Atomoxetine for amphetamine-type stimulant dependence during buprenorphine treatment: A randomized controlled trial

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Full length article

Atomoxetine for amphetamine-type stimulant dependence during buprenorphine treatment: A randomized controlled trial

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Richard S. Schottenfelda, Marek C. Chawarskia, , Mehmet Sofuoglua, Weng-Tink Chooib, Norzarina M. Zaharimb, M. Azhar M. Yasinc, Imran Ahmadc, Sharifah Zubaidiah Syed Jaaparc, Vicknasingam B. Kasinatherd a

Yale School of Medicine, New Haven, CT, United States School of Social Sciences, Universiti Sains Malaysia, 11800, Penang, Malaysia c School of Medical Sciences, Universiti Sains Malaysia, Health Campus 16150, Kelantan, Malaysia d Centre for Drug Research, Universiti Sains Malaysia, 11800, Penang, Malaysia b

A R T I C LE I N FO

A B S T R A C T

Keywords: Amphetamine-type stimulants Opioids Substance use disorder Atomoxetine Pharmacotherapy

Background: Amphetamine type stimulants (ATS) use is highly prevalent and frequently co-occurs with opioid dependence in Malaysia and Asian countries. No medications have established efficacy for treating ATS use disorder. This study evaluated the safety, tolerability, and potential efficacy of atomoxetine for treating ATS use disorder. Methods: Participants with opioid and ATS dependence (N = 69) were enrolled in a pilot, double-blind, placebocontrolled randomized clinical trial; all received buprenorphine/naloxone and behavioral counseling and were randomized to atomoxetine 80 mg daily (n = 33) or placebo (n = 33). The effect size of the between-group difference on the primary outcome, proportion of ATS-negative urine tests, was estimated using Cohen’s d for the intention-to-treat (ITT) sample and for higher adherence subsample (≥60 days of atomoxetine or placebo ingestion). Results: Participants were all male with mean (SD) age 39.4 (6.8) years. The proportion of ATS-negative urine tests was higher in atomoxetine- compared to placebo-treated participants: 0.77 (0.63–0.91) vs. 0.67 (0.53–0.81, d = 0.26) in the ITT sample and 0.90 (0.75–1.00) vs. 0.64 (0.51–0.78, d = 0.56) in the higher adherence subsample. The proportion of days abstinent from ATS increased from baseline in both groups (p < 0.001) and did not differ significantly between atomoxetine- and placebo-treated participants (p = 0.42). Depressive symptoms were reduced from baseline in both groups (p < 0.02) with a greater reduction for atomoxetine- than placebo-treated participants (p < 0.02). There were no serious adverse events or adverse events leading to medication discontinuation. Conclusions: The findings support clinical tolerability and safety and suggest potential efficacy of atomoxetine for treating ATS use disorder in this population.

1. Introduction Co-occurring amphetamine type stimulants (ATS) and opioid use is highly prevalent in Malaysia and throughout the Asian region (United Nations Office on Drugs and Crime, 2016). In Malaysia, primarily used ATS include crystalline methamphetamine and amphetamine/methamphetamine tablets (Chooi et al., 2017; Desrosiers et al., 2016). The consequences of ATS and opioid use drive major public health problems, including HIV/AIDS (Chawarski et al., 2008; Colfax et al., 2018; Degenhardt et al., 2014, 2010; Mathers et al., 2008; Mazlan et al., 2006; McKetin et al., 2008; Singh et al., 2013; Strathdee and Stockman,

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2010). In Malaysia, most of the > 300,000 registered drug using individuals (estimated > 500,000 total) use heroin, morphine, or other opioids, mostly by injection, and frequently also use ATS by smoking or injection. An estimated 16.6% of people who inject drugs are infected with HIV, and injection drug use accounts for approximately 65% of HIV infections in Malaysia (105,189 registered between 1986 and 2015) (Ministry of Health Malaysia, 2010; Ministry of Health Malaysia, 2015; Ministry of Health Malaysia, 2016). In recent surveys of people who inject heroin or other opioids in Malaysia, 75% reported lifetime ATS use (21% inject ATS), and lifetime ATS use was significantly associated with HIV infection (Chawarski et al., 2012).

Corresponding author at: Yale School of Medicine, 34 Park St S206, New Haven, CT 06519, United States. E-mail address: [email protected] (M.C. Chawarski).

https://doi.org/10.1016/j.drugalcdep.2018.01.017 Received 27 September 2017; Received in revised form 24 January 2018; Accepted 24 January 2018 Available online 10 March 2018 0376-8716/ © 2018 Elsevier B.V. All rights reserved.

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the transition to the general population.

