Evidence (-based medicine) in manual medicine/manual therapy—a summary review

The aim of this summary review is to analyse the current state of evidence in manual medicine or manual therapy. The literature search focussed on systematic reviews listed in PubMed referring to manual medicine treatment until the beginning of 2022, limited to publications in English or German. The search concentrates on (1) manipulation, (2) mobilization, (3) functional/musculoskeletal and (4) fascia. The CASP Checklist for Systematic Reviews was used to present the included reviews in a clear way. A total of 67 publications were included and herewith five categories: low back pain, neck pain, extremities, temporomandibular disorders and additional effects. The results were grouped in accordance with study questions. Based on the current systematic reviews, a general evidence-based medicine level III is available, with individual studies reaching level II or Ib. This allows manual medicine treatment or manual therapy to be used in a valid manner.


Background
In recent years, the European Scientific Society of Manual Medicine (ESSOMM) has developed "the European core curriculum and principles of manual medicine" (MM) [40]. Many authors from all of the member countries of ESSOMMhave contributed substantially to the important issues. They state in their introduction: "The techniques and methods of manual medicine are diverse and innumerable, therefore, it was necessary to delineate the scientific background in anatomy and physiology on which they were based, to gather proof of their effectiveness in reported clinical studies and to identify the positioning of manual medicine in complex clinical therapeutic regimens" [40].
MM consists of "manual diagnostic examination of the locomotor system, the head and connective tissue structures and of manual techniques to treat reversible dysfunction and the pain associated with it aiming to prevention, cure and rehabilitation. Diagnostic and therapeutic procedures are based on scientific neurophysiological and biomechanical principles" [40].
The procedures described in this curriculum relate specifically to investigating and treating tension and pain in muscles, joints and connective tissues as well as structures located withinthesetissues. The main goal of the therapeutic techniques is to eliminate or reduce movement restrictions and pain.
In Germany, MM is practiced by doctors specialized in this field and as "manual therapy" (MT) by physical therapists (PT). In the United States of America, MM is taught and practiced by doctors of osteopathy(DO). TheGermanSociety of Manual Medicine (DGMM) considers osteopathy as a part and an extension of MM.
Chiropractic, as a form of so-called complementary medicine, aims also on motor dysfunction and pain in the movement system. In the USA, osteopathy is taught at universities offering a DO degree. In Europe, MM is taught through non-academic seminars whose teachers and, to a large extent, their graduates are organized into national scientific societies. MT is also taught through schools run by professional physical therapy organizations. The criteria and rules for training and further education in MM and MT are specified and controlled by the medical association and the health insurance companies. In contrast, there are no such controlled rules for training in osteopathy and it is taught, learned and used by doctors, PT, and lay people alike. On this inconsistent basis, there are a variety of different textbooks, most of which were written by experienced users of MM. Greenman's book "Principles of Manual Medicine" can be considered as a basic textbook in MM, which received the title Lehrbuch der osteopathischen Medizin in the German translation [23,24].
MM, MT and osteopathy are now widely used worldwide as proven conservative methods in the treatment of functional limitations and pain in the musculoskeletal system. However, the terms MM, osteopathy and MT are used inconsistently and promiscuously. This inconsistency is reflected by a wide spectrum in the different variables of clinical practice: -Techniques for treatment are commonly described as manipulation, mostly as a thrust (impulse) with high velocity and low amplitude (HVLA technique); mobilization, as passive, mostly repeated movement by traction and/or rotation, e.g. joint mobilization; soft tissue techniques or muscle energy techniques, as massage-like techniques, e.g. "strain-counter strain" and others. -The specific path and level of training and skills of the acting people, i.e. physicians, physical therapists, osteopaths, chiropractors, laymen. -The spectrum of diagnosed and treated complaints and disorders: j Pain: low back pain (LBP), neck pain (NP), headache, muscle or joint pain. j Restricted spine or joint movement (hypomobility), hypermobility, elevated muscle tone.
In the past three decades, a growing number of case reports, retrospective analyses and randomized controlled trials (RCTs) have accumulated in the literature, which has also resulted in a greater number of published systematic reviews. The authors of these studies are looking for answers about the strength and effectiveness of their MM-based intervention. This is mostly done directly or in comparison versus an alternative treatment. The outcomes are discussed very differently. The focus is on the special conditions of the execution of the treatment in the context of study quality, as well as on the criteria for the statement about the evidence. Because there have been a large number of reviews on this problem in recent years, it is our goal to analyse the current state of evidence in MM based on the available reviews regarding the varying influencing factors on the effects of MM and MT treatment. The aim of this summarizing review is to give an overview of the current state of evidence for hands-on techniques, independent of special techniques or localization of complaints.

