Commentary on Amin‐Esmaeili <i>et al</i> .: Non‐abstinence outcomes in stimulant clinical trials—Why deny improvement?

A new study found that reduction in drug use is associated with reduction in craving, depressive symptoms and increased functionality in clinical trials with stimulants. Incorporating non-abstinence based outcomes in clinical trials will increase the sensitivity of candidate interventions that could help patients in real-world scenarios. The study by Amin-Esmaeili and colleagues [1] is a very well-conducted and methodologically sound analysis regarding a topic of utter importance in psychostimulant use disorder (PSUD) trials and consequently care. Earlier trials on PSUD have relied mostly on abstinence-based outcomes to define therapeutic success [1]. Little research has evaluated the adequacy of this practice, which is likely related to the illegal status of cocaine in most countries worldwide, so that, unlike alcohol and tobacco, there is no amount of cocaine use considered as ‘normative’. Abstinence and non-abstinence-based measures have been tested as trial outcomes in a recent study by Carroll and colleagues [2], who have explored their relationship with cocaine use and functionality during follow-up. Yet they did not find outstanding results for any of the 15 outcomes evaluated; some endpoints, such as total abstinence and retention, have been suggested as poor performers [2]. Amin-Esmaeili et al.'s [1] study brings timely new information on this topic, showing a strong relationship between reduction in drug use and patient-important outcomes such as decreases in craving, drug-seeking behaviors and depression severity, establishing reduction in drug use as a clinically relevant endpoint. Their study has shown that 18.0% of patients were able to achieve reduction in stimulant use, whereas 14.2% of the study patients were able to achieve abstinence. Resetting the threshold of therapeutic success to reduction in substance use rather than abstinence would more than double the number of patients achieving a successful outcome. Stimulants such as cocaine and methamphetamine, endemic in many areas worldwide, have no approved pharmacological treatments by regulatory agencies in the United States, Canada, Europe, Brazil or other countries, however, stimulant use is closely associated with medical and social consequences such as polydrug use, risky behaviors, sexually transmitted diseases (STDs), psychosis and overdoses. The lack of available pharmacotherapies is regarded as a barrier to treatment for patients with methamphetamine use disorder, reflected in the belief that treatment was unnecessary and that withdrawing alone was preferable [3]. Together with stigma, the lack of useful medications to treat PSUD contributes to keeping patients who could benefit from treatment away from healthcare settings [3]. The use of non-abstinence outcomes for other substances, such as alcohol, has been successfully implemented in recent clinical research [4]. The World Health Organisation risk drinking levels have been a revolutionary realistic measurement of drinking patterns. They are accurately related to alcohol-related harms, and a pattern reduction (i.e. from high to moderate) is a valid measurement for alcohol use disorder treatment efficacy [5]. Studies using non-abstinence based outcomes will be more sensitive to patient-important changes as they will capture more individuals who improved in functionality, depressive symptoms and quality of life, according to this new study by Amin-Esmaeili and colleagues [1]. This is a crucial feature for trials for PSUD, especially with pharmacotherapy, as most trials have used abstinence-based endpoints and, as a result, a few medications have shown promise for cocaine, mostly bupropion [6], prescription psychostimulants [7] and topiramate [8]. Nevertheless, none of those has gained regulatory approval because of efficacy and safety concerns. Focusing on drug reduction instead of abstinence could change our perspective about these potential pharmacotherapies. For methamphetamine, with rising rates of use and harm related to use in North America in recent years [9], abstinence-based studies have found even less compelling results [10]. Conversely, more recent studies with drugs such a bupropion-naloxone combination [11] and mirtazapine [12] have found promising results using non-abstinence measures including reduction in drug use. Setting the bar too high with success endpoints in stimulant trials might underestimate the clinical utility of medications that are able to not only reduce drug use significantly, but also improve depression symptoms and functionality. Focusing too much on abstinence-based goals might cause a delay in the election of useful pharmacotherapy for PSUD. Beyond clinical trials, it is well-known in addiction medicine clinical practice that not all patients have abstinence as their personal goals. Patients might seek treatment for self-improvement, for reducing their chances of contracting STDs and other drug-related harms, or increasing their functionality as a worker or family member [13]. This is part of patient autonomy, and individual goals should be respected, with healthcare professionals serving as facilitators and educators. Furthermore, even patients who initially aim for abstinence might feel substantial benefits from reducing drug use without necessarily reaching abstinence. Reducing success endpoints in clinical trials to abstinence is to blatantly ignore therapeutic success and gains in functionality that are importantly recognized by clients in everyday clinical practice—and state the medications/interventions that cause such improvements simply do not work, which is both inaccurate and reductionist. It is time to start acknowledging actual improvement in PSUD clinical trials, rather than seeking for interventions with perfect results. No financial topic or other relevant links to companies with an interest in the topic of this article. There are no funders to report.

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