ORIGINAL ARTICLE

Pain Catastrophizing Mediates the Effect of Psychological Inflexibility on Pain Intensity and Upper Extremity Physical Function in Patients with Upper Extremity Illness

Mojtaba Talaei-Khoei, MD*; Stefan F. Fischerauer, MD*,†; Sang-Gil Lee, MD*; David Ring, MD*; Ana-Maria Vranceanu, PhD‡ *Orthopaedic Hand and Upper Extremity Service, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A.; †Department of Orthopaedics and Traumatology, University Hospital Graz, Medical University of Graz, Graz, Austria; ‡Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A.

& Abstract intensity, upper extremity physical function, psychological inflexibility, pain catastrophizing, depression, and anxiety in Background: Psychological inflexibility—the inability to this cross-sectional study. take value-based actions in the presence of unwanted Results: We found that psychological inflexibility affected thoughts, feelings, or bodily symptoms—is associated with pain intensity and upper extremity physical function directly negative health outcomes including depression and anxiety. and indirectly. Pain catastrophizing but not depression or Objective: We aimed to determine the association between anxiety mediated the association of psychological inflexibility the general construct of psychological inflexibility and pain to pain intensity and upper extremity physical function. intensity, and upper extremity physical function in patients Conclusions: Psychological inflexibility plays an important with musculoskeletal illness in an orthopedics practice. We role in understanding the increased pain and decreased also set out to test multiple-mediator models proposing that upper extremity physical function in patients with muscu- psychological inflexibility affects pain intensity and upper loskeletal pain. It also suggests that the cognitive error of extremity physical function directly, as well as indirectly pain catastrophizing is one of the mechanisms through which through depression, anxiety, and pain catastrophizing. the general construct of psychological inflexibility may Methods: One hundred and eight patients with upper influence pain intensity and upper extremity physical func- extremity illness completed self-report measures of pain tion. Psychological treatments aimed at decreasing pain and increasing upper extremity physical function should target both pain catastrophizing and psychological inflexibility. & Address correspondence and reprint requests to: Ana-Maria Vran- ceanu, PhD, Behavioral Medicine Service, Massachusetts General Hospital, One Bowdoin Square, 7th Floor, Boston, MA 02114, U.S.A. E-mail: Key Words: pain, physical function, psychological inflexi- [email protected]. bility, pain catastrophizing, depression, anxiety Submitted: February 29, 2016; Revised May 18, 2016; Revision accepted: June 21, 2016 DOI. 10.1111/papr.12494 INTRODUCTION Acceptance and commitment therapy (ACT)1 empha- © 2016 World Institute of Pain, 1530-7085/16/$15.00 Pain Practice, Volume , Issue , 2016 – sizes the benefits of acceptance and willingness rather 2 TALAEI-KHOEI ET AL.

