Medicine, Faculty of
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Population and Public Health (SPPH), School of
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Chiropractic & Manual Therapies. 2021 Feb 17;29(1):8
The Author(s)
Côté, Pierre
Hartvigsen, Jan
Axén, Iben
Leboeuf-Yde, Charlotte
Corso, Melissa
Shearer, Heather
Wong, Jessica
Marchand, Andrée-Anne
Cassidy, J. D.
French, Simon
Kawchuk, Gregory N.
Mior, Silvano
Poulsen, Erik
Srbely, John
Ammendolia, Carlo
Blanchette, Marc-André
Busse, Jason W.
Bussières, André
Cancelliere, Carolina
Christensen, Henrik W.
De Carvalho, Diana
De Luca, Katie
Du Rose, Alister
Eklund, Andreas
Engel, Roger
Goncalves, Guillaume
Hebert, Jeffrey
Hincapié, Cesar A.
Hondras, Maria
Kimpton, Amanda
Lauridsen, Henrik H.
Innes, Stanley
Meyer, Anne-Laure
Newell, David
O’Neill, Søren
Pagé, Isabelle
Passmore, Steven
Perle, Stephen M.
Quon, Jeffrey A.
Rezai, Mana
Stupar, Maja
Swain, Michael
Vitello, Andrew
Weber, Kenneth
Young, Kenneth J.
Yu, Hainan
Background: A small proportion of chiropractors, osteopaths, and other manual medicine providers use spinal manipulative therapy (SMT) to manage non-musculoskeletal disorders. However, the efficacy and effectiveness of these interventions to prevent or treat non-musculoskeletal disorders remain controversial. Objectives: We convened a Global Summit of international scientists to conduct a systematic review of the literature to determine the efficacy and effectiveness of SMT for the primary, secondary and tertiary prevention of non-musculoskeletal disorders. Global summit: The Global Summit took place on September 14–15, 2019 in Toronto, Canada. It was attended by 50 researchers from 8 countries and 28 observers from 18 chiropractic organizations. At the summit, participants critically appraised the literature and synthesized the evidence. Systematic review of the literature: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, the Cumulative Index to Nursing and Allied Health, and the Index to Chiropractic Literature from inception to May 15, 2019 using subject headings specific to each database and free text words relevant to manipulation/manual therapy, effectiveness, prevention, treatment, and non-musculoskeletal disorders. Eligible for review were randomized controlled trials published in English. The methodological quality of eligible studies was assessed independently by reviewers using the Scottish Intercollegiate Guidelines Network (SIGN) criteria for randomized controlled trials. We synthesized the evidence from articles with high or acceptable methodological quality according to the Synthesis without Meta-Analysis (SWiM) Guideline. The final risk of bias and evidence tables were reviewed by researchers who attended the Global Summit and 75% (38/50) had to approve the content to reach consensus. Results: We retrieved 4997 citations, removed 1123 duplicates and screened 3874 citations. Of those, the eligibility of 32 articles was evaluated at the Global Summit and 16 articles were included in our systematic review. Our synthesis included six randomized controlled trials with acceptable or high methodological quality (reported in seven articles). These trials investigated the efficacy or effectiveness of SMT for the management of infantile colic, childhood asthma, hypertension, primary dysmenorrhea, and migraine. None of the trials evaluated the effectiveness of SMT in preventing the occurrence of non-musculoskeletal disorders. Consensus was reached on the content of all risk of bias and evidence tables. All randomized controlled trials with high or acceptable quality found that SMT was not superior to sham interventions for the treatment of these non-musculoskeletal disorders. Six of 50 participants (12%) in the Global Summit did not approve the final report. Conclusion: Our systematic review included six randomized clinical trials (534 participants) of acceptable or high quality investigating the efficacy or effectiveness of SMT for the treatment of non-musculoskeletal disorders. We found no evidence of an effect of SMT for the management of non-musculoskeletal disorders including infantile colic, childhood asthma, hypertension, primary dysmenorrhea, and migraine. This finding challenges the validity of the theory that treating spinal dysfunctions with SMT has a physiological effect on organs and their function. Governments, payers, regulators, educators, and clinicians should consider this evidence when developing policies about the use and reimbursement of SMT for non-musculoskeletal disorders.
SYSTEMATIC REVIEW Open AccessThe global summit on the efficacy andeffectiveness of spinal manipulativetherapy for the prevention and treatmentof non-musculoskeletal disorders: asystematic review of the literaturePierre Côté1,2,3,4* , Jan Hartvigsen5,6, Iben Axén7,8, Charlotte Leboeuf-Yde9, Melissa Corso1,2, Heather Shearer2,4,Jessica Wong1,2,3, Andrée-Anne Marchand10, J. David Cassidy3, Simon French11, Gregory N. Kawchuk12,Silvano Mior2,13, Erik Poulsen5, John Srbely14, Carlo Ammendolia4,15, Marc-André Blanchette10, Jason W. Busse16,André Bussières10,17, Carolina Cancelliere1,2, Henrik Wulff Christensen6, Diana De Carvalho18, Katie De Luca11,Alister Du Rose19, Andreas Eklund7, Roger Engel11, Guillaume Goncalves20, Jeffrey Hebert21, Cesar A. Hincapié22,Maria Hondras23, Amanda Kimpton24, Henrik Hein Lauridsen5, Stanley Innes25, Anne-Laure Meyer20,David Newell26, Søren O’Neill9,27, Isabelle Pagé10, Steven Passmore28, Stephen M. Perle29, Jeffrey Quon30,Mana Rezai2, Maja Stupar13, Michael Swain11, Andrew Vitello31, Kenneth Weber32, Kenneth J. Young33 andHainan Yu1,2AbstractBackground: A small proportion of chiropractors, osteopaths, and other manual medicine providers use spinalmanipulative therapy (SMT) to manage non-musculoskeletal disorders. However, the efficacy and effectiveness ofthese interventions to prevent or treat non-musculoskeletal disorders remain controversial.Objectives: We convened a Global Summit of international scientists to conduct a systematic review of theliterature to determine the efficacy and effectiveness of SMT for the primary, secondary and tertiary prevention ofnon-musculoskeletal disorders.Global summit: The Global Summit took place on September 14–15, 2019 in Toronto, Canada. It was attended by50 researchers from 8 countries and 28 observers from 18 chiropractic organizations. At the summit, participantscritically appraised the literature and synthesized the evidence.(Continued on next page)© The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.* Correspondence: pierre.cote@uoit.ca1Faculty of Health Sciences, Ontario Tech University, Oshawa, Canada2Centre for Disability Prevention and Rehabilitation at Ontario TechUniversity and CMCC, Oshawa, CanadaFull list of author information is available at the end of the articleCôté et al. Chiropractic & Manual Therapies (2021) 29:8 https://doi.org/10.1186/s12998-021-00362-9(Continued from previous page)Systematic review of the literature: We searched MEDLINE, Embase, the Cochrane Central Register of ControlledTrials, the Cumulative Index to Nursing and Allied Health, and the Index to Chiropractic Literature from inception toMay 15, 2019 using subject headings specific to each database and free text words relevant to manipulation/manual therapy, effectiveness, prevention, treatment, and non-musculoskeletal disorders. Eligible for review wererandomized controlled trials published in English. The methodological quality of eligible studies was assessedindependently by reviewers using the Scottish Intercollegiate Guidelines Network (SIGN) criteria for randomizedcontrolled trials. We synthesized the evidence from articles with high or acceptable methodological qualityaccording to the Synthesis without Meta-Analysis (SWiM) Guideline. The final risk of bias and evidence tables werereviewed by researchers who attended the Global Summit and 75% (38/50) had to approve the content to reachconsensus.Results: We retrieved 4997 citations, removed 1123 duplicates and screened 3874 citations. Of those, the eligibilityof 32 articles was evaluated at the Global Summit and 16 articles were included in our systematic review. Oursynthesis included six randomized controlled trials with acceptable or high methodological quality (reported inseven articles). These trials investigated the efficacy or effectiveness of SMT for the management of infantile colic,childhood asthma, hypertension, primary dysmenorrhea, and migraine. None of the trials evaluated theeffectiveness of SMT in preventing the occurrence of non-musculoskeletal disorders. Consensus was reached on thecontent of all risk of bias and evidence tables. All randomized controlled trials with high or acceptable qualityfound that SMT was not superior to sham interventions for the treatment of these non-musculoskeletal disorders.Six of 50 participants (12%) in the Global Summit did not approve the final report.Conclusion: Our systematic review included six randomized clinical trials (534 participants) of acceptable or highquality investigating the efficacy or effectiveness of SMT for the treatment of non-musculoskeletal disorders. Wefound no evidence of an effect of SMT for the management of non-musculoskeletal disorders including infantilecolic, childhood asthma, hypertension, primary dysmenorrhea, and migraine. This finding challenges the validity ofthe theory that treating spinal dysfunctions with SMT has a physiological effect on organs and their function.Governments, payers, regulators, educators, and clinicians should consider this evidence when developing policiesabout the use and reimbursement of SMT for non-musculoskeletal disorders.Keywords: Spinal manipulation, Mobilization, Effectiveness, Efficacy, Systematic review, Non-musculoskeletal,ChiropracticBackgroundSome evidence-based clinical practice guidelines recom-mend that spinal manipulative therapy (SMT) be usedalone, or in addition to other interventions for the man-agement of back pain, neck pain, and headaches associ-ated with neck pain [1–5]. Although health professionalswho deliver SMT are primarily consulted for spinal pain,some patients are treated for non-musculoskeletal disor-ders [6–8]. Specifically, between 3 and 10% of patientswho receive care from chiropractors and osteopaths aretreated for non-musculoskeletal disorders [1, 6]. In relativeterms, these figures suggest that only a small proportionof patients receive SMT for non-musculoskeletal disor-ders; however, in absolute terms, it indicates that a sub-stantial number of patients globally receive such careevery year.The treatment of non-musculoskeletal disorders has along tradition among chiropractors and osteopaths. Thistradition is based on two foundational concepts. Thefirst concept implies that spinal dysfunctions, or sublux-ations, can have a negative effect on the body’s innateability to heal itself, and that these dysfunctions can berectified through SMT [9–11]. The second concept pro-poses that spinal dysfunction can negatively impact theautonomic nervous system, which in turn may cause dis-ease including organ dysfunctions [10–12]. Some arguethat they may influence the autonomic nervous systemand thereby improve physiologic function by correctingspinal dysfunctions through SMT [13, 14]. Many chiro-practors do not endorse this thinking and use anevidence-based approach to clinical care [15–17].Laboratory studies of physiological mechanisms reportthat certain types of manual therapies can indeed affectbody functions, such as heart rate variability or inflamma-tory cytokines in healthy individuals [18, 19], thus sup-porting the notion that SMT can be used to treat non-musculoskeletal disorders. However, two systematic re-views suggest that such effects, if they occur, are short-lasting and without clinical consequences [13, 20]. More-over, a recent randomized controlled trial which com-pared SMT to a successful sham control found no sucheffect [21]. Although essential to the understanding ofphysiological mechanisms of action of interventions, la-boratory experiments alone have not provided aCôté et al. Chiropractic & Manual Therapies (2021) 29:8 Page 2 of 