Implementation of an integrated primary care prevention and management program for chronic low back pain (LBP): patient-reported outcomes and predictors of pain interference after six months.

BACKGROUND: Integrated primary care programs for patients living with chronic pain which are accessible, interdisciplinary, and patient-centered are needed for preventing chronicity and improving outcomes. Evaluation of the implementation and impact of such programs supports further development of primary care chronic pain management. This study examined patient-reported outcomes among individuals with low back pain (LBP) receiving care in a novel interdisciplinary primary care program. METHODS: Patients were referred by primary care physicians in four regions of Quebec, Canada, and eligible patients received an evidence-based interdisciplinary pain management program over a six-month period. Patients were screened for risk of chronicity. Patient-reported outcome measures of pain interference and intensity, physical function, depression, and anxiety were evaluated at regular intervals over the six-month follow-up. A multilevel regression analysis was performed to evaluate the association between patient characteristics at baseline, including risk of chronicity, and change in pain outcomes. RESULTS: Four hundred and sixty-four individuals (mean age 55.4y, 63% female) completed the program. The majority (≥ 60%) experienced a clinically meaningful improvement in pain intensity and interference at six months. Patients with moderate (71%) or high risk (81%) of chronicity showed greater improvement in pain interference than those with low risk (51%). Significant predictors of improvement in pain interference included a higher risk of chronicity, younger age, female sex, and lower baseline disability. CONCLUSION: The outcomes of this novel LBP program will inform wider implementation considerations by identifying key components for further effectiveness, sustainability, and scale-up of the program.

Pharmacokinetics of cannabichromene in a medical cannabis product also containing cannabidiol and Δ9-tetrahydrocannabinol: a pilot study.

PURPOSE: Cannabichromene (CBC) is a phytocannabinoid commonly found in cannabis, yet its acute post-dose pharmacokinetics (PK) have not been examined in humans. This is a secondary data analysis from a trial investigating Spectrum Yellow oil, an oral cannabis product used for medical purposes that contained 20 mg cannabidiol (CBD), 0.9 mg Δ9-tetrahydrocannabinol (THC), and 1.1 mg CBC, per 1 mL of oil. METHODS: Participants (N = 43) were randomized to one of 5 groups: 120 mg CBD, 5.4 mg THC, and 6.6 mg CBC daily; 240 mg CBD, 10.8 mg THC, and 13.2 mg CBC daily; 360 mg CBD, 16.2 mg THC, and 19.8 mg CBC daily; 480 mg CBD, 21.6 mg THC, and 26.4 mg CBC daily; or placebo. Study medication was administered every 12 h for 7 days. Plasma CBC concentrations were analyzed by a validated two-dimensional high-performance liquid chromatography-tandem mass spectrometry assay. RESULTS: After a single dose and after the final dose, the Cmax of CBC increased by 1.3-1.8-fold for each twofold increase in dose; the tmax range was 1.6-4.3 h. Based on the ratio of administered CBD, THC, and CBC to the plasma concentration, the dose of CBD was 18 times higher than the dose of CBC, yet the AUC0-t of CBD was only 6.6-9.8-fold higher than the AUC0-t of CBC; the dose of THC was similar to the dose of CBC, yet THC was quantifiable in fewer plasma samples than was CBC. CONCLUSIONS: CBC may have preferential absorption over CBD and THC when administered together. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry #ACTRN12619001450101, registered 18 October 2019.

Effectiveness and Tolerability of Dronabinol Use in Patients with Chronic Pain: A Retrospective Analysis of 12-Week Open-Label Real-World Data Provided by the German Pain e-Registry.

