Dr. Gustin's Blog

Dr. Gustin's Blog

Melatonin is Over-rated as a Sleeping Aid


Experts say that other issues pertaining to poor sleep quality, such as light exposure and certain behaviors, should be tackled ahead of resorting to use of the hormone melatonin to regulate sleep.  But if it is used, an individual's daily onset of natural melatonin production should be taken into account before deciding on an appropriate dose to supplement, they say. 

Melatonin, which is available over-the-counter in the United States but restricted in other developed countries, is typically recommended acutely for sleep schedules thrown off by, for example, jet lag or chronically for certain circadian rhythm disorders.  It has also been touted as something close to a panacea, with some even suggesting it can treat cancer, cognitive dysfunction, and obesity.  However, it is the explosion in the use of melatonin to regulate general sleep in otherwise healthy individuals that has led to US consumers reportedly spending more than $400 million on melatonin supplements in 2018.

This has raised concerns over its safety among healthcare professionals and led to questions as to whether the hormone should be taken for jet lag at all and whether its use should be restricted in children.  This ongoing debate led the American Chemical Society to recently produce a video produce a video that debunks many of the myths around melatonin and its effects, including the magnitude of its benefits in improving sleep.  

Now, José Cipolla-Neto, MD, PhD, Institute of Biomedical Sciences, University of São Paulo, and Fernanda Gaspar do Amaral, PhD, a professor at the Federal University of São Paulo, Brazil, have conducted an in-depth review of the literature on melatonin and its uses.  Moreover, they have produced a series of recommendations, published in the December issue of Endocrine Reviews, that set out how best to use the hormone, including advice on the most effective dosage and timing.

But others question whether people should look to melatonin to regulate sleep at all, suggesting that, instead, individuals should be looking at controlling night-time light exposure and even regulating light levels in shops.  The sheer amount of research that has been conducted into melatonin in recent years is staggering. Cipolla-Neto and Amaral point out more than 4000 studies have been published in the last 20 years, of which 200 were randomized controlled trials and 195 systematic reviews.

Melatonin has been shown to affect a number of physiological processes, including downstream effects on the cardiovascular, reproductive, immune, respiratory, and endocrine systems, alongside energy metabolism.  Melatonin synchronizes our organism's temporal order both daily and on the seasonal time scale.  Consequently, multiple modes of action should be taken into account both when performing laboratory experiments and conducting clinical studies into melatonin's use as a treatment.

Melatonin's effects depend not just on the route of administration and concentration but also on the time of administration, among other factors.  Additionally, the daily variation in melatonin levels varies between individuals.  For example, those who prefer to get up early start daily melatonin production earlier than those who prefer to stay up later, while long sleepers tend to produce the hormone for longer periods than those who sleep less.

A given dose of melatonin may, moreover, result in different plasma levels between individuals, owing to pharmacokinetic differences in the way that it is absorbed, distributed, metabolized, and eliminated.  These processes can themselves be affected by an individual's age and clinical condition, the presence of pathological conditions, and the physiological performance of the gastrointestinal tract, liver, and kidneys.  If these factors are not adequately considered, they say that the clinical efficacy of melatonin will be altered.

How Should Melatonin Be Best Used?

The first recommendation is to determine the start of melatonin production, known as the dim light melatonin onset (DLMO), and its duration in each patient, and use that to guide prescribing. This is because, without using the DLMO as an indicator of the timing of administration, melatonin could advance, delay, or even have no effect on the timing of endogenous circadian rhythms.

However, is not typically feasible to determine the DLMO in everyday clinical practice.  A more practical surrogate is to take the time at which the patient usually goes to sleep at night.  Because of bioavaiability, melatonin should be taken around an hour before the usual bedtime at exactly the same time every day.

In terms of the dose, there is no consensus in the literature.  What is known is that young people who take approximately 0.1 to 0.3 mg of melatonin will have a plasma concentration in the range of 100 to 200 pg/mL, which is considered to be within the physiological range.


A dose of 1.0 mg would result in a plasma concentration of approximately 500 to 600 pg/mL, which is far higher than the physiological concentration.  For example, if the outcome is an acute phase displacing, as it is desired for jet lag treatment, a fast-release pulse correctly timed is perfectly adequate.  However, if the desired effect is a sustained phase displacement as, for example, in non-24-hour sleep disorder or circadian dysfunction in totally blind people, the synchronizing effect requires chronic continuous daily intake of melatonin.  For this purpose, a slow-release or dual-release formulation is the most appropriate."

