| March 25, 2026 | v0.15 | Added authorship and provenance disclosure to opening section. |
| April 1, 2026 | v0.16 | - Added citations throughout, with new supporting sentences for Prossin et al. (2010) on PET neuroimaging evidence for μ-opioid receptor availability in BPD, New and Stanley (2010) on the endogenous opioid deficit synthesis, Gescher et al. (2024) on trauma-linked OPRK1 methylation changes, and Khalili et al. (2019) in the bipolar spectrum section.
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| April 4, 2026 | v0.17 | - Refined naltrexone contraindication language throughout — replaced "absolutely contraindicated" with "contraindicated in primary care settings," scoped the contraindication explicitly to milligram-dosed formulations, and added a carve-out acknowledging experimental concurrent ultra-low-dose naltrexone (ULDN, <10 mcg) use in the pain management literature while noting it falls outside routine primary care protocols.
- Updated the PDMP section to clarify that only concurrent milligram-dosed naltrexone is contraindicated.
- Added Section 6.3 on the Norelli et al. (2013) case series on buprenorphine for treatment-refractory NSSI, with aggregate outcome data, prior naltrexone failure across cases, and tolerability considerations.
- New citations: Toljan and Vrooman (2018) on LDN, supporting the ULDN concurrent use statement; Norelli et al. (2013) added to the Section 13 evidence summary; Bershad et al. (2015) as a new Section 13 evidence thread on buprenorphine's attenuation of psychosocial stress responses in a controlled human experimental paradigm.
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| April 8, 2026 | v0.18 | - Refined prevalence language in Section 1 — distinguished point prevalence from lifetime prevalence estimates, and disaggregated clinical setting figures by care context (primary care, psychiatric outpatient, psychiatric inpatient).
- Added citations throughout, grouped as follows:
- Prevalence: Lenzenweger et al. (2007), Grant et al. (2008), Gross et al. (2002), Lieb et al. (2004), and Riihimäki et al. (2014) on BPD prevalence among primary care depressive patients.
- Outcomes and utilization: Paris and Zweig-Frank (2001), Temes et al. (2019), and Wu et al. (2022) supporting suicide mortality figures; Bender et al. (2001) on healthcare utilization; Sansone and Sansone (2012) on chronic pain comorbidity.
- Mechanism: Eisenberger et al. (2003) on the neural overlap of social and physical pain; Pitman et al. (1990) on naloxone-reversible stress-induced analgesia in PTSD; Lutz and Kieffer (2013) on opioid receptor roles in mood disorders; McEwen (2017) on neuroplastic effects of chronic stress; Linehan (1993) on the biosocial theory of BPD.
- Pharmacology: Lutfy and Cowan (2004) and Pergolizzi et al. (2010) on buprenorphine; Strain et al. (2004) on naloxone sublingual bioavailability; Simeon and Knutelska (2005) on naltrexone in depersonalization disorder; Roth et al. (1996) on naltrexone for repetitive self-injurious behavior; Younger et al. (2014) on low-dose naltrexone mechanism.
- Treatment and measurement: Stoffers-Winterling et al. (2022) on pharmacological interventions for BPD; Posner et al. (2011) on the C-SSRS.
- Regulatory: FDA Suboxone prescribing information; FDA benzodiazepine drug class boxed warning (2020); ACOG Committee Opinion (2017) on opioid use in pregnancy.
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| May 11, 2026 | v0.19 | - Removed naloxone-as-deterrent framing — buprenorphine/naloxone is now presented as an availability-based formulation option rather than a clinical upgrade (§6.2, §7.2).
- Removed ongoing urine drug screening from the monitoring protocol; retained baseline screening for precipitated withdrawal risk; reframed PDMP review around drug interaction safety (§7.3).
- Removed "misuse or diversion" language from continued prescribing conditions and discontinuation criteria (§7.3), with addiction medicine referral language (§10) and the addiction risk FAQ (§12) revised accordingly.
- New FAQ on opioid-induced hyperalgesia, discussing buprenorphine's antihyperalgesic profile and kappa-antagonism mechanism. Added Koppert et al. (2005) on differential analgesic and antihyperalgesic profiles of buprenorphine in a human pain model.
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| May 14, 2026 | v0.20 | - Qualified sublingual naloxone tolerability (§6.2) — noted that it is detectable in nearly all patients with inter-individual variability, and can contribute to adverse, occasionally treatment-limiting side effects in a minority.
- Added Norelli et al. (2013) Patient 1 detail (§6.3) — a buprenorphine/naltrexone combination reduced from 2/0.5 mg to 1/0.25 mg because of dizziness, with discussion of why naltrexone rather than naloxone is the more pharmacologically coherent co-formulated antagonist.
- Expanded formulation guidance (§7.2) with the Braun et al. (2024) case of post-administration nausea and anxiety that resolved on transition to the buprenorphine monoproduct, and reasoning that monotherapy is the safer default absent a specific indication for the combination product.
- New citations: Braun et al. (2024) on buprenorphine/naloxone formulation tolerability; Blazes and Morrow (2020) on the limited evidence that naloxone deters injection misuse.
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| May 16, 2026 | v0.21 | - Added buccal buprenorphine film (Belbuca) to §7.2 as a commercially available option for low-dose initiation, expanding the below-2-mg practicalities subsection from two options to three, and noting that its chronic pain indication can support insurance coverage where pain is comorbid.
