Randomised Controlled Trial (RCT) of cannabinoid replacement therapy (Nabiximols) for the management of treatment-resistant cannabis dependent patients: a study protocol.

BACKGROUND: The cannabis extract nabiximols (Sativex®) effectively supresses withdrawal symptoms and cravings in treatment resistant cannabis dependent individuals, who have high relapse rates following conventional withdrawal treatments. This study examines the efficacy, safety and cost-effectiveness of longer-term nabiximols treatment for outpatient cannabis dependent patients who have not responded to previous conventional treatment approaches. METHODS/DESIGN: A phase III multi-site outpatient, randomised, double-blinded, placebo controlled parallel design, comparing a 12-week course of nabiximols to placebo, with follow up at 24 weeks after enrolment. Four specialist drug and alcohol outpatient clinics in New South Wales, Australia. One hundred forty-two treatment seeking cannabis dependent adults, with no significant medical, psychiatric or other substance use disorders. Nabiximols is an oromucosal spray prescribed on a flexible dose regimen to a maximum daily dose of 32 sprays; 8 sprays (total 21.6 mg tetrahydrocannabinol (THC) and 20 mg cannabidiol (CBD)) four times a day, or matching placebo, dispensed weekly. All participants will receive six-sessions of individual cognitive behavioural therapy (CBT) and weekly clinical reviews. Primary endpoints are use of non-prescribed cannabis (self-reported cannabis use days, urine toxicology), safety measures (adverse events and abuse liability), and cost effectiveness (incremental cost effectiveness in achieving additional Quality Adjusted Life Years). Secondary outcomes include, improvement in physical and mental health parameters, substance use other than cannabis, cognitive functioning and patient satisfaction measures. DISCUSSION: This is the first outpatient community-based randomised controlled study of nabiximols as an agonist replacement medication for treating cannabis dependence, targeting individuals who have not previously responded to conventional treatment approaches. The study and treatment design is modelled upon an earlier study with this population and more generally on other agonist replacement treatments (e.g. nicotine, opioids). TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry: ACTRN12616000103460 (Registered 1st February 2016).

Cost Differences Between Teaching and Nonteaching Hospitals for Older Adults Requiring Emergency General Surgery Procedures in the State of Maryland.

BACKGROUND: Older adults (OAs; ≥ 65 years) comprise a growing population in the United States and are anticipated to require an increasing number of emergency general surgery procedures (EGSPs). The aims of this study were to identify the frequency of EGSPs and compare cost of care in OAs managed at teaching hospitals (THs) vs nonteaching hospitals (NTHs). METHODS: A retrospective review of data from the Maryland Health Services Cost Review Commission database from 2009 to 2018 for OAs undergoing EGSPs was undertaken. Data collected included demographics, all patient-refined (APR)-severity of illness (SOI), APR-risk of mortality (ROM), Charlson Comorbidity Index (CCI), EGSPs (partial colectomy (PC), small bowel resection, cholecystectomy, operative management of peptic ulcers, lysis of adhesions, appendectomy, and laparotomy, categorized hospital charges, length of stay (LOS), and mortality. RESULTS: Of the 55,401 OAs undergoing EGSPs in this study, 28,575 (51.6%) were treated at THs and 26,826 (48.4%) at NTHs. OAs at THs presented with greater APR-ROM (major 25.6% vs 24.9%, extreme 22.6% vs 22.0%, P=.01), and CCI (3.1±3 vs 2.7±2.8, P<.001) compared to NTHs. Lysis of adhesions, cholecystectomy, and PC comprised the overall most common EGSPs. Older adults at THs incurred comparatively higher median hospital charges for every EGSP due to increased room charges and LOS. Mortality was higher at THs (6.13% vs 5.33%, P<.001). CONCLUSION: While acuity of illness appears similar, cost of undergoing EGSPs for OAs is higher in THs vs NTHs due to increased LOS. Future work is warranted to determine and mitigate factors that increase LOS at THs.

Surgical Faculty Perception of Service-Based Advanced Practice Provider Impact: A Southwestern Surgical Congress Multicenter Survey.

BACKGROUND: A previous single-center survey of trauma and general surgery faculty demonstrated perceived positive impact of trauma and surgical subspecialty service-based advanced practice providers (SB APPs). The aim of this multicenter survey was to further validate these findings. METHODS: Faculty surgeons on teams that employ SB APPs at 8 academic centers completed an electronic survey querying perception about advanced practice provider (APP) competency and impact. RESULTS: Respondents agreed that SB APPs decrease workload (88%), length of stay (72%), contribute to continuity (92%), facilitate care coordination (87%), enhance patient satisfaction (88%), and contribute to best practice/safe patient care (83%). Fewer agreed that APPs contribute to resident education (50%) and quality improvement (QI)/research (36%). Although 93% acknowledged variability in the APP level of function, 91% reported trusting their clinical judgment. CONCLUSION: This study supports the perception that SB APPs have a positive impact on patient care and quality indicators. Areas for potential improvement include APP contribution to resident education and research/QI initiatives.

