The combined effects of manual therapy and exercise on pain and related disability for individuals with nonspecific neck pain: A systematic review with meta-analysis

ABSTRACT

Background

Neck pain is among the most prevalent and costly musculoskeletal disorders. Manual therapy and exercise are two standard treatment approaches to manage neck pain. In addition, clinical practice guidelines recommend a multi-modal approach, including both manual therapy and exercise for the treatment of neck pain; however, the specific effects of these combined interventions have not recently been reported in the literature.

Objective

To perform a systematic review and meta-analysis to determine the effect of manual therapy combined with exercise on pain, disability, and quality of life in individuals with nonspecific neck pain.

Design

Systematic Review and Meta-Analysis

Methods

Electronic database searches were completed in PubMed, CINAHL, Cochrane, EMBASE, Ovid, and SportDiscus, with publication dates of January 2000 to December 2022. The risk of bias in the included articles was completed using the Revised Cochrane Risk of Bias Tool (RoB 2). Raw data were pooled using standardized mean differences and mean differences for pain, disability, and quality of life outcomes, and forest plots were computed in the meta-analysis.

Results

Twenty-two studies were included in the final review. With moderate certainty of evidence, three studies demonstrated no significant difference between manual therapy plus exercise and manual therapy alone in pain (SMD of −0.25 (95% CI: −0.52, 0.02)) or disability (−0.37 (95% CI: −0.92, 0.18)). With a low certainty of evidence, 16 studies demonstrated that manual therapy plus exercise is significantly better than exercise alone for reducing pain (−0.95 (95%CI: −1.38, −0.51)). Similarly, with low certainty of evidence, 13 studies demonstrated that manual therapy plus exercise is significantly better than exercise alone for reducing disability (−0.59 (95% CI: −0.90, −0.28)). Four studies demonstrated that manual therapy plus exercise is significantly better than a control intervention for reducing pain (moderate certainty) (−2.15 (95%CI: −3.58, −0.73)) and disability (low certainty) (−2.39 (95% CI: −3.80, −0.98)). With a high certainty of evidence, four studies demonstrated no significant difference between manual therapy plus exercise and exercise alone in quality of life (SMD of −0.02 (95% CI: −0.21, 0.18)).

Conclusion

Based on this systematic review and meta-analysis, a multi-modal treatment approach including exercise and manual therapy appears to provide similar effects as manual therapy alone, but is more effective than exercise alone or other interventions (control, placebo, ‘conventional physical therapy’, etc.) for the treatment of nonspecific neck pain and related disability. Some caution needs to be taken when interpreting these results given the general low to moderate certainty of the quality of the evidence.

Introduction

Musculoskeletal (MSK) diseases are the second-leading cause of years lived with disability worldwide. In 2017, the global prevalence of neck pain was over 288 million, with an age-standardized incidence of 3551 per 100,000. Low back and neck pain are the most significant healthcare expenditure in the United States, accounting for an estimated $134 Billion in healthcare expenditures annually [1]. This prevalence of neck pain and disability and the associated societal burden creates an ongoing need to evaluate the effective management and treatment of nonspecific neck pain conditions.

Evidence regarding the effectiveness of individual interventions for neck pain is often contradictory due to the tendency for interventions to be given in combination and for RCTs to be conducted in heterogenous groups. However, these RCTs are the best available evidence despite many methodological limitations. This lack of consistency in study design makes it difficult to isolate which intervention may be used in which type of neck pain [2]. Several treatment approaches have been utilized to manage individuals with nonspecific neck. Nonspecific neck pain commonly arises insidiously and is generally multifactorial in origin, including one or more of the following: poor posture, anxiety, depression, neck strain, and sporting or occupational activities [3]. Recent evidence-based clinical practice guidelines for neck pain treatment suggest combinations of exercise, manual therapy, and other multi-modal interventions [4].

Manual therapy, including mobilization and manipulation techniques, is often used to treat nonspecific neck pain in the absence of red flags, perhaps suggesting sinister pathology. Manual therapy can be targeted at the cervical spine and/or thoracic spine in combination with exercise, education, and physical agents [5–8]. This treatment approach for nonspecific neck pain is consistent within physical therapy practice and rarely includes a single treatment modality but instead uses multi-modal interventions. For example, a recent study compared manual therapy and exercise to treat neck pain and found a faster reduction in pain perception resulting from the addition of manual therapy. In comparison, exercise alone resulted in an earlier reduction in disability [6]. Additionally, a recent systematic review assessing the influence of exercise dosing on neck pain found that exercise is beneficial for reducing neck pain and disability outcome measures. However, there were no specific recommendations regarding exercise dosing due to the heterogeneity within studies [8].

Many studies have investigated interventions in isolation (including manual therapy and exercise) versus combining the benefit suggested within clinical practice and the most recent published guidelines [4]. Nevertheless, the synthesis of this information is clinically relevant for practicing clinicians to determine the management of patients with nonspecific neck pain. Additionally, it’s important to frequently analyze the current evidence for intervention approaches to determine if their use is supported or refuted by the current literature. Thus, this systematic review and meta-analysis aimed to determine the effect of the addition of manual therapy combined with exercise on pain and disability in individuals with nonspecific neck pain.

Methods

This systematic review and meta-analysis was prospectively submitted to PROSPERO on 22 October 2021 and subsequently approved on 22 November 2021 (CRD42021286865). The authors used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines throughout this systematic review’s design, conduct, and reporting [9].