23mechanistic understanding of these hypotheses nor pro-vided evidence of clinical efficacy or effectiveness [22].Therefore, as emphasized by Bialosky et al. [23], the hy-pothesized causal chain between SMT, the autonomicnervous system, and clinical outcomes remains hypothet-ical and has yet to be established.Some clinicians and patients report favorable out-comes when SMT is used to treat a variety of non-musculoskeletal complaints, such as allergies, breathingproblems, digestive problems, and tinnitus [24]. More-over, case reports suggest that SMT may benefit patientswho consult for conditions such as bedwetting [25, 26],multiple sclerosis [27], autism spectrum disorder [28],and ischemic stroke [29]. However, it is important tonote that observations, including case-reports that shapeclinical experience may be misleading for several reasons[30]. First, it is possible that the observed improvementis due to the natural course of the disease rather thanthe treatment that has been delivered. Second, context-ual effects associated with the treatment may accountfor the reported improvements, rather than the treat-ment itself [19, 22, 31]. Moreover, whenever a treatmentis provided, the patient may have expectations of theoutcome, positive or negative, and it is well known thatpositive expectations of recovery are associated with fa-vorable health outcomes [32]. Fourth, it is possible thatthe observed changes are due to concurrent treatments[33]. Finally, the observed improvement can be due toregression to the mean, whereby patients with more se-vere symptoms tend to show greater levels of improve-ments independently of the treatment they receive [34–36]. Consequently, RCTs are necessary to determinewhether the benefits noticed in clinical practice and re-ported in case reports and case series are due to the pro-posed mechanisms of SMT or if they can be explainedby other factors [33]. Without rigorously conductedRCTs, clinicians and patients may assume that SMT ismore or even less effective than it is.Several previous reviews have evaluated the efficacyand effectiveness of SMT for non-musculoskeletal disor-ders [20, 37–41]. Overall, these reviews found no strongevidence for the benefit of such treatment regardless oftheir scope, definitions of SMT, search strategies, and re-view methodology [20, 37–41]. Interestingly, these previ-ous reviews have not had an obvious impact on healthcare and clinical policies, at least not within the chiro-practic profession. We believe that this failed to occurbecause a broad-based consensus about the implicationsof this research has not yet been achieved within thechiropractic profession. Therefore, we convened a largegroup of international chiropractic researchers with dif-ferent scientific backgrounds and expertise to anchor anew systematic review. Furthermore, to promote know-ledge and understanding of our study to the chiropracticprofession at large, we invited representatives fromchiropractic associations and organisations to observeour research.The purpose of our study was to systematically reviewthe body of evidence on the efficacy and effectiveness ofSMT for the prevention and treatment of non-musculoskeletal disorders. Based on the osteopathic andchiropractic theories described above [9–14], we as-sumed that the rationale for this treatment was the sameacross non-musculoskeletal disorders conditions; specif-ically, that treating spinal dysfunctions with SMT has aphysiological effect on organs and their function. We ad-dressed two main research questions for each of pri-mary, secondary and tertiary prevention:1. Compared to sham or placebo interventions, isspinal manipulation, spinal mobilization or spinaltraction efficacious for the prevention ormanagement of non-musculoskeletal disorders?2. Compared to other interventions (including shamintervention when delivered in a pragmatic plan ofmanagement or no intervention), is spinalmanipulation, spinal mobilization or spinal tractioneffective in the prevention or management of non-musculoskeletal disorders?The primary target audience for our systematic reviewis policy makers (governments, insurers and regulators).We targeted policy makers because they are well posi-tioned to facilitate the development of clinical practiceguidelines and implement evidence-based policies thatwill serve and protect the public’s best interest. We alsoaim to provide educators, researchers and health careproviders with the best evidence to inform their contri-bution to the policy development process.ContextThe global summit on the efficacy and effectiveness ofspinal manipulation for the management of non-musculoskeletal disordersThe two research questions were the focus of the GlobalSummit on the Efficacy and Effectiveness of Spinal Ma-nipulation for the Management of Non-musculoskeletalDisorders (Global Summit). The initiation of the GlobalSummit was prompted by international public concernsabout chiropractic care for the management of non-musculoskeletal disorders [42–45].Steering committee and writing teamThe Global Summit was organized by a steering com-mittee which included PC (chair), CLY, IA and JH. Thesteering committee developed the methodology for thesystematic review, oversaw its conduct and implementa-tion, led the evidence synthesis, and published theCôté et al. Chiropractic & Manual Therapies (2021) 29:8 Page 3 of 23report. The steering committee was assisted in this workby a research assistant (MC). The final report wasdrafted by a writing team consisting of the steering com-mittee and senior researchers with expertise and experi-ence in evidence synthesis and scientific writing (JDC,SDF, GNK, SM, EP, JW). The writing team provided on-going feedback and quality assurance to drafts of evi-dence tables and sections of the manuscript.ParticipantsThe Global Summit brought together researchers whowere invited by the steering committee. Participants metthe following criteria: 1) chiropractor with a PhD, or aresearcher with a PhD (not a chiropractor) with researchexpertise in chiropractic; 2) actively involved in research(defined as having published at least 5 peer-reviewed pa-pers over the past 5 years); and 3) appointed at an aca-demic or educational institution. In addition, a smallgroup of researchers who did not meet these criteriawere invited. These included three chiropractors with astrong publication and scientific editorial record who didnot have a PhD (SMP, JW and HS) and two early careerresearchers with an expertise within the area of chiro-practic and pseudoscience (ALM, GG). Participants wereinvited by the Steering Committee using purposive andsnowball sampling methods.Pre-summit activitiesFrom January 5, 2019 to September 13, 2019, the Steer-ing Committee held regular meetings to organize theGlobal Summit. The presummit activities included: 1)identification and invitation of participants and ob-servers; 2) design of the systematic review; 3) search ofthe literature; 4) submission of the review protocol toInternational Prospective Register of Systematic Reviews(PROSPERO); 5) development of the instruction manualfor critical appraisal; 6) screening of articles; 7) creationof three review groups of researchers for studies relatedto primary, secondary and tertiary prevention; 8) criticalappraisal of the literature (first round) conducted byeach review group; and 9) preparation of structure andfirst draft of evidence tables.Global summit meetingOn September 14–15, 2019, 50 researchers (31 males; 19females) from eight countries met in Toronto, Canadafor the Global Summit. Twenty-eight researchers werefrom North America, 14 from Europe and eight fromAustralia. There were no participants from Asia, Africaor South America. In addition, 28 observers from vari-ous chiropractic organizations and educational institu-tions from North America, Europe and Australia werepresent to observe the meeting. At the Global Summit,researchers worked in their pre-assigned review groups.Each group reviewed the eligibility of RCTs that weredeemed to be relevant by participants prior to the GlobalSummit, rated and discussed the methodological qualityof studies, and extracted data from eligible studies. Thiswas one of four phases in the risk of bias assessment, asdescribed in detail below.ObserversThe steering committee invited representatives fromchiropractic organizations to observe the scientific delib-erations during the Global Summit. The organizationsrepresented at the Global Summit included 28 represen-tatives from 18 international, national and provincialassociations, regulators, one malpractice protective asso-ciation, and one chiropractic college. We invited chiro-practic organizations so that they could witness thescientific discussion and learn about the methods in-volved in the conduct of systematic reviews. There wereno formal criteria to invite observers, but it followed apurposive process. Observers held separate meetingsduring the Global Summit to discuss the implications ofthe research. Although they were invited to observe thescientific discussion, they did not participate in or influ-ence the scientific deliberations.Post-summit activitiesFollowing the Global Summit, the steering committeeensured that all relevant studies were critically re-appraised using a standardized method and finalized therisk of bias assessment and evidence tables. The steeringcommittee also led an online consensus process with allparticipants of the Global Summit, who were asked toreview and approve/reject/modify the final risk of biastables and evidence tables. These activities are discussedin detail below.MethodsProtocol registration and reportingWe registered our systematic review with PROSPERO(CRD42019140194). We structured our report according tothe Preferred Reporting Items for Systematic Reviews andMeta-Analysis (PRISMA) [46], the PRISMA Harms check-lists [47] and synthesized the results according to the Synthe-sis without Meta-Analysis (SWiM) Guideline [48].Eligibility criteriaStudies eligible for our systematic review met the follow-ing inclusion criteria: 1) English language; 2) publishedfrom database inception to May 15, 2019 in a peer-reviewed journal; 3) investigated non-musculoskeletaldisorders; 4) randomized controlled trial that investi-gated the efficacy or effectiveness of spinal manipulation,mobilization, or traction (all types including manual/assisted); 5) study population included all ages; 6)Côté et al. Chiropractic & Manual Therapies (2021) 29:8 Page 4 of 23included at least one outcome that is specific to thenon-musculoskeletal disorder under investigation andmeasured at the patient level; and 7) the number of ran-domized participants per group was ≥20.We did not include the following study types: 1)guidelines, letters, editorials, commentaries, unpublishedmanuscripts, dissertations, government reports, books orbook chapters, conference proceedings, meeting ab-stracts, lectures and addresses, consensus developmentstatements, or guideline statements; 2) cadaveric or ani-mal studies; 3) non-clinical studies (studies that aim tounderstand the physiological effects of spinal manipula-tion); 4) pilot studies aimed at demonstrating the feasi-bility of conducting an RCT; and 5) studies in which theeffect of spinal manipulation, mobilization, or tractioncould not be isolated (e.g, studies where spinal manipu-lation was included in a multimodal program of care).Definitions of key conceptsEfficacyStudies of efficacy are designed to investigate the bene-fits and adverse events of an intervention under idealand highly controlled conditions. The preferred designfor efficacy studies is the RCT using a sham or placebogroup as a comparison [49].EffectivenessStudies of effectiveness seek to examine the outcomes ofinterventions under circumstances that more closely ap-proximate a real-world setting. Effectiveness studies,therefore, typically use an RCT design, where the newtreatment is compared to other interventions (includingsham intervention when delivered in a pragmatic plan ofmanagement), such as the standard of practice for thepatient population being studied [49]. In our review, weclassified an RCT as an effectiveness