Measuring Objective and Subjective Sleep during Lisdexamfetamine Treatment of Acute Methamphetamine Withdrawal: A Feasibility Study.

INTRODUCTION: Sleep disturbance is common during methamphetamine (MA) use and withdrawal; however, the feasibility of combined subjective-objective measurement of sleep-wake has not been shown in this population. Actigraphy is a well-established, non-invasive measure of sleep-wake cycles with good concordance with polysomnography. This study aimed to investigate the feasibility and utility of using actigraphy and sleep diaries to investigate sleep during MA withdrawal. METHODS: We conducted a feasibility and utility study of actigraphy and sleep diaries during a clinical trial of lisdexamfetamine for MA withdrawal. Participants were inpatients for 7 days, wore an actigraph (Philips Actiwatch 2) and completed a modified Consensus Sleep Diary each morning. Participants were interviewed between days 3-5. RESULTS: Ten participants (mean age 37 years, 90% male) were enrolled. No participant removed the device prematurely. Participants interviewed (n = 8) reported that the actigraph was not difficult or distracting to wear or completion of daily sleep diary onerous. Actigraphic average daily sleep duration over 7 days was 568 min, sleep onset latency 22.4 min, wake after sleep onset (WASO) 75.2 min, and sleep efficiency 83.6%. Sleep diaries underreported daily sleep compared with actigraphy (sleep duration was 56 min (p = 0.008) and WASO 47 min (p < 0.001) less). Overall sleep quality was 4.4 on a nine-point Likert scale within the diary. CONCLUSIONS: Continuous actigraphy is feasible to measure sleep-wake in people withdrawing from MA, with low participant burden. We found important differences in self-reported and actigraphic sleep, which need to be explored in more detail.

Participant experiences in a pilot study for methamphetamine withdrawal treatment: Implications for retention.

INTRODUCTION: There is little knowledge of the perspectives of people who use methamphetamine and have participated in clinical trials, and none for interventions not intended to address abstinence. A better understanding of these experiences could lead to more patient centred clinical trial design. This study seeks to understand the experiences of people who completed a clinical trial of lisdexamfetamine for the treatment of acute methamphetamine withdrawal. METHODS: Thematic analysis of open-ended, semi-structured interviews with eight people who participated in an inpatient clinical trial of lisdexamfetamine for acute methamphetamine withdrawal. Interviews were conducted between days 3 and 6 of admission to an inner-city Sydney hospital. RESULTS: Participants described how research procedures, the research setting, and the investigational product affected their experiences while enrolled in a clinical trial. Of particular importance to participants were transparent and low burden trial procedures, a welcoming trial environment, trusting relationships and effective communication, which were linked with the participants' subsequent decision to remain enrolled in the trial. DISCUSSION: The experiences of participants in this clinical trial can be distilled into four meta-themes: agency, caring-trust, safety, and communication. Participants spontaneously linked these experiences with a capacity to remain enrolled in the study. By considering the experiences of trial participants in clinical trial design, researchers can improve the experiences of future trial participants and facilitate their choice to remain enrolled in clinical trials.

Pharmacological treatment for methamphetamine withdrawal: A systematic review and meta-analysis of randomised controlled trials.

ISSUES: Cessation of methamphetamine use may result in a characteristic withdrawal syndrome, no medication has been approved for this indication. This systematic review aims to assess the efficacy of pharmacotherapy for methamphetamine withdrawal, the first comprehensive meta-analysis since 2008. APPROACH: MEDLINE (1966-2020), CINAHL (1982-2020), PsychINFO (1806-2020) and EMBASE (1947-2020) were systematically searched. Studies were included if they were randomised controlled trials (RCT) investigating pharmacological treatments for methamphetamine withdrawal, reviewing outcomes of treatment discontinuation, mental health outcomes, withdrawal symptoms (including craving) and patient safety. The relative risk (RR) and weighted mean difference (MD) were used to meta-analyse dichotomous and continuous data respectively, with 95% confidence intervals. Risk of bias and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) assessments were conducted. KEY FINDINGS: Nine RCTs of six medications (n = 242 participants) met inclusion criteria, however, only six trials of four medications (n = 186) could be meta-analysed. Mean sample size across studies was 27 participants, and 88% of participants were male. The quality of evidence in this review varies from low to very low on GRADE assessments. Amineptine may reduce discontinuation rates (RR 0.22, 95% confidence interval [CI] 0.07, 0.72, p = 0.01), and improve global state (MD -0.49, 95% CI -0.80, -0.17), compared with placebo, however, this medication is no longer approved. No other medications improved any domain when compared with placebo. Due to lack of reporting safety profiles could not be established. CONCLUSIONS: There is insufficient evidence to indicate any medication is effective for the treatment of methamphetamine withdrawal. The poor quality of the evidence indicates a need for better powered, high-quality trials.

