10:07 AM

449 - COVID Rebound?, Melatonin Primer, Winning the Lottery

Take 3 – Practical Practice Pointers©

From the CDC and the NIH

1)  Concerns about COVID-19 “Rebound” with Paxlovid


Paxlovid (Ritonavir-boosted Nirmatrelvir) is one of two oral medications currently recommended by the NIH and CDC for the management of mild-moderate COVID-19 in outpatients who are at high-risk of progression to severe infection or complications.

Paxlovid is known to be associated with many potential drug-drug interactions, due especially to the ritonavir component, which makes prescribing difficult enough. The NIH information includes links to a list of the clinically important interactions and an interaction checker, as well as the FDA’s checklist for prescribers.

However, new information published at the CDC and NIH sites warn of a “Paxlovid rebound.” This rebound causes a return of symptoms including fever and a recurrence of a positive COVID-19 test (after initially reverting to a negative test) within 2-8 days of finishing the five-day Paxlovid course. There are insufficient data so far about progression or complications from this rebound.

The CDC, despite the paucity of data, recommend the following for patients with rebound symptoms and testing after Paxlovid:

·         They should re-isolate and follow the same isolation recommendations as those who are newly diagnosed with COVID-19 (may terminate isolation at 5 days after the rebound test if fever is resolved but should wear a tight-fitting mask in public for the following 5 days).

·         No new treatment is recommended for these patients and there is no recommendation to extend or change the Paxlovid course of treatment at this time.

·         They should seek medical attention if rebound symptoms become more severe.

·         Clinicians caring for patients with rebound should report these cases to Pfizer Safety Reporting and to FDA MedWatch.

The CDC and NIH both continue to recommend Paxlovid for outpatients with mild- moderate COVID-19 who are at high-risk for severe disease or complications but are closely monitoring this situation.

John’s Comments:

I happen to have two friends who have experienced this phenomenon recently – neither of which became very ill but were disconcerted by the experience. I will continue to prescribe Paxlovid for those at high-risk, especially since the injectable agents are less useful with the new Omicron variants, but will warn patients about this phenomenon.


·         Centers for Disease Control and Prevention, HAN Archive - 00467 | Health Alert Network (HAN). Published May 24, 2022. Accessed May 25, 2022. Link

·         National Institutes of Health, Ritonavir-Boosted Nirmatrelvir (Paxlovid). COVID-19 Treatment Guidelines. Accessed May 25, 2022. Link

From the Literature

2)    Melatonin Primer 2022


Up to 25% of children and 50% of adults experience difficulty sleeping. Because of this, and the fact that many of the traditional sedative-hypnotic medications have the potential to be habit forming (benzodiazepines, Z-hypnotics, barbiturates) or have potential long-term risk on memory (anti-cholinergics), interest in and the use of melatonin has grown rapidly.

Melatonin is hormone present in almost every life form from bacteria to humans. In vertebrates, melatonin is centrally synthetized by the neuroendocrine organ, the pineal gland.              Endogenous melatonin production is influenced by day/night cycles. In the brain, melatonin increases the binding of gamma-aminobenzoic acid (GABA) to its receptors. Its primary roles seem to be regulation of the body’s circadian rhythm, endocrine secretions, and sleep patterns.

Disruption of the timing of melatonin release or decreased melatonin production can contribute to insomnia. The problem is particularly pronounced when changing time zones or during shift work. Melatonin production also wanes with age, which may be partially responsible for the sleep difficulties experienced by older adults.

Melatonin has been extensively studied. A 2013 meta-analysis found that melatonin at doses of 0.1 mg to 5 mg decreased sleep latency by 7.1 minutes, increased total sleep time by 8.3 minutes, improved overall sleep quality, and had minimal side-effects. The impact on sleep latency is only slightly less that that from prescription medications.

When considering whether to recommend melatonin, sleep hygiene should be a first priority (see references). The presence of indoor lights during the night and the profuse use of electronic devices whose screens are rich in blue wavelength light during the night are a particular problem, as they delay the beginning of the secretory episode of melatonin and blunt its peak. This includes cell phones and laptop computers.

How Should Melatonin Be Best Used?

·         The majority of formulations take 45 minutes to become bioavailable, so it should be taken around an hour before the usual bedtime and targeted for the same time if taken over multiple days. The immediate release formulation is recommended.

·         A dose of 1.0 mg would result in a plasma concentration of approximately 500 to 600 pg/mL, which is much higher than the physiological concentration. The standard starting does is 2-6 mg/day for adults. While it can be used in children as a chronobiotic (time zone changes), the routine use of hypnotics in children is discouraged.

