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PROTOCOL

Pain management with acupuncture in osteoarthritis: a systematic review and meta-analysis

Reviewer Authors: Taru Manyanga1, 2

, Maria Froese2, Ryan Zarychanski

3, 4, 5, Ahmed Abou-Setta

5, Carol

Friesen6, Michael Tennenhouse

6, and Barbara L. Shay

7.

1. Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada

2. Surgery Rehabilitation Department, Seven Oaks General Hospital, Winnipeg, Manitoba, Canada

3. Department of Internal Medicine, Section of Critical Care, University of Manitoba, Winnipeg,

Manitoba, Canada

4. Department of Haematology and Medical Oncology, Cancer Care Manitoba, Winnipeg, Manitoba,

Canada.

5. George & Fay Yee Center for Healthcare Innovation, University of Manitoba/Winnipeg Regional

Health Authority, Winnipeg, Manitoba, Canada

6. Neil John Maclean Health Sciences Library, University of Manitoba, Winnipeg, Manitoba, Canada

7. School of Medical Rehabilitation, Department of Physiotherapy, University of Manitoba, Winnipeg,

Manitoba, Canada

Sources of Support: No funding was specifically obtained for this systematic review. The authors

declare no conflict of interest.

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Background:

Osteoarthritis, the most common form of arthritis is a progressive degenerative disease

characterised by gradual loss of cartilage1,2

resulting in loss of movement and pain3,4

. It is the

leading cause of disability among non-institutionalized adults2, and is associated with major

impacts on physical function and mobility5. Diagnosis is based on radiological changes, and

clinical presentation of joint pain, which includes tenderness, limitation of movement, crepitus,

joint effusion, and variable degrees of localized inflammation5. The prevalence, disability, and

associated costs of treating osteoarthritis are expected to steadily increase over the next decades

because of an aging population6-8

. Worldwide estimates are that roughly 10% of men and 18% of

women aged sixty years or older have symptomatic osteoarthritis8,9

. In the USA, job related

osteoarthritis is estimated to cost up to 13 billion dollars per year10

. With no known cure1,

treatment is focused on symptom management.

Pharmacological agents commonly used include non-steroidal analgesics (NSAIDs),

acetaminophen, and in severe cases narcotics4,11

. NSAIDs and acetaminophen are only

marginally effective for short term relief of osteoarthritic pain11-13

and NSAIDs are associated

with common side effects (e.g. upset stomach)1,13

. Analgesics are frequently prescribed in

combination other non-pharmacological therapies to decrease the dependency on analgesics1,2,13

.

These therapies include exercises6,14

weight reduction5,6,11

and other complimentary/alternative

therapies such as acupuncture2,5,15

.

Acupuncture is reported to be effective in treating many conditions including

fibromyalgia15

, low back pain16

as well as chronic pain caused by osteoarthritis17

. Due to its

analgesic effects, acupuncture is widely used11

, cost effective18,19

and reported to be a relatively

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safe non-pharmacological treatment1,2,20

. The ability of acupuncture to successfully manage

osteoarthritic symptoms, either as monotherapy or as an adjunct to standard medical care,

remains uncertain21

. Inferences from previous systematic reviews that evaluated the effects of

acupuncture on osteoarthritis have been limited due to important methodological challenges2.

Some have evaluated the efficacy of acupuncture for specific joints (e.g. a single joint13

or

peripheral joints only2) or included data from non-randomized trials and quasi experiments

22.

The purpose of this systematic review is to analyze data from prospective randomized

controlled trials comparing the efficacy and safety of acupuncture versus other treatments in

adults diagnosed with osteoarthritis.

Research Question:

What is the comparative efficacy and safety of acupuncture compared to sham treatment, no

treatment, or standard care in reducing pain intensity for adults diagnosed with osteoarthritis?

Structured Question

Population:

Majority of studies (>80%) where participants are adults (18 years and older) diagnosed

with osteoarthritis.

