Karen Ng, RPh, BScPhm, PharmD
Toronto Academic Pain Medicine Institute
Women’s College Hospital, Toronto
Juno Kim, RPh, BScPhm, PharmD
Centre for Addiction and Mental Health, Toronto
Sandra Veljovic, RPh, BScPhm, PharmD
Centre for Addiction and Mental Health, Toronto
Maria Zhang, RPh, BScPhm, PharmD, MSc
Centre for Addiction and Mental Health, Toronto
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto
Opioid use disorder (OUD) is a public healthcare challenge with significant morbidity and mortality. Opioid-related hospitalizations and death continue to rise in Ontario, with a fourfold increase in deaths and a doubling of hospitalization between 2003 to 2018.1,2 Approximately one-third of opioid-related deaths occur among people with active opioid prescriptions.3 Prescription opioids dispensed by pharmacies are a source of diverted opioids.4 These opioids contribute to the opioid crisis and pharmacists play an important role in reducing opioid-related sequelae. Pharmacists interact with patients most frequently, and are well positioned to foster opioid stewardship practices throughout the spectrum of opioid use. These practices include evaluating opioid prescriptions for appropriateness and safety, promoting structured prescribing and dispensing and assessing for problematic opioid use. In addition, for patients diagnosed with OUD, pharmacists can implement harm reduction strategies, educate and engage patients who are receiving OUD treatment.
Buprenorphine–naloxone (BUP/NLX) and methadone are the most effective, evidence-based opioid agonist therapies (OAT) used to treat adult patients with OUD. Both retain patients in treatment, sustain abstinence from illicit opioid use, and reduce morbidity and mortality.5
Recent Canadian guidelines recommend treatment with BUP/NLX first given its superior safety profile and flexibility in dosing compared to methadone.5,6 If BUP/NLX is ineffective or not preferable, methadone is recommended. This article will provide pharmacists with an update on new formulations of buprenorphine, along with alternative induction protocols.
In Ontario, there are three available formulations of buprenorphine indicated for OUD: a sublingual tablet combined with naloxone, a subdermal implant and an extended release subcutaneous injection.
Both the buprenorphine subdermal implant and extended release subcutaneous injection have recently come onto the Canadian market and are covered under ODB with limited use criteria. In addition to their extended duration of action, both products are only accessible via a controlled distribution process.
|Buprenorphine/naloxone (4:1 ratio; Suboxone® and generics)||Buprenorphine subdermal implants (PROBUPHINE®)||Buprenorphine extended release injection (Sublocade®)|
|Formulation||Sublingual tablet with naloxone||Subdermal implants inserted every 6 months||Monthly extended-release subcutaneous injection|
|ODB coverage||General benefit for 2mg/0.5mg and 8mg/2mg tablets||Limited use - For the management of opioid use disorder in combination with counseling and psychosocial support in adult patients who meet the following criteria: - The patient is stabilized on a dose of no more than 8mg per day of sublingual buprenorphine for the preceding 90 days; AND - The patient is under the care of a healthcare provider with experience in the diagnosis and management of opioid use disorder and has been trained to implant and remove the buprenorphine subdermal implant.||Limited use - For the management of moderate to severe opioid use disorder as a part of a complete treatment plan that includes counselling and psychosocial support in adult patients who meet the following criteria: - The patient has been induced and is stabilized on an equivalent of 8mg to 24mg per day of transmucosal buprenorphine for a minimum of seven days; AND - The patient is under the care of a healthcare provider with experience in the diagnosis and management of opioid use disorder; AND - Each dose is administered subcutaneously in the abdominal region by a certified healthcare provider who has received instruction and training.|
|Training for prescribers||Advised by CPSO (for medical doctors); no formal requirement from manufacturer||Live training required for all healthcare providers performing insertions and/or removals of PROBUPHINE® and arranged by manufacturer7||Online training required by manufacturer; must submit certification of training to dispensing pharmacy|
|Training for pharmacists||No||No||Online training advised by manufacturer|
|Closed distribution network||No, available from drug wholesaler||Yes, register through Knight Therapeutics Inc.||Yes, register through Indivior UK Limited|
DOSING CONSIDERATIONS FOR BUP/NLX
Buprenorphine’s activity as a partial mu opioid receptor agonist confers its safety advantages relative to full agonists in overdose, and in many opioid-related side effects. At the same time, care must be taken upon initiation of buprenorphine to minimize precipitated opioid withdrawal in patients with physical dependence to opioids. Several techniques can be used for buprenorphine induction:
Traditional induction of BUP/NLX typically occurs in an observed clinical setting such as a physician office or pharmacy. Prior to initiating BUP/NLX, it is recommended that patients be in at least moderate opioid withdrawal defined by a Clinical Opiate Withdrawal Scale (COWS) score greater than 12. This is to ensure that the full opioid agonist is adequately eliminated to avoid precipitation of opioid withdrawal with BUP/NLX. Patients should wait at least:
- 6-12 hours (preferably 12 hours) after use of short-acting opioids (e.g. heroin, oxycodone), or
- 12-24 hours (preferably 24 hours) after the use of a slow release opioid (e.g. oxycodone controlled-release formulations), or
- 24 hours (preferably 36-72 hours) after use of long-acting opioid (e.g. transdermal fentanyl, methadone).
