While the literature on low-dose buprenorphine/naloxone induction is currently limited to several case series, growing evidence and clinical experience in BC highlight the important role of this approach. While research is ongoing to determine optimal low-dose  induction protocols, a number of protocols have been developed that are in use across BC care setting. 

Tables 7 and 8 offer examples of commonly utilized low-dose induction protocols. 

Table 7. Sample 7-day Low-dose Induction Protocol

Table 8. Sample 8-day Low-dose Induction Protocol

Note: May be preferable for some patients due to consistent BID dosing during induction

Additional low-dose induction protocols are available from the BC Pharmacy Association, published in the Canadian Medical Association Journal, and reported in peer-reviewed studies (see supplemental material to Moe, et al., 2021). In the absence of a widely established evidence-based protocol, clinicians may consult the 24/7 Addiction Medicine Clinician Support Line or RACEapp for specialized support.

If clinically indicated, co-prescribing a full agonist (e.g., SROM, hydromorphone, methadone) during low-dose induction can help reduce or eliminate patients’ reliance on the unregulated drug supply and reduce the risk of overdoses while titrating the buprenorphine/naloxone dose. 

Mild to moderate withdrawal symptoms are not uncommon during low-dose induction, and can generally be managed by slowing down the titration process or providing adjunct medications to mitigate withdrawal (e.g., dimenhydrinate, clonidine, ibuprofen). It is important to maintain close contact with the patient throughout the titration process in order to make necessary adjustments in a timely manner. 

To reduce patient confusion regarding dosing, prescribers should include instructions for blister packaging in prescriptions for low-dose inductions.

The following is a sample prescription for low-dose induction:

Instruct patient to discontinue opioid use prior to the first day of scheduled induction. In order to avoid precipitated withdrawal, patient should reach moderate withdrawal (COWS score>12)  prior to induction. In general, the duration of time between last opioid dose and onset of moderate withdrawal is as follows:

Box 9. Recommended Duration of Time Since Last Opioid Use to Prevent Precipitated Withdrawal

* Note on fentanyl: Although fentanyl has a rapid and intense onset with a relatively short duration of action (1–2 hours),467 it has a long terminal half-life, likely due its lipophilic nature (which enables its rapid distribution into the body’s tissues).468 Emerging evidence and clinical experience suggests that inductions may be particularly challenging in patients using fentanyl. 153,154 For such patients, time elapsed since last use may be a more relevant indicator for safe buprenorphine/naloxone initiation than the COWS score. A 2022 Vancouver-based case series involving fentanyl-exposed patients reported 3 cases where patients experienced unexpected precipitated withdrawal following buprenorphine/naloxone initiation despite reaching COWS>12 prior to induction.153 Based on these findings, a 48-hour period of abstinence prior to traditional induction may be preferable in order to minimize the risk of precipitated withdrawal, regardless of the COWS score.153 However, the patient’s tolerance of the pre-induction withdrawal period and their risk of drop out should also be considered. In general, a minimum of 24 hours of withdrawal from fentanyl is recommended for people who use fentanyl. Patients should be supported to sustain this withdrawal period for as long as tolerable beyond the 24-hour point in order to minimize their risk of precipitated withdrawal. Alternatively, a low-dose induction method may be preferable for fentanyl-exposed patients.

• Emphasize to patient that starting buprenorphine/naloxone too early may worsen withdrawal symptoms
• Ensure patient is aware to not drive or operate heavy machinery during induction and the early titration phase
• Emphasize that induction cannot take place during acute alcohol intoxication, and that dosing and titration may be adjusted or reduced for patients who are actively using alcohol, benzodiazepines, or other sedative medications due to increased overdose risk
• Utilize the Clinical Opiate Withdrawal Scale (COWS; see  Appendix 8) to assess withdrawal symptom severity
• If possible, plan induction of buprenorphine/naloxone for earlier in the week to allow for monitoring and re-assessment over the week (if prescriber is not available on weekends)
• For patients transitioning from methadone to buprenorphine/naloxone, see the Methadone to Buprenorphine/naloxone section 
   

1. The risk of precipitated withdrawal is lower if the patient has signs of at least moderate opioid withdrawal (COWS>12), before receiving the first dose of buprenorphine/naloxone. 
   1.  For a COWS score of 12 or less, consider postponing the first dose of buprenorphine/naloxone until later in the day or the following day, when the patient is demonstrating more severe withdrawal.  
       
