The short-term use of ultra-low-dose buprenorphine (multiple brands) may reduce suicidal ideation in severely depressed patients, new research shows.

"If our results are corroborated by further studies, the short-term use of ultra-low-dose sublingual buprenorphine may emerge as an acute, symptomatic, safe treatment for suicidal ideation," lead author Yoram Yovell, MD, PhD, of the Institute for the Study of Affective Neuroscience, University of Haifa, in Israel, told Medscape Medical News.

The study was published online December 18 in the American Journal of Psychiatry.

Limited Treatment Options

Options for the rapid treatment of suicidal ideation are limited. Conventional antidepressants show some efficacy, but results are inconsistent, and it can take several weeks for the drugs to kick in.

Faster-acting treatments, such as ketamine (Ketalar, Par Sterile Products, LLC), also have limitations. For example, ketamine requires repeated administration under medical supervision.

To evaluate the potential benefits of a low-dose approach with the opioid buprenorphine, the investigators recruited patients from four medical and psychiatric centers in Israel. Patients were free of substance abuse, had a score of 11 or higher on the self-report version of the Beck Scale for Suicide Ideation, and had suffered from clinically significant suicidal ideation for a period of at least 1 week.

The patients were randomly assigned in a double-blind fashion to treatment either with ultra-low-dose sublingual buprenorphine (n = 40) or placebo (n = 22). More than half (64.5%) had had at least one previous suicide attempt, and 56.8% met criteria for borderline personality disorder. Both groups continued with individual treatments.

For patients receiving buprenorphine, the initial dose was 0.1 mg once or twice daily. Doses were increased to a mean final dosage of 0.44 mg/day.

"This approach utilized the lowest possible dosages of a potentially addictive drug and minimized side effects that might reduce adherence, increase dropout, and unblind study drug assignment," the authors write.

On follow-up assessment, patients in the buprenorphine group were found to have a significantly greater reduction in suicide ideation, as determined on the basis of Beck Suicide Ideation Scale scores, in comparison with patients receiving placebo after 2 weeks (mean difference, -4.3; 95% confidence interval [CI], -8.5 to 0.2) and after 4 weeks (mean difference -7.1; 95% CI, - 12.0 to - 2.3).

Surprisingly, outcomes in buprenorphine response were not changed with or without concurrent use of antidepressants, which could underscore its unique benefits, said Dr Yovell.

"Many researchers and clinicians believe that suicidality is simply a symptom of depression. If that were the case, one would expect that the efficacy of buprenorphine for suicidal ideation would be somewhat attenuated in those already treated by antidepressants," he said.

"The fact that it wasn't suggests that ultra-low-dose buprenorphine probably treats suicidal ideation in a mechanism which is distinct from that of all traditional antidepressants.

"This makes it a plausible add-on treatment for the many patients who are being treated by standard antidepressants but are still suicidal."

"Dramatic" Improvement in Compliance

The results were consistent irrespective of a diagnosis of borderline personality disorder, which was even more surprising, Dr Yovell added.

"Patients who suffer from borderline personality disorder are often treatment-refractory and respond poorly to most psychopharmacological interventions. The fact that patients with borderline personality disorder in our study responded equally well suggests that ultra-low-dose buprenorphine may treat a core symptom of borderline personality disorder which is associated with suicidal ideation: their extreme sensitivity to separations from people whom they love and feel close to."

Withdrawal symptoms were absent following discontinuation of treatment. There were reports of one or more adverse events in 77.2% of participants in the buprenorphine group and in 54.8% of those in the placebo group (P = .03).

The most common adverse events were fatigue (49.1% in the buprenorphine group, 22.6% in the placebo group), nausea (36.8% vs 12.9%), dry mouth (29.8% vs 9.7%), and constipation (26.3% vs 9.7%).

Dr Yovell told Medscape Medical News that on post hoc analysis, the dropout rate of patients who received an initial buprenorphine dose of 0.2 mg was 10-fold higher than the dropout rate of those who received an initial dose of 0.1 mg (30% vs 3%).

"This means that starting with extremely low doses improves compliance dramatically and may thus improve outcome," he said.

Buprenorphine's complex pharmacologic profile makes it a more appropriate candidate than other opioids for the treatment of suicidality, the authors note. The drug, a partial mu agonist, is a potent kappa antagonist with various active metabolites.

"[Buprenorphine's] kappa antagonism may enhance its antidepressant action. It causes much less respiratory depression than other opioids and is therefore safer in overdose," the authors write.

At such low doses, that risk is minimized, making it convenient as a fast-acting treatment for suicidality, Dr Yovell added.

"Sublingual ultra-low-dose buprenorphine can be taken independently by suicidal patients at home, since the doses are so low that even a week's supply of the drug is not dangerous if taken in overdose," he said.

"Thus, we may soon have a treatment that gives clinicians and patients an option to avoid a psychiatric inpatient admission in case of severe suicidality, as is often currently practiced, until the treatment kicks in.

"Furthermore, ultra-low-dose buprenorphine may be given as an adjunctive treatment for patients who are being treated with standard antidepressants but are still suicidal."

Dr Yovell noted that "critical caveats" need to be emphasized in the consideration of the ultra-low-dose treatment for suicidality to prevent problems of abuse and addition that are a significant concern with opioid use.

"First, this treatment is not recommended for patients who have a history of any substance abuse, and guidelines to reduce the risk of addiction need to be developed before we can adopt it as a standard treatment," he said.

"Second, it has only been tested, and is thus only recommended, for short-term use. And third, replication studies are required before we can use sublingual ultra-low-dose buprenorphine as a standard treatment for suicidal ideation."

These findings come on the heels of other research on the novel combination of buprenorphine and samidorphan in the treatment of refractory major depression. The formulation is designed to prevent abuse and addiction, as reported by Medscape Medical News.

"Back to the Future"

In an accompanying editorial, Alan Schatzberg, MD, Stanford University School of Medicine, in California, notes that the new study of low-dose buprenorphine suggests that opioids, which took a back seat to antidepressants when they were introduced decades ago, may have come full circle.

"Issues regarding opioid use for depression were mitigated largely by the introduction of effective antidepressants half a century ago, but we are now being forced to face them again, largely because of the unmet need of many patients with refractory depression and suicidal ideation," said Dr Schatzberg.

"The time has come for the specialty and regulators to begin to formally address the issues associated with the potential off-label use of drugs of potential abuse for severely ill and refractory patients," he added.

Although noting that the risks associated with the use of low-dose buprenorphine in the treatment of suicidality still need to be worked out, Frances R. Levin, MD, the Kennedy-Leavy Professor of Clinical Psychiatry at Columbia University and director of the Division on Substance Abuse, New York Presbyterian Hospital, in New York City, underscored the fact that when it comes to the need for rapid treatment of severely suicidal patients, potential benefit becomes uniquely important.

"Most things you do in medicine involve a risk-benefit analysis, so in this case, even though there may be a concern about the risk of making someone opioid addicted, if that person is actively or chronically suicidal, then that risk may be higher than the risk of the addiction," she told Medscape Medical News.

"So as the severity of the illness goes up, the potential risks of the treatment, to some degree, become less of an issue compared to the benefit of possibly preventing a suicide."

The authors have several relationships with industry, which are listed in the original article. Dr Levin has disclosed no relevant financial relationships.

Am J Psychiatry. Published online December 18, 2016. Abstract, Editorial