RAPID TRANSITION FROM METHADONE TO BUPRENORPHINE UTILIZING A MICRO-DOSING PROTOCOL IN THE OUTPATIENT VETERAN AFFAIRS SETTING

Abstract

Objectives:

Alternative transition protocols from methadone to buprenorphine in the treatment of opioid use disorder (OUD) are needed to reduce the risk of precipitated withdrawal and opioid use during induction.

Methods:

Case report (n = 1).

Results:

One patient with OUD underwent a rapid microinduction outpatient protocol that did not cause precipitated withdrawal or require preceding taper before cessation of methadone. The induction was carried out safely in the outpatient setting.

Conclusions:

This report provides a patient-centered approach demonstrating feasibility and cost-effectiveness of rapid transition to buprenorphine in the US outpatient psychiatry setting. Barriers to adherence to opioid agonist therapy may be reduced using this protocol.

The United States is in the midst of an opioid epidemic, with the annual death toll from opioid overdoses surpassing the total American death count from the Vietnam War (Rudd, 2016). The economic burden of this crisis, each year, in terms of medical, social welfare, and correctional services, is approaching a cumulative cost of $ 1 trillion (Rudd, 2016). These consequences have led to efforts to increase access and adherence to medication-assisted treatment (MAT) with methadone, buprenorphine, or extended-release naltrexone.

Available since 1972, methadone was the first pharmacotherapy for opioid use disorder (OUD), with demonstrated efficacy measured through treatment retention rates and reduction of nonmedical opioid use (Fullerton et al., 2014). Still, methadone may be considered unsuitable for particular individuals due to adverse effects or logistical barriers. As a full agonist at the mu-opioid receptor (MOR), it is associated with dose-dependent cardiac, respiratory, gastrointestinal, immune, and endocrine adverse effects (Fareed, 2012; Spasovska Trajanovska et al., 2013; Lugoboni et al., 2016). Moreover, within the United States, methadone treatment for OUD is restricted to federally regulated opioid treatment programs (OTPs), with limitations on the number of take-home medication doses. As a result, for some individuals with OUD, regular OTP attendance may not be feasible due to driving distances, changes in work schedule, or problems with insurance coverage. Collectively, these challenges may contribute to low quality of life, incomplete clinical response, and high utilization of healthcare services, occasionally justifying transitions from methadone to other forms of MAT (Mancino et al., 2010; Muller et al., 2018).

Unlike methadone, buprenorphine is a partial agonist at the MOR, having a higher therapeutic index, a lower rate of adverse effects, and fewer logistical constraints than those associated with OTPs (Bell et al., 2009; Fareed, 2012; Kelty and Hulse, 2017). Because of its high affinity for the MOR, buprenorphine may displace other opioids early in treatment, provoking the acute onset of opioid withdrawal symptoms (Rosado et al., 2007). To avoid precipitated withdrawal, individuals must be in moderate withdrawal at the time of initiation, which may take 48 hours or more after the last dose of a long-acting opioid such as methadone (Treatment, 2004). Furthermore, before discontinuing methadone and transitioning to buprenorphine, current treatment guidelines recommend methadone be tapered to 30 to 40mg daily and maintained for 1 week. This process takes time and increases the vulnerability for relapse and overdose (Termorshuizen et al., 2005). Hence, there is an urgent need for faster and safer transition protocols from methadone to buprenorphine.

In recent years, buprenorphine “microdosing” inductions, which do not require patients to be in opioid withdrawal, have been described in the inpatient setting both in Canada and the United States (Cortina et al., 2017; Klaire et al., 2019; Terasaki et al., 2019; Ward et al., 2019). To our knowledge, however, no outpatient transition from methadone to buprenorphine has been reported. Further, our patient was successfully transitioned at a US Veteran Affairs (VA) outpatient setting, suggesting feasibility of this approach within the VA Healthcare System. The patient provided consent for participation in off label treatment and for publication of the case in the medical literature.

METHODS

A 60-year-old male Veteran with OUD presented to an US VA OTP after 20 years of methadone treatment at a non-VA facility, located closer to his hometown. His need to transfer care to the VA was driven by challenges with his medical insurance. Transferring care required a 2-hour commute, which posed a significant logistical barrier.

The patient reported using prescribed oxycodone 30 years ago after a back injury. His oxycodone use escalated, and 5 years later, the patient transitioned to inhaled heroin with heaviest use being 10 to 15 bags (0.03 – 0.05 g of heroin each) per day. After 1 inpatient admission for medically assisted withdrawal, he enrolled at a non-VA OTP and was prescribed methadone (dose range 75 – 120 mg) for 20 years, with 1 episode of resumed illicit opioid use after the loss of a family member. He described 1 episode of buprenorphine-induced precipitated withdrawal after an attempt to switch MAT without medical assistance. Before transfer to the VA OTP, he was maintained on 75 mg of oral methadone. Medical history consisted of congestive heart failure (with a left ventricular ejection fraction of 40%), hypertension, hyperlipidemia, gout, and migraine headaches. In addition, he reported methadone-induced endocrine adverse effects, including decreased libido, low energy, and erectile dysfunction, which affected his marital life and self-image. Physical examination was remarkable for gynecomastia and laboratory tests, and breathalyzer and EKG were all within normal limits.

First, the patient received a buprenorphine transcutaneous patch, transitioning to sublingual (SL) buprenorphine after 3 days. The methadone dose was maintained until the 10th day of the induction. Over the course of 11 days, the dose of SL buprenorphine was successfully titrated to a stabilizing dose of 16 mg SL daily as indicated in Table 1, with sporadic use of ancillary medications for suppression of withdrawal symptoms, which did not interfere with the patient’s work. Given his clinical stability and personal preference, patient care was transferred to a VA satellite clinic located closer to his home, enhancing the chance of long-term treatment retention.

