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J Rehabil Med 2019; 51: 319–330 REVIEW ARTICLE SAFETY AND EFFICACY OF RECOVERY-PROMOTING DRUGS FOR MOTOR FUNCTION AFTER STROKE: A SYSTEMATIC REVIEW OF RANDOMIZED CONTROLLED TRIALS Nerida FIRTH, BPharm (Hons) 1 , Ruth N. BARKER, PhD 2 , Kathryn S. HAYWARD, PhD 3,4,5 , Julie BERNHARDT, PhD 3,4 , Michelle BELLINGAN, PhD 1 and Ronny GUNNARSSON, PhD 6 From the 1 College of Medicine and Dentistry, James Cook University, Townsville, 2 College of Healthcare Sciences, James Cook University, Cairns, 3 AVERT Early Rehabilitation Research Group, Stroke Theme, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg, Australia, 4 NHMRC CRE in Stroke Rehabilitation and Brain Recovery, 5 Department of Physical Therapy, University of British Columbia, Vancouver, Canada and 6 Institute of Medicine, The Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden Objective: To investigate the efficacy and safety of drug interventions to promote motor recovery post- stroke. Data sources: CENTRAL, CINAHL, Embase, MEDLINE, SCOPUS and Web of Science. Study selection: Published human randomized con- trolled trials in which the primary intervention was a drug administered to promote motor recovery post- stroke, vs placebo. Data extraction: Standardized pro forma used to ex- tract safety and efficacy data; Cochrane Collabora- tion risk of bias assessment tool performed to assess risk of bias. Data synthesis: Fifty randomized controlled trials from 4,779 citations were included. An overall trend of high risk of attrition (n  = 27) and reporting bias (n  = 36) was observed. Twenty-eight different drug interventions were investigated, 18 of which de- monstrated statistically significant results favouring increased motor recovery compared with control in- tervention. Forty-four studies measured safety; no major safety concerns were reported. Conclusion: Candidate drug interventions promoting motor recovery post-stroke were identified, specifi- cally selective serotonin reuptake inhibitors and le- vodopa; however, the high risk of bias in many trials is concerning. Drugs to improve motor function re- main an important area of enquiry. Future research must focus on establishing the right drug interven- tion to be administered at an optimal dose and time, combined with the most effective adjuvant physical therapy to drive stroke recovery. Key words: pharmaceutical preparations; stroke; rehabilita- tion. Accepted Feb 5, 2019; Epub ahead of print Feb 25, 2019 J Rehabil Med 2019; 51: 319–330 Correspondence address: Nerida Firth, College of Medicine & Dentistry, James Cook University, 1 James Cook Drive, Townsville QLD 4811, Australia. E-mail: [email protected] D rug interventions are known to be effective for primary and secondary stroke prevention, and to promote reperfusion of penumbra within hours of stroke onset (1, 2). Neuroprotective drugs seem LAY ABSTRACT Several drugs, administered in combination with reha- bilitation, have been found to increase the amount of physical recovery achieved by a stroke survivor. This pa- per reviews the published literature to investigate which drugs have the best evidence of efficacy and safety to promote motor recovery after stroke. However, many studies investigating these drugs lack rigor and have little consistency between how trials were performed. Consequently, it is difficult to make a definitive judge- ment on how safe and effective these drugs are, or to compare drugs to determine superiority. To overcome this, a reporting standard must be developed for trials of these particular drugs. In addition, stricter adherence is necessary to already established reporting standards, including those that outline how parallel group randomi- zed trials and physical interventions embedded within them are described (the Template for Intervention De- scription and Replication checklist and the Consolidated Standards of Reporting Trials statement, respectively). promising, but outcomes have failed to translate in human trials (2). As many people lack access to time- sensitive stroke interventions targeting prevention and reperfusion, drug interventions that mediate recovery beyond the window for effective reperfusion are im- portant research targets. The treatment window for recovery-promoting drugs (RPD) ranges from days to years post-stroke, increasing the potential for survivors to be eligible, and benefit from treatment (3–5). Whilst rehabilitation has been proven to be of great benefit, RPDs may have a place in enhancing recovery in in- stances where stroke survivors receive little therapy and have low levels of physical activity (6). Recovery-promoting drug interventions have been investigated for many years; however, there has been little consistency in clinical trials to allow for rigorous comparison or meta-analysis of outcomes across dif- ferent drug classes. To date, systematic reviews of RPDs have been limited to specific classes of drugs. A Cochrane Review investigating the effect of am­ phetamine treatment (compared with placebo) in 10 trials (n = 287 patients) found no evidence to support routine use in stroke survivors to reduce death or This is an open access article under the CC BY-NC license. www.medicaljournals.se/jrm Journal Compilation © 2019 Foundation of Rehabilitation Information. ISSN 1650-1977 doi: 10.2340/16501977-2536