Search strategy

A health sciences research librarian conducted an electronic database search of PubMed, CINAHL, Cochrane, EMBASE, Ovid, and SportDiscus for articles with publication dates of January 2000 to 12/20/2022. We chose to limit the electronic starting in the year 2000 because a recent SR was published in 2017 with a similar search and did not identify any articles published prior to 2005 [10]. Additionally, we wanted the included manuscripts in this systematic review and meta-analysis to represent contemporary clinical practice and evidence. Searches were completed using Medical Subject Headings (MeSH) terms, keywords, and text words associated with manual therapy, exercise, and neck pain. Search strategies were optimized for each database searched using database-specific terminology and filters. In addition, search results were limited to manuscripts published in the English language. The entire PubMed search strategy is available in Appendix A.

Inclusion criteria

Articles were considered for inclusion in the review if they were (1) randomized controlled trials; (2) included individuals with nonspecific (or mechanical) neck pain; (3) contained a treatment group with combined manual therapy and exercise intervention; (4) included a comparison intervention of manual therapy alone, exercise alone, or a control/sham intervention group; (5) included pain or disability outcomes using validated outcome measures; and (6) adequately described the manual therapy and exercise interventions delivered. However, articles were excluded if they (1) included individuals with radicular symptoms, cervicogenic headaches, or whiplash-associated disorder; (2) included non-joint-targeted manual therapy interventions; (3) only included stretching as a form of exercise therapy; and (4) contained duplicate data from another included study.

Study selection and data extraction

After duplicate articles were removed, titles, abstracts, and full-text manuscripts were reviewed for inclusion during two sequential steps by two authors (MW and MD). First, the authors reviewed articles by title/abstract and then by full-text review. Disagreements were resolved by the consensus of the two review authors. Next, data were extracted by three review authors (MM, MJ, and NS) and placed into a standardized data extraction form. The accuracy of the extracted data was reviewed by one of the three authors and a fourth author not involved in the initial data extraction (AC). Extracted data included (1) sample size, (2) participant demographics, (3) manual therapy and exercise intervention descriptions, (4) treatment and follow-up timeframes, (5) outcome measures utilized for the primary outcome of pain and the secondary outcomes of disability and quality of life, (6) measures of central tendency and dispersion related to the primary outcome of pain, and (7) measures of central tendency and dispersion related to the secondary outcomes of disability and quality of life. The authors manually calculated these values from the presented data for articles where mean and standard deviations were absent.

Risk of bias

Two authors AC and MM) completed the risk of bias assessment for all included articles, with a third author reviewing all risk of bias assessments (JC). The revised Cochrane Risk of Bias tool (RoB 2) assesses the risk of bias across five domains, including (1) randomization process; (2) deviation from intended intervention; (3) missing outcome data; (4) measurement of the outcome; and (5) selection of the reported results. Within each domain, multiple signaling questions guide reviewers through an algorithm to determine the appropriate risk of bias for each of the five domains, ultimately resulting in a determination of ‘low risk,’ ‘some concerns,’ or ‘high risk’ of bias for each domain. For study-level assessment of bias, to have a low risk of bias, the study must be at low risk of bias for all domains; for ‘some concerns,’ the study must have some concerns in at least one domain but not have a high risk of bias in any domains. A study is determined to have a high risk of bias in any one or more domains or if more than two domains are determined to have some concerns [11]. Studies were not excluded from this review based on the risk of bias findings.

Data synthesis and analysis

Data were pooled across studies for the primary outcome (pain) and the secondary outcomes (disability and quality of life) based on the interventions performed in the study. This resulted in separate analyses for manual therapy and exercise compared to exercise alone, manual therapy, and exercise compared to manual therapy alone, and manual therapy and exercise compared to control (usual care, sham, etc.). The comparison of combined manual therapy and exercise vs manual therapy alone was unintentionally excluded from the PROSPERO registration. However, to fully present the multiple comparisons possible with this combination of interventions, the results of this comparison were also included in this manuscript. Individual study data were used for pooling, including the data closest to the treatment protocol’s end. Data are presented as both pooled standardized mean differences (SMD) and mean differences (MD). Pooled SMD and MD and 95% confidence intervals (CIs) were calculated for pain, disability, and quality of life outcomes. Pain measures were converted to a common 0–100 scale. Data were calculated as MD as well as SMD as all included studies used similar outcome measures to quantify both constructs of pain and disability. Additionally, MD allows the results data to be presented in values in the same units of the outcome (0–100 points for pain and 0–50 points for NDI), aiding in the clinical interpretation of the presented results.

Heterogeneity was assessed using the I² statistic using the following corresponding levels: 25% is low heterogeneity, 50% is medium heterogeneity, and 75% or greater is high heterogeneity. Heterogeneity for each pooled analysis ranged from 0% to 94%. As a result, the random effects model was used for each analysis due to a large amount of variance within studies. Pooled results were considered significant when the 95% confidence interval for the estimate did not include zero, and the p-value was less than or equal to 0.05. Between-group differences were considered clinically meaningful, with an MD of 10% on the respective outcome (10 points for pain and 5 points for disability) [12,13]. Point estimates and 95% CI for individual studies as well as p-values, point estimates, and 95% CI for the pooled effect were calculated and presented in the forest plots.

To determine the impact of studies with high risk of bias, pooled analyses that included any studies with high risk of bias were run both with and without the inclusion of these studies. Pooled effects and statistical significance were then compared between the two separate analyses.