- Expanded the transdermal formulation note (§7.2) to identify branded Butrans and generic patches, their strength range, and the chronic pain indication that can likewise support coverage — with a caution that the lowest patch strength sits at the upper end of the low-dose range and may exceed the tolerance of highly sensitive patients.
- Added a baseline assessment item (§7.3) on naloxone rescue and overdose education, recommending take-home naloxone and overdose counseling, particularly where benzodiazepines or other CNS depressants are co-prescribed.
- Revised the sample patient script (§11) — softened the endogenous opioid mechanism description to match the hypothesized framing used elsewhere, and added physical dependence and gradual discontinuation, the possible attenuation of opioid analgesia, the need to disclose opioid antagonist use before initiation, and the time-limited nature of the trial.
- Revised the perioperative pain management answer (§12) — removed a claim of a rapid, well-tolerated taper that was inconsistent with §7.3, reframing perioperative buprenorphine management as an evolving area best decided with the surgical and anesthesia team.
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| July 28, 2026 | v0.22 | - Retitled from A Primary Care Consideration Guide to A Clinician Consideration Guide, reflecting an intended audience that includes psychiatry as well as primary care.
- Revised Section 1.1 — the audience statement no longer addresses primary care clinicians exclusively, and a new paragraph identifies the division between the two specialties as itself part of the clinical problem: psychiatry holds the diagnosis but is frequently least comfortable with opioid prescribing, while primary care holds the prescribing familiarity and the pain-labeled buprenorphine formulations but may not regard BPD as within scope, leaving patients in the gap between them. Primary-care-specific sections on prevalence, presentation, and prescribing infrastructure are retained and identified as such.
- Added the Tucciarone and Bandeira trial as a new §6.2 — a 2026 randomized controlled trial (Am J Psychiatry) in which low-dose sublingual buprenorphine, given as follow-on treatment beginning 48 hours after a single ketamine infusion, produced substantially greater reduction in suicidal ideation than placebo in outpatients with major depressive disorder (78% vs 48% response at day 31; NNT 3), with no significant separation on depression. The section states plainly that BPD was an exclusion criterion and that the trial supplies no direct evidence in BPD populations, then sets out why it matters here regardless: it is independent controlled replication of the buprenorphine signal, it locates that signal in a sample from which BPD was removed, it was conducted entirely in outpatients where Yovell was inpatient, and it contributes dose and tolerability data within the range this guide describes. The case report and case series renumber to §6.3 and §6.4.
- Sharpened the trans-diagnostic argument in §3.1 — the previous text stated that the direct evidence reviewed in this guide "specifically addresses BPD populations," which is no longer accurate. The passage now separates outcome-level evidence, which is not diagnosis-bound (Yovell found benefit in participants both with and without the diagnosis; the new trial excluded BPD and included 24% with PTSD), from mechanism-level evidence, which is still drawn from BPD samples and does not establish that equivalent endogenous opioid dysregulation underlies CPTSD.
- Anchored the expected response range in §7.2 to both controlled trials — Yovell reached a mean of 0.44 mg/day, and the new trial a mean of 0.77 mg/day at four weeks using 0.2 mg weekly increments. Both sit within the 0.1–1 mg range the guide describes as the primary expectation when initiating.
- Added prospective discontinuation data to §7.3 — the only such data available at these doses. Where four weeks at 0.6–0.8 mg/day was stopped abruptly, formal opioid withdrawal was minimal (COWS in the "minimal to none" range), but suicidal ideation and depression scores rebounded significantly within the first week off medication, with no further worsening in the second. The clinical point is that the absence of physical withdrawal signs does not mean discontinuation is uneventful: what returns is the target symptom rather than withdrawal, and monitoring during and after a taper should be oriented toward ideation and affective state rather than withdrawal scales alone.
- Reframed the "Buprenorphine and suicidality" paragraph in §13 around two randomized controlled trials rather than one.
- Corrected four claims about the Hansen case report (§6.3, §7.2, §7.3, §13), present since v0.20, which described the dose escalation as "driven by persistence of crisis behaviors" and crisis call frequency as the titration endpoint. The report concerns crisis calls, not crisis behaviors, and does not state the rationale for any individual dose increase; the published utilization dataset was assembled retrospectively. These passages now report the schedule and the outcome — contacts with community crisis services ceased entirely after the increase to 6 mg — and mark the titration rationale as a reasonable inference rather than a stated method, noting that the patient remained under continuous clinical follow-up, with a nurse case manager engaged throughout and the treating physician among the authors.
- Added interpretive context to the Hansen discussion (§6.3) — two details that cut in opposite directions. The patient was engaged in DBT and CBT both before and during treatment with no material change in the therapy she received, which makes concurrent psychotherapy an unlikely explanation for the change; but the post-treatment period fell in the first part of the COVID-19 pandemic, when opportunities for activity outside the home were limited generally, a confounder the authors themselves note.
- Replaced the 8–12 week "adequate trial" threshold (§7.2, §7.3, §9) with a dose-anchored standard. Both randomized trials separated from placebo within the first one to two weeks and ran only four weeks in total, so response to an adequate dose appears quickly; what legitimately takes longer is reaching that dose. The guide now frames the relevant interval as one to two weeks at each dose level before deciding to increase, hold, or stop. The previous threshold also obscured a safety point now made explicit: physical dependence accrues with duration of exposure, so time at a dose producing no effect adds to the eventual taper without any prospect of benefit. An extended trial is justified by active titration, not by waiting.
- New citation: Tucciarone, Bandeira, et al. (2026) on low-dose buprenorphine following ketamine treatment for suicidal ideation in major depressive disorder.
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