Transition from methadone to subcutaneous buprenorphine depot in patients with opioid use disorder in custodial setting – a case series

ABSTRACT

Background

Methadone, a full opioid agonist, and buprenorphine, a partial agonist at the opioid receptor, are established first-line medications for opioid maintenance therapy. Transition from methadone to sublingual buprenorphine may precipitate withdrawal and is usually performed only in patients on low dose of methadone (<30–40 mg). Transition from methadone to a novel subcutaneous buprenorphine depot (Buvidal) has not been previously described.

Objectives

To test the hypothesis that a rapid transition from methadone to buprenorphine depot after a single dose of buprenorphine 4 mg sublingual is safe and well tolerated.

Methods

Retrospective chart analysis of a case series of seven opioid users under custodial setting (prison) who were switched from methadone to buprenorphine depot (initial dose 16 mg weekly subcutaneously) after an initial test dose of buprenorphine 4 mg sublingual within 48 hours.

Results

Clinical data indicate that a rapid transition from methadone to depot buprenorphine is feasible (six patients within 48 hours, one within 4 days). All patients were successfully switched to buprenorphine depot and the transfer period was completed without dropouts or major medical problems. Further dose adjustments were performed in 4 of 7 patients.

Conclusions

Transition of opioid users from methadone to buprenorphine depot is feasible and safe via 4 mg buprenorphine sublingual. This procedure may facilitate induction of buprenorphine depot formulations in patients treated with methadone.

KEYWORDS:

• Opioids
• opioid use disorders
• methadone
• buprenorphine
• depot
• transition

Introduction

Opioid use disorder (OUD) is a chronic relapsing disorder causing significant social and economic harm (1). About 80% of all drug-related deaths are attributed to opioid use, with overdose still being by far the leading cause of death, followed by suicide, accidents and infectious diseases (2–4). For decades opioid maintenance treatment (OMT) has established the first-line treatment for OUD (3,5–8). Its effect on mortality, somatic and psychosocial disorders and criminality has been shown in numerous studies (9–11). Still there is robust evidence that the mortality in OMT is high, especially during the first 4 weeks of treatment and after treatment cessation (2,12,13). A meta-analysis clearly showed that the mortality is highest in the induction phase of OMT and in patients after leaving maintenance therapy (14).

Methadone and buprenorphine are the two established first-line medications in OMT (5,7,15,16). Methadone, a synthetic full mu opioid agonist, is orally active and has a high opioid receptor binding. Buprenorphine is a partial agonist with a higher affinity to the mu-opioid receptor than methadone and an antagonistic effect at the kappa receptor (5). Buprenorphine appears to have a ceiling effect on respiratory depression, and thus a lesser risk of opioid overdose compared to full opioid agonists at the mu opioid receptor. In some studies, the retention rate in buprenorphine patients was somewhat lower than for methadone although data are mixed (16). For the treatment of OUD, buprenorphine is typically administered sublingually as it is subject to high first pass metabolism. Sublingual buprenorphine is also available in combination with naloxone in a ratio 4:1 to lower risk of diversion and i.v.use. The benefit of the addition of naloxone is controversial (17).

Retention in OMT is critical with many patients dropping out especially in the early phase of treatment (18). A recent meta-analysis showed a median retention rate of 57% at 12 months and of 38.4% after 3 years (19). The introduction of novel long-acting depot or implant formulations may lower the dropout rate (20). The transition from a full opioid agonist like methadone to a partial agonist like buprenorphine will induce precipitated withdrawal (21,22). No accepted algorithm for switching methadone to buprenorphine exits (5). Typically, a reduction of methadone to about 30–40 mg and transition to buprenorphine sublingual after 24–48 hours is recommended (5,23,24). The time interval between the methadone and buprenorphine exposure and the level of physical dependence are of relevance for the development of withdrawal symptoms.

Recently, three novel long-acting buprenorphine medications have been approved for use in some countries for the treatment of OUD (20). CAM 2038 (Buvidal) is a s.c. depot buprenorphine injection approved in Europe and currently under consideration in the US for approval by FDA. Here, there are four different dosages available for either weekly (8, 16, 24 or 32 mg) or monthly injections (64, 96, 128 mg). Treatment is usually initiated with weekly injections. A number of pharmacological studies indicate this depot buprenorphine to be suitable for OMT (25). Its efficacy has been demonstrated in a double-blind, double-dummy, randomized phase phase-III-study (26). There are two other buprenorphine long-acting formulations. RBP-6000 (Sublocade™) is a buprenorphine depot injection (100 and 300 mg), marketed in the US since 2018, which will very probably be introduced in Europe soon. There is also good evidence for efficacy (27) for a buprenorphine implant (Probuphine, Sixmo), which has been approved in the US by the FDA in 2016 for long-term treatment of patients with OUD who are on a stable medication of 8 mg (license agreement terminated in 2018 by manufacturer) and in Europe in 2019 (28–30). One of the target groups for these novel long-acting buprenorphine medications can be opioid users in custody or prison. OUD is frequent in prison inmates, and OMT has been shown to reduce criminality in this population (9,31–35, meta-analysis by 36). In addition, there is evidence that treatment with depot buprenorphine may contribute to a reduction in disciplinary sanctions during the course of incarceration (37).

