Non-Pharmacological Interventions For Chronic Pain in Multiple Sclerosis

Cochrane Database of Systematic Reviews
Non-pharmacological interventions for chronic pain in

multiple sclerosis (Review)
Amatya B, Young J, Khan F
Amatya B, Young J, Khan F.

Non-pharmacological interventions for chronic pain in multiple sclerosis.
Cochrane Database of Systematic Reviews 2018, Issue 12. Art. No.: CD012622.
DOI: 10.1002/14651858.CD012622.pub2.
www.cochranelibrary.com
Non-pharmacological interventions for chronic pain in multiple sclerosis (Review)

Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 3
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . 16
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 57
Non-pharmacological interventions for chronic pain in multiple sclerosis (Review) i

[Intervention Review]
Non-pharmacological interventions for chronic pain in

multiple sclerosis
Bhasker Amatya1 , Jamie Young2 , Fary Khan1

1 Departmentof Rehabilitation Medicine, Royal Melbourne Hospital, Royal Park Campus, Melbourne, Australia. 2 Rehabilitation
Medicine, Melbourne Health, Melbourne, Australia
Contact address: Bhasker Amatya, Department of Rehabilitation Medicine, Royal Melbourne Hospital, Royal Park Campus, Poplar
Road, Parkville, Melbourne, Victoria, 3052, Australia. [email protected].
Editorial group: Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group.
Publication status and date: New, published in Issue 12, 2018.
Citation: Amatya B, Young J, Khan F. Non-pharmacological interventions for chronic pain in multiple sclerosis. Cochrane Database
of Systematic Reviews 2018, Issue 12. Art. No.: CD012622. DOI: 10.1002/14651858.CD012622.pub2.
ABSTRACT
Background
Chronic pain is common and significantly impacts on the lives of persons with multiple sclerosis (pwMS). Various types of non-
pharmacological interventions are widely used, both in hospital and ambulatory/mobility settings to improve pain control in pwMS,
but the effectiveness and safety of many non-pharmacological modalities is still unknown.
Objectives
This review aimed to investigate the effectiveness and safety of non-pharmacological therapies for the management of chronic pain in
pwMS. Specific questions to be addressed by this review include the following.
Are non-pharmacological interventions (unidisciplinary and/or multidisciplinary rehabilitation) effective in reducing chronic pain in
pwMS?
What type of non-pharmacological interventions (unidisciplinary and/or multidisciplinary rehabilitation) are effective (least and most
effective) and in what setting, in reducing chronic pain in pwMS?
Search methods
A literature search was performed using the specialised register of the Cochrane MS and Rare Diseases of the Central Nervous
System Review Group, using the Cochrane MS Group Trials Register which contains CENTRAL, MEDLINE, Embase, CINAHL,
LILACUS, Clinical trials.gov and the World Health Organization International Clinical Trials Registry Platform on 10 December
2017. Handsearching of relevant journals and screening of reference lists of relevant studies was carried out.
Selection criteria
All published randomised controlled trials (RCTs)and cross-over studies that compared non-pharmacological therapies with a control
intervention for managing chronic pain in pwMS were included. Clinical controlled trials (CCTs) were eligible for inclusion.
Data collection and analysis
All three review authors independently selected studies, extracted data and assessed the methodological quality of the studies using the
Grades of Recommendation, Assessment, Development and Evaluation (GRADE) tool for best-evidence synthesis. Pooling data for
meta-analysis was not possible due to methodological, clinical and statistically heterogeneity of the included studies.
Non-pharmacological interventions for chronic pain in multiple sclerosis (Review) 1
Main results
Overall, 10 RCTs with 565 participants which investigated different non-pharmacological interventions for the management of chronic
pain in MS fulfilled the review inclusion criteria. The non-pharmacological interventions evaluated included: transcutaneous electrical
nerve stimulation (TENS), psychotherapy (telephone self-management, hypnosis and electroencephalogram (EEG) biofeedback),
transcranial random noise stimulation (tRNS), transcranial direct stimulation (tDCS), hydrotherapy (Ai Chi) and reflexology.
There is very low-level evidence for the use of non-pharmacological interventions for chronic pain such as TENS, Ai Chi, tDCS, tRNS,
telephone-delivered self-management program, EEG biofeedback and reflexology in pain intensity in pwMS. Although there were
improved changes in pain scores and secondary outcomes (such as fatigue, psychological symptoms, spasm in some interventions),
these were limited by methodological biases within the studies.
Authors’ conclusions
Despite the use of a wide range of non-pharmacological interventions for the treatment of chronic pain in pwMS, the evidence for
these interventions is still limited or insufficient, or both. More studies with robust methodology and greater numbers of participants
are needed to justify the effect of these interventions for the management of chronic pain in pwMS.
PLAIN LANGUAGE SUMMARY

[Non-pharmacological interventions for chronic pain in multiple sclerosis]
Review Question
Do non-medication treatments improve chronic pain in multiple sclerosis (MS) in comparison to inactive treatment?
Background
Chronic pain in people with MS (pwMS) is common, and treatment with medications can be associated with and limited by side
effects such as confusion, falls, dizziness and drowsiness. Many non-medication treatments are used to treat chronic pain in pwMS,
which include exercise, psychology, electrical stimulation therapy, reflexology and others.
Search Date
We included all randomised clinical trials (clinical studies where people are randomly put into one of two or more intervention groups),
which were published up to December 2017.
Study Characteristics
Overall, we found 10 studies evaluating different non-medication treatments to treat chronic pain in persons with MS. The treatments
evaluated included: transcutaneous electrical nerve stimulation, transcranial direct stimulation, transcranial random noise stimulation,
reflexology, psychotherapy and hydrotherapy. These studies included 565 participants and used a range of different methods to measure
pain and other outcomes. Comparison groups also varied.
Key Results
Results from these studies show a very low level of evidence for the use of any non-medication treatments for chronic pain in persons
with MS.
Quality of Evidence
We assessed the overall quality of the studies as very low, as many studies included only small numbers of participants and had other
methodological issues. More research with good methodological quality and greater number of participants are needed to determine
the effectiveness of such treatments.

Non-pharmacological interventions for chronic pain in multiple sclerosis (Review) S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Transcutaneous electrical nerve stimulation (TENS) compared to sham for chronic back pain in M S
Patient or population: chronic back pain in M S

Setting: participants f rom M ultiple Sclerosis Society in Northern Ireland
Intervention: TENS
Comparison: sham
Outcomes Impact of participants Certainty of the evidence

(studies) (GRADE)
Reduction in pain intensity Decrease in low back pain scores over- 90 ⊕

assessed with: VAS, M PQ tim e f or all groups, however, none (1 RCT) VERY LOW 1,2
reached clinical or statistical signif icance
in VAS scores. No statistically signif icant
changes in M PQ (Warke 2006). VAS m ean
reduction f or TENS low f requency at week
6 was -16.59 (weekly low back pain) and -
19.76 (average low back pain)
Reduction in disability No signif icant changes in disability m ea- 90 ⊕

assessed with: RM DQ, BI sured by RM DQ and BI between treatm ent (1 RCT) VERY LOW1,2
and placebo groups and within-groups
(Warke 2006).
Quality of Life No signif icant dif f erence in quality of lif e 90 ⊕

assessed with: LM SQoLQ, SF-36 m easured by LM SQoLQ or SF-36 between (1 RCT) VERY LOW1,2
treatm ent and placebo groups (Warke
2006).
BI: Barthel Index; M PQ: M cGill Pain Questionnaire; LM SQoLQ: Leeds M ultiple Sclerosis Quality of Lif e Questionnaire; RM DQ: Roland M orris Disability Questionnaire; SF- 36:
Short Form 36; VAS: Visual Analogue Scale
3
GRADE Working Group grades of evidence

High certainty: We are very conf ident that the true ef f ect lies close to that of the estim ate of the ef f ect
M oderate certainty: We are m oderately conf ident in the ef f ect estim ate: The true ef f ect is likely to be close to the estim ate of the ef f ect, but there is a possibility that it is
substantially dif f erent
Low certainty: Our conf idence in the ef f ect estim ate is lim ited: The true ef f ect m ay be substantially dif f erent f rom the estim ate of the ef f ect
Very low certainty: We have very little conf idence in the ef f ect estim ate: The true ef f ect is likely to be substantially dif f erent f rom the estim ate of ef f ect
1
Downgraded two levels due to high risk f or bias (unclear allocation concealm ent)
2
Downgraded two levels due to high risk of bias f or im precision (singular study of sm all sam ple size)
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4
BACKGROUND Pain can be a significant problem for a substantial proportion
of pwMS (Ehde 2005; Khan 2007a). It is estimated that 42%
All technical terms used are listed in a Glossary (Appendix 1). to 90% pwMS experience pain (Clifford 1984; Heckman-Stone
2001; Moulin 1988; Stenager 1991; Vermote 1986), and occurs at
Multiple sclerosis (MS) is a chronic neurological disease charac-
all stages of the disease. MS-related pain can cause both acute and
terised by unpredictable patchy inflammation, scarring and de-
chronic symptoms. It is associated with active inflammation from
myelination of the central nervous system (CNS). Despite ad-
the MS process itself (central neuropathic pain such as trigemi-
vances in MS management, it remains one of the most common
nal neuropathic pain) and from MS-related complications (tonic
causes of neurological disability in young adults, affecting 1.3 mil-
spasms, headaches and musculoskeletal problems such as posture
lion people worldwide (WHO 2008) and approximately 20,000
and gait anomalies) (Khan 2011). Pain is reported as one of the
persons in Australia (MS Society 2011). The median estimated
most severe symptoms in 8% to 32% of pwMS (Albert 1969;
incidence of MS globally is 2.5 per 100,000 (range of 1.1 to 4)
Shibasaki 1974; Stenager 1991) and it often co-exists as a mix of
(WHO 2008), while the prevalence rate is about 30 per 100,000
acute, paroxysmal and chronic pain in the same or various parts
population (range 5 to 80) (Trisolini 2010; WHO 2008). It is
of the body (Foley 2013; Von Korff 1992).
more common in women (3:1 ratio) and patterns of MS presenta-
Based on the underlying pathophysiological mechanism, MS-re-
tion can vary significantly between individuals (Compston 1998;
lated pain can be classified into 5 categories (Truini 2013).
Detels 1978; Hammond 1988). The exact aetiology of MS is still
• Neuropathic pain, defined by the IASP (Merskey 1994) as
unclear, but it is associated with an abnormal immune response
pain arising directly from a lesion or disease affecting the
within the CNS, possibly due to an infectious agent (Kurtzke
somatosensory system (Treede 2008), which can consist of
1983). Genetic risk has also been shown in recent literature, indi-
persistent extremity pain and dysaesthesia, trigeminal
cating an association between HLA-DRB1 and HLA-DR4 genes
neuropathic pain, and Lhermitte’s phenomenon (defined as a
and MS susceptibility (O’Gormann 2012). MS is associated with
transient sensation related to neck movements felt in the back of
long-term physical, cognitive and behavioural disabilities, restric-
the neck, lower back and other parts of the body) (Al-Araji
tions in participation, medical complications, and symptoms in-
2005).
cluding pain (Khan 2007b; Khan 2013).
• Nociceptive pain, either inflammatory or non-inflammatory,
includes musculoskeletal and low back pain that may be posture-
related, optic neuritis (Truini 2013), headaches and treatment-
Description of the condition induced pain.
• Psychogenic pain is difficult to define and refers to
According to the International Association of the Study of Pain
somatoform pain associated with psychiatric conditions such as
(IASP), chronic pain is defined as “pain presenting continuously or
depression and anxiety or pain behaviours that have evolved in
intermittently for at least three months past the normal time of heal-
patients with chronic refractory pain.
ing” (Merskey 1994). Chronic pain impacts on activities of daily
• Idiopathic pain includes conditions which are either poorly
living, relationships, and social roles (Archibald 1994; Ehde 2003;
understood or controversial such as fibromyalgia, interstitial
Khan 2007a; Svendson 2003; Warnell 1991), interferes with work
cystitis and atypical facial pain.
(Archibald 1994), and has been associated with increased psycho-
• Mixed pain encompasses a heterogeneous group of pain with
logical impairment, such as depression (Ehde 2003). Many psy-
different pathophysiological mechanisms caused by MS (such as
chosocial factors influence adjustment to chronic pain, includ-
painful tonic spasms which may involve unilateral, bilateral or
ing pain-related beliefs, coping behaviours, family members’ re-
stereotyped involuntary muscle spasms and spasticity pain).
sponses to pain behaviours (Fordyce 1973), psychological distress,
and pain-related disability (Jensen 1999). Chronic pain is asso-
ciated with poorer general health, increased fatigue, and higher
rates of healthcare utilisation (Blyth 2003; Ehde 2003; Ma 2014;
Description of the intervention
Sullivan 1992; Vickrey 1995;). It is a significant health problem, In general, pain in MS is treated with pharmacological agents
impacting working-age populations and causing social disadvan- (Cutter 2000; Rog 2005; Rossi 2009; Shakespeare 2003) and non-
tage (Blyth 2003; Shahrbanian 2013), with an estimated cost of pharmacological modalities, or a combination of both (Saifuddin
approximately $34 billion per annum in Australia alone (Blyth 2014). For the purpose of this review, non-pharmacological ther-
2001). apies or interventions refer to treatments and management strategies
In persons with MS (pwMS), symptoms such as headache and that do not involve the use of medications or surgery (Amatya 2013;
neuropathic extremity pain, back pain, painful spasms and Lher- Boldt 2011). A wide range of non-pharmacological interventions
mitte’s phenomenon are common and trigeminal neuropathic pain have been trialled for the management of pain in pwMS. Previous
is least common. However, there is no confirmed prevalence and/ studies (Heckman-Stone 2001; Khan 2007a; Khan 2013) have
or incidence rate of these symptoms in the literature. found that MS patients in the community setting frequently use

