Abstract
Context
Reviews exploring harm outcomes such as adverse effects (AE), all cause dropouts (ACD), dropouts due to inefficacy, and dropouts due to AE associated with osteopathic manipulative treatment (OMT) or osteopathic manual therapy (OMTh) are scant.
Objectives
To explore the overall AE, ACD, dropouts due to inefficacy, and AE in chronic noncancerous pain (CNCP) patients receiving OMTh through a systematic review of previous literature.
Methods
For this systematic review and meta-analysis, the authors searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Physiotherapy Evidence Database (PEDro), EMCare, and Allied and Complementary Medicine Database (AMED), and Ostmed.Dr, as well as the bibliographical references of previous systematic reviews evaluating OMTh for pain severity, disability, quality of life, and return to work outcomes. Randomized controlled trials with CNCP patients 18 years or older with OMTh as an active or combination intervention and the presence of a control or combination group were eligible for inclusion. In this sub-study of a previous, larger systematic review, 11 studies (n=1,015) reported data that allowed the authors to perform meta-analyses on ACD and dropouts due to AE. The risk of bias (ROB) was assessed with the Cochrane ROB tool and the quality of evidence was determined with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.
Results
The pooled analysis showed that ACD was not significantly different for visceral OMTh (vOMTh) vs. OMTh control (odds ratio [OR]=2.66 [95% confidence interval [[CI]], 0.28, 24.93]) or for OMTh vs. standard care (OR=1.26 [95% CI, 0.84, 1.89]; I2=0%). Single study analysis showed that OMTh results were nonsignificant in comparison with chemonucleolysis, gabapentin, and exercise. OMTh in combination with gabapentin (vs. gabapentin alone) and OMTh in combination with exercise (vs. exercise alone) showed nonsignificant ACD. Dropouts due to AE were not significantly different, but the results could not be pooled due to an insufficient number of studies.
Conclusions
Most articles did not explicitly report AEs, ACD rates, or dropouts due to AEs and inefficacy. The limited data available on dropouts showed that OMTh was well tolerated compared with control interventions, and that the ACD and dropouts due to AEs were not significantly different than comparators. Future trials should focus on explicit reporting of dropouts along with beneficial outcomes to provide a better understanding of OMTh efficacy.
Chronic noncancerous pain (CNCP) is among the most common reasons for patients to consult general practitioners and specialist pain clinics, with back pain being the most common reason for osteopathic consultations [1], [2], [3], [4]. Management of CNCP is multidisciplinary and, depending on the underlying cause, treatments for CNCP range from pharmacological interventions and psychotherapy to physical treatments such as physiotherapy, chiropractic treatments, massage therapy, and osteopathic manipulative treatment (OMT) or osteopathic manual therapy (OMTh) [5], [6]. Although the same principles are followed in either manual treatment approach, OMT is performed by physicians, whereas OMTh is performed by nonphysicians [7]. Since OMT and OMTh are defined differently based on the specific licensure of the practitioner, we will be referring to both as OMTh throughout the rest of the article. OMTh is reportedly a safe and effective treatment approach and is employed as a primary or adjunctive treatment to manage CNCP [6], [7], [8], [9]. OMTh requires a comprehensive understanding of anatomy and physiology based on osteopathic principles, and practitioners use that knowledge to mobilize and influence the patient’s body. The risk of complications and adverse effects with OMTh is lesser than with other manipulation techniques [10]; the scope and acceptance of OMTh continues to broaden as considerable advances continue to be made by the osteopathic profession in both research and the politics of healthcare [11], [12], [13], [14]. Considering both the benefits and potential risks of any treatment is vital for both patients and healthcare providers to establish realistic expectations and to make informed decisions [15], [16].
Most systematic reviews focus on beneficial outcomes for intervention; however, less than 10% of systematic reviews and meta-analyses explore harm outcomes such as tolerability and adverse effects (AE) [17], [18]. One potential reason that authors of review articles do not focus on harm outcomes is inconsistent reporting of harm outcomes and lack of standardized reporting methods [19]. A meta-analysis as part of a systematic review aims to provide a thorough, comprehensive, and unbiased statistical summary of data from the literature [20], [21]. We recently published another systematic review and meta-analysis exploring the effectiveness of OMTh in CNCP patients [22]. During that review, it became apparent that there is a need to report transparent and critically appraised results from existing literature about the harm effects of OMTh in the management of CNCP.
