Author Insights: Legalizing Medical Marijuana May Reduce Opioid Deaths

Marcus A. Bachhuber, MD, a Robert Wood Johnson Foundation Clinical Scholar at the Philadelphia Veterans Affairs Medical Center, and colleagues found that states that legalize marijuana experience lower rates of opioid deaths, on average, compared with states that don’t allow medical marijuana. Image: University of Pennsylvania

Marcus A. Bachhuber, MD, a Robert Wood Johnson Foundation Clinical Scholar at the Philadelphia Veterans Affairs Medical Center, and colleagues found that states that legalize marijuana experience lower rates of opioid deaths, on average, compared with states that don’t allow medical marijuana. Image: University of Pennsylvania

Opioid-overdose deaths increased in states across the country between 1999 and 2010, but states that legalized medical marijuana saw less-steep increases than those without, according to a study published in JAMA Internal Medicine this week.

Growing use of prescription opioids over the past 2 decades to treat chronic pain has helped drive increasing rates of opioid overdoses. To help reduce the problem, state and federal governments have instituted prescription monitoring programs and drug safety plans and tightened restrictions on prescribing popular opioids. Some of these efforts have yielded reductions in opioid overdoses on a state level, but national rates continue to rise.

At the same time, a growing number of states have legalized medical marijuana. In states like Colorado, where medical marijuana has been legal since 2000, the primary reason for a physician to recommend medical marijuana is pain. Some of the other indications for prescribing medical marijuana include nausea from cancer chemotherapy and poor appetite and accompanying weight loss resulting from a chronic illness such as HIV infection.

Marcus A. Bachhuber, MD, a Robert Wood Johnson Foundation Clinical Scholar at the Philadelphia Veterans Affairs Medical Center, and his colleagues analyzed opioid overdose rates in states with or without legalized medical marijuana to see whether its availability to treat pain helps reduce opioid deaths. They found that while opioid overdose deaths have continued to increase in all states, states that permit prescribing medical marijuana had lower rates of opioid overdose deaths compared with those that do not.

Bachhuber discussed his results with news@JAMA.

news@JAMA: Why did you decide to do the study?

Dr Bachhuber: I’m a primary care physician and I’ve talked to many patients with chronic pain. In the past, I’ve had patients who said they’ve tried prescription opioid painkillers but the only thing that worked to reduce their pain was marijuana. So, my colleagues and I wondered whether people might be choosing to treat their pain with marijuana in states where this is legal, and if these states might see lower rates of painkiller overdoses or deaths.

news@JAMA: You found that the rates of opioid overdose were lower in states allowing medical marijuana. Can you explain what that means?

Dr Bachhuber: We found that rates of opioid overdose deaths have increased in all states. But in the years after the legalization of medical marijuana, states that did so had a rate that was 25% lower than what we’d expect to see in that state, given past trends and what was going on in the rest of the country.

news@JAMA: Why might making medical cannabis available reduce opioid overdose rates?

Dr Bachhuber: Going into the study, we hypothesized that patients with chronic pain might replace opioids with medical marijuana or supplement opioid medications with medical marijuana, allowing them to reduce their opioid dose. Alternatively, there is still a debate about whether medical marijuana might lead patients to use other drugs, so rates of opioid overdose might have increased. We thought there could be a change in either direction, and that’s why we decided to study it.

news@JAMA: Your study can’t prove that medical marijuana was the factor that reduced opioid overdoses. Might there be other explanations?

Dr Bachhuber: One of the limitations of our study is that we can’t identify, measure, and control for every factor that was different between the states and might be contributing to our results. If broader changes were happening in states that also implemented medical marijuana laws, such as changes in patterns of pain treatment or illicit drug use, those could be influencing our results and have nothing to do with medical marijuana. But, if medical marijuana laws are in fact reducing opioid overdose deaths, we would need studies following individuals over time to see how exactly these laws are shifting behavior.

news@JAMA: How much do we know about the use of opioids or marijuana for pain treatment?