Certainty of evidence

The overall certainty of evidence for each meta-analysis comparison was assessed by one author (MW) using the Grading of Recommendations, Assessment, Development, and evaluation (GRADE) [14]. Certainty of evidence for each comparison can be determined to be ‘high certainty’ (further research is very unlikely to change the confidence in the estimate of effect), ‘moderate certainty’ (further research is likely to have an important impact in the confidence in the estimate of effect), ‘low certainty’ (further research is very likely to have an important impact on confidence in the estimate of effect, and is likely to change the estimate), or ‘very low certainty’ (little evidence confidence in the effect estimate) [15]. Comparisons with all randomized controlled trials begin as ‘high certainty’ and are subsequently downgraded one level for each of the following: 1) Risk of bias (≥25% of the trials had a high ROB), 2) inconsistency (heterogeneity): when point estimates vary widely across studies, confidence intervals (CIs) show minimal or no overlap and/or significant substantial heterogeneity was presented by I² test ≥ 50%. 3) the imprecision of results (sample size <400 for continuous outcome) or the 95% CI around the estimate of effect covered no effect and a SMD of ±0.5. 4) Indirectness (inability to generalize) of results and 5) publication of bias (selective publication of studies) assessed using funnel plot analysis [15].

Results

Study selection

The search of electronic databases resulted in 5,068 titles (Figure 1). After 2,232 duplicates were removed, 2,836 records were screened at the title and abstract levels. From the title/abstract review, 64 full-text articles were screened for eligibility, with 22 articles deemed to meet the eligibility requirements for inclusion. Data (mean and SD) from one article was not able to be accurately calculated and as a result, the data were not included in the meta-analyses. However, study results were still included in the individual results sections. The most common reason for exclusion at the full-text level was wrong intervention (10), the wrong route of administration (8), duplicate study data (8), wrong study design (6), and wrong patient population (5).

Figure 1.

PRISMA flow diagram.

Study characteristics

Twenty-two randomized controlled clinical trials comparing the effectiveness of manual therapy and exercise combined against exercise alone or control were selected. Studies used comparable outcomes on pain and disability. Characteristics of the 22 included trials can be found in Table 1 [16–37]. Sample sizes for included studies ranged from 15 to 346, with a total of 2,207 individuals (mean = 100.32). The length of pain duration varied among included studies from less than one month [23] to three studies [20,26,27] that included individuals with less than three months of pain. Sixteen studies [16–19,21,24,25,28–32,34–37] included individuals with pain duration of three months or greater. One study including patients with pain of any duration, but results show that the two groups have mean pain duration of 75.0 and 79.2 weeks [33]. One study by Duymaz and colleagues [22] did not describe the duration of symptoms for included individuals.

Table 1.

Characteristics of included studies.

