ACRT Journal

Abbreviations: am morning; bid: twice a day; DSM-5: Diagnostic and Statistical Manual of Mental Disorders, 5th Edition; h/o: history of; MAT: medication assisted treatment; MEDD: morphine equivalent daily dose; n/a: not applicable; OTC: over the counter; pm: evening; qd: once a day in the morning; s/p: status post; tid: three times a day.

Introduction

In 2020, Israel was ranked number one in the world in opioid consumption per capita as measured by morphine equivalents [1]. Chronic opioid use is associated with numerous serious risks including misuse, addiction and overdose [2]. Furthermore, it was shown that Israel is just like other countries in that increased opioid use is associated with increased all-cause mortality among non-oncological patients [3]. Beginning with the publication of the seminal paper on methadone as treatment for heroin addiction in 1965 [4], there has been more than 50 years of data showing that the best way to alter the course of the fatal disease of opioid addiction is medication treatment with either methadone, buprenorphine or naltrexone, along with biopsychosocial support [5].

Buprenorphine’s potential utility for the management of addiction, the most severe form of opioid use disorder, has been discussed in the literature since the 1970s [6]. Buprenorphine offers several advantages as a treatment medication, which include its high binding affinity to the mu opioid receptor and slow dissociation kinetics. Due to its high affinity, buprenorphine will displace other opioids such as fentanyl, oxycodone, morphine and methadone, and bind to the receptors in their place. In addition, the slow dissociation or disengagement from the receptors contributes to its long duration of action and blocks other opioids from binding [7].

Buprenorphine is a partial mu receptor agonist, which means that its maximal effect is less than that of the aforementioned full agonists and at a certain dose, it reaches a ceiling. This ceiling makes it much safer than full opioid agonists because respiratory depression, which can be the cause of overdose death, is limited. However, unlike full agonists where an increase in dose equates to a stronger effect, once buprenorphine reaches its ceiling, higher doses do not increase the effectiveness of the medication [7,8].

Buprenorphine as part of medication assisted treatment (MAT) for opioid use disorder has the ability to both relieve and induce opioid withdrawals depending upon when it is ingested. When a patient has stopped using opioids and is in withdrawals, buprenorphine will bring relief through its partial agonist effect. However, because of buprenorphine’s high affinity and only partial agonism, if it is consumed while other high efficacy full agonist opioids are occupying the mu receptors, it will displace them and precipitate severe withdrawals. Therefore, patients regularly using opioids must completely stop taking them before beginning treatment using traditional buprenorphine protocols, which many individuals are unable to do because of their addiction. Furthermore, despite these precautions, the induction of buprenorphine can precipitate severe opioid withdrawals resulting in physical and psychological agony, dropping out of treatment, resistance to reengaging in treatment, and relapse with the risk of overdose and death [9]. For all of these reasons, traditional buprenorphine initiation methods remain challenging both for clinicians and patients.

To overcome the roadblocks that prevent buprenorphine initiation, a breakthrough low dose buprenorphine induction protocol was developed in Switzerland, originally called the Bernese method. It was published in German in 2010 [10] and then in English in 2016 [9]. Low dose initiation protocols are based upon induction of buprenorphine treatment with overlapping full opioid agonist use. They work by repetitive administration of very small buprenorphine doses, previously called microdoses, with sufficient dosing intervals, such as every 12 hours, to allow for the buprenorphine to gradually accumulate at the mu opioid receptors. Over time, an increasing amount of buprenorphine will slowly displace and replace the full mu agonist, thereby avoiding precipitated withdrawals. Because of the high affinity and long receptor binding time, buprenorphine will preferentially accumulate at the mu receptors until it is the only bound opioid. Therefore, using a low dose protocol, overlapping induction of buprenorphine with ongoing use of opioids, whether prescribed or illicit, is possible without precipitating severe opioid withdrawals [11].