TABLE 1.

Individualized Microdosing Protocol for Methadone to Buprenorphine Transition in the Outpatient Setting

Day	Buprenorphine Induction	Methadone Dose	Ancillary Medications	Clinic Visit/COWS	Phone Visit
1	Buprenorphine 5-mcg/h transcutaneous patch	75 mg PO daily	None	Yes COWS = 0
2		75 mg PO daily			Yes
3		75 mg PO daily			Yes
4	Buprenorphine 0.5 mg to naloxone 0.125 mg SL BID	75 mg PO daily	None		Yes
5	Buprenorphine 0.5 mg to naloxone 0.125 mg SL TID	75 mg PO daily	None		Yes
6	Buprenorphine 1 mg to naloxone 0.25 mg SL BID	75 mg PO daily	None		Yes
7	Buprenorphine 2 mg to naloxone 0.5 mg SL BID	75 mg PO daily	None		Yes
8	Buprenorphine 2 mg to naloxone 0.5 mg SL TID	75 mg PO daily	Clonidine 0.1 PO mg once	Yes COWS = 3
9	Buprenorphine 2 mg to naloxone 0.5 mg SL QID	75 mg PO daily	None		Yes
10	Buprenorphine 4 mg to naloxone 1 mg SL TID	75 mg PO daily			Yes
11	Buprenorphine 12 mg to naloxone 3 mg SL QD Additional 4 mg buprenorphine to naloxone 1 mg sublingual SL once	Methadone discontinued	Clonidine 0.1 mg PO BID Loperamide 2 mg PO BID Ibuprofen 200 mg PO BID		Yes
12	Buprenorphine 16 mg to naloxone 4 mg SL QD	None	None		Yes

Buprenorphine supplies were dispensed on two occasions – once during each clinic visit. BID, twice daily; COWS, Clinical Opioid Withdrawal Scale; PO, orally; QID, 4 times daily; SL, sublingual; TID, 3 times daily.

DISCUSSION

We described the case of a US veteran with OUD who was successfully and safely transitioned from methadone to buprenorphine using a rapid microdosing induction in the outpatient setting. An individualized patient-centered approach allowed us to optimize buprenorphine to a therapeutic dose in less than 2 weeks. Notably, the patient received his usual dose of methadone throughout the induction and discontinued it on the 11th day.

A few international case reports of inpatient transitions from methadone to buprenorphine have been published (Cortina et al., 2017; Klaire et al., 2019; Terasaki et al., 2019; Ward et al., 2019), along with 1 US inpatient case report (Terasaki et al., 2019). To our knowledge, this is the first microinduction methadone to buprenorphine transition carried out in a US outpatient setting, demanding fewer resources than those associated with an inpatient admission. Our report is consistent with that of Hess et al. and Cortina et al., who also initiated the induction with a buprenorphine patch, although our dose was lower (5 mcg/h, compared with 35 mcg/h and 20 mcg/h, respectively) and applied in conjunction with the patient’s usual dose of methadone (rather than 12 hours or 3 after the last methadone dose, respectively) (Hess et al., 2011; Cortina et al., 2017). As in both prior reports, our patient experienced the onset of mild withdrawal after the last dose of methadone (Hess et al., 2011; Cortina et al., 2017). The gradual onset of these mild symptoms is in stark contrast with the abrupt form of precipitated withdrawal often seen with traditional buprenorphine initiations. The use of the buprenorphine patch may facilitate a steady transition by slowly displacing methadone from the MOR. Consistent with this, the serum levels of buprenorphine achieved by the 5- mcg/h patch are lower than a comparable SL buprenorphine dose (Coe et al., 2019). Moreover, the peak serum level of buprenorphine occurs in up to 3 days with the patch formulation, compared with approximately 90 minutes with a SL dose (Coe et al., 2019). This gradual absorption of buprenorphine may facilitate binding to MORs that are unoccupied by methadone, in addition to displacing small amounts of methadone from other MORs.

To our knowledge, only 1 outpatient microdosing protocol has been described by Hammig et al. in a Swiss case series (Hammig et al., 2016). Although the duration of the transition from full agonist to buprenorphine was similar (9 days), Hammig et al. did not utilize a buprenorphine patch. In their report, however, the patient was transitioned from 2.5 mg of inhaled heroin daily, which is short-acting, and has a lower morphine milligram equivalency (MME), compared with 75 mg of methadone in our report. Future studies should clarify whether the slow accumulation of buprenorphine at the MOR produced by successive low sublingual doses provides sufficient receptor activity to prevent precipitated withdrawal, with concurrent administration of a therapeutic dose of methadone. Although faster micro-dosing protocols have been described by Klaire et al., taking between 3 and 5 days in an inpatient case series, such protocols may not be ideal for an outpatient clinical scenario (Klaire et al., 2019). The patient described here had clinically significant medical comorbidities, but remained medically stable and able to manage emerging withdrawal symptoms from home, assisted mostly by telephone contact with medical staff. Patients with more severe medical problems or comorbid active substance use may still be better served by pharmacologic transitions carried out in the inpatient setting (Hassanian- Moghaddam et al., 2014).

CONCLUSIONS

Our outpatient case report describes a safe and cost-effective rapid microdosing buprenorphine protocol. Randomized controlled trials are necessary for establishing a consensus regarding optimal microdosing protocols for specific patients and clinical settings. Developing such patient-centered protocols will increase access to treatment and help lower the stigma associated with the management of OUD.