Spinal rehabilitative exercise and manual treatment for the prevention of migraine attacks in adults

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

The objectives of the review are to quantify and compare the short‐ and long‐term effects of manual treatment and spinal rehabilitative exercise for episodic and chronic migraine classified according to the International Headache Societies (IHS) diagnostic criteria.

Background

Migraine headache is a common condition with a world‐wide lifetime prevalence of 14% (Stovner 2007; Vos 2012). The prevalence of migraine is highest in adults aged 25‐55 years, and is roughly three times higher in females than in males (Bigal 2009). Migraine is a substantial public health problem due to the large burden it places on the individual patient and on society. Roughly half of those with migraine report severe impairment or the need for bed rest during an attack (Lipton 2007). The financial burden of migraine is large with annual costs in Europe (including both direct healthcare costs and indirect costs due to reduced productivity) estimated at up to €111 billion (Linde 2012). Reduced work productivity (including absenteeism and reduced productivity while at work) accounts for 93% of total annual migraine costs in Europe (Linde 2012). While prophylactic medications are commonly recommended as first‐line treatments for the prevention of migraines (Loder 2012), concerns regarding side effects and potential contraindications (Shamliyan 2013), lead some migraineurs to seek non‐pharmacological interventions. Spinal rehabilitative exercise and manual treatments are among the more frequently used non‐pharmacological treatments for migraine (Wells 2010), which often presents with neck pain.

Description of the condition

The International Headache Society (IHS) defines migraine as recurrent headaches characterized by attacks that are usually unilateral, pulsating, and have moderate or severe intensity. The headaches are typically aggravated by routine physical activity, and are associated with at least one of the following: nausea and/or vomiting or photophobia and phonophobia (IHS 2013). The IHS has divided migraine headache into two major sub‐types. Migraine without aura is characterized by headache with the specific features and associated symptoms listed previously. Migraine with aura is primarily characterized by the focal neurological symptoms that often precede a headache with the features of migraine without aura. Migraine with aura infrequently occurs prior to a headache without the features of a migraine or no headache at all (IHS 2013).

In the past decade, the IHS has distinguished episodic migraine from chronic migraine, although there is still debate regarding the proper classification of chronic migraine (Katsarava 2011).

Description of the intervention

For the purpose of this review, manual treatment is defined as the therapeutic application of manual force and may include manipulation, mobilization, or massage primarily applied to the cervical spine and surrounding structures. Spinal manipulation is characterized by the application of a high‐velocity, low amplitude force resulting in motion slightly beyond the passive range of the targeted joint (Evans 2010; Haldeman 2005). Spinal mobilization is characterized by the application of low‐velocity, variable amplitude force resulting in motion within the passive range of the targeted joint (Haldeman 2005). Massage is characterized by the manipulation of muscles and other soft tissues of the body. Many distinct forms of massage therapy exist such as Swedish, structural, relaxation, myofascial or connective tissue release, and cross‐friction massage. Trigger point therapy is another form of massage involving direct manual pressure to taut bands of myofascial tissue or “trigger points” proposed to be responsible for local and referred pain (Simons 2008). Exercise therapy is defined as planned or structured physical activity to improve or maintain components of physical fitness (Caspersen 1985). For the purpose of this review, we will focus on spinal rehabilitative exercises for the improvement of spinal muscle strength, endurance, flexibility or motor control of the cervical spine. Spinal rehabilitative exercises may be implemented in one‐on‐one or group sessions.

How the intervention might work

There is emerging evidence of a connection between neck dysfunction and migraine. Neck pain and stiffness are common among patients with migraine, maybe even more common than nausea (Ashina 2015; Blau 1994; Calhoun 2010). In addition, recent studies have demonstrated a positive association between neck disability and migraine frequency (Carvalho 2014; Florencio 2014). The underlying pathophysiology of migraine is still unclear, but there is general consensus that the condition is primarily neurological. Migraine may represent a heterogeneous mixture of neurological dysfunction culminating in the sensory sensitivity that characterizes the condition (Charles 2009; Goadsby 2009). Dysfunction of the neuromodulatory structures in the brainstem including the trigeminocervical complex has been implicated as a potential mechanism in migraine (Goadsby 2009). Referral of head pain from the upper cervical spine structures has been observed and induced experimentally in migraine patients and is possible through the conversion of cervical and trigeminal nociceptive afferent input into the trigeminal‐cervical nucleus (Watson 2012). This convergence phenomenon has been demonstrated in humans (Busch 2006; Piovesan 2001).