Switching from methadone requires that the patient's methadone dose be first tapered down to 30 mg or less before buprenorphine treatment is initiated to minimize the risk of precipitated withdrawal. It is recommended to wait at least 3 days after the last dose of methadone before starting BUP/NLX.8
Advise patients that relief of opioid withdrawal symptoms generally occur 20-40 minutes after the initial dose of buprenorphine. Clinical practice guidelines have been developed by the Centre for Addiction and Mental Health (CAMH) that detail the initiation of BUP/NLX in the outpatient management of OUD in Ontario. These guidelines should be reviewed before dispensing buprenorphine.9
Although buprenorphine guidelines have recommended that buprenorphine induction occur in an observed clinical setting, for some patients, the logistics of getting to a clinic are prohibitive. For clinicians, buprenorphine inductions can be an onerous process with barriers such as insufficient time and a lack of space.10 Recent studies have shown that home inductions are safe, support patient autonomy and are cost effective.6,11,12
An ideal candidate for home induction is one who is motivated, has fairly good cognition, and does not have severe concurrent mental health or substance use disorders. A supportive family network is helpful.
As with traditional inductions, patients should abstain from opioids prior to initial buprenorphine dose and be in moderate withdrawal before initiation defined as COWS>12 or Subjective Opioid Withdrawal Scale (SOWS) >16. As the last point of contact between the prescription and the patient, pharmacists are well situated to provide counselling on how to administer their take-home doses of BUP/NLX, how to monitor for side effects, and how to reduce the risk of precipitated withdrawal. Pharmacists can provide education on symptomatic management of opiate withdrawal symptoms with over the counter medications. Readers are encouraged to review RxFile’s document on Opioid Tapering 2018 where detailed management of opioid withdrawal related side effects are provided.13
Table 1: Sample Protocol - Home induction schedule14
Day 1: 2mg/0.5mg-4mg/1mg
If after 2 hours, there are no withdrawal symptoms, no further doses are required.
If withdrawal symptoms are still present, the patient may take another 2mg/0.5mg-4mg/1mg.
** This process may be repeated once more to a maximum buprenorphine dose of 12 mg in 24 h.
Day 2: Consolidate the dose from previous day
If, after 2 hours withdrawal symptoms are still present the patient may take another 2mg/0.5mg to 4 mg/1mg, up to a maximum dose of 16 mg in 24 h.
Day 3 and until next visit:
Take total daily dose from Day 2 as a single dose first thing every morning.
The above dosing protocol also incorporates the collective experience from our centres, and reflects a conservative and slower approach. Given BUP/NLX’s long half-life it takes a few days to attain full effect and a gradual titration also reduces risks of over-sedation.
Patients would benefit from pharmacist follow up to assess for withdrawal symptoms, side effects of BUP/NLX, and pain management (if applicable) for three consecutive days after induction.