The existing studies supporting OMTh safety and efficacy suffer from limitations that may contribute to OMTh being misunderstood and underutilized [23], [24], [25]. Previous studies [26] have explored the tolerability of OMTh by CNCP in cross-sectional surveys or prospective observational studies; however, since OMTh is a therapeutic hands-on intervention, randomized controlled trials (RCT) are considered a more suitable study design to assess dropout rates and AE. The goal of this review was to explore the tolerability, all cause dropout (ACD), and dropouts due to AE from OMTh.
Methods
To describe harm outcomes such as ACD rates and dropouts due to AE, we reviewed the data from individual studies that were previously reported in a separate systematic review that explored the effectiveness of OMTh in CNCP [22]. The original study was registered with Prospero (#CRD42019125659).
We developed keywords using the MeSH word analyzer (http://MeSH.med.yale.edu/) and developed a broad search strategy that was implemented from database inception to July 2019. We utilized Ovid to search MEDLINE, Embase, EMCare, Allied and Complementary Medicine (AMED), Physiotherapy Evidence Database (PEDRO), and Cochrane Central Register of Controlled Trials (CENTRAL) databases, as well as Ostmed.Dr, for eligible studies. The bibliographical references of previous systematic reviews were also searched for eligible trials. As our goal was to report the AE and dropouts associated with OMTh in relation to studies included in our previous review [22], we did not update our search strategy. The search strategy is provided in the Supplemental Material, which was also published with our previous review [22].
Our eligibility criteria included RCT enrolling patients 18 years or older with CNCP that employed OMTh as an active or combination intervention and involved comparison with any other intervention or control. Eligible trials explored the effectiveness of OMTh on pain severity, disability, QOL, or RTW in CNCP. The methodology, inclusion criteria, and exclusion criteria are reported in the previously published study [22] and we conducted our meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [27]. For this review, we included the studies among those reviewed that reported tolerability outcomes such as AE, as well as ACD due to AE and inefficacy.
We excluded RCT that enrolled fewer than 10 participants per arm at baseline or if the author(s) reported composite score. Studies with a focus on cancerous pain, pain developed during pregnancy, headaches, pain due to gynecological abnormalities, irritable bowel syndrome (IBS), or other visceral pain such as prostatitis were also excluded. We excluded crossover trials, as there is a possibility of carry-over effect and methodological challenges limits their applicability [20], [28]. Given that OMTh is governed by a set of principles and uses a combination of methods to treat the body [29], we excluded studies that specifically investigated a single technique without employing additional use of general OMTh.
Data collection and analysis plan
Title, abstract, full text screening, data abstraction, and risk of bias (ROB) were compiled in duplicates and independently by a team of reviewers (H.F., J.B., A.B., A.A.). Included studies and results were compared between independent reviewers and teams, and any discrepancies were reviewed with adjudication with third reviewer (Y.R.). We extracted information about the number of events associated with ACD and dropouts due to AE according to the definition previously reported [30], [31], [32]. In previous reviews, all comparators in varying osteopathic studies would be pooled together resulting in high heterogeneity and, therefore, less reliable results. We employed the same strategy from the primary study [22] to pool according to the homogeneity between OMTh and the comparator type(s). A previous systematic review with meta-analysis [33] reported no significant difference between exercise and physiotherapy; therefore, in our meta-analysis, we merged physiotherapy and group exercise comparators. Albers et al. [34] and Licciardone et al. [35] were three-arm studies and, based on the similarities between the OMTh applied and comparators, respectively, we merged those two arms.
Quality of evidence
The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool [36], [37], [38], [39]. GRADE consists of five components: ROB, inconsistency, imprecision, publication bias, and indirectness.
Risk of bias
ROB was analyzed using modified Cochrane ROB tools on the following components: random sequence generation, allocation concealment, blinding of participants, health care providers, outcome assessors, and dropout rates [40].
Heterogeneity (Inconsistency)
The heterogeneity of the pooled studies was determined by visual inspection of forest plots and using the I2 statistic [20]. For heterogeneity, we used a cutoff of 60% or inconsistency in the effect estimates of individual studies on visual inspection of the forest plot [35].