Manual treatments and spinal rehabilitative exercise are performed to reduce pain and improve the biomechanical function of the spine including intersegmental and global range of motion, muscle strength, endurance and motor control (Benjamin 2009; Boyling 2004; Jull 2008; O'Leary 2003). There is evidence that manual treatment and spinal rehabilitative exercise decrease nociceptive input from cervical spine structures (Coronado 2012; Jull 2002; O'Leary 2007). Migraine commonly presents with neck pain and stiffness (Ashina 2015; Calhoun 2010) and the reduction of nociceptive afferent input from the cervical spine and surrounding tissues to the trigeminal‐cervical nucleus, a structure implicated in the pathophysiology of migraine, may explain how manual treatment and spinal rehabilitative exercise can improve migraine. Additionally, there is emerging evidence manual treatment can modulate pain centrally through spinal and supraspinal mechanisms (Bialosky 2009; Bialosky 2014; Pickar 2012). The supraspinal mechanisms may be related directly to mechanical input into the spine, as well as expectancy, placebo, and other nonspecific effects. The effect of manual treatment on central mechanisms of pain processing may provide an additional pathway for the reduction of migraine symptoms.

Why it is important to do this review

Often, migraine is treated pharmacologically, but many patients also receive various forms of non‐pharmacological treatment for migraine including manual treatment and spinal rehabilitative exercise (Rasmussen 1992; Wells 2010). This protocol is one of a series of planned new reviews that will serve to update the original review to provide a comprehensive evaluation of the evidence regarding the efficacy of manual treatment and spinal rehabilitative exercise for migraine (Bronfort 2014). We will also conduct reviews of spinal rehabilitative exercise and manual treatment for tension type and cervicogenic headache (Bronfort 2014). We will compare our findings with other systematic reviews published after our original review (Biondi 2005; Bronfort 2010; Bryans 2011; Chaibi 2011; Chaibi 2014; Clar 2014; Gil‐Martinez 2013; Posadzki 2011). We will utilize risk of bias and quality of evidence assessments recommended by Cochrane for the updated systematic review (Higgins 2011).

Objectives

The objectives of the review are to quantify and compare the short‐ and long‐term effects of manual treatment and spinal rehabilitative exercise for episodic and chronic migraine classified according to the International Headache Societies (IHS) diagnostic criteria.

Methods

Criteria for considering studies for this review

Types of studies

We will only include randomized controlled trials (RCTs). We will exclude quasi‐randomized studies (e.g., treatment allocation by date of birth, hospital record number, or alternation). We will include study reports in any language. We will not exclude RCTs on the basis of methodological quality. We will limit studies to those that isolate the effects of the target manual treatment, spinal rehabilitative exercise, or combination of both. We will conduct separate analyses for studies using only manual treatment or spinal rehabilitative exercise and studies combining the interventions.

Types of participants

We will include studies reporting on individuals 18 and older with episodic and chronic migraine classified according to the International Headache Societies (IHS) 2013 criteria (IHS 2013). Some studies are anticipated to pre‐date or not utilize the IHS classification system. Two review authors, including one neurologist, will determine if studies pre‐dating or not utilizing the IHS classification system can be classified as episodic migraine using reported data (e.g., inclusion/exclusion criteria, diagnostic criteria, baseline clinical characteristics) (McCrory 2005). Trials may include mixed populations of episodic and chronic migraine patients. We will contact the authors of trials with mixed populations to acquire data for the episodic and chronic migraine population separately. If we cannot acquire data stratified by episodic and chronic migraine, we will analyze the mixed trial(s) separately.

Types of interventions

Included studies must assess the effect of one or more types of manual treatment or spinal rehabilitative exercise primarily applied to the cervical spine and surrounding structures. Manual treatment can consist of spinal manipulation, mobilization, or massage techniques. Spinal rehabilitative exercise can consist of strengthening, stretching, or motor control exercises (including proprioceptive exercises). Interventions can be used alone or in combination with other active treatments (e.g., general physical therapy) but the manual treatment or spinal rehabilitative exercise must be the primary therapy assessed in the study. We will analyze single intervention studies (e.g., manual treatment or spinal rehabilitative exercise alone) independently from studies including a combination of therapies. In general, acceptable comparison groups will include placebo, no treatment (e.g., wait‐list control), and any other type of active intervention.

