Terminology

Both buprenorphine and buprenorphine-naloxone are referred to as buprenorphine, with specific formulations listed in Table 2.

Patients and prescribers

Patients selected for ketamine prescription were either (1) seeking transition to buprenorphine from fentanyl and highly apprehensive of withdrawal symptoms after previous incomplete attempts, or (2) undergoing transition to buprenorphine from fentanyl or methadone and experiencing severe withdrawal symptoms. At the time of data analysis, LG conducted a registry search of the clinic’s electronic health record to identify patients prescribed ketamine between 5/24/2022 and 7/28/2023 for assistance with buprenorphine initiation. She entered these patients, along with patients #2 and #4 (prescribed ketamine by KJ and JG, respectively) into an Excel spreadsheet. She reviewed clinic notes, prescription records, email exchanges between herself and the other prescribers, and text message exchanges with patients to complete the spreadsheet. The co-authors provided clarification and missing details on their patients.

Most patients were prescribed buprenorphine by WM, KJ, JI or MMR at We Care Daily Clinics (WCDC), an accredited and federally certified OTP, and then were referred to LG for ketamine prescription. Patient #1 was prescribed buprenorphine at another clinic and was referred to LG by the patient’s mother for assistance managing withdrawal. Some later patients were referred to LG for both buprenorphine and ketamine by local outreach workers or by earlier patients in the treatment series. Two patients were prescribed both buprenorphine and ketamine by another prescriber under LG’s guidance: patient #2 by KJ at WCDC and patient #4 by JG, sole proprietor of Conquer Addiction PLLC in Monroe, WA, an office-based opioid treatment (OBOT) clinic. Adjunctive medications were prescribed by the buprenorphine prescriber, LG, or both. LG was the sole prescriber of clonazepam. Medicaid covered the cost of buprenorphine and adjunctive medications for all patients.

Ketamine dose selection

From clinical experience, LG found that the oral ketamine dose at which dissociative cognitive effects began to occur varied between individuals; these effects could be avoided completely by slow upward titration and spacing doses by at least one hour. She identified patient characteristics associated with benefit from a higher starting dose while avoiding cognitive effects, and developed a dosing protocol based on points assigned for the following factors: high opioid tolerance, good general health, severe depression or pain, age less than 65, low anxiety, and no history of drug sensitivities. Weight did not seem relevant except in cases of BMI 40 or higher. For the current treatment trial, the selected starting dose was 16 mg for highly opioid tolerant patients in good general health with severe depression or pain and without limiting factors., This dose could likely be administered up to four times daily without dissociative effects, with suitable spacing between doses. In a 70 kg person, with a bioavailability of approximately 25% [18], ketamine at 16 mg administered sublingually is equivalent to less than 0.06 mg/kg administered intravenously, representing 3–6% of an anesthetic dose [10] and 14% of the standard infusion dose (0.5 mg/kg) for treatment-resistant depression [13].

Ketamine number of doses

LG initially prescribed ketamine to be dispensed as four 16-mg doses. However, she found that more doses were usually required to complete initiation, and access to a refill was almost always limited by a lack of transportation and/or incompatible pharmacy hours. She therefore increased the prescription to eight doses in most cases (except only four for patient #20, reason undocumented). She set a limit of eight doses, as using all at once instead of as directed would result in a total of 128 mg, which is less than the typical amount needed for one recreational experience [28] (see Box with ketamine bioequivalent doses for different uses). LG weighed the risk of misuse causing a single episode of temporary incapacitation (considered low in these highly motivated patients) against the daily risk of overdose death from continued fentanyl use.

Monitoring

Patients self-administered all medications at home. LG managed the transition process mostly via telehealth (HIPAA-compliant video calls, telephone, or text messaging on a near-daily, daily, or multiple-times-per-day basis), with occasional in-person visits. Additionally, WCDC patients visited the OTP sometimes repeatedly during the transition process. LG and the WCDC team maintained close communication. Baseline urine drug testing was performed at WCDC per opioid treatment program regulations. Follow-up urine drug testing was not conducted as it was not part of routine care and would not have altered treatment plans.

