WASHINGTON — In an effort to curb what many consider the worst public health drug crisis in decades, the federal government on Tuesday published the first national standards for prescription painkillers, recommending that doctors try pain relievers like ibuprofen before prescribing the highly addictive pills, and that they give most patients only a few days’ supply.
JAMA Guidlines RecommendationsThere are 12 recommendations. Of primary importance, nonopioid therapy is preferred for treatment of chronic pain. Opioids should be used only when benefits for pain and function are expected to outweigh risks. Before starting opioids, clinicians should establish treatment goals with patients and consider how opioids will be discontinued if benefits do not outweigh risks. When opioids are used, clinicians should prescribe the lowest effective dosage, carefully reassess benefits and risks when considering increasing dosage to 50 morphine milligram equivalents or more per day, and avoid concurrent opioids and benzodiazepines whenever possible. Clinicians should evaluate benefits and harms of continued opioid therapy with patients every 3 months or more frequently and review prescription drug monitoring program data, when available, for high-risk combinations or dosages. For patients with opioid use disorder, clinicians should offer or arrange evidence-based treatment, such as medication-assisted treatment with buprenorphine or methadone.
Besides Maria Sharapova, above, other athletes to test positive for meldonium include an Olympic gold medalist in short-track speedskating, a world champion speedskater, an Olympic silver medalist in wrestling and a world champion runner.CreditAlastair Grant/Associated Press
More than 60 athletes, including Olympic medalists and world champions, have tested positive this year for meldonium, the performance-enhancing drug that Maria Sharapova admitted to using, according to antidoping officials.
Meldonium, originally developed in Latvia for heart patients, aids blood flow and is not approved for sale in the United States. It was placed on the World Anti-Doping Agency’s banned list this year after being monitored by agency in 2015.
“Regarding the number of Meldonium positives, I can tell you that it was at 60 adverse analytical findings (since January 1st) recorded on Monday and that number is growing,” Ben Nichols, a spokesman for the World Anti-Doping Agency, said in an email message.
Most of the athletes who have tested positive have not been publicly identified because all the cases are still being adjudicated. Besides Sharapova, other athletes to test positive include: Semion Elistratov of Russia, an Olympic gold medalist in short-track speedskating; Pavel Kulizhnikov of Russia, a world champion speedskater; Davit Modzmanashvili of Georgia, an Olympic silver medalist in wrestling; and Abeba Aregawi of Sweden, a world champion runner.
When asked Thursday if he was surprised by the high number of athletes who have been caught since the ban, David Howman, WADA’s director general, said, “We are not really at any stage surprised when a substance is put on the list and all of the sudden there are positive cases.”
“The reason for it being on the list is it’s being used and has been used to enhance people’s performance, and that was the reason for this substance first to be monitored for 12 months,” he added. “There was ample warning if you like given when it was put on the monitoring list in 2014 for people to say, hey, we have to be careful here. And they weren’t.”
Howman resisted attributing the wave of positive tests largely to negligence.
“I don’t know if you can say what any main reason is,” he said. “We’ve got to wait for the cases to run their course and see what athletes are saying, and you’ve got to give them the opportunity of being heard, and I think we stand by that process.”
Sharapova, the 28-year-old tennis star and commercial powerhouse who is the most prominent athlete affected so far, made her case public on Monday by announcing that she had failed a test for meldonium and attributing the result to being unaware that it had been placed on the banned list.
She has taken full responsibility for being unaware and is not contesting the finding. Sharapova said her family doctor began prescribing the drug mildronate, also known as meldonium, in 2006 after several health issues arose. Her lawyer, John Haggerty, has said that Sharapova was unaware the drug had performance-enhancing capabilities.
“I was getting sick very often,” she said. “I had a deficiency in magnesium. I had irregular EKG results, and I had a family history of diabetes and there were signs of diabetes.”
Nichols said in an email on Monday that meldonium had been moved from the monitored list to the banned list “because of evidence of its use by athletes with the intention of enhancing performance.”