than a desire to change or control the content of inner significantly associated with pain catastrophizing.13 states in experiencing bodily sensations, emotions, and Further, psychological flexibility, the opposite con- thoughts. For patients experiencing pain, ACT encour- struct, is associated with decreased disability in patients ages engagement in value-driven behaviors even if those with low-to-moderate pain.14 However, to our knowl- activities possibly elicit pain or provoke fear of pain.2 edge, the general construct of psychological inflexibility The central construct targeted within ACT is psycho- has not been studied in patients with musculoskeletal logical inflexibility1,3 defined as responding in a reflex- pain presenting to an orthopedic surgeon. ive, habitual, or impulsive manner to internal private The main goal of the study is to determine the events (eg, thoughts, emotions, and sensations) or association of psychological inflexibility to pain inten- external situations, and often relying on avoidant coping sity and upper extremity physical function in patients strategies.4 For patients experiencing pain, this means who present to an outpatient orthopedic surgical prac- inability to move beyond thoughts, feelings, and sensa- tice with musculoskeletal pain complaints. A second tions about pain and, as a consequence, avoiding value- goal of this study is to test potential mechanisms of related behaviors that may be cognitively fused with development of pain and upper extremity physical pain or fear of pain. In other words, psychological function in this population. Prior research in this inflexibility allows difficult internal experiences (eg, population has shown the pivotal roles of pain catas- – pain) to limit the extent to which goals and values- trophizing,15 17 anxiety,16,18,19 and depression3,18,20 in related contingencies guide behaviors.2 reports of pain intensity and upper extremity disability, Psychological inflexibility entails 6 overlapping pro- but the relationships of a general construct of psycho- cesses5: (1) cognitive fusion—when an individual logical inflexibility to pain catastrophizing, anxiety, and becomes “entangled” with their own thoughts and depression in patients with musculoskeletal pain in feelings making them the absolute reality when in fact orthopedic surgical practices have not been studied. We they are the product of the mind6; (2) experiential propose that psychological inflexibility will impact pain avoidance—unwillingness to endure any unpleasant intensity and upper extremity physical function both thoughts, emotions, and physical sensations, which are directly, as well as indirectly through increased pain pushed away to achieve short-term relief; (3) preoccu- catastrophizing, depression, and anxiety. Specifically, pation with past or future—overfocusing on thoughts we hypothesize that high psychological inflexibility will about the past or future without regard for the present be independently associated with increased pain catas- moment; (4) inability to take a perspective separate from trophizing, anxiety, depression, and pain intensity, as thoughts and feelings—belief that thoughts and feelings well as decreased physical function. Pain catastrophiz- are the same as the person, rather than separate; (5) ing, anxiety, and depression will mediate the association failures in clarity or pursuit of values—lack of knowl- between psychological inflexibility and upper extremity edge of own values; and (6) rigid persistence or physical function and pain intensity, while controlling impulsive avoidance—inability to act on the things that for relevant demographic and clinical covariates. are important. For a person with pain, psychological inflexibility means that automatic negative thoughts triggered by pain become a person’s reality due to METHODS inability to develop purposeful contact with their own Participants thoughts and feelings, assess the situation objectively, and focus on one’s goals and values. One hundred and eight patients with upper extremity An emerging body of research supports the relation- illness presenting to the Hand and Upper Extremity ship of the general psychological inflexibility construct Service of Massachusetts General Hospital—a multispe- – to negative health outcomes in various populations.7 10 cialty large urban teaching hospital—participated in the Among pain populations, the general psychological study. Patients (new and follow-up) were recruited from inflexibility is associated with disability, anxiety, and the practice of 2 orthopedic surgeons (D.R. and S.L.). quality of life in adolescents with juvenile idiopathic Consecutive patients were enrolled 2 clinic days a week, arthritis11 and plays a central role in the improvement in during the month of August 2015. Patients had a variety disability and life satisfaction following ACT for of upper extremity conditions such as distal radius patients with chronic pain after whiplash.12 Cognitive fracture, carpal tunnel syndrome, lateral epicondylitis, fusion, a component of psychological inflexibility, is De Quervain’s tenosynovitis, and elbow dislocation. Effect of Psychological Inflexibility on Pain 3

