Acupuncture for Chronic Pain: Update of an Individual Patient Data Meta-Analysis

The Journal of Pain Volume 19, Issue 5, May 2018, Pages 455-474 The Journal of Pain Critical Reviews Author links open overlay panelAndrew J.Vickers*Emily A.Vertosick*GeorgeLewith†HughMacPherson‡Nadine E.Foster§Karen J.Sherman¶DominikIrnich‖Claudia M.Witt**††‡‡KlausLinde§§on behalf of theAcupuncture Trialists' Collaboration * Memorial Sloan Kettering Cancer Center, New York, New York † University of Southampton, Southampton, United Kingdom (deceased) ‡ University of York, York, United Kingdom § Keele University, Newcastle-under-Lyme, United Kingdom ¶ Kaiser Permanente Washington Health Research Institute, Seattle, Washington ‖ Ludwig-Maximilians-Universität München, Munich, Germany ** University Hospital Zurich, University of Zurich, Zurich, Switzerland †† Charite-Universitätsmedizin, Berlin, Germany ‡‡ University of Maryland School of Medicine, Baltimore, Maryland §§ Technical University Munich, Germany Available online 2 December 2017. crossmark-logo https://doi.org/10.1016/j.jpain.2017.11.005 Get rights and content Highlights • Acupuncture has a clinically relevant effect on chronic pain that persists over time. • The effect of acupuncture cannot be explained only by placebo effects. • Factors in addition to the specific effects of needling are important contributors. • Referral for acupuncture treatment is a reasonable option for chronic pain patients. Abstract Despite wide use in clinical practice, acupuncture remains a controversial treatment for chronic pain. Our objective was to update an individual patient data meta-analysis to determine the effect size of acupuncture for 4 chronic pain conditions. We searched MEDLINE and the Cochrane Central Registry of Controlled Trials randomized trials published up until December 31, 2015. We included randomized trials of acupuncture needling versus either sham acupuncture or no acupuncture control for nonspecific musculoskeletal pain, osteoarthritis, chronic headache, or shoulder pain. Trials were only included if allocation concealment was unambiguously determined to be adequate. Raw data were obtained from study authors and entered into an individual patient data meta-analysis. The main outcome measures were pain and function. An additional 13 trials were identified, with data received for a total of 20,827 patients from 39 trials. Acupuncture was superior to sham as well as no acupuncture control for each pain condition (all P < .001) with differences between groups close to .5 SDs compared with no acupuncture control and close to .2 SDs compared with sham. We also found clear evidence that the effects of acupuncture persist over time with only a small decrease, approximately 15%, in treatment effect at 1 year. In secondary analyses, we found no obvious association between trial outcome and characteristics of acupuncture treatment, but effect sizes of acupuncture were associated with the type of control group, with smaller effects sizes for sham controlled trials that used a penetrating needle for sham, and for trials that had high intensity of intervention in the control arm. We conclude that acupuncture is effective for the treatment of chronic pain, with treatment effects persisting over time. Although factors in addition to the specific effects of needling at correct acupuncture point locations are important contributors to the treatment effect, decreases in pain after acupuncture cannot be explained solely in terms of placebo effects. Variations in the effect size of acupuncture in different trials are driven predominantly by differences in treatments received by the control group rather than by differences in the characteristics of acupuncture treatment. Perspective Acupuncture is effective for the treatment of chronic musculoskeletal, headache, and osteoarthritis pain. Treatment effects of acupuncture persist over time and cannot be explained solely in terms of placebo effects. Referral for a course of acupuncture treatment is a reasonable option for a patient with chronic pain. Previous article Next article Key words Acupuncture chronic pain meta-analysis osteoarthritis back pain neck pain migraine Acupuncture remains a controversial treatment for chronic pain, largely because of a provenance outside biomedicine. Traditional acupuncture theory invokes nonanatomical structures such as meridians and nonphysiological processes such as the flow of qi energy. Although many contemporary practitioners do not rely on such concepts, there remains a dearth of data on how insertion of needles at specific points on the body could lead to long-term decreases in pain. Acupuncture undoubtedly has short-term physiological effects, several of which are relevant to pain,7, 76, 119 but there is as yet no explanation as to how such effects could persist. We previously reported an individual patient data meta-analysis of high-quality trials of acupuncture for chronic pain.93 Differences between acupuncture and control in trials without sham (placebo) control were statistically as well as clinically significant. Acupuncture was significantly superior to sham control, suggesting that acupuncture effects are not solely explicable in terms of placebo, although these differences were relatively modest. We have separately reported secondary analyses examining whether characteristics of acupuncture treatment66 or control groups68 influence effect size, and whether the effects of acupuncture treatment persist over time.69 In this article we update our previous analyses now including studies published during the past 7 years. Methods The full protocol of the meta-analysis92 and the results of the first individual patient data meta-analysis including randomized controlled trials (RCTs) published up to November 200893 have been published. The literature search was repeated to identify eligible RCTs published between December 2008 and December 2015. Trials were considered eligible if they accrued patients with nonspecific back or neck pain, shoulder pain, chronic headache, or osteoarthritis; pain duration was at least 4 weeks for musculoskeletal disorders; at least 1 group received acupuncture needling and 1 group received either sham acupuncture or no acupuncture control; the primary end point was measured more than 4 weeks after the initial acupuncture treatment; and allocation concealment was determined unambiguously to be adequate. Principal investigators of eligible studies were asked to provide raw data. These raw data were used to