Opioid agonist maintenance treatment with methadone or buprenorphine has been scaled up in Malaysia and other countries in the region over the past 15 years to treat opioid use disorder and reduce HIV transmission risk (Schottenfeld et al., 2008; Vicknasingam et al., 2015). Currently, approximately 380 physicians in Malaysia treat approximately 10,000 patients with buprenorphine/naloxone in general medical practice settings (Vicknasingam et al., 2015), but the effectiveness of these public health efforts may be reduced because of the high prevalence of co-occurring ATS and opioid dependence. Buprenorphine and methadone do not specifically target co-occurring ATS use, and co-occurring stimulant use is associated with more severe HIV risk behaviors, a higher prevalence of HIV infection, and high attrition from and persistent drug use during methadone or buprenorphine treatment (Corsi and Booth, 2008; Marquez et al., 2006; Molitor et al., 1999; Rawson et al., 2008; van Griensvan et al., 2004; Volkow et al., 2007). Despite the critical need, there are currently no efficacious medications for treating ATS use disorder either as a primary disorder or co-occurring with opioid use disorder (Brensilver et al., 2013; Carson and Taylor, 2014; Elkashef et al., 2008; Karila et al., 2010; Phillips et al., 2014). Findings from pre-clinical and clinical studies support the safety, tolerability, and potential efficacy of the selective norepinephrine transporter (NET) inhibitor atomoxetine for treating ATS use disorder. Initially developed as an antidepressant medication, atomoxetine is approved to treat Attention Deficit Hyperactivity Disorder (ADHD) (Savill et al., 2015; Simpson and Plosker, 2004). Atomoxetine increases synaptic norepinephrine (NE) levels throughout the central nervous system and increases dopamine (DA) levels in the prefrontal cortex, where the NET (which binds to both NE and DA) is primarily responsible for DA reuptake (Bymaster et al., 2002; Swanson et al., 2006). Through these effects, atomoxetine targets many of the core features of ADHD that are also associated with ATS use disorder and relapse risk following discontinuation of ATS use, including impairments of executive function (attention, concentration, working memory, planning, and decision-making) and emotional dysregulation (irritability, affective lability, and emotional over-reactivity) (Economidou et al., 2009; Ersche et al., 2006; Gowin et al., 2014; Hoffman et al., 2006; Karila et al., 2010; Kohno et al., 2014; Monterosso et al., 2005; Paulus et al., 2005; Reimherr et al., 2005; Salo et al., 2007; Shoptaw et al., 2009; Sofuoglu and Sewell, 2009; Volkow et al., 2001). Human laboratory studies support the safety and potential efficacy of atomoxetine for treating ATS use disorder (Kelly et al., 2005; Lile et al., 2006; Rush et al., 2011; Sofuoglu et al., 2009), and unlike stimulant medications (amphetamine or methylphenidate) used to treat ADHD and investigated as potential treatments for ATS use disorder, atomoxetine has little to no abuse liability (Jasinski et al., 2008; Lile et al., 2006; Upadhyaya et al., 2013). One small randomized clinical trial did not find significant effects of atomoxetine compared to placebo for treating cocaine use disorder (Walsh et al., 2013), but there are no published, randomized, placebo-controlled studies of atomoxetine for treating ATS use disorder or co-occurring ATS and opioid use disorder. Consequently, we conducted a pilot, randomized, placebo-controlled, double-blind clinical trial of atomoxetine during buprenorphine treatment of participants with co-occurring ATS and opioid dependence. The specific aims of the pilot clinical trial were to evaluate the tolerability and safety of atomoxetine and obtain estimates of its potential efficacy for reducing ATS use in this population. To conduct the pilot study and other studies of treatments for these co-occurring disorders, we first developed a substance use disorder clinical research program, including inpatient and outpatient units, at the health campus of Universiti Sains Malaysia in Kota Bharu, Malaysia. Located on the Thailand border in northeast peninsular Malaysia, Kota Bharu has experienced the most explosive growth in ATS problems over the past 5 years and has a high prevalence of ATS use (∼75%) and of HIV (∼45%) among people who inject opioids, and it has the highest number of women with HIV in Malaysia, suggesting that HIV is making