Whereas buprenorphine is available for treatment of opioid use disorder in many countries, only a few have published reports of low dose buprenorphine initiations [12], none of which were from Israel. Since 2002, buprenorphine as part of MAT has been prescribed in Israel by doctors who have undergone a two day specialized training course and work in either public MAT centers or are private providers [13]. Since then, the only protocols used in Israel to date are the traditional ones. This four case series is the first of its kind done in Israel using low dose buprenorphine initiations to treat patients who suffer from opioid addiction. Furthermore, this is the first case in the literature of a person suffering from tramadol use disorder to undergo low dose buprenorphine induction. Four individuals presented to an outpatient public MAT and requested treatment with buprenorphine (as opposed to methadone), but could not stop their opioid medication before starting treatment. They were offered to be the first individuals in the country to undergo low dose buprenorphine initiations.

Case Presentations

Between May – October 2022, four patients who met DSM5 criteria for severe opioid use disorder due to prescription medications presented to an outpatient public MAT center in Israel.

Each patient insisted on treatment with buprenorphine, they were not willing to take methadone. These four patients were offered an overlapping low dose buprenorphine initiation because they were unable to stop their opioid use for a sufficient amount of time to begin buprenorphine without being at high risk of precipitated withdrawals.

The four patients were all males, two Israeli Arab individuals and two Israeli Jewish individuals. None suffered from the daily pain issues which had initially led to their being prescribed opioids. One patient had occasional neck and back pain, which had been the original reason he was prescribed opioids, and managed his pain using over the counter (OTC) medications as the prescribed opioid he was still taking and had become addicted to (fentanyl patch), was no longer effective. At presentation to the MAT Center, the four patients were taking the following opioids daily: 60 tablets of oxycodone 20mg, 75mcg fentanyl patch every 3 days, 12 tablets of tramadol 100mg (down from 50 tablets of oxycodone 20mg), and 5 tablets of oxycodone/paracetamol 10mg. Table 1 summarizes the demographics, medical history and morphine equivalent daily dose (MEDD) at buprenorphine initiation. All buprenorphine medication was in the form of buprenorphine/naloxone film, either 2mg/0.5mg film that was used whole, or cut as needed in quarters (0.5mg) or halves (1mg), or 8mg/2mg film.

Results

Using low dose buprenorphine initiation protocols, all four patients were successfully stabilized on a therapeutic dose of buprenorphine in parallel to being completely tapered off the opioid medication to which they were addicted as shown in Tables 2-5. All four patients tolerated low dose buprenorphine initiation without precipitated withdrawal. All of the patients were offered supportive medications in case they experienced withdrawals symptoms: clonidine for anxiety/restlessness/ diaphoresis, olanzapine for agitation, loperamide for diarrhea, ondansetron for nausea/vomiting, paracetamol or ibuprofen for pain, and trazodone for insomnia [14,15,16]. Only one patient used olanzapine, otherwise, none of the patients required any supportive medications while transitioning onto buprenorphine. The treatment day at which stabilization occurred involved full induction on a therapeutic dose of buprenorphine (at least 8mg) and was the time point at which the prescribed opioid medication to which they were addicted was stopped.

Of note, Patient 1 overcame many challenges before stabilizing in treatment. Besides opioid addiction, he also suffered from addiction to stimulants and benzodiazepines. The low dose protocol had to be modified from its original schedule, and he did not always follow the agreed upon schedule, as noted in Table 2. Nonetheless, by Day 9, he had completely stopped using oxycodone as he both stated and was evidenced by his ongoing urine drug screens in which he consistently tested negative for oxycodone. On Day 15 of buprenorphine, the patient did not show up for treatment but instead took 14mg buprenorphine and an unknown amount of benzodiazepines until he lost consciousness. Nonetheless, despite overdosing on benzodiazepines, he restabilized on buprenorphine. Ultimately, he did not feel that buprenorphine 24mg daily adequately managed his cravings, and on Day 30 he switched to methadone.

Table 1: Demographics and Clinical Features of Patients.

Table 2: Patient 1 Low Dose Buprenorphine Initiation Protocol.

Table 3: Patient 2 Low Dose Buprenorphine Initiation Protocol.

Table 4: Patient 3 Low Dose Buprenorphine Initiation Protocol.

Table 5: Patient 4 Low Dose Buprenorphine Initiation Protocol.

Table 6: 10 Factors that led to successful low dose buprenorphine initiations.