High opioid doses could be marker for suicide risk

In a VA study of nearly 124,000 Veterans, those receiving the highest doses of opioid painkillers were more than twice as likely to die by suicide, compared with those receiving the lowest doses. But it's unclear from the study whether there's a direct causal link between the pain medications and suicide risk. Rather, the high doses may be a marker for other factors that drive suicide—including unresolved severe chronic pain.

The findings appeared online Jan. 5, 2016, in the journal Pain.

"This relationship is likely more complicated than an increase in access to opioids leading to an increase in intentional overdoses," wrote the authors, led by Dr. Mark Ilgen.

Ilgen, based in Ann Arbor, Mich., is with the VA Serious Mental Illness Treatment Resource and Evaluation Center, and the VA Center for Clinical Management Research. He is also on the psychiatry faculty at the University of Michigan.

The study analyzed data on 123,946 Veterans who received VA care in 2004 and 2005. All of them had non-cancer chronic pain and received prescriptions for opioids. Using the National Death Index, the researchers identified 2,601 of these patients who died by suicide before the end of 2009. Then they compared prescribed daily doses of opioids between the suicide group and the overall group. They also looked at the types of prescriptions the Veterans had received: regularly scheduled doses, only as needed, or a combination.

The researchers controlled for an array of demographic and clinical factors, to tease out the dose-suicide relationships. They used a standard formula to calculate morphine equivalencies for the different opioid drugs that patients may have received.

The main finding was that suicide risk rose as dose increased. Compared with patients taking 20 milligrams a day or less, those in the highest dose category—100 or more milligrams per day—were more than twice as likely to die by suicide.

Not clear from study that opioids are a causal factor

Ilgen stressed in an interview that "this was an observational study. We can't say what's causing the association we're seeing between opioids and suicide. It's not clear at all that opioids are a causal factor. It could be factors other than the dose or the medication itself that are putting people at greater risk."

Notably, most of the suicides—64 percent—were committed with firearms. Only about 21 percent were due to an intentional overdose, either of opioids or another substance. Dose had roughly the same magnitude of association with suicide by any means as it did with suicide by overdose.

Ilgen points out that in any study that considers cause of death, "there's a lot of uncertainty about the coding of suicide"—that is, whether the death was intentional or accidental. "It's up to a medical examiner, typically, to determine how someone died. Differentiating between an intentional and unintentional overdose is often very difficult. In cases where someone leaves a note, or had talked openly about suicide, you can assume that the death was more likely to be intentional. But there are plenty of other situations that are ambiguous."

Opioids are potentially lethal because they depress the central nervous system. This means that functions like breathing and heartbeat can slow down—and, in the case of an overdose, eventually stop.

The new study by Ilgen's group focused only on suicides. A past study of theirs, published in JAMA in 2011, looked only at unintentional overdose deaths. As with suicides, the overall percentage of patients who died from an accidental overdose was small—0.04 percent, or 750 out of 154,684. But the same pattern was seen, with higher doses of opioids related to a higher risk of death.

Natural opiates, such as morphine and codeine, are found in the resin of the opium poppy. Semisynthetic opioids contain these naturally occurring compounds plus others made in the lab. For purposes of the current study, Ilgen's group used the general term "opioids" for both classes of painkillers.

The use of opioids to treat chronic pain—as opposed to short-term pain after surgery or for cancer—is controversial. On the one hand, many experts say there is a lack of evidence that the drugs help patients long-term. And they point to known risks such as the potential for abuse or addiction, or a list of other mental and physical side effects.

On the other hand, many clinicians who treat patients with anguishing chronic pain say the drugs can bring relief in dire situations—and that withholding or limiting them because of concerns over adverse effects can actually heighten the risk for suicide.

With increased attention to pain treatment in the past two decades or so, the use of opioids has skyrocketed. And naturally, the problems that go along with them have soared as well.

VA programs encourage safe use

For its part, VA has introduced programs, such as the Opioid Safety Initiative, to better educate clinicians and patients and help ensure that the medications are used safely and cautiously. One goal is to encourage more conversation about their risks and benefits between providers and patients. Another is to increase efforts to detect problems early and monitor for adverse effects. Yet another is to expand the use of other treatments that could be effective, such as cognitive behavioral therapy, acupuncture, or various forms of exercise or physical therapy.