Fifty-two patients were male, while 56 were female. The to assess all outcomes except pain intensity. CAT mean age of patients was 54.07 years. The mean of optimizes the item bank administration by choosing reported pain duration was 804.91 days. Seventy-three relevant questions through recruiting a dynamic item patients had nontrauma-related pain and 35 patients selection algorithm to target the next items based on had pain that can be attributed to a recent trauma. The already given responses to previous questions.23,25 This approval was obtained from the institutional review prevents unnecessary and redundant items to be admin- board for this observational cross-sectional study before istered resulting in lowering the burden on the respon- the enrollment of participants. Inclusion criteria were dent while increasing the level of efficiency and being at least 18 years old, fluency and literacy in precision.26 Participants completed the PROMIS mea- English, and being able to provide informed consent. sures via an encrypted computer on https://www.assess- Exclusion criteria were being pregnant and significant mentcenter.net. axis I or II psychopathology that would interfere with participation in the study such as active substance abuse, PROMIS Scale (v1.0) Pain Intensity 3a. Patient- untreated bipolar disorder, schizophrenia, or psychotic Reported Outcomes Measurement Information System symptoms. pain intensity was used to measure pain intensity. It consisted of three questions asking (1) In the past 7 days, how intense was your pain at its worst? (2) In the Procedures past 7 days, how intense was your average pain? (3) Potential study participants were approached while they What is your level of pain right now? Respondents chose were waiting for their meeting with the treating physi- the appropriate level of pain for each question from no cian. The study procedures were explained to eligible pain, mild, moderate, severe, and very severe. Using patients, and informed consent was obtained from those item-level calibrations, assessment center produces who agreed to participate. The participants were told scores for each patient based on 50 10 being the that their participation was voluntary and that they mean SD of samples from U.S. population. could stop participation at any time without affecting their medical care. No one requested to discontinue the PROMIS Bank (v1.2) Upper extremity physical study. All participants met inclusionary/exclusionary function CAT. Patient-Reported Outcomes Measure- criteria. Participants completed self-report study mea- ment Information System Upper Extremity was used to sures on an encrypted computer. These included demo- measure physical function in upper extremity. The item graphics, clinical variables (eg, pain duration), and bank PROMIS physical function CAT measures the measures of pain intensity, physical function, psycho- patient’s self-reported level of physical activities.27 The logical inflexibility, pain catastrophizing, depression, PROMIS upper extremity is a subdomain of physical and anxiety. function and measures the level of physical function that involves different upper extremity activities such as opening a can with a hand can opener, putting on a Measures pullover sweater, and reaching into a high cup- Patient-Reported Outcomes Measurement Information board.28,29 Respondents answered on a scale from System. The National Institutes of Health (NIH) devel- “without any difficulty” to “unable to do”. PROMIS oped the Patient-Reported Outcomes Measurement upper extremity is a valid and reliable measure com- Information System (PROMIS) to standardize and pared with QuickDASH.30 Compared with legacy fixed- promote the assessment of health outcomes as reported item questionnaire like QuickDASH, it is also easier to by the patients.21 Upper extremity physical function, use and has less burden on patient (mean completion pain intensity, depression, and anxiety PROMIS time in second 70 vs. 116 in QuickDASH) and no floor domains were used in this study to measure patient- and ceiling effect, and the scores can be comparable to reported relevant outcomes. PROMIS item banks are U.S. population norm.28 modeled based on unidimensional item response theory, which uses graded response parameters to fit the data PROMIS Bank (v1.0) Depression CAT. Patient- and produce scores.22,23 PROMIS scores are given as Reported Outcomes Measurement Information System T-scores with a mean of 50 and standard deviation (SD) Depression was used to assess the symptoms of depres- of 10.23,24 Computer Adaptive Testing (CAT) was used sion. It showed strong convergent validity with the 4 TALAEI-KHOEI ET AL.

