Predictive factors for reporting adverse events following spinal manipulation in randomized clinical trials – secondary analysis of a systematic review

Musculoskeletal Science and Practice 30 (2017) 34e41

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Review article

Predictive factors for reporting adverse events following spinal manipulation in randomized clinical trials e secondary analysis of a systematic review Lindsay M. Gorrell a, *, Benjamin Brown b, Reidar P. Lystad c, Roger M. Engel b a b c

Human Performance Laboratory, KNB 222, Faculty of Kinesiology, University of Calgary, Calgary, Alberta, T2N 1N4, Canada Department of Chiropractic, Macquarie University, Building C5C West, Sydney, 2109, Australia Australian Institute of Health Innovation, Faculty of Medicine and Health Sciences, Macquarie University, Level 6, 75 Talavera Road, NSW, 2109, Australia

a r t i c l e i n f o

a b s t r a c t

Article history: Received 19 September 2016 Received in revised form 11 April 2017 Accepted 8 May 2017

While spinal manipulative therapy (SMT) is recommended for the treatment of spinal disorders, concerns exist about adverse events associated with the intervention. Adequate reporting of adverse events in clinical trials would allow for more accurate estimations of incidence statistics through meta-analysis. However, it is not currently known if there are factors influencing adverse events reporting following SMT in randomized clinical trials (RCTs). Thus our objective was to investigate predictive factors for the reporting of adverse events in published RCTs involving SMT. The Physiotherapy Evidence Database (PEDro) and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for RCTs involving SMT. Domains of interest included: sample size; publication date relative to the 2010 CONSORT statement; risk of bias; the region treated; and number of intervention sessions. 7398 records were identified, of which 368 articles were eligible for inclusion. A total of 140 (38.0%) articles reported on adverse events. Articles were more likely to report on adverse events if they possessed larger sample sizes, were published after the 2010 CONSORT statement, had a low risk of bias and involved multiple intervention sessions. The region treated was not a significant predictor for reporting on adverse events. Predictors for reporting on adverse events included larger sample size, publication after the 2010 CONSORT statement, low risk of bias and trials involving multiple intervention sessions. We recommend that researchers focus on developing robust methodologies and participant follow-up regimens for RCTs involving SMT. © 2017 Elsevier Ltd. All rights reserved.

Keywords: Adverse events Harms Spinal manipulative therapy Manipulation Spinal

1. Introduction Manual therapy is a commonly used intervention to treat musculoskeletal disorders of the spine (Bronfort et al., 2010; Clar et al., 2014). It includes spinal manipulative therapy (SMT) directed at a vertebral joint with the intention of moving the joint past its physiological range of motion without exceeding the anatomical limit (Bergmann and Peterson, 2011; Herzog, 2010). While clinical practice guidelines recommend the use of SMT in the treatment of neck and back disorders (Airaksinen et al., 2006; Koes et al., 2010; The Canadian Chiropractic A et al., 2005), concern still exists about adverse events associated with this type of

* Corresponding author. E-mail addresses: [email protected] (L.M. Gorrell), benjamin.brown@ mq.edu.au (B. Brown), [email protected] (R.P. Lystad), [email protected]. au (R.M. Engel). http://dx.doi.org/10.1016/j.msksp.2017.05.002 2468-7812/© 2017 Elsevier Ltd. All rights reserved.

intervention, particularly when applied to the cervical spine (Ernst, 2007; Carnes et al., 2010a; Gouveia et al., 2009; Rubinstein et al., 2005; Carlesso et al., 2010). Well-designed randomized clinical trials (RCTs) provide the most reliable results when investigating the efficacy of healthcare interventions (Cartwright, 2007; Sibbald and Roland, 1998). However, poorly designed RCTs tend to exaggerate treatment effects, which, when combined with inadequate reporting, may misinform the decision making process at all levels of health care, and negatively influence the development of clinical practice guidelines and health care policy (Moher et al., 1998, 2010). In an effort to reduce the reporting of exaggerated treatment effects and bias, the Consolidated Standards of Reporting Trials (CONSORT) statement was first published in 1996 and subsequently updated in 2001 and 2010 respectively (Begg et al., 1996; Altman et al., 2001; Schulz et al., 2010). In 2004, an extension to the statement, specifically addressing the reporting of adverse events,

