Clinical Therapeutics/Volume 35, Number 11, 2013

Original Research

Efficacy of Periosteal Stimulation for Chronic Pain Associated With Advanced Knee Osteoarthritis: A Randomized, Controlled Clinical Trial Debra K. Weiner, MD1,3,4,5,6; Charity G. Moore, PhD3,6; Natalia E. Morone, MD, MS1,3,6; Edward S. Lee, MD2,3; and C. Kent Kwoh, MD7 1

Geriatric Research, Education, and Clinical Center, Veterans Administration Pittsburgh Healthcare System, Pittsburgh, Pennsylvania; 2Primary Care Service Line, Veterans Administration Pittsburgh Healthcare System, Pittsburgh, Pennsylvania; 3Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; 4Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania; 5 Department of Anesthesiology, University of Pittsburgh, Pittsburgh, Pennsylvania; 6Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, Pennsylvania; and 7Division of Rheumatology and Clinical Immunology and University of Arizona Arthritis Center, University of Arizona, Tucson, Arizona ABSTRACT Background: Because of morbidity associated with painful knee osteoarthritis (OA) and commonly prescribed analgesics, patients often pursue complementary and alternative modalities (eg, acupuncture). Clinical trials have demonstrated modest therapeutic efficacy of traditional Chinese acupuncture for knee OA pain, and patients with advanced disease have largely been excluded. We have previously demonstrated preliminary short-term tolerability and efficacy of periosteal stimulation therapy (PST) (ie, electrical stimulation of the periosteum facilitated by acupuncture needles) for older adults with advanced knee OA. Objective: This study evaluated the sustained efficacy of PST and boosters for treating chronic pain with advanced knee OA. Methods: One hundred ninety participants age 450 years with Kellgren-Lawrence grade 3 or 4 knee OA and chronic pain were randomized to (1) PST (once a week for 10 weeks) followed by PST boosters for 6 months (once every 2 weeks 2 times, then once a month), (2) control PST (ie, periosteal needles and brief electrical stimulation of control points) once a week for 10 weeks, or (3) PST for 10 weeks followed by control PST boosters for 6 months. Change in the Western Ontario and McMaster Universities Osteoarthritis Index pain score immediately after the 10-week intervention and at 6-month follow-up (9 months after baseline) was the

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primary outcome. OMERACT-OARSI (Outcome Measures in Rheumatology Clinical Trials–Osteoarthritis Research Society International) criteria also were evaluated. Secondary measures of outcome included (1) physical performance (Short Physical Performance Battery, gait speed, Timed Up and Go, and timed stair climb); (2) psychological factors (depressive symptoms measured with the Center for Epidemiologic Studies– Depression scale, coping measured with the catastrophizing subscale of the Coping Strategies Questionnaire, and self-efficacy measured with the Arthritis SelfEfficacy Scale); (3) health-related quality of life measured with the Medical Outcomes Study 36-Item ShortForm Health Survey; (4) rescue pain medication use tracked with diaries; and (5) health care utilization and interim physical activity were monitored via monthly telephone calls. Results: After adjustment for pain at baseline, the PST and control booster did not differ from controls at 10 weeks (difference, 1.3; 95% CI,
0.10 to 2.8; P ¼ 0.0683) or 9 months (difference, 1.1; 95% CI,
0.32 to 2.6; P ¼ 0.13). The PST and PST booster group had similar improvement compared with

Accepted for publication September 30, 2013. http://dx.doi.org/10.1016/j.clinthera.2013.09.025 0149-2918/$ - see front matter Published by Elsevier HS Journals, Inc.

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Clinical Therapeutics controls at 10 weeks (baseline adjusted difference, 1.1; 95% CI,
0.34 to 2.5; P ¼ 0.1369) but significantly more improvement at 9 months (baseline adjusted difference, 1.5; 95% CI, 0.069 to 3.0; P ¼ 0.0401). Baseline depressive symptoms, low self-efficacy, higher difficulty performing daily activities, and greater knee stiffness predicted a lower likelihood of response. Conclusion: PST plus PST boosters in patients age 450 with advanced knee OA were well-tolerated and modestly reduced pain. ClinicalTrials.gov identifier: NCT00865046. (Clin Ther. 2013;35:1703–1720) Published by Elsevier HS Journals, Inc. Key words: acupuncture, chronic pain, knee osteoarthritis, older adults, periosteal stimulation.

INTRODUCTION Approximately 20 million Americans have chronic pain associated with knee osteoarthritis (OA).1 Lower-extremity OA is the most common cause of difficulty with walking or climbing stairs, thus preventing an estimated 100,000 elderly Americans from independently walking from bed to bathroom. Osteoarthritis of the knee and/or hip is associated with limitations in physical activities, mobility, and self-care, as well as with loss of earnings and work disability.2 The 2012 American College of Rheumatology guidelines recommend nonpharmacologic interventions, such as weight loss and exercise, as the first-line treatment for knee OA pain.3 Many patients also rely on oral analgesics for pain management, such as acetaminophen, nonsteroidal anti-inflammatory drugs, and opioids. These medications are often associated with serious adverse effects, however, including renal impairment, cerebrovascular accidents, heart failure, and gastrointestinal bleeding with nonsteroidal anti-inflammatory drugs4,5 and delirium, falls, and hip fractures with opioids.6–8 Glucosamine, chondroitin, and intra-articular hyaluronic acid injection have met with mixed results.9–11 Intra-articular glucocorticoid injections may provide modest, typically transient benefits.12 Neither arthroscopic debridement nor lavage is recommended for pain management.13 The standard-of-care fallback intervention for those with recalcitrant pain and functional compromise is knee replacement surgery. Older adults with limiting comorbidities may not be surgical candidates, and advanced age is the major predictor of mortality after these joint replacement procedures.14 Further, few patients appear willing to undergo such surgery.15 Clearly, for older

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adults with advanced OA and chronic pain, safe and effective analgesic options are needed. Because of the limitations associated with traditional therapeutics, use of complementary and alternative medicine (CAM) interventions has increased steadily. An estimated 3 million Americans have used acupuncture, most commonly for chronic pain.16 The efficacy of traditional Chinese acupuncture for the treatment of knee OA has been examined in the context of 3 large randomized clinical trials, but participants with advanced disease (ie, Kellgren-Lawrence [KL] grade 4) were largely excluded.17–19 In addition, the magnitude of pain reduction in the most rigorous of the 3 trials was very modest (0.87 points lower on the Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] pain scale in the acupuncture group compared with the sham acupuncture group), and no long-term follow-up was performed.17 Two recent trials of acupuncture for knee OA have not included radiographic data (ie, unknown disease severity among participants).20,21 Extrapolating from these trials and a recent meta-analysis,22 traditional Chinese acupuncture (TCA) is associated with modest pain reduction in patients with early and moderately advanced knee OA. A 2010 Cochrane review concluded that acupuncture provides clinically insignificant pain reduction for appendicular OA and that observed benefits are likely related to expectancy-mediated placebo analgesia.23 Periosteal stimulation therapy (PST) is a technique that delivers high-frequency electrical stimulation to periosteum using acupuncture needles. It has been hypothesized that PST exerts its effect primarily by stimulating sympathetic fibers in proximity to the periosteum, which in turn stimulates a local increase in blood flow that then modifies vascular sympathetic and segmental nerve responses.24–26 Electrical stimulation of acupuncture needles is associated with decreased levels of the proinflammatory cytokine interleukin 627 and with release of endogenous opioids28–31 that may have anti-inflammatory effects on peripheral receptors.32,33 Because inflammation plays a central role in OA pathogenesis,34–36 this may be a target for the intervention. Although PST is typically administered by acupuncturists using acupuncture needles, the technique and underlying principles that guide PST are distinct from those of TCA. Traditional Chinese acupuncture involves placing needles at precise points (that may be near or far the site of pain) along channels called meridians and manipulating the needles until “te chi” is achieved

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D.K. Weiner et al. (a sensation that the muscle is grabbing the needle), then stimulating the needles either manually or with heat or electricity.37 Periosteal stimulation therapy is easier to perform than TCA because “te chi” is not required, fewer needles are used, and, because of its potency, fewer treatments may be required to achieve an effect. Before conducting the clinical trial described in this report, we conducted a randomized, controlled pilot study in 88 community-dwelling older adults (mean [SD] age, 71.5 [5.4] years; approximately 50% male) with chronic knee pain, which demonstrated that PST administered once a week for 6 weeks reduces pain and improves function38 significantly more than control PST and that it has short-term tolerability (4.5% dropout rate). These results were noteworthy because 80% of participants had advanced OA (radiographic severity: KL grade 4; ie, bone on bone). Participants were followed up for 3 months after the completion of PST, and treatment efficacy had waned at 2 months. The magnitude of the initial pain reduction was significantly greater than that reported in TCA trials; thus, PST is the focus of the study described in this report. The purpose of this randomized, controlled clinical trial was to evaluate the efficacy of PST for older adults with advanced knee OA using a larger sample size, a longer intervention period that included booster treatments, and longer duration of follow-up.