One significant barrier to initiating BUP/NLX is the need for the patient to be in moderate opioid withdrawal. Micro-induction is an alternative approach for patients which eliminates the need for the patient to be in moderate withdrawal prior to initiating BUP/NLX. Traditional induction is also challenging with methadone and transdermal fentanyl due to their long half-lives resulting in an increased risk of precipitated withdrawal.15
Micro-induction is based on the “Bernese method” which involves ‘micro-dosing’ of buprenorphine with incremental increases to both dose and frequency over several days while the patient continues to use full mu opioid agonists. This method requires splitting of the BUP/NLX tablet to obtain the required doses. Micro doses given at regular intervals should not cause precipitated withdrawal. Buprenorphine slowly accumulates on the mu opioid receptor, replacing the full mu opioid agonist. The dose of buprenorphine needed to fully replace the full mu agonist has not been clearly defined in the literature. Anecdotal evidence has found that as doses increase above 8mg daily, patients may start to experience some mild to moderate symptoms of opioid withdrawal and this may as buprenorphine displaces the full mu agonist on the mu opioid receptor. In cases reports and from our clinical experience, when buprenorphine doses reach 12mg/day the full opioid agonist can be stopped and the buprenorphine dose can then be titrated up quickly. Micro-induction can be a valuable alternative to traditional induction, as it potentially minimizes opioid cravings and reduces the need for the patient to be in moderate opioid withdrawal.16 It should be recognized that this approach is considered off label and lacks strong evidence.
Table 2: Sample Protocol - Outpatient micro-dosing induction schedule for buprenorphine/naloxone15
The below refers to milligram dose of buprenorphine.
Day 1: 0.5mg loading dose
Day 2: 0.5mg BID (1mg total)
Day 3: 1mg BID (2mg total)
Day 4: 2mg BID (4mg total)
Day 5: 3mg BID (6mg total)
Day 6: 4mg BID (8mg total)
Day 7: 12 mg (12mg total and discontinue other opioids)
BUP/NLX is gradually titrated based on the patient’s opioid withdrawal symptoms and presence of medication side effects. An optimal dose is reached when opioid withdrawal is relieved for at least 24 hours, with minimal or no adverse effects. It is important to note that opioid cravings may not always be eliminated with OAT, and additional psychotherapy support may be needed to address cravings.17 BUP/NLX should be dispensed daily with supervised dosing by a health professional (e.g. a pharmacist) for the first 2 months of treatment.8,9 Supervised dosing by the pharmacist is part of a structured opioid treatment program that supports adherence and promotes positive treatment outcomes for patients with OUD.
Furthermore, improved patient outcomes occur with frequent pharmacist and prescriber collaboration throughout all aspects of OUD treatment. Where guest dosing is required for patients whom are dispensed BUP/NLX from two different pharmacies, a process of communication between both pharmacies is required so that missed doses and/or dose changes can be clearly tracked.
Opioid agonist therapies such as buprenorphine or methadone are part of a comprehensive treatment plan that incorporates counseling and other behavioral therapies to provide patients with a holistic approach to the management of OUD. When compared to methadone, buprenorphine has reduced overdose risks due to its partial agonist properties and ceiling effect for respiratory depression, less adverse effects and fewer drug interactions.8 From a public health perspective, buprenorphine has a lower risk of harms compared to full opioid agonists if diverted.6,8 The availability of two new buprenorphine formulations, Sublocade® and PROBUPHINE®allows for more flexible dosing schedules, improved patient convenience and adherence to treatment. As such, buprenorphine is considered first line for OUD treatment.
Pharmacists are involved in the full continuum of OAT from collaborating and coordinating care with the prescriber, to developing treatment plans, supervising administration, and monitoring patients. Alternative induction methods for buprenorphine may increase access and engage patients with this important therapy. Optimal patient outcomes are achieved when care is provided in a non-stigmatizing environment, which encourages and supports the patient and includes frequent collaboration between the prescriber, pharmacist and patient throughout treatment.