trial if SMT was de-livered according to a pragmatic plan of management re-gardless of the comparison group.Non-musculoskeletal disordersDisorders that are not related to the locomotor system,including those not related to disorders of muscles,bones, joints and associated tissues such as tendons andligaments. These include but are not limited to asthma,stroke, migraine, dysmenorrhea and hypertension.Primary preventionIntervening to prevent disease or injury from everoccurring.Secondary preventionIntervening to cure or reduce the impact of a disease orinjury that has already occurred.Tertiary preventionIntervening to improve the impact of a persistent illnessor injury that has lasting effects.Spinal manipulationManual therapy applied to the spine that involves a highvelocity, low amplitude impulse or thrust applied at ornear the end of a joint’s passive range of motion [50].Spinal manipulation can be applied manually or with amechanical device.Spinal mobilizationManual treatment applied to the spine that incorporatesmovements, within a joint’s passive range of motion [50,51]. Spinal mobilization can be applied manually or witha mechanical device.Spinal tractionManual or mechanically assisted application of an inter-mittent or continuous distractive force [52, 53].Spinal manipulative therapyIn this report, spinal manipulation, spinal mobilizationand spinal traction are referred to collectively as “spinalmanipulative therapy”.Information sources and search strategyWe developed our search strategy in consultation with ahealth sciences librarian from the Centre for DisabilityPrevention and Rehabilitation at Ontario Tech Univer-sity and CMCC. A second librarian from the CanadianMemorial Chiropractic College reviewed the strategy toensure accuracy using the Peer Review of ElectronicSearch Strategies (PRESS) checklist [54, 55]. We system-atically searched MEDLINE U.S. National Library ofMedicine (through Ovid Technologies Inc.), Embase, theCochrane Central Register of Controlled Trials, Cumula-tive Index to Nursing and Allied Health (CINAHL,through EBSCOhost), and Index to Chiropractic Litera-ture (ICL, Chiropractic Library Collaboration) from in-ception to May 15, 2019. Search terms consisted ofsubject headings specific to each database (e.g., MeSH inMEDLINE) and free text words relevant tomanipulation/manual therapy, effectiveness, prevention,treatment, and non-musculoskeletal disorders (Add-itional file 1). We also asked participants to identify andsubmit any citations or articles that may be relevant tothe literature review.Study selectionAll articles retrieved through the literature searches wereexported into EndNote X7.0.2 for reference managementand tracking of the screening process. Four pairs oftrained and experienced reviewers (HS, IA; SM, JH; CC,Côté et al. Chiropractic & Manual Therapies (2021) 29:8 Page 5 of 23JW; AAM, PC) independently screened all potentiallyeligible articles in three phases. In phase one screening,titles and abstracts were reviewed and classified as rele-vant, possibly relevant or irrelevant according to the eli-gibility criteria. During phase two screening, the full textof possibly relevant articles was reviewed for final deter-mination of eligibility. Pairs of reviewers discussed eligi-bility to reach consensus for both phases of screening.Finally, in phase three, the eligibility of studies identifiedin phase two was reviewed and adjudicated at the GlobalSummit by the primary, secondary and tertiary groups.In cases of disagreement between reviewers during phaseone or phase two screening, a third independent re-viewer (CLY) was consulted to achieve consensus.Data collection process and data itemsWe extracted the following descriptive variables from allrelevant studies: First author’s name, year of publication,description of participants, case definition, health caresetting where the study was conducted, sampling frame,total number of participants enrolled, treatment andcontrol interventions (description, type of provider,number of participants at baseline), duration of follow-up; outcome measurement(s), results (between-groupdifferences, risk ratio (RR) and 95% CI or p-values (when95% CI were not reported or could not be computed)).The data were entered directly into evidence tables. Pairsof researchers extracted data during the Global Summitand independent reviewers validated the data extractionfollowing the Global Summit. The steering committeesubsequently validated the content of the evidence tablesfor completeness, accuracy and consistency of reporting.Finally, the content of the evidence tables was submittedto all participants for review and approval through anelectronic survey. We used 75% agreement (38/50 par-ticipants) as the threshold for consensus.Risk of bias in individual studiesWe critically appraised articles using the Scottish Inter-collegiate Guidelines Network (SIGN) criteria for ran-domized controlled trials [56]. The SIGN criteria wereselected by the steering committee for ease of use andrelevance, and adapted for the purpose of our review byadding the following questions to the generic checklists:– “The definition of the non-musculoskeletal conditionis clear?” (Yes/No)– “The participants are free from the non-musculoskeletal condition studied at the beginningof the study?” (Yes/No/Can’t say) (only for studiesinvestigating primary prevention)– “The spinal manipulative therapy (spinalmanipulation, spinal mobilization, and spinaltraction) intervention is described in sufficientdetail?” (Yes/No)– “The control intervention (if any) is described insufficient detail?” (Yes/No)– “The follow-up period is sufficient (long enough forthe outcome to occur) to answer the research ques-tion?” (Yes/No/Can’t say)In addition, we edited the following item (in the primaryprevention form) to ensure that the measurement propertiesof the method used to identify the non-musculoskeletal con-dition were clearly captured. The item “Are all outcomesmeasured in a standard, valid and reliable way?” was splitinto two questions, “The non-musculoskeletal condition ismeasured in a reliable way” (Yes/No/Can’t say) and “Thenon-musculoskeletal condition is measured in a valid way”(Yes/No/Can’t say). Detailed notes accompanied the SIGNgeneric checklists, and these were also edited to match thepurpose of this review.The risk of bias assessment was informed by the items fromthe SIGN checklists that focused on methodological quality.All risk of bias assessments were conducted by two independ-ent investigators who were unaware of each other’s ratings.The risk of bias items included: clarity of the research ques-tion, definition of the non-musculoskeletal condition,randomization procedure, blinding of participants, cliniciansand investigators, description of manipulation and controlinterventions, outcome measurements, drop-outs, co-interventions, intention-to-treat analysis and follow-upperiod.The risk of bias assessment was conducted in four se-quential steps. Prior to the Global Summit, independentpairs of reviewers (within each of the primary, secondaryand tertiary prevention review groups) critically ap-praised relevant RCTs to determine their methodologicalquality. At the Global Summit, the quality was discussedand agreed upon by the respective group. After the sum-mit, all RCTs were critically appraised a third time bytwo independent experienced methodologists (CLY, JW,IA, SM, JH, PC) to ensure that the SIGN criteria wereinterpreted and applied in a similar manner across re-viewers and review groups. Two participants (SF, EP)then performed quality assurance by reviewing all SIGNforms and risk of bias tables developed from the thirdround of reviews to ensure their accuracy and standardapplication.A study was rated as low risk of bias (high or accept-able quality according to the SIGN methodology) if re-viewers judged that potential sources of selection bias,information bias and confounding were minimal or ac-ceptable [56]. In particular, reviewers focused on poten-tial biases related to the randomization procedure,concealment of treatment allocation, blinding, adminis-tration of sham intervention, and attrition [57–61]. TheCôté et al. Chiropractic & Manual Therapies (2021) 29:8 Page 6 of 23presence of a validated sham procedure was consideredparticularly important.Finally, all researchers involved in the systematic re-view of the literature reviewed the risk of bias tables andwere asked to vote on the outcome of the critical ap-praisal through an electronic survey. We used 75%agreement (38/50 participants) as the threshold for con-sensus. One researcher (CLY) was not involved in thesystematic review at the Global Summit but was, in caseof problems, available as referee, to thereafter participatein the validation process and therefore also in the twovoting sessions.Standardized metricsWe used RR and between-group difference in means toquantify the effect of interventions. We reported theintervention-specific incidence of adverse events. Whenthese summary measurements were not reported in thepublished article, we used data reported in the paper toattempt to compute these statistics.Synthesis of resultsWe synthesized the evidence from acceptable or high-quality RCTs according to the SWiM Guideline andreported them in evidence tables [48]. We used twocriteria to determine whether SMT was efficacious oreffective. First, a study had to provide evidence thatthe null hypothesis was an unlikely hypothesis (p <0.05) for the observed between-group difference inthe primary outcome [62]. Second, if a difference wasfound, we determined whether the difference wasclinically important. When available, we used stan-dardized measurements (minimal clinically importantdifference [MCID]) to determine whether clinicallyimportant differences were reached in each trial. Ifthe clinical importance of a statistically significant dif-ference was not reported in the article, we planned todiscuss the findings among Global Summit partici-pants and reach consensus on its clinical importance.We used 75% agreement (38/50 participants) as thethreshold for consensus.We restricted our synthesis to RCTs with accept-able/high methodological quality because low/un-acceptable quality trials are more likely to yieldbiased estimates of effect sizes [57–61]. To under-stand the impact of methodological quality on trialresults, we contrasted results from methodologicallyacceptable studies with those from the unacceptablestudies. The SWiM guideline was published after theregistration of our protocol on PROSPERO [48].Nevertheless, we adopted it to ensure that our evi-dence synthesis complied with the most currentmethods of reporting. We had initially planned tostratify the synthesis by primary prevention, secondaryprevention and tertiary prevention. However, we re-vised this plan and synthesized the evidence by non-musculoskeletal disorder because there were no stud-ies, and very few studies, to inform primary and ter-tiary prevention, respectively. We further synthesizedthe evidence, based on the study design (efficacy ver-sus effectiveness).We tabulated disease-specific outcomes as reported inthe individual papers by comparing the outcomes forSMT to the outcomes for control interventions. Thesecomparisons informed the development of an evidencestatement for each non-musculoskeletal disorder. Be-cause the studies were clinically heterogeneous, we didnot assess for statistical heterogeneity of effects acrossstudies.We present our main results in a series of tables. First,we report our consensus methodological quality assess-ment in the risk of bias table. Second, the study charac-teristics and key study results are presented in theevidence table. Finally, we provide a succinct evidencetable, which summarizes the key characteristics and re-sults of all studies to facilitate the comparison of studyresults according to study quality. We examined the dir-ection and magnitude of effect sizes across RCTs ac-cording to methodological quality by comparing studiesrated as high/acceptable quality versus those rated aslow/unacceptable quality.We developed a consensus-based, narrative evidencestatement for each