METHODS Participant Recruitment Before recruitment, this study was approved by the Veterans Administration Pittsburgh Healthcare System (VAPHS) Institutional Review Board (IRB) and registered with ClinicalTrials.gov (identifier NCT00865046). One hundred ninety English-speaking participants age 450 years with knee OA as defined by American College of Rheumatology classification criteria (pain for 425 of the past 30 days and osteophytes on knee radiography) were recruited. Several methods were used. First, the VAPHS data warehouse was queried to identify potential participants with upcoming primary care appointments. Letters signed by primary care physicians of these potential participants were mailed along with an IRB-approved brochure describing the study. Second, study brochures were placed in VAPHS clinic waiting rooms. Third, advertisements approved by the VAPHS IRB were placed in local newspapers. Fourth, a targeted mailing of brochures was done to residents of Allegheny County guided by

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a mailing list purchased from a private company (Lorton, Arden Hills, Minnesota). Those interested called a research associate for telephone screening. The following inclusion criteria were queried: knee pain for at least 3 months with pain of at least moderate intensity (measured with a verbal descriptor scale) every day or almost every day; knee pain severity greater than pain severity in other parts of body; ambulatory with or without a cane; Folstein Mini-Mental State Examination score Z24; adequate vision and hearing (with or without correction) to hear over the telephone and read the newspaper; absence of non-OA causes of knee pain (eg, rheumatoid arthritis and gout); no large knee effusion; absence of recent diagnosis of cancer; no knee injections (corticosteroid or hyaluronic acid) within the previous 3 months; no acute or terminal illness; no anticoagulation; not taking corticosteroids or other immune suppressants; no HIV/AIDS; no pacemaker; and no previous exposure to PST. In addition to these criteria, KL grade 3 or 4 knee OA was required and evaluated by knee radiographs performed on site (see below). Those who met inclusion and exclusion criteria according to the telephone screen were invited to come to VAPHS for the on-site study procedures: (1) signing of informed consent forms and a screening history and physical examination (performed by one of the study physicians [D.K.W., N.E.M.]) to verify that all inclusion and exclusion criteria were met; (2) collection of baseline measures (see below); and (3) bilateral weight-bearing knee radiographs.

Baseline Assessment Pain, our primary outcome, was assessed with the WOMAC (collected on each knee).39 The WOMAC stiffness and difficulty subscales also were administered. Physical performance was assessed with measures that focus on lower-extremity function. The Short Physical Performance Battery (SPPB), found to strongly predict disability and mortality, includes tasks that produce stress on the knees (eg, gait speed, standing balance, and timed chair rise).40,41 Stair climbing predicts treatment outcome for older adults with chronic pain42 and is sensitive to treatment effects.43 Participants were timed as they ascended and descended 5 steps, a task with a test-retest reliability 0.88.44 The Timed Up and Go test, a measure of balance and mobility, is reliable and valid in community-dwelling older adults45 and in

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Clinical Therapeutics participants with knee OA,46,47 with test-retest and interrater reliability intraclass correlation coefficients of 0.98 and 0.99, respectively, and internal consistency (α = 0.96).45 Psychological factors were collected as potential covariates and measures of outcome. Given the strong association between chronic pain and depression,48 mood was measured with the Center for Epidemiologic Studies–Depression (CES-D) scale, which was administered to all participants.49 An important contributor to disability in young people with chronic pain, coping has remained unexplored in older adults. We administered the catastrophizing subscale of the Coping Strategies Questionnaire (CSQ) that in knee OA patients has an internal consistency α ¼ 0.7450 and test-retest reliability of 0.71.51 Self-efficacy has been reported to predict task performance52,53 and to mediate the response to interventions in patients with knee pain.44 We measured this construct with the well-validated Arthritis Self-Efficacy Scale.54 The Arthritis Self-Efficacy Scale has 3 subscales—pain self-efficacy (PSE), function self-efficacy (FSE), and other symptoms selfefficacy (OSE)—that have excellent internal reliability (coefficient α estimates ¼ 0.76 for PSE, 0.89 for FSE, and 0.87 for OSE) and test-retest reliability (0.87 for PSE, 0.85 for FSE, and 0.90 for OSE).54 Health-related quality of life was assessed with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), which measures both physical and emotional health.55 The mean reliability coefficient for all subscales is 0.85,55–58 and its discriminant validity (older adults with and without poor health) has been demonstrated.59 All current prescription and over-the-counter medications were recorded by the examining study physician (D.K.W. or N.E.M.) and tracked weekly during the initial intervention period, then monthly by participants using diaries (strength and number of doses of regularly scheduled and rescue analgesics taken). Participants were instructed not to change any of their regularly scheduled analgesics. In addition to primary and secondary measures of outcome, the following data were collected at pretreatment because of the potential for these factors to act as covariates. Demographic factors were identified, including age, sex, ethnicity, and marital and educational status. Biomedical factors, including comorbidity and body mass index, were identified as part of the on-site

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history and physical examination. Because of its independent contribution to functional status in older adults,60 comorbidity was assessed with the Cumulative Illness Rating Scale, an instrument that has a high interrater reliability (Kendall W ¼ 0.83–0.91).61 The Cumulative Illness Rating Scale was scored by summing the number of items with a score of moderate or greater.62 Body mass index was calculated, using measured height and weight, given its inverse association with dependence in basic and instrumental activities of daily living63 and its impact on knee pain64 and postural stability65 in patients with knee OA.

Randomization and Allocation Concealment Randomization was fixed allocation by permuted blocks with random block sizes of 3 and 6 stratified by age (50–64 or Z65 years) and reported disease burden (unilateral or bilateral) at screening. The trial statistician generated the randomization lists with SAS statistical software, version 9 (SAS Institute Inc, Cary, North Carolina), which were then uploaded into the Access data management database. Allocation was determined for each participant once he/she was determined to be eligible with the next assignment concealed within the electronic database until the next participant was deemed eligible.

Intervention Participants were randomized to 1 of the following 3 groups: (1) PST (ie, PST once a week for 10 weeks) followed by PST boosters for 6 months (2 booster sessions spaced by 2 weeks, then 5 booster sessions spaced by 1 month); (2) control PST (ie, placement of needles in locations identical to that for PST and brief electrical stimulation at nonperiosteal points to control for treatment expectancy, described below) once a week for 10 weeks; no booster sessions were administered during the 6-months follow-up period; or (3) PST once a week for 10 weeks followed by control PST boosters administered exactly according to the schedule of PST boosters in group 1. All PST was performed by 1 of 3 trained acupuncturists (D.K.W., E.S.L, or David Mortell, LAc). All PST sessions lasted 30 minutes. Attendance was recorded. To allow for travel or transient illness, we allowed a 12-week window for completing the initial 10 intervention sessions.

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D.K. Weiner et al. The PST procedure started with sterile skin preparation (using povidone iodine 10% solution or chlorhexidine for those with iodine allergy) over one or both knees (ie, the knee[s] in which the participant reports at least moderate pain on a daily or almost daily basis for Z3 months, defined at baseline) with the participant seated, followed by insertion of four 30-gauge acupuncture needles (see Supplemental Figure 1 in the online version at http://dx.doi.org/10. 1016/j.clinthera.2013.09.025). The 4 PST needles just touched bone, and electrical stimulation was delivered using a Pantheon electroacupuncture unit (model 12c) at 100 Hz. The waveform delivered by this unit is symmetrical biphasic (modified square wave). The stimulus is neither constant voltage nor constant current; it changes according to the load. The pulse width is 0.4 milliseconds with a stimulus intensity range of 0 to 60 V. The Pantheon unit was recalibrated monthly to ensure stimulus consistency for the entire study. For each session, stimulus intensity was adjusted so that it was clearly perceptible but not painful. Because participants can become accustomed to the stimulus, the acupuncturist adjusted the input so that the intensity remained clearly perceptible but not painful for the entire 30 minutes. Electrical stimulation was delivered to the 2 control needles in an identical fashion as described in the control procedure below. The control PST procedure (see Supplemental Figure 2 in the online version at http://dx.doi.org/10. 1016/j.clinthera.2013.09.025) consisted of the insertion of 4 acupuncture needles in identical locations as in the PST group. Electrical stimulation, however, was not delivered to these periosteal needles. To control for treatment expectancy and, therefore, credibility, 2 extra needles were placed subcutaneously in nonacupuncture points in the upper pretibial region just below the knee, and 100-Hz stimulation was delivered to these needles only. The stimulation was applied as in the intervention group until the stimulus was clearly perceptible but not painful; however, the duration of stimulation was limited to 1 minute rather than given for the entire 30-minute treatment period. Participants were questioned after sessions 1 and 10 to determine their perception of treatment credibility. Questions included participants’ rating of their level of confidence with the treatment, whether they would recommend the treatment to a friend, perceived expertness of the treating clinicians, and credibility

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and expectation of positive treatment outcomes, according to standard procedure.66,67

Retention Strategies To optimize retention, participants were called monthly during follow-up and were paid for the visits that involved data collection only. Each participant was paid $75 for participating in collection of the baseline data, $100 for the postintervention data collection (ie, immediately after the 10-week intervention), and $150 at 6 months.

