Transitioning a patient from injectable opioid agonist therapy to sublingual buprenorphine/naloxone for the treatment of opioid use disorder using a microdosing approach

Abstract

In the wake of North America’s opioid crisis, access to evidence-based treatment for opioid use disorder (OUD) is of critical importance. While buprenorphine/naloxone and methadone are currently indicated as first-line medications for the treatment of OUD, there are a proportion of individuals who do not benefit from these therapies. Recent Canadian guidelines suggest the use of alternate therapies, including slow-release oral morphine or injectable opioid agonist therapy (iOAT) for individuals unsuccessful with either methadone or buprenorphine/naloxone. While the guidelines highlight the need to intensify OUD treatment as disease severity increases, equally important is the consideration for deintensification of treatment (eg, from iOAT to an oral opioid agonist treatment (OAT) option) following successful stabilisation. Literature addressing how best to accomplish this, however, is currently lacking. Accordingly, the case presented here describes a patient that successfully transitions from iOAT to oral buprenorphine/naloxone using a novel induction approach termed microdosing.

Background

The Centre for Disease Control estimates in 2016 an average of 115 Americans died every day from a drug overdose (OD).¹ This figure increased by 12% in 2017 and, though preliminary analysis suggest a possible plateau in deaths in 2018, the incidence of OD deaths remains at an all-time high.² Since approximately 68% of these deaths involve opioids, this phenomenon has become known as the opioid crisis. The most recent contributor to the opioid crisis is illicitly manufactured fentanyl, which is estimated to have increased by 540% across the USA in 2015 and accounts for the vast majority of non-fatal and fatal drug ODs between 2015 and 2017.^{2 3} Although the opioid crisis has arguably had its epicentre in the USA, it is by no means confined by its borders. With a population approximately one-tenth that of the USA, an estimated eight people died each day in Canada from an opioid OD.^{4 5} Canada’s opioid-related death rate increased by 45% between 2016 and 2017. North America aside, research suggests the opioid crisis could be spreading to Europe and other parts of the globe.^{6 7}

The opioid crisis is an escalating public health emergency and the need to devise new strategies to combat it is critical. Canadian national guidelines encourage buprenorphine/naloxone or methadone as first-line treatment options for opioid use disorder (OUD).⁸ If unsuccessful, the guidelines suggest specialist-led approaches to treatment that include either slow-release oral morphine (SROM) or injectable opioid agonist therapy (iOAT). Though direction has been provided to guide the transition of patients from illicit opioid use or oral opioid agonist treatment (OAT) to iOAT, there is a paucity of data on how to deintensify treatment following successful stabilisation (ie, iOAT to oral OAT).

We present a case of a patient who successfully transitioned from iOAT to oral buprenorphine/naloxone using a novel microdosing approach. While traditional buprenorphine/naloxone induction requires a period of abstinence from opioid use (to avoid the risk for precipitated withdrawal), microdosing negates these challenges by initiating buprenorphine/naloxone at smaller doses that are incrementally increased overtime.^{9 10} Furthermore, patients seem to be able to continue illicit opioid use or remain on other oral OAT medications for the duration of the induction period, resulting in anecdotal reports of improved tolerability for the induction procedure. While the evidence to date supporting this practice is limited to a few case reports,^11–13 none includes patients in receipt of iOAT. Accordingly, the case report presented here offers microdosing as a potential strategy to transition a patient from an iOAT to an oral OAT option following successful stabilisation.

Case presentation

A 45-year-old man with OUD and no fixed address presented to a community health clinic seeking to be considered for the clinic’s iOAT programme. The patient was not taking any medications, reported no allergies and had a medical history significant for depression with intermittent insomnia. The patient’s substance use history revealed his illicit opioid use started at the age of 25 years when he first smoked heroin. This progressed to injection approximately 4 months later. At the time of presentation, the patient was reportedly injecting approximately one quarter of a gram of heroin daily. The severity of his OUD was characterised by approximately 50 previous non-fatal ODs, numerous hospital admissions and engagement in criminal activity. Regarding previous OUD treatment, the patient reported at least four previous treatment attempts—twice with methadone and twice with buprenorphine/naloxone. Neither medication was successful in reducing his illicit opioid use or achieving sustained abstinence. Beyond opioids, the patient also reported intermittent injection of both crystal methamphetamine and cocaine. Though he was unable to provide further details regarding the frequency of this, he did admit to daily stimulant use. He denied the use of tobacco, alcohol or other illicit substances. His family history was significant for addiction, with his father having a cocaine use disorder. The patient was supported financially through a combination of intermittent employment, financial assistance programmes and theft.

Physical examination was unremarkable and vitals were stable. No signs of intoxication or withdrawal were noted. His mental status examination revealed normal thought process and content, normal speech. The patient was goal directed, and displayed no evidence of perceptual disturbances.

Investigations

His most recent investigations were completed 2 days prior to presentation and revealed a normal complete blood count, electrolytes, renal and liver profile. His urine drug test was positive for fentanyl, opioids and cocaine.