OBJECTIVE: To evaluate the effectiveness of Δ9-tetrahydrocannabinol (dronabinol [DRO]) as an add-on treatment in patients with refractory chronic pain (CP). METHODS: An exploratory retrospective analysis of 12-week data provided by the German Pain e-Registry on adult patients with treatment refractory CP who received DRO. RESULTS: Between March 10, 2017, and June 30, 2019, the German Pain e-Registry collected information on 89,095 patients with pain, of whom 1,145 patients (1.3%) received DRO (53.8% female, mean ± standard deviation age: 56.9 ± 10.6 years), and 70.0% documented use for the entire 12-week evaluation period. The average DRO daily dose was 15.8 ± 7.5 mg, typically in three divided doses (average DRO dose of 5.3 ± 2.1 mg). Average 24-hour pain intensity decreased from 46.3 ± 16.1 to 26.8 ± 18.7 mm on a visual analog scale (absolute visual analog scale difference: -19.5 ± 17.3; P < 0.001). Among patients who completed follow-up, an improvement from baseline of at least 50% was documented for pain (46.5%), activities of daily living (39%), quality of life (31.4%), and sleep (35.3%). A total of 536 patients (46.8%) reported at least one of 1,617 drug-related adverse events, none of which were serious, and 248 patients (21.7%) stopped treatment. Over the 12-week period, 59.0% of patients reported a reduction of other pain treatments, and 7.8% reported a complete cessation of any other pharmacological pain treatments. CONCLUSION: Add-on treatment with DRO in patients with refractory CP was well tolerated and associated with a significant improvement.

Longitudinal Relationship between the Introduction of Medicinal Cannabis and Polypharmacy: An Australian Real-World Evidence Study.

Background: Recent studies recommend medicinal cannabis (MC) as a potential treatment for chronic pain (CP) when conventional therapies are not successful; however, data from Australia is limited. This real-world evidence study explored how the introduction of MC related to concomitant medication use over time. Long-term safety also was examined. Methods: Data were collected by the Emerald Clinics (a network of seven clinics located across Australia) as part of routine practice from Jan 2020 toJan 2021. Medications were classified by group: antidepressants, benzodiazepines, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and total number of medications. Adverse events (AEs) were collected at each visit and subsequently coded using the Medical Dictionary for Regulatory Activities version 23 into the system organ class (SOC) and preferred term (PT). A total of 535 patients were analyzed. Results: The most common daily oral dose was 10 mg for delta-9-tetrahydrocannabinol (THC) and 15 mg for cannabidiol (CBD). With the introduction of MC, patients' total number of medications consumed decreased over the course of one year; significant reductions in NSAIDs, benzodiazepines, and antidepressants were observed (p < .001). However, the number of prescribed opioid medications did not differ from baseline to the end of one year (p = .49). Only 6% of patients discontinued MC treatment during the study. A total of 600 AEs were reported in 310 patients during the reporting period and 97% of them were classified as nonserious. Discussion. Though observational in nature, these findings suggest MC is generally well-tolerated, consistent with the previous literature, and may reduce concomitant use of some medications. Due to study limitations, concomitant medication reductions cannot be causally attributed to MC. Nevertheless, these data underscore early signals that warrant further exploration in randomized trials.

Clinical Profiles of Concurrent Cannabis Use in Chronic Pain: A CHOIR Study.

OBJECTIVE: Despite evidence of the analgesic benefits of cannabis, there remains a relative scarcity of research on the short- and long-term effects of cannabis use in individuals with chronic pain. DESIGN: The current study is a secondary analysis of clinical data from the Collaborative Health Outcomes Information Registry (CHOIR). SETTING: Data were drawn from a cohort of patients of a multidisciplinary tertiary care pain clinic. SUBJECTS: The study sample consisted of data from 7,026 new patient visits from CHOIR; of these, 1,668 patients with a follow-up time point within 180 days were included in a longitudinal analysis. METHODS: Clinical data were analyzed to characterize cross-sectional differences in pain and indicators of psychological and physical function according to self-reported, concurrent cannabis use. Additionally, a propensity score-weighted longitudinal analysis was conducted, examining cannabis use as a predictor of changes in clinical variables across time. RESULTS: Cross-sectional analyses suggested significantly poorer sleep and significantly higher intensities of pain, emotional distress, and physical and social dysfunction in patients reporting ongoing cannabis use; however, these differences were relatively small in magnitude. However, no differences between cannabis users and nonusers in terms of longitudinal changes in clinical variables were noted. DISCUSSION: Our results are among the first to examine concurrent cannabis use as a prognostic variable regarding trajectories of pain-related variables in tertiary care. Future studies may benefit from examining the effect of cannabis initiation, concurrent medication use, and specific aspects of cannabis use (dose, duration of use, or cannabis type) on clinical outcomes.