Imprecision
Imprecision was determined with 95% confidence interval (CI).
Publication bias
We did not have 10 or more studies in the pooled analysis and therefore could not assess publication bias.
Indirectness, inconsistency
The clinical characteristics of the participants and width of the 95% CI, respectively, were assessed for indirectness and inconsistency.
Analysis
When possible, we performed meta-analysis in random effect model (REM) and reported results with odds ratio (OR) with 95% CI. The statistical analysis was performed with Review Manager 5.3 (Review Manager RevMan; computer program, version 5.3. Copenhagen: The Nordic Cochrane Centre, the Cochrane Collaboration, 2014).
Results
Our search from all databases collectively yielded 2,956 studies by title and abstract screening (Figure 1) [22]. Of the 2,956 titles and abstracts, we included 16 studies in our initial review [22], but only 11 studies [34], [35], [41], [42], [43], [44], [45], [46], [47], [48], [49] reported AE and dropout rates in patients (n=1,015). Descriptions of the study characteristics and reported dropouts are given in Table 1 and Table 2.
PRISMA flowchart of the included studies.
Characteristics of the included studies.
| Study | Mean age, years (SD) | Female patients, % | Pain region | Were patients with comorbid psychological and medical conditions included? | Was disability/litigation considered part of exclusion criteria? | Were other medications allowed? | Duration of trial or follow up period, days | Number of participants in intervention group | Number of participants in control or comparison groups |
|---|---|---|---|---|---|---|---|---|---|
| Albers 2017 [34] | 54.9 (13.1) | 3.3 | Fibromyalgia | No | NR | NR | 84 | 34 | 14 |
| Altinbilek 2018 [42] | 54.8 (8.4) | 89.4 | Knee OA | Yes | NR | No; except for paracetamol | 151 | 44 | 41 |
| Burton 2000 [41] | 41.9 (10.6) | 52.5 | LBP/LDH | Yes | Yes | NR | 365 | 15 | 15 |
| Chown 2008 [43] | 43.6 | 58.5 | Chronic LBP | Yes | NR | Steroids were not allowed | 365 | 39 | 59 |
| Knebl 2002 [49] | 65-85* | 62.1 | Chronic shoulder pain | Yes | NR | NR | 105 | 29+ | |
| Licciardone 2003 [35] | 49.9 (8.0) | 64.6 | Chronic nonspecific LBP | Yes | Yes | Yes | 84 | 32 | 34 |
| Licciardone 2013 [44] | 40.5 (16.3) | 62.5 | Chronic nonspecific LBP | Yes | Yes | Yes | 56 | 230 | 225 |
| Marske 2018 [45] | 51.2 | 93.2 | Fibromyalgia | No | NR | NR | 42 | 21 | 8 |
| Marti Salvador 2018 [46] | 18-60* | NR | Chronic nonspecific LBP | No | NR | No | 56 | 33 | 33 |
| Papa 2012 [47] | 77 (6.7) | 70.5 | Chronic nonspecific body pain | Yes | NR | NR | 42 | 37 | 35 |
| Schwerla 2008 [48] | 35.4–54.2* | 75.6 | Chronic nonspecific neck pain | No | Yes | NR | 84 | 21 | 16 |
OA, Osteoarthritis; LBP, low back pain; LDH, lumbar disc herniation; NR, not reported.
*Studies did not report a mean age, only provided a range with no SD.
+Knebl [49] only reported the total number of patients involved but did not distinguish between intervention or control groups.
Summary of the OMTh and the comparator interventions.