Author (Year)	Participants Analyzed	Baseline Participant Characteristics (sex, pain duration)	Neck Pain Classification	Multimodal Intervention Group Treatment	Comparison Group Treatment	Treatment Duration
Ahkter et al. 2014	62	39 Females, 23 Males; Neck pain duration: >3 months	Non-specific chronic neck	Manual Therapy + Exercise Group: manual therapy targeting the cervical spine plus supervised exercise matching the control group	Supervised Exercise Group: Isometric and Isotonic strengthening exercises, stretching exercises of the cervical spine, sternocleidomastoid, levator scapula, pectoralis major/minor	3 weeks, 6 sessions maximum
Beltran-Alacreu et al. 2015	29	22 Females, 7 Males Neck pain duration: at least 12 weeks	Non-specific chronic neck	Manual Therapy + Exercise + Education Group: Manual therapy of the cervical spine, cervical stabilization exercises of the deep neck flexors and extensors, neural self -mobilization, and patient education.	Manual Therapy Only: Passive movements and mobilizations of the cervical spine	4 weeks
Bronfort et al. 2001	120	78 Females, 42 Males; Neck pain duration: 12 weeks or more	Mechanical neck pain	Manual Therapy and Exercise Group: spinal manipulation and supervised progressive strengthening exercises for the cervical spine and upper body preceded by a short aerobic warmup and light stretching.	Manual therapy only group: spinal manipulative therapy to the cervical and thoracic spine, and soft tissue massage. Exercise only group: stretching, upper body strengthening, and aerobic exercise.	11 weeks
Celenay et al. 2016	102	74 Females, 28 Males; Neck pain duration: more than 3 months	Mechanical neck pain	Manual Therapy + Exercise Group: manual mobilizations of the cervical spine with exercise matching the exercise group.	Exercise Only Group: Warm up exercises, stabilization exercises, stretching of the neck and shoulder girdle	3 days per week x 4 weeks
Copurgensil et al. 2017	30	15 per group Neck pain duration: longer than 30 days.	Non-specific chronic neck	Conventional rehab + Manual Therapy Group: Patients received a hot pack, tens and exercise consisting of dynamic isometrics with a red elastic resistant band Exercise included chin tucks into flexion, neck extension, lateral flexion and rotation. Manual therapy included mobilizations of the cer	Conventional Rehab Only Group: The patients received the same treatment as the multimodal group, excluding the manual therapy,	3 weeks, 15 sessions
Domingues et al. 2019	64	51 Females, 13 Males; Neck pain duration: for at least 3 months.	Non-specific chronic neck pain	Manual therapy and exercise group: Manual therapy targeting the cervical spine into flexion, rotation, lateral flexion and extension. The exercises focused on the deep neck flexors muscles, consisted of three phases and was structured according to what was described by Jull et al.	Usual Care Group: electrotherapy, massage, stretching, postural correction exercises, aerobic exercise and education.	6 weeks
Duymaz et al. 2018	40	35 Females, 5 Males	Mechanical neck pain	Manual Therapy + Home Exercise Group: Manual therapy utilizing passive manual therapy targeting the cervical spine was performed. The patient then performed a home exercise program consisting of 3 sets of self-mobilization techniques 3x10 each exercise 3x/day.	Home Exercise Group: ROM/Stretching exercises targeting cervical flexion/extension/lateral flexion, upper trapezius, posterior deltoid and pectoral muscles	2 weeks
Dziedzic et al. 2005	200	221 Females, 129 Males Neck pain duration: 0–3 months	Non-specific neck pain	Advice, Exercise and Manual Therapy: Included advice and exercise with manual passive or active assisted movements, mobilizations, or manipulations to the joints and soft tissue, graded as appropriate to the patient’s signs and symptoms	Advice + Exercise Group: All participants received individualized education, advice and were instructed on exercises/HEP. Exercises included active and resisted neck movements in sitting.	6 weeks
Evans et al. 2012	180	130 Females, 50 Males Neck pain duration: at least 12 weeks.	Non-specific chronic neck pain	ET+SMT: Exercise therapy was the same as Supervised Exercise Group, with the addition of manipulation to the cervical and thoracic spine and no > 5 minutes of light soft tissue massage	ET: Neck/Upper body strengthening with individualized rep/load intensity.	12 weeks
Ferooq et al. 2018	68	44 Females, 24 Males Neck pain > 3 months	Mechanical neck pain	Manual Therapy + Exercise: Cervical mobilization: CPA/UPAs using the Maitland model for dosage + Routine physiotherapy.	Routine physiotherapy: consisting of education, and a HEP that included neck stretching/active mobility, and isometric exercise, superficial thermal therapy, continuous ultrasound, TENS	4 weeks (10 sessions required)
Fathollahnejad et al. 2019	40	40 Females Neck pain at least 3 months in duration	Non-specific neck pain (Reproduced by neck movement or provocation tests in the location of the neck)	Manipulation Plus Exercise Group: spinal manipulation plus supervised exercise	Exercise Group: Supervised periscapular muscular/cervical deep neck flexor and extensor with cervical extensor, Pec Major/Minor stretches	6 weeks
Ganesh et al. 2015	42	18 Females, 24 Males Neck pain duration: less than 12 weeks	Mechanical neck pain	Manual Therapy + Exercise Group: Mulligan SNAGS plus supervised exercise	Supervised Exercise Group: consisting of flexibility and strengthening exercises targeting cervical/scapulothoracic musculature	2 weeks
Groisman et al. 2020	90	74 Females, 9 Males Neck pain duration: >3 months	Non-specific chronic neck pain	Manual Therapy + Exercise Group: Same supervised ex plus treatments consisting of HVLAs, MET, Myofascial Release, Balanced Ligamentous Tension and visceral/cranial techniques.	Supervised exercise Group: This program included stabilization, Cervical flexion, extension and rotation exercises, self-mobilization of the deep neck flexors.	4 weeks
Lee et al. 2016	46	Neck pain duration: >3 months	Chronic mechanical neck pain	Manual Therapy + Exercise Group: Thoracic spine manipulation deep cervical flexor exercises, and self-stretching of the levator scapulae and upper trapezius muscles.	Exercise Only Group: deep cervical flexor training with self-stretching of the levator scapulae and upper trapezius muscles Control group: Active ROM self-exercise (neck flexion, extension, lateral flexion, and rotation	10 weeks
Lopez-De-Uralde-Villanueva et al. 2020	31	23 Females, 8 Males Neck pain duration: at least 12 weeks	Non-specific chronic pain	Manual Therapy + Exercise Group: manual therapy targeting the cervical and thoracic spine plus deep neck flexor and extensor exercises, spine ROM exercises, HEP and education.	Manual Therapy Only: manual therapy targeting the cervical and thoracic spine plus therapeutic patient education	1 month
Lytras et al 2022.	80	80 Females Neck pain duration: at least 3 months	Chronic neck pain	Manual Therapy + Exercise group: Manual therapy targeting the spin including soft tissue warmup followed by spinal manipulation, in addition to 45 minutes of exercise targeting the neck flexors, scapular, and upper limb muscles.	Exercise only: 45 minutes of exercise targeting endurance and resistance training for the neck flexors, scapular, and upper limb muscles.	10 weeks
Maiers et al. 2014	162	78 Females, 84 Males Neck pain duration: ≥ 12 weeks criteria	Chronic mechanical neck pain	Manual Therapy and HEP Group: Manual therapy targeting the spine, in addition to a home exercise program consisting of basic instruction on posture and body mechanics, pain management, simple body weight and cervical ROM exercises	Supervised Ex + HEP Group: Supervised exercise program focused on stretching, strengthening, endurance, and balance with the addition of cervical ROM, shoulder shrugs and trunk extension + HEP consisting of basic instruction on posture and body mechanics, pain management, simple body weight and cervical ROM exercises	12 weeks
Murphy et al. 2010	15	11 Females, 4 Males Neck pain duration: >3months or recurrent > 2 years	Chronic nonspecific neck pain	Manual Therapy + Exercise Group: high-velocity, low-amplitude cervical and upper thoracic spine, sacroiliac joint with myofascial trigger point release as plus exercise that included shoulder, scapular, cervical and core strengthening, general patient education and a HEP	Exercise Group: included shoulder, scapular, cervical and core strengthening, general pt education and a HEP	12 weeks
Peterson et al. 2015	69	41 Female, 28 Males Neck pain of any duration	Mechanical neck pain	Manual Therapy + Exercise Group: manual therapy targeting the cervical spine, SNAGS, AROM and suboccipital stretches	Manual Therapy Only Group: performed on initial visit; lateral flexion and rotation thrust to non-thrust + cervical AROM in all directions	4 days
Rodriguez-Sanz et al. 2020	58	41 Females, 17 Males Neck Pain Duration: >3 months	Chronic nonspecific neck pain	Manual Therapy + Exercise Group: cervical manual therapy plus deep neck flexor and extensor training, and a daily HEP	Exercise Only Group: plus, deep neck flexor and extensor training, and a daily HEP	4 weeks
Rodriguez-Sanz et al. 2021	48	36 Females, 12 Males Neck Pain Duration: Chronicity: >3 months criteria	Chronic nonspecific neck pain	Manual Therapy + Exercise Group: cervical spine manual therapy plus deep neck flexor training	Exercise Only Group: deep neck flexor training	1 session
Walker et al. 2008	94	63 Females, 31 Males Neck Pain of any duration	Nonspecific neck pain	Manual Therapy + Exercise Group: manual therapy of the spine, stretching and a HEP consisting of deep neck flexor strengthening, and cervical rotation ROM	Minimal Intervention Group: postural advice, patient education about movement patterns and instructions for continued prescription med use, cervical ROM ex, ultrasound with cervical ROM ex	3 weeks

