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Evidence-Based Evaluation of Complementary Health Approaches for Pain Management in the United States

      Abstract

      Although most pain is acute and resolves within a few days or weeks, millions of Americans have persistent or recurring pain that may become chronic and debilitating. Medications may provide only partial relief from this chronic pain and can be associated with unwanted effects. As a result, many individuals turn to complementary health approaches as part of their pain management strategy. This article examines the clinical trial evidence for the efficacy and safety of several specific approaches—acupuncture, manipulation, massage therapy, relaxation techniques including meditation, selected natural product supplements (chondroitin, glucosamine, methylsulfonylmethane, S-adenosylmethionine), tai chi, and yoga—as used to manage chronic pain and related disability associated with back pain, fibromyalgia, osteoarthritis, neck pain, and severe headaches or migraines.

      Abbreviations and Acronyms:

      ACR (American College of Rheumatology), cLBP (chronic low back pain), FIQ (Fibromyalgia Impact Questionnaire), HCl (hydrochloride), LBP (low back pain), MSM (methylsulfonylmethane), NDI (Neck Disability Index), OA (osteoarthritis), ODI (Oswestry Disability Index), OMT (osteopathic manipulative therapy), RCT (randomized, controlled clinical trial), SAMe (S-adenosylmethionine), SM (spinal manipulation), VAS (visual analog scale), WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index)
      CME Activity
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      Learning Objectives: On completion of this article, you should be able to (1) name complementary health approaches used for pain management; (2) discuss the evidence supporting the use of complementary health approaches for pain management; and (3) provide examples to your patients of complementary health approaches that might be considered as part of a comprehensive pain management plan.
      Disclosures: As a provider accredited by ACCME, Mayo Clinic College of Medicine (Mayo School of Continuous Professional Development) must ensure balance, independence, objectivity, and scientificfic rigor in its educational activities. Course Director(s), Planning Committee members, Faculty, and all others who are in a position to control the content of this educational activity are required to disclose all relevant financial relationships with any commercial interest related to the subject matter of the educational activity. Safeguards against commercial bias have been put in place. Faculty also will disclose any off-label and/or investigational use of pharmaceuticals or instruments discussed in their presentation.
      Disclosure of this information will be published in course materials so that those participants in the activity may formulate their own judgments regarding the presentation.
      In their editorial and administrative roles, William L. Lanier, Jr, MD, Terry L. Jopke, Kimberly D. Sankey, and Nicki M. Smith, MPA, have control of the content of this program but have no relevant financial relationship(s) with industry.
      The authors report no competing interests.
      Method of Participation: In order to claim credit, participants must complete the following:
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      Date of Release: 9/1/2016
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      Questions? Contact [email protected] .
      The most recent national estimate suggests that 126 million adults experience some pain in a given year,
      • Nahin R.L.
      Estimates of pain prevalence and severity in adults: United States, 2012.
      with about one-third (40 million adults) having severe pain. Pain is often associated with poor general health, health-related disability, and increased health care utilization.
      Institute of Medicine Committee on Advancing Pain Research and Education
      Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research.
      Yet according to the Institute of Medicine,
      Institute of Medicine Committee on Advancing Pain Research and Education
      Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research.
      pain is routinely undertreated in health care; pain care that is provided is often fragmented, without a comprehensive assessment or treatment plan, and patients may encounter difficulty obtaining the full range of potential treatments.
      Back pain, joint pain, neck pain, and headaches are among the most common types of pain experienced by US adults (Table 1).
      • Lethbridge-Cejku M.
      • Schiller J.S.
      • Bernadel L.
      Summary health statistics for U.S. adults: National Health Interview Survey, 2002.
      • Pleis J.R.
      • Lucas J.W.
      Summary health statistics for U.S. adults: National Health Interview Survey, 2007.
      • Blackwell D.L.
      • Lucas J.W.
      • Clarke T.C.
      Summary health statistics for U.S. adults: National Health Interview Survey, 2012.
      • Walitt B.
      • Nahin R.L.
      • Katz R.S.
      • Bergman M.J.
      • Wolfe F.
      The prevalence and characteristics of fibromyalgia in the 2012 National Health Interview Survey.
      The prevalence rates for these conditions have remained relatively stable over time. Among the many pharmacological and nonpharmacological approaches that have been incorporated into pain management strategies are complementary health approaches. This broad category of care includes procedures by licensed practitioners such as acupuncturists, chiropractors, and massage therapists, as well as self-care approaches such as relaxation techniques (eg, meditation) and meditative movement-based approaches (eg, yoga and tai chi) and natural products such a glucosamine and herbal medicines. National surveys going back more than 25 years have consistently found that these complementary approaches are used by about 30% to 40% of the US public in a given year,
      • Barnes P.M.
      • Bloom B.
      • Nahin R.L.
      Complementary and alternative medicine use among adults and children: United States, 2007.
      • Barnes P.M.
      • Powell-Griner E.
      • McFann K.
      • Nahin R.L.
      Complementary and alternative medicine use among adults: United States, 2002.
      • Clarke T.C.
      • Black L.I.
      • Stussman B.J.
      • Barnes P.M.
      • Nahin R.L.
      Trends in the use of complementary health approaches among adults: United States, 2002-2012.
      • Eisenberg D.M.
      • Davis R.B.
      • Ettner S.L.
      • et al.
      Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey.
      • Eisenberg D.M.
      • Kessler R.C.
      • Foster C.
      • Norlock F.E.
      • Calkins D.R.
      • Delbanco T.L.
      Unconventional medicine in the United States: prevalence, costs, and patterns of use.
      although use of a given approach may wax and wane over time (Table 2).
      Table 1Age-Adjusted Percentages of Selected Health Conditions Among US Adults, NHIS 2002, 2007, 2012
      NA = not available; NHIS = National Health Interview Survey.
      Health condition2002
      • Lethbridge-Cejku M.
      • Schiller J.S.
      • Bernadel L.
      Summary health statistics for U.S. adults: National Health Interview Survey, 2002.
      2007
      • Pleis J.R.
      • Lucas J.W.
      Summary health statistics for U.S. adults: National Health Interview Survey, 2007.
      2012
      • Blackwell D.L.
      • Lucas J.W.
      • Clarke T.C.
      Summary health statistics for U.S. adults: National Health Interview Survey, 2012.
      • Walitt B.
      • Nahin R.L.
      • Katz R.S.
      • Bergman M.J.
      • Wolfe F.
      The prevalence and characteristics of fibromyalgia in the 2012 National Health Interview Survey.
      Low back pain in the past 3 mo26.4%25.4%27.6%
      Arthritis20.9%20.3%20.6%
      Neck pain in the past 3 mo13.8%12.8%13.9%
      Severe headache or migraine in the past 3 mo15.0%12.3%14.1%
      Fibromyalgia during lifetimeNANA1.75%
      a NA = not available; NHIS = National Health Interview Survey.
      Table 2Age-Adjusted Percentages of Use for Selected Complementary Health Approaches by US Adults, 2002-2012
      Complementary health approach2002
      • Barnes P.M.
      • Bloom B.
      • Nahin R.L.
      Complementary and alternative medicine use among adults and children: United States, 2007.
      2007
      • Barnes P.M.
      • Powell-Griner E.
      • McFann K.
      • Nahin R.L.
      Complementary and alternative medicine use among adults: United States, 2002.
      2012
      • Clarke T.C.
      • Black L.I.
      • Stussman B.J.
      • Barnes P.M.
      • Nahin R.L.
      Trends in the use of complementary health approaches among adults: United States, 2002-2012.
      Acupuncture1.1%1.4%1.5%
      Manipulation7.5%8.6%8.4%
      Massage therapy5.0%8.3%6.9%
      Meditation7.6%9.4%8.0%
      Natural product supplements18.9%17.7%17.7%
      Yoga, tai chi, and qigong5.8%6.7%10.1%
      Although a substantial part of this use is for overall wellness and prevention,
      • Stussman B.J.
      • Black L.I.
      • Barnes P.M.
      • Clarke T.C.
      • Nahin R.L.
      Wellness-related use of common complementary health approaches among adults: United States, 2012.
      • Upchurch D.M.
      • Rainisch B.W.
      The importance of wellness among users of complementary and alternative medicine: findings from the 2007 National Health Interview Survey.
      painful conditions are the most common health conditions for which individuals turn to these complementary approaches.
      • Barnes P.M.
      • Bloom B.
      • Nahin R.L.
      Complementary and alternative medicine use among adults and children: United States, 2007.
      • Barnes P.M.
      • Powell-Griner E.
      • McFann K.
      • Nahin R.L.
      Complementary and alternative medicine use among adults: United States, 2002.
      • Eisenberg D.M.
      • Davis R.B.
      • Ettner S.L.
      • et al.
      Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey.
      • Eisenberg D.M.
      • Kessler R.C.
      • Foster C.
      • Norlock F.E.
      • Calkins D.R.
      • Delbanco T.L.
      Unconventional medicine in the United States: prevalence, costs, and patterns of use.
      • Nahin R.L.
      • Stussman B.J.
      • Herman P.M.
      Out-of-pocket expenditures on complementary health approaches associated with painful health conditions in a nationally representative adult sample.
      In 2007, for example, about 14.3 million adults used a complementary health approach for their back pain, about 5.0 million used these approaches for their neck pain, and 3.1 million for their arthritis.
      • Barnes P.M.
      • Bloom B.
      • Nahin R.L.
      Complementary and alternative medicine use among adults and children: United States, 2007.
      Far fewer individuals used complementary health approaches for other chronic diseases such as depression (1.0 million), hypertension (0.8 million), diabetes (0.7 million), or cancer (0.4 million).
      Based on national survey data,
      • Nahin R.L.
      • Stussman B.J.
      • Herman P.M.
      Out-of-pocket expenditures on complementary health approaches associated with painful health conditions in a nationally representative adult sample.
      this high use of complementary health approaches for painful conditions translated into $8.5 billion in out-of-pocket payments for these approaches to manage back pain, $3.6 billion to manage neck pain, and $2.3 billion to manage arthritis. Substantially less is spent out-of-pocket on complementary health approaches to treat other chronic health conditions such as depression ($1.1 billion), hypertension ($0.7 billion), diabetes ($0.3 billion), and cancer ($0.2 billion).
      Given the high use of complementary health approaches for pain, a number of specific complementary approaches have undergone mechanistic and clinical evaluations culminating in phase 3 trials. This article examines the clinical trial evidence for the efficacy and safety of several widely used approaches—acupuncture, manipulation, massage therapy, relaxation techniques including meditation, selected natural product supplements (eg, chondroitin and glucosamine), tai chi, and yoga (defined in Supplemental Appendix 1, available online at http://www.mayoclinicproceedings.org)—as used to manage chronic pain and related disability associated with back pain, osteoarthritis (OA), neck pain, and severe headaches or migraines, conditions frequently seen and managed in the primary care setting. Fibromyalgia was included in this review as an example of a complex pain syndrome that is often managed with a multimodal approach that may include complementary approaches. Cancer pain is certainly a major public health concern but is more likely to be addressed outside the primary care setting (eg, by oncologists, at cancer centers, as part of palliative care).
      The randomized, controlled clinical trial (RCT) is considered the strongest study design for investigating the efficacy and safety of pharmacological, behavioral, and physical interventions. To identify examples of RCTs for each complementary approach, we performed searches of the MEDLINE database for articles published from January 1, 1966, through March 31, 2016, using the search strategy outlined in Supplemental Appendix 2 (available online at http://www.mayoclinicproceedings.org). In order to make this review as relevant as possible to primary care physicians in the United States, we limited this review to RCTs either proformed in the United States or that included participants from the United States. This decision was based on 2 factors. First, the unique health care system in the United States vs other countries means that the standard care or usual care control groups used in the United States and other countries may vary substantially. Thus, whether a given complementary approach performs better than usual care in another country may not reflect how the approach would perform in US trials. Another factor is that the training and licensure of acupuncturists, chiropractors, and naturopathic doctors vary substantially among countries, as does the marketing, regulation, and use of dietary supplements. For instance, in Germany, the location of some of the largest acupuncture trials, acupuncture is only practiced by medical doctors, whereas the vast majority of acupuncture treatment in the United States is provided by licensed acupuncturists. Thus, the findings from German trials may not be directly comparable to acupuncture as practiced in the United States.
      Brief summaries of the reviewed RCTs are presented with details provided in online supplemental tables. The findings of these RCTs also illustrate several methodological issues that should be considered when interpreting the trial data. These issues are summarized briefly at the end of this article.

