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. Author manuscript; available in PMC: 2023 Jul 14.
Published in final edited form as: J Subst Abuse Treat. 2020 May 11;115:108031. doi: 10.1016/j.jsat.2020.108031

One year of methadone maintenance treatment in a fentanyl endemic area: Safety, repeated exposure, retention, and remission

Andrew C Stone a,*, Jennifer J Carroll b, Josiah D Rich c, Traci C Green d
PMCID: PMC10347815  NIHMSID: NIHMS1893788  PMID: 32600619

Abstract

Introduction:

Fentanyl is a potent synthetic opioid that has contributed to increasing overdose deaths in the United States in recent years. Concern over safety and efficacy of agonist treatment for fentanyl use may limit access to treatment. This study sought to address these potential concerns in a naturalistic setting.

Objectives:

Measure 12-month treatment outcomes for methadone maintenance treatment (MMT) in a fentanyl endemic area.

Outcomes:

Primary: 1) Treatment retention; 2) sustained remission (defined as 3 consecutive negative screens); 3) return to use; 4) methadone dosage required; and 5) number of days to achieve remission.

Secondary:

Mortality.

Methods:

A naturalistic follow-up study and retrospective review of consecutive patients newly admitted to a single methadone maintenance treatment program in Rhode Island.

Results:

We observed 154 unique intake events (representing 151 patients). Eighty percent (n = 121) tested positive for fentanyl at intake. Seventy-five percent of patients achieved remission within the 12-month study period. One-year retention was 53% for fentanyl-exposed individuals and 47% for those not exposed. The majority (99%) of patients who remained in treatment at 12 months achieved remission. We saw prolonged, sustained remission in 44% of patients exposed to fentanyl at intake and 47% of those who were not. Dose and time to remission were similar. Unfortunately, 4 patients died after leaving MMT prematurely. Conclusions: This study suggests MMT is safe despite repeated exposure to fentanyl while taking methadone. Remission is achievable, and MMT is protective against death among fentanyl-exposed patients while in treatment.

1. Introduction

Fentanyl is a potent synthetic opioid that has contributed to the rate of fatal overdose in the United States in recent years (O’Donnell, Halpin, Mattson, Goldberger, & Gladden, 2017; Rudd, Aleshire, Zibbell, & Gladden, 2016; Somerville et al., 2017; O’Donnell et al., 2018). In many areas of the United States, fentanyl is now the most commonly seized illicit opioid (DEA, 2018). In 2018, 71% of overdose deaths in the U.S. state of Rhode Island were fentanyl-involved (Marshall et al., 2017; RI OD Taskforce, 2019). This high prevalence of fentanyl in the local drug market is changing how users of illicit opioids in Rhode Island talk about opioid use and treatment-seeking behavior for opioid use disorder (Carroll, Marshall, Rich, & Green, 2017). We hypothesize that changing patterns in the local drug market and opioid consumption practices are affecting the treatment trajectory of individuals who seek and receive medication for opioid use disorder (MOUD) (Wakeman, 2017).

Methadone maintenance treatment (MMT) is an evidence-based treatment for opioid use disorder (Mattick, Breen, Kimber, & Davoli, 2009; Nielsen et al., 2016; Nielsen, Bruno, Degenhardt, Demirkol, & Lintzeris, 2017). A retrospective chart review of 368 MMT patients in Wayne County, Michigan, found that nearly 40% of patients had at least one fentanyl-positive urine drug test result during the 16-month follow-up period (Arfken, Suchanek, & Greenwald, 2017). Fentanyl continues to be present in the intake screens of patients seeking treatment for opioid use disorder in the Northeast U.S. and elsewhere (Gryczynski et al., 2019; Kenney, Anderson, Conti, Bailey, & Stein, 2018).

Our prior study (Stone, Carroll, Rich, & Green, 2018) described the prevalence of fentanyl among individuals starting MMT for opioid use disorder in a single treatment center in northern RI. The study evaluated outcomes for MMT in patients presenting with fentanyl exposure for a follow-up period of 6 months. Since then, Wakeman and colleagues published a similar study evaluating treatment outcomes among fentanyl-exposed participants in a buprenorphine-based MOUD program over a follow-up period of 6 months (Wakeman et al., 2019). That study found that treatment retention and ability to achieve remission among fentanyl-exposed patients in the buprenorphine program was not worse than patients who were unexposed to fentanyl at treatment initiation.

