Pharmacodynamic effects following co-administration of cannabinoids and opioids: a scoping review of human experimental studies.

BACKGROUND: Cannabinoids are increasingly used in the management of chronic pain. Although analgesic potential has been demonstrated, cannabinoids interact with a range of bodily functions that are also influenced by chronic pain medications, including opioids. OBJECTIVE: We performed a scoping review of literature on the pharmacodynamic effects following the co-administration of cannabinoids and opioids. METHODS: We systematically searched EMBASE, PubMed, and PsycINFO for studies that experimentally investigated the co-effects of cannabinoids and opioids in human subjects. Available evidence was summarized by clinical population and organ system. A risk of bias assessment was performed. RESULTS: A total of 16 studies met the inclusion criteria. Study populations included patients with chronic non-cancer and cancer pain on long-term opioid regimens and healthy young adults without prior exposure to opioids who were subject to experimental nociceptive stimuli. Commonly administered cannabinoid agents included Δ9-tetrahydrocannabinol and/or cannabidiol. Co-administration of cannabinoids and opioids did not consistently improve pain outcomes; however, sleep and mood benefits were observed in chronic pain patients. Increased somnolence, memory and attention impairment, dizziness, gait disturbance, and nauseousness and vomiting were noted with co-administration of cannabinoids and opioids. Cardiorespiratory effects following co-administration appeared to vary according to duration of exposure, population type, and prior exposure to cannabinoids and opioids. CONCLUSIONS: The available evidence directly investigating the pharmacodynamic effects following co-administration of cannabinoids and opioids for non-analgesic outcomes is scarce and suffers from a lack of methodological reporting. As such, further research in this area with comprehensive methodologic reporting is warranted.

Metastatic progression following multimodal therapy for unfavorable-risk prostate cancer.

INTRODUCTION: Identifying the optimal management of unfavorable-risk (Prostate Cancer Risk Stratification [ProCaRS] high intermediate-, high-, and very high-risk categories) non-metastatic prostate cancer is an important public health concern given the large burden of this disease. We compared the rate of metastatic progression-free survival among men diagnosed with unfavorable-risk non-metastatic prostate cancer who were initially treated with radiation therapy or radical prostatectomy. METHODS: Information was obtained from medical records at two academic centers in Canada from 333 men diagnosed with unfavorable-risk non-metastatic prostate cancer between 2007 and 2012. Median followup was 90.4 months. Men were eligible for the study if they received either primary radiation therapy (n=164) or radical prostatectomy (n=169), in addition to various adjuvant and salvage therapies when deemed clinically appropriate. Patients were matched on prognostic covariates using two matching techniques. Multivariable Cox proportional hazards models were used to estimate the hazard ratios (HR) and confidence intervals (CI) for metastatic progression-free survival between groups. RESULTS: After matching, treatment groups were balanced on prognostic variables except for percent core positivity. Hazard ratios from all Cox proportional hazards models (i.e., before and after matching, and with and without multivariable adjustment) showed no difference in the rate of metastatic progression-free survival between groups (adjusted unmatched HR 1.16, 95% CI 0.63, 2.13, p=0.64). CONCLUSIONS: Metastatic progression-free survival did not differ between men diagnosed with unfavorable risk non-metastatic prostate cancer who were treated with either radiation therapy or radical prostatectomy.

Characterizing Surgical and Radiotherapy Outcomes in Non-metastatic High-Risk Prostate Cancer: A Systematic Review and Meta-Analysis.

Background Identifying the optimal management of high-risk non-metastatic prostate cancer (PCa) is an important public health concern, given the large burden of this disease. We performed a meta-analysis of studies comparing PCa-specific mortality (CSM) among men diagnosed with high-risk non-metastatic PCa who were treated with primary radiotherapy (RT) and radical prostatectomy (RP). Methods Medline and Embase were searched for articles between January 1, 2005, and February 11, 2020. After title and abstract screening, two authors independently reviewed full-text articles for inclusion. Data were abstracted, and a modified version of the Newcastle-Ottawa Scale, involving a comprehensive list of confounding variables, was used to assess the risk of bias. Results Fifteen studies involving 131,392 patients were included. No difference in adjusted CSM in RT relative to RP was shown (hazard ratio, 1.02 [95% confidence interval: 0.84, 1.25]). Increased CSM was found in a subgroup analysis comparing external beam radiation therapy (EBRT) with RP (1.35 [1.10, 1.68]), whereas EBRT combined with brachytherapy (BT) versus RP showed lower CSM (0.68 [0.48, 0.95]). All studies demonstrated a high risk of bias as none fully adjusted for all confounding variables. Conclusion We found no difference in CSM between men diagnosed with non-metastatic high-risk PCa and treated with RP or RT; however, this is likely explained by increased CSM in men treated with EBRT and decreased CSM in men treated with EBRT + BT studies relative to RP. High risk of bias in all studies identifies the need for better data collection and confounding control in the PCa research.