      Low Back Pain

       Acupuncture

      We found 4 RCTs (total participants, 1092)
      • Cherkin D.C.
      • Eisenberg D.
      • Sherman K.J.
      • et al.
      Randomized trial comparing traditional Chinese medical acupuncture, therapeutic massage, and self-care education for chronic low back pain.
      • Cherkin D.C.
      • Sherman K.J.
      • Avins A.L.
      • et al.
      A randomized trial comparing acupuncture, simulated acupuncture, and usual care for chronic low back pain.
      • Wang S.M.
      • Dezinno P.
      • Lin E.C.
      • et al.
      Auricular acupuncture as a treatment for pregnant women who have low back and posterior pelvic pain: a pilot study.
      • Wasan A.D.
      • Kong J.
      • Pham L.D.
      • Kaptchuk T.J.
      • Edwards R.
      • Gollub R.L.
      The impact of placebo, psychopathology, and expectations on the response to acupuncture needling in patients with chronic low back pain.
      that assessed the clinical benefit of acupuncture for treatment of low back pain (LBP) (age range, 28-60 years; most participants were white) and used primary study outcomes of self-report of pain intensity (numeric rating scale or visual analog scale [VAS]) and/or functional disability (Roland-Morris Disability Questionnaire, Oswestry Disability Index [ODI], or Disability Rating Index). Cherkin et al
      • Cherkin D.C.
      • Eisenberg D.
      • Sherman K.J.
      • et al.
      Randomized trial comparing traditional Chinese medical acupuncture, therapeutic massage, and self-care education for chronic low back pain.
      • Cherkin D.C.
      • Sherman K.J.
      • Avins A.L.
      • et al.
      A randomized trial comparing acupuncture, simulated acupuncture, and usual care for chronic low back pain.
      reported modest improvement in pain intensity and function compared with usual care. In pregnant women using auricular acupuncture, Wang et al
      • Wang S.M.
      • Dezinno P.
      • Lin E.C.
      • et al.
      Auricular acupuncture as a treatment for pregnant women who have low back and posterior pelvic pain: a pilot study.
      found a significant reduction in pain intensity and improved functional status compared with no treatment. Comparison of verum to sham acupuncture had mixed results, with 2 RCTS
      • Cherkin D.C.
      • Sherman K.J.
      • Avins A.L.
      • et al.
      A randomized trial comparing acupuncture, simulated acupuncture, and usual care for chronic low back pain.
      • Wasan A.D.
      • Kong J.
      • Pham L.D.
      • Kaptchuk T.J.
      • Edwards R.
      • Gollub R.L.
      The impact of placebo, psychopathology, and expectations on the response to acupuncture needling in patients with chronic low back pain.
      finding no significant difference and 1 RCT
      • Wang S.M.
      • Dezinno P.
      • Lin E.C.
      • et al.
      Auricular acupuncture as a treatment for pregnant women who have low back and posterior pelvic pain: a pilot study.
      finding a slight but significant difference. No significant adverse events were reported.

       Massage Therapy

      We identified 8 RCTs that studied the use of massage for LBP
      • Cherkin D.C.
      • Eisenberg D.
      • Sherman K.J.
      • et al.
      Randomized trial comparing traditional Chinese medical acupuncture, therapeutic massage, and self-care education for chronic low back pain.
      • Cherkin D.C.
      • Sherman K.J.
      • Kahn J.
      • et al.
      A comparison of the effects of 2 types of massage and usual care on chronic low back pain: a randomized, controlled trial.
      • Eisenberg D.M.
      • Post D.E.
      • Davis R.B.
      • et al.
      Addition of choice of complementary therapies to usual care for acute low back pain: a randomized controlled trial.
      • Field T.
      • Figueiredo B.
      • Hernandez-Reif M.
      • Diego M.
      • Deeds O.
      • Ascencio A.
      Massage therapy reduces pain in pregnant women, alleviates prenatal depression in both parents and improves their relationships.
      • Field T.
      • Hernandez-Reif M.
      • Diego M.
      • Fraser M.
      Lower back pain and sleep disturbance are reduced following massage therapy.
      • Hernandez-Reif M.
      • Field T.
      • Krasnegor J.
      • Theakston H.
      Lower back pain is reduced and range of motion increased after massage therapy.
      • Jacobson E.E.
      • Meleger A.L.
      • Bonato P.
      • et al.
      Structural integration as an adjunct to outpatient rehabilitation for chronic nonspecific low back pain: a randomized pilot clinical trial.
      • Wilson E.
      • Payton O.
      • Donegan-Shoaf L.
      • Dec K.
      Muscle energy technique in patients with acute low back pain: a pilot clinical trial.
      (total participants, 829). Massage types included Swedish/relaxation, structural, structural integration, and muscle energy; sessions varied in duration from 15 to 90 minutes. For chronic LBP (cLBP), 2 larger studies
      • Cherkin D.C.
      • Eisenberg D.
      • Sherman K.J.
      • et al.
      Randomized trial comparing traditional Chinese medical acupuncture, therapeutic massage, and self-care education for chronic low back pain.
      • Cherkin D.C.
      • Sherman K.J.
      • Kahn J.
      • et al.
      A comparison of the effects of 2 types of massage and usual care on chronic low back pain: a randomized, controlled trial.
      comparing massage with usual care reported modest improvements in pain and function at 10 weeks, but the benefit was not sustained at 52 weeks.
      • Cherkin D.C.
      • Eisenberg D.
      • Sherman K.J.
      • et al.
      Randomized trial comparing traditional Chinese medical acupuncture, therapeutic massage, and self-care education for chronic low back pain.
      Three smaller studies compared massage to either usual outpatient rehabilitation
      • Jacobson E.E.
      • Meleger A.L.
      • Bonato P.
      • et al.
      Structural integration as an adjunct to outpatient rehabilitation for chronic nonspecific low back pain: a randomized pilot clinical trial.
      or relaxation
      • Field T.
      • Hernandez-Reif M.
      • Diego M.
      • Fraser M.
      Lower back pain and sleep disturbance are reduced following massage therapy.
      • Hernandez-Reif M.
      • Field T.
      • Krasnegor J.
      • Theakston H.
      Lower back pain is reduced and range of motion increased after massage therapy.
      and did not observe significant between-group differences for pain and/or function. For acute or subacute LBP, 2 smaller studies found significant, albeit modest, improvements in pain compared with no treatment (−1.5 points on a numeric rating scale)
      • Field T.
      • Figueiredo B.
      • Hernandez-Reif M.
      • Diego M.
      • Deeds O.
      • Ascencio A.
      Massage therapy reduces pain in pregnant women, alleviates prenatal depression in both parents and improves their relationships.
      or function (−18% on the ODI)
      • Wilson E.
      • Payton O.
      • Donegan-Shoaf L.
      • Dec K.
      Muscle energy technique in patients with acute low back pain: a pilot clinical trial.
      compared with a putative placebo. No RCTs reported significant adverse events.

       Osteopathic Manipulative Therapy

      Six RCTs of osteopathic manipulative therapy (OMT) for LBP were identified (total participants, 1308).
      • Andersson G.B.
      • Lucente T.
      • Davis A.M.
      • Kappler R.E.
      • Lipton J.A.
      • Leurgans S.
      A comparison of osteopathic spinal manipulation with standard care for patients with low back pain.
      • Cruser dA.
      • Maurer D.
      • Hensel K.
      • Brown S.K.
      • White K.
      • Stoll S.T.
      A randomized, controlled trial of osteopathic manipulative treatment for acute low back pain in active duty military personnel.
      • Hensel K.L.
      • Buchanan S.
      • Brown S.K.
      • Rodriguez M.
      • Cruser dA.
      Pregnancy research on osteopathic manipulation optimizing treatment effects: the PROMOTE study.
      • Licciardone J.C.
      • Buchanan S.
      • Hensel K.L.
      • King H.H.
      • Fulda K.G.
      • Stoll S.T.
      Osteopathic manipulative treatment of back pain and related symptoms during pregnancy: a randomized controlled trial.
      • Licciardone J.C.
      • Minotti D.E.
      • Gatchel R.J.
      • Kearns C.M.
      • Singh K.P.
      Osteopathic manual treatment and ultrasound therapy for chronic low back pain: a randomized controlled trial.
      • Licciardone J.C.
      • Stoll S.T.
      • Fulda K.G.
      • et al.
      Osteopathic manipulative treatment for chronic low back pain: a randomized controlled trial.
      Two RCTs examined OMT compared with sham OMT for cLBP
      • Licciardone J.C.
      • Minotti D.E.
      • Gatchel R.J.
      • Kearns C.M.
      • Singh K.P.
      Osteopathic manual treatment and ultrasound therapy for chronic low back pain: a randomized controlled trial.
      • Licciardone J.C.
      • Stoll S.T.
      • Fulda K.G.
      • et al.
      Osteopathic manipulative treatment for chronic low back pain: a randomized controlled trial.
      using similar intervention paradigms and reported mixed results, with 1 finding no significant difference and 1 reporting a 9-mm reduction in pain intensity on a VAS. Two RCTs compared OMT with usual care for acute or subacute LBP,
      • Andersson G.B.
      • Lucente T.
      • Davis A.M.
      • Kappler R.E.
      • Lipton J.A.
      • Leurgans S.
      A comparison of osteopathic spinal manipulation with standard care for patients with low back pain.
      • Cruser dA.
      • Maurer D.
      • Hensel K.
      • Brown S.K.
      • White K.
      • Stoll S.T.
      A randomized, controlled trial of osteopathic manipulative treatment for acute low back pain in active duty military personnel.
      and both reported no significant improvement for function/disability but mixed results for pain intensity for between-group differences. In pregnant women with LBP, 2 studies compared the benefit of adding OMT or placebo ultrasound treatment to usual obstetric care and reported significant modest improvements with added care but no significant between-group differences.
      • Hensel K.L.
      • Buchanan S.
      • Brown S.K.
      • Rodriguez M.
      • Cruser dA.
      Pregnancy research on osteopathic manipulation optimizing treatment effects: the PROMOTE study.
      • Licciardone J.C.
      • Buchanan S.
      • Hensel K.L.
      • King H.H.
      • Fulda K.G.
      • Stoll S.T.
      Osteopathic manipulative treatment of back pain and related symptoms during pregnancy: a randomized controlled trial.
      No RCTs reported significant adverse events.

       Spinal Manipulation

      We reviewed 24 RCTs
      • Bialosky J.E.
      • George S.Z.
      • Horn M.E.
      • Price D.D.
      • Staud R.
      • Robinson M.E.
      Spinal manipulative therapy-specific changes in pain sensitivity in individuals with low back pain (NCT01168999).
      • Brennan G.P.
      • Fritz J.M.
      • Hunter S.J.
      • Thackeray A.
      • Delitto A.
      • Erhard R.E.
      Identifying subgroups of patients with acute/subacute “nonspecific” low back pain: results of a randomized clinical trial.
      • Bronfort G.
      • Evans R.L.
      • Maiers M.
      • Anderson A.V.
      Spinal manipulation, epidural injections, and self-care for sciatica: a pilot study for a randomized clinical trial.
      • Bronfort G.
      • Goldsmith C.H.
      • Nelson C.F.
      • Boline P.D.
      • Anderson A.V.
      Trunk exercise combined with spinal manipulative or NSAID therapy for chronic low back pain: a randomized, observer-blinded clinical trial.
      • Bronfort G.
      • Hondras M.A.
      • Schulz C.A.
      • Evans R.L.
      • Long C.R.
      • Grimm R.
      Spinal manipulation and home exercise with advice for subacute and chronic back-related leg pain: a trial with adaptive allocation.
      • Bronfort G.
      • Maiers M.J.
      • Evans R.L.
      • et al.
      Supervised exercise, spinal manipulation, and home exercise for chronic low back pain: a randomized clinical trial.
      • Cherkin D.C.
      • Deyo R.A.
      • Battié M.
      • Street J.
      • Barlow W.
      A comparison of physical therapy, chiropractic manipulation, and provision of an educational booklet for the treatment of patients with low back pain.
      • Cleland J.A.
      • Fritz J.M.
      • Kulig K.
      • et al.
      Comparison of the effectiveness of three manual physical therapy techniques in a subgroup of patients with low back pain who satisfy a clinical prediction rule: a randomized clinical trial.
      • Cook C.
      • Learman K.
      • Showalter C.
      • Kabbaz V.
      • O'Halloran B.
      Early use of thrust manipulation versus non-thrust manipulation: a randomized clinical trial.
      • Fritz J.M.
      • Magel J.S.
      • McFadden M.
      • et al.
      Early physical therapy vs usual care in patients with recent-onset low back pain: a randomized clinical trial.
      • George J.W.
      • Skaggs C.D.
      • Thompson P.A.
      • Nelson D.M.
      • Gavard J.A.
      • Gross G.A.
      A randomized controlled trial comparing a multimodal intervention and standard obstetrics care for low back and pelvic pain in pregnancy.
      • Goertz C.M.
      • Long C.R.
      • Hondras M.A.
      • et al.
      Adding chiropractic manipulative therapy to standard medical care for patients with acute low back pain: results of a pragmatic randomized comparative effectiveness study.
      • Gudavalli M.R.
      • Cambron J.A.
      • McGregor M.
      • et al.
      A randomized clinical trial and subgroup analysis to compare flexion-distraction with active exercise for chronic low back pain.
      • Haas M.
      • Groupp E.
      • Kraemer D.F.
      Dose-response for chiropractic care of chronic low back pain.
      • Haas M.
      • Vavrek D.
      • Peterson D.
      • Polissar N.
      • Neradilek M.B.
      Dose-response and efficacy of spinal manipulation for care of chronic low back pain: a randomized controlled trial.
      • Hadler N.M.
      • Curtis P.
      • Gillings D.B.
      • Stinnett S.
      A benefit of spinal manipulation as adjunctive therapy for acute low-back pain: a stratified controlled trial.
      • Hoehler F.K.
      • Tobis J.S.
      • Buerger A.A.
      Spinal manipulation for low back pain.
      • Hoiriis K.T.
      • Pfleger B.
      • McDuffie F.C.
      • et al.
      A randomized clinical trial comparing chiropractic adjustments to muscle relaxants for subacute low back pain.
      • Hondras M.A.
      • Long C.R.
      • Cao Y.
      • Rowell R.M.
      • Meeker W.C.
      A randomized controlled trial comparing 2 types of spinal manipulation and minimal conservative medical care for adults 55 years and older with subacute or chronic low back pain.
      • Hsieh C.Y.
      • Adams A.H.
      • Tobis J.
      • et al.
      Effectiveness of four conservative treatments for subacute low back pain: a randomized clinical trial.
      • Hurwitz E.L.
      • Morgenstern H.
      • Harber P.
      • et al.
      A randomized trial of medical care with and without physical therapy and chiropractic care with and without physical modalities for patients with low back pain: 6-month follow-up outcomes from the UCLA low back pain study.
      • Pope M.H.
      • Phillips R.B.
      • Haugh L.D.
      • Hsieh C.Y.
      • MacDonald L.
      • Haldeman S.
      A prospective randomized three-week trial of spinal manipulation, transcutaneous muscle stimulation, massage and corset in the treatment of subacute low back pain.
      • Schneider M.
      • Haas M.
      • Glick R.
      • Stevans J.
      • Landsittel D.
      Comparison of spinal manipulation methods and usual medical care for acute and subacute low back pain: a randomized clinical trial.
      • Sutlive T.G.
      • Mabry L.M.
      • Easterling E.J.
      • et al.
      Comparison of short-term response to two spinal manipulation techniques for patients with low back pain in a military beneficiary population.
      (total participants, 4503; all adults) of spinal manipulation (SM) for LBP. Recent data suggest that for cLBP, the “dose” of SM (defined as the number of sessions) may affect outcomes,
      • Haas M.
      • Groupp E.
      • Kraemer D.F.
      Dose-response for chiropractic care of chronic low back pain.
      • Haas M.
      • Vavrek D.
      • Peterson D.
      • Polissar N.
      • Neradilek M.B.
      Dose-response and efficacy of spinal manipulation for care of chronic low back pain: a randomized controlled trial.
      • Nyiendo J.
      • Haas M.
      • Goldberg B.
      • Sexton G.
      Patient characteristics and physicians' practice activities for patients with chronic low back pain: a practice-based study of primary care and chiropractic physicians.
      and hence the dose utilized was dichotomized for this report depending on whether 6 or more sessions of SM were provided in a given study. No RCTs reported significant adverse events.

