Search

Acute upper respiratory tract infections (URTIs) result from viral or bacterial pathogens that infect the upper airways. 1 URTIs comprise a range of conditions and symptoms such as cough, sore throat, acute otitis media (AOM), pharyngitis, tonsillitis, rhinitis, common cold, influenza, and sinusitis. 1 While serious complications are rare, patients can develop pneumonia and associated adverse sequelae. 1 A substantial proportion of health care visits to primary care and other family medicine settings are due to suspected URTIs. 2 Most URTIs are viral in origin, meaning they are unlikely to benefit from antibiotics and can often be effectively managed remotely with supportive treatments. Despite this knowledge, antibiotics are often inappropriately prescribed. 3 , 4 A descriptive analysis in Ontario estimated unnecessary antibiotic prescribing in primary care at rates of 48.4% for acute sinusitis and 52.6% for acute bronchitis. 5 Further, more than 80% of unnecessary antibiotic prescriptions were attributed to respiratory tract conditions and infections. 5 Overprescribing contributes to excessive use, unwanted side effects (e.g., allergic reactions, gastrointestinal symptoms, emergency department visits), 6 and antibiotic resistance. 7 Antibiotic resistance is a global public health threat and its reduction is a priority. 8 Initiatives such as Choosing Wisely aim to reduce antibiotic overuse and advise against using antibiotics for URTIs that are viral in origin. 7 However, while the risks of inappropriate and overuse are established, antibiotic prescribing is challenging and providers must balance the pressure of diagnostic uncertainty, time constraints, and patient expectations and preferences against the undesirable consequences of overprescribing. 8 Thus, there is interest in management approaches that aid decision-making and reduce excessive prescribing and use. Various interventions are available that address inappropriate antibiotic prescribing and the pressures of providing in-person care for patients with URTIs. These include delayed (post-dated) antibiotic prescriptions 9 Practical guidance and interventions continue to be required to assist clinicians in making care decisions for patients with upper respiratory tract symptoms. Resources such as the Using Antibiotics Wisely campaign’s updated 10 The desired outcome is to reduce the overprescribing of antibiotics and antibiotic resistance, and potentially to improve clinical outcomes (e.g., reduce harms from antibiotics) and reduce health care utilization such as hospital and emergency department visits. Changes to health care service delivery and organization due to the COVID-19 pandemic mean providers in primary care face difficulty in caring for patients with URTIs. 7 Practical guidance and interventions continue to be required to assist clinicians in making care decisions for patients with upper respiratory tract symptoms. Resources such as the Using Antibiotics Wisely campaign’s updated The Cold Standard toolkit provide resources for clinicians to support virtual and in-person management. 11 However, there continues to be an interest and need for evaluating contemporary evidence to identify which interventions might be most effective for supporting shared decision-making and optimizing the care of people with URTIs. This report aims to summarize the evidence regarding the clinical effectiveness of delayed antibiotic prescription-filling interventions and other family medicine interventions to influence the use of antibiotics for suspected acute URTIs., (Copyright © 2021 Canadian Agency for Drugs and Technologies in Health.)

Chronic post-operative pain (or chronic post-surgical pain [CPSP]) is a potential long-term complication of surgical interventions. CPSP is generally defined as pain that develops after a surgical intervention, lasts greater than 2 months, interferes with quality of life, is a continuation of pain developed in the acute phase post-surgery, or develops after a period with no pain, localized to the surgical area, and is not caused by other factors. 1 Prolonged post-operative pain can lead to high health care utilization and costs, poorer clinical outcomes for patients, and lower quality of life. 2 Depending on which surgery is performed, the incidence of lasting chronic pain can be from 5% to 85%. 3 In Ontario, chronic pain (in general) costs CA$1,742 per person in 2014 (approximately CA$10 billion per year). As CPSP is a common driver of the rates of chronic pain, CPSP contributes to a large portion of health care spending in Ontario, not including a patient’s direct or indirect out-of-pocket costs. 1 Additionally, the development of CPSP is linked to higher rates of opioid consumption. Persistent opioid use is associated with higher mortality and morbidity, and patients taking opioids to help with CPSP still report moderate to severe pain, higher disability, and lower overall global health. 4 As opioid use and misuse is a global epidemic, strategies to reduce the development of CPSP may lower the use of opioids for pain relief. Risk factors for the development of CPSP can include pain before and after the operation (and severity of that pain), the type of surgery being performed, posttraumatic negative affect, and pain catastrophizing (i.e., exaggeration of a negative mental health state). 1 In 1 systematic review examining factors related to the development of CPSP, 5 preoperative factors that showed significant correlation with pain development were younger age (excluding pediatric patients), female sex, smoking, history of depressive or anxiety symptoms, sleep difficulties, higher body mass index, preoperative pain, and use of preoperative analgesia. 6 Other suggested factors included genetics, length of surgery, and surgical techniques (e.g., type of surgical method, amount of trauma to area, and amount of tissue handling). 7 , 8 It has been proposed that tools that are used to measure these factors may be applicable in both predicting patients who may develop chronic pain and in the prevention of chronic pain. Tools that can classify patients as a higher risk may help physicians tailor both treatment and preventive measures for these patients or may prompt them to provide more intensive care. Validated tools to assess risk factors associated with CPSP include psychological assessments (e.g., Hospital Anxiety and Depression Scale, 9 Pain Anxiety Symptoms Scale, 10 Beck Depression Inventory, 11 Amsterdam Preoperative Anxiety and Information Scale), pain catastrophizing (e.g., pain catastrophizing scale 12 ), pain assessments (e.g., 6-factor risk model for CPSP 13 ), and quality of life assessments (e.g., EuroQuol 5-Dimensions Questionnaire 14 ). However, some models used to predict chronic pain can be narrow in that they do not include multiple surgical factors (e.g., laparoscopy versus open surgery) that can contribute to CPSP; specifically, they may not provide consistent definitions of psychosocial factors leading to CPSP and may not be fully validated in certain populations. 15 Additionally, these models may be underpowered (lacking large datasets required for accuracy) and do not identify all the factors relevant to CPSP. 15 With the goal of using validated tools for predicting the development of CPSP, it has been suggested that, if a patient is identified to be at high risk of developing CPSP, preventive measures could be taken. Some potential measures include providing preoperative analgesia, providing selective norepinephrine and serotonin reuptake inhibitors, using laparoscopic or less invasive surgery when possible, using regional anesthesia, and providing other pain-minimizing pharmaceuticals such as IV lidocaine, ketamine, or glucocorticoids. 8 The objective of this report is to summarize evidence regarding the clinical utility of perioperative screening or prediction tools for preventing CPSP., (Copyright © 2021 Canadian Agency for Drugs and Technologies in Health.)

Nutritional deficits can lead to side effects such as diarrhea, weight loss, inflammation of the tongue, and anemia, among other symptoms. 1 , 2 Malabsorption issues (issues absorbing macronutrients and micronutrients from food) can cause nutrient deficits and may be caused by damage to the intestines, (such as damage through gastrointestinal disorders) or through surgery (such as a removal of a portion of the intestine). Examples of other causes of nutrient deficits include major burns (causing hypermetabolism), 3 or acute kidney injury requiring renal replacement therapy. 4 Other solutions are colloquially termed “Myer’s cocktails” and may contain vitamin C, B complex, magnesium chloride, calcium gluconate, hydroxocobalamin, pyridoxine hydrochloride, and dexpanthenol. 5 Some IV administered solutions of multivitamins are colloquially termed “banana bags” and may contain a litre of IV fluid infused over 24 hours with a combination of thiamine, folic acid, magnesium, and a multivitamin. 5 Other solutions are colloquially termed “Myer’s cocktails” and may contain vitamin C, B complex, magnesium chloride, calcium gluconate, hydroxocobalamin, pyridoxine hydrochloride, and dexpanthenol. 6 The purpose of this review is to examine the clinical effectiveness of IV multivitamin therapy in patients that may require nutrient supplementation, who are not on total parenteral nutrition. This is in comparison to either no supplementation, or standard oral supplementation in patients who can orally ingest food. Additionally, the purpose of the review is to examine evidence-based guidelines regarding the use of IV multivitamin therapy. For the purposes of this report, “IV multivitamin therapy” includes vitamins and other micronutrients, such as minerals, as the classic “Myer’s cocktail” and “banana bags” both contain a mixture of vitamins and minerals. This report is an upgrade of a previous 2020 CADTH Reference List titled “Intravenous Multivitamin Therapy Use in Hospital or Outpatient Settings: Clinical Effectiveness and Guidelines”; 6 or in emergency departments, but its efficacy in certain populations, such as in individuals with alcohol use disorders is debated. 7 The purpose of this review is to examine the clinical effectiveness of IV multivitamin therapy in patients that may require nutrient supplementation, who are not on total parenteral nutrition. This is in comparison to either no supplementation, or standard oral supplementation in patients who can orally ingest food. Additionally, the purpose of the review is to examine evidence-based guidelines regarding the use of IV multivitamin therapy. For the purposes of this report, “IV multivitamin therapy” includes vitamins and other micronutrients, such as minerals, as the classic “Myer’s cocktail” and “banana bags” both contain a mixture of vitamins and minerals. This report is an upgrade of a previous 2020 CADTH Reference List titled “Intravenous Multivitamin Therapy Use in Hospital or Outpatient Settings: Clinical Effectiveness and Guidelines”; 8 therefore, studies identified in that report were evaluated for potential inclusion in this review., (Copyright © 2020 Canadian Agency for Drugs and Technologies in Health.)

The prevalence of valvular heart disease is around 2.5% in industrialized countries. 1 Valvular heart disease can occur in any of the four valves in the heart (pulmonary, mitral, aortic, and/or tricuspid valve) and can involve stiffening of the valve (stenosis), prolapse, or leaking (regurgitation). 2 These diseases can be congenital (developing at or before birth) or acquired (e.g. due to degeneration with age or an infection). 2 Symptoms may vary according to the severity of damage to the valve and its function, and include chest pain or tightness, palpitations, shortness of breath, and fatigue, among others. 2 In some patients, surgery may be required to repair or replace the heart valves. 2 One approach is to replace the damaged valve via open heart surgery, with a mechanical or biological valve (bioprosthesis). 2 An alternative approach, which is indicated and funded in Canada for the aortic valve, is to use a transcatheter procedure such as transcatheter aortic valve implantation (TAVI). 3 Here, the replacement valve is inserted using a catheter instead of via open heart surgery. 2 In recent years, transcatheter interventions have also been used off-label for tricuspid and mitral valves, where aortic valves are implanted in damaged tricuspid or mitral valves. 4 Among valvular heart disease interventions, those performed in the aortic position are by far the most common, followed by procedures in the mitral position, then tricuspid position. 5 In patients who initially received a mitral or tricuspid bioprosthesis, the bioprosthesis may degenerate over time, prompting consideration of additional repair or replacement. These patients can represent a challenge for further interventions in general, because they are often considered high risk for another surgery due to multiple co-morbidities or left ventricular dysfunction or pulmonary hypertension, or because there is limited evidence supporting surgical intervention of a degenerated mitral or tricuspid valve relative to medical management. 4 , 6 – 8 A less invasive approach such as transcatheter valve replacement, may be an attractive option in situations where there is a mitral or tricuspid bioprosthesis which has degenerated. 8 One approach is to insert an aortic valve in an existing degenerated mitral or tricuspid bioprosthesis using a catheter, which is termed a valve-in-valve (VIV or ViV) intervention. 4 The United States Food and Drug Administration approved use of the Edwards Sapien 3 valve for mitral VIV procedures in 2017, which is indicated “for patients with symptomatic heart disease due to failure of a previously placed bioprosthetic aortic or mitral valve whose risk of death or severe complications from repeat surgery is high or greater.” 9 Health Canada also approved the Edwards Sapien 3 in 2019 for “symptomatic heart disease due to a failing mitral surgical bioprosthetic valve (stenosed, insufficient, or combined) who are judged by a heart team to be at high or greater risk for open surgical therapy.” 10 However, there remains limited clinical experience with this technique and its use has been regarded as being at an early stage. 4 Therefore, it would be helpful to understand what evidence exists surrounding clinical effectiveness and cost-effectiveness of transcatheter aortic valves for degenerated mitral or tricuspid bioprostheses. Such evidence would be useful in informing whether this technique can be more widely adopted in a Canadian context, or whether more research is needed to inform decision and policy-making. The objective of this report is to summarize the evidence regarding the clinical effectiveness and cost-effectiveness of transcatheter aortic valve implantation for degenerated mitral or tricuspid bioprostheses., (Copyright © 2020 Canadian Agency for Drugs and Technologies in Health.)