2. Table 10 presents recommended starting doses in reference to common practice. 

Table 10. Initial Buprenoprhine/naloxone Dose Based on Risk of Precipitated Withdrawal 
 

3. Offer patient education on taking the sublingual buprenorphine/naloxone tablet. While not necessary, you can offer to witness the ingestion of the first dose to ensure that the tablet is appropriately taken and fully dissolved.
   1. Instruct the patient to keep the tablet under their tongue until it dissolves, which may take up to 10–15 minutes, and to avoid swallowing, talking, eating, drinking, or smoking during this time.
       
4. Since precipitated withdrawal (see Managing Precipitated Withdrawal below) can become evident within 30 minutes of the first dose of buprenorphine/naloxone, reassess 30–60 minutes from the time of first dose.
   1. If withdrawal symptoms are adequately relieved after 1–3 hours: Day 1 is complete. Prescribe the same total dose for the following day.
   2. If withdrawal symptoms are not adequately relieved after 1–3 hours: Administer additional doses 2mg/0.5mg to 4mg/1mg at a time.
      • The Suboxone Product Monograph suggests a maximum total of 16mg/4mg buprenorphine/naloxone on Day 1. However, more recent clinical experience suggests that a higher maximum Day 1 dose may be needed to adequately address persisting withdrawal symptoms in people with high opioid tolerance, including those who use fentanyl.
      • If uncertain about the need for an additional dose, consider prescribing 2mg/0.5mg buprenorphine/naloxone tablets as take-home doses in case withdrawal symptoms occur later in the evening.
   3. If withdrawal symptoms are adequately relieved with additional dose(s): Day 1 is complete. Prescribe the same total dose for the following day.
   4. If withdrawal symptoms are not adequately treated with additional dose(s): manage withdrawal symptoms symptomatically (see step 5, below) while continuing to dose with buprenorphine/naloxone.
       
5. When needed, short-term symptomatic relief may be offered. For example:
   • Clonidine tablets (instruct patients to take 0.1–0.2mg every 4 hours PRN for <12 hours)

   • As-needed (PRN) oral anti-emetics, antidiarrheals, NSAIDs, or acetaminophen can also be considered

For challenging inductions (e.g., severe concurrent substance use disorders, challenging co-morbidities), referral to an inpatient withdrawal management program, community withdrawal management team, or a bed-based facility for induction can be considered.

1. Assess withdrawal symptoms to determine Day 2 starting dose.
   • If no withdrawal symptoms present since last dose: 
     • Continue a once-daily dose equal to the total amount of buprenorphine/naloxone administered on Day 1. 
     • When necessary, titrate up by 2mg/0.5mg–4mg/1mg buprenorphine/naloxone as needed. 
   • If withdrawal symptoms present since last dose:
     • Administer dose equal to the total amount administered on previous day, plus an additional 2mg/0.5mg–4mg/1mg buprenorphine/naloxone. 
2. Assess the presence of withdrawal symptoms at 2–3 hours after first dose.
   1. If symptoms are relieved 2–3 hours after first dose:
      • Day 2 is complete. Prescribe this total dose for the next day.
   2. If symptoms are not relieved 2–3 hours after first dose:
      • Give 2mg/0.5mg–4mg/1mg buprenorphine/naloxone every 1–3 hours as needed
        • According to the therapeutic range described in the Suboxone Product Monograph, the daily maximum dose of buprenorphine/naloxone is 24mg/6mg. However, this recommendation is based on data collected before the infiltration of fentanyl into the unregulated drug market. More recent data suggests that a daily dose of up to 32mg/8mg buprenorphine/naloxone may be reasonable and can be provided safely to address the high opioid tolerance of patients who use fantanyl.137
      • If patient has already reached the maximum daily dose of 32mg/8mg buprenorphine/naloxone and is still experiencing withdrawal symptoms, provide symptomatic management for the remainder of Day 2 (see Step 5, Day 1 above). 
      • If withdrawal symptoms are not relieved with initial or repeated buprenorphine/naloxone doses, it is important to confirm that tablets are being taken and/or administered correctly (i.e., placed under tongue, waiting for tablet(s) to dissolve completely, no swallowing, eating, drinking, or smoking until tablet has fully dissolved).
         