Methods
The aim of this summarizing review is to gain a picture of the level of evidence in MM. For this purpose, a corresponding literature search was conducted in autumn 2019 using the PubMed database. In order to keep the review up to date, the literature search was repeated at the beginning of 2022. In this way, numerous reviews could be added.
The search strategy included various terms, which were divided into four categories: -First category, manipulation: spinal manipulation OR manipulation thrust OR HVLA OR high-velocity low-amplitude OR HVT OR high-velocity thrust OR OMT OR osteopathic manipulative treatment OR manipulation with impulse OR musculoskeletal manipulation. -Second category, mobilization: (mobilization OR mobilization) AND (manual OR joint OR spine OR extremity) -Third category, functional/ musculoskeletal: ("manual medicine" OR "manual therapy") and (functional OR musculoskeletal OR disorder) -Fourth category, fascia: ("manual medicine" OR "manual therapy") AND (fascia OR myofascial OR neurofascial) The search was limited to the last 10 years, to studies with humans and to full texts of clinical studies and reviews in German or English language. First, the literature was narrowed down by title. The second step in the selection process was to review the available abstracts. Furthermore, only the reviews were extracted from this large number of hits, in order to avoid duplication of content that had already been summarized.
In addition, a free search was carried out on the topic of manual therapy in subjectspecific databases of the Dutch manual medicine association and the Ärztevereinigung Manuelle Medizin, Berlin, whereby here, again, only reviews were included into the overview.
To sum up, publications were included if they address manual medicine or manual therapy treatment in an original manner and if they were presented as a systematic review. Studies were excluded if they concentrate on concomitant factors like cost effectiveness or topics other than therapy. Furthermore, single trials, conference papers and so on were ruled out.
Currently, there is no systematically developed reporting guideline for overviews [56]. The CASP Checklist for Systematic Reviews was used to present the studies found in a meaningful and clear way [7]. It must be emphasized that the aim of this checklist is not to evaluate the included research. Rather, the three sections of the CASP checklist support answering of the questions about validity, the results and the consequences that can be drawn for clinicians and researchers. Therefore, the referring tables can be found in the supplementary material.
Two reviewers extracted the data regarding target/treatment, the used assessments, the studies included and the found outcome. Furthermore, the CASP scale was used by both, to allow a better overview. Disagreements were resolved by a third opinion.

Search results
With the chosen search strategy, 4720 hits were obtained in the specialist literature via the PubMed database and an additional free search. Screening the records by title and abstract left 378 hits. To concentrate on realistic and generally valid statements concerning the evidence of MM or MT, only the reviews were selected (n = 88). The published papers were assessed for eligibility, with a final number of 67 records; 21 reports had to be excluded for different reasons, e.g. topics other than therapy, focus on cost effectiveness or the small number of included studies, etc.
The remaining studies could be divided into five categories: 1) low back pain (LBP) with n = 17 reviews, neck pain (NP) with n = 12 reviews, extremities with n = 11 re-Hier steht eine Anzeige. K views, temporomandibular disorder (TMD) with n = 8 reviews and additional or other effects with n = 19 reviews. The literature search is illustrated in . Fig. 1.
. Table 1 gives a summary of the treatment and intention of treatment, the assessments and included studies, and a summary of the results. Outcome in pain reduction is proved by a visual analogue scale (VAS) or numeric rating scale (NRS), functional enhancement by questionnaires such as the Oswestry Disability Questionnaire, Roland-Morris Disability Questionnaire or Short Form-36 Health Survey; occasionally by range of motion (ROM). The reviews that focused on nonspecific LBP included up to 46 [20] studies, most more than 10 studies. One review has a summary of 6000 patients [59]. The quality of the studies evaluated in the reviews was not sufficient for meta-anal-ysis, or meta-analysis could not include all studies from the review [65] because of deficits due to study quality.