 Should Melatonin Be Taken at All?

A question nevertheless remains as to whether melatonin should be taken at all by individuals who do not have a recognized clinical condition, or indeed whether it is the most appropriate treatment in those who do.

Satchidananda Panda, PhD, and his colleagues at the Salk Institute for Biological Studies, La Jolla, California, published a study in mice showing how the protein melanopsin in retinal cells continually responds to light. Melanopsin, which is tuned to blue light, is essentially checking whether it's daylight still out there and, if there is daylight, then it will tell the brain to avoid sleeping and stay awake.  It does that by two ways, one is increasing the circadian clock, telling that it's still daytime, and the second is it tells the pineal gland to slow down production of melatonin.  Melatonin, threfore, has a big impact on sleep and it should not be seen as a panacea, and should be heavily regulated, which it's not.  At the present time melatonin is the only hormone produced in the human body that's not heavily regulated.

Not Harmful, But Not That Effective

That said, currently, there isn't any hard  evidence to say that taking melatonin on a daily basis is harmful; there aren't large-scale multicenter clinical trials to really test that.  Most of the ongoing research is now being focused on reduction of light exposure in the hours prior to bedtime.  


Drug Overdose Deaths Increasing in U.S.

Deaths from drug overdose in the United States increased by 54% from 2011 to 2016 — with opioids, benzodiazepines (benzos), and stimulants the most commonly used drug classes involved, a new report released today by the Centers for Disease Control and Prevention's National Center for Health Statistics (NCHS), shows.

 The report notes that there were 41,340 drug overdose deaths in 2011 vs 63,632 such deaths in 2016.

 Although the opioid oxycodone was the most cited drug in overdose death records in 2011, heroin took the top spot from 2012 to 2015.

The story around fentanyl may be even more troubling. The rate of overdose deaths involving it or one of its analogs doubled each year from 2013 through 2016, when it finally took the lead in becoming the most mentioned drug. In 2016, 29% of all overdose deaths involved fentanyl (n = 18,335).

In addition, cocaine was the second or third most cited drug in the overdose death records throughout the entire study period.

The CDC's list of the 10 most frequently mentioned drugs also included the opioids, methadone, morphine, and hydrocodone;  the benzos, alprazolam and diazepam; and the stimulant methamphetamine.

Of all 10 drugs, only methadone was associated with a decreasing overdose death rate from 2011 to 2016.

"While the ranking changed from year to year, the top 10 drugs involved in overdose deaths remained consistent throughout the 6-year period," note the investigators, led by Holly Hedegaard, MD, NCHS.

"This report identifies patterns in the specific drugs most frequently involved in drug overdose deaths…and highlights the importance of complete and accurate reporting in the literal text on death certificates," they write.

The data were published online in the December 12 issue of the National Vital Statistics Reports.

Rise in Overdose Death Toll

An NCHS report released last year showed the age-adjusted rate of US drug overdose deaths increased dramatically from 1999 (6.1 per 100,000 population) to 2016 (19.8 per 100,000).

Although several previous studies on drug overdoses have used National Vital Statistics System-Mortality (NVSS-M) information, this data is coded using the International Classification of Diseases, Tenth Revision(ICD-10); and these ICD-10 codes focus on broad drug categories rather than on individual drugs, note the investigators.

In answer to this, the NCHS and the US Food and Drug Administration "collaboratively developed methods to search the literal text from death certificates to identify mentions of specific drugs and other substances, and to search contextual terms to identify involvement of the drug(s) or substance(s) in the death," the researchers write.

They defined "literal text" as written information from the medical certifier on cause or circumstances related to a death.

For the current report, they examined NVSS-M data from 2011 through 2016. These data were linked to electronic files containing death certificate information.

In addition to the top 10 drugs involved in overdose deaths, drugs that held the number 11 through number 15 ranking throughout the 6-year study period included diphenhydramine, acetaminophen, citalopram, carisoprodol, oxymorphone, tramadol, amitryptyline, clonazepam, gabapentin, and amphetamine. 