replicate all analyses published in the original RCT publication to ensure data accuracy. Each trial was reanalyzed using analysis of covariance with the standardized primary end point (scores divided by pooled SD) as the dependent variable, and the baseline measure of the primary end point and variables used to stratify randomization as covariates. The primary outcome for each study was that identified by the responding author of each study. The effect sizes for each study were then entered into a meta-analysis using the metan command in Stata (version 13, StataCorp, College Station, TX). Fixed effects as well as random effects estimates were calculated. Fixed effects weights were calculated using inverse-variance weighting, and random effects weights were calculated using the DerSimonian and Laird method. We prespecified that meta-analyses would be conducted separately for comparisons of acupuncture versus sham and acupuncture versus no acupuncture control, and within each pain type, and the hypothesis test would be on the basis of the fixed effects analysis. In the original article, trials for which individual patient data were not available were included as a sensitivity analysis; in this update, we include summary data for such trials in the main meta-analysis and exclude them as a sensitivity analysis. As secondary analyses, we examined whether characteristics of acupuncture treatment modified treatment effects. Trial-level as well as patient-level analyses were performed. For trial-level analyses, we used random effects meta-regression to test the effect of each characteristic on the main effect estimate using the Stata command metareg. For patient-level analyses, we created a linear regression as for the main analysis of effect size, but included the characteristic and an interaction term between the characteristic and treatment allocation. The coefficient was then entered into a meta-analysis. In both analyses, random effects estimates and 95% confidence intervals were reported; P values were on the basis of the fixed effects analysis. We also analyzed the effect of acupuncture relative to different types of sham acupuncture and different types of no acupuncture control group. Three comparisons of sham acupuncture were investigated: penetrating needle versus nonpenetrating needle as well as non-needle sham; nonpenetrating needle versus non-needle sham; and the use of true acupuncture points versus nonacupuncture points among trials using nonpenetrating or non-needle sham. For sham arms using penetrating needles, there was also a comparison done between the use of deep needle penetration and shallow needle penetration. We entered the effect size and standard error for each trial into a meta-regression along with the type of sham acupuncture used in that trial. For this analysis, smaller effect sizes indicate a smaller difference in effect between verum acupuncture and sham acupuncture, implying that the type of sham acupuncture used is more active and therefore more similar to verum acupuncture. For the analysis of acupuncture effect relative to the no acupuncture control group, we used meta-regression to compare the effects of trials using no acupuncture control groups characterized as high intensity, usual care, or low intensity. We also repeated our previous analyses exploring possible effects of publication bias and exploring differences between sham acupuncture and no treatment. Results Systematic Review Our systematic review93 was updated to include trials published after November 2008 and before December 31, 2015. We identified 75 additional RCTs, of which 13 were eligible (Fig 1). These 13 studies include 4 trials19, 56, 75, 85 included as summary data only in a sensitivity analysis in our first report. Figure 1 Download high-res image (150KB)Download full-size image Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram. Data Extraction and Quality Assessment Individual patient data for 2,905 patients were received from 10 of these 13 studies and included patients from the United States, Australia, China, Germany, and the United Kingdom. For 1 of the 3 studies for which we did not receive data, the statisticians involved in the RCT failed to respond to repeated inquiries despite approval for data sharing being obtained from the principal investigator. For the other 2 studies, the trial authors were contacted and invited to participate but we received no further response. These 3 studies were included in the analysis as summary data only using the published estimates of effect size.31, 70, 75 Two trials from the original systematic review for which data were not received were also included as summary data in these analyses.23, 74 A total of 20,827 patients were included in the total 39 trials (Table 1). The trials comprised 25 comparisons with 16,041 patients of acupuncture and no acupuncture control, and 26 comparisons with 7,237 patients of acupuncture and sham acupuncture control. Of the trials on musculoskeletal pain, most had an eligibility criterion of a minimum 3 or 6 months' pain duration. Among those for which individual patient data on chronicity were available, the median duration was 4 years (quartiles: 1.1 years, 10 years). There were 2 trials for which the time period between first symptom and evaluation of outcome could theoretically have been <3 months on the basis of eligibility criteria and timing of assessment. For Irnich et al, the duration of disease was “4 to 52 weeks” for 19% of patients and >1 year for the remainder.41 In the case of Kleinhenz et al, no data were provided on chronicity, however, the indication was rotator cuff tendinitis, which is rarely treated in the acute phase.52 We conclude that all but a trivial proportion of patients included in the analysis would have met the conventional definition of chronic pain, that is, pain lasting at least 3 to 6 months. Six sham RCTs were determined to have an intermediate likelihood of bias from unblinding.13, 26, 41, 49, 59, 103 In 1 trial, 2 types of sham acupuncture were used, although only 1 type (non-needle sham acupuncture) was found to have an intermediate likelihood of bias from unblinding.103 One trial (Hinman et al) was determined to have a sham acupuncture arm with a high likelihood of bias from unblinding.39 This trial was excluded from the main analyses comparing acupuncture with sham acupuncture, but a sensitivity analysis including this trial was performed. None of the 10 new trials included in this analysis had dropout rates of >25%. Table 