Types of outcome measures

The primary and secondary outcome measures will follow the recommendations of the 2012 IHS guidelines on controlled trials of drugs in migraine (Tfelt‐Hansen 2012).

Primary outcomes

We will use patient‐rated headache frequency measured in number of migraine days or number of migraine episodes per four weeks as the primary outcome measures if available. Migraine frequency measured by days or episodes is recommended as a primary outcome by the 2012 episodic migraine guidelines for controlled trials (Tfelt‐Hansen 2012).

Secondary outcomes

We will include the following secondary outcomes, if available: headache intensity, duration, headache disability (e.g., headache disability index, migraine disability assessment), analgesic use, quality of life, or other pain or disability patient reported outcomes. We anticipate that many studies will use a headache index as a primary outcome. We will only include headache index measures as a secondary outcome if the authors incorporated frequency data in the composite measure which is not reported independently (McCrory 2005). We will report responder rates of patients achieving 30 and 50% improvement in the primary outcome measure along with number needed to treat (NNT), if available (Silberstein 2008). We will also report data on costs and adverse events if available. For adverse events, we will describe the collection methods used (active/passive surveillance), the definition of adverse events, the proportion of subjects reporting adverse and serious adverse events, and the number of withdrawals from treatment due to adverse events.

Timing of outcome assessments

We will define short‐term follow up as outcomes evaluated up to three months after the initial study treatment. Long‐term follow up will be defined as outcomes evaluated more than three months after onset of study therapy.

Search methods for identification of studies

Electronic searches

We will identify studies by a comprehensive computerized search of the following databases:

• MEDLINE;

• EMBASE;

• BIOSIS;

• CINAHL;

• Science Citation Index;

• Dissertation Abstracts;

• Cochrane Central Register of Controlled Trials (CENTRAL);

• MANTIS;

• Index to Chiropractic Literature;

• Chiropractic Research Archives/Abstracts Collection;

• Physiotherapy Evidence Database.

In MEDLINE, we will apply a published search strategy for identifying RCTs in combination with specific search terms, without language restriction (Higgins 2011) (Appendix 1). We will modify the full MEDLINE search strategy for use in the other electronic databases.

Searching other resources

We will hand search non‐indexed physical therapy, chiropractic, osteopathic, manual medicine journals, and exercise journals going back to 1960. We will conduct an online search to identify which journals were not indexed in this timeframe. We will check the citations in included publications for additional studies that may qualify for this review.

In addition, we will search the following trial registries for completed and ongoing studies:

• ClinicalTrials.gov (https://clinicaltrials.gov/);

• metaRegister of Controlled Trials (mRCT) (http://www.isrctn.com/page/mrct);

• World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) Search Portal (http://apps.who.int/trialsearch/).

We will atempt to obtain horizon estimation after the second and subsequent searches to estimate how many articles are missing with 95% confidence intervals (CIs) using Poisson regression (Kastner 2007).

Data collection and analysis

Selection of studies

Two authors (GB, BL) will independently select trials to be included in the review based on the explicit inclusion criteria. We will resolve differences in the results of selection by discussion or consult a third author (MH) if disagreements cannot be resolved. Prior to resolution of disagreements, we will calculate agreement between authors. We will select articles initially on the basis of their abstracts; if a determination cannot be made based on the abstracts, we will retrieve the full articles for review. Authors responsible for the conduct of a RCT considered for inclusion will not participate in decisions regarding inclusion/exclusion or quality assessment of their trial.

Data extraction and management

We will record explicit information about patient demographics, type of migraine, clinical characteristics, interventions, and outcome measures using standardized abstracting forms. Two non‐blinded authors (BL, JS) will independently extract and record relevant data from each article. Similar headache outcome constructs (e.g., intensity, frequency) will likely be measured on different scales (e.g., intensity of 0‐10, 0‐3, 0‐100 or frequency per 7, 14 or 28 days). We will normalize outcomes to a common 0‐100 scale (also referred to as a percentage point scale) to facilitate analysis using mean differences (MDs), a more clinically intuitive measure than standardized mean differences (SMDs). We will use SMDs for outcomes with conceptually different domains (e.g., disability measured with different individual domains). We will enter all original data on outcomes as normalized mean percentage point scores. We will attempt to standardize headache frequency outcomes to four weeks (28 days). We will enter data into Cochrane's statistical software, Review Manager 2014, to create normalized MD scores and SMD scores whenever possible. We will attempt to contact authors if there is uncertainty about important aspects of methods or data in the published report.