a wide variety of non-pharmacological techniques, which include mobility settings, to improve pain control, coping ability, daily
passive strategies such as transcutaneous electrical nerve stimula- function and QoL in pwMS. Chronic pain is found to be amenable
tion (TENS), heat and/or cold therapy, supportive braces, alter- to multidisciplinary rehabilitation management (Finlayson 2011;
native therapies; and active strategies such as exercise, biofeed- Karjalainen 2003; Khan 2007b; Kraft 2005; Saifuddin 2014). Psy-
back, relaxation, distraction, and psychosocial interventions (Khan chological interventions have shown potential beneficial impact on
2007a; Khan 2013). The availability of a variety of therapeutic pwMS, including the management of symptoms such as pain and
techniques was postulated to empower patients with greater con- fatigue (Thomas 2006). Further, TENS is commonly trialled for
trol of their pain management and possibly allow more optimal chronic low back pain in pwMS and hypoalgesic effects (Al Smadi
adaptation to a progressive condition. 2003). Similarly, anodal transcranial Direct Current Stimulation
(tDCS) has demonstrated effectiveness in reducing central chronic
pain in the MS population (Mori 2010). To our knowledge, there
How the intervention might work is only one published systematic review on non-pharmacologi-
cal management in pwMS (Jawahar 2014), which excluded non-
The underlying mechanisms of pain in MS are unclear and have spastic and non-trigeminal pain. This review identified the main
been linked with the differentiation and disinhibition of central categories of non-pharmacological interventions, which included
and peripheral pathways, CNS lesions causing hyperexcitability, education, electrical and physical therapy. The reviewers found
and increased neuronal (nerve cell) activity at the site of the lesion that low-frequency TENS had the greatest reduction in pain scores
in the spinal cord (Beric 1998; Boivie 1999; Hans 2003; Lalkhen (Jawahar 2014). This systematic review did have several limita-
2012). Chronic pain may develop and evolve as a maladaptive re- tions, including inclusion of non-randomised clinical trials and
sponse involving neuronal pathways that are affected by internal pilot studies, and exclusion of various non-pharmacological in-
and environmental influences in a complex interplay that is then terventions, such acupuncture, massage therapy, thermotherapy,
perceived in a highly subjective fashion by each individual. It can electrical therapy such as transmagnetic stimulation (TMS) and
arise both centrally and peripherally, and may be triggered by ei- tDCS. An updated systematic evaluation of the existing evidence
ther a noxious or a non-noxious stimulus or can also occur spon- is therefore needed to determine the effectiveness and safety of
taneously in the absence of any definable trigger (Boivie 1999; all non-pharmacological modalities to provide treating clinicians
Jensen 1994; Jensen 1999;). Due to this heterogeneity of chronic clear guidance for clinical decision-making for appropriate pain
pain aetiology amongst pwMS, modalities that act at different sites management in pwMS.
along the pain processing pathway may have variable degrees of
effectiveness (Khan 2011; Lalkhen 2012).
Although the exact role of physiological deconditioning in no-
ciceptive input or perceived pain is not well defined, it is clear OBJECTIVES
that improvement in overall physical function is linked with im-
provement in psychosocial function and mood (Simmonds 1996), This review aimed to investigate the effectiveness and safety of
which in turn influences levels of pain. There is evidence that non-pharmacological therapies for the management of chronic
motor control and proprioceptive efficiency are altered, balance pain in persons with multiple sclerosis (pwMS).
is compromised, and reaction times are slower in persons with Specific questions to be addressed by this review include the fol-
pain (Harding 1998). TENS and acupuncture attempt to mod- lowing.
ulate pain from the periphery, whilst dorsal column stimulation
intercepts the nociceptive signal at the level of the spinal cord. • Are non-pharmacological interventions (unidisciplinary or
Cognitive behavioural therapy and other psychotherapies, on the multidisciplinary, or both, rehabilitation interventions) effective
other hand, utilise strategies that modify perception and cognition in reducing chronic pain in pwMS?
to enact a positive change in behaviour and mood.
• What type of non-pharmacological interventions
(unidisciplinary or multidisciplinary, or both, rehabilitation
interventions) are effective (least and most effective) and in what
Why it is important to do this review setting, in reducing chronic pain in pwMS?
Pain is prevalent in pwMS and tends to increase over time, due to
the disease process itself and from MS-related complications, and is
associated with a great interference with pwMS’ daily life activities METHODS
(Khan 2013). Several studies have demonstrated that those with
higher pain grades reported more disability and healthcare visits,
and lower quality of life (QoL) (Khan 2007a). Non-pharmacolog- Criteria for considering studies for this review
ical therapies are widely used, both in hospital and ambulatory/

Types of studies Diverse outcomes were expected, given the varied presentations
All published randomised controlled trials (RCTs), including of pain-related problems and goals of treatment related to pain
cross-over studies that compared non-pharmacological interven- severity in MS.
tions with no treatment, sham and usual care, for managing
chronic pain in pwMS were included. Clinical controlled trials Primary outcomes
(CCTs) were eligible for inclusion, but none were identified. We
The primary outcome determined whether the intervention pro-
included only trials with a full journal publication, with a mini-
duces reduction in pain measured by validated measurers, such
mum treatment period of two weeks or more, with greater atten-
as a visual analogue scale (VAS) or numerical rating scale (NRS)
tion given to studies with a duration of eight weeks or greater. We
(Jensen 2001), Likert scale such as the Patient’s Global Impression
excluded studies of experimental pain, observational studies, case
of Change (PGIC, Hurst 2004), or Clinical Global Impression of
reports, and clinical observations.
Change (CGIC, Zaider 2003), or specific pain scales such as the
McGill Pain Questionnaire (MPQ, Melzack 1975), Short Form
Types of participants McGill Pain Questionnaire (SFMPQ, Melzack 1987), or Brief
Pain Inventory (BPI, Cleeland 1989), and others (subjective or
We included trials if the study population had a confirmed di- objective). We used the Initiative on Methods, Measurement, and
agnosis of MS based on standard criteria (McDonald 2001) and Pain Assessment in Clinical Trials (IMMPACT) (Dworkin 2008)
participants were aged 18 years and older with chronic pain. All criteria, defined as:
studies with participants with ’chronic pain’ or participants suffer- • at least 30% pain relief over baseline (moderate);
ing from pain longer than three months were included, irrespec- • at least 50% pain relief over baseline (substantial);
tive of the use of varying definitions for chronicity of pain. We in- • much improved on Patient Global Impression of Change
cluded studies that recruited participants with the minimum levels Scale (PGIC; moderate);
of pain on visual analogue scale (VAS) of 3/10. Studies including • very much improved on PGIC (substantial).
participants with other diagnoses were excluded unless individual
data for the pwMS could be obtained either from the published
results or through contact with authors. Secondary outcomes
Due to the multidimensional model of pain, we included sec-
ondary outcomes determining whether the change in pain by the
Types of interventions intervention affects the other specific outcome(s) measured by val-
All non-pharmacological interventions to manage chronic pain in idated tools, which included:
pwMS delivered in any settings (inpatient, outpatient, commu- • other symptoms or impairments, such as spasticity, fatigue,
nity, or home-based) were included. e.g. Multiple Sclerosis Spasticity Scale (MSSS-88, Hobart 2006);
• Unidisciplinary: physiotherapy, occupational therapy, and Modified Ashworth Scale (MAS, Ansari 2009); Fatigue Impacts
individual treatment modalities, thermotherapy such as heat and Scale (FIS, Fisk 1994); Modified Fatigue Impact Scale
cold application, psychological and behavioural therapies (MFIS,Larson 2013); Fatigue Severity Score (FSS,Krupp 1989);
including cognitive behavioural therapy and hypnosis, relaxation • functional activity, e.g. Functional Independence Measure
training, yoga, massage, chiropractic manipulation, acupuncture, (FIM, Granger 1998); Barthel index (BI, Mahoney 1965);
other alternative and complementary therapies, TMS, TENS, Rowland Morris Disability Questionnaire (RMDQ, Stevens
tDCS, dorsal root entry zone (DREZ) lesioning and others. 2016);
• Multidisciplinary rehabilitation programmes, defined as • psychosocial outcomes, e.g. Beck Depression Inventory
any co-ordinated therapy programme delivered by two or more (BDI, Beck 1961); Depression, Stress and Anxiety Scale (DASS,
disciplines (occupational therapy, physiotherapy, exercise Lovibond 1995); Hospital Anxiety Depression Scale (HADS,
physiology, orthotics, other allied health and nursing) in Snaith 2003); Patient Health Questionnaire 9 (PHQ-9, Kroenke
conjunction with medical input (neurologist or rehabilitation 2001);
medicine physician) that aims to achieve patient-centred goals • restriction in participation/impact on carers, e.g. Caregiver
related to reducing chronic pain. Strain Index (CSI, Robinson 1983);
• vocational outcomes, e.g. Work Instability Scale (WIS,
Control interventions that are likely used for comparison with the Gilworth 2003);
above mentioned interventions include no treatment, sham and • quality of life, e.g. Multiple Sclerosis Quality of Life
usual care. (MSQOL54, Vickrey 1995); Short Form Health Survey (SF-36,
Ware 2000); Leeds Multiple Sclerosis Quality of Life
(LMSQOL, Ensari 2016); Multiple Sclerosis Impact Scale
Types of outcome measures
(MSIS-29, Hobart 2001);

• withdrawals, due to lack of efficacy; Searching other resources
• outcomes that reflect utilisation of healthcare resources and We conducted an expanded search to identify articles potentially
associated cost (reported, where possible); missed through the database searches and articles from ‘grey liter-
• participants experiencing any adverse effects; ature’. These were:
• participants experiencing any serious adverse effects, which • related articles feature (via PubMed);
include any untoward medical occurrence or effect that results in • ProQuest Dissertations and Theses;
death, is life-threatening, requires hospitalisation or prolongation • Web of Science for citation of key authors;
of existing hospital stay, results in persistent or significant • SIGLE (System for Information on Grey Literature in
disability or incapacity, congenital anomaly or birth defect, that Europe); and
may jeopardise the person or may require intervention. • contact authors and researchers active in this field.
Timing of outcome measures

Data collection and analysis
We divided outcome time points into short term (up to three
months) and long term (greater than three months) from the start
of the intervention. Selection of studies
Two review authors (BA, JY) independently screened and short-
listed all abstracts and titles of studies identified by the search strat-
Search methods for identification of studies egy for appropriateness based on the selection criteria. The same
review authors (BA, JY) independently reviewed the abstract of
We considered articles in all languages with a view to translation,
each study from the short list of potentially appropriate studies
if necessary.
for inclusion or exclusion. The full text of the article was obtained
to determine if the study met the inclusion/exclusion criteria. Ar-
ticles assessed in full text that did not meet the inclusion crite-
Electronic searches
ria were listed in the Characteristics of excluded studies with the
The Information Specialist searched (up to 10 December 2017) reasons for exclusion. If no consensus was met about the possible
the Trials Register of the Cochrane MS and Rare Diseases of the inclusion/exclusion of any individual study, a final consensus de-
CNS Group, which, among other sources, contains trials from: cision was made by discussion with the third author (FK). Review
• Cochrane Central Register of Controlled Trials authors were not masked to the name(s) of the author(s), insti-
(CENTRAL) (2017, issue 12); tution(s) or publication source at any level of the review. Further
• MEDLINE (PubMed) (1966 to 10 December 2017); information was sought about the method of randomisation and
• Embase (Embase.com) (1974 10 December 2017); other methodological issues, if required. We excluded studies with
• Cumulative Index to Nursing and Allied Health Literature fatal flaws (for instance, withdrawals by more than 40% of the
(CINAHL) (EBSCOhost) (1981 to 10 December 2017); participants, or nearly total non-adherence to the protocol, or very
• Latin American and Caribbean Health Science Information poor or non-adjusted comparability in the baseline criteria).
Database (LILACS) (Bireme) (1982 to 10 December 2017);
• ClinicalTrials.gov (https://clinicaltrials.gov/); and
• World Health Organization ( WHO) International Clinical Data extraction and management
Trials Registry Platform ( http://apps.who.int/trialsearch/). Two review authors (BA, JY) independently extracted the data
from the included trials using a standardised form and entered the
The keywords that were used to search for trials for this review are data into the RevMan software (Review Manager 2014), which
listed in Appendix 2. included:
Information on the Group’s Trials Register and details of search • year of publication, year the study was undertaken, and
strategies used to identify trials can be found in the ’Specialised geographical location of the study;
Register’ section within the Cochrane MS and Rare Diseases of • number of participants included, their age, gender, and type
the Central Nervous System Group’s module. of MS;
In addition we searched the following databases: • information about the type of pain (neuropathic/
• PsycINFO (1980 to 10 December 2017), (Appendix 3); nociceptive) that is targeted by the study intervention;
• Allied and Complementary Medicine Database (AMED) • type of study intervention and treatment duration;
(1985 to 10 December 2017) (Appendix 4); and • information about the control intervention(s);
• MANTIS/Ovid (for most recent data available) (Appendix • duration of the study recruitment and follow-up time;
5). • information about adverse events;