1. Characteristics of Included Studies Indication (n = 44) Pain Type Control Group Primary Outcome Measure Time Point Chronic headache (n = 9) Migraine (n = 3),26, 59, 63 tension-type headache (n = 3),23, 28, 71 both31, 43, 95 (n = 3) Sham control (n = 5)26, 28, 59, 63, 71; no acupuncture control (n = 7); ancillary care (n = 2)23, 31; usual care (n = 4)43, 63, 71, 95; guideline care (n = 1)26 Severity score (n = 2)23, 95; days with headache (n = 3)28, 43, 71; days with migraine (n = 2)26, 59; days with moderate to severe pain (n = 1)63; Migraine Disability Assessment (n = 1)31 1 Month (n = 1)23 2 Month (n = 1)31 3 Month (n = 3)43, 63, 71 4 Month (n = 1)59 6 Month (n = 2)26, 28 12 Month (n = 1)95 Nonspecific musculoskeletal pain (back and neck; n = 18) Back (n = 12)11, 13, 18, 19, 36, 40, 48, 49, 74, 87, 102, 111; neck (n = 6)41, 67, 79, 91, 104, 109 Sham control (n = 10)11, 13, 19, 36, 41, 48, 49, 74, 91, 104; no acupuncture control (n = 12); ancillary care (n = 3)40, 74, 102; usual care (n = 7)11, 19, 67, 79, 87, 109, 111; nonspecific advice (n = 1)18; guideline care (n = 1)36 VAS (n = 7)11, 13, 41, 49, 74, 91, 104; Roland Morris Disability Questionnaire (n = 3)18, 19, 48; Northwick Park Neck Pain Questionnaire (n = 2)67, 79; SF-36 bodily pain (n = 2)87, 102; Hannover Functional Questionnaire (n = 1)111; Von Korff pain score (n = 1)36; Oswestry Disability Index (n = 1)40 1 Month (n = 4)41, 49, 91, 104 2 Month (n = 3)11, 18, 19 3 Month (n = 5)48, 74, 79, 109, 111 4 Month (n = 1)102 6 Month (n = 2)36, 40 8 Month (n = 1)13 12 Month (n = 1)67 24 Month (n = 1)87 Osteoarthritis (n = 13) Sham control (n = 10)8, 16, 33, 39, 70, 80, 85, 89, 103, 108; no acupuncture control (n = 10); ancillary care (n = 3)33, 70, 80; usual care (n = 5)39, 56, 85, 108, 110; nonspecific advice (n = 2)8, 107 WOMAC (n = 5)16, 56, 70, 108, 110; WOMAC pain subscore (n = 4)8, 33, 80, 89; Oxford Knee score questionnaire (n = 1)107; VAS103 (n = 1); knee pain (0–10) (n = 1)39; joint-specific Multidimensional Assessment of Pain (n = 1)85 1 Month (n = 1)103 2 Month (n = 3)70, 107, 108 3 Month (n = 6)16, 39, 56, 85, 89, 110 6 Month (n = 3)8, 33, 80 Shoulder pain (n = 4) Sham control (n = 4)35, 52, 75, 90 No-acupuncture control (n = 1); ancillary care (n = 1)75 Constant-Murley score (n = 2)52, 90; VAS (n = 2)35, 75 1 Month (n = 2)52, 90 6 Month (n = 2)35, 75 Abbreviations: VAS, visual analog scale; SF-36, 36-Item Short Form Health Survey; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index. Meta-Analysis Forest plots for acupuncture against sham acupuncture and against no acupuncture control are shown separately for each of the 4 pain conditions in Fig 2 and Fig 3. Fixed effects weights are reported in Figure 2, Figure 3; forest plots with random effects weights reported are presented in Supplementary Fig 1, Supplementary Fig 2. Meta-analytic statistics are shown in Table 2. Consistent with the results of the originally published meta-analysis, acupuncture is found to be statistically superior to control for all analyses (P < .001). Effect sizes in the updated analyses are similar to those in the original analyses, with effect sizes changing by ≤.02 for most comparisons. Effect sizes are close to .5 compared with no acupuncture control and .2 compared with sham. To illustrate these effect sizes in more clinically applicable terms, if baseline pain score in a typical RCT was 60 on a scale of 0 to 100, with an SD of 25, follow-up scores might be 43 in a no acupuncture control group, 35 in a sham acupuncture group, and 30 among true acupuncture patients. If response was defined as a pain reduction of 50% or more, response rates would be approximately 30%, 42.5%, and 50%, respectively. Also in keeping with the original analyses, significant heterogeneity was found in 5 of 7 comparisons. Significant heterogeneity remained for sham-controlled musculoskeletal pain and osteoarthritis (P = .001 and P < .001, respectively) even after excluding the outlying Vas et al trials.89, 90, 91 There was also significant heterogeneity for all indications in the comparison of acupuncture with no acupuncture control. Heterogeneity is further explored (see the section on “Modifiers of Trial Outcome”). Figure 2 Download high-res image (263KB)Download full-size image Figure 2. Forest plots for the comparison of acupuncture with no acupuncture control. There were fewer than 3 trials for shoulder pain, so no meta-analyses were performed. Weights reported are fixed effects weights calculated using inverse variance weighting. Figure 3 Download high-res image (273KB)Download full-size image Figure 3. Forest plots for the comparison of true and sham acupuncture. Weights reported are fixed effects weights calculated using inverse variance weighting. Table 2. Primary Analyses (N = 44 Trials) Analysis Indication Sham No Acupuncture Control Studies, n FE (95% CI) Heterogeneity P RE (95% CI) Studies, n FE (95% CI) Heterogeneity P RE (95% CI) Main analysis Nonspecific musculoskeletal pain 10 .30 (.21–.38) < .001 .49 (.16–.81) 12 .54 (.50–.57) < .001 .50 (.38–.63) Osteoarthritis 9 .24 (.17–.31) < .001 .45 (.15–.75) 10 .63 (.56–.69) < .001 .74 (.46–1.01) Chronic headache 5 .16 (.08–.25) .4 .16 (.08–.25) 7 .44 (.39–.48) < .001 .56 (.35–.76) Shoulder 4 .57 (.44–.69) .4 .57 (.44–.69) 0 No trials Exclusion of Vas trials Nonspecific musculoskeletal pain 9 .19 (.11–.28) .001 .31 (.13–.48) Osteoarthritis 8 .18 (.10–.25) < .001 .35 (.07–.62) Shoulder 3 .58 (.42–.74) .2 .61 (.40–.81) Separate pain types Back pain 7 .17 (.07–.26) < .001 .30 (.08–.52) 9 .46 (.41–.50) < .001 .52 (.37–.67) Neck pain 3 .83 (.64–1.01) < .001 .82 (−.11 to 1.75) Excluding trials with summary data only Nonspecific musculoskeletal pain 9 .27 (.19–.35) < .001 .44 (.11–.78) 11 .53 (.50–.56) < .001 .45 (.33–.57) Osteoarthritis 8 .19 (.12–.26) < .001 .26 (.04–.48) 9 .59 (.52–.65) < .001 .59 (.37–.82) Chronic headache 5 .43 (.38–.47) < .001 .44 (.24–.64) Shoulder 3 .62 (.46–.77) .4 .62 (.46–.77) Excluding trials with possible bias due to blinding Nonspecific musculoskeletal pain 7 .28 (.19–.37) < .001 .51 (.09–.93) Osteoarthritis 9 .23 (.16–.31) < .001 .44 (.13–.75) Chronic headache* 3 .15 (.03–.26) .15 .12 (−.05 to .29) Including trials with high likelihood of bias due to blinding Osteoarthritis 10 .23 (.17–.30) < .001 .42 (.14–.70) Multiple imputation Nonspecific musculoskeletal pain 10 .29 (.21–.38) < .001 .48 (.16–.81) 12 .54 (.50–.57) < .001 .51 (.38–.64) Osteoarthritis 9 .24 (.17–.31) < .001 .45 (.15–.75) 10 .63 (.57–.70) < .001 .74 (.46–1.01) Chronic