Assessment of risk of bias in included studies

This review will include the latest Cochrane Collaboration's tool for assessing risk of bias (Higgins 2011). At least two authors (GB, BL) will independently assess the risk of bias in each included outcome per study. We will resolve differences in ratings by discussion or by consulting a third author (MH) if disagreements cannot be resolved. Prior to resolution of disagreements, we will calculate agreement between authors. We will assess the following seven domains for risk of bias:

1. random sequence generation;

2. concealment of treatment allocation;

3. blinding of participants and/or personnel (blinding of treatment providers is not possible for clinical trials investigating manual treatment or spinal rehabilitative exercise);

4. blinding of outcome assessment;

5. incomplete outcome data: withdrawal/drop‐out rate and intention‐to‐treat analysis;

6. selective outcome reporting;

7. other bias: similar at baseline, similar co‐interventions, acceptable compliance, similar timing of assessment.

We will not exclude outcomes from individual studies from further analyses based on the results of risk of bias assessments. We will rate each domain as 'Low risk', 'High risk', or 'Unclear risk' based on the criteria recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) (Appendix 2). In addition, we will assess the quality of each outcome using the Oxford quality scale (Jadad 1996).

Risk of bias assessments can vary among authors of Cochrane reviews, and the Cochrane Handbook for Systematic Reviews of Interventions does not specify how review authors should summarize overall risk of bias for a particular outcome (Furlan 2009; Higgins 2011).

We will use the following operational definitions when judging individual outcomes within studies for overall risk of bias (Higgins 2011; Jadad 1996).

• We will judge outcomes for individual studies scoring ≥ 3/5 on the Oxford scale as low risk of bias if the remaining domains recommended by the Cochrane Handbook for Systematic Reviews of Interventions, but not assessed by the Oxford scale (i.e. allocation concealment, selective outcome reporting, other risk of bias), have no more than one rating of unclear risk of bias.

• for outcomes scoring ≥ 3/5 on the Oxford scale, but with either high risk of bias in one domain or unclear risk of bias in two domains not assessed by the Oxford scale, we will judge them as being at moderate risk of bias.

• we will judge all outcomes failing to meet the criteria for low or moderate risk of bias as high risk of bias.

Measures of treatment effect

We will use MDs and SMDs as the effect measures for continuous outcomes. We will compute SMDs as described in Cohen 1988 and Glass 1981: difference in treatment and control group means divided by the pooled standard deviation. Correction for SMD estimate bias associated with small sample sizes (n < 50) will be accomplished using the method described in Hedges 1985. For dichotomous outcomes, we will calculate risk differences (RDs) and NNT. We will assess the clinical importance by following the guidance by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) Group (Dworkin 2009). Determination of the clinical importance of between‐group MDs has not been well‐standardized; however, we will facilitate interpretation by considering many factors in aggregate, including the magnitude of group differences, responder analyses (e.g., 50% improvement), type of comparison, durability of treatment effect, intervention safety and tolerance, cost, and patients' ability to adhere to treatment.

Unit of analysis issues

For studies that include three or more interventions, we will combine the comparison groups in the meta‐analysis to allow for one "pair‐wise" comparison, if clinically possible. This will prevent double counting of the participants in the manual treatment or spinal rehabilitative exercise group. We will include cross‐over studies in the review; however, we will analyze only data from the first period of the trial prior to the cross‐over. For cluster‐randomized trials, we will include the direct treatment effect estimate if the trial author(s) properly accounted for the clustered design within the analysis. If the clustered design is not appropriately accounted for in the analysis, we will treat the individual clusters as the unit of analysis.

Dealing with missing data

We will contact the corresponding author of clinical trials with unclear reporting of trial methodology or results for additional information. If we are unable to secure additional information pertaining to study results, we will use the following strategy for dealing with missing data. Where data are reported in a graph and not in a table, we will estimate the means and standard deviations. If the standard deviation for follow‐up measurements is missing, the standard deviation for that measure at baseline will be used for subsequent follow‐up measurements. When standard deviations are not reported, these will be estimated from the confidence intervals if possible. In the absence of these statistics, standard deviations will be calculated from T‐scores, P values, and F‐values, provided sample sizes are given (Higgins 2011). Finally, if no measure of variation is reported anywhere in the text, the standard deviation will be estimated based upon other studies with a similar population and risk of bias.