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was published. This extension discussed the inadequacy of current reporting and provided 10 recommendations which were later adopted in the 2010 version of the statement (Ioannidis et al., 2004). Recent reviews investigating the overall quality (Karpouzis et al., 2016) and adequacy of adverse events reporting (Gorrell et al., 2016) in RCTs involving SMT have highlighted that the current level is inadequate and unacceptable. Trial sample size was recently reported as a factor influencing the overall quality of reporting in RCTs involving chiropractic (Karpouzis et al., 2016), however, factors influencing the reporting of adverse events in published RCTs involving SMT have not been previously reported. The objective of this secondary analysis is to investigate possible predictive factors for the reporting of adverse events in published RCTs involving SMT. 2. Methods This is a secondary analysis of a systematic literature review (Gorrell et al., 2016) which was written adhering to the PRISMA guidelines (Higgins et al., 2011). 2.1. Eligibility criteria Spinal manipulative therapy (SMT) was defined as manual therapy involving a high-velocity, low amplitude manipulation directed at a vertebral joint with the intention of moving the joint past its physiological range of motion without exceeding the anatomical limit (Bergmann and Peterson, 2011; Herzog, 2010). Spinal manipulation delivered using mechanical instruments and/ or drop-table mechanisms were included in this review as they have been classified as high-velocity, low amplitude procedures in the literature (Bergmann and Peterson, 2011; Ostenbauer et al., 1992; Pickar, 2002). Randomized clinical trials that reported original data from SMT, either as the sole intervention or as part of a multi-modal intervention, delivered by a regulated manual therapy practitioner were eligible for inclusion in this review. We excluded: manuscripts reporting all other trial designs; commentaries; editorials; reviews; trial protocols; conference proceedings; manuscripts not available in English; retracted manuscripts; secondary analyses; if the intervention was applied to a region other than the spine; if the intervention was self-administered (e.g. exercise); and if it was unclear if the SMT applied was high-velocity, low amplitude in nature. 2.2. Search strategy PEDro (Physiotherapy Evidence Database) and Cochrane CENTRAL (Central Register of Controlled Trials) were electronically searched from inception to February 2016. The following terms and derivatives were adapted for each search engine: (spine, spinal, manipulation, musculoskeletal, chiropractic, osteopathy) AND (clinical trial). See Appendix 1 for the complete search strategy for the Cochrane CENTRAL database. 2.3. Study selection process Records retrieved from the electronic searches were exported to the EndNote X7® program. Duplicate records were removed prior to titles and abstracts being screened. Two authors (LG and BB) independently conducted the study selection process. Full-text versions of the remaining potentially eligible articles were retrieved and subsequently subjected to the eligibility criteria. Any disagreements were resolved by consensus; if consensus could not be reached, disagreements were resolved using a third author (RE).

