverse reactions. And the Epworth differences at the two lower doses are small enough to question their practical significance, even where statistically detectable.

Pitolisant

Efficacy was evaluated in two multicentre, randomised, double blind, placebo controlled studies in 261 patients with narcolepsy, with and without cataplexy. Both demonstrated statistically significant improvement in Epworth Sleepiness Scale scores.

Pitolisant is the only drug in this group with an approved indication covering cataplexy as well as sleepiness, and the only one with a paediatric indication.

Drug	Primary evidence	Cataplexy	Controlled substance
Modafinil	Multiple RCTs across narcolepsy, OSA and shift work	No	Schedule IV
Armodafinil	RCTs in the same indications, longer late shift wakefulness	No	Schedule IV
Solriamfetol	Phase 3, 239 patients, clear dose response	No	Schedule IV
Pitolisant	Two RCTs, 261 patients	Yes	Not scheduled

These are separate placebo controlled trials, not a head to head comparison. The rows are not directly comparable to one another.

Where the class does not work

Worth stating, because it illustrates that approval for one fatigue related condition does not generalise.

Off label fatigue

Neither armodafinil nor modafinil demonstrated significant benefit over placebo for cancer related fatigue in post treatment survivors. Both are nonetheless sometimes prescribed off label for it.

Results have also been mixed and less consistent than the sleep disorder findings across the broader literature on fatigue in neurological conditions, including multiple sclerosis and Parkinson’s disease.

What can reasonably be concluded

All four drugs have randomised placebo controlled evidence supporting efficacy for excessive daytime sleepiness in their approved populations. None has been shown superior to another in a direct comparison, with the partial exception of armodafinil against modafinil in the specific setting of late night shift wakefulness.

The practical differences between them are pharmacokinetic and mechanistic rather than differences in demonstrated efficacy: clearance route, duration, cataplexy coverage, controlled substance status and interaction profile. Those are the grounds on which the choice is actually made.

Clinicians who treat narcolepsy describe individual response as difficult to predict in advance, with patients sometimes responding well to an agent that would not have been the obvious choice. That observation is consistent with the absence of a demonstrated hierarchy in the trial data.

Frequently asked questions

Which wakefulness agent is most effective?

No direct head to head trial supports ranking them. Each was tested against placebo in its own population, so cross trial comparison is unreliable.

What is the difference between the ESS and the MWT?

The Epworth Sleepiness Scale is a subjective questionnaire scored out of 24. The Maintenance of Wakefulness Test objectively measures how long a person can stay awake in a quiet, dim room.

Is armodafinil better than modafinil?

In one shift work study using comparative doses, armodafinil sustained wakefulness longer late in the night shift. That is the scenario most favourable to armodafinil, and it is the only comparative signal of note.

Does solriamfetol show a dose response?

Yes, unusually clearly. MWT treatment effect differences were 4.5 minutes at 37.5 mg, 8.9 minutes at 75 mg and 10.7 minutes at 150 mg.

Do these drugs work for other kinds of fatigue?

Not reliably. Neither armodafinil nor modafinil beat placebo for cancer related fatigue in post treatment survivors, and results in neurological fatigue have been mixed.