Abbreviations: HEP: Home Exercise Program; ROM: Range of Motion; AROM: Active Range of Motion; SNAGS: Sustained Natural Apophyseal Glide; HVLA: High Velocity, Low Amplitude; MET: Muscle Energy Technique; ET: Exercise Therapy; SMT: Spinal Manipulation Therapy; TENS: Transcutaneous Electrical Nerve Stimulation; CPA: Central Posteroanterior mobilization; UPA: Unilateral Posteroanterior mobilization.

As evidenced within Table 2, in summary, there are 14 of the studies categorized as chronic nonspecific neck pain (12) or nonspecific neck pain (2), and eight of the studies described patients with mechanical neck pain. There appears to be a lack of reporting on adverse effects from the included trials, but all studies that provided information on dropouts were reported with rationale. The population age of the included studies ranged from 18 to 65, with many studies having a mean age in the mid ’40-’50s. However, all studies that utilized manual therapy as part of the treatment approach included a screening of red flags. The combination of exercise and manual therapy appears to be conducted safely and effectively for the targeted condition and aged adults included in their studies.

Table 2.

Risk of bias of included studies.

Study	Randomization Process	Intended Intervention Deviation	Missing Outcome Data	Outcome Measurement	Selected Reporting	Overall Risk of Bias
Akhter et al. 2014	Some Concerns	Some Concerns	Low Risk	Some Concerns	Low Risk	High Risk
Beltran-Alacreu et al. 2015	Low Risk	Low Risk	Low Risk	Some Concerns	Low Risk	Some Concerns
Bronfort et al. 2001	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk
Celenay et al. 2016	Low Risk	Some Concerns	Low Risk	Low Risk	Low Risk	Some Concerns
Copurgensil et al. 2017	Low Risk	Some Concerns	Low Risk	Some Concerns	Low Risk	Some Concerns
Domingues et al. 2019	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk
Duymaz et al. 2018	Some Concerns	High Risk	Low Risk	Some Concerns	Low Risk	High Risk
Dziedzic et al. 2005	Low Risk	Low Risk	Low Risk	Low Risk	Some Concerns	Some Concerns
Evans et al. 2012	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk
Farooq et al. 2018	Low Risk	Some Concerns	Low Risk	Low Risk	Low Risk	Some Concerns
Fathollahnejad et al. 2019	Low Risk	Some Concerns	Low Risk	Low Risk	Low Risk	Some Concerns
Ganesh et al. 2015	Low Risk	Some Concerns	Low Risk	Low Risk	Low Risk	Some Concerns
Groisman et al. 2020	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk
Lee et al. 2016	Some Concerns	Some Concerns	Low Risk	Low Risk	Low Risk	Some Concerns
Lopez-de-uralde-villanueva et al. 2020	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk
Lytras et al. 2022	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk
Maiers et al. 2014	Low Risk	Low Risk	Low Risk	Low Risk	Some Concerns	Some Concerns
Murphy et al. 2010	Some Concerns	High Risk	Some Concerns	Some Concerns	Low Risk	High Risk
Petersen et al. 2015	Low Risk	Some Concerns	Low Risk	Low Risk	Low Risk	Some Concerns
Rodriguez-Sanz et al. 2020	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk
Rodriguez-Sanz et al. 2021	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk
Walker et al. 2008	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk

Risk of bias

Of the 22 included articles, three studies (13.6%) were classified as ‘high risk’ primarily due to issues concerning intended intervention deviation. In addition, 10 studies [17,19,20,23,25–27,29,31,33] were classified as ‘some concerns’ (45.5%) based on issues with intended intervention deviation and outcome measurement concerns. The remaining nine articles [18,21,24,28,30,34–37] (40.9%) were all classified as low risk. Table 2 shows the risk-of-bias scores for individual studies.

Effects of combined treatment

Summary statistics for SMD and MD along with the certainty of evidence for each analysis can be found in Table 3.

Table 3.

Pooled effects for combined manual therapy and exercise.

Comparison	Pooled Results – SMD (95% CI)	Pooled Results – MD (95% CI)	Certainty of Evidence
MT&E vs MT – Pain	−0.25 (95% CI: −0.52, 0.02)	−4.77 (95% CI: −9.88, 0.35)	Moderate
MT&E vs exercise – Pain	−0.95 (95% CI: −1.38, −0.51)*	−9.77 (95% CI: −13.64, −5.90)	Moderate
MT&E vs control – Pain	−2.15 (95%CI: −3.58, −0.73)*	−19.59 (95% CI: −26.78, −12.40)**	Low
MT&E vs MT – Disability	−0.37 (95% CI: −0.92, 0.18)	−2.64 (95% CI: −5.95, 0.67)	Low
MT&E vs exercise – Disability	−0.59 (95% CI: −0.90, −0.28)*	−3.34 (95% CI: −4.85, −1.84)	Moderate
MT&E vs control – Disability	−2.39 (95% CI: −3.80, −0.98)*	−8.99 (95% CI: −13.46, −4.52)**	Low
MT&E vs exercise – QoL	−0.02 (95% CI: −0.21, 0.18	NA	High

Abbreviations: SMD, Standardized Mean Difference; MD, Mean Difference, MT&E, Manual Therapy and Exercise; MT, Manual Therapy; CI, Confidence Interval; QoL, Quality of Life. *Statistically significant differences; **Clinically meaningful difference.