Clinicians and administrators may have concerns about the safety and efficacy of agonist treatment for fentanyl use (especially frequent, persistent use during agonist treatment) due to fear of overdose; this may limit access to treatment (Bisaga, 2019). This study sought to address these potential concerns in a naturalistic setting.

2. Objective

The study presented here extends previously published findings (Stone et al., 2018) by examining intake toxicology and 12-month treatment outcomes (including number of repeat fentanyl exposures while in treatment) for patients newly admitted to a single methadone maintenance treatment program (MMTP) in a fentanyl-endemic area of Rhode Island. Clinicians and administrators may use these results to relieve fears of overdose deaths while on MMT due to highly potent fentanyl and encourage continued participation in MMT despite frequent and/or continued use of fentanyl.

3. Methods

We conducted a naturalistic follow-up study and retrospective review of consecutive patients newly admitted to a single MMTP in a fentanyl-endemic area of Rhode Island between November 1, 2016, and August 31, 2017. Clinic practice was to conduct urine drug screening for all patients at intake into treatment and then randomly at least three times per month until achieving three consecutive tests without unexpected results (i.e., no opioids other than methadone present). Subsequent random screenings were conducted at least monthly. MMT staff performed confirmatory LC/MS testing at their discretion. Dosing nurses observed all urine testing via closed circuit camera. An outside lab used immunoassay to test urines (Clinical Science Laboratories, Mansfield, MA). We entered all toxicological testing results into the electronic medical record.

Treatment staff at the MMTP set methadone dosages for each patient by gradually adjusting dosing levels until illicit use was extinguished and cravings for use were reduced. New (i.e., nontransfer) patients who were assessed to be high tolerance were started at 30 mg on the first day, then titrated up 10 mg per day until 50 mg was reached, according to patient need. We considered further dose increases every 7 days. Dose increases did not exceed a total of 20 mg per week, as tolerated. Nursing assessed patients daily during induction.

Counselors were required to see new patients upon admission and for at least 1 h monthly while in treatment. Medical staff and counselors saw patients who continued to use more frequently (up to once per week) for methadone dose reviews. Staff reached out to patients missing doses by telephone. The study provided transportation to and from the clinic at no cost, if needed. Patients were automatically discharged from clinic if they missed 7 consecutive days of dosing. They could return immediately for intake upon request and there was no waitlist.

We followed all patients for a period of 12 months following initial intake. The medical director of the clinic performed data collection and data were anonymized. Study staff created a spread sheet to input data manually obtained from the electronic medical record on site.

Outcomes measured included: 1) retention in treatment at 12 months; 2) evidence of sustained remission (defined as three consecutive urine drug tests without unexpected opioids); 3) return to use (relapse), defined as the presence of an unexpected opioid (i.e., an opioid other than methadone) in a screen after having obtained three consecutive screens without unexpected opioids; 4) methadone dosage required to achieve sustained remission (defined as the dose dispensed on the date of the third consecutive screen without unexpected opioids); and 5) the number of days required to achieve remission.

A secondary outcome of this study is mortality. Treatment staff identified mortality when, as part of routine aftercare follow-up, former patients were called periodically to encourage re-engagement in treatment if needed and/or current patients informed the clinic. All reported deaths were verified by obituary records, and thus may be an underestimate.

We generated descriptive statistics to describe the demographics and treatment characteristics of the study population. We used Chi squared analysis to assess differences between groups, according to the results of intake drug screening, for all binary variables. We used Mann-Whitney tests to assess these differences in continuous variables (specifically, dosage at remission and days to achieve remission). Multiple logistic regression models considered factors putatively associated with attaining retention, achieving remission, subsequent fentanyl-positive urine screens, and relapse, controlling for patient demographics (e.g., age, gender). We performed survival analysis using Mantel-Haenzel log rank test for the days to remission.

The Institutional Review Board at the Miriam Hospital in Providence, Rhode Island, approved this study.

4. Outcomes

Primary outcomes included the following: 1) Treatment retention; 2) sustained remission; 3) return to use; 4) methadone dosage required; and 5) number of days to achieve remission. Secondary outcome was mortality.