• information about withdrawals; methods as low risk of bias (all of the study’s prespecified
• information whether the study was specifically designed to outcomes and protocol is available), unclear risk (insufficient
measure pain in MS; information) or high risk (not all of the study’s prespecified
• information about study quality; and outcomes is reported).
• measures of treatment effect (outcome measures). • Other bias: we assessed other bias as low risk (free of other
sources of bias), unclear risk (insufficient information) or high
A final check was made by a third review author (FK). To sum- risk (potential source of bias).
marise all data on reduction in pain, we used the benchmarks of
the IMMPACT recommendations for the evaluation of reduction Any disagreements or lack of consensus was resolved by the third
in pain (Dworkin 2008). We summarised all studies that met the review author (FK).
inclusion criteria in the Characteristics of included studies table.
Measures of treatment effect
Assessment of risk of bias in included studies All quantitative data were entered and analysed in the RevMan
software (Review Manager 2014). For each outcome of interest,
Two review authors (BA, JY) independently assessed the method-
summary estimates of treatment effect (with 95% confidence in-
ological quality of the included studies using the ’Risk of bias’
tervals (CIs)) for each comparison were calculated. Where pos-
tool outlined in the Cochrane Handbook for Systematic Reviews of
sible, risk ratios (RRs) with 95% CIs for dichotomous data and
Interventions (Higgins 2011). We assessed the following for each
difference in means or standardised difference in means (SMD)
study:
with 95% CIs for continuous data were calculated. The results
• Random sequence generation (selection bias): we assessed the
of individual studies were discussed and presented in table and
method used to generate the allocation sequence as: low risk of
graphical format, where data aggregation was not possible.
bias (any truly random process, random number table, computer
random generator) and unclear risk of bias (when the method is
not clearly stated). We excluded studies with a non-random Unit of analysis issues
process. The appropriate unit of analysis involved the type, intensity, and
• Allocation concealment (selection bias): we assessed method setting of non-pharmacological interventions. A qualitative anal-
used to conceal the allocation to interventions prior to ysis using the GRADE approach for existing evidence was at-
assignment determines whether the intervention allocation could tempted in any event (Higgins 2011). Trials with multiple ob-
have been foreseen in advance, during recruitment, or changed servations for the same outcome were assessed according to ran-
after assignment. We assessed methods as low risk of bias domisation and types of interventions, and separate analyses based
(telephone or central randomisation; consecutively numbered, on different periods were performed. Studies with parallel groups
sealed, opaque envelopes) or unclear risk of bias (when method is were included, but only data from the first phase of cross-over
not clearly stated). trials were included, due to the potential carry-over effects in the
• Blinding of participants and personnel (performance bias): we second phase.
assessed the methods used to blind study participants, personnel.
We assessed methods as low risk of bias (study states it was
Dealing with missing data
blinded and described the method used to achieve the blinding)
and unclear risk of bias (study stated it was blinded but did not Insufficient data that were not available were reported but not
provide adequate description of how this was achieved). included in the final analysis. We assumed the data were missing
• Blinding of outcome assessment (detection bias): we assessed at random and only available data were analysed.
the methods used to blind the allocated interventions by
outcome assessors.We assessed methods as low risk of bias (study Assessment of heterogeneity
states blinding of outcome assessments ensured) or unclear risk We conducted statistically analysis, as described in the Cochrane
of bias (when method is not clearly stated) and high risk (no Handbook for Systematic Reviews of Interventions (Higgins 2011).
blinding of outcome assessment)
• Incomplete outcome data (attrition bias): we assessed the
methods used to deal with incomplete data as low risk of bias Assessment of reporting biases
(fewer than 10% of participants did not complete the study or Publication bias was minimised by performing comprehensive
used ’baseline observation carried forward’ analysis or both), searches of multiple databases (Egger 1998). Where data were not
unclear risk of bias (used ’last observation carried forward’ reported in full for certain outcomes, we contacted the trial authors
analysis) or high risk of bias (used ’completer’ analysis). for the full data set or the reason for not publishing the data. Where
• Selective reporting (reporting bias): we assessed the methods sufficient studies (at least 10) were identified, we assessed poten-
used to report outcomes and selective reporting. We assessed tial biases of reporting using funnel plots and visual inspection for

asymmetry according to the approach outlined in the Cochrane Interventions (version 5.1.0). We included an overall grading of
Handbook for Systematic Reviews of Interventions (Higgins 2011). the evidence for the following patient-important outcomes:
• reduction in pain intensity;
• reduction in disability;
Data synthesis • improvement in quality of life;
A meta-analysis was not possible due to methodological, clinical • reduction in fatigue;
and statistically heterogeneity of included studies. We would have • reduction in depression and anxiety;
pooled results from clinically similar studies for the meta-analysis, • reduction in pain interference, depression, fatigue;
if sufficient studies were available. • improvement in pain, self efficacy, patient activation,
health-related quality of life, social role satisfaction,
resilience,positive and negative affect.
Subgroup analysis and investigation of heterogeneity
We graded the quality of evidence for each outcome considering
Treatment effects in subgroups of trials were analysed and com-
study limitations, indirectness, inconsistency, imprecision of effect
pared. With data that were available, we performed subgroup anal-
estimates, and risk of reporting bias. According to the software
ysis for the following:
GRADEpro 2008, we assigned four levels of quality of evidence:
• sex (male/female);
high, moderate, low, and very low.
• type of MS (relapsing remitting, progressive);
• Expanded Disability Status Scale (EDSS) (< 6, > 6);
• duration of follow-up of the participants (three months; >
three months);
• type of non-pharmacological intervention (unidisciplinary RESULTS
and/or multidisciplinary rehabilitation); and
• settings (i.e. inpatient, ambulatory care, community).
Description of studies
See: Characteristics of included studies and Characteristics of
Sensitivity analysis
excluded studies
We were unable to perform sensitivity analysis because the findings
from included studies evidence were too small to allow reliable
analysis. Further, we were not able to pool results from chronic Results of the search
pain of different central origins in the primary analyses, due to Electronic and manual searches identified 558 references (MED-
lack of data. LINE =361; Embase = 138; CINAHL = 21; Central = 9; CRD
’Summary of findings’ table database = 4; Handsearch = 7; WHO portal =4; Cinicaltrials.gov =
We presented the main results of the review in ’Summary of find- 14). Of these 30 passed the first screening review and were selected
ings’ (SoF) tables, according to recommendations described in for closer review. In total 10 articles fulfilled the inclusion criteria
Chapter 11 of the Cochrane Handbook for Systematic Reviews of and were included. See Figure 1 for Study flow chart.

Figure 1. Study flow diagram.

• one study (Palm 2016) evaluated tRNS, which used a form
Included studies
of neuromodulation through rapidly changing current
Overall, 10 randomised controlled trials (RCTs) (Ayache 2016; frequencies.
Castro-Sanchez 2012; Ehde 2015; Hughes 2009; Jensen 2009;
Jensen 2016; Mori 2010; Nazari 2016; Palm 2016; Warke 2006
(extension of Warke 2004)) involving 565 participants fulfilled Excluded studies
the inclusion criteria for this review. Two studies were conducted Detailed descriptions of excluded studies with reason for exclu-
in Northern Ireland (Hughes 2009; Warke 2006); three studies sion is provided in Characteristics of excluded studies. Overall, 20
in the USA (Ehde 2015; Jensen 2009; Jensen 2016); two studies studies were excluded (Anninos 2016; Backus 2016; Barlow 2009;
were from France (Ayache 2016; Palm 2016); and one study each Catena 2014; Doulatabad 2012; Hasanpour-Dehkordi 2015;
from Spain (Castro-Sanchez 2012), Italy (Mori 2010) and Iran Hasanpour-Dehkordi 2016; Jensen 2007; Jensen 2011; Marinelli
(Nazari 2016).The included studies evaluated various non-phar- 2015; Mathiowetz 2005; McGuire 2015; Negahban 2013; Oken
macological interventions, which included: 2004; Pilutti 2013; Pozzilli 2002; Seada 2013; Smedal 2011; Storr
• one study (Warke 2006) evaluated the effects of TENS, 2006; Van der Linden 2013). Reasons for exclusion included:
which used alternating currents by cutaneous electrodes 13 studies did not define chronic pain as a criteria (Doulatabad
positioned near the painful area; 2012; Hasanpour-Dehkordi 2015; Hasanpour-Dehkordi 2016;
• two studies (Ayache 2016; Mori 2010) investigated the Marinelli 2015; Mathiowetz 2005; McGuire 2015; Negahban
effects of tDCS, which used a low current directly delivered to 2013; Oken 2004; Pilutti 2013; Pozzilli 2002; Smedal 2011;
the brain for neuromodulation; Storr 2006; Van der Linden 2013), two were abstracts only
• two studies (Hughes 2009; Nazari 2016) investigated the (Catena 2014; Jensen 2007), three were not clinical controlled
effects of reflexology, which involves the massaging of the feet trials (Backus 2016; Jensen 2011; Seada 2013), and two trials did
which corresponds to different parts of the body; not have pain as an outcome (Anninos 2016; Barlow 2009).
• one study (Castro-Sanchez 2012) evaluated hydrotherapy;
• three studies (Ehde 2015; Jensen 2009; Jensen 2016)
evaluated psychotherapy, which used a telephone-based self-
Risk of bias in included studies
management educational program, self-hypnosis and For a summary, please see Risk of bias’ tables in the Characteristics
neurofeedback; of included studies and Figure 2 and Figure 3.

Figure 2. ’Risk of bias’ summary: review authors’ judgements about each risk of bias item for each included
study.

