Medicinal Cannabis Guidance and Resources for Health Professionals to Inform Clinical Decision Making.

PURPOSE: Interest in the use of cannabis as a medicine has markedly increased during the last decade, with an unprecedented number of patients now seeking advice or prescriptions for medicinal cannabis. Unlike other medicines prescribed by physicians, many medicinal cannabis products have not undergone standard clinical trial development required by regulatory authorities. Different formulations with varying strengths and ratios of tetrahydrocannabinol and cannabidiol are available, and this diversity of medicinal cannabis products available for a myriad of therapeutic indications adds to the complexity. Physicians face challenges and barriers in their clinical decision making with medicinal cannabis because of current evidence limitations. Research efforts to address evidence limitations are ongoing; in the interim, educational resources and clinical guidance are being developed to address the gap in clinical information and support the needs of health professionals. METHODS: This article provides an overview of various resources that health professionals may use when seeking information about medicinal cannabis in the absence of high-quality evidence and clinical guidelines. It also identifies examples of international evidence-based resources that support clinical decision making with medicinal cannabis. FINDINGS: Similarities and differences between international examples of guidance and guideline documents are identified and summarized. IMPLICATIONS: Guidance can help guide physicians in the individualized choice and dose of medicinal cannabis. Before quality clinical trials and regulator-approved products with risk management programs, safety data require clinical and academic collaborative pharmacovigilance.

Cannabidiol drug interaction considerations for prescribers and pharmacists.

INTRODUCTION: In light of the widespread use of non-prescribed and prescribed cannabidiol, the use of cannabidiol with other medications is likely, and this may result in drug interactions. AREAS COVERED: We aimed to ascertain if clinical guidance could be provided on the dose range at which cannabidiol drug interactions are likely to occur with concurrently prescribed medicines. Literature searches were conducted in Embase, MEDLINE, and PubMed from database inception to January 2022 using Emtree and MeSH terms. Reference list screening yielded further studies. Using currently available data, likely drug interactions of which prescribers of cannabidiol need to be aware, at the doses likely to cause clinically significant interactions, and drug dosing changes that may be needed are highlighted. EXPERT OPINION: We have provided an overview of evidence-based pharmacokinetic predictions and general guidance about the dose range at which clinically relevant cannabidiol drug interactions are likely. For an individual patient, there are inherent limitations in providing clinical guidance due to gaps in specific drug dose-response data and knowledge of individual pharmacokinetic profiles, including different co-morbidities, and concurrent medicines. Clinician awareness of cannabinoid pharmacology, along with clinical and therapeutic drug monitoring, are current best practice approaches to manage cannabinoid drug interactions.

NSW Cannabis Medicines Advisory Service preliminary survey results: enquirer perceptions and patient outcomes.

BACKGROUND: In 2018, an innovative, State government-funded cannabis medicines drug information service was established for health professionals in New South Wales (NSW). The NSW Cannabis Medicines Advisory Service (CMAS) provides expert clinical guidance and support to medical practitioners considering prescribing a cannabis medicine to their patient(s). AIMS: This research examines quality assurance and patient outcomes related to enquirers' experience with NSW CMAS. METHODS: Data collection involved an online, anonymous survey with two components. Following a health professional enquiry, quality assurance data were collected about the enquirers' experience with NSW CMAS. The second survey focussed on patient outcomes and provides real-world observational data about cannabis medicines safety and effectiveness across a wide range of indications. RESULTS: Data collection occurred between January 2020 and June 2021. Preliminary analyses were based on 68 quality assurance and 50 patient outcomes survey responses. General practitioners represented the highest proportion of survey responses (n = 33; 49%). The most common enquiry involved 'patient-specific advice' (n = 50; 74%). Patient-specific information provided by the service was mainly used for prescribing decision support (n = 45; 90%). CONCLUSIONS: Preliminary findings highlight the impact of an innovative cannabis medicines drug information service in supporting health professional clinical practice in an area of rapid knowledge translation. Quality assurance data indicate that the service is perceived well by the majority of enquirers. Patient outcomes data across a wide range of indications suggest some effectiveness and a reasonable safety profile for prescribed cannabis medicines for most patients.

Translational hurdles with cannabis medicines.