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2.4. Data extraction Articles used in this secondary analysis had previously been classified as either reporting or not reporting adverse events. The determination of whether to classify an event as ‘adverse’ was based on the description of the event within the manuscript and included terms such as ‘adverse events’, ‘side effects’, ‘adverse effects’ and ‘harms’ (Gorrell et al., 2016). Data extraction for this analysis was performed independently by two authors (LG and BB) using the previously established reference sample (Gorrell et al., 2016). Any disagreements were resolved by consensus; if consensus could not be reached, disagreements were resolved using a third author (RE). We extracted data for six predictive variables of interest that were chosen a priori. The authors discussed the selection of predictive variables in several consensus meetings. Two important selection considerations were: availability of data (i.e. that the variable could be consistently extracted from the published articles) and statistical power (i.e. to limit the number of variables and collapse categories while still being able to perform meaningful analyses). Specific data included: sample size; publication date; risk of bias; the region treated, classified as either ‘back’ or ‘neck’; and number of intervention sessions. Publication date was dichotomized into before or after the publication of the 2010 CONSORT statement. Region treated was dichotomized into treatment of the neck (cervical spine only) or back (other regions of the spine, in addition to or in place of treatment of the neck). Number of intervention sessions was dichotomized into single intervention session or multiple intervention sessions. Methodological quality of the trial was assessed using the Cochrane risk of bias (ROB) assessment tool (Moher et al., 2009) and dichotomized into high risk or low risk. The ROB assessment was conducted independently by two authors (LG and RE). Any disagreements were resolved by consensus; if consensus could not be reached, disagreements were resolved using a third author (BB). 2.5. Data analysis All statistical analyses were performed using the statistical computing software R version 3.3.1 (The R Foundation for Statistical Computing, Vienna, Austria). Descriptive statistics were produced for both the continuous and categorical variables of interest. Any observed differences between the articles that reported adverse events and those that did not were evaluated i): univariately, with t-tests for the continuous variables and Pearson's chi squared test with Yates' continuity correction for categorical variables; and ii) multivariately, with binomial logistic regression. All univariate and multivariate results were reported with 95% confidence intervals and test statistics with corresponding p-values. The following assumptions for statistical tests were checked: t-test, independence of observations, normal distribution of the dependent variable (assessed using Shapiro-Wilk test), and equal variance across groups (assessed using Levene's test); chi-square test, independence of observations, and sufficient sample size and expected cell counts (assessed by evaluating contingency table cell counts); binomial logistic regression, independence of observations, and no multicollinearity (assessed using generalised variable inflation factor). 3. Results There were 7398 records initially identified by the electronic searches. A total of 6382 unique records remained after the removal of duplicates. After screening titles and abstracts, a total of 710 potentially eligible articles remained, of which 368 articles fulfilled the eligibility criteria. See Fig. 1 for a detailed description of the

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Fig. 1. PRISMA flow-chart of review. SMT: spinal manipulative therapy; n: number of articles; HVLA: high-velocity, low amplitude.

study selection process, including the reasons for exclusion. A total of 140 articles reported on adverse events with a median participant number of 77.5 (interquartile range: 92). Of the 228 articles not reporting on adverse events, the median participant number was 42 (interquartile range: 55). Of the articles reporting on adverse events: 80 (57.1%) were published pre-CONSORT and 60 (42.9%) were published post-CONSORT; 50 (35.7%) had a low risk of bias and 90 (64.3%) had a high risk of bias; 112 (80%) reported on manipulation of the back and 23 (16.4%) on the neck, while it was unclear in 5 (3.6%) articles where the manipulation was applied; and 111 (79.3%) involved a single intervention session and 29 (20.7%) involved multiple intervention sessions. 3.1. Univariate analyses Because the distribution of sample sizes was substantially skewed to the right, a log transformation was performed prior to the univariate analysis. There was very strong evidence that the log mean sample size was greater for trials reporting adverse events (mean difference: 0.41 [95%CI: 0.21e0.61]; p < 0.001). The ShapiroWilk test (p ¼ 0.162) and the Levene's test (p ¼ 0.144) did not reveal any violation of the normality or equal variance assumptions, respectively. There was also strong evidence that trials published pre-CONSORT (OR: 0.48 [95%CI: 0.30e0.75]; p ¼ 0.002), trials with high risk of bias (OR: 0.42 [95%CI: 0.26e0.68]; p < 0.001), and trials with only a single intervention session (OR: 0.32 [95%CI: 0.19e0.51]; p < 0.001) were less likely to report adverse events, whereas there was little or no evidence that trials with neck manipulation were less likely to report adverse events (OR: 0.60 [95%CI: 0.34e1.02); p ¼ 0.080). All cell counts for all chi squared tests were greater than 10. 3.2. Multivariate analyses The results of the binomial logistic regression were similar to the univariate analyses. That is, the odds of reporting adverse events was significantly lower in trials with smaller sample sizes,

trials published pre-CONSORT, trials with high risk of bias, and trials with only a single intervention session, whereas there was no significant difference in the odds of reporting adverse events between trials with neck manipulation compared to trials with back manipulation. See Table 1 for further details. There was no evidence of multicollinearity among the predictor variables in the fitted model (i.e. generalised variable inflation factor was <2 for all predictor variables). 4. Discussion To the authors' best knowledge, this is the first review to investigate possible predictive factors for the reporting of adverse events in RCTs involving SMT. Our findings are consistent with the literature that there has been an improvement in the reporting of adverse events in RCTs involving SMT since the introduction of the 2010 CONSORT statement (Karpouzis et al., 2016; Gorrell et al., 2016). The purpose of an RCT is to collect and appropriately report both beneficial and harmful effects of an intervention and to compare these outcomes across groups (Zorzela et al., 2014). It has been reported that smaller trials often report larger treatment effects than those with more participants (Dechartres et al., 2013; Hettinga et al., 2008) which may result in a focus on beneficial effects and an under-reporting of adverse events. This is congruent with our finding that trials with greater participant numbers were more likely to report on adverse events and thus present a balanced