Threefold Increase in Heroin Deaths

The involvement of heroin in overdose deaths rose threefold from 4571 deaths in 2011 to 15,961 deaths in 2016. This made it the second-most mentioned drug in 2016, behind fentanyl.

Mentions of cocaine increased from 5892 overdose deaths in 2014 to 11,316 deaths in 2016, giving it that year's number 3 ranking.

The fourth most mentioned drug in overdose deaths in 2016 was methamphetamine. Its 6762 related deaths signified a sharp increase from the 1887 related deaths in 2011.

"An analysis of trends…showed that, for several drugs, the age-adjusted rate of drug overdose deaths increased considerably within a relatively short period," the investigators write.

Heroin, cocaine, and methamphetamine all showed significant increasing trends for age-adjusted rates of drug overdose deaths between 2011 and 2016 (1.5 vs 5.1 per 100,000 population; 1.6 vs 3.6 per 100,000; and 0.6 vs 2.1 per 100,000, respectively; all, P< .05).

Fentanyl showed a significant increasing trend between 2013 and 2016 (0.6 vs 5.9 per 100,000; P< .05).

The only decrease for a specific drug came from methadone, which was mentioned in 4545 overdose deaths in 2011 vs 3493 deaths in 2016 (1.4 vs 1.1 per 100,000). Still, it was the eighth most mentioned drug in 2016.

 For the 2016 top 10 drugs, "the proportion of deaths involving both the referent drug and at least one other concomitant drug ranged from 50% for methamphetamine to 96% for alprazolam or diazepam," the researchers report.

Finally, drugs most frequently recorded in unintentional overdose deaths in 2016 were fentanyl, heroin, and cocaine. The most frequently cited drugs in suicide by overdose were oxycodone, diphenhydramine, hydrocodone, and alprazolam.

NCHS National Vital Statistics Reports. Published December 12, 2018. Full text

Narcan and ER Treatment of Opiate Overdose

Recently published in the Acad. Emerg. Med. December 28, 2018

Most patients who overdose on opioids can be safely discharged from the emergency department (ED) as early as an hour after prehospital administration of the opioid antagonist naloxone, the study has found.

Opioid-related ED visits nearly doubled in the United States from 2005 to 2014. 

The researchers conducted a prospective study to validate the early discharge rule practiced at St. Paul's Hospital, Vancouver, Canada, which allows for discharge after 1 hour for those in whom the following six criteria are within normal limits: ambulation, oxygen saturation (> 95%), respiratory rate (>10 and <20 breaths/min), temperature (>35.0° C and <37.5° C), heart rate (>50 and <100 beats/min), and Glasgow Coma Scale score (15).

The study included 538 adult patients who presented by ambulance to the ED from 2016 to 2017, who had been administered at least one dose of naloxone before entering the hospital, and who underwent evaluation by an emergency medicine provider 1 hour after naloxone administration. (The typical observation period at the hospital is 4 hours.) The mean age of the patients was 33.4 years, and 69.5% were male.

The researchers examined whether clinical judgment, the St. Paul's Early Discharge Rule, or both, when utilized 1 hour after prehospital administration of naloxone, could predict who would have an adverse event (AE) within 24 hours.

AEs occurred in 82 patients (15.4%), but none died within 48 hours. The most common AEs were need for supplemental oxygen (11.3%), repeat naloxone for hypoventilation (3%), and assisted ventilation (2.6%).

Overall, the rule had a sensitivity of 84.1% (95% confidence interval [CI], 76.2 - 92.1), a specificity of 62.1% (95% CI, 57.6 - 66.5), and a negative predictive value of 95.6% (95% CI, 93.3 - 97.9). The inability to mobilize normally had the greatest sensitivity (58.0%) for predicting AEs; an abnormal temperature had the greatest specificity (99.1%). The rule failed to predict AEs in just 13 of 538 cases (2.4%).

These results are in line with the derivation study by the rule's originators, which found that the AE rate was 16% and the negative predictive value was 99%.

Only one patient in the study whose 1-hour evaluation results were normal subsequently needed additional naloxone following another presumed heroin overdose.