5. Results

During the 10-month intake period, the MMTP observed 219 treatment admissions, representing 212 unique individuals. Of these, 57 patients were transfers from another treatment program and eight did not test positive for opioids at intake. These individuals were excluded from this analysis, resulting in 154 unique treatment intake events (representing a total of 151 unique patients who tested positive for opioids at these intake events) included in the current study (80% positive for fentanyl). We chose to exclude transfer patients from this study because many had been on stable doses for many years without illicit use, some may have been tapering their dose in consideration of completing treatment and we felt they would not represent the more concerning patients who came to clinic directly from acute illicit opioid use. If a patient had two admissions in the study period we studied only the later admission and followed for 1 year (n = 3).

All descriptive statistics are presented in Table 1. Patients were an average age of 37 years old (SD = 11); 61% were male, and 82% were white. There were no significant differences in demographics between those exposed to fentanyl at intake and those not. According to urine drug screens performed on the day of admission, 80% (n = 121) of these treatment initiates tested positive for fentanyl at intake. Of those, 50 individuals (32% of the entire study population) tested positive for fentanyl only with no other opioids detected. The remaining 20% (n = 30) of intakes had positive screens for opioids without evidence of fentanyl in the intake urine drug test.

Table 1.

Demographics and outcomes based on time spent in treatment on methadone maintenance. Less than one year (right side of table) was associated with poorer outcomes including increased mortality. Remission is defined as 3 consecutive screens with no unexpected opioid. Prolonged sustained remission is defined as continuous no evidence of fentanyl or illicit opioid use in last 6 months of MMT. Relapse is defined as a subsequent urine test containing an opioid (other than methadone).

Treatment ≥ 1 year
 Treatment < 1 year
Fentanyl Opiates Total Fentanyl Opiates Total
N = 64 (53%) N = 14 (47%) N = 78 (52%) N = 57 (47%) N = 16 (53%) N = 73 (48%)
Demographics
Age median (IQR) 38 (20)* 40 (9) 38 (19) 32 (11)*
*p = 0.002		 40 (22) 33 (14)
Gender % male (N) 67% (43) 50% (7) 65% (50) 56% (32) 56% (9) 56% (41)
Ethnicity % white non-Hispanic (N) 81% (52) 93% (13) 84% (65) 82% (47) 81% (13) 82% (60)
Intake urine drug test
 Benzodiazepines % (N) 19% (12) 7% (1) 17% (13) 12% (7) 13% (2) 12% (9)
p = 0.29 (NS) p = 0.98 (NS) p = 0.45 (NS)
 Cocaine % (N) 38% (24) 29% (4) 36% (28) 40% (23) 44% (7) 41%(30)
p = 0.53 (NS) p = 0.81 (NS) p = 0.51 (NS)
Fentanyl % (N) 100% (64) 0 (0%) 82% (64) 100% (57) 0 (0%) 78% (57)
NA NA p = 0.54 (NS)
Opiates % (N) 53% (34) 100% (14) 62% (48) 65% (37) 100% (16) 66% (53)
NA NA p = 0.15 (NS)
Oxycodone % (N) 22% (14) 14% (2) 21% (16) 5% (3) 31% (5) 11% (8)
p = 0.52 (NS) p = 0.03 p = 0.11 (NS)
Outcomes
Retention ≥ 60 days % (N) 100% (64) 100% (14) 100% (78%) 72% (41) 63% (10) 70% (51)
 Median days in treatment (IQR)* N/A N/A N/A 179 (159) 231 (94) 183 (132)
Remission
 Able to achieve remission % (N)* 98% (63) 100% (14) 99% (77) 71% (29/41) 70% (7/10) 71% (36/51)
p < 0.00001
 Days to remission - Median (IQR)* 64 (72) 66 (36) 63 (62) 77 (41) 80 (57) 77 (59)
 Dose of methadone (mg) at remission - Median (IQR)* 100 (68) 100 (39) 100 (60) 100 (68) 60 (35) 90 (61)
 Prolonged sustained remission 44% (28) 47% (7) 45% (35) N/A N/A N/A
Relapse
 Relapse after any period of remission % (N) 70% (44)** 43% (6)**
**p = 0.06 N.S.		 64% (50) N/A N/A N/A
 Mean, median fentanyl containing UDT (range)* 9,6 (1–40)*** 4,3 (0−20)***
***p = 0.02		 8,5 (0–40) 8,6 (1–27) 5,1 (0−23) 7,5 (0–27)
Mortality 0 0 0 7% (4) 0 5% (4)
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*

Remission and retention outcomes where calculated based on those who remained in treatment at least 60 days. Mantel-Haenzel log rank test for the days to remission (p = 0.97). UDT = urine drug test.

