There are currently no approved pharmacotherapies for managing methamphetamine dependence. N-acetylcysteine (NAC) has been found to reduce the craving for methamphetamine and other drugs, but its ...effect on methamphetamine use and other clinically related endpoints are uncertain. The N-ICE trial is evaluating the safety and efficacy of NAC as a take-home pharmacotherapy for methamphetamine dependence.
This is a two-arm parallel double-blind placebo-controlled three-site randomised trial (ratio 1:1) using permuted block randomisation, with variable block sizes. It is stratified by site, sex and whether the methamphetamine is injected or not. Participants (N = 180; 60 per site) need to be dependent on methamphetamine, interested in reducing their methamphetamine use and not currently receiving treatment for substance use disorders. The trial is being conducted in outpatient settings in Melbourne, Geelong and Wollongong, Australia. Participants will receive either 2400 mg oral NAC or a matched placebo, delivered as a take-home medication for 12 weeks. Two 600 mg capsules are self-administered in the morning and two more in the evening. Adherence is being monitored using eCAP™ medication bottle lids, which record the date and time of each occasion the bottle is opened. The primary outcome is methamphetamine use during the 12-week trial medication period, measured as (a) days of use, assessed using the timeline followback, and (b) methamphetamine-positive saliva tests, taken weekly. Secondary measures include weekly assessment of methamphetamine craving, severity of methamphetamine dependence, methamphetamine withdrawal symptoms and psychiatric symptoms (depression, suicidality, psychotic symptoms and hostility). Adverse events are monitored at each weekly assessment. Tolerability is assessed using the Treatment Satisfaction Questionnaire for Medication.
The N-ICE trial is the first clinical trial to assess whether NAC can reduce methamphetamine use. This trial will improve our understanding of the potential utility of NAC in managing methamphetamine dependence and clinically related outcomes. If found to be effective, take-home NAC could be a potentially scalable and affordable pharmacotherapy option for treating methamphetamine dependence.
Australian and New Zealand Clinical Trials Registry, ACTRN12618000366257 . Registered on 29 May 2018.
Globally, methamphetamine use has increased in prevalence in recent years. In Australia, there has been a dramatic increase in numbers of people seeking treatment, including residential ...rehabilitation, for methamphetamine use disorder (MUD). While residential rehabilitation is more effective for MUD than withdrawal treatment (i.e. "detoxification") alone, relapse rates remain high, with approximately half of rehabilitation clients using methamphetamine within 3 months of rehabilitation. "Approach bias modification" (ABM) is a computerised cognitive training approach that aims to dampen automatically triggered impulses to approach drugs and drug-related stimuli. ABM has been demonstrated to reduce alcohol relapse rates, but no randomised controlled trials of ABM for MUD have yet been conducted. We aim to test whether a novel "personalised" form of ABM, delivered during rehabilitation, reduces post-treatment methamphetamine use, relative to a sham-training control condition. Secondary outcomes will include dependence symptoms, cravings, and approach bias.
We aim to recruit 100 participants attending residential rehabilitation for MUD at 3 sites in the Melbourne metropolitan area. Participants will complete baseline measures of methamphetamine use, craving, dependence severity, and approach bias before being randomised to receiving 6 sessions of ABM or "sham" training. In the active condition, ABM will be personalised for each participant, using those methamphetamine images that they rate as most relevant to their recent methods of methamphetamine use as "avoidance" images and using positive images representing their goals or healthy sources of pleasure as "approach" images. Approach bias and craving will be re-assessed following completion of training, and methamphetamine use, dependence, and craving will be assessed 4 weeks and 3 months following discharge from residential treatment.
This study is the first randomised controlled trial of ABM for MUD and also the first ABM study to test using a personalised set of both approach and avoid images for ABM training. If effective, the low cost and easy implementation of ABM means it could be widely implemented as a standard part of MUD treatment.
Australian New Zealand Clinical Trials Registry ACTRN12620000072910. Registered on 30 January 2020 (prospectively registered): https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378804&isReview=true.