Spinal Muscular Atrophy (SMA) is a neuromuscular disorder characterized by the degeneration of alpha motor neurons in the anterior horn of the spinal cord, which leads to progressive weakness of the muscles. 1 , 2 The majority of SMA cases (95%) are due to an autosomal recessive disorder caused by homozygous deletion and/or mutation of the alleles of the survival motor neuron 1 (SMN1) gene, causing deficiency in the survival motor neuron protein. 3 Nusinersen (Spinraza) has Health Canada’s approval for the treatment of 5q SMA. Nusinersen is an antisense oligonucleotide that binds to the SMN2 pre-messenger ribonucleic acid, this leads to increasing the proportion of exon 7 in SMN2 messenger ribonucleic acid transcripts, which ultimately is translated into functional SMN protein. , 4 A second set of genes, SMN2, is able to produce small amounts of the SMN protein. 3 , 4 The number of available SMN2 gene copies and the extent of the expression of these genes modulate the severity of the disease. 1 – 3 Nusinersen (Spinraza) has Health Canada’s approval for the treatment of 5q SMA. Nusinersen is an antisense oligonucleotide that binds to the SMN2 pre-messenger ribonucleic acid, this leads to increasing the proportion of exon 7 in SMN2 messenger ribonucleic acid transcripts, which ultimately is translated into functional SMN protein. 5 Nusinersen is administered via intrathecal injections of 12 mg in 5 mL solution at day 0, 14, 28, and 63, then given at four month intervals. 5 Nusinersen was reviewed through the CADTH Common Drug Review originally in 2017 and as a resubmission in 2019. On February 20, 2019, the CADTH Canadian Drug Expert Committee (CDEC) issued a recommendation to reimburse nusinersen for the treatment of 5q SMA if patients met the following conditions: 1. Genetic documentation of 5q SMA homozygous gene deletion, homozygous mutation, or compound heterozygote. 2. Patients who: a. are pre-symptomatic with two or three copies of SMN2, or b. have had disease duration of less than six months, two copies of SMN2, and symptom onset after the first week after birth and on or before seven months of age, or c. are 12 years of age or younger with symptom onset after six months of age, and never achieved the ability to walk independently. 3. Patient is not currently requiring permanent invasive ventilation. 6 . The CADTH CDEC recommendation identified the effectiveness of nusinersen treatment in patients older than 12 years of age as an evidence gap. The health technology assessment report that was the basis of this CDEC recommendation included two abstracts of descriptive case series of adult patients treated with nusinersen. However, these two abstracts did not provide sufficient information regarding the study design, patient information, or clinical outcomes, and could not be used as valid sources to inform on the potential effectiveness or safety of nusinersen in adolescent and adult patients with SMA. 7 Since then, new studies examining nusinersen treatment in adult patients with SMA have been published. The aim of this Rapid Response is to provide a peer-reviewed summary with critical appraisal of the recent evidence on the clinical effectiveness of nusinersen for the treatment of adult and adolescent patients with SMA who are older than 12 years of age., (Copyright © 2020 Canadian Agency for Drugs and Technologies in Health.)

Bronchoscopy is the insertion of an endoscope in the airways and is generally used for the diagnosis and management of a variety of lung conditions and respiratory disorders. 1 – 3 The two main types of bronchoscopy include rigid bronchoscopy and flexible bronchoscopy. 1 Sedation is used during bronchoscopy procedures to facilitate examination of the airways, decrease patient movement, and improve patient safety and comfort. Sedation can be induced with drugs such as benzodiazepines (e.g., midazolam), opioids (e.g., fentanyl), propofol, and ketamine. 2 Ketamine is a N-methyl-D aspartate receptor antagonist that produces a dissociative state, in which normally perceived sensory input (sight, hearing, touch) is blocked from reaching consciousness. 2 There is growing interest regarding the use for ketamine and how it compares with other agents for bronchoscopy procedures. The purpose of this report is to review the clinical effectiveness, and safety of ketamine use for bronchoscopy, and to review the evidence-based guidelines regarding the use of ketamine during bronchoscopy., (Copyright © 2020 Canadian Agency for Drugs and Technologies in Health.)

Nausea is defined as a subjectively unpleasant sensation associated with awareness of the urge to vomit, and vomiting refers to a forceful expulsion of gastric contents from the mouth, or labored, spasmodic, rhythmic contractions of the respiratory muscles without expulsion of gastric contents. 1 The conditions may be caused by multiple factors including organ failure, central nervous system disease, drug therapy, radiation, and gastrointestinal obstruction and pathology. 2 Nausea and vomiting are often associated with other symptoms such as pain, anxiety, depression, shortness of breath, drowsiness, loss of appetite, and tiredness that can negatively influence patients’ activities of daily living and significantly impact their quality of life. 3 The management of nausea and vomiting involves treatment of the underlying cause(s), supportive care measures, and the use of anti-emetics. , 4 The management of nausea and vomiting involves treatment of the underlying cause(s), supportive care measures, and the use of anti-emetics. 2 , 4 Anti-emetics are medications prescribed for the prevention of nausea and vomiting or use as a rescue treatment once symptoms develop. 5 There are many classes of anti-emetic drugs, including 5-HT3 receptor antagonists, NK-1 receptor antagonists, corticosteroids, butyrophenones, antihistamines, anticholinergics, and phenothiazines. 6 Ondansetron is the most well-studied 5-HT3 receptor antagonist and is considered by some to be the gold standard to which other anti-emetics are compared. 6 Ondansetron is commonly prescribed in the form of standard oral pills or tablets. 7 However, there are patients, including those in the palliative setting, for whom such formulations may not be suitable due to difficulty with swallowing caused by co-morbidities such as dysphagia. 8 This report aims to identify and summarize evidence on the comparative clinical effectiveness of oral versus injectable ondansetron formulations in adult patients requiring medication to control nausea or vomiting. An additional objective is to synthesize evidence on the comparative clinical effectiveness and cost-effectiveness of ondansetron versus other anti-emetic agents for palliative patients, as well as evidence-based guidelines for the use of ondansetron to control nausea or vomiting in that population., (Copyright © 2020 Canadian Agency for Drugs and Technologies in Health.)

Pain is a common experience. Generally, acute pain is defined as lasting less than three months, and chronic pain is defined as pain lasting three months or longer. 1 Acute pain includes pain from sprains, strains, and tendonitis; and muscle aches. Chronic pain includes pain associated with osteoarthritis (OA), neuropathic pain (NP), and back pain. 1 According to the Canadian Community Health Survey of individuals during the period 2007 to 2008, the prevalence of chronic pain in adults over the age of 18 years was 18.9% in Canada, and ranged between 16% and 22% for the different provinces. 2 Pain is associated with reduced quality of life, absenteeism from work, and substantial healthcare costs. 1 There are several treatment options for managing pain; both pharmacological and non-pharmacological options. A variety of pharmacological options such as non-steroidal anti-inflammatory drugs (NSAIDs), local anesthetics, tricyclic antidepressants, and capsaicin have been used for pain management. 1 , 3 Capsaicin, which is found in chili peppers, has been used as a topical agent to relieve pain. 4 It is a transient receptor potential vanilloid 1 receptor (TRPV1) agonist; it binds to nociceptors (sensory receptors responsible for sending signals that cause the perception of pain) in the skin, specifically to the TRVP1 receptor. This binding initially results in depolarization, initiation of action potential, and pain signal transmission to the spinal cord, and subsequently causes desensitization of the sensory axons and inhibition of pain transmission. 4 – 6 There are various formulations for capsaicin: cream, gel, lotion and patch. 5 It is available as low concentration (e.g., 0.025%, 0.075%, and 0.25%) and high concentration (e.g., 8%) product. 4 – 6 Several capsaicin products are available over-the-counter in Canada. According to a report dated 2018, capsaicin is available in Canada as a cream (0.025%, 0.05%, and 0.075%), gel (0.025%), and patch (0.025%), as well as in creams, gels, or lotions (0.025% or 0.035%) in combination with other active ingredients. 7 There appears to be some uncertainty regarding the therapeutic efficacy of capsaicin for the management of pain. 8 A recent CADTH rapid response report, 9 presented a summary and critical appraisal of evidence-based guidelines regarding capsaicin products for the treatment of acute and chronic non-cancer pain. There was variability in the recommendations for use of capsaicin for the management of pain due to OA. Two guidelines recommended the use of capsaicin (8%) patch as second line therapy for NP. The purpose of this report is to review the clinical effectiveness, safety and cost-effectiveness of capsaicin products for the treatment of acute and chronic non-cancer pain., (Copyright © 2020 Canadian Agency for Drugs and Technologies in Health.)

Pain is a common experience. Generally, acute pain is defined as lasting less than three months, and chronic pain is defined as pain lasting three months or longer. 1 Acute pain includes pain from sprains, strains, and tendonitis; and muscle aches. Chronic pain includes pain associated with osteoarthritis (OA), neuropathic pain (NP), and back pain. 1 According to the Canadian Community Health Survey of individuals during the period 2007 to 2008, the prevalence of chronic pain in adults over the age of 18 years was 18.9% in Canada, and ranged between 16% and 22% for the different provinces. 2 Pain is associated with reduced quality of life, absenteeism from work, and substantial healthcare costs. 1 There are several treatment options for managing pain; both pharmacological and non-pharmacological options. Capsaicin, which is found in chili peppers, has been used as a topical agent to relieve pain. 3 It is a transient receptor potential vanilloid 1 receptor (TRPV1) agonist; it binds to nociceptors (sensory receptors responsible for sending signals that cause the perception of pain) in the skin, specifically to the TRVP1 receptor. This binding initially results in depolarization, initiation of action potential, and pain signal transmission to the spinal cord, and subsequently causes desensitization of the sensory axons and inhibition of pain transmission. 3 – 5 There are various formulations for capsaicin: cream, gel, lotion and patch. 4 It is available as low concentration (e.g., 0.025%, 0.075%, and 0.25%) and high concentration (e.g., 8%) product. 3 – 5 According to a report dated 2018, capsaicin is available in Canada as a cream (0.025%, 0.05%, and 0.075%), gel (0.025%), and patch (0.025%), as well as in creams, gels, or lotions (0.025% or 0.035%) in combination with other active ingredients. 6 There appears to be some uncertainty regarding the therapeutic efficacy of capsaicin for the management of pain. 7 The purpose of this report is to review the evidence-based guidelines regarding capsaicin products for the treatment of acute and chronic non-cancer pain. A subsequent report will review the comparative clinical effectiveness, safety, and cost-effectiveness regarding capsaicin products for the treatment of acute and chronic non-cancer pain., (Copyright © 2020 Canadian Agency for Drugs and Technologies in Health.)