non-musculoskeletal disorder. How-ever, since the rationale for treatment is the same acrossconditions, these statements synthesize the evidenceabout the efficacy and effectiveness of SMT for the pre-vention and management of the specific non-musculoskeletal disorder in general, in accordance withour research questions.Publication bias and selective reportingWe did not assess publication bias. We checked report-ing of outcomes for the acceptable- and high-quality tri-als against registered protocols by 1) scrutinizing thepapers for mentioning of published or registered proto-cols; 2) searching for protocol papers in PubMed; and 3)accessing clinicaltrials.gov.Approval of the final manuscript and authorshipThe final manuscript was submitted to all participants tothe Global Summit for review. Participants were askedto vote electronically on whether they approved the finalversion of the paper and whether they wanted to co-author the published paper. Participants who declinedauthorship were asked to provide the reason for theirdecision. This process was repeated after the submittedmanuscript had been reviewed by the journal.Côté et al. Chiropractic & Manual Therapies (2021) 29:8 Page 7 of 23ResultsStudy selectionOur search retrieved 4997 citations (Fig. 1). No additionalarticles were submitted by participants. We removed 1123duplicates and screened the titles and abstracts of 3874 ci-tations (phase one screening). Of those, 219 citations werescreened in phase two and the eligibility of 32 articles wasreviewed at the Global Summit (phase three). The primaryreasons for excluding 187 articles are presented in Fig. 1.Sixteen articles were excluded in phase three screening(Table 1) [18, 63–77]. Therefore, 16 articles (reporting on14 RCTs) were included in the review and were criticallyappraised [37, 78–90]. We did not identify any RCTs re-lated to primary prevention, 14 trials addressed secondaryprevention, and six of the secondary prevention trials alsoincluded outcomes related to tertiary prevention. Of theacceptable and high-quality trials, one trial assessed effi-cacy [80] while five trials evaluated effectiveness [37, 81,82, 84, 87].Risk of bias within studiesOf the 14 included RCTs, three were rated as high qual-ity [37, 81, 84], two were deemed to be of acceptablequality [80, 87], three were of low quality [79, 85, 89],and five were rated as unacceptable quality [78, 83, 86,88, 90] (Table 2). The study by Chaibi et al. [82] receivedtwo quality ratings as the component of the trial com-paring SMT to sham was rated to be of acceptable qual-ity and sham was included in the evidence synthesis,whereas the component comparing SMT to the controlintervention was rated as low quality because of the dif-ferentially high drop-out rate in the control group andthat study was, therefore, not included in the evidencesynthesis [82].Differences in the methodological quality betweenRCTs rated as high/acceptable quality and those rated aslow/unacceptable quality were mainly related to themethod of randomization, concealment of treatment al-location, successful blinding of participants (inability toidentify the treatment), and blinding of outcome asses-sors and investigators (those who collected outcome dataand investigators were unaware of the treatment re-ceived by participants) (Table 2).Our qualitative synthesis therefore includes three highquality RCTs [37, 81, 84] and three RCTs of acceptablequality [80, 82, 87]. Of these, none evaluated the efficacyor effectiveness of SMT for the primary prevention ofnon-MSK disorders, six RCTs evaluated spinal manipu-lation for secondary prevention [37, 80, 82, 84, 87] andtwo studies evaluated spinal manipulation for tertiaryFig. 1 PRISMA Flow diagramCôté et al. Chiropractic & Manual Therapies (2021) 29:8 Page 8 of 23prevention of non-musculoskeletal disorders [37, 84].Both studies included in the tertiary prevention groupwere also included in the secondary prevention group.Of the six trials of acceptable-or high-quality, two hadbeen registered in clinicaltrials.gov [81, 82] and both re-ported outcomes in accordance with their protocols.Study characteristicsHigh and acceptable methodological qualitySix RCTs were rated as high or acceptable quality(Table 2). Of those, one investigated the efficacy of onesession of diversified manipulation to T1-T4 for themanagement of adults with hypertension [80] (Table 3).Table 1 Primary reason for exclusion of RCTs in phase 3 screeningFirst author, Year Population Primary reason for ineligibilityAttali 2013 [63]a Patients with irritablebowel syndromeThe sample size was < 20 per group.Bevilaqua-Grossi 2016[64]aPatients with migraineand neck painSMT was part of a multimodal intervention. The effect of SMT could not be isolated.The multimodal intervention included medication plus a physiotherapy protocoldiaphragm training, cervical mobilization and training, massage, myofascial release,trigger point therapy, passive stretching. The control group received medicationalone.Budgell 2006 [18] Healthy adults Experimental trial with physiological outcome (heart rate variability) not related toprimary prevention of a non-musculoskeletal disorderde Araujo 2018 [65] Healthy asymptomaticindividualsExperimental trial with physiological outcome (heart rate variability) not related toprimary prevention of a non-musculoskeletal disorderDavidson 2018 [66]a Patients with migraine SMT was part of a multimodal intervention. The effect of SMT could not be isolated.The multimodal intervention included Maitland C0-C3 mobilization and WatsonHeadache Approach (exercise and advice). The control intervention was ‘wait list’.Goertz 2002 [67] Patients with high blood pressureor stage 1 hypertensionSMT was part of a multimodal intervention. The effect of SMT could not be isolated.The multimodal intervention included dietary modification, SMT and ultrasound,moist heat, soft-tissue massage. The control group received dietary modificationalone.Hensel 2013 [68] Pregnant women at the 30thweek of pregnancyExperimental trial with physiological outcomes (arterial pressure and heart ratevariability) not related to primary prevention of a non-musculoskeletal disorderHolt 2016 [69] Community-dwelling adults65 years or olderExperimental trial with physiological/ biomechanical outcomes (joint position sense,choice stepping reaction time, postural stability, multisensory processing, health-related quality of life) not related to primary prevention of a non-musculoskeletaldisorderJones 2015 [70] Patients with dysfunctionalbreathingSMT was part of a multimodal intervention. The effect of SMT could not be isolated.The multimodal intervention included respiratory physiotherapy plus Maitlandmobilization, muscle energy technique, trigger point therapy, myofascial release,diaphragm and rib cage mobilization. The control group received respiratoryphysiotherapy alone.Kachmar 2018 [71] Patients with spastic formsof cerebral palsyExperimental trial with outcomes (muscle spasticity, manual dexterity) not related totertiary prevention of a non-musculoskeletal disorderNelson 1998 [72]a Patients with migraine SMT was part of a multimodal intervention. The effect of SMT could not be isolated.The multimodal intervention included SMT, massage and/or trigger point therapywith or without amitriptyline. The control intervention was amitriptyline alone.Nielsen 1995 [73] Patients with chronic asthma The sample size was < 20 per group.Noll 2000 [74] Patients (≥ 60 years of age) hospitalizedwith acute pneumonia.The osteopathic manipulative therapy did not include SMT.Pizzolorusso 2014 [75] Pre-term birth in infants The osteopathic manipulative therapy did not include SMT.Schwerla 2014 [76]a Patients with primary dysmenorrhea SMT was part of a multimodal intervention. The effect of SMT could not be isolated.The multimodal intervention included high velocity thrust, muscle energytechnique, myofascial release, balanced ligamentous tension, visceral and cranialtechniques. The control group was not treated.Steele 2014 [77] Patients enrolled in the study werebetween the ages of 6 months and24months with acute otitis media andan abnormal tympanogram.SMT was part of a multimodal intervention. The effect of SMT could not be isolated.The multimodal intervention included combinations of Sacroiliac mobilization,myofascial release, balance ligamentous tension, suboccipital inhibition, venoussinus draining, occipital decompression, sphenobasilar decompressionSMT spinal manipulative therapyaThese studies were considered for both secondary and tertiary preventionCôté et al. Chiropractic & Manual Therapies (2021) 29:8 Page 9 of 23The remaining five RCTs investigated the effectivenessof spinal manipulation for the management of: infantswith colic [87]; children with asthma [84]; women withprimary dysmenorrhea [37]; adults with hypertension[81]; and adults with migraines [82] (Table 3). These tri-als were clinically heterogeneous and therefore couldTable 2 Risk of bias tableAuthor, Year 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 2.10 2.11a 2.12a 2.13 2.14 2.15 3.5 Overall AxGoertz 2016 [81] Y Y Y Y Y Y N Y Y Y Y Y SMT: 0%Sham: 1/27 = 4%Y N/A Y High Quality(++)Hondras 1999[37]Y Y Y Y Y Y Y Y Y CS Y Y SMT: 2/69 = 3%Sham: 1/69 = 1%Y N/A Y High Quality(++)Balon 1998 [84] Y Y Y Y Y Y Y Y Y Y Y Y SMT: 7/45 = 16%Sham: 4/46 = 9%CS CS Y High Quality(++)Olafsdottir 2001[87]Y Y CS Y Y Y Y Y Y CS Y Y SMT: 1/46 = 2%No SMT: 4/40 = 10%Y N/A Y Acceptable(+)Ward 2015 [80] Y N Y Y CS Y Y Y Y Y Y Y SMT: 0%No contact control: 0%Y N/A Y Acceptable(+)Chaibi 2017 [82] Y Y Y Y Y Y Y Y Y Y Y Y SMT: 8/35 = 23%Sham: 9/35 = 26%Usual pharmacological care:14/34 = 41%N N/A Y OverallAcceptable(+)SMT vs.ControlLow Quality(−)Miller 2012 [89] Y N Y Y CS CS Y Y Y CS Y Y Not blinded SMT: 7/33 =21.2%bBlinded SMT: 5/35 = 14.3%bNo SMT: 12/34 = 35.3%CS N/A N Low Quality(−)Molins-Cubero2014 [79]Y Y Y Y N Y N Y Y Y Y Y SMT: 0%Sham: 0%Y N/A N Low Quality(−)Wiberg 1999 [85] Y Y Y N N Y Y Y Y CS Y Y SMT: 0%Advice: 9/25 = 36%CS N/A N Low Quality(−)Qu 2012 [90] Y Y CS CS N CS Y Y Y CS Y Y SMT: 0%Medication: 0%Y N/A Y Unacceptable(0)Bakris 2007 [88] N N Y CS CS CS Y Y Y CS Y Y SMT: 0/25 = 0%Sham: 1/25 = 4%Y N/A Y Unacceptable(0)Tuchin 2000 [86] Y Y N N N CS Y Y N CS CS Y SMT: max 4cDe-tuned IFT: max 4cCS N/A N Unacceptable(0)Kokjohn 1992 [83] Y Y CS N CS CS CS Y Y CS Y Y SMT: 1/24 = 4.2%Sham: 0/21 = 0%Y N/A Y Unacceptable(0)Parker 1978 [78] Y Y CS N N CS N N N Y Y Y SMT: at least 2/85 = 2.4%cMob: max 4/85 = 4.7%cY CS N Unacceptable(0)CS: can’t say; N: no; N/A: not applicable; Y: yes; ++: high quality; +: acceptable quality; −: low quality; 0: unacceptable quality/rejectedIFT interferential therapy, Mob mobilization2.1 Research Question2.2 Definition of non-MSK condition2.3 Randomization2.4 Concealment2.5 Participant blinding2.6 Investigator blinding2.7 Groups are similar at start of trial2.8 Description of manipulation intervention2.9 Description of control intervention2.10 Only difference between groups is the treatment2.11 Reliability of outcome2.12 Validity of outcome2.13 Drop-out percentage2.14 Subject analysis/Intention-to-treat2.15 Comparable sites (if multiple)3.5 Appropriate analysisaRisk of bias table addresses primary outcome measuresbParticipants were discharged but criteria for discharge were not outlinedcDid not outline which groups the drop-outs belonged toCôté et al. Chiropractic & Manual Therapies (2021) 29:8 Page 10 of 23not be pooled in a meta-analysis. Specifically, the trialsincluded different populations, used different outcomemeasurements and were managed according to differenttherapeutic protocols.Low and unacceptable methodological qualityNine RCTs were rated as low or unacceptable quality(Table 1). Two of these were conducted in infants withcolic [85, 89], two in women with dysmenorrhea [79,83], one in adults with hypertension [88], one in adultswith irritable bowel syndrome [90], and three in adultswith migraines [78, 82, 86] (Table 4). Two studies evalu-ated the efficacy of spinal manipulation [79, 83] andseven evaluated effectiveness of spinal manipulation [78,82, 85, 86, 88–90].Evidence summary for the secondary and tertiaryprevention of non-MSK disordersStudies of high/acceptable qualityNone of the six RCTs of high or acceptable quality dem-onstrated that SMT is efficacious or effective for the sec-ondary or tertiary prevention of non-MSK disorders(Tables 3-4) and there were no studies on primaryprevention.Childhood asthma One high quality RCT by Balon et al.