Safety and effectiveness of cannabinoids to Danish patients with treatment refractory chronic pain-A retrospective observational real-world study.

BACKGROUND: Cannabinoids are considered a therapeutic option to patients suffering from treatment refractory chronic pain (TRCP) insufficiently relieved by conventional analgesics or experiencing intolerable adverse events (AEs) from those. This study aimed to explore safety and effectiveness of oral cannabinoids among patients with TRCP. METHODS: A retrospective study was conducted among Danish patients with TRCP being prescribed oral cannabinoids. Data on AEs and changes in pain intensity by numeric rating scale (NRS) before and after initiation of oral cannabinoid therapy were analysed. RESULTS: Among 826 eligible patients ≥18 years old, 529 (64%) were included for data analysis at first follow-up (F/U1) (median 56 days from baseline) and 214 (26%) for second follow-up (F/U2) (median 126 days from F/U1). Mean age was 60 ± 15.9 years and 70% were females. AEs were in general reported mild to moderate by 42% of patients at F/U1 and 34% at F/U2. AEs were mainly related to gastrointestinal (F/U1: 17% and F/U2: 13%) and nervous system disorders (F/U1: 14% and F/U2: 11%). Reduction in NRS was significantly different at both follow-up consultations compared with baseline (<0.0001). Clinically relevant pain reduction (NRS ≥30%) was reported by 17% at F/U1 and 10% of patients at F/U2 in intention-to-treat analysis whereas the figures were 32% and 45% respectively, in per-protocol analysis. CONCLUSION: Oral cannabinoid therapy seems to be safe and mildly effective in patients with TRCP. Randomized controlled trials with focus on comparable pain characteristics in diagnostical homogenous patient subgroups are needed for further improvement of evidence level for relief of chronic pain using oral cannabinoids. SIGNIFICANCE: The findings in this retrospective study conducted in a real-world clinical setting suggest a favourable safety profile of cannabinoids. Moreover, one-sixth (intention-to-treat) and one-third (per-protocol) of patients with chronic pain refractory to conventional analgesics, or experiencing intolerable adverse effects, benefited significantly from therapy with oral cannabinoid regimens. Combination of THC and CBD seems overall more effective than cannabinoid monotherapy. Conduction of randomized controlled trials investigating safety and efficacy of cannabinoid therapy to diagnosis specific patient subgroups with comparable clinical and pathophysiological chronic pain characteristics is warranted, hence contributing further to the process of clinical evidence clarification currently in progress.

A Multicriteria Decision Analysis Comparing Pharmacotherapy for Chronic Neuropathic Pain, Including Cannabinoids and Cannabis-Based Medical Products.

Background: Pharmacological management of chronic neuropathic pain (CNP) still represents a major clinical challenge. Collective harnessing of both the scientific evidence base and clinical experience (of clinicians and patients) can play a key role in informing treatment pathways and contribute to the debate on specific treatments (e.g., cannabinoids). A group of expert clinicians (pain specialists and psychiatrists), scientists, and patient representatives convened to assess the relative benefit-safety balance of 12 pharmacological treatments, including orally administered cannabinoids/cannabis-based medicinal products, for the treatment of CNP in adults. Methods: A decision conference provided the process of creating a multicriteria decision analysis (MCDA) model, in which the group collectively scored the drugs on 17 effect criteria relevant to benefits and safety and then weighted the criteria for their clinical relevance. Findings: Cannabis-based medicinal products consisting of tetrahydrocannabinol/cannabidiol (THC/CBD), in a 1:1 ratio, achieved the highest overall score, 79 (out of 100), followed by CBD dominant at 75, then THC dominant at 72. Duloxetine and the gabapentinoids scored in the 60s, amitriptyline, tramadol, and ibuprofen in the 50s, methadone and oxycodone in the 40s, and morphine and fentanyl in the 30s. Sensitivity analyses showed that even if the pain reduction and quality-of-life scores for THC/CBD and THC are halved, their benefit-safety balances remain better than those of the noncannabinoid drugs. Interpretation: The benefit-safety profiles for cannabinoids were higher than for other commonly used medications for CNP largely because they contribute more to quality of life and have a more favorable side effect profile. The results also reflect the shortcomings of alternative pharmacological treatments with respect to safety and mitigation of neuropathic pain symptoms. Further high-quality clinical trials and systematic comprehensive capture of clinical experience with cannabinoids is warranted. These results demonstrate once again the complexity and multimodal mechanisms underlying the clinical experience and impact of chronic pain.