Figure 3. ’Risk of bias’ graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.
Allocation
Blinding of participants and personnel (detection bias)
Random sequence generation Two studies were assessed as unclear risk for blinding of outcome
Nine studies were considered to have a low risk of bias for this assessment as blinding was not described (Nazari 2016; Palm
domain (Ayache 2016; Castro-Sanchez 2012; Ehde 2015; Hughes 2016) and two studies were assessed as high risk (Ehde 2015;
2009; Jensen 2009; Jensen 2016; Mori 2010; Nazari 2016; Warke Jensen 2016).
2006). Palm 2016 was considered to have an unclear risk of bias
for this domain as randomisation not discussed.
Allocation concealment
One study (Ehde 2015) was considered to have a low risk of bias for Incomplete outcome data
allocation concealment as the allocation sequence was concealed All studies provided information on participant withdrawals and
from the research assistants who enrolled participants via a limited loss to follow-up. Two studies ( Ehde 2015; Hughes 2009) reported
access database program. The other nine studies were considered loss of participants to follow-up and were assessed as high risk; the
to have an unclear risk of bias for allocation concealment (Ayache remaining studies were considered to be at low risk of bas.
2016; Castro-Sanchez 2012; Hughes 2009; Jensen 2009; Jensen
2016; Mori 2010; Nazari 2016; Palm 2016; Warke 2006).
Selective reporting
Blinding All included studies assessed pre-specified primary and secondary
Blinding of participants and personnel (performance bias) outcomes and were assessed as ’low’ risk.
Blinding of participants for performance bias was assessed as high
risk in two studies (Castro-Sanchez 2012;Jensen 2009), as the
study could not guarantee the study was blinded and no blinding
Other potential sources of bias
reported, respectively. Two studies had an unclear risk of bias (
Jensen 2016; Nazari 2016). The remaining six studies had a low Two studies (Palm 2016; Warke 2006) were assessed as unclear
risk of bias (Ayache 2016; Ehde 2015; Hughes 2009; Mori 2010; risk as funding was received but it was unclear if it had an impact
Palm 2016; Warke 2006). on results.
Effects of interventions nificant pain reduction at week 20 in MPQ and was maintained
up to week 24 (P < 0.021). There were significant decreases in dis-
See: Summary of findings for the main comparison
ability (RMDQ) scores in both groups at week 20. The treatment
Transcutaneous Electrical Nerve Stimulation (TENS) compared
group also showed a significant decrease in spasm VAS score at
to Sham for Chronic Back Pain in Multiple Sclerosis (MS);
week 20 compared to the control group (P = 0.039). Both groups
Summary of findings 2 Ai Chi Exercises compared to Sham
showed a significant reduction in the Multiple sclerosis Impact
for Chronic Musculoskeletal pain in Multiple Sclerosis (MS);
scale 29 (MSIS-29) psychological score at week 20. (Summary of
Summary of findings 3 Transcranial Direct Current Stimulation
findings 2)
(tDCS) compared to Sham for Chronic Neuropathic Pain in
Multiple Sclerosis (MS); Summary of findings 4 Transcranial
Random Noise Stimulation (tRNS)compared to Sham for Transcranial direct stimulation (tDCS)
Chronic Neuropathic Pain in Multiple Sclerosis (MS); Summary
Two studies (Ayache 2016; Mori 2010) evaluated the effectiveness
of findings 5 Telephone-Delivered Education Group compared
of tDCS in pwMS. (Summary of findings 3)
to Sham for Chronic pain in Multiple Sclerosis (MS); Summary
One RCT (Ayache 2016) (N = 16) randomised participants to
of findings 6 Hypnosis compared to relaxation control for
either anodal tDCS (N = 8) or sham (N = 8) groups. The findings
chronic pain in Multiple Sclerosis (MS); Summary of findings 7
showed a statistically significant difference between before and af-
Neurofeedback compared to relaxation control for chronic pain
ter treatment for mean pain VAS scores in the treatment group
in Multiple Sclerosis (MS); Summary of findings 8 Reflexology
(P = 0.024). There were no statistically significant changes in the
compared to Sham for Chronic Pain in Multiple Sclerosis (MS)
sham group. Active stimulation resulted in significant improve-
As aforementioned, the included studies used a wide range of non-
ment in pain ( Brief Pain Inventory (BPI) global score) (P = 0.02),
pharmacological interventions and used various assessments relat-
but no significant effects on severity, or in the sham group. There
ing to pain measures. Key findings based on the interventions eval-
were no significant differences observed through stimulation for
uated and summary of findings are described below and tabulated
both groups for functional and psychological outcomes for MFIS
in ’Summary of Finding’ tables. A meta-analysis was not possible
and HADS.
and narrative descriptions of the findings are presented instead.
In another study (Mori 2010), participants (N = 19) were ran-
domised to anodal tDCS (N = 10) or sham (N = 9) groups. There
Transcutaneous electrical nerve stimulation (TENS) were statistically and clinical significant changes for pain VAS and
MPQ scores in the anodal tDCS group compared to the control
One study (Warke 2006) evaluated the effects of TENS on sham group (P < 0.05). The authors also reported statistically sig-
chronic low back pain in persons with multiple sclerosis (pwMS). nificant changes for the treatment effect over time in quality of life
(Summary of findings for the main comparison) (QoL) for the Multiple Sclerosis Quality of Life-54 (MSQOL54)
In this study, 90 participants were randomised into three groups and the Short Form Mcgill Pain Questionnaire (SFMPQ). There
(N = 30 in each): low-frequency TENS, high-frequency TENS were no statistically significant changes for other psychological
and placebo (sham). There was a decrease in low back pain scores outcomes ( Beck Depression Inventory (BDI) and VAS for anxi-
overtime in all three groups in visual analogue scores (VAS), how- ety) in both groups.
ever, none reached statistical significance. Similarly, no statistically
significant changes in the McGIll Pain Questionnaire (MPQ) was
found in all three groups. All three groups showed improvement Transcranial random noise stimulation (tRNS)
in patient-reported disability scores ( Roland Morris Disability One RCT (N = 16 participants) (Palm 2016) examined the effect
Questionnaire (RMDQ)), however, it was not statistically signifi- of tRNS in comparison with the sham. The authors found no
cant. statistically significant changes for mean pain VAS score before
and after treatment for both tRNS and sham groups. There was
a significant change in BPI in the treatment group but not in
Hydrotherapy
the sham group. Further, there were no statistically significant
One RCT (N = 73 participants) (Castro-Sanchez 2012) evaluated changes for any psychological and functional outcomes ( Hospital
the effectiveness of Ai Chi water-based exercise program compared Anxiety and Depression Scale HADS), Modified Fatigue Impact
to placebo. The participants in the intervention group received Scale (MFIS) scores) in both groups. (Summary of findings 4)
Ai Chi water exercises twice a week for 20 weeks. The authors
reported significant reduction in pain VAS score in the treatment
group immediately after treatment (P = 0.028), which was main- Psychotherapy
tained up to 30 weeks (P = 0.047). There were no statistical signif- Three RCTs (Ehde 2015; Jensen 2009; Jensen 2016) evaluated dif-
icance changes in the control group at any time point. Similarly, ferent forms of psychotherapy. (Summary of findings 5, Summary
compared to the control group, the treatment group showed a sig- of findings 6 and Summary of findings 7)

One RCT (Ehde 2015) (N = 163 participants) compared a tele- in the intervention group with moderate to large effect size.
phone-delivered self-management program with the control group
receiving telephone-delivered educational program. The authors
Reflexology
reported that > 50% reduction in one or more symptoms (fatigue,
pain interference and depression severity) was achieved in 58% Reflexology was evaluated in two studies (Hughes 2009; Nazari
of the intervention group and 46% of the control group. How- 2016). (Summary of findings 8)
ever, this was not statistically significant. There were no clinical One RCT (Hughes 2009) (N = 71 participants) compared re-
significant changes in pain intensity after treatment and at follow- flexology with a control group with sham intervention. The au-
up in both intervention and control group. The authors reported thors found clinical and statistically significant reduction in pain
statistically significant improvements in all secondary outcomes VAS scores at 10 weeks compared to baseline in both groups (P
(fatigue, self-efficacy, pain interference quality of life) for both = 0.0001), which was maintained up to 22 weeks. Both groups
groups, which was maintained up to six- and 12-month follow- demonstrated significant reduction in MPQ pain rating index at
up. week 10. For MPQ pain index there were no changes in the sham
Another RCT (Jensen 2009) evaluating the effectiveness of self- group, but a statistically significant change at week 10 for the re-
hypnosis on pain in pwMS, randomised (N = 22) participants flexology group (P < 0.012). Both groups showed a significant re-
to self-hypnosis (N = 15) and progressive muscle relaxation (N duction in disability score measured by RMDQ at 10 weeks . Fur-
= 7) groups. The authors found statistically and clinically signif- ther, both groups had a similar statistically significant decrease in
icant changes pre- and post- treatment in the hypnosis group in VAS spasm score by the end of the treatment period. Both groups
reduction in daily pain intensity but not in the control group (P showed significant reductions in psychology and physical subscales
< 0.001). There was also statistically significant change pre- to of MSIS at week 10. There was a significant reduction by week
post-treatment in the hypnosis group, but not in the progressive 10 in both groups in fatigue (MFIS, Fatigue Severity Scale (FSS)
relaxation group for pain interference (P < 0.001). scores), with no significant differences between groups. There was
Another RCT (Jensen 2016) randomised (N = 20) participants to a significant reduction in psychological outcomes (BDI scores) by
the EEG biofeedback (N = 10) group or relaxation control group week 10 in both groups. Functional improvements (measured by
(N = 10). Both groups improved in pain scores soon after treatment the Barthel Index (BI)) in both groups remained stable throughout
and at one-month follow-up, however this was not statistically treatment by week 10 .
significant. There was a moderate to large improvement in the Another RCT (Nazari 2016) (N = 75 participants) randomised
neurofeedback group after treatment (effect size, ES = 0.70) and 1 participants to either reflexology, relaxation or control groups.
month after follow-up (ES = 1.04), but effect size of improvement There were statistically and clinical significant differences in pain
was much lower in the control group. There were improvements scores in the reflexology group (P < 0.001) and relaxation group
for other pain scores (BPI, worst pain intensity) and fatigue severity (P = 0.01) pre- and post-treatment, while no significant changes
were found in the control group (P = 0.34).

Non-pharmacological interventions for chronic pain in multiple sclerosis (Review) A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]
Ai Chi exercises compared to sham for chronic musculoskeletal pain in multiple sclerosis
Patient or population: chronic m usculoskeletal pain in people with M S

Setting: participants were recruited f rom M S Association of Alm eria in Spain
Intervention: Ai Chi exercises
Comparison: sham

(studies) (GRADE)
Reduction in pain intensity Signif icant reduction in pain scores m ea- 73 ⊕

assessed with: VAS, M PQ sured by VAS in the treatm ent group im m e- (1 RCT) VERY LOW 1,2
diately af ter treatm ent and no signif icant
change f rom baseline in the control group.
Pain VAS at week 20 was 50% (experim en-
tal) and 23% (control)
Signif icant pain reduction f or M PQ in the
treatm ent group and no signif icant change
f rom baseline in the control group (Castro-
Sanchez 2012).
Reduction in disability Signif icant reduction in disability m ea- 73 ⊕

assessed with: RM DQ sured by RM DQ in intervention and control (1 RCT) VERY LOW 1,2
group at week 20 (Castro-Sanchez 2012).
Quality of Life Both groups showed a signif icant reduc- 73 ⊕

assessed with: M SIS-29 tion in the psychological sub scale of the (1 RCT) VERY LOW 1,2
M FIS at week 20. Treatm ent group showed
signif icant score reduction but the control
group showed no signif icant dif f erence
with baseline score in the physical sub
scale at week 20 (Castro-Sanchez 2012).
17
Reduction in Fatigue Treatm ent group showed a signif icant 73 ⊕

assessed with:M FIS score reduction com pared with baseline (1 RCT) VERY LOW 1,2
at week 20, but no signif icant dif f er-
ence in control group. Treatm ent group
showed a signif icant reduction in cogni-
tive scale com pared with the control group
(Castro-Sanchez 2012).
M FIS: M odif ied Fatigue Im pact Scale; M PQ: M cGill Pain Questionnaire; M SIS- 29: M ultiple Sclerosis Im pact Scale-29; RM DQ: Roland M orris Disability Questionnaire, SF- 36:
Short Form 36; VAS: Visual Analogue Scale

1 Downgraded two levels because the singular study was considered at serious risk of perf orm ance bias ( blinding of
participants and personnel ) and unclear risk of allocation concealm ent
2 Downgraded two levels due to im precision (sm all sam ple size)
18
Transcranial direct current stimulation (tDCS) compared to sham for chronic neuropathic pain in M S
Patient or population: chronic neuropathic pain in M S

Setting: com m unity neurology clinic
Intervention: tDCS
Comparison: sham

(studies) (GRADE)
Reduction in Pain Intensity M ean pain VAS showed signif icant de- 35 ⊕
assessed with: VAS, BPI, M PQ crease af ter active tDCS (m ean baseline (2 RCTs) VERY LOW 1,2
51.2; af ter treatm ent 43.1) but no signif i-
cant change af ter sham (m ean baseline 52.
1; af ter treatm ent 50.3). BPI global score
f or active tDCS resulted in signif icant im -
provem ent on the interf erence sub scale
but no signif icant ef f ects on the severity
sub scale (Ayache 2016).
Signif icant m ain ef f ect of tim e f or de-
creased daily pain VAS (M ori 2010).
Reduction in fatigue There was no signif icant dif f erence in 16 ⊕

assessed with: M FIS f atigue m easured by the M FIS between (1 RCT) VERY LOW 1,2
groups (Ayache 2016).
Reduction in depression and anxiety No signif icant dif f erences in depression 35 ⊕

assessed with: BDI, HADS, VAS f or anxiety and anxiety were observed f or both groups (2 RCTs) VERY LOW 1,2
on HADS (Ayache 2016).
No signif icant changes f or BDI and VAS f or
anxiety with tim e as within subjects and
group of treatm ent as between subjects.
(M ori 2010)
19
Improvement in QoL Signif icant ef f ect of tim e and group x tim e 19 ⊕

assessed with: M SQOL54 interaction f or im proved quality of lif e m ea- (1 RCT) VERY LOW 1,2
sured by the M SQOL54 (M ori 2010).
BDI: Beck Depression Inventory; HADS: Hospital Anxiety and Depression Scale; M PQ: M cGill Pain Questionnaire; M SQOL54: M ultiple Sclerosis Quality of Lif e 54. QoL: Quality
of lif e, VAS; Visual Analogue Scale

1 Downgraded one level f or risk f or bias (the two studies at unclear risk of bias in allocation concealm ent)
2 Downgraded two levels f or high risk f or im precision (sm all sam ple sizes of both studies)
20
Transcranial Random Noise Stimulation (tRNS) compared to sham for chronic neuropathic pain in M S
Patient or population: chronic neuropathic pain in M S

Setting: hospital M S clinics
Intervention: tRNS
Comparison: sham

(studies) (GRADE)
Reduction in pain No statistically signif icant changes f or 16 ⊕

assessed with: VAS, BPI m ean pain VAS treatm ent (m ean VAS be- (1 RCT) VERY LOW 1,2
f ore 50.1; m ean
VAS af ter 47.2) and sham groups (m ean
VAS bef ore: 52.1; m ean VAS af ter:50.3)
No statistical signif icance bef ore and af ter
stim ulation sham and treatm ent f or BPI
(Palm 2016).
Reduction in anxiety and depression No statistical signif icance bef ore and af ter 16 ⊕
assessed with: HADS f or treatm ent and sham f or m ean HADS (1 RCT) VERY LOW 1,2
(Palm 2016).
Reduction in fatigue No statistical signif icance bef ore and af ter 16 ⊕

assessed with: M FIS sham and treatm ent f or m ean total score (1 RCT) VERY LOW 1,2
(Palm 2016).
BPI: Beck Pain Inventory; HADS: Hospital Anxiety and Depression Scale; M FIS: M odif ied Fatigue Im pact Scale; VAS; Visual Analogue Scale

21
1 Downgraded two levels because the singular study was considered at high risk of bias (unclear risk of bias in random isation
sequence generation, allocation concealm ent and blinding of outcom e assessors)
2 Downgraded two levels due to high risk f or im precision (singular study of sm all sam ple size)
22
Telephone- delivered education compared to sham for chronic pain in M S
Patient or population: chronic pain in M S