Assessment of Treatment Outcomes Our primary outcome was pain assessed with the WOMAC (collected on each knee). The research coordinator who collected the outcomes data was kept masked to participants’ assigned treatment groups. Participants were asked not to discuss any aspects of their treatment with the research coordinator collecting the outcome measures. Two research assistants were responsible for recruiting participants and for scheduling all appointments with the acupuncturists to ensure that the research coordinator assessor was kept masked to participant group. The following outcome measures were collected. A brief battery (o10 minutes) that included a subset of the baseline measures, including gait speed, WOMAC score, and participants’ reports of any pain medication use (including over-the-counter) during the previous week (type, dosage, and frequency), tracked with diaries, was collected weekly just before each PST or control PST session during the initial 10-week intervention period. Within 1 week after completing the 10-week treatment protocol (referred to as immediately after treatment), pain (WOMAC score) and the measures of physical performance, quality of life, and psychological factors described under the section “Baseline Assessment” were collected. We also asked participants to rate their perceived global improvement on a 5-point scale.68 The OMERACT-OARSI criteria for response to the intervention, our second primary outcome measure, was calculated (ie, improvement in pain or function Z50% and absolute change Z20 OR improvement in at least 2 of the following 3 items: pain [WOMAC pain subscale score], function [WOMAC function subscale score], and/or global assessment [using a 5-point scale from 1 (very poor) to 5 (very good), rescaled from 0 to 100 for the

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Clinical Therapeutics purpose of analysis; Z20% and absolute change Z10).69 We defined OMERACT-OARSI response as per scenario D in the original publication.69 Monthly for 6 months, after completing the 10week treatment protocol, participants were interviewed by telephone and the following data collected: pain (WOMAC score), as-needed pain medication use (number of doses per their diary documentation), and interim disabling pain and illness during the prior month using well-validated methods.70 Specifically, participants were asked whether during the past month they had been hospitalized or disabled (more than half day in bed or required to cut back on routine activities) because of pain or illness. Health care utilization also was reported; specifically, participants were asked if during the past month they had seen a health care practitioner in the office, seen a health care practitioner in the emergency department, been hospitalized, been a patient in a nursing home, or seen a psychiatrist, psychologist, or counselor. The reasons for this health care use also were queried and categorized as being directly related to their knee pain or not. The type of facility in which the participant was seen (ie, Veterans Administration or non– Veterans Administration) also was recorded. Interim change in physical activity level was measured with the Physical Activity Scale for Individuals with Physical Disabilities.71 Nine months after baseline (ie, 6 months after completing the 10-week treatment protocol), an onsite evaluation was conducted that was identical to that performed within 1 week after completing the 10week treatment protocol.

Statistical Analysis Participants in the PST arm from our pilot study had a 33% reduction in pain at 6 weeks and sustained a 10% reduction in pain at 3 months relative to a baseline mean of 9.1.38 We hypothesized that both booster groups would have the same amount of reduction in pain at the end of PST treatment (approximately 12 weeks from baseline, within 1 week after completing the 10-week treatment protocol) with sustained reduction in pain at the end of PST boosters (9 months from baseline and 6 months after completing the 10-week treatment protocol) for the true booster group and return to baseline levels in the PST control booster and control PST groups. Previous data indicated that the SDs of the WOMAC pain scale

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ranged from 3.1 to 3.9.38 With 60 per group and 15% attrition, we had 80% power to detect a sustained 23% reduction in pain (Δ ¼ 2.1 for pain scale) between any 2 groups at 9 months using a 2-sample t test (α ¼ 0.05, s ¼ 3.7). For our main secondary outcome (OMERACT-OARSI response), 51 per group provided 80% power to detect an absolute increase of 21% to 28% in response to treatment between any 2 groups at 6-month follow-up using a Fisher exact test, assuming the response in the control group is between 5% and 20% (α ¼ 0.05). We compared demographic characteristics, clinical characteristics, and outcome measures at baseline using analysis of variance and χ2 tests. The primary aim of this study was to test the effectiveness of boosters in sustaining pain reduction with pain measured by the WOMAC pain subscale. Primary analyses compared the 3 treatment arms according to the intent-to-treat approach. We used mixed models with fixed effects of group (PST-PST, PST-control, and control PST), time (immediately after treatment and at 9 months), and the group  time interaction controlling for the baseline pain measure.72 We used the knee-specific version of the WOMAC pain scale such that participants with unilateral disease contributed 1 data point per time point but participants with bilateral disease contributed 2 data points per time point (1 measure per knee). The mixed models take into account not only the correlation among measurements within a person over time but also the nesting of knees within a person with bilateral disease at any time point (via specification of random effects for participant, participant  time, and participant  knee).73 In all models we controlled for age and disease burden because these were the variables used for stratification in the randomization. We compared mean change in pain for each intervention group to control using least-square means and corresponding 95% CIs and P values. Although the amount of attrition was relatively small, we used multiple imputation in a sensitivity analyses to see the effect of attrition on our results. Missing knee pain data were imputed with M ¼ 10 imputations, using age, disease burden (bilateral or unilateral knee pain), depression, body mass index, Arthritis Self-Efficacy subscales (pain, function, and other symptoms), short physical performance battery score, and the catastrophizing scale from the cognitive strategies questionnaire. Linear mixed models were run on each imputed data

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D.K. Weiner et al. set, and coefficient results were combined using the PROC MIANALYZE procedure in SAS. We compared responses to treatment for osteoarthritis using the OMERACT-OARSI criteria via Fisher exact tests immediately after treatment and at 9 months. Physical performance, psychological measures, and as needed analgesics (opioid and nonopioid were compared using mixed models similar to the WOMAC pain subscale analyses. Health care use was compared between groups over time using generalized estimating equations with a logit link. We used linear mixed models and generalized estimating equations with a logit link to ascertain baseline physical and psychological predictors of response (change in pain and OMERACT-OARSI, respectively) immediately after treatment and at longer-term follow-up (9 months from baseline). Mixed models and generalized estimating equations were used to control for the correlation among knee outcomes within an individual. We used SAS statistical software, version 9.3, and Stata statistical software, version 12 (Stata Corp, College Station, Texas), for all analyses. Analysis of predictors of pain reduction included the entire sample with all 3 groups combined.

RESULTS Participants and Treatment Adherence A total of 190 participants (from 962 screened) underwent randomization, with 63 assigned to the control PST group (ie, no boosters were administered), 63 to the PST and PST boosters group, and 64 to the PST and control PST boosters group (Figure 1). All randomized participants were included in the intention-to-treat population. Six of these individuals did not receive any PST or control PST. Demographic and clinical characteristics are presented in Table I. These characteristics were similar in all 3 groups with the exception of scores on the catastrophizing scale of the Cognitive Strategies Questionnaire and WOMAC pain at baseline, with those in the PST and control PST boosters group having more catastrophizing and the control PST group having more knee pain. Treatment adherence was similar across groups. The mean (SD) number of sessions attended was 8.7 (2.4) (range, 1–10) for the initial 10 sessions and 4.6 (2.8) (range, 0–7) for the boosters in the PST and PST boosters group, 8.5 (2.7) (range, 1–10) for the initial 10 and 4.6 (2.9) for the

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boosters in the PST and control PST boosters group, and 9.0 (2.2) (range, 1–10) in the control PST group.

Adverse Events There were 4 adverse events that were clearly attributable to PST and control PST. The fifth participant’s adverse event was not clearly attributable to the intervention. One participant experienced an increase in knee pain after the treatment. One participant reported local bruising. Two participants had vasovagal symptoms; 1 reported sweating during 1 session that resulted in premature interruption of the session, and 1 reported feeling lightheaded, which also resulted in premature interruption of the session. A fifth participant reported experiencing foot pain the evening after an afternoon PST session. Examination indicated findings consistent with plantar fasciitis that eventually resolved.

Primary Outcomes All 3 groups experienced significant improvement in the WOMAC pain subscale (Table II), with the unadjusted trajectory of improvement shown in Figure 2. At baseline, the mean pain levels differed across groups (P ¼ 0.0189), with the control group having more pain than the PST and PST booster group (P ¼ 0.0049). Baseline pain severity was strongly associated with change in pain scores, with higher pain severity being associated with more change over time (r ¼
0.41, P o 0.0001, at 10 weeks and r ¼
0.50, P o 0.0001 at 6 months). Adjusting for pain at baseline, PST and control booster patients did not differ from controls at 10 weeks (difference, 1.3; 95% CI,
0.10 to 2.8; P ¼ 0.0683) or 9 months (difference, 1.1; 95% CI,
0.32 to 2.6; P ¼ 0.13). The PST and PST booster group had similar improvement compared with controls at 10 weeks (baseline adjusted difference, 1.1; 95% CI,
0.34 to 2.5; P ¼ 0.1369) but significantly more improvement at 9 months (baseline adjusted difference, 1.5; 95% CI, 0.069 to 3.0; P ¼ 0.0401) (Table II). No WOMAC pain reduction differences were detected between the PST and PST boosters and the PST and control PST boosters groups. Although the amount of missing data was small, sensitivity analyses using multiple imputation did not alter the conclusions for the primary outcome of pain. There were no significant between-group differences in treatment credibility at 1 week or 10 weeks (data not shown).