One factor in its change in status was a 2015 study, funded in part by the Partnership for Clean Competition, that analyzed 8,300 urine samples collected at doping control sessions and found that 182 (2.2 percent) contained the substance.
A study of last year’s European Games in Baku, Azerbaijan, published Wednesday in the British Journal of Sports Medicine, found an “alarmingly high prevalence of meldonium use by athletes.” According to the study, 13 winners or medalists were taking meldonium, and 66 athletes tested positive for it.
Growth in the use of meldonium was a subject of the latest documentaryfrom the German network ARD, which first reported on systematic Russian doping in 2014. The investigation cited a 2015 Russian study that found meldonium in 17 percent of 4,316 urine samples tested.
Dr. Steven Nissen, chairman of the department of cardiovascular medicine at the Cleveland Clinic, said that the drug seemed to be used to treat chest pains from severe heart disease.
“There is no way it would be clinically indicated in a healthy young athlete,” he said.
The Zika virus damages many fetuses carried by infected and symptomatic mothers, regardless of when in pregnancy the infection occurs, according to a small but frightening study released on Friday by Brazilian and American researchers.
In a separate report published on Friday, other scientists suggested a mechanism for the damage, showing in laboratory experiments that the virus targets and destroys fetal cells that eventually form the brain’s cortex.
The reports are far from conclusive, but the studies help shed light on a mysterious epidemic that has swept across more than two dozen countries in the Western Hemisphere, alarming citizens and unnerving public health officials.
In the first study, published in The New England Journal of Medicine, researchers found that 29 percent of women who had ultrasoundexaminations after testing positive for infection with the Zika virus had fetuses that suffered “grave outcomes.”
They included fetal death, tiny heads, shrunken placentas and nerve damage that suggested blindness.
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Neural progenitor cells exposed to Zika virus. The virus is shown in green, and cells that have died are shown in red.CreditSarah C. Ogden/Johns Hopkins Medicine
“This is going to have a chilling effect,” said Dr. Anthony S. Fauci, the director of the National Institute of Allergy and Infectious Diseases. “Now there’s almost no doubt that Zika is the cause.”
The small size of the study, which looked at 88 women at one clinic in Rio de Janeiro, was a limitation, Dr. Fauci added. From such a small sample, it is impossible to be certain how often fetal damage may occur in a much larger population.
Still, the high percentage of fetuses damaged is “very concerning,” he said. “There will be other studies that I believe will corroborate this.”
Two fetuses died even though the mothers were infected relatively late in pregnancy, at 25 and 32 weeks — and even after earlier ultrasounds had shown the fetuses to be normal.
“We were just blown away by that,” said Dr. Karin Nielsen-Saines of the David Geffen Medical School at the University of California, Los Angeles, and one of the lead authors. “We weren’t expecting to find problems in all trimesters.”
Other fetuses whose mothers were infected late in pregnancy suffered brain calcifications or abnormally slow growth.
Doctors in Brazil had previously said that the worst damage appeared in fetuses whose mothers were infected in the first trimester.
Zika has been likened to rubella because both cause mild symptoms in adults but maim or kill fetuses, and the new report’s authors compared their findings to the devastating American rubella outbreak of 1964.
Back then, almost 80 percent of American women had survived childhood infections with rubella and were immune. Nonetheless, that outbreak, the last before a vaccine was invented, killed at least 2,100 children and caused 20,000 others to be born with disabilities, including severe intellectual disabilities, blindness and deafness.
Virtually no women in the Western Hemisphere are now immune to Zika, so many more children could be affected, the authors said.
The disease is not expected to have the same consequences in the United States because it is spread primarily by mosquitoes that thrive in tropical regions, but there is mounting evidence that it is also spread by sex.
Other scientists echoed Dr. Fauci’s assessment that the new research strongly indicated that the Zika virus, and nothing else, is behind Brazil’s wave of fetal brain damage.