| Study | Treatment groups | Osteopathic manipulation | Comparator | Per protocol or clinician-directed | Cointerventions use allowed |
|---|---|---|---|---|---|
| Description | |||||
| Albers 2017 [34] | OMTh | Direct and indirect techniques (muscle energy, MFR, HVLA, functional techniques, and balanced ligamentous tension) and cranial/sacral techniques | SC | Clinician directed | Pharmaceutical use NR but patients were excluded if they underwent manual therapy treatment or alternative treatment procedures during the study period |
| Altinbilek 2018 [42] | OMTh + Exercise | Standardized mobilization and compression for bilateral patellofemoral and tibiofemoral joints followed by a lower extremity pumping technique. These techniques are taught to the patient to apply at home as well | Exercise consisted of quadriceps muscle strengthening exercise, leg lifting, and muscle stretching such as iliotibial band, hamstring stretching, strengthening abductor and adductor muscles of the hip | Per protocol | No – Prevented from taking non-steroidal antiinflammatory drugs 1 week before and during the study. Paracetamol up to 3 g/daily was allowed and drugs for systemic conditions continued |
| Burton 2000 [41] | OMTh | Soft tissue stretching in combination with low amplitude passive articulatory maneuvers and high velocity thrust to the lumbar spine and buttock musculature | Chemonucleolysis under general anesthesia, a single dose of chymopapain | Clinician directed | No – patients with previous manipulations on the same area were excluded |
| Chown 2008 [43] | OMTh | Soft tissue massage, inhibition, muscle stretching, muscle energy, high velocity thrust (varying), articulation, mobilization, exercise advice, discussion of psychosocial issues, education, nutritional/dietary advice |
| Clinician directed | No – patients with manipulations such as physiotherapy, acupuncture in the previous 3 months were excluded as well as users of steroids and anticoagulants |
| Knebl 2002 [49] | OMTh | Treatment was defined as administration of the seven-step Spencer technique which is an articular treatment involving compression, traction, and muscle energy in various planes and axes | The positions of the Spencer technique without administration of the actual corrective forces (isometric muscle contraction) | Per protocol | NR |
| Licciardone 2003 [35] | OMTh | Combination of MFR, strain–counter strain, muscle energy, soft tissue, high-velocity–low-amplitude thrusts, and cranial–sacral | ROM activities, light touch, and simulated OMTh techniques | Clinician directed | Yes – Usual or other low back care allowed in both arms except OMTh or chiropractic manipulation |
| Licciardone 2013 [44] | OMTh | The lumbosacral, iliac, and pubic regions were targeted using high-velocity, low-amplitude thrusts; moderate velocity, moderate-amplitude thrusts; soft tissue stretching, kneading, and pressure; MFR; positional treatment of myofascial tender points; and isometric muscle activation | Sham OMTh involved hand contact, active and passive range of motion, and techniques that simulated OMTh but used such maneuvers as light touch, improper patient positioning, purposefully misdirected movements, and diminished physician force | Clinician directed | Yes – patients could self-initiate LB cotreatments including prescription and non-prescription drugs, exercise programs, lumbar supports, complementary, alternative medicine, and physical therapies |
| Marske 2018 [45] | OMTh & OMTh + Gabapentin | Treatment modalities included MFR, muscle energy, counter strain, facilitated positional release, articular ligamentous, high velocity/low amplitude, and cranial sacral OMTh. Indirect moving to direct as tolerated by the patient | Gabapentin with variable dose (300 –900 mg/day) | Clinician directed | Concurrent medications were continued |
| Marti Salvador 2018 [46] | Diaphragm OMTh | Lumbar MFR, normalization of the iliolumbar ligament, pumping, traction to the lumbar and sacral regions, techniques directed to the diaphragm included pumping, inhibition, muscle stretching, and a global abdominal hemodynamic maneuver | Manual contact was applied but with no therapeutic intention | Per protocol | Yes – Cointerventions were not analyzed, a noted limitation of the study |
| Papa 2012 [47] | OMTh | Different techniques were used based on the results of the exam, objective techniques were performed on any body part that the osteopath found to be correlated with the disorder and the patient’s functional limitation with considerations to myofascial, visceral, articulating and head structures | Postural examination and palpation of non-specific different parts of the body in different positions supine | Clinician directed | Yes – patients were subjected to the usual therapy established as a result of medical specialist visits but were not reported |
| Schwerla 2008 [48] | OMTh | Osteopathic techniques included direct techniques (high velocity, muscle energy, MFR), indirect techniques (functional techniques, balanced ligamentous tension), visceral and/or cranial techniques | Inert therapeutic ultrasound | Clinician directed | Yes – Excluded patients with concomitant physical therapy, corticosteroid use, anticoagulants. Patients kept a diary of analgesic and muscle relaxant use |
MT, manual therapy; MFR, myofascial release; HVLA, high velocity low amplitude; OMTh, osteopathic manual therapy; CCT, conventional conservative therapy; ROM, range of motion; SC, standard care; vOMTh, visceral osteopathic manual treatment; SE, specific exercise; NR, not reported.
