Key Message

What Is the Issue?

• Many drug treatments are available for depression, but 22% of people in Canada with the condition have treatment-resistant depression (TRD). For people with TRD, standard drug treatments do not improve their symptoms or do not work for long, and their depression persists.
• Posttraumatic stress disorder (PTSD) is a disabling mental health condition that affects about 9% of people in Canada in their lifetime. Few drugs are available for treating PTSD, none of which are considered effective.
• Ketamine is a hallucinogenic drug used primarily for anesthesia. Ketamine has also been explored for other indications, such as TRD and PTSD, generating questions about whether it could be a treatment option for these conditions.

What Did We Do?

• We conducted a review of the clinical effectiveness, cost-effectiveness, and evidence-based guidelines on the use of ketamine in adults with TRD or PTSD, to help guide decisions on the use of ketamine for managing these conditions.
• An information specialist conducted a search of peer-reviewed and grey literature sources published in March 2022 or later. One reviewer screened citations and selected and critically appraised the included studies.
• Canada's Drug Agency engaged a patient with lived experience of TRD who shared their experiences and perspectives on ketamine-assisted psychotherapy. These perspectives helped us to contextualize the literature and appreciate nuances of the experience.

What Did We Find?

• Ketamine could lead to an immediate improvement in depressive symptoms and suicidal ideation compared to placebo or midazolam in adults with TRD. The longest follow-up was 90 days, and the longest lasting effect after a dose was 28 days. Serious side effects of ketamine — such as dissociation — were rare and short-lived, lasting hours, in adults with TRD.
• It is uncertain if ketamine is an effective and safe treatment for symptoms of PTSD, due to little to no evidence suggesting its effectiveness or safety against placebo, midazolam, or opioids.
• Most studies evaluated ketamine given intravenously, and we found limited evidence on intramuscular (IM), subcutaneous, and intranasal routes of administration. We found no studies on oral or sublingual administration of ketamine and no studies comparing the different ways that ketamine can be given for TRD or PTSD.
• An economic evaluation found that IV ketamine was likely to be cost-effective compared to intranasal esketamine in adults with TRD from a health care perspective in the US. However, from a patient perspective, IV ketamine was unlikely to be cost-effective compared to esketamine, due to comparable levels of clinical effectiveness and lower costs of esketamine attributable to commercial insurance coverage and manufacturer assistance programs.
• A US guideline on TRD suggests ketamine as augmentation to antidepressants. A US guideline on PTSD does not suggest the use of ketamine as therapy.
• The patient contributor Canada's Drug Agency engaged for this review highlighted the benefits, stigma, and barriers of ketamine therapy, including financial implications.

What Does This Mean?

• There is some clinical effectiveness and cost-effectiveness evidence and a guideline recommendation to support the short-term use of ketamine in adults with TRD.
• Clinical effectiveness evidence and a guideline recommendation do not support the use of ketamine in adults with PTSD.
• Future research is necessary to understand the effectiveness and safety of ketamine as therapy for TRD in larger populations over longer periods and for PTSD for any follow-up duration.
• Decision-makers should consider offering ketamine in an equitable manner.

Key Message

​What Is the Issue?

• People with severe emphysema who do not experience relief with non-invasive therapies such as medication, physical activity, and smoking cessation may need advanced treatments.
• Endobronchial valves are an alternative therapy that may improve exercise capacity and quality of life, and are less invasive compared to lung reduction surgery or transplants.

What Did We Do?

• A 2019 Canada's Drug Agency report summarized clinical effectiveness evidence for valves compared to standard care. Canada's Drug Agency sought to update this evidence with new clinical research and include information on cost-effectiveness, which was not part of the previous report.
• A research information specialist conducted a literature search of the peer-reviewed and grey literature with a search strategy focused on emphysema and endobronchial valves. The search was limited to English-language documents published since 2018. One reviewer screened articles for inclusion based on predefined criteria, critically appraised the included studies, and narratively summarized the findings.

What Did We Find?

• We did not find systematic reviews or health technology assessments published since 2018 that contained clinical evidence not already captured in the 2019 Canada's Drug Agency report. Two RCTs provide updated clinical evidence for endobronchial valves compared to standard care, and 1 RCT contains evidence on valves compared to lung surgery.
• The evidence suggests that valves may improve lung function, breathing ability, and physical activity in middle-aged and older adults with emphysema compared to standard care; the effect on quality of life and safety is unclear. The previous Canada's Drug Agency report showed lung function, breathing ability, physical activity, and quality of life were favourable for valve treatment compared to standard care.
• The previous Canada's Drug Agency report showed that valves resulted in harmful outcomes compared to standard care; however, in the current review, safety was difficult to assess due to poor reporting.
• When comparing valves to lung surgery, lung surgery may improve quality of life compared to valves; other outcomes did not favour one therapy over another.
• For cost-effectiveness, valves may be favourable compared to standard medical care, while their cost-effectiveness compared to lung volume reduction surgery is unclear.
• One study was conducted in Canada, and no studies were conducted in children and younger adults.