[84] compared the outcome of spinal manipulation to thatof simulated spinal manipulation for the management ofmild or moderate asthma in individuals aged 7–16 years(Table 3). Both treatment groups received usual medicalcare. No statistically significant differences in morningpeak expiratory volume were found between groups at thetwo- and four-months follow-ups. Similarly, there were nodifferences in secondary outcomes at follow-up (airway re-sponsiveness, forced expiratory volume (FEV1), daytimesymptoms of asthma, need for inhaled beta-agonists, useof oral corticosteroids, or quality of life). No adverseevents were reported except exacerbations of asthmasymptoms. This trial found that spinal manipulation is noteffective for the management of mild or moderate asthmain individuals aged 7–16 years.Infantile colic One RCT of acceptable quality by Olafs-dottir et al. [87] compared the outcome of spinal ma-nipulation and mobilization using light fingertippressure to the spine of an infant being held by a nursefor 10 min for the management of colic in infants aged 3to 9 weeks (Table 3). Both groups also received parentcounselling and support on feeding, baby care and familyinteractions. The authors found no difference in globalimprovement as perceived by parents or crying time at 8to 14 days follow-up. This trial suggested that spinal ma-nipulation and mobilization are not effective for themanagement of colic in infants aged 3 to 9 weeks. Theauthors did not report on adverse events.Primary dysmenorrhea In one high quality RCT, Hon-dras et al. [37] compared the outcome of high-velocitylow-amplitude manipulation targeting the lower thoracicspine, lumbar spine and sacro-iliac joints to that of a lowforce mimic maneuver in females aged 18–45 years withprimary dysmenorrhea (Table 3). The authors reported nodifference in pain and prostaglandin levels in four subse-quent menstrual cycles. Mild adverse events (transientpost-treatment soreness in the low back) were reported bya few women in both groups. This RCT suggested thatspinal manipulation is not effective for the management ofprimary dysmenorrhea in females aged 18–45 years.Hypertension One acceptable quality RCT [80] and onehigh quality RCT [81] informed the management ofhypertension using spinal manipulation in adults. Thefirst trial by Ward et al. evaluated the efficacy by com-paring a supine diversified high-velocity low-amplitudemanipulation to the T1–4 region to a sham procedure inadults between the ages of 18–65 with pre-hypertensionor hypertension (Table 3) [80]. No differences in bloodpressure, arterial pressure or heart rate were found be-tween groups one- and 10-min post-treatment. These re-sults agree with the findings of an effectiveness trial whichcompared toggle recoil thrust delivered to the C1-C2 re-gion to sham manipulation in adults between the ages of21–75 years with hypertension. In their RCT, Goertz et al.[81] found no differences between groups in blood pres-sure, health-related quality of life or perceived stress im-mediately after the intervention and at 6 weeks follow-up.Adverse events included three people with headaches andone with neck and upper thoracic pain [81]. These twoRCTs suggested that spinal manipulation is neither effica-cious nor effective for the management of hypertension inadults 18 years and older.Migraine An RCT of acceptable quality by Chaibi et al.[82] compared the outcomes of full-spine Gonsteadhigh-velocity low-amplitude manipulation to sham ma-nipulation for the management of adults with migraineheadaches (Table 3). The results indicate that partici-pants who received the sham manipulations had fewermigraine days per month during the one-year follow-up compared to the group receiving SMT (calculationbased on published estimates, available from the au-thors on request). There were no differences betweengroups in migraine duration, intensity and medicineconsumption at follow-up. Minor and transient ad-verse events (local tenderness and neck pain) were atleast twice as common in the SMT group (73/355) asin the sham spinal manipulation group (29/348). ThisCôté et al. Chiropractic & Manual Therapies (2021) 29:8 Page 11 of 23Table 3 Evidence table for randomized controlled trials of high- and acceptable quality stratified by condition1st Author,Year,Study qualityParticipants, Casedefinition, Setting,Number (n) enrolledInterventions,Provider, Number(n) of subjects atbaselineControl, Provider,Number (n) ofsubjects at baselineFollow-up OutcomemeasurementsResultsMean (95%CI)AsthmaBalon 1998[84]Quality:High QualityChildren, 7 to 16 yrs.;physician diagnosedmild or moderateasthma > 1 yr, usebronchodilator atleast three timesweekly, andconfirmed by lungfunction testing.Participants recruitedthrough advertising.Private chiropracticclinics in Ontario,Canada.(n = 91)SMT-HVLA determinedand gentle soft-tissuetherapy by chiropractorwith usual medical care.3x weekly for 4 weeks,2x weekly for 4 weeks,then 1x weekly for 8weeks, (range 20 to36 Tx over 4-mths).Chiropractors with5 years of clinicalexperience(n = 45)Non-directional lowamplitude, lowvelocity impulse togluteals, scapulaeand externaloccipitalprotuberance; andsoft-tissue massageand gentle palpation;by chiropractor withusual medical care.3x weekly for 4 weeks,2x weekly for 4 weeks,then 1x weekly for 8weeks, (range 20 to36 Tx over 4-mths).Chiropractors with 5years of clinicalexperience(n = 46)2 and 4mthsPrimary outcome:morning PEF priorto use ofbronchodilator andfrequency of morningPEF of < 85% ofbaseline.Secondary outcomes:airway responsiveness;FEV1; daytimesymptoms of asthma;need for inhaled beta-agonists; use of oralcorticosteroids; Q ofL; overall treatmentsatisfactionAdverse eventsNS between groupdifferences2 mths (meanbetween groupdifferences):PEF (% baseline):2.1 (−3.9, 8.0)FEV1(liters):− 0.28 (− 0.61, 0.05)Overall Q of L:0.29 (− 0.10, 0.69)Activity: 0.34(− 0.13, 0.81)Symptoms: 0.29(− 0.21, 0.78)Emotions: 0.26(− 0.14, 0.66)Change insymptoms: p = 0.59Use of Beta-agonists:p = 0.554 mths (meanbetween groupdifferences):PEF: − 0.7 (− 6.7, 5.3)FEV1(liters): − 0.28(− 0.61, 0.04)Overall Q of L: 0.32(− 0.12, 0.75)Activity: 0.42(− 0.10, 0.93)Symptoms: 0.15(− 0.39, 0.69)Emotions: 0.29(− 0.15, 0.73)Change in symptoms:p = 0.84Use of Beta-agonists:p = 0.35Between groupdifferences in dayswith PEF < 85%:− 2.9 (− 11.1, 5.3)Mean satisfaction-Intervention: 6.22/7.0Mean satisfaction-Control: 6.46/7.0No adverse events,apart fromexacerbations ofasthma.Infantile ColicOlafsdottir2001 [87]Quality:AcceptableInfants (born at termwith a birth weight >2.5 Kg; appropriategain in weight, height andhead circumference)recruited in Bergen,Norway from publichealth clinics thepaediatric outpatientclinic at the UniversityHospital, generalpractitioners,chiropractors, andfrom direct referralsSMT and mobilizationdetermined by treatingchiropractor by areas ofdysfunction identifiedby palpation;dysfunctionalarticulations manipulatedand mobilized usinglight fingertip pressure.Counselling and supporton feeding, babycare, and familyinteraction.Infants held by anurse for 10 min (theapproximate time oftreatment) after beingpartially undressed ina similar way astreated infants.Counselling and supporton feeding, baby care,and family interaction.3 sessions with intervalsof 2–5 days over 8 days8–14 dayspost-interventionParent’s globalperceivedimprovement(“getting worse”,“no improvement”,“some improvement”,“markedimprovement”,“completely well”)Crying time (hours/day)No Improvement inSMT group vs.control group(marked improvementor completely well)Relative Risk =0.97(95% CI: 0.59, 1.60)Crying time (hours/day):SMT/mobilization vs.Control1st visit: − 0.6(− 1.47, 0.27)2nd visit: − 0.5Côté et al. Chiropractic & Manual Therapies (2021) 29:8 Page 12 of 23Table 3 Evidence table for randomized controlled trials of high- and acceptable quality stratified by condition (Continued)1st Author,Year,Study qualityParticipants, Casedefinition, Setting,Number (n) enrolledInterventions,Provider, Number(n) of subjects atbaselineControl, Provider,Number (n) ofsubjects at baselineFollow-up OutcomemeasurementsResultsMean (95%CI)from parents whowere informedabout the project atthe maternity unitsin Bergen and by themedia from April 1998to December 1999.Infantile colic definedas ≥3 h crying/day,3 days per week forthe last 3 weeks.(n = 100)3 sessions withintervals of 2–5days over 8 daysby a licensedchiropractor(n = 46)by a nurse(n = 40)(− 1.34, 0.37)3rd visit: − 0.3(− 1.17, 0.57)HypertensionGoertz 2016[81]Quality:High QualityAdults (21–75 yrs),recruited from thecommunity throughtargeted direct mailers,American HeartAssociation events,and press releases inIowa, USA.Hypertension withsystolic blood pressureranging from 135 to159 mmHg or diastolicblood pressure rangingfrom 85 to 99 mmHgand misalignment ofeither or both of thefirst 2 cervical spinalsegments based onstandardizedradiography.Research clinic of thePalmer Center forChiropractic Research,Davenport, IA(n = 51)Toggle recoilconsisting of HVLAthrust delivered tothe C1 and/or C2vertebra withparticipants in aside-lying positionon the treatmenttable.2 sessions/week over6 weeksChiropractors with> 5 years’ experiencetrained in togglerecoil SMT(n = 24)Sham manipulationconsisting of nothrust delivered tothe participant’shead or neck.Delivered at 1stsession and then for4–8 visits at randomintervals over 6 weeksChiropractors with> 5 years’ experiencetrained in toggle recoilSMT(n = 27)Immediatelyafterinterventionand 6 weeksPrimary outcome:Blood pressureSecondary outcome:SF–36 (Pain andGeneral Health Sub-Scales), PerceivedStress ScaleAdverse eventsNS difference inblood pressurechange betweengroups following theintervention.CRUDE:Mean differencechange score3 weeks:Systolic BP: − 0.3(− 6.2, –5.3)Diastolic BP − 0.3(− 4.0, –3.5)6 weeks:Systolic BP: 3.5(− 1.9, –8.9)Diastolic BP: 1.5(− 2.1, –5.0)ADJUSTED (age, sex,BMI, baseline BP):Mean differencechange score3 weeks:Systolic BP: 0.9(− 5.0, –6.9)Diastolic BP: 1.0(− 2.8, –4.9)6 weeks:Systolic BP: 4.8(− 0.4, –10.0)Diastolic BP: 2.3(− 1.2, –5.8)SF-36: Pain:Mean change (95% CI)SMT vs. Sham: 0.6(− 2.18, 3.38)SF-36: General Health:Mean change (95% CI)SMT vs. Sham: − 1.1(− 3.18, 0.98)Perceived Stress ScaleMean change (95% CI)SMT vs. Sham: 0.1(− 1.70, 1.90)Adverse eventsincluded 4 relatedto study treatments:3 headaches,1 neck and upperthoracic pain. Threeadditional: footCôté et al. Chiropractic & Manual Therapies (2021) 29:8 Page 13 of 23Table 3 Evidence table for randomized controlled trials of high- and acceptable quality stratified by condition (Continued)1st Author,Year,Study qualityParticipants, Casedefinition, Setting,Number (n) enrolledInterventions,Provider, Number(n) of subjects atbaselineControl, Provider,Number (n) ofsubjects at baselineFollow-up OutcomemeasurementsResultsMean (95%CI)numbness andtingling after aneck examination,fainting episode24 h after treatment,mild nausea andvertigo at firsttreatment.Ward 2015 [80]Quality:AcceptableAdults (18–65 yrs),recruited via onlineadvertisements andword-of-mouth inTexas, USA.Proof of high bloodpressure (hypertensionmedications) or initialblood pressure reading> 140/90 mmHg.