Modafinil (Provigil)

This podcast provides general information, not a substitute for professional medical advice. Please consult your physician for personalized guidance. Hello, hello, welcome back to PsychRounds, a resident-run educational psychiatry podcast. I'm Dr. Tanner Hewitt and I'm joined by my co-host Dr. Bradley Miller, as Dr. Wing is out for this episode as he takes a well-deserved vacation. Now today we will be discussing the Daffinal, also known by its brand name ProVigil. Now over the past several years, the Daffinal has gained increasing attention within psychiatry because of its potential off-label use as an alternative to traditional stimulants such as infatomates. There's also become popular as well within cognitive enhancement or an atropic communities online where it's often promoted for improving weightfulness, focus, and productivity. Now Daffinal does have several FDA-approved indications, which includes excessive daytime sleepiness that is associated with obstructive sleep apnea, narcolepsy, and shift work sleep disorder. However, much of the growing interest in psychiatry centers around its off-label applications, including potential augmentation for depression, treatment of fatigue, incognitive slowing, and use in patients who may not tolerate or respond well to conventional stimulant medications. So in this episode, we'll review Daffinal's mechanism action, discuss the evidence behind its psychiatric uses, compare it with traditional stimulants, and talk through some important clinical considerations to see if it lives up to a type. So as usual, let's start with a little bit of history behind this medication. Daffinal's story actually begins overseas in France, and of course Tanner wants me to pronounce the French name, and I am not fluent in French, but the pharmaceutical company's called Labratoire Laffan was investigating a novel compound known as a Draftanel. Researchers observed that a Draftanel increased motor activity and wakefulness in mice, but interestingly did so without the significant peripheral sympatoma-medic effects typically seen with traditional stimulants. Now, if you're thinking that a Draftanel sounds a lot like Medaphinal, you'd be correct, because Medaphinal is the primary active metabolite of a Draftanel. But please don't confuse this with our Medaphinal or New Vigil, which is the active R enantiomer of Medaphinal, which we will discuss in a few episodes. And I want to jump in here briefly because it is worth noting here that a Draftanel was actually historically available as a supplement in the United States, at least marketed as such, but there has been some pretty significant crack down from the FDA here in the States, particularly because a Draftanel is a pro-drug. It is not approved for use here. That undergoes hepatic metabolism into Provigil with the active R enantiomer New Vigil, as Dr. Miller just said. And just some recent events within the past several years here. There have been several publications from the FDA noting supplement company seizure, heavy fines in prison time for some of these online, utropic companies selling these unapproved substances. Yes, word to the wise probably best not to take unapproved and unregulated substances from the internet. But back to the history in the early 1980s, researchers including Jufei and Betzouji began studying a Draftanel in patients with narcolepsy. Our studies appeared to demonstrate reductions in sleep tax and improvements in excessive daytime sleepiness. As interest grew in the substance, additional small clinical trials were conducted throughout Europe, and eventually gained enough traction that France reportedly incorporated it into certain military settings during the Gulf War because of its wakefulness promoting effects. These early findings prompted several multi-center trials in the United States, which showed similar benefits. Medaphinal was ultimately approved by the FDA in December 1998 for narcolepsy. And later in January 2004 for excessive sleepiness associated with obstructive sleep apnea and shift work sleep disorder. Now why not target approval for a Draftanel? Well like Dr. Huadard mentioned, the answer is likely multifactorial, as a Draftanel is a pro drug with further considerations for hepatic metabolism and drug drug interaction, whereas Medaphinal can mitigate that hepatic metabolism. Yes, definitely to a certain extent. Now reviewing the FDA product labeling, there are several dosing recommendations depending on the specific indication for narcolepsy and obstructive sleep apnea. The FDA package answer recommends dose of 200 milligrams once daily, typically administered in the morning. Now for shift work sleep disorder, the recommended dosage is also 200 milligrams, but taken approximately one hour prior to the start of the work shift. In patients with severe hepatic impairment, the manufacturer recommends reducing the dose by approximately half because of decreased drug clearance. And there's also consideration for lower starting doses in the geriatric population given the potential for altered metabolism and increased sensitivity. Medaphinal is also commonly available in both 100 milligrams and 200 milligrams tablet formulations. And generic versions are widely available. Now while doses up to 400 milligrams per day are considered within the FDA labeled maximum dosing range. They have been generally reported as well tolerated, but the labeled does note that studies have not consistently demonstrated additional clinical benefit at doses above 200 milligrams daily. There are several important warnings that were in discussion, including Stephen Johnson's syndrome or SJS, angiodema and anaphylactic reactions, multi-organ hypersensitivity