“It does not close the deal, but it’s a huge step forward,” said Dr. Ernesto T. A. Marques, who studies Zika in Brazil and at the University of Pittsburgh Graduate School of Public Health but was not involved in the new research.
The World Health Organization is awaiting results from a similar but much larger study involving 5,000 women, mostly from Colombia. They are not expected until May or June, when large numbers of the babies will come to term.
The Brazilian study, which is still in progress, followed 88 pregnant women who visited a fever clinic at the Oswaldo Cruz Foundation hospital in Rio de Janeiro, one of Brazil’s leading research hospitals, between September and February.
Every woman with a rash, the most characteristic symptom of infection, was tested for the Zika virus, and 72 were positive. The tests looked for the virus itself; they work only if done early in an infection, but are considered more accurate than later tests for antibodies.
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Guo-li Ming, left, and Hongjun Song at Johns Hopkins in front of images from a high-powered microscope.CreditJohns Hopkins Medicine
Forty-two of the infected women agreed to have a series of ultrasound scans, as did all 16 uninfected women.
Of the remaining 30 infected women, two miscarried and 28 declined the scans, the study’s authors said.
“Some women who said no said the campus where the ultrasounds were done was too far away,” Dr. Nielsen-Saines said. “But we think it was also not wanting to know. There’s a tendency to be fatalistic, to say, ‘God willing, everything will be fine,’ or ‘I’ll deal with it when the baby is born.’ ”
The bleakness of the results was startling. Of the 42 infected women receiving regular ultrasounds, a dozen had babies who died in utero or suffered serious birth defects. Only eight of the babies carried by the 42 women have been born so far, but the ultrasound scans for them turned out to be accurate. None of 16 uninfected women had problems in their scans.
The new study does not answer an important question: whether Zika infections so mild that they produce no symptoms in the mother can damage a fetus.
Doctors say four out of five Zika victims have no symptoms. When they do, the most common are rash, joint pain, red eyes and headaches.
Still, although it was small, “this kind of study is the gold standard,” Dr. Fauci said.
In the second study, published in the journal Cell Stem Cell, researchers at Johns Hopkins and elsewhere cultured several types of cells present in early fetal development, including so-called cortical neural progenitor cells, which form the cortex, the outer brain layer responsible for many higher functions.
Three days after they infected all the cells with the Zika virus, 90 percent of the progenitor cells were damaged: They were unable to divide normally and often died.
By comparison, the other two types of fetal cells were much less affected.
“The cell types responsible for forming the cortex are the target of the Zika virus,” said Hongjun Song, a neurologist at Johns Hopkins University School of Medicine and a senior author of the study.
Some experts cautioned that, because the experiment was conducted with laboratory-grown cells, the results might not apply to humans.
“It might be that the results wouldn’t be the same in a living system of actual cortical stem cells,” said Dr. Catherine Y. Spong, acting director of the National Institute of Child Health and Human Development.
Cultured cells may be more susceptible to infections, she added.
Sara Cherry, a microbiologist at the University of Pennsylvania, called the study “really important” but noted that the cells were infected with a Zika strain “quite distinct” from the one now infecting people in Latin America.
Dr. William B. Dobyns, a pediatric neurologist at Seattle Children’s Research Institute, called the work “highly significant.”
If the cells that should form the brain cortex grow too slowly, he said, “you get a small brain, but on top of that there’s cell death, which means whatever the size the brain is, it will shrink.” That reduction may lead to a conspicuous space between the skull and brain.
“This paper fits like a glove what I’m seeing,” said Dr. Dobyns, who has reviewed brain scans from Brazil. Those scans have shown gaps between severely shrunken brains and the inner skull, unusually smooth brain surfaces and other anomalies.
Dr. Guo-li Ming, a Johns Hopkins neurologist and a senior author of the study, said the scientists’ experimental model could be used to test drugs that could prevent brain damage in fetuses.