(n = 50)Supine diversified anteriorupper thoracic SMT tothe T1–4 region with aHVLA thrust of the upperbody of the chiropractorover the participant’schest to achievecavitation of the T1–4segments of thethoracic spine.1 session by chiropractorwith 20 years ofexperience and 15 yearsof SMT techniqueteaching experience atTexas Chiropractic College(n = 25)Participants’ arms foldedacross their chest for afew seconds and thenthe chiropractor unfoldedthe arms.1 session by chiropractorwith 20 years of experienceand 15 years of SMTtechnique teachingexperience atTexas Chiropractic College(n = 25)1- and 10-min post-interventionBilateral bloodpressureArterial pressureHeart rateAdverse eventsnot assessedNS differences inmean bloodpressurechange betweengroups.Control vs SMT -Meandifference (95% CI)Right systolic BP1 min: 3.4(− 4.06, 10.86)10 min: 2.9(− 4.01, 9.81)Right diastolic BP1 min: 2 (− 2.49, 6.49)10 min: − 0.2(− 4.69, 4.29)Left systolic BP1 min: − 1.8(− 8.67, 5.07)10 min: 4(− 3.39, 11.39)Left diastolic BP1 min: − 0.6(− 5.51, 4.31)10 min: 1(− 3.75, 5.75)Pulse pressure1 min: 1.3(− 3.84, 6.44)10 min: 3.1(− 1.51, 7.71)Mean arterial pressure1 min: 2.5 (− 2.62, 7.62)10 min: 0.9(− 4.08, 5.88)Heart rate1 min: 1.1 (− 2.97, 5.17)10 min: 1 (− 3.12, 5.12)DysmenorrheaHondras 1999 [37]Quality:High QualityWomen, 18–45 yrs.;sexually active, non-pregnant, goodgeneral health, regularmenstrual cyclesaccompanied bymoderate to severepain; diagnosis ofprimary dysmenorrhearecruited through localadvertisements inChicago metropolitannewspapers.National CollegeChiropractic Centeroutpatient clinic,Chicago, USA.SMT-HVLA > 750 N to allclinically relevant levelsfrom T10-L5 andsacroiliac joints, bilaterally.3x/week beginning theweek before expectedonset of menstruationfor next two cycles(cycles 3 and 4)Chiropractors practicingat National CollegeChiropractic Center(n = 69)LFM-high-velocity, short-lever, low amplitudethrust between 200 to400 N to L2–3 vertebralby chiropractorChiropractors practicingat National CollegeChiropractic Center(n = 69)4 menstrualcyclesPrimary outcome:Pain intensity (VAS)Secondary outcome:MDQAdverse eventsNS between groupdifferences at anyfollow-up menstrualcycle for pain intensity(p = 0.65) or menstrualdistress (p = 0.78)2 women in the LFMgroup and 3 womenin the SMT groupreported soreness inthe low back region24–48 h followingintervention at 1 visit.Côté et al. Chiropractic & Manual Therapies (2021) 29:8 Page 14 of 23Table 3 Evidence table for randomized controlled trials of high- and acceptable quality stratified by condition (Continued)1st Author,Year,Study qualityParticipants, Casedefinition, Setting,Number (n) enrolledInterventions,Provider, Number(n) of subjects atbaselineControl, Provider,Number (n) ofsubjects at baselineFollow-up OutcomemeasurementsResultsMean (95%CI)(n = 138)MigraineChaibi 2017 [82]Quality:AcceptableAdults (18–70 yrs)recruited from AkershusUniversity Hospital,general practitionersand mediaadvertisements inAkershus and OsloCounties, Norway.Migraine diagnosedaccording to theICHD-II (ICHD, 2004)and with ≥ onemigraine attack permonth.Akershus UniversityHospital, Norway(n = 104)aGonstead method,specific contact,HVLA, short-leverSMT with nopost-adjustmentrecoil that wasdirected to spinalbiomechanicaldysfunction (fullspinal columnapproach)12 sessions over 3 mthsExperienced chiropractor(n = 34)Sham SMT consistingof a broad, non-specificcontact, low velocity,low amplitude shampush maneuver12 sessions over3 mthsExperienced chiropractor(n = 34)Immediatelyaftertreatment, 3,6 and 12mths.Primary outcome:Number of migrainedays per mthSecondary outcomes:migraine duration,migraine intensityand headache index,medicineconsumption andadverse eventsSignificant differencesin mean changein migraine daysfavoring shamtreatments. Nodifference in secondaryoutcomes.Sham vs. CSMTMigraine daysPost-treatment: − 1.6(− 3.09, − 0.10)3 months: − 1.7(− 3.28, − 0.12)6 months: − 0.8(− 2.50, 0.90)12 months: − 2.1(− 3.84, − 0.36)DurationPost-treatment: − 1.1(− 3.19, 0.98)3 months: − 1.2(− 3.51, 1.10)6 months: 2.0(− 0.38, 4.38)12 months: − 1.5(− 4.05, 1.04)IntensityPost-treatment: − 0.1(− 1.06, 0.86)3 months: − 0.5(− 1.49, 0.49)6 months: 0.4(− 0.77, 1.57)12 months: − 1.1(− 2.34, 0.14)Headache IndexPost-treatment:− 170.4 (− 346.30,5.50)3 mths: − 143.4(− 323.24, 35.45)6 mths: − 115.2(− 296.07, 65.67)12 mths: − 232.9(− 429.06, − 36.74)NS difference inmedicine consumptionMinor, transientadverse events [localtenderness and neckpain] were morecommonly reportedin CSMT (73/355)than sham SMT group(29/348). There wereno severe or seriousAEs reported.FEV1 forced expiratory volume in 1 s, HVLA high velocity, low amplitude, mths months, NS non-significant, PEF peak expiratory flow, Q of L quality of life, SMTspinal manipulative therapy, Tx treatment, yrs years, LFM low force mimic, MDQ Moos’ menstrual distress questionnaire, VAS visual analog scale, AE adverse eventsaResults only reported from intervention (SMT) and sham groupCôté et al. Chiropractic & Manual Therapies (2021) 29:8 Page 15 of 23RCT suggested that spinal manipulation is not effect-ive in the management of adults with migraineheadaches.Results of studies of low/unacceptable qualityAll studies of low or unacceptable quality reported somepositive results (Table 5). Eight RCTs rated as low or un-acceptable quality reported at least some results supportingthe efficacy [79, 83] or effectiveness of spinal manipulation[82, 85, 86, 88–90]. These studies reported on high bloodpressure [88], infantile colic [85, 89], dysmenorrhoea [79,83], irritable bowel syndrome [90], and migraine [82, 86].A ninth study (of unacceptable quality) reported a signifi-cant improvement in migraine for its three study groups,but all groups received some type of manual therapy [78].Review of risk of bias and evidence tables by globalsummit participantsThe risk of bias table was approved by 98.0% (49/50)of participants (Table 2). Similarly, 98.0% (49/50) ofparticipants approved the content of the evidencetable (Table 3). The content of the evidence sum-mary was approved by 100% (50/50) of participantsfor hypertension, 98% (48/49) for infantile colic,94.0% (47/50) for dysmenorrhea, 94.0% (47/50) forasthma, and 90.0% (45/50) for migraine.Approval of the final manuscript and authorshipEighty-eight percent of Global Summit participants ap-proved the final paper and agreed to be co-authors.However, six participants declined authorship becausethey did not agree with the overall conclusion.DiscussionSummary of findingsOur systematic review of the best available evidence sug-gests that SMT is not effective or efficacious for treatinginfantile colic, childhood asthma, hypertension, primarydysmenorrhea, or migraine. Collectively, the evidencefrom six high and acceptable quality RCTs casts doubtTable 4 Summary of findings for studies of acceptable qualityAuthor,YearOrigin of study sample StudypopulationInterventions Time offollow-upOutcome variables SMTsuperior tocontrolAsthmaBalon,1998 [84]Chiropractic patients Children (7–16years) with mildor moderateasthmaSMT vs. Sham 2 and 4monthsFEV1PEFQuality of lifeNoInfantile ColicOlafsdottir,2001 [87]Public health care clinics, pediatricoutpatient clinic at University hospital,general practitioners, chiropractors anddirect referralsInfants with colic SMT vs. Sham 8–14 daysafterinterventionParent’s globalperceivedimprovement orcrying timeNoHypertensionGoertz,2016 [81]Community in Iowa, USA Adults with pre-hypertension orhypertensionSMT vs. Sham Immediatelyand 6 weeksBlood pressure NoWard, 2015[80]Community in Texas, USA Adults withhypertensionSMT vs. Sham Immediatelyand 10minBlood pressure, pulsepressure, mean arterialpressure and heartrateNoDysmenorrheaHondras,1999 [37]Chiropractic patients Women withprimarydysmenorrheaSMT vs. Sham 1 h VAS or MMDQ NoMigraineChaibi,2017 [82]University hospital, general practitionersand community in Oslo Counties, NorwayAdults withmigraineSMT vs. Sham Immediately,3 monthsMigraine days No (Shamsignificantlysuperior toSMT)6 and 12monthsMigraine duration,intensity or headacheindexNoLegend: FEV1 forced expiratory volume in 1 s, PEF peak expiratory flow, SMT spinal manipulative therapy, MDQ Moos’ menstrual distress questionnaire, mthsmonths, NS non-significant, VAS visual analog scaleCôté et al. Chiropractic & Manual Therapies (2021) 29:8 Page 16 of 23on the hypothesis that SMT is efficacious or effective forthe management of non-musculoskeletal disorders [37,80–82, 84, 87] and thereby also challenge the validity ofthe underlying theories relating to the subluxation andthe autonomic nervous system [10, 11, 14].Previous literatureOur conclusions agree with several previous reviews.Clar et al., who comprehensively reviewed the literatureon the clinical effectiveness of spinal manipulation forthe management of musculoskeletal and non-musculoskeletal disorders, only found evidence for theeffectiveness for the treatment of some musculoskeletaldisorders [20]. Similarly, Goncalves et al., who reviewedevidence for spinal manipulation or chiropractic care asprimary- or early secondary prevention for disease ingeneral, failed to find any supportive evidence [42].Ferrance and Miller, who reviewed the literature dealingwith chiropractic diagnosis and management of non-musculoskeletal disorders in children broadly, includingall types of studies, even case-reports, concluded that“The efficacy of chiropractic care in the treatment ofnon-musculoskeletal disorders has yet to be proven ordisproven” [38]. Conversely, Kaminskyj et al. includedcase-reports, case-series, surveys, cohort studies and twoRCTs and concluded that “it is obvious that some asth-matic patients may benefit from [chiropractic] treatmentapproach” but added that it should not replace trad-itional medical therapy [39]. Likewise, Pohlman andHolton-Brown reviewed 49 studies including commen-taries, case-reports and case-series and concluded thatpossibly some children with otitis media may benefitfrom SMT [40]. Rist et al. reviewed RCTs of SMT astreatment for migraine headaches and included trialsTable 5 Summary of findings for studies of unacceptable qualityAuthor,YearOrigin of study sample StudypopulationInterventions Time offollow-upOutcome variables Results fromauthors – SMTsuperior to controlInfantile ColicMiller,2012 [89]Chiropractic teaching clinic atAnglo-European College ofChiropracticInfants withcolicSMT vs.Parent-blindedcontrol10 days or atdischarge24 h crying diary, Globalimprovement scaleYesWiberg,1999 [85]Suburb of Copenhagen, Denmark Infants withcolicSMT vs. Usualcare12 to 15 days 24 h crying diary,parents’ subjectiveevaluation of changeYesHypertensionBakris,2007 [88]Unknown, USA Adults withhypertensionSMT vs. Sham 8 weeks Blood pressure YesMolins-Cubero,2014 [79]Physiotherapy private practice;Madrid, SpainWomen withprimarydysmenorrheaSMT vs. Sham Post-interventionVAS YesKokjohn,1992 [83]Local community, localchiropractors or gynecologists;Illinois, USAWomen withprimarydysmenorrheaSMT vs. Sham 1-h post-interventionVAS or MDQ YesMigraineChaibi,2017 [82]University hospital, generalpractitioners and community inOslo Counties, NorwayAdults withmigraineSMT vs.ControlImmediately,3 monthsMigraine days, headacheindexYes6 and 12monthsMigraine duration orintensityNoTuchin,2000 [86]Radio and newspaperadvertisements in Sydney regionAdults withmigraineSMT vs.Control6 months Frequency, duration,disability, use ofmedicationYesIntensity, associatedsymptomsNoParker,1978 [78]Unknown; Australia Adults withmigraineSMT vs.Mobilization2 months Duration, intensity,disabilityNoIrritable Bowel SyndromeQu, 2012[90]Outpatient department fromZhongda HospitalAdults withirritable bowelsyndromeSMT vs. Drug Post-interventionVAS, Bowel symptomscaleYesLegend: SMT spinal manipulative therapy, MDQ Moos’ menstrual distress questionnaire, mths months, NS non-significant, VAS visual analog scaleCôté et al. Chiropractic & Manual Therapies (2021) 29:8 Page 17 of 23with high risk of bias where the effect of SMT could notbe disentangled from the effect of co-interventions [91].Nonetheless, they concluded that “SMT may be an ef-fective therapeutic technique to reduce migraine daysand pain intensity. However, given the methodologicallimitations to studies included [ …] we consider theseresults to be preliminary” [91]. Finally, Parnell Prevostet al. reviewed and critically appraised 50 studies of vari-ous designs dealing with manual therapy for a wide var-iety of pediatric conditions and concluded that theevidence was inconclusive but favorable for some non-musculoskeletal disorders including infantile colic (4RCTs included), nocturnal enuresis (no RCTs included),sub-optimal infant breastfeeding (no RCTs included), re-spiratory, eyes, ears, nose and throat conditions (3 RCTsincluded) [43]. However, the review by Parnell Prevostet al. suffers from significant methodological