While the transition from sublingual buprenorphine to subcutaneous buprenorphine depot is considered straightforward and does not warrant further discussion, a possible initiation of a depot buprenorphine medication in methadone patients has not been studied. Here we report data of a retrospective chart review (case series) in people with OUD in custody (prison inmates) in OMT with methadone who wished to be transferred to a buprenorphine depot formulation.

Methods and material

This was a retrospective chart review of all male prison inmates with OUD at the Straubing prison who were switched from methadone onto a weekly subcutaneous buprenorphine depot formulation between March 2019 and May 2020. All patients expressed their wish to be treated with a buprenorphine depot formulation (voluntary treatment) and gave informed consent. Gradual reduction of methadone dose could be performed prior to the switch of medication but was not required in all cases since some patients in custodial setting requested rapid transition, two of them because of painful edema related to methadone use. Within 2 days of the last methadone dose, 4 mg of sublingual buprenorphine was administered. If well tolerated without induction of further major withdrawal symptoms (precipitated withdrawal), a dose of buprenorphine s.c. weekly 16 mg was given subcutaneously an hour later. Further dosing was done according to clinical needs. In addition, any additional medication could be given based upon clinical needs and the clinician’s decision. Gabapentin was offered as a possible “rescue medication“ (see cases 3 and 5). During methadone withdrawal patients could be prescribed gabapentin up to 3–4 × 400 mg/day. The return to methadone was possible at any time. No other transitions apart from the ones reported were performed in this treatment period.

Results

Case 1

Thirty-two-year-old patient, 12 year opioid and cocaine history, no sedatives were used. The patient was maintained on methadone 70 mg with a gradual reduction to 20 mg/day over a 33 day period. No other medication was given. The patient was given a subcutaneous buprenorphine 16 mg injection after 4 mg buprenorphine sublingual. The patient experienced mild opioid withdrawal symptoms for three days after the first buprenorphine injection which decreased after injection of further 8 mg buprenorphine dose. Long-term stable treatment was maintained with subcutaneous buprenorphine depot 24 mg.

Case 2

Twenty-seven-year-old patient, 5-year history of opioid use. He was on maintenance treatment with methadone 120 mg/day. Over 5 weeks the dose was reduced to methadone 20 mg/day. He also received quetiapin 600 mg/day because of a previous psychotic disorder. The patient was stabilized on sublingual treatment for 4 days, starting with 4 mg/day and a gradual increase in dose to 12 mg/day, then received an injection of 24 mg subcutaneous buprenorphine. The patient is now stabilized on 32 mg subcutaneous buprenorphine depot weekly.

Case 3

Thirty-year-old patient, 11-year history of opioid use, also cannabis, stimulants but no sedatives. Direct transition without reduction from 80 mg methadone, with emergence of moderate withdrawal symptoms 24 hours after the last dose. The patient was also on gabapentin 125 mg/day. Then the patient was given 4 mg buprenorphine sublingual, followed by 16 mg buprenorphine depot subcutaneously. No other medication was given. The patient was on a stable dose for 5 months without withdrawal symptoms but then requested to be switched to sublingual burprenophine.

Case 4

Thirty-eight-year-old patient, 14-year history of opioid use, as well as very high use of sedatives, mostly benzodiazepines, and cannabis. Long-term therapeutic use of methadone up to 140 mg/day, also on a constant medication with doxepin 100 mg/day. The patient’s current maintenance dose of 100 mg/day was tapered to 30 mg/day over a 16 day period. About 36 hours after the last methadone dose, sublingual buprenorphine was administered, followed by 16 mg subcutaneous buprenorphine. No further withdrawal symptoms were observed. After 5 months, the patient was switched back to sublingual buprenorphine because of inflammation at the injection site.

Case 5

Forty-one-year-old patient, 25-year history of opioid, polydrug (mostly sedatives such as benzodiazepines) and alcohol use. The patient was on methadone treatment of 120 mg/day and tapered down to 30 mg over 5 weeks. For the last 5 days before transition he also received gabapentin 3 × 400 mg/day. After about 2 days the patient was experiencing mild withdrawal symptoms and 4 mg buprenorphine sublingual was administered. An hour later subcutaneous buprenorphine weekly 16 mg was given. Because of withdrawal symptoms and craving a further 8 mg buprenorphine was administered subcutaneously the next day.