Patient Health Questionnaire (PHQ)31 and the Center all” to 4 “all the time.” The PCS total score is calculated for Epidemiological Studies Depression scale (CES-D)32 by adding the individual score of all 13 items (range: 0 to (r = 0.72 to 0.84 across different timelines). However, it 52). Higher scores translate into more amplified nega- has some advantage over PHQ and CES-D psychome- tive orientation toward pain. The PCS has good relia- trically with increased precision and broader effective bility and construct validity.37 range of measurement. Also, due to being administered through CAT, it has less burden on patient with median Statistical Approach number of 4 items administered compared with 9 in PHQ and 20 in CES-D.33 In another study, PROMIS Pearson product–moment correlations were computed depression showed a convergent validity (r = 0.83) with to examine zero-order correlations between continuous CES-D and also correlation between each of its item demographic and descriptive variables (age and pain with related item in legacy measure was demonstrated duration) and study variables (pain intensity, upper (median r = 0.72).34 extremity physical function, psychological inflexibility, pain catastrophizing, anxiety, and depression) and PROMIS Bank (v1.0) Anxiety CAT. Patient-Reported among study variables themselves. Independent-samples Outcomes Measurement Information System anxiety t-tests were used to explore the differences in the study was utilized to measure anxiety level among partici- variables by dichotomous descriptive and demographic pants. It has shown convergent validity (r = 0.80) with variables (gender and trauma). the general distress subscale of legacy measure the Mood and Anxiety Symptom Questionnaire (MASQ)35,36 and Model Building each item in PROMIS anxiety has been demonstrated to correlate with relevant item in legacy measure (median Identification of Candidate Mediators. We had r = 0.65).33 PROMIS anxiety asks about the level of hypothesized that pain catastrophizing, anxiety, and anxiety in the past 7 days and respondents choose the depression can potentially mediate the effect of psycho- answer from never, rarely, sometimes, often, to always logical inflexibility (exposure/independent variable) on (the same for PROMIS depression). Through item-level pain intensity and upper extremity physical function calibrations, assessment center calculates the score for (outcome/dependent variables). Therefore, pain catas- anxiety for each patient with 50 10 being the trophizing, anxiety, and depression were assessed in mean SD of samples from U.S. population. zero-order correlations with both exposure and out- come variables. Any of these variables that correlated Acceptance and Action Questionnaire-II. The Accep- with both the independent and dependent variables were tance and Action Questionnaire-II (AAQ-II)2 was used considered as candidate mediators and included in the to assess the general construct of psychological inflex- model; if they did not meet criteria, they were assessed ibility. The scale has 7 items scored on a 7-point Likert for potential covariates in the models. type scale, from 1 “never true” to 7 “always true”. The construct score is calculated by summation of the Identification of Covariates. Any variable that corre- individual scores of all 7 items (range: 7 to 49). Higher lated with a candidate mediator, an outcome variable, scores mean greater psychological inflexibility. Across 6 or both were considered a covariate and included in samples, this scale exhibited high internal reliability models. Demographic and descriptive variables (age, (mean a coefficient: 0.84; range: 0.78 to 0.88). The 3- gender, pain duration, and trauma) and ruled-out and 12-month test–retest reliability studies revealed mediators were all assessed for their potential to be a AAQ-II had 0.81 and 0.79 mean a coefficients, respec- covariate. We ran the mediation models with or without tively. The AAQ-II also showed proper discriminant controlling for covariates and then compared the validity.2 models.

Pain Catastrophizing Scale. The Pain Catastrophizing Mediation Analysis. Multiple-mediator models were fit Scale (PCS) was used to measure catastrophic thinking based on the criteria for candidate mediators and about pain. This measure asks participants to rate their covariates. Both the mediation analyses and the quan- pain-associated thoughts and feelings when experienc- tification of the total, direct, and indirect paths were ing pain on a 5-point Likert type scale, from 0 “not at performed via Hayes’ PROCESS macro tool, (http:// Effect of Psychological Inflexibility on Pain 5

www.processmacro.org), for SPSS (IBM Corp. Released demonstrated that bootstrapping, especially when incor- 2013. IBM SPSS Statistics for Windows, Version 22.0.; porating bias correction in it, had the highest power IBM Corporation, Armonk, NY, U.S.A.). The causal compared with the traditional product of coefficients steps approach was recruited to establish whether or not approach and other methods requiring a smaller sample 42 the ai path (effect of independent variable on mediator) size to detect an indirect effect. and bi path (effect of mediator on outcome), which together represented a specific indirect effect path