Lisdexamfetamine for the treatment of acute methamphetamine withdrawal: A pilot feasibility and safety trial.

BACKGROUND: There is no effective treatment for methamphetamine withdrawal. This study aimed to determine the feasibility and safety of a tapering dose of lisdexamfetamine for the treatment of acute methamphetamine (MA) withdrawal. METHODS: Open-label, single-arm pilot study, in an inpatient drug and alcohol withdrawal unit assessing a tapering dose of oral lisdexamfetamine dimesylate commencing at 250 mg once daily, reducing by 50 mg per day to 50 mg on Day 5. Measures were assessed daily (days 0-7) with 21-day telephone follow-up. Feasibility was measured by the time taken to enrol the sample. Safety was the number of adverse events (AEs) by system organ class. Retention was the proportion to complete treatment. Other measures included the Treatment Satisfaction Questionnaire for Medication (TSQM), the Amphetamine Withdrawal Questionnaire and craving (Visual Analogue Scale). RESULTS: Ten adults seeking inpatient treatment for MA withdrawal (9 male, median age 37.1 years [IQR 31.7-41.9]), diagnosed with MA use disorder were recruited. The trial was open for 126 days; enroling one participant every 12.6 days. Eight of ten participants completed treatment (Day 5). Two participants left treatment early. There were no treatment-related serious adverse events (SAEs). Forty-seven AEs were recorded, 17 (36%) of which were potentially causally related, all graded as mild severity. Acceptability of the study drug by TSQM was rated at 100% at treatment completion. Withdrawal severity and craving reduced through the admission. CONCLUSION: A tapering dose regimen of lisdexamfetamine was safe and feasible for the treatment of acute methamphetamine withdrawal in an inpatient setting.

Trial protocol of an open label pilot study of lisdexamfetamine for the treatment of acute methamphetamine withdrawal.

INTRODUCTION: Methamphetamine (MA) use disorder is an important public health concern. MA withdrawal is often the first step in ceasing or reducing use. There are no evidence-based withdrawal treatments, and no medication is approved for the treatment of MA withdrawal. Lisdexamfetamine (LDX) dimesilate, used in the treatment of attention deficit hyperactivity disorder and binge eating disorder has the potential as an agonist therapy to ameliorate withdrawal symptoms, and improve outcomes for patients. METHODS: A single arm, open-label pilot study to test the safety and feasibility of LDX for the treatment of MA withdrawal. Participants will be inpatients in a drug and alcohol withdrawal unit, and will receive a tapering dose of LDX over five days: 250mg LDX on Day 1, reducing by 50mg per day to 50mg on Day 5. Optional inpatient Days 6 and 7 will allow for participants to transition to ongoing treatment. Participants will be followed-up on Days 14, 21 and 28. All participants will also receive standard inpatient withdrawal care. The primary outcomes are safety (measured by adverse events, changes in vital signs, changes in suicidality and psychosis) and feasibility (the time taken to enrol the sample, proportion of screen / pre-screen failures). Secondary outcomes are acceptability (treatment satisfaction questionnaire, medication adherence, concomitant medications, qualitative interviews), retention to protocol (proportion retained to primary and secondary endpoints), changes in withdrawal symptoms (Amphetamine Withdrawal Questionnaire) and craving for MA (visual analogue scale), and sleep outcomes (continuous actigraphy and daily sleep diary). DISCUSSION: This is the first study to assess lisdexamfetamine for the treatment of acute MA withdrawal. If safe and feasible results will go to informing the development of multi-centre randomised controlled trials to determine the efficacy of the intervention.

One-third of people who inject drugs are at risk of incomplete treatment for Staphylococcus aureus bacteraemia: a retrospective medical record review.

