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 Quebec Cannabis Registry: Investigating the Safety and Effectiveness of Medical Cannabis.

Objective: To investigate the safety and effectiveness of medical cannabis (MC) in the real-world clinical practice setting. Design: A 4-year prospective noncomparative registry of adult patients who initiated MC for a variety of indications. This paper reports on patients followed for up to 12 months, with interim visits at 3, 6, and 9 months after enrollment. Setting: Public or private outpatient clinics certified to authorize MC in the province of Quebec, Canada. Participants: Overall, 2991 adult (age ≥18 years) patients (mean age 51 years; 50.2% women) were enrolled between May 2015 and October 2018, with the last follow-up ending in May 2019. Interventions/Exposures: Cannabis products (dried, oil, or other) purchased from a Canadian licensed cannabis producer as authorized by physicians. Main Outcome Measures: The primary outcomes were self-reported pain severity, interference and relief (Brief Pain Inventory [BPI]), symptoms using the Revised Edmonton Symptom Assessment System (ESAS-r) and health-related quality of life dimensions (EQ-5D-5L) at baseline and each follow-up visit. The secondary outcomes were self-reported adverse events (AEs) and characteristics of cannabis treatment. Results: All patient-reported outcomes (BPI, ESAS-r, and EQ-5D-5L) showed a statistically significant improvement at 3 months (all p<0.01), which was maintained or further improved (for pain interference, tiredness, and well-being) over the remainder of the 12-month follow-up. Results also revealed clinically significant improvements in pain interference and tiredness, anxiety, and well-being from baseline. There were 79 AE reports (77 patients), 16 met the regulatory definition of seriousness, in which only 8 AEs were certainly or probably related to MC. Conclusions: MC directed by physicians appears to be safe and effective within 3 months of initiation for a variety of medical indications.

Opioid Induced Hyperalgesia, a Research Phenomenon or a Clinical Reality? Results of a Canadian Survey.

BACKGROUND: Very little is known regarding the prevalence of opioid induced hyperalgesia (OIH) in day to day medical practice. The aim of this study was to evaluate the physician's perception of the prevalence of OIH within their practice, and to assess the level of physician's knowledge with respect to the identification and treatment of this problem. METHODS: An electronic questionnaire was distributed to physicians who work in anesthesiology, chronic pain, and/or palliative care in Canada. RESULTS: Of the 462 responses received, most were from male (69%) anesthesiologists (89.6%), in the age range of 36 to 64 years old (79.8%). In this study, the suspected prevalence of OIH using the average number of patients treated per year with opioids was 0.002% per patient per physician practice year for acute pain, and 0.01% per patient per physician practice year for chronic pain. Most physicians (70.2%) did not use clinical tests to help make a diagnosis of OIH. The treatment modalities most frequently used were the addition of an NMDA antagonist, combined with lowering the opioid doses and using opioid rotation. CONCLUSIONS: The perceived prevalence of OIH in clinical practice is a relatively rare phenomenon. Furthermore, more than half of physicians did not use a clinical test to confirm the diagnosis of OIH. The two main treatment modalities used were NMDA antagonists and opioid rotation. The criteria for the diagnosis of OIH still need to be accurately defined.

Cannabis in palliative care: current challenges and practical recommendations.

Pain and symptom control challenges are common in palliative care, and the search for other therapeutic strategies is ongoing. Unfortunately, patients and their caregivers are receiving little information or support from healthcare providers regarding the increasingly popular cannabinoid-based medicines (CBM). Clinicians, meanwhile, feel understandably perplexed by the discrepancy between the available evidence and the rapid interest in which patients and their families have demonstrated for CBM. There is an urgent need to address the many challenges that are delaying the appropriate integration of CBM into clinical practice, notwithstanding the obvious need for a solid general knowledge of pharmacology, mechanism of action and available clinical evidence supporting its use. The authors will address these challenges and provide practical recommendations regarding patient assessment for the use of CBM. The authors will also make suggestions regarding patient expectations in order to define clear objectives, review the necessary precautions prior to initiating treatment, aid in selecting the appropriate strain and route of administration as well as establishing proper titration and monitoring protocols. The authors will also discuss the lesser known but potentially therapeutic psychoactive effects of cannabis. As this class of therapeutic agents are likely to play a major role in palliative medicine in the near future, clinicians would benefit from familiarizing themselves with CBM and we can expect that patients and their caregivers will appreciate receiving support in their search for safe and effective therapeutic alternatives.

Relative frequency and risk factors for long-term opioid therapy following surgery and trauma among adults: a systematic review protocol.

