Stents are a popular treatment for angina pectoris, or chest pain usually resulting from narrowed arteries. Getting a stent is a serious procedure, with no small risk associated with it. And recent studies indicate that stents don’t do much to reduce recipients’ chance of future heart problems. They do offer some pain relief, but research indicates that may just be our old friend, the placebo effect.
The following originally appeared on The Upshot (copyright 2018, The New York Times Company).
More people in the United States are on antidepressants, as a percentage of the population, than any other country in the world. And yet the drugs’ efficacy has been hotly debated.
Some believe that the short-term benefits are much more modest than widely thought, and that harms may outweigh benefits in the long run. Others believe that they work, and that they can be life-changing.
Settling this debate has been much harder than you might think.
It’s not that we lack research. Many, many studies of antidepressants can be found in the peer-reviewed literature. The problem is that this has been a prime example of publication bias: Positive studies are likely to be released, with negative ones more likely to be buried in a drawer.
In 2008, a group of researchers made this point by doing a meta-analysis of antidepressant trials that were registered with the Food and Drug Administration as evidence in support of approvals for marketing or changes in labeling. Companies had to submit the results of registered trials to the F.D.A. regardless of the result. These trials also tend to have less data massaging — such as the cherry-picking of outcomes — than might be possible in journals.
The researchers found 74 studies, with more than 12,500 patients, for drugs approved between 1987 and 2004. About half of these trials had “positive” results, in that the antidepressant performed better than a placebo; the other half were “negative.” But if you looked only in the published literature, you’d get a much different picture. Nearly all of the positive studies are there. Only three of the negative studies appear in the literature as negative. Twenty-two were never published, and 11 were published but repackaged so that they appeared positive.
A second meta-analysis published that year also used F.D.A. data instead of the peer-reviewed literature, but asked a different question. Researchers wondered if the effectiveness of a study was related to the baseline levels of depression of its participants. The results suggested yes. The effectiveness of antidepressants was limited for those with moderate depression, and small for those with severe depression.
The take-home message from these two studies was that the effectiveness of antidepressants had been overstated, and that the benefit might be limited to far fewer patients than were actually using the drugs.
These points, and more, were made in a paper written by John Ioannidis in the journal Philosophy, Ethics, and Humanities in Medicine in 2008. He argued that the study designs and populations selected, especially the short length of many studies, biased them to positive results. He argued that while many studies achieved statistical significance, they failed to achieve clinical significance. He argued that we knew too little about long-term harms, and that we were being presented with biased information by looking only at published data.
This paper — “Effectiveness of Antidepressants: An Evidence Myth Constructed From a Thousand Randomized Trials?” — sowed lingering doubts about the use of antidepressants and the conduct of medical research. But recently, the most comprehensive antidepressants study to date was published, and it appears to be a thorough effort to overcome the hurdles of the past.
Researchers, including Dr. Ioannidis this time, searched the medical literature, regulatory agency websites and international registers for both published and unpublished double-blind randomized controlled trials, all the way till the beginning of 2016.
They looked for both placebo-controlled and head-to-head trials of 21 antidepressants used to treat adults for major depressive disorder. They used a “network meta-analysis technique,” which allows multiple treatments to be compared both within individual trials directly and across trials indirectly to a common comparator. They examined not only how well the drugs worked, but also how tolerated the treatment was — what they called acceptability.
They found 522 trials that included more than 116,000 participants. Of those, 86 were unpublished studies found on trial registries and company websites. An additional 15 were discovered through personal communication or by hand-searching review articles. The authors went an extra step and asked for unpublished data on the studies they found, getting it for more than half of the included trials.
The reassuring news is that all of the antidepressants were more effective than placebos. They varied modestly in terms of efficacy and acceptability, so each patient and doctor should discuss potential benefits and harms of individual drugs.
Further good news is that smaller trials did not have substantially different results from larger trials.
It also did not appear that industry sponsoring of trials correlated with significant differences in response or dropout rates. But — and this is a big “but” — the vast majority of trials are funded by industry. As a result, this meta-analysis may not have had enough data on non-industry trials to accurately determine if a difference exists.
