Discontinuing Buprenorphine Too Soon 'Life-Threatening'

Pauline Anderson

December 03, 2019

Individuals with opioid use disorder are at high risk for overdose even after 18 months of treatment, new research shows.

Investigators found that among patients who were treated with buprenorphine continuously for 6 to 18 months, about 5% were treated for an opioid overdose within 6 months of stopping the drug.

The true rate is likely higher, inasmuch as the researchers were unable to take into account patients who overdosed but who did not present at the hospital for treatment.

Dr Arthur Robin Williams

"The rate at which individuals relapsed and overdosed after ending treatment was alarmingly high, suggesting that discontinuing buprenorphine is a life-threatening event," study investigator Arthur Robin Williams, MD, assistant professor of clinical psychiatry at Columbia University and a research scientist at New York State Psychiatric Institute, New York City, said in a statement.

Because of this risk, "retention on buprenorphine in this population is of the utmost importance," he told Medscape Medical News.

The study was published online December 2 in the American Journal of Psychiatry.

Longer Is Better

The study included 8996 adult Medicaid recipients who initiated buprenorphine therapy, continued on this treatment for a minimum of 6 months, and maintained Medicaid enrollment for at least 6 months after stopping their use of buprenorphine.

Most of the participants were women (61%) and white (91.5%), and more than three quarters (76.4%) were aged 25 to 44 years.

Researchers divided the patients into cohorts on the basis of buprenorphine treatment duration (6–9 months, 9–12 months, 12–15 months, and 15–18 months). Four outcomes were assessed during the 6-month period following buprenorphine discontinuation.

Results showed that, compared with the 6 to 9 month reference group, the 15 to 18 month group had significantly lower rates of Emergency Department [ED] visits (41.2% vs 48.6%; P = .001), inpatient hospitalizations (11.3% vs 13.9%; P = .05), and opioid prescription claims (19.1% vs 25.9%; P = .001).

Overdose rates were comparable across all groups.

Although there were similar patterns for the 9 to 12 month and the 12 to 15 month groups compared with the reference group, these didn't reach the same level of statistical significance.

After controlling for baseline characteristics, compared with patients who took buprenorphine for 6 to 9 months, those who continued the treatment for 15 to 18 months were also significantly less likely to visit the ED (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.65 – 0.86; P = .001), be hospitalized (OR, 0.79; 95% CI, 0.64 – 0.99; P = .05), and have an opioid prescription filled (OR, 0.67; 95% CI, 0.56 – 0.80; P = .001) in the 6 months following treatment discontinuation.

Patients who remained on treatment for 12 to 15 months also had significantly lower adjusted odds of ED visits and opioid prescription fills. Similar trends for all outcomes were observed for those who remained on treatment for 9 to 12 months, but these did not reach significance.

"Artificially Low" Overdose Rates

Just over than 5% of all study participants experienced at least one overdose in the 6 months after buprenorphine discontinuation.

Williams noted that this rate included only overdoses billed to Medicaid, so it does not include overdoses that were reversed by paramedics, bystanders, or friends, nor does it include fatalities from overdoses.

"This 5% rate is artificially low, which is one of the limitations of the study," he said.

Williams also noted that this percentage doesn't reflect the fact that some of the individuals had two or three overdoses following buprenorphine discontinuation.

Buprenorphine treatment for up to 18 months had no relationship with the likelihood of overdose after treatment discontinuation.

Patients who had been diagnosed with a comorbid psychiatric disorder or substance use disorder (alcohol or nonopioid drug) were more likely than those without such disorders to be hospitalized or to visit an ER following buprenorphine discontinuation.

Those with a psychiatric disorder were also more likely to have an overdose or to fill an opioid prescription; and those with an alcohol use disorder were more than twice as likely to overdose (OR, 2.02).

Williams said the investigators were "astonished" by the high rates of some of the outcomes. "For example, almost half of these people are in the emergency room within a few months," he noted.

Optimal Duration Unclear

It's clear from the study that "18 months is still far too short for the average person" and that "longer is better" when it comes to buprenorphine treatment, said Williams.

Owing to a lack of research, the optimal duration of buprenorphine treatment is still unclear. However, Williams said, "in general, the expert consensus has been a minimum of 1 to 2 years if not indefinite treatment."

It's not clear from the study why buprenorphine discontinuations occur, but patient factors such as stigma, as well as provider factors, likely contribute, he noted.

"Plenty of insurance companies limit prior authorizations to only 6 months or 12 months, and this is a huge problem that we clinicians encounter all the time with opioid use disorder," Williams said.

There are also "unfounded ideological biases" against treating patients with buprenorphine long term.

"There are still very loud voices in the 12-step community that do not consider patients to be in 'true' recovery if they take medication," Williams said.

This bias extends to clinicians. "I have certainly seen a hesitancy among physician colleagues to provide buprenorphine for more than a month or two because they're worried that patients will get 'addicted' to it," he added.

This practice "flies in the face" of the evidence showing that use of buprenorphine is strongly associated with reductions in opioid use, overdoses, and mortality, said Williams.

A benefit of buprenorphine is that patients can take it once a day or even once every other day because of its relatively long half-life. As well, it "staves off withdrawal," blocks the effects of other opioids, and has a "ceiling effect" on respiratory depression.

Pharmacologically, buprenorphine, which is a partial agonist at the μ-opioid receptor, is similar to methadone, a full agonist at the μ-opioid receptor. However, methadone is available only through highly regulated opioid treatment programs, whereas buprenorphine can be obtained at a physician's office.

Dangerous Care?

Commenting on the study for Medscape Medical News, Lynn Webster, MD, vice president of scientific affairs at PRA Health Sciences, Salt Lake City, Utah, said the findings are consistent with other studies of the use of methadone to treat opioid use disorder.

"Methadone has been prescribed for opioid addiction since the 1950s and is very effective when prescribed appropriately. In most cases, that involves very long-term therapy; it's not a short course," he said.

Webster, who is a past president of American Academy of Pain Medicine, was not involved with the current research.

When buprenorphine "came on the scene" after its approval by the US Food and Drug Administration in 2002 for opioid dependence, many clinicians thought they could give this drug to a patient for just 3 to 5 days and then discontinue it, said Webster.

"I think that is inappropriate care and dangerous," he added.

He emphasized that there is a difference between a physical dependence and addiction. Physically dependent patients are able to stop taking an opioid sooner than those who suffer severe cravings and who face "significant challenges" in discontinuing therapy, Webster said.

"I think that creates a risk of overdose and death," he said. He noted that he blames insurance companies for some of this, because limiting coverage basically forces patients into abstinence.

"Some patients will go back and use their drug and will use it at the same dose as before, and that may lead to overdose," said Webster.

He noted that the study's finding that patients with comorbid psychiatric disorders are at higher risk for adverse events following buprenorphine discontinuation makes sense.

"We know that people with more mental health disorders are going to be more challenging and that they likely are going to require longer treatment," he said.

One of the difficulties in conducting studies that use claims-based data, such as this one did, is that the reason the drug is prescribed isn't always accurate, said Webster.

"You don't know if a patient was prescribed buprenorphine for an opioid use disorder or mostly for pain but the doctor wrote down 'opioid use disorder' so they could get some coverage," he said.

The study was funded by grants from NIDA and the Agency for Healthcare Research and Quality and by the National Institutes of Health's (NIH) National Center for Advancing Translational Sciences. William's research is funded by the NIH. Webster reports that he consults with pharmaceutical companies that make opioids as well as buprenorphine.

Am J Psychiatry. Published online December 2, 2019. Abstract

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