In Canada, about one in five adults older than 18 years of age live with chronic pain. 1 Pain can be sub-defined by three main biological mechanisms: 1) Nociceptive pain (from damage to body tissue, as in injury, disease or inflammation); 2) Neuropathic pain (from direct damage of the nervous system); and 3) Nociplastic pain (from a change in sensory neurons function). 1 Chronic pain is associated with significant emotional distress, like anxiety, anger, frustration and depression, and is recognized by the World Health Organization as a disease by itself listed in the International Classification of Disease version 11. 1 Treatment and management of chronic pain are complex and difficult, involving multiple interventions, including pharmacological and psychological interventions. 1 Pharmacological interventions considered for chronic pain include nonopioid analgesics (e.g., nonsteroidal anti-inflammatory drugs, acetaminophen), antidepressants, antiepileptic drugs, other adjuvant medications (e.g., topical agents, cannabis and cannabinoids), opioid, and infusion therapies (e.g., ketamine, lidocaine). 2 Ketamine, an N -methyl-D-aspartate (NMDA) receptor antagonist, has been approved and primarily used as an anesthetic induction agent in doses ranging between 1 and 4.5 mg/kg. 3 As it also interacts with other receptors, ketamine has been explored for other indications such as depressive disorders, suicidal ideation, substance-use disorders, anxiety disorders, refractory status epilepticus, bronchial asthma exacerbations, and pain management. 4 In hospital and emergency department, ketamine has been used for pain management of acute conditions such as burns, trauma, or post-operative pain. 2 Recently, intravenous (IV) ketamine infusions has been increasingly used as a treatment option for acute pain as well as chronic non-cancer pain such as complex regional pain syndrome (CRPS), neuropathic pain, and other refractory chronic pain conditions. 2 Despite potential opportunities of ketamine for numerous indications, the use of ketamine is known to be associated with psychotomimetic effects such as euphoria, dysphoria, psychomotor retardation, hallucinations, vivid dreams, and nightmares, as common side effects. Given the availability of ketamine of different formulations and its potential opportunities in pain management, there is a need to determine its benefits and risks in the treatment of chronic pain. The aim of this report is to review the evidence regarding the clinical effectiveness and cost-effectiveness of ketamine for treating chronic non-cancer pain in adults. This report also aims to review the evidence-based guidelines regarding the use of ketamine for chronic non-cancer pain., (Copyright © 2020 Canadian Agency for Drugs and Technologies in Health.)

Type 1 diabetes is a chronic autoimmune disease characterized by the destruction of pancreatic beta cells which leads to an insulin deficiency. 1 The onset of type 1 diabetes mostly occurs before 25 years of age, but can also occur later in life. 1 In 2015, 3.4 million Canadians were living with diabetes, of which an estimated 9% of adult patients and most pediatric patients are classified as type 1. Of this cohort, 0.3% of patients suffer from labile diabetes (also referred to as brittle or unstable diabetes and meaning hard to control) and may experience frequent episodes of hyperglycemia and hypoglycemia, diabetic ketoacidosis, and hypoglycemic unawareness. 2 The lability of these patients’ blood glucose levels leads to a decreased quality of life and may reduce life expectancy. 2 Type 1 diabetes is generally treated with insulin replacement therapy in the form of multiple daily injections. 1 However, one alternative to insulin therapy, which may be beneficial to patients with labile diabetes, involves restoring endogenous insulin production via islet cell transplantation. 3 Islet cell transplantation involves the infusion of purified islet cells from a deceased donor pancreas into the liver through the portal vein. 3 As such, islet cell transplantation recipients require life-long treatment with immunosuppressive agents. 3 With the introduction of ever improving, steroid free immunosuppression regimens (the first of which was the Edmonton Protocol in the year 2000), islet cell transplantation has become an increasingly feasible treatment option for patients with labile diabetes. 2 In patients with type 1 diabetes, islet cell transplantation may result in glucose stability (i.e., a reduction or elimination of hypoglycemia), improvement in glycated hemoglobin A1c (HbA1c), insulin independence, and may stabilize or improve microvascular complications (retinopathy and neuropathy) of diabetes. 3 However, as a result of the small number of specialized transplantation centers and donor pancreases, the availability of treatment with islet cell transplantations for patients with type 1 diabetes has been limited. 3 A CADTH report 4 published in 2014 reviewed the clinical effectiveness, cost-effectiveness, and evidence-based guidelines regarding islet cell transplantation in patients with unstable diabetes. The report concluded that there was limited evidence to suggest that islet transplantation was effective in improving clinical outcomes in patients with unstable type 1 diabetes. 4 Another CADTH report, 5 which examined islet cell transplantation relative to different interventions, was published in March 2020 and provided a reference list of studies and evidence-based guidelines published since the end of the aforementioned report’s literature search. This report aims to provide a summary and critical appraisal of the evidence regarding the clinical effectiveness, cost-effectiveness, and evidence-based guidelines regarding the use of islet cell transplantation in patients with unstable type I diabetes mellitus which was identified in the previous CADTH Reference List report. 5, (Copyright © 2020 Canadian Agency for Drugs and Technologies in Health.)

In Canada, 35% of injuries are related to sport or exercise. 1 Ankle injuries (sprain or strain) are among the most common types of injury (51%) presenting to the primary care offices and emergency departments. 1 There are three types of ankle sprain, the location of which is determined by the mechanism of injury: lateral ankle sprain (most common), medial ankle sprain, and syndesmotic sprain (high ankle sprain). 2 Ankle sprain is classified based on clinical signs and functional loss, as follows: grade 1 (mild stretching of a ligament), grade 2 (more severe injury involving incomplete tear of a ligament), and grade 3 (complete tear of a ligament). 2 The immediate goal for treatment of ankle sprain is to reduce pain and swelling. The RICE (rest, ice, compression, elevation) approach has been commonly used in the first two to three days following injury, although evidence on the effectiveness of RICE alone is still lacking. 2 Non-steroidal anti-inflammatory drugs (NSAIDs) can be used to reduce pain. However, the use of NSAIDs may delay the natural healing process due to their inflammatory suppressed mechanism. 3 Other modes of non-pharmacological treatment of ankle sprain, depending on the severity of the injury, include exercise, immobilization, manual mobilization and rehabilitation. 2 Early mobilization through exercise right after lateral ankle sprain is often the integral component of the treatment. 2 However, this is in direct contrast to the RICE method, and the clinical effectiveness of exercise remains controversial, despite the existence of multiple exercise-based physiotherapy programs with different content and parameters for treatment of ankle sprain. 4 – 6 The aim of this report is to review the evidence regarding the clinical effectiveness of exercise for the treatment of individuals with ankle sprain. This report also aims to review the evidence-based guidelines regarding the use of non-pharmacological interventions for the treatment of individuals with ankle sprain., (Copyright © 2020 Canadian Agency for Drugs and Technologies in Health.)

Dehydration occurs when losses of water and electrolytes are not adequately replaced, 1 , 2 often secondary to vomiting and diarrhea related to gastroenteritis. 2 Severe dehydration and the resultant decreased blood volume results in decreased tissue perfusion and can cause ischemic end-organ damage if not corrected with fluid repletion. 2 Oral rehydration solution was an important medical advance, resulting in decreased mortality from diarrheal illness. 3 Several methods of defining and categorizing severity of dehydration have been used in the literature. The World Health Organization (WHO) categorizes dehydration as severe dehydration (two or more signs of severe dehydration), some dehydration (two or more signs of dehydration that are not severe), or no dehydration (not meeting the criteria for some or severe). 1 The Clinical Dehydration Scale is a validated four-item scale categorizing dehydration as mild, moderate or severe according to physical exam findings; 4 the clinical features assessed are appearance, eyes, mucous membranes, and tears. A score between 1 and 4 is considered mild dehydration, whereas a score of 5 to 8 is considered moderate to severe. Dehydration can also be categorized according to percentage of body weight lost; mild dehydration corresponds to a loss of 3% to 5% of body weight, moderate 6% to 9%, and severe 10% or greater. 2 , 4 Oral rehydration therapy refers to the frequent administration of small amounts of fluid in order to prevent or treat dehydration. The oral rehydration solution recommended by the WHO contains 75 mEq/L of sodium and 75 mmol/L of glucose, with a total osmolarity of 245 mOsm/L. 3 For severe dehydration, WHO recommends intravenous administration of isotonic fluid as well as oral rehydration therapy with oral rehydration solution if feasible. Oral rehydration therapy (with oral rehydration solution) is recommended for children with some dehydration. Administration of extra oral fluids at home is recommended for children with no dehydration. 1 A number of antiemetics have been studied in children with gastroenteritis, including dexamethasone, dimenhydrinate, domperidone, granisetron, metoclopramide, and ondansetron. 5 Apart from ondansetron, evidence to support the use of other antiemetics in children with acute gastroenteritis is lacking. 5 , 6 Ondansetron is a serotonin receptor antagonist, selective for the 5-HT3 subtype. It is indicated for the prevention and treatment of nausea and vomiting related to chemotherapy or radiotherapy, as well as post-operative nausea and vomiting, in children age 4-18 and adults. Ondansetron is available in Canada as an oral solution, tablet, and oral disintegrating tablet (ODT). 7 It is typically well-tolerated; the most common adverse effects include mild headache, asthenia, constipation, and dizziness. 7 , 8 Although, an increased risk of diarrhea up to 48 hours after administration of ondansetron was the most commonly reported adverse effect in studies of children with gastroenteritis. 9 Ondansetron causes dose-dependent prolongation of the QT-interval, and cases of torsades de pointes have been reported. Ondansetron should be avoided in patients with congenital long QT syndrome and used with caution in individuals at risk of torsades de pointes. 7 The Canadian pediatric society recommends considering a single dose of ondansetron for children between 6 months to 12 years old presenting to the emergency department with vomiting related to suspected acute gastroenteritis, and mild to moderate dehydration or failed oral rehydration therapy. They recommend initiation of oral rehydration therapy 15 min to 30 min after administration of oral ondansetron. 9 The objective of this review was to summarize the evidence surrounding the clinical effectiveness of ondansetron for pediatric patients with or at risk of mild to moderate dehydration. For the purposes of this report, dehydration is categorized as mild to moderate according to the definitions used within the included studies. The population considered to be “at risk” of dehydration includes those who do not meet the criteria for mild or moderate dehydration according to the study definition but in whom oral rehydration therapy is deemed necessary., (Copyright © 2020 Canadian Agency for Drugs and Technologies in Health.)

Clozapine is a second generation antipsychotic indicated for patients with treatment-resistant schizophrenia (TRS). 1 TRS is schizophrenia that does not respond fully to conventional schizophrenia treatments, including first-line antipsychotics. 1 According to the Canadian Schizophrenia Guidelines (CSG), treatment-resistance is indicated after failure of two antipsychotics, although definitions of TRS vary among clinical trials. 2 It has been estimated that in patients receiving conventional pharmacotherapy for schizophrenia, 50% of these patients do not respond adequately to prescribed pharmacotherapy (30% may exhibit a partial response, and 20% may exhibit no response). 3 Clozapine is associated with a variety of side-effects, including drowsiness, dizziness, tachycardia (high resting heart rate), constipation, weight gain, lowered white blood cell count, and excess saliva production. 1 Serious side effects include myocarditis, pericarditis, neutropenia, cardiomyopathy, and death. 1 Some side effects, such as myocarditis, can occur relatively quickly (within two weeks) after initiation of the medication. 4 Clozapine must be initiated at a low dose and titrated up to the therapeutic dose over time to avoid side effects. Therapeutic doses can range from 200 mg to 450 mg per day and are generally not exceeding 900 mg per day (although doses of more than 900 mg per day are possible). 5 – 7 Initiation of clozapine may start as low as 12.5 mg per day, titrating upwards until individual effectiveness is seen (for example, resolution of psychosis symptoms). 6 , 7 Initiation on clozapine requires strict monitoring protocols to ensure compliance and to address the side effects associated with the medication. For example, in the United States, the Clozapine Risk Evaluation and Mitigation Strategy requires all prescribers and pharmacies to be certified in order to prescribe or dispense clozapine. 8 Part of the Clozapine Risk Evaluation and Mitigation Strategy program includes regular absolute neutrophil counts for patients on clozapine to monitor for neutropenia. 8 In Canada, after reintroduction of clozapine in 1991 (after removal from the market in 1975 because of reported infections due to low white blood cell counts), patients were required to join a patient registry program (e.g., Sandoz Clozapine Risk Management Program 1 ) to monitor white blood cell counts. 9 When switching to a new brand of clozapine, patients must join the manufacturer-specific registry upon changing medications. 1 Guidelines outlining appropriate use of clozapine are important to ensure timely, safe, and suitable prescribing of clozapine in a variety of settings. The objective of the current review is to summarize clinical effectiveness of clozapine during the initiation phase of treatment in adult patients with schizophrenia and summarize recommendations regarding monitoring of adult patients during this initiation phase., (Copyright © 2020 Canadian Agency for Drugs and Technologies in Health.)