There was variety in the type of pain between the included studies: five included patients with low back pain [35], [41], [43], [44], [46], while one study was specific to those with sciatica related to lumbar disc herniation (LDH) [41]. Two studies included patients with fibromyalgia [34], [45], one included patients with osteoarthritis [42], one with unspecified musculoskeletal pain [47], one study included patients with chronic shoulder pain [44], and one study with chronic neck pain [48]. The follow up duration ranged from 42 to 365 days. Only three studies explicitly reported [35], [42], [44] that cointerventions were allowed during the trial period.
Descriptions of the OMTh approach for each study are given in Table 2. Overall, methods of osteopathic treatment used were directed to superficial, intermediate, and deep structures with a combination of direct or indirect methods using a type of activating force (compression or traction) with the patient active or passive (respiration, isometric contraction). Comparators varied and included exercise [42], [43], pharmacological [45], standard care [35], [44], and general OMTh [46].
Risk of bias
A summary of the ROB is given in Table 3. None of the included studies met all criteria of the ROB. All studies were high risk for blinding of participants, health care providers, and high dropout rates. Except for three studies [34], [41], [48], all studies performed independent outcome assessments.
Risk of bias in the included studies.
| Study | Random sequence generation | Allocation concealment | Blinding of the participants | Blinding of the health care provider | Blinding of the outcome assessors | Drop out >20%` |
|---|---|---|---|---|---|---|
| Albers 2017 [34] | Low risk | Low risk | High risk | High risk | High risk | Low risk |
| Altinbilek 2018 [42] | Low risk | Low risk | High risk | High risk | Low risk | Low risk |
| Burton 2000 [41] | Low risk | Low risk | High risk | High risk | High risk | High risk |
| Chown 2008 [43] | Low risk | Low risk | High risk | High risk | Low risk | High risk |
| Knebl 2002 [49] | Low risk | Low risk | Low risk | High risk | Low risk | High risk |
| Licciardone 2003 [35] | Low risk | Low risk | High risk | High risk | Low risk | High risk |
| Licciardone 2013 [44] | Low risk | Low risk | High risk | High risk | Low risk | High risk |
| Marske 2018 [45] | Low risk | Low risk | High risk | High risk | Low risk | Low risk |
| Marti Salvador 2018 [46] | Low risk | Low risk | High risk | High risk | Low risk | High risk |
| Papa 2012 [47] | Low risk | Low risk | High risk | High risk | Low risk | Low risk |
| Schwerla 2008 [48] | Low risk | Low risk | High risk | High risk | High risk | Low risk |
Adverse events and drop out due to adverse events
A summary of adverse events outcomes is reported in Table 4. Only one study [44] explicitly reported an AE associated with OMTh that led to dropout. In Licciardone et al. [44], one patient reported recurring increase in back spasticity after treatments, which was attributed to OMTh. Overall in Licciardone et al. [44], 27 (6%) patients experienced AE; 16 (6.95%) from OMTh and 11 (4.88%) from the control group. Six patients from OMTh and three patients from the control group were considered to have serious AE; however, no events were explicitly related to the study intervention and there were no significant differences between the main effects’ group in the frequency of AEs.
Outcomes of the unpooled studies.
