The opioid crisis is one of the most serious public health issues in North America in recent years. In the United States, over 45,000 people died from using opioids in 2018, and in Canada, over 17,000 opioid-related deaths have occurred since 2016 [1,2,3,4]. Opioid-related deaths have surpassed motor vehicle incidents and homicide deaths combined, resulting in decreases in life expectancy in North America [1, 5].
These deaths are primarily driven by untreated opioid use disorder (OUD), a common disorder affecting millions of individuals worldwide . Current North American guidelines strongly endorse opioid agonist treatment (OAT) with buprenorphine/naloxone as the first-line treatment of OUD, because of its superior safety profile and comparable efficacy over other forms of OAT [7, 8]. OAT is associated with reducing mortality, illicit drug use, and improving physical and mental health outcomes .
Buprenorphine is a partial μ-opioid receptor agonist. The partial agonism results in a ceiling effect on respiratory depression and lower risk for overdose . To prevent abuse and minimize diversion, buprenorphine is co-formulated with naloxone, an opioid antagonist, in a 4:1 ratio as buprenorphine/naloxone (brand name: SUBOXONE®) . When buprenorphine/naloxone is injected by individuals with OUD, naloxone precipitates withdrawal. When buprenorphine/naloxone is taken as prescribed, that is sublingually, naloxone is poorly absorbed and does not exert any significant clinical effect, leaving the opioid agonist effects of buprenorphine to predominate.
Buprenorphine exhibits a strong biding affinity to the μ-opioid receptor . When it is introduced in the presence of other opioids with weaker binding affinities, such as heroin, buprenorphine can precipitate withdrawal by displacing other opioids from the receptor. To avoid precipitated withdrawal, the standard method of induction of buprenorphine/naloxone requires patients to be abstinent from other opioids for a set period of time and thus requires patients to be in at least mild withdrawal before its administration [7, 8]. Standard buprenorphine/naloxone induction can thereby be very distressing and time-consuming for patients to tolerate, which can be a barrier for many patients who need this potentially life-saving therapy. Patients who experience precipitated withdrawal or significant levels of withdrawal during the induction process may also be less likely to be retained in treatment .
To overcome the difficulties of a standard induction method of buprenorphine, a novel induction method, known as micro-induction (also called micro-dosing), is being explored and increasingly employed by many clinicians in Canada, the United States, and other parts of the world [13,14,15,16,17,18,19,20,21]. This induction method was first described as the Bernese method in a Swiss case series in 2016 . The method involves administering buprenorphine at micro-doses once to twice daily, concurrently with the use of a full μ-opioid receptor agonist, to avoid precipitated withdrawal. It did not require the two outpatients to go through withdrawal from opioids prior to induction, and they reached therapeutic doses in 10 or more days.
Recently, our team developed a more rapid variation of micro-induction, known as rapid micro-induction, which was developed to be primarily used in an inpatient setting. It involves the administration of buprenorphine/naloxone every 3 to 4 h along with the use of a full μ-opioid receptor agonist, resulting in patients reaching therapeutic doses in just three to five days . The rationale of this rapid dosing is based on the hypothesis that buprenorphine reaches peak plasma concentration in approximately an hour . Rapid micro-induction offers several advantages over a standard induction method—eliminating the abstinence period preceding induction, reducing the risk of precipitated withdrawal, minimizing the symptoms of withdrawal and craving, potentially improving treatment retention, and reducing the time spent in hospital [17, 19].
Rapid micro-induction and variations of this novel induction method have been extensively described in several case reports and in a recent review, however, they have never been systematically evaluated in a clinical trial [13,14,15,16,17,18,19,20,21]. To generate the evidence for this induction method in the midst of the ongoing opioid crisis, the first randomized controlled trial was developed to compare the effectiveness and safety of rapid micro-induction versus standard induction of buprenorphine/naloxone.