A3.4 Slow-release Oral Morphine-specific Guidance
Slow-release oral morphine (SROM; brand name Kadian) is a long-acting, 24-hour formulation of oral morphine available in BC to treat opioid use disorder. Like methadone, SROM does not have a ceiling effect, requiring a similar level of monitoring during initiation to ensure patient safety.
In the absence of clear, evidence-based clinical treatment protocols established for slow-release oral morphine, the guidance in this document is based on clinical experience and expert clinical consensus. It is important to note that only the once-daily, 24-hour formulation of slow-release oral morphine has been studied in clinical trials for the treatment of opioid use disorder. Other formulations of oral morphine, such as twice-daily, 12-hour sustained- or extended-release formulations (brand name M-Eslon), have been used in BC in response to shortages of SROM and the need for expanded harm reduction measures across the province.484 However, these formulations have not been empirically studied in the context of OAT and are not recommended by this committee for treatment of opioid use disorder. The BCCSU’s Risk Mitigation in the Context of Dual Public Health Emergencies and the Opioid Use Disorder Practice Update provide guidance on prescribing M-Eslon as a harm reduction intervention.
A3.4.i Assessment
Slow-release oral morphine-specific contraindications
- Hypersensitivity to morphine sulfate or any component of the formulation
- Known or suspected paralytic ileus
- Currently taking monoamine oxidase inhibitors (MAOIs) or use within past 14 days
- Severe respiratory compromise or obstructive disease
- Chronic kidney disease
Cautions
- Adrenal insufficiency
- Gastrointestinal issues (e.g., obstruction, diarrhea, abnormal gut anatomy) that affect the amount of time medication remains in the stomach
- Pregnancy or breastfeeding
- People who are stable on SROM when they become pregnant should be informed that switching between OAT options during pregnancy and post-partum periods is generally not recommended. For patients starting OAT during pregnancy, SROM should only be considered when other OAT options are deemed inappropriate; this is due to the comparatively small body of literature supporting the use of SROM for this population.485
- People who are stable on SROM when they become pregnant should be informed that switching between OAT options during pregnancy and post-partum periods is generally not recommended. For patients starting OAT during pregnancy, SROM should only be considered when other OAT options are deemed inappropriate; this is due to the comparatively small body of literature supporting the use of SROM for this population.485
Additional prescribing considerations
Prescribers and pharmacists should be aware that that co-prescription of naltrexone and Kadian for OAT will not be automatically flagged by PharmaCare, due to the use of a PIN for Kadian. Additional caution should be exercised to ensure that these medications are not co-prescribed. Naltrexone is contraindicated for patients receiving SROM as it blocks the effect of opioids and may precipitate withdrawal.
A3.4.ii Pharmacology
- Slow-release oral morphine is administered via once-daily oral doses
- Slow-release oral morphine is released over 24 hours
- Peak plasma levels are achieved within 8.5 to 10 hours
- Elimination half-life: The terminal elimination half-life of morphine following a single dose of slow-release oral morphine administration is approximately 11 to 13 hours. However, this is primarily due to the delayed absorption of the pellets. Once absorption is complete, the plasma elimination half-life is the same as immediate-release morphine (2 to 4 hours)
A3.4.iii Initiation and Dosing
Administration
- Slow-release oral morphine capsules can be provided whole to be swallowed. Alternatively, based on patient preference or clinician assessment, the pellets contained in the capsule may be sprinkled into a cup for immediate ingestion.
- Slow-release oral morphine pellets must be swallowed whole. Crushing, chewing, or dissolving capsules or pellets can cause rapid release and absorption of a potentially fatal dose of morphine sulphate.
- Following the ingestion of SROM, drinking water is preferred to acidic beverages (e.g., cola, sparkling water, coffee, orange juice), as acidic liquids may affect the absorption kinetics of the medication.
Initiation
- Because of the sustained-release properties of slow-release oral morphine (see Pharmacology section above), dosage increases should generally be separated by at least 24 hours.
- For individuals using unregulated opioids other than methadone, refer to dosing schedules below
Dosing schedules
There are a variety of dosing schedules described in the literature. The average (mean) daily SROM dose presented in the literature ranges from 235mg/day to 791mg/day, and the full range of SROM daily doses described is 60–1200mg. Clinical experience suggests that higher doses are often needed for many patients, especially in the context of fentanyl dominating the unregulated drug supply.