| Study | Interventions | ACD, n(%) | Dropout due to AE, n(%) | Dropout due to inefficacy | Comments |
|---|---|---|---|---|---|
| Albers 2017 [34] | vOMTh (n=36) | 1 (2.77) | 0 | NR | n=1 dropped out due to not able to meet with study demand |
| Control (n=14) | 0 | 0 | NR | NA | |
| *Altinbilek 2018 [42] | OMTh + Exercise (n=50) | 6 (12%) | NR | NR | Patients in both arms dropped out on their own will ES=0.62 [0.20, 1.90] |
| Exercise (n=50) | 9 (6%) | NR | NR | ||
| *Burton 2000 [41] | OMTh (n=15) | 5 (33.33%) | NR | NR | No explanation about the dropout rate was given ES=0.62 [0.20, 1.90] |
| Chemonucleolysis (n=15) | 5 (33.33%) | NR | NR | ||
| *Chown 2008 [43] | OMTh (n=79) | 40 (50.63%) | NR | NR | Difficulties with scheduling and administrative time to conduct follow-ups was reported. One on one OMT sessions were more likely to be attended compared to group sessions ES=0.60 [0.35, 1.03] |
| Exercise (n=160) | 101 (63.12%) | NR | NR | ||
| Knebl 2002 [49] | OMTh group + control group (n=31) | 2 (6.4%) | NR | NR | One patient died and one patient refused. Not clearly stated which arm patients were in |
| Licciardone 2003 [35] | OMTh (n=48) | 16 (33.33%) | NR | NR | ACD was 24.17%. Further detail for dropout rates was not given |
| Control (n=43) | 9 (20.93%) | NR | NR | ||
| Licciardone 2013 [44] | OMTh (n=230) | 33 (14.345) | 1 (0.43%) | NR | n=1 developed back spasticity due to OMT |
| Control (n=225) | 26 (11.55%) | 0 | NR | No further detail given | |
| *Marske 2018 [45] | OMTh (n=13) | 2 (15.38) | 1 (7.69%) | NR | Total two patients dropped from OMTh group, n=1 developed AE due to OMTh, transportation problems for 2nd loss *ES (OMT vs. Gabapentin) =0.36 [0.05, 2.50] |
| Gabapentin (n=12) | 4 (33.33%) | 1 (8.33%) | NR | Notes treatment reaction, transportation and pregnancy but did not note how many in each category | |
| OMTh + Gabapentin (n=10) | 0 | 0 | NR | NA *ES (OMTh + Gabapentin vs. Gabapentin)=0.08 [0.00, 1.74] | |
| Martí-Salvador 2018 [46] | vOMTh (n=33) | 2 (6.06%) | 0 | NR | Two patients in OMTh group got pregnant due to which patients had to discontinue OMTh |
| Control (n=33) | 0 | 0 | NR | NA | |
| Papa 2012 [47] | OMTh (n=37) | 24 | NR | NR | n=24 dropped out from the study. Author did not specified number of dropouts for each arm; n=4 dropped out due to underlying medical conditions, n=6 dropped out due to transportation problems |
| Control (n=35) | NR | NR | |||
| Schwerla 2008 [48] | OMTh (n=23) | 2 (8.69%) | 0 | NR | 1 dropped out for reason not given; 1 had incomplete data |
| Control (n=18) | 2 (11.11%) | 2 (5.55%) | NR | 2 dropped due to aggravation in pain in control group |
ACD, all cause dropouts; AE, adverse events; ES, effect size; OMTh, osteopathic treatment; SC, standard care; vOMTh, visceral osteopathic treatments; gOMTh, general osteopathic treatment.
*Studies were not poolable/outcome was reported by single study. ES (odd ratio) with 95% confidence interval was calculated to determine the significance level between OMT and control group.
In Marske et al. [45], one patient from each arm – OMTh and OMTh combined with gabapentin – reported an AE; however, the authors did not specify what the AE were. The AE were mild-to-moderate in severity and none required intervention [45]. The number of reported AE decreased with time in all groups but there was a significant difference in OMTh only (mean difference, −5.7; p<0.01) and combination groups (mean difference, −3.7; p=0.03) [43].
Two patients (5.5%) from the control group in Schwerla et al. [48] dropped out due to aggravation in pain.
All cause dropout rate
Two hundred and 87 out of total 1,015 participants (28.28%) had ACD. The overall ACD rate in OMTh vs. controls was 22.67 vs. 30.07%, respectively (n=107 and n=156, respectively). Some reported reasons for dropouts included patients who were unable to meet the study demands [34], patients who chose to cease treatment [42], patients had flare up in previously diagnosed conditions [38], or patients who became pregnant [46]. Unfortunately, in most studies, the reasons for ACD were not specified [35], [41], [43], [48], [49]. In Papa et al. [47] and Knebl et al. [49], the patients’ reasons for dropping out were not reported nor did the authors report ACD rates for each arm; therefore, we did not include Papa et al. [47] and Knebl et al. [49] in the pooled analysis. One study [38] reported high ACD in both arms, OMTh vs. exercise at 50.64 and 63.12% respectively. The authors noted major problems with recruitment and retention of patients, finding that patients were more likely to show up to one-on-one sessions. They cited dual pressures of scheduling with both the patients and the practitioners and a lack of administrative time, which impacted retrieval of follow up statistics [38].
