Continuing Increase in Stimulant Dependence – Time to Implement Medical Treatment

The Scope of the Problem

The use of stimulant substances for non-medical purposes critically contributes to global problems related to substance use. Over 27 million people worldwide have used amphetamines, methamphetamines, and prescription psychostimulants, and around 19 million have used cocaine in 2018. ¹ An increase in the burden of (psycho)stimulant use disorder (PSUD), both amphetamine-type (AUD) and cocaine-type (CUD), reflect those trends. From 2008 to 2017, the disability-adjusted life years (DALYs) attributable to CUD increased by 17% and AUD by 5%. The economic burden of PSUD varies across income status with CUD and AUD accounting in 2019 for 0.01 and 0.02% of the DALYs in low income and lower-middle income countries, as compared to 0.16% and 0.09 respectively in high income countries. ² However, regional differences are also relevant: CUD is particularly burdensome in Tropical Latin America, where its prevalence is only outnumbered by North America; meanwhile, the regions with highest prevalence of AUD are East and South-East Asia. ³ Moreover, around 11.3 million people worldwide use drugs intravenously including opioids, amphetamines, methamphetamines, and cocaine. The concurrent use of an injected stimulant and an opioid increases the risk of medical problems, overdoses, and deaths in comparison to the injection of only one substance. ^{1 , 3} In the US, up to a third of opioid overdose deaths involved the concurrent use of a stimulant.

Current Treatment Approach

In the face of immense public health impact, treatment of PSUD should be prioritized. The Member States of the United Nations included strengthening the prevention and treatment of substance use disorders among the targets of the 2030 Agenda for Sustainable Development. One of the two indicators used to evaluate this target's progress is the “measure of the coverage of treatment interventions, including pharmacological, psychosocial and rehabilitation and aftercare services for substance use disorders”. These treatments should focus on individual needs according to the patient's circumstances and be evidence-based. However, finding an effective psychosocial or pharmacological intervention for PSUD has been challenging, and no evidence-based treatment model within the healthcare setting has been widely adopted.

Currently, dominant models of PSUD treatment use a combination of various psychosocial and educational interventions such as cognitive-behavioral therapy and contingency management, which are supported with the evidence of limited and short-term efficacy. However, their implementation has faced many challenges, with limited clinical application, and failure to attract and retain patients.

In contrast to existing PSUD treatment models, the current treatment model for individuals with opioid use disorder (OUD) has proven to attract and engage patients to decrease opioid use, address their health and social needs, and result in the quality-of-life improvement. This model of OUD treatment includes medication combined with psychosocial and other services and is often delivered by the multidisciplinary team. OUD treatment can be delivered in a specialty setting (Opioid Agonist Maintenance Treatment), in the primary care setting (e.g., the One-Stop-Shop model), and in prisons. The primary OUD medications used are opioid agonists methadone or buprenorphine, though the opioid antagonist naltrexone, especially its extended-release form, is also used after detoxification to prevent relapse.

Treatment with prescription opioid agonists reduces craving and the use of the illicit opioids with acceptable safety profile. Agonist medications have similar pharmacological effects and are usually orally administered with slow onset of action and a long half-life providing inter-dose stability, and can be given under medical supervision to minimize misuse and diversion. The acceptance of this model has steadily increased with many countries implementing this treatment approach as part of a continuum of care with individual and public health benefits. A Cochrane review shows a relative effect of 4.44 for retention in treatment and relative risks of 0.66 for morphine positive urine, 0.39 for criminal activity, and 0.48 for mortality when comparing maintenance treatment with methadone to treatment without methadone. ⁴ Buprenorphine maintenance at high dose is also associated with higher retention rates and fewer morphine-positive urines compared to placebo. ⁵ A parallel model of pharmacological intervention has been proposed for PSUD using extended-release preparations of prescription psychostimulants.

New Treatment Paradigm

In consideration of urgent public needs and the demand from health professionals and people who use stimulants, we propose a model of PSUD treatment that parallels the OUD treatment model with a prescribed stimulant agonist medication as a framework for delivery of psychosocial and other healthcare intervention. Individuals who use cocaine and/or amphetamines do not search for treatment due to a lack of an effective treatment specific for stimulant users and the absence of medications comparable to those available for OUD. We believe a treatment that includes medication as an essential service combined with medical and psychosocial interventions, social supports, and harm reduction interventions will find acceptance and reduce the treatment gap. Several medications have been tested for PSUD and some were found to have clinical utility, including topiramate and naltrexone. ⁶ Mirtazapine has shown promise in the treatment of MUD for selected subgroups, but warrants further research to elucidate its true potential. ⁷ Prescription psychostimulants have been clinically evaluated for more than 20 years for the treatment of CUD and AUD and emerge as the most effective agonist medications for use in the PSUD treatment. ⁸ The candidates include prescription amphetamines (lisdexamphetamine, dexamphetamine, or mixed amphetamine salts) or methylphenidate, all of them found safe and effective and, therefore, approved in many countries for clinical use in other disorders.