There were also signs of “novelty” bias: Antidepressants seemed to perform better when they were newly released in the market but seemed to lose efficacy and acceptability in later years.
The bad news is that even though there were statistically significant differences, the effect sizes were still mostly modest. The benefits also applied only to people who were suffering from major depression, specifically in the short term. In other words, this study provides evidence that when people are found to have acute major depression, treatment with antidepressants works to improve outcomes in the first two months of therapy.
Because we lack good data, we still do not know how well antidepressants work for those with milder symptoms that fall short of major depression, especially if patients have been on the drugs for months or even years. Many people probably fall into that category, yet are still regularly prescribed antidepressants for extended periods. We don’t know how much of the benefit received from such use is a placebo effect versus a biological one.
I asked Dr. Ioannidis if the results of this new study were as radical as many news articles had suggested. He confirmed that this was a much-larger meta-analysis — with about 10 times more information — than the ones from a decade ago, with more unpublished data and more antidepressants covered. He’s also hopeful that future studies will be even better at informing individual-level responses, which might help to see if some patients benefit substantially even when others don’t seem to benefit at all.
But he thought that some of the exuberance in the news media might be a little overblown. “I am afraid that some news stories gave very crude interpretations that may be misleading, especially when their titles were too absolute, like ‘the drugs work’, ‘the debate is over’ and so forth,” he said. “The clinical (as opposed to statistical) significance of the treatment effects that we detected will continue to be contested, and it is still important to find ways that one can identify the specific patients who get the maximum benefit.”
Even with so much research on antidepressants, there are still many unanswered questions. It’s unclear if drug companies would be interested in the results, or indeed why they would be. The drugs are already being widely used, and no regulatory agency is requiring more data. If patients want answers, they will need to demand the research themselves.
Erika Cheng, who is a health services researcher and faculty member at IUSM with me, is a star. We’ll all be working for her someday. She and I wrote a commentary that discusses a study published in JAMA that examined whether the dependent coverage provision of the Affordable Care Act was associated with changes in payment for birth, prenatal care, and birth outcomes among married and unmarried women.
You should go read both the original study and our thoughts on it.
Retiring early may lengthen your life. Several recent studies have noted that retiring early can increase life expectancy. It worked for the Dutch, so it might work for you. Conventional wisdom often points to work keeping you young and giving you purpose and camaraderie. But, the number seems to indicate that cutting out of work can delay shuffling off this mortal coil.
Jennifer Doleac and Anita Mukherjee (D & M) have a controversial paper about policies to increase the use of Naloxone and the effects of those policies on the opioid epidemic. Opioids suppress respiration and overdoses can suppress it entirely. Naloxone is an opioid antagonist which can be administered to overdosed users to block this effect and keep the patient breathing. All 50 US states enacted laws to make the drug more available with the expectation that this would decrease the opioid death rate. D & M argued, however, that these laws had the unintended and paradoxical consequence of increasing opioid use to such a degree that there was no change in the opioid death rate.
Some people believe that this paper implies that doctors and first responders (I’ll just say doctors from here on) should not use Naloxone on overdosed opioid users. Or they believe that it implies that states should not work to increase access to Naloxone. Those people are outraged.* However, those policies don’t follow from D & M’s paper, and I’ll say why here.
From D & M’s abstract:
…many states have increased access to Naloxone, a drug that can save lives when administered during an overdose. However, Naloxone access may unintentionally increase opioid abuse… We exploit the staggered timing of Naloxone access laws to estimate the total effects of these laws. We find that broadening Naloxone access led to more opioid-related emergency room visits… with no reduction in opioid-related mortality. These effects are driven by urban areas and vary by region. We find the most detrimental effects in the Midwest, including a 14% increase in opioid-related mortality in that region.