Staphylococcus aureus bacteraemia (SAB) is often a complication of injecting drug use, and is associated with high morbidity and mortality. This article reports the first audit of inpatient parenteral treatment of SAB completion among people who inject drugs (PWID) in Australia. Of 198 patients admitted with SAB, 106 were analysed. Twelve PWID had an inpatient stay <14 days compared with seven non-PWID (34% vs 10%; P=0.002). Sixteen PWID experienced discharge against medical advice compared with zero non-PWID (46% vs 0%; P<0.001). Re-admission to hospital within 28 days was 2.5 times greater among PWID than non-PWID (31% vs 15%; P=0.026). Methadone dose <60 mg/day was associated with premature discharge in opioid-dependent PWID receiving methadone (n=21, 100% vs 31%; P=0.012).

Acute cardiopulmonary responses during expert trumpet performance.

Lung function and vascular effects of expert trumpet performance has not been elucidated. Airway mechanics, gas exchange and cardiovascular function were investigated in expert trumpeters during a challenging performance. Respiratory impedance was measured in expert trumpeters and violinist controls prior to and following performance. Electrocardiography, pulse oximetry, transcutaneous CO2 and pulse transit time were monitored continuously. Performance did not alter lung function or gas exchange, except for a reduction in transcutaneous CO2 in 14 expert trumpeters compared to 4 expert violinists. Heart rate variability and pulse transit time were significantly altered in the trumpeters only, associated with the performance ventilatory requirements with a weight to low frequency band reflecting elevated baroreflex feedback. Trumpet performance at an expert level does not have an acute effect on airway mechanics and gas exchange was maintained. Repetitive increased intrathoracic pressure during performance resulted in marked heart rate and vagal tone variability. This study reveals the high demands placed on autonomic modulation of the cardiac response to expert trumpet performance.

Pharmacological Treatment of Methamphetamine/Amphetamine Dependence: A Systematic Review.

BACKGROUND: Stimulant drugs are second only to cannabis as the most widely used class of illicit drug globally, accounting for 68 million past-year consumers. Dependence on amphetamines (AMPH) or methamphetamine (MA) is a growing global concern. Yet, there is no established pharmacotherapy for AMPH/MA dependence. A comprehensive assessment of the research literature on pharmacotherapy for AMPH/MA dependence may inform treatment guidelines and future research directions. METHODS: We systematically reviewed the peer-reviewed literature via the electronic databases PubMed, EMBASE, CINAHL and SCOPUS for randomised controlled trials reported in the English language examining a pharmacological treatment for AMPH/MA dependence or use disorder. We included all studies published to 19 June 2019. The selected studies were evaluated for design; methodology; inclusion and exclusion criteria; sample size; pharmacological and (if included) psychosocial interventions; length of follow-up and follow-up schedules; outcome variables and measures; results; overall conclusions and risk of bias. Outcome measures were any reported impact of treatment related to AMPH/MA use. RESULTS: Our search returned 43 studies that met our criteria, collectively enrolling 4065 participants and reporting on 23 individual pharmacotherapies, alone or in combination. Disparate outcomes and measures (n = 55 for the primary outcomes) across studies did not allow for meta-analyses. Some studies demonstrated mixed or weak positive signals (often in defined populations, e.g. men who have sex with men), with some variation in efficacy signals dependent on baseline frequency of AMPH/MA use. The most consistent positive findings have been demonstrated with stimulant agonist treatment (dexamphetamine and methylphenidate), naltrexone and topiramate. Less consistent benefits have been shown with the antidepressants bupropion and mirtazapine, the glutamatergic agent riluzole and the corticotropin releasing factor (CRF-1) antagonist pexacerfont; whilst in general, antidepressant medications (e.g. selective serotonin reuptake inhibitors [SSRIs], tricyclic antidepressants [TCAs]) have not been effective in reducing AMPH/MA use. CONCLUSIONS: No pharmacotherapy yielded convincing results for the treatment of AMPH/MA dependence; mostly studies were underpowered and had low treatment completion rates. However, there were positive signals from several agents that warrant further investigation in larger scale studies; agonist therapies show promise. Common outcome measures should include change in use days. Future research must address the heterogeneity of AMPH/MA dependence (e.g. coexisting conditions, severity of disorder, differences between MA and AMPH dependence) and the role of psychosocial intervention.