BACKGROUND: When patients have been on opioid therapy for more than 90 days, more than half of them continue using opioids years later. Knowing that long-term opioid consumption could lead to harmful side effects including misuse, abuse, and addiction, it is important to understand the risks of transitioning to prolonged opioid therapy to reduce its occurrence. Perioperative and trauma contexts are ideal models commonly used to study such transition. Long-term use of opioids might be associated with transformation of acute pain to chronic, which might be an example of a risk factor. The objectives of this knowledge synthesis are to examine the relative frequency and the risk factors for transitioning to long-term opioid therapy among patients who have undergone a surgical procedure or experienced a trauma. METHODS: The proposed study methodology is based on Preferred ReportIng Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) statements on the conduct of systematic review and meta-analysis, the MOOSE Guidelines for Meta-Analyses and Systematic Reviews of Observational Studies, and the Cochrane Handbook for Systematic Review of Interventions. A systematic literature search will include multiple databases: Cochrane Central, EMBASE, MEDLINE, PsycINFO, CINHAL, PubMed, and the grey literature. We will identify studies related to opioid use beyond acute/subacute pain control after surgery or trauma. Two of the reviewers will screen all retrieved articles for eligibility and data extraction then critically appraise all identified studies. We will compile a narrative synthesis of all results and conduct a meta-analysis when feasible. As available data permits, we will perform a subgroup analysis of vulnerable populations. DISCUSSION: This systematic review will contribute to the prevention and harm reduction strategies associated with prescription opioids by identifying risk factors leading to the unwarranted long-term opioid therapy. The identification of common risk factors for long-term opioid therapy will help to orient further research on pain management as well as offer key therapeutic targets for the development of strategies to prevent prolonged opioid use. SYSTEMATIC REVIEW REGISTRATION: This protocol was registered in PROSPERO on March 2, 2018; registration number CRD42012018089907 .

Methadone as a Coanalgesic for Palliative Care Cancer Patients.

BACKGROUND: Methadone offers many advantages for treating cancer pain. However, its pharmacokinetic profile makes its use as a full-dose opioid challenging. OBJECTIVES: To evaluate the efficacy and safety of low-dose methadone as an adjunct to opioids in the treatment of cancer pain in palliative care patients. DESIGN: A cohort was followed retrospectively for up to 60 days after the initiation of methadone as a coanalgesic. SETTING/SUBJECTS: Patients were eligible if they were prescribed methadone as a coanalgesic for cancer pain management and followed by the palliative care team. MEASUREMENTS: The primary efficacy end point was reduction of pain intensity (11-point numerical rating scale). Variables associated with pain intensity reduction were explored using logistic regressions. Adverse events were collected throughout the follow-up. RESULTS: Seventy-two of the 146 subjects (49%) qualified as significant responders (≥30% reduction in pain intensity). Median time to significant response was seven days, and pain intensity on the day of methadone initiation predicted the response to treatment. The most frequently reported adverse events were drowsiness, confusion, constipation, and nausea. As expected in a palliative care population, there was a substantial amount of missing data. CONCLUSIONS: A significant reduction in pain can be seen rapidly after the addition of methadone as a coanalgesic, particularly among patients with high pain intensity. More studies are needed to corroborate the efficacy of methadone as an adjunct to opioids.

Efficacy of an intrathecal multidrug infusion for pain control in older adults and in end-stage malignancies: A report of three cases.

The aim of the present study was to explore the effectiveness of an alternative method to manage pain based on a time-limited intrathecal (IT) infusion of an analgesic medication mixture. Three patients (69, 64 and 94 years of age) with intractable and poorly controlled pain due to bed sores, pelvic metastatic mass, and thoracic vertebra and rib fractures, respectively, were treated. Daily doses of opioids could not be increased due to side effects. An IT catheter (20 G) was placed by percutaneous approach in the lumbar area while advancing toward the thoracic region, and was then tunnelled and fixed subcutaneously. It was connected to an external infusion pump with a mixture of bupivacaine 1 mg/mL, naloxone 0.02 ng/mL, ketamine 100 µg/mL, morphine 0.01 mg/mL and clonidine 0.75 µg/mL. The starting rate was 1 mL/h. The pain was mostly controlled at a rate of <1 mL/h. Opioid consumption was reduced dramatically. The catheter was kept in place for one month in the first and third patients, and for six months in the second patient, until his death. Major side effects, such as hypotension, constipation, muscle weakness, sphincter dysfunction, and cognitive or mood deterioration, were not observed with this approach. One patient experienced a urinary tract infection followed by sepsis and meningitis, which was cured by antibiotics. The catheter was removed in this patient. IT infusion with a low-concentration multidrug mixture could be considered as an alternative modality for intractable pain relief in older adults or in malignancies.