Intervention:

Acupuncture, regardless of chosen acu-points, or frequency of administration

Comparators:

Sham acupuncture, other active treatment, standard of care, no treatment

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Outcome measures:

Primary Outcome:

Pain intensity reduction measured using a validated pain scale (e.g. Visual Analogue

Scale, Numeric Pain Intensity Scale)

Secondary Outcomes:

Functional mobility (WOMAC index)

Health-Related Quality of Life (Short Form - 36)

Adverse events:

Any reported adverse events such as infections, stroke, fainting, hemorrhage, hematoma,

needle site pain, nausea, dizziness, severe fatigue, headaches, and reactions to needles.

Study design: A systematic review of only prospective randomized controlled trials.

Eligibility Criteria

Inclusion Criteria:

1. Majority of studies (>80%) where participants are adults (18 years and older))

diagnosed with osteoarthritis.

2. Prospective, randomized controlled trials.

3. Traditional acupuncture administration.

Exclusion Criteria:

1. Studies involving animals.

2. All patients received some sort of acupuncture-based intervention

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3. Quasi-randomized controlled trials (e.g., alternate randomization, randomization

according to hospital number) and non-randomized trials (e.g. cohort and case-

control studies).

4. Studies in which electro-acupuncture was the intervention, or electrical

stimulation of the needles was performed

5. Studies in which minimally penetrating acupuncture was used as the control.

Systematic Review Team Members

A graduate student (TM) will lead and coordinate all aspects of the review, including

preparing the literature search strategy, screening relevant material, extracting and analyzing data,

interpreting the results of the meta-analytic procedures, investigating bias, and preparing the final

report; one practising physiotherapist (MF) will assist with independent secondary screening and

data extraction of relevant materials; two clinician/researchers, with experience conducting

systematic reviews (AMAS, RZ) will provide methodological expertise. Two librarians (CF and

MT), with experience conducting searches for systematic reviews will assist with the

development of a search strategy and data management. A senior physiotherapist (BLS) with

extensive clinical and research experience in acupuncture and other therapeutic modalities; will

provide content expertise throughout the review process.

Search strategy for identification of studies

We will perform a search of PubMed (National Library of Medicine), EMBASE (Ovid),

Cochrane Central Register of Controlled Trials (Central Wiley), CINAHL (EbscoHost) and

Natural Standard for reports of relevant published trials. The search strategy for PubMed is

presented in appendix 1. Forward searches will be performed in Scopus and Web of Science to

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identify additional relevant citations. Conference proceedings on Osteoarthritis as well as grey

literature will also be searched. In order to identify ongoing or planned trials of acupuncture and

osteoarthritis, the World Health Organization’s International Clinical Trials Registry Platform

and clinicaltrials.gov will be searched. Lastly, Reference lists of relevant systematic reviews and

included trials will be hand-searched for possible relevant citations. Reference Management will

be performed in EndNote (X6). A PRISMA flow diagram that illustrates the records under

consideration and those selected or withdrawn will be constructed at the end of the review.

Justification for any rejected record(s) will be provided. Studies published in languages other

than English will be removed at the full-text (level two screening) stage of studies review.

Study Selection

A two-step process will be used for study selection. First, two reviewers (TM and MF)

will independently screen the titles and abstracts (when available) of search results to determine

if a study meets the general inclusion criteria. Each report will be classified as: include, exclude,

unsure, or duplicate of another citation. Discrepancies between the two reviewers will be

resolved through consensus dialogue, or third-party adjudication by the content expert as needed.

The full texts of all reports classified as “include” or “unsure” will be retrieved for formal review.

Next, the two reviewers will independently assess the full text of each report by using a

standardized form that outlines the predetermined inclusion and exclusion criteria. The form will

be pilot tested on a sample of studies. After the form is tested, disagreements will be resolved by

discussion between the two reviewers or by third-party adjudication, as needed.

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Data abstraction and management

Data will be extracted by using a standardized form and entered into a Microsoft Excel™

database (Microsoft Corp., Redmond, WA). The form will be pilot tested on a sample of studies.

Data from full-text study reports will be extracted by two reviewers (TM and MF) independently

with disagreements resolved through consensus, and with the assistance of a third party if

consensus cannot be achieved. The following data will be extracted from each study: author

identification, year of publication, language of publication, source of study funding, study design,

setting, methodological quality criteria (see below), study population (including study inclusion

and exclusion criteria), patient characteristics (age, and sex), intervention details (acupuncture

regardless of chosen acu-points, or frequency of administration) and its comparators, relevant

co-interventions and results reported for the outcomes of interest.