Dr Bachhuber: Opioids are approved by the FDA for the treatment of pain; they have undergone randomized trials, but there is very little evidence for long-term use for more than a few months. Marijuana is still considered a Schedule I drug, meaning the FDA says there is no valid medical use. Because of this, there is not much research out there to help us understand the risks and benefits of medical marijuana, including what conditions could be successfully treated, which patients might benefit the most, and what the risks may be. Also, head-to-head studies of marijuana and opioids would be incredibly useful for clinical practice.

news@JAMA: What is the main take-home message from your study?

Dr Bachhuber: Our study provides evidence of a possible unexpected public health benefit of medical marijuana legalization. Medical marijuana may have other possible impacts on public health, and as more states enact these laws, it will be worth continuing to look at this issue.

More Flu Patients Get Antibiotics Than Antivirals, Study Reports

Antiviral medications such as oseltamivir are too infrequently prescribed for patients with the flu, according to a new study. (Image: ©

Antiviral medications such as oseltamivir are too infrequently prescribed for patients with the flu, according to a new study. (Image: ©

Prescriptions for antibiotics outpaced those for antiviral medications by 2 to 1 among patients with confirmed influenza at several care centers during the 2012-2013 flu season, according to a new study.

The findings, published today in Clinical Infectious Diseases, show that many patients at high risk of developing complications from the flu missed out on antiviral medications’ potential benefits. At the same time, others were exposed to adverse effects from antibiotics that offered them little or no benefit and contribute to antibiotic resistance.

The investigators analyzed data from 6766 patients treated for acute respiratory illness at 5 ambulatory care centers in the US Influenza Vaccine Effectiveness Network. Participants in the study were at least 6 months old, had a cough for not more than 7 days, and were tested for influenza with polymerase chain reaction (PCR).

Among all participants, 7.5% received a prescription for an antiviral medication—oseltamivir or zanamivir, which are neuraminidase inhibitors that specifically target the influenza virus. Of the entire group, 35% had PCR-confirmed influenza.

However, the investigators noted that few clinicians adhered to published guidelines. Antiviral medication is recommended for patients whose flu symptoms began within the previous 2 days and have risk factors for developing complications: being aged 2 years or younger or 65 years or older, pregnant, morbidly obese, or having 1 or more chronic illnesses, including compromised immunity.

But only 19% of the 1021 high-risk patients in the study who presented within 2 days of symptom onset were prescribed antiviral medications. Among the 2366 participants with PCR-confirmed influenza, 15% received an antiviral prescription. Of the 1825 patients with PCR-confirmed influenza for whom antiviral and antibiotic data were available, 30% were prescribed an antibiotic and 16% received an antiviral prescription. Antibiotic prescribing data covered amoxicillin-clavulanate, amoxicillin, and azithromycin.

The investigators noted that antiviral prescribing patterns varied widely among the 5 study sites, from 9% to 19% of patients with PCR-confirmed influenza. Antiviral prescriptions also were less frequent among children than adults, including high-risk children younger than 2 years.

In an accompanying editorial, Michael G. Ison, MD, MS, of the Northwestern University Feinberg School of Medicine in Chicago, wrote that the study “clearly demonstrates that antiviral treatment was underutilized and antibacterial therapy was likely overutilized by clinicians caring for outpatients with influenza.”

Ison added that a particularly troubling aspect of the findings “is that these [participants] were seen at centers with expertise in influenza research that should, theoretically, be more attuned to the importance of antiviral therapy, particularly in the high-risk [patients].”

He also noted that the study may underestimate antibiotic prescriptions for influenza because, in addition to the 3 for which data were available, other antibiotics such as cephalosporins and fluoroquinolones may be prescribed for acute respiratory infections. The drugs not only contribute to major public health risks from antibiotic resistance, they also expose patients to the risk of adverse effects including diarrhea and severe inflammation of the colon caused by Clostridium difficile infection.

The study’s authors wrote that their findings “reinforce the need for continuing education on the appropriate use of antibiotic and antiviral agents for patients presenting with acute respiratory illness.”


Using Teaspoons for Giving Medicine to Kids Often Results in Dosing Errors

Many parents find dosing instructions that use teaspoons as a measure confusing and reach for a kitchen teaspoon, which delivers an imprecise dose. Image:©

Many parents find dosing instructions that use teaspoons as a measure confusing and reach for a kitchen teaspoon, which delivers an imprecise dose. Image:©

Doling out a dose of liquid medication for a child can be confusing and stressful for parents. They may fumble to find the right dosing device, struggle to understand the dosing directions, and have difficulty getting their child to take the medication. Under these circumstances, dosing errors are common and result in more than 10 000 calls to poison control centers and 3000 to 4000 emergency department visits each year.