Propensity score matching versus coarsened exact matching in observational comparative effectiveness research.

Aim & methods: We compared propensity score matching (PSM) and coarsened exact matching (CEM) in balancing baseline characteristics between treatment groups using observational data obtained from a pan-Canadian prostate cancer radiotherapy database. Changes in effect estimates were evaluated as a function of improvements in balance, using results from randomized clinical trials to guide interpretation. Results: CEM and PSM improved balance between groups in both comparisons, while retaining the majority of original data. Improvements in balance were associated with effect estimates closer to those obtained in randomized clinical trials. Conclusion: CEM and PSM led to substantial improvements in balance between comparison groups, while retaining a considerable proportion of original data. This could lead to improved accuracy in effect estimates obtained using observational data in a variety of clinical situations.

Total energy expenditure and vigorous-intensity physical activity are associated with reduced odds of reclassification among men on active surveillance.

BACKGROUND: Research examining the association between physical activity (PA) and prostate cancer (PCa) has accumulated; however, few studies have examined this association in the context of active surveillance. The current study examines this among men initially diagnosed with favorable-risk PCa and managed by active surveillance at Sunnybrook Health Sciences Centre in Canada and the Royal Marsden Hospital in the United Kingdom. METHODS: Participants completed a questionnaire on daily participation in non-leisure, transport, and recreational PA. A logistic regression was employed using PA as the independent variable and whether the patient reclassified to higher-risk PCa while on active surveillance as the dependent variable. Demographic and lifestyle covariates were incorporated in the analysis to assess potential confounding and effect modification. RESULTS: Men from both hospitals presented with similar clinical and demographic characteristics. Total PA was inversely associated with odds of reclassification while on active surveillance (p-trend = 0.027). A weaker inverse association was observed with recreational PA (p-trend = 0.30). Men who participated in weekly vigorous PA were less likely to reclassify than those who did not (odds ratio (95% confidence interval): 0.42 (0.20-0.85)). CONCLUSIONS: Total and vigorous PA were inversely associated with odds of reclassification in two active surveillance cohorts. Given the limitations of this study, more robust prospective observational studies involving objective PA measures are warranted to confirm findings.

Diagnosis, referral, and primary treatment decisions in newly diagnosed prostate cancer patients in a multidisciplinary diagnostic assessment program.

INTRODUCTION: We aimed to report on data from the multidisciplinary diagnostic assessment program (DAP) at the Gale and Graham Wright Prostate Centre (GGWPC) at North York General Hospital (NYGH). We assessed referral, diagnosis, and treatment decisions for newly diagnosed prostate cancer (PCa) patients as seen over time, risk stratification, and clinic type to establish a deeper understanding of current decision-making trends. METHODS: From June 2007 to April 2012, 1277 patients who were diagnosed with PCa at the GGWPC were included in this study. Data was collected and reviewed retrospectively using electronic patient records. RESULTS: 1031 of 1260 patients (81.8%) were seen in a multidisciplinary clinic (MDC). Over time, a decrease in low-risk (LR) diagnoses and an increase intermediate-risk (IR) diagnoses was observed (p<0.0001). With respect to overall treatment decisions 474 (37.1%) of patients received primary radiotherapy, 340 (26.6%) received surgical therapy, and 426 (33.4%) had conservative management; 57% of patients who were candidates for active surveillance were managed this way. No significant treatment trends were observed over time (p=0.8440). Significantly, different management decisions were made in those who attended the MDC compared to those who only saw a urologist (p<0.0001). CONCLUSIONS: In our DAP, the vast majority of patients presented with screen-detected disease, but there was a gradual shift from low- to intermediate-risk disease over time. Timely multidisciplinary consultation was achievable in over 80% of patients and was associated with different management decisions. We recommend that all patients at risk for prostate cancer be worked up in a multi-disciplinary DAP.