Here’s the mechanism that, in D & M’s view, explains the paradox. Greater Naloxone availability made opioid use less dangerous. When users learned this, they responded by consuming more opioids. Increased opioid use led to more overdoses. So although a smaller proportion of overdoses were fatal, the death rate stayed the same, and in some regions may have increased. An increase in a risky behaviour in response to measures that reduce its harm is an example of a ‘moral hazard’ problem.‡
For the sake of argument, let’s assume that the moral hazard is real† and see what would follow. Imagine that a doctor is working in a Midwestern ED and that she knows about D & M’s findings. A man stumbles into the ED lobby with shallow breathing and contracted pupils. He falls unconscious to the floor. The doctor recognises an opioid overdose and concludes that the patient will likely die if she doesn’t administer Naloxone. She reflects, however, that the widespread availability of Naloxone in her region has increased the opioid death rate. Should she administer Naloxone?
The doctor can approach this question from at least two moral frameworks. The consequentialist framework looks at all the outcomes of giving or not giving the drug and chooses the action that does the most good (in this example, we’ll reduce ‘doing the most good’ to ‘saving the most lives’). The other framework says that a doctor who can save a patient’s life has the duty to do so, and except in extraordinary circumstances this duty overrides any calculations the doctor might make about outcomes for the population.
So, what does the doctor’s choice look like to a consequentialist? If the doctor gives Naloxone, she will save one life. However, because we have assumed that the moral hazard is real, saving that life will also promote opioid use. In calculating the lives saved, she must subtract an increase in deaths from the life of the patient that she saved in the ED. Conversely, not giving the patient Naloxone costs the ED patient his life but may reduce mortality for other users.
The doctor’s choice is simple. To justify not saving the patient, she would have to believe that her killing the ED patient would save more than one life among the users outside the ED. However, it’s implausible that one additional death on top of more than 50,000 annual opioid deaths would have such an effect. The consequentialist doctor will administer Naloxone.
But, she asks, what if all doctors stopped using Naloxone? Perhaps that would increase the danger of opioid use in a discernible way, possibly leading to fewer total deaths.
This calculation might favour withholding treatment, but only if other doctors also withhold Naloxone. However, other doctors won’t do this because most believe that if they can rescue a dying patient they must do so (this is the second framework). There are many explanations for why doctors have this duty, but almost everyone agrees that there is such a duty.
Moreover, a sophisticated consequentialist doctor would likewise affirm that she has this duty. Medicine wouldn’t work if doctors didn’t behave this way. Health care requires patients to trust doctors to an extraordinary degree: patients allow themselves to be rendered unconscious on tables so that surgeons can cut into them! We wouldn’t do this if we didn’t trust in doctors’ commitments to our well-being. Except in battlefield triage, doctors should not and do not calculate whether to allow one patient to die to save others. Doing so would damage medicine as an institution, with consequences outweighing any possible benefit from undoing the moral hazard of Naloxone.
Bottom line: a possible Naloxone moral hazard raises no questions about the ethical practice of medicine. It may, however, be relevant to public policy choices, including laws affecting the practice of medicine. But do D & M’s findings imply that restricting access to Naloxone is the right policy choice? D & M do not think so.
Our findings do not necessarily imply that we should stop making Naloxone available to individuals suffering from opioid addiction, or those who are at risk of overdose. They do imply that the public health community should acknowledge and prepare for the behavioral effects we find here. Our results show that broad Naloxone access may be limited in its ability to reduce the epidemic’s death toll because not only does it not address the root causes of addiction, but it may exacerbate them. Looking forward, our results suggest that Naloxone’s effects may depend on the availability of local drug treatment: when treatment is available to people who need help overcoming their addiction, broad Naloxone access results in more beneficial effects. Increasing access to drug treatment, then, might be a necessary complement to Naloxone access in curbing the opioid overdose epidemic.
Our policy choices are not limited to ‘increase Naloxone availability’ vs ‘keep Naloxone restricted’. The space of policy choices is much bigger. A third choice would be to:
- Do better at preventing opioid addiction (e.g., by changing opioid prescription strategies and reducing the diversion of prescription drugs),
- Provide better access to addiction treatment for current users, and
- Increase the availability of Naloxone to reduce the harm of overdoses.