But physicians can make the process easier and more error free by simplifying dosing directions, according to a study published today in the journal Pediatrics.

Many organizations, including the US Centers for Disease Control and Prevention, the Institute for Safe Medication Practices, and organizations representing retail pharmacies, have suggested switching to metric-only dosing for liquid medications to reduce dosing errors. But there has been some concern that US parents might be confused by milliliter doses. To assess the risks and benefits of milliliter vs teaspoon dosing, a team of researchers compared dosing error rates among 287 parents whose children were prescribed a liquid medication in either teaspoons or milliliters after visiting 1 of 2 emergency departments.

The researchers found that mistakes are common, regardless of the unit of measure. More than one-third of the parents made an error in measuring their child’s dose and an 41% didn’t understand the prescribed dose.

Many (16.7%) reached for implements such as kitchen spoons, which are vary in size and may lead to an incorrect dose. Parents who were given a prescription in teaspoons were more likely to make a measurement error than parents given a metric measurement(42.5% vs 27.6%). Many, but not all, of these errors occurred because parents given a prescription in teaspoons used a kitchen spoon or other nonstandard device. Parents with low health literacy and non-English speakers were particularly prone to errors when teaspoons were used as a measure.

Some of the confusion likely stems from different units of measurements on the bottle label, in the prescription, or in verbal instructions from health care professionals or pharmacists, according to the authors. This suggests that clinicians and pharmacies are exacerbating parents’ confusion by using different units of measure.

The authors conclude that the findings support the safety of switching to milliliters-only dosing, especially for parents who have low health literacy or who do not speak English.

“Our findings provide evidence in support of a growing national initiative to move to a milliliter-only standard and may allay fears about the elimination of teaspoon and tablespoon terms,” the authors wrote.

Author Insights: Overtreatment of Diabetes in Elderly Patients Remains Underrecognized

Patrick O'Malley, MD, MPH of the Uniformed Services University of the Health Sciences in Maryland, speaks about overtreatment of diabetes among elderly patients.

Patrick O’Malley, MD, MPH of the Uniformed Services University of the Health Sciences in Maryland, speaks about the overtreatment of diabetes among elderly patients.

The primary goal of treatment for diabetes, as for many chronic conditions, is to lower rates of death and complications from the disease. But an equally important goal in medicine, one recognized over 2 millennia ago, is to “do no harm,” and sometimes this balance between help and harm can be difficult to accomplish.

In this week’s issue of JAMA, a theme issue on diabetes, a viewpoint discusses the overtreatment of diabetes in certain patient populations—that is, the overuse of blood sugar–lowering medications to the point at which average blood sugar levels may be too low and cause more harm than benefit. The authors refer back to a study published about 6 months ago in JAMA Internal Medicine, in which researchers looked at administrative data from a large population of Veterans Affairs patients and found surprisingly high rates of overtreatment.

The JAMA Internal Medicine study focused on patients with diabetes who were most susceptible to hypoglycemia (low blood sugar) caused by diabetes overtreatment, which included patients older than 75 years of age, those who had poor kidney function, and those who had a diagnosis of cognitive impairment or dementia. Overtreatment among these patients was defined as having a hemoglobin A1c (HbA1c) level (a measure of average blood sugar values over a 3-month period) that was less than 6.0% (roughly corresponding to a blood sugar of 126 mg/dL), less than 6.5% (blood sugar of 140 mg/dL), or less than 7.5% (blood sugar of 154 mg/dL).

The researchers found that rates of overtreatment were 10.1% for HbA1c less than 6.0%, 25.2% for HbA1c less than 6.5%, and 44.3% for HbA1c less than 7.0%. However, no information on actual rates of hypoglycemia or the complications thereof (such as emergency department visits or hospitalizations) was collected.