Setting: participants’ hom e across United States
Intervention: telephone-delivered education group
Comparison: sham

(studies) (GRADE)
Reduction in pain interference, depres- 58% of telephone self -m anagem ent group 163 ⊕
sion,fatigue and 46% of telephone education group had (1 RCT) VERY LOW1,2
assessed with: BPI, PHQ-9, M FIS > 50% reduction in 1 or m ore sym ptom s
(f atigue, pain, depression), but not statis-
tically signif icant (Ehde 2015).
Improvement in pain, self efficacy,pa- Statistically signif icant im provem ents in 163 ⊕
tient activation, health- related quality of all secondary outcom es f or f atigue, pain in- (1 RCT) VERY LOW 1,2
life, social role satisfaction,resilience, terf erence, self ef f icacy and QoLcom pared
positive and negative affect with telephone education group (Ehde
assessed with: Average Pain Intensity, 2015).
UWSES, Patient Activation M easure, M ed-
ical Outcom es Study 8 Item Short Form
Heath Survey, Patient Reported Outcom es
M easurem ent Inf orm ation System Short-
Form ,Connor-Davidson Resilience Scale
BPI: Brief Pain Inventory; M FIS: M odif ied Fatigue Im pact Scale; M PQ: M cGill Pain Questionnaire; PHQ- 9:Patient Health Questionnaire 9; QoL: quality of lif e; UWSES:University
of Washington Self Ef f icacy Scale

23
1 Downgraded two levels due to high risk of bias (the singular study at high risk of bias in blinding of outcom e assessor and
attrition)
2 Downgraded two levels due to high risk of bias f or im precision (sm all sam ple size)
24
Hypnosis compared to relaxation/ control for chronic pain in M S

Setting: M S clinics
Intervention: hypnosis
Comparison: relaxation/ control

(studies) (GRADE)
Reduction in pain intensity Statistically signif icant changes pre and 22 ⊕

assessed with: Average Pain Intensity, post treatm ent f or hypnosis group but not (1 RCT) VERY LOW 1,2
Daily Pain Intensity (Num eric Rating Scale) in progressive relaxation group. Statisti-
cally signif icant decrease in daily/ average
pain scores f or the self hypnosis group but
not signif icant in the progressive m uscle
relaxation group (Jensen 2009).
Reduction in pain interference Statistically signif icant change pre to post 22 ⊕

assessed with: BPI treatm ent in the hypnosis group but not in (1 RCT) VERY LOW 1,2
the progressive relaxation group (Jensen
2009).
BPI: Brief Pain Inventory

1 Downgraded two levels due to high risk f or bias (the singular study did not describe whether blinding had occurred f or
participants)
25
Neurofeedback compared to relaxation/ control for chronic pain in M S

Setting: M S clinics
Intervention: neurof eedback
Comparison: relaxation/ control

(studies) (GRADE)
Reduction in pain Intensity Both groups im proved soon af ter interven- 20 ⊕

assessed with: Num erical Rating Scale (av- tion and at 1-m onth f ollow-up, but not stat- (1 RCT) VERY LOW 1,2
erage) ically signif icant. Average m ean pain in-
tensity f or intervention (bef ore 5.30; af ter:
4.41; 1 m onth 3.98) and control (bef ore 5.
24; af ter 4.32; 1 m onth 4.31). Worst pain
intensity score im provem ents in interven-
tion (bef ore 6.68; af ter 5.90; 1 m onth 5.
18) and control (bef ore 6.38; af ter 5.49; 1
m onth 5.35) (Jensen 2016).
Reduction in fatigue Im provem ents over tim e pre to post treat- 20 ⊕

assessed with: FSS m ent in intervention (Jensen 2016). (1 RCT) VERY LOW 1,2
Reduction in pain interference BPI score im provem ent in both groups 20 ⊕

assessed with: BPI (Jensen 2016). (1 RCT) VERY LOW 1,2
BPI: Brief Pain Inventory;FSS: Fatigue Severity Scale

1 Downgraded two levels due to high risk f or bias (unclear allocation concealm ent and no blinding of outcom e assessors)
26
27
Reflexology compared to sham for chronic pain in M S

Setting: M S clinics, M S society
Intervention: ref lexology
Comparison: sham

(studies) (GRADE)
Reduction in pain Com pared to baseline; signif icant de- 110 ⊕

assessed with: VAS, M PQ crease in m edian pain VAS in both ref lexol- (2 RCTs) VERY LOW 1,2
ogy (50% decrease at week 10) and sham
(50%decrease at week 10) (Hughes 2009).
Signif icant reduction in BPI scores in both
groups, ref lex group but no signif icant dif -
f erences between groups. (Hughes 2009).
There were changes in m ean pain VAS in
both ref lexology (pre-test 5.72, post-test 3.
16, 2 m onths 4.64) and control (pre-test 5.
88, post-test 5.60, 2 m onths 5.32) (Nazari
2016).
Reduction in disability Both the intervention and sham groups 71 ⊕

assessed with: BI, RM DQ showed a signif icant decrease in RM DQ by (1 RCT) VERY LOW 1,2
the end of the treatm ent period.BI scores
in both groups rem ained relatively stable
throughout the duration of the trial in both
groups (Hughes 2009).
Improvement in Quality of Life M SIS-29 psychological sub scale im proved 71 ⊕

assessed with: M SIS-29 in both intervention and sham by week 10 (1 RCT) VERY LOW 1,2
Physical sub scale signif icant decrease
in both intervention and sham , however
this reduction was greater in the treatm ent
group by week 10 (Hughes 2009).
28
Reduction in Fatigue M FIS physical sub scale score signif icantly 71 ⊕

assessed with: M FIS, FSS im proved in both sham and treatm ent by (1 RCT) VERY LOW 1,2
week 10
Signif icant reduction M FIS cognitive sub
scale score in both sham and treatm ent by
week 10
Signif icant reduction in M FIS psychologi-
cal sub scale in both sham and treatm ent
by the end of the treatm ent period
Both sham and treatm ent dem onstrated a
signif icant reduction in f atigue by week 10
(Hughes 2009).
Reduction in depression Both sham and treatm ent groups showed 71 ⊕

assessed with: BDI -II a signif icant reduction in values by week (1 RCT) VERY LOW 1,2
10 (Hughes 2009).
Reduction in Spasms Both sham and treatm ent dem onstrated a 71 ⊕

assessed with: VAS f or spasm statistically signif icant decrease in spasm (1 RCT) VERY LOW 1,2
by the end of the treatm ent (Hughes 2009)
..
BDI: Beck Depression Inventory; BI: Barthel Index; FSS: Fatigue Severity ScLE; M FIS: M odif ied Fatigue Im pact Scale; M SIS- 29: M ultiple Sclerosis Im pact Scale-29; VAS; Visual
Analogue Scale

1
Downgraded two levels due to high risk of attrition bias and unclear risk of bias in blinding and allocation concealm ent
2 Downgraded two levels due to high risk f or im precision (sm all sam ple size)
29
DISCUSSION yoga, massage therapy and radial shock wave therapy) which have
been used for pain relief in pwMS, however, studies evaluating
these interventions did not fulfil the inclusion criteria for this re-
view. Cost-effectiveness of the intervention and reporting of safety
Summary of main results
or adverse events for participants were not evaluated in any of the
Overall, 10 RCTs with 565 participants fulfilled the inclusion cri- included trials. Ovwerall, the review identified many issues relat-
teria of this review, which evaluated various non-pharmacological ing to the studies evaluating non-pharmacological interventions
interventions for the management of chronic pain in persons with in chronic pain in MS; which could affect the overall complete-
multiple sclerosis (pwMS), which included: physical therapy (Ai ness and applicability of evidence. The gaps in the evidence base
Chi water exercise), psychotherapy (telephone self-management, for non-pharmacological management of chronic pain in pwMS
cognitive restructuring, neurofeedback and hypnosis), neuromod- include the following.
ulatory techniques (transcranial direct stimulation (tDCS), tran- • Limited and/or lack of high-quality evidence for the
scranial random noise stimulation (tRNS)), reflexology and tran- effectiveness of non-pharmacological interventions.
scutaneous electrical nerve stimulation (TENS). The included tri- • Complexity and different mechanisms related to chronic
als were heterogeneous in terms of: type and intensity of inter- pain in MS.
ventions evaluated and outcome measures used. The study quality • Broad range of non-pharmacological interventions used in
varied and formulating pooled evidence was limited due to high different context and with scope.
risk of bias, underpowered studies (small sample size) and lack • Difficulty of blinding and incorporation of a control or
of data on changes of pain outcomes in majority of the studies. placebo (sham).
Therefore, quantitative synthesis was not possible and a qualitative • Lack of use of Initiative on Methods, Measurement, and
synthesis of ’best evidence ’ was summarised. Pain Assessment in Clinical Trials (IMMPACT)
The findings suggest that there is ’very low level’ evidence for the recommendations for measures of significance and standardised
following interventions. measurement outcomes.
• TENS in reducing lower back pain. • Difficultty with knowing the effective dose or duration for
• Ai Chi water exercises in improving pain intensity which many non-pharmacological interventions due to lack of
was maintained up to 30 weeks. There were also improvements definitive mechanisms.
in spasm, quality of life(QoL) and fatigue.
• tDCS in reduction in pain intensity and up to three weeks Non-pharmacological interventions are therapist- and operator-
after treatment and improvement in QoL, but not in fatigue and dependent and may be prone to multiple combined mechanisms
anxiety and depression. or ’bundled effects’ (Bennett 2011). Suggestions for future im-
• tRNS in improving pain scores, depression or anxiety or provements in quality of evidence include robust studies empha-
fatigue. sising on the mechanisms of pain in MS.
• Telephone-delivered self-management program for the
reduction of pain intensity, catastrophisation, self-efficacy,
fatigue and QoL in chronic pain.
• EEG biofeedback for reduction in pain intensity and Quality of the evidence
fatigue and pain interference.
• Reflexology in reducing pain intensity, disability, fatigue, All 10 included studies were rated as ’ very low’ quality for method-
psychological and physical impact and depression up to 22 ological evidence due to risk of bias and flaws in their method-
weeks. ological design (Figure 2; Figure 3).
• Lack of reporting of blinding and blinding processes
(Castro-Sanchez 2012; Ehde 2015; Jensen 2009; Jensen 2016;
Nazari 2016; Palm 2016).
Overall completeness and applicability of • Underpowered from low sample size and lack of study
evidence power calculation.
Despite a comprehensive search of the literature, only 10 trials eval- • Lack of reporting in IMMPACT suggestion of > 30% or
uating a wide variety of non-pharmacological treatments fulfilled 50% change in pain scores for clinical significance.
the inclusion criteria. Due to the quality of the published studies, • Limited reporting of complete data.
many aspects of non-pharmacological interventions for multiple • Lack of allocation concealment (Ayache 2016;
sclerosis (MS) pain remain unproven. Further, there were only few Castro-Sanchez 2012; Hughes 2009; Jensen 2009; Jensen 2016;
studies (which were heterogeneous) that evaluated a given type of Mori 2010; Nazari 2016; Palm 2016; Warke 2006).
intervention, which did not permit pooling data for quantitative • Unclear in the reporting of study authors’ conflicts of
analyses. There are other non-pharmacological interventions (e.g. interest, funding sources (Palm 2016; Warke 2006).