Suppose that we could hold the population rate of opioid use constant through (1) and (2) or, better, reduce it. Then increasing Naloxone availability (3) in that context would lower the opioid death toll, despite the moral hazard. Moral hazard models do us a service by showing that harm reduction strategies, although potentially beneficial, may not be sufficient.
*I believe that the outrage is motivated by a concern that viewing Naloxone as a moral hazard will contribute to the devaluing of the lives of opioid users. That those lives are devalued is beyond question. How else to explain the lack of effort to address the epidemic of opioid deaths? What I argue here is that even if Naloxone availability creates a moral hazard, that does not imply that we should not make Naloxone available.
‡’Moral Hazard’ is a deeply unfortunate misnomer. The construct says nothing about the moral character of opioid users.
†The empirical validity of D & M’s paper is, of course, important. It’s just a different question than the one I am addressing here.
Credit where credit is due: the Trump administration announced yesterday that it won’t look the other way if Idaho flouts the Affordable Care Act. The ACA “remains the law and we have a duty to enforce and uphold the law,” CMS administrator Seema Verma explained in a letter to Idaho’s governor and its insurance director.
Maybe it’s a mark of how low we’ve sunk that I’m surprised, happy, and relieved to see the Trump administration acknowledge that the law is the law. But politics ain’t beanbag, and Azar and Verma were under immense pressure to allow Idaho to regulate its health insurers without regard to the ACA. That they chose to push back is a testament to their integrity.
Not that the ACA is out of the woods. In her letter, Verma notes that HHS has issued a proposed rule to allow for the sale of short-term health plans that would offer coverage for up to 364 days in a year. By statute, “short-term, limited duration insurance” are exempted from the ACA’s rules. If the rule is finalized, Verma believes that Idaho could allow for the sale of exactly the same noncompliant plans, so long as those plans trim their coverage by one day. Idaho can’t ignore the ACA, but it can bypass it.
Can this be right, though? Can it really be against the law to sell a noncompliant health plan that offers coverage for the whole year, but completely OK to sell the exact same plan if it covers someone for the whole year less one day?
I’m skeptical. Health insurance is typically sold on a one-year basis. If 365 days is the relevant baseline, how can you say with a straight face that a 364-day plan is “short term limited duration insurance”? The statute doesn’t define the term, which means that HHS has some discretion to set a standard. But HHS doesn’t have the discretion to interpret the exception to swallow the rule.
Not only does HHS’s proposed interpretation do violence to the language of the statute. Verma’s letter stands as a tacit acknowledgment that Idaho can achieve its goal of subverting the ACA by exploiting a loophole for short-term plans. How can the agency claim that it’s being faithful to the statutory plan if its interpretation would countenance such flagrant disregard of the law?
The best argument I’ve heard in defense of HHS’s proposal is that it would simply restore a rule that was on the books for twenty years before the Obama administration decided, in 2016, to clamp down and limit “short-term, limited duration insurance” to three months. That argument does give me pause: an agency interpretation of longstanding vintage is entitled to some respect.
But the courts have no problem striking down old rules if they’re inconsistent with statutory text. And, for my part, I’m struggling to understand how a plan that’s 0.27% shorter than a typical insurance plan can possibly count as “short-term limited duration insurance.”
Guns are in the news A LOT these days. The RAND Corporation recently unveiled a huge study on guns. We’re going to talk about the minuscule amounts that are spent on studying guns, and look at the evidence around regulating guns and the effects that can have on public health.
You should also go watch our playlist on guns and public health.
The following originally appeared on The Upshot (copyright 2018, The New York Times Company).
The opioid epidemic just keeps getting worse, presenting challenges discussed at length at a White House summit last week. But opioids are not America’s only significant drug problem. Among illicit drugs, cocaine is the No. 2 killer and claims the lives of more African-Americans than heroin does.