Author Patrick O’Malley, MD, MPH, discusses his views on the implications of this study with news@JAMA.

news@JAMA: The study showed that 44% of VA patients with diabetes and risk factors for serious hypoglycemia may be getting overtreated to some degree. In your article, you state that these results are “sobering.” Why do you think overtreatment happens so often?

Dr O’Malley: In general, overtreatment is a multifactorial issue related to the culture of care. In medicine, physicians always want to do something, to take something, such as a blood sugar value, from abnormal to normal. We rely on clinical evidence for these treatment goals, but sometimes, in the absence of good clinical evidence, we must instead rely on biologic plausibility, and extrapolate data from one population to another. This extrapolation often happens with the elderly, who are not included as participants in many clinical trials on which many general clinical guidelines and recommendations are based. That’s why overtreatment tends to happen in the elderly, not just for diabetes, but for other diseases as well.

Another issue is the use of quality metrics, or A1c in the case of diabetes, with the notion of “lower is better” driving this culture of aggressive care. The VA system in particular is very good at driving such quality metrics to success, which probably leads to higher rates of overtreatment. It’s basically a case of good intentions and good systems gone awry.

news@JAMA: It seems that since elderly individuals are underrepresented in several of the major diabetes trials, evidence on the benefits vs harms of intensive glucose control might be difficult to interpret, and the ideal A1c level for elderly people is still a mystery. Is there a bottom line that can be drawn from these studies?

Dr O’Malley: Yes, the bottom line is that for anyone who has a life expectancy greater than 15 years, an A1c goal of less than 7 is reasonable. For all other people, which includes elderly individuals as well as younger individuals with multiple comorbidities and lower life expectancies, an A1c goal of less than 7 might be more harmful than beneficial. Providers should be tailoring A1c goals to the individual, and life expectancy should be a major part of that equation.

news@JAMA: For individuals with a life expectancy of less than 15 years, what is a reasonable A1c goal? Is there an upper limit?

Dr O’Malley: There’s not a whole lot of great evidence to support a specific upper limit, but in general, a blood glucose consistently over 200 is where people start running into problems with immune system dysfunction and increased risk of infections. This corresponds to an A1c of about 9.

news@JAMA: What can doctors and hospital systems do to address the issue of overtreatment?

Dr O’Malley: On a systems level, we have to be smarter about choosing metrics, and smarter about individualizing metrics to individual patients—older patients should have different metrics than younger ones. On an individual physician level, we should strive to be less pharmacologically oriented, especially in the elderly. There is a lot that therapeutic lifestyle changes can achieve. We also tend to be overly aggressive with monitoring, ordering A1c tests too frequently, and telling our patients to check blood sugars four times a day. Checking blood sugars three times a week is plenty for most stable patients with diabetes.

news@JAMA: What about for patients who might be skeptical or resistant toward the idea of withdrawing or decreasing the intensity of care?

Dr O’Malley: It’s true that this might be a major barrier, as patients are sometimes reluctant to do this, or confused as to why the same doctor who told them to intensify their diabetes control is now telling them to scale back. This is why it’s so important to have a trusting and invested doctor-patient relationship.

Sometimes as doctors, in an effort to stay as up to date and proactive as possible, we change our culture toward treatment before the evidence is truly there, and this ends up harming patients, wasting resources, and engendering distrust among patients toward their physicians and the healthcare system as a whole. Another example of this is what happened with hormone replacement therapy for menopausal women back in the ’90s—we were so quick to act on the benefits of hormone replacement before the long-term evidence was available and then realized it was actually more harmful than beneficial.

news@JAMA: Is there anything else you think patients should be aware of in terms of diabetes overtreatment?

Dr O’Malley: Patients should realize that in general, no medical therapy is perfect, and every therapy has risks. In the case of diabetes, patients should be aware of just how serious and life-threatening hypoglycemia can be. It’s important to educate them about this.

Spotlight on Marijuana: Evidence and Anecdotes Highlight Harms

Recent evidence and anecdotes published about the adverse effects of marijuana use continue to highlight issues surrounding legalization. Image:

Recent evidence and anecdotes published about the adverse effects of marijuana continue to raise issues surrounding its legalization. Image: ©

Marijuana is a drug of many faces—used for recreational or medical purposes, illegally or legally, depending on geography and circumstance. The current landscape of marijuana legalization in the United States is highly dynamic and controversial and will continue to grow more so as patients, healthcare providers, and the general public ask more questions about just how harmful the substance is.