2. Methods 2.1. Study design The study design was a single-site, pilot, double-blind, placebocontrolled, randomized clinical trial. Participants were treated in the inpatient program for 10 days to achieve an initial period of documented abstinence from ATS, induction and stabilization on buprenorphine/naloxone, initiation of behavioral drug counseling, and randomization (after 5–7 days) to atomoxetine or placebo. Following hospital discharge, participants were treated as outpatients for 16 weeks. The study protocol was reviewed and approved by the Human Investigation Committee of Yale School of Medicine and the Universiti Sains Malaysia Research Ethics Committee and registered as a clinical trial at https://clinicaltrials.gov/under NCT01863251. 2.1.1. Participants and location The enrollment period lasted from March 2013 to April 2014. The study enrolled treatment-seeking volunteers meeting DSM-IV-TR criteria for both opioid and ATS dependence who reported ATS use on two or more days per week in the month prior to study admission and had opioid- and ATS-positive urine toxicology test results at study enrolment. Exclusion criteria included history of hypersensitivity to atomoxetine, narrow angle glaucoma, pheochromocytoma, or severe cardiovascular disorder, hypertension, liver enzymes greater than 3 times the upper limit of normal, liver failure or acute hepatitis, current suicide or homicide risk, current psychotic disorder or major depression or taking a neurolopetic or anti-depressant medication (including using a monoamine oxidase inhibitor (MAOI) within the preceding 2 weeks), current participation in treatment for substance use disorder, or inability to understand the protocol or assessment questions. The study population was all male because of very low prevalence of co-occurring opioid and ATS dependence among females in the region. Additionally, stigma associated with drug use among females precluded identification and enrollment of sufficient number of females in the study. One female seeking treatment was treated outside of the study protocol. All participants provided written, voluntary informed consent. All clinical and research activities were conducted at the Department of Psychiatry in the Hospital Universiti Sains Malaysia in Kota Bharu, Malaysia. Research and clinical staff were trained in the study protocol during a pre-pilot phase and treated 13 participants with buprenorphine/naloxone and open-label atomoxetine in the pre-pilot phase before the start of the pilot randomized clinical trial. 2.1.2. Randomization and masking The simple randomization sequence was computer-generated in the US by an investigator who had no contact with study participants (MCC). To allow sufficient time for preparation of study medications (active and placebo), treatment group assignment was communicated to the study pharmacist at Hospital Universiti Sains Malaysia, who also had no direct contact with participants or clinical staff, approximately 2 days in advance of administering the first dose of atomoxetine or placebo. Atomoxetine 40 mg tablets were purchased from the local distributor. The study pharmacist prepared identical-appearing capsules containing atomoxetine 40 mg or placebo. Atomoxetine was crushed and packed into empty capsules, and sodium bicarbonate was used for placebo. 2.1.3. Interventions 2.1.3.1. Buprenorphine/Naloxone (8 or 2 mg, containing buprenorphine and naloxone in 4:1 ratio) induction and maintenance (all participants). Participants were inducted onto buprenorphine/ naloxone with an initial dose of 4 mg administered when the participant was exhibiting mild signs of withdrawal during day one of 131

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enzymes and depression symptoms were assessed monthly. All study participants received 50 MYR (equivalent of 12 USD) for each of the monthly assessments.

the inpatient stay. The buprenorphine/naloxone dose could be increased to a targeted maintenance dose of 16 mg daily (maximum 24 mg daily) based on the participant’s symptoms and response. All study participants were referred to available treatment options for their opioid dependence after completion of the study treatments.

2.2. Outcomes

2.1.3.2. Atomoxetine and placebo. Participants received the first dose of active atomoxetine or placebo capsules beginning 5–7 days following inpatient admission. Participants assigned to atomoxetine initially received one capsule containing 40 mg of atomoxetine and one placebo capsule daily for the first 7 days and subsequently received two 40 mg atomoxetine capsules daily for the remainder of the study. Because this was the first study of atomoxetine in this population, a dose of 80 mg daily was selected; this dose has shown efficacy for treating ADHD (Clemow and Bushe, 2015; Simpson and Plosker, 2004) in adults and has been documented to have minimal adverse effects. Participants assigned to placebo received two placebo capsules throughout the study. Buprenorphine/naloxone and active or placebo atomoxetine were administered under direct observation by study personnel during the inpatient phase and were provided to participants at weekly visits for unsupervised daily administration outside of the clinic during the outpatient phase.

Because clinical effects are typically observed only after several weeks of atomoxetine treatment (Clemow and Bushe, 2015; Sobanski et al., 2015), the primary outcome of interest was reduction in ATS use, assessed as the proportions of urine tests negative for ATS during weeks 9–16 of the outpatient treatment phase of the study. Additional outcomes included the proportion of days abstinent from ATS, reductions in illicit opioid use (proportion of morphine-negative urine tests), reductions of depressive symptoms (total score of CES-D), and treatment retention (number of treatment days during outpatient treatment until the last clinical contact). All outcomes were evaluated at enrollment and during the 16-week post-hospitalization study period.