(ai 9 bi), were statistically significant. Also, the direct RESULTS effect (c0) path (eg, the direct effect of psychological Sample Characteristics and Description inflexibility on pain intensity controlling for other mediators and covariates) compared with the total One hundred and eight patients with upper extremity effect (c) path was examined. The effect of the indepen- illness were enrolled in this study. Descriptive, demo- dent variable (psychological inflexibility) on the depen- graphic, and main study variables are presented in dent variable (eg, pain intensity) was fully mediated Table 1. Older age correlated with lower pain intensity through a specific mediator in the model when c0 path (r = 0.174, P = 0.036), lower pain catastrophizing was not significant but relevant ai and bi paths were. (r = 0.261, P = 0.003), lower anxiety (r = 0.200, Partial mediation was noted when c0 path remained P = 0.019), and lower depression (r = 0.252, significant but was smaller than c path in the presence of P = 0.004). Pain duration showed significant correla- the significant specific ai and bi paths. If either the tion with pain intensity (r = 0.189, P = 0.025) and specific ai or bi paths for a candidate mediator were not anxiety (r = 0.233, P = 0.008). As compared to men, significant, that theorized candidate mediator was ruled women had lower level of upper extremity physical out as an actual mediator. function (M (SD) = 32.64 (8.37) vs. 38.14 (8.78), While the causal steps approach is beneficial for t = 3.321, P = 0.001) and higher level of pain inten- establishing the existence of a mediation effect, it does sity (M (SD) = 50.74 (7.32) vs. 48.34 (6.22), t = 1.842, not investigate the indirect effect directly.38 Therefore, P = 0.034). Patients with pain related to trauma we recruited PROCESS macro to rectify this issue, reported less upper extremity physical function than through the Preacher and Hayes bootstrapping those with pain not associated with trauma (M method38,39 that directly estimates and infers the indi- (SD) = 32.73 (8.83) vs. 36.81 (8.81), t = 2.251, rect effects. Bootstrapped resampling with 5,000 sam- P = 0.013). ples was iterated to get robust bootstrapped standard errors (SE) and 95% bias-corrected accelerated (BCa) Zero-order Bivariate Correlations Among Study CIs for the mediation effects. If bootstrapped CIs Variables crossed zero, the significance of the indirect effect was ruled out. PROCESS macro also produced point esti- Table 2 displays the correlation coefficients among the mate of indirect effect through the product of coeffi- study variables. All study variables were intercorrelated cients strategy (a.k.a., Sobel test40). The bootstrapped except depression (r = 0.136, P = 0.080), which was CI is superior for mediation analysis as it overcomes the not significantly correlated with upper extremity assumption of normality requirement of other meth- Table 1. Descriptive and Study Variables (N = 108) ods.38 The sample size was determined based on Fritz and Variables n (%) or Mean (SD) 41 Mackinnon’s sample size simulation, which estimated Age (years) 54.07 (16.01) a minimum sample size of 71, which was required to Gender (Female) 52 (48.2%) Trauma detect a medium effect size (0.13) with 0.80 power when Yes 35 (32.4%) using a bias-corrected bootstrapped mediation approach No 73 (67.6%) Pain duration (in days) 804.91 (396.44) for inferring an indirect effect. Fritz and Mackinnon Pain intensity 49.50 (6.85) performed the simulation with the assumption of no Physical function 35.49 (8.98) measurement error. To account for an inherent mea- Psychological inflexibility 14.56 (7.32) Pain catastrophizing 12.30 (9.59) surement error existing within any measures, we Anxiety 52.65 (7.91) enrolled a larger sample size of 108 patients (about Depression 47.07 (7.88) 50% more). In a large-scale simulation study, it was N, Number; SD, standard deviation. 6 TALAEI-KHOEI ET AL.

Table 2. Zero-Order Pearson Product–Moment Correla- catastrophizing, anxiety, and depression demonstrated tion of Study Variables significant correlations (P < 0.05) with psychological

Variables 1 2 3 4 5 inflexibility (dependent variable) and pain intensity (outcome variable), making them eligible candidates to 1. Pain intensity 2. Physical 0.458** be assessed as mediators. Among the demographic and function descriptive variables (age, gender, pain duration, and 3. Psychological 0.404** 0.405** inflexibility trauma), gender showed correlation with the outcome, 4. Pain 0.429** 0.409** 0.612** and age and pain duration correlated with both at least 1 catastrophizing 5. Anxiety 0.169* 0.199* 0.423** 0.420** candidate mediator and outcome, making them eligible 6. Depression 0.182* 0.136 0.421** 0.328** 0.748** covariates in the model. Trauma was ruled out as a