What Does it Mean?

• Endobronchial valves are a potential therapy for people with severe emphysema with some favourable clinical and cost outcomes, but the evidence for their safety is unclear.
• Decision-makers may wish to consider the balance of favourable and harmful effects in existing evidence before more high-quality evidence in Canada, especially for safety, is available.

Key Message

What Is the Issue?

• Renal colic is a common problem that is primarily caused by kidney stones. Renal colic, specifically kidney stones, can be a recurrent condition that can negatively impact a person's quality of life and health system utilization.
• Ketorolac through IV or intramuscular routes is a common nonsteroidal anti-inflammatory drug (NSAID) used in hospital to treat renal colic. Oral ketorolac for the management of renal colic may reduce patients' need for opioids after discharge but it is unclear if it is clinically effective when compared to alternative analgesics or whether it is recommended for use in the management of people with renal colic.

What Did We Do?

• To inform decisions about oral ketorolac for the management of outpatients with renal colic, we sought to identify and summarize literature comparing the clinical effectiveness of oral ketorolac and alternative analgesics. We also searched for evidence-based guidelines that provide recommendations about the use of oral ketorolac for the management of people with renal colic.
• A research information specialist conducted literature searches of peer-reviewed and grey literature sources published between January 1, 2013, and December 4, 2023. The search was limited to English-language documents. One reviewer screened articles for inclusion based on predefined criteria.

What Did We Find?

• The tailored search for this rapid review did not find any studies evaluating the clinical effectiveness of oral ketorolac versus alternative analgesics for the management of people with renal colic in outpatient settings that met our criteria for this review. There is therefore no specific evidence available on the efficacy oral ketorolac in the management of renal colic in the community setting in this review.
• We did not find any eligible evidence-based guidelines concerning the use of oral ketorolac for the management of people with renal colic in outpatient settings. NSAIDs have been generally mentioned as an option for renal colic in the available guidance.
• Research regarding ketorolac for renal colic published since 2013 has focused on IV or intramuscular administration. Research regarding oral ketorolac focused on indications other than renal colic (e.g., postoperative pain) may be of interest; these are listed in the appendix. These studies suggest the effectiveness of ketorolac for pain management for other indications, such as pain management following endoscopy.

What Does It Mean?

• Without comparative evidence, decision-makers may want to consider how oral ketorolac is used for related indications (e.g., procedures for removing kidney stones, ureteroscopies) to examine how it performed compared with alternative analgesics.
• Research focused on the management of renal colic is needed to evaluate the clinical effectiveness of oral ketorolac and inform guidance concerning oral ketorolac in outpatient settings.

Key Message

What Is the Issue? Since 2008, the shortage of leucovorin has had a significant impact on fluorouracil-based chemotherapy. Many institutions worldwide provided possible options to relieve the leucovorin shortage, including using treatment without leucovorin, lowering the standard leucovorin dose, or using alternative drugs.If lowering the body surface area-adjusted standard dose of leucovorin does not affect efficacy and safety, then implementation of a low flat-dose protocol may prevent mistakes that result during dose calculation and save pharmacy compounding time and costs.Decision-makers want to know if any clinical evidence supports a low flat-dose protocol for leucovorin.

What Did We Do? To inform decisions about using flat-dose leucovorin in conjunction with fluorouracil-based chemotherapy, Canada's Drug Agency sought to identify and summarize literature comparing the clinical effectiveness of flat dosing versus weight-based leucovorin dosing. We also attempted to identify evidence-based recommendations for leucovorin dosing for colorectal or upper gastrointestinal cancer.A research information specialist conducted a literature search of the peer-reviewed and grey literature with a search strategy focused on leucovorin, dosing, and colorectal or gastrointestinal cancers. 

The search was limited to English-language documents published since 2013. One reviewer screened articles for inclusion based on predefined criteria, critically appraised the included studies, and narratively summarized the findings.

What Did We Find? We found 1 small retrospective cohort study (58 patients) comparing low flat-dose 50 mg leucovorin with body surface area-adjusted to high-dose 200 mg/m2 to 500 mg/m2 leucovorin in patients with colorectal cancer. The study found no statistically significant differences between the 2 doses in survival or complication rates.We found no evidence-based guidelines regarding leucovorin dosing for colorectal or upper gastrointestinal cancer. However, we found several guidelines with unclear methodology reporting leucovorin doses used in different fluorouracil-based regimens.

What Does it Mean? Limited evidence from this review suggests that the standard weight-based dosing of leucovorin may be reduced to a low flat-dose. However, we require a larger and well conducted trial to confirm the findings of that study.Decision-makers may wish to consider that reducing the dose of leucovorin may conserve the supply, reduce pharmacy compounding time and control acquisition costs.