2.3. Statistical power and sample size The study was designed as a pilot randomized clinical trial to obtain data regarding the tolerability and safety of atomoxetine in this population and preliminary pilot data on the effect size of the potential efficacy of atomoxetine for reducing ATS use. The effect size is calculated based on measures of central tendency (the mean) and the variability or spread (standard deviation); therefore, approximately 30 participants in each group was adequate to obtain stable and reliable measures and Cohen’s d estimates of the effect size (Cohen, 1988).

2.1.3.3. Physician management and behavioral counseling.. All study participants received both Physician Management and Behavioral Counseling. The Physician Management was provided by the prescribing study physicians (MDs). The Behavioral Counseling was provided by trained and supervised nursing personnel, licensed in Malaysia to provide such intervention in the healthcare settings where the study was conducted. Physician Management, provided daily during the inpatient phase and weekly during the outpatient phase, included brief medical advice about recovering from substance use disorder, information about the medications and their role in recovery, and assessment and management of adverse effects and response to treatment. Behavioral Counseling was individual, manual-guided behavioral drug and HIV risk reduction counseling adapted from a treatment manual evaluated in earlier studies in Malaysia (Chawarski et al., 2008). During the inpatient phase, participants were provided counseling daily (except for Fridays and Saturdays – the weekend days in Khota Bharu) and also participated in exercise programs and other activities designed for the inpatient program. During the outpatient phase, participants were provided counseling weekly. Counseling focused on 1) educating participants about opioid and ATS use disorders and their treatment, the role of medications (buprenorphine/naloxone and possibly atomoxetine) in treating the disorder, and HIV risk behaviors and risk reduction and 2) developing and reviewing progress completing short-term behavioral contracts aimed at improving medication adherence and counseling attendance and at taking small but persistent steps to increase engagement in rewarding and non-drugrelated social, family, recreational, or work activities.

2.4. Statistical analyses Consistent with this study’s design as a pilot clinical trial, the main findings regarding outcomes are reported as indices of observed effect sizes (Cohen’s d: small (0.2), medium (0.5) and large (0.8)) (Cohen, 1988; Kistin and Silverstein, 2015; Lee et al., 2014). Urine test results and self-report data were aggregated into two successive 8-week intervals and also analyzed using the linear MIXED models repeated measures procedures in SPSS 21 statistical software. The MIXED models are advantageous in that they use all available data on each randomized participant; therefore, all study participants, including those with missing data, are included in the analyses and no imputations of missing data are required. The MIXED models procedures provided means and 95% confidence intervals (CI) used in calculations of Cohen’s d effect size indicators and were used to evaluate between group differences, time effects, and the interactions between treatment assignment and time factors (weeks 1–8 and 9–16 for the proportions of negative urine tests and baseline and weeks 1–8 and 9–16 for self-reported percent days ATS use and CES-D scores). The effects of treatment conditions on retention were evaluated using the Life Table method and the Wilcoxon test (Lawless, 2002). Tolerability and safety of atomoxetine were evaluated by comparing reports of adverse effects and retention between the two medication groups. Statistical analyses were conducted for the intention-to-treat sample, based on all randomized participants except for one atomoxetine-treated participant who was lost-to-follow-up and provided no data following randomization. Additionally, because the overall medication adherence was suboptimal, evaluating potential differences among higher and lower medication adherence groups afforded a possibility of better evaluating the potential medication efficacy among those who took higher prescribed doses and/or took their dosesmore frequently. Consequently, a subsample of participants who reported taking at least 60 days, corresponding to approximately half of days of study treatment course of atomoxetine (n = 12) or placebo (n = 16) during the outpatient phase, were analyzed.

2.1.4. Assessments Baseline assessments included self-reported lifetime and past 30 days drug use history, urine toxicology tests, evaluation of liver enzymes (blood tests), and evaluation of depression symptoms using the Center for Epidemiological Studies Depression Scale (CES-D) (Radloff, 1977). Self-reported drug use and adherence with buprenorphine/naloxone and with atomoxetine were assessed weekly following the inpatient phase using a timeline follow back methodology (Robinson et al., 2014). Adverse medication effects were assessed clinically at weekly visits with a study physician and through spontaneous reports to research assistants. Following the inpatient phase, urine samples were collected weekly, tested immediately for temperature to deter tampering, and then tested for ATS (amphetamine and methamphetamine) and morphine using rapid immunoassay test strips. Repeat liver 132

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Fig. 1. Participant flow (CONSORT Data).

3. Results

placebo-treated groups (p = 0.42; see Table 3a). The mean (SD) selfreported days atomoxeinte or placebo was taken was 47 (35) in the atomoxetine group and 63 (33) in the placebo group; this difference was not statistically significant (p = 0.10).