*P < 0.05. covariate and was not inserted into controlled model for **P < 0.001. pain intensity, because it did not show correlation with either the outcome or any of candidate mediators. physical function. As all correlation coefficients were The multiple-mediator model of the effect of psycho- below 0.90, multicollinearity was ruled out.43 logical inflexibility on pain intensity was assessed both uncontrolled and controlled excluding the effect of covariates (age, gender, and pain duration). The total Pain Catastrophizing Mediates the Effect of effects, direct effects, and specific indirect effects are Psychological Inflexibility on Pain Intensity shown in Table 3. While remaining significant, the total Figure 1 shows the multiple-mediator model that was effect (c) decreased when controlled for covariates built following criteria delineated in the statistical (b = 0.378, P < 0.001 vs. b = 0.335, P < 0.001). The 0 approach section. In zero-order correlations, pain direct effect (c ) shrank and became nonsignificant

Psychological Pain Intensity Inflexibility Total Effect (c)

Pain Catastrophizing

a1 b1

Psychological Pain Intensity Inflexibility Direct Effect (c') Figure 1. Multiple-mediator model for the effect of psychological inflexi- bility on pain intensity. Total effect (c) represents the total effect (direct plus

a2 b2 indirect effects) of psychological inflexibility on pain intensity. The Anxiety indirect effect (c0) is the effect of psychological inflexibility after account- a3 b3 ing for mediators and covariates. The

ai paths represent the paths between psychological inflexibility (independent variable) and candidate mediators. The effects of candidate mediators on pain Depression intensity (dependent variable) are

indexed as bi paths. Covariates are age, gender, and pain duration. Effect of Psychological Inflexibility on Pain 7

Table 3. Results of Multiple-mediator Models for the Effect of Psychological Inflexibility on Pain Intensity

Indirect Effect (Path ai 9 Path bi)

95% BCa CI

Model Mediator Path b (SE) t Score b (SE) Lower Upper z Score

Uncontrolled c 0.378* (0.083) 4.549 c0 0.218* (0.108) 2.023 Pain 0.178* (0.089) 0.006 0.360 2.573*

catastrophizing a1 0.802* (0.101) 7.970 b1 0.222* (0.081) 2.740 Anxiety 0.041 (0.059) 0.161 0.079 0.734

a2 0.457* (0.095) 4.800 b2 0.090 (0.118) 0.759 Depression 0.023 (0.057) 0.089 0.138 0.431

a3 0.454* (0.095) 4.782 b3 0.051 (0.116) 0.442 Controlled c 0.335* (0.084) 3.972 c0 0.203 (0.106) 1.907 Pain 0.155* (0.078) 0.006 0.315 2.383*

catastrophizing a1 0.756* (0.104) 7.251 b1 0.205* (0.081) 2.548 Anxiety 0.044 (0.054) 0.159 0.054 0.830

a2 0.421* (0.097) 4.337 b2 0.105 (0.121) 0.868 Depression 0.021 (0.047) 0.069 0.123 0.429

