Dr. Anil Rama, MD is at the forefront of sleep medicine and serves as Adjunct Clinical Faculty at the world-renowned Stanford Center for Sleep Sciences and Medicine. As the Medical Director and Founder of Kaiser Permanente’s tertiary sleep medicine laboratory, he has successfully treated thousands of patients with complex sleep disorders. Dr. Rama is also an editorial board member of the Sleep Science and Practice Journal and has authored several book chapters and seminal peer-reviewed journal articles in sleep medicine. In addition, he has been a Principal Investigator in clinical trials for drugs or devices designed to improve sleep. Several national newspapers, local news stations, and health newsletters consult with him on a regular basis.
He has graciously volunteered to assist answering questions and to contribute on this website. He is in the process of getting his book published, regarding mouth breathing and how to improve sleep quality. You may read more about him and his book at https://www.shutupandsleep.com/
Dr. Rama, nor the Narcolepsy Support Organization endorse any specific treatment for narcolepsy. The statements made by Dr. Rama are his opinion and should be considered informational only and not specific medical advice.
*From the Admins* We just wanted to say thank you so much to Dr. Rama for volunteering his time to help. It’s been a challenge to find someone like him to volunteer his time and he has been remarkable. I’ve personally spent several hours on the phone with him and he’s genuinely excited to help out here.
Questions and Answers
1. What made you interested in sleep medicine in particular?
Sleep disorders often have a severe and pervasive impact on health, wellbeing, productivity, and enjoyment of waking hours. When I am not able to deduce a diagnosis or provide effective treatment, I face desperate patients and disappointed family members, not to mention frustrated physicians.
Having said that, the most rewarding aspect of sleep medicine is that for most patients, I do arrive at a logical diagnosis and, more importantly, highly effective treatment. For the patient, this can be life-changing. For myself, I have the pleasure and satisfaction of knowing I’ve contributed something with enormous benefit.
2. Are there any new treatments on the horizon that look promising?
We have gone over a decade without new treatments in Narcolepsy. The most recently approved drugs have been Provigil in 1998, Xyrem in 2002, and Nuvigil in 2007. The next few years will be exciting and confusing as several new medications will reach the market. Some medicines have entirely novel mechanisms of action while others are a pharmacokinetic and chemical variant of what currently exists. There will be more questions than answers initially. Which medications can be used as monotherapy? Which combination or cocktail of drugs is best? How important is convenience? Is sodium an issue for many people? What effects will replacing sodium with magnesium and calcium have long term on someone’s health? Which medications will insurance companies require to be used first?
JZP-110 is a selective dopamine and norepinephrine reuptake inhibitor in development for the treatment of excessive sleepiness in adult patients with narcolepsy, OSA, and Parkinson’s disease. My best guess based upon the review of public data is that it will be a stronger version of Modafinil with similar side effects.
Avadel’s Micropump®-based formulation of sodium oxybate, FT218, is designed to be administered in one single dose, before bedtime, to treat EDS and cataplexy in patients suffering from narcolepsy. My best guess is the smoother pharmacokinetics will render FT218 a bit more effective than Xyrem. Compliance should be enhanced with the once a night formulation. However, the sodium content will remain high which may be problematic for some.
JZP 258 is an oral formulation for the treatment of cataplexy and narcolepsy. JZP 258 is an oxybate mixed salt solution having sodium oxybate, potassium oxybate, calcium oxybate, and magnesium oxybate but with 90% less sodium than sodium oxybate (Xyrem). My best guess is that the low sodium content will be the critical decider for some to use this as a first line agent. However, what is unknown is the long-term effects of magnesium and calcium, which are used in lieu.
Pitolisant is an inverse agonist/antagonist of the H3 receptor that is approved in the European Union for the treatment of both type 1 and type 2 narcolepsy. My take is that, unlike Modafinil, Pitolisant reduces cataplexy, hypnagogic hallucinations, and sleep paralysis. It is unclear if will have any effect on sleep fragmentation (like Xyrem does). It is also unclear how alerting Pitolisant will be relative to Xyrem, Provigil, and JZP 110. Also, can Pitolisant be used in combination with other drugs, and if so, which ones?
In the end, it will be the practice of medicine that determines which medications or combination of drugs are right for an individual patient suffering from narcolepsy.
3. Are there any theories on why PWN so frequently have paradoxically disturbed nocturnal sleep?
The anterior hypothalamus contains gabaergic neurons that are necessary for healthy sleep. The posterior hypothalamus contains hypocretin neurons crucial for maintaining wakefulness. The wake and sleep promoting areas inhibit each other, which results in stable sleep and wakefulness. Disruption of this process, for example, by a deficiency of hypocretin results in sleep-wake instability.