Table 1 Binomial logistic regression results. Factor

Odds ratio (95% CI)

P-value

Sample size (per 100 unit increase) Publication date (Ref. post-CONSORT) Risk of bias (Ref. high) Region treated (Ref. back) Number of intervention sessions (Ref. >1)

1.54 0.44 0.55 0.73 0.34

0.002 0.001 0.029 0.282 <0.001

(1.18e2.05) (0.27e0.72) (0.33e0.94) (0.40e1.29) (0.20e0.56)

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account of both the risks and benefits associated with SMT. We acknowledge that it is not always possible to conduct large-scale clinical trials investigating SMT, and as such, it is recommended that researchers designing small trials attempt to achieve a low risk of bias in their trial. Furthermore, the adequate reporting of both beneficial and harmful effects of the treatment is recommended (Gorrell et al., 2016). Meta-analysis of adverse events results obtained from many well-designed, smaller trials may indeed be more useful than the results from a single, larger trial for the calculation of accurate incidence rates for all adverse events classifications e mild, moderate and major (Carnes et al., 2010a, 2010b) e associated with the application of SMT (Schulz and Grimes, 1348; Freiman et al., 1978; Sackett and Cook, 1993). For this reason small, well-designed studies are encouraged in the absence of large-scale trials. While we acknowledge that there are obstacles to the consistent reporting of adverse events such as differing opinions as to what constitutes an event between authors and also between practitioners and patients, the development of standardized definitions and reporting tools with input from all involved parties (e.g. practitioners, researchers and patients) would alleviate this difficulty and is thus recommended (Carnes et al., 2010a, 2010b; Carlesso et al., 2011). Regardless of sample size, trials rated at a low risk of bias were more likely to report on adverse events. As discussed above, causal inferences from RCTs can be affected by improper methodological design, ineffectual data collection/analyses and incomplete reporting which may lead to imprecise estimates of treatment effect and potential bias within the trial (Wood et al., 2008). The Cochrane ROB assessment tool (Higgins et al., 2011) is designed to detect these flaws and specifically evaluate whether complete outcomes data has been reported, in addition to scoring the trial on selective reporting (e.g. whether the trial protocol is available). It is not surprising that a trial at a low risk of bias would adequately report both the beneficial and harmful effects of a treatment. Articles published after the 2010 CONSORT statement were more likely to report on adverse events. As discussed previously, the CONSORT statement was first published in 1996 to provide authors with a scaffold with which to standardize and improve the reporting of RCTs and has been updated several times to reflect advances within scientific research (Begg et al., 1996; Altman et al., 2001; Schulz et al., 2010; Ioannidis et al., 2004). The most recent statement published in 2010 specifically includes recommendations concerning the reporting of adverse events thus, it is to be expected that articles published after 2010 would be more likely to include information pertaining to adverse events. Articles reporting on trials involving multiple intervention sessions were more likely to report on adverse events. Approximately one third of all articles included in this review reported on a single session which may have resulted in significant underreporting on adverse events. This is of significance as the literature identifies the first treatment session as a risk factor associated with adverse events related to SMT (Senstad et al., 1996) meaning that is possible these articles may not have captured information pertaining to adverse events which occurred following the intervention, that is those occurring later that day or within the following week. We recommend that for trials with a single intervention session, some method of active follow-up is included in the design to ensure that important information is not lost. A possible method could include a telephone call or text message sent to participants at a later time point, that is, the following day or at 7-days post-intervention asking them to report any changes or adverse effects they may have experienced. Passive follow-up strategies could also be implemented to maximize data capture in this domain.