Primary outcome: pain

Manual therapy and exercise vs. manual therapy alone

Three studies assessed the combined effect of manual therapy and exercise on pain outcomes compared to manual therapy alone (Figure 2). These studies had a combined sample size of 212 (105 M+E, 107 Manual only). For manual therapy and exercise vs manual therapy alone, there was moderate certainty of evidence (downgraded one level due to imprecision) that there is no statistically significant difference between the groups, with a pooled SMD of −0.25 (95% CI: −0.52, 0.02) (MD of −4.77 (95% CI: −9.88, 0.35)) in favor of combined manual therapy and exercise. The pooled mean difference did not demonstrate statistical significance (p = 0.07) or clinically meaningful differences between groups.

Figure 2.

Meta-analysis of manual therapy and exercise versus manual therapy alone – pain.

Manual therapy and exercise vs. exercise alone

Seventeen studies assessed the combined effect of manual therapy and exercise compared to exercise alone for pain outcomes. Sixteen studies were able to be included in the meta-analysis (Figure 3). These 16 studies had a combined sample size of 1282 (649 in M+E, 633 exercises only). For manual therapy and exercise vs exercise alone, there was a moderate certainty of evidence (downgraded one level due to inconsistency) that there is a statistically significant difference in pain between the two groups (p < 0.0001) with a pooled SMD of −0.95 (95%CI: −1.38, −0.51) (MD of −9.77 (95% CI: −13.64, −5.90)) in favor of combined manual therapy and exercise compared to exercise alone. However, although the results are statistically significant, the pooled effect did not meet the 10% threshold for a clinically meaningful difference. One additional study [20] compared manual therapy combined with exercise vs exercise alone and found no significant group/time interaction (p > 0.05) but did find decreased pain in all groups over time (p < 0.001).

Figure 3.

Meta-analysis of manual therapy and exercise versus exercise alone – pain.

To determine the effect of the three studies with a high risk of bias [16,22,32], data were pooled with and without these studies included. Pooled analyses without these studies included continued to demonstrate a statistically significant difference in pain between the two groups (p = 0.0002) with a pooled SMD of −0.89 (95%CI: −1.36, −0.43) (MD of −8.05 (95% CI: −11.73, −4.36)) in favor of combined manual therapy and exercise compared to exercise alone.

Manual therapy and exercise vs. control

Four included studies assessed the combined effect of manual therapy and exercise compared to a control or ‘usual care’ intervention for pain outcome (Figure 4). These three studies had a combined sample size of 225 individuals (113 in M+E, 112 in control). For manual therapy and exercise vs control intervention, there was a low certainty of evidence (downgraded one level due to inconsistency and one level for imprecision) that there is a statistically significant (p = 0.003) effect in favor of combined manual therapy and exercise compared to a control intervention with a pooled SMD of −2.15 (95%CI: −3.58, −0.73) (MD of −19.59 (95% CI: −26.78, −12.40)). The pooled MD of −19.59 surpassed the threshold to demonstrate a clinically meaningful benefit of combined manual therapy and exercise compared to a control intervention.

Figure 4.

Meta-analysis of manual therapy and exercise control – pain.

Secondary outcome: disability

Manual therapy and exercise vs. manual therapy alone

Three studies assessed the effects of manual therapy and exercise compared to manual therapy alone for the outcome of disability (Figure 5). These three studies had a combined sample size of 110 (104 for M+E, 106 manual only). For manual therapy and exercise vs manual therapy alone, there was low certainty of evidence (downgraded one level due to inconsistency and one level for imprecision) that there are no significant differences (p = 0.18) in disability for the combined effect of manual therapy and exercise compared to manual therapy alone, with a pooled SMD of −0.37 (95% CI: −0.92, 0.18) (MD of −2.64 (95% CI: −5.95, 0.67)). The pooled mean difference did not demonstrate statistical significance or clinically meaningful differences between groups.

Figure 5.

Meta-analysis of manual therapy and exercise versus manual therapy alone – disability.

Manual therapy and exercise vs. exercise alone

Fourteen studies assessed the effects of manual therapy combined with exercise compared to exercise only for the outcome of disability. Thirteen studies were able to be included in the meta-analysis (Figure 6). These 13 studies had a pooled sample size of 994 (502 in M+E, 492 in exercise only). For manual therapy and exercise vs exercise alone, there was a moderate certainty of evidence (downgraded one level due to inconsistency) that there is a statistically significant difference (p = 0.0002) in favor of combined manual therapy and exercise when compared to exercise alone for the outcome of disability with a pooled SMD of −0.59 (95% CI: −0.90, −0.28) (MD of −3.34 (95% CI: −4.85, −1.84)). However, these results did not meet the threshold for a clinically meaningful difference in disability. One additional study [20] compared manual therapy combined with exercise vs exercise alone and found no significant group/time interaction (p > 0.05) for disability, but did find decreased disability in all groups over time (p < 0.001).

Figure 6.

Meta-analysis of manual therapy and exercise versus exercise alone – disability.

To determine the effect of the three studies with a high risk of bias [16,22,32], data were pooled with and without these studies included. Pooled analyses without these studies included continued to demonstrate a statistically significant difference in disability between the two groups (p < 0.00001) with a pooled SMD of −0.45 (95%CI: −0.75, −0.14) (MD of −2.93 (95% CI: −4.60, −1.25)) in favor of combined manual therapy and exercise compared to exercise alone.