Bedside Incentive Spirometry Predicts Risk of Pulmonary Complication in Patients with Rib Fractures.

This retrospective chart review demonstrates the relationship between bedside incentive spirometry (ICS) volumes and risk of pulmonary complications. Two hundred patients admitted for rib fractures between April and October 2016 were reviewed. The inclusion criteria were age 18-98 years, diagnosis of rib or sternal fractures, and no procedures requiring postoperative intubation within 48 hours of admission. The exclusion criteria were intubation before arrival, unable to participate in ICS, or previous tracheostomy. ICS volumes recorded in daily progress notes were collected. Of 200 charts reviewed, 154 met the inclusion criteria. In all, 25 endured at least one pulmonary complication. The average ICS on admission was 1355 cc. Patients who did not experience a complication had significantly higher admission ICS volumes than those who did (1441 ± 660 cc vs 920 ± 451 cc, P = 0.0003). They also achieved higher volumes at discharge (1705 ± 662 cc vs 1211 ± 453 cc, P = 0.006). The groups had similar demographics. An admission ICS volume <1 L was associated with 3.3× relative risk of pulmonary complication. Lower volumes were also associated with discharge to nonhome locations. Bedside ICS is a useful tool to identify patients at risk of pulmonary complications from rib fractures. Patients with admission ICS volume <1 L carry a higher risk of complication.

Continuous Renal Replacement Therapy: Case Vignettes.

The most common indication for continuous renal replacement therapy (CRRT) in critically ill patients is acute kidney injury with hemodynamic instability. Typically, the patient has metabolic disturbances and potential or actual fluid overload that require intervention. Certain critical care diagnoses and/or conditions or therapies present unique CRRT management approaches. Case vignettes are used to present the unique management of CRRT in critically ill patients with rhabdomyolysis, heart failure, and respiratory failure requiring extracorporeal membrane oxygenation.

The prevalence of QT prolongation in a population of patients with substance use disorders.

INTRODUCTION AND AIMS: Drug induced QT prolongation occurs in patients with substance use disorders from prescription medications that prolong the QT, such as methadone. Knowing the prevalence of QT prolongation in this population is important for prescribers. This study aimed to investigate the prevalence of QT prolongation in patients with current substance use disorders. DESIGN AND METHODS: We undertook a retrospective review of electrocardiograms (ECG) from patients with substance use disorders from an urban general hospital with a large drug and alcohol service and toxicology unit. ECGs were taken from patients seen by the alcohol and drug unit over three years. The QT interval was measured manually on each ECG and defined as abnormal if above the line on the QT nomogram. The QT was also heart rate corrected using Fridericia's formula (QTcF) to investigate associated factors. RESULTS: Nine of 446 (2.0%; 95% confidence interval 1.0-3.9%) patients had an ECG with a prolonged QT interval. Three were prescribed methadone for opiate dependence (80, 90 and 125 mg daily), one also with hypokalemia; one prescribed escitalopram with hypokalaemia/hypomagnesaemia; three more with hypokalaemia alone. Only two patients had a prolonged QT with no identifiable cause. There was no association between QTcF and sex (P = 0.34), but there was a statistically significant association with age (Pearson R = 0.19, 95% confidence interval 0.10-0.28, P < 0.0001). DISCUSSION AND CONCLUSIONS: QT prolongation is rare in patients with substance use disorders and is most likely similar to the general population once cases related to methadone use and electrolyte abnormalities are excluded. [Scott AJ, Dunlop AJ, Brown A, Craig S. The prevalence of QT prolongation in a population of patients with substance use disorders. Drug Alcohol Rev 2017;36:239-244].

Effectiveness and cost-effectiveness of unsupervised buprenorphine-naloxone for the treatment of heroin dependence in a randomized waitlist controlled trial.