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4.1. Limitations There are several limitations to this secondary analysis. Firstly, electronic searches were performed in two databases only (PEDro and Cochrane CENTRAL), which may have resulted in the omission of eligible articles indexed in other databases. However, we believe this is unlikely as both PEDro and Cochrane CENTRAL index RCTs published in all journals and Cochrane CENTRAL also indexes grey literature. Secondly, the review only included articles published in English and it has been reported that significant results are more likely to be published in a journal using the English language (Senstad et al., 1996). However, we do not believe this affected the results in any meaningful way (Juni et al., 2002; Morrison et al., 2012). Thirdly, the decision to categorize articles depending on their publication prior to or after the 2010 CONSORT statement rather than the 2004 extension (specific to the reporting of adverse events) was arbitrary (Schulz et al., 2010; Ioannidis et al., 2004). As the content of the 2004 extension was used to inform the 2010 statement, we do not believe this choice affected the results. Fourthly, it is unknown if the difference in reporting on adverse events between trials involving a single vs. multiple intervention sessions is due to an under-reporting (i.e. events were missed due to ineffectual data collection) or there were more adverse events reported in trials involving multiple intervention sessions due to a higher exposure to SMT. Furthermore, inadequate reporting of the number of manipulations applied meant that calculation of an accurate incidence rate for any of the classifications of adverse events was not possible. It is also possible that there may exist other predictive factors for the reporting of adverse events (e.g. how the event was ascertained, publication bias or selective reporting within studies) however, due to the poor level of reporting in the included studies, it was not possible to investigate such factors. Finally, it is possible that information concerning the region treated was lost due to dichotomization of the data into treatment of the neck (cervical spine only) vs. back (all other spinal regions including the neck), which may in turn create uncertainty in the null result. However, to the authors' best knowledge, there is currently no literature suggesting an inequality in the adequacy of adverse events reporting and the region treated. 4.2. Conclusions Trials with smaller sample sizes, a publication date prior to the 2010 CONSORT statement, a high risk of bias and involving only a single intervention session were significantly less likely to report on adverse events. We recommend that researchers focus on strengthening methodologies and participant follow-up regimens in the trial design phase, which will improve the reporting of adverse events in RCTs involving SMT. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflicts of interest None. Appendix Appendix 1. Cochrane CENTRAL search string. #1 “spine”:ti, ab, kw or “spinal”:ti, ab, kw #2 “manip*”

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#3 MeSH descriptor: [Musculoskeletal, Manipulations] explode all trees #4 MeSH descriptor: [Manipulation, Spinal] explode all trees #5 MeSH descriptor: [Manipulation, Chiropractic] explode all trees #6 MeSH descriptor: [Manipulation, Osteopathic] explode all trees #7 “osteopath*” #8 “chiropract*” #9 #1 and #2 #10 #3 or #4 or #5 or #6 or #7 or #8 or #9