Prescription psychostimulants produce increase in dopamine and noradrenaline, analogous to that caused by cocaine, amphetamines, and methamphetamines, which may relieve craving and withdrawal and, therefore, diminish use of illicit stimulants and prevent relapse in recently abstinent individuals. ⁸ Patients adherent to prescription psychostimulants are more likely to attend the program and take advantage of co-administered psychosocial interventions leading to decrease in the amount and frequency of illicit psychostimulant use as well as learning skills to achieve prolonged abstinence and yield improvement in health and quality of life.

Prescription psychostimulants fulfill many of the criteria for a suitable agonist medication. ⁹ However, the main concern with their maintenance was related to safety, considering illicit amphetamines use is associated with risk of cardiovascular ¹⁰ and neurological ¹¹ events as well as adverse psychotic and mood symptoms. ¹² Multiple studies and metanalyses have been conducted in the past decade, evaluating efficacy and safety profile of these medications, with generally favorable results. ^{8 , 13 , 14} The most recent and comprehensive metanalysis of 38 controlled trials, found treatment with prescription psychostimulants promoted sustained drug abstinence, reduced stimulant use, and extended the duration of abstinence in patients with PSUD. ⁸ In further support of the agonist effect as responsible for the clinical benefit, medications with a more potent agonist effect (i.e., dextroamphetamine) were more effective than medications that are less potent (i.e., modafinil), and higher doses produced more significant benefit than lower doses. ⁸ A 2016 meta-analysis ¹³ highlighted the safety of treatment with prescription psychostimulants, finding the rates of the most severe adverse events (AEs) (dropout rate due to AEs, cardiovascular AEs, or the incidence of severe AEs) similar to placebo. ¹³ However, the authors emphasized the need for a comprehensive review of prescription psychostimulants safety evaluating mild and long-term adverse events. The most frequent side effects of a commonly prescribed mixed salt of amphetamines formulation are dry mouth, loss of appetite, insomnia, headache, weight loss, nausea, anxiety, agitation, dizziness, tachycardia, diarrhea, asthenia, and urinary tract infections, affecting over 5% of the adults using the medication. ¹⁵

The 2020 meta-analysis ⁸ found an overall effect of prescription psychostimulants on promoting abstinence mostly driven by studies using prescription amphetamines for the treatment of CUD, with no effects among individuals with MUD treated with modafinil or methylphenidate. This agrees with two earlier meta-analyses. ^{14 , 16} which found no effect of prescription psychostimulants on promoting sustained abstinence in patients with MUD. There is an ongoing study assessing whether high-dose prescription amphetamine could promote abstinence for MUD patients. ¹⁷

While the available evidence supports the safety and effectiveness of the proposed intervention, ^{8 , 13 , 14} most of the published trials were conducted in high-income countries. Since a significant amount of people with a PSUD reside in low- and middle-income countries (LMIC), with often underfunded healthcare systems and limited trained workforce, it is important to replicate controlled trials of stimulant assisted treatment in LMICs. ¹⁸ Furthermore, trials conducted to date have high attrition rates, which limits the quality of evidence derived from them. ^{8 , 16} Additional studies may be needed to evaluate the effectiveness of optimized prescription psychostimulants treatment protocols for treatment of AUD.

Design of Future Studies

Available evidence can inform the design of future studies. We propose prescription stimulant-assisted treatment should be initially offered in the specialty setting, offering daily medication visits. Though the cost may be a limiting factor, the Opioid Agonist Maintenance Treatment model in a specialty setting has been found to have a favorable cost-benefit. ¹⁹ Daily visits to the facility for the administration of medication can maximize safety and minimize diversion potential and offer close monitoring of clinical and safety outcomes, ²⁰ yet a recent Cochrane review was not conclusive about differences in efficacy and safety between supervised and unsupervised medication for opioid dependence. ²¹ Behavioral or psychosocial interventions should be combined with the medication to maximize medication adherence and minimize treatment dropout. ²² Where possible, patients should receive case-management services and harm-reduction interventions, further improving attractiveness of the program.