The outcomes of SMT or MT are described as "to offer significant benefits in management of pain and function" [18,33,39,52,64], "to be better than usual medical care" as well as "short-term effects on pain relief and functional status" or significant benefit up to 6 weeks. One review with 26 RCTs and about 6000 participants in total [59] demonstrated highquality evidence that spinal manipulation therapy in non-specific LBP has a statistically significant short-term effect on pain relief and functional status in comparison with other interventions. Evidence suggests that SMT causes neurophysiological effects (local hypoalgesia, sympathoexcitation, improved muscle function) [38,50,59]. Spinal manipulation in addition to general practitioner care was relatively cost effective [18,20,33]. The reviews support that "manipulative treatment should be part of musculoskeletal rehabilitation of LBP" [22].
No serious aversive events were reported.
Ten studies with 1198 pregnant women suffering from LBP and pelvic girdle pain report "limited evidence to support the use of MT on pain intensity as an option during pregnancy" [26,72] whereas SMT "showed a significant effect on reducing pain in women with primary dysmenorrhea" [1], with the shortfall that not all studies reported dosage or session duration. Chiropractic care in postpartum LBP was not identified as a treatment option.
Studies in lumbar spine stenosis "showed better results in surgery for pain, disability and quality of life when continued conservative treatment has failed for 3 to 6 months" [34].

Neck pain
From the reviews found and selected, we classified 12 publications in the group "treatment of NP with MM" [11,12,16,19,25,28,30,36,47,61,75,76]. NP is described as non-specific, mechanical or cervicogenic NP with or without headache or radicular findings. One review focused on cervicogenic dizziness treated with HVLA or mobilization [42]. . Table 2 gives a summary of the treatment and intention to treat, the assessments and included studies, and a summary of the results. Measurement of the results in pain reduction and functional improvement is by VAS, cervical ROM, NRS, neck pain questionnaire and/or dizziness handicap inventory. The 11 reviews that focused on NP included 3 to 23 studies.
Manual interventions consisted mostly of manipulation (with or without thrust), mobilizationor myofascial techniques. The term "manual therapy" is inconsistently used for all hands-on interventions.
Two reviews including 23 RCTs with 680 patients with acute NP and 929 patients with chronic NP [28] and six studies with around 600 patients [61] stated positive effects for HVLA as statistically significant and clinically relevant improvements for pain and disability immediately and for up to 1 week to 6 months.
Two large reviews [25,47], both from the same research group, included 1400 and 1900 patients. In their conclusions they state a "support for combined mobilization, manipulation and exercise for short-term pain reduction" and found "low-quality evidence suggesting manipulation, mobilization and exercise to produce greater long-term pain reduction compared to no treatment and low-quality evidence for improvement in function" [47] and concluded "moderate-quality evidence after cervical manipulation and mobilization for similar effects on pain, function and patient satisfaction at intermediate-term follow-up than in control group" [25]. These findings are congruent with the outcome of the other reviews [12,16,19,30]. It is mentioned that "outcome is consistent with evidence from previous systematic reviews" [28]. A longterm follow-up with low-quality evidence shows a non-significant difference be-tween spinal manipulative treatment and other manual therapies [16]. The treatment period is reported mostly up to several weeks and follow-up-until 1 year. No serious adverse events were reported.
There is "moderate evidence in a favourable direction to support the use of HVLA or mobilization for cervicogenic dizziness" [42].

Temporomandibular disorder
Eight of the reviews found belong to the category "treatment of temporomandibular (joint) disorder (TMD) with MM" [3,6,19,29,37,43,46,69]. The symptoms to treat are also called orofacial (myogenous and arthrogenous) disorder, sometimes accompanied by headache or myofascial pain. The intention of treatment is referred to as "orofacial myofunctional therapy" in these reviews [29]. One review included treatment of cardiovascular performance with C5/C5 HVLA manipulation [19].
. Table 3 summarizes the treatments and intention of treatment, the assessments, included studies and results. The results were evaluated by VAS, maximal mouth opening (MMO) and pain pressure threshold (PPT). The eight reviews comprise 95 studies with about 2000 patients. These reviews report mostly a high risk of bias.
The outcomes are shown as evidence of orthopaedic manual therapy (OMT) in correcting "dentofacial deformities when combined with orthodontic treatment" [6,29,37,43], "greater MMO (high evidence) [6], pain (moderate evidence) and PPT, compared to a usual care group", "MT targeted to the cervical spine decreased pain and increased mouth ROM" [3,19,37] and "significant large effect on active mouth opening and on cervicogenic headaches" [43]. In subjects with hypertension, blood pressure seemed to decrease after cervical HVLA manipulation [19].