limitations[92]. Our review adds to the literature because of fourmethodological differences between ours and some ofthe previous reviews. First, our research questions weredifferent and focused on determining the efficacy and ef-fectiveness of SMT for non-MSK disorders. Second, werestricted our search strategy to RCTs, which was neces-sary to assess efficacy and effectiveness. Third, we useddifferent criteria to evaluate the methodological qualityof RCTs. Finally, our evidence synthesis only includedacceptable and high quality RCTs.Strengths and limitationsOur systematic review has several strengths. First, ourresearch questions focused on determining the efficacyand effectiveness of SMT for both the prevention andmanagement of non-musculoskeletal disorders. Thesequestions required that we focus our review on evidencefrom high (n = 3) and acceptable (n = 3) quality random-ized clinical trials. Second, the literature search was con-ducted by an expert librarian and independentlyreviewed by a second librarian to minimize errors. Third,our critical appraisal of the literature included four se-quential steps to ensure that the risk of bias assessmentwas conducted in a transparent, standardized, and rigor-ous manner. Fourth, the evidence synthesis includedonly high and acceptable quality RCTs and was con-ducted according to the SWiM Guideline and reportedin transparent evidence tables [48].The findings of our review should, nevertheless, beinterpreted in light of the following limitations. First, al-though our search method was thorough, it is possiblethat studies of high or acceptable quality were not re-trieved because our literature search was restricted tothe English language. However, it has been reported thatexcluding articles written in a language other than Eng-lish does not lead to bias because most trials are pub-lished in the English literature [93–97]. Furthermore,authors included academics in the field with knowledgeof German, Danish, Swedish, Norwegian, and Frenchand none were aware of RCTs dealing with SMT pub-lished in those languages. This is supported by oursearch of the Index to Chiropractic Literature (ICL)which only identified RCTs published in English. Sec-ond, the critical appraisal of articles may vary among re-viewers. However, our four-step approach to assessingrisk of bias likely minimized this potential problem. Fi-nally, publication bias may be present in this field of re-search. However, it is unlikely that publication biascompromised the validity of our results because studiesmost unlikely to be published are those that failed to ob-tain a ‘positive’ result. Further, all the low risk of biasRCTs included in our review show that SMT is not ef-fective for the management of non-musculoskeletaldisorders.Future review updatesOur findings, which are based on the best current evi-dence, may need to be modified with the publication offindings from new high-quality RCTs. Therefore, we rec-ommend that our systematic review be updated every 2to 3 years when new evidence becomes available. This isnecessary to ensure that our findings are up to date withthe most recent published literature. This is particularlyimportant since our findings and conclusions are basedon a limited number of high and acceptable quality tri-als, and only single trials for all but one conditions.Therefore, future trials can potentially alter our find-ings and conclusions. For example, we are aware ofone ongoing RCT on the effectiveness of manipula-tion/mobilization for the management of infantilecolic [98]. Once published, the quality of this trialshould be evaluated, and its results integrated in anupdated review. We recommend that governments,payers, regulators, educators and clinicians regularlyadapt their policies and practices with new emergingevidence.ImplicationsThe findings from the Global Summit call for the devel-opment and implementation of evidence-based policiesregarding the use of SMT in the treatment of non-MSKdisorders at several levels, as explained below. We antici-pate that system-level polices will eventually impact clin-ical practice and change clinical behaviours. Policiesshould be based on the best available evidence with con-sideration of its strength and limitations.i) Implications for healthcare delivery systems andregulatory agenciesCôté et al. Chiropractic & Manual Therapies (2021) 29:8 Page 18 of 23Our systematic review highlights the need for health-care delivery systems and regulatory agencies to considerthe lack of evidence supporting the prevention and treat-ment of non-musculoskeletal disorders using SMT whendeveloping policies.ii) Implications for educational institutions andeducational regulatorsEducational institutions for the chiropractic, osteo-pathic and other manual medicine health professionshave the opportunity to implement our findings intotheir curricula to train their students as modern,evidence-based clinicians. This will ensure that students’future clinical activities are consistent with the bestavailable evidence and viable within modern healthcaresystems. Implementing our findings will require signifi-cant changes in curriculum in some institutions wherethere is a need to communicate to students when theirteaching content is not supported by valid evidence. It isof utmost importance that educational institutions edu-cate students to be competent consumers of research,thereby enabling the next generation of clinicians to dif-ferentiate high from low quality research. This should bea priority because, as we have demonstrated, sometimesvery different conclusions can be drawn from high ver-sus low quality research.Educational regulators, who oversee the educationalquality of practitioners of manual medicine, should alsoalign their standards with best evidence and ensureconsistency across educational institutions and, ultimately,of practitioners of manual medicine around the world. Ac-cording to the Council for Higher Education Accredit-ation (CHEA) International Quality Group (CIQG) [99]this could be achieved by: 1) guiding institutions and orga-nizations in developing capacity for academic quality; 2)advancing understanding of international quality assur-ance; and 3) providing research and policy direction [99].Finally, the findings from the Global Summit shouldbe incorporated into continuing education programs anddisseminated to clinicians, and professional organiza-tions should align their policies and communicationswith the current evidence.iii) Implications for clinical practiceOur systematic review helps clinicians by providingthem with necessary knowledge to deliver evidence-based care to their patients. Even though non-musculoskeletal disorders make up a small proportion ofpatients in chiropractic and osteopathic practice [6, 8],implementing our findings will require changes for someclinicians in the way they communicate and practice. Itis important to emphasize that patients with non-musculoskeletal disorders might still benefit from seeingpractitioners of SMT. First, because many people withnon-musculoskeletal disorders have musculoskeletal co-morbidities that significantly impact their overall healthand well-being [100]. Alleviating pain and discomfortoriginating from the musculoskeletal system can be animportant contribution to the care of people with multi-comorbidities. Second, contextual effects, associated withany clinical encounter can have important psychologicaland physical effects on patients. However, the best avail-able evidence suggests that it is not the SMT that is re-sponsible for the observed treatment outcomes [37, 80–82, 84, 87].Importantly, clinicians need to be aware that low- andpoor-quality studies can lead to deceptive results. Thiswas the case in our review; all low-quality studies re-ported “good” results whereas high-quality studies all re-ported null results. Therefore, studies with poormethodological quality should not be used to informclinical practice.iv) Implications for future researchAlthough we found consistent evidence that SMT isnot efficacious or effective for the management of non-MSK conditions, our conclusions are based on a limitednumber of high and acceptable quality RCTs. Therefore,more and better RCTs should be conducted if the man-agement of non-musculoskeletal disorders with SMT isa priority for patients, clinicians and decision-makers.However, this will require that the preliminary researchleading to the design and conduct of an RCT follows asequential and logical approach, where adequate pre-trial data allows for the formulation of rational inclusioncriteria, power calculations and interventions that have aclear biological target [101].Reflections about the global summitOur research brought together an international group ofresearchers who used established methods to search,screen, critically appraise, and synthesize the literature.We ensured that our methods and deliberations weretransparent by inviting chiropractic stakeholder organi-sations to attend and observe the Global Summit pro-ceedings. The observers are, therefore, able to testify tothe rigor and the transparency of the work conducted atthe Global Summit proceedings. Including these ob-servers in our process was important due to the consid-erable debate in the chiropractic and other manualmedicine professions about the efficacy and effectivenessof SMT to prevent and treat non-MSK disorders.The Global Summit was a unique and historic event.Never in the history of chiropractic or any manual medi-cine profession has such a large international group ofCôté et al. Chiropractic & Manual Therapies (2021) 29:8 Page 19 of 23active researchers collaborated to produce such a com-prehensive scientific report. Representatives from profes-sional organizations observed the scientific process anddiscussions, and they were able to interact with the sci-entists during breaks and provided all participants withthe opportunity to discuss scientific, professional andpolitical issues in an informal and friendly atmosphere.In spite of involving a large group of researchers and thecomplicated logistics of the Summit, we were able tostrictly adhere to our pre-determined methods. It is alsonoteworthy that 88% of all researchers who attended theGlobal Summit agreed with the final conclusions of thiscomprehensive review. The six participants, who choseto abstain from authorship, did so because they did notagree that the overall conclusion represented the resultsof the review.ConclusionsOur systematic review included six randomized clinicaltrials (534 participants) of acceptable or high quality in-vestigating the efficacy or effectiveness of SMT for thetreatment of non-musculoskeletal disorders. We foundno evidence of an effect of SMT for the management ofnon-musculoskeletal disorders including infantile colic,childhood asthma, hypertension, primary dysmenorrhea,and migraine. This finding challenges the validity of thetheory that treating spinal dysfunctions with SMT has aphysiological effect on organs and their function. Gov-ernments, payers, regulators, educators, and cliniciansshould consider this evidence when developing policiesabout the use and reimbursement of SMT for non-musculoskeletal disorders.Supplementary InformationThe online version contains supplementary material available at https://doi.org/10.1186/s12998-021-00362-9.Additional file 1.AbbreviationsMSK: Musculoskeletal; SMT: Spinal manipulative therapy; RCT: Randomizedclinical trialAcknowledgementsWe thank Professor Olivier Gagey MD, PhD for providing guidance with thepreparation of the Global Summit and for attending the Global Summit. Wethank Drs. Lise Hestbæk DC, PhD, Michele Maiers DC, MPH, PhD, BernadetteMurphy DC, PhD, and Katie Pohlman DC, PhD for their contribution to thecritical appraisal of the literature and for attending the Global Summit. Weacknowledge the expertise of Anne Taylor-Vaisey, BA, MLS, who designedand conducted the systematic search of the literature and Kent MurnaghanBA, MA, MIS who reviewed the systematic search of the literature. We thankPoonam Cardoso BA for organizing all logistical aspects of the Global Sum-mit and acknowledge the contribution of Leslie Verville