This may be an oversimplification but think of sleep and wake as a light switch in a room. Hypocretin helps keep the light on when it is supposed to be on and off when it is supposed to be off. Deficiency of hypocretin causes the light switch to turn off during the day and on during the night at random times. This is why patients with narcolepsy do not necessarily have increased total sleep times, but the usual total sleep time just spread in small periods throughout the day and night.
4. There’s been a lot of chatter about a recent study involving opiates increasing the number of orexin neurons in chronic opiate users and restoring orexin in a narcolepsy mouse model. If you are familiar with this work, what is your opinion on the possible implications or future regarding treatment?
A quick recap. In that study, postmortem brains from heroin addicts demonstrated 54% more hypocretin neurons than neurologically normal human brains. Similar changes were induced with long-term (but not short-term) administration of morphine in mice. The increased number of hypocretin neurons was not due to neurogenesis and outlasted morphine administration by weeks. Interestingly, the amount of melanin-concentrating hormone, which are in the same hypothalamic regions as the hypocretin-producing cells, did not change in response to morphine administration. Morphine administration restored the populated of hypocretin cells and reduced cataplexy in mice who had these neurons partially depleted.
My takeaway is that there is a possibility that long-term opiate agonists might play a role in the future treatment of narcolepsy by restoring hypocretin-producing cells. Though promising, many questions remain. Questions such as what changes in brain function perpetuate opiate addiction? Is there a genetic predisposition to opiate addiction? Would long term opioid administration, though carefully administered, cause other adverse effects. I will keep my eye out for more research on this subject that will undoubtedly come out over the next few years.
5. Do you have any tips or suggestions that may help improve sleep or alertness that do not involve medication?
There are a plethora of tips and suggestions on the internet, not all of which are soundly grounded in science. I hope to provide some tips on here in the future.
6. What got you interested in narcolepsy?
At first, I laughed, but then an incredible sadness overcame me. I felt terrible for the young beagle. He was excited to see his owner and then just collapsed. I am not a fan of animal experimentation, but it was a beagle bred to have narcolepsy that made enamored with the condition.
7. How long have you been practicing sleep medicine?
I was a resident in neurology at Stanford in 1999 when I did a one-month elective rotation through the sleep medicine clinics. I was hooked ever since and never looked back.
8. Are there any particular challenges treating pregnant PWN?
The management of patients with narcolepsy who are pregnant raises many issues, including the risk to the mother and fetus related to the disease, potential dangers at the time of conception, the threat to both the mother and the embryo of the medications used to treat narcolepsy, and the risk to the infant from drugs that might be secreted in breast milk.
In my experience, though I prefer to have patients remain off medication during the course of the pregnancy, when drugs are necessary, there have been no adverse effects I have seen to either the mother or fetus. The teratogenic effects of narcolepsy medications taken in therapeutic doses seem to be low. However, the potential for rare complications during pregnancy and congenital abnormalities exists and needs to be carefully considered before taking any medications during pregnancy. Most narcolepsy patients can safely have a vaginal delivery without complications. In rare cases, it has been reported that cataplexy can interfere with delivery, but if a cesarean is required there appears to be no increased anesthetic or surgical risks.
9. What is your opinion on idiopathic hypersomnia with symptoms suggestive of narcolepsy? We have heard various theories, including that narcolepsy w/o cataplexy and IH may be more of a spectrum of the same disorder or that sometimes IH will evolve into narcolepsy.
Narcolepsy with cataplexy is a definitive diagnosis. If cataplexy is absent, then the determination of narcolepsy versus IH versus another cause of excessive daytime sleepiness becomes murky. The problem is that hypocretin CSF testing is still not something routinely performed by most labs. Also, the multiple sleep latency test is notorious for providing results that are neither entirely reliable nor reproducible. My personal view is that if cataplexy is not present, then many patients with narcolepsy without cataplexy, idiopathic hypersomnia, sleep apnea, and for that matter, fibromyalgia, chronic fatigue syndrome, et cetera are at a high risk of being misdiagnosed. I have never seen a case of IH evolve into narcolepsy except in a child who initially presents with sleepiness and the cataplexy develops months later.
10. Does aging play a role in the condition’s severity?
Narcolepsy is a chronic neurological disorder of excessive daytime sleepiness with childhood onset and associated with hypocretin deficiency. Symptoms such as depressed mood, drowsiness, and cognitive difficulties, though separate, may worsen a bit with age.