Assessment of heterogeneity

Prior to calculation of a pooled effect measure, we will assess the reasonableness of pooling on clinical grounds. The possible sources of clinical heterogeneity to be considered are: migraine type (i.e. with or without aura), patient population, intervention, comparison group, outcomes, and follow‐up time point. If pooling seems appropriate on clinical grounds, we will then test for statistical heterogeneity across studies using chi‐squared and the I² statistic (proportion of variation between studies due to heterogeneity).

Assessment of reporting biases

We will use funnel plots as one tool for assessing potential publication bias. We will also consider the number and size of published clinical trials in addition to evidence of smaller treatment effects in unpublished trials located by our search strategy.

Data synthesis

For the main analyses, we will pool outcomes with low or moderate risk of bias by type of intervention (i.e. manual therapy, exercise therapy, combined manual and exercise therapy), migraine frequency (episodic, chronic, mixed), and comparison (i.e. active comparison, placebo/sham, waitlist) using random‐effects models. If outcomes with low or moderate risk of bias are not available, we will pool outcomes with high risk of bias. If I² ≥ 50%, (Higgins 2002) we will acknowledge the difficulty of making inference from pooled estimates and emphasize individual trial results using best‐evidence synthesis methodology. We will assess the quality of the body of the evidence and synthesize the findings of multiple studies using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach (Higgins 2011). We will use the GRADE approach for all outcomes, independent of the decision to pool trials for meta‐analysis. Domains that may decrease the quality of the evidence are:

1. study design;

2. risk of bias;

3. consistency of results;

4. directness (generalizability);

5. precision (sufficient data) and

6. publication bias.

Domains that may increase the quality of the evidence are:

• large magnitude of effect;

• all residual confounding would have reduced the observed effect (true effect underestimated); and

• a dose‐response gradient is evident.

High quality evidence is defined as outcomes from RCTs with low risk of bias that provide consistent, direct, and precise results for the outcome. The quality of the evidence will be reduced by one level for each of the six domains not met or increased by one level for each of three factors. If only studies with high risk of bias are present for a given outcome, the quality of evidence will decrease by two levels for the risk of bias domain. We will assess the level of quality of evidence as follows.

• High quality evidence: Further research is very unlikely to change our confidence in the estimate of effect. There are consistent findings among 75% of RCTs with low risk of bias that are generalizable to the population in question. There are sufficient data, with narrow confidence intervals. There are no known or suspected reporting biases (All of the domains are met).

• Moderate quality evidence: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate (One of the domains is not met).

• Low quality evidence: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate (Two of the domains are not met or only high risk of bias studies are included).

• Very low quality evidence: We are very uncertain about the estimate (Three of the domains are not met).

We also will consider adverse events and costs to place the results into a larger clinical context.

Subgroup analysis and investigation of heterogeneity

Subgroup analyses are planned to assess the influence of type of manual therapy (manipulation, mobilization, massage, mixed), type of exercise therapy (strengthening, stretching, motor control, mixed), and type of migraine (migraine without aura and migraine with aura) on the overall results. We will emphasize the subgroup analyses in the narrative because of their different interpretations.

Sensitivity analysis

We will include outcomes with a high risk of bias in the main analyses as a sensitivity analysis. In addition, we will reclassify outcomes originally rated as low risk of bias, but containing domains rated as unclear, as moderate risk of bias. Data synthesis will then be repeated and the new quality of evidence ratings will be compared with the original ones.

'Summary of findings' table

We will present results for all outcomes using 'Summary of findings' tables from the GRADE system. We will report the number of studies and participants addressing each outcome, the magnitude of treatment effect, the overall quality, and reasons for up or down‐grading the evidence.

Appendices

Appendix 1. MEDLINE (Ovid) search strategy

1   exp Headache Disorders/

2   Headache/

3   (migrain* or headache* or cephalgi* or cephalalgi*).mp.

4   1 or 2 or 3

5   exp Exercise/

6   exp Physical Therapy Modalities/

7   exp Physical Medicine/

8   Osteopathic Medicine/

9   Chiropractic/

10 (manual* adj5 (treat* or therap*)).mp.

11 ((spine or spinal) adj5 (manipulat* or mobili*)).mp.

12 (trigger point adj5 therap*).mp.

13 (exercis* or strength* or aerobic* or yoga or pilates or tai chi or tai ji or stretch* or danc*).mp.