       Chronic LBP

      There were 9 studies of SM for cLBP (total participants, 1882),
      • Bialosky J.E.
      • George S.Z.
      • Horn M.E.
      • Price D.D.
      • Staud R.
      • Robinson M.E.
      Spinal manipulative therapy-specific changes in pain sensitivity in individuals with low back pain (NCT01168999).
      • Bronfort G.
      • Goldsmith C.H.
      • Nelson C.F.
      • Boline P.D.
      • Anderson A.V.
      Trunk exercise combined with spinal manipulative or NSAID therapy for chronic low back pain: a randomized, observer-blinded clinical trial.
      • Bronfort G.
      • Hondras M.A.
      • Schulz C.A.
      • Evans R.L.
      • Long C.R.
      • Grimm R.
      Spinal manipulation and home exercise with advice for subacute and chronic back-related leg pain: a trial with adaptive allocation.
      • Bronfort G.
      • Maiers M.J.
      • Evans R.L.
      • et al.
      Supervised exercise, spinal manipulation, and home exercise for chronic low back pain: a randomized clinical trial.
      • Cook C.
      • Learman K.
      • Showalter C.
      • Kabbaz V.
      • O'Halloran B.
      Early use of thrust manipulation versus non-thrust manipulation: a randomized clinical trial.
      • Gudavalli M.R.
      • Cambron J.A.
      • McGregor M.
      • et al.
      A randomized clinical trial and subgroup analysis to compare flexion-distraction with active exercise for chronic low back pain.
      • Haas M.
      • Groupp E.
      • Kraemer D.F.
      Dose-response for chiropractic care of chronic low back pain.
      • Haas M.
      • Vavrek D.
      • Peterson D.
      • Polissar N.
      • Neradilek M.B.
      Dose-response and efficacy of spinal manipulation for care of chronic low back pain: a randomized controlled trial.
      • Hondras M.A.
      • Long C.R.
      • Cao Y.
      • Rowell R.M.
      • Meeker W.C.
      A randomized controlled trial comparing 2 types of spinal manipulation and minimal conservative medical care for adults 55 years and older with subacute or chronic low back pain.
      8 of which employed 6 or more sessions for treatment, and 1 of these studies included principally (more than two-thirds) adult women.
      • Bialosky J.E.
      • George S.Z.
      • Horn M.E.
      • Price D.D.
      • Staud R.
      • Robinson M.E.
      Spinal manipulative therapy-specific changes in pain sensitivity in individuals with low back pain (NCT01168999).
      Among the 4 larger RCTs (each with 200 or more participants)
      • Bronfort G.
      • Maiers M.J.
      • Evans R.L.
      • et al.
      Supervised exercise, spinal manipulation, and home exercise for chronic low back pain: a randomized clinical trial.
      • Gudavalli M.R.
      • Cambron J.A.
      • McGregor M.
      • et al.
      A randomized clinical trial and subgroup analysis to compare flexion-distraction with active exercise for chronic low back pain.
      • Haas M.
      • Vavrek D.
      • Peterson D.
      • Polissar N.
      • Neradilek M.B.
      Dose-response and efficacy of spinal manipulation for care of chronic low back pain: a randomized controlled trial.
      • Hondras M.A.
      • Long C.R.
      • Cao Y.
      • Rowell R.M.
      • Meeker W.C.
      A randomized controlled trial comparing 2 types of spinal manipulation and minimal conservative medical care for adults 55 years and older with subacute or chronic low back pain.
      that compared high-velocity low-amplitude SM with an active comparison (exercise, usual care, physical therapy, light touch), 3 found significant, albeit modest, between-group differences for pain intensity and/or function. Two studies directly examined the dose of high-velocity low-amplitude SM,
      • Haas M.
      • Groupp E.
      • Kraemer D.F.
      Dose-response for chiropractic care of chronic low back pain.
      • Haas M.
      • Vavrek D.
      • Peterson D.
      • Polissar N.
      • Neradilek M.B.
      Dose-response and efficacy of spinal manipulation for care of chronic low back pain: a randomized controlled trial.
      and both found that higher doses (12 and 18 sessions of SM) provided larger improvement at 12 and 52 weeks, respectively. One RCT utilized a putative placebo SM
      • Bialosky J.E.
      • George S.Z.
      • Horn M.E.
      • Price D.D.
      • Staud R.
      • Robinson M.E.
      Spinal manipulative therapy-specific changes in pain sensitivity in individuals with low back pain (NCT01168999).
      and found that after the first session, the results of verum SM were better than sham SM and better than no treatment, but at 2 weeks, there were no significant between-group differences. One RCT compared thrust to nonthrust SM
      • Cook C.
      • Learman K.
      • Showalter C.
      • Kabbaz V.
      • O'Halloran B.
      Early use of thrust manipulation versus non-thrust manipulation: a randomized clinical trial.
      (less than 6 sessions) and reported no significant between-group differences.

       Acute, Subacute, or Mixed LBP

      There were 15 studies of SM for either acute, subacute, or a mixture of types of LBP (total participants, 2621).
      • Brennan G.P.
      • Fritz J.M.
      • Hunter S.J.
      • Thackeray A.
      • Delitto A.
      • Erhard R.E.
      Identifying subgroups of patients with acute/subacute “nonspecific” low back pain: results of a randomized clinical trial.
      • Bronfort G.
      • Evans R.L.
      • Maiers M.
      • Anderson A.V.
      Spinal manipulation, epidural injections, and self-care for sciatica: a pilot study for a randomized clinical trial.
      • Cherkin D.C.
      • Deyo R.A.
      • Battié M.
      • Street J.
      • Barlow W.
      A comparison of physical therapy, chiropractic manipulation, and provision of an educational booklet for the treatment of patients with low back pain.
      • Cleland J.A.
      • Fritz J.M.
      • Kulig K.
      • et al.
      Comparison of the effectiveness of three manual physical therapy techniques in a subgroup of patients with low back pain who satisfy a clinical prediction rule: a randomized clinical trial.
      • Fritz J.M.
      • Magel J.S.
      • McFadden M.
      • et al.
      Early physical therapy vs usual care in patients with recent-onset low back pain: a randomized clinical trial.
      • George J.W.
      • Skaggs C.D.
      • Thompson P.A.
      • Nelson D.M.
      • Gavard J.A.
      • Gross G.A.
      A randomized controlled trial comparing a multimodal intervention and standard obstetrics care for low back and pelvic pain in pregnancy.
      • Goertz C.M.
      • Long C.R.
      • Hondras M.A.
      • et al.
      Adding chiropractic manipulative therapy to standard medical care for patients with acute low back pain: results of a pragmatic randomized comparative effectiveness study.
      • Hadler N.M.
      • Curtis P.
      • Gillings D.B.
      • Stinnett S.
      A benefit of spinal manipulation as adjunctive therapy for acute low-back pain: a stratified controlled trial.
      • Hoehler F.K.
      • Tobis J.S.
      • Buerger A.A.
      Spinal manipulation for low back pain.
      • Hoiriis K.T.
      • Pfleger B.
      • McDuffie F.C.
      • et al.
      A randomized clinical trial comparing chiropractic adjustments to muscle relaxants for subacute low back pain.
      • Hsieh C.Y.
      • Adams A.H.
      • Tobis J.
      • et al.
      Effectiveness of four conservative treatments for subacute low back pain: a randomized clinical trial.
      • Hurwitz E.L.
      • Morgenstern H.
      • Harber P.
      • et al.
      A randomized trial of medical care with and without physical therapy and chiropractic care with and without physical modalities for patients with low back pain: 6-month follow-up outcomes from the UCLA low back pain study.
      • Pope M.H.
      • Phillips R.B.
      • Haugh L.D.
      • Hsieh C.Y.
      • MacDonald L.
      • Haldeman S.
      A prospective randomized three-week trial of spinal manipulation, transcutaneous muscle stimulation, massage and corset in the treatment of subacute low back pain.
      • Schneider M.
      • Haas M.
      • Glick R.
      • Stevans J.
      • Landsittel D.
      Comparison of spinal manipulation methods and usual medical care for acute and subacute low back pain: a randomized clinical trial.
      • Sutlive T.G.
      • Mabry L.M.
      • Easterling E.J.
      • et al.
      Comparison of short-term response to two spinal manipulation techniques for patients with low back pain in a military beneficiary population.
      Six of these studies were of modest to moderate size (ie, >100 participants) and utilized 6 or more sessions of SM.
      • Cherkin D.C.
      • Deyo R.A.
      • Battié M.
      • Street J.
      • Barlow W.
      A comparison of physical therapy, chiropractic manipulation, and provision of an educational booklet for the treatment of patients with low back pain.
      • George J.W.
      • Skaggs C.D.
      • Thompson P.A.
      • Nelson D.M.
      • Gavard J.A.
      • Gross G.A.
      A randomized controlled trial comparing a multimodal intervention and standard obstetrics care for low back and pelvic pain in pregnancy.
      • Hoiriis K.T.
      • Pfleger B.
      • McDuffie F.C.
      • et al.
      A randomized clinical trial comparing chiropractic adjustments to muscle relaxants for subacute low back pain.
      • Hsieh C.Y.
      • Adams A.H.
      • Tobis J.
      • et al.
      Effectiveness of four conservative treatments for subacute low back pain: a randomized clinical trial.
      • Pope M.H.
      • Phillips R.B.
      • Haugh L.D.
      • Hsieh C.Y.
      • MacDonald L.
      • Haldeman S.
      A prospective randomized three-week trial of spinal manipulation, transcutaneous muscle stimulation, massage and corset in the treatment of subacute low back pain.
      • Schneider M.
      • Haas M.
      • Glick R.
      • Stevans J.
      • Landsittel D.
      Comparison of spinal manipulation methods and usual medical care for acute and subacute low back pain: a randomized clinical trial.
      The results of these studies were mixed, with some reporting modest significant benefit of SM compared with active intervention (physical therapy, education [“back school”], medication, usual care) at about 4 weeks for pain intensity and/or function,
      • George J.W.
      • Skaggs C.D.
      • Thompson P.A.
      • Nelson D.M.
      • Gavard J.A.
      • Gross G.A.
      A randomized controlled trial comparing a multimodal intervention and standard obstetrics care for low back and pelvic pain in pregnancy.
      • Hoiriis K.T.
      • Pfleger B.
      • McDuffie F.C.
      • et al.
      A randomized clinical trial comparing chiropractic adjustments to muscle relaxants for subacute low back pain.
      • Schneider M.
      • Haas M.
      • Glick R.
      • Stevans J.
      • Landsittel D.
      Comparison of spinal manipulation methods and usual medical care for acute and subacute low back pain: a randomized clinical trial.
      but others reporting no significant between-group differences.
      • Cherkin D.C.
      • Deyo R.A.
      • Battié M.
      • Street J.
      • Barlow W.
      A comparison of physical therapy, chiropractic manipulation, and provision of an educational booklet for the treatment of patients with low back pain.
      • Hsieh C.Y.
      • Adams A.H.
      • Tobis J.
      • et al.
      Effectiveness of four conservative treatments for subacute low back pain: a randomized clinical trial.
      • Pope M.H.
      • Phillips R.B.
      • Haugh L.D.
      • Hsieh C.Y.
      • MacDonald L.
      • Haldeman S.
      A prospective randomized three-week trial of spinal manipulation, transcutaneous muscle stimulation, massage and corset in the treatment of subacute low back pain.
      One RCT examined pregnant women with LBP
      • George J.W.
      • Skaggs C.D.
      • Thompson P.A.
      • Nelson D.M.
      • Gavard J.A.
      • Gross G.A.
      A randomized controlled trial comparing a multimodal intervention and standard obstetrics care for low back and pelvic pain in pregnancy.
      and found that adding SM and exercise to usual obstetric care provided modest improvement in pain and function/disability.
      There were 5 studies of SM for either acute and/or subacute LBP that used less than 6 treatment sessions,
      • Brennan G.P.
      • Fritz J.M.
      • Hunter S.J.
      • Thackeray A.
      • Delitto A.
      • Erhard R.E.
      Identifying subgroups of patients with acute/subacute “nonspecific” low back pain: results of a randomized clinical trial.
      • Cleland J.A.
      • Fritz J.M.
      • Kulig K.
      • et al.
      Comparison of the effectiveness of three manual physical therapy techniques in a subgroup of patients with low back pain who satisfy a clinical prediction rule: a randomized clinical trial.
      • Fritz J.M.
      • Magel J.S.
      • McFadden M.
      • et al.
      Early physical therapy vs usual care in patients with recent-onset low back pain: a randomized clinical trial.
      • Hadler N.M.
      • Curtis P.
      • Gillings D.B.
      • Stinnett S.
      A benefit of spinal manipulation as adjunctive therapy for acute low-back pain: a stratified controlled trial.
      • Sutlive T.G.
      • Mabry L.M.
      • Easterling E.J.
      • et al.
      Comparison of short-term response to two spinal manipulation techniques for patients with low back pain in a military beneficiary population.
      but only 1 of these (and the largest) was an effectiveness study: Fritz et al
      • Fritz J.M.
      • Magel J.S.
      • McFadden M.
      • et al.
      Early physical therapy vs usual care in patients with recent-onset low back pain: a randomized clinical trial.
      conducted an RCT of 4 sessions over 4 weeks of SM plus exercise vs usual primary care and at 3 months found significant between-group improvement in function (−3.2 points on the ODI). The other 4 studies (sample sizes ranged from 54 to 123 patients) compared different types of SM and/or SM with an active intervention (eg, exercise). In general, these 4 studies reported that all groups had improvement in back pain, and there were very small or no significant between-group differences. However, it is unclear whether these 4 studies were sufficiently powered to definitively ascertain whether differences existed.
      There were 4 studies of SM that by design addressed mixed LBP
      • Bronfort G.
      • Evans R.L.
      • Maiers M.
      • Anderson A.V.
      Spinal manipulation, epidural injections, and self-care for sciatica: a pilot study for a randomized clinical trial.
      • Hoehler F.K.
      • Tobis J.S.
      • Buerger A.A.
      Spinal manipulation for low back pain.
      • Hurwitz E.L.
      • Morgenstern H.
      • Harber P.
      • et al.
      A randomized trial of medical care with and without physical therapy and chiropractic care with and without physical modalities for patients with low back pain: 6-month follow-up outcomes from the UCLA low back pain study.
      • Pope M.H.
      • Phillips R.B.
      • Haugh L.D.
      • Hsieh C.Y.
      • MacDonald L.
      • Haldeman S.
      A prospective randomized three-week trial of spinal manipulation, transcutaneous muscle stimulation, massage and corset in the treatment of subacute low back pain.
      (ie, the inclusion criteria allowed participants with acute, subacute, or chronic LBP); 3 of these studies utilized 6 or more treatment sessions. All studies had one or more active comparison groups (eg, massage, electrical stimulation, usual care, corticosteroid injection, physical therapy), and in all studies, all groups improved but there were no significant between-group differences.

