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

Highlights

• This pilot study evaluated atomoxetine for treating amphetamine type stimulant (ATS) use disorder.

• Atomoxetine 80 mg was well tolerated, safe, and effective for reducing ATS use.

• Atomoxetine was also associated with greater improvements in depressive symptoms.

Abstract

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, placebo-controlled 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.

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, Degenhardt et al., 2010; Mathers et al., 2008; Mazlan et al., 2006; McKetin et al., 2008; Singh et al., 2013; Strathdee and Stockman, 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).

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 the transition to the general population.