·         Studies indicate there is great intra- and inter manufacturer variation regarding the actual amount of melatonin in any product. Most commercial melatonin that is found in supplements is synthesized in the laboratory. There has been concern about product content variation as well as purity. Advise patients to select a single- ingredient product with the “USP Verified” mark.

·         To prevent daytime sleepiness and fatigue, travelers going eastward through two or more (especially five or more) time zones can take melatonin at the local bedtime on the day of arrival and for two to five nights thereafter (NNT = 2)

If it doesn’t work after a few weeks, it probably is not going to help. Long term safety and impact on normal physiological function is unknown.

Mark’s Comments:

My sense is that many of us are recommending melatonin as being a “benign option” compared with alternatives. My rule is that there is no such thing as a “benign” pill, so the more we know about what we’re recommending, the better. Melatonin appears to be “relatively” benign based on what we know, but as noted above, long term safety at the standard dose is unknown. Sleep hygiene is still a vital first step, and in particular nocturnal screen time (see references). One review described nocturnal light as an “environmental toxin.” Also, remember that because melatonin is not regulated by the FDA and purity varies widely among products, reviewing third-party product evaluations is recommended to determine product quality.


·         Hershner S. and Matsumura A. Melatonin: Academy of Sleep Medicine Sleep Education. Updated October 2020. Link

·         Pharmacist’s Letter: Considerations for Use of Melatonin. March 2022: Link by Subscription

·         Li J, et al. Trends in Use of Melatonin Supplements Among US Adults, 1999-2018. Research Letter. JAMA February 1, 2022; 327(5) :483-484. Link

·         Sleep Tips: 10 Tips for a better night’s sleep. National Sleep Foundation: Link

·         Sleep Hygiene: Sleep Foundation. Updated March 11, 2022: Link

·         Wright S. Benzodiazepine and Z-hypnotic stewardship. J Fam Pract. 2022 April;71(3):103-107 | doi: 10.12788/jfp.0381. Article

From PeerRxMed ( www.PeerRxMed.org )

3)    How Would Your Life Be Different If You Won The Lottery?


“The good news is that you are living the dream life. The bad news is the dream in question probably isn’t being had by you.” William Irvine, PhD

I will never win the “Mega-millions” or “Powerball” lotteries. Beyond the fact that the odds would not be in my favor to start with, the reason I will never win the lottery is because I don’t buy lottery tickets. However, even for those who do play (and “win”), the vast majority will never receive a financial windfall from doing so. But perhaps our good fortune has nothing to do with money. As a 3rd year resident, I won the “perspective lottery” without ever buying a ticket.

While working on the inpatient service during that time, I cared for a patient who had terminal cancer and who’s death was imminent. Remarkably, if I hadn’t known his prognosis, I would have had no idea other than his significant physical wasting that he had at most weeks to live. He was perpetually smiling, radiating love, and lifting up those around him.

One day while rounding, I had some extra time and sat down at his bedside to see how he was really processing his illness, expecting that he had some unexpressed fear, doubt, or worry. Perhaps a bit skeptically, I said to him, “I want to be sure you fully understand what is going on with your illness and what is likely to happen. What questions or concerns do you have?” He smiled broadly and replied, “Doc, I have none. As I look back on it, I now understand I’ve had a blessed life. Indeed, in my later years I realize that it’s like I won the lottery on the day I was born. I only wish I hadn’t waited so long to live like it. So now I want to live as fully as possible with whatever time I have.

And for me, living fully means lifting others up as much as I can.”

It was the last time we spoke as he died soon after, and over the many years since, I’ve found myself often thinking about him and the impact he had on me, particularly when I have one of those “woe is me” days. You likely have them as well.

I received one final gift from him which arrived in the form of a thank you card on the day he died. Inside, it said the following: “Hey Doc, Thanks so much for all you did for me. When we last spoke, I forget to tell you something. You also won the lottery on the day you were born. You are so Blessed. Please don’t wait like I did to live like it. And remember, living fully means lifting others up as much as you can. Pay it forward, Doc.”

With all we’ve been going through, it is understandable if you feel nothing like how you might imagine you’d feel if you were holding the winning Mega-Millions lottery ticket.

And yet, the odds of any of us being here are infinitesimally less than the odds of holding that ticket – kind of like holding the winning “Mega-Miracle” ticket. That often provides me some much-needed perspective, such as right now. Let’s not wait to live like it … and remember to pay it forward.


Mark and John

Carilion Clinic Department of Family and Community Medicine

Feel free to forward Take 3 to your colleagues. Glad to add them to the distribution list.

Email: mhgreenawald@carilionclinic.org