Fig. 1 shows the recruitment, enrollment, and follow-up of study participants. Participants were all male, with mean (SD) age 39.4 (6.8) years and 14.2 (7.6) years lifetime history of opioid use and 11.2 (5.1) years lifetime history of ATS use. The demographic and clinical characteristics of the participants randomized to the two study treatment conditions are displayed in Table 1. None of the baseline differences presented in Table 1 were statistically significant.

3.2. Reductions in illicit opioid use The proportion of morphine-negative urine tests during weeks 9–16 was lower for placebo- versus atomoxetine-treated participants, with observed effect sizes of d = 0.25 (small effect size) in the intention to treat sample and d = 0.33 (small effect size) in the higher adherence subsample (see Table 2b). The proportions of days abstinent from illicit opioids increased significantly from baseline for both treatment groups (time effects, p < 0.001) and did not differ significantly between atomoxetine- and placebo-treated groups (p = 0.60; see Table 3b). The mean (SD) of self-reported days buprenorphine/naloxone was taken was 51 (37) in the atomoxetine group and 67 (33) in the placebo group; this was not a statistically significant difference (p = 0.11).

3.1. Atomoxetine effects on reducing ATS use The proportions of ATS-negative urine tests were higher in atomoxetine-treated than placebo-treated participants during weeks 9–16 (see Table 2a). The effect size of the observed differences in the proportion of ATS-negative urine tests between atomoxetine and placebo groups during weeks 9–16 was d = 0.26 (small effect size) in the intention-to-treat and d = 0.56 (medium effect size) in the higher adherence samples. The proportions of days abstinent from ATS increased significantly from baseline for both treatment groups (time effects, p < 0.001) but did not differ significantly between atomoxetine- and 133

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3.3. Depressive symptoms and treatment retention

Table 1 Baseline characteristics of study participants.

Mean (SD) Age

Income (group median)

Placebo (n = 33)

Atomoxetine (n = 32)

33.9 (7.0) years (range: 20–49 years) RM675 (about USD153)

35.8 (6.6) years (range: 22–50 years)

Education (years of schooling) Completed high school (11) 15/33 (45.5%) Completed junior high (9) 16/33 (48.5%) Completed primary school (6) 2/33 (6.1%) Marital status Never married 19/33 (57.6%) Married 12/33 (36.4%) Divorced/Widowed 2/33 (6.0%) Employment status Full-time 13/33 (39.4%) Part-time 16/33 (48.5%) Unemployed 4/33 (12.1%) Did not report 0/33 (0%) Relatives who also use drugs Yes 6/33 (18.2%) No 25/33 (75.8%) Did not report 2/33 (6.0%) Past treatment for substance use Yes 9/33 (27.3%) No 21/33 (63.6%) Did not report 3/33 (9.1%) Number of times in compulsory drug rehabilitation Never 19/33 (57.6%) At least once 7/33 (21.2%) More than once 5/33 (15.2%) Did not report 2/33 (6.0%) Lifetime history of arrests on drug-related offences Yes 28/33 (84.8%) No 4/33 (12.1%) Did not report 1/34 (3.0%) Number of times in imprisoned for non-drug offences Never 8/33 (24.2%) At least once 12/33 (36.4%) More than once 12/33 (30.4%) Did not report 1/33 (3.0%) HIV status (self-report) Positive 7/23 (30.4%) Negative 16/23 (69.6%) Never tested 9/33 (27.3%) Did not report 1/33 (3.0%) Mean (SD) Age of first heroin use 20.5 (4.9) y.o. Mean (SD) Duration of heroin use 13.4 (7.9) years 29.9 (0.9) days Mean (SD) Days of heroin use in the month prior to study admission Mean (SD) Daily frequency of 4.7 (2.2) heroin use times/day Method of heroin use “Chase”* 8/33 (24.2%) Inject 25/33 (75.8%) Mean (SD) Age of first ATS use 24.0 (7.1) y. o. Mean (SD) Duration of ATS use 9.9 (4.3) years 19.1 (9.3) days Mean (SD) Days of ATS use in the month prior to study admission Method of ATS use “Chase” 19/33 (57.6%) Inject 11/33 (33.3%) “Chase” & Inject 3/33 (9.1%)

CES-D scores reduced significantly from baseline during treatment for both treatment groups (time effect, p = 0.02), and the reductions in atomoxetine treated patients were significantly greater. For the atomoxetine treated patients, baseline mean (95%CI) CES-D score = 19.50 (15.98–23.03); weeks 1–8 mean (95%CI) CES-D score = 14.48 (11.25–17.71); weeks 9–16 mean (95%CI) CES-D score = 13.75 (9.73–17.77). In comparison, for placebo-treated participants the baseline mean (95%CI) CES-D score = 21.25 (17.73–24.78); weeks 1–8 mean (95%CI) CES-D score = 17.90 (14.81–20.99); weeks 9–16 mean (95%CI) CES-D score = 18.42 (14.87–21.96) (medication effects, p = 0.02) (see Table 4). The median (95% CI) days of treatment retention in the atomoxetine and placebo groups was 107 (100–114) and 104 (99–109) days, respectively (Wilcoxon χ2 (1) = 0.011, p = 0.916).