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Appendix 2 e References for studies included in analysis. Akhter, S., Khan, M., Ali, S.S., Soomro, R.R., 2014. Role of manual therapy with exercise regime versus exercise regime alone in the management of non- specific chronic neck pain. Pak J. Pharm. Sci. 27 (6 Suppl. l), 2125e2128. Allan, M., Brantingham, J.W., Menezes, A., 2003. Stretching as an adjunct to chiropractic manipulation of chronic neck pain e before, after or not at all? A prospective randomized controlled clinical trial. Eur. J. Chiropr. 50 (2), 41e52. Balon, J., Aker, P.D., Crowther, E.R., Danielson, C., Cox, P.G., O'Shaughnessy, D., et al., 1998. A comparison of active and simulated chiropractic manipulation as adjunctive treatment for childhood asthma. N. Engl. J. Med. 339 (15), 1013e1020. Balthazard, P., de Goumoens, P., Rivier, G., Demeulenaere, P., Ballabeni, P., Deriaz, O., 2012. Manual therapy followed by specific active exercises versus a placebo followed by specific active exercises on the improvement of functional disability in patients with chronic non specific low back pain: a randomized controlled trial. BMC Musculoskelet. Disord. 13, 162. Beyerman, K.L., Palmerino, M.B., Zohn, L.E., Kane, G.M., Foster, K.A., 2006. Efficacy of treating low back pain and dysfunction secondary to osteoarthritis: chiropractic care compared with moist heat alone. J. Manip. Physiol. Ther. 29 (2), 107e114. Bishop, P.B., Quon, J.A., Fisher, C.G., Dvorak, M.F., 2010. The Chiropractic Hospitalbased Interventions Research Outcomes (CHIRO) study: a randomized controlled trial on the effectiveness of clinical practice guidelines in the medical and chiropractic management of patients with acute mechanical low back pain. Spine J. 10 (12), 1055e1064. Boline, P.D., Kassak, K., Bronfort, G., Nelson, C., Anderson, A.V., 1995. Spinal manipulation versus amitriptyline for the treatment of chronic tension-type headaches: a randomized clinical trial. J. Manip. Physiol. Ther. 18 (3), 148e154. Borusiak, P., Biedermann, H., Bosserhoff, S., Opp, J., 2010. Lack of efficacy of manual therapy in children and adolescents with suspected cervicogenic headache: results of a prospective, randomized, placebo-controlled, and blinded trial. Headache 50 (2), 224e230. Botelho, M.B., Andrade, B.B., 2012. Effect of cervical spine manipulative therapy on judo athletes' grip strength. J. Manip. Physiol. Ther. 35 (1), 38e44. Bove, G., Nilsson, N., 1998. Spinal manipulation in the treatment of episodic tensiontype headache: a randomized controlled trial. JAMA 280 (18), 1576e1579. Brantingham, J.W., Globe, G.A., Jensen, M.L., Cassa, T.K., Globe, D.R., Price, J.L., et al., 2009. A feasibility study comparing two chiropractic protocols in the treatment of patellofemoral pain syndrome. J. Manip. Physiol. Ther. 32 (7), 536e548.