Assessment of Methodological Quality

The internal validity of RCTs will be assessed by using the Cochrane Collaboration Risk

of Bias tool23

. This tool consists of six domains (sequence generation, allocation concealment,

blinding, incomplete outcome data, selective outcome reporting, and “other” sources of bias) and

a categorization of the overall risk of bias. Each separate domain is rated “low risk,” “unclear

risk,” or “high risk.” The overall assessment is based on the responses to individual domains. If

one or more individual domains are assessed as having a high risk of bias, the overall assessment

will be rated as having a high risk of bias. The overall risk of bias will be considered low only if

all components are rated as having a low risk of bias. The risk of bias for all other studies will be

rated as unclear. In addition, information on the source of funding will be collected for each

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study. Information regarding methodological quality will be used to guide sensitivity analyses

and explore sources of heterogeneity.

Measures of Treatment Effect

The data from included studies will be analyzed using RevMan (version 5.2)24

. A formal

meta-analysis will be conducted if the data are sufficiently statistically and clinically

homogeneous. Effects of interventions on outcomes will be evaluated at the end of the study, 6

weeks post intervention and at the longest point of follow-up. Pooled continuous data will be

expressed as a weighted mean difference (WMD), or standardized mean difference (SMD) where

multiple scales are used to measure the same outcome, with 95% confidence intervals (CI).

Pooled dichotomous data will be presented as an odds ratio (OR). Statistical heterogeneity of the

data will be explored and quantified, using the chi-square or the I-squared tests. If significant

heterogeneity is suspected, further analysis including subgroup analysis will be conducted.

Publication bias will be assessed by viewing the overlap of the study confidence intervals and

using funnel plot techniques given the known limitations of these methods.

Subgroup/ Sensitivity Analysis

The following a priori subgroup and sensitivity analyses are proposed. Such analyses

will depend on the number of studies included and the availability of appropriate outcomes and

covariates.

Methodological:

Quality (Low risk of bias vs. unclear/ high risk of bias)

Source (Published vs. Grey literature/ abstracts)

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Centres (Single versus Multicentre trials)

Clinical:

Area of diagnosis (peripheral vs. spinal joints)

Use of co-interventions (continued vs. discontinued use)

Type of comparator (active intervention vs. placebo/ no treatment)

Duration of study protocol (as per included studies)

Study follow-up (as per included studies)

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References

1. Ezzo J, Hadhazy V, Birch S, et al. Acupuncture for osteoarthritis of the knee: a systematic review. Arthritis Rheum. Apr 2001;44(4):819-825.

2. Manheimer E, Cheng K, Linde K, et al. Acupuncture for peripheral joint osteoarthritis. Cochrane database of systematic reviews (Online). 2010(1):CD001977.

3. Sovani S, Grogan SP. Osteoarthritis: detection, pathophysiology, and current/future treatment strategies. Orthop. Nurs. Jan-Feb 2013;32(1):25-36; quiz 37-28.

4. Balanescu AR, Feist E, Wolfram G, et al. Efficacy and safety of tanezumab added on to diclofenac sustained release in patients with knee or hip osteoarthritis: a double-blind, placebo-controlled, parallel-group, multicentre phase III randomised clinical trial. Ann. Rheum. Dis. Jul 12 2013.

5. Manheimer E, Linde K, Lao L, Bouter LM, Berman BM. Meta-analysis: Acupuncture for osteoarthritis of the knee. Ann. Intern. Med. 05 Jun 2007;146(12):868-877.

6. Wang SY, Olson-Kellogg B, Shamliyan TA, Choi JY, Ramakrishnan R, Kane RL. Physical therapy interventions for knee pain secondary to osteoarthritis: a systematic review. Ann. Intern. Med. Nov 6 2012;157(9):632-644.

7. Prieto-Alhambra D, Judge A, Javaid MK, Cooper C, Diez-Perez A, Arden NK. Incidence and risk factors for clinically diagnosed knee, hip and hand osteoarthritis: influences of age, gender and osteoarthritis affecting other joints. Ann. Rheum. Dis. Jun 6 2013.