The jaw, larynx, nasopharynx, mouth, ears, and salivary glands are some of the most common areas affected when referring to head and neck cancers. 1 The yearly incidence of head and neck cancer in Canada is over 4,300. 2 A common side-effect of radiation therapy for head and neck cancer is damage to the salivary glands which results in dry mouth (xerostomia), 1 , This adversely impacts the patient’s quality of life and can lead to further complications such as dental caries. 3 , 4 lasting weeks and in some cases, can be permanent. 1 , 4 This adversely impacts the patient’s quality of life and can lead to further complications such as dental caries. 1 , 3 Similarly, radiation therapy for the head and neck can damage lacrimal glands which results in dry eyes, affecting quality of life and leading to visual compromise. 5 The clinical management of dry mouth and dry eyes includes the use of lifestyle modifications (e.g., use of a room humidifier, eating moist foods), 3 , 4 saliva substitutes, 3 While another summary with critical appraisal focused on dry mouth and dry eyes in patients with Sjögren’s syndrome. , 4 tear replacement drops, 6 nonpharmacological interventions, 3 , 4 , 6 and pharmacological interventions. 3 , 4 , 6 The later include a variety of sialagogues (agents that promote the secretion of saliva), such as pilocarpine, 3 which can also be used to promote lacrimal secretions. 7 However, it is important to note that the drug may only stimulate secretion if there remains viable gland function. 4 In Canada, pilocarpine is currently marketed as a tablet and an ophthalmic solution. 8 Because of its cholinergic agonist mechanism of action, it may cause frequent side effects including sweating, flushing, increased bowel and bladder motility, tachycardia, and hypertension. 3 , 9 As such, pharmacological and nonpharmacological alternatives are often sought in an effort to expose patients to fewer side effects. This report is part of a series on the use of pilocarpine for dry mouth and dry eyes. 10 , 11 One report was a summary with critical appraisal of evidence available in November 2019 on medication induced dry mouth and dry eyes, 10 While another summary with critical appraisal focused on dry mouth and dry eyes in patients with Sjögren’s syndrome. 11 The objective of this report is to summarize the evidence regarding the clinical effectiveness, cost-effectiveness, and evidence-based guidelines regarding the use of pilocarpine for the treatment of dry mouth and dry eyes caused by radiotherapy for cancer of the head or neck., (Copyright © 2020 Canadian Agency for Drugs and Technologies in Health.)

Iron deficiency is a major cause of anemia. 1 Other causes of anemia include deficiency in nutrients (e.g., vitamin B12 and folate), inflammation, parasitic infections and disorders in hemoglobin (Hb) synthesis or red blood cell production and survival (e.g., hemoglobinopathies). 1 Iron deficiency anemia is defined as blood Hb concentrations of less than 110 g/L in the first trimester, less than 105 g/L in the second and third trimesters of pregnancy, and less than 100 g/L postpartum. 2 The serum ferritin level provides information about the capacity of the body to reserve iron and its concentration of less than 15 µg/L (a cut off that is associated with higher specificity) during pregnancy is diagnostic of iron deficiency anemia. 2 , 3 A level of less than 30 µg/L of ferritin (a cut off that is associated with higher sensitivity) should prompt treatment. 2 , 3 However, serum ferritin measurement may not be accurate during infection or inflammation, as it can be normal or elevated despite a low Hb concentration. 1 Iron deficiency in pregnancy has significant negative effects on both maternal and fetal outcomes, including low birthweight, prematurity, perinatal mortality, increased risk of maternal infections and lowered tolerance to blood loss and infection. 1 It also affects immediate and long term neurodevelopment of infants. 4 It was found that low maternal iron intake is associated with increased risk of autism, schizophrenia and abnormal brain structure in the offspring. 4 A review reported that findings from several cross-sectional studies suggested that the prevalence of iron deficiency among pregnant Canadians and pregnant adolescents ranged from 3% to 66%. 5 Given the negative impacts of iron deficiency on maternal and child health, there is still uncertainty as whether screening of iron deficiency anemia in pregnancy should be part of routine care, and which type of testing (e.g., Hb or ferritin) is more effective to improve maternal and infant health outcomes. The aim of this report is to evaluate the clinical effectiveness and cost-effectiveness of screening obstetric iron deficiency in the first or second trimester using ferritin testing, and to review evidence-based guidelines for assessing and treating obstetric iron deficiency. In this report, gender-neutral language has been used where possible in order to be inclusive of all gender identities. When reporting results from the published manuscript, gender-neutral language was not used in order to be consistent with the terms used in the source material., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

Breast cancer is one of the most commonly diagnosed cancers in Canada, accounting for 25% of all cancers among females and 1% among males. 1 Approximately 26,300 Canadian females were diagnosed with breast cancer in 2017 in Canada, yet breast cancer mortality rates have declined in the last thirty years, 1 which could be a result of increased availability of mammography screening (the vast majority of Canadian provinces have implemented breast cancer screening programs since the 1990s) and effective breast cancer therapies. 1 For women between the ages of 50–74 living in Canada, the Canadian Task Force on Preventative Health Care has conditionally recommended screening with mammography every two to three years in Canada. For those who are between the ages of 40–49, screening with mammography is not recommended. These recommendations are “conditional on the relative value a woman places on possible benefits and harms for screening.”(p.E1443) 2 Diagnostic mammography is used to take more detailed images of the breast from more angles, to inspect things like self-identified lumps or suspicious areas identified through screening mammography or clinical exam. 3 In Canada, both screening and diagnostic mammography are read by radiologists accredited by the Canadian Association of Radiologists. The number of mammograms required to remain an accredited radiologist was recently doubled from 500 to 1,000. This change to accreditation guidelines may mean that radiologists located in smaller, more rural centres may not read the required volume, while those in the large urban centres read a volume of exams far exceeding the requirement. This discrepancy poses a challenge for jurisdictions with large rural populations and breast cancer screening programs that provide multiple rural screening locations for these populations. Adapting programs to fit these new accreditation requirements for radiologists could mean that jurisdictions are faced with challenging options like limiting the number of screening centres available in rural settings where radiologists are less likely to read the required number of mammograms annually or keeping these rural centres in operation and sending images to radiologists located in higher density settings. Were screening centres limited to higher density settings, people eligible for screening or requiring diagnostic mammography would need to travel farther to these centres. Considering these issues, this qualitative rapid review aims to provide a better understanding of the perspectives and experiences of people eligible for breast cancer screening or diagnostic mammography, and the health care professionals working with these people., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

Orthopedic (i.e., musculoskeletal) surgery, as with most surgical procedures, can bring about inflammation, tissue injury (e.g., mechanical, thermal, chemical), or nerve injury (e.g., transection, stretching, compression). 1 These three noxious stimuli cause specialised sensory nerves located almost everywhere in the body, called nociceptors, to send an impulse along their nerve fiber to the dorsal horn of the spinal cord which then relays the signal to neurones projecting to the brain. 2 , 3 and subject to modulation by many additional factors such as chemical mediators of pain, the endogenous opiate system, and other domains such as a person’s personality, circumstances, and emotional state. 3 Although the physiology of pain is elaborate and poorly understood, it is thought that at this point in transmission, pain becomes a conscious experience, 3 and subject to modulation by many additional factors such as chemical mediators of pain, the endogenous opiate system, and other domains such as a person’s personality, circumstances, and emotional state. 2 Pain can be classified as acute (lasting for minutes to several weeks), or chronic (lasting months to years). 3 Typically, therapeutic options for orthopedic postoperative pain control are multimodal and tailored to the patient’s characteristics, their needs, and the level of pain associated with the surgery. , 4 This report will focus on acute pain as a result of orthopedic surgery. The goals of therapy for postoperative acute pain include the recognition that the patient is experiencing pain, to anticipate and pre-emptively relieve the pain, to rapidly reduce the intensity of the pain, and to generally minimise discomfort. 1 , 3 – 5 Treatment should be continued as long as the patient is experiencing pain. 5 Typically, therapeutic options for orthopedic postoperative pain control are multimodal and tailored to the patient’s characteristics, their needs, and the level of pain associated with the surgery. 1 These factors will determine the type of analgesic technique (systemic, regional, local), as well as the category of pharmacotherapy (e.g., opioid, non-opioid) that should be privileged. Opioids (e.g., morphine, fentanyl, hydromorphone, oxycodone, codeine) are the most widely used treatment of postoperative pain; 1 , 3 however, non-opioids (e.g., non steroidal anti-inflammatory drugs, acetaminophen, salicylates) can also be used. 3 , 4 This being said, opioid prescribing practices have come under scrutiny in recent years as Canada battles with an opioid epidemic. 6 Overprescribing by physicians, 7 – 9 and the diversion of non-consumed supplies, have been recognised as a contributor to the national opioid epidemic. 10 As a result there has been a desire to optimize opioid prescribing after surgery, when patient and surgical factors make this possible. 9 Specifically, the role of codeine in orthopedic post-operative pain management is being questioned and will be the focus of the present report. In Canada, several formulations of codeine are available for treatment of pain. Codeine primarily agonises the mu receptor. 11 , 12 It is metabolised in the liver by the cytochrome P450 system, specifically via the CYP2D6 isoenzyme, to various metabolites including morphine, 4 , 11 which accounts for some of its analgesic effect. 4 , 11 , 12 The rate of metabolism by the CYP2D6 isoenzyme is known to vary in the general population, 4 , 11 which highlights the variety of pain relief that can been observed when codeine is used as a single agent. 4 It is a relatively weak opioid, 12 and may also be used in combination with acetaminophen, where an additive analgesic effect is seen. 4 A previous CADTH report, published in 2010, sought clinical effectiveness and guideline evidence on pre-hospital orthopedic injury or fracture pain management. 13 The objective of the present report is to investigate the clinical effectiveness of codeine or codeine with acetaminophen for the management of acute pain in adults post orthopedic surgery., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

Chronic pain affects 20% of Canadians. 1 This persisting pain can negatively affect all aspects of a person’s life. Thanks to the World Health Organization (WHO), global consensus is acknowledging chronic pain as a legitimate disease in its own right and not merely as a symptom of another disease. 1 Chronic pain persists or reoccurs for greater than three months, causes significant emotional distress, can emerge as a symptom of another disease but persist after that disease has been treated. 1 However, chronic pain is difficult to manage due to the costs, addictiveness, and stigma surrounding pharmacological pain treatments, including opioids. Chronic pain, managed and unmanaged, also has direct costs on the community and healthcare system itself through loss of productivity. 1 Acupuncture has been used for pain relief for thousands of years in China and may be a credible alternative to pharmacological treatments for people experiencing chronic pain, particularly when they are non-responsive or intolerant of usual care, or even want to avoid pharmacological treatment. 2 The objective of this report is to summarize the evidence regarding the clinical and cost effectiveness of acupuncture for chronic non-cancer pain as well as relevant evidence-based guidelines regarding acupuncture for chronic non-cancer pain., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