RM600 (about USD136)

15/32 (46.8%) 11/32 (34.4%) 6/32 (18.8%) 16/32 (50.0%) 6/32 (18.8%) 10/35 (31.2%)

3.4. Adverse events

11/32 (34.4%) 9/32 (28.1%) 10/32 (31.3%) 2/32 (6.2%)

One placebo-treated patient died at week 14 of sepsis associated with AIDS; there were no other serious adverse events or reports of adverse effects leading to medication discontinuation.

7/32 (21.9%) 25/32 (78.1%) 0/32 (0%)

4. Discussion The main study findings are based on differential response to atomoxetine as compared to placebo, not on overall effects observed on all patients receiving buprenorphine/naloxone treatment. These findings provide preliminary support for the tolerability and safety of atomoxetine and for its potential efficacy for reducing ATS use during buprenorphine treatment of co-occurring ATS and opioid use disorder. Atomoxetine was well-tolerated by study participants and not associated with significantly greater rates of serious adverse events, adverse events leading to medication discontinuation, or treatment attrition. The observed effect sizes of the differences favoring atomoxetine in the proportions of ATS-negative tests were small (d = 0.26) in the intention-to-treat and were in the medium (d = 0.56) range for the higher adherence subsample. The more robust findings supporting the efficacy of atomoxetine in the subsample of participants who took medications (atomoxetine or placebo) on 60 or more days is also consistent with a medication effect of atomoxetine, which could only be obtained if the medication is taken for a sufficient time period. Consistent with a potential delayed onset of atomoxetine effects, which is also reported for atomoxetine effects on symptoms of ADHD (Clemow and Bushe, 2015; Savill et al., 2015; Sobanski et al., 2015), the proportions of ATS-negative urine tests and of days ATS abstinent increased from the first to the second 8-week period in the atomoxetine-treated group but decreased in the placebo-treated group, and a similar pattern of greater improvement over time with atomoxetine compared to placebo was also observed for CES-D measures of depression symptoms. The study finding of greater reductions in depressive symptoms among atomoxetine- compared to placebo-treated participants is of interest with regard to a potential mechanism of action of atomoxetine for treating ATS use disorder. Initially evaluated as an antidepressant, atomoxetine improves symptoms of depressed mood and emotional dysregulation (irritability, affective lability, and emotional over reactivity) as well as impairments of executive function (including impaired attention, working memory, planning, and decision-making) in adults with attention-deficit disorder and other disorders (Adler et al., 2014a,b; Adler et al., 2014a,b; Borchert et al., 2016; Bymaster et al., 2002; Chamberlain et al., 2006; Epperson et al., 2011; Reimherr et al., 2005; Simpson and Plosker, 2004; Swanson et al., 2006). These symptoms are prominent features during early abstinence from ATS and are associated with increased relapse risk (Ersche et al., 2006; Gowin et al., 2014; Kohno et al., 2014; Monterosso et al., 2005; Paulus et al., 2005; Salo et al., 2007; Shoptaw et al., 2009; Volkow et al., 2001), and

10/32 (31.3%) 18/32 (56.3%) 4/32 (12.5%) 18/32 (56.3%) 4/32 (12.5%) 7/32 (21.9%) 3/32 (9.4%) 23/32 (71.9%) 6/32 (18.8%) 3/32 (9.4%) 9/32 (28.1%) 6/32 (18.8%) 16/32 (50.0%) 1/32 (3.1%) 4/21 (19.0%) 17/21 (81.0%) 9/35 (28.1%) 2/35 (6.3%) 20.0 (4.5) y.o. 15.3 (7.2) years 30.0 (0.0) days

4.6 (1.7) times/day

7/32 (21.9%) 25/32 (78.1%) 23.2 (7.8) y. o. 12.8 (5.5) years 17.0 (10.9) days

18/32 (56.3%) 12/32 (37.5%) 2/32 (6.3%)

“Chase” refers to inhalation of the drug vapor/smoke after the drug is heated to a temperature of it’s burning point. Typically it is done in a pipe, or on a piece of tinfoil.