- Opioid mortality surveillance report: analysis of opioid-related deaths in Ontario July 2017-June 2018. Toronto, ON: Queen’s Printer for Ontario; 2019 Ontario Agency for Health Protection and Promotion (Public Health Ontario); Office of the Chief Coroner; Ontario Forensic Pathology Service; Ontario Drug Policy Research Network. [internet]. Available from: https://www.publichealthontario.ca/-/media/documents/o/2019/opioid-mortality-surveillance-report.pdf?la=en
- Public Health Ontario. Interactive Opioid Tool Opioid-related morbidity and mortality in Ontario [internet]. Ontario: Ontario Agency for Health Protection and Promotion; 2020 [updated 2020 March 16; cited 2020 May 28]. Available from: https://www.publichealthontario.ca/en/data-and-analysis/substance-use/interactive-opioid-tool#/trends
- Gomes T, Khuu W, Martins D, Tadrous M, Mamdani MM, Paterson JM, et al. Contributions of prescribed and non-prescribed opioids to opioid related deaths: population based cohort study in Ontario, Canada. BMJ. 2018;362:k3207.
- Cicero, Kurtz SP, Surratt HL, Ibanez GE, Ellis MS, Levi-Minzi MA, et al. Multiple determinants of specific modes of prescription opioid diversion. J Drug Issues. 2011;41(2):283–304.
- Bruneau J, Ahamad K, Goyer ME et al. CMAJ 2018 March 5;190:E247-57. Available from: DOI: https://doi.org/10.1503/cmaj.170958
- CRISM National Guideline for the Clinical Manager of Opioid Use Disorder 2018. Available from: https://crism.ca/wp-content/uploads/2018/03/CRISM_NationalGuideline_OUD-ENG.pdf
- Knight Therapeutics Inc, Probuphine ® Product Monograph. May 2020. Available from: https://pdf.hres.ca/dpd_pm/00056235.PDF
- Isaac P, Janecek E, Kalvik A et al. Opioid Agonist Maintenance Treatment-A pharmacist’s guide to methadone and buprenorphine for opioid use disorder CAMH 3rd edition 2016
- Handford C, Kahan M, Srivastava A et al. Buprenorphine/Naloxonefor Opioid Dependence: Clinical Practice Guideline. CAMH.2012. Available from: http://cpsa.ca/wp-content/uploads/2015/07/buprenorphine_naloxone_CAMH2012.pdf?x91570
- Srivastava, A., Kahan, M., Leece, P. et al. Buprenorphine unobserved “home” induction: a survey of Ontario’s addiction physicians. Addict Sci Clin Pract 2019;14:18. Available from: doi: https://dx.doi.org/10.1186%2Fs13722-019-0146-4
- Lee JD, Grossman E, DiRocco D, Gourevitch MN. Home buprenorphine/naloxone induction in primary care. J Gen Intern Med. 2009;24(2):226–32.
- Lee JD, Vocci F, Fiellin DA. Unobserved “home” induction onto buprenorphine. J Addict Med. 2014;8(5):299–308.
- Regier L. RxFile Tapering Opioids How to Explore and Pursue the Option for Patients Who Stand to Benefit CHRONIC PAIN/OPIOIDS Part 2 2018. Available from: https://www.rxfiles.ca/rxfiles/uploads/documents/Opioid-Tapering-Newsletter-Compilation.pdf
- Kahan, M. (2017). Safe opioid prescribing and managing opioid use disorder: A pocket reference for primary care providers. Safe prescribing practices for addictive medications and management of substance use disorders in primary care: a pocket reference for primary care providers. Toronto, ON: Women’s College Hospital.
- Randhawa PA, Brar P, Nolan S. Buprenorphine–naloxone “microdosing”: an alternative induction approach for the treatment of opioid use disorder in the wake of North America’s increasingly potent illicit drug market. CMAJ. January 20, 2020 192 (3) E73. Available from: https://doi.org/10.1503/cmaj.74018
- Hammig R, Kemter A, Strasser J et al. Use of microdoses for induction of Buprenorphine treatment with overlapping full opioid agonist use: the Bernese method. Subst Abuse Rehabil 2016;7:99-105
- Melemis SM. Relapse Prevention and the Five Rules of Recovery. Yale J Biol Med. 2015;88(3):325?332. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4553654/