headache 5 .16 (.08–.25) .4 .16 (.08–.25) 7 .44 (.40–.49) < .001 .55 (.35–.75) Shoulder 4 .56 (.44–.69) .4 .56 (.44–.69) Excluding trials in which acupuncture and control groups received additional treatments Nonspecific musculoskeletal pain 10 .54 (.51–.57) < .001 .54 (.40–.67) Osteoarthritis 4 .21 (.11–.31) .081 .22 (.07–.38) 7 .70 (.62–.78) < .001 .70 (.47–.93) Chronic headache 5 .43 (.38–.47) < .001 .44 (.24–.64) Shoulder 3 .58 (.42–.74) .2 .61 (.40–.81) Abbreviations: FE, fixed effects estimate; RE, random effects estimate. NOTE. Acupuncture is superior to control at P < .001 except where indicated. * P = .015. Sensitivity Analyses Prespecified sensitivity analyses are also shown in Table 2. The exclusion of the RCTs by Vas et al89, 90, 91 repeats our previous finding that the effect sizes for comparison with sham are similar for musculoskeletal pain, osteoarthritis, and chronic headache. However, there are now sufficient trials for a meta-analysis of shoulder pain trials without inclusion of Vas et al90 and the effect size for this indication is clearly much greater. There is also a large effect size for sham controlled neck pain trials when these are analyzed separately from back pain. Most other sensitivity analyses had little effect on the main findings. Analyses incorporating assessment of patient blinding, missing data, or trials without individual patient data, all had results very similar to the primary analysis. Because the primary outcome included in the analysis was the outcome specified by the trial authors, we also performed a sensitivity analysis restricted to a single end point (pain intensity) at a fixed follow-up time (2–3 months after randomization). Results were again very similar apart from sham-controlled trials of musculoskeletal pain (Table 3), in which effect size decreased from .30 to .13, but this appears to be attributable to there being only 5 of 11 trials that measured pain intensity at 2 to 3 months, and the trials excluded happened to be those with the larger effect sizes. Table 3. Sensitivity Analyses Including Only Pain End Points Measured Between 2 and 3 Months After Randomization Analysis Indication Sham No Acupuncture Control Studies, n FE (95% CI) Heterogeneity P RE (95% CI) Studies, n FE (95% CI) Heterogeneity P RE (95% CI) Main analysis Nonspecific musculoskeletal pain 5 .13 (.01–.25) .005 .23 (−.03 to .49) 9 .60 (.56–.64) < .0001 .47 (.34–.61) Osteoarthritis 7 .31 (.23–.39) < .0001 .69 (.24–1.14) 9 .73 (.66–.80) < .0001 .88 (.61–1.15) Chronic headache 5 .14 (.06–.22) .4 .14 (.06–.22) 7 .43 (.38–.47) < .0001 .45 (.27–.63) Shoulder 2 No meta-analysis Abbreviations: FE, fixed effects estimate; RE, random effects estimate. We combined all trials into 1 meta-analysis for all indications to assess the possible effect of publication bias. As in the original analyses, we found some evidence that smaller studies had larger effect sizes for the sham comparison (P = .024), but not for the no acupuncture comparisons (P = .75). No significant asymmetry was seen after excluding the Vas trials89, 90, 91 and shoulder pain trials35, 52, 75, 90 from the sham comparison (n = 21, P = .13), and also when excluding any trials with fewer than 100 patients (n = 21, P = .069). We found that the difference between acupuncture and control would become nonsignificant only if there were 51 and >100 unpublished trials with 100 patients and effect sizes in favor of control of .25 SD for sham and no acupuncture control, respectively. We also repeated our exploratory analysis comparing sham control with no acupuncture control. In a meta-analysis of 12 RCTs that had sham as well as no acupuncture control arms, the effect sizes for sham were .39 (95% confidence interval [CI] = .33–.45) and .45 (95% CI = .29–.61) for fixed and random effects, respectively (P < .0001 for tests of effect as well as heterogeneity). Modifiers of Trial Outcome In addition to updating the primary analyses, we also updated previously published analyses on how characteristics of the acupuncture and control interventions influence trial outcomes. Trial-level and patient-level characteristics are shown in Table 4, Table 5, respectively. Table 4. Trial-Level Acupuncture Characteristics (N = 39) Characteristic n (%) Style of acupuncture  Combination of traditional Chinese and Western 9 (23)  Traditional Chinese techniques 23 (59)  Western 7 (18) Point prescription  Fixed needle formula 9 (23)  Flexible formula 18 (45)  Individualized 13 (33) Location of needles  Local as well as distal points 37 (95)  Distal points only 2 (5.1) Electrical stimulation allowed 11 (28) Manual stimulation allowed 36 (92) Moxibustion allowed 6 (15) Other adjunctive therapies allowed 8 (21) De Qi attempted (n = 35) 33 (94) Acupuncture-specific patient practitioner interactions 16 (40) Minimum years of experience required  No requirement specified (0 years) 14 (36)  6 Months to 2 years 7 (18)  3 to 4 Years 13 (33)  5 to 9 Years 3 (7.7)  10 Years 2 (5.1) Maximum number of sessions  1 to 5 3 (7.7)  6 to 10 19 (49)  11 to 15 12 (31)  16 to 20 1 (2.6)  21 to 25 2 (5.1)  26 to 30 2 (5.1) Frequency of sessions (mean number of sessions per week)  .88 1 (2.6)  1 19 (49)  1.43 1 (2.6)  1.5 7 (18)  1.67 1 (2.6)  2 9 (23)  5 1 (2.6) Mean duration of sessions, rounded to whole numbers (n = 34)  15 to 19 Minutes 1 (2.9)  20 to 24 Minutes 11 (32)  25 to 29 Minutes 6 (18)  30 Minutes or more 16 (47) Mean number of needles used (n = 33)  1 to 4 3 (9.1)  5 to 9 11 (33)  10 to 14 12 (36)  15 to 20 7 (21) NOTE. Counts for point prescription sum to 40 because 1 trial had 2 acupuncture groups, with each group receiving acupuncture on the basis of a different point prescription. Table 5. Patient-Level Acupuncture Characteristics, N = 20,827 Characteristic n (%) Number of sessions  0 441 (2.1)  1 to 5 515 (2.5)  6 to 10 8,003 (38)  11 to 15 2,065 (10)  16 to 20 40 (.2)  21 to 30 15 (<.1)  Missing 1,989 (10)  Not reported 7,759 (37) Average session duration  2 to 15 Minutes 163 (.8)  15 to 30 Minutes 2,668 (13)  31 to 45 Minutes 377 (1.8)  46 to 60 Minutes 25 (.1)   60 or more Minutes 1 (<.1)  Missing 896 (4.3)  Not reported 16,697 (80) Average number of needles  2 to 5 22 (.1)  6 to 10 910 (4.4)  11 to 15 762 (3.7)  16 to 20 825 (4.0)  21 to 25 199 (1.0)  26 or more 30 (.1)  Missing 1,621 (7.8)  Not reported 16,458 (79) Age of physician/acupuncturist, years  30 to 35 298 (1.4)  36 to 40 2,119 (10)  41 to 45 2,630 (13)  46 to 50 2,407 (12)  51 to 55 1,701 (8.2)  56 to 60 872 (4.2)  60 or more 303 (1.5)  Missing 368 (1.8)  Not reported 10,129 (49) Physician/acupuncturist sex  Female 3,626 (17)  Male 7,002 (34)  Missing 70 (.3)  Not reported 10,129 (49) Acupuncture Characteristics Analysis We updated previously reported analyses examining whether characteristics of acupuncture treatment modified the effect of acupuncture relative to control. These analyses include trial-level analysis, on the basis of characteristics described in the study protocol, as well as patient-level analyses, on the basis of data related to the individual patient. The results are shown in Table 6. We did not find any obvious association between trial outcome and characteristics such as the style of acupuncture (traditional or Western), use of fixed versus individualized point selection, or the use of electrical stimulation. The only clear finding was a dose-response effect to number of acupuncture treatments in trials with a no acupuncture control group (increase in effect size of .10 per 5 sessions, 95% CI = −.01 to .21, P = .001). Table 6. Results of Univariate Metaregression Analyses for the Effect of Acupuncture Characteristics on Acupuncture Effect Characteristic Sham Acupuncture No Acupuncture Control Trials, n β 95% CI P Trials, n β 95% CI P Style of acupuncture 25 25  Some TCM versus Western only −.00 −.49 to .48 >.9 .10 −.55 to .74 .8  TCM only versus some Western .02 −.38 to .42 .9 −.07 −.42 to .28 .7 Point prescription 25 25  Fixed needle formula Reference .6 Reference .075  Flexible formula .20 −.21 to .60 .01 −.45 to .46  Fully individualized −.01 −.75 to .73 −.34 −.79 to .10 Electrical stimulation allowed 25 .32 −.11 to .75 .14 25 −.12 −.50 to .26 .5 Manual stimulation allowed 25 .26 −.42 to .95 .5 25 −.38 −.99 to .23 .2 Moxibustion allowed No trials allowed 25 −.32 −.71, .06 .10 Other adjunctive treatment allowed 25 −.04 −1.00 to .92 .9 25 −.22 −.59 to .16 .3 De qi attempted 25 .29 −.67 to 1.24 .6 21 .74 −.04 to 1.52 .063 Acupuncture-specific patient practitioner interactions allowed 25 −.03 −.50 to .44 .9 25 −.05 −.38 to .28 .8 Minimum years of experience required 25 .04 −.05 to .13 .4 25 .05 −.03 to .12 .2 Maximum number of sessions (per 5 sessions) 25 −.01 −.23 to .22 .9 25 .01 −.12 to .14 .9  Patient-level analysis 5 (1,317/1,377) .09 −.31 to .48 .7 5 (8,036/10,157) .10 −.01 to .21 .001  Patient-level analysis, including Hinman et al39 6 (1,421/1,517) −.03 −.36 to −.30 .9 Frequency of sessions (per week) 25 −.06 −.29 to .18 .6 25 .21 −.22 to .64 .3 Duration of sessions (per 5 minutes) 25 .06 −.13 to .25 .5 20 −.06 −.25 to .13 .5  Patient-level analysis 6 (2,863/2,969) .01 −.08 to .09 .9 Number of needles used (per 5 needles) 25 .05 −.17 to .27 .6 19 .16 −.05 to .38 .13  Patient-level analysis 5 (2,232/2,317) .04 −.08 to .16 .5 Age of practitioner (per 5 years)  Patient-level analysis 6 (9,127/10,550) −.01 −.04 to .02 .5 Male practitioner  Patient-level analysis 6 (9,384/10,550) −.07 −.16 to .02 .084 Abbreviation: TCM, traditional Chinese medicine. NOTE. β is an estimate of the change in the effect of acupuncture in terms of standardized difference compared with controls for each characteristic; a positive β indicates a larger effect of acupuncture compared with controls for trials. The number of patients in the analysis and number of patients in included trials are given in parentheses where applicable. Sham Acupuncture Control Analysis We also updated a previously published analysis investigating the effects of acupuncture relative to different types of sham acupuncture and no acupuncture control groups. Differences in effect between acupuncture and the different sham acupuncture groups are shown in Table 7. The largest difference in effect between acupuncture and sham acupuncture was seen in trials using nonpenetrating needles, whereas the smallest difference was seen in trials using needle penetration. Significant differences were found between trials using penetrating needle sham and trials that used nonpenetrating or non-needle sham (difference in SD = −.30, 95% CI = −.60 to −.00, P = .047), although this result was sensitive to the exclusion of the outlying Vas trials89, 90, 91 (difference in SD = −.07, 95% CI = −.24 to .10, P = .4, Table 8), 2 of which used nonpenetrating controls. Table 7. Differences in Effect Size (in SD) Between Acupuncture and Sham Acupuncture Groups (n = 25) and Between Acupuncture and No Acupuncture Control Groups (n = 24) n Effect Size (95% CI) P Sham acupuncture, type of control group Penetrating needle sham 11 .17 (.11–.22) <.0001  Excluding B blinding grades 9 .16 (.09–.24) <.0001 Nonpenetrating needle and non-needle sham 15 .48 (.22–.74) .0003  Excluding B blinding grades 11 .51 (.16–.86) .004  Including Hinman et al39 16 .46 (.21–.70) .0003  Excluding Vas trials89, 90, 91 12 .27 (.10–.44) .002 Nonpenetrating needle sham 10 .52 (.14–.91) .007  Excluding Vas trials89, 90, 91 7 .22 (−.05–.49) .11 Non-needle sham 5 .37 (.21–.52) <.0001  Including Hinman et al39 6 .32 (.18–.46) <.0001 True acupuncture points (no penetrating needle sham) 12 .48 (.15–.80) .004  Excluding B blinding grades 10 .51 (.12–.89) .010  Including Hinman et al39 13 .45 (.15–.75) .003  Excluding Vas trials89, 91 10 .25 (.06–.44) .011 Nonacupuncture points (no penetrating needle sham) 3 .52 (.35–.69) <.0001  Excluding Vas trials90 2 .47 (.13–.81) .007 No acupuncture control, type of control group High-intensity 5 .34 (.11–.57) .003 Usual care and low-intensity 19 .56 (.43–.69) <.0001 Usual care 17 .50 (.40–.60) <.0001 Low-intensity 2 1.14 (.71–1.58) <.0001 NOTE. Total number of sham acupuncture-controlled trials sums to 26 because 1 trial had 2 different types of sham acupuncture control. Table 8. Differences in Effect Size Between Different Types of Control Group Group 1 Group 2 Effect Size (95% CI) P Sham acupuncture Penetrating needle sham Nonpenetrating and non-needle sham −.30 (−.60 to −.00) .047  Excluding B blinding grades −.33 (−.72 to .05) .088  Including Hinman et al39 −.28 (−.57 to .01) .061  Excluding Vas trials89, 90, 91 −.07 (−.24 to .10) .4 Nonpenetrating needle sham Non-needle sham .13 (−.44 to .70) .6  Including Hinman et al39 .18 (−.34 to .70) .5  Excluding Vas trials89, 90, 91 −.18 (−.52 to .17) .3 True acupuncture points, excluding penetrating needle sham Non-acupuncture points to excluding penetrating needle sham −.02 (−.70 to .66) .9  Including Hinman et al39 −.05 (−.71 to .61) .9  Excluding Vas trials89, 90, 91 −.22 (−.75 to .30) .4 No acupuncture controls High-intensity Usual care and low-intensity −.23 (−.50 to .05) .11 High-intensity