Background
Injectable opioid agonist treatment (iOAT) with either hydromorphone (an opioid analgesic) or diacetylmorphine (pharmaceutical-grade heroin) is an effective treatment for opioid use disorder among people not benefitting from oral opioid agonist treatments (OAT) [
1,
2]. A high proportion of people receiving both oral and injectable OAT have been found to report concurrent use of stimulants (i.e. cocaine and or amphetamines) [
3‐
5]. While OAT has not been associated with increases in illicit stimulant use, reductions overall remain modest and the ongoing use of illicit stimulants in OAT has been associated with higher rates of continued illicit opioid use and treatment dropout [
6,
7].
While a number of clinical trials have investigated various pharmacological treatments for stimulant use disorder, many of these trials have had small sample sizes and high treatment discontinuation rates [
8,
9]. Therefore, there has been a paucity of evidence derived from clinical trials regarding the overall effectiveness of pharmacological treatments for stimulant use disorder. Nevertheless, the Cochrane Collaboration’s review of psychostimulant drugs for the treatment of cocaine use disorder concluded that promising although modest results existed for dextroamphetamine (a pharmacological stimulant) [
8]. As such, in 2016, a double-blind randomized controlled trial was conducted in the Netherlands to investigate the effectiveness of dextroamphetamine for the treatment of cocaine use disorder among iOAT patients [
10]. Based on the primary outcome of abstinence (i.e. no use of illicit stimulants), the authors concluded effectiveness of the medication compared to placebo. The authors also considered secondary outcomes, including cravings, days of cocaine use (to measure reductions in use where abstinence was not achieved), and health and psychosocial outcomes [
11].
The transition toward incorporating a diverse range of outcome measures in the study of treatments for stimulant use disorder has been acknowledged in recent literature in the field. For example, a systematic review concluded that abstinence as a primary study endpoint may not reflect patient treatment goals for patients with stimulant use disorder and therefore does not reflect a sensitive marker of clinically meaningful change in substance use [
12]. Furthermore, a recent meta-analysis of prescription psychostimulants for the treatment of stimulant use disorder found these medications to be efficacious for the treatment of cocaine use disorder when provided in higher doses [
13].
Following the evidence from the Netherlands, dextroamphetamine prescribing was integrated into standard of care for patients with stimulant use disorder in an iOAT clinic in Vancouver (Canada) in 2018. This is the first time to our knowledge that dextroamphetamine has been offered to iOAT patients outside of clinical trial, and represents the first clinical setting in North America to routinely offer dextroamphetamine as a treatment for stimulant use disorder alongside treatment for opioid use disorder. Given the modest effects of prescribed stimulants to date, and continued study of pharmacological stimulants, it is important to consider the nuances of how the medication works for each patient. Since there is little empirical and clinical literature on dextroamphetamine in the context of opioid use disorder, there is still much to know about how the medication works and an important first step is to discuss treatment experiences with patients.
Dextroamphetamine prescribing in this iOAT clinic offers a unique opportunity to capture patient perceptions of the medication. The study inquired about patients’ experiences receiving dextroamphetamine for the treatment of stimulant use disorder, accounting for their views of both the medication itself and the way it was delivered (process of delivery) with the intention of understanding how these experiences impacted on their perceptions of its effectiveness. The central research question investigated was: “What experiences influence patients’ perceptions of the effectiveness of dextroamphetamine for the treatment of stimulant use disorder?”
Discussion
In this study, three central themes were identified as influencing participants’ perceptions of the effectiveness of dextroamphetamine as a treatment for stimulant use disorder. These themes extend beyond traditional operationalizations of effectiveness in the study of pharmacological treatment for stimulant use disorder, which have often been focused on the pharmacological action of the medication and its impact on achieving abstinence [
8,
9], and in some cases extend to consideration of secondary outcomes including reduced craving, and improved health and psychosocial outcomes [
11]. In the present study, motivations for illicit stimulant use were diverse. Perceptions of dextroamphetamine’s effectiveness were often influenced by the extent to which this medication could provide a substitute for the effects offered by illicit stimulant use. This substitution effect often served as a pre-condition for supporting reduced illicit stimulant use, or abstinence in cases where this was the participant’s goal.
Participants who reported using illicit stimulants to gain a boost of energy in many cases reported that dextroamphetamine provided a substitute for these effects. This was true in the context of concurrent diagnosis of ADHD, where a few participants reported achieving improved alertness, and focus from dextroamphetamine. This is consistent with prior clinical trials, where dextroamphetamine has been shown to reduce cravings and use of cocaine, and to improve ADHD symptoms when prescribed to people with concurrent ADHD and cocaine use disorder [
21]. Given the high rates of ADHD among people with stimulant use disorder [
22,
23], and the indication of dextroamphetamine for the treatment of ADHD, ADHD screening could be incorporated into assessments for patients seeking treatment for stimulant use disorder with potential for dual benefits.
