Methadone maintenance treatment among patients exposed to illicit fentanyl in Rhode Island: Safety, dose, retention, and relapse at 6 months

Abstract

Introduction:

Illicitly manufactured fentanyl (IMF) is a potent synthetic opioid that has been contributing to overdose deaths in the United States. This study examined intake toxicology and six-month treatment outcomes for patients newly admitted to a single methadone maintenance treatment program (MMTP) in Rhode Island with a high prevalence of illicit fentanyl.

Methods:

We conducted a retrospective chart review of patients admitted to a single MMTP between November 1^st, 2016 and August 31^st, 2017 followed for six months. Outcomes measured included: 1) retention in treatment at 6 months; 2) evidence of sustained abstinence; 3) relapse; 4) methadone dosage required to achieve sustained abstinence; and 5) the number of days required to achieve abstinence.

Results:

We observed 154 unique intake events (representing 147 patients). 80% (n = 123) tested positive for fentanyl at intake. During the six-month follow up period, 32% (n = 49) left treatment before six months, two individuals died within five weeks of discontinuation. No deaths were seen among those remaining in treatment. The majority (89%) who remained in treatment at six months achieved abstinence. No significant difference was seen for dose or time to achieve abstinence. Relapse was common (57%). Repeated exposure to fentanyl was seen frequently (71%) while in MMT before and after achieving abstinence.

Conclusion:

While there is concern that the potency of IMF may reduce the effectiveness of MAT, this study suggests that MMT is safe, abstinence achievable, and MMT is protective against death among fentanyl-exposed patients.

1. Introduction

Illicitly manufactured fentanyl (IMF) is a potent synthetic opioid that has been contributing to overdose deaths in the United States in recent years (O’Donnell et al., 2017; Rudd et al., 2016; Somerville et al., 2017). In many areas of the U.S., it has recently become the most commonly found illicit opioid (DEA, 2018). In parts of the northeast U.S., many users are uncertain of the extent of heroin adulterated with fentanyl (Ciccarone et al., 2017). Yet, fentanyl was seen in over 85% of urine toxicology for those seeking opioid withdrawal management in Massachusetts many users remain unaware (Kenney et al., 2018).

In the first six months of 2017 (most recently available data), 67% of overdose deaths in the U.S. state of Rhode Island were fentanyl-involved (Marshall et al., 2017). CDC reports a doubling of fentanyl-involved deaths in 10 U.S. states in the first six months of 2017 compared to the first six months of 2016 (O’Donnell et al., 2018). Similar increases are seen in Canada (Special Advisory Committee on the Epidemic of Opioid Overdoses, 2018) where 72% of opioid overdose deaths were fentanyl related in 2017.

The 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 et al., 2017). We hypothesize that changing patterns in the local drug market and opioid consumption practices (Wakeman, 2017) are affecting the treatment trajectory of individuals who seek out and receive medication for addiction treatment for opioid use disorder.

Methadone maintenance treatment (MMT) is an evidence-based treatment for opioid use disorder (Nielsen et al., 2016, 2017; Mattick et al., 2009). A recent study, consisting of 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 et al., 2017). To our knowledge, no studies have described the prevalence of fentanyl among those starting MMT for opioid use disorder nor evaluated outcomes for MMT in the population of people presenting with fentanyl exposure.

This study examines intake toxicology and six-month treatment outcomes for patients newly admitted to a single methadone maintenance treatment program (MMTP) in an area of Rhode Island with a high prevalence of illicit fentanyl use.

2. Methods

We conducted a retrospective chart review and analysis of all patients admitted to a single MMTP in a fentanyl-endemic area of Rhode Island between November 1^st, 2016 and August 31^st, 2017. Urine drug screening was performed for all patients at intake into treatment and then randomly at least three times per month until achieving three consecutive tests without unexpected results. All observed urines were tested by immunoassay at an outside lab (Clinical Science Laboratories, Mansfield, MA). Subsequently, random screenings were conducted at least monthly. Confirmatory LC/MS testing was done at the discretion of the MMT staff. All toxicological testing results were entered into the electronic medical record.

Treatment staff at the MMTP set methadone dosages for each patient by gradually adjusting the dose until illicit use was extinguished and cravings for use was reduced. New (i.e., non-transfer) 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. Further dose increases were considered every seven days. Dose increases did not exceed a total of 20 mg per week, as tolerated. Patients were assessed daily during induction.