*

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Table 2a Proportions of ATS-negative urine tests. Means (95% CI) Intention-to-treat sample

Weeks 1–8

Weeks 9–16

P values

Placebo (n = 32) Atomoxetine (n = 33)

0.74 (0.63–0.85) 0.74 (0.63–0.85)

0.67 (0.53–0.81) 0.77 (0.63–0.91)

Medication: p = 0.41 Time: p = 0.74 Med × Time interaction: p = 0.45

Means (95% CI) Higher adherence subsample Placebo (n = 16) Atomoxetine (n = 12)

Weeks 1–8 0.70 (0.54–0.86) 0.77 (0.58–0.96)

Weeks 9–16 0.64 (0.51–0.78) 0.90 (0.75–1.00)

P values Medication: p = 0.04 Time: p = 0.64 Med × Time interaction: p = 0.22

Means (95% CI) Intention-to-treat sample

Weeks 1–8

Weeks 9–16

P values

Placebo (n = 32) Atomoxetine (n = 33)

0.64 (0.51–0.77) 0.62 (0.49–0.76)

0.55 (040–0.70) 0.65 (0.50–0.81)

Medication: p = 0.55 Time: p = 0.69 Med × Time interaction: p = 0.41

Means (95% CI) Higher adherence subsample Placebo (n = 16) Atomoxetine (n = 12)

Weeks 1–8 0.65 (0.49–0.82) 0.66 (0.46–0.85)

Weeks 9–16 0.63 (0.48–0.78) 0.77 (0.60–0.94)

P values Medication: p = 0.41 Time: p = 0.62 Med × Time interaction: p = 0.44

Table 2b Proportions of opioid-negative urine tests.

Table 3a Proportions of days ATS abstinent. Means (95% CI) Intention-to-treat sample

Baseline

Weeks 1–8

Weeks 9–16

P values

Placebo (n = 32) Atomoxetine (n = 33)

0.37 (0.24–0.49) 0.44 (0.32–0.56)

0.91 (0.85–0.98) 0.90 (0.84–0.97)

0.90 (0.82–0.97) 0.92 (0.84–1.00)

Medication: p = 0.42 Time: p < 0.001 Med × Time interaction: p = 0.63

Means (95% CI) Higher adherence subsample Placebo (n = 16) Atomoxetine (n = 12)

Baseline 0.38 (0.20–0.55) 0.42 (0.22–0.63)

Weeks 1–8 0.88 (0.79–0.98) 0.97 (0.86–1.00)

Weeks 9–16 0.87 (0.78–0.96) 0.98 (0.88–1.00)

P values Medication: p = 0.14 Time: p < 0.001 Med × Time interaction: p = 0.89

Means (95% CI) Intention-to-treat sample

Baseline

Weeks 1–8

Weeks 9–16

P values

Placebo (n = 32) Atomoxetine (n = 33)

0.02 (0.00–0.07) 0.02 (0.00–0.04)

0.92 (0.84–0.99) 0.85 (0.77–0.92)

0.91 (0.83–0.98) 0.83 (0.75–0.91)

Medication: p = 0.60 Time: p < 0.001 Med × Time interaction: p = 0.94

Means (95% CI) Higher adherence subsample Placebo (n = 16) Atomoxetine (n = 12)

Baseline 0.04 (0.00–0.13) 0.00 (0.00–0.00)

Weeks 1–8 0.92 (0.83–1.00) 0.90 (0.80–1.00)

Weeks 9–16 0.91 (0.86–0.97) 0.93 (0.86–1.00)

P values Medication: p = 0.96 Time: p < 0.001 Med × Time interaction: p = 0.66

Table 3b Proportions of days opioid abstinent.

Table 4 CES-D total scores. Means (95% CI)

Baseline

Weeks 1–8

Weeks 9–16

P values

Placebo Atomoxetine

21.25 (17.73–24.78) 19.50 (15.98–23.03)

17.90 (14.81–20.99) 14.48 (11.25–17.71)

18.42 (14.87–21.96) 13.75 (9.73–17.77)