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Assessed for eligibility by telephone screen (n = 962) 436 Excluded Refused/not completed (n = 43) Lower body pain (n = 112) Knee pain infrequent/not severe/short duration (n = 84) Taking warfarin (n = 47) Steriod injection (n = 33) Cancer (n = 22) Age ineligible (n = 19) Other (n = 76) 140 Eligible but did not show for medical evaluation

On-site medical evaluation (n = 386) 89 Excluded Lower body pain (n = 44) Other history and physical examination screening (n = 25) On-site medical evaluation not completed (n = 17) MMSE (n = 2) Ineligible on recommendations (n = 1) 8 Eligible but knee radiography not performed Knee radiography (n = 289) 87 Excluded Ineligible on knee radiography (n = 87) 12 Ineligible/excluded before randomization

Randomized (n = 190)

PST and PST boosters (n = 63)

PST and control PST boosters (n = 64)

5 Treatment withdrawn 1 Lost to follow-up 4 Excluded after randomization

7 Treatment withdrawn 6 Lost to follow-up 1 Deceased 1 Excluded after randomization

Included in analyses 57 with 3-month follow-up 57 with 6-month follow-up 57 with 9-month follow-up

Included in analyses 58 with 3-month follow-up 59 with 6-month follow-up 59 with 9-month follow-up

Control PST (n = 63)

3 Treatment withdrawn 2 Lost to follow-up 1 Deceased

Included in analyses 61 with 3-month follow-up 61 with 6-month follow-up 62 with 9-month follow-up

Figure 1. Study flow diagram. MMSE ¼ Mini-Mental State Examination; PST ¼ periosteal stimulation therapy.

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D.K. Weiner et al. Table I. Comparison of demographic characteristics and other assessments at baseline by treatment group (N ¼ 190 randomized participants). Characteristic Age, mean (SD), y Male, No. (%) White race, No. (%) Hispanic, No. (%) Last grade completed, No. (%) Elementary school High school Some college/college Postgraduate Married, No. (%) Comorbidity Cumulative Illness Rating, mean (SD) BMI, mean (SD), kg/m2 Pain medications, No. (%) No. pain medications, mean (SD) No. opioid pain medications, mean (SD) Duration of knee pain, mean (SD), y Pain in both knees at screening, No. (%) Both knees treated, No. (%) Short Physical Performance Battery score, mean (SD) Time to complete stair climbing, mean (SD), sec Timed Up and Go test, mean (SD), sec Gait speed, mean (SD), m/sec Radiographic disease severity,* No. (%) CES-D score, mean (SD) Cognitive Strategies Questionnaire, catastrophizing scale score, mean (SD) Considering all the ways your knee arthritis affects you, how well are you doing?,† mean (SD) Arthritis Self-Efficacy Scale scores, mean (SD) Pain subscale Function subscale Other symptoms subscale WOMAC scores Bilateral left Pain Stiffness Difficulty performing daily activities Bilateral right Pain Stiffness Difficulty performing daily activities Unilateral Pain Stiffness Difficulty performing daily activities

PST and PST Booster (n ¼ 63)

PST and Control Booster (n ¼ 64)

Control PST (n ¼ 63)

67.1 55 45 2

(8.9) (87.3) (71.4) (3.2)

65.8 (8.7) 54 (84.4) 42 (65.6) 0

66.8 (10.4) 52 (82.5) 47 (74.6) 0

2 24 30 7 35 4.4 31.6 42 1.1 0.1 5.7 44 45 6.1 12.5 12.3 0.80 38 11.7 7.9

(3.2) (38.1) (47.6) (11.1) (55.6) (2.0) (6.5) (66.7) (1.0) (0.3) (6.4) (69.8) (71.4) (1.8) (4.7) (3.4) (0.14) (60.3) (10.3) (7.8)

3 26 29 6 27 4.5 33.1 47 1.2 0.3 6.2 46 45 6.1 14.5 13.1 0.78 37 14.7 12.1

31 25 7 29 4.4 32.5 40 1.0 0.2 7.2 45 41 6.2 13.9 13.9 0.76 43 12.3 8.8

(4.7) (40.6) (45.3) (9.4) (42.2) (2.2) (6.2) (73.4) (0.9) (0.6) (6.8) (71.9) (70.3) (1.9) (7.8) (3.8) (0.18) (57.8) (11.2) (9.7)

0 (49.2) (39.7) (11.1) (46.0) (2.0) (6.9) (63.5) (0.9) (0.4) (8.3) (71.4) (65.1) (1.5) (7.3) (6.9) (0.20) (68.3) (9.6) (9.2)

3.4 (1.1)

P 0.7322 0.7550 0.5305 0.2175 0.6395

0.3005 0.9359 0.4019 0.4710 0.4907 0.0856 0.4972 0.9655 0.7128 0.9471 0.2231 0.1935 0.3757 0.4496 0.2171 0.0219

3.5 (1.0)

3.2 (1.0)

0.3926

64.3 (21.6) 77.5 (17.0) 70.5 (21.1)

59.5 (22.6) 76.3 (16.9) 65.9 (20.3)

63.9 (21.7) 0.3977 76.1 (16.4) 0.8798 68.6 (20.9) 0.4578

9.0 (3.2) 4.3 (1.7) 33.1 (12.1)

9.9 (4.0) 4.5 (1.9) 33.6 (13.5)

10.6 (3.6) 4.7 (1.8) 34.7 (12.0)

0.1001 0.6426 0.8447

8.7 (3.3) 4.2 (1.7) 32.5 (12.2)

10.0 (3.8) 4.6 (1.7) 34.3 (12.8)

10.6 (3.5) 4.7 (1.8) 34.4 (11.9)

0.0415 0.4087 0.7321

9.2 (3.8) 4.8 (1.4) 32.7 (12.4)

9.4 (3.6) 3.9 (2.4) 31.6 (13.4)

10.6 (3.1) 4.2 (2.0) 34.2 (10.9)

0.3660 0.3787 0.8004

BMI ¼ body mass index; CES-D ¼ Center for Epidemiologic Studies–Depression; PST ¼ periosteal stimulation therapy; WOMAC ¼ Western Ontario and McMaster Universities Osteoarthritis Index. *Kellgren-Lawrence score for at least one knee. † Global rating on a scale of 1 (very poor) to 5 (very good).

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WOMAC Pain Outcome Baseline No. of knees Total Mean (SD) No. of participants Immediately after treatment No. of knees Total Mean (SD) Adjusted mean (SE)† Δ (95% CI)‡ No. (%) of participants 9 Months after baseline No. of knees Total Mean (SE) Adjusted mean (SE)† Δ (95% CI)‡ No. (%) of participants

OMERACT-OARSI*

PST and PST

PST and Control

Control

108 8.9 (3.3)

109 9.8 (3.8)

104 10.6 (3.4)

96 6.8 (4.2) 6.8 (0.53) 1.1 (
0.34 to 2.5)

91 6.1 (3.5) 6.2 (0.54) 1.5 (0.069 to 3.0)

92 6.7 (4.1) 6.5 (0.54) 1.3 (
0.10 to 2.8)

91 6.6 (3.6) 6.6 (0.54) 1.1 (
0.32 to 2.6)

PST and PST

PST and Control

Control

63

64

63

56 (42.9)

54 (37.0)

59 (32.2)

53 (47.2)

54 (40.7)

55 (30.9)

99 8.3 (4.4) 7.9 (0.52)

93 7.9 (4.3) 7.7 (0.53)

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OMERACT-OARSI ¼ Outcome Measures in Rheumatology Clinical Trials - Osteoarthritis Research Society International; PST ¼ periosteal stimulation therapy; WOMAC ¼ Western Ontario and McMaster Universities Osteoarthritis Index. *Person level response: indicated if unilateral disease burden knee had positive response and if bilateral disease burden then at least 1 knee had positive response. † Adjusted means are estimated from a mixed-effects linear regression model with the immediately after treatment and 9 months from baseline modeled as outcomes, controlling for baseline pain and the randomization stratification factors. Joint model effects for group and group  time (P ¼ 0.2137).72 ‡ Adjusted difference and 95% CI compared with control.

Clinical Therapeutics

1712 Table II. Outcomes at baseline, immediately after treatment (12 weeks), and at 9 months (WOMAC for each knee) controlling for age and disease burden.

D.K. Weiner et al.