All patients were followed for a period of six months following initial intake. Outcomes measured included: 1) retention in treatment at six months; 2) evidence of sustained abstinence (defined as three consecutive urine drug tests without unexpected opioids); 3) relapse (defined as the presence of an unexpected opioid in a screen after having obtained three consecutive screens without unexpected opioids); 4) methadone dosage required to achieve sustained abstinence (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 abstinence.

Descriptive statistics were generated to describe the demographics and treatment characteristics of the study population. Chi squared analysis was used to assess differences between groups, according to the results of intake drug screening, for all binary variables. Mann-Whitney tests were used to assess these differences in continuous variables (specifically, dosage at abstinence and days to achieve abstinence). Multiple logistic regression models considered factors putatively associated with retention, achieving abstinence, subsequent fentanyl-positive urine screens, and relapse, controlling for patient demographics (i.e., age, gender).

This study was approved by the Institutional Review Board at the Miriam Hospital in Providence, Rhode Island.

3. Results

During the 10-month study 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 thus excluded from this analysis, resulting in 154 unique treatment intake events (representing a total of 147 patients who tested positive for opioids at these intake events) being included in this study.

All descriptive statistics are presented in Table 1. Patients were an average age of 37 (SD = 11); 61% were male, and 82% were white. There were no significant differences in demographics among groups. According to urine drug screens performed on the day of admission, 80% (n = 123) of these treatment initiates tested positive for fentanyl at intake. Of those, 50 (32% of the entire study population) tested positive for fentanyl only, with no other opioids detected. The remaining 20% (n = 31) of intakes had positive screens for opiates without evidence of fentanyl in the intake urine drug test.

Table 1.

Demographics, intake data and outcomes for all individuals admitted to MMT during a 10 month period, followed for 6 months.

	All intakes	Fentanyl only	Both fentanyl and other opioids	Other opioids only (opiates)
	N = 154	N = 50	N = 73	N = 31
Age (mean, SD)	37, 11	37, 11	36, 10	39, 12
	% (n)
Male	61% (94)	56% (28)	67% (49)	55% (17)
Caucasian (non-Hispanic/Latino)	82% (126)	76% (38)	85% (62)	84% (26)
Intake urine screen also containing:
Benzodiazepine	15% (23)	14% (7)	16% (12)	13% (4)
Cocaine	38% (59)	36% (18)	40% (29)	39% (12)
Oxycodone	16% (24)	14% (7)	14% (10)	23% (7)
Retention at six months	68% (105)	72% (36)	67% (49)	65% (20)
	Among patients who were retained in MMTP at six months, % (n)
	N = 105	N = 36	N = 49	N = 20
At least one subsequent fentanyl-positive urine screen	71% (75)	80% (28)	75% (36)	55% (11)
Abstinence = Three consecutive urine screens without unexpected opioid	89% (93)	92% (33)	88% (43)	85% (17)
	Median (Q1;Q3)
Dose at abstinence (mg)	100 (70;130)	90 (75;120)	100 (73;140)	100 (70;120)
Days until abstinence	64 (39;97)	57 (34;105)	71 (40;94)	59 (45;83)
	Among patients retained in MMTP who achieved abstinance, % (n)
	(N = 93)	(N = 33)	(N = 43)	(N = 17)
Relapse	57% (53)	61% (20)	58% (25)	47% (8)

During the six-month follow up period, 32% (n = 49) of patients left treatment before six months. Rates of retention in treatment at six months were not significantly different regardless of screening results at intake, with 72% (n = 36) of those testing positive for only fentanyl, 65% (n = 20) of those testing positive only for other opiates, and 67% (n = 49) of those testing positive for both at intake remaining in care. The majority (89%) of patients who remained in treatment at six months after intake achieved three consecutive urine drug screens with no unexpected results (i.e., abstinence), during the six-month follow-up period, with no significant differences in rates of abstinence between groups.