Manual therapy and exercise vs. control

Four studies assessed the effect of combined manual therapy and exercise compared to a control group for the outcome of disability (Figure 7). These three studies had a combined sample size of 225 individuals (113 in M+E, 112 in control). For manual therapy and exercise vs control intervention, there was a low certainty of evidence (downgraded one level due to inconsistency and one level for imprecision) that there is a statistically significant difference (p = 0.0009) in favor of combined manual therapy and exercise and revealed a SMD of −2.39 (95% CI: −3.80, −0.98) (MD of −8.99 (95% CI: −13.46, −4.52)). The pooled mean difference did reach the threshold (5 points) for a clinically meaningful difference in disability.

Figure 7.

Meta-analysis of manual therapy and exercise versus control – disability.

Secondary outcome: quality of life

Manual therapy and exercise vs. exercise alone

Four studies assessed the effects of manual therapy combined with exercise compared to exercise only for the outcome of quality of life (Figure 8). These four studies had a pooled sample size of 549 (277 in M+E, 272 in exercise only). For manual therapy and exercise vs exercise alone, there was high certainty of evidence that there is no statistically significant difference between the groups, with a pooled SMD of −0.02 (95% CI: −0.21, 0.18). The pooled mean difference did not demonstrate statistical significance (p = 0.85) between groups.

Figure 8.

Meta-analysis of manual therapy and exercise versus control – quality of life.

Discussion

This systematic review and meta-analysis aimed to determine the effect of manual therapy combined with exercise on the primary outcome of pain and the secondary outcomes of disability and quality of life in individuals with nonspecific neck pain. This multi-modal approach is clinically relevant for clinicians who often use these interventions in combination. Research often separates the interventions for effect size and determination of impact. However, the benefit of exploring the combined benefit of interventions is that this multi-modal approach is in line with clinical practice guideline recommendations for how clinicians should treat these patients [4].

For the primary outcome of pain, it appears that a multi-modal treatment approach of exercise combined with manual therapy resulted in statistically significant improvement compared to control and isolated exercise treatments. Interestingly, in the few studies that compared the multi-modal treatment to manual therapy alone, the addition of exercise did not significantly reduce pain outcome measures. For the secondary outcome of disability, the findings demonstrate a similar pattern when using a multi-modal treatment approach. This resulted in manual therapy significantly reducing disability compared to control treatment and exercise alone, but not when comparing the multi-modal treatment to manual therapy alone. These findings suggest that although a multi-modal approach is recommended within the clinical practice guidelines [4], the specific exercises in these studies, when added to a manual therapy treatment, did not lead to statistically significant improvements in either pain or disability.

These findings are consistent with the results from another systematic review, which found that manual therapy was superior to exercise alone for individuals with nonspecific neck pain [38]. Additionally, a recent systematic review found that adding exercise to manual therapy did not improve clinical outcomes for individuals with chronic neck pain during the short and mid-term follow-up periods [10]. Conversely, based on seven clinical trials, Fredin and colleagues found significant but small benefits when adding exercise to manual therapy to improve pain, function, and quality of life. The difference between their findings and ours might be the exclusion of several studies that we included based on eligibility criteria.

The clinical practice guidelines suggest that manual therapy plus exercise should be the first line of defense for individuals with nonspecific neck pain without red flags [4]. These findings could be the result of several variables identified in each study. The potential explanation for the added benefits of improving pain and function found in the meta-analysis conducted in our study may be related to the ‘neurophysiological response’ within the peripheral and central nervous system. In a compilation of the literature, Bialosky and colleagues suggested that manual therapy can potentially have peripherally mediated effects, spinal cord mediated effects, supraspinal mediated effects, and biomechanical effects, which could decrease pain and improve function in individuals with neck pain [39].

Furthermore, it is plausible that manual therapy could impact the dorsal horn resulting in an inhibitory effect. Additionally, these studies have shown that manual therapy techniques can effectively reduce pain sensitivity [40–44]. Finally, it has been found [45] that manipulation may be associated with hypoalgesia and a reduction in cortical activity correlated to decreased pain perception. Studies investigating the effects of exercise therapy as an individual treatment for neck pain and disability report consistent positive outcomes but have variable effect sizes. The inconsistent effect sizes found within the Cochrane review update may be partially due to the different exercise therapy dosages, thus highlighting the need to explore optimal exercise therapy dosage to reach efficacy [46]. This should be applied to clinical trials in the future when combined with manual therapy.

Indeed, applying evidence-based practice is a three-legged stool when considering the selection and application of interventions. The evidence continues to suggest that combined effects of manual therapy and exercise with the patients should be a treatment approach for managing adults and older adults with mechanical or nonspecific neck pain and pain-related disability. However, clinicians recognize that patient preferences also drive the selection and application of the intervention [47]. Most commonly, patients are seeking the interventions that have the most impactful results. The third leg is the clinician’s preferences toward the selected interventions, and manual therapy has been debated as to its utility. The evidence and clinicians’ backgrounds are also moderately predictive of whether or not manual therapy is a utilized intervention [48]. However, over the past few years, social media and blogs have also been identified as influential in biasing and shaping the interventions selected by physical therapists. Social media works best for health professionals when it is used to combat misinformation as vigorously as propagating information [49]. This requires an environment where users respectfully debate information to challenge one another’s thoughts and correct misrepresentation. Unfortunately, people tend to follow those on social media with similar thoughts and beliefs [50]. The bias can include endorsing a clinical philosophy tied to one’s continuing education platform, clinical practice, and livelihood or supporting a concept that leads to purchasing products in which one has a financial interest rather than what is supported within the evidence. Thus, this study adds to the evidence that suggests that manual therapy in combination with exercise should be the first line of defense for individuals with nonspecific neck pain.