In a recent study published in the Annals of Internal Medicine, researchers from the National Cancer Institute and the National Institute on Drug Abuse found that drug-related deaths have grown across all racial groups and among both men and women. The analysis found that between 1999 and 2015, overdose deaths of any kind of drug for Americans 20 to 64 years old increased 5.5 percent per year.
For the most recent years of analysis (2012-15), the study found that deaths of men from heroin exceeded those from any other type of opioid, such as those found in pain medications. For women, deaths related to opioid medications were the most common.
But among non-Hispanic black Americans, cocaine has been a larger problem than heroin for nearly 20 years. For example, over 2012-15, cocaine overdoses claimed 7.6 per 100,000 black men. In contrast, heroin overdoses claimed 5.45 per 100,000 black men. Black women use both drugs at lower rates than men, but cocaine overdoses exceed those from heroin for them as well.
“We have multiple drug problems in the U.S.,” said Keith Humphreys, a professor at Stanford University School of Medicine who advises governments on drug prevention and treatment policies. “We need to focus on more than one drug at a time.”
That doesn’t mean opioids aren’t also a problem in the black population. They are. When you combine all types of opioids — including heroin, prescribed opioids and fentanyl — they claim more lives than any other drug from every racial group.
For a time, it appeared cocaine didn’t require as much attention. A study by RAND found that cocaine consumption fell 50 percent between 2006 and 2010. But in the past few years, the cocaine supply from Colombia has climbed to a record high in part because of a peace settlement that includes payments to farmers who stop growing coca. To be in a position to qualify for those payments in the future, many farmers started growing it. As a result, Mr. Humphreys said, cocaine prices have fallen, leading to an increase in cocaine use in the United States and some European countries.
Mr. Humphreys said one pathway to cocaine use is encountering the illegal drug market through an opioid addiction and then adding cocaine.
The surge in cocaine deaths has received relatively little attention. The trouble is, there’s a lot less we can do for cocaine than opioids. In contrast with addiction to opioids, there is no medication to treat addiction to cocaine. Though substantial investments have been made in search of drugs to treat cocaine addiction — including a vaccine — none are yet available.
Having fewer solutions doesn’t mean we can’t do anything about cocaine. Cognitive behavioral therapy can be effective in treating cocaine addiction, as well as other substance-use disorders. The defining feature of this therapy is learning to recognize patterns of thought that lead to problematic behavior and redirect them toward more positive behavior. Contingency management is also effective in treating cocaine addiction. In this approach, patients receive small rewards contingent on positive behavior (a cocaine-free urine test, for example).
Kicking cocaine with these treatment methods works only if access and staffing are adequate. Multiple federal laws, most notably the Affordable Care Act, made major strides by extending coverage and including substance-use disorder treatment as an essential benefit that health insurance plans had to cover.
But the new tax law undermines the A.C.A. by repealing the individual mandate. And changes to Medicaid being considered in many states — like adding work requirements or increasing premiums and other cost sharing — would also erode coverage. If insurance support is withdrawn, some addiction treatment agencies will lose staff or close, and some desperately needy addicted people will be cut off from care.
At the White House opioid summit, President Trump said his administration would be “rolling out policy over the next three weeks, and it will be very, very strong.”
But, as the evidence shows, even if we do respond to the opioid epidemic, it isn’t the only drug problem worthy of attention.
I’m pleased to announce the release of the ninth edition of Health Care Law and Ethics, on which I am now a co-author, along with Mark Hall, Mary Anne Bobinski, David Orentlicher, and Glenn Cohen.
One of the challenges of teaching health law is that the field changes so quickly. We’ve aimed to keep the book current without losing sight of the bedrock legal principles that structure the field. I encourage you all to use the book in your health law courses!
American healthcare spending is still WAY higher than pretty much all other industrialized countries. But not that long ago, things were different. The US didn’t spend nearly as much in this realm. What changed? Demographics? More sickness? Nah. Spoiler alert, prices have risen much, much faster than the rate of inflation. We’ve got a few suggestions for getting it under control.
This video was adapted from a column Austin and I wrote for the Upshot. Links to further reading can be found there.