8. Bhatia D, Bejarano T, Novo M. Current interventions in the management of knee osteoarthritis. J. Pharm. Bioallied Sci. Jan 2013;5(1):30-38.

9. Woolf AD, Pfleger B. Burden of major musculoskeletal conditions. Bull. World Health Organ. 2003;81(9):646-656.

10. Leigh JP, Seavey W, Leistikow B. Estimating the costs of job related arthritis. J. Rheumatol. Jul 2001;28(7):1647-1654.

11. Manheimer E, Cheng K, Linde K, et al. Acupuncture for peripheral joint osteoarthritis. Cochrane database of systematic reviews (Online). 2010(1):CD001977.

12. Karner M, Brazkiewicz F, Remppis A, et al. Objectifying specific and nonspecific effects of acupuncture: a double-blinded randomised trial in osteoarthritis of the knee. Evid. Based Complement. Alternat. Med. 2013;2013:427265.

13. Manheimer E, Linde K, Lao L, Bouter LM, Berman BM. Meta-analysis: acupuncture for osteoarthritis of the knee. Ann. Intern. Med. Jun 19 2007;146(12):868-877.

14. Roos EM, Juhl CB. Osteoarthritis 2012 year in review: rehabilitation and outcomes. Osteoarthritis Cartilage. Dec 2012;20(12):1477-1483.

15. Witt CM, Jena S, Brinkhaus B, Liecker B, Wegscheider K, Willich SN. Acupuncture in patients with osteoarthritis of the knee or hip: a randomized, controlled trial with an additional nonrandomized arm. Arthritis Rheum. Nov 2006;54(11):3485-3493.

16. Lee JH, Choi TY, Lee MS, Lee H, Shin BC, Lee H. Acupuncture for acute low back pain: a systematic review. Clin. J. Pain. Feb 2013;29(2):172-185.

17. Witt C, Brinkhaus B, Jena S, et al. Acupuncture in patients with osteoarthritis of the knee: a randomised trial. Lancet. Jul 9-15 2005;366(9480):136-143.

18. Kim SY, Lee H, Chae Y, Park HJ, Lee H. A systematic review of cost-effectiveness analyses alongside randomised controlled trials of acupuncture. Acupunct. Med. Dec 2012;30(4):273-285.

19. Reinhold T, Witt CM, Jena S, Brinkhaus B, Willich SN. Quality of life and cost-effectiveness of acupuncture treatment in patients with osteoarthritis pain. European Journal of Health Economics. // 2008;9(3):209-219.

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20. Deare JC, Zheng Z, Xue CC, et al. Acupuncture for treating fibromyalgia. Cochrane database of systematic reviews (Online). 2013;5:CD007070.

21. Kim EJ, Lim CY, Lee EY, Lee SD, Kim KS. Comparing the effects of individualized, standard, sham and no acupuncture in the treatment of knee osteoarthritis: a multicenter randomized controlled trial. Trials. 2013;14:129.

22. Green S, Buchbinder R, Hetrick S. Acupuncture for shoulder pain. Cochrane database of systematic reviews (Online). 2005(2):CD005319.

23. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.

24. Moher D. Corrigendum to: Preferred Reporting Items For Systematic Reviews And Meta-Analyses: The PRISMA Statement International Journal of Surgery 2010; 8: 336-341. Int. J. Surg. Aug 3 2010.

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Appendix 1:

PubMed Search Terms:

("osteoarthritis"[MeSH Terms] OR "osteoarthritis"[All Fields] OR "osteoarthritides"[All Fields]

OR "osteoarthroses"[All Fields] OR "degenerative arthritis"[all fields] OR "Degenerative

Arthritides"[all fields] OR "Osteoarthrosis Deformans"[all fields]) AND ("acupuncture"[MeSH

Terms] OR "acupuncture"[All Fields] OR "acupuncture therapy"[MeSH Terms] OR

("acupuncture"[All Fields] AND "therap*"[All Fields ])) AND (randomized controlled trial[pt]

OR controlled clinical trial[pt] OR randomized[tiab] OR placebo[tiab] OR "drug

therapy"[Subheading] OR randomly[tiab] OR trial[tiab] OR groups[tiab] NOT ("animals"[MeSH

Terms] NOT "humans"[MeSH Terms]))