Treatment

Given the severity of the patient’s OUD and unsuccessful treatment attempts with both buprenorphine/naloxone and methadone, he was deemed eligible for iOAT. Initial treatment consisted of hydromorphone (HM) intravenous or intramuscular two times per day at a medical clinic and SROM before bedtime to prevent overnight withdrawal symptoms. The iOAT induction protocol used is highlighted in table 1. Doses were gradually titrated over the course of 6 weeks until the patient was stabilised at a dose of 200 mg intravenous or intramuscular HM two times per day and 700 mg of SROM.

Table 1.

Injectable opioid agonist therapy (iOAT) induction protocol

Date	Intravenous hydromorphone (HM) (mg/route/frequency)	Slow-release oral morphine (SROM) (mg/route/frequency)	Notes
30 October	0	0	Interested in iOAT due to frequent overdose (OD) and fear of dying.
1 November	0	200 mg PO dwi	Feeling ‘dope sick’ Would like to increase SROM dose.
6 November	15 mg intravenous × one dose administered. Patient monitored for x mins postdose and subsequent 30 mg intravenous × 1 dose administered.	300 mg PO dwi	6 ODs last week. Wants to initiate iOAT.
7 November	45 mg intravenous × 1 dose administered. Patient monitored for x mins postdose and subsequent 30 mg intravenous × 1 dose administered (morning). 50 mg intravenous × 1 dose administered. Patient monitored for x mins postdose and subsequent 30 mg intravenous × 1 dose administered (afternoon).	300 mg PO dwi	Diarrhoea.
8 November	80 mg + 20 mg intravenous × 1 dose (morning) 100 mg intravenous × 1 dose (afternoon)	300 mg PO dwi	Ongoing diarrhoea. States current Kadian dose to low. Denies concomitant street drug use. Feels sick in the morning.
9 November	110 mg intravenous two times per day	400 mg PO dwi	Dose is ‘not cutting it’. Has not used since Monday.
10 November	125 mg intravenous two times per day	550 mg PO dwi	Intense cravings. Opioid agonist treatment doing ‘nothing’. GI discomfort, diarrhoea resolved.
15 November	135 mg intravenous two times per day	600 mg PO dwi	Persistent cravings, GI symptoms, poor sleep and fatigue.
17 November	145 mg intravenous two times per day	600 mg PO dwi	Strong urges to use. Poor sleep. Persistent fatigue
20 November	Missed dose	0	Reports missing doses due to being in jail. Used heroin due to cravings.
22 November	155 mg intravenous two times per day	600 mg PO dwi	States current dose controlling cravings. No symptoms of withdrawal.
29 November	155 mg intravenous two times per day	600 mg PO dwi	Cravings come and go, but overall improved. Interested in dose escalation as current dose ‘does nothing’. Still occasionally uses when money available.
4 December	Missed dose	0	Was in Jail.
5 December	165 mg intravenous two times per day	700 mg PO dwi	‘Cannot even feel dose anymore’. Wants escalation.
6 December	175 mg intravenous two times per day	700 mg PO dwi	Reports intermittent use of crystal methamphetamine. Interested in dose escalation.
11 December	185 mg intravenous two times per day	700 mg PO dwi	Still uses when money available. Disappointed no euphoria. Interested in treating depression. Pelvis pain from old fracture.
18 December	200 mg intravenous two times per day	700 mg PO dwi	Cravings, but no withdrawal. No effect from Wellbutrin. Reports twitch in hands since starting HM. Insomnia.

dwi, daily witnessed ingestion; GI, gastrointestinal; PO, per os.

Over the next 2 months, the patient denied active cravings or symptoms of opioid withdrawal. Furthermore, he began gaining weight and engaging more regularly with the healthcare system to treat his comorbid depression and insomnia. Approximately 15 weeks after iOAT initiation, however, the patient experienced a non-fatal OD after using illicit opioids concurrently with iOAT. Following this, the patient expressed a desire to transition from iOAT to oral buprenorphine/naloxone for treatment of his OUD. Despite his expressed desire, he was hesitant to proceed with the transition as he wanted to avoid any precipitated withdrawal, which he had previously experienced with buprenorphine/naloxone. To address this, a novel induction approach was adopted, whereby a very low dose of buprenorphine/naloxone (eg, 0.5 mg sublingual) was initially prescribed and gradually increased over the course of several weeks. At the same time buprenorphine/naloxone was being titrated, the patient was tapered off his iOAT and SROM medications. Details regarding the buprenorphine/naloxone micro-induction can be found in table 2.

Table 2.