PURPOSE: Internationally, there has been widespread medical use of cannabis medicines before rigorous evaluations in randomised controlled trials (RCTs). Some advocates of medicinal use of cannabis argue that real-world evidence (RWE) can be a substitute for or at least supplement evidence from RCTs. We explore the utility, limitations and impact of RWE in the translation of cannabis medicines research into clinical practice using the established literature. METHODS: A literature search was performed via Embase and Medline using a diverse range of cannabinoid and RWE search terms. The review provides a snapshot of cannabis medicine RWE initiatives from around the world. RESULTS: Diverse and novel sources of real-world data and RWE include international cannabis registries, surveys, post-marketing data collection and use of electronic or digital health records. The strengths and limitations of using RWE in translational research are highlighted, along with the identification of barriers to RCTs involving cannabis medicines. CONCLUSIONS: RWE promises to play a significant role in the evaluation of cannabis medicines around the world. When used appropriately RWE may complement RCT data by providing valuable insights into cannabis medicine safety and effectiveness. TAKE HOME MESSAGES: It is important that real-world evidence (RWE) is used to complement rather than replace randomised controlled trial (RCT) evidence on cannabis medicines. Technological advances have created the opportunity to explore diverse and novel sources of cannabis medicine RWE. Although RWE may be more reflective of real-world clinical practice, it cannot provide conclusive evidence of the safety and efficacy of cannabis medicines. While acknowledging its limitations, RWE may nonetheless provide some guidance on safety and adverse events of cannabis medicines. RWE has already had a significant impact on the regulation of cannabis medicines.

Vancomycin therapeutic drug monitoring in paediatrics.

AIM: Vancomycin guidelines for therapeutic drug monitoring (TDM) aim to maximise efficacy while minimising toxicity and resistance. Vancomycin is effective against Staphylococcus aureus when it achieves area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC) > 400. Studies in children have shown that target trough concentrations poorly correlate to AUC/MIC > 400; however, they are used in practice for clinical convenience. This review in paediatric inpatients aims to audit performance against TDM guidelines and consider what changes are needed to optimise vancomycin monitoring. METHODS: Vancomycin prescriptions in patients younger than 18 years old were collected over a 15-month period. Primary outcome measures were vancomycin initial dose (mg/kg/day) and the timing and result of first trough concentration (mg/L). Secondary outcome measures were the numbers achieving recommended targets and whether appropriate dose adjustments were made in response to TDM. RESULTS: A total of 133 courses reached the time when TDM should occur. Average patient age was 6.5 years, and the average initial dose was 52.55 mg/kg/day (range 19.05-86.54 mg/kg). Only 25% of courses (n = 34) had a trough concentration measured at the recommended time. The mean trough concentration was 11.6 mg/L (range < 2.0-39.7). Of 40 patients with a low trough concentration, 50% continued without dose adjustment. CONCLUSION: As shown in the literature, there is a poor correlation between the vancomycin dose given and the trough concentration achieved. Given that recommendations for trough concentration monitoring are designed to simplify the process yet are poorly adhered to, a strategic plan to address these issues is needed.

Nutrition information in pregnancy: Where do women seek advice and has this changed over time?

AIM: Nutrition during pregnancy is fundamental to both the health of the mother and her baby. Sources of nutrition-related information are available via many sources but their accuracy is unknown. The present study aimed to (a) identify where women source their nutrition information during pregnancy and (2) assess the accuracy of nutrition information for pregnancy that is available on the internet. METHODS: A survey instrument that identified the main sources of nutrition information was administered to 68 pregnant women recruited online. Data from this survey were compared to previous similar surveys conducted with pregnant mothers across years 2008, 2011 and 2014. A content analysis of websites was simultaneously conducted to assess the accuracy of available information. RESULTS: The main source of nutrition information for a variety of topics was verbal communication from health professionals (% responses affirmative for that source ranged from 6.6% to 69% across survey years). There was an increasing trend in internet sourced information for most nutrition topics, but this source remained low for iodine across all years (range: 7.3%-15.9%). The internet was the main source of information for listeria/food safety (15.3%-32.4%) and healthy eating (25%-42%). Of the n = 165 websites identified by the content analysis, 82.4% (n = 136) were rated as accurate, with government (96.9%) and business/company (100%) sites having the highest accuracy. CONCLUSION: Verbal communication from health professionals remains the most important source of nutrition information for pregnancy. The high credibility of websites indicates this to be an additional resource. Further study into health literacy levels among women visiting these sites is needed to assess impact on dietary behaviour.