Upper and lower extremities
Eleven of the publications found were assignable to the category "treatment of pain and dysfunctions in upper or lower extremities with MM" [2,5,15,27,41,45,54,55,60,67,74]: three reviews fo-cused on knee osteoarthritis (KOA) [60,67,74], one on plantar heel pain [55], one on lateral ankle sprains [41], two on thumb carpometacarpal osteoarthritis [5,27] and three further reviews on shoulder or elbow [2,54] or on MT for rotator cuff tendinopathy [15]. . Table 4 gives a summary of the treatments with the intention of treatment, the assessments, the included studies and the results. Outcome is measured with VAS or other NRS, ROM, and WOMAC for KOA, regional typical functional tests and/or electromyography. The reports on KOA are based on 32 studies with more than 1000 patients. MT is meant as technique with contact to the soft tissues, bones, and joints, often "individualized based on examination findings" [60]. Results of treatment are described as preliminary evidence: "manual therapy significantly relieves pain, significantly improves physical function for > 4 weeks [74], specifically as an adjunct to another treatment and versus comparators of no treatment" [60]. Regarding the long-term benefits of MT, the research findings were inadequate for making safe and reliable conclusions [67].
For MT containing joint manipulation in glenohumeral cuff tendinopathy, a "small but statistically significant overall effect for pain reduction compared with a placebo or in addition to another intervention" could be reported [15], whereas spinal manipulation on shoulder and upper limb pain "is not as effective as local treatment in reducing upper limb pain".
For upper limb pain, the overall quality of evidence was very low; no strong recommendations can be made for the use of spinal manipulation (SM) in these patients [2]. In patients with lateral epicondylalgia, cervical HVLA manipulation resulted in increased pain-free handgrip [19].
The reviews on carpal tunnel syndrome or thumb carpometocarpal osteoarthritis showed ashort-term improvementof function with pain relief when MT was combined with therapeutic exercise [5] and also better outcome when compared with electrotherapy [27]. Additional effects of manual medicine treatment Of the reviews found and selected, we classified 19 publications in the group of reviews searching for additional treatment effects after applying MM. Four reviews searched for changes in biochemical markers or for influence on the autonomic nervous system (ANS) after mobilization or MT [35,49,57,58]. Outcome was measured with biochemical markers (neuropeptides, inflammatory and endocrine biomarkers from blood, urine or saliva) or via cardiovascular parameters, skin conductance or skin temperature. One reason that there are many studies referring to effects accom-panying MM-and MT-induced pain relief and motor function improvement (> 60) may be the insufficient knowledge about the mechanisms of MM treatment. On the other hand, the connections between pain, inflammatory activity and stress response suggest that changes triggered here can be measured-since pain itself is a subjective phenomenon. Changes in cardiac parameters were expected when acting on the cervical or thoracic spine. Moderate-quality evidence on influencing biochemical markers is described, but was only followed up for a short time: modulation of pain and inflammation is possible, but without a statement on clinical importance [35] Results of OMT and MT are scarce in subjects, heterogeneous and limited inthe methodological quality. No conclusive statement about influencing the ANS by cranial OMT can be reported, there may be responders and non-responders [57]. No declaration can be made on whether a certain treatment in an area can have more influence on the sympathetic or parasympathetic nervous system. Two reviews focus on pelvic manual treatment. One shows significant evidence of pain reduction in primary dysmenorrhea [1]. The results of the second review including 18 studies might not necessarily apply to sustained application of external pelvic compression [4]. In all the studies, surgery showed better results for pain, disability and quality of life, although not for walking ability (more effective than continued conservative treatment when the latter has failed for 3-6 months) To explore whether SMT applied at a candidate site is superior to SMT applied at a non-candidate site in relation to the clinical outcome. Cervical pain (n = 6) Lumbar pain (n = 4) Pain intensity or disability. Secondary outcomes included objective measurements, e.g. pressure pain detection threshold (PPT) and range of motion N = 9 + 1 (944 patients); 4 reported funding SMT at the candidate site compared to SMT to the opposite side of the indication (i.e. at the same spinal level but on the contralateral side-"same level") SMT at the candidate site compared to SMT elsewhere in the same spinal region (i.e. cervical, thoracic or lumbar-"same region") SMT at the candidate site compared to SMT to a distant spinal region None of these nine studies detected any statistically significant differences in the outcome measurements for the two treatment approaches: SMT given at a clinician-determined "correct" vertebral level did not have better outcomes than treatment given more haphazardly. Not retested if patients recognized that SMT was applied at the non-candidate site.

