Abstract
Background:
Methamphetamine use is increasing among persons with opioid use disorder (OUD). The study aims were to describe methamphetamine/amphetamine (MA/A) use among patients treated for OUD with buprenorphine/naloxone (BUP-NX) or extended-release naltrexone (XR-NTX), and to explore associations between treatment arm and MA/A use.
Methods:
Secondary analysis of data from a multi-site, open-label, randomized controlled trial of XR-NTX versus BUP-NX for 24 weeks. The outcome variable was MA/A use defined by either positive urine drug toxicology or self-report. The main predictor was treatment assignment (BUP-NX v. XR-NTX). Longitudinal mixed-effects logistic regression models were fit to model the odds of MA/A use during the study. Additional predictors included study visit and baseline MA/A use.
Results:
Among the sample of 570 participants with OUD, baseline use of MA/A was observed in 105 (18.4%). There was no significant treatment effect over the study period, though BUP-NX subjects, on average, had about half the odds of MA/A use compared to XR-NTX subjects (OR=0.50; p=0.051). In the same model, baseline MA/A use and study visit were both significantly associated with MA/A use over time.
Conclusion:
In this sample of treated OUD patients, nearly a fifth (18.4%) of participants had MA/A use at baseline and the frequency of use did not decline over time: in fact, the odds of use slightly increased for each later visit. These secondary analyses found no significant difference in MA/A use between BUP-NX and XR-NTX treatment arms, however, the observation of less MA/A in the buprenorphine arm merits further investigation.
Keywords: Opioid use disorder, methamphetamine use, amphetamine use, substance use treatment
1. INTRODUCTION
While substantial attention and investments have been paid to the opioid epidemic, methamphetamine use has also emerged as a major public health crisis. In the past decade, data from sentinel sites suggest increasing public health burden of methamphetamine in the form of treatment admissions, overdose and law enforcement interventions in states west of the Mississippi (Artigiani, 2018), and surveys of persons who inject drugs show increasing use of methamphetamine with heroin (Al-Tayyib et al., 2017; Glick et al., 2018). Substance use treatment data demonstrate patterns of increasing methamphetamine use nationally (Cicero et al., 2020; Ellis et al., 2018), along with synthetic opioids, suggesting that we are now in a “fourth wave” of the opioid epidemic characterized by concurrent use of methamphetamine (Jenkins, 2021). Use of methamphetamine with opioids is associated with unique harms: the practice of mixing heroin and methamphetamine is associated with overdose (Al-Tayyib et al., 2017) and HIV infection (Golden et al., 2019). Since the COVID-19 pandemic, the proportion of overdose deaths that involve methamphetamine has been increasing (Stephenson, 2021). As such, there is an urgent need to intervene upon methamphetamine use from a public health standpoint.
Providers who treat patients with opioid use disorder (OUD) are increasingly challenged to address patients’ concurrent methamphetamine use. A survey of persons with opioid use entering substance use disorder treatment found that past month methamphetamine use increased 83% from 18.8% in 2011 to 34.1% in 2017 (Ellis et al., 2018). Such an increase is of concern as there is evidence that methamphetamine use can jeopardize OUD treatment outcomes (Simon et al., 2017; Tsui et al., 2020). In a study of 799 patients with OUD who initiated treatment with buprenorphine in 3 programs in WA State from 2015–2018 (Tsui et al., 2020), it was observed that nearly a third (30%) had used methamphetamine in the past 30 days, and baseline methamphetamine use was associated with more than twice the relative hazards for non-retention in treatment over time. Options for treating methamphetamine use among patients who are receiving treatment for OUD with opioid agonist therapy are limited. Contingency management has been shown to be effective in reducing methamphetamine use, yet there are major barriers to implementation due to financial restrictions (Glass et al., 2020) and stakeholder objections (Petry, 2010). Currently there are no Food and Drug Administration (FDA) approved medications for methamphetamine use disorder. A recent study demonstrated modest benefits of bupropion/naltrexone for reducing methamphetamine use (Trivedi et al., 2021) and among men who have sex with men and transgender women mirtazapine has demonstrated modest benefits for reducing methamphetamine use (Coffin et al., 2019). Yet, studies testing use of those medications among persons with treated OUD are lacking and some research suggests individuals are less receptive to medications for mental health as a means of treating methamphetamine use (McMahan et al., 2020).