12

Mean Score

10 8 6 4 2 0 0

1

2

3

4 5 6 Time From Baseline, mo

PST and PST

7

PST and Control PST

8

9

Control PST

Figure 2. Western Ontario and McMaster Universities Osteoarthritis Index pain subscale scores across time for all knees.

Predictors of WOMAC pain reduction immediately after completion of the 10-week intervention period (pooled data) (Table III) included depressive symptoms (higher CES-D score associated with less pain reduction), sex (females had greater pain reduction), race (blacks had less improvement in pain; whites had a decrease of 2.9 and blacks had a decrease of 1.6 in unadjusted analyses), WOMAC difficulty performing daily activities (more difficulty at baseline was associated with less improvement in pain), and WOMAC stiffness (higher stiffness score at baseline associated with less improvement in pain). At 9 months after baseline, depressive symptoms, sex, and race were no longer predictive of WOMAC pain reduction, and WOMAC difficulty performing daily activities and stiffness remained predictive. Duration of knee pain also was significantly predictive of WOMAC pain reduction at 9 months with less improvement associated with longer duration of pain. As indicated in Table II, the rate of clinically significant response based on the OMERACTOARSI criteria immediately after treatment was 32.2% in the control PST group, 37% in the PST and control PST boosters group, and 42.9% in the PST and PST boosters group. At the end of the boosters period (9 months after baseline data were collected), response based on the OMERACT-OARSI

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criteria was 30.9% in the control PST group, 40.7% in the PST and control PST boosters group, and 47.2% in the PST and PST boosters group. The between-groups differences did not reach statistical significance. Predictors of OMERACT-OARSI response immediately after completion of the 10-week intervention period (pooled data) (Table III) included depressive symptoms (higher CES-D score associated with poorer pain response), self-efficacy (other symptoms; ie, for controlling arthritis), WOMAC difficulty performing daily activities (more difficulty at baseline was associated with less improvement in pain), and WOMAC stiffness (higher stiffness score at baseline associated with less improvement in pain). At 6 months after completion of the initial intervention period (9 months after baseline), depressive symptoms, self-efficacy (other symptoms), and WOMAC difficulty performing daily activities and stiffness remained predictive. The catastrophizing scale of the CSQ and self-efficacy for function also were significantly predictive of OMERACT-OARSI response at 6 months after the end of the 10-week intervention.

Secondary Outcomes Results of the secondary measures of outcome are displayed in Supplemental Tables I, II, and III in the online version at http://dx.doi.org/10.1016/j.clin

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WOMAC Pain Immediately After Treatment Change From Baseline Characteristic

β (SE)

P

OMERACT-OARSI

9-Month Change From Baseline β (SE)

Immediately After Treatment P

OR (95% CI)

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Age 0.047 (0.035) 0.1810 0.049 (0.035) 0.1632 0.99 (0.99–1.00) Sex (female)
1.76 (0.88) 0.0476
1.27 (0.89) 0.1546 1.02 (0.83–1.25) Race (black) 1.62 (0.70) 0.0230 0.65 (0.71) 0.3602 0.92 (0.79–1.09) BMI
0.076 (0.048) 0.1158
0.062 (0.048) 0.1948 1.01 (1.00–1.02) CES-D 0.066 (0.031) 0.0373 0.017 (0.030) 0.5753 0.99 (0.98–0.99) CSQ catastrophizing 0.021 (0.035) 0.5461
0.013 (0.035) 0.7102 0.99 (0.99–1.00) Self-efficacy function
0.015 (0.019) 0.4410
0.016 (0.019) 0.4091 1.00 (1.00–1.01) Self-efficacy other symptoms
0.020 (0.015) 0.1988
0.012 (0.015) 0.4355 1.00 (1.00–1.01) Self-efficacy pain 0.0013 (0.016) 0.9307 0.015 (0.014) 0.3055 1.00 (1.00–1.00) WOMAC pain
0.8963 (0.038) o.0001
0.6798 (0.067) o.0001 1.00 (0.98–1.02) WOMAC difficulty performing 0.18 (0.018) o.0001 0.19 (0.017) o.0001 0.98 (0.97–0.98) daily activities WOMAC stiffness 1.14 (0.15) o.0001 1.36 (0.13) o.0001 0.88 (0.86–0.91) Short Physical Performance Battery 0.0090 (0.18) 0.9611
0.15 (0.18) 0.4080 0.99 (0.95–1.04) Duration of knee pain
0.014 (0.044) 0.7520 0.10 (0.042) 0.0144 1.01 (1.00–1.02) Kellgren-Lawrence score 1.03 (0.67) 0.1239 1.08 (0.65) 0.1014 0.98 (0.84–1.15)

P

At 9 Months OR (95% CI)

P

0.1617 0.8412 0.3381 0.1549 0.0004 0.1652 0.1306 0.0104 0.5520 0.9669 o.0001

1.00 1.22 0.97 1.01 0.99 0.99 1.01 1.00 1.00 1.02 0.98

(0.99–1.00) (0.98–1.51) (0.82–1.14) (1.00–1.02) (0.99–1.00) (0.98–1.00) (1.00–1.01) (1.00–1.01) (1.00–1.00) (1.00–1.04) (0.97–0.98)

0.2540 0.0702 0.6917 0.0912 0.0069 0.0135 0.0040 0.0053 0.4892 0.0609 o.0001

o.0001 0.7290 0.2541 0.8414

0.90 1.04 0.99 0.93

(0.87–0.93) (1.00–1.08) (0.98–1.00) (0.79–1.08)

o.0001 0.0673 0.0802 0.3499

BMI ¼ body mass index; CES-D ¼ Center for Epidemiologic Studies–Depression; CSQ ¼ Coping Strategies Questionnaire; OMERACT-OARSI ¼ Outcome Measures in Rheumatology Clinical Trials-Osteoarthritis Research Society International; OR ¼ odds ratio; WOMAC ¼ Western Ontario and McMaster Universities Osteoarthritis Index.

Clinical Therapeutics

1714 Table III. Predictors of change from baseline on the WOMAC pain scale and OMERACT-OARSI response immediately after treatment following completion of the 10-week intervention and 9 months from baseline (approximately 6 months after treatment).

D.K. Weiner et al. thera.2013.09.025 and include the other WOMAC scales; global rating of improvement; SPPB, stair climbing, and Timed Up and Go test performance; gait speed; CES-D score; CSQ catastrophizing scale score; self-efficacy; SF-36 score; as-needed pain medication use; health care use; restricted activity; and interim physical activity. As indicated in Supplemental Table I, there were significant differences for the following parameters compared with the control PST group: global rating of improvement in the PST and PST boosters and the PST and control PST boosters groups at 9 months from baseline (
0.34; 95% CI,
0.67 to
0.0039; and
0.36; 95% CI,
0.69 to
0.026, respectively); SPPB performance in the PST and PST boosters group at 9 months (
0.76; 95% CI,
1.4 to
0.11); gait speed in the PST and PST boosters group at 9 months (
0.051; 95% CI,
0.10 to
0.00059); self-efficacy for pain in the PST and PST boosters group immediately after the 10-week intervention (
7.4; 95% CI,
14.0 to
0.78) and at 9 months (
9.6; 95% CI,
16.4 to
2.8); self-efficacy for control of other symptoms in the PST and control PST boosters group at 9 months (
5.9; 95% CI,
11.3 to
0.42); SF-36 mental health composite total score in the PST and control PST boosters group at 9 months (
2.9; 95% CI,
5.5 to 0.27); global health composite total score in the PST and control PST boosters group at 9 months (
2.2; 95% CI,
4.2 to
0.27); and the number of as-needed doses per week of opioids in the PST and control PST boosters group immediately after the 10-week intervention (
0.27; 95% CI,
0.48 to
0.054). Readers should note that results were not adjusted for multiple testing and should be interpreted with caution. No differences were detected in any of the secondary outcomes between the PST and PST boosters and the PST and control PST boosters groups.

