Text adapted in 2023 from "Opioid Use and Opioid Use Disorders" in The Primary Care Addiction Toolkit. Available online only.

Prescribing buprenorphine-naloxone

Canadian guidelines recommend buprenorphine-naloxone as the first-line treatment for opioid use disorder due to its superior safety profile compared with methadone (Centre for Addiction and Mental Health [CAMH], 2021; Canadian Research Initiative in Substance Misuse [CRISM], 2018).

There are no restrictions on prescribing buprenorphine-naloxone; however, physicians are expected to obtain necessary training and education to prescribe opioid agonist therapy (OAT). The most recent drug monograph (Canadian Pharmacists Association, 2021) indicates that this medication should only be prescribed by physicians who have experience using OAT to treat opioid use disorder and who have completed a recognized training program.
  

How buprenorphine-naloxone works

Buprenorphine-naloxone is a sublingual tablet containing buprenorphine and naloxone in a 4:1 ratio. Buprenorphine is a partial mu opioid agonist with an average half-life of 37 hours (range 2469 hours). It has a maximal opioid agonist effect above which there is no relative efficacy at doses above 24 mg total daily dose (American Society of Addiction Medicine [ASAM], 2020). This ceiling effect carries less risk of respiratory depression and death compared with the effects of full agonists such as methadone (Auriacombe et al., 2004; Borron et al., 2002).

Buprenorphine has a high receptor affinity and binds tightly to mu-opioid receptors, preventing other opioids from binding. It also dissociates slowly from opioid receptors, giving it a slow onset and a long duration of action. Clinically, this means that buprenorphine does not cause sedation or euphoria at an appropriate dose and it relieves withdrawal and reduces cravings for 24 hours or longer.

Oral buprenorphine is co-formulated with the opioid antagonist naloxone to reduce the risk of diversion and non-medical use. Naloxone is not absorbed sublingually and thus cannot exert any antagonist effects; however, it may precipitate withdrawal if it is injected by patients with physical dependence on opioids.

At the beginning of treatment, buprenorphine-naloxone is dispensed daily under the observation of a pharmacist. Patients may receive take-home doses once they have reached a stable dose.
  

Precipitated withdrawal

The main risk of buprenorphine induction is precipitated withdrawal. Buprenorphine binds more tightly than other opioids to the mu opioid receptors. If a patient with physical dependence to opioids takes buprenorphine while experiencing withdrawal, they will feel relief from the partial agonist activity. However, if a patient with physical dependence takes buprenorphine while other opioids are bound to the opioid receptors, buprenorphine will displace the other opioids, replacing full agonist activity with partial agonist activity. This triggers rapid onset of withdrawal, known as precipitated withdrawal.
  

Buprenorphine-naloxone induction strategies

Standard induction protocol

There are several strategies for reducing the risk of precipitating withdrawal. The traditional approach is for the patient to take the first dose of buprenorphine only once they are in moderate to severe opioid withdrawal. This means waiting for 612 hours after last use of a short-acting opioid such as heroin, or 24–72 hours after last use of a long-acting opioid such as methadone or fentanyl (ASAM, 2020; CAMH, 2022).

Withdrawal can be determined by a standardized scale such as the Clinical Opiate Withdrawal Scale (COWS). A score of 13 or more indicates that the patient is in significant withdrawal and that it is safe to give the first dose of buprenorphine (ASAM, 2020). The patient takes an initial dose of 2–4 mg, is reassessed after one to three hours and receives additional doses as necessary (CAMH, 2021).
  

Buprenorphine microdosing

Other approaches to initiating buprenorphine do not require the patient to be in withdrawal. Microdosing involves prescribing small doses of buprenorphine-naloxone and titrating up over several days to achieve a starting dose. The pharmacological rationale for this approach is that repeated administration of small doses of buprenorphine-naloxone allows buprenorophine to accumulate at opioid receptors and to gradually displace full agonist opioids, which reduces or prevents opioid withdrawal. The goal is for the patient to discontinue the full agonist opioid once the buprenorphine dose reaches 4–12 mg.

There is no standard microdosing protocol, but the CAMH (2021) synthesis guidelines suggest two approaches:

• microdosing, starting with 0.5 mg twice per day, with increasing doses to a total daily dosage of 12 mg over 5–7 days for patients who cannot tolerate the significant period of abstinence needed to start buprenorphine-naloxone with a conventional induction
• rapid microdosing, administering 0.5–1 mg at shorter intervals, up to 12 mg total in a 24-hour period.
    

Buprenorphine macrodosing

A newer strategy for induction is the use of larger than standard doses of buprenorphine-naloxone in specific clinical situations. The pharmacological explanation for this approach is that the higher doses of buprenorphine may be able to extend beyond precipitated withdrawal by rapidly binding to a significant number of opioid receptors. One such protocol is particularly useful for induction with patients who were given naloxone in response to an opioid overdose (CA Bridge Program, 2020).
  

Buprenorphine-naloxone titration and maintenance

Patients initiated on buprenorphine-naloxone may require further dose titration until they reach an optimal daily dose. Clinical assessment every five to seven days is suggested during the titration phase. Due to buprenorphine’s long half-life, it may take two to three weeks of daily dosing to achieve steady serum levels. Once a patient is maintained on a stable daily dose, the frequency of assessment can decrease (CAMH, 2021).
  

Candidates for buprenorphine-naloxone

Buprenorphine-naloxone may be the best OAT option for patients who:

• find take-home methadone restrictions unacceptable because of work or family commitments, or lack of transportation
• have medical contraindications to methadone (e.g., the patient has a condition or takes medication associated with a prolonged QT interval; the patient uses sedatives such as benzodiazepines).
    

Formulations of buprenorphine

There are several buprenorphine formulations to treat opioid use disorder in Canada (Canadian Agency for Drugs and Technologies in Health, 2019). The most common is the buprenorphine-naloxone sublingual tablet. Newer buprenorphine formulations include:

• buprenorphine buccal film: available only through Health Canada’s Special Access Program
• extended-release subcutaneous injection (Sublocade).

Another extended-release formulation, the subcutaneous implant, was discontinued in May 2023 in Canada due to supply issues reported by the manufacturer (Drug Shortages Canada, 2023).

Patients taking buprenorphine-naloxone may switch to the more convenient monthly injection to support treatment retention.
  

Buprenorphine formulations to treat opioid use disorder

Sources: Canadian Agency for Drugs and Technologies in Health. (2017). Buprenorphine-Formulations for the Treatment of Opioid Use Disorders: A Review of Comparative Clinical Effectiveness, Cost-Effectiveness and Guidelines.

Canadian Agency for Drugs and Technologies in Health. (2019). CADTH Common Drug Review. Buprenorphine Extended-Release Injection (Sublocade).

In Opioid Use and Opioid Use Disorder:

• Screening
  • Identifying unhealthy opioid use
  • Identifying opioid use disorder
  • Screening tools for unhealthy opioid use
• Assessment
  • Clinical assessment of opioid use disorder
  • Urine drug testing  
• Pain management
  • Prescribing opioids for pain patients at risk of unhealthy use
  • Opioid dosing in pain patients at risk of unhealthy use
  • Tapering opioids in pain patients at risk of unhealthy use
  • Prescribing opioids for pain patients with opioid use disorder
• Opioid use disorder treatment
  • Managing opioid withdrawal
  • Treatment options for opioid use disorder
  • Buprenorphine
  • Methadone
  • Slow-release oral morphine
  • Injectable opioid agonist therapy
• Tools and resources
• References
• About the editors and contributors