14 (massag* or reflexology or physiotherap* or physical therap* or acupressure or osteopath* or chiropract* or shiatsu or kinesiology or ((cranio sacral or craniosacral) and therap*)).mp.

15 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14

16 randomized controlled trial.pt.

17 controlled clinical trial.pt.

18 randomized.ab.

19 placebo.ab.

20 drug therapy.fs.

21 randomly.ab.

22 trial.ab.

23 groups.ab.

24 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23

25 exp animals/ not humans.sh.

26 24 not 25

27 4 and 15 and 26

key:

mp=protocol supplementary concept, rare disease supplementary concept, title, original title,abstract, name of substance word, subject heading word, unique identifier

pt=publication type

ab=abstract

sh=subject heading

ti=title

 

Appendix 2. Operational criteria for risk of bias assessment

RANDOM SEQUENCE GENERATION Selection bias (biased allocation to interventions) due to inadequate generation of a randomized sequence.
Criteria for a judgement of ‘Low risk’ of bias.	The investigators describe a random component in the sequence generation process such as: Referring to a random number table; Using a computer random number generator; Coin tossing; Shuffling cards or envelopes; Throwing dice; Drawing of lots; Minimization*. *Minimization may be implemented without a random element, and this is considered to be equivalent to being random.
Criteria for the judgement of ‘High risk’ of bias.	The investigators describe a non‐random component in the sequence generation process. Usually, the description would involve some systematic, non‐random approach, for example: Sequence generated by odd or even date of birth; Sequence generated by some rule based on date (or day) of admission; Sequence generated by some rule based on hospital or clinic record number. Other non‐random approaches happen much less frequently than the systematic approaches mentioned above and tend to be obvious. They usually involve judgement or some method of non‐random categorization of participants, for example: Allocation by judgement of the clinician; Allocation by preference of the participant; Allocation based on the results of a laboratory test or a series of tests; Allocation by availability of the intervention.
Criteria for the judgement of ‘Unclear risk’ of bias.	Insufficient information about the sequence generation process to permit judgement of ‘Low risk’ or ‘High risk’.
ALLOCATION CONCEALMENT Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment.
Criteria for a judgement of ‘Low risk’ of bias.	Participants and investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: Central allocation (including telephone, web‐based and pharmacy‐controlled randomization); Sequentially numbered drug containers of identical appearance; Sequentially numbered, opaque, sealed envelopes.
Criteria for the judgement of ‘High risk’ of bias.	Participants or investigators enrolling participants could possibly foresee assignments and thus introduce selection bias, such as allocation based on: Using an open random allocation schedule (e.g., a list of random numbers); Assignment envelopes were used without appropriate safeguards (e.g., if envelopes were unsealed or non­opaque or not sequentially numbered); Alternation or rotation; Date of birth; Case record number; Any other explicitly unconcealed procedure.
Criteria for the judgement of ‘Unclear risk’ of bias.	Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’. This is usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite judgement – for example if the use of assignment envelopes is described, but it remains unclear whether envelopes were sequentially numbered, opaque and sealed.
BLINDING OF PARTICIPANTS AND PERSONNEL Performance bias due to knowledge of the allocated interventions by participants and personnel during the study.
Criteria for a judgement of ‘Low risk’ of bias.	Any one of the following: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
Criteria for the judgement of ‘High risk’ of bias.	Any one of the following: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
Criteria for the judgement of ‘Unclear risk’ of bias.	Any one of the following: Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’; The study did not address this outcome.
BLINDING OF OUTCOME ASSESSMENT Detection bias due to knowledge of the allocated interventions by outcome assessors.
Criteria for a judgement of ‘Low risk’ of bias.	Any one of the following: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; Blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
Criteria for the judgement of ‘High risk’ of bias.	Any one of the following: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; Blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
Criteria for the judgement of ‘Unclear risk’ of bias.	Any one of the following: Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’; The study did not address this outcome.
INCOMPLETE OUTCOME DATA Attrition bias due to amount, nature or handling of incomplete outcome data.
Criteria for a judgement of ‘Low risk’ of bias.	Any one of the following: No missing outcome data; Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; For continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; Missing data have been imputed using appropriate methods.
Criteria for the judgement of ‘High risk’ of bias.	Any one of the following: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; For continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘As‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomization; Potentially inappropriate application of simple imputation.
Criteria for the judgement of ‘Unclear risk’ of bias.	Any one of the following: Insufficient reporting of attrition/exclusions to permit judgement of ‘Low risk’ or ‘High risk’ (e.g., number randomized not stated, no reasons for missing data provided); The study did not address this outcome.
SELECTIVE REPORTING Reporting bias due to selective outcome reporting.
Criteria for a judgement of ‘Low risk’ of bias.	Any of the following: The study protocol is available and all of the study’s pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way; The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).
Criteria for the judgement of ‘High risk’ of bias.	Any one of the following: Not all of the study’s pre‐specified primary outcomes have been reported; One or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g., subscales) that were not pre‐specified; One or more reported primary outcomes were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis; The study report fails to include results for a key outcome that would be expected to have been reported for such a study.
Criteria for the judgement of ‘Unclear risk’ of bias.	Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’. It is likely that the majority of studies will fall into this category.
OTHER BIAS Bias due to problems not covered elsewhere in the table.
Criteria for a judgement of ‘Low risk’ of bias.	The study appears to be free of other sources of bias.
Criteria for the judgement of ‘High risk’ of bias.	There is at least one important risk of bias. For example, the study: Had a potential source of bias related to the specific study design used; or Has been claimed to have been fraudulent; or Had some other problem.
Criteria for the judgement of ‘Unclear risk’ of bias.	There may be a risk of bias, but there is either: Insufficient information to assess whether an important risk of bias exists; or Insufficient rationale or evidence that an identified problem will introduce bias.