Consensus recommendations on dosing and administration of medical cannabis to treat chronic pain: results of a modified Delphi process.

BACKGROUND: Globally, medical cannabis legalization has increased in recent years and medical cannabis is commonly used to treat chronic pain. However, there are few randomized control trials studying medical cannabis indicating expert guidance on how to dose and administer medical cannabis safely and effectively is needed. METHODS: Using a multistage modified Delphi process, twenty global experts across nine countries developed consensus-based recommendations on how to dose and administer medical cannabis in patients with chronic pain. RESULTS: There was consensus that medical cannabis may be considered for patients experiencing neuropathic, inflammatory, nociplastic, and mixed pain. Three treatment protocols were developed. A routine protocol where the clinician initiates the patient on a CBD-predominant variety at a dose of 5 mg CBD twice daily and titrates the CBD-predominant dose by 10 mg every 2 to 3 days until the patient reaches their goals, or up to 40 mg/day. At a CBD-predominant dose of 40 mg/day, clinicians may consider adding THC at 2.5 mg and titrate by 2.5 mg every 2 to 7 days until a maximum daily dose of 40 mg/day of THC. A conservative protocol where the clinician initiates the patient on a CBD-predominant variety at a dose of 5 mg once daily and titrates the CBD-predominant dose by 10 mg every 2 to 3 days until the patient reaches their goals, or up to 40 mg/day. At a CBD-predominant dose of 40 mg/day, clinicians may consider adding THC at 1 mg/day and titrate by 1 mg every 7 days until a maximum daily dose of 40 mg/day of THC. A rapid protocol where the clinician initiates the patient on a balanced THC:CBD variety at 2.5-5 mg of each cannabinoid once or twice daily and titrates by 2.5-5 mg of each cannabinoid every 2 to 3 days until the patient reaches his/her goals or to a maximum THC dose of 40 mg/day. CONCLUSIONS: In summary, using a modified Delphi process, expert consensus-based recommendations were developed on how to dose and administer medical cannabis for the treatment of patients with chronic pain.

Efficacy and safety of cannabidiol followed by an open label add-on of tetrahydrocannabinol for the treatment of chronic pain in patients with rheumatoid arthritis or ankylosing spondylitis: protocol for a multicentre, randomised, placebo-controlled study.

INTRODUCTION: Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are chronic, systemic, inflammatory diseases, primarily in the musculoskeletal system. Pain and fatigue are key symptoms of RA and AS. Treatment presents a clinical challenge for several reasons, including the progressive nature of the diseases and the involvement of multiple pain mechanisms. Moreover, side effects of pain treatment pose an implicit risk. Currently, no well-controlled studies have investigated how medical cannabis affects pain and cognitive functions in RA and AS. The present study aims to evaluate the efficacy and safety of medical cannabis in the treatment of persistent pain in patients with RA and AS with low disease activity. METHODS AND ANALYSIS: A double-blinded, randomised, placebo-controlled study of cannabidiol (CBD), followed by an open label add-on of tetrahydrocannabinol (THC) with collection of clinical data and biological materials in RA and AS patients treated in routine care. The oral treatment with CBD in the experimental group is compared with placebo in a control group for 12 weeks, followed by an observational 12-week period with an open label add-on of THC in the primary CBD non-responders. Disease characteristics, psychological parameters, demographics, comorbidities, lifestyle factors, blood samples and serious adverse events are collected at baseline, after 12 and 24 weeks of treatment, and at a follow-up visit at 36 weeks. Data will be analysed in accordance with a predefined statistical analysis plan. ETHICS AND DISSEMINATION: The Danish Ethics Committee (S-20170217), the Danish Medicines Agency (S-2018010018) and the Danish Data Protection Agency approved the protocol. The project is registered in the European Clinical Trials Database (EudraCT 2017-004226-15). All participants will give written informed consent to participate prior to any study-related procedures. The results will be presented at international conferences and published in peer-reviewed journals.

The role of capnography in endoscopy patients undergoing nurse-administered propofol sedation: a randomized study.