Developing professional education for primary healthcare providers about nutrition.

Nutrition care is an important component of primary health care as a way to promote positive lifestyle behaviours and reduce risks of chronic disease. Despite this, it appears that primary healthcare settings, including antenatal care, miss opportunities to deliver nutrition care. Time constraints, lack of nutrition knowledge and lack of confidence have been identified as barriers for primary healthcare providers in delivering nutrition care. Nutrition training to upskill primary healthcare providers to deliver nutrition care in a timely manner therefore appears warranted. This forum article discusses models and methods of continuing professional development (CPD) and the effectiveness of nutrition CPD for primary healthcare professionals. It includes a case study as an example of developing nutrition CPD for midwives using adult learning theory and concludes with implications for developing nutrition education resources for primary healthcare providers.

Optimising low-dose methotrexate for rheumatoid arthritis-A review.

Methotrexate at low doses (5-25 mg/week) is first-line therapy for rheumatoid arthritis. However, there is inter- and intrapatient variability in response, with contribution of variability in concentrations of active polyglutamate metabolites, associated with clinical efficacy and toxicity. Prescribing remains heterogeneous across population groups, disease states and regimens. This review examines current knowledge of dose-response of oral methotrexate in the setting of rheumatoid arthritis, and how this could help inform dosage regimens.

The pharmacokinetics and the pharmacodynamics of cannabinoids.

There is increasing interest in the use of cannabinoids for disease and symptom management, but limited information available regarding their pharmacokinetics and pharmacodynamics to guide prescribers. Cannabis medicines contain a wide variety of chemical compounds, including the cannabinoids delta-9-tetrahydrocannabinol (THC), which is psychoactive, and the nonpsychoactive cannabidiol (CBD). Cannabis use is associated with both pathological and behavioural toxicity and, accordingly, is contraindicated in the context of significant psychiatric, cardiovascular, renal or hepatic illness. The pharmacokinetics of cannabinoids and the effects observed depend on the formulation and route of administration, which should be tailored to individual patient requirements. As both THC and CBD are hepatically metabolized, the potential exists for pharmacokinetic drug interactions via inhibition or induction of enzymes or transporters. An important example is the CBD-mediated inhibition of clobazam metabolism. Pharmacodynamic interactions may occur if cannabis is administered with other central nervous system depressant drugs, and cardiac toxicity may occur via additive hypertension and tachycardia with sympathomimetic agents. More vulnerable populations, such as older patients, may benefit from the potential symptomatic and palliative benefits of cannabinoids but are at increased risk of adverse effects. The limited availability of applicable pharmacokinetic and pharmacodynamic information highlights the need to initiate prescribing cannabis medicines using a 'start low and go slow' approach, carefully observing the patient for desired and adverse effects. Further clinical studies in the actual patient populations for whom prescribing may be considered are needed, to derive a better understanding of these drugs and enhance safe and optimal prescribing.

Cannabis contaminants: sources, distribution, human toxicity and pharmacologic effects.

There has been a resurgence in interest and use of the cannabis plant for medical purposes. However, an in-depth understanding of plant contaminants and toxin effects on stability of plant compounds and human bioavailability is needed. This systematic review aims to assess current understanding of the contaminants of cannabis and their effect on human health, leading to the identification of knowledge gaps for future investigation. A systematic search of seven indexed biological and biomedical databases and the Cochrane library was undertaken from inception up to December 2017. A qualitative synthesis of filtered results was undertaken after independent assessment for eligibility by two reviewers. The common cannabis contaminants include microbes, heavy metals and pesticides. Their direct human toxicity is poorly quantified but include infection, carcinogenicity, reproductive and developmental impacts. Cannabis dosing formulations and administration routes affect the transformation and bioavailability of contaminants. There may be important pharmacokinetic interactions between the alkaloid active ingredients of cannabis (i.e. phytocannabinoids) and contaminants but these are not yet identified nor quantified. There is significant paucity in the literature describing the prevalence and human impact of cannabis contaminants. Advances in the availability of cannabis globally warrant further research in this area, particularly when being used for patients.