       Yoga

      We identified 6 RCTs of yoga for cLBP
      • Saper R.B.
      • Boah A.R.
      • Keosaian J.
      • Cerrada C.
      • Weinberg J.
      • Sherman K.J.
      Comparing once- versus twice-weekly yoga classes for chronic low back pain in predominantly low income minorities: a randomized dosing trial.
      • Saper R.B.
      • Sherman K.J.
      • Cullum-Dugan D.
      • Davis R.B.
      • Phillips R.S.
      • Culpepper L.
      Yoga for chronic low back pain in a predominantly minority population: a pilot randomized controlled trial.
      • Sherman K.J.
      • Cherkin D.C.
      • Erro J.
      • Miglioretti D.L.
      • Deyo R.A.
      Comparing yoga, exercise, and a self-care book for chronic low back pain: a randomized, controlled trial.
      • Sherman K.J.
      • Cherkin D.C.
      • Wellman R.D.
      • et al.
      A randomized trial comparing yoga, stretching, and a self-care book for chronic low back pain.
      • Williams K.
      • Abildso C.
      • Steinberg L.
      • et al.
      Evaluation of the effectiveness and efficacy of iyengar yoga therapy on chronic low back pain.
      • Williams K.A.
      • Petronis J.
      • Smith D.
      • et al.
      Effect of iyengar yoga therapy for chronic low back pain.
      (total participants, 596; all adults, predominantly female). Three named forms of yoga were studied: hatha,
      • Saper R.B.
      • Boah A.R.
      • Keosaian J.
      • Cerrada C.
      • Weinberg J.
      • Sherman K.J.
      Comparing once- versus twice-weekly yoga classes for chronic low back pain in predominantly low income minorities: a randomized dosing trial.
      • Saper R.B.
      • Sherman K.J.
      • Cullum-Dugan D.
      • Davis R.B.
      • Phillips R.S.
      • Culpepper L.
      Yoga for chronic low back pain in a predominantly minority population: a pilot randomized controlled trial.
      viniyoga,
      • Sherman K.J.
      • Cherkin D.C.
      • Erro J.
      • Miglioretti D.L.
      • Deyo R.A.
      Comparing yoga, exercise, and a self-care book for chronic low back pain: a randomized, controlled trial.
      • Sherman K.J.
      • Cherkin D.C.
      • Wellman R.D.
      • et al.
      A randomized trial comparing yoga, stretching, and a self-care book for chronic low back pain.
      and iyengar
      • Williams K.
      • Abildso C.
      • Steinberg L.
      • et al.
      Evaluation of the effectiveness and efficacy of iyengar yoga therapy on chronic low back pain.
      • Williams K.A.
      • Petronis J.
      • Smith D.
      • et al.
      Effect of iyengar yoga therapy for chronic low back pain.
      ; all were performed in group settings, with class durations from 60 to 90 minutes and the number of sessions ranging from 12 to 24, either once or twice per week, with recommendations for home practice. Compared with usual care, 2 studies
      • Sherman K.J.
      • Cherkin D.C.
      • Erro J.
      • Miglioretti D.L.
      • Deyo R.A.
      Comparing yoga, exercise, and a self-care book for chronic low back pain: a randomized, controlled trial.
      • Sherman K.J.
      • Cherkin D.C.
      • Wellman R.D.
      • et al.
      A randomized trial comparing yoga, stretching, and a self-care book for chronic low back pain.
      found that yoga provided improvements in pain and function, but the results were mixed when compared with exercise/stretching. A dose-response study
      • Saper R.B.
      • Boah A.R.
      • Keosaian J.
      • Cerrada C.
      • Weinberg J.
      • Sherman K.J.
      Comparing once- versus twice-weekly yoga classes for chronic low back pain in predominantly low income minorities: a randomized dosing trial.
      compared once-weekly to twice-weekly classes and found that they produced equivalent improvements in pain intensity and function. Three smaller studies compared yoga with wait list
      • Saper R.B.
      • Sherman K.J.
      • Cullum-Dugan D.
      • Davis R.B.
      • Phillips R.S.
      • Culpepper L.
      Yoga for chronic low back pain in a predominantly minority population: a pilot randomized controlled trial.
      • Williams K.
      • Abildso C.
      • Steinberg L.
      • et al.
      Evaluation of the effectiveness and efficacy of iyengar yoga therapy on chronic low back pain.
      or education control
      • Williams K.A.
      • Petronis J.
      • Smith D.
      • et al.
      Effect of iyengar yoga therapy for chronic low back pain.
      and reported significant modest reductions in pain intensity and function/disability. No RCTs reported significant adverse events.
      Additional information on all back pain RCTs can be found in Supplemental Table 1 (available online at http://www.mayoclinicproceedings.org).

      Fibromylgia

      All trials we reviewed for fibromyalgia used the 1990 American College of Rheumatology (ACR) classification criteria,
      • Wolfe F.
      • Smythe H.A.
      • Yunus M.B.
      • et al.
      The American College of Rheumatology 1990 criteria for the classification of fibromyalgia: report of the Multicenter Criteria Committee.
      except one
      • Buckelew S.P.
      • Conway R.
      • Parker J.
      • et al.
      Biofeedback/relaxation training and exercise interventions for fibromyalgia: a prospective trial.
      that used an older definition.

       Acupuncture

      Four RCTs examined acupuncture vs sham acupuncture for pain, physical function, global well-being, sleep, fatigue, and adverse events.
      • Assefi N.P.
      • Sherman K.J.
      • Jacobsen C.
      • et al.
      A randomized clinical trial of acupuncture compared with sham acupuncture in fibromyalgia.
      • Harris R.E.
      • Tian X.
      • Williams D.A.
      • et al.
      Treatment of fibromyalgia with formula acupuncture: investigation of needle placement, needle stimulation, and treatment frequency.
      • Harris R.E.
      • Zubieta J.K.
      • Scott D.J.
      • Napadow V.
      • Gracely R.H.
      • Clauw D.J.
      Traditional Chinese acupuncture and placebo (sham) acupuncture are differentiated by their effects on mu-opioid receptors (MORs).
      • Martin D.P.
      • Sletten C.D.
      • Williams B.A.
      • Berger I.H.
      Improvement in fibromyalgia symptoms with acupuncture: results of a randomized controlled trial.
      Martin et al
      • Martin D.P.
      • Sletten C.D.
      • Williams B.A.
      • Berger I.H.
      Improvement in fibromyalgia symptoms with acupuncture: results of a randomized controlled trial.
      found a significant improvement between electroacupuncture vs sham electroacupuncture. Differences were seen on the Fibromyalgia Impact Questionnaire (FIQ) scores for fatigue and anxiety. No other trial found significant differences between groups on any outcome. There were no serious adverse events reported in any of these studies. In one study, minor adverse events (eg, discomfort at the site of needle insertion or simulation of needles) were reported by 89% of participants.
      • Assefi N.P.
      • Sherman K.J.
      • Jacobsen C.
      • et al.
      A randomized clinical trial of acupuncture compared with sham acupuncture in fibromyalgia.

       Relaxation Techniques

      Two studies (93 total participants, mostly female and white) investigated biofeedback vs control groups (attention control and placebo) as a treatment for symptoms of fibromyalgia.
      • Buckelew S.P.
      • Conway R.
      • Parker J.
      • et al.
      Biofeedback/relaxation training and exercise interventions for fibromyalgia: a prospective trial.
      • Nelson D.V.
      • Bennett R.M.
      • Barkhuizen A.
      • et al.
      Neurotherapy of fibromyalgia?.
      Buckelew et al
      • Buckelew S.P.
      • Conway R.
      • Parker J.
      • et al.
      Biofeedback/relaxation training and exercise interventions for fibromyalgia: a prospective trial.
      found a significant improvement in the Tender Point Index score in the biofeedback group vs an attention control group but not for any other outcome measure. Nelson et al
      • Nelson D.V.
      • Bennett R.M.
      • Barkhuizen A.
      • et al.
      Neurotherapy of fibromyalgia?.
      did not find any differences between biofeedback and a placebo biofeedback. A small study (90 women) found that mindfulness-based stress reduction significantly reduced perceived stress and sleep disturbance and lessened the severity of symptoms in persons with fibromyalgia vs a wait list control group.
      • Cash E.
      • Salmon P.
      • Weissbecker I.
      • et al.
      Mindfulness meditation alleviates fibromyalgia symptoms in women: results of a randomized clinical trial.
      Another RCT examined the effects of affective self-awareness, a technique that places primary importance on the awareness and expression of emotions underlying fibromyalgia symptoms, in 45 women with fibromyalgia and found significant pain reduction and improved physical functioning vs a wait list control group.
      • Hsu M.C.
      • Schubiner H.
      • Lumley M.A.
      • Stracks J.S.
      • Clauw D.J.
      • Williams D.A.
      Sustained pain reduction through affective self-awareness in fibromyalgia: a randomized controlled trial.
      Astin et al
      • Astin J.A.
      • Berman B.M.
      • Bausell B.
      • Lee W.L.
      • Hochberg M.
      • Forys K.L.
      The efficacy of mindfulness meditation plus Qigong movement therapy in the treatment of fibromyalgia: a randomized controlled trial.
      examined the effects of an intervention combining mindfulness meditation and qigong and found that the combined intervention yielded no better results than an educational/support control group for pain, depression, and physical functioning. Two studies
      • Menzies V.
      • Lyon D.E.
      • Elswick Jr., R.K.
      • McCain N.L.
      • Gray D.P.
      Effects of guided imagery on biobehavioral factors in women with fibromyalgia.
      • Menzies V.
      • Taylor A.G.
      • Bourguignon C.
      Effects of guided imagery on outcomes of pain, functional status, and self-efficacy in persons diagnosed with fibromyalgia.
      (112 total participants, mostly female) examined guided imagery vs usual care as a treatment for symptoms of fibromyalgia. One study
      • Menzies V.
      • Taylor A.G.
      • Bourguignon C.
      Effects of guided imagery on outcomes of pain, functional status, and self-efficacy in persons diagnosed with fibromyalgia.
      found a significant decrease in the FIQ score compared with the usual care control group. The second study
      • Menzies V.
      • Lyon D.E.
      • Elswick Jr., R.K.
      • McCain N.L.
      • Gray D.P.
      Effects of guided imagery on biobehavioral factors in women with fibromyalgia.
      found positive effects of guided imagery on pain intensity, fatigue, and depression vs the control group. Both studies found improvements in self-efficacy for managing symptoms. Only one study
      • Nelson D.V.
      • Bennett R.M.
      • Barkhuizen A.
      • et al.
      Neurotherapy of fibromyalgia?.
      reported on adverse events, and none were noted.