Unfortunately, high-quality studies in this arena are lacking. Because recreational marijuana remains illegal in all but 2 states (Colorado and Washington), well-controlled, unbiased studies on the long-term effects of marijuana are impossible to conduct for the time being. As such, criticism and skepticism regarding the current evidence runs high, and future legislation on recreational marijuana will depend on how these 2 states fare. Last Sunday, an article in the New York Times highlighted some recent cautionary tales seen in Colorado since the legalization of recreational marijuana there in January, including some particularly alarming incidents that occurred after ingesting edible versions of the drug. However, comprehensive health statistics on adverse outcomes will take years to collect and analyze.

In the meantime, a review article published yesterday in the New England Journal of Medicine by authors from the National Institutes of Health’s National Institute on Drug Abuse summarizes the current evidence available on the adverse health effects of marijuana use. In the article, the authors discuss several of the most commonly studied and reported effects of marijuana use from studies on both animals and humans and present their take on how “real” these adverse effects are by dividing them into categories of high, medium, and low levels of confidence in the quality of the evidence.

Adverse health effects that the authors attribute to marijuana use with high confidence include

  • Addiction, with an estimated 9% of those who experiment with marijuana eventually becoming addicted. This number increases to 16% among those who start using marijuana as teenagers. The clinical observation of a cannabis withdrawal syndrome upon cessation also supports the addictive nature of the chemicals in marijuana.
  • Diminished lifetime achievement, which includes poorer academic performance in school and an increased risk of dropping out of school for children and adolescents
  • Increased risk of motor vehicle accidents due to impaired driving ability
  • Increased symptoms of chronic bronchitis

Adverse health effects that the authors attribute to marijuana use with medium confidence include

  • Abnormal brain development, which can occur if marijuana is used regularly through childhood and adolescence, until the age of approximately 21 years. Although there is ample evidence suggesting that adults who used marijuana in their youth have impaired brain connectivity, it is difficult to establish a cause-effect relationship (as opposed to simply an association) among these individuals. The basis for this concern over brain development largely comes from animal studies that provide more compelling evidence for causality.
  • Gateway to use of other drugs, which follows as a result of the abnormal brain development described above. It is possible that marijuana use during brain development alters the brain’s natural reward system and makes one more prone to addictive behaviors.
  • Mental illness, including depression, anxiety, and psychosis. Although studies have shown association between these conditions and marijuana use, causality has not been established.

The authors note low confidence in evidence suggesting a link between marijuana use and lung cancer.

Details on the literature search (for example, the numbers of studies reviewed and the dates of those studies) is not provided, nor is information about how the authors developed the rating system for the high, medium, and low levels of confidence.

Medical marijuana, on the other hand, has been more widely studied (with both observational studies and randomized trials), and currently medical marijuana is legal in 22 states and in Washington, DC. Medical marijuana is used to treat certain medical conditions such as chronic pain, nausea, and anorexia (“wasting”) in patients with end-stage AIDS. Still, evidence on its effectiveness has been varied and not definitive, and accidental ingestion and poisoning among children remains ongoing concern. The use of medical marijuana in Colorado is discussed in a recent JAMA audio interview with Larry Wolk, MD, MSPH, executive director and chief medical officer for the Colorado Department of Public Health and Environment.

Statin Use Can Stop When Illness Is Terminal, Study Reports

Patients whose life expectancy is less than a year can safely stop using statins, a new study reports. (Image: ©

Patients whose life expectancy is less than a year can safely stop using statins, a new study reports. (Image: ©

Discontinuing statin use in patients with late-stage cancer or other terminal illnesses isn’t harmful and may help improve patients’ quality of life, according to new research.

Data presented today at the American Society for Clinical Oncology’s annual meeting in Chicago show that ending statin use in patients with advanced diseases appears to offer several benefits. The study’s lead author, Jean Kutner, MD, MSPH, of the University of Colorado Cancer Center in Aurora, called research on when to stop preventive medications “a new line of investigation.”

Statins are among the most prescribed medications for their ability to lower cholesterol and reduce the risk of heart attack and stroke. About 40% of the drugs are prescribed to prevent a first heart attack or stroke and often patients take them for the rest of their lives.

