We describe a group of patients, highly tolerant to opioids and actively using illicit fentanyl, who were hospitalized for rapid methadone (+/- SROM) titration. Admissions to hospital for primary OAT titration are available only to pregnant patients in our geographical area. Therefore, this is a unique population where admissions for primary OAT titration in an inpatient setting are possible. The population identified in this study had evidence of psychosocial instability: over 50% were homeless, almost half were not partnered, and over 90% were unemployed and/or on social assistance. All women were actively using fentanyl via injection. To our knowledge, this represents the first case series of patients using fentanyl in pregnancy in which OAT was rapidly titrated, complementing a recent case study showing feasibility of this method of titration(17).
There is an emerging concern that current methadone guidelines internationally are inadequate to retain patients in care and reduce their illicit substance use, especially in light of the increase in highly potent fentanyl analogues (25). It is also felt that patients who use fentanyl are even less likely to experience methadone toxicity because of a high degree of opiate tolerance(26). Fentanyl is associated with an increase in overdose deaths, and higher doses of methadone may be more protective against overdose death(27). Furthermore, higher doses of methadone (considered to be > 80mg/day) have been associated with reduced illicit drug use in non-fentanyl using pregnant populations(28). In pregnancy, doses over 60 mg of methadone are associated with better treatment retention and reduction in illicit substance use(29), however these data are not available for primarily fentanyl-using populations. It is reasonable to assume that higher doses may be required in fentanyl-using populations. Therefore, there is an urgent need for protocols that will allow rapid titration of methadone and full-opioid agonists that will stabilize patients on methadone equivalents in the 60–80 mg range as a minimum. Our protocol demonstrates that in an inpatient-setting we are able to exceed or meet this target more rapidly than as an typical outpatient titration would allow.
Guidelines, both national and international, have similar recommendations for initial dosing of methadone for opioid use disorder. Dose initiation in the WHO guidelines is suggested to be much lower than our local guidelines, with starting doses of less than 20 mg recommended (30). Local protocols for methadone titration in Canada, suggest an outpatient starting doses of 10-30mg with subsequent dose increases up to 10mg every 3–5 days (31). Locally, the fastest titration to a dose of 80mg of methadone requires a minimum of 15 days. It is often also difficult to get patients to a therapeutic dose of methadone due to limitations in outpatient protocols including missed doses, and missed appointments for titration. As such, many patients are maintained on subtherapeutic doses below 60–100 mg, which impacts continuation of OAT (30). Previous cases reported by our group have highlighted novel approaches to OAT where methadone and SROM were rapidly titrated (15–18). These rapid initiation and titrations have been reported in a non-pregnant patient as well as in pregnancy. Like these cases, there were no documented adverse events within this cohort of rapid titrations based on review of the medical charts, including no doses withheld secondary to sedation, respiratory suppression or overdose, and no in-hospital complications. All women remained in hospital for at least 7 days.
Treatment retention is challenging with patients with severe opioid use disorder. In non-pregnant patients, younger age, specific substance used (cocaine and heroin), lower doses of methadone, criminal activity or incarceration, and negative attitudes towards methadone are associated with reduced retention(32). Overall, methadone is associated with longer treatment retention and fewer relapses when compared to nonpharmacologic therapy, especially at doses greater than 60–80 mg daily(14, 30, 33, 34). Rates of discontinuation of OAT in pregnancy are generally cited to be in the 0–33% range and are higher in the post-partum period(34). In this study, discontinuation, as measured by the number of patients initiated on OAT in hospital and presenting in labour on OAT, was high in our patient population. Further research is needed to determine whether a) patients using fentanyl have higher discontinuation rates (particularly on doses < 80mg of methadone) and b) whether patients who inject drugs may have higher discontinuation rates as well. It is possible that these two factors play into the discontinuation rates seen in this study, but also the lack of housing, minimal financial and social supports may also play into the rates of discontinuation.
This is a descriptive study which describes a small number of cases, adding to three cases previously published in pregnancy(15–17) and one case in a non-pregnant individual(18). Limitations of this study include important pharmacokinetic considerations in pregnancy, with the physiologic changes in pregnancy impacting methadone dosing(35, 36). Specifically, methadone clearance increases in the third trimester which can cause withdrawal symptoms necessitating a dose increases as the pregnancy continues(35). The generalizability is low, given the availability of on-demand beds specifically for the purpose of rapid methadone titrations are rare and highly experienced inpatient addiction medicine clinicians are not available routinely in acute care hospital. We acknowledge that the treatment in these cases was not in keeping with current guidelines locally or internationally. However, given the increasingly toxic illicit opioid supply and associated morbidity and mortality, trialing aggressive and novel treatment approaches in a monitored, acute care setting is warranted. There is no proposed protocol of how to titrate unstable pregnant women who are actively using fentanyl effectively on opiate agonist therapy.