       Massage

      A small study (12 women) examined Swedish massage vs myofascial release therapy for fibromyalgia symptoms.
      • Liptan G.
      • Mist S.
      • Wright C.
      • Arzt A.
      • Jones K.D.
      A pilot study of myofascial release therapy compared to Swedish massage in fibromyalgia.
      No difference was seen between groups on the FIQ.

       Tai Chi

      A study of 98 adults with fibromyalgia (aged 40 years and older, mostly white and female) compared Yang-style tai chi (modified for fibromyalgia patients) with an educational control and found that the tai chi group had a greater decrease in the FIQ score.
      • Jones K.D.
      • Sherman C.A.
      • Mist S.D.
      • Carson J.W.
      • Bennett R.M.
      • Li F.
      A randomized controlled trial of 8-form Tai chi improves symptoms and functional mobility in fibromyalgia patients.
      Another study (59 adults with fibromyalgia) compared Yang-style tai chi with a control combining wellness education and stretching classes and found that the tai chi group had greater improvement in the FIQ score.
      • Wang C.
      • Schmid C.H.
      • Rones R.
      • et al.
      A randomized trial of tai chi for fibromyalgia.

       Yoga

      A small study (53 women) investigated yoga vs wait list for management of fibromyalgia symptoms and found that those practicing yoga had significant improvement in the FIQ score.
      • Carson J.W.
      • Carson K.M.
      • Jones K.D.
      • Bennett R.M.
      • Wright C.L.
      • Mist S.D.
      A pilot randomized controlled trial of the Yoga of Awareness program in the management of fibromyalgia.
      No adverse events were noted.
      Additional information on all fibromyalgia RCTs can be found in Supplemental Table 2 (available online at http://www.mayoclinicproceedings.org).

      Neck Pain

       Massage

      Four randomized controlled trials examined whether massage could relieve symptoms associated with chronic neck pain.
      • Cook A.J.
      • Wellman R.D.
      • Cherkin D.C.
      • Kahn J.R.
      • Sherman K.J.
      Randomized clinical trial assessing whether additional massage treatments for chronic neck pain improve 12- and 26-week outcomes.
      • Field T.
      • Diego M.
      • Gonzalez G.
      • Funk C.G.
      Neck arthritis pain is reduced and range of motion is increased by massage therapy.
      • Sherman K.J.
      • Cherkin D.C.
      • Hawkes R.J.
      • Miglioretti D.L.
      • Deyo R.A.
      Randomized trial of therapeutic massage for chronic neck pain.
      • Sherman K.J.
      • Cook A.J.
      • Wellman R.D.
      • et al.
      Five-week outcomes from a dosing trial of therapeutic massage for chronic neck pain.
      One study did not report patient demographic characteristics, and the others studied patients aged 20 to 64 years. Primary outcomes included scores on the Neck Disability Index (NDI) (a 10-item neck pain questionnaire), the pain VAS, and range of motion. Sherman et al
      • Sherman K.J.
      • Cherkin D.C.
      • Hawkes R.J.
      • Miglioretti D.L.
      • Deyo R.A.
      Randomized trial of therapeutic massage for chronic neck pain.
      found significant improvement of the NDI score for those randomized to 10 massage therapy session over 10 weeks vs those assigned to a self-care book on managing neck problems. In an RCT by Field et al,
      • Field T.
      • Diego M.
      • Gonzalez G.
      • Funk C.G.
      Neck arthritis pain is reduced and range of motion is increased by massage therapy.
      individuals were randomized to either a wait list control or 30 minutes of massage therapy weekly for 4 weeks combined with daily self-massage. At the completion of the intervention, those assigned to massage therapy had improvements in pain and range of motion compared with the control group. Sherman et al
      • Sherman K.J.
      • Cook A.J.
      • Wellman R.D.
      • et al.
      Five-week outcomes from a dosing trial of therapeutic massage for chronic neck pain.
      reported a dose-response relationship between the number and duration of massage sessions per week and improvement in the NDI score and neck pain intensity. The findings indicated that 60 minutes of massage 2 to 3 times per week was significantly better than either 30 or 60 minutes of massage once per week after the 4 weeks of treatment. In a follow-up to the study by Sherman et al,
      • Sherman K.J.
      • Cook A.J.
      • Wellman R.D.
      • et al.
      Five-week outcomes from a dosing trial of therapeutic massage for chronic neck pain.
      Cook et al
      • Cook A.J.
      • Wellman R.D.
      • Cherkin D.C.
      • Kahn J.R.
      • Sherman K.J.
      Randomized clinical trial assessing whether additional massage treatments for chronic neck pain improve 12- and 26-week outcomes.
      obtained repeated consent from the participants and randomized them to one additional massage therapy session per week for 6 additional weeks. At the end of treatment, those randomized to the additional sessions had significantly improved pain and function vs those who did not receive the additional sessions; the difference between groups was no longer significant after 14 weeks of follow-up.

       Spinal Manipulation

      We reviewed 3 randomized trials of SM for neck pain.
      • Evans R.
      • Bronfort G.
      • Schulz C.
      • et al.
      Supervised exercise with and without spinal manipulation performs similarly and better than home exercise for chronic neck pain: a randomized controlled trial.
      • Hurwitz E.L.
      • Morgenstern H.
      • Harber P.
      • Kominski G.F.
      • Yu F.
      • Adams A.H.
      A randomized trial of chiropractic manipulation and mobilization for patients with neck pain: clinical outcomes from the UCLA neck-pain study.
      • Maiers M.
      • Bronfort G.
      • Evans R.
      • et al.
      Spinal manipulative therapy and exercise for seniors with chronic neck pain.
      One study assessed manipulation compared with mobilization with a 2×2×2 factorial design: with or without heat or with or without electrical muscle stimulation
      • Hurwitz E.L.
      • Morgenstern H.
      • Harber P.
      • Kominski G.F.
      • Yu F.
      • Adams A.H.
      A randomized trial of chiropractic manipulation and mobilization for patients with neck pain: clinical outcomes from the UCLA neck-pain study.
      ; no significant differences in outcomes were seen between groups. Evans et al
      • Evans R.
      • Bronfort G.
      • Schulz C.
      • et al.
      Supervised exercise with and without spinal manipulation performs similarly and better than home exercise for chronic neck pain: a randomized controlled trial.
      compared SM combined with supervised exercising to supervised exercising alone and also to home exercise. After completion of the 12-week intervention, no difference was seen between SM combined with supervised exercising and supervised exercising alone; however, both these groups had significant improvement in neck pain vs only home exercise. Maiers et al
      • Maiers M.
      • Bronfort G.
      • Evans R.
      • et al.
      Spinal manipulative therapy and exercise for seniors with chronic neck pain.
      assessed the efficacy of 3 treatments: (1) SM plus home exercise, (2) supervised rehabilitation exercise plus home exercise, and (3) home exercise alone. Spinal manipulation with home exercise produced significantly better reduction in pain than home exercise alone. No significant difference was seen between SM and home exercise vs supervised rehabilitation exercise plus home exercise.
      There was one RCT of manual cervical distraction,
      • Gudavalli M.R.
      • Salsbury S.A.
      • Vining R.D.
      • et al.
      Development of an attention-touch control for manual cervical distraction: a pilot randomized clinical trial for patients with neck pain.
      a traction-based therapy with low, medium, and high forces assessed. The goal of the study was to identify a viable sham control. The study end points included pain VAS, NDI score, and a credibility and expectancy questionnaire. The investigators did report benefit in medium- or high-force interventions.
      Additional information on all neck pain RCTs can be found in Supplemental Table 3 (available online at http://www.mayoclinicproceedings.org).

      OA of the Knee

       Acupuncture

      Four RCTs examined whether acupuncture could relieve symptoms associated with OA of the knee.
      • Berman B.M.
      • Lao L.
      • Langenberg P.
      • Lee W.L.
      • Gilpin A.M.
      • Hochberg M.C.
      Effectiveness of acupuncture as adjunctive therapy in osteoarthritis of the knee: a randomized, controlled trial.
      • Berman B.M.
      • Singh B.B.
      • Lao L.
      • et al.
      A randomized trial of acupuncture as an adjunctive therapy in osteoarthritis of the knee.
      • Chen L.X.
      • Mao J.J.
      • Fernandes S.
      • et al.
      Integrating acupuncture with exercise-based physical therapy for knee osteoarthritis: a randomized controlled trial.
      • Suarez-Almazor M.E.
      • Looney C.
      • Liu Y.
      • et al.
      A randomized controlled trial of acupuncture for osteoarthritis of the knee: effects of patient-provider communication.
      These studies used similar definitions of knee OA. Participants were predominantly female, had mean ages between 60 and 65 years, and had knee pain for an average of 9 to 11 years. All studies incorporated either the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score or the WOMAC pain subscore as the primary outcomes. In 2 of the trials,
      • Chen L.X.
      • Mao J.J.
      • Fernandes S.
      • et al.
      Integrating acupuncture with exercise-based physical therapy for knee osteoarthritis: a randomized controlled trial.
      • Suarez-Almazor M.E.
      • Looney C.
      • Liu Y.
      • et al.
      A randomized controlled trial of acupuncture for osteoarthritis of the knee: effects of patient-provider communication.
      no difference was seen between verum acupuncture and sham acupuncture for either the primary or secondary outcome measure. The third trial,
      • Berman B.M.
      • Lao L.
      • Langenberg P.
      • Lee W.L.
      • Gilpin A.M.
      • Hochberg M.C.
      Effectiveness of acupuncture as adjunctive therapy in osteoarthritis of the knee: a randomized, controlled trial.
      which used a sham control, found significantly better improvement in both the WOMAC pain subscale and function subscale after 14 weeks of treatment. For the 3 trials that also incorporated either an attention control
      • Berman B.M.
      • Lao L.
      • Langenberg P.
      • Lee W.L.
      • Gilpin A.M.
      • Hochberg M.C.
      Effectiveness of acupuncture as adjunctive therapy in osteoarthritis of the knee: a randomized, controlled trial.
      or standard care controls,
      • Berman B.M.
      • Singh B.B.
      • Lao L.
      • et al.
      A randomized trial of acupuncture as an adjunctive therapy in osteoarthritis of the knee.
      • Suarez-Almazor M.E.
      • Looney C.
      • Liu Y.
      • et al.
      A randomized controlled trial of acupuncture for osteoarthritis of the knee: effects of patient-provider communication.
      verum acupuncture produced significantly better improvement in primary and secondary outcomes than that observed in the control group. Across trials, adverse events associated with acupuncture were few, with the most common complaints being pain at the needling site and muscle soreness that resolved soon after the treatment session ended.