ACDs: pooled analysis
OMTh vs. standard care
Three studies [35], [44], [48] (n=587) reported ACD in comparison with 20.78% ACDs (122 of 587 participants; 22.59 vs. 18.88% for OMTh vs. control groups, respectively; Figure 2). There is moderate quality evidence that ACD rates between OMTh and standard care were not significant (OR=1.26 [CI, 0.84, 1.89]; I2=0%].
All cause dropouts (comparison: osteopathic manipulative therapy vs. control).
Visceral OMTh vs. OMTh control
Two studies [34], [46] (n=116) reported ACD in this comparison with 2.5% ACDs (three of 116 participants; 4.34 vs. 0% for OMTh and control group, respectively; Figure 3). Moderate quality evidence showed no statistically significant difference in ACD between visceral OMTh (vOMTh) and control OMTh (OR=2.66 [CI, 0.28, 24.93]; I2=0%].
All cause dropouts (comparison: general osteopathic treatments vs viscerall osteopathic treatment).
The GRADE assessment for the ACD and dropouts due to AE is reported in Table 5. The quality of evidence for pooled analyses was moderate due to a high ROB result.
GRADE quality of evidence.
| Outcome | Number of studies | Risk of bias | Inconsistency | Imprecision | Indirectness | Publication bias | Quality of evidence |
|---|---|---|---|---|---|---|---|
| All cause dropouts | |||||||
| OMTh vs. SC | 3 (n=587) | High | Low | Low | Not detected | Not detected | Moderate |
| vOMhT vs. gOMTh | 2 (n=116) | High | Low | Low | Not detected | Not detected | Moderate |
GRADE, Grading of Recommendations, Assessment, Development, and Evaluations; OMTh, osteopathic treatment; SC, standard care; vOMTh, visceral osteopathic treatments; gOMTh, general osteopathic treatment.
Dropout rates due to inefficacy
No study reported dropouts due to inefficacy.
Discussion
In this review, we critically appraised tolerability outcomes reported as AE, ACD, dropouts due to AE, and inefficacy within RCTs, exploring the effectiveness of OMTh in CNCP after we noticed a degree of oversight in the currently-available literature and were unable to address this fully in our previous systematic review and meta-analysis [22]. To the best of our knowledge, this is the first review that has attempted to specifically explore the risks and reasons for dropouts from OMTh in comparison to other interventions in CNCP RCT studies. Our results indicated that although ACD were higher in OMTh groups compared with control groups, there was no significant difference noted. Aggravation of pain was specified within the OMTh group in two studies [44], [48] and one study [48] within the control group. One study [45] noted a treatment reaction to the control medication. Differences between OMTh and control group dropouts due to AE were not significant. Unfortunately, only five studies [34], [44], [45], [46], [48] out of 11 reported specific data on AE. From our main review, we found that with important patient outcomes such as pain, disability, QOL, and RTW, OMTh was well tolerated and was not statistically different from the comparators. From our initial review [22] including 16 studies, there were only 11 studies that included any data on ACD or AEs which could be included in this review. Few of those studies included details on why patients dropped out or provided insights on how to improve the problem in the future, and fewer reported complete data on AE (Table 4). Overall, the current literature reporting AE of OMTh is lacking and our hope is that this review will encourage improved reporting in future studies to build the strength and confidence in OMTh research.
Strengths and limitations
A key strength of our review was that we focused on specific outcomes, which are often underreported and overlooked: tolerability outcomes of ACD, dropout rates due to AE, and inefficacy. Our search strategy was broad, and our review was methodologically rigorous because we reported our results clearly and transparently, allowing for more precise interpretation of our results.
Our review also had several limitations. First, we inherited limitations from the primary studies having high ROB, which we downrated for major bias components such as random sequence generation and blinding. Although none of the included studies met all criteria of ROB, this is a common limitation to all procedure-based clinical trials since it is nearly impossible to blind both patients and practitioner(s). Second, the eligible studies were not sufficiently powered and the dropout rate in the eligible studies was very high. Third, due to the nature and reporting of current evidence, we were unable to pool the dropout rates for many important comparisons.