BACKGROUND: Access to opioid agonist treatment can be associated with extensive waiting periods with significant health and financial burdens. This study aimed to determine whether patients with heroin dependence dispensed buprenorphine-naloxone weekly have greater reductions in heroin use and related adverse health effects 12-weeks after commencing treatment, compared to waitlist controls and to examine the cost-effectiveness of this strategy. METHODS: An open-label waitlist RCT was conducted in an opioid treatment clinic in Newcastle, Australia. Fifty patients with DSM-IV-TR heroin dependence (and no other substance dependence) were recruited. The intervention group (n=25) received take-home self-administered sublingual buprenorphine-naloxone weekly (mean dose, 22.7±5.7mg) and weekly clinical review. Waitlist controls (n=25) received no clinical intervention. The primary outcome was heroin use (self-report, urine toxicology verified) at weeks four, eight and 12. The primary cost-effectiveness outcome was incremental cost per additional heroin-free-day. RESULTS: Outcome data were available for 80% of all randomized participants. Across the 12-weeks, treatment group heroin use was on average 19.02days less/month (95% CI -22.98, -15.06, p<0.0001). A total 12-week reduction in adjusted costs including crime of $A5,722 (95% CI 3299, 8154) in favor of treatment was observed. Excluding crime, incremental cost per heroin-free-day gained from treatment was $A18.24 (95% CI 4.50, 28.49). CONCLUSION: When compared to remaining on a waitlist, take-home self-administered buprenorphine-naloxone treatment is associated with significant reductions in heroin use for people with DSM-IV-TR heroin dependence. This cost-effective approach may be an efficient strategy to enhance treatment capacity.

The medical complications of alcohol use: understanding mechanisms to improve management.

The use of alcohol in a dependent or even a regular heavy pattern predisposes the drinker to a range of adverse consequences. These include a risk of direct harm from alcohol, including organ damage, mental health disorders and a range of social and legal problems associated with behaviours due to alcohol's effects. The range of organ damage associated with regular heavy alcohol consumption is well described. Much new information on the mechanisms by which damage occurs is available and is reviewed in this paper. New knowledge can assist in the development of more appropriate management strategies for those affected by the medical complications of alcohol use. Genetic susceptibility to tissue injury is explored and the reasons why many heavy drinkers do not appear to experience organ damage are considered. Approaches to the management of certain alcohol-related disorders are outlined.

Nabiximols as an agonist replacement therapy during cannabis withdrawal: a randomized clinical trial.

IMPORTANCE: There are no medications approved for treating cannabis dependence or withdrawal. The cannabis extract nabiximols (Sativex), developed as a multiple sclerosis treatment, offers a potential agonist medication for cannabis withdrawal. OBJECTIVE: To evaluate the safety and efficacy of nabiximols in treating cannabis withdrawal. DESIGN, SETTING, AND PARTICIPANTS: A 2-site, double-blind randomized clinical inpatient trial with a 28-day follow-up was conducted in New South Wales, Australia. Participants included 51 DSM-IV-TR cannabis-dependent treatment seekers. INTERVENTIONS: A 6-day regimen of nabiximols (maximum daily dose, 86.4 mg of Δ9-tetrahydrocannabinol and 80 mg of cannabidiol) or placebo with standardized psychosocial interventions during a 9-day admission. MAIN OUTCOMES AND MEASURES: Severity of cannabis withdrawal and cravings (Cannabis Withdrawal Scale), retention in withdrawal treatment, and adverse events. Secondary outcomes include postwithdrawal cannabis use, health outcomes, and psychosocial outcomes. RESULTS: Nabiximols treatment significantly reduced the overall severity of cannabis withdrawal relative to placebo (F8,377.97 = 2.39; P = .01), including effects on withdrawal-related irritability, depression, and cannabis cravings. Nabiximols had a more limited, but still positive, therapeutic benefit on sleep disturbance, anxiety, appetite loss, physical symptoms, and restlessness. Nabiximols patients remained in treatment longer during medication use (unadjusted hazard ratio, 3.66 [95% CI, 1.18-11.37]; P = .02), with 2.84 the number needed to treat to achieve successful retention in treatment. Participants could not reliably differentiate between nabiximols and placebo treatment (χ21 = 0.79; P = .67), and those receiving nabiximols did not report greater intoxication (F1,6 = 0.22; P = .97). The number (F1,50 = 0.3; P = .59) and severity (F1,50 = 2.69; P = .10) of adverse events did not differ significantly between groups. Both groups showed reduced cannabis use at follow-up, with no advantage of nabiximols over placebo for self-reported cannabis use (F1,48 = 0.29; P = .75), cannabis-related problems (F1,49 = 2.33; P = .14), or cannabis dependence (F1,50 < 0.01; P = .89). CONCLUSIONS AND RELEVANCE: In a treatment-seeking cohort, nabiximols attenuated cannabis withdrawal symptoms and improved patient retention in treatment. However, placebo was as effective as nabiximols in promoting long-term reductions in cannabis use following medication cessation. The data support further evaluation of nabiximols for management of cannabis dependence and withdrawal in treatment-seeking populations. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12611000398909.