3. On the following induction days, if withdrawal symptoms, craving, or unregulated opioid use persists, continue dose increases as per the above schedule.
   • Titrate as needed by 2mg/0.5mg–4mg/1mg buprenorphine/naloxone at a time to achieve an optimal stable daily dose that can sustain an entire 24-hour dosing interval with no withdrawal symptoms and no medication-related intoxication or sedation. 
   • Hold buprenorphine/naloxone dose if intoxicated or sedated.
   • Historically, the typical therapeutic daily dose has been 24mg/6mg buprenorphine/naloxone per day. However, due to the prevalence of exposure to fentanyl and other highly potent synthetic opioids, daily doses of up to 32mg/8mg may be needed in some cases.137
      
4. Once optimal dose is achieved, follow up as needed.
    

A patient handout is available to help guide patients through home induction. General instructions 

• Wait until moderate withdrawal occurs to prevent precipitated withdrawal
  • At least 12 hours for short-acting opioids (e.g., heroin, hydromorphone, oxycodone)
  • At least 24 hours for intermediate-acting and slow-release preparations (e.g., slow-release oral morphine) or for confirmed or suspected fentanyl
  • At least 48–72 hours for methadone
• Do not use any opioids or other sedatives during initiation (e.g., alcohol, benzodiazepines, or z-drugs)
• Put the tablet(s) under your tongue and let them dissolve completely 
• Do not consume food or drink while the tablet is dissolving. Avoid smoking 
• Do not give up if symptoms persist after the initial doses. After taking 4 or more tabs, most people will start feeling improvement of withdrawal symptoms
• Return to care (specialist, general practitioner, or emergency department) if symptoms of precipitated withdrawal develop and you are unable to cope 
  • Prescribers should provide preliminary information on the possibility of precipitated withdrawal, its cause, and how to identify and manage it

For missed doses without return to full agonist opioid use, the following considerations are advised for patients who wish to resume buprenorphine/naloxone:

• 5 or fewer consecutive once-daily missed doses, without return to full agonist opioid use: 
  • No change in dose is required. Resume previous dose without dose reduction. 
  • The reasons for the missed doses should be discussed and documented at the next visit.  
• 6 or more consecutive once-daily missed doses, without return to full agonist opioid use: 
  • Buprenorphine/naloxone should be held pending virtual or in-person assessment, and the remainder of the prescription should be cancelled. 
  • Reasons for missed doses should be discussed and documented during the subsequent clinical visit, with attention to supporting the patient for better OAT retention. 
  • Re-titration is required. The re-titration process should be individually tailored; the goal is to re-titrate to previous stable dose within a few days. 

Table 11. Protocol for Missed Buprenorphine/naloxone Doses Without Return to Full Opioid Agonist Use 

For missed doses with return to full agonist opioid use, the following considerations are advised for patients who wish to resume buprenorphine/naloxone:

• One to three consecutive once-daily missed doses, with return to full opioid agonist use: 
  • No change in dose is required. It is likely safe to continue buprenorphine/naloxone without re-induction. 
  • The reasons for the missed doses should be discussed and documented at the next visit.  
  • The decision to continue buprenorphine/naloxone may also depend on additional factors, including the amount of the last buprenorphine/naloxone dose and the amount and time of the most recent full agonist use. 
  • Providers may seek specialist consultation to discuss patient-specific factors, particularly if the patient experiences significant discomfort upon resumption of medication.  
• Four consecutive once-daily missed doses, with return to full opioid agonist use:
  • Buprenorphine/naloxone should be held pending virtual or in-person reassessment, and the remainder of the prescription should be cancelled. 
  • Reasons for missed doses should be discussed and documented during the subsequent clinical visit, with attention to supporting the patient for better OAT retention. 
  • Clinicians should discuss the risk of precipitated withdrawal with the patients and weigh them against the benefits of continuing buprenorphine/naloxone. Less experienced providers are encouraged to first contact RACEapp or 24/7 Addiction Medicine Clinician Support Line to discuss patient-specific factors in order to select between resumption and re-titration of buprenorphine/naloxone. For patients who prefer to continue buprenorphine/naloxone, a test dose and plan for managing precipitated withdrawal should be discussed. 
• Five or more consecutive once-daily missed doses, with return to full opioid agonist use:
  • Buprenorphine/naloxone should be held pending virtual or in-person reassessment, and the remainder of the prescription should be cancelled. 
  • Reasons for missed doses should be discussed and documented during the subsequent clinical visit, with attention to supporting the patient for better OAT retention. 
  • A new induction may be required; proceed as described in Low-dose or Traditional Induction, above. 