What is clear is that unmitigated pain—by itself—is a strong risk factor for suicide.

"We don't know for sure why the dose of opioids appears to be related to suicide, but we do know from almost 30 years of research now that people who report greater pain tend to be at greater risk for suicide," says Ilgen. "And that risk, for the most part, persists even after you control for other factors like depression, anxiety, or substance use, which sometimes go along with pain. So there's something unique about the unpleasant experience of pain that puts people at greater risk."

So it could be that patients receiving the highest doses, at least in some cases, just had more severe, unrelenting pain. They may have developed a tolerance to lower doses.

Another theory is that many of the patients who received higher doses might have had certain characteristics—such as hopelessness or frustration—that weren't measured in the study but that might have contributed to their suicide risk.

To the extent that opioids are directly tied to suicide risk, the mechanism might be something other than patients' gaining access to a potentially lethal tool to commit the act. For instance, it could be that the disinhibiting effects of higher doses increase the chance that someone will act on a suicidal impulse—whether using a gun or other means.

Ilgen acknowledges that the current study may raise more questions than it answers. He says the best way to get more insight, at least in theory, would be to follow patients long-term in a randomized clinical trial.

"If you were able to look at randomization to different doses, you would get a much clearer answer about the role of these medications in suicide risk, versus the characteristics that lead someone to be prescribed those medications in the first place."

But conducting such a trial could be fraught with methodological and ethical challenges. There are already extensive guidelines in place for prescribing opioids, and generally, providers are advised to use the lowest effective dose for a patient. So enrolling a group of patients who all have similar pain symptoms at baseline—as rated on some type of scale—and who are otherwise similar clinically and demographically, but then randomly assigning them to different doses, may not be practical.

Seeking better understanding of opioids' pros and cons

Meanwhile, the Ann Arbor group and others are trying to learn more by poring over data in observational studies. They hope to home in on factors that make opioid prescribing riskier for some patients.

One recent study, for example, published in the British Medical Journal in 2015, looked at the potentially dangerous combination of opioids plus benzodiazepines, commonly known as "benzos." The class includes sedatives such as Valium and Xanax. In a Veteran population with high rates of co-occurring conditions such as PTSD, anxiety, traumatic brain injury, and chronic physical pain, the combination is not uncommon. In fact, in the study, among a group of more than 420,000 Veterans, 27 percent had prescriptions for benzos while also receiving opioids. The study identified 2,400 overdose deaths overall—either intentional, unintentional, or indeterminate—and about half the deaths occurred when patients were taking opioids and benzos at the same time. Ilgen was a coauthor on the work.

The new suicide study by Ilgen's group did not look specifically at whether such prescribing practices were a factor.

Another study, involving VA and Harvard authors and published in 2015 in JAMA Internal Medicine, found that unintentional overdose was more common with longer-acting opioids, versus shorter-acting formulations. Long-acting opioids are favored by many pain specialists, as they can do a better job of proving round-the-clock relief.

Yet another study, published in the Journal of Clinical Pain in 2014, looked at different regions within the VA health system to see if there were differences in how providers prescribe opioids, and in overdose rates. The study team, which included Ilgen, did in fact find such differences, which they say can "inform region-specific prevention strategies and opioid policy."

Ideally, as findings from these and other studies are reviewed and synthesized, providers will get a clearer picture of the pros and cons of opioids for chronic pain, and a better understanding of which patients are most at risk.

Ilgen says the tentative message from his group's latest findings is that "we're not seeing signs of a protective effect from opioids—and in fact, at least in terms of general rates, those receiving higher doses are those at higher risk of suicide."

He and his coauthors include the caveat that "additional research is needed on opioid use, pain treatment, and suicide."

On a more basic level, though, he says the new findings reinforce a message that is already out there for providers:

"They should know that when they're treating patients with pain, they're treating a group that's at elevated risk for suicide. So they need to be vigilant about asking about mental health symptoms—including directly asking about or screening for suicide risk, as appropriate—and they need to be thinking about referrals and risk management for these patients."