Cannabinoids are pharmacologically active agents extracted from the cannabis plant. 1 Cannabidiol and tetrahydrocannabinol (THC) are the most studied cannabinoids and both interact with endocannabinoid receptors in various human tissues. 1 The endocannabinoid system moderates physiological functions, such as neurodevelopment, cognition, and motor control. 2 The products naturally derived from cannabis include marijuana (dried leaves and flowers, mostly for smoking) and oral cannabinoid extracts with varying concentrations of cannabinoids, including cannabidiol and THC. 1 THC is the main psychoactive constituent and cannabidiol seems to have no psychoactive properties. 2 In addition, there are two synthetical cannabinoids approved by the Food and Drug Administration (FDA) in the United States, dronabinol and nabilone, which are molecules similar to a type of THC (δ-9-THC) 1 Nabilone is also approved in Canada. 3 Dronabinol is indicated for chemotherapy-induced nausea and vomiting in children. 1 The use of nabilone in children is not recommended. 1 In Canada, the minimum age for cannabis consumption varies by provinces and territories, and is either 18 or 19 years. 4 A prescription is required to administer cannabinoids among children. 4 Clinically, cannabis has been used to treat children with epilepsy, 5 cancer palliation and primary treatment, chronic pain, and Parkinson disease. 6 The adverse events that clinicians need to monitor for include negative psychoactive sequelae and development of tolerance. 6 Psychoactive sequelae may be positive, such as relaxation and euphoria, or negative, such as anxiety and irritability. 2 In 2016, CADTH completed a Summary of Abstracts report on the use of cannabis in children with medical conditions such as attention deficit hyperactivity disorder, autism spectrum disorder, Tourette syndrome, epilepsy, posttraumatic stress disorder, or neurodegenerative diseases, and five non-randomized studies were identified. 7 However, there were no control groups in the five studies included in the report. 8 – 12 It is unclear whether there is new evidence or clinical guidance for the use of medical cannabis in children with mental health conditions, neurodegenerative diseases, or pain disorders, particularly in comparison with other possible therapies for those conditions. There is a need to review the clinical effectiveness of cannabis for pediatric care, as well as clinical guidelines., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

Chronic pain involves persistent or recurrent pain lasting longer than three months. 1 It is a global health issue that is common in both developed and developing countries. 2 For example, nearly one in four Canadian adults has a chronic pain condition. 3 , 4 Medications, such as opioids, are frequently prescribed for patients experiencing chronic non-malignant (i.e., non-cancer) pain to alleviate their symptoms. Given the side effects of their use (e.g., nausea, constipation, respiratory depression), potential for addiction and misuse, and uncertainty in their long-term effectiveness for treating chronic non-malignant pain, alternative strategies should be explored. 5 Complementary and alternative medicine therapies, such as mindfulness training and yoga, are potential treatment options for individuals who have chronic non-malignant pain. 6 , 7 Mindfulness is defined as the intentional and non-judgmental conscious awareness of the present moment. 7 Yoga is a mind-body practice with three main components: physical poses/postures, breathing control, and meditation/relaxation. 8 Most recently, two CADTH Rapid Response reports examined the clinical effectiveness, cost-effectiveness, and evidence-based guidelines regarding the use of mindfulness training (published in June 2019) 9 and yoga (published in July 2019) 10 for chronic pain management in adults. The report on mindfulness found insufficient evidence to draw conclusions about its potential clinical effectiveness. 9 The report on yoga found evidence from one randomized study suggesting that yoga plus conventional treatment with analgesics was effective for reducing chronic pelvic pain, while conventional treatment with analgesics alone was not. 10 No economic evaluations were identified in either report. 9 , 10 Notably, both reviews focused on comparing mindfulness or yoga with or without pharmacotherapy to pharmacotherapy alone (e.g., opioids, nonsteroidal anti-inflammatory drugs, acetaminophen). 9 , 10 To inform policy decisions, further exploration of mindfulness or yoga compared with no treatment may provide additional insight on the clinical and cost-effectiveness of these complementary and alternative medicine therapies for management of chronic non-malignant pain. The aim of this report is to summarize the evidence regarding both the clinical effectiveness and cost-effectiveness of the use of mindfulness training or yoga for the management of chronic non-malignant pain., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

Heart failure (HF) is a complex condition, in which the heart is unable to pump enough blood to meet all the needs of the body. 1 , 2 HF is mainly of two types: heart failure with a reduced ejection fraction (HFrEF) and heart failure with a preserved ejection fraction (HFpEF). 2 HFrEF is caused by left ventricular systolic dysfunction because the left ventricle becomes weak and is unable to contract properly. 2 In HFpEF, the left ventricle becomes stiff, making it difficult for the heart chamber to fill with blood. 2 Typical symptoms include breathlessness, ankle swelling and fatigue. 1 Heart failure is a costly health condition and is a major public health concern. 3 In Canada, approximately 669,600 (3.6%) persons aged 40 years or older, live with diagnosed HF. 4 The estimated cost resulting from hospital admissions for which HF was the primary diagnosis was $482 million in 2013; the number of HF patients admitted being 45,600. By 2030, the number of patients admitted with HF is expected to rise to 54,000 and the associated cost to increase to $2.8 billion. 3 Pharmacological treatment for HF includes drugs such as angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, beta-blocker, and mineralocorticoid receptor antagonist. 5 It has been reported that it may be difficult to recognize the early signs of worsening HF and that sometimes sub-optimal doses of drugs are used for fear of adverse events such as renal dysfunction and hypotension. 6 Biomarkers such as neuropeptides (NPs) may provide an objective assessment of HF severity and enable use of appropriate drug doses for HF therapy. 6 The NPs, B-type natriuretic peptide (BNP) and N (or amino) terminal pro-B-type natriuretic peptide (NT-proBNP) are released by the myocardium in response to volume and pressure overload. 7 In HF patients natriuretic peptide (NP) levels are elevated. 7 Measurement of NP levels in plasma has been used for diagnosis and prognosis of HF patients, but its role. in guiding therapy for patients with HF appears uncertain. 7 – 9 The purpose of this report is to review the clinical effectiveness, clinical utility, and cost-effectiveness of. natriuretic peptide testing for monitoring of heart failure therapy. Additionally, this report aims to review the evidence-based guidelines regarding natriuretic peptide testing for monitoring of heart failure therapy., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

Bronchoscopy is a commonly-used procedure that allows for the visualization of the lungs and air passages using a bronchoscope, a narrow tube with attached lighting and real-time video equipment. 1 Bronchoscopy may be performed for several reasons, including the diagnosis of disease (e.g., lung cancer, tuberculosis, pneumonia, infections), foreign body removal, stent insertion, and biopsy. 1 , NAC’s mechanism of action involves the cleavage of disulfide bonds in heavily cross-linked mucus glycoproteins, resulting in decreased mucus viscosity, thereby facilitating its clearance. 2 These procedures may be impeded in cases where the patient is experiencing impaired mucus secretion clearance as a result of various pathologies. Mucolytic agents (a class of drugs which aid in the clearance of mucus in the airways), such as N-acetylcysteine (NAC), may be administered prior to bronchoscopic examination in order to increase visibility and access to the underlying tissue. 3 , 4 NAC’s mechanism of action involves the cleavage of disulfide bonds in heavily cross-linked mucus glycoproteins, resulting in decreased mucus viscosity, thereby facilitating its clearance. 5 , 6 The purpose of the current report is to evaluate the clinical effectiveness and evidence-based guidelines regarding NAC instillation during bronchoscopy for non-cystic fibrosis patients requiring mucus secretion clearance. The findings of this review are complimented by two additional reports on the use of NAC in patients requiring mucus secretion clearance (not specific to bronchoscopy), conducted separately by CADTH. 7 , 8, (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

Maternal blood loss occurs after child birth and the amount of blood loss varies between individuals. Post-partum hemorrhage (PPH) is generally defined as bleeding in excess of 500 mL after a vaginal birth or 1000 mL after a cesarean section in Canada. 1 PPH has been defined differently by various guideline development groups. 1 In clinical practice, PPH should be considered when signs of hypovolemic shock or hemodynamic instability are present. 1 In Canada, the incidence of PPH is 4.8% (95% CI, 4.7 to 4.9) overall and 5.3% (95% CI, 5.2 to 5.4) after vaginal births in 2013. 2 There are risk factors associated with the occurrence of PPH, including retained placenta, coagulopathy, and vaginal injury. 3 Placenta retention and hemostasis are affected by myometrial contractions. 4 Prophylactic use of uterotonics is the standard of care globally. 4 Two uterotonics, oxytocin and carbetocin are in the Essential Medicines List by the World Health Organization. 5 Oxytocin works on receptors of smooth muscle and stimulate the upper uterine to contract regularly. 1 Carbetocin is a long-acting synthetic oxytocin analogue and also works by stimulating the uterus. 1 There are adverse effects common to both drugs, such as nausea and vomiting. 1 One advantage of carbetocin is its tolerance to heat and does not require cold-chain transport and storage that is needed for oxytocin use. 5 There are studies showing similar or superior effectiveness of carbetocin for the prevention of PPH, when compared to oxytocin. 6 However, the use of carbetocin has not been popular in Canada. 7 There is a need to review the clinical effectiveness, cost-effectiveness, and clinical guidelines to understand the potential role of carbetocin in Canada., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

Chronic pain is defined as pain that persists for more than three months. 1 It may present as headache, musculoskeletal pain, visceral pain, neuropathic pain, pain arising from rheumatic disease, and cancer pain. 1 Chronic pain is a global problem. 2 In Canada, approximately 25% adults have a chronic pain condition. 2 The prevalence estimates of chronic pain are likely to vary depending on the sample population surveyed, and the assessment method. 3 Costs associated with chronic pain include both direct and indirect costs. It is estimated that in Canada the annual direct cost to the healthcare system is over six billion dollars and the annual indirect cost due to job loss and sick days is over 37 billion dollars. 2 Chronic pain is a problem for the individual suffering, and also a societal burden. Therapies for management for chronic pain include several pharmacological agents (such as tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and opioid analgesics). 4 , 5 However, these medications offer limited pain relief and are associated with adverse effects. 4 , 5 There is increasing interest in the use of cannabis-based medicines. Cannabis-based medicines contain cannabinoids derived from the cannabis plant, including delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), or a combination of THC and CBD 6 . There is, however, uncertainty and controversy regarding the use of cannabis-based medicines for the management of chronic pain. 7 The purpose of this report is to review the clinical effectiveness of medical cannabis for the treatment of chronic pain. Additionally, this report aims to review the evidence-based guidelines regarding associated with the use of medical cannabis for the treatment of chronic pain., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

