Research Article Review: Buprenorphine for Severe Suicidal Ideation

February 28, 2021

This post will consist of an overview of one particular research report, and some of my thoughts about it. Here is the citation of the paper I’ll be discussing:

Yovell, Y., Bar, G., Mashiah, M., Baruch, Y., Briskman, I., Asherov, J., Lotan, A., Rigbi, A. & Panksepp, J. (2016). Ultra-Low-Dose Buprenorphine as a Time-Limited Treatment for Severe Suicidal Ideation: A Randomized Controlled Trial. American Journal of Psychiatry. 173:5.

Numerous things in this article concern me. I’ve been meditating on it since around 2017. At this point I’ve decided to share the citation for the paper, quotations from the article that draw my particular attention, and some of my thoughts about those quotations.

Here’s the study objective from the top of the first page.

Objective: Suicidal ideation and behavior currently have no quick-acting pharmacological treatments that are suitable for independent outpatient use. Suicidality is linked to mental pain, which is modulated by the separation distress system through endogenous opioids. The authors tested the efficacy and safety of very low dosages of sublingual buprenorphine as a time-limited treatment for severe suicidal ideation.

Here’s the study population

The study was performed on “Severely suicidal patients without substance abuse…”

Here’s the study intervention

The study examined “…ultra-low-dose buprenorphine (initial dosage, 0.1 mg once or twice daily)…”

The results

Participants in the experimental group receiving buprenorphine “…had a greater reduction in Beck Suicide Ideation Scale scores than patients who received placebo (N=22), both after 2 weeks (mean difference 24.3, 95% CI=28.5, 20.2) and after 4 weeks (mean difference=27.1, 95% CI=212.0, 22.3).”

Statements about history, rationale, and safety

Opioids were widely used to treat depression from about 1850 to 1956. Because of their addictive potential and lethality in overdose, opioids were replaced by standard antidepressants once these became available. However, several studies since then have found them to be effective for treating depression.

Read those sentences again. I find that passage particularly odd.

Opioids are involved in more deaths than any other drug class in fatal pharmaceutical overdoses in the United States. Thus, the lower lethality of buprenorphine and the very low dosages employed in this study were crucial for enabling its independent, home-based use. However, buprenorphine is potentially addictive and possibly lethal. We therefore designed this study as a time-limited trial for severely suicidal patients without substance abuse.

Exclusion criteria were a lifetime history of opioid abuse…substance or alcohol abuse within the past 2 years, and benzodiazepine dependence within the past 2 years.

Adherence to the protocol

“Outpatients received the study medication for the following week during their weekly visits, and took it independently at home. Average adherence, measured by pill counts, was 92%.”

I wonder if the medication was not taken.
And I wonder what happened with the unused opioids.

Comorbidities

“More than half (56.8%) met criteria for borderline personality disorder…”

What characterological or environmental context must be present for this buprenorphine protocol to be declared unsafe in a community setting?

Clinical history vs. follow-up

“All participants denied withdrawal symptoms during their follow-up appointment 1 week later. It is possible that in this opioid-naive population, the short duration and low dosages protected against dependence.”

The bottom line

“In this study, the time-limited use of very low dosages of buprenorphine was associated with a decrease in severe suicidal ideation.”

Beyond a measurable decrease, I am curious what kind and level of suicidal ideation is clinically relevant regardless of a measurable decrease.

Required disclosure

“Dr. Yovell reports being listed as an inventor on a patent application for the use of low-dose buprenorphine for suicidality; he has assigned his rights in the patent to the University of Haifa but will share a percentage of any royalties that may be received by the university.”

Why not simply remove this person from the research project due to conflict of interest or the potential appearance of a conflict of interest?

The following points have also occurred to me over my years of considering this study:

The authors discuss neural processing leading to psychic pain as the medication target. The thinking and behavior they are attempting to change are merely downstream from the medication target. Thus, acetaminophen could also have been tried at 3 doses beyond the inclusion of a placebo group – it dampens the neural processing that produces psychic pain, just as it does with physical pain.
We know opioids blunt awareness of pain, and do not diminish the neural activity that produces pain (as acetaminophen does, while leaving the mind clear). I wonder what an imaging study would show?
Linking of opioids, mental pain, and suicidality seems to indicate that pain management is the goal. Should we reify psychic pain as another vital sign? What were the unintended consequences of establishing physical pain as the fifth vital sign?
Thousands of years of human history were enough to already show us that opioids decrease the experience and report of pain. Were we in doubt of this?
We already know that some people find that taking some drugs makes them feel less bad, temporarily. Were we in doubt of this?
You cannot prove the null hypothesis (prove a negative). Concerning their selection criteria, rather than say “without substance abuse” they could have said, “Presenting no evidence of a current and active SUD”.
Was this a first exposure to prescription opioids for some in the study? If so, might it flip the genetic switch for atypical responders (not just atypical metabolizers)? Was that possibility screened for? How long should atypical responders in such a study be followed after the study is concluded?
Is “ultra-low-dose” a standard and recognized term, or used here as a descriptive label for other purposes? They could simply name the compound and dose.
Is the reduction in the Beck score clinically significant or an arbitrary metric – one that is reliable, valid, and irrelevant (Hart & Jaccard, 2006)?
Generally speaking, any score that is initially extreme will, over time, tend to regress to the mean. That is, extreme scores don’t last long and tend to become less extreme over time. So, did they obtain a treatment result, or was this treatment superimposed over an already improving picture?
How would we know if the change they report is clinically significant?
Did the suicide rate in the treatment group and the placebo group differ after the study?
What is the base rate of suicide among individuals matched to those in this study (with no treatment and on the same array of psychotropic medicines)? If we don’t know the base rate, to what do we compare the results of this study – just their scores at the beginning of the study?
How was it decided to place opioids among a suicidally depressed patient group located in the community (outside an institutional setting) during an opioid epidemic?
The researchers screened against “lifetime history of opioid abuse” and excluded participants accordingly. But non-problematic use of opioids (aka successful use) was not mentioned as an exclusion criterion.
“Exclusion criteria were a lifetime history of opioid abuse…substance or alcohol abuse within the past 2 years, and benzodiazepine dependence within the past 2 years.” But addiction illness is one illness, even if multiple substance classes are involved.
I wonder how many of the study participants had 2 or more of the Big 5 SUD criteria (desire or efforts to control, craving, diminished role function, loss of activities, and withdrawal) as part of their “abuse” diagnosis at the time that diagnosis was active? That is to say, I wonder if some of the participants with no “substance abuse” within the past 2 years were actually in the course of illness for developing SUD moderate-to-severe at the time their problematic substance use was active. And if so, could the presence of Big 5 SUD criteria be considered as possible exclusion criteria for participation in such a study?
The authors declare their participants were opioid naïve. But lack of a clinical diagnosis of a use disorder is not the same as naïve to use of the drug.

In conclusion I’ll say that this paper was one of the research reports that developed my focus some years ago on what I simply call “Harms of Use”. That focus led to me gather such papers (and related papers) over a series of a few years, read and study them, and prepare materials for education, training, etc. based on their content.

References

Hart, B. & Jaccard, J. (2006). Arbitrary Metrics in Psychology. American Psychologist. 61(1): 27-41.

Ioannidis, J. P. A. (2006). Why Most Published Research Findings Are False. PLoS Medicine. 2(8) e: 124. DOI: 10.1371/journal.pmed.0020124

Suggested Reading

DeWall, C. N., Chester, D. S. & White, D. S. (2015). Can Acetaminophen Reduce the Pain of Decision-Making? Journal of Experimental Social Psychology. 56:117–120.

DeWall, C. N., MacDonald, G. M., Webster, G. D., Masten, C. L., Baumeister, R. F., Powell, C., Combs, D., Schurtz, D. R., Stillman, T. F., Tice, D. M. & Eisenberger, N. I. (2010). Acetaminophen Reduces Social Pain: Behavioral and neural evidence. Psychological Science. 21(7):931-937. DOI: 10.1177/0956797610374741

Durso, G. R. O., Luttrell, A. & Way, B. M. (2015). Over-the-Counter Relief From Pains and Pleasures Alike: Acetaminophen blunts evaluation sensitivity to both negative and positive stimuli. Psychological Science. 26(6):750–758. doi:10.1177/0956797615570366.

Maughan, B. C., Hersh, E. V., Shofer, F. S., Wanner, K. J., Archer, E., Carrasco, L. R. & Rhodes, K. V. (2016). Unused Opioid Analgesics and Drug Disposal Following Outpatient Dental Surgery: A randomized controlled trial. Drug and Alcohol Dependence. 168(1): 328-334.

Randles, D., Heine, S. J. & Santos, N. (2013). The Common Pain of Surrealism and Death: Acetaminophen reduces compensatory affirmation following meaning threats. Psychological Science. 24(6) 966 –973.