Table 12. Protocol for Missed Buprenorphine/naloxone Doses with Return to Full Opioid Agonist Use 

• For missed doses with an alternating day schedule, follow missed doses protocol above. Patients should be returned to a daily dose schedule, possibly at a lowered dose, to re-stabilize prior to resuming an alternating day schedule.

This section provides brief guidance on dosing and administration of extended-release buprenorphine in reference to the Sublocade Product Monograph.475 The manufacturer of Sublocade requires that all prescribers interested in prescribing Sublocade complete training through www.sublocadecertification.ca. The manufacturer’s website provides additional information on Sublocade.

• Patients should generally be inducted and stabilized on sublingual buprenorphine/naloxone (8–24mg/day) for a minimum of 7 days prior to receiving extended-release buprenorphine. 
  • Qualifying note: While the product monograph requires a 7-day stabilization on buprenorphine/naloxone prior to extended-release buprenorphine initiation,475 emerging evidence supports the feasibility of a more rapid transition to extended-release buprenorphine, which may facilitate treatment retention.476,477 
• Patients starting extended-release buprenorphine should be prescribed 300mg for the first two months, followed by a maintenance dose of 100mg/month from the 3rd month.
  • Qualifying note: According to recent updates to the product monograph, patients who have been stable on 8mg/2mg–18mg/4.5mg of sublingual buprenorphine/naloxone may begin to receive their maintenance dose of 100mg/month once a month after a single induction dose of 300mg. 
• Prescribers may consider providing supplemental sublingual buprenorphine/naloxone for patients who continue to experience opioid withdrawal and cravings. 
  • There is evidence of significant fluctuation in plasma concentration and mu opioid receptor occupancy prior to reaching stability on extended-release buprenorphine.1 This may result in the emergence or persistence of some withdrawal symptoms in the initial months of treatment, which can be addressed with sublingual buprenorphine/naloxone top off.
  • Prescribed supplemental dosing should be determined on a case-by-case basis and may vary over time. A 2021 case series (n=40) reported supplemental sublingual doses ranging from 4mg to 24mg as needed in 25% of participants.476
• At the discretion of the treating prescriber, the maintenance dose may be increased to 300mg/ month if the patient experiences ongoing opioid cravings or ongoing unregulated opioid use. 
  • In published clinical trials, the 300mg/month maintenance dose did not provide additional efficacy compared to the 100mg/month dose, and was associated with a higher incidence of adverse events and study discontinuations.125 However, one study comparing the benefits of 300mg and 100mg monthly extended-release buprenorphine found that, although there was no difference in efficacy for participants who did not inject drugs, the 300mg/month  dose was associated with higher rates of treatment retention and abstinence from unregulated drug use specifically among participants who injected drugs.478 A 2021 case series (n=40) examining the process and outcomes of treatment with Sublocade in a low-threshold clinic also reported that 25% of patients were receiving a maintenance dose of 300mg/month.476 More research is required to characterize the effectiveness of higher doses among individuals with established opioid tolerance who inject opioids.
• Extended-release buprenorphine doses must be administered monthly. A minimum length of 26 days is required between doses. (See Missed extended-release buprenorphine doses for guidance on addressing delays)

A sample prescription for extended-release buprenorphine is provided below.

Notes: 

• Administration of extended-release buprenorphine can be performed by an MD, NP, pharmacist, or nurse (RN, RPN, or LPN) 
• Prescribers can consider indicating the date of administration/clinic appointment on the prescription
• To avoid errors, best practice is to write “sub cut” or “subcutaneously”1 on the prescription
• Prescription may be written as a partfill, for example: “600mg six hundred, inject 300mg subcut once a month as a single dose by MD x 2 months (May, June), dispense 300mg in 25- to 30-day intervals.” 
• To avoid errors, the reduction in dose to 100mg after two months should be written as a separate prescription, ideally after reassessment
   

• Up to 2 weeks delay in monthly injection (i.e., up to 42 days after last dose): Occasional delays of up to 2 weeks are not expected to significantly impact treatment effect. If a patient misses a monthly extended-release buprenorphine injection, they should receive their next dose as soon as possible, and monthly injections should be resumed thereafter. 
• More than 2 weeks delay in monthly injection (i.e., >42 days after last dose): Re-induction is warranted. Patient should be restarted on sublingual buprenorphine/naloxone followed by a rapid transition to extended-release buprenorphine (see General initiation and dosing information above).