Attention Ontario Drug Benefit Program:

This letter is signed and endorsed by addiction clinicians affiliated with various organizations and clinical services. The letter requests that the Ontario Drug Benefit (ODB) program list extended-release buprenorphine (buprenorphine ER, or Sublocade), as a General Benefit rather than a Limited Use product.    

We commend ODB’s coverage of this critically important medication. However, we are concerned that the Clinical Criteria under the LU code, and its interpretation and enforcement, are significant obstacles to the optimal and evidence-informed use of buprenorphine ER and a barrier to continuity of care.

The benefits of buprenorphine ER are summarized below:

●        Treatment adherence: Buprenorphine ER has an extremely long duration of effect. Injections are typically given once every 28–42 days, which makes it a useful option for patients who have difficulty attending the pharmacy daily. In contrast, if a patient on methadone misses their daily observed dose for several consecutive days, the prescriber lowers the dose to avoid toxicity, resulting in subtherapeutic doses and a high chance of relapse and treatment drop-out.

●        Efficacy: Buprenorphine ER produces a much higher and steadier buprenorphine level than sublingual buprenorphine/naloxone (buprenorphine SL), potentially making the former more effective at relieving withdrawal symptoms and retaining patients in treatment. In a multi-site, open-label, 24-week trial (Marsden 2023), 314 patients with opioid use disorder were randomized to receive either buprenorphine ER or standard of care treatment with methadone or buprenorphine SL. The buprenorphine ER group had more opioid-abstinent days and a higher treatment retention rate. This result is consistent with other studies (Lee 2021, Nunes 2024).

●        Overdose prevention: Buprenorphine blocks the attachment of other opioids to the receptor. In a preclinical study of opioid-tolerant volunteers given intravenous fentanyl and different doses of intravenous buprenorphine, high buprenorphine plasma levels (similar to those produced by buprenorphine ER) prevented respiratory depression more effectively than lower levels (such as those produced by buprenorphine SL) (Moss 2022). Preventing respiratory depression prevents death from opioid overdoses. In a retrospective cohort study conducted in London, Ontario, patients on buprenorphine ER had significantly lower rates of non-fatal overdose than those on methadone (Lee 2023). Buprenorphine SL also blocks the opioid receptor for 24 to 48 hours, whereas with a single buprenorphine ER injection, buprenorphine remains in the body for several weeks.

Recovery: Clinicians are reporting that because buprenorphine ER is administered monthly rather than daily, many of their patients have been able to resume a fully engaged life involving work, school, and family.  
●        Misuse and diversion: Buprenorphine ER is administered by a health care professional, eliminating the possibility of misuse and diversion.  In contrast, unobserved doses of buprenorphine SL and methadone can be diverted and injected. Notably, diverted methadone can cause a fatal overdose if taken by a non-tolerant individual.  

We believe that the current LU criteria do not reflect evidence-informed strategies for optimal use of this medication during our ongoing opioid crisis.  Our concerns about three of the criteria are summarized below:

1.       “A minimum of 26 days is required between consecutive doses.”  

There are clinical circumstances where a dose of buprenorphine ER is appropriate before the 26-day mark. In our clinical experience, patients who are on buprenorphine ER for fentanyl use sometimes experience cravings and withdrawal symptoms earlier than 26 days, especially in the first few months of treatment. These patients are at high risk of relapse and treatment discontinuation if they do not get prompt relief of their symptoms. We are also aware that on occasion, pharmacists decline to dispense buprenorphine ER earlier than 26 days even if the prescriber indicates that they approve early administration. This is likely due to their concern that ODB will not reimburse the pharmacist for the medication if it is dispensed early.

It appears that many prescribers are attempting to manage post-dose withdrawal symptoms with buprenorphine SL. In a population-based study of buprenorphine ER use in Ontario (Iacono 2023), 52% of the 2633 patients who received buprenorphine ER had at least one prescription for buprenorphine SL. It is likely that a portion of these prescriptions were intended to relieve withdrawal symptoms and cravings caused by a declining serum buprenorphine level several weeks post-dose. This practice is almost certainly less effective at retaining patients in treatment than administering buprenorphine ER early; buprenorphine ER produces a much higher plasma buprenorphine level than the SL product. Furthermore, dispensing take-home tablets of SL buprenorphine increases the risk of diversion and injection and increases the burden on pharmacists.  

2.       “Maintenance dose may be increased to 300 mg/month only if the patient does not demonstrate satisfactory clinical response to the 100 mg dose.” 