Frequency of cannabis and illicit opioid use among people who use drugs and report chronic pain: A longitudinal analysis.

BACKGROUND: Ecological research suggests that increased access to cannabis may facilitate reductions in opioid use and harms, and medical cannabis patients describe the substitution of opioids with cannabis for pain management. However, there is a lack of research using individual-level data to explore this question. We aimed to investigate the longitudinal association between frequency of cannabis use and illicit opioid use among people who use drugs (PWUD) experiencing chronic pain. METHODS AND FINDINGS: This study included data from people in 2 prospective cohorts of PWUD in Vancouver, Canada, who reported major or persistent pain from June 1, 2014, to December 1, 2017 (n = 1,152). We used descriptive statistics to examine reasons for cannabis use and a multivariable generalized linear mixed-effects model to estimate the relationship between daily (once or more per day) cannabis use and daily illicit opioid use. There were 424 (36.8%) women in the study, and the median age at baseline was 49.3 years (IQR 42.3-54.9). In total, 455 (40%) reported daily illicit opioid use, and 410 (36%) reported daily cannabis use during at least one 6-month follow-up period. The most commonly reported therapeutic reasons for cannabis use were pain (36%), sleep (35%), stress (31%), and nausea (30%). After adjusting for demographic characteristics, substance use, and health-related factors, daily cannabis use was associated with significantly lower odds of daily illicit opioid use (adjusted odds ratio 0.50, 95% CI 0.34-0.74, p < 0.001). Limitations of the study included self-reported measures of substance use and chronic pain, and a lack of data for cannabis preparations, dosages, and modes of administration. CONCLUSIONS: We observed an independent negative association between frequent cannabis use and frequent illicit opioid use among PWUD with chronic pain. These findings provide longitudinal observational evidence that cannabis may serve as an adjunct to or substitute for illicit opioid use among PWUD with chronic pain.

Examination of the Course of Low Back Pain Intensity Based on Baseline Predictors and Health Care Utilization Among Patients Treated in Multidisciplinary Pain Clinics: A Quebec Pain Registry Study.

OBJECTIVES: The study objectives were to identify baseline predictors of low back pain severity changes over a one-year period among patients attending multidisciplinary tertiary clinics and determine whether health care utilization impacts this outcome. METHODS: This is a retrospective cohort study using the Quebec Pain Registry (QPR). A total of 686 low back pain (LBP) patients (55.8% females, mean age = 56.51 ± 14.5 years) from the QPR were selected for this study. Patients completed self-report questionnaires and nurse-administered questionnaires before their first appointment at a multidisciplinary pain treatment center. Analysis was conducted using a linear growth model. RESULTS: There was a modest (10%) improvement in pain severity scores over a 12-month period. Pain catastrophizing and depressive symptoms predicted higher baseline levels of pain severity (P < 0.001). Having used self-management approaches over the past six months was associated with higher levels of pain severity at 12 months (P < 0.001). DISCUSSION: Results from this study showed no clear pattern of association between the use of different treatment disciplines and pain severiy over the first year after multidisciplinary treatment intervention. These results raise an important question as to the best way of utilizing scarce multidisciplinary resources to optimize cost-effectiveness and improve outcomes among complex, chronic LBP patients.

Long-Term Outcomes in the Management of Central Neuropathic Pain Syndromes: A Prospective Observational Cohort Study.