Case 6

Forty-four-year-old patient, 29-year history of opioid, cocaine and hallucinogen use. Methadone was maintained at 70 mg/day, and tapered down to 30 mg/day prior to switching. He also was on mirtazapin 30 mg/day. When the patient experienced moderate withdrawal symptoms, he was switched to sublingual buprenorphine 4 mg and one hour later 16 mg buprenorphine depot weekly was administered. The patient experienced strong cravings three days after initiation and 8 mg buprenorphine was given subcutaneously. The patient was stabilized on a 32 mg dose of buprenorphine subcutaneously.

Case 7

Thirty-year-old patient, 10-year history of opioid use as well as sedatives and pregabalin which were withdrawn. Treatment was methadone 110 mg/day. After 1 day, a direct transition to sublingual buprenorphine 4 mg was performed, followed by 16 mg buprenorphine subcutaneously and a further 8 mg buprenorphine was administered the next day. No other medication was given. The buprenorphine weekly dose was stabilized at 32 mg, then the patient was transferred to 128 mg of buprenorphine monthly and treatment continued at this dose.

Discussion

It is reported that 16–20% of German prisoners have a history of opioid use, many of them in OMT (38,39). OMT is effective in reducing criminality in OUD (36). As diversion and substance use are frequent in this environment, depot buprenorphine formulations can be useful in this group of patients.

While the direct transition from sublingual buprenorphine to depot buprenorphine is straightforward, there are no data on direct or rapid transition from methadone to depot buprenorphine. To date there is no clear algorithm for the transition of methadone to sublingual buprenorphine either (5,23,24). For transition to sublingual burprenorphine, a reduction to 30–40 mg methadone and initiation of burprenorphine treatment after the first withdrawal symptoms appear is usually recommended (5). Recently, the use of buprenorphine microdosing to facilitate transition to sublingual buprenorphine has been suggested as a possible approach (40,41).

To our knowledge, these are the first cases of patients with OUD in whom a rapid introduction of depot buprenorphine in patients treated with methadone has been perfomed. This retrospective chart review and case series shows that a transition from methadone to buprenorphine depot via a single test dose of buprenorphine 4 mg sublingual is possible. After an optional reduction of methadone dose and maximum 2 days after discontinuation of methadone, patients were given 4 mg of sublingual buprenorphine. If tolerated, 16 mg of subcutaneous buprenorphine was administered an hour later. In the following days, the dose was adjusted upon clinical need, with a further 8 mg buprenorphine given subcutaneously as needed to treat withdrawal symptoms and/or cravings in 4 of 7 patients. All patients managed to switch from methadone to subcutaneous depot buprenorphine with only minor or moderate withdrawal symptoms.

Limitations

This is a case series. There was no standard protocol with defined inclusion or exclusion criteria and withdrawal symptoms were not recorded using an established opioid withdrawal symptom scale such as the Clinical Opiate Withdrawal Scale (42). Although the individual treatment approach was according to clinical needs of each patient, the therapeutic regime followed a defined approach with tapering down of methadone to a moderate dose and then switching to buprenorphine 16 mg injection subcutaneously after a single dose of buprenorphine 4 mg, followed by possible dose adjustments.

Conclusions

Patients with OUD in custody represent a special subgroup of patients as they are treated in an “inpatient-like“ environment. However, the limitation of personal freedom is a discriminating factor between settings and can influence in different ways treatment decisions and outcome. Setting effects are probably of great relevance for tolerance and acceptability of transition procedures to buprenorphine depot. The number of these individuals in opioid maintenance therapy is increasing (43,44). While the efficacy of psychosocial interventions in OUDs is still a matter of debate (45) the efficacy of phamacotherapies is not. A systematic review on opioid-related treatments and interventions showed that methadone or buprenorphine reduce opioid use and increase adherence to treatment (46). Buprenorphine depot may be an alternative in patients with low adherence to treatment and high risk of diversion (20). The present findings suggest that a rapid transition from methadone treatment to subcutaneous buprenorphine via a single sublingual dose of buprenorphine 4 mg as a “bridge“ in incarcerated individuals is possible and can be performed without major discomfort for the patient. If the sublingual 4 mg buprenorphine dose is tolerated the patient can be given buprenorphine depot followed by dose adjustments, if necessary. This technique may facilitate induction of buprenorphine depot formulations in patients previously treated with methadone. If this technique can also be used for transition from other opioids must be studied. More systematic studies including further assessment of possible “rescue“ medications (gabapentin, lofexidine, others) and relevance of methadone dose prior to transition are necessary to elucidate therapeutic strategies to optimize transition of patients on methadone to depot buprenorphine formulations.

Conflict of interest

For the past 3 years MS has received speakers fee or support for research from Camurus, Indivior, Amomed.