When used in tandem with healthcare provider judgment, the rule had a sensitivity of 87.8% (95% CI, 80.7% - 94.9%), a specificity of 53.0% (95% CI, 48.4% - 57.7%), and a negative predictive value of 96.0% (95% CI, 93.5 - 98.4%). Used together, provider judgment and the St. Paul's Early Discharge Rule predicted AEs in all but 10 of 529 patients (1.9%) .

 "Applying the prediction rule for patients for whom providers have a low clinical suspicion for AEs is a reasonable approach for risk stratifying patients for early discharge following naloxone administration for suspected opioid overdose," the authors write. They add, however, that the rule should be used with caution in cases of known oral or mixed overdose. They also call for further study to determine the rule's effectiveness in the context of overdoses of different drugs, drug combinations, and routes of administration.

Acad Emerg Med. Published online December 28, 2018. Full text


Medication Errors: #3 Cause of Death in U.S.

Medical error is the third leading cause of death in the United States, after heart disease and cancer, according to findings published in a recent issue of the British Medical Journal.

As such, medical errors should be a top priority for research and resources, say authors Martin Makary, MD, MPH, professor of surgery, and research fellow Michael Daniel, from Johns Hopkins University School of Medicine in Baltimore, Maryland.

Read more: Medication Errors: #3 Cause of Death in U.S.

FDA Declares Quinolones Drug Non-Gratis

Fluoroquinolones like Cipro, Avelox, and Levaquin are commonly used by clinicians to treat a host of bacterial infections including, urinary tract infections, pneumonia, diarrhea, sinusitis, bronchitis and others.  Because of common musculoskeletal complications the FDA recently made rulings.

The US Food and Drug Administration (FDA) said today that unless they lack other treatment options, patients with uncomplicated infections should not receive fluoroquinolones, given the risk for disabling and potentially permanent adverse events.

Read more: FDA Declares Quinolones Drug Non-Gratis

Medication Errors and Mortality

Medical error is the third leading cause of death in the United States, after heart disease and cancer, according to findings in the British Medical Journal, 253:i2139, 2016.

As such, medical errors should be a top priority for research and resources, say authors Martin Makary, MD, MPH, professor of surgery, and research fellow Michael Daniel, from Johns Hopkins University School of Medicine in Baltimore, Maryland.

Read more: Medication Errors and Mortality

Adverse Reactions to Anti-Histamines

Antihistamines are amongst the most widely prescribed drugs.  Although easily tolerated by most, there are clearly adverse reactions in some patients, especially children.  Here is a summary of a new study that documents these problems.

Antihistamines are associated with a variety of adverse reactions in children, including headaches, sleepiness, rashes, behavioral changes, and convulsions, new research suggests.

Read more: Adverse Reactions to Anti-Histamines

A New Hallucinogen: "Legal LSD"

A novel psychoactive substance, or "legal high," that has hallucinogenic effects and potentially severe adverse effects is being sold to partygoers as lysergic acid diethylamide (LSD).

Although the use of 25I-NBOMe, also known as "legal LSD," is currently relatively rare, it is sold under various names and in a range of forms, making it difficult for users to know what they are taking and for clinicians to develop effective treatments.

Read more: A New Hallucinogen: "Legal LSD"

Opioid Policy Changed by FDA

FDA Unveils Sweeping Changes to Opioid Policies

In response to the ongoing opioid abuse epidemic, top officials at the US Food and Drug Administration (FDA) today announced plans to reassess the agency's approach to opioid medications.

"We are determined to help defeat this epidemic through a science-based and continuously evolving approach," Robert Califf, MD, the FDA's Deputy Commissioner for Medical Products and Tobacco, said in a news release. "This plan contains real measures this agency can take to make a difference in the lives of so many people who are struggling under the weight of this terrible crisis."

Read more: Opioid Policy Changed by FDA

SINGLE-PAYER System Will Not Work in the U.S.

Single-Payer System: Why It Would Ruin US Healthcare

Single-Payer Would Be Bad for Doctors

A single-payer system—government-run healthcare for all—sounds like a noble ideal, but things quickly fall apart in the execution, according to its critics.

Michel Accad, MD, a cardiologist in San Francisco, says that because a single-payer system makes healthcare virtually free, "demand is almost unlimited," and the government has to set limits on what will be provided. Dr Accad writes a blog called "Alert & Oriented," which provides alternative views on healthcare systems.

Read more: SINGLE-PAYER System Will Not Work in the U.S.


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