In general, falls are defined as sudden unintentional changes in position resulting in an individual landing on a lower level. 1 Falls incur two billion dollars per year of direct health care costs in Canada and cause 95% of hip fractures. Falls resulting in injuries increased 43% between 2003 and 2008 while falls resulting in death increased 65% over the same period. Falls are the leading cause of injury among seniors with 20 to 30% experiencing at least one fall per year, accounting for 85% of seniors’ injury-related hospitalizations and over 30% of seniors’ subsequent admissions to long-term care. 2 , 3 While in theory assistive devices such as wheelchairs promote independence, mobility, and fall prevention, they are not always properly used or maintained. Falls during transfer – defined as transferring one’s body from one surface to another – may result from an improperly maintained wheelchair. For example, if a wheelchair’s locking mechanism is not functioning properly or is not appropriately engaged, then the wheelchair becomes unsafe and can then lead to falls instead of preventing them. 3 , 4 Fall prevention may reduce injuries, long-term care admissions, hospitalizations, and overall health care costs; preventing 20% of falls could reduce 7,500 hospitalizations and save the Canadian health care system $138 million per year. 4 While in theory assistive devices such as wheelchairs promote independence, mobility, and fall prevention, they are not always properly used or maintained. Falls during transfer – defined as transferring one’s body from one surface to another – may result from an improperly maintained wheelchair. For example, if a wheelchair’s locking mechanism is not functioning properly or is not appropriately engaged, then the wheelchair becomes unsafe and can then lead to falls instead of preventing them. 4 , 5 Installation of automatic or more robust wheel locks as well as use of a wheelchair maintenance schedule may reduce injurious falls. 5 , As Canada’s population continues to age, falls and fall prevention will continue to be a growing public health issue. Effective fall prevention accounts for the combination of fall risk factors unique to each senior, tailoring the intervention to target the individual’s specific health status, situation, and environment. Evidence-based fall-prevention guidelines can assist in assessment of individual patients’ fall risks as well as establish standards to decrease the number and effect of falls. 6 Improper transfer techniques (from wheelchair to and from bed or toilet) as well as unassisted transfers may also increase the risk of injurious falls. 5 , 6 Nearly 60% of people using manual wheelchairs experience falls and face the challenges of independent or assisted recovery. Independent recovery relies on the patient maintaining contact with the wheelchair and having the physical capacity to recover on their own. If independent recovery is not possible, then the patient remains on the ground until assistance is available. If a patient remains on the ground for a prolonged period of time, it is predictive of future injurious falls and is also associated with declines in activities of daily living, increased hospital admissions, and increased long-term care admissions. 5 Another consideration for fall risk is delirium. Delirium, also known as acute confusional state, has an acute onset, developing over one to two days and is a common clinical symptom characterized by fluctuating consciousness, cognitive function, attention, thinking, or perception. 7 , 8 Patients presenting with delirium may be: restless, agitated, and aggressive; withdrawn, sleepy, and quiet; or a mixture of these characteristics. 7 Delirium and subsequent confusion are risk factors for falls. Additionally, older patients are at risk of developing delirium after a hip fracture, which itself is a serious consequence of a fall. 4 , 7 , 9 Patients with a hip fracture and delirium have increased hospital stays, falls, pressure sore development, and risk of death than those without delirium. 7 , 9 Fall prevention for patients with delirium thus involves preventing delirium or identifying and managing the underlying causes of the delirium such as: orienting the patient to person, place, and time (who the people around them are, their location, what the time and date are); providing an environment with context and familiarity (e.g., a room with a window or clock filled with personal belongings or pictures); talking and providing explanations in a calm, reassuring voice; as well as reviewing and changing medications to limit those that may cause or worsen delirium. 7 – 9 As Canada’s population continues to age, falls and fall prevention will continue to be a growing public health issue. Effective fall prevention accounts for the combination of fall risk factors unique to each senior, tailoring the intervention to target the individual’s specific health status, situation, and environment. Evidence-based fall-prevention guidelines can assist in assessment of individual patients’ fall risks as well as establish standards to decrease the number and effect of falls. 3 The objective of this report is to summarize the relevant evidence-based guidelines associated with the prevention of falls in patients requiring wheelchairs and patients with delirium in institutionalized care., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

Dementia refers to a set of symptoms and signs associated with a progressive deterioration of cognitive functions that affects daily activities. 1 Symptoms may include memory loss and difficulties with thinking, problem-solving or language, as well as changes in mood, perception, personality, or behaviour. 2 , 3 According to the World Alzheimer Report 2018, about 50 million people worldwide lived with dementia in 2018, with the number projected to increase to 152 million by 2050. 4 Alzheimer’s disease is the most common type of dementia, accounting for about two thirds of all dementia. 5 The total health care system costs and out of pocket costs of caring for people with dementia were $10.4 billion in 2016, and are projected to double by 2031. 5 Alzheimer’s disease is the most common type of dementia, accounting for about two thirds of all dementia. 4 Other types of dementia that occur less frequently include vascular dementia, mixed dementia, Lewy body dementia, frontotemporal dementia, and young-onset dementia. 1 , 3 Neuropsychiatric symptoms (NPS) are common to all dementia types and may manifest as agitation, aggression, wandering, apathy, sleep disorders, depression, anxiety, psychosis, and eating disorders. 3 These behavioral symptoms of dementia present significant risks of injury to the patients and caregivers, reduce quality of life, and may cause distress or depression. The progressive course of dementia cannot be altered since there is no known cure or disease-modifying therapy. 6 However, there are interventions to manage NPS, although they are based on limited and disparate evidence. 3 The first-line treatment of NPS comprises a range of nonpharmacological interventions based on identifying unmet physical and emotional needs, such as inadequately treated pain and unpleasant environmental factors, which may trigger the symptoms. Pharmacological therapies are the second-line treatment in patients for whom nonpharmacological interventions were unsuccessful and who present a potential risk of injury to either themselves or others. Pharmacological interventions commonly involve off-label use of atypical antipsychotics or second-generation antidepressants, usually in combination the nonpharmacological strategies. 3 Given the limited currently available therapeutic options, their side-effect profiles, and inconsistent evidence base, there is a need for alternate therapies in the growing population of dementia patients. 7 – 9 Medical cannabis has been investigated as one the potential alternative treatments for dementia. 10 , 11 Cannabis (also known as marijuana) is a plant that contains over 70 different chemical compounds called cannabinoids. 2 Although their mechanism of action in dementia is not well elucidated, they have been shown to interact with neurotransmitter systems that have been implicated in the manifestations of NPS. 11 Currently, patients living in Canada who have a prescription from an authorized health care professional can legally use cannabis for medical purposes, if they are registered with a licensed producer or Health Canada. 12 , 13 The objective of this report is to summarize the evidence regarding the clinical effectiveness of medical cannabis for the treatment of dementia and the evidence-based guidelines for its use in this condition., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

Dental pulp is a type of connective tissue found within the hard tissues (dentine and enamel) of the teeth. 1 When exposed to damage such as caries or tooth fracture, dental pulp is at risk of infection, which can lead to pain, necrosis, and infection of the jaw bone and surrounding tissues. 1 Currently in permanent teeth (secondary dentition), root canal (usually compromised of a pulpectomy [removal of the vital pulp in the tooth], refilling with synthetic material, and sealing), is the most common treatment for infected pulp. Vital pulp therapy (VPT) is a potential alternative to root canal treatment (RC). 2 VPT is a restorative dental procedure that aims to treat teeth with compromised dental pulp without the full removal or excavation of all healthy pulp tissue. 2 It is commonly performed in primary dentition (also known as baby teeth), as primary dentition has not fully developed the apical root, but is less commonly performed in secondary dentition. VPT can include indirect or direct pulp capping (i.e., placement of a protective material over the pulp) and partial or full pulpotomy (i.e., removal of part or all of the coronal pulp). Dressings used in VPT can include resin modified glass ionomers, adhesive resins, calcium hydroxide (CaOH), mineral trioxide aggregate (MTA), and bioceramics. 2 VPT may be of benefit to patients with secondary dentition as it may help prolong survival of the tooth, especially molar teeth. 2 As the forces exerted on teeth during mastication (i.e., chewing) are very high, endodontically-treated teeth with RC can be at risk of structural failure. Teeth treated with RC are also at risk of loss of sensation of environmental changes (potentially leading to more or worse caries), rejection of the foreign material, reinfection, and occurrence of apical periodontitis. 1 , 2 Success of VPT is dependent on a variety of factors, including the amount of infected tissue, an adequate blood supply to the tooth, healthy periodontium, and the opportunity to create an appropriate coronal seal. 2 VPT is of interest to dentists as an alternative to RC, as the ability to restore or salvage vital pulp can be beneficial to patients, despite the generally successful results with RC treatment. 1 The purpose of this report is to evaluate the clinical evidence regarding the clinical effectiveness and safety of vital pulp therapies compared with RC, and to evaluate available cost-effectiveness data to support reimbursement decision making. Additionally, evidence-based recommendations were sought to provide guidance on the use of VPT in secondary dentition., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

Chronic pain serves no biological purpose in contrast with acute pain, which warns of disease or injury, and is characterized by significant emotional distress or functional disability. 1 Definitions of chronic pain vary across classification systems. 1 The World Health Organization defines recurrent or persistent pain as chronic if it lasts longer than three months in duration, 2 whereas the American Psychological Association considers pain lasting longer than six months as chronic. 3 Chronic pain affects millions of Canadians. The prevalence of chronic pain not associated with cancer (also called non-malignant) among Canadian adults has been estimated between 19% and 29%. 1 Treatments for chronic pain tend to be only partially effective, and unrelieved pain costs Canada approximately $43 to $60 billion dollars per year in health care expenditures and lost productivity. 4 In Canada, opioids are commonly prescribed to treat chronic non-malignant pain. Alternative strategies are being sought due to the side effects of opioids (e.g., nausea, constipation, respiratory depression), potential for addiction and misuse, and uncertain long-term effectiveness for the treatment of chronic non-cancer pain. 5 Complementary and alternative medicine therapies are commonly sought to overcome the limitations of pharmacological treatments. 6 Yoga, which consists of physical postures, breathing techniques, relaxation, and meditation, has been proposed as a potential intervention for chronic non-malignant pain in adults as it is thought to target the physical and psychological aspects of pain. 6 The objective of this report is to summarize the evidence concerning the clinical effectiveness, cost-effectiveness, and guidelines regarding yoga for chronic non-malignant pain in adults., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

Mucus secretion clearance is a defense mechanism used by the lung to protect itself from pathogens and particles present in the inhaled air. 1 , 2 Mucus traps pathogens and particles in inhaled air, and is usually cleared from the lungs and airways by airflow and ciliary hairs. 2 Impaired mucous clearance results in abnormal lung function. 3 Mucus is a viscoelastic gel-like substance and consists of glycoproteins known as mucins, mixed with other proteins, lipids and water. 2 In healthy individuals, mucus has low viscosity and elasticity and is easily cleared, however in certain lung diseases the mucus has higher viscosity and elasticity and is not easily cleared. Pharmacologic treatments for impaired mucous secretion clearance include agents such as isotonic saline, hypertonic saline, and mucolytics such as dornase alpha, and acetylcysteine (also known as N-acetylcysteine [NAC]). NAC hydrolyzes the disulfide bonds of mucus proteins to decrease mucus viscosity, thereby facilitating its clearance. 4 NAC is used as a treatment option in various conditions in which there are problems with clearance of lung mucosal secretions (such as chronic obstructive pulmonary disease [COPD], chronic bronchitis, and intubated or post-operative patients). 1 , 4 – 7 A recent CADTH report 8 reviewed the clinical effectiveness and safety of use of NAC for patients requiring mucous clearance. It reported that relevant clinical effectiveness and safety data for NAC compared with other treatment modalities were sparse and no definitive conclusions were possible. For NAC compared with placebo, safety data in terms of adverse events, hospitalization, atelectasis, and mortality were variable or sparse, and definitive conclusions were not possible. The purpose of this report is to review the evidence-based guidelines regarding the use of acetylcysteine for patients requiring mucous secretion clearance., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

Chronic pain is a pervasive health issue that adversely affects both the patient and society, including loss of productivity, decreased quality of life, and an increased burden on the health care system. 1 – 4 The International Classification of Diseases (ICD) of the World Health Organization defines chronic pain as persistent or recurrent pain lasting longer than three months. 5 Non-malignant (non-cancer) related types of chronic pain may include low back pain, osteoarthritis, rheumatoid arthritis, headache, neck pain, fibromyalgia, and irritable bowel syndrome. 6 The prevalence of chronic pain is estimated to be 21% among the general Canadian population, a prevalence rate that has increased over time. 2 Chronic pain has substantial economic implications and has been estimated to cost Canada over six billion dollars per year in direct health care costs and 37 billion per year in productivity costs (e.g., job loss, sick days). 1 , 7 , 8 Given the prevalence and burden of chronic pain, a variety of treatment options have been explored to help patients manage their symptoms of pain, including pharmacological approaches (i.e., prescription or non-prescription drugs), physical therapy, exercise, surgery, psychological therapy, and complementary and alternative therapies. 4 In order to decide what treatment is best for the patient, careful consideration should be given to the benefits and risks of the available treatment options. 9 Medications, such as opioids, are commonly prescribed for pain, with approximately three to four percent of the adult population in the United States prescribed long-term opioid therapy. 9 , 10 However, long-term opioid therapy presents some serious risks, including addiction, accidental overdose, hyperalgesia, and diversion for non-medical use. 10 Mindfulness training is another potential treatment option for individuals who suffer from chronic pain. 11 Mindfulness is defined as the intentional and non-judgmental conscious awareness of the present moment. 12 A previous CADTH rapid response report that was published in 2012 11 examined the clinical effectiveness and evidence-based guidelines regarding the use of mindfulness training for chronic pain management in adults and found insufficient evidence to draw conclusions about its potential effectiveness. An update is needed to determine if the evidence surrounding mindfulness for chronic pain management is more conclusive to inform future policy decisions. The aim of this report is to summarize the evidence regarding both the clinical and cost-effectiveness, as well as guidelines for the use of mindfulness training for chronic non-malignant pain management., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