The cognitive profiles of people with methamphetamine use disorder are characterized by impulsivity and impairment in social cognition. However, previous studies have not fully accounted for the ...presence and impact of co-occurring mental health problems on these domains. For instance, psychotic symptoms are commonly experienced by people who use methamphetamine and may influence cognitive performance. We aimed to examine decision making and emotion recognition in individuals with methamphetamine use, compared to healthy controls, to map the nature and degree of impairments in relation to the presence of psychotic symptoms.
In this naturalistic study, we assessed reward-based decision-making and facial emotion recognition across three groups, methamphetamine-using individuals with (MAP, n = 29) and without psychotic symptoms (MNP, n = 70), and healthy controls (HC, n = 32).
In comparison to healthy controls, methamphetamine-using individuals presented with poorer performance on tasks of decision-making and emotion recognition. Emotion recognition was impaired across all methamphetamine-using individuals, with significantly poorer recognition of anger and sadness in those with psychotic symptoms.
We found specific impairments in emotion recognition in relation to psychotic symptoms in people who use methamphetamine regularly. This builds on previous evidence on cognitive profiles in methamphetamine use disorder, highlighting the need to assess co-morbid mental health and psychotic symptoms. Our finding that methamphetamine-using individuals with psychotic symptoms present with particular difficulties recognizing anger has implications for frontline clinicians.
Background: High-dose opioid prescribing is associated with an increased risk of harms, including death.
Objective: The aim of this article is to discuss the concept of high-risk opioid prescribing, ...as well as relevant management strategies for patients on >100 mg oral morphine equivalent daily dose (OMEDD). The six 'Rs' approach to managing high-risk opioid prescribing (Rotation of opioids; Reduction; Replacement pharmacotherapy; Reversal with naloxone; Referral; Restriction of supply) is discussed.
Discussion: The six Rs is an aide-memoire that summarises the management options available to mitigate the risk of high OMEDDs. However, an effective therapeutic alliance between clinician and patient remains the foundation of all risk mitigation strategies.
Methamphetamine dependence is a significant global health concern for which there are no approved medications. The cysteine prodrug, N-acetylcysteine (NAC), has been found to ameliorate glutamate ...dysregulation in addiction, and to reduce craving for methamphetamine and other drugs. We evaluated the efficacy and safety of NAC as a pharmacotherapy for methamphetamine dependence.
A parallel double-blind randomised placebo-controlled trial of people dependent on methamphetamine recruited from Geelong, Melbourne and Wollongong, Australia, between July 2018 and December 2019. Participants were randomised to receive either 12 weeks of oral NAC (2400 mg/day) or matched placebo, delivered as a take-home medication. The primary outcome was methamphetamine use, measured in two ways: (a) change in days of use in the past 4 weeks from baseline to weeks 4, 8 and 12, assessed using the Timeline Followback; and (b) methamphetamine-positive oral fluid samples taken weekly. Analyses were intention-to-treat and based on imputed data. Secondary outcomes were craving, severity of dependence, withdrawal severity and psychiatric symptoms (depression, suicidality, hostility and psychotic symptoms). Significance levels were p < 0.025 for primary outcomes and p < 0.01 for secondary outcomes. Adverse events were compared between groups by system organ class. The study was prospectively registered, ACTRN12618000366257.
Participants (N = 153; 59% male, mean SD age 38 8) were randomised to placebo (n = 77) or NAC (n = 76). Both groups had a median (IQR) of 24 (15–28) days of methamphetamine use in the 4 weeks prior to baseline. Both groups significantly reduced methamphetamine use (mean SE reduction of 7.3 1.2) days for placebo, 6.8 1.2 for NAC) but NAC did not reduce days of methamphetamine use more than placebo (group difference of 0.5 days, 97.5% CI -3.4–4.3). There was no significant effect of NAC on methamphetamine-positive oral fluid samples (placebo 79%, NAC 76%; mean difference -2.6, 97.5% CI -12.6–7.4). NAC did not significantly reduce craving, severity of dependence, withdrawal, suicidality, depression, hostility or psychotic symptoms relative to placebo. Adverse events did not differ significantly between placebo and NAC groups.
These findings suggest that take-home oral NAC has no significant effect on methamphetamine use or most clinically related outcomes amongst people who are dependent on the drug.
This research was funded by the Australian NHMRC (Project Grant No. 1128147).
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