L.M. Gorrell et al. / Musculoskeletal Science and Practice 30 (2017) 34e41 Bronfort, G., Evans, R., Anderson, A.V., Schellhas, K.P., Garvey, T.A., Marks, R.A., et al., 2000. Nonoperative treatments for sciatica: a pilot study for a randomized clinical trial. J. Manip. Physiol. Ther. 23 (8), 536e544. Bronfort, G., Evans, R., Anderson, A.V., Svendsen, K.H., Bracha, Y., Grimm, R.H., 2012. Spinal manipulation, medication, or home exercise with advice for acute and subacute neck pain: a randomized trial. Ann. Int. Med. 156, 1e10. Bronfort, G., Evans, R., Maiers, M., Anderson, A.V., 2004. Spinal manipulation, epidural injections, and self-care for sciatica: a pilot study for a randomized clinical trial. J. Manip. Physiol. Ther. 27 (8), 503e508. Bronfort, G., Evans, R., Nelson, B., Aker, P.D., Goldsmith, C.H., Vernon, H., 2001. A randomized clinical trial of exercise and spinal manipulation for patients with chronic neck pain. Spine 26 (7), 788e797. Bronfort, G., Goldsmith, C.H., Nelson, C.F., Boline, P.D., Anderson, A.V., 1996. Trunk exercise combined with spinal manipulative or NSAID therapy for chronic low back pain: a randomized, observer-blinded clinical trial. J. Manip. Physiol. Ther. 19 (9), 570e582. Bronfort, G., Hondras, M.A., Schulz, C.A., Evans, R.L., Long, C.R., Grimm, R., 2014. Spinal manipulation and home exercise with advice for subacute and chronic back-related leg pain: a trial with adaptive allocation. Ann. Int. Med. 161 (6), 381e391. Bronfort, G., Maiers, M.J., Evans, R.L., Schulz, C.A., Bracha, Y., Svendsen, K.H., et al., 2011. Supervised exercise, spinal manipulation, and home exercise for chronic low back pain: a randomized clinical trial. Spine J. 11 (7), 585e598. Burton, A.K., Tillotson, K.M., Cleary, J., 2000. Single-blind randomised controlled trial of chemonucleolysis and manipulation in the treatment of symptomatic lumbar disc herniation. Eur. Spine J. 9 (3), 202e207. Casanova-Mendez, A., Oliva-Pascual-Vaca, A., Rodriguez-Blanco, C., HerediaRizo, A.M., Gogorza-Arroitaonandia, K., Almazan-Campos, G., 2014. Comparative short-term effects of two thoracic spinal manipulation techniques in subjects with chronic mechanical neck pain: a randomized controlled trial. Man. Ther. 19 (4), 331e337. Cassidy, J.D., Lopes, A.A., Yong-Hing, K., 1992. The immediate effect of manipulation versus mobilization on pain and range of motion in the cervical spine: a randomized controlled trial. J. Manip. Physiol. Ther. 15 (9), 570e575. Cecchi, F., Molino-Lova, R., Chiti, M., Pasquini, G., Paperini, A., Conti, A.A., et al., 2010. Spinal manipulation compared with back school and with individually delivered physiotherapy for the treatment of chronic low back pain: a randomized trial with one-year follow-up. Clin. Rehabil. 24 (1), 26e36.
, M., Street, J., Barlow, W., 1998. A comparison of Cherkin, D.C., Deyo, R.A., Battie physical therapy, chiropractic manipulation, and provision of an educational booklet for the treatment of patients with low back pain. N. Engl. J. Med. 339 (15), 1021e1029. Cleland, J.A., Childs, J.D., McRae, M., Palmer, J.A., Stowell, T., 2005. Immediate effects of thoracic manipulation in patients with neck pain: a randomized clinical trial. Man. Ther. 10 (2), 127e135. Cleland, J.A., Fritz, J.M., Kulig, K., Davenport, T.E., Eberhart, S., Magel, J., et al., 2009. Comparison of the effectiveness of three manual physical therapy techniques in a subgroup of patients with low back pain who satisfy a clinical prediction rule: a randomized clinical trial. Spine 34 (25), 2720e2729. Cleland, J.A., Glynn, P., Whitman, J.M., Eberhart, S.L., MacDonald, C., Childs, J.D., 2007. Short-term effects of thrust versus nonthrust mobilization/manipulation directed at the thoracic spine in patients with neck pain: a randomized clinical trial. Phys. Ther. 87 (4), 431e440. Cleland, J.A., Mintken, P.E., Carpenter, K., Fritz, J.M., Glynn, P., Whitman, J., et al., 2010. Examination of a clinical prediction rule to identify patients with neck pain likely to benefit from thoracic spine thrust manipulation and a general cervical range of motion exercise: multi-center randomized clinical trial. Phys. Ther. 90 (9), 1239e1250. Cook, C., Learman, K., Showalter, C., Kabbaz, V., O'Halloran, B., 2013. Early use of thrust manipulation versus non-thrust manipulation: a randomized clinical trial. Man. Ther. 18 (3), 191e198. Cramer, G.D., Gregerson, D.M., Knudsen, J.T., Hubbard, B.B., Ustas, L.M., Cantu, J.A., 2002. The effects of side-posture positioning and spinal adjusting on the lumbar Z joints: a randomized controlled trial with sixty-four subjects. Spine 27 (22), 2459e2466. Dougherty, P.E., Karuza, J., Dunn, A.S., Savino, D., Katz, P., 2014a. Spinal manipulative therapy for chronic lower back pain in older veterans: a prospective, randomized, placebo-controlled trial. Geriatr. Orthop. Surg. Rehabil. 5 (4), 154e164. Dougherty, P.E., Karuza, J., Savino, D., Katz, P., 2014b. Evaluation of a modified clinical prediction rule for use with spinal manipulative therapy in patients with chronic low back pain: a randomized clinical trial. Chiropr. Man. Ther. 22 (1), 41. Dunning, J., Cleland, J.A., Waldrop, M.A., Arnot, C.F., Young, I.A., Turner, M., et al., 2012. Upper cervical and upper thoracic thrust manipulation versus nonthrust mobilization in patients with mechanical neck pain: a multicenter randomized clinical trial. J. Orthop. Sports Phys. Ther. 42 (1), 5e18. Engel, R.M., Vemulpad, S.R., Beath, K., 2013. Short-term effects of a course of manual therapy and exercise in people with moderate chronic obstructive pulmonary disease: a preliminary clinical trial. J. Manip. Physiol. Ther. 36 (8), 490e496. Espi-Lopez, G., Gomez-Conesa, A., 2014. Efficacy of manual and manipulative therapy in the perception of pain and cervical motion in patients with tensiontype headache: a randomized, controlled clinical trial. J. Chiropr. Med. 13 (1), 4e13.

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