Low-intensity −.81 (−1.26 to −.36) .0004 Usual care Low-intensity −.65 (−.98 to −.31) .0002 NOTE. A negative effect size indicates that there is a smaller difference in effect between acupuncture and control for group 1 than for group 2, for instance, the effect of control group 1 is more similar to verum acupuncture than the effect of control group 2. No Acupuncture Control Analysis In addition to updating the analysis comparing types of sham acupuncture control, we also updated the analysis comparing types of no acupuncture control. We updated the categorization of no acupuncture control groups, and categorized trials as having a high-intensity, usual care, or low-intensity control group. In a “high-intensity” control group, patients received a specified course of protocol-guided treatment. For instance, the United Kingdom Acupuncture, Physiotherapy and Exercise (APEX) trial by Foster et al33 is considered a high-intensity control because patients were randomized to receive a course of individualized, supervised physical therapy plus acupuncture versus physical therapy alone. In a trial with “usual care” control, patients are able to access whatever care they might reasonably receive outside of the study. As an example, in the United Kingdom National Health Service (NHS) study, patients were randomized to “use” versus “avoid” acupuncture and could receive whatever other treatments were offered to them.95 A control group was defined as “low-intensity” if patients were not allowed to receive certain treatments that might otherwise be available. For instance, the Acupuncture Randomized Trials for low back pain and osteoarthritis limited treatment of pain in the control group to oral nonsteroidal anti-inflammatory drugs (NSAIDs), excluding other types of treatment, such as steroids and other classes of analgesics.11, 108 Trials were assessed and assigned a control group type by 3 collaborators, with disagreements resolved by consensus. One trial was excluded from this analysis because there was a reasonable argument that it involved active control, prespecified to be excluded.26 Differences in effect between acupuncture and no acupuncture control groups are presented in Table 7. Significant differences were found between acupuncture and control for all types of no acupuncture control group. Notably, however, in trials that had high-intensity control groups, acupuncture had smaller effect sizes compared with those with low-intensity controls groups (difference = −.81, 95% CI = −1.26 to −.36, P = .0004); similarly, in trials with usual care control acupuncture had smaller effect sizes than trials with a low-intensity control group (difference in SD = −.65, 95% CI = −.98 to −.31, P = .0002, Table 8). Time Course of Acupuncture Effects Analysis We updated a previously published analysis assessing change in the effects of acupuncture over time relative to sham acupuncture and no acupuncture control.69 Number of weeks of acupuncture treatment and the time points used in this analysis are reported in Table 9. A total of 14 trials and 4,124 patients were included in the analysis of acupuncture versus no acupuncture control. The fixed effects estimate for the between group comparison of acupuncture versus no acupuncture controls showed a decrease in the effect size of acupuncture of .019 SD per 3 months (95% CI = −.041 to .003, P = .096, P = .011 for heterogeneity, Fig 4A). With a difference between acupuncture and no acupuncture control of approximately .5 SD, this is equivalent to approximately a 15% decrease in acupuncture effect relative to control at 1 year after randomization, which was usually between 9 and 10 months after the end of treatment. In the analysis of acupuncture versus sham acupuncture, a total of 21 trials and 6,276 patients were included. There was a nonsignificant decrease of .012 SD per 3 months in acupuncture relative to sham acupuncture (95% CI = −.035 to .011, P = .3, Fig 4B), approximately a 25% decrease in acupuncture effect at 1 year after randomization. Significant heterogeneity among trials was seen (P < .0001). The previous analysis reported that the decrease in effect of acupuncture relative to sham was driven by the decrease in neck pain trials (a decrease of .587 SD per 3 months, 95% CI = −.767 to −.406, P < .0001). We also analyzed the change in acupuncture relative to sham excluding these trials and found a nonsignificant decrease of −.003 SD per 3 months (95% CI = −.026 to .020, P = .8) with no significant heterogeneity among trials (P = .12). Hence almost all the decrease in acupuncture effects in this analysis seems attributable to neck pain. Table 9. Trials With Sham and No Acupuncture Control and Time Points Assessed After the End of Treatment Reference Pain Condition Average Length of Treatment, Weeks Sham Acupuncture No Acupuncture Control Time Points After End of Treatment Included in Meta-Analysis Control Patients Offered Acupuncture Treatment (Crossover) Time Points After End of Treatment Included in Meta-Analysis Carlsson et al13 Low back pain 8 Weeks 5 and 18 Yes Chen et al16 Osteoarthritis 12 End of treatment and week 14 Yes Endres et al28 Headache 6 End of treatment and weeks 7 and 20 Yes Guerra de Hoyos et al35 Shoulder 8 Weeks 5 and 18 Yes Irnich et al41 Neck 3 Weeks 1 and 10 Yes Kennedy et al48 Low back pain 5 End of treatment and week 7 Yes Kerr et al49 Low back pain 6 None No Kleinhenz et al52 Shoulder 4 End of treatment No Li et al59 Migraine 4 End of treatment and week 4 Yes Vas et al89 Osteoarthritis 12 Week 1 No Vas et al91 Neck 3 Weeks 1 and 25 Yes Vas et al90 Shoulder 3 Weeks 1 and 10 Yes White et al104 Neck 4 End of treatment and weeks 1 through 8 Yes White et al103 Osteoarthritis 4 End of treatment and week 1 Yes Berman et al8 Osteoarthritis 26 End of treatment No No End of treatment No Brinkhaus et al11 Low back pain 8 End of treatment and weeks 18 and 44 Yes At 8 weeks End of treatment No Cherkin et al19 Low back pain 7 Weeks 1, 19, and 45 Yes No Weeks 1, 19, and 45 Yes Diener et al26 Migraine 6 End of treatment and weeks 7 and 20 Yes No End of treatment and weeks 7 and 20 Yes Foster et al33 Osteoarthritis 3 Weeks 3, 23, and 49 Yes No Weeks 3, 23, and 49 Yes Haake et al36 Low back pain 6 End of treatment and weeks 7 and 20 Yes No End of treatment and weeks 7 and 20 Yes Linde et al63 Migraine 8 End of treatment and weeks 4 and 16 Yes At 12 weeks Week 4 No Melchart et al71 Headache 8 End of treatment and weeks 4 and 16 Yes At 12 weeks Week 4 No Scharf et al80 Osteoarthritis 6 Weeks 7 and 20 Yes No