BACKGROUND: Central neuropathic pain syndromes are a result of central nervous system injury, most commonly related to stroke, traumatic spinal cord injury, or multiple sclerosis. These syndromes are distinctly less common than peripheral neuropathic pain, and less is known regarding the underlying pathophysiology, appropriate pharmacotherapy, and long-term outcomes. The objective of this study was to determine the long-term clinical effectiveness of the management of central neuropathic pain relative to peripheral neuropathic pain at tertiary pain centers. METHODS: Patients diagnosed with central (n=79) and peripheral (n=710) neuropathic pain were identified for analysis from a prospective observational cohort study of patients with chronic neuropathic pain recruited from seven Canadian tertiary pain centers. Data regarding patient characteristics, analgesic use, and patient-reported outcomes were collected at baseline and 12-month follow-up. The primary outcome measure was the composite of a reduction in average pain intensity and pain interference. Secondary outcome measures included assessments of function, mood, quality of life, catastrophizing, and patient satisfaction. RESULTS: At 12-month follow-up, 13.5% (95% confidence interval [CI], 5.6-25.8) of patients with central neuropathic pain and complete data sets (n=52) achieved a ≥30% reduction in pain, whereas 38.5% (95% CI, 25.3-53.0) achieved a reduction of at least 1 point on the Pain Interference Scale. The proportion of patients with central neuropathic pain achieving both these measures, and thus the primary outcome, was 9.6% (95% CI, 3.2-21.0). Patients with peripheral neuropathic pain and complete data sets (n=463) were more likely to achieve this primary outcome at 12 months (25.3% of patients; 95% CI, 21.4-29.5) (p=0.012). CONCLUSION: Patients with central neuropathic pain syndromes managed in tertiary care centers were less likely to achieve a meaningful improvement in pain and function compared with patients with peripheral neuropathic pain at 12-month follow-up.

Cannabis and the Health and Performance of the Elite Athlete.

OBJECTIVE: Cannabis (marijuana) is undergoing extensive regulatory review in many global jurisdictions for medical and nonmedical access. Cannabis has potential impact on the health of athletes as well as on performance in both training and in competition. The aim of this general review is to identify and highlight the challenges in interpreting information with respect to elite athletic performance, and to point to important research areas that need to be addressed. DATA SOURCES: A nonsystematic literature review was conducted using Medline and PubMed for articles related to cannabis/marijuana use and sports/athletic performance; abstracts were reviewed by lead author and key themes identified and explored. MAIN RESULTS: Cannabis may be primarily inhaled or ingested orally for a range of medical and nonmedical reasons; evidence for efficacy is limited but promising for chronic pain management. Although evidence for serious harms from cannabis use on health of athletes is limited, one should be cognizant of the potential for abuse and mental health issues. Although the prevalence of cannabis use among elite athletes is not well-known, use is associated with certain high-risk sports. There is no evidence for cannabis use as a performance-enhancing drug. CONCLUSIONS: Medical and nonmedical cannabis use among athletes reflects changing societal and cultural norms and experiences. Although cannabis use is more prevalent in some athletes engaged in high-risk sports, there is no direct evidence of performance-enhancing effects in athletes. The potential beneficial effects of cannabis as part of a pain management protocol, including reducing concussion-related symptoms, deserve further attention.

Long-Term Outcomes in the Management of Painful Diabetic Neuropathy.

BACKGROUND: Painful diabetic neuropathy (PDN) is a frequent complication of diabetes mellitus. Current treatment recommendations are based on short-term trials, generally of ≤3 months' duration. Limited data are available on the long-term outcomes of this chronic disease. The objective of this study was to determine the long-term clinical effectiveness of the management of chronic PDN at tertiary pain centres. METHODS: From a prospective observational cohort study of patients with chronic neuropathic non-cancer pain recruited from seven Canadian tertiary pain centres, 60 patients diagnosed with PDN were identified for analysis. Data were collected according to Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials guidelines including the Brief Pain Inventory. RESULTS: At 12-month follow-up, 37.2% (95% confidence interval [CI], 23.0-53.3) of 43 patients with complete data achieved pain reduction of ≥30%, 51.2% (95% CI, 35.5-66.7) achieved functional improvement with a reduction of ≥1 on the Pain Interference Scale (0-10, Brief Pain Inventory) and 30.2% (95% CI, 17.2-46.1) had achieved both these measures. Symptom management included at least two medication classes in 55.3% and three medication classes in 25.5% (opioids, antidepressants, anticonvulsants). CONCLUSIONS: Almost one-third of patients being managed for PDN in a tertiary care setting achieve meaningful improvements in pain and function in the long term. Polypharmacy including analgesic antidepressants and anticonvulsants were the mainstays of effective symptom management.