Strengths and limitations

Several limitations of this systematic review may influence the generalizability of the current pooled findings. First, this systematic review included manuscripts that were rated as ‘poor quality’ and were published in English and may have missed relevant articles published in other languages. Several of the included studies were rated as having ‘some concerns’ in various categories in the Cochrane Risk of Bias tool with three studies being rated as having ‘high risk’ of bias. As with all systematic reviews, despite a thorough electronic search, we may have missed qualified articles not identified by our selected search strategy. One study that was identified for inclusion did not present data that were able to be used for calculations in the meta-analysis, so this manuscript was included as a narrative synthesis. Additionally, the exercise and manual therapy approach varied widely within the included studies. This was evidenced by the study descriptions and larger heterogeneity values in the pooled analyses. The heterogeneity can be partially addressed by using the random effects model for the meta-analyses. To systematically review all available evidence, we did not limit the meta-analysis to include only studies with low risk of bias. We felt that it was appropriate to include all available evidence and avoid incorporating any bias by the author team based on our subjective interpretation of the methods of the included articles.

Similarly, we did not specifically differentiate and perform sub analyses for different techniques, including the differentiation of thrust and non-thrust manual therapy techniques. However, previous research has suggested that both thrust and non-thrust manipulations are similarly beneficial [51]. Finally, this systematic review did not intentionally include articles that focused on other types of neck pain, including cervical radiculopathy and whiplash-associated disorders. As a result, findings from this manuscript cannot be generalized to populations outside of those with nonspecific neck pain.

Conclusion

Based on this systematic review and meta-analysis, a multi-modal treatment approach including exercise and manual therapy appears to provide similar effects as manual therapy alone, but is more effective than exercise alone or other interventions (control, placebo, ‘conventional physical therapy’, etc.) for the treatment of nonspecific neck pain and related disability. Some caution needs to be taken when interpreting these results given the general low to moderate quality of evidence available.

Biographies

Mark Wilhelm PT, DPT, PhD, serves as the Director of Admissions and core faculty in the Doctor of Physical Therapy Program at Tufts University School of Medicine. He completed his Bachelor of Science in Exercise Science from the University of Akron, and his Doctor of Physical Therapy from Walsh University in Ohio. Dr. Wilhelm completed his Doctor of Philosophy in Rehabilitation Sciences from Texas Tech University Health Sciences Center. Dr. Wilhelm’s scholarship includes over 20 peer reviewed journal articles and he has co-authored two book chapters.

Josh Cleland PT, PhD, FAAOMPT, FAPTA, is a professor and core faculty in the Doctor of Physical Therapy Program at Tufts University School of Medicine. He has published over 300 manuscripts in peer-reviewed journals and is an Editor for the Journal of Orthopaedic and Sports Physical Therapy. He is currently an author/editor on four textbooks, one of which has been published in nine different languages. Dr. Cleland is a well-known speaker at both the national and international levels and has delivered more than 225 keynote lectures and presentations in over 25 different countries. He is the recipient of numerous awards from the American Physical Therapy.

Anthony Carroll PT, DPT, OCS, CSCS, FAAOMPT, serves as the assistant director of clinical education. Carroll is a board-certified orthopedic clinical specialist and fellow of the American Academy of Manual Physical Therapists. He has served as a clinical educator in various capacities since 2012, including developing and directing a Manual Fellowship Program, providing clinical training for DPT students, residents, and fellows. He has significant teaching experience in an entry-level DPT program and serving as faculty in both a Sports and Orthopedic Residency Program. In addition, he has experience as a site coordinator of clinical education and course coordinator for integrated clinical experiences. Clinically his expertise is in the treatment of spine and chronic pain disorders.

Mark Marinch PT, DPT completed his Bachelor of Science in Interdisciplinary Studies from Utah Tech University in St. George, Utah and his Doctor of Physical Therapy from Tufts University. He practices in Las Vegas.

Margaret Imhoff PT, DPT, graduated from the Doctor of Physical Therapy Program at Tufts University School of Medicine in December 2022. She completed her Bachelor of Science in Biology & Environmental Studies from Gonzaga University in Spokane, WA. Margaret’s scholarship includes previous peer reviewed journal article on high pressure diesel fuel before making her career change to physical therapy, where she now works as a PT at an outpatient clinic in Oregon.

Nick Severini PT, DPT, CSCS, is a Performance Physical Therapist at SPARK Physiotherapy in Alexandria, VA. He completed his Bachelor of Science in Political Science from James Madison University and his Doctor of Physical Therapy from Tufts University in Boston.

Megan Donaldson PT, PhD, FAAOMPT, is a Professor and serves as the Department Chair of Rehabilitation Sciences at the Medical University of South Carolina. She completed her bachelor’s and master's degrees at D’Youville College and her PhD from Nova Southeastern University and is a Fellow American Academy of Orthopaedic Manual Physical Therapists. She has been a faculty member for 15 years and has over 40 peer-reviewed publications, two book chapters, presents nationally on musculoskeletal health and manual therapy related topics. She currently serves nationally as the American Physical Therapy Association (APTA) as an Ohio Delegate and serves the Ohio Chapter as an Executive Board member. Dr. Donaldson has earned numerous awards for research, education, and professional service to include being named Ohio Physical Therapy Association Outstanding PT Award, and Chamber of Commerce Award Top 20 under 40.

Funding Statement

This project was not supported by grant funding.

Disclosure statement

No potential conflict of interest was reported by the author(s).

PROSPERO registration

CRD42021286865

Supplemental data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/10669817.2023.2202895