A burn is an injury to the skin or other organic tissue primarily caused by heat or due to radiation, radioactivity, electricity, friction, or contact with chemicals.1 The World Health organization has stated that every year burns cause an estimated 180,000 deaths, and non-fatal burn injuries are a leading cause of morbidity.1 According to the Canadian Skin Patient Alliance, more than 3,200 people were admitted to Canadian hospitals for burns in 2005 to 2006, when the latest statistics are available.2 Based on data from the Canadian Hospitals Injury Reporting and Prevention Program, the Public Health Agency of Canada identified 1,682 cases of thermal burns and scalds, representing 1.2% of injuries reported in 2013. The report did not include burns from friction, chemical or caustic agents, or direct contact with lightning, which were considered to present unique circumstances. For survivors with severe scars, significantly diminished quality of life often persists despite traditional scar management, due to disfigurement, pain, itchiness, and contractures restraining the motion of body and joints. 3 Thus, trauma from burn injuries may continue to bother patients long after their wounds have healed and their hospital stay is over. 4 Treatment may be associated with substantial financial costs for modern health-care systems. For example, the direct costs for care of children with burns in the United States of America exceeded US$211 million in 2000, and the costs for hospital burn management in Norway exceeded €10.5 million in 2007. 1 The cost burden of burn-related treatment to the Canadian health system was not immediately available, at the time of compiling this report. For contracted scars, surgery is the primary therapeutic approach to relieve tension and ultimately improve the range of motion of the affected areas. However, the efficacy of surgical treatment is limited to the surgical site, and the procedure is associated with considerable morbidity and high recurrence rates. 3 Non-surgical interventions that are often used in clinical practice to improve burn scar management include silicone gel preparations, the use of pressure garments, physical therapy, compression, onion extract-based products, local medical therapy, and different types of laser treatments. 3 , 4 The three main groups of lasers that can be used to improve scars include pulsed dye lasers and devices that use similar technology, Q-switched neodymium-doped yttrium aluminum garnet (Nd:YAG) lasers, and ablative and non-ablative fractional lasers (e.g., fractionated CO2 laser). 5 The objective of this report is to summarize the evidence regarding the clinical effectiveness of fractionated CO2 laser for burn scar improvement and the cost-effectiveness of its use for this condition., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

Mucus secretion clearance is a defense mechanism used by the lung to protect itself from pathogens and particles present in the inhaled air. 1 , 2 Mucus traps pathogens and particles in inhaled air, and is usually cleared from the lungs and airways by airflow and ciliary hairs. 2 Impaired mucous clearance results in abnormal lung function. 3 Mucus is a viscoelastic gel-like substance and consists of glycoproteins known as mucins, mixed with other proteins, lipids and water. 2 In healthy individuals, mucus has low viscosity and elasticity and is easily cleared, however in certain lung diseases the mucus has higher viscosity and elasticity and is not easily cleared. Pharmacologic treatments for impaired mucous secretion clearance include agents such as isotonic saline, hypertonic saline, dornase alpha, and acetylcysteine (also known as N-acetylcysteine [NAC]). NAC hydrolyzes the disulfide bonds of mucus proteins to decrease mucus viscosity, thereby facilitating its clearance. 4 NAC is used as a treatment option in various conditions in which there are problems with clearance of lung mucosal secretions (such as chronic obstructive pulmonary disease [COPD], chronic bronchitis, and intubated or post-operative patients). 1 , 4 – 7 The purpose of this report is to review the comparative clinical effectiveness and safety of NAC for treating adult patients requiring mucous secretion clearance. Additionally, tfor this patient population, the clinical effectiveness of treatment with nebulized acetylcysteine versus oral acetylcysteine will be reviewed. A subsequent report will review the evidence-based guidelines regarding NAC for the treatment of adult patients requiring mucous secretion clearance., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

Prostate cancer is the most common cancer in men and is the fourth most common cancer in Canada. 1 Approximately 1 in 7 men will be diagnosed with prostate cancer in their lifetime, and 1 in 27 will die from the disease. 1 , 2 However, the age-standardized mortality rate for all stages of prostate cancer have decreased by an average of 2.9% per year, or 41.0% from 1995 to 2012. 3 , 4 The majority (75%) of diagnosed prostate cancer are stage I or stage II (localized), and the age-standardized incidence rate of these cancer stages have decreased by 3.2% per year from 2005 to 2015. 4 The age-standardized incidence rate of stage III and IV cancers have remained relatively unchanged. 4 Androgen deprivation therapy (ADT) has been the mainstay treatment for metastatic prostate cancer. 5 Current ADT approaches include surgical castration or medical castration using a gonadotropin releasing hormone agonist with or without an anti-androgen drug. 6 Although over 80% of patients respond to ADT initially, nearly all eventually develop progressive disease following castration, a lethal stage known as metastatic castration-resistant prostate cancer (mCRPC). 7 In 2004, docetaxel (DTX) was the first chemotherapy approved by the US Food and Drug Administration for treatment of mCRPC. 8 , 9 Since then, five newly developed agents were approved including a second generation taxane cabazitaxel (CTX), 10 cellular immunotherapy sipuleucel-T, 11 radiopharmaceutical radium-223, 12 and two androgen receptor-targeted agents (ARTA) abiraterone acetate (AA) 13 – 15 and enzalutamide (ENZ). 16 , 17 Since ARTA have been demonstrated by recent studies in improving overall survival (OS) in both chemotherapy-pretreated and chemotherapy-naïve patients with mCRPC, both AA and ENZ have been approved as first-line treatment, instead of DTX. 13 – 17 However, some patients have rapidly progressed on ARTA treatments despite the initial clinical effectiveness. 18 After progression on first-line ARTA, it was unclear which subsequent therapy, such as second-line chemotherapy, an alternative ARTA, or an alternative ARTA with chemotherapy in between, would improve clinical outcomes. The aim of this report is to review the comparative clinical effectiveness and cost-effectiveness of varying treatment sequences of ARTA in patients with CRPC., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

The introduction of cervical cancer screening and timely intervention is associated with the recent decrease in cervical cancer incidence. 1 There are several options to screen cervical cancer. Two of the methods commonly used in Canada are cytology and human papillomavirus (HPV) tests. 2 Cytology requires clinicians to obtain samples from the cervix for further examination. 2 HPV tests that detect the infection of HPV also requires samples from the cervix. 2 The HPV tests that detect certain types of carcinogenic HPV genotypes, especially genotypes 16 and 18, are called high-risk HPV tests. 3 The samples can be obtained via brushes or swabs or other devices not only by clinicians, but also by screening participants. 3 Clinician-sampled HPV tests are used in screening program in several countries, such as Italy 4 and Denmark. 5 Self-sampled HPV tests have been tested in the capital region in Denmark but have not replaced clinician-sampled tests. 5 With feasibility to conduct at home and potentially better acceptability to participants, self-sampled HPV tests have been used to reach individuals that are unscreened or under-screened for cervical cancer. 4 In a previous CADTH report, there was some evidence to show similar diagnostic test accuracy between self- and clinician-sampled HPV tests. 6 For example, the diagnostic test accuracy of GP5+/6+ polymerase chain reaction (PCR) HPV tests using samples taken with brushes is similar for self- and clinician-collected samples. 7 In several primary studies, fair to high agreement between self- and clinician-sampled HPV tests has been found. 6 Since the previous CADTH review, there have been primary studies comparing self- and clinician-sampled HPV tests published 8 , 9 and a systematic review has been updated. 3 This report updates the previous review on the difference in the diagnostic test accuracy of self-sampled HPV tests and the agreement between self- and clinician-sampled HPV tests., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

About one half of people living with congenital anomalies have not had a specific cause or diagnosis identified based on their clinical presentation or examination of environmental causes. Such individuals are given a label of “unexplained developmental delay”, and it is not uncommon for them to be subjected to multiple diagnostic tests venturing on what some refer to as the ‘diagnostic odyssey’. Genetic sequencing has the potential to alleviate these diagnostic odysseys and provide definitive diagnoses otherwise undetectable by clinical history, physical examination, and biochemical or metabolic tests, or to do so sooner than current practice. Next generation sequencing technologies, like chromosomal microarray (CMA) and whole exome sequencing (WES), require patients to undergo a standard blood draw that is sent off to a laboratory for analysis. The sequencing, analysis and interpretation of these technologies, however, is situated within complex bioclinical collectives 1 made up of highly specialized professionals such as molecular analysts, bioinformaticians, and laboratory geneticists. While the sequencing itself is automated, and algorithms do exist to help identify notable mutations, these collectives must collaboratively interpret sequencing results to connect phenotype to genotype and establish whether identified variants should be considered pathogenic. 2 For technologies like WES and CMA, pathogenicity is labeled along a scale from pathogenic to benign. For example, the American College of Medical Genetics (ACMG) has developed and standardized five descriptive reporting categories: pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, or benign. Interpretations are based on known phenotypic associations as documented in open access databases (e.g., Online Mendelian Inheritance in Man, Human Gene Mutation Database) as well as group discussions around natural history and clinical presentation. 2 Unlike single gene or gene panel sequencing methods that focus on single or small sets of genetic material information, next-generation sequencing reads millions of fragments of genetic information in parallel. This makes the process substantially faster, but it also requires those within the bioclinical collective to be broadly familiar with potential genetic variations. 2 This also has the effect of increasing the amounts of variants returned that may be causally relevant to the person’s condition (i.e., VUS), but cannot be determined with certainty. Test results and subsequent interpretations of pathogenicity confirmed, they are then returned to the clinic and shared with patients and their families who necessarily find ways of incorporating them into their lived worlds. The purpose of this report is to identify and describe families’ and clinicians’ experiences with, and perspectives on, using genetic testing when seeking clarity on a person’s unexplained developmental delay or multiple congenital anomalies., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

Breast cancer is one of the most common cancers among women in Canada and is the second leading cause of death from cancer in this population. 1 As of 2017, an estimated 26,300 new cases of breast cancer were diagnosed annually in Canada. 1 When patients are diagnosed with early stage breast cancer, breast-conserving surgery may be offered (following an assessment of risk factors) as an alternative to mastectomy. 2 The goal of breast-conserving surgery is to excise cancerous tissue with adequate disease-free (i.e., negative) margins, in order to control disease, limit recurrence, maximize disease survival rates, and maintain cosmetic integrity of the breast. 2 , 3 Standard of care requires excised specimens to be prepared and transferred to a pathology laboratory for evaluation or margin status assessment. 2 Excised specimens with disease close to or at the boundary (i.e., positive margins) are an indication for re-excision, cavity shaving, or re-operation. 2 To minimize the probability of recalling patients for repeat surgeries on a different day following pathology assessment, intraoperative assessment of excised specimens is being explored. 2 With intraoperative margin assessment, the probability of residual disease at or near the boundaries of the excised specimen may be determined in real-time within the operating room while the patient is under anesthesia. 4 Intraoperative margin assessment can inform surgical decision-making and may potentially decrease the incidence of re-excisions 5 without significantly increasing operating time. 6 Different radiology options for intraoperative margin assessment are available, such as conventional specimen radiography (CSR), standard specimen mammography (SSM), intraoperative specimen mammography (IOSM), and intraoperative ultrasound (IOUS). CSR and SSM involve the acquisition of two-dimensional radiographic images of excised specimens outside the operating room with or without compression to confirm the presence of the target lesion or cancerous tissue and to assess the margin status. 5 Images are reviewed by radiologists and the results are conveyed to surgeons. With IOSM, radiographic images of excised specimens are acquired inside or adjacent to the operating room and are immediately interpreted by surgeons with or without the support of radiologists. 5 Similarly, IOUS involves the acquisition of ultrasonographic images of excised specimen inside the operating room for immediate interpretation by surgeons with or without radiologists. 7 Notwithstanding these benefits, sonographically occult lesions (i.e., undetectable or not easily visualized with ultrasound) and microcalcifications present a challenge to IOUS, thereby potentially limiting the technique’s clinical effectiveness and its impact on decision-making by surgeons. 5 While IOSM may detect microcalcifications, the technique’s sensitivity decreases in dense breast parenchyma. , 7 , 8 IOUS does not involve x-rays or other forms of harmful radiation and may be more accessible (physically and financially) than IOSM. 9 Notwithstanding these benefits, sonographically occult lesions (i.e., undetectable or not easily visualized with ultrasound) and microcalcifications present a challenge to IOUS, thereby potentially limiting the technique’s clinical effectiveness and its impact on decision-making by surgeons. 9 While IOSM may detect microcalcifications, the technique’s sensitivity decreases in dense breast parenchyma. 10 As such, there remains uncertainty regarding the comparative clinical effectiveness of various intraoperative margin status assessment techniques and their impact on clinical decision-making. The objective of this report is to assess the comparative clinical effectiveness and cost-effectiveness of intraoperative imaging with mammography (i.e., intraoperative specimen mammography or intraoperative mammography) for breast cancer surgery, and to evaluate relevant evidence-based guidelines., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