DISCUSSION This is the first randomized controlled trial of PST with booster PST for the treatment of chronic knee pain in people with advanced knee OA. The intervention was well tolerated, with only an approximately 8% intervention withdrawal rate. According to the OMERACT-OARSI response criteria, 42.9% in the PST and PST boosters group, 37% in the PST and control PST boosters group, and 32.2% in the control PST group experienced clinically significant improvement immediately after completion of the 10-week

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intervention (PST and PST boosters vs control, P ¼ 0.24; PST and control booster vs control, P ¼ 0.59); at 9 months after baseline response rates were 47.2% in the PST and PST boosters group, 40.7% in the PST and control PST boosters group, and 30.9% in the control PST group (PST and PST boosters vs control, P ¼ 0.083; PST and control booster vs control, P ¼ 0.28). Mean pain reduction based on the WOMAC pain scale was approximately Z30% in all 3 groups (P o 0.0001 for time in each group), a significant reduction according to the chronic pain literature.74 Controlling for pain baseline, mean pain reduction in the PST and PST booster group was higher than the reduction in the controls (1.52; 95% CI, 0.69 to 2.97; P ¼ 0.0401) but not in the PST and control booster group compared with the controls (1.12; 95% CI,
0.32 to 2.56; P ¼ 0.13). Thus, our findings support modest efficacy of PST and PST boosters for the treatment of chronic pain associated with advanced knee OA. Readers may be perplexed by the capacity of individuals with advanced knee OA to experience clinically significant and sustained pain reduction, particularly in response to the control PST procedure. In pondering this phenomenon, it is important to recognize that pain generation in patients with OA does not emanate entirely from peripheral nociceptors. Further, disease severity measured by radiography (ie, KL grade) did not affect treatment response in our study, whereas severity of depressive symptoms affected response. Higher scores on the CES-D were associated with lesser reductions in pain during the study, suggesting central sensitization may have been involved in participants with greater depressive symptoms. Mounting data support that central sensitization plays an important role in generating pain in patients with OA and other disorders once thought to be driven entirely by peripheral tissue disease, such as rheumatoid arthritis, neck pain associated with whiplash injury, and tennis elbow.75 These discoveries have led to shifts in therapeutic developments. The Food and Drug Administration has, for example, approved the use of duloxetine, a serotonin norepinephrine reuptake inhibitor, for the treatment of OA. In the not-too-distant future it is likely that we will see additional new treatments that target central sensitization. The control PST group in this trial experienced substantial pain reduction during the study, whereas control group participants in our prior study

1715

Clinical Therapeutics experienced no pain reduction whatsoever. There are a number of potential reasons for the between-studies discrepancy in response to the control PST procedure that suggests treatment expectancy–mediated placebo analgesia may have affected outcomes in this trial but not in our pilot study. The sociodemographic characteristics of the participants in our full-scale trial were distinct from those in our pilot study. Those in the pilot study were of higher socioeconomic status than those in this trial. The full-scale trial was of longer duration; therefore, participants were reimbursed a greater amount, which may have affected the outcomes reported. Participants in the pilot study also were slightly older than those in the full-scale trial, with a mean age of 71 years in the pilot trial and 67 years in the full-scale trial. Participants being somewhat older in the pilot study may have inhibited the placebo response in the control group. Evidence indicates that the structure and function of the prefrontal cortex deteriorates as part of healthy aging76 and that the frontal and prefrontal cortices play an important role in placebo analgesia.77 Further, 480% of participants in the full-scale trial were male, whereas in the pilot study, 40% of participants in the PST and 50% of participants in the control PST group were male. Evidence suggests that the significantly greater proportion of men in the full-scale trial compared with the pilot study may have enhanced the likelihood of a placebo response. Experimental data indicate that men are more prone to responding to placebo analgesia and the anticipatory stress associated with painful stimuli.78 Clearly, the results of our studies highlight the complexities associated with designing an inert placebo control for randomized placebo-controlled trials of CAM interventions. In addition to the sociodemographic factors discussed above, other nonspecific factors (ie, factors that may not be specifically related to the intervention that a trial is designed to test) consistently contribute to treatment response (ie, placebo effect) regardless of randomization status, such as the therapeutic relationship between physician and patient;79,80 patient characteristics, such as optimism;81,82 and positive attitudes toward CAM.83 We already have highlighted the significant effect expectation plays in treatment response, an effect that in our trial may in part have been related to the intensive observation and touch that comprised both our PST and our control PST procedures. Many research

1716

participants communicate that they enjoy participating in research studies because of the thorough evaluation and care that they receive. In our current health care climate, which allows primary care physicians little time with their patients, it is not a stretch to imagine that simply being involved in a research study that incorporates intensive interpersonal interaction would in and of itself be therapeutic. This may have accounted for the low dropout rates and lack of between-group difference in health care use. That these nonspecific factors played a strong role across groups in our study is demonstrated by participants’ high expectancy scores present throughout the study, as well their perception of significant improvement when asked to report their global impression of change at trial completion. The fact that the control PST group maintained some pain reduction at 9 months supports the likelihood of treatment expectancy–mediated analgesia being responsible for at least some of the pain reduction in all 3 groups. A robust placebo response is not uncommon in acupuncture trials, and the mechanism by which such a response is achieved may in part overlap with that of acupuncture. Investigations have demonstrated, for example, that placebo analgesia is mediated by the release of endogenous neuromodulators that include opioids.84 Release of endogenous opioids also plays a role in acupuncture analgesia.28–31 Evidence highlights that mechanisms unique to placebo analgesia also are operative.84 Using a verum and sham acupuncture experimental paradigm, Kong et al85 demonstrated that although the magnitude of acupuncture and placebo response may be comparable, the central nervous system mechanism underlying these responses appears to be distinct. In their study, the frontal gyrus was activated significantly in the sham acupuncture group but not in the verum group. Our inability to directly measure the interaction between treatment expectancy and the specific effects of the PST prevents us from being able to disentangle the magnitude of these differential effects. Our low dropout rates and adverse effects highlight the feasibility of PST. The procedure can be administered by acupuncturists. A major barrier to dissemination is the fact that most CAM interventions, including acupuncture, are not covered by most third-party payers. Although our study was a rigorous randomized controlled trial that had many strengths and used a

Volume 35 Number 11

D.K. Weiner et al. broad range of biopsychosocial outcomes in keeping with the standards of chronic pain research,86 its limitations also should be noted. We powered our study using WOMAC as our primary outcome and demonstrated the superior efficacy of PST and PST boosters at 9 months after baseline assessment (ie, after completion of boosters). Although there also was a clear trend for superior efficacy of PST and PST boosters according to the OMERACT-OARSI criteria, our sample size was insufficient to achieve statistical significance. As with many clinical trials, the sociodemographic and clinical characteristics of our population (eg, individuals who were immunocompromised, had undergone anticoagulation, or had pacemakers were excluded) may prevent the results from being broadly applied. In addition, although our measures were broad, they were not comprehensive, so we may have failed to identify other key factors that mediated treatment response. Finally, as noted in the Results section, we examined a number of secondary outcomes, some of which demonstrated statistically significant improvement during the study; readers should view these results as preliminary, however, because we did not analyze using multiple comparisons. Should practitioners who care for older adults with painful advanced knee OA and limited therapeutic alternatives recommend PST as a viable treatment option? Our results support the following: (1) PST is well tolerated, (2) the likelihood of an initially significant clinical response appears to be approximately 4 in 10, and (3) the response can be maintained for at least 6 months with boosters in men with KL grade 3 and grade 4 disease. Additional research that uses other study designs (eg, comparative effectiveness and adaptive design) is needed, and, perhaps more importantly, thoughtful discussions between patient and physician are necessary so that well-informed and reasonable decisions can be made.

ACKNOWLEDGMENTS This material is based on work supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Rehabilitation Research and Development Service. The contents of this report do not represent the views of the Department of Veterans Affairs or the US government. The authors thank David Mortell, LAc, for his participation in the intervention portion of the study; Ms. Kimberly Hayes, Ms. Lisa Gaston,

November 2013

Mr. Wilbert Schrader, Mr. Jonathan Squeglia, and Ms. Catherine Harris for their assistance with preparation of regulatory documents and data collection; Ms. Diane Comer for her assistance with data analysis; and Ms. Terry Sefcik for her assistance with data management and processing.

CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest regarding the content of this article.

SUPPLEMENTAL MATERIAL Supplemental appendixes accompanying this article can be found in the online version at http://dx.doi.org/ 10.1016/j.clinthera.2013.09.025.

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53. Maly MR, Costigan PA, Olney SJ. Self-efficacy mediates walking performance in older adults with knee osteoarthritis. J Gerontol. 2007;62A: 1142–1146. 54. Lorig K, Chastain RL, Shoor S, Holman HR. Developement and evaluation of a scale to measure perceived self-efficacy in people with arthritis. Arthritis Rheum. 1989;32:37–44. 55. Ware JE, Sherbourne C. The MOS 36-item short-form survey (SF-36), I: conceptual framework and item selection. Med Care. 1992;30:473– 483. 56. McHorney CA, Ware JE, Raczek AE. The MOS 36-item Short-Form Health Survey (SF-36), II: psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care. 1993; 31:247–263. 57. McHorney C, Ware J, Lu J, Sherbourne C. The MOS 36-item SortForm Health Survey (SF-36), III: tests of data quality, scaling assumptions, and reliability across diverse patient groups. Med Care. 1994;32:40–66. 58. Brazier J, Harper R, Jones N, et al. Validating the SF-36 health survey questionnaire: new outcome measure for primary care. BMJ. 1992;305:160–164. 59. Lyons R, Perry H, Littlepage B. Evidence for the validity of the Short-form 36 Questionnaire (SF36) in an elderly population. Age Ageing. 1994;23:182–184. 60. Farrell MJ, Gerontol M, Gibson SJ, Helme RD. The effect of medical status on the activity level of older pain clinic patients. J Am Geriatr Soc. 1995;43:102–107. 61. Linn BS, Linn MW, Gurel L. Cumulative Illness Rating Scale. J AmGeriatr Soc. 1968;16:622–626. 62. Parmelee PA, Thuras PD, Katz IR, Lawton MP. Validation of the Cumulative Illness Rating Scale in a geriatric residential population. J Am Geriatr Soc. 1995;43:130–137.