The pivotal phase 3 trial that informed the buprenorphine ER product monograph concluded that the 300 mg maintenance dose was not more effective than the 100 mg dose; however, the trial took place before fentanyl began to dominate the unregulated opioid market. There is emerging evidence that the 300 mg dose is more effective for people who use fentanyl. Two recent studies, an open label trial (Marianni 2024) and a retrospective cohort study (Marion-Bellemare in prep), both found that a maintenance dose of 300 mg had good treatment retention among people who use fentanyl. In the population study cited above (Iacono 2023), 47% of the patients were maintained on the 300 mg dose, suggesting that the 100 mg dose is often insufficient.

A double-blind randomized trial comparing treatment retention rates of the 100 mg versus the 300 mg maintenance dose is currently underway. In the meantime, we are concerned that the current criterion is resulting in clinicians prescribing the 100 mg dose even when the 300 mg dose would likely be more effective. For example, a 300 mg maintenance dose would probably be more effective than a 100 mg dose in a patient who has reduced but not stopped their fentanyl use and still reports cravings. While the criterion does permit clinicians to raise the dose to 300 mg, the dose reduction could cause people with very high opioid tolerance from fentanyl use to relapse and discontinue treatment before their dose is raised.

This change would not increase costs, as the formulary costs of the 300 mg and 100 mg dose are the same.

3.       “The patient has been induced and is stabilized on an equivalent of 8 to 24 mg of transmucosal buprenorphine per day for a minimum of seven days.”

Several open-label studies have demonstrated that it is safe to administer buprenorphine ER in an emergency department (ED) or hospital setting within a day or two of admission (Marianni 2024, Hassman 2023). As explained above, evidence suggests that people who use fentanyl are more likely to engage in treatment if they receive buprenorphine ER in a hospital setting than if they are given a discharge prescription for daily buprenorphine SL (Marsden 2023, Lee 2021, Nunes 2024).

A recently completed retrospective cohort study (Marion-Bellemare in prep) illustrates how clinicians have modified buprenorphine ER protocols for people who use fentanyl. The study analyzed charts of ninety people who use fentanyl that received buprenorphine ER while at Timmins General Hospital. The treatment retention rates at three, six, and twelve months were 58%, 44%, and 36% respectively; these rates are excellent considering that the patients attending the ED were not necessarily seeking opioid agonist treatment. In the year following treatment initiation, 21.9%, 78.1%, and 77.1% had a reduction in non-fatal overdoses, ED visits, and hospital admissions respectively, compared to the year prior to treatment initiation.  

In this study, buprenorphine ER was not prescribed according to the LU criteria; all subjects received buprenorphine ER within one to two days while still in the ED or hospital. The authors report that all patients were maintained on the 300 mg dose, and many patients received doses earlier than 26 days apart.  

Recommendations:

We recommend that ODB list buprenorphine ER as a General Benefit. This will allow clinicians to use their own clinical judgment in prescribing buprenorphine ER. It should be noted that Alberta and BC public drug programs and the NIHB program list buprenorphine ER as a General Benefit.

If it is not possible to list buprenorphine ER as a General Benefit, then we recommend that either (a) the three LU criteria discussed above be removed, or (b) the LU Notes specify that clinicians should use their own judgment when prescribing buprenorphine ER to patients who inject or smoke fentanyl or other high-potency opioids. We also recommend that the ODB program inform all pharmacies that the clinical criteria listed for this medication is for clinical guidance only and will not be used for reimbursement decisions.

We understand that this will result in more doses being dispensed and a higher cost to ODB. Buprenorphine ER given earlier than 26 days is done only for patients at the highest risk, and clinicians report that patients usually extend the interval between doses once they are stable. The cost is likely to be modest and will be outweighed by savings in health care costs. A double-blind study (Marsden 2023) found that, despite higher medication costs, buprenorphine ER was cost-effective relative to methadone and buprenorphine SL. In a retrospective cohort study conducted at Timmins General Hospital, people who use fentanyl receiving buprenorphine ER in the ED had a marked drop in ED visits in the year following their injection compared to the year before, indicating a decrease in health care costs (Marion-Bellemare in prep).

We understand that the LU criteria are taken directly from the product monograph, but the product monograph was written well before fentanyl became prevalent in the unregulated opioid supply.

Thank you for considering this request.  We would be pleased to meet with you to discuss this further.  We would ask that you review this request urgently, as we believe that the current LU criteria are impeding the effective use of buprenorphine ER, without any compensating safety or cost benefit.  

Sincerely,                                                                                                  

Meldon Kahan, Medical Director, META:PHI; Katie Dunham, Nursing Educator, META:PHI; Hasan Sheikh, Assistant Professor, University of Toronto Department of Family and Community Medicine; Ainko Ramanathan, Clinical Pharmacist, Niagara Health System Hamilton