International Olympic Committee consensus statement on pain management in elite athletes.

Pain is a common problem among elite athletes and is frequently associated with sport injury. Both pain and injury interfere with the performance of elite athletes. There are currently no evidence-based or consensus-based guidelines for the management of pain in elite athletes. Typically, pain management consists of the provision of analgesics, rest and physical therapy. More appropriately, a treatment strategy should address all contributors to pain including underlying pathophysiology, biomechanical abnormalities and psychosocial issues, and should employ therapies providing optimal benefit and minimal harm. To advance the development of a more standardised, evidence-informed approach to pain management in elite athletes, an IOC Consensus Group critically evaluated the current state of the science and practice of pain management in sport and prepared recommendations for a more unified approach to this important topic.

Partial recovery of abnormal insula and dorsolateral prefrontal connectivity to cognitive networks in chronic low back pain after treatment.

We previously reported that effective treatment of chronic low back pain (CLBP) reversed abnormal brain structure and functional MRI (fMRI) activity during cognitive task performance, particularly in the left dorsolateral prefrontal cortex (DLPFC). Here, we used resting-state fMRI to examine how chronic pain affects connectivity of brain networks supporting cognitive functioning and the effect of treatment in 14 CLBP patients and 16 healthy, pain-free controls (scans were acquired at baseline for all subjects and at 6-months post-treatment for patients and a matched time-point for 10 controls). The main networks activated during cognitive task performance, task-positive network (TPN) and task-negative network (TNN) (aka default mode) network, were identified in subjects' task fMRI data and used to define matching networks in resting-state data. The connectivity of these cognitive resting-state networks was compared between groups, and before and after treatment. Our findings converged on the bilateral insula (INS) as the region of aberrant cognitive resting-state connectivity in patients pretreatment versus controls. These findings were complemented by an independent, data-driven approach showing altered global connectivity of the INS. Detailed investigation of the INS confirmed reduced connectivity to widespread TPN and TNN areas, which was partially restored post-treatment. Furthermore, analysis of diffusion-tensor imaging (DTI) data revealed structural changes in white matter supporting these findings. The left DLPFC also showed aberrant connectivity that was restored post-treatment. Altogether, our findings implicate the bilateral INS and left DLPFC as key nodes of disrupted cognition-related intrinsic connectivity in CLBP, and the resulting imbalance between TPN and TNN function is partially restored with treatment.

Is the Quebec provincial administrative database a valid source for research on chronic non-cancer pain?

PURPOSE: The objective of this study was to evaluate the validity of diagnostic codes recorded in the Régie de l'assurance maladie du Québec (RAMQ) administrative database for identifying patients suffering from various types of chronic non-cancer pain. METHODS: The validity of published International Classification of Diseases, Ninth Revision, coding algorithms for identifying patients with particular chronic pain syndromes in the RAMQ database was tested using pain specialist-established diagnostic data of 561 patients enrolled in the Quebec Pain Registry, which was used as the reference standard. Modified versions of these algorithms (i.e., adaptation of the number of healthcare encounters) were also tested. For each algorithm, sensitivity, specificity, positive/negative predictive values, and their respective 95% confidence intervals (95%CI) were calculated. RESULTS: In the RAMQ database, some previously published algorithms and modified versions of these algorithms were found to be valid for identifying patients suffering from chronic lumbar pain (sensitivity: 0.65, 95%CI: 0.59-0.71; specificity: 0.83, 95%CI: 0.79-0.87), chronic back pain (sensitivity: 0.70, 95%CI: 0.64-0.76; specificity: 0.73, 95%CI: 0.68-0.78), and chronic neck/back pain (sensitivity: 0.71, 95%CI: 0.65-0.76; specificity: 0.78, 95%CI: 0.72-0.82). Algorithms to identify patients with other types of chronic pain showed low sensitivity: complex regional pain syndrome (≤0.07), fibromyalgia (≤0.42), and neuropathic pain (≤0.39). CONCLUSIONS: Our study provides evidence supporting the value of the RAMQ administrative database for conducting research on certain types of chronic pain disorders including back and neck pain. Users should, however, be cautious about the limitations of this database for studying other types of chronic pain syndromes such as complex regional pain syndrome, fibromyalgia, and neuropathic pain.