BSC, MHSc for hercontribution with to the critical appraisal of the literature. Finally, we thankDrs. Melissa Belchos BSc, DC, Daphne To BSc, DC, Darrin Germann BSc, DC,Orion Katayama BSc, DC, and Fabrice Mallard DC, MSc for practical assistanceduring the Summit.Authors’ contributionsPC, CLY, IA and JH developed the research questions and methodology.They were responsible for the coordination and quality assurance of articlescreening, critical appraisal and data extraction. They drafted the manuscript,and reviewed co-authors comments and revised the manuscript. Finally, theyorganized and supervised all activities at the Global Summit. JDC, SM andJJW were co-leaders of critical appraisal teams (with PV, JH and IA) at theGlobal Summit. PC, AAM, JJW, CC, JH, SM, HS and IA screened titles sand ab-stracts for eligibility. JDC, SDF, GNK, SM, EP, JS, JJW and MC attended the Glo-bal Summit, critically appraised papers, extracted data, reviewed theevidence tables/risk of bias tables and were members of the editorial com-mittee. CA, MAB, JB, AB, CC, HWC, CCD, KD, ADR, AE, RE, GG, JH, CAH, MH,AK, HHL, SI, AAM, ALM, DN, SO, IP, SP, SMP, JQ, MR, HS, MS, MS AV, KW, KJYattended the Global Summit, critically appraised papers, extracted data,reviewed the evidence tables/risk of bias tables and reviewed the final paper.MC and HY critically appraised papers, extracted data and drafted evidencetables/risk of bias, but did not vote on the outcomes of the critical appraisal.All co-authors approved the final manuscript.FundingThe Canadian Memorial Chiropractic College hosted the Global Summit.Financial assistance for travel, accommodation and food was provided forthe participants of the Global Summit by Association Francaise deChiropraxie, Chiropractic Australia, Canadian Memorial Chiropractic College,Canadian Chiropractic Protective Association, ChiroSuisse, Institute Franco-Europeen de Chiropraxie, Nordic Institute of Chiropractic and Clinical Bio-mechanics, and the Swedish Chiropractic Association (LKR). All funds weregranted to Ontario Tech University. The funding organizations were not in-volved in the design, conduct or interpretation of the research and they didnot review the final version of the paper.Availability of data and materialsThe datasets used and/or analyzed during the current study are availablefrom the corresponding author on reasonable request.Ethics approval and consent to participateNot applicableConsent for publicationNot applicableCompeting interestsThe following individuals had nothing to declare: CA, IA, JB, DDC, JDC, AE,RE, GG, CAH, MH, SI, AK, AAM, ALM, DN, ADR, HS, MS, AV, JJW.MA Blanchette reports research grants unrelated to this work from Universityof Quebec-Trois-Rivieres; fees medical-legal expertise from the CanadianChiropractic Protective Association and Intact Assurance. A Bussières is anEditorial Board member of Chiropractic & Manual Therapies but had no partin the editorial or peer-review process. He reports receiving grants unrelatedto this work from the Canadian Chiropractic Research Foundation. C Cancel-liere is funded by the Canadian Chiropractic Research Foundation. HW Chris-tensen has received grants unrelated to this work from The DanishChiropractic Research Fund and my institution has paid for accommodationand travel expenses. P Côté reports research grants unrelated to this workfrom Aviva Canada, Canadian Institutes of Health Research-Canada ResearchChair Program, Canadian Chiropractic Association, Canadian Chiropractic Re-search Foundation, College of Chiropractors of British Columbia, Et liv i beve-gelse” (ELIB), French Chiropractic Association, Financial Services Commissionof Ontario, Ontario Ministry of Finance, Ontario Trillium Foundation; travel ex-penditures unrelated to this work from Griffith University - Whiplash Sympo-sium 2017, Eurospine, Southern Denmark University, Institut Franco-Europeende Chiropraxie, Karolinska Institutet, North American Spine Society, Universityof Quebec-Trois-Rivieres, University of Zurich, World Federation of Chiroprac-tic; fees for medical-legal expertise from the Canadian Chiropractic ProtectiveAssociation. K Deluca reports she has multiple research grants from Austra-lian funding agencies, unrelated to this work. She has received coverage oftravel expenditures associated with the Global Summit. SD French is a Dep-uty Editor-in-Chief of Chiropractic & Manual Therapies but had no part in theeditorial or peer-review process of this manuscript. He has received researchgrants unrelated to this work from Australian and international funding agen-cies and from chiropractic professional associations. J Hartvigsen reports thatCôté et al. Chiropractic & Manual Therapies (2021) 29:8 Page 20 of 23he holds multiple research grants from Danish and international fundingagencies and charities. He has received coverage of travel expenditures frommultiple sources internationally in connection with speaking engagements.Within the past year he has received speaking fees from Parker Seminars andNovartis. J Hébert receives salary support from the Canadian Chiropractic Re-search Foundation and the New Brunswick Health Research Foundation. Heis also an Associate Editor of Chiropractic and Manual Therapies but playedno part in the review of this submission and was blinded to the process. GKawchuk reports active research grants unrelated to this work from The Nat-ural Sciences and Engineering Research, The National Institutes of Health,The Alberta Spine Foundation, The American Orthotic and Prosthetic Associ-ation, The New Frontiers in Research Fund and the Canadian Chiropractic Re-search Foundation. Travel expenditures unrelated to this work in the pastyear include Kiropraktik i Sverige Live, Et liv i bevegelse” (ELIB), the Nordic In-stitute of Chiropractic and Clinical Biomechanics, The American ChiropracticAssociation, The National Institutes of Health, The British Columbia Chiroprac-tic Association, and The World Federation of Chiropractic. Fees for medical-legal expertise unrelated to this work from the Canadian Chiropractic Pro-tective Association. HH Lauridsen holds multiple research grants from fund-ing agencies and charities of which the main contributor is the DanishFoundation for Chiropractic Research and Postgraduate Education. HHL ispresently employed as associate professor and head of chiropractic studiesat University of Southern Denmark. No funding has been received for thepresent project. C Leboeuf-Yde reports no competing interests as she ob-tains no funding from the chiropractic profession. S Mior reports receivinggrants unrelated to this work from the Canadian Chiropractic Association,Ontario Chiropractic Association, and Canadian Chiropractic Research Foun-dation. S O’Neill reports funding by local, regional health authorities and bythe Danish chiropractic foundation for research and postgraduate education,but not in relation specifically to this project I Pagé has received grants unre-lated to this work. S Perle is an Associate Editor of Chiropractic & ManualTherapies but had no part in the editorial or peer-review process. He has re-ceived grants unrelated to this work from the West Hartford Group, Inc. andNCMIC Foundation, Inc. E Poulsen reports research grants from the DanishFoundation for Chiropractic Research and Postgraduate Education, which isfunded by the Danish chiropractors, and the Danish Regions. No funding hasbeen received for the present project. J Quon has funding unrelated to thiswork from the Canadian Chiropractic Guideline Initiative and The VancouverFoundation. He is a member of the editorial board of Chiropractic & ManualTherapies but had no part in the editorial or peer-review process for thismanuscript. M Rezai is a member of the World Federation of Chiropractic Re-search Disability and Rehabilitation Committee. JS is am active licensedmember of Ontario and Canadian Chiropractic Associations. He is currentlyreceiving research support from the Ontario Chiropractic Association. Previ-ously received research support from Canadian Chiropractic Research Foun-dation and Ontario Chiropractic Association. M Swain holds research grantsunrelated to this work. He received the Chiropractic Australia Research Foun-dation Travel Grant 2019 to cover travel expenses associated with the GlobalSummit. Within the past year he has received consultation fees unrelated tothis work. He is a non-executive director of Chiropractic Australia. He is agovernor of the Sydney College of Chiropractic. K Weber was supported bygrants from the National Institute of Neurological Disorders and Stroke(K23NS104211 and L30NS108301) of the National Institutes of Health (Be-thesda, Maryland, USA). The content is solely the responsibility of the authorsand does not necessarily represent the official views of the National Institutesof Health. K J Young received a Personal PhD Grant (2018) from the RoyalCollege of Chiropractors (UK - £1600) that partially funded two papers unre-lated to this work.Author details1Faculty of Health Sciences, Ontario Tech University, Oshawa, Canada.2Centre for Disability Prevention and Rehabilitation at Ontario TechUniversity and CMCC, Oshawa, Canada. 3Division of Epidemiology, Dalla LanaSchool of Public Health, University of Toronto, Toronto, Canada. 4IHPME,Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.5Department of Sports Science and Clinical Biomechanics, University ofSouthern Denmark, Odense, Denmark. 6Nordic Institute of Chiropractic andClinical Biomechanics, Odense, Denmark. 7Intervention & ImplementationResearch for Worker Health, Institute of Environmental Medicine, KarolinskaInstitutet, Stockholm, Sweden. 8ELIB - et liv i bevegelse, Oslo, Norway.9Department for Regional Health Research, University of Southern Denmark,Odense, Denmark. 10Department de Chiropractique, Université du Québec àTrois-Rivières, Trois-Rivières, Canada. 11Department of Chiropractic, Faculty ofScience and Engineering, Macquarie University, Sydney, Australia.12Department of Physical Therapy, Faculty of Rehabilitation Medicine,University of Alberta, Edmonton, Canada. 13Canadian Memorial ChiropracticCollege, Toronto, Canada. 14Department of Human Health & NutritionalSciences, University of Guelph, Guelph, Canada. 15Rebecca MacDonaldCentre, Mount Sinai Hospital, Toronto, Canada. 16Department of HealthResearch Methods, Evidence & Impact, Faculty of Health Sciences, McMasterUniversity, Hamilton, Canada. 17School of Physical & Occupational Therapy,McGill University, Montreal, Canada. 18Faculty of Medicine, MemorialUniversity of Newfoundland, St. John’s, Canada. 19Faculty of Life Sciences andEducation University of South Wales, Cardiff, UK. 20Institut Franco-Européende Chiropraxie, Ivry-Sur-Seine, France. 21Faculty of Kinesiology, University ofNew Brunswick, Fredericton, Canada. 22Department of Chiropractic Medicine,Faculty of Medicine, University of Zurich & Balgrist University Hospital, Zurich,Switzerland. 23Department of Anesthesiology, University of Kansas MedicalCenter, Kansas City, USA. 24RMIT University, Melbourne, Australia. 25College ofScience, Health, Engineering and Education, Murdoch University, Murdoch,Australia. 26AECC University College, Bournemouth, UK. 27Spine Center ofSouthern Denmark, University Hospital of Southern Denmark, Middelfart,Denmark. 28Faculty of Kinesiology & Recreation Management University ofManitoba, Winnipeg, Canada. 29School of Chiropractic, University ofBridgeport, Bridgeport, USA. 30School of Population and Public Health,Faculty of Medicine, University of British Columbia, Vancouver, Canada.31School of Health, Medical and Applied Sciences, CQ University, Sydney,Australia. 32Stanford University School of Medicine, Stanford University,Stanford, USA. 33School of Sport and Health Sciences, University of CentralLancashire, Preston, England.Received: 9 July 2020 Accepted: 1 January 2021References1. 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The global summit on the efficacy and effectiveness of spinal manipulative therapy for the prevention and treatment of non-musculoskeletal disorders: a systematic review of the literature
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