During the follow-up period, we retained 53% (n = 64) of individuals exposed to fentanyl at intake and 47% (n = 14) of those not exposed in treatment for the full 12 moths. Rates of retention in treatment were not significantly different. The majority (99%) of patients who remained in treatment at 12 months after intake achieved three consecutive urine drug screens with no unexpected results (i.e., remission), during the 1-year follow-up period, with no significant differences in rates of achieved remission between groups. Among those who remained in treatment for the full 12-month follow-up period, prolonged, sustained remission (defined as continuous no fentanyl or other illicit opioids in last 6 months of follow-up) was seen in 44% (n = 28) of patients exposed to fentanyl at intake and 47% (n = 7) of those who were not. Further, no significant differences were detected between those fentanyl-exposed and unexposed at intake in dose required to achieve remission (median = 100 mg for both groups) or time to remission from initiating treatment (median of 64 and 66 days for those fentanyl-exposed and -unexposed at intake, respectively).

Among all 151 unique individuals included in this study, 75% of patients achieved remission within the 12-month study period. Among only those patients who were retained in treatment at 12 months, 98% of fentanyl exposed at intake (n = 63) and 100% of those not exposed (n = 14) achieved remission during that time. Rates of remission were not significantly different across the intake groups regardless of the denominator used (the entire cohort or only those patients retained at 12 months). Unsurprisingly, staying in treatment for at least 12 months was associated with higher remission rates as compared with the total cohort (p < 0.00001), irrespective of drug screen results at intake.

Repeated fentanyl exposure while in treatment, as determined by positive results in subsequent (post-intake) urine drug tests, was slightly but not significantly more common in patients who were fentanyl-exposed at intake: over the 12-month follow-up period, 70% (n = 21) of patients not exposed to fentanyl at intake had at least one urine screen containing fentanyl after the initial intake screen, compared with 78% (n = 94) of those who were fentanyl exposed at intake (p = 0.42).

The number of fentanyl-present urine screens during the 12-month follow up period was also higher for the fentanyl-exposed group (mean = 9, median = 6, range 1–40) versus the nonexposed group (mean = 4, median = 3, range 0–20). Relapse to any illicit opioid use (including fentanyl) was less common in the group not exposed to fentanyl at intake compared with the patients who were fentanyl-exposed (43% versus 69%); however, this difference did not reach statistical significance (p = 0.07).

Despite frequent fentanyl exposures while in treatment, no deaths occurred in any individuals who were retained in treatment for the full 12 months. Among those individuals who completed intake but ceased treatment early, 4 are known to have died during the follow-up period (2.6% of the entire cohort, 5.5% of those who left treatment early). One of these showed poor attendance, stopped coming to the program, and died suddenly four weeks later at age 38. The second was forced to detox while incarcerated for 28 days in a neighboring state (where MOUD is not available in jails or prisons) and died suddenly one week after release from incarceration at age 32. The third left methadone treatment abruptly after multiple denied doses for presumed benzodiazepine intoxication and died 8 weeks later at age 25. The fourth dosed twice on methadone, never returned, and died 5 months later at age 32.

6. Discussion

This study explored treatment outcomes among individuals newly initiating MMT whose urine drug testing at intake indicated a reactive test result for opioids (with or without fentanyl onboard). No significant differences in rates of treatment retention, remission, or relapse were found between patients who presented at intake with positive screens for fentanyl or for other opioids only. Further, neither dosages required to achieve remission nor days to achieving remission were significantly different between these groups. We saw repeated fentanyl exposure in both groups of patients but appeared more frequently in those who were fentanyl exposed at intake. Continuous prolonged sustained remission from illicit opioid use was possible and observed in nearly half of patients in both groups who had no evidence of fentanyl or other opioid use in the last 6 of the 12-month study.

For the purpose of this study, we defined remission as 3 consecutive urine drug tests without the presence of unexpected opioids. This may represent a decrease in illicit use rather than true abstinence given the relative short half-life of fentanyl.

Return to use was common among all patients, and retention at one year was similar to and consistent with historical comparisons (Simpson, Joe, Brown, & Barry, 1997). These findings suggest that MMT remains a safe and effective treatment for OUD for all individuals—including those who are repeatedly exposed to fentanyl prior to and during treatment. In areas where fentanyl is endemic in the drug supply, if people remain in MMT, higher methadone doses may be needed to completely extinguish use; however relapse may be common and frequent, regardless of dose, due to the potency of fentanyl. It is important to note that a return to use may be less likely to result in a lethal event if patients are retained in care during relapse, and, as this study shows, many are also able to return to remission.