Beyond the desire for a boost of energy, many participants reported presenting to treatment with the goal of managing their cravings for illicit stimulant use. For some participants, dextroamphetamine was seen to be effective at reducing craving. This finding has been reflected in prior clinical trials, where subjective craving scores have been reduced among people receiving dextroamphetamine (compared to placebo) for both cocaine [
10,
24] and amphetamine use disorder [
25]. Lastly, some patients reported the euphoric effect or “rush” as their motivation for illicit stimulant use. In the present study, patients received extended-release dextroamphetamine. Extended-release stimulants are less likely to produce subjective effects compared to short-acting or instant release prescription stimulants, and can also decrease the euphoriant and reinforcing effects of (illicit) stimulant use due to cross-tolerance [
26]. As such, for patients for whom the goal of illicit stimulant use was to achieve a euphoric effect, dextroamphetamine did not provide an effective “substitute”. As with treatment of other substance use disorders, not everyone will be engaged by currently available (while limited) treatments, and some will continue to use illicit stimulants. Nevertheless, in the absence of availability of alternative medications, the potential benefit of dextroamphetamine remains among people who continue to use illicit stimulants to achieve euphoric effects. For example, dextroamphetamine could support patients to reduce the frequency of illicit stimulant use [
10,
11].
Another important contributor to perceptions of the effectiveness of dextroamphetamine in the present study was the dose received. Participants all received dextroamphetamine following a standard dosing protocol, beginning at 15 mg twice per day, and titrating up as tolerated. For many patients there was no perceived effect until a dose of up 90 or 120 mg was reached. Communication with the prescriber in this process was found to be important to remaining engaged with the treatment. This finding is consistent with what is known from prior studies on the delivery of other treatments for substance use disorder such as opioid agonist treatment, where regular check-ins with the prescriber during titration are important to foster discussions about expectations of the medication (e.g. potential effects, side-effects) [
27‐
29]. Patients in the present study received a maximum daily dose of 120 mg (60 mg twice per day).
This follows from recent advances and conclusions drawn from the literature, for example, where a recent meta-analysis has revealed positive outcomes for patients receiving robust doses (defined as at least 60 mg/day) [
13]. In studies where dextroamphetamine has been provided at lower fixed doses (e.g. maximum of either 30 or 60 mg/day) higher dropout rates and poorer outcomes have been reported [
30] compared to in studies where higher doses have been offered (e.g. up to 110 mg/day) [
31]. As known from the delivery of other pharmacological treatments such as oral methadone, while there are standardized thresholds for optimal dosing, positive outcomes are promoted when prescribers work with each patient to meet their personalized dosing needs [
32].
Further to the medication dose, the ease with which patients could access dextroamphetamine also impacted on perceptions of the effectiveness of this medication. For example, some participants outlined the convenience of the on-site medication at the iOAT clinic. In prior studies, oral and injectable OAT clinics have been highlighted as suitable environments for the delivery of dextroamphetamine, whereby allied health professionals, including pharmacists, have a role to play in providing patients with medication reminders to promote adherence [
10]. In this study however, the daily observed dispensation was seen to limit the potential effectiveness of the medication for many participants, by regimenting when the medication could be taken. For example, Dean reported wanting to take dextroamphetamine in line with his cravings, which did not always align with the time he visited the clinic for his iOAT dose. Similarly, William reported wanting to take the medication at different times each day depending on his work and sleep schedule. These findings suggest that where dextroamphetamine is delivered, flexibility around the timing of dose administration will be important to better engaging patients, particularly given the wide heterogeneity in substance use patterns, including different types of stimulant use, routes of administration, and frequencies of use [
33].
This heterogeneity in stimulant use profiles provides further justification for considering diverse approaches to the delivery of dextroamphetamine in order to best respond to patients’ preferences. In this study, there was a preference among many participants for access to take-home (i.e. carries) doses. The provision of take-home doses of pharmacological treatments for substance use disorder have been greatly limited as a means of reducing possible medication diversion and promoting safety [
34]. These restrictions directly affect the approach that can be taken with patients receiving dextroamphetamine in order to increase its uptake and effectiveness. In the context of COVID-19, there are increasing examples of the implementation of take-home doses being provided in the context of substance use disorder treatment to mitigate risks. If these measures are feasible and effective during COVID-19, implementation can continue post-COVID-19. For example, Switzerland offers up to seven days of take-home doses of iOAT [
35], and take-home doses have also been provided in this study’s iOAT clinic to patients who are self-isolating [
36]. Furthermore, in response to patient preferences, clinical protocols have been recently adjusted in the present study setting, allowing patients to take home their second dextroamphetamine dose of the day. Providing effective, patient-centered approaches means patient preferences must be acknowledged and incorporated into care [
28,
37]. Take-home dosing can be implemented to respond to patients’ preferences and needs while also balancing potential concerns for safety, for example by scheduling regular visits, especially during medication initiation, to monitor for adverse events. In discussions about take-home dosing, concerns for medication diversion are often raised, however there has been relatively little consideration in the literature given to understanding factors (e.g. social, economic) that influence diversion [
36].