63. Landi F, Zuccala G, Gambassi G, et al. Body mass index and mortality among older people living in the community. J Am Geriatr Soc. 1999;47:1072–1076. 64. Jinks C, Jordan K, Croft P. Measuring the population impact of knee pain and disability with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Pain. 2002;100:55–64. 65. Jadelis K, Miller ME, Ettinger WH, Messier SP. Strength, balance, and the modifying effects of obesity and knee pain: results from the observational arthritis study in seniors. J Am Geriatr Soc. 2001;49:884–891. 66. Kazdin AE. Acceptability of alternative treatments for deviant child behavior. J Appl Behav Anal. 1980;13: 259–273. 67. Borkovec TD, Nau SD. Credibility of analogue therapy rationales. J Behav Ther Exp Psychiatry. 1972;3: 257–260. 68. Vignon E, Conrozier T, Piperno M, Richard S, Carillon Y, Fantino O. Radiographic assessment of hip and knee osteoarthritis: recommendations: recommended guidelines. Osteoarthritis Cartilage. 1999;7: 434–436. 69. Pham T, van der Heijde D, Altman RD, et al. OMERACT-OARSI Initiative: Osteoarthritis Research Society International set of responder criteria for osteoarthritis clinical trials revisited. Osteoarthritis Cartilage. 2004;12:389–399. 70. Gill TM, Desai MM, Gahbauer EA, Holford TR, Williams CS. Restricted activity among community-living older persons: incidence, precipitants, and health care utilization. Ann Intern Med. 2001;135:313–321. 71. Washburn RA, Zhu W, McAuley E, Frogley M, Figoni SF. The Physical Activity Scale for Individuals with Physical Disabilities: development and evaluation. Arch Phys Med Rehabil. 2002;83:193–200. 72. Fitzmaurice G, Laird N, Ware J. Applied Longitudinal Analysis.

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and current thought. Ann Rev Psychol. 2008;59:565–590. 83. Hyland ME, Whalley B. Motivational concordance: an important mechanism in self-help therapeutic rituals involving inert (placebo) substances. J Psychosom Res. 2008;65:405–413. 84. Colloca L, Klinger R, Flor H, Bingel U. Placebo analgesia: psychological and neurobiological mechanisms. Pain. 2013;154:511–514.

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Address correspondence to: Debra K. Weiner, MD, VA Pittsburgh Healthcare System, University Drive C, Pittsburgh, PA 15240. E-mail: [email protected]

Volume 35 Number 11

November 2013

Supplemental Table I. Secondary outcomes at baseline, immediately after treatment, at and 9 months (WOMAC for each knee).* Baseline Group

No. Mean (SD)

No. Mean (SD)

108 109 104

96 92 99

4.3 (1.7) 4.4 (1.9) 4.6 (1.9)

3.4 (1.9) 3.3 (1.5) 3.6 (2.1)

108 32.8 (12.1) 96 23.8 (13.7) 109 33.6 (13.1) 92 24.4 (13.6) 104 34.4 (11.7) 99 27.0 (14.6)

Δ (95% CI)

No. Mean (SD)

Δ (95% CI)

0.33 (
0.30 to 0.97) 0.37 (
0.27 to 1.0) —

91 91 93

3.0 (1.7) 3.3 (1.6) 3.3 (2.2)

0.42 (
0.23 to 1.1) 0.078 (
0.57 to 0.73) —

2.5 (
1.9 to 6.9) 1.8 (
2.6 to 6.2) —

91 91 93

22.2 (12.2) 22.9 (14.1) 26.1 (16.1)

3.8 (
0.64 to 8.3) 2.6 (
1.8 to 7.1) —

63 64 63

3.5 (1.0) 3.2 (1.0) 3.4 (1.1)

56 54 59

3.8 (0.9) 3.6 (0.9) 3.6 (1.0)


0.17 (
0.49 to 0.15)
0.063 (
0.39 to 0.26) —

53 54 55

3.8 (1.0) 3.8 (0.9) 3.5 (1.2)


0.34 (
0.67 to
0.0039)
0.36 (
0.69 to
0.026) —

63 64 63

6.1 (1.8) 6.1 (1.9) 6.2 (1.5)

56 53 59

6.6 (1.9) 6.7 (1.9) 6.5 (1.8)


0.20 (
0.82 to 0.43)
0.15 (
0.78 to 0.48) —

52 54 55

7.2 (2.3) 6.9 (2.3) 6.5 (1.9)


0.76 (
1.4 to
0.11)
0.35 (
0.99 to 0.28) —

63 12.5 (4.7) 62 14.5 (7.8) 61 13.9 (7.3)

55 51 58

12.3 (5.5) 12.1 (4.8) 13.6 (11.3)

0.21 (
1.8 to 2.2) 1.2 (
0.83 to 3.3) —

51 49 52

11.5 (5.3) 12.0 (6.0) 12.1 (5.4)

0.85 (
1.2 to 2.9) 1.05 (
1.0 to 3.1) —

63 12.3 (3.4) 64 13.0 (3.8)

56 53

11.4 (2.7) 12.1 (3.8)

0.30 (
0.90 to 1.5)
0.048 (
1.3 to 1.2)

51 54

11.4 (3.4) 12.2 (4.1)

0.49 (
0.75 to 1.7) 0.18 (
1.0 to 1.4) (continued)

D.K. Weiner et al.

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WOMAC stiffness* PST and PST PST and control Control WOMAC difficulty performing daily activities* PST and PST PST and control control Considering knee OA, how well are you doing?† PST and PST PST and control Control Short Physical Performance Battery PST and PST PST and control Control Time to complete stair climbing test, sec PST and PST PST and control Control Time to complete Timed Up and Go test, sec PST and PST PST and control

Immediately Baseline-Adjusted Differences 9 Months From Baseline-Adjusted Differences After Treatment Compared With Control Baseline Compared With Control

Baseline

Immediately Baseline-Adjusted Differences 9 Months From Baseline-Adjusted Differences After Treatment Compared With Control Baseline Compared With Control

Volume 35 Number 11

Group

No. Mean (SD)

No. Mean (SD)

Control Gait speed, m/sec PST and PST PST and control Control CES-D PST and PST PST and control Control CSQ catastrophizing PST and PST PST and control Control Self-efficacy pain PST and PST PST and control Control Self-efficacy function PST and PST PST and control Control Self-efficacy other symptoms PST and PST PST and control Control SF-36 physical health composite total score PST and PST

63

59

13.9 (6.9)

12.5 (5.4)

Δ (95% CI) —

No. Mean (SD) 54

12.4 (4.4)

Δ (95% CI) —

63 0.80 (0.14) 56 0.84 (0.20)
0.012 (
0.061 to 0.037) 51 64 0.78 (0.18) 53 0.82 (0.20)
0.0072 (
0.056 to 0.042) 54 63 0.76 (0.20) 59 0.80 (0.18) — 54

0.88 (0.20)
0.051 (
0.10 to
0.00059) 0.84 (0.22)
0.029 (
0.079 to 0.021) 0.80 (0.18) —

63 64 63

11.7 (10.3) 56 14.7 (11.2) 54 12.3 ( 9.6) 59

63 64 63

7.9 (7.8) 12.1 (9.7) 8.8 (9.2)

56 54 59

9.2 (10.2) 10.1 (9.7) 10.5 (9.7) 6.6 (7.2) 8.2 (8.3) 6.7 (8.7)

0.61 (
1.9 to 3.2) 1.1 (
1.5 to 3.7) —

53 54 55

8.7 (7.8) 9.6 (9.5) 11.4 (10.5)


0.13 (
2.3 to 2.0) 0.25 (
2.0 to 2.4) —

53 54 55

6.2 (6.7) 8.4 (7.9) 7.5 (8.4)

1.6 (
1.1 to 4.2) 2.5 (
0.13 to 5.1) — 0.37 (
1.8 to 2.6) 0.65 (
1.6 to 2.9) —

63 64.3 (21.6) 56 72.4 (21.0) 64 59.5 ( 22.6) 54 68.6 (16.8) 63 63.9 (21.7) 59 64.7 (21.9)


7.4 (
14.0 to
0.78)
5.4 (
12.1 to 1.3) —

53 54 55

71.1 (21.4) 63.6 (16.8) 60.6 (23.2)


9.6 (
16.4 to
2.8)
4.3 (
11.1 to 2.4) —

63 64 63


1.2 (
5.8 to 3.5) 0.43 (
4.3 to 5.1) —

53 54 55

82.7 (16.2) 83.2 (14.6) 80.5 (18.3)


1.9 (
6.6 to 2.9)
2.5 (
7.3 to 2.3) —


1.1 (
6.4 to 4.2)
2.7 (
8.1 to 2.6) —

53 54 55

78.5 (18.4) 76.4 (17.2) 71.1 (22.7)


5.0 (
10.4 to 0.49)
5.9 (
11.3 to
0.42) —


1.2 (
2.8 to 0.36)

53 44.0 (5.5)

77.5 (17.0) 56 83.6 (16.1) 76.3 (16.9) 54 81.6 (13.9) 76.1 (16.4) 59 81.6 (15.7)

63 70.5 (21.1) 56 64 65.9 (20.3) 54 63 68.6 (20.9) 59

62 43.2 (5.3)

76.8 (19.8) 76.4 (18.5) 74.4 (18.9)

55 43.9 (6.1)


1.2 (
2.8 to 0.041) (continued)

Clinical Therapeutics

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Supplemental Table I. (continued).