reactions, possibility of precipitated psychosis and media. Additionally, increased monitoring is recommended in patients with underlying cardiovascular disease. And I want to briefly sidebar here, focusing specifically on risk of SJS, as this is a notable adverse effect that should be included in the informed consent discussion. In the initial clinical trial data referenced by FDA, it looks like approximately 0.8% of pediatric patients under age 17 experience a rash. Following these reported cases, there was one possible case of SJS and one apparent case of multi-organ hypersensitivity reaction. Neither occurred in the placebo arm. The medium time to rash onset was about 13 days. Another important aspect of informed consent is counseling patients about driving risk. Some patients experience persistent solvenilists or excessive sleepiness. So caution should be advised when operating a motor vehicle and other potentially hazardous machinery. I want to add psychiatric adverse effects as the FDA label describes higher rates of several psychiatric symptoms in adults receiving the medication compared with placebo, including anxiety, nervousness, insomnia, confusion, agitation and depression. And all of these are at 1% or less than 1%. In addition, postmarketing case reports have described associations with more severe nervous psychiatric symptoms, including mania, delusions, hallucinations, suicidal ideation and aggression. While these events appear to be rare, they are important to include in the informed consent discussion, particularly in patients with prior psychiatric history or other predisposing factors. The theoretical implication is definitely there. Because the primary mechanism of action is currently understood via weak dopamine transport inhibition, thus increasing dopamine in certain brain regions. Additional mechanisms are also considered to be a rexin activation histamine and glutamate GABA modulation. And you can tell the mechanism of action of this medication is pretty complex. And we're not going to go with a super deep dive as all the receptor binding affinities, but those are the main ones to consider. Yeah, I want to hop in and talk about cardiovascular risk because that's always a hot topic. Now the cardiovascular risk with metaphanel appears to be somewhat nuanced. In the short-term controlled trials, lasting up to three months, patients taking ProVigil did not demonstrate clinically meaningful differences and either mean systolic or diastolic bug pressure compared to placebo. However, retrospective analysis did find a greater proportion of metaphanel treated patients. Desiring initiation or escalation of antihypertensive therapy compared to placebo, which in the initial FDA product labeling raised some concern for possible cardiovascular effects ins susceptible individuals, hence wink wink obstructive sleep apnea. One of the more recent studies evaluating this issue was coming from Kaplanet L 2018 published in Fremiko epidemiology and drug safety, which examined cardiovascular outcomes associated with medaphonal use across three large US claims databases. This was a retrospective cohort study, which compared new medaphonal users with matched non-users and stratified additionally by obstructive sleep apnea status since OSA itself is independently associated with increased cardiovascular risk. Now, overall, the study did not suggest increased cardiovascular risk with medaphonal across the different databases. The primary exception did involve stroke risk in patients with obstructive sleep apnea with a prior history of stroke, where medaphonal use was associated with nearly double the stroke rate. However, this finding was not replicated in the non-obstructive sleep apnea patients with prior stroke. Results among patients without prior stroke were inconsistent across the databases. But do keep in mind the study I just mentioned was a retrospective cohort and obviously cannot establish causation. Nevertheless, because of the mixed findings and limitations in here in direct respective claims based research, the FDA continues to recommend increased cardiovascular monitoring in patients with underlining cardiac disease or hypertension. All right, we talked about hepatic metabolism recently earlier on and also maybe the lack thereof. So let's go into a little bit more of hepatic interactions. Medaphinal is a CIP-3A4 inducer, which could arguably be relevant in consideration with many of our psychiatric medications that goes through this enzyme. So how much is it a CIP-3A4 inducer? Well, that kind of depends. The FDA did zero in on steroid-based contraceptives with product label reflecting reduced exposure to ethanol estradiol by about 11%, which is the C-max and 18% for the total area under the curve without affecting elimination. So the change is modest pharmacokinmetically. And although that's the case, the FDA warns that the steroidal contraceptive effectiveness may be reduced. So backup or alternative non-hormonal contraception is recommended during use of provigial. So the FDA in product labeling does reference another such study. And this is regarding quityping. So keep in mind, this study looks more at armodaphinal than medaphinal, so that's new vigil versus provigial. And it was 250 milligrams of armodaphinal with use of quityping. And it was either 300 to 600 daily doses, somewhere in that range. And this resulted in a reduction in the mean systemic exposure of quityping by approximately 29%. Which could be theoretically significant. It's worth noting that medaphinal can also inhibit C2C19, which is a consideration for some SSRI therapies. So again, if you hear C2C19, think Citalipram and Sitalipram. I could not find a lot of case reports in this, but a