Physical Functioning and Opioid use in Patients with Neuropathic Pain.

OBJECTIVE: To evaluate the association between opioid dosage and ongoing therapy with physical function and disability in patients with neuropathic pain (NeP). DESIGN: Secondary analysis of a prospective cohort. SETTING: Multicenter clinical NeP registry. SUBJECTS: Seven hundred eighty-nine patients treated for various NeP diagnoses. METHODS: The following measures were included: dependent variables. 12-month self-reported physical function (pain disability index [PDI] and medical outcomes study short form-12 physical function [PCSS-12]); independent variables: baseline opioid dose (none, ≤200 mg and >200 mg of morphine equivalent), ongoing opioid use; potential confounding variables: age, sex, baseline pain intensity, and psychological distress (profile of mood states). Analysis of covariance models was created to examine the relationship between opioid therapy and both physical functioning outcomes with adjustment for confounding. RESULTS: Complete data was available for 535 patients (68%). Compared with the lower and high dose opioid groups, NeP patients not taking opioids had statistically lower disability and higher physical functioning scores, after adjusting for disease severity. Compared with patients prescribed opioid therapy on an ongoing basis, NeP patients who were not prescribed had statistically lower disability and higher physical functioning scores, after adjusting for disease severity. Improvements in disability and physical functioning scores from baseline and 12-months in all groups were modest and may not be clinically significant. CONCLUSIONS: Physical functioning and disability did not improve in patients with NeP who were prescribed opioids compared with those who are not prescribed, even after adjusting for disease severity.

Cannabis in medicine: a national educational needs assessment among Canadian physicians.

BACKGROUND: There is increasing global awareness and interest in the use of cannabis for therapeutic purposes (CTP). It is clear that health care professionals need to be involved in these decisions, but often lack the education needed to engage in informed discussions with patients. This study was conducted to determine the educational needs of Canadian physicians regarding CTP. METHODS: A national needs assessment survey was developed based on previous survey tools. The survey was approved by the Research Ethics Board of the McGill University Health Centre Research Institute and was provided online using LimeSurvey®. Several national physician organizations and medical education organizations informed their members of the survey. The target audience was Canadian physicians. We sought to identify and rank using 5-point Likert scales the most common factors involved in decision making about using CTP in the following categories: knowledge, experience, attitudes, and barriers. Preferred educational approaches and physician demographics were collected. Gap analysis was conducted to determine the magnitude and importance of differences between perceived and desired knowledge on all decision factors. RESULTS: Four hundred and twenty six responses were received, and physician responses were distributed across Canada consistent with national physician distribution. The most desired knowledge concerned "potential risks of using CTP" and "safety, warning signs and precautions for patients using CTP". The largest gap between perceived current and desired knowledge levels was "dosing" and "the development of treatment plans". CONCLUSIONS: We have identified several key educational needs among Canadian physicians regarding CTP. These data can be used to develop resources and educational programs to support clinicians in this area, as well as to guide further research to inform these gaps.

A Descriptive Analysis of Adverse Event Reports from the Quebec Cannabis Registry.