Weeks 7 and 20 Yes Suarez-Almazor et al85 Osteoarthritis 6 End of treatment and week 7 Yes No Week 7 No Witt et al108 Osteoarthritis 8 End of treatment and weeks 18 and 44 Yes At 8 weeks End of treatment No Cherkin et al18 Low back pain 10 No End of treatment and week 42 Yes Hinman et al39 Osteoarthritis 12 No End of treatment and week 40 Yes Hunter et al40 Low back pain 6 No Weeks 2, 7, and 20 Yes Jena et al43 Headache 12 At 12 weeks All measurements after crossover No Lansdown et al56 Osteoarthritis 10 No Weeks 3 and 42 Yes MacPherson et al67 Neck 16 No Weeks 10 and 36 Yes Thomas et al87 Low back pain 12 No Weeks 1, 40, and 92 Yes Salter et al79 Neck 12 No Week 1 No Vickers et al95 Headache 6 No Weeks 1 and 40 Yes Weiss et al102 Low back pain 4 No End of treatment and week 13 Yes Williamson et al107 Osteoarthritis 6 No Weeks 1 and 6 Yes Witt et al109 Neck 12 At 12 weeks All measurements after crossover No Witt et al110 Osteoarthritis 12 At 12 weeks All measurements after crossover No Witt et al111 Low back pain 12 At 12 weeks All measurements after crossover No Figure 4 Download high-res image (334KB)Download full-size image Figure 4. Forest plot showing the difference in pain change scores between acupuncture and no acupuncture control groups (A) and between acupuncture and sham acupuncture groups (B) over time. A coefficient of .01 means that the difference between acupuncture and control increases by .01 SD for each 3 months after the end of treatment. As a sensitivity analysis, we repeated the analyses including only trials that reported a significant difference between acupuncture and control, because trials that showed no difference between groups cannot show a reduction in acupuncture effects over time. Nine trials with 2,997 patients were included in this analysis for the comparison between acupuncture and no acupuncture controls. A smaller and still nonsignificant decrease in the effect of acupuncture was found (−.008 SD per 3 months, 95% CI = −.034 to .018, P = .5) and heterogeneity between trials was reduced (P = .082). None of the newly included trials showed a significant effect of acupuncture versus sham and so this analysis of sham-controlled trials with a significant effect contains the same 7 trials and 1,450 patients and has the same results as reported in the original publication (−.049 SD per 3 months, 95% CI = −.086 to −.013, P = .008, heterogeneity P < .0001). Discussion We updated an individual patient data meta-analysis of high-quality trials of acupuncture for chronic pain with 7 additional years of data. An additional 10 studies were included with nearly 3,000 patients. In total, our analyses include 39 studies and 20,827 patients. The results confirm and strengthen previous key findings that acupuncture has a clinically relevant effect compared with no acupuncture control. Moreover, we confirmed that, although the effects of acupuncture are not completely explicable in terms of placebo effects, factors other than the specific effects of needling at correct acupuncture point locations are important contributors to acupuncture treatment benefit. Effects of acupuncture appear to persist over at least a 12-month period. Heterogeneity continues to be an obvious aspect of our findings, with the results of trials varying by more than would be expected by chance. We have presented data that heterogeneity is predominately driven by differences between control groups rather than by differences between acupuncture treatment characteristics. We did not find any obvious differences between the results of trials depending on treatment characteristics such as style of acupuncture, duration of treatment sessions, or training of acupuncturists. In contrast, we found evidence that effect sizes of acupuncture were smaller for sham-controlled trials with penetrating needles and for no acupuncture controlled trials in which patients received high-intensity care (eg, a trial of acupuncture plus physical therapy vs physical therapy alone). In some cases, heterogeneity was also driven by a set of outlying trials with large effect sizes. We have presented these analyses with and without the outlying trials to provide all necessary information for interpreting these results and drawing conclusions. Another novel finding is the higher than average effects of acupuncture on upper body musculoskeletal pain. We now have sufficient data to conduct a meta-analysis for neck pain and for shoulder pain, even after exclusion of outlying trials. The effect sizes versus sham, .57 for shoulder and .83 for neck pain, were much larger than for low back pain, osteoarthritis, and headache, although we also saw evidence that treatment benefits did not persist for neck pain. Since publication of our results, there has been no substantive critique of our methodology in the peer-reviewed literature. The main issue under discussion seems to be whether the effect size of acupuncture is clinically relevant,94 specifically, whether clinical relevance is determined by the comparison with no acupuncture control or by comparison with sham. We have previously argued in favor of the former, on the grounds that the clinical decision made by a referring clinician in discussion with their patient is not between acupuncture and sham but between acupuncture and no acupuncture. Our argument is given the context of the excellent safety profile of acupuncture,65 evidence that the nonspecific effects of acupuncture are particular to acupuncture and are not easily reproduced,46, 54 and evidence provided here and elsewhere9 that some interventions used as sham acupuncture may be physiologically active. It is also illustrative to compare our results with those of other interventions routinely used in clinical practice. For instance, in one meta-analysis of NSAIDs for osteoarthritis of the knee, the effect size for NSAIDs versus placebo for trials that did not preselect NSAID responders was .2310; for chronic low back pain, the effect size for NSAIDs was < .20.29 We find several implications for research. In terms of the methodology of subsequent acupuncture trials for chronic pain, we find that the balance of evidence is to give a higher dose of acupuncture in terms of a greater number of treatments in trials without sham control. Although the nature of the control group in trials will naturally be driven by the research question, investigators should be aware of the evidence that control arms that incorporate a relatively intense level of intervention, such as when acupuncture is added