consideration given this potential interaction could be QTC prolongation with elevated levels of Citalipram, especially in the elderly. So that may necessitate dose reduction or further monitoring. So just kind of some theoretical considerations to keep in mind with this medication. All right. And now the question that most of our listeners may be wondering, what about the psychiatric implications? So we will start with ADHD. Now the data I'm about to discuss comes straight from the FDA product label where there were three, seven to nine week double blind placebo controlled parallel group studies in children and adolescents aged six to 17 years old, all with attention deficit hyperactivity disorder. Now two of those studies were flexible dose studies up to 425 milligrams a day, and the third was a fixed dose study based on the patient's weight. In summary, these studies did show statistically significant differences favoring the definal over placebo in the pediatric population. However, and this is important, three serious cases of rash were noted among the 933 patients included in these studies and one possible case of SJS, which alarmed the FDA enough to deny approval for the indication of treatment with ADHD. But what about the adult population? Well, I'm going to be honest in in layman's terms, the results are not as impressive. The study I'm going to reference here is Cortisse at L 2018, which was published in the Lancet Psychiatric Journal, titled Comparative Ethicacy and Tolerability of Medications for Attention Deficit hyperactivity disorder and Children's Adolescence in Adults, a Systematic Review and Network at Analysis. So I'll keep it brief for them that title, but Modaphanil was not superior to placebo in adults, whereas expectedly in fetamine, methylphenidate, and even etymoxetine stratera did separate from placebo with greater effect sizes. Now in the child and adolescent population, there was separation from placebo based on teacher ratings, although the confidence interval in this metanausus was quite large, making it difficult to draw conclusions. So what about Modaphanil for treatment of unipolar depression? Well, Modaphanil has been studied as an adjunctive treatment with reported benefits in associated symptoms, specifically fatigue as you might guess. There was a metanausus in 2013 by Gross et al, which found that adjunctive Modaphanil or Armedaphanil significantly improved overall depression scores and remission rates with a positive effect on fatigue symptoms as well. But a later study, a systematic review and network of metanausus titled comparative efficacy and safety of stimulant type medications for depression in 2021, compared stimulant type medications for depression. And found that methylphenidate was the only psychostimulant demonstrating consistent efficacy for both symptom severity and response rates. Now for the Modaphanil fans in our audience, there may be some more utility in bipolar depression, a metanausus by Nunez et al 2020 in adults, found that adjunctive Modaphanil and Armedaphanil significantly improved both response and remission rates in bipolar depression with good tolerability and importantly, no increased risk of treatment emergent mania or hypomania compared to placebo. Now this study was quite interesting and that it included RCTs from both bipolar one and bipolar two depression, as well as containing both ProVigil and NewVigil. Now for RCTs included patients with bipolar one, assessing the efficacy and safety of Armedaphanil and the other study was that Modaphanil study that I just mentioned that had bipolar one and bipolar two patients involved. All of these studies took place for eight weeks with the exception of Modaphanil, which took place for six weeks. Now caution of course with the finding of it having a quote unquote, no increased risk of treatment emergent mania or hypomania compared to placebo, it's worth noting that patients were taking one or two maintenance treatments, specifically lithium, Velcroate, limotrogen, olansopene, Quattitipine, Arab-Prippresol, Risperdol, or Ziprazitone, which likely contributes to that finding of no increased risk of emergent mania. Furthermore, to keep it brief, again, the number needed to treat for remission from this meta-analysis was 16. And in other words, for our audience that is 16 patients with bipolar depression need to be treated for one additional subject to achieve remission, which is not to be honest, a very robust response. - Yeah, I guess just for my final thoughts here, just a little bit more opinion, I would be a little bit hesitant to start medaphonal on all my bipolar depression patients at this point, I think that this article is interesting, but there probably needs to be a little bit more evidence to be confident in maybe pursuing this. And I've not seen a lot of attendings or fellow residents utilize medaphonal in an adjunctive way, except for its odd label indications. So I'm curious if any of our audience members have off label experience or utilize it frequently, please throw a message. I'd be very curious to hear. We'll be of course covering new vigil in a future episode, so that's our medaphonal. But I do want to mention that there could be some advantages with that formulation, which was previously limited by cost. So again, that's the RN-antie winner of medaphonal and it went generic in 2016. So hopefully you could look forward to a brief episode that on that in the near future. - As always, feel free to contact us at [email protected]. If you're a fan of the podcast, please drop us a follow, comment, rating, or review as this helps us reach larger audiences. Thank you for listening. As always, we will see you next time and have a great rest of the week.