Given the magnitude of harms related to the surge in methamphetamine use during the opioid epidemic, there is a compelling need to understand patterns of its use among patients who are treated with medications for OUD. For patients who seek treatment for OUD in office-based settings they may now choose between medications that have been proven effective to reduce opioid use such as extended-release injectable naltrexone (XR-NTX) and buprenorphine/naloxone (BUP-NX) (Lee et al., 2018). Both medications are approved by the FDA for treatment of OUD (not methamphetamine use) yet have different mechanisms of action. Naltrexone is a mu opioid receptor antagonist that blocks the effects of opioids without producing opioid effects (positive or negative). Buprenorphine is a partial agonist at the mu opioid receptor and an antagonist at the kappa receptor. Its high affinity and low activity at the mu receptor allow it to compete with/displace other opioids while conferring less abuse potential and a better safety profile. If a differential impact on concurrent methamphetamine use were to exist for one of these medications this would be relevant information to share with patients to inform their decision-making. To date it has been relatively unexplored whether XR-NTX or BUP-NX may be associated with reductions in methamphetamine use over time. A prior study demonstrated modest benefits of the combination of XR-NTX and bupropion for methamphetamine(Trivedi et al., 2021) and buprenorphine has been associated with less cocaine use in another study (Ling et al., 2016). Given that many patients presenting for OUD treatment now use methamphetamine, clinicians may wonder if one medication may have greater secondary benefits for methamphetamine use than the other.
The “Extended-Release Naltrexone vs. Buprenorphine for Opioid Treatment” (X:BOT) study, a randomized trial comparing the effectiveness of XR-NTX versus BUP-NX for treatment of opioid use disorder at 8 sites across the U.S., provides a unique opportunity to examine patterns of MA/A use in a sample with treated OUD. We undertook this secondary analysis to describe the frequency of methamphetamine use at baseline and over time among patients treated for OUD, and to explore whether BUP-NX is associated with a difference in stimulant use over time compared to XR-NTX.
2. METHODS
2.a. Study Design:
This study was a secondary analysis of data from the X:BOT study, a 24 week multi-site, open-label, randomized controlled trial of XR-NTX versus BUP-NX for treatment of opioid use disorder conducted within the National Institute on Drug Abuse National Drug Abuse Treatment Clinical Trials Network. Detail on study design and procedures have been published (Lee et al., 2018).
2.b. Study Participants and Parent Study Procedures:
All participants enrolled in the parent study were included in the analytic sample for this study. Participants were recruited from 8 addiction specialty treatment sites in different states (CA, FL, MA, MD, NM, NY, OH, WA) between Jan 30, 2014 and May 25, 2016. Eligibility criteria included: ≥18 years of age, English speaking, diagnosis of opioid use disorder per Diagnostic and Statistical Manual of Mental Disorders-5, and use of non-prescribed opioids within the prior 30 days. Exclusion criteria included other serious medical, psychiatric or substance use disorders, or disorders that deemed injection unsafe, liver tests (transaminases) >5x upper limit of normal, suicidality or homicidality, evidence of prior allergy/sensitivity to XR-NTX or BUP-NX, methadone maintenance ≥30 mg/day, prescribed opioids for chronic pain, and legal status that might preclude study completion. After providing informed consent, participants were randomized in a 1:1 allocation ratio to receive either monthly injectable XR-NTX or daily sub-lingual BUP-NX. Patients underwent induction to assigned medication in medically supervised inpatient settings then continued to receive outpatient medication for 24 weeks. Patients completed weekly study visits for 24 weeks, and follow-up visits at 28 and 36 weeks. Assessments included measures of recent drug use and urine toxicology. There was no study requirement that urine specimens be observed although it was allowed if the site did this as part of standard clinic procedure. However, urine collection cups had temperature strips and a dipstick was used to assess for the presence of adulterants (UrineCheck 7). Rapid, point-of-care dipcard/dipsticks (QuickTox Drug Screen, BUP10 and OPI300) were used to assess for benzodiazepines, amphetamines, THC, methamphetamine, opiates, cocaine, MDMA, oxycodone, methadone and barbiturates and buprenorphine. Data were collected by trained research staff primarily via direct entry. Participants were provided with financial compensation for study visits (maximum compensation for attending all study visits was $710): $50 each for screening, induction, and weeks 24, 28, 36; and $20 each for visits 1–23. Strategies to maximize follow-up/minimize missing data included conducting visits in the community, home and jail/prison, as needed. Visits could be conducted by phone as a last resort for data collection (as urine toxicology could not be completed). Extensive efforts were used to maintain contact with participants more generally including locator forms with frequent updating (at least every 4 weeks), visit reminders, and periodic mailed cards (e.g., holiday). The study was approved by local institutional review boards.