a3 0.411* (0.098) 4.188 b3 0.052 (0.117) 0.443

95% BCa CI, 95% Bias-corrected and accelerated confidence interval; SE, standard error. 95% BCa CI and SE for indirect effects were calculated based on 5,000-sample bootstrapping. A 95% BCa CI that does not cross 0 represents a statistically significant indirect effect. Asterisk represents a statistically significant effect. Controlled covariates: age, gender, and pain duration. accounting for the effects of covariates and mediator P = 0.017). In sum, pain catastrophizing mediated the variables compared with only accounting for mediators effect of psychological inflexibility on pain intensity (b = 0.203, P = 0.059 vs. b = 0.218, P = 0.046). through a specific indirect path controlling for anxiety, Pain catastrophizing partly mediated the effect of depression, age, gender, and pain duration. psychological inflexibility on pain intensity in the Anxiety was not a mediator of the effect in both uncontrolled model. Path a1 (b = 0.802, P < 0.001) uncontrolled and controlled models. Path b2, the effect and path b1 (b = 0.222, P = 0.007) were significant. of anxiety on pain intensity, was not significant (uncon- While path c0 was significant, path c0 was smaller than trolled; b = 0.090, P = 0.450 and controlled; path c (c = 0.378 vs. c0 = 218). In the controlled model, b = 0.105, P = 0.387). The 95% BCa CI of the while path a1 and path b1 were significant (b = 0.756, unstandardized coefficient of the indirect effect (path 0 P < 0.001 and b = 0.205, P = 0.012), path c a2 9 path b2) also crossed the zero mark, which (b = 0.203, P = 0.059) became nonsignificant after confirmed that the indirect effect path was not signifi- controlling for covariates. In other words, after control- cant (uncontrolled; b = 0.041, 95% BCa CI [0.161, ling for the covariates (age, gender, and pain duration), 0.079] and controlled; b = 0.044, 95% BCa CI mediation became complete. The CI and SE for the [0.159, 0.054]). Normal theory approach also failed indirect effect (path a1 9 path b1) were obtained as to show any significant indirect effect through anxiety 95% BCa bootstrapped CI and robust bootstrapped SE (uncontrolled; z = 0.734, P = 0.463 and controlled; based on 5,000-sample bootstrapping. As the 95% BCa z = 0.830, P = 0.406). CI did not cross 0, the results demonstrated that the Depression was also ruled as a mediator in both indirect effect paths of psychological inflexibility on uncontrolled and controlled models. The path b3,the pain intensity through pain catastrophizing were signif- effect of depression on pain intensity, was not significant icant in both models (uncontrolled; b = 0.178, 95% accounting for other candidate mediators in the uncon- BCa CI [0.006, 0.360] and controlled; b = 0.155, 95% trolled model and other candidate mediators and covari- BCa CI [0.006, 0.315]). Sobel test also confirmed the ates in controlled model (uncontrolled; b = 0.051, significance of the indirect effect (uncontrolled; P = 0.659 and controlled; b = 0.052, P = 0.658). z = 2.573, P = 0.010 and controlled; z = 2.383, The 95% BCa CI of the unstandardized coefficient of 8 TALAEI-KHOEI ET AL.

theindirecteffect(patha2 9 path b2) contained zero The multiple-mediator model of the effect of psycho- ruling out a significant depression-specific indirect effect logical inflexibility on physical function was investi- path (uncontrolled; b = 0.023, 95% BCa CI [0.089, gated both uncontrolled and controlling for the effect of 0.138] and controlled; b = 0.021, 95% BCa CI [0.069, covariates (age, gender, pain duration, trauma, and 0.123]). Normal theory test, also, did not show any depression). The total effects, direct effects, and specific significant indirect effect through depression (uncon- indirect effects are shown in Table 4. While remaining trolled; z = 0.431, P = 0.667 and controlled; z = 0.429, significant, the total effect (c) decreased after controlling P = 0.668). for covariates (b = 0.497, P < 0.001 vs. b = 0.456, P < 0.001). The direct effect (c0) also decreased but remained significant after controlling for the effects of Pain Catastrophizing Mediates the Effect of covariates and mediator variables compared with the Psychological Inflexibility on Upper Extremity Physical model that only accounted for mediators (b = 0.267, Function P = 0.049 vs. b = 0.309, P = 0.029). Figure 2 shows the multiple-mediator model for upper Pain catastrophizing partly mediated the effect of extremity physical function. In zero-order correlations, psychological inflexibility on physical function in the pain catastrophizing and anxiety showed significant uncontrolled and controlled conditions. Path a1 (uncon- correlations with psychological inflexibility and upper trolled; b = 0.802, P < 0.001 and controlled; extremity physical function, making them eligible can- b = 0.732, P < 0.001) and path b1 (uncontrolled; didates to be assessed as mediator variables. Depression b = 0.246, P = 0.023 and controlled; b = 0.239, did not correlate significantly with physical function P = 0.020) were significant. While in both models path (r = 0.136, P = 0.080), but met the criteria for inclu- c0 was significant, path c0 was smaller than path c sion in the model as a covariate because it correlated (uncontrolled; c = 0.497 vs. c0 = 0.309 and con- with both pain catastrophizing and anxiety (candidate trolled; c = 0.456 vs. c0 = 0.267). The 95% BCa mediators). Age, gender, pain duration, and trauma also bootstrapped CI and robust bootstrapped SE based on were put in the model as covariates because they either 5,000 resampling for the indirect effects (path a1 9 path correlated with a candidate mediator or physical func- b1) were calculated for both models. As the 95% BCa CI tion (outcome). did not cross 0, the indirect effect of psychological

