What is the Difference between Pitolisant (Wakix) and Modafinil (Provigil)?


This is a question we get a lot. At the most superficial level, they appear to be the same. They are both prescribed for the treatment of narcolepsy. That is, however, where the similarity ends.

The two medications have little in common. They work on completely different pathways in the brain, and have completely different safety profiles.

Scientists are still not completely sure how modafinil works (https://www.drugs.com/cdi/modafinil.html). It may work via the neurotransmitters noradrenaline and dopamine (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3849275/).

In contrast, pitolisant has a known mechanism of action. It binds to the histamine 3 receptor (H3R) and acts as an inverse agonist (https://www.drugs.com/uk/wakix.html). The H3R modulates numerous neurotransmitters including dopamine, serotonin, oxytocin, and acetylcholine (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3111674/). The fact that the H3R is upstream of so many different neurotransmitters has led researchers to hypothesize that treatment with pitolisant may result in many neurological benefits. Pitolisant is thus being investigated for the treatment of various conditions including epilepsy, dementia, schizophrenia, depression, pain, metabolic disease, and various neurotoxicities (https://clinicaltrials.gov/ct2/results?term=pitolisant&Search=Search). Additionally, the effect of pitolisant on dopamine levels in the basal ganglia suggest that it may be effective in normalizing not only schizophrenia, but also addiction (https://www.ncbi.nlm.nih.gov/pubmed/27363923).

There is one study comparing pitolisant to modafinil for the treatment of narcolepsy (http://www.ncbi.nlm.nih.gov/pubmed/24107292). It was a non-inferiority study, so it was not designed to see if pitolisant is better than modafinil, but only to see whether or not it is worse. Pitolisant was found to be almost as good as modafinil for the relief of excessive daytime sleepiness. Moreover, when the two were compared, pitolisant had a much better safety profile.

This brings us to another big difference between the two medications. Modafinil is potentially addictive. It is a schedule IV controlled substance (https://www.drugs.com/pro/provigil.html). In this sense, it is like methylphenidate (i.e., Ritalin).

In contrast, pitolisant does not appear to have abuse potential (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682710/). As the authors (Uguen, et al., 2004) explained in their discussion, “Potent wake-promoting agents of the amphetamine class present, among other drawbacks, a clear propensity to induce drug abuse in humans and psychomotor activation in rodents, both effects that many studies show as being related to their propensity to release dopamine in the nucleus accumbens. Pitolisant, in spite of its marked wake-promoting actions in animals (Ligneau et al., 2007b) as well as in humans (Lin et al., 2008, Schwartz 2011), clearly contrasts with these psychostimulants prone to addiction liability as shown hereafter on a large panel on most relevant in vivo models for drug abuse risk evaluation in rodents and monkeys.”

Many individuals with Prader-Willi Syndrome (PWS) and narcolepsy take modafinil. They report that it is critical for staying awake and maintaining mood, and they describe the medication as very important for their well-being. Unfortunately, some individuals are unable to tolerate modafinil because its use is associated with anxiety and abdominal pain.

Thus, at a minimum, pitolisant represents a narcolepsy treatment for individuals who do not tolerate modafinil. The research in histaminergic neurons, however, also raises the intriguing possibility that treatment with pitolisant could also result in other benefits for individuals with narcolepsy and/or PWS. At the Chion Foundation, we are working to provide the option of pitolisant to individuals who may benefit from a normalization of the histaminergic neurons.


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