The aim of this report is to review the clinical effectiveness and evidence-based guidelines on the use of non-manual ultraviolet light disinfection for reducing rates of infection and colonization in healthcare facilities., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

Preoperative anemia, which is often associated with iron deficiency, is a risk factor for poor outcome in patients undergoing surgery. 1 According to the World Health Organization, anemia is defined as a circulating hemoglobin concentration of less than 130 g/L for men and less than 120 g/L for women. 2 Iron deficiency is categorized as either absolute (iron deficiency anemia) or functional (anemia of inflammation, and also referred to as anemia of chronic disease). 3 Several factors may contribute to iron deficiency anemia such as inadequate iron absorption, and bleeding due to an underlying disease condition. 1 Iron is needed as a substrate for the bone marrow to produce erythrocytes. 4 The prevalence of preoperative anemia varies between 5% and 76% depending on the age of the patient, the nature of the condition and the type of surgery planned; 5 the prevalence being 26% for major orthopedic surgery, 3 and 50% for cardiac surgery. 2 Treatment options for iron deficiency anemia include blood transfusion, oral iron, and intravenous iron. 4 Traditionally, the focus was on the use of blood transfusion to manage anemia in the preoperative phase. 6 However, blood transfusion is associated with risks such as infection, transfusion reaction, postoperative complications, and extended hospital stay. 1 , 2 , 6 Furthermore, blood transfusion may have substantial cost implications. 1 Oral iron is inexpensive and easy to administer but is associated with gastrointestinal side effects such as abdominal pain, diarrhea, constipation and dyspepsia which negatively impact compliance. 5 Iron dextran formulations were developed both for intramuscular and intravenous administration, however due to the associated adverse effects, they were phased out. Since then, various formulations of intravenous iron (such as iron sucrose, ferric gluconate, ferrumoxytol, ferric carboxymaltose, iron isomaltiside) have been developed. These newer formulations have shown promise in treating anemia in a number of disease conditions (such as inflammatory bowel disease, chronic heart failure and chronic kidney disease. 5 There is some suggestion that intravenous iron may be a useful treatment option for iron deficient anemia in patients undergoing surgery. The purpose of this report is to review the clinical effectiveness and cost-effectiveness of intravenous iron preparations administered preoperatively, for iron deficient adult patients undergoing elective surgery. Additionally, this report aims to review the evidence-based guidelines regarding the use of intravenous iron preparations administered preoperatively, for iron deficient adult patients undergoing elective surgery (i.e., any surgery scheduled in advance of the operation)., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

In Canada, cancer is the leading cause of death, comprising 30% of all death events. 1 Radiation therapy is a common treatment option used in approximately two-thirds of all cancer patients, 2 and can be used on its own or in combination with chemotherapy and/or surgery. 1 , 3 Image-guided radiotherapy facilitates tracking the location of the tumour and surrounding organs, and may result in less radiation treatment-related morbidity for patients compared those without image-guided radiotherapy. 4 While using computed tomography (CT) for image-guided radiotherapy is the current standard of care, the field of radiation oncology is constantly evolving with the emergence of new technologies for cancer treatment. 5 , 6 In 2017, the first magnetic resonance imaging-guided radiotherapy (MRgRT) delivery system was approved by Health Canada. 7 MRgRT delivery systems combine a linear accelerator system and a magnetic resonance imaging (MRI) scanner into one therapeutic device. 6 , 8 MRgRT delivery systems enable “cross-sectional, beam-on imaging,”(p.1058) which aids in monitoring motion of the tumour and organs at risk (OAR) while delivering radiotherapy treatment. 6 Compared to CT, MRI has superior tissue contrast resolution providing improved visibility of soft issues and has less motion blurring issues because a slice of MR data can be acquired in a fraction of a second. 6 , 9 This is particularly important for target areas susceptible to respiratory motion and bowel motility. 6 Given that MRgRT requires significant health care resources (e.g., financial, physical space to house the delivery system), 10 there is a need to determine whether MRgRT may offer a more clinical and cost-effective form of treatment for purchasing decisions by health care decision-makers. Ultimately, the feasibility of novel MRgRT delivery systems as a standard of care for patients with cancer will depend on its clinical and cost-effectiveness compared to other cancer treatments. The aim of this report is to summarize the evidence regarding the clinical and cost-effectiveness, as well as guidelines for the use of MRgRT delivery systems for the treatment of patients with cancer requiring radiotherapy., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

The aim of this report is to review the clinical effectiveness of the use of intranasal corticosteroids for the management of cystic fibrosis related chronic rhinosinusitis or nasal polyposis., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

Cystic fibrosis (CF) is a rare chronic genetic disease that affects multiple systems in the body including the respiratory tract, pancreas, gastro-intestinal tract and liver. 1 , 2 The disorder is caused by mutations of the CF transmembrane conductance regulator (CFTR) gene. Approximately, one in 25 Canadians carries an abnormal CFTR gene, and CF occurs in children who inherit two abnormal genes, one from each parent. 3 It is estimated that one in every 3,600 children born in Canada has CF, with more than 4,300 Canadian children, adolescents, and adults with CF attending specialized CF clinics. 3 The disease has no cure at present, and it is the most common fatal genetic disease affecting Canadian children and young adults 3 Lung disease is the most prominent manifestation of CF, and it is reported to account for nearly 85% of deaths. 4 Respiratory tract abnormalities in CF patients cause mucus plugging of the airways, bronchial wall thickening due to inflammation, increased susceptibility to respiratory tract infection, and airway destruction. 1 , 2 Much of the pulmonary damage begins with lung inflammation. 5 Although a normal inflammatory response is beneficial to host defence mechanisms, and helps to prevent the spread of infection, the excessive inflammation seen in CF patients is harmful as it contributes to the disease and associated death. 1 One of the goals in the treatment of cystic fibrosis is to reduce lung inflammation. 4 Corticosteroids are potent anti-inflammatory drugs which have been widely used in the treatment of a variety of diseases with underlying inflammation including asthma and chronic obstructive pulmonary disease (COPD). 1 , 4 They exert direct inhibitory effects on many inflammatory cells, and regular use of inhaled corticosteroids (ICS) has been reported to reduce the number of mast cells within the airways, decrease airway microvascular leakage, and lessen mucus production. 4 Although benefit of its use in CF has not been proven, ICS has been widely prescribed as anti-inflammatory agents to treat children and adults with CF empirically. 1 , 4 , 5 The objective of this report is to summarize the evidence regarding the clinical effectiveness of ICS for the treatment of CF., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

Radiation therapy is a common type of local therapy used to treat cancer, and can be used alone or in combination with chemotherapy, surgery, or both. 1 , 2 Approximately 470,000 patients receive radiation therapy each year in the United States of America. 3 In part, this has enabled the field of radiation oncology to investigate other important health outcomes in addition to mortality, such as patient’s quality of life and adverse effects associated with radiation therapy. 2 This progress has translated into decreased rates of cancer death within Canada over the last three decades (17% in females, 32% in males). 2 In part, this has enabled the field of radiation oncology to investigate other important health outcomes in addition to mortality, such as patient’s quality of life and adverse effects associated with radiation therapy. 1 Accurate treatment planning (e.g., tumor volume, organs at risk) before patients undergo radiation therapy is one way to reduce unnecessary treatment. 4 Computed tomography (CT) simulation is the current gold standard for radiation therapy treatment planning. 5 , 6 Radiation treatment planning using CT typically involves obtaining a set of CT images while the patient is immobilized in an adequate position for radiation therapy. 1 These CT images can be used to define the extent of the tumor (i.e., target delineation) and plan treatment delivery (e.g., dose calculation). 1 More recently, magnetic resonance imaging (MRI) has also been used for radiation therapy planning due to its superior soft tissue contrast compared with CT; 7 improved soft tissue contrast may provide more precisely targeted treatment sparing healthy organs at risk of developing comorbidities from radiation. 8 To truly discern whether MRI simulation improves health outcomes and, thus, should be considered for treatment planning for patients who require radiation therapy, a synthesis of the currently available literature is required. The current report aims to summarize evidence regarding the clinical and cost-effectiveness, as well as guidelines for the use of MRI simulators for simulation and treatment planning for patients requiring radiation therapy., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

The Eczema Society of Canada has a Seal of Acceptance program “where products are reviewed to earn recognition from the Eczema Society as an accepted choice for people with sensitive skin.” This report aimed to summarize the evidence regarding the clinical effectiveness, cost-effectiveness and guidelines of emollient treatments with “Seal of Acceptance” from the Eczema Society of Canada for atopic dermatitis. However, no evidence of cost-effectiveness was identified specific to these products, so only evidence of clinical effectiveness and guidelines are reported., (Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.)

The purpose of this report is to examine the clinical effectiveness, cost-effectiveness, and evidence-based guidelines regarding the use of guanfacine hydrochloride extended-release for the treatment of adults with attention deficit hyperactivity disorder (ADHD)., (Copyright © 2018 Canadian Agency for Drugs and Technologies in Health.)

A 2015 CADTH Rapid Response report identified systematic reviews, meta-analyses, and economic evaluations on the clinical and cost-effectiveness of yttrium-90 microsphere radioembolization for the treatment of primary or secondary liver cancer, but no evidence on uveal melanoma liver metastasis was found. With increasing interest in comparing the impact of selective internal radiotherapy with radioisotopes (SIRT) to other treatment therapies such as transarterial chemoembolization (TACE), this Rapid Response report aims to review the comparative clinical and cost-effectiveness of radioembolization with yttrium-90 microspheres versus other options for the treatment of adult patients with uveal melanoma liver metastasis., (Copyright © 2018 Canadian Agency for Drugs and Technologies in Health.)

The coverage of rituximab, under the various government-sponsored drug plans, includes a maximum of two courses per year; rituximab is not currently reimbursed for maintenance treatment. In 2007, the Canadian Agency for Drugs and Technologies in Health reviewed rituximab under the Common Drug Review. Rituximab was given a positive recommendation, however the Committee noted that the evidence for repeated doses was insufficient and that retreatment should be considered only in patients who achieved a response followed by a loss of effect. Clinicians would like to prescribe rituximab to patients, prior to a flare or loss of effect. Therefore, a review of the evidence is needed to support the administration of rituximab as regularly scheduled therapy to maintain remission or low disease activity in patients with moderate to severe rheumatoid arthritis., (Copyright © 2018 Canadian Agency for Drugs and Technologies in Health.)