Psychological Physical Function Inflexibility Total Effect (c)

Pain Figure 2. Multiple-mediator model Catastrophizing for the effect of psychological a1 b1 inflexibility on physical function. Total effect (c) represents the total effect (direct plus indirect effects) of psychological inflexibility on physical 0 Psychological function. The indirect effect (c ) is the Physical Function Inflexibility effect of psychological inflexibility Direct Effect (c') after accounting for mediators and

covariates. The ai paths represent the effects of independent variable (psychological inflexibility) on candi-

a2 b2 date mediators, and the bi paths show the effects of candidate mediators on Anxiety outcome variable (physical function). Covariates are depression, age, gender, pain duration, and trauma. Effect of Psychological Inflexibility on Pain 9

Table 4. Results of Multiple-mediator Model for the Effect of Psychological Inflexibility on Physical Function

Indirect Effect (Path ai 9 Path bi)

95% BCa CI

Model Mediator Path b (SE) t Score b (SE) Lower Upper z Score

Uncontrolled c 0.497* (0.109) 4.559 c0 0.309* (0.139) 2.216 Pain 0.197* (106) 0.433 0.014 2.208*

Catastrophizing a1 0.802* (0.101) 7.970 b1 0.246* (0.106) 0.2.316 Anxiety 0.009 (0.057) 0.110 0.117 0.178

a2 0.457* (0.095) 4.800 b2 0.020 (0.112) 0.182 Controlled c 0.456* (0.115) 3.950 c0 0.267* (0.134) 1.993 Pain 0.175*(0.093) 0.393 0.027 2.200*

Catastrophizing a1 0.732* (0.114) 6.429 b1 0.239* (0.101) 2.370 Anxiety 0.014 (0.030) 0.107 0.024 0.566

a2 0.142 (076) 1.870 b2 0.101 (0.151) 0.673

95% BCa CI, 95% Bias-corrected and accelerated confidence interval; SE, standard error. 95% BCa CI and SE for indirect effect were calculated based on 5,000-sample bootstrapping. A 95% BCa CI that does not cross 0 represents a statistically significant indirect effect. Asterisk represents a statistically significant effect. Controlled covariates: depression, age, gender, pain duration, and trauma. inflexibility on physical function through pain catastro- DISCUSSION phizing accounting for anxiety, depression, and other covariates was deemed significant (uncontrolled; Psychological inflexibility, defined as the inability to b = 0.197, 95% BCa CI [0.433, 0.014] and take value-based actions in the presence of unwanted controlled; b = 0.175, 95% BCa CI [0.393, thoughts, feelings, or bodily symptoms,4 is associated 0.027]). The Sobel test also confirmed the significance with negative health outcomes including depression and of the indirect effect (uncontrolled; z = 2.208, anxiety.8,10,11 The purpose of the current study was to P = 0.027 and controlled; z = 2.200, P = 0.028). In determine the association between the general construct other words, pain catastrophizing mediated the effect of of psychological inflexibility and pain intensity and psychological inflexibility on upper extremity physical upper extremity physical function in patients with function through a specific indirect path controlling for musculoskeletal illness in an orthopedics surgical prac- anxiety, depression, age, gender, pain duration, and tice. We also set out to test mediation models proposing trauma. that psychological inflexibility impacts pain intensity Anxiety was