Those testing positive for both fentanyl and other opioids at intake had the longest median time to achieve abstinence (median = 71 days, 25^th percentile = 40, 75^th percentile = 94) versus the group testing positive for fentanyl only (median = 57 days, [34, 105]) and those testing positive for other opiates only (median = 59 days, [43, 83]). Nevertheless, these differences were not statistically significant. Differences in the median methadone dosage required to achieve abstinence between groups also were not significantly different. The highest doses were recorded for those patients who tested positive for both fentanyl and other opioids at intake (median = 100 mg, [73, 140]).

Among all 154 unique treatment intake events, 71% of patients achieved abstinence within six months. Among only those patients who were retained in treatment at six months, 89% achieved abstinence during that time. Rates of abstinence were not significantly different across the three intake groups regardless of which denominator (the entire cohort or only those patients retained at six months) was used. Unsurprisingly, staying in treatment for at least six months was associated with higher abstinence rates as compared with the total cohort (p < 0.05), irrespective of drug screen results at intake.

Repeated fentanyl exposure while in treatment, as determined by positive results of subsequent urine drug tests, was significantly more common (p < 0.05) in patients whose intake screen also contained fentanyl. Among patients retained at six months, just over half (55%, n = 11) of the opiates only group at intake had subsequent urine screens test positive for fentanyl, compared to 80% (n = 28) in the group positive at intake for fentanyl only and 75% (n = 36) in the group positive for both fentanyl and other opioids. Patients in these last two (fentanyl-positive) groups had between one and 24 subsequent tests return positive results for fentanyl (median = 7). This relationship between fentanyl-positive screens at intake and subsequent fentanyl-positive screens during treatment remained significant when adjusted for age and gender.

Despite frequent fentanyl exposures while in treatment, there were no deaths for those who remained in treatment. Two individuals (1.3%) who ceased treatment early died during the follow-up period. One of these showed poor attendance, stopped coming to program, and died suddenly four weeks later. The second was forced to detox while incarcerated for 28 days in a neighboring state (where MAT is not available in jails or prisons) and died suddenly one week after release from incarceration.

4. Discussion

This study explored treatment outcomes among individuals newly initiating MMT and tested positive for opioids via urine drug testing at intake. No significant differences in rates of treatment retention, abstinence, or relapse were found between patients who presented at intake with positive screens for fentanyl only, for other opioids only, or for both. Though dosages required to achieve abstinence trended higher among those who tested positive for fentanyl at intake, neither dosage nor days to achieving abstinence were significantly different between these groups.

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.

Relapse was common among all patients, but those with fentanyl-positive urine drug tests at intake were more likely to submit subsequent fentanyl-positive urines upon relapse, compared to those who did not screen positive for fentanyl at intake. These data suggest that MMT remains safe and effective, even for individuals who have been exposed to fentanyl recently prior to initiating care. These data also suggest that relapse to any use—even relapse into fentanyl use—while on MMT, is still associated with survival. In areas where IMF is endemic, if people remain in MMT, their doses may be higher to extinguish use, relapse may be more common and more frequent, but a return to use may be less likely to result in a lethal event.

Continued fentanyl use and relapse appears to be a problem in this cohort of methadone patients; however, sustained abstinence was achievable for the majority of patients, and no deaths occurred while on methadone. This suggests that MMT may be protective against mortality despite a potentially higher relapse rate in this cohort. Even if methadone is able to increase tolerance and prevent overdose deaths, our findings do not rule out the possibility that current practice standards in 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 current treatment standards for opioid use disorder.

Should it be the case that higher subsequent dose titration would extinguish illicit use, further research is needed to assess whether a higher dose of methadone can block the euphoric effects of fentanyl as well as whether or not 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 EtOH 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 study is required.

It bears highlighting that the only deaths observed during the follow-up period were seen in two 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 MAT in criminal justice settings. Given the startling decreases in mortality observed during a study of MAT implementation in criminal justice settings in Rhode Island (Green et al., 2018), it is likely that one of the two 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). Treatment retention is hampered by multiple factors such as homelessness and mental illness (Parpouchi et al., 2017). Addressing factors to improve treatment retention will likely help decrease overdose deaths and improve outcomes for those exposed to fentanyl, but more study is warranted.

5. Conclusion

While there is concern that the potency of IMF may reduce the effectiveness of MAT, this study suggests that MMT is safe, that abstinence is achievable, and that MMT is protective against death among fentanyl-exposed patients.