What's new

Date	Event	Description
18 July 2017	Amended	See Published notes.

Contributions of authors

Gert Bronfort registered the title, drafted the protocol, will develop the search strategy, search for studies, select studies for inclusion, provide clinical guidance, complete and interpret the analysis, draft and finalize the review.

Roni Evans will select studies for inclusion, draft and finalize the review.

Charlie Goldsmith will provide methodological and statistical guidance, complete and interpret the analysis.

Mitchell Haas registered the title, drafted the protocol, will develop the search strategy, search for studies, select studies for inclusion, provide clinical guidance, complete and interpret the analysis, draft and finalize the review.

Brent Leininger registered the title, drafted the protocol, will search for and obtain copies of studies, extract and enter data into Review Manager, draft and finalize the review.

Morris Levin will provide clinical guidance, complete and interpret the analysis, draft and finalize the review

John Schmitt will extract data and provide clinical guidance

Kristine Westrom will participate in drafting and finalizing the review

All authors contributed to and approve the version of the protocol. Gert Bronfort, Mitchell Haas, Roni Evans and John Schmitt will be responsible for updating the review.

Sources of support

Internal sources

• Center for Spirituality & Healing, University of Minnesota, USA.

  Provided salary support for Gert Bronfort and Roni Evans

• Simon Fraser University, Canada.

  Provided salary support for Charles Goldsmith

• University of Western States, USA.

  Provided salary support for Mitchell Haas

• UCSF School of Medicine, USA.

  Provided salary support for Morris Levin

• Doctor of Physical Therapy Program, St Catherine's University, USA.

  Provided salary support for John Schmitt

External sources

• National Center for Complementary and Integrative Health, National Institute of Health, USA.

  Provided salary support for Brent Leininger through a post‐doctoral fellowship training grant (#F32AT007507). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Declarations of interest

Four authors are researchers with chiropractic training, one is a physical therapy researcher, one is a statistician and two are medical doctors with research background. All members may have a potential special professional interest in the effectiveness of these interventions.

Gert Bronfort declares no financial conflicts of interest.

Roni Evans declares no financial conflicts of interest.

Mitchell Haas declares no financial conflicts of interest.

Charlie Goldsmith declares no financial conflicts of interest.

Brent Leininger declares no financial conflicts of interest.

Morris Levin declares no financial conflicts of interest. ML has received small honoraria for consulting with Depomed and Allergan who produce medications for migraine headache and related conditions. These companies did not fund this review.

John Schmitt declares no financial conflicts of interest.

Kristine Westrom declares no financial conflicts of interest.

Review authors who have been authors of clinical trials that may be included in the review will not be involved in decisions regarding the inclusion or risk of bias assessment of such trials to minimize potential personal conflicts of interest.

Notes

At July 2017, this protocol has been withdrawn. It was part of a series of three reviews (intended to update and replace the original review (Bronfort 2014)), but was not able to be completed within the available editorial resource.

Withdrawn from publication for reasons stated in the review