Injectable opioid agonist therapy (iOAT) to buprenorphine/naloxone transition protocol using a micro-induction approach

Date	Intravenous hydromorphone (HM) (mg/route/frequency)	Slow-release oral morphine (SROM) (mg/route/frequency)	Buprenorphine/ naloxone (mg/route/frequency)	Notes
Day 1	170 mg intravenous or intramuscular two times per day	500 mg PO dwi	0.5 mg SL QD
Day 2	Missed dose	Missed dose	0.5 mg SL QD
Day 3	Missed dose	Missed dose	1 mg SL QD
Day 4	170 mg intravenous or intramuscular two times per day	300 mg PO dwi	1 mg SL QD	COWs score 7.
Day 5	170 mg intravenous or intramuscular two times per day	300 mg PO dwi	1.5 mg SL QD	Denied illicit use during days of missed doses.
Day 6	170 mg intravenous or intramuscular two times per day	300 mg PO dwi	1.5 mg SL QD	Missed HM and SROM ×4. Wants to go onto buprenorphine/naloxone more quickly. Reports mild withdrawal (night sweats and chills).
Day 7	Missed dose	Missed dose	2 mg SL QD
Day 8	Missed dose	Missed dose	2 mg SL QD
Day 9	Missed dose	Missed dose	3 mg SL QD
Day 10	Missed dose	Missed dose	3 mg SL QD
Day 11	Missed dose	Missed dose	Missed dose
Day 12	Missed dose	Missed dose	4 mg SL QD	States that he wants to continue with microdosing.
Day 13	170 mg intravenous or intramuscular two times per day	300 mg PO dwi	4 mg SL QD	Frustrated with microdosing and how long it is taking.
Day 14	Missed dose	Missed dose	Missed dose	Precipitated withdrawal after taking higher than recommended dose (against medical advice).
Day 20	Discontinued	Discontinued	16 mg SL QD	Was using street heroin.
				Insomnia ×5 days. Reports mild withdrawal.
Day 24	Discontinued	Discontinued	16 mg SL QD	Reports mild withdrawal over weekend.

COWs, Clinical Opiate Withdrawal Scale; dwi, daily witnessed ingestion; PO, oral route of administration; QD, once daily dosing; SL, sublingual route of administration.

Outcome and follow-up

Overall, the transition from iOAT to oral buprenorphine/naloxone was successful, though the patient did report intermittent symptoms of feeling ‘dope-sick’ at various points during the process. He also had one precipitated withdrawal that occurred on day 14 of treatment after taking a higher dose of buprenorphine/naloxone than recommended. An eventual dose of 16 mg/day was required for stabilisation.

Discussion

This case report describes the adoption of a novel microdosing approach to facilitate a transition from iOAT to oral buprenorphine/naloxone in a patient with severe, refractory OUD. Such an induction approach can be a useful strategy to minimise or eliminate the potential for a patient to have to experience opioid withdrawal prior to initiation of the medication, and minimises the risk for precipitated withdrawal. While buprenorphine/naloxone is a commonly used medication for OUD treatment, a transition from iOAT to buprenorphine/naloxone is less commonly reported.

‘Microdosing’ of buprenorphine/naloxone is a recently adopted clinical practice in Vancouver, Canada, though its use is not widely studied. Only three case studies and one small case series currently exist.^11–13 Hammig et al published the first case report in 2010 for the treatment of a woman with post-traumatic stress disorder and concomitant OUD who had been previously unsuccessful with standard buprenorphine/naloxone inductions due to symptoms of withdrawal.¹¹ ‘The Bernese Method’ of microdosing was adopted and successfully negated withdrawal symptoms by using small doses of buprenorphine/naloxone with incremental increases over a 6-day induction period. Two subsequent case reports of successful buprenorphine/naloxone micro-inductions were described by the same author in 2016.¹² The first patient was a woman who previously experienced intolerable opioid withdrawal from standard induction but was successful with microdosing while continuing to use illicit heroin. The second patient was a man who transitioned from methadone to buprenorphine/naloxone. More recently, a small case series (n=2) was published in which two patients with OUD were started on buprenorphine/naloxone using a rapid micro-induction without precipitating withdrawal.¹³ The first was a 33-year-old woman reportedly using 0.5 mg intravenous heroin daily who was admitted with serious injuries following a motor vehicle accident. While continuing to receive intravenous HM in hospital, she was initiated on buprenorphine/naloxone using a micro-induction approach over 5 days. The second patient was a 40-year-old man admitted to hospital after being found unresponsive in a residential drug treatment facility who was revived with naloxone. After undergoing surgery for compartment syndrome, he was put on fentanyl, and transitioned to HM before being initiated on buprenorphine/naloxone using micro-induction over a 3-day period.

The case report described here further demonstrates the potential for successful buprenorphine/naloxone induction using a microdosing approach. Furthermore, our description of a successful transition from iOAT to buprenorphine/naloxone using this induction strategy is also novel.

Despite the potential buprenorphine/naloxone microdosing may offer, many questions remain outstanding and warrant further research. More specifically, future efforts should provide clarification around the most efficacious micro-induction protocol as well as the patient who is best positioned for success with this treatment strategy. Such knowledge will help to inform healthcare providers to provide an additional treatment strategy to help combat North America’s growing opioid epidemic.

Learning points.

• The opioid overdose crisis is a growing public health concern, which warrants the development and refinement of treatment strategies.

• Injectable opioid agonist therapy (iOAT) is a specialist-led approach, which can be used to stabilise a patient who is refractory to first-line or second-line treatment options.

• Buprenorphine/naloxone is an effective and safe medication for opioid use disorder treatment.

• Transitioning from iOAT to buprenorphine/naloxone is feasible using a microdosing approach, though the optimal protocol for this is unknown.