Continued fentanyl use and relapse are common in this cohort of methadone patients; however, many patients succeeded in achieving prolonged sustained remission. Further, no deaths occurred in this cohort while patients were retained on MMT. This study is further evidence that MMT is protective against mortality despite a potentially higher relapse rate in this cohort. Even if MMT is able to increase tolerance and prevent overdose deaths, our findings do not rule out the possibility that MMT may be insufficient to completely extinguish illicit opioid use in a fentanyl-endemic area. It is possible that the effect of fentanyl is less visible in this study cohort, as it is likely that many MMT patients, including those who did not test positive for fentanyl at intake, have been exposed to fentanyl due to its prevalence in the local drug supply. Further research is needed to explore these connections between the characteristics of the local drug market and the effectiveness of MMT for opioid use disorder.

Further research is needed to assess whether higher dosages of methadone are able to block the euphoric effects of fentanyl as well as whether the tolerance to respiratory depression effects remain robust. Animal studies have shown methadone to prevent respiratory depression where high dose morphine is administered in the presence of alcohol to mice treated with methadone for several days prior to receiving the challenge dose of morphine (Hill et al., 2016). This animal model indicates that methadone may be protective against respiratory depression despite repeated exposures to potent opioids including fentanyl; however, more research is required. Buprenorphine may have a greater protective effect against respiratory depression than methadone, although documenting compliance with treatment may make comparisons between the two treatment modalities difficult outside of a head-to-head clinical trial with directly observed dosing.

It bears noting that the only deaths observed during the follow-up period were seen in four individuals who left treatment prematurely. One of these deaths involved someone who likely lost tolerance to potent opioids while incarcerated in a neighboring state that does not offer MOUD in criminal justice settings. Given the promising reduction in mortality observed during a preliminary analysis of MOUD implementation in criminal justice settings in Rhode Island (Clarke, Martin, Gresko, & Rich, 2018; Green et al., 2018), it is likely that one of the four deaths could have been prevented had the patient been continued on treatment while incarcerated.

A large meta-analysis of studies prior to the current fentanyl epidemic concluded the mortality risk among opioid users during MMT is less than a third of those who leave treatment (Sordo et al., 2017). Other large studies, mostly predating the fentanyl epidemic, also showed mortality benefit from remaining on MOUD (Bahji, Cheng, Gray, & Stuart, 2019; Fugelstad, Stenbacka, Leifman, Nylander, & Thiblin, 2007; Larochelle et al., 2018; Wakeman, Larochelle, Ameli, et al., 2020.), especially for methadone and buprenorphine. The mortality benefit from naltrexone is less clear (Morgan, Schackman, Weinstein, Walley, & Linas, 2019; Wakeman et al., 2020). Treatment retention is hampered by multiple factors, such as homelessness and mental illness (Parpouchi, Moniruzzaman, Rezansoff, Russolillo, & Somers, 2017). Addressing factors to improve treatment retention will likely help decrease overdose deaths and improve outcomes for those exposed to fentanyl, but more research is warranted.

7. Conclusion

While there is concern that the potency of fentanyl may reduce the effectiveness of MOUD, this study suggests that MMT is safe despite frequent subsequent exposure to fentanyl while on MOUD. Remission is achievable, and MMT is protective against death among fentanyl-exposed patients while in treatment.

8. Limitations

All of these findings were limited by population size and the length of the follow-up period. The patient population at the MMTP that participated in this study may not be representative of methadone patients in other regions. The data presented here should be interpreted with these considerations in mind.

Role of the funding source

No funding sources had any involvement in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Dr. Rich states that his work was supported, in part by grants K24DA022112, T32DA013911 and P30AI042853 from the National Institutes of Health.

Footnotes

Declaration of competing interest

We wish to draw the attention of the Editor to the following facts, which may be considered as potential conflicts of interest, and to note significant financial contributions to this work:

Dr. Stone was a full-time contract employee and Medical Director at Discovery House CTC at the time of this study. He is also a paid member of the Scientific and Addiction Advisory Board at Dominion Diagnostics.

Dr. Green and Dr. Carroll report no conflicts of interest.

We wish to confirm that there are no other known conflicts of interest associated with this publication and there has been no other significant financial support for this work that could have influenced its outcome.

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