Author Correction: Exogenous Cannabinoid Efficacy: Merely a Pharmacokinetic Interaction?

In the original publication, Page 3, Sect. 4.3, the first sentence was incorrectly published.

Cannabinoid Disposition After Human Intraperitoneal Use: AnInsight Into Intraperitoneal Pharmacokinetic Properties in Metastatic Cancer.

BACKGROUND: Medicinal cannabis is prescribed under the provision of a controlled drug in the Australian Poisons Standard. However, multiple laws must be navigated in order for patients to obtain access and imported products can be expensive. Dose-response information for both efficacy and toxicity pertaining to medicinal cannabis is lacking. The pharmacokinetic properties of cannabis administered by traditional routes has been described but to date, there is no literature on the pharmacokinetic properties of an intraperitoneal cannabinoid emulsion. CASE DESCRIPTION: A cachectic 56-year-old female with stage IV ovarian cancer and peritoneal metastases presented to hospital with fevers, abdominal distension and severe pain, vomiting, anorexia, dehydration and confusion. The patient reported receiving an intraperitoneal injection, purported to contain 12g of mixed cannabinoid (administered by a deregistered medical practitioner) two days prior to presentation. Additionally, cannabis oil oral capsules were administered in the hours prior to hospital admission. RESULTS: THC concentrations were consistent with the clinical state but not with the known pharmacokinetic properties of cannabis nor of intraperitoneal absorption. THC concentrations at the time of presentation were predicted to be ~60ng/mL. Evidence suggests that blood THC concentrations >5ng/mL are associated with substantial cognitive and psychomotor impairment. The predicted time for concentrations to drop <5ng/mL was 49days after administration. DISCUSSION: The unusual pharmacokinetic properties of the case suggest that there is a large amount unknown about cannabis pharmacokinetic properties. The pharmacokinetic properties of a large amount of a lipid soluble compound given intraperitoneally gave insights into the absorption and distribution of cannabinoids, particularly in the setting of metastatic malignancy.

Laxative Use in Inpatients on Oxycodone/Naloxone Prolonged Release and Oxycodone Prolonged Release for Cancer and Non-cancer Pain.

OBJECTIVE: To examine the laxative prescriptions in hospital inpatients with cancer and non-cancer pain on oxycodone compared to oxycodone plus naloxone combination. DESIGN: Retrospective case note review. SETTING: A palliative care inpatient unit and a general medical ward in a large tertiary referral hospital. PARTICIPANTS: Eighty-four patients receiving oxycodone or combination oxycodone/naloxone on general medical (45 patients) and palliative care wards (39 patients). MAIN OUTCOME MEASURES: The primary recorded outcomes were regular opioid dose (milligrams per day) and number of prescribed laxatives (type, doses, and frequency per day). RESULTS: Sixty-three (75%) patients in the study were on at least one laxative. In the general medicine inpatients, those on combined oxycodone/naloxone received on average 3.7 laxative doses per day compared to the oxycodone patients receiving 1.6 doses a day. In the palliative medicine population, both groups received a similar number of laxatives, despite the oxycodone/naloxone patients being on lower opioid doses. CONCLUSION: This retrospective study of hospital inpatients with cancer and non-cancer pain found that laxative use was not reduced in those on combined oxycodone/naloxone compared to oxycodone alone, suggesting that despite the interpretations of the clinical trials in the phase IV setting, the addition of naloxone had no effect on reducing laxative use.

Exogenous Cannabinoid Efficacy: Merely a Pharmacokinetic Interaction?