• Diffilculty controlling for therapist-dependent bias, patient management of chronic pain in pwMS (Bennett 2011). This is re-
motivation and activity/interventions outside of treatment. flected in the findings of various issues within the included studies
in this review, included blinding, small sample sizes, determina-
In summary, these limitations affected the quality of the evidence tion of the right dose/duration of treatment and focus on other
and highlights the importance of good methodological practices outcome measures other than pain intensity such as adverse effects
in research. This is specially important given the difficulty in re- and patient compliance and adherence to therapy.
cruitment of targeted study cohorts (with adequate sample sizes)
and difficulties associated with controlling for patients’ personal
and other confounding factors such as, patient motivation and
self-efficacy, comorbidity and activity level outside of therapy pro-
grammes), which influence compliance and delivery of therapy, AUTHORS’ CONCLUSIONS
thus impacting on outcomes.
Implications for practice
Despite use of a range of non-pharmacological interventions for
Potential biases in the review process the treatment of chronic pain in persons with multiple sclerosis
(pwMS), this review found ’very low-level’ evidence for the use of
The review authors followed a number of steps to ensure the re- such interventions. Therefore, it is difficult to recommend routine
duction of bias in the review process. First, the review authors in- use of non-pharmacological interventions alone for the treatment
dependently reviewed and assessed all articles. Second, the review of chronic pain in an MS population. However, findings suggest
authors adhered strictly to the inclusion and exclusion criteria for that use of non-pharmacological intervention in combination with
the studies and extraction and interpretation of the data, and fol- pharmacological agents is reasonable. The findings of this review
lowed the GRADE handbook. However, a number of limitations also highlight the existing gaps in the literature and emphasise
in the methodological quality of the review itself, and the com- the need for robust evidence to support these modalities. Clini-
pleteness of the retrieved literature, cannot be ruled out. Despite cian involvement is vital to build evidence from everyday clinical
the extended range of terms that were used to capture the widest practice. The clinical applicability of findings of this review need
possible selection of the relevant literature, we were not able to to be confirmed in future studies with robust study design, larger
rule out some degree of selection bias from the literature search sample sizes and long-term follow-up.
(van Tulder 2003). Possibility of publication bias cannot be omit-
ted as we were not able to include negative trials or other trials
Implications for research
which are yet to be published in academic literature (Egger 1998).
Further, reference bias (Goetzsche 1987) is a further possibility, This review shows that there are significant gaps in the literature on
as we searched only reference lists within the relevant papers for non-pharmacological management of chronic pain in MS. Future
additional articles. We welcome contact from any readers who are research implications include the following.
aware of important high-quality studies which are not included in
this review. • Robust studies with reduced risk of bias, with adequate
allocation, randomisation procedures
• Standard reporting of pain as defined by the Initiative on
Agreements and disagreements with other Methods, Measurement, and Pain Assessment in Clinical Trials
studies or reviews (IMMPACT) (Dworkin 2008)
There are limited systematic reviews in the area of non-pharma- • Reporting pain measures desired by patients (Moore 2013)
cological management of chronic pain in MS. This review high-
lights existing evidence and gaps in the literature. There are some • Appropriate and careful selection of study cohort and larger
similarities which are consistent between this review and another sample size
published non-Cochrane systematic review (Jawahar 2014). How- • Emphasise on details of pain mechanism, localisation
ever, there are methodological differences of this review and the pattern, severity and impact on everyday function
review by Jawar et al (Jawahar 2014). specifically inclusion of
only high-quality studies (randomised controlled trials (RCTs) and • Impact and burden on carer and family, or both
clinical controlled trials (CCTs)) and use of standardised tools • Intervention-related adverse effects/complications
- theCochrane Handbook for Systematic Reviews of Interventions
(Higgins 2011) and the ’GRADE’ for the methodology and inter- • Long-term impact of interventions
pretation of findings. We think this review addressed the method- • Cost associated with the interventions
ological issues in systematically reviewing the evidence for the

ACKNOWLEDGEMENTS
We are grateful to the Cochrane Multiple Sclerosis and Rare Dis-
eases of the CNS Group Editorial Board for their support and as-
sistance and Dr Kevin Young for his assistance in protocol prepa-
ration. We also like to thank Professor Andrew Moore and the
editors for reviewing the manuscript.
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CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Ayache 2016
Methods • Randomised sham-controlled trial,cross-over and double-blinded study

• Randomisation through computer generation
• Study conducted in France
• Allocation concealment not stated
Participants Population source: participants enrolled from Neurology Department of Henri Mondor
Hospital
Numbers: randomised 16, anodal transcranial direct current stimulation 8, sham 8
Inclusion criteria:age 18-70 years,definitively diagnosed with multiple according to
McDonalds Criteria, right-handedness based on Edinburgh Inventory, neuropathic pain
> 3 months as per Neuropathic Pain Symptom Inventory, VAS > 40 over average 1 week
Exclusion criteria: multiple sclerosis relapses within last 2 months, changes in phar-
macological and physiotherapy in last month, presence of comorbid neurodegenerative
or psychiatric disorders, history of substance abuse, absence of measurable pain-related
evoked potentials at right hand, severe deficits in visual acuity and fields by examination,
severe upper limb impairment by Medical Research Council for muscle power
Age: mean age 48.9 years, range 38-67 years
Gender: women 13, men 3
Type of MS: relapsing remitting 11, secondary progressive 4, primary progressive 1
Pain type: neuropathic pain
Interventions Treatment: anodal tDCS, 2mA current

Control: sham tDCS
Duration: 3
consecutive days of tDCS stimulation (20-minute sessions), at least 3 weeks washout
period
Outcomes • VAS
• BPI
• MFIS
• HADS
• CRQ
• CGI
Notes Funding: authors had received grants and gave lectures.

Conflicts of interest: authors declared no commercial of financial relationships that
could act as conflict of interest
Risk of bias
Bias Authors’ judgement Support for judgement

Ayache 2016 (Continued)
Random sequence generation (selection Low risk The randomisation schedule was generated
bias) prior to the beginning of the study using a
dedicated software
Allocation concealment (selection bias) Unclear risk No information provided
Blinding of participants and personnel Low risk Participants were blind to treatment
(performance bias)
All outcomes
Blinding of outcome assessment (detection Low risk Participants were blind to treatment
bias)
All outcomes
Incomplete outcome data (attrition bias) Low risk Attrition rated reported. None lost to fol-
All outcomes low-up
Selective reporting (reporting bias) Low risk All outcomes reported
Other bias Low risk No other bias detected
Castro-Sanchez 2012
Methods • Randomised controlled trial

• Study conducted in Spain
• Allocation concealment not described
Participants Population source: participants were recruited from MS Association of Almeria in Spain
Numbers: randomised 73, Ai Chi 36, control 37
Inclusion criteria: MS diagnosis, age between 18 and 75 years, VAS pain score > 4 for
at least two months, EDSS ≤ 7.5
Exclusion criteria: treatment with another complementary and alternative medicine
(either current or within the previous 3 month, relapse requiring hospitalisation or steroid
treatment within the past 2 months
Age: experimental group (mean age 46 years, range 25-75), control group (mean age 50
years, range 29-75)
Gender: experimental group(26 women,10 men), control group (24 women,13 men)
Type of MS: experimental group (6 primary progressive,9 secondary progressive, 21
unknown), control group (9 primary progressive, 12 secondary progressive, 16 unknown)
Pain type: musculoskeletal pain (back, cervical, legs, feet, arms, shoulder)
Interventions Treatment: Ai Chi exercises

Control: relaxation
Duration: 20 weeks (twice a week), 4 sessions
Outcomes Primary
• VAS

Castro-Sanchez 2012 (Continued)
• MPQ
• RMDQ
Secondary
• Spasm VAS
• MSIS29
• MFIS
• FSS
Notes Funding: not described

Conflicts of interest: not described
Risk of bias
Random sequence generation (selection Low risk Computer-generated randomised list

bias)
Allocation concealment (selection bias) Unclear risk Allocation concealment not described
Blinding of participants and personnel High risk Study could not guarantee that participants
(performance bias) were blinded to the nature of their group
All outcomes because they were all members of the same
association
Blinding of outcome assessment (detection Low risk Researcher blinded to group allocation
bias)
All outcomes
Incomplete outcome data (attrition bias) Low risk None lost to follow-up
All outcomes
Ehde 2015
Methods • Randomised controlled trial, single-blinded, parallel group and single centre
• Study conducted in the USA
• Allocation by limited access database program
Participants Population source: recruited from University of Washington Department of Rehabili-

tation Medicine Research. Registry and advertisements through National MS organisa-
tions. Flyers and referrals from University of Washington Multiple Sclerosis Centre
Numbers: randomised 163, telephone self-management 75, control (telephone educa-
tion) 88
Inclusion criteria: >18 years, self-reported physician diagnosis of MS and 1 or more

Ehde 2015 (Continued)
of the following: (1) moderate depressive symptoms indicated by a score of 10 to 14

on the PHQ-9, presence of chronic pain (average pain intensity 3 in the past week) or
significant fatigue symptoms, defined as a score 10 on the 5-item (MFIS)
Exclusion criteria: cognitive impairment (1 error on 6-item Cognitive Screener), psy-
chotherapy more than once a month, had participated in another study for fatigue, de-
pression, or pain, moderate-severe to severe depressive symptoms (PHQ-9 score 15)
Age: treatment group (mean age 51 years,range 25-76), control group (mean age 53.2
years, range 26-76)
Gender: treatment group (women 67, men 8), control group (women 75, men 13)
Type of MS: treatment group (relapsing remitting 46, progressive 29), control group
(relapsing remitting 45, progressive 43)
Pain type: chronic pain
Interventions Treatment: telephone self-management skills training

Control: education on MS symptoms
Duration: 8 weekly individual telephone calls delivered, 45-60 minute sessions
Outcomes Primary
• MFIS
• BPI
• PHQ-9
Secondary
• Pain NRS
• SES
• PANAS
• PAM
• SF8 Health Survey
• Patient Reported Outcomes Measurement Information System
• Conner Davidson Resilience Scale
Notes Funding: not described

Conflicts of interest: not described
Risk of bias
Random sequence generation (selection Low risk Random numbers were generated by com-
bias) puter software
Allocation concealment (selection bias) Low risk The allocation sequence was concealed
from the research assistants who enrolled
participants via a limited access database
program
Blinding of participants and personnel Low risk On 2 occasions research assistants became
(performance bias) aware of a participant’s allocation
All outcomes

Ehde 2015 (Continued)
Blinding of outcome assessment (detection High risk On 2 occasions research assistants became
bias) aware of a participant’s allocation
All outcomes
Incomplete outcome data (attrition bias) High risk For the telephone self-management group
All outcomes there were 10 withdrawals during sessions
and 4 during assessments. For the control
group there were 6 withdrawals during ses-
sions and 2 withdrawals during assessments
Hughes 2009
Methods • Randomised controlled trial,double-blinded

• Study in Northern Ireland
• Randomisation through computer-generated lists
Participants Population source: responses to advertisement in local advertisement and MS charities

Numbers: randomised 71,intervention 35, sham 36
Inclusion criteria: 18-75 years of age, definite diagnosis of MS, pain greater than 4 on
VAS of at least 2 months, EDSS of 7.5
Exclusion criteria: previous experience of reflexology, participation in research studies
currently or within the previous 3 months relapse (requiring hospitalisation or steroid
treatment) within the past 2 months
Age: reflexology group (mean age 50 years, range 26-75), sham group (mean age 53,
range 34-74)
Gender: reflexology group (30 women,5 men),sham group (29 women,7 men)
Type of MS: precision reflexology group (benign 0, relapsing remitting 16, primary
progressive 4, secondary progressive 6, unknown 9), sham group (benign 1, relapsing
remitting 12, primary progressive 4, secondary progressive 13, unknown 6)
Pain type: musculoskeletal (low back pain, legs,feet,shoulders,hips arms,eye)
Interventions Intervention: reflexology by accredited reflexology specialist.

Control: standardised foot massage
Duration: 45-minute sessions weekly for 10 weeks
Outcomes Primary
• VAS (Pain)
Secondary
• VAS (weekly pain scores)
• MPQ
• PRI
• PPI
• RMDQ

Hughes 2009 (Continued)
• VAS (Spasticity)
• MSIS29
• MFIS
• FSS
• BDI2
• BI
Notes Funding: National MS Society, USA and Action MS for their assistance with recruitment
and the use of facilities
Conflicts of interest: none to declare
Risk of bias
Random sequence generation (selection Low risk Randomised by computer-generated list

bias)
Blinding of participants and personnel Low risk Participants were blinded to group alloca-
(performance bias) tion.
All outcomes
Blinding of outcome assessment (detection Low risk Investigator who was blinded to group al-
bias) location
All outcomes
Incomplete outcome data (attrition bias) High risk Five participants were lost to follow-up
All outcomes
Selective reporting (reporting bias) Low risk All outcomes in the review reported
Jensen 2009
Methods • Randomised controlled clinical trial

Participants Population source: recruited from previously completed survey of study of pain
Numbers: randomised 22, self-hypnosis first 8, self-hypnosis 7, progressive muscle re-
laxation 7
Inclusion criteria: diagnosis of MS, at least 18 years old, reported chronic daily pain
that was rated as being at least 4/10, on average, on a 0 to 10 numerical rating scale of
intensity and indicated on the survey that they would be willing to be contacted about
possible participation in future research studies

Jensen 2009 (Continued)
Exclusion criteria: evidence of severe psychopathology symptoms or psychosis on in-

terview or endorsement of active suicidal ideation with intent within the past 6 months,
score of 21 or greater on the Telephone Interview of Cognitive Status indicative of severe
cognitive deficits that could potentially interfere with the focused attention required for
hypnosis
Age: mean age 51.7 years (27-75 years)
Gender: 16 women, 6 men
Type of MS: not reported
Pain type: not reported
Interventions Intervention: self-hypnosis training

Control: progressive relaxation
Duration: 10 sessions
Outcomes Primary outcome

• NRS
Secondary outcomes
• BPI
• Amount and effects of hypnosis (pain relief 0 to 10, number of days listened,
usual number of times listened, hours of relief they experiences after listening)
Notes Funding: not reported

Conflicts of interest: not reported
Risk of bias
Random sequence generation (selection Low risk Participants were randomly assigned via a
bias) computer-generated list of random num-
bers
Allocation concealment (selection bias) Unclear risk No allocation concealment described
Blinding of participants and personnel High risk No blinding reported

(performance bias)
All outcomes
Blinding of outcome assessment (detection Low risk Blinding of assessors

bias)
All outcomes
Incomplete outcome data (attrition bias) Low risk Two of the participants did not provide
All outcomes complete data
Selective reporting (reporting bias) Low risk All data presented

