TITLE: Ketorolac versus Other Non-Steroidal Anti-Inflammatory Drugs for the Management of Acute Pain: Comparative Clinical Effectiveness DATE: 16 January 2017 RESEARCH QUESTION What is the comparative clinical effectiveness of ketorolac versus any other non-steroidal anti- inflammatory drug for the management of acute pain? KEY FINDINGS Four randomized controlled trials were identified regarding the comparative clinical effectiveness of ketorolac versus any other non-steroidal anti-inflammatory drug for the management of acute pain. METHODS A limited literature search was conducted on key resources including PubMed, The Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. To Methodological filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, non-randomized studies, and guidelines. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2012 and December 20, 2016. Internet links were provided, where available. The summary of findings was prepared from the abstracts of the relevant information. Please note that data contained in abstracts may not always be an accurate reflection of the data contained within the full article. SELECTION CRITERIA One reviewer screened citations and selected studies based on the inclusion criteria presented in Table 1. Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic review s. The intent is to provide a list of sources of the best evidence on the topic that the Canadian Agency for Drugs and Technologies in Health (CADTH) could identify using all reasonable efforts within the time allow ed. Rapid responses should be considered along w ith other ty pes of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for w hich little information can be found, but w hich may in future prove to be effective. 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Table 1: Selection Criteria Population Any patient with acute pain Intervention Ketorolac (Toradol) Comparator Non-steroidal anti-inflammatory drugs (e.g., ibuprofen, naproxen, etc.); Excluding aspirin and celecoxib Outcomes Clinical effectiveness, pain management, adverse events Study Designs Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, non-randomized studies RESULTS Rapid Response reports are organized so that the higher quality evidence is presented first. Therefore, health technology assessment reports, systematic reviews, and meta-analyses are presented first. These are followed by randomized controlled trials, and non-randomized studies. Four randomized controlled trials were identified regarding the comparative clinical effectiveness of ketorolac versus any other non-steroidal anti-inflammatory drug for the management of acute pain. No relevant health technology assessments, systematic reviews, meta-analyses, or non-randomized studies were identified. Additional references of potential interest are provided in the appendix. OVERALL SUMMARY OF FINDINGS Four randomized controlled trials1-4 (RCTs) were identified comparing the effectiveness of ketorolac to other non-steroidal anti-inflammatory drugs. For the management of acute low back pain, one RCT1 determined that sublingual ketorolac was non-inferior to naproxen for the reduction of pain over five days. A higher percentage of patients in the ketorolac group reported improved pain relief within the first 60 minutes after the initial dose. Adverse events included heartburn, nausea, and vomiting.1 Two RCTs2,4 compared intravenous (IV) ketorolac with injectable diclofenac and placebo for the management of post-operative pain. In one RCT,2 acute pain was managed within six hours following orthopedic surgery.2 Mean pain scores were significantly improved in the ketorolac and diclofenac groups when compared with placebo. Significantly better pain scale scores, a lower opioid requirement, and faster onset of pain relief were observed in the diclofenac group as compared to the ketorolac group.2 A second RCT4 compared IV ketorolac with injectable diclofenac and placebo for the management of acute pain following abdominal or pelvic surgery. Both the ketorolac and diclofenac groups reported a significant reduction in pain and requirements for additional morphine when compared with placebo. One serious treatment- related adverse event was reported in the ketorolac group.4 One RCT3 compared the effectiveness of intramuscular ketorolac with diclofenac for the management of pain associated with acute renal colic in the emergency department. A significant difference in pain scores between groups was reported only at 15 minutes following treatment and favored the ketorolac group. There was no significant difference in pain relief between groups at any other time point. No significant differences in adverse events were observed between groups.3 Ketorolac versus Other Non-Steroidal Anti-Inflammatory Drugs for the Management of Acute Pain 2 REFERENCES SUMMARIZED Health Technology Assessments No literature identified. Systematic Reviews and Meta-analyses No literature identified. Randomized Controlled Trials 1. Plapler PG, Scheinberg MA, Ecclissato Cda C, Bocchi de Oliveira MF, Amazonas RB. Double-blind, randomized, double-dummy clinical trial comparing the efficacy of ketorolac trometamol and naproxen for acute low back pain. Drug Des Devel Ther [Internet]. 2016 [cited 2017 Jan 11];10:1987-93. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918732 PubMed: PM27382251 2. Daniels S, Melson T, Hamilton DA, Lang E, Carr DB. Analgesic efficacy and safety of a novel injectable formulation of diclofenac compared with intravenous ketorolac and placebo after orthopedic surgery: a multicenter, randomized, double-blinded, multiple- dose trial. Clin J Pain. 2013 Aug;29(8):655-63. PubMed: PM23328337 3. Kolasani B, Juturu J. Intramuscular ketorolac versus diclofenac in acute renal colic: A comparative study of efficacy and safety. Indian Journal of Basic & Applied Medical Research [Internet]. 2013 Sep [cited 2017 Jan 11];8(2): 923-931. Available from: http://ijbamr.com/pdf/923-931.pdf.pdf 4. Gan TJ, Daniels SE, Singla N, Hamilton DA, Carr DB. A novel injectable formulation of diclofenac compared with intravenous ketorolac or placebo for acute moderate-to-severe pain after abdominal or pelvic surgery: a multicenter, double-blind, randomized, multiple- dose study. Anesth Analg. 2012 Nov;115(5):1212-20. PubMed: PM22886837 Non-Randomized Studies No literature identified. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca Ketorolac versus Other Non-Steroidal Anti-Inflammatory Drugs for the Management of Acute Pain 3 APPENDIX – FURTHER INFORMATION: Previous CADTH Reports 5. Canadian Agency for Drugs and Technologies in Health. Ketorolac for pain management: a review of the clinical evidence [Internet]. Ottawa (ON): CADTH; 2014 Jun 30. (CADTH rapid response reports: Summary with critical appraisal). [cited 2017 Jan 11]. Available from: https://www.cadth.ca/ketorolac-pain-management-review-clinical-evidence Systematic Reviews – Comparison to Other NSAIDs Not Specified in Abstract 6. Marmura MJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine in adults: the american headache society evidence assessment of migraine pharmacotherapies. Headache. 2015 Jan;55(1):3-20. PubMed: PM25600718 7. Orr SL, Aube M, Becker WJ, Davenport WJ, Dilli E, Dodick D, et al. Canadian Headache Society systematic review and recommendations on the treatment of migraine pain in emergency settings. Cephalalgia. 2015 Mar;35(3):271-84. PubMed: PM24875925 8. Taggart E, Doran S, Kokotillo A, Campbell S, Villa-Roel C, Rowe BH. Ketorolac in the treatment of acute migraine: a systematic review. Headache. 2013 Feb;53(2):277-87. PubMed: PM23298250 Randomized Controlled Trials – Different Doses of Ketorolac 9. Motov S, Yasavolian M, Likourezos A, Pushkar