Kutner and her colleagues with the Palliative Care Research Cooperative Group, which includes more than 20 US member institutions, enrolled 381 patients whose estimated life expectancy was 7 months. About half had cancer and all had taken a statin for at least 3 months. Two-thirds of the patients had taken a statin for more than 5 years.

Half of the patients were randomized to continue the drug, and the other half to stop taking it. Patients were monitored for up to a year to track cardiovascular events, changes in quality of life, and survival.

Death rates within 60 days were similar in both groups, about 20%. Rates of cardiovascular events were approximately 6% in each group. Median survival was 190 days among patients who continued taking a statin compared with 229 days among those who stopped the drug. Patients who quit statins had significant improvements in quality of life, especially in feelings of well-being and support. Stopping the drug also saves money.

Whether or when to stop preventive medications is an important issue in end-of-life care, the investigators noted. Some patients may start anticancer drugs or opioids for pain, increasing the risk of adverse events as their medications accumulate.

Kutner advised that patients with a life expectancy of less than 1 year who take a statin but haven’t recently had a heart attack or stroke talk with their physician about stopping the drug.

“One thing we found during the study was clinicians saying, ‘Hey, I never thought about stopping people’s statins,’ ” Kutner said in a statement. “Here’s a setting in which these drugs may not be doing most patients any good any more, and bringing up the subject of stopping unneeded medications offers the opportunity for shared decision making.”

Medications to prevent osteoporosis, blood clots, high blood pressure, and diabetes are candidates for future studies, Kutner added.





FDA Plans to Reduce Liver Damage Risk by Asking Physicians to Stop Prescribing High-Dose Acetaminophen Products

The US Food and Drug Administration is asking physicians to stop prescribing and dispensing medications containing high doses of acetaminophen to reduce the risk of liver damage. (Credit: JAMA, ©AMA)

To reduce the risk of liver damage, the US Food and Drug Administration is asking physicians to stop prescribing and dispensing medications containing high doses of acetaminophen. (Credit: JAMA, ©AMA)

After only limited success in persuading drug manufacturers to reduce the amount of the painkiller acetaminophen in prescription combination products, the US Food and Drug Administration (FDA) has now called on physicians to avoid prescribing these products if the acetaminophen content is too high. Liver failure, a need for liver transplantation, or death can occur when individuals exceed a certain daily dosage.

In 2011, the FDA gave manufacturers 3 years to voluntarily limit the amount of  acetaminophen in prescription combination drugs to no more than 325 mg in each tablet or capsule. The 3-year window closed this week, and although more than half of manufacturers have complied, some have not.

Acetaminophen, used to relieve pain and fever, can be found in over-the- counter products, such as Tylenol, and in prescription products combined with other ingredients, usually opioids such as codeine (Tylenol with Codeine), oxycodone (Percocet), and hydrocodone (Vicodin).

However, severe liver injury can occur when acetaminophen use exceeds maximum dosage (currently 4000 mg within a 24-hour period) or when an individual takes the drug and also consumes alcohol. Researchers estimate that in the United States, there are about 44 000 acetaminophen overdose–related emergency department visits each year, with about half being unintentional.

This week, the FDA issued a recommendation to physicians and other health care professionals to discontinue prescribing and dispensing prescription combination drug products that contain more than 325 mg of acetaminophen. The agency noted that no available data show that taking higher doses per pill or tablet provides additional benefit that outweighs the added risks for liver injury. This limitation should help reduce the risk of severe liver injury from inadvertent acetaminophen overdose.

The FDA said that it will soon begin proceedings to withdraw approval of prescription combination drug products containing more than 325 mg of acetaminophen per dosage unit that remain on the market.

The FDA’s action this week does not apply to products sold over the counter that contain acetaminophen as the sole active ingredient or combined with other drugs, such as ingredients found in cough and cold medicine. As ProPublica, an independent, nonprofit news group points out, some over-the-counter products contain as much as 625 mg of acetaminophen per dose. However, the agency said it will address over-the-counter acetaminophen products in another regulatory action because many consumers are unaware that overuse of acetaminophen poses a liver damage risk.