2.d. Measures:
For this secondary analysis, the main outcome/dependent variable was use of methamphetamine or amphetamine (MA/A) at each visit. The variable for MA/A use at baseline and all follow-up visits was defined by either having urine drug toxicology positive for methamphetamine or amphetamine or self-report of having used either within the past 7 days using a weekly Timeline Followback (TLFB) method (Sobell and Sobell, 1995). Thus, a positive urine drug test or a positive self-report was taken as evidence of recent use. Discordant results could occur in the setting of use within 7 days for two plausible scenarios: 1) having used within the past 7 days and disclosed this by self-report, but not recently enough (i.e. within the past 24–48 hours) to be detected on urine drug test, or 2) if a participant had recently used but did not disclose this on self-report. Out of 7630 study encounters there were 965 (13%) instances of the first scenario (i.e. positive self-report and negative urine drug test) and 91 (1%) instances of the second (i.e. negative self-report and positive urine drug test). The main independent variable was treatment assignment (BUP-NX v. XR-NTX).
2.e. Statistical Analyses:
Using the intention-to-treat (ITT) sample, baseline differences in demographic, clinical, and substance use measures between baseline MA/A users and non-users were compared using t-tests and Chi-square tests. Patterns of MA/A use over time were descriptively evaluated graphing the proportion of MA/A use at each study visit. Mixed effects logistic regression models were fit to model the odds of MA/A use as the outcome, for Visits 1–24. The outcome was missing if both TLFB and urine toxicology were missing for a given week. Missingness was treated as missing at random. Models featured random intercepts for site and subject, and an AR(1) correlation structure for within subject observations, and were adjusted for baseline MA/A use (positive baseline urine toxicology and any use reported in the 30 days prior to randomization via the TLFB). First, a model was fit with treatment group, visit (as continuous variable) and the interaction of treatment group and visit as predictors. As the interaction was not found significant (p=0.95, the model was re-run with only the main effects of treatment group and visit. Sensitivity analyses were also conducted using a per-protocol (PP) sample consisting of only those participants who were successfully inducted onto an initial dose of study medication. Analyses were conducted with SAS® version 9.4 (SAS Institute, Cary, NC). All statistical tests were two-sided with a significance level threshold p<0.05.
3. RESULTS
Among the sample of 570 participants with OUD, baseline use of MA/A was observed in 105 (18.4%). Baseline MA/A use across the 8 sites ranged from 1.6% to 62.5% with the highest prevalence on the west coast and the lowest on east coast. Baseline users of MA/A appeared relatively similar to non-users with regards to demographic factors with the exception of being slightly younger in age (mean age (SD): 31.0 (8.2) v. 34.5 (9.8)), see Table 1. In this inpatient setting, persons with baseline MA/A use did not appear to be any less likely to achieve a successful induction compared to those without use (86% v. 83%). The proportion of MA/A use at each study visit in the sample overall by treatment arm is shown in Figure 1.
Table 1.
Baseline Characteristics by Methamphetamine Use of Sample (N=570)
| MA/A Use* at Baseline (n=105) | No MA/A* at Baseline (n=465) | Total (N=570) | |
|---|---|---|---|
| Treatment Arm | |||
| BUP-NX | 59 (56%) | 228 (49%) | 287 (50%) |
| XR-NTX | 46 (44%) | 237 (51%) | 283 (50%) |
| Induction Success | |||
| Yes | 90 (86%) | 384 (83%) | 474 (83%) |
| Gender | |||
| Male | 71 (68%) | 330 (71%) | 401 (70%) |
| Female | 34 (32%) | 135 (29%) | 169 (30%) |
| Age at Randomization [Mean (SD)] | 31.0 (8.2) | 34.5 (9.8) | 33.9 (9.6) |
| Education Level | |||
| <HS | 22 (21%) | 110 (24%) | 132 (23%) |
| HS/GED | 44 (42%) | 146 (31%) | 190 (33%) |
| >HS | 39 (37%) | 209 (45%) | 248 (44%) |
| Race | |||
| White Only | 78 (74%) | 343 (74%) | 421 (74%) |
| Black Only | 4 (4%) | 53 (11%) | 57 (10%) |
| Other | 23 (22%) | 69 (15%) | 92 (16%) |
| Injection Drug Use | |||
| Yes | 76 (72%) | 309 (67%) | 385 (68%) |
| MA/A Use (UDS) | |||
| Yes | 23 (22%) | N/A | N/A |
| MA/A Use-past 30 days (TLFB) | |||
| Yes | 95 (91%) | N/A | N/A |
| % Past 30 days MA/A Use (TLFB) [Median (IQR)] | 9% (4%−24%) | N/A | N/A |
MA/A use definition is either report of use over the past 30 days by TLFB or UDS positive.