OBJECTIVE. Standard benzodiazepine/opioid cocktail has proven inferior to propofol sedation during complicated endoscopic procedures and in low-tolerance patients. Propofol is a short-acting hypnotic with a potential risk of respiratory depression at levels of moderate to deep sedation. The existing literature on capnography for endoscopy patients sedated with nurse-administered propofol sedation (NAPS) is limited. Can the addition of capnography to standard monitoring during endoscopy with NAPS reduce the number, duration, and level of hypoxia. MATERIALS AND METHODS. This study was a randomized controlled trial with an intervention group (capnography) and a control group (without capnography). Eligible subjects were consecutive patients for endoscopy at Gentofte Hospital compliant with the criteria of NAPS. RESULTS. Five hundred and forty patients, 263 with capnography and 277 without capnography, were included in the analysis. The number and total duration of hypoxia was reduced by 39.3% and 21.1% in the intervention group compared to the control group (p > 0.05). No differences in actions taken against insufficient respiration were found. Changes in end-tidal carbon dioxide (R = 0.177, p-value < 0.001) and respiratory rate (R = 0.092, p-value < 0.001) were correlated to oxygen saturation (SpO2) up to 36 s prior to changes in SpO2. CONCLUSIONS. Capnography seems to reduce the number and duration of hypoxia in NAPS patients (p > 0.05). Capnography is able to detect insufficient respiration that may lead to hypoxia prior to changes in pulse oximetry. However, due to a limited clinical benefit and additional costs associated with capnography, we do not find capnography necessary during the use of NAPS.

Nurse administered propofol sedation for pulmonary endoscopies requires a specific protocol.

INTRODUCTION: This study provides an evaluation and risk analysis of propofol sedation for endoscopic pulmonary procedures according to our unit's "gastroenterologic nurse-administered propofol sedation (NAPS) guideline". MATERIAL AND METHODS: The present study is a prospective descriptive study performed at the Endoscopy Unit, Gentofte Hospital, Copenhagen, from May to July 2009. The study comprised at total of 51 consecutive patients who underwent 77 endoscopic procedures. Only patients above the age of 16 years were eligible for treatment. The exclusion criteria were as follows: American Society of Anesthesiologists (ASA) class > 3, history of sedation-related complications, severe chronic obstructive pulmonary disease. Excluded were patients with a potentially difficult airway and ventricular retention. Data on the number and type of procedure, baseline characteristics, sedation time, propofol dose administered and adverse events were obtained from medical histories. RESULTS: A total of 23 cases of adverse events were recorded, including one event of hypotension and 22 events of hypoxaemia. Five patients needed assisted ventilation. The frequency of hypoxaemia in sessions involving bronchoscopy was 17 of 26 (65%) compared with transoesophageal endoscopic ultrasound (EUS) (17 of 45, 35%) and endoscopic bronchial ultrasound (EBUS) (three of six, 50%). Endoscopist assessment of working conditions was good and patient assessment of discomfort was low. No patients required endotracheal intubation and there was no mortality. CONCLUSION: This study supports the conclusion that propofol administered by nurses provides for good working conditions and satisfied patients. But our "NAPS for endoscopic gastroenterologic procedures" guideline was unsuited for endoscopic pulmonary procedures including EUS. FUNDING: This work was supported by the START research foundation at Gentofte Hospital. TRIAL REGISTRATION: not relevant.

The impact of therapeutic hypothermia on neurological function and quality of life after cardiac arrest.

AIMS: To assess the impact of therapeutic hypothermia on cognitive function and quality of life in comatose survivors of out of Hospital Cardiac arrest (OHCA). METHODS: We prospectively studied comatose survivors of OHCA consecutively admitted in a 4-year period. Therapeutic hypothermia was implemented in the last 2-year period, intervention period (n=79), and this group was compared to patients admitted the 2 previous years, control period (n=77). We assessed Cerebral Performance Category (CPC), survival, Mini Mental State Examination (MMSE) and self-rated quality of life (SF-36) 6 months after OHCA in the subgroup with VF/VT as initial rhythm. RESULTS: CPC in patients alive at hospital discharge was significantly better in the intervention period with a CPC of 1-2 in 97% vs. 71% in the control period, p=0.003, corresponding to an adjusted odds ratio of a favourable cerebral outcome of 17, p=0.01. No significant differences were found in long-term survival (57% vs. 56% alive at 30 months), MMSE, or SF-36. Therapeutic hypothermia (hazard ratio: 0.15, p=0.007) and bystander CPR (hazard ratio 0.19, p=0.002) were significantly related to survival in the intervention period. CONCLUSION: CPC at discharge from hospital was significantly improved following implementation of therapeutic hypothermia in comatose patients resuscitated from OCHA with VF/VT. However, significant improvement in survival, cognitive status or quality of life could not be detected at long-term follow-up.