INTRODUCTION: Published data on the safety of natural medical cannabis (MC) when used in the real-world clinical practice setting are lacking. This study aimed to describe adverse events (AEs) reported across three years following MC initiation. METHODS: The Quebec Cannabis Registry (QCR) was a prospective registry of adults enrolled through participating physicians when they initiated MC between May 2015 and October 2018. Follow-up ended at MC discontinuation, loss to follow-up, three years, or end of data collection (May 2019). Data were collected at baseline and at follow-up visits every three months for the first two years, then once in the third year. Physicians filled adverse event (AE) reports, which were coded using MedDRA® preferred terms (PTs), and descriptive analyses were conducted. RESULTS: A total of 2991 patients were enrolled (mean age 50.9 years, 50.2% females). During follow-up, 108 patients (3.6%) experienced moderate or severe AEs, yielding 111 AE reports (three patients had two reports) and 214 AEs (average 1.9 AEs per report). Mild AEs were recorded as a reason for MC discontinuation for nine patients, but no AE reports were available. The most common PTs for ingested MC (62 reports) were dizziness (12.9%), nausea (11.3%), somnolence (9.7%), and vomiting (8.1%), and for inhaled MC (23 reports), headache (13.0%) was the most common. The most frequent PTs associated with tetrahydrocannabinol (THC)-dominant MC (25 reports) were dizziness and somnolence (12.0% each); for cannabidiol (CBD)-dominant MC (20 reports), vomiting (20.0%) was most common; and dizziness (17.2%), nausea (13.8%), somnolence (10.3%), and headache (8.6%) were the most frequent for balanced MC (58 reports). CONCLUSION: No new safety concerns were identified relative to the published literature, although notable differences in AE profile between modes of administration and cannabinoid content ratios should be considered by health professionals. Further work identifying and managing risk factors for AEs is warranted to maintain a favorable benefit-risk balance for MC.

The medicinal use of cannabis and cannabinoids--an international cross-sectional survey on administration forms.

Cannabinoids, including tetrahydrocannabinol and cannabidiol, are the most important active constituents of the cannabis plant. Over recent years, cannabinoid-based medicines (CBMs) have become increasingly available to patients in many countries, both as pharmaceutical products and as herbal cannabis (marijuana). While there seems to be a demand for multiple cannabinoid-based therapeutic products, specifically for symptomatic amelioration in chronic diseases, therapeutic effects of different CBMs have only been directly compared in a few clinical studies. The survey presented here was performed by the International Association for Cannabinoid Medicines (IACM), and is meant to contribute to the understanding of cannabinoid-based medicine by asking patients who used cannabis or cannabinoids detailed questions about their experiences with different methods of intake. The survey was completed by 953 participants from 31 countries, making this the largest international survey on a wide variety of users of cannabinoid-based medicine performed so far. In general, herbal non-pharmaceutical CBMs received higher appreciation scores by participants than pharmaceutical products containing cannabinoids. However, the number of patients who reported experience with pharmaceutical products was low, limiting conclusions on preferences. Nevertheless, the reported data may be useful for further development of safe and effective medications based on cannabis and single cannabinoids.

Residues from Homologous Transmembrane Helices 4 and 10 Are Critical for P-Glycoprotein (ABCB1)-Mediated Drug Transport.

P-glycoprotein (P-gp, ABCB1) transports structurally dissimilar hydrophobic and amphipathic compounds, including anticancer drugs, thus contributing to multidrug-resistant cancer. Cryo-EM structures of human P-gp revealed that TMHs 4 and 10 contribute to the formation of the drug-binding cavity and undergo conformational changes during drug transport. To assess the role of the conformational changes in TMH4 and TMH10 during drug transport, we generated two mutants (TMH4-7A and TMH10-7A), each containing seven alanine substitutions. Analysis of the drug efflux function of these mutants using 15 fluorescent substrates revealed that most of the substrates were transported, indicating that even seven mutations in an individual helix have no significant effect on transport function. We then designed the TMH4,10-14A mutant combining seven mutations in both TMHs 4 and 10. Interestingly, when the TMH4,10-14A mutant was tested with 15 substrates, there was no efflux observed for fourteen. The basal ATPase activity of the TMH4,10-14A mutant, similar to that of the WT protein, was inhibited by zosuquidar but was not stimulated by verapamil or rhodamine 6G. Molecular dynamics simulations indicated that the mutations cause TMHs 4 and 10 to pack tighter to their proximal helices, reducing their independent mobility. In aggregate, our findings demonstrate the critical role of the residues of homologous TMHs 4 and 10 for substrate transport, consistent with conformational changes observed in the structure of P-gp.