Acute urinary retention in an adolescent girl and important learning points.

We presented a case of a 13-year-old girl who attended the emergency department with acute urinary retention and 1400 mL residual urine after catheterisation. She had no significant medical history, neurological examination was normal and she had not reached menarche. She was found to have a haematocolpos on ultrasound scan which was compressing the urinary bladder. Examination under anaesthesia confirmed an imperforate hymen and therefore an incision was performed and the haematocolpos drained. She managed to pass urine normally the day following her procedure. In this article, we emphasise on the differential diagnosis in this case and the learning points derived from it.

Trisomy of the G protein-coupled K+ channel gene, Kcnj6, affects reward mechanisms, cognitive functions, and synaptic plasticity in mice.

G protein-activated inwardly rectifying K+ channels (GIRK) generate slow inhibitory postsynaptic potentials in the brain via G(i/o) protein-coupled receptors. GIRK2, a GIRK subunit, is widely abundant in the brain and has been implicated in various functions and pathologies, such as learning and memory, reward, motor coordination, and Down syndrome. Down syndrome, the most prevalent cause of mental retardation, results from the presence of an extra maternal chromosome 21 (trisomy 21), which comprises the Kcnj6 gene (GIRK2). The present study examined the behaviors and cellular physiology properties in mice harboring a single trisomy of the Kcnj6 gene. Kcnj6 triploid mice exhibit deficits in hippocampal-dependent learning and memory, altered responses to rewards, hampered depotentiation, a form of excitatory synaptic plasticity, and have accentuated long-term synaptic depression. Collectively the findings suggest that triplication of Kcnj6 gene may play an active role in some of the abnormal neurological phenotypes found in Down syndrome.

Nonenzymatic rapid control of GIRK channel function by a G protein-coupled receptor kinase.

G protein-coupled receptors (GPCRs) respond to agonists to activate downstream enzymatic pathways or to gate ion channel function. Turning off GPCR signaling is known to involve phosphorylation of the GPCR by GPCR kinases (GRKs) to initiate their internalization. The process, however, is relatively slow and cannot account for the faster desensitization responses required to regulate channel gating. Here, we show that GRKs enable rapid desensitization of the G protein-coupled potassium channel (GIRK/Kir3.x) through a mechanism independent of their kinase activity. On GPCR activation, GRKs translocate to the membrane and quench channel activation by competitively binding and titrating G protein ßγ subunits away from the channel. Of interest, the ability of GRKs to effect this rapid desensitization depends on the receptor type. The findings thus reveal a stimulus-specific, phosphorylation-independent mechanism for rapidly downregulating GPCR activity at the effector level.

Automated QT analysis that learns from cardiologist annotations.

BACKGROUND: Reliable, automated QT analysis would allow the use of all the ECG data recorded during continuous Holter monitoring, rather than just intermittent 10-second ECGs. METHODS: BioQT is an automated ECG analysis system based on a Hidden Markov Model, which is trained to segment ECG signals using a database of thousands of annotated waveforms. Each sample of the ECG signal is encoded by its wavelet transform coefficients. BioQT also produces a confidence measure which can be used to identify unreliable segmentations. The automatic generation of templates based on shape descriptors allows an entire 24 hours of QT data to be rapidly reviewed by a human expert, after which the template annotations can automatically be applied to all beats in the recording. RESULTS: The BioQT software has been used to show that drug-related perturbation of the T wave is greater in subjects receiving sotalol than in those receiving moxifloxacin. Chronological dissociation of T-wave morphology changes from the QT prolonging effect of the drug was observed with sotalol. In a definitive QT study, the percentage increase of standard deviation of QT(c) for the standard manual method with respect to that obtained with BioQT analysis was shown to be 44% and 30% for the placebo and moxifloxacin treatments, respectively. CONCLUSIONS: BioQT provides fully automated analysis, with confidence values for self-checking, on very large data sets such as Holter recordings. Automatic templating and expert reannotation of a small number of templates lead to a reduction in the sample size requirements for definitive QT studies.

PIP2--the master key.

The function of inwardly rectifying K+ (Kir) channels is highly diverse and therefore is tightly regulated by various environmental factors. In their article in this issue of Neuron, Rapedius et al. recognize a conserved structural mechanism for Kir channels gating by both pH and PIP2. In light of these findings and accumulated knowledge, PIP2 is suggested to have a common coregulatory role in the gating of Kir channels by all their soluble modulators.