Reasons for findings:
The candidate site is a subjective concept The manipulation is not specific A neuromuscular or biomechanical mechanism might explain the positive results of SMT Some positive effects of SMT may be due to nonspecific mechanisms Paige NM et al. [52] Is the use of SMT in the management of acute (≤ 6 weeks) LBP associated with improvements in pain or function? SMT was given alone or as part of a package of therapies There were short-term beneficial effects of massage and spinal manipulation Acute LBP: spinal manipulations combined with icing and stretching improved pain by an average of 2 points (VAS 0-10) 24 h after one treatment Weiss CA (1) et al. [71] To assess effectiveness of chiropractic care options commonly used for pregnancyrelated LBP, pelvic girdle pain (PGP) Osteopathic manipulative treatment Self-reported changes in pain or disability N = 50 studies, pregnancy Postpartum n = 16 studies 2 SRs of high and acceptable quality with 1 RCT each that examined OMT as part of a plan of management for managing LBP or PGP Both SRs reported improvements in pain and disability with OMT as a treatment modality. Moderate, favourable evidence for electrotherapy and osteopathic manipulative therapy Weiss CA (2) et al. [72] To assess the effectiveness of specific chiropractic care options commonly used for postpartum LBP, pelvic girdle pain (PGP), or combination Self-reported changes in pain or disability self-reported outcomes N = 16; 5 SR, 10 RCT, 1 cohort study No treatment option was identified as having sufficient evidence to make a clear recommendation CAM complementary alternative medicine, EMG electromyography, HVLA high-velocity low-amplitude thrust, LBP low back pain, MFR myofascial release, MT manual therapy, NP neck pain, NRS numeric rating scale, NS-CLBP non-specific chronic LBP, OMT osteopathic manipulative treatment, PGP pelvic girdle pain, SR systematic review; ST sham treatment, SF-36 short form-36 questionnaire, SM/SMT spinal manipulation /therapy, RCT randomized controlled trial, SMT spinal manipulative therapy Two reviews show significant treatment effects of myofascial techniques on ROM and pain [70] and reduction of tender points [73].
One review found preliminary evidence supporting the effectiveness of subgroupspecific manual therapy in LBP, mostly in the short-term range [63]. Two reviews looked for the effect of manipulation and MT on vertigo and unsteadiness. 31 studies used balance tests, stabilography and a dizziness handicap inventory. The results show no correlation between pain reduction and stability, which limits the ability to generalize [32,66].
Few studies are devoted to fibromyalgia [62,68]. They are heterogeneous and usually only examine short-term effects. Results are insufficient to support and recommend the use of manual therapy.
One review (five studies) reports a positive effect on upper limbs and the thorax of female breast cancer survivors. MT decreased chronic musculoskeletal pain intensity and increased pain pressure threshold [13].
Nine studies focused on the effects of MT on the diaphragm. An immediate significant short-term effect on parameters related to costal, spinal and posterior muscle chain mobility could be shown [17].
Manual therapy is not significantly different to no treatment in terms of reducing fear-avoidance in individuals with chronic musculoskeletal pain [31].
No clinical studies support or refute the efficacy or effectiveness of SMT in preventing the development of infectious disease or improving disease-specific outcomes [8].
To date, there is no evidence for an effect of SMT in the management of nonmusculoskeletal disorders including infantile colic, childhood asthma, hypertension, primary dysmenorrhea and migraine [10].
There are no studies measuring the incidence or association of cervical spine manipulation and internal carotid artery dissection [9]. . Table 5 summarizes the treatments and intention of treatment, the assessments, included studies and results.
Manual medicine treatments, especially myofascial techniques, are common and effective in a variety of complaints, e.g. in conditions after breast cancer or with fibromyalgia, dysmenorrhea, migraine, hypertension, infantile colitis, asthma or balance disorders-MM does not prevent their occurrence, but is helpful and fa-cilitates in the management of several diseases.
Manual therapy influences the range of motion, pain intensity, flexibility and parts of the autonomic nervous system. However, the level of heterogeneity between studies concerning intervention, outcome measures, comparison groups and implementation makes it difficult to draw consistent conclusions and give binding recommendations.