Clinical experience in BC indicates that the dosing and titration schedules described in the literature, while appropriate for patients requiring a more conservative titration, are often too conservative to retain patients in care. Depending on the patient’s level of opioid tolerance, starting doses as high as 300mg are commonly used, with increases of up to 100mg every 24 to 48 hours. Suggested starting doses based on opioid tolerance are provided in Table 17.
Table 17. SROM Starting Doses Based on Patients’ Opioid Tolerance.
| Level of tolerance | Suggested starting dose |
|
No/low tolerance | opioid-naïve
Includes patients who have completed withdrawal management, those not currently using opioids but at risk of relapse, patients with heavy use of other sedating agents, and patients with severe comorbidities that affect toxicity risks |
50mg/day |
|
Unknown/moderate tolerance
Includes patients who use benzodiazepines or other sedatives (prescribed or unprescribed), patients with alcohol use disorder |
100¬–150mg/day |
|
Known high tolerance
Patients actively using opioids |
200mg/day |
|
Known very high tolerance
Characterized specifically by previous SROM experience and current fentanyl use |
300mg/day* |
| *Higher doses may be considered with caution on a case-by-case assessment of risks and benefits; rationale for higher doses should be documented and patient’s informed consent should be obtained. | |
The example protocol provided below is based on clinical experience and expertise, and is intended for individuals with known tolerance who are currently using opioids. To date, there is an absence of evidence to guide titration schedules for slow-release oral morphine. Clinical judgement based on individual circumstances should determine which titration protocol is used and frequent assessment should determine whether titration should be maintained, slowed, or sped up.
A patient should be assessed prior to dose increases. Where appropriate, virtual assessment may be considered. Clinicians are encouraged to consult the 24/7 Line or RACE app when determining a titration protocol.
Table 18. Sample SROM Titration Schedule
| Day | SROM dose (moderate tolerance) |
| 1 | 200mg |
| 2 | 300mg |
| 3 | 400mg |
| 4 | 500mg |
| 5 | 600mg |
| 6 | 700mg |
| 7 | 800mg |
There is no defined maximum dose for slow-release oral morphine. The highest dose described in the literature to date is 1200mg216; however, clinical experience indicates that patients often require doses above 1200mg to manage cravings and withdrawal symptoms, due to high tolerance developed due to sustained exposure to fentanyl through the unregulated drug supply.217 Prescribers should use caution with respect to side effects when prescribing above 1200mg and clearly document the rationale for doses above 1200mg. Patients should be assessed for sedation with dose increases.
For SROM prescriptions, it is no longer necessary to write “for OAT” in the Directions for Use Field if the information in the OAT shaded section indicates clearly that the prescription is for OAT. This ensures that it will be correctly entered into PharmaNet using the Product Identification Number (PIN), which indicates slow-release oral morphine is used for OAT rather than analgesia. Clinical discretion and individual circumstances should determine which titration protocol is used and frequent assessment should determine whether titration should be maintained, slowed, or sped up.
Switching from methadone oral solution to slow-release oral morphine:
- No wash-out of previous treatment is required (to minimize potential for withdrawal symptoms). Withdrawal symptoms may recur temporarily during the switch-over period.
- Determining the slow-release oral morphine dose will depend on the current methadone dose. Generally, a ratio of 1:6 to 1:8 (methadone: SROM) can be used to determine dose. Clinicians are encouraged to consult the 24/7 Line or RACEapp for case-based support to determine conversion ratio for patients receiving high methadone doses or those who use additional unregulated opioids.
- See Methadone to Slow-release Oral Morphine, below
A3.4.iv Stabilization
The goal is to stabilize the once-daily dose at the lowest dose that relieves withdrawal symptoms and suppresses unregulated opioid use. Currently, there is no published literature to guide treatment decisions beyond the 36-week duration of clinical trials. The guideline committee supports following similar stabilization and tapering practices as those used for methadone and buprenorphine/naloxone
A3.4.v Missed Doses
Despite delayed absorption, the underlying short morphine half-life results in the potential for rapid loss of tolerance following missed doses and the possibility of harmful over-sedation or overdose. To mitigate this, prescribers should work very closely with pharmacists regarding missed doses and daily patient assessments.
To avoid overdose as a result of lost tolerance, BC pharmacists are required to notify prescribers of missed doses and clinicians must review and document PharmaNet profiles. Under current regulations, the dispensing pharmacy is also required to cancel the prescription if the patient misses 4 consecutive days of SROM, and notify the prescribing clinician.