into an intensive rehabilitation regimen, tend to lead to smaller effect sizes, as do sham controls that involve needle penetration. Further research is warranted on whether acupuncture is particularly effective for upper body musculoskeletal pain. An associated hypothesis is whether there are subtypes of other chronic pain indications that have differential response to acupuncture. It would naturally be ideal to know before referring a patient for treatment whether, say, the type of back pain they are experiencing is one that would be amenable to treatment with acupuncture. We will also repeat our previous call for research on how best to incorporate acupuncture into the multidisciplinary care of chronic pain patients. Conclusions We have confirmed that acupuncture has a clinically relevant, persistent effect on chronic pain that is not completely explained by placebo effects. Referral for a course of acupuncture treatment is therefore a reasonable option for a patient with chronic pain. Acknowledgments Acupuncture Trialists' Collaboration Members Claire Allen, BA, Evidence Aid, Oxford, United Kingdom. Brian Berman, MD, University of Maryland School of Medicine and Center for Integrative Medicine, College Park, Maryland. Benno Brinkhaus, MD, Institute for Social Medicine, Epidemiology and Health Economics, Charité University Medical Center, Berlin, Germany. Remy Coeytaux, MD, PhD, Department of Community and Family Medicine, Duke University, Durham, North Carolina. Hans-Christoph Diener, MD, PhD, Department of Neurology, University of Duisburg-Essen, Germany. Heinz G. Endres, MD, Ruhr-University Bochum, Bochum, Germany. Nadine E. Foster, DPhil, BSc(Hons), Arthritis Research UK Primary Care Centre, Research Institute of Primary Care and Health Sciences, Keele University, Newcastle-under-Lyme, Staffordshire, England. Michael Haake, MD, PhD, Department of Orthopedics and Traumatology, SLK Hospitals, Heilbronn, Germany. Rana S. Hinman, PhD, University of Melbourne, Melbourne, Australia. Dominik Irnich, MD, Multidisciplinary Pain Centre, Department of Anesthesiology, Ludwig-Maximilians-Universität München (LMU Munich), Germany. Wayne B. Jonas, MD, Samueli Institute, Alexandria, Virginia. Kai Kronfeld, PhD, Interdisciplinary Centre for Clinical Trials (IZKS Mainz), University Medical Centre Mainz, Mainz, Germany. Lixing Lao, PhD, University of Maryland and Center for Integrative Medicine, College Park, Maryland. George Lewith, MD, FRCP, Primary Care and Population Sciences, Faculty of Medicine, University of Southampton, Southampton, England. Klaus Linde, MD, Institute of General Practice, Technical University Munich, Munich, Germany. Hugh MacPherson, PhD, Professor of Acupuncture Research, Department of Health Sciences, University of York, York, England. Eric Manheimer, MS, Center for Integrative Medicine, University of Maryland School of Medicine, College Park, Maryland. Dieter Melchart, MD, PhD, Competence Centre for Complementary Medicine and Naturopathy, Technical University Munich, Munich, Germany. Albrecht Molsberger, MD, PhD, German Acupuncture Research Group, Duesseldorf, Germany. Karen J. Sherman, PhD, MPH, Group Health Research Institute, Seattle, Washington. Maria Suarez-Almazor, MD, PhD, M.D. Anderson Cancer Center, Houston, Texas. Hans Trampisch, PhD, Department of Medical Statistics and Epidemiology, Ruhr-University Bochum, Germany. Jorge Vas, MD, PhD, Pain Treatment Unit, Dos Hermanas Primary Care Health Center (Andalusia Public Health System), Dos Hermanas, Spain. Andrew J. Vickers (collaboration chair), DPhil, Memorial Sloan Kettering Cancer Center, New York, New York. Peter White, PhD, School of Health Sciences, University of Southampton, England. Lyn Williamson, MD, MA (Oxon), MRCGP, FRCP, Great Western Hospital, Swindon, United Kingdom. Stefan N. Willich, MD, MPH, MBA, Institute for Social Medicine, Epidemiology and Health Economics, Charité University Medical Center, Berlin, Germany. Claudia M. Witt, MD, MBA, Institute for Complementary and Integrative Medicine, University of Zurich and University Hospital Zurich, Zurich, Switzerland; Institute for Social Medicine, Epidemiology and Health Economics, Charite-Universitätsmedizin, Berlin, Germany; Center for Integrative Medicine, University of Maryland School of Medicine, Baltimore, Maryland. Supplementary Data The following is the supplementary data to this article: Download zip file (1MB) Help with zip files Supplementary Fig 1. Forest plots for the comparison of acupuncture with no-acupuncture control. There were fewer than 3 trials for shoulder pain, so no meta-analyses were performed. Weights reported are random-effects weights calculated using the DerSimonian and Laird method. Download zip file (1MB) Help with zip files Supplementary Fig 2. Forest plots for the comparison of true and sham acupuncture. Weights reported are random-effects weights calculated using the DerSimonian and Laird method. References 1 C.B. Ahn, S.J. Lee, J.C. Lee, J.P. Fossion, A. Sant'Ana A clinical pilot study comparing traditional acupuncture to combined acupuncture for treating headache, trigeminal neuralgia and retro-auricular pain in facial palsy J Acupunct Meridian Stud, 4 (2011), pp. 29-43 ArticleDownload PDFView Record in Scopus 2 S. Ahsin, S. Saleem, A.M. Bhatti, R.K. Iles, M. 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Effects of long-term acupuncture treatment on resting-state brain activity in migraine patients: A randomized controlled trial on active acupoints and inactive acupoints PLoS One, 9 (2014) e99538 The Acupuncture Trialists' Collaboration is funded by an R21 (AT004189I and an R01 (AT006794) from the National Center for Complementary and Alternative Medicine at the National Institutes of Health to Dr. Vickers) and by a grant from the Samueli Institute. Dr. MacPherson's work on this project was funded in part by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707-10186). Prof. Foster, an NIHR Senior Investigator, was supported through an NIHR Research Professorship (RP-011-015). The views expressed in this publication are those of the author(s) and not necessarily those of the National Center for Complementary and Alternative Medicine, National Health Service (NHS), NIHR, or the Department of Health in England. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the report. The authors have no conflicts of interest to declare. Supplementary data accompanying this article are available online at www.jpain.org and www.sciencedirect.com. © 2017 by the American Pain Society