Jensen 2016
Methods • Randomised controlled trial

Participants Population source: recruited from former participants of an ongoing MS symptom self-
management study (who did not receive intervention), University of Washington Medical
Center (UWMC) MS Clinic, Harborview and/or UWMC Rehabilitation Clinicand
self-referrals from study brochures and flyers
Numbers: randomised 20, EEG biofeedback (NF-HYP) 10, relaxation control group
10
Incusion criteria: 18 years or older, >= 6 months post-MS diagnosis, otherwise healthy,
daily pain related to their MS that has been present for at least 6 months,average MS
pain intensity over the past week of at least 4 on a 0 to 10 numerical rating scale, and
able to read, write, and understand English
Exclusion criteria: history of a seizure disorder, significant psychological or psychiatric
disturbance, intermittent pain, hospitalisation or psychiatric reasons in the past 6 months,
or failure to pass a cognitive screening test and experiencing an MS exacerbation
Age: mean age (50 years)
Type of MS: relapsing remitting 12, secondary progressive 5, primary progressive 0,
progressive relapsing 0, unknown 2
Pain type: not reported
Adverse effects: not reported
Interventions Intervention: hypnosis preceded by neurofeedback

Control: hypnosis preceded relaxation
Duration: 5 sessions of self-hypnosis training (1 face-to-face and 4 pre-recorded sessions
Neurofeedback: 20 minutes of neurofeedback
Relaxation: 20 minutes of relaxation through headphones
Outcomes Primary outcomes

• Average NRS
Secondary outcomes
• NRS (Worst pain intensity)
• FSS
• BPI
Notes Funding: not reported

Conflicts of interest: not reported
Risk of bias
Random sequence generation (selection Low risk Randomisation through computer-gener-

bias) ated numbers
Allocation concealment (selection bias) Unclear risk No allocation concealment described

Jensen 2016 (Continued)
Blinding of participants and personnel Unclear risk Blinding was not described
(performance bias)
All outcomes
Blinding of outcome assessment (detection High risk No blinding for assessors

bias)
All outcomes
Incomplete outcome data (attrition bias) Low risk One participant’s data not collected
All outcomes
Mori 2010
Methods • Randomised controlled trial and double-blinded

• Study conducted in Italy
Participants Population source: randomised 19 intervention group (transcranial direct current stim-
ulation) 10, control 9
Inclusion criteria: diagnosis of MS established by Mcdonalds Criteria, chronic neuro-
pathic pain >1 month (stereotyped neurological distribution and superficial location),
VAS >= 4
Exclusion criteria: pain relating to spasticity
Age: mean age 44.8
Gender: women 11, men 8
Interventions Treatment: anodal tDCS, 2mA current

Control: sham tDCS
Duration: 5 consecutive daily stimulation (20-minute sessions)
Outcomes • VAS (Pain)

• VAS (Anxiety)
• SFMPQ
• MSQOL54
• BDI
Notes Funding: none to declare

Risk of bias

Mori 2010 (Continued)
Random sequence generation (selection Low risk Randomisation list generated by a com-
bias) puter software
Blinding of participants and personnel Low risk Patients and assessing physician were
(performance bias) blinded to group allocation
All outcomes
Blinding of outcome assessment (detection Low risk Patients and assessing physician were
bias) blinded to group allocation
All outcomes
All outcomes
Selective reporting (reporting bias) Low risk All outcomes in the review reported
Nazari 2016
Methods • Randomised controlled trial,single-blinded

• Study conducted in Iran
Participants Population source: MS patients referred to the Clinic of Ayatollah Kashani Hospital
(Isfahan, Iran) in 2014,
Numbers: randomised 75; relaxation 25, reflexology 25, control 25
Inclusion criteria: female, definite diagnosis of MS, 18-75 years of age,healthy legs, not
suffering from diseases other than MS,willing to participate in the study, not having a
drug addiction, not being pregnant,not being medical staff, feeling chronic pain in at
least one body organ,having a history of pain medication use, NRS >= 4 for at least 6
months,expanded disability status scale of 0 to 7.5
Exclusion criteria: receiving other complementary and alternative treatment during the
study period and reflexology treatment,receiving formal training and practicing relax-
ation in the previous 6 months, acute relapse 1 month preceding or during the study
period, not wanting to continue their co-operation in the research
Age: reflexology group (mean 34.4), relaxation (mean 33.9), control group (mean 34.4)
Gender: female only
Type of MS: relapsing remitting (reflexology 88%, relaxation 84%, control 80%)
Interventions Treatment: relaxation(Audio tape guided relaxation), reflexology (general reflexology

massage technique)
Control: routine care 4 weeks

Nazari 2016 (Continued)
Duration: twice a week, each session lasting 40 minutes
Outcomes • Pain (NRS)
Notes Funding: research conducted under financial support of the Vice Chancellor for Research
of Isfahan University of Medical Sciences
Risk of bias
Random sequence generation (selection Low risk Participants were randomly assigned, using
bias) minimisation method with MiniPy soft-
ware
Blinding of participants and personnel Unclear risk Did not describe which group was blinded
(performance bias)
All outcomes
Blinding of outcome assessment (detection Unclear risk Did not describe which group was blinded
bias)
All outcomes
All outcomes
Other bias Low risk The funding organisation(s) played no role

in the study design; in the collection, anal-
ysis,and interpretation of data; in the writ-
ing of the report; or in the decision to sub-
mit the report for publication
Palm 2016
Methods • Randomised controlled, cross-over, double-blinded trial

• Study conducted in France
• Randomisation method not discussed
• Allocation concealment not discussed
Participants Population source: MS patients recruited from inpatient and outpatient neurology
departments at Henri Mondor hospital, Creteil,France
Numbers: randomised 16 (not reported number in each group)
Inclusion criteria: age 18-70 years of age, right-handedness as per Edinburgh Inventory,
a definitive diagnosis of MS according to McDonalds Criteria, presence of neuropathic

Palm 2016 (Continued)
pain as per neuropathic pain symptom inventory >3 months, VAS (0-100) > 40mm on
a daily basis during a representative week, stable pharmacological and physical therapies
since at least 1 month, the presence of measurable pain related evoked potentials at the
right hand, the absence of MS relapses within the last 2 months and other neurological
or psychiatric conditions
Exclusion criteria: patients unable to perform the attention network test, deficits in
visual fields or severe upper limb impairment based on medical research council scale
score of less than 12
Age: mean age 47.4 years, age range 38-64 years
Type of MS: 11 relapsing remitting, 4 secondary progressive,1 primary progressive
Adverse effects: phosphenes (1 sham),insomnia (6 sham, 5 treatment), nausea (4 sham,
2 treatment), headache (1 sham)
Interventions Treatment: tRNS

Control: sham controlled
Duration: 3 daily consecutive sessions of sham or tRNS
Outcomes • VAS
• BPI
• ATN
• HADS
• MFIS
• PREP
• FMTA
Notes Funding: received grants

Conflicts of interest: none
Risk of bias
Random sequence generation (selection Unclear risk Randomisation not discussed

bias)
Blinding of participants and personnel Low risk Blinding was achieved

(performance bias)
All outcomes
Blinding of outcome assessment (detection Unclear risk Blinding of assessors was not described, or
bias) if it was achieved
All outcomes
All outcomes

Palm 2016 (Continued)
Other bias Unclear risk Received grants, not discussed if affected

results.
Warke 2006
Methods • Randomised controlled trial, single-blinded

• Study conducted in Northern Ireland
Participants Population source: recruited from MS hospital clinics and other clinics within Northern
Ireland
Numbers: randomised 90, low frequency (4hz) 30, high frequency (110hz) 30, placebo
30
Inclusion criteria: 18-80 years,chronic (>3 months), stable lumbar back pain, partici-
pants undergoing concomitant treatments and stable for 30 days before and throughout
the duration of the trial
Exclusion criteria: comorbidity including serious spinal pathology or psychosocial risk
factors,or both, acute MS relapse 1 month preceding or during the trial period,any
contraindication to TENS, judged not competent to give informed consent,analgesic
abuse, sacral pressure ulcers, participation in other research studies within the previous
3 months
Age: range 21-78 years, low frequency (mean 45.6), high frequency (mean 47.8), placebo
(mean 48.7)
Gender: low frequency (24 women, 6 men), high frequency (22 women, 8 men), placebo
23 women, 7 men)
Pain type: low back pain
Interventions Treatment: low frequency (4hz), high frequency (110hz)

Control: placebo TENS
Duration: lumbar spine application, >= twice daily application, 45 minutes for 6 weeks
and anytime pain occurred
Outcomes Primary
• VAS (Average)
• MPQ
Secondary
• VAS (Worst)
• RMDQ
• BI
• RMI
• MSQOL54
Notes Funding: financial support from MS Society of Great Britain and Northern Ireland
Conflicts of interest: no other conflicts of interest listed

Warke 2006 (Continued)
Risk of bias
Random sequence generation (selection Low risk Randomisation was achieved using a com-
bias) puter-generated list
Blinding of participants and personnel Low risk The frequencies set on the TENS units
(performance bias) were masked and participants were blind to
All outcomes the treatment group
Blinding of outcome assessment (detection Low risk Investigator allocating each unit to partici-
bias) pants was blinded
All outcomes
Incomplete outcome data (attrition bias) Low risk five participants lost to follow-up
All outcomes
Other bias Unclear risk Did not describe if funding had impact on
results
ATN: Attention Network Test, BDI: Beck Depression Inventory, BDI2: Becks Depression Inventory 2, BI: Barthel Index, BPI:
Brief Pain Inventory, CGI: Clinical Global Impression, CRQ: Comfort Rating Questionnaire,EEG: Electroencephalogram, EDSS:
Expanded Disability Status Scale, FMTA: Frontal Midline Theta Activity, FSS: Fatigue Severity Scale, HADS: Hospital Anxiety
and Depression Scale, Questionnaire, MFIS: Modified Fatigue Impact Scale, MPQ: McGIll Pain Questionnaire,MS: Multiple
Sclerosis, MSIS29: Multiple sclerosis Impact scale 29, MSQOL54: Multiple Sclerosis Quality of Life-54, NRS: Numerical Rating
Scale, PAM: Patient Activation Measure, PANAS: Positive and Negative Affect Scale, PHQ-9: Patient Health Questionnaire-9,
PREP: Pain Related Evoked Potential, PRI: Pain Rating Index, PPI: Present Pain Intensity, RMDQ: Roland Morris Disability
Questionnaire, RMI: Rivermead Mobility Index, SES: Self Efficacy Scale, SF8: Short Form 8 Health Survey, SFMPQ: Short Form
McGill Pain Questionnaire, tDCS: Transcranial Direct Current Stimulation, tRNS: Transcranial random noise stimulation, TENS:
Transcutaneous Electrical Nerve Stimulation, VAS: Visual Analogue Scale
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Anninos 2016 Pain not an outcome criteria
Backus 2016 Not a clinical controlled trial

(Continued)
Barlow 2009 Pain not an outcome criteria
Catena 2014 Abstract
Doulatabad 2012 Chronic pain not a criteria
Hasanpour-Dehkordi 2015 Chronic pain not a criteria
Hasanpour-Dehkordi 2016 Chronic pain not criteria
Jensen 2007 Abstract
Jensen 2011 Not a controlled clinical trial
Marinelli 2015 Chronic pain not a criteria
Mathiowetz 2005 Chronic pain not a criteria
McGuire 2015 Chronic pain not a criteria
Negahban 2013 Chronic pain not a criteria
Oken 2004 Chronic pain not a criteria
Pilutti 2013 Chronic pain not a criteria
Pozzilli 2002 Chronic pain not a criteria
Seada 2013 Not controlled clinical trial.
Smedal 2011 Chronic pain not a criteria
Storr 2006 Chronic pain not a criteria
Van der Linden 2013 Chronic pain not a criteria