The possible risks of diversion must be weighed against the challenges of more restrictive measures, which often come at the expense of patient autonomy, and which in some cases could deter patients from engaging at all with an otherwise potentially beneficial treatment. The illicit drug supply in British Columbia has become increasingly contaminated in recent years, and has contributed to record-high overdose mortality rates in the context of COVID-19. In this context, the possible elevated risk of harms for people relying on an illicit rather than prescribed stimulant supply must be also be considered in decisions about whether and how (i.e. take home or on-site) dextroamphetamine is prescribed. In the present study, and in the present moment of overlapping dual public health crises of overdose and COVID-19, there is an overwhelming patient preference for, and opportunity to offer and implement take-home dosing to meet patient needs and improve medication uptake and effectiveness.
There are a number of important limitations of the present study that must be considered in interpreting findings. First, this analysis was conducted with a very unique and specific sample of people with concurrent opioid and stimulant use disorder diagnoses, who were receiving treatment with dextroamphetamine and who had been regularly engaged in treatment at an iOAT clinic. Findings may not be generalizable to people with different demographic profiles receiving treatment in other settings. For example, participants had an average age of nearly 54 years, and may hold different substance use and treatment histories and treatment goals as compared to younger people who use illicit stimulants.
Furthermore, the concurrent opioid and stimulant use profile of participants is quite unique to this specific clinical setting, where patients are the only people in North America who have been receiving injectable diacetylmophine (pharmaceutical-grade heroin) or hydromorphone (an opioid analgesic) for the treatment of opioid use disorder for many years (nearly 10 years for some). These patients have shown significant reductions in illicit opioid use, and visit the clinic up to three times a day for their opioid medication [
38]. This consistent daily (up to three times per day) engagement with the iOAT clinic persisted following access to dextroamphetamine, and there were no reported interactions between dextroamphetamine and the iOAT medication. Possible interactions of stimulant and opioid medications could be the focus of further pharmacologic studies, in particular among people who engage in daily illicit opioid use who might report on drug interactions which were not reported on in this study.
Second, the sample includes only a small number of women, which reflects the underrepresentation of women in the iOAT study setting [
18]. As this medication expands to other settings, further work can be done to identify potential gender differences in preferences for the delivery of dextroamphetamine. Third, participants were eligible for inclusion in the study based on ever having attempted dextroamphetamine. As such, participants included in the study represent people who have had a wide range of exposure to the medication which could impact on the diversity of overall experiences and perceptions of effectiveness. Fourth, while many clinical trials have investigated the effectiveness of this medication separately among people with cocaine or methamphetamine use disorder, participants in the present study reported cocaine and/or methamphetamine use. Nevertheless, a prior qualitative study investigating patients’ illicit stimulant use in this study setting (iOAT clinic) found no differences across themes by reported illicit stimulant use type [
17]. Furthermore, the present study includes only participants who remained engaged with the iOAT clinic and thus the perspective of people who received dextroamphetamine but were not well engaged in iOAT are not represented. People who were hesitant or resistant to attempting dextroamphetamine were not included in the study sample. This presents a sample that could be the focus of future research to help inform modifications to the delivery of dextroamphetamine prescribing to engage a broader range of patients in treatment.
It is also important to highlight that this study took place both prior to and following the declaration of COVID-19 as a public health emergency in British Columbia. This meant that data were collected both in person, at a confidential research office, and by telephone. We acknowledge that the strengths of qualitative data collection rest heavily on both the context and setting of the interview. In our experience, in person data collection has yielded rich insights and discussion. Nevertheless, we were able to rely on pre-existing rapport with participants when conducting telephone interviews, to maintain rich discussion. Furthermore, prior studies have found that telephone interviews may allow respondents to feel more comfortable and relaxed, and that there is no evidence to suggest that telephone interviews produce lower quality data [
39].
This qualitative study relied on participants’ accounts of their experiences with dextroamphetamine, and self-reported patterns of illicit stimulant use. Prior studies have concluded the reliability of participants’ accounts of their substance use where rapport exists, and where the person inquiring has no power or control over their treatment or care [
40]. In the present study, the interviewer held existing rapport with participants, having regularly administered self-reported questionnaires about their illicit substance use patterns for related studies in prior years. Furthermore, given previous regular contact for existing research, the boundary between research team and the clinical team was already well established and understood by participants.
Lastly, this study cannot confirm or deny the efficacy of dextroamphetamine for the treatment of stimulant use disorder. Instead, this study offers an exploration of patient perceptions of dextroamphetamine, which cannot be captured by other study designs (e.g. clinical trials) where quantitative outcome assessments are made to determine effectiveness.
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