Diversity of research objectives
It is the aim of this summarizing review to evaluate the level of evidence for treatment with specific methods of MM for pain and functional disorders in the musculoskeletal system. The distribution of the keywords used for the search strategy describing the content of the evaluated literature is shown in . Fig. 2. Manipulation and mobilization give 45%, MT results in 25%, and other manual or non-manual techniques add up to 30% of the keywords. Paying attention to the fact that the included reviews were published in about 30 different journals, these results speak for different intentions and aims of the single reviews. This is underlined by   [76] To assess effects of cervical manipulation compared with no treatment, placebo or conventional therapies on pain measurement in patients with degenerative cervical radiculopathy VAS, syndromes in TCM N = 3 trials (502 participants) Each systematic review included a variety of conservative interventions or complex interventions Above all, cervical SM showed significant immediate effects in improving pain scores compared with cervical computer traction. Long-term effects of cervical rotational manipulation were not observed CGHA cervicogenic headache, CROM cervical range of motion, DHI dizziness handicap inventory, HIT-6 Headache Impact Test, HVLA high-velocity lowamplitude thrust, MT manual therapy, MR myofascial release, SM spinal manipulation, NDI neck disability index, NP neck pain, NPQ Northwick Park Neck Pain Questionnaire; NPRS numeric pain rating scale, RCT randomized controlled trial, ROM range of motion, SMT spinal manipulative therapy, TMC traditional Chinese medicine, TTH tension-type headache, VAS visual analogue scale an even broader spread in the so-called clearly focused questions targeted to different complaints: LBP and NP together result in 44%, extremity pain is about 16% and TMD adds up to 12% of the questions. Other targets are fascia, muscles, vegetative or physiological effects, as shown in . Fig. 3.

Discussion
The quality of the studies integrated into a review is based on proven criteria for assessing a risk of bias. The weakest points in almost all studies are blinding of patients and care providers (treating person, outcome-assessors) and selective reporting. Not all studies reported session duration of treatments [26]. Cross et al. (2011) stated "it is impossible to blind the care provider in manual treatments and, when self-reported measures are used, the trials do not meet the observer blinding criteria" [11]. Only a few trials avoided cointervention [11]. One criterion, which upgrades the body of evidence, is a large amplitude of effects. An overall strength of "high" means we have high confidence that the evidence reflects the true effect and further research is very unlikely to change our confidence in the estimation of the effect [64]. Quality decreases by inadequate execution and reporting, by the MT was better than no treatment in one study and better than counselling in another study; however, MT combined with counselling was not statistically better than counselling alone; MT alone was not better than botulinum toxin. MT combined with home therapy was better than home therapy alone in one study Galindez-Ibarbengoetxea G et al. [19] To describe the effects of cervical HVLA manipulation techniques on range of motion, strength, and cardiovascular performance Perception of subjective pain N = 11 studies (553 patients) Cervical HVLA manipulation results in improvements in mobility as well as in the cardiovascular system. A large effect size was found in CROM improvement, especially for patients with neck pain. Rotation was the most clearly improved movement. In addition, mouth opening without pain was improved after upper cervical HVLA manipulation, mainly in patients with neck pain Homem MA et al. [29] To determine the existence of scientific evidence demonstrating the effectiveness of OMT as an adjuvant to orthodontic treatment in individuals with orofacial disorders  To assess the effectiveness of SM in patients with upper limb pain as part of the concept of regional interdependence ROM, NPRS, PPT, HPT (hot pain threshold), CPT (cold pain threshold) N = 6 studies (201 patients), 3 for meta-analysis Meta-analysis results suggested there were no statistical differences between SM and other interventions in terms of effects on reducing upper limb pain. The overall quality of evidence was very low; no strong recommendations can be made for the use of SM in these patients Bertozzi L et al. (2015) [5] To assess the effect of conservative interventions (exercise, MT) on pain and function in people with thumb carpometacarpal OA Hand pain, hand physical function or other secondary measures of hand impairment such as grip or pinch strength, ROM or stiffness N = 13 RCT, meta-analysis Follow-up to 12 months MT = 4 studies vs. control Moderate-quality evidence that MT and therapeutic exercise combined with MT improve pain in thumb carpometacarpal OA at short-and intermediate-term follow-up Desjardins-Charbonneau A et al. [15] To search for efficacy of MT