Medication: p = 0.02 Time: p = 0.02 Med × Time interaction: p = 0.72

The lack of systematic assessment of adverse medication effects using a validated assessment tool may have resulted in a lower reported rate of adverse effects than would have been reported in response to the use of a standardized assessment instruments. The generalizability of the study findings is also limited because participants in the study were all male (consistent with the low prevalence of opioid and ATS use disorder among females in Malaysia), mostly ethnic Malay, experiencing problems with both ATS and opioid use, and receiving buprenorphine/ naloxone treatment. Additionally, there are no reliable data or estimates of ADHD prevalence in the studied population and no validated ADHD assessments available in Bahasa Melayu (the local language of Malaysia). While none of the study participants had a prior diagnosis of ADHD, we could not reliably assess the participants on the presence of ADHD symptoms at the start of treatment when they were initiating abstinence from prolonged periods of ATS use and beginning induction of buprenorphine/naloxone to treat opioid dependence. It is possible

atomoxetine-induced improvement in mood, emotional dysregulation, or executive function may contribute to reductions in ATS use (Shoptaw et al., 2009). Although the study findings are consistent with this potential mechanism, improved mood might also result from greater abstinence from ATS. Study limitations include use of a single atomoxetine dose, reliance on self-report to assess medication adherence, small sample size, and suboptimal medication adherence. Medication adherence was suboptimal in both the atomoxetine and placebo groups, suggesting that low adherence did not result from problems with the tolerability of atomoxetine. In future studies, increasing the frequency of clinical contact or calling or text messaging patients daily as a reminder to take the medications might improve adherence, as supported by recent a meta-analysis of this approach for a broad range of chronic medical conditions (Thakkar et al., 2016). Urine toxicology tests were conducted weekly, which potentially missed some ATS or other drug use. 135

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that observed response to atomoxetine might vary depending on a diagnosis of ADHD.

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4.1. Conclusions The findings of this pilot, placebo-controlled, randomized clinical trial provide preliminary support for the tolerability and safety of atomoxetine and suggest its potential efficacy for decreasing ATS use during buprenorphine/naloxone treatment of participants with co-occurring ATS and opioid use disorder. Given the high prevalence and severe adverse consequences of co-occurring ATS and opioid use disorder and the lack of any medications with proven efficacy for treating ATS use disorder, full-scale efficacy studies evaluating a broader range of atomoxetine doses, with a larger sample sizes to ensure sufficient power to detect both statistically significant and clinically meaningful effects, are necessary. 5. Contributors Authors Schottenfeld, Chawarski, Sofuoglu, and Vicknasingam designed the study and obtained funding support. Authors Schottenfeld, Chawarski, Vicknasingam, Chooi, and Zaharim conducted literature searches and provided summaries of previous research studies. Author Chawarski conducted the statistical analyses. Authors Chooi and Zaharim coordinated participant recruitment and research data collection. Authors Ahmad, Mohd Yasin, and Syed Jaapar provided medical evaluation, delivered medical treatments, and collected clinical data in the study. Author Zaharim coordinated and supervised psychosocial and behavioral treatments for all participants. Author Schottenfeld wrote the first draft of the manuscript. All authors have contributed to writing and revising of the manuscript and have approved the final manuscript for submission. 6. Conflict of interest All authors declare no conflicts of interest. 7. Role of funding source Funding for the study was provided by the National Institutes of Health (NIDA #’s K24 DA000445, R01 DA14718), the State of Connecticut, Department of Mental Health and Addiction Services, and Universiti Sains Malaysia (1001.CDADAH.852003). The funding agencies did not have any role in the design or conduct of the study, interpretation of study findings, or preparation of publications. Acknowledgments The study was approved by the Human Investigation Committee of Yale School of Medicine and the Universiti Sains Malaysia Research Ethics Committee and registered as a clinical trial at https:// clinicaltrials.gov/under NCT01863251. References Adler, L.A., Clemow, D.B., Williams, D.W., Durell, T.M., 2014a. Atomoxetine effects on executive function as measured by the BRIEF-a in young adults with ADHD: a randomized, double-blind, placebo-controlled study. PLoS One 9, e104175. Adler, L., Tanaka, Y., Williams, D., Trzepacz, P.T., Goto, T., Allen, A.J., Escobar, R., Upadhyaya, H.P., 2014b. Executive function in adults with attention-deficit/hyperactivity disorder during treatment with atomoxetine in a randomized, placebo-controlled, withdrawal study. J. Clin. Psychopharmacol. 34, 461–466. Borchert, R.J., Rittman, T., Passamonti, L., Ye, Z., Sami, S., Jones, S.P., Nombela, C., Vazquez Rodriguez, P., Vatansever, D., Rae, C.L., Hughes, L.E., Robbins, T.W., Rowe, J.B., 2016. Atomoxetine enhances connectivity of prefrontal networks in Parkinson’s disease. Neuropsychopharmacology 41, 2171–2177. Brensilver, M., Heinzerling, K.G., Shoptaw, S., 2013. Pharmacotherapy of amphetaminetype stimulant dependence: an update. Drug Alcohol Rev. 32, 449–460. Bymaster, F.P., Katner, J.S., Nelson, D.L., Hemrick-Luecke, S.K., Threlkeld, P.G.,

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