In the context of existing literature exploring the tolerability outcomes of OMTh in CNCP, our review is unique in its study design. In a survey of 884 patients by Degenhardt et al. [26], the incidence of AE due to OMTh was 2.5% (95% CI, 1.3–4.7%). Women (n=44; 97.8%) reportedly experienced more AE than men (n=1; 2.23) (OR, 13.9; 95% CI, 1.7–115.6; p=0.01), with pain/discomfort the most commonly identified type of AE at 0.9% (95% CI, 0.5–1.6%). Vogel et al. [50] reported AE from OMTh in 2039 patients, of which 4% (n=82) patients reported mild disability and 10% (n=130) sought attention from other health care providers during treatment [50]. However, Degenhardt et al. [26] and Vogel et al. [50] explored dropout rates in observational studies and did not compare the dropout rates to other interventions. Our review is unique in that we explored the ACD and AE of OMTh compared with controls in CNCP reported in previously published RCT. RCTs are a more suitable study design to explore the effectiveness and tolerability of a treatment compared with observational studies due to an increase in control as well as being able to more critically assess variables and bias, and it is important to compare the AE of OMTh to other recommended treatment modalities. Therefore, our review provides better evidence for the safety of OMTh compared with previous studies.
Clinical implications and future directions
There was moderate quality evidence that OMTh in managing CNCP is associated with low ACD and dropouts due to AE. For this review, we extracted tolerability outcomes from studies that were included in our previous systematic review [22]. Making multiple publications using the same data set can be acceptable, provided the goals are explained explicitly and the research question and rationale are adding significant contribution to the scientific community [51], [52]. As mentioned, most systematic reviews and metaanalyses focus on beneficial outcomes of an intervention with little to no emphasis on tolerability outcomes [17], [18], [19]. For any intervention and especially within osteopathic practice, treatment philosophy is based on safety, equitability, effectiveness, and orientation to patients [53], [54], [55]. As OMTh is increasingly utilized and is considered a safe and effective method of treatment, it is imperative to fully understand both the benefits and potential harms. Understanding the risks of treatment is important for both the healthcare provider and patients, as having an understanding of OMTh-associated ACD and dropouts due to AE will allow clinicians to create a safe practice and patients to establish realistic expectations, give adequate consent, and make an informed choice among all available interventions. Our goal was to emphasize the importance of exploring the tolerability of OMTh in the management of CNCP patients in osteopathic research. We hope that future studies reporting on the effectiveness of OMTh will also report reasons for dropouts, ACD rates, and any AE experienced during the study.
Conclusions
In this systematic review with meta-analysis, we critically appraised the existing literature to explore OMTh in CNCP patients with a focus on tolerability and drop out effects. The current evidence is based on studies with high risk of bias and small sample sizes. Like any other intervention and manipulation therapy, OMTh is not exempt from AE and dropouts, and was not significantly different than comparators such as physiotherapy and standard care (e.g., drug intervention). Moderate quality evidence showed that ACD from OMTh were not significantly different than the control interventions; however, data on reporting AE and dropout rates with osteopathic treatment in RCTs were sparse and not explicitly reported in the included trials. Information about tolerability and AE is important for patients to make informed decisions and establish realistic expectations of treatment. Therefore, more pragmatic RCTs comparing the effectiveness of OMTh with other treatment modalities such as pharmacological agents and physical therapies are required to determine the overall effectiveness of OMTh in the management of CNCP while trying to keep data transparent so that it can be compared with other studies. It is also imperative that future research should focus on OMTh in the management of specific CNCP conditions and include general and visceral treatments to determine the relative effectiveness of various OMTh approaches.
Research funding: None declared.
Author contributions: Dr Rehman, Ms Ferguson, Mr Blair, Ms Bozek, and Ms Alison provided substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; Dr Rehman, Ms Ferguson, and Mr Blair drafted the article or revised it critically for important intellectual content; Dr Rehman and Mr Johnston authors gave final approval of the version of the article to be published; and all authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Competing interests: None declared.
Ethical approval: A previous systematic review from which the data in this review was taken was registered with Prospero (#CRD42019125659).
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Supplementary Material
The online version of this article offers supplementary material (https://doi.org/10.1515/jom-2020-0240).
© 2020 Yasir Rehman et al., published by De Gruyter, Berlin/Boston
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