for rotator cuff tendinopathy Pain at rest, VAS, ROM, NPRS N = 21 studies (n = 880) Only 5 studies had a moderate to low risk of bias Small but statistically significant overall effect for pain reduction of MT (low-to moderate-quality evidence) compared with a placebo or in addition to another intervention Hernandez-Secorun M et al. [27] To evaluate the effectiveness of conservative treatment ( MT appears to be moderately effective for improved self-reported function, specifically as an adjunct to another treatment and versus comparators of no treatment or other treatments; support the clinical utility of MT for knee OA  [67] To evaluate the shortand long-term efficacy of MT in knee OA in terms of decreasing pain and improving knee ROM and functionality VAS, ROM, WOMAC, muscle strength N = 6 RCTs; (40-300 patients) Intervention 2 to 24 weeks Re-evaluation differed MT can induce a short-term reduction in pain and an increase in knee ROM Regarding the long-term benefits of MT, the research findings were inadequate for making safe and reliable conclusions large and non-quantified variation in the spinal manipulation, and by the unknown heterogeneity of LBP patients [18,21,59]. There are a great number of studies which report that the manual techniques are provided by persons skilled and experienced in manual medicine treatment techniques and show a high intra-and interrater reliability, equivalent to high quality in the provided treatment variations.
Again, it should be particularly emphasized that adequate execution of both the examination and the treatment techniques is a combination of haptic and fine motor perception abilities. These skills are only perfected in a motor learning process in practical lifelong everyday activity. There are a large number of factors and variables influencing the success of MM. However, we do not think that this is fundamentally different from the conditions in other clinical disciplines.
Concentrating on the form used to describe treating pain and discomfort in the musculoskeletal system in the different parts of the body, it is noticeable that we not only encounter different treatment techniques but also differently qualified therapists and treatment providers, named as practitioners, doctors, manual medicine specialists, osteopaths, chiropractors and physiotherapists. One reason for this may be that there are different occupational titles and training paths in the single countries. The included studies are mostly in English language, some in Spanish or Por-tuguese, but the authors are from all over the world. There is also a great variety in the applied techniques described: different forms of MT, SMT, manipulation therapy, manipulation, HVLA, spine thrust, mobilization, hands-on therapy, physical therapy, osteopathic manipulative treatment, etc. With few exceptions, the individual treatment methods are not defined. The biggest shortcoming, however, is the missing description of the treatment carried out, the sequence and duration of treatment, and the procedure of the treatment technique itself. This makes it extremely difficult to compare treatments from different studies and prevents the studies from being repeated by other investigators for verification.
Masic et al. stated in 2008: "Evidencebased medicine (EBM) is the conscientious, explicit, judicious and reasonable use of modern, bestevidenceinmakingdecisions about the care of individual patients. EBM integrates clinical experience and patient values with the best available research information. . . . The practice of evidencebased medicine is a process of lifelong, selfdirected, problem-based learning in which caring for one's own patients creates the need for clinically important information about diagnosis, prognosis, therapy and other clinical and health care issues. It is not a 'cookbook' with recipes, but its good application brings cost-effective and better health care. The key difference between evidence-based medicine and traditional medicine is not that EBM considers the evidence while the latter does not. Both take evidence into account; however, EBM demands better evidence than has traditionally been used" [44].
In regular meetings of the MM societies, academies, teachers and expert commissions, opinions and convictions from clinical experience are agreed on and published in relevant international journals. This corresponds to level IV of the evidence classes according to the recommendations of the Agency for Healthcare Research and Quality (AHRQ). A higher level of evidence is dependent on methodologically high-quality non-experimental studies such as comparative studies, correlation studies or case-control studies (level III) and on methodologically high-quality non-experimental studies such as comparative studies, correlation studies or case-control studies (level III) and high-quality studies without randomization (level IIb) as well as sufficiently large, methodologically highquality RCTs (level Ib).
The levels are explained as follows [47]: -High quality of evidence: further research is unlikely to change our confidence in the estimate of effect.