       Glucosamine and Chondroitin

      We reviewed 8 RCTs examining the efficacy of 2 dietary supplements, glucosamine and/or chondroitin, in individuals with knee OA.
      • Clegg D.O.
      • Reda D.J.
      • Harris C.L.
      • et al.
      Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis.
      • Frestedt J.L.
      • Walsh M.
      • Kuskowski M.A.
      • Zenk J.L.
      A natural mineral supplement provides relief from knee osteoarthritis symptoms: a randomized controlled pilot trial.
      • Leffler C.T.
      • Philippi A.F.
      • Leffler S.G.
      • Mosure J.C.
      • Kim P.D.
      Glucosamine, chondroitin, and manganese ascorbate for degenerative joint disease of the knee or low back: a randomized, double-blind, placebo-controlled pilot study.
      • McAlindon T.
      • Formica M.
      • LaValley M.
      • Lehmer M.
      • Kabbara K.
      Effectiveness of glucosamine for symptoms of knee osteoarthritis: results from an Internet-based randomized double-blind controlled trial.
      • Messier S.P.
      • Mihalko S.
      • Loeser R.F.
      • et al.
      Glucosamine/chondroitin combined with exercise for the treatment of knee osteoarthritis: a preliminary study.
      • Rindone J.P.
      • Hiller D.
      • Collacott E.
      • Nordhaugen N.
      • Arriola G.
      Randomized, controlled trial of glucosamine for treating osteoarthritis of the knee.
      • Rubin B.R.
      • Talent J.M.
      • Kongtawelert P.
      • Pertusi R.M.
      • Forman M.D.
      • Gracy R.W.
      Oral polymeric N-acetyl-D-glucosamine and osteoarthritis.
      • Zenk J.L.
      • Helmer T.R.
      • Kuskowski M.A.
      The effects of milk protein concentrate on the symptoms of osteoarthritis in adults: an exploratory, randomized, double-blind, placebo-controlled trial.
      These studies varied substantially in how knee OA was defined, as well as in the primary outcome measures used.
      Three different configurations of glucosamine were used: glucosamine hydrochloride (HCl),
      • Leffler C.T.
      • Philippi A.F.
      • Leffler S.G.
      • Mosure J.C.
      • Kim P.D.
      Glucosamine, chondroitin, and manganese ascorbate for degenerative joint disease of the knee or low back: a randomized, double-blind, placebo-controlled pilot study.
      • McAlindon T.
      • Formica M.
      • LaValley M.
      • Lehmer M.
      • Kabbara K.
      Effectiveness of glucosamine for symptoms of knee osteoarthritis: results from an Internet-based randomized double-blind controlled trial.
      • Messier S.P.
      • Mihalko S.
      • Loeser R.F.
      • et al.
      Glucosamine/chondroitin combined with exercise for the treatment of knee osteoarthritis: a preliminary study.
      glucosamine sulfate,
      • Clegg D.O.
      • Reda D.J.
      • Harris C.L.
      • et al.
      Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis.
      • Frestedt J.L.
      • Walsh M.
      • Kuskowski M.A.
      • Zenk J.L.
      A natural mineral supplement provides relief from knee osteoarthritis symptoms: a randomized controlled pilot trial.
      • Zenk J.L.
      • Helmer T.R.
      • Kuskowski M.A.
      The effects of milk protein concentrate on the symptoms of osteoarthritis in adults: an exploratory, randomized, double-blind, placebo-controlled trial.
      and glucosamine bound to a polymer.
      • Rubin B.R.
      • Talent J.M.
      • Kongtawelert P.
      • Pertusi R.M.
      • Forman M.D.
      • Gracy R.W.
      Oral polymeric N-acetyl-D-glucosamine and osteoarthritis.
      One trial did not identify the configuration of glucosamine.
      • Rindone J.P.
      • Hiller D.
      • Collacott E.
      • Nordhaugen N.
      • Arriola G.
      Randomized, controlled trial of glucosamine for treating osteoarthritis of the knee.
      Doses of glucosamine varied from 1000 mg/d for 6 weeks
      • Zenk J.L.
      • Helmer T.R.
      • Kuskowski M.A.
      The effects of milk protein concentrate on the symptoms of osteoarthritis in adults: an exploratory, randomized, double-blind, placebo-controlled trial.
      to 1500 mg/d for 24 weeks.
      • Clegg D.O.
      • Reda D.J.
      • Harris C.L.
      • et al.
      Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis.
      • Messier S.P.
      • Mihalko S.
      • Loeser R.F.
      • et al.
      Glucosamine/chondroitin combined with exercise for the treatment of knee osteoarthritis: a preliminary study.
      Chondroitin sulfate was studied in 2 trials at a dose of 1200 mg/d for 6 months
      • Clegg D.O.
      • Reda D.J.
      • Harris C.L.
      • et al.
      Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis.
      • Messier S.P.
      • Mihalko S.
      • Loeser R.F.
      • et al.
      Glucosamine/chondroitin combined with exercise for the treatment of knee osteoarthritis: a preliminary study.
      and in 1 trial at the same dose but for 8 weeks.
      • Leffler C.T.
      • Philippi A.F.
      • Leffler S.G.
      • Mosure J.C.
      • Kim P.D.
      Glucosamine, chondroitin, and manganese ascorbate for degenerative joint disease of the knee or low back: a randomized, double-blind, placebo-controlled pilot study.
      All studies employed a placebo control group. Participants in 2 trials were exclusively
      • Leffler C.T.
      • Philippi A.F.
      • Leffler S.G.
      • Mosure J.C.
      • Kim P.D.
      Glucosamine, chondroitin, and manganese ascorbate for degenerative joint disease of the knee or low back: a randomized, double-blind, placebo-controlled pilot study.
      or predominantly
      • Rindone J.P.
      • Hiller D.
      • Collacott E.
      • Nordhaugen N.
      • Arriola G.
      Randomized, controlled trial of glucosamine for treating osteoarthritis of the knee.
      males, participants in 4 other trials were predominantly females,
      • Clegg D.O.
      • Reda D.J.
      • Harris C.L.
      • et al.
      Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis.
      • McAlindon T.
      • Formica M.
      • LaValley M.
      • Lehmer M.
      • Kabbara K.
      Effectiveness of glucosamine for symptoms of knee osteoarthritis: results from an Internet-based randomized double-blind controlled trial.
      • Messier S.P.
      • Mihalko S.
      • Loeser R.F.
      • et al.
      Glucosamine/chondroitin combined with exercise for the treatment of knee osteoarthritis: a preliminary study.
      • Zenk J.L.
      • Helmer T.R.
      • Kuskowski M.A.
      The effects of milk protein concentrate on the symptoms of osteoarthritis in adults: an exploratory, randomized, double-blind, placebo-controlled trial.
      and the remaining 2 trials had a close balance of men and women.
      • Frestedt J.L.
      • Walsh M.
      • Kuskowski M.A.
      • Zenk J.L.
      A natural mineral supplement provides relief from knee osteoarthritis symptoms: a randomized controlled pilot trial.
      • Rubin B.R.
      • Talent J.M.
      • Kongtawelert P.
      • Pertusi R.M.
      • Forman M.D.
      • Gracy R.W.
      Oral polymeric N-acetyl-D-glucosamine and osteoarthritis.
      The mean age of the trial participants varied from 45 years
      • Leffler C.T.
      • Philippi A.F.
      • Leffler S.G.
      • Mosure J.C.
      • Kim P.D.
      Glucosamine, chondroitin, and manganese ascorbate for degenerative joint disease of the knee or low back: a randomized, double-blind, placebo-controlled pilot study.
      to 72 years.
      • Messier S.P.
      • Mihalko S.
      • Loeser R.F.
      • et al.
      Glucosamine/chondroitin combined with exercise for the treatment of knee osteoarthritis: a preliminary study.
      Mixed results were found in trials comparing glucosamine vs a placebo control with pain relief or functional improvement as the primary outcomes. Three trials found glucosamine superior to placebo,
      • Frestedt J.L.
      • Walsh M.
      • Kuskowski M.A.
      • Zenk J.L.
      A natural mineral supplement provides relief from knee osteoarthritis symptoms: a randomized controlled pilot trial.
      • Rubin B.R.
      • Talent J.M.
      • Kongtawelert P.
      • Pertusi R.M.
      • Forman M.D.
      • Gracy R.W.
      Oral polymeric N-acetyl-D-glucosamine and osteoarthritis.
      • Zenk J.L.
      • Helmer T.R.
      • Kuskowski M.A.
      The effects of milk protein concentrate on the symptoms of osteoarthritis in adults: an exploratory, randomized, double-blind, placebo-controlled trial.
      and 3 trials found no difference between groups.
      • Clegg D.O.
      • Reda D.J.
      • Harris C.L.
      • et al.
      Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis.
      • McAlindon T.
      • Formica M.
      • LaValley M.
      • Lehmer M.
      • Kabbara K.
      Effectiveness of glucosamine for symptoms of knee osteoarthritis: results from an Internet-based randomized double-blind controlled trial.
      • Rindone J.P.
      • Hiller D.
      • Collacott E.
      • Nordhaugen N.
      • Arriola G.
      Randomized, controlled trial of glucosamine for treating osteoarthritis of the knee.
      Mixed results were seen in the 3 trials studying a combination of glucosamine and chondroitin. Leffler et al
      • Leffler C.T.
      • Philippi A.F.
      • Leffler S.G.
      • Mosure J.C.
      • Kim P.D.
      Glucosamine, chondroitin, and manganese ascorbate for degenerative joint disease of the knee or low back: a randomized, double-blind, placebo-controlled pilot study.
      found that a combination of glucosamine HCl and chondroitin sulfate (and manganese acerbate) was superior to placebo for providing pain relief. In 2 other trials, the combination of glucosamine (either sulfate or HCl) and chondroitin sulfate were no better than placebo for either pain relief or function.
      • Clegg D.O.
      • Reda D.J.
      • Harris C.L.
      • et al.
      Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis.
      • Messier S.P.
      • Mihalko S.
      • Loeser R.F.
      • et al.
      Glucosamine/chondroitin combined with exercise for the treatment of knee osteoarthritis: a preliminary study.
      Across trials, adverse events were generally mild (gastrointestinal distress being the most common) with no differences seen between those taking glucosamine or chondroitin and those taking placebo.

       Massage Therapy

      Two RCTs studied the efficacy of Swedish massage therapy for symptoms associated with OA of the knee.
      • Perlman A.I.
      • Ali A.
      • Njike V.Y.
      • et al.
      Massage therapy for osteoarthritis of the knee: a randomized dose-finding trial.
      • Perlman A.I.
      • Sabina A.
      • Williams A.L.
      • Njike V.Y.
      • Katz D.L.
      Massage therapy for osteoarthritis of the knee: a randomized controlled trial.
      The 2 studies were similar in that both defined knee OA using the ACR criteria,
      • Altman R.
      • Asch E.
      • Bloch D.
      • et al.
      Development of criteria for the classification and reporting of osteoarthritis: classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association.
      required a baseline score of at least 40 on the pain VAS, and included participants who were predominantly white females. In the earlier study,
      • Perlman A.I.
      • Sabina A.
      • Williams A.L.
      • Njike V.Y.
      • Katz D.L.
      Massage therapy for osteoarthritis of the knee: a randomized controlled trial.
      after completing the 8-week intervention, participants in the massage group had significant improvement vs those randomized to usual care in the WOMAC total score as well as in each of the WOMAC subscale scores (pain, function, and joint stiffness). In a dosing study,
      • Perlman A.I.
      • Ali A.
      • Njike V.Y.
      • et al.
      Massage therapy for osteoarthritis of the knee: a randomized dose-finding trial.
      individuals were randomized to 1 of 5 groups for 8 weeks: (1) usual care, (2) 240 minutes of massage over 8 weeks, (3) 360 minutes of massage, (4) 480 minutes of massage, and (5) 600 minutes of massage. Only individuals receiving at least 480 minutes of massage therapy (groups 4 and 5) had substantial improvement in the WOMAC total score and the WOMAC pain subscale score vs the usual care group. Across the 2 trials, only one adverse event, discomfort at the knee in one participant, was noted.

       Methylsulfonylmethane

      One RCT compared methylsulfonylmethane (MSM) (6 g/d for 12 weeks) with a placebo control.
      • Kim L.S.
      • Axelrod L.J.
      • Howard P.
      • Buratovich N.
      • Waters R.F.
      Efficacy of methylsulfonylmethane (MSM) in osteoarthritis pain of the knee: a pilot clinical trial.
      Knee OA was based on ACR criteria.
      • Altman R.
      • Asch E.
      • Bloch D.
      • et al.
      Development of criteria for the classification and reporting of osteoarthritis: classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association.
      Outcome measures were the WOMAC subscale scores for pain, function, and stiffness. Individuals randomized to MSM had significant improvement in both the WOMAC pain and functions scale scores. However, the authors cautioned that the differences between groups were small (<20%) and probably not clinical meaningful. No difference in adverse events was seen between groups.

       S-Adenoyslmethionine

      One RCT compared the dietary supplement S-adenoyslmethionine (SAMe) (1200 mg/d) with celecoxib (200 mg/d for 16 weeks) in a crossover design that included a 1-week washout period.
      • Najm W.I.
      • Reinsch S.
      • Hoehler F.
      • Tobis J.S.
      • Harvey P.W.
      S-adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: a double-blind cross-over trial [ISRCTN36233495].
      Knee OA was defined by ACR criteria,
      • Kim L.S.
      • Axelrod L.J.
      • Howard P.
      • Buratovich N.
      • Waters R.F.
      Efficacy of methylsulfonylmethane (MSM) in osteoarthritis pain of the knee: a pilot clinical trial.
      and the study population was primarily female and white. The primary outcomes were pain VAS scores, WOMAC subscale scores for pain, function, and stiffness, and clinician assessments of OA severity. By the end of the trial, no differences were seen between the 2 treatment arms on any of the outcome measures. However, the sample size was insufficient to establish equivalency. Overall, adverse events were less common in those taking SAMe than in those taking celecoxib.