Compounding

Quality Compounding Solutions in Kent, WA prepared a batch of 16-mg ketamine troches to be dispensed in packets of four for $12.50 or eight for $15. Some patients were dispensed ketamine from other compounding pharmacies as 16 mg/ml syrup to be self-administered sublingually with a 1 ml dropper (with unit markings to allow 0.5 ml dosing), at a price of $20–25 for 8 ml. A typical prescription was written as follows: ketamine 16 mg troche [or 16 mg/ml syrup] 8–16 mg sublingual 2–3 times per day as needed for withdrawal symptoms, maximum 48 mg/day, quantity 8 troches [or 8 ml].

Since insurance typically does not cover compounded medications, WCDC or LG absorbed the cost of the ketamine, integrating it into their existing budgets without additional cost to patients. To overcome patient transportation barriers, WCDC transported some patients to the pharmacy in a van. Postal mail was avoided due to delay and unreliable postal addresses.

Initial inclusion criteria

Patients were considered for ketamine treatment if they met the following criteria: (1) requesting transition to buprenorphine from fentanyl, (2) age 60 or younger, (3) no active cardiac disease or uncontrolled bipolar or psychotic disorder, and (4) a reliable shelter and phone number. Exceptions were made for patients #17, #29, #31 and #34 (transition to buprenorphine from methadone), patient #21 (age 62), and patients #18 and #29 (cardiac dysrhythmia discovered while on methadone treatment) after consideration of relative risks of treatment vs. non-treatment for those patients.

Informed consent

During the initial consultation, LG explained that use of ketamine was off-label for this indication and exploratory in nature, the effective dose and dose timing was unknown, and side effects such as dissociation could occur but were unlikely at the prescribed dose. Patients referred from WCDC were additionally provided a written explanatory handout. Patients could ask questions, and patient preferences regarding the pace of initiation and adjunctive medications were usually accommodated. The patients signed a release of information form at the time of referral from WCDC to LG, and these were retained in the patient’s medical record at both sites. We did not ask patients to sign informed consent as they were not enrolled in formal research.

Patient instructions

The treatment strategy evolved over the course of 14 months, as described in the Discussion. Individual patients’ treatment response led to adjustments during their treatment. Many of the earlier patients were instructed to use ketamine as a supplement to a low-dose initiation protocol previously established at WCDC, which involved a steady increase in buprenorphine dose over 10 days while supplementing with methadone dispensed daily at the OTP, or with continued illicit fentanyl use, or both. Patients were also encouraged to use adjunctive medications (clonidine, gabapentin, etc.) if needed. We offered and encouraged extended-release buprenorphine (XR-BUP) following completion. LG asked patients to make notes on doses, timing, adjunctive medications and symptoms and to remain in contact daily. Patients recorded these notes inconsistently, so only major features of treatment in each case are available and shown in Table 2.

Initiation outcome categories

Outcome categories were established at the time of data analysis to describe meaningful distinctions in treatment outcomes. Patients who “completed initiation” were those who reported use of ketamine and were later able to tolerate buprenorphine ≥ 8 mg within a 24-hour period without worsening of withdrawal symptoms. The remaining patients were divided into two groups: (1) those who reported trying ketamine but did not complete initiation, and (2) those with “no outcome information.” Patients in the second group were either (1) not dispensed ketamine per the state Prescription Monitoring Program (PMP) or (2) dispensed ketamine per the PMP and either (a) denied using it or (b) could not be contacted after attempts on at least two days. Patients with 30-day retention status were those who remained in contact with the team on or after 30 days after completing initiation, and reported continued use of buprenorphine at that time.

“Earlier” and “Later” categories

At the time of data analysis, the 24 patients who confirmed using ketamine were divided into an “Earlier” group (8 patients starting before 2/23/2023) and a “Later” group (16 patients starting on or after 2/23/2023). The chosen boundary was the starting date of the first patient who discontinued fentanyl and used ketamine to manage withdrawal symptoms, a strategy which later became a routine component of initiation instructions because of its observed effectiveness.

Ethical considerations

Institutional Review Board exemption was obtained from WCG IRB (Puyallup, WA) for publication of de-identified case descriptions.