A third use for opioid medications

Filing

Following its September 9 public meeting on Addressing the Public Health Effects of Opioid Medications, the Reagan-Udall Foundation for the FDA took written comments through September 23. Its questions covered opioids for pain and for addiction. We submitted a comment about a third use: low-dose buprenorphine for social pain. This is what we said, with links to the evidence.

The use that was left out

Social pain, the distress of rejection and lost connection, runs on the same mu-opioid system that opioid medications act on. The conditions defined by it, including borderline personality disorder (BPD), complex PTSD, and some presentations of autism, have few effective medications. BPD has none approved, and one of the highest suicide attempt rates in psychiatry.

People whose main problem is social pain fit neither route on offer. Addiction treatment requires an opioid use disorder diagnosis, and pain treatment requires a pain condition.

Social pain may connect pain and addiction

65% of BPD outpatients in one sample met criteria for a pain disorder, and about 30% of chronic pain patients meet BPD criteria (Nance et al., 2024). 18.2% of people with opioid use disorder have BPD (Santo et al., 2022), about three times the general population rate (Grant et al., 2008).

Nance et al. cite the opioid-deficiency hypothesis for BPD, then recommend only extra monitoring and psychosocial support. They don’t consider buprenorphine, which treats pain, treats opioid use disorder, has been proposed for BPD, and is safer than full agonists alongside other substances.

Adding an option, not replacing one

At the September 9 meeting, patients described losing function and quality of life after opioid treatment they said had worked was taken away. Nothing in our comment should be used to move people off full agonists that work for them. Some patients do poorly on buprenorphine, and they should be believed.

The evidence

Social pain runs on the opioid system. Social exclusion activates regions involved in physical pain (Eisenberger et al., 2003). PET imaging shows rejection triggers mu-opioid release in humans (Hsu et al., 2013). Naltrexone, which blocks opioid receptors, reduces everyday feelings of social connection (Inagaki et al., 2016).

Low-dose buprenorphine acts on social stress below the dose that produces a high. In healthy adults, 0.2 mg blocked the cortisol response to a social stress test with no rise in feeling high (Bershad et al., 2015), and reduced attention to fearful faces, most in people with more depression and anxiety (Bershad et al., 2018).

It helps the population most at risk. In a randomized controlled trial of severely suicidal patients without substance use disorders, 0.1 to 0.8 mg a day reduced suicidal ideation more than placebo, and a BPD diagnosis did not affect response (Yovell et al., 2016). After ketamine infusion, 0.2 to 0.8 mg a day kept 78% of patients responding at one month, against 48% on placebo (Tucciarone et al., 2026).

The mechanism fits BPD and autism. PET shows dysregulated opioid function in BPD (Prossin et al., 2010), and Stanley and Siever proposed buprenorphine for it (2010). PET shows altered mu-opioid receptors in autism (Noppari et al., 2025), and an autistic adult had confirmed long-term social improvement on low-dose buprenorphine that reversed when it stopped (Skoglund et al., 2022).

Benefit and risk. These doses are a small fraction of the 8 to 24 mg used for opioid use disorder, and buprenorphine has a ceiling on respiratory depression. An assessment that counts misuse and overdose but not untreated suicidality is incomplete. Blocking the system isn’t neutral either: in autism, naltrexone hasn’t improved core social symptoms (Roy et al., 2015).

Research on these uses largely stopped as the overdose epidemic grew. The gap is missing investigation, not negative results.

Where regulation gets in the way

We asked FDA to stop describing every non-pain, non-addiction use as misuse, to acknowledge that opioid medications act on affective and social systems and not only on pain and reward, and to encourage low-dose formulations and the studies that would support a psychiatric indication.

What we asked for

  1. Bring this population into scope. Include psychiatric and social pain uses in future FDA and Reagan-Udall work, and invite psychiatry alongside pain and addiction medicine.
  2. Fund the next trials. Low-dose buprenorphine for suicidal ideation has two positive trials; the 2026 one was funded by AFSP, the Pritzker Foundation, NIDA, and NCATS. The same support should go to trials in BPD, complex PTSD, and autism with social functioning as a primary outcome, and in people with both BPD and chronic pain.
  3. Study buprenorphine alongside full agonists, and study the switch. In a post hoc analysis of a Purdue-sponsored trial, patients using immediate-release opioids for breakthrough pain on the buprenorphine patch reached pain scores similar to patch-only patients, without more adverse events (Silverman et al., 2017). Combination treatment deserves independent, controlled study so it can become a standard option. Low-dose initiation, which keeps the full agonist until buprenorphine takes over, has never been compared head to head with standard initiation (Zimmerman et al., 2023). Some bad experiences with buprenorphine may come from how patients were switched.
  4. Measure what restrictions cost. Track psychiatric outcomes and suicide, not only overdose. In our screen of the HHS 7-OH docket, 20.7% of 19,344 distinct comments mentioned a psychiatric or neurodevelopmental condition, and 5.6% raised one with no pain condition. These people are self-treating with no supervised route.
  5. Give clinicians guidance. None exists for a psychiatrist whose patient benefits from low-dose buprenorphine and doesn’t meet criteria for opioid use disorder. Developing it would move this care from the unregulated market to the clinic.

References