November 2013

Supplemental Table I. (continued) Baseline

Immediately Baseline-Adjusted Differences 9 Months From Baseline-Adjusted Differences After Treatment Compared With Control Baseline Compared With Control

Group

No. Mean (SD)

No. Mean (SD)

PST and control Control SF-36 mental health composite total score PST and PST PST and control Control Global health composite total score PST and PST PST and control Control No. of as-needed doses per week of nonopioid pain medication PST and PST PST and control Control No. of as-needed doses per week of opioid pain medication PST and PST PST and control Control

64 40.9 (5.0) 62 41.8 (5.8)

54 41.9 (4.2) 58 42.2 (5.3)

Δ (95% CI)

No. Mean (SD)

Δ (95% CI)


0.38 (
2.0 to 1.2) —

52 52

43.0 (4.9) 42.2 (6.0)


1.3 (
3.0 to 0.28) —

63 41.8 (10.3) 56 43.3 (10.9) 64 38.5 (9.9) 54 41.3 (9.5) 63 39.5 (9.9) 59 41.4 (10.6)


0.34 (
2.9 to 2.2)
0.46 (
3.1 to 2.1) —

53 54 55

43.8 (10.4) 42.9 (9.8) 40.3 (11.5)


1.2 (
3.9 to 1.4)
2.9 (
5.5 to
0.27) —

62 41.9 (7.9) 64 38.7 (7.0) 62 39.9 (7.4)

55 43.2 (8.3) 54 40.9 (7.1) 58 41.1 (8.0)


0.70 (
2.6 to 1.2)
0.51 (
2.4 to 1.4) —

53 52 52

43.3 (7.7) 42.7 (7.0) 40.8 (8.4)


0.80 (
2.8 to 1.2)
2.2 (
4.2 to
0.27) —

63 64 63

1.5 (4.4) 0.9 (2.5) 1.1 (4.1)

55 53 56

0.4 (1.0) 0.4 (1.1) 0.2 (0.7)


0.19 (
0.61 to 0.23)
0.23 (
0.65 to 0.19) —

49 53 54

0.3 (0.7) 0.5 (1.2) 0.5 (1.6)

0.18 (
0.25 to 0.62)
0.014 (
0.44 to 0.41) —

63 64 63

0.2 (1.0) 0.8 (3.2) 0.4 (1.7)

55 53 56

0.0 (0.0) 0.3 (1.3) 0.0 (0.1)

0.018 (
0.19 to 0.23) 49
0.27 (
0.48 to
0.054) 53 — 54

0.0 (0.0) 0.1 (0.4) 0.0 (0.3)

0.037 (
0.18 to 0.25)
0.020 (
0.23 to 0.19) — D.K. Weiner et al.

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CES-D ¼ Center for Epidemiologic Studies–Depression; CSQ ¼ Coping Strategies Questionnaire; OA ¼ osteoarthritis; PST ¼ periosteal stimulation therapy; SF-36 ¼ Medical Outcomes Study 36-Item Short-Form Health Survey; WOMAC ¼ Western Ontario and McMaster Universities Osteoarthritis Index. *Person level response: indicated if unilateral disease burden knee had positive response and if bilateral disease burden then at least 1 knee had positive response. † 1 indicates very poor and 5 indicates very good.

No. (%) of Patients Group

Volume 35 Number 11

Health Care Use* During the past month have you seen a health care professional in their office? PST and PST PST and control Control During the past month have you seen a health care professional in the emergency department? PST and PST PST and control Control During the past month have you been hospitalized? PST and PST PST and control Control During the past month have you seen a psychiatrist, psychologist, or counselor? PST and PST PST and control Control Restricted Activity Stayed in bed at least half the day due to illness or injury PST and PST PST and control Control Cut down on your usual activities due to illness or injury PST and PST PST and control Control

Followup 1

Followup 2

Followup 3

Followup 4

Followup 5

Followup 6

24 (44.4) 24 (46.2) 15 (31.9) 21 (46.7) 19 (40.4) 12 (26.7) 21 (41.2) 17 (34.7) 13 (30.2) 16 (34.8) 12 (27.3) 10 (23.3) 24 (43.6) 28 (54.9) 19 (37.3) 23 (47.9) 18 (36.7) 17 (36.2)

Model Results for Group/Time/Group  Time

0.9336/0.4631/0.9163

3 (5.6) 1 (2.0) 4 (7.3)

3 (5.8) 4 (8.2) 6 (11.8)

2 (4.3) 3 (7.0) 5 (9.8)

3 (6.7) 2 (4.3) 4 (8.3)

3 (6.4) 3 (6.8) 4 (8.2)

2 (4.4) 2 (4.7) 4 (8.5)

0.3590/0.7309/0.9926

1 (1.9) 0 1 (1.8)

1 (1.9) 2 (4.1) 1 (2.0)

0 2 (4.7) 0

0 2 (4.3) 2 (4.2)

2 (4.3) 1 (2.3) 5 (10.2)

1 (2.2) 1 (2.3) 2 (4.3)

Too few; did not converge

8 (14.8) 6 (11.8) 6 (10.9)

5 (9.6) 3 (6.1) 3 (5.9)

6 (12.8) 2 (4.7) 4 (7.8)

5 (11.1) 3 (6.5) 5 (10.4)

8 (17.0) 3 (6.8) 5 (10.2)

5 (11.1) 2 (4.7) 5 (10.6)

0.8295/0.5014/0.4518

4 (7.4) 4 (7.8) 6 (10.9)

9 (17.3) 5 (10.2) 6 (11.8)

3 (6.4) 7 (15.6) 4 (9.3) 10 (21.7) 7 (13.7) 5 (10.4)

7 (14.9) 3 (6.7) 9 (20.5) 6 (14.0) 9 (18.4) 10 (21.3)

0.8161/0.0782/0.3017

6 (12.8) 7 (16.3) 7 (13.7)

8 (17.0) 6 (13.3) 8 (18.2) 3 (7.0) 9 (18.4) 10 (21.3)

0.4683/0.1223/0.3035

7 (13.0) 11 (21.2) 11 (21.6) 9 (18.4) 9 (16.4) 5 (9.8)

9 (20.0) 7 (15.2) 5 (10.4)

PST ¼ periosteal stimulation therapy. *Of 333 total health care professional office visits during follow-up, 62 visits were due to knee pain; of 58 total emergency department visits during follow-up, 4 visits were due to knee pain; of 24 total hospital admissions during follow-up, 6 admissions were due to knee pain; of 1 total nursing home admission during follow-up in the PST and PST, the admission was not due to knee pain; and of 84 total psychiatrist, psychologist, or counselor office visits during follow-up, 1 visit was due to knee pain.

Clinical Therapeutics

1720.e4

Supplemental Table II. Health care use and restricted activity by treatment group over time.

November 2013

Supplemental Table III. Physical Activity Scale for Individuals with Physical Disabilities scores by treatment group over time. Follow-up 1

Follow-up 2

Follow-up 3

Follow-up 4

Follow-up 5

Follow-up 6

Group

No.

Mean (SD) Score

No.

Mean (SD) Score

No.

Mean (SD) Score

No.

Mean (SD) Score

No.

Mean (SD) Score

No.

Mean (SD) Score

Model Results for Group/ Time/Group  Time

PST and PST PST and control Control

54 51 55

17.1 (9.5) 16.1 (12.2) 15.7 (12.4)

52 49 51

18.6 (15.0) 14.7 (12.2) 16.2 (12.4)

47 43 51

17.5 (11.8) 14.2 (10.3) 14.9 (10.3)

45 46 48

14.9 (12.7) 14.9 (12.2) 13.4 (11.1)

47 44 49

13.2 (10.3) 14.2 (9.4) 13.5 (12.8)

45 43 47

13.7 (8.9) 15.1 (10.3) 12.5 (10.9)

0.5951/0.0140/0.1482

PST ¼ periosteal stimulation therapy.

D.K. Weiner et al.

Supplemental Figure 1. Periosteal stimulation therapy procedure.

Supplemental Figure 2. Control periosteal stimulation therapy procedure.

1720.e5