An optimal trial should include a high dose of a most potent prescription psychostimulant (amphetamine analogue), using extended-release formulations administered daily under supervision. As with opioids, supervised medication intake is commonly done to prevent diversion and overdose, though those benefits may be limited ²¹ with recent evidence showing safety of take-home doses even for medications with high toxicity, such as methadone. ²³ An option to increase the dose for patients who tolerated but did not respond to lower doses should be available, as the insufficient dose is a frequent reason for the limited response to agonists. Preferably, treatment should last for at least six months to allow for longer period of observation to assess the maintenance of clinical improvement and prolonged safety monitoring for side-effects, drug-drug interactions, or misuse potential. The primary measure of treatment success should be the percentage of patients achieving prolonged abstinence (e.g., three-week sustained abstinence) combined with non-abstinence-based outcomes, such as a decrease in frequency and quantity of drug use. Improvement in the quality of life, positive health outcomes, and the restoration of the social and occupational functionality should also be included.

Studies suggest PSUD patients who are frequent stimulant users benefit most from the agonist treatment ²⁴ and, therefore, the initial studies should include patients with an active and severe form of the disorder (e.g., daily use, large amounts, and intravenous use), based on thorough “treatment qualification” assessment. Treatment may be particularly impactful in this group which is less likely to respond to non-pharmacological interventions, ²⁵ with benefits likely outweighing risks. Patients with less severe disorder may be more subject to harms from daily exposure to high-dose prescription psychostimulants, including the worsening of their disorder or medical complications.

Because nearly all published trials excluded patients with severe psychiatric and cardiovascular disorders, ²⁶ such patients should be excluded from the initial trials. However, many individuals presenting for treatment have those comorbidities, ²⁷ therefore, patients with milder forms of those conditions may be gradually included in treatment, provided that careful psychiatric and medical monitoring can be implemented. These studies will be a source of systematic safety data collection, which is essential for further dissemination of this approach. To maximize the public health impact, studies should collect data on the effectiveness and safety, as well as implementation factors and the cost-effectiveness of this approach.

Next Steps

The United Nations Office on Drugs and Crime (UNODC) has recently convened an Expert Group Meeting on the Promising Perspectives for Treatment of Stimulant Dependence where current evidence for the PSUD treatment was discussed. Psychosocial and pharmacological treatment options were summarized in a Discussion Paper which aimed to encourage the Member States, treatment service providers, and researchers to consider including pharmacological treatment interventions for individuals affected by PSUD. ²⁸ The expert group concluded there is sufficient evidence to support the development of prescription psychostimulants assisted treatment protocols and conduct multi-country effectiveness and safety trials. A Research Collaborative Initiative was proposed, consisting of a coordinating node and a network of community-based treatment programs available to conduct clinical trials located in various countries, including the LMICs. The research consortium would focus on developing streamlined study designs and harmonizing outcome measures to permit data aggregation. The coordinating node would provide research, administrative, and data management support as well as training and technical assistance to all sites to maximize the efficient, coordinated approach to clinical trials research.

One of the Collaborative's first projects would be the pilot study of the stimulant-assisted outpatient treatment of individuals with severe PSUD, according to the previously mentioned recommendations. If this study shows promise, the next step might involve a multi-country study, in the model of the WHO Collaborative Study of opioid agonist use for the treatment of OUD, which has demonstrated effectiveness in culturally diverse settings in low-middle and high-income countries.

We note potential barriers for the implementation of the proposed approach. As many clinicians are concerned about the safety of prescription psychostimulant and therefore patients should be assessed prior to initiating treatment with a baseline electrocardiogram. Moreover, agonist-assisted treatments often face resistance from providers who believe that patients are replacing one drug with another and this skepticism can undermine the implementation efforts. Finally, it is possible that local regulatory agencies may have objections to treatment with high doses, as suggested here. To address that, safety studies have been conducted with lisdexamphetamine for AUD ²⁹ and CUD ³⁰ using up to 250mg/day, and that dose was safe and well-tolerated in both trials. As evidence of the safety of higher-dose prescription psychostimulants builds up, regulatory bodies around the world could be more prone to adopting them.

Conclusion

PSUD is a global problem with significant public health impact and no effective treatment. A medical model of treatment may be particularly impactful as it is likely to attract and engage patients currently not receiving care. Available evidence supports the effectiveness of the prescription stimulant agonist approach, combined with psychosocial interventions, with limited concerns about the safety or misuse of these medications. Using this approach, as modelled on the treatment of OUD, may lead to a decrease in stimulant use and related clinical and quality of life improvements. Considering the urgency of the problems, we argue that effectiveness and safety trials combined with implementation outcomes in community settings, including LMICs, should be initiated in a selected group of patients with severe forms of the disorder under close monitoring. Communities that seek solutions should not wait for additional confirmatory efficacy studies conducted only in high-income countries.