       Tai Chi

      We reviewed 4 RCTs that examined the efficacy of tai chi in patients with confirmed knee OA using various criteria for diagnosis.
      • Brismée J.M.
      • Paige R.L.
      • Chyu M.C.
      • et al.
      Group and home-based tai chi in elderly subjects with knee osteoarthritis: a randomized controlled trial.
      • Hartman C.A.
      • Manos T.M.
      • Winter C.
      • Hartman D.M.
      • Li B.
      • Smith J.C.
      Effects of T'ai Chi training on function and quality of life indicators in older adults with osteoarthritis.
      • Tsai P.F.
      • Chang J.Y.
      • Beck C.
      • Kuo Y.F.
      • Keefe F.J.
      A pilot cluster-randomized trial of a 20-week Tai Chi program in elders with cognitive impairment and osteoarthritic knee: effects on pain and other health outcomes.
      • Wang C.
      • Schmid C.H.
      • Hibberd P.L.
      • et al.
      Tai Chi is effective in treating knee osteoarthritis: a randomized controlled trial.
      The 4 RCTs had similar study populations, primarily white and female, with mean ages ranging from 65 to 79 years. Mean body mass index (calculated as weight in kilograms divided by height in meters squared) was also similar across the studies, ranging from 27.8 to 30.0 kg/m2.
      In the study by Hartman et al,
      • Hartman C.A.
      • Manos T.M.
      • Winter C.
      • Hartman D.M.
      • Li B.
      • Smith J.C.
      Effects of T'ai Chi training on function and quality of life indicators in older adults with osteoarthritis.
      participants randomized to a Yang-style tai chi group had significant improvement on the Arthritis Self-Efficacy Scale vs those in the routine care group. The remaining trials compared tai chi to attention controls.
      • Brismée J.M.
      • Paige R.L.
      • Chyu M.C.
      • et al.
      Group and home-based tai chi in elderly subjects with knee osteoarthritis: a randomized controlled trial.
      • Tsai P.F.
      • Chang J.Y.
      • Beck C.
      • Kuo Y.F.
      • Keefe F.J.
      A pilot cluster-randomized trial of a 20-week Tai Chi program in elders with cognitive impairment and osteoarthritic knee: effects on pain and other health outcomes.
      • Wang C.
      • Schmid C.H.
      • Hibberd P.L.
      • et al.
      Tai Chi is effective in treating knee osteoarthritis: a randomized controlled trial.
      All found that the tai chi (either Yang style or Sun style) groups did better than the attention control groups on both primary and secondary outcomes. Across trials, the most common adverse event associated with tai chi was minor muscle soreness that resolved after a few days.

       Yoga

      Park et al
      • Park J.
      • McCaffrey R.
      • Dunn D.
      • Goodman R.
      Managing osteoarthritis: comparisons of chair yoga, Reiki, and education (pilot study).
      completed a quasi-experimental trial with participants randomized to either sitting yoga or Reiki; however, the attention control group was chosen as a convenience sample from other participants meeting the inclusion/exclusion criteria. The primary outcome measures were the WOMAC total score and the WOMAC pain, function, and stiffness subscale scores. The mean age of participants was 80 years, with 68.7% being male. Individuals randomized to yoga had substantially better reduction in the WOMAC function score than either the Reiki group or the attention control group (P<.02). No other differences were seen between the 3 groups. No adverse advents were reported for any of the groups in this study.
      Additional information on all OA RCTs can be found in Supplemental Table 4 (available online at http://www.mayoclinicproceedings.org).

      Severe Headache and Migraine

      Most of the studies we reviewed defined cervicogenic headache, migraine, and tension-type headache with criteria from the International Classification of Headache Disorders, second edition.
      Headache Classification Subcommittee of the International Headache Society
      The International Classification of Headache Disorders: 2nd edition.
      Headache Classification Committee of the International Headache Society (IHS)
      The International Classification of Headache Disorders, 3rd edition (beta version).

       Acupuncture

      Coeytaux et al
      • Coeytaux R.R.
      • Kaufman J.S.
      • Kaptchuk T.J.
      • et al.
      A randomized, controlled trial of acupuncture for chronic daily headache.
      randomized patients with chronic daily headache to management by a neurologist with or without acupuncture. The acupuncture group had significantly reduced headache impact test scores vs the control group, but there were no significant differences in pain severity.

       Massage

      One small study that compared myofascial trigger point massage, a sham device, and wait list found that massage reduced headache frequency but did not significantly reduce the intensity or duration of headaches.
      • Moraska A.F.
      • Stenerson L.
      • Butryn N.
      • Krutsch J.P.
      • Schmiege S.J.
      • Mann J.D.
      Myofascial trigger point-focused head and neck massage for recurrent tension-type headache: a randomized, placebo-controlled clinical trial.

       Omega-3 Fatty Acids

      One study randomized adolescents with migraine to omega-3 fatty acid or placebo in a crossover study.
      • Harel Z.
      • Gascon G.
      • Riggs S.
      • Vaz R.
      • Brown W.
      • Exil G.
      Supplementation with omega-3 polyunsaturated fatty acids in the management of recurrent migraines in adolescents.
      Adolescents experienced a reduction in headache frequency when taking either fish oil or placebo, but there was no significant difference between the treatments. Another study randomized patients with chronic headaches to increased omega-3 and lower omega-6 fatty acids in the diet or to lower omega-6 fatty acids in the diet.
      • Ramsden C.E.
      • Faurot K.R.
      • Zamora D.
      • et al.
      Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: a randomized trial.
      The participants on high omega-3 and low omega-6 fatty acid diets had greater improvement on the Headache Impact Test and in the number of headache days.

       Relaxation Techniques

      Six trials that we reviewed evaluated stress management, relaxation, or biofeedback for headache disorders.
      • Blanchard E.B.
      • Appelbaum K.A.
      • Nicholson N.L.
      • et al.
      A controlled evaluation of the addition of cognitive therapy to a home-based biofeedback and relaxation treatment of vascular headache.
      • Devineni T.
      • Blanchard E.B.
      A randomized controlled trial of an Internet-based treatment for chronic headache.
      • D'Souza P.J.
      • Lumley M.A.
      • Kraft C.A.
      • Dooley J.A.
      Relaxation training and written emotional disclosure for tension or migraine headaches: a randomized, controlled trial.
      • Holroyd K.A.
      • O'Donnell F.J.
      • Stensland M.
      • Lipchik G.L.
      • Cordingley G.E.
      • Carlson B.W.
      Management of chronic tension-type headache with tricyclic antidepressant medication, stress management therapy, and their combination: a randomized controlled trial.
      • Scharff L.
      • Marcus D.A.
      • Masek B.J.
      A controlled study of minimal-contact thermal biofeedback treatment in children with migraine.
      • Slavin-Spenny O.
      • Lumley M.A.
      • Thakur E.R.
      • Nevedal D.C.
      • Hijazi A.M.
      Effects of anger awareness and expression training versus relaxation training on headaches: a randomized trial.
      Slavin-Spenny et al
      • Slavin-Spenny O.
      • Lumley M.A.
      • Thakur E.R.
      • Nevedal D.C.
      • Hijazi A.M.
      Effects of anger awareness and expression training versus relaxation training on headaches: a randomized trial.
      randomized students with chronic headache to expression training, relaxation training, or wait list. Both active treatments produced significant decreases in headache frequency vs the wait list control but did not differ among themselves. Two trials examined complementary approaches to either tension headaches or migraine.
      • Devineni T.
      • Blanchard E.B.
      A randomized controlled trial of an Internet-based treatment for chronic headache.
      • D'Souza P.J.
      • Lumley M.A.
      • Kraft C.A.
      • Dooley J.A.
      Relaxation training and written emotional disclosure for tension or migraine headaches: a randomized, controlled trial.
      D'Souza et al
      • D'Souza P.J.
      • Lumley M.A.
      • Kraft C.A.
      • Dooley J.A.
      Relaxation training and written emotional disclosure for tension or migraine headaches: a randomized, controlled trial.
      randomized students to relaxation training, written emotional disclosure, or neutral writing. The relaxation group had greater reductions in headache frequency and the associated headache disability compared with the other 2 groups. Devineni and Blanchard
      • Devineni T.
      • Blanchard E.B.
      A randomized controlled trial of an Internet-based treatment for chronic headache.
      randomized participants to an Internet behavioral intervention or a wait list. Participants in the behavioral intervention had improvement in the headache index score vs those in the wait list group. A trial randomized children with migraine to hand-warming biofeedback with stress management, hand-cooling biofeedback (attention control), or wait list.
      • Scharff L.
      • Marcus D.A.
      • Masek B.J.
      A controlled study of minimal-contact thermal biofeedback treatment in children with migraine.
      The warming biofeedback group had improved headache index scores compared with the other groups. Holroyd et al
      • Holroyd K.A.
      • O'Donnell F.J.
      • Stensland M.
      • Lipchik G.L.
      • Cordingley G.E.
      • Carlson B.W.
      Management of chronic tension-type headache with tricyclic antidepressant medication, stress management therapy, and their combination: a randomized controlled trial.
      randomized participants with chronic tension headache to tricyclic antidepressant, placebo, stress management, or stress management plus tricyclic antidepressant. Both the medication and stress management groups had improvements over placebo, but the combination produced the best outcomes. Blanchard et al
      • Blanchard E.B.
      • Appelbaum K.A.
      • Nicholson N.L.
      • et al.
      A controlled evaluation of the addition of cognitive therapy to a home-based biofeedback and relaxation treatment of vascular headache.
      randomized patients with headache to biofeedback with relaxation training, biofeedback plus cognitive therapy, sham meditation, or a headache monitoring control condition. All of the treatment groups including the sham meditation group had improvements in the headache index score in comparison with the monitoring control group.

       Spinal and Osteopathic Manipulation

      One trial randomized patients with chronic cervicogenic headache to 2 doses of SM or light massage.
      • Haas M.
      • Spegman A.
      • Peterson D.
      • Aickin M.
      • Vavrek D.
      Dose response and efficacy of spinal manipulation for chronic cervicogenic headache: a pilot randomized controlled trial.
      Based on the literature, the light massage should have little, if any, specific effects and was therefore chosen as a control for time and physical contract with the patient. Haas et al
      • Haas M.
      • Spegman A.
      • Peterson D.
      • Aickin M.
      • Vavrek D.
      Dose response and efficacy of spinal manipulation for chronic cervicogenic headache: a pilot randomized controlled trial.
      found improvement over all time points favoring SM compared with light massage and a dose effect with the SM. Two RCTs were identified that assessed manipulation in individuals with tension headache.
      • Boline P.D.
      • Kassak K.
      • Bronfort G.
      • Nelson C.
      • Anderson A.V.
      Spinal manipulation vs. amitriptyline for the treatment of chronic tension-type headaches: a randomized clinical trial.
      • Hoyt W.H.
      • Shaffer F.
      • Bard D.A.
      • et al.
      Osteopathic manipulation in the treatment of muscle-contraction headache.
      The first trial randomized patients with chronic tension-type headache to SM or amitriptyline and found no differences between the groups
      • Boline P.D.
      • Kassak K.
      • Bronfort G.
      • Nelson C.
      • Anderson A.V.
      Spinal manipulation vs. amitriptyline for the treatment of chronic tension-type headaches: a randomized clinical trial.
      ; however, the trial did not appear to be powered to detect noninferiority. The second study was a small trial that randomized patients to osteopathic manipulation, a palpation examination, or no treatment.
      • Hoyt W.H.
      • Shaffer F.
      • Bard D.A.
      • et al.
      Osteopathic manipulation in the treatment of muscle-contraction headache.
      The authors noted an improvement in headache severity for the SM group; however, no statistical comparisons were made between groups. Nelson et al
      • Nelson C.F.
      • Bronfort G.
      • Evans R.
      • Boline P.
      • Goldsmith C.
      • Anderson A.V.
      The efficacy of spinal manipulation, amitriptyline and the combination of both therapies for the prophylaxis of migraine headache.
      randomized patients with migraine to amitriptyline, SM, or both treatments. Their study found no significant differences between the groups; however, it did not appear that the trial was powered to detect noninferiority.
      Additional information on all headache RCTs can be found in Supplemental Table 5 (available online at http://www.mayoclinicproceedings.org).