In the absence of established evidence-based protocols, approaches to dealing with missed SROM doses are based on expert opinion and local clinical experience. Since this medication was a relatively new addition to the province’s continuum of OUD care, previous BC guidelines provided a conservative protocol for addressing missed SROM doses, recommending that dose reductions be considered after 2 missed dose. However, increasing clinical experience with SROM has informed the revision of this protocol in order to minimize treatment disruption. This guideline endorses the resumption of the patient’s usual dose after 3 consecutive missed once-daily doses. An assessment for dose reduction should be conducted after 4 consecutive missed once-daily doses, and titration should be restarted after 5 or more consecutive missed once-daily doses, as outlined below.
- One to three consecutive once-daily doses missed: No change in dose is required, as long as there is no other reason to withhold SROM. The reasons for the missed doses should be discussed and documented at the next visit.
- Four consecutive once-daily doses missed: Slow-release oral morphine 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, and patients should receive advice and support for removing perceived barriers to taking SROM doses as prescribed. Following assessment, SROM may be restarted at 50% of previous dose or the patient’s initiation dose, whichever is higher (see Table 19).
- Five or more consecutive once-daily doses missed: Slow-release oral morphine 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. Restart at the patient's initiation dose and titrate as needed according to guidelines. If clinical judgement indicates adjustments to the pace of re-titration (e.g., a more aggressive pace for patients who were on a high dose of SROM within the past 4–7 days or those who have continued using unregulated opioids), prescribers may seek specialist consultation. Additionally, patients should discuss the risks of more rapid titration schedules with patients, obtain verbal consent, and plan for frequent re-evaluations until the patient is stable.
Clinicians should address missed doses on a case-by-case basis, and may use a modified approach in consideration of individual factors that affect opioid tolerance. In determining dose adjustments after missed doses, clinical judgment must take into account:
- Total daily dose
- Number of missed doses
- Possibility of diversion
- Other opioid use during periods of missed dosing
- Type and amount of opioids used most recently
- Previous experience with SROM treatment
Consultation with the patient about past experiences with missed doses, restarts, and other similar circumstances is crucial in determining an appropriate missed dose schedule for each patient.
Table 19. Suggested Protocol for Managing Missed SROM Doses
| Number of consecutive missed once-daily doses | Action | Explanation | Example |
| 1-3 | No action | Up to three consecutive once-daily doses can be missed without a dose change. This means on the 4th day since the last dose, the person can receive their full dose. | Anne gets her regular dose on Monday, and then misses Tuesday, Wednesday, and Thursday. When she arrives at the pharmacy on Friday, she receives her normal dose. |
| 4 | Cancel prescription. Reassess. Can restart at 50% of dose* or initiation dose (whichever is higher) | Missing 4 consecutive once-daily doses requires the dose to be reduced by half or to the initiation dose. This means on the 5th day since the last dose, the person could receive 50% of their dose or their initiation dose following assessment by the prescriber. | Nish gets his regular dose on Monday, and then misses Tuesday–Friday and goes to the pharmacy on Saturday. His prescription must be cancelled. If he can see his prescriber today, he can resume his dose at 50% or at his initiation dose. |
| 5+ | Cancel prescription. Reassess. Restart titration. | Missing 5 or more consecutive once-daily doses requires the titration to be restarted. This means on the 6thday since the last dose, the person must restart titration following assessment by the prescriber. | Zola gets her regular dose on Monday. She then misses Tues–Saturday. When she returns to pharmacy on Sunday, she is told she must see her prescriber again to restart her SROM titration. |
| *For patients whose risk of lost tolerance is assessed to be lower (e.g., those who have continued using other opioids since last SROM dose), a smaller dose reduction may be considered after individualised assessment of risks, benefits, and safety considerations. On the other hand, a more conservative dose adjustment schedule may be considered for individuals who have not used unregulated opioids since their last SROM dose. | |||
The above appendix was developed to support clinical practice using a different methodology from the process utilized for the main body of the guideline.
The clinical guidance provided in the appendix has been derived through guideline committee consensus following iterative discussions in reference to existing evidence and national and international evidence-based clinical practice guidelines.
- The content presented in the appendix is also informed by the opinion of expert reviewers, personal communication with study authors, and a review of position papers and practice bulletins issued by recognized addiction medicine professional organizations and authorities. In addition, where appropriate, Health Canada-approved drug product monographs, and previous and current guidance from the College of Physicians and Surgeons of BC (CPSBC) and Health Canada were consulted to ensure compliance with provincial and national safety regulations and standards for practice.