Figure 1:
Proportion with Methamphetamine/Amphetamine Use (TLFB or Urine Toxicology) at Weekly Visits by Treatment Randomization Arm (Intention-to-Treat)
Longitudinal mixed-effects regression models demonstrated that participants randomized to BUP-NX, on average, had about half the odds of MA/A use compared to XR-NTX participants (OR=0.50; 95%CI: 0.25–1.00; p=0.051). In the same model, baseline use and study visit were both significantly associated with MA/A use. Odds of use increase by 4% for each later visit compared to the prior visit (OR=1.04; 95% CI: 1.02–1.05; p<0.01). Odds of use across weeks were almost 16 times greater for those who used at baseline compared to those who did not (OR=15.88; 95% CI: 6.89–36.64; p<0.01). Sensitivity analyses using the PP sample did not substantively change results. The odds ratio for the treatment effect comparing BUP-NX to XR-NTX was again non-significant and in the same direction of effect (OR=0.61; 95% CI: 0.29–1.28; p=0.19). Odds of use increased by 3% for each later visit and odds of use across weeks were more than 15 times greater for those who used at baseline compared to those who did not (both p<0.01).
4. DISCUSSION
This secondary analysis of a trial comparing XR-NTX to BUP-NX for treatment of OUD observed that nearly one-fifth of patients had evidence of MA/A use by urine toxicology or self-report at baseline, and a similar proportion was observed to be using at each weekly study visit over the 24-week period. Participants who were randomized to BUP-NX had about half the odds of using MA/A compared to XR-NTX participants, on average, although the difference did not meet the threshold for statistical significance. Baseline MA/A use was a strong predictor of subsequent use, and there was no evidence that MA/A use significantly declined over time: rather there was a small (4%), but statistically significant increase in use at each visit.
This study adds to the body of literature demonstrating the overlap of MA/A use among treated OUD patients. We observed variation in the prevalence of use by site, with western states reporting higher prevalence. This is consistent with prior research showing substantial regional variation of MA/A use among national addiction treatment samples of patients who use opioids with Western states having the highest prevalence, followed by the Midwest, then South (Ellis et al., 2018). Furthermore, the research confirms that baseline methamphetamine use strongly predicts future use, suggesting that screening for, and addressing, methamphetamine use early in treatment may be warranted.
Our study did not demonstrate a statistically significant difference in MA/A use over time among BUP-NX versus XR-NTX treated patients, however, the magnitude and direction of the OR favored BUP-NX. We are unaware of any other studies that have examined this specific research question to date, although a few studies have focused on each drug separately. A recent study demonstrated modest efficacy of XR-NTX with bupropion to reduce methamphetamine use, but only 7% of the sample had concurrent OUD (Trivedi et al., 2021). A study conducted among opioid and amphetamine users in Russia found naltrexone implants to be associated with improved retention, but not amphetamine use (Tiihonen et al., 2012). Methamphetamine use has been observed to go down over time among buprenorphine treated patients in some, but not all, studies (Hood et al., 2019; Tsui et al., 2020), and a randomized, blinded, placebo-controlled trial demonstrated that therapeutic doses of buprenorphine (16mg) were associated with cocaine abstinence (Ling et al., 2016).
Although results may suggest a therapeutic benefit of BUP-NX over XR-NTX, there may be other explanations. One hypothesis is that MA/A may be used as a substitute for heroin and other opioids, and this may occur more frequently among patients who are treated with an opioid antagonist (XR-NTX) who can experience little to no opioid effect. On the other hand, patients who were treated with sub-lingual buprenorphine had opportunity to sell or trade their medication in a way that those treated with injectable did not, which in theory could promote use of substances like MA/A. More research is needed to test these findings in other samples and explore potential underlying mechanisms. Currently, neither medication is FDA approved for treatment of methamphetamine use disorder and Drug Enforcement Administration (DEA) regulation of controlled substances like buprenorphine discourages off-label use. However, since we are witnessing a substantial overlap of opioid and methamphetamine use today, many patients with methamphetamine use disorder may have also have OUD diagnosis and FDA indication for buprenorphine.
There are several limitations to this study. First, these were secondary analyses conducted post-hoc and therefore should be interpreted cautiously. Second, the use of MA/A was relatively low in the overall sample, reflecting the years that the study was conducted (2014–16), which potentially limited study power as well as the ability to generalize the findings to current patients/settings. There was also a considerable amount of missing data for our study outcome (MA/A). Our models somewhat accounted for missing data through the use of mixed effects models, however, the assumption that data were missing at random may be questioned.
Given the rise in methamphetamine use among persons with OUD and the substantial health and social consequences (overdose, HIV, Hepatitis C, psychosis, incarceration, etc.), elucidating OUD medication effects on methamphetamine use is important. Our finding that those randomized to BUP-NX were half as likely to use MA/A compared to XR-NTX points to the need for future research to understand buprenorphine pharmacological effects and other pathways that may alter MA/A use.
Footnotes
Clinical trial registration: ClinicalTrials.gov (NCT02032433)
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