Endocannabinoid pharmacology is now relatively well understood with a number of endocannabinoids and endogenous cannabinoid neurotransmitters identified and the pharmacokinetics relatively well ascertained. Further, the cannabinoid receptors are now molecularly and pharmacologically characterised and the cell processes involved in endocannabinoid transcription, synthesis, post-translational modification and protein expression are reported. Endogenous cannabinoids have been shown to have key roles in immune and pain pathways and neuro-behavioural signalling including appetite regulation. Significant recent interest has thus been shown in understanding these pathways to guide the development of agents that inhibit the natural catabolism of endogenous cannabinoids to modify pain and appetite, and to synthesise antagonists for the treatment of disease such as obesity. This research is concurrent with the renewed clinical interest in exogenous cannabinoids and their use in disease. However, the complex pharmacology and physiological effects of exogenous cannabinoids, either as individual components or in combination, as extracts or via administration of the whole plant in humans, are less well known. Yet as with all other therapeutics, including those derived from plants, knowledge of the pharmacokinetics and dynamics of the complete plant, the individual chemical molecules and their synthetic versions, including formulations and excipients is a standard part of drug development. This article covers the key pharmacological knowledge required to guide further exploration of the toxicity and efficacy of different cannabinoids and their formulations in blinded placebo-controlled studies.

Pharmacokinetic-Guided Dosing of New Oral Cancer Agents.

Generally, licensed drug-dosing recommendations for chemotherapy are based on results from clinical trials in which subjects are usually of relatively normal body size, middle-aged, and are relatively racially homogeneous, with minimal comorbidity and specific tumor characteristics. Very few nontrial patients meet these characteristics, resulting in clinical practice having to extrapolate dosing recommendations to the specific patient. There is insufficient research on the impact of obesity-associated physiological changes prevalent in patients with common cancers on standard pharmacokinetic and pharmacodynamic parameters. Yet quantifying the influence of obesity on the pharmacology of chemotherapy is vital, as dosing inappropriate for body composition (ie, flat dosing or mg/kg based on total body weight) may increase the risk of adverse events and reduce clinical effectiveness. Unfortunately, there are few cancer guidelines to aid clinicians in selecting the optimal dose in the obese-even recent guidelines are based predominantly on clinical opinion/current practice in treating obese patients, rather than evidence. Data in many other vulnerable groups, for example, those with significant comorbidity and older patients, are also scarce. Because of the known limitations of body surface area-guided dosing, therapeutic drug monitoring or pharmacokinetic-guided dosing, which predicts an individual's exposure, has increasingly been shown to be a powerful tool in cancer therapy. Used appropriately, it can adjust for differences in pharmacokinetic parameters not considered when body size-based dosing or "one dose fits all" is used. This review will focus predominantly on the rationale for pharmacokinetic-guided dosing of the newer oral molecularly targeted antineoplastics in people whose drug exposure is not predicted by their physiology or body composition.

Predicting drug interactions in addiction treatment.

It is not uncommon to be treating people with addiction who also have significant other health problems, including heart, renal or liver failure, diabetes and vascular disease. These conditions require regular medications to be taken. This can be a problem for people living with addiction and difficult social circumstances affecting compliance, among other issues. Our perspective provides a summary of general pharmacological factors affecting medicine taking in people with addiction problems, to provide a guide for hospital doctors in this setting.

Antenatal shared care: are pregnant women being adequately informed about iodine and nutritional supplementation?

OBJECTIVES: To assess nutrition-related knowledge and practices, including supplement use, of both pregnant women and healthcare providers that participate in antenatal shared care (ANSC). METHODS: Pregnant women enrolled in ANSC (n = 142) completed a knowledge and practices survey and a validated iodine-specific Food Frequency Questionnaire. General practitioners (GP) and nurses (N = 61) participating in the ANSC program completed a short survey which assessed their knowledge about nutrition for pregnancy, focussing on iodine. RESULTS: Both groups had poor knowledge about the importance and roles of iodine during pregnancy. Most women (82%) reported taking a supplement during their current pregnancy, and 70% were taking a supplement containing iodine. Only 26% of GPs discussed iodine supplementation with pregnant patients. The median (IQR) iodine intake of pregnant women was 189 (129-260) µg/day which meets the estimated average requirement (160 µg/day). Half (52%) of women's dietary iodine was provided by dairy foods, and only 7% came from fish and seafood. Most healthcare providers (74%) expressed interest in receiving ongoing professional education about iodine in pregnancy. CONCLUSION AND IMPLICATIONS: Ongoing nutrition education for ANSC health practitioners is required to ensure that women receive sufficient dietary advice for optimal pregnancy outcomes. Further research is required to address reasons behind dietary choices of Australian pregnant women.