Long-term prognosis after out-of-hospital cardiac arrest.

OBJECTIVE: In this study we aimed to report survival beyond 6 months, including quality of life, for patients after out-of-hospital cardiac arrest (OHCA) with a physician-based EMS in an urban area. METHODS: We collected data related to OHCA prospectively during a 2-year period. Long-term survival was determined by cross-referencing our database with two Danish national registries. Patients older than 18 years who had survived for more than 6 months after OHCA were contacted, and after informed written consent was obtained, an interview was conducted in their home and a questionnaire on quality of life (SF-36) and the mini mental state examination (MMSE) were administered. RESULTS: We had data on 984 cases of OHCA. In 512 cases CPR was attempted and at 6 months, a total of 63 patients were alive corresponding to 12.3% [95% CI: 9.7-15.5%] of all who were treated. Of the 33 patients examined, the median MMSE was 29 (16-30) and two patients, corresponding to 6%, [95% CI: 0.7-20.6%] had an MMSE below 24. Two out of eight aspects of the SF-36 were significantly worse than national norms at the same age, but none of the summary scores differed significantly. CONCLUSION: Survival beyond 6 months was found in 12.3% OHCA in a physician-based EMS. Summary scores of quality of life were not significantly different from the national norm but 2 out of 8 subscores were lower. Signs of dementia were uncommon as only 6% had an MMSE score below 24.

[Therapeutic hypothermia after cardiac arrest--status]. / Hypotermibehandling efter hjertestop--en status.

Induced hypothermia in comatose patients resuscitated from cardiac arrest improves survival and neurological outcome when the initial rhythm is ventricular fibrillation. Results from 26 patients treated with early prehospital cooling, continued in hospital with cold fluids and body surface cooling, are presented. Sixteen patients had no or only minor neurological defects at discharge. Thirteen of 17 patients treated for ventricular fibrillation had a good cerebral outcome at discharge. Two patients had minor complications resulting from the treatment.

Outcome of out-of-hospital cardiac arrest--why do physicians withhold resuscitation attempts?

OBJECTIVE: To describe the outcome of out-of-hospital cardiac arrest (OHCA) with a focus on why physicians withhold resuscitation attempts. METHODS: Prospective collection of data during 12 months by the anaesthesiologists from the Advanced Life Support unit (ALS) of the Emergency Medical Service (EMS) according to the Utstein template. RESULTS: In total, 499 OHCA were analysed and 266 patients received cardiopulmonary resuscitation (CPR) by the ALS unit. Initial rhythm was ventricular fibrillation (VF)/pulseless ventricular tachycardia (VT) in 35%, asystole in 38%, and other rhythm in 27%. Of the 266 treated patients, 83 (31%) patients had a spontaneous circulation on admission to hospital. Survival to discharge from hospital was 6.2% for all cases of OHCA, 11.7% for all 266 treated patients, and 20.5% for patients with witnessed cardiac arrest and presumed cardiac aetiology in VF. On arrival, the physician decided in 233 cases to withhold or discontinue CPR. The explanation for this was prolonged anoxia (74%), terminal cancer (8%), and severe trauma (7%). The most common incident locations were the patient's home and nursing homes. These locations were more common in the group where resuscitation was not attempted and these patients were older and the proportions of females and asystole were significantly higher. Bystander CPR was provided in 82 (16%) overall, but only in 8 (3%) in the group where resuscitation was not attempted. CONCLUSION: Survival to discharge from hospital in all cases of OHCA was 6.2% but 20.5% in witnessed, presumed cardiac aetiology in VF. The decision to withhold resuscitation was based upon presumed prolonged anoxia in the majority of cases.