      Overall Summary of RCT Data

      Tables 3 and 4 provide concise summaries of the reviewed clinical trial data for each complementary approach stratified by painful health conditions and various control groups. In these tables, positive trials are those in which the complementary approach provided statistically significant improvements in pain severity or pain-related disability or function compared with the control group. Negative trials are those in which no difference was seen between groups. Based on a preponderance of positive trials vs negative trials, current evidence suggests that the following complementary approaches may help some patients manage their painful health conditions: acupuncture and yoga for back pain; acupuncture and tai chi for OA of the knee; massage therapy for neck pain with adequate doses and for short-term benefit; and relaxation techniques for severe headaches and migraine. Weaker evidence suggests that massage therapy, SM, and osteopathic manipulation might also be of some benefit to those with back pain, and relaxation approaches and tai chi might help those with fibromyalgia.
      Table 3Summary of Evidence for Selected Complementary Health Approaches by Type of Pain (Sham or Placebo and/or Attention Controls)
      MSM = methylsulfonylmethane; OA = osteoarthritis; NA = no US randomized controlled trials identified; SAMe = S-adenoyslmethionine.
      ,
      Positive trials are those in which the complementary approach provided statistically significant improvements in pain severity or pain-related disability or function compared with the control group. Negative trials are those in which no difference was seen between groups.
      ApproachBack painFibromyalgiaOA of kneeNeck painSevere headache/migraine
      Acupuncture1 Positive trial, 2 negative1 Positive trial, 3 negative trials1 Positive trial, 3 negativeNANA
      ChondroitinNANA1 Negative trialNANA
      GlucosamineNANA2 Positive trials, 3 negative trialsNANA
      Chondroitin and glucosamineNANA1 Positive trial, 2 negative trialsNANA
      Massage therapy1 Positive trialNANA2 Positive trials1 Positive trial
      MSMNANA1 Positive trialNANA
      Omega-3 fatty acidsNANANANA1 Negative trial
      Relaxation approachesNA1 Positive trial, 2 negativeNANA3 Positive trials
      SAMeNANANANANA
      Spinal manipulation6 Positive trials, 3 negativeNANA1 Negative trial1 Positive trial
      Osteopathic manipulation1 Positive trial, 1 negativeNANANANA
      Tai chiNA2 Positive trials3 Positive trialsNANA
      Yoga1 Positive trialNA1 Positive trialNANA
      a MSM = methylsulfonylmethane; OA = osteoarthritis; NA = no US randomized controlled trials identified; SAMe = S-adenoyslmethionine.
      b Positive trials are those in which the complementary approach provided statistically significant improvements in pain severity or pain-related disability or function compared with the control group. Negative trials are those in which no difference was seen between groups.
      Table 4Summary of Evidence for Selected Complementary Health Approaches by Type of Pain (Wait List, Usual Care, or Routine Care Controls)
      No US RCTs identified; OA = osteoarthritis.
      ,
      Positive trials are those in which the complementary approach provided statistically significant improvements in pain severity or pain-related disability or function compared with the control group. Negative trials are those in which no difference was seen between groups.
      ApproachBack painFibromyalgiaOA of kneeNeck painSevere headache/migraine
      Acupuncture2 Positive trialsNA2 Positive trialsNA1 Positive trial
      Massage therapy3 Positive trials, 1 negativeNA2 Positive trials3 Positive trialsNA
      Natural products supplementsNANANANANA
      Relaxation approachesNA4 Positive trialsNANA4 Positive trials
      Spinal manipulation4 Positive trials, 3 negativeNANANANA
      Osteopathic manipulation2 Positive trials, 2 negativeNANANANA
      Tai chiNANA1 Positive trialNANA
      Yoga4 Positive trials1 Positive trialNANANA
      a No US RCTs identified; OA = osteoarthritis.
      b Positive trials are those in which the complementary approach provided statistically significant improvements in pain severity or pain-related disability or function compared with the control group. Negative trials are those in which no difference was seen between groups.

      Safety

      Generally, the reporting of safety data in the reviewed RCTs was minimal. For those trials that did report safety data, we have summarized this information in the text for each painful health condition. In no case did an RCT identify a serious adverse event associated with any of the complementary approaches examined. The most common adverse events (gastrointestinal distress) were noted in trials of dietary supplements (glucosamine, chondroitin, MSM, SAMe). In some trials, tai chi and yoga were associated with minor muscle or joint soreness, and acupuncture was associated with minor pain and/or bruising at the needling site.

       Comparisons to Recent Systematic Reviews

      Our search criteria identified a number of recent (2010 or later) systematic reviews that covered our topics of interest.
      • Chou R.
      • Deyo R.
      • Friedly J.
      • et al.
      Noninvasive Treatments for Low Back Pain.
      • Deare J.C.
      • Zheng Z.
      • Xue C.C.
      • et al.
      Acupuncture for treating fibromyalgia.
      • Manheimer E.
      • Cheng K.
      • Linde K.
      • et al.
      Acupuncture for peripheral joint osteoarthritis.
      • Posadzki P.
      • Ernst E.
      Spinal manipulations for the treatment of migraine: a systematic review of randomized clinical trials.
      • Haaz S.
      • Bartlett S.J.
      Yoga for arthritis: a scoping review.
      • Sharma M.
      Yoga as an alternative and complementary approach for arthritis: a systematic review.
      • Franke H.
      • Franke J.D.
      • Fryer G.
      Osteopathic manipulative treatment for nonspecific low back pain: a systematic review and meta-analysis.
      • Wu D.
      • Huang Y.
      • Gu Y.
      • Fan W.
      Efficacies of different preparations of glucosamine for the treatment of osteoarthritis: a meta-analysis of randomised, double-blind, placebo-controlled trials.
      • Rubinstein S.M.
      • Terwee C.B.
      • Assendelft W.J.
      • de Boer M.R.
      • van Tulder M.W.
      Spinal manipulative therapy for acute low back pain: an update of the Cochrane review.
      Conclusions from these systematic reviews for practitioner approaches (acupuncture, chiropractic, massage therapy)
      • Chou R.
      • Deyo R.
      • Friedly J.
      • et al.
      Noninvasive Treatments for Low Back Pain.
      • Deare J.C.
      • Zheng Z.
      • Xue C.C.
      • et al.
      Acupuncture for treating fibromyalgia.
      • Manheimer E.
      • Cheng K.
      • Linde K.
      • et al.
      Acupuncture for peripheral joint osteoarthritis.
      • Posadzki P.
      • Ernst E.
      Spinal manipulations for the treatment of migraine: a systematic review of randomized clinical trials.
      • Haaz S.
      • Bartlett S.J.
      Yoga for arthritis: a scoping review.
      • Sharma M.
      Yoga as an alternative and complementary approach for arthritis: a systematic review.
      • Franke H.
      • Franke J.D.
      • Fryer G.
      Osteopathic manipulative treatment for nonspecific low back pain: a systematic review and meta-analysis.
      and dietary supplements
      • Wu D.
      • Huang Y.
      • Gu Y.
      • Fan W.
      Efficacies of different preparations of glucosamine for the treatment of osteoarthritis: a meta-analysis of randomised, double-blind, placebo-controlled trials.
      were generally consistent with our findings. For instance, in a comprehensive review of both pharmacological and nonpharmacological approaches to management of back pain, Chou et al
      • Chou R.
      • Deyo R.
      • Friedly J.
      • et al.
      Noninvasive Treatments for Low Back Pain.
      found that acupuncture and yoga appear to be effective for improving pain and/or function in patients with back pain. A Cochrane systematic review concluded that acupuncture was a viable treatment option for OA of the knee.
      • Manheimer E.
      • Cheng K.
      • Linde K.
      • et al.
      Acupuncture for peripheral joint osteoarthritis.
      Also concurring with the present analysis, the meta-analysis by Deare et al
      • Deare J.C.
      • Zheng Z.
      • Xue C.C.
      • et al.
      Acupuncture for treating fibromyalgia.
      concluded that acupuncture was not an effective therapy for pain or function in individuals with fibromyalgia. In their systematic review, Posadzki and Ernst
      • Posadzki P.
      • Ernst E.
      Spinal manipulations for the treatment of migraine: a systematic review of randomized clinical trials.
      found little data supporting the use of SM for headaches. Supporting our conclusions is a recent comprehensive meta-analysis of trials studying glucosamine for OA,
      • Wu D.
      • Huang Y.
      • Gu Y.
      • Fan W.
      Efficacies of different preparations of glucosamine for the treatment of osteoarthritis: a meta-analysis of randomised, double-blind, placebo-controlled trials.
      which found considerable variability in results across trials and concluded that neither glucosamine sulfate nor glucosamine HCl provides pain relief. The RCTs examined in 2 systematic reviews of yoga for arthritis
      • Haaz S.
      • Bartlett S.J.
      Yoga for arthritis: a scoping review.
      • Sharma M.
      Yoga as an alternative and complementary approach for arthritis: a systematic review.
      overlapped considerably with RCTs in the present review. The authors of the systematic reviews concluded that yoga appears to be a viable option for relieving pain and discomfort associated with arthritis but that larger, better designed trials were needed. A recent systematic review
      • Franke H.
      • Franke J.D.
      • Fryer G.
      Osteopathic manipulative treatment for nonspecific low back pain: a systematic review and meta-analysis.
      that included international trials found that “clinically relevant effects of OMT were found for reducing pain and improving functional status” for those with back pain. Although this conclusion is stronger than ours, the authors identified deficiencies in trial methodology and called for larger, better quality RCTs to provide firm conclusions. Not all recent systematic reviews agreed with our conclusions. A recent Cochrane Collaboration meta-analysis
      • Rubinstein S.M.
      • Terwee C.B.
      • Assendelft W.J.
      • de Boer M.R.
      • van Tulder M.W.
      Spinal manipulative therapy for acute low back pain: an update of the Cochrane review.
      concluded that SM was no more effective than “inert” interventions for managing back pain and related disability. However, this review only included RCTs published through 2009. We reviewed 8 RCTs published since then. Of these 8 later RCTs, 2 were negative trials
      • Cruser dA.
      • Maurer D.
      • Hensel K.
      • Brown S.K.
      • White K.
      • Stoll S.T.
      A randomized, controlled trial of osteopathic manipulative treatment for acute low back pain in active duty military personnel.
      • Bialosky J.E.
      • George S.Z.
      • Horn M.E.
      • Price D.D.
      • Staud R.
      • Robinson M.E.
      Spinal manipulative therapy-specific changes in pain sensitivity in individuals with low back pain (NCT01168999).
      and 6 were positive trials.
      • Bronfort G.
      • Hondras M.A.
      • Schulz C.A.
      • Evans R.L.
      • Long C.R.
      • Grimm R.
      Spinal manipulation and home exercise with advice for subacute and chronic back-related leg pain: a trial with adaptive allocation.
      • Fritz J.M.
      • Magel J.S.
      • McFadden M.
      • et al.
      Early physical therapy vs usual care in patients with recent-onset low back pain: a randomized clinical trial.
      • George J.W.
      • Skaggs C.D.
      • Thompson P.A.
      • Nelson D.M.
      • Gavard J.A.
      • Gross G.A.
      A randomized controlled trial comparing a multimodal intervention and standard obstetrics care for low back and pelvic pain in pregnancy.
      • Goertz C.M.
      • Long C.R.
      • Hondras M.A.
      • et al.
      Adding chiropractic manipulative therapy to standard medical care for patients with acute low back pain: results of a pragmatic randomized comparative effectiveness study.
      • Haas M.
      • Vavrek D.
      • Peterson D.
      • Polissar N.
      • Neradilek M.B.
      Dose-response and efficacy of spinal manipulation for care of chronic low back pain: a randomized controlled trial.
      • Schneider M.
      • Haas M.
      • Glick R.
      • Stevans J.
      • Landsittel D.
      Comparison of spinal manipulation methods and usual medical care for acute and subacute low back pain: a randomized clinical trial.
      Inclusion of these trials into the meta-analysis might have lead Rubinstein et al
      • Rubinstein S.M.
      • Terwee C.B.
      • Assendelft W.J.
      • de Boer M.R.
      • van Tulder M.W.
      Spinal manipulative therapy for acute low back pain: an update of the Cochrane review.
      to draw a different conclusion.

       Caveats

      A number of methodological issues temper our conclusions. The trial samples tend to be white, female, and older, with very few, if any, minority group participants; as such, the generalizability of the findings to the breadth of patients seen by primary care physicians in the United States is still unresolved. Often, the trials reviewed were small, with fewer than 100 total participants. Small trials are prone to more variability and to false-negative results. In many of the trials in which the statistical superiority of a given complementary health approach was reported, it was not clear if the differences vs the control group were clinically relevant. For the given painful health condition, a wide number of outcome measures were often used to assess pain and function. This plethora of outcomes may partly explain the conflicting results seen across trials. For most complementary approaches, there are no standard treatment protocols or algorithms, and in the case of dietary supplements, no rigorously established dosages and products; as such, trials of a given complementary approach rarely compare the exact same intervention. Our findings that relatively few mild adverse events and no serious adverse events were associated with complementary approaches are consistent with the findings from a number of systematic reviews.
      • Chou R.
      • Deyo R.
      • Friedly J.
      • et al.
      Noninvasive Treatments for Low Back Pain.
      • Deare J.C.
      • Zheng Z.
      • Xue C.C.
      • et al.
      Acupuncture for treating fibromyalgia.
      • Manheimer E.
      • Cheng K.
      • Linde K.
      • et al.
      Acupuncture for peripheral joint osteoarthritis.
      • Posadzki P.
      • Ernst E.
      Spinal manipulations for the treatment of migraine: a systematic review of randomized clinical trials.
      • Haaz S.
      • Bartlett S.J.
      Yoga for arthritis: a scoping review.
      • Sharma M.
      Yoga as an alternative and complementary approach for arthritis: a systematic review.
      • Franke H.
      • Franke J.D.
      • Fryer G.
      Osteopathic manipulative treatment for nonspecific low back pain: a systematic review and meta-analysis.
      • Wu D.
      • Huang Y.
      • Gu Y.
      • Fan W.
      Efficacies of different preparations of glucosamine for the treatment of osteoarthritis: a meta-analysis of randomised, double-blind, placebo-controlled trials.
      • Rubinstein S.M.
      • Terwee C.B.
      • Assendelft W.J.
      • de Boer M.R.
      • van Tulder M.W.
      Spinal manipulative therapy for acute low back pain: an update of the Cochrane review.
      However, even large clinical trials are not powered to identify infrequent adverse events, and therefore, it is likely that this review underestimates the entire range of events associated with the complementary approaches examined. Finally, our review was intended to be an overview of data from RCTs performed in the United States. The inclusion of RCTs performed outside the United States may have resulted in a different set of recommendations.

      Supplemental Online Material

      Supplemental Online Material

      Supplemental material can be found online at http://www.mayoclinicproceedings.org. Supplemental material attached to journal articles has not been edited, and the authors take responsibility for the accuracy of all data.

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