APPENDICES
Appendix 1. Glossary
• Dorsal column: spinal pathways located at the rear of the spinal cord
• Dysesthesia: an unpleasant abnormal sensation that can occur spontaneously or when touched; the sensation can be felt as pain,
burning, wetness, itching, electric shock or ‘pins and needles’
• Fibromyalgia: condition characterised by widespread pain; the cause is unknown
• Hypoalgesia: reduced experience of pain to a normally painful stimulus
• Idiopathic pain: pain with a cause that cannot be identified
• Interstitial cystitis: a long-term painful bladder condition also known as ‘painful bladder syndrome’ or ‘bladder pain syndrome’
• Lhermitte phenomenon: a brief electric shock or vibration which runs from the neck down the spine and is uncomfortable
• Neuropathic pain: pain arising because of disease in the nervous system
• Nociceptive pain: pain caused by tissue damage, usually described as a sharp, aching, or throbbing pain.
• Optic neuritis: inflammatory damage to optic nerve (nerve from brainstem) that may lead to complete or partial loss of vision
• Paroxysmal: a sudden occurrence or intensification of symptoms
• Proprioception: the perception of outside stimuli that informs the body of the relative position of its parts
• Psychogenic pain: physical pain that is caused, increased, or prolonged by mental, emotional, or behavioural factors
• Refractory: a disease or condition which does not respond to attempted forms of treatment, for example poor pain of relief after
pain-relieving medicine
• Somatosensory: sensory system in the body involved in detecting touch, pressure, pain, temperature, movement and vibration
• Thermotherapy: application of heat or cold to the body for pain relief
• Tonic spasms: sudden abnormal muscle contraction
• Transcranial direct cranial stimulation: non-invasive brain stimulation using low currents
• Transmagnetic stimulation: application of brief magnetic pulses that stimulate the brain
• Trigeminal neuralgia: nerve pain involving the trigeminal nerve which is responsible for sensation in the face and for
controlling biting and chewing
Appendix 2. Keywords
{Pain} OR {chronic pain} OR {pain management} OR {pain intractable} OR {pain measurement} OR {pain threshold} OR {nociceptors}
AND {rehabilitation } OR {exercise} OR {exercise therapy} OR {physical therapy} OR {psychotherapy} OR {hydrotherapy} OR
{complementary therapies} OR {transcutaneous electric nerve stimulation} OR {transcranial magnetic stimulation} OR {dorsal colum
stimulation} OR {spinal cord stimulation} OR {peripheral field stimulation} OR {dorsal root entry zone lesion} OR {DREZ}
Appendix 3. PsycINFO
S1 TX multiple sclerosis
S2 DE “Multiple Sclerosis”
S3 TX demyelinating disease*
S4 DE “Demyelination”
S5 TX transverse myelitis
S6 DE “Myelitis”
S7 TX neuromyelitis optica
S8 TX optic neuritis
S9 TX encephalomyelitis acute disseminated
S10 DE “Encephalopathies”
S11 TX devic
S12 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10 or S11
S13 DE “Somatosensory Disorders”
S14 DE “Pain” OR DE “Aphagia” OR DE “Back Pain” OR DE “Chronic Pain” OR DE “Headache” OR DE “Myofascial Pain” OR
DE “Neuralgia” OR DE “Neuropathic Pain” OR DE “Somatoform Pain Disorder”
S15 TX pain
S16 TX central pain
S17 TX dys#esthesia or TX dys#esthetic
S18 S13 or S14 or S15 or S16 or S17
S19 TX intractable
S20 DE “Pain Measurement”
S21 DE “Pain Perception”
S22 DE “Pain Thresholds” or DE “Pain Management”
S23 DE “Nociceptors”
S24 AB pain N5 (refer* or refractory or intractable or receptor* or nocicept* or muskuloskeletal or chronic or intens* or threshold* or
shoulder* or abdominal* or back or neuropath*)
S25 TI pain N5 (refer* or refractory or intractable or receptor* or nocicept* or muskuloskeletal or chronic or intens* or threshold* or
S26 (TI nocicept* N3 neuron*) OR TI pain*
S27 S19 or S20 or S21 or S22 or S23 or S24 or S25 or S26
S28 S12 and S18 and S27
S29 DE “Rehabilitation” OR DE “Cognitive Rehabilitation” OR DE “Neuropsychological Rehabilitation” OR DE “Neurorehabilita-
tion” OR DE “Occupational Therapy” OR DE “Physical Therapy” OR DE “Psychosocial Rehabilitation”
S30 DE “Exercise” OR DE “Aerobic Exercise” OR DE “Weightlifting” OR DE “Yoga”
S31 TX exercise therap* or TX stretching or TX tai chi or TX yoga
S32 DE “Psychotherapy” OR DE “Adlerian Psychotherapy” OR DE “Adolescent Psychotherapy” OR DE “Analytical Psychotherapy”
OR DE “Autogenic Training” OR DE “Behavior Therapy” OR DE “Brief Psychotherapy” OR DE “Child Psychotherapy” OR DE
“Client Centered Therapy” OR DE “Cognitive Behavior Therapy” OR DE “Conversion Therapy” OR DE “Eclectic Psychotherapy”
OR DE “Emotion Focused Therapy” OR DE “Existential Therapy” OR DE “Experiential Psychotherapy” OR DE “Expressive
Psychotherapy” OR DE “Eye Movement Desensitization Therapy” OR DE “Feminist Therapy” OR DE “Geriatric Psychotherapy”
OR DE “Gestalt Therapy” OR DE “Group Psychotherapy” OR DE “Guided Imagery” OR DE “Humanistic Psychotherapy” OR
DE “Hypnotherapy” OR DE “Individual Psychotherapy” OR DE “Insight Therapy” OR DE “Integrative Psychotherapy” OR DE
“Interpersonal Psychotherapy” OR DE “Logotherapy” OR DE “Narrative Therapy” OR DE “Persuasion Therapy” OR DE “Primal
Therapy” OR DE “Psychoanalysis” OR DE “Psychodrama” OR DE “Psychodynamic Psychotherapy” OR DE “Psychotherapeutic
Counseling” OR DE “Rational Emotive Behavior Therapy” OR DE “Reality Therapy” OR DE “Relationship Therapy” OR DE
“Solution Focused Therapy” OR DE “Supportive Psychotherapy” OR DE “Transactional Analysis”
S33 TX cognitive behavio#ral or TX relaxation or TX breathing or TX hypnosis
S34 DE “Relaxation” OR DE “Relaxation Therapy” OR DE “Progressive Relaxation Therapy”
S35 DE “Hypnosis” OR DE “Autohypnosis”
S36 TX hydrotherap* or TX thermo* or TX heat or TX warm or TX cold or TX cool
S37 DE “Alternative Medicine”
S38 DE “Acupuncture” OR DE “Aromatherapy” OR DE “Massage” OR DE “Medicinal Herbs and Plants” OR DE “Meditation” OR
DE “Osteopathic Medicine”
S39 TX massage or TX chiropractic or TX manipulation or TX acupuncture or TX acupressure or TX osteopath* or TX homeopath*
or TX naturopath* or TX aromathera* or TX art or TX music or TX alternative or TX complementary or TX CAM
S40 TX transcutaneous electrical stimulation
S41 DE “Electrical Stimulation” OR DE “Electrical Brain Stimulation” OR DE “Electroconvulsive Shock”
S42 DE “Transcranial Magnetic Stimulation”
S43 TX transcranial magnetic stimulation
S44 TX dorsal column stimulation
S45 TX spinal cord stimulation
S46 TX peripheral field stimulation
S47 TX dorsal root entry zone lesion*
S48 TX DREZ
S49 DE “Osteopathic Medicine”
S50 TX orthotics or TX orthosis or TX brace*
S51 TX nonpharmaco* or TX non-pharmaco*

S52 S29 or S30 or S31 or S32 or S33 or S34 or S35 or S36 or S37 or S38 or S39 or S40 or S41 or S42 or S43 or S44 or S45 or S46
or S47 or S48 or S49 or S50 or S51
S53 S28 and S52
S54 AB randomi#ed OR TI randomi#ed
S55 DE “Clinical Trials”
S56 AB placebo
S57 AB randomly
S58 TI trial
S59 S53 or S54 or S55 or S56 or S57 or S58
S60 S59 andS53
Appendix 4. AMED
S1 TX multiple sclerosis
S2 (DE “MULTIPLE SCLEROSIS”)
S3 TX demyelinating disease*
S4 TX transverse myelitis
S5 TX neuromyelitis optica
S6 TX optic neuritis
S7 TX encephalomyelitis acute disseminated
S8 (DE “ENCEPHALOMYELITIS”)
S9 TX devic
S10 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9
S11 (DE “PARESTHESIA”)
S12 (DE “PAIN”)
S13 TX pain
S14 TX central pain
S15 TX dys#esthesia or TX dys#esthetic
S16 S11 or S12 or S13 or S14 or S15
S17 (DE “PAIN INTRACTABLE”)
S18 (DE “PAIN MEASUREMENT”)
S19 (DE “PAIN THRESHOLD”)
S20 TX nociceptor*
S21 AB pain N5 (refer* or refractory or intractable or receptor* or nocicept* or muskuloskeletal or chronic or intens* or threshold* or
S22 TI pain N5 (refer* or refractory or intractable or receptor* or nocicept* or muskuloskeletal or chronic or intens* or threshold* or
S23 (TI nocicept* N3 neuron*) OR TI pain*
S24 S17 or S18 or S19 or S20 or S21 or S22 or S23
S25 S10 and S16 and S24
Appendix 5. MANTIS/Ovid
1 multiple sclerosis.mp.
2 multiple sclerosis.sh.
3 demyelinating disease*.mp.
4 demyelinating diseases.sh.
5 transverse myelitis.mp
6 myelitis, transverse.sh.
7 neuromyelitis optica.mp
8 optic neuritis.mp
9 optic neuritis.sh
10 encephalomyelitis acute disseminated.mp
11 encephalomyelitis, acute disseminated.sh
12 devic.mp
13 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12
14 paresthesia.sh
15 pain.sh
16 pain.mp
17 central pain.mp
18 (dys?esthesia or dys?esthetic).mp.
19 14 or 15 or 16 or 17 or 18
20 pain, intractable.sh
21 pain measurement.sh
22 pain threshold.sh
23 nociceptors.sh.
24 (pain adj5 (refer* OR refractory OR intractable OR receptor* OR nocicept* OR muskuloskeletal OR chronic OR intens* OR
threshold* OR shoulder* OR abdominal* OR back OR neuropath*)).ab,ti.
25 ((nocicept* adj3 neuron*) OR pain*).ti.
26 20 or 21 or 22 or 23 or 24 or 25
27 13 or 19 or 26
CONTRIBUTIONS OF AUTHORS
Bhasker Amatya (BA) and Fary Khan (FK) were involved in all aspects of the protocol. All authors were involved at the review stage.
DECLARATIONS OF INTEREST
The review authors are clinicians in the field of Physical and Medical Rehabilitation who wish to provide the best possible service to
their patients.
BA: has no personal or financial conflicts of interest in the findings of this review.
JY: has no personal or financial conflicts of interest in the findings of this review.
FK: has no personal or financial conflicts of interest in the findings of this review.
SOURCES OF SUPPORT
Internal sources
• Department of Rehabilitation Medicine, Royal Melbourne Hospital, Australia.

External sources
• None, Other.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
• A meta-analysis was not possible due to methodological, clinical and statistically heterogeneity of included studies
• Change of number of risk of bias items to include ’other bias’ and ’blinding of outcome assessment’.


Non-Pharmacological Interventions For Chronic Pain in Multiple Sclerosis

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Cochrane Database of Systematic Reviews

Non-pharmacological interventions for chronic pain in

Amatya B, Young J, Khan F

Amatya B, Young J, Khan F.

Non-pharmacological interventions for chronic pain in multiple sclerosis (Review)

Non-pharmacological interventions for chronic pain in multiple sclerosis (Review) i

Non-pharmacological interventions for chronic pain in

Bhasker Amatya1 , Jamie Young2 , Fary Khan1

PLAIN LANGUAGE SUMMARY

Non-pharmacological interventions for chronic pain in multiple sclerosis (Review) 2

Patient or population: chronic back pain in M S

Outcomes Impact of participants Certainty of the evidence

Reduction in pain intensity Decrease in low back pain scores over- 90 ⊕

Reduction in disability No signif icant changes in disability m ea- 90 ⊕

Quality of Life No signif icant dif f erence in quality of lif e 90 ⊕

GRADE Working Group grades of evidence

Non-pharmacological interventions for chronic pain in multiple sclerosis (Review) 5

Non-pharmacological interventions for chronic pain in multiple sclerosis (Review) 6

Non-pharmacological interventions for chronic pain in multiple sclerosis (Review) 7

Timing of outcome measures

Non-pharmacological interventions for chronic pain in multiple sclerosis (Review) 8

Non-pharmacological interventions for chronic pain in multiple sclerosis (Review) 9

Non-pharmacological interventions for chronic pain in multiple sclerosis (Review) 10

Non-pharmacological interventions for chronic pain in multiple sclerosis (Review) 11

Non-pharmacological interventions for chronic pain in multiple sclerosis (Review) 12

Non-pharmacological interventions for chronic pain in multiple sclerosis (Review) 13

Non-pharmacological interventions for chronic pain in multiple sclerosis (Review) 15

Non-pharmacological interventions for chronic pain in multiple sclerosis (Review) 16

Patient or population: chronic m usculoskeletal pain in people with M S

Outcomes Impact of participants Certainty of the evidence

Reduction in pain intensity Signif icant reduction in pain scores m ea- 73 ⊕

Reduction in disability Signif icant reduction in disability m ea- 73 ⊕

Quality of Life Both groups showed a signif icant reduc- 73 ⊕

Reduction in Fatigue Treatm ent group showed a signif icant 73 ⊕

GRADE Working Group grades of evidence

Patient or population: chronic neuropathic pain in M S

Outcomes Impact of participants Certainty of the evidence

Reduction in fatigue There was no signif icant dif f erence in 16 ⊕

Reduction in depression and anxiety No signif icant dif f erences in depression 35 ⊕

Improvement in QoL Signif icant ef f ect of tim e and group x tim e 19 ⊕

GRADE Working Group grades of evidence

Patient or population: chronic neuropathic pain in M S

Outcomes Impact of participants Certainty of the evidence

Reduction in pain No statistically signif icant changes f or 16 ⊕

Reduction in fatigue No statistical signif icance bef ore and af ter 16 ⊕

GRADE Working Group grades of evidence

Telephone- delivered education compared to sham for chronic pain in M S

Patient or population: chronic pain in M S

Outcomes Impact of participants Certainty of the evidence

GRADE Working Group grades of evidence

Hypnosis compared to relaxation/ control for chronic pain in M S

Patient or population: chronic pain in M S

Outcomes Impact of participants Certainty of the evidence

Reduction in pain intensity Statistically signif icant changes pre and 22 ⊕

Reduction in pain interference Statistically signif icant change pre to post 22 ⊕

BPI: Brief Pain Inventory

GRADE Working Group grades of evidence

Neurofeedback compared to relaxation/ control for chronic pain in M S

Patient or population: chronic pain in M S