There are consistent findings among 75% of RCTs with a low risk of bias that can be generalized to the population in question. There are sufficient data, with narrow confidence intervals. There are Assessment of studies evaluating spinal manipulative therapy (SMT) and infectious disease and immune system outcomes Level of selected immunological biomarkers n = 13 studies, 6 thereof RCTs No clinical studies to support or refute the efficacy or effectiveness of SMT in preventing the development of infectious disease or improving diseasespecific outcomes Preliminary data that SMT has short-term changes in selected immunological and endocrine biomarkers among asymptomatic participants Chung et al. [9] The association between cervical spine manipulation and internal carotid artery (ICA) dissection-safety of cervical spine manipulation n.a.
No studies were found measuring the incidence or association of cervical spine manipulation and ICA dissection Incidence of ICA dissection and cervical manipulation is unknown Besides some case reports, there is no epidemiologic evidence for association to validate this hypothesis Coté et al. [10] The global summit on the efficacy and effectiveness of spinal manipulative therapy for the prevention and treatment of nonmusculoskeletal disorders    Every single trial concluded the positive effect of myofascial techniques on range of motion and pain Moderate effect size for jaw opening with latent trigger points in masseter muscle High levels of data heterogeneity within the other trials Lack of power calculation, bias prevention, validated outcome measures, reporting betweengroup differences, effect sizes and confidence intervals Wong et al. [73] Strain counterstrain (SCS) technique to decrease tender point palpation pain compared to control conditions Palpation pain on visual analogue scale (VAS) or numeric rating scale (NRS) n = 5 studies, 2 thereof for meta-analysis Randomized controlled trials with isolated SCS treatment 8 or more of the 12 methodological criteria were fulfilled Pooled: significant reduction of tender point palpation pain Low evidence quality No statement on long-term pain, impairment or dysfunction Prerequisites for evidence-based diagnostics in MM are good reproducibility, validity, sensitivity and specificity studies of the diagnostic procedures. To ensure the quality of such studies, the International Academy for Manual Musculoskeletal Medicine has developed a "reproducibility protocol for diagnostic procedures in MM" in recent years. "The protocol can be used as a kind of 'cook book format' to perform reproducibility studies with kappa statistics. It makes it feasible to perform reproducibility studies in MM clinics and by educational boards of the MM societies" [53].

Conclusion
Based on the available scientific material, it can be concluded that a general EBM level III is available, with individual studies reaching level II or Ib, which creates the prerequisite and the ability to perform tasks to a satisfactory or expected verification (validity) of MM diagnostic and therapeutic techniques. The results of this systematic review show that -Spinal manipulation and mobilization and MT were significantly more efficacious for neck/low back pain than no treatment, placebo, physical therapy or usual care in reducing pain. -SMT is a cost-effective treatment to manage spinal pain when used alone or in combination with general practitioner (GP) care or advice and exercise compared to GP care alone, exercise or any combination of these. -SMT has a statistically significant association with improvements in function and pain improvement in patients with acute low back pain. -Preliminary evidence that subgroupspecific manual therapy may produce a greater reduction in pain and increase in activity in people with LBP when compared with other treatments. Individual trials with a low risk of bias found large and significant effect sizes in favour of specific manual therapy. -Upper cervical manipulation or mobilization and protocols of mixed manual therapy techniques presented the strongest evidence for symptom control and improvement of maximum mouth opening. -Musculoskeletal manipulation approaches are effective for the treatment of temporomandibular joint disorders-here is a larger effect for musculoskeletal manual approaches/ manipulations compared to other conservative treatments for temporomandibular joint disorder. -MM is helpful and facilitating in the management of several diseases, with an influence on range of motion, pain intensity, flexibility and parts of the autonomic nervous system.
The results of the available reviews and the evidence found on the effect of manual medicine treatment with the view to inclusion of manual therapy in guidelines are regarding treatment of acute and chronic pain due to the musculoskeletal system, especially including spine, joints and muscles. All reviews mentioned call for further qualitative studies in order to consolidate and increase the level of evidence. The previous initial shortcomings of the studies must be overcome: -Clear elaboration of questions.
-Exact description of manual medicine practice/manual techniques. -Lowering the bias in patient inclusion.
The EBM-oriented physicians and therapists of tomorrow's manual medicine treatment have three tasks [44]: -To use evidence summaries in clinical practice. -To help develop and update selected systematic reviews or evidence-based guidelines in their area of expertise. -To enrol patients in studies of treatment, diagnosis and prognosis on which medical practice is based.
The topicality of this statement has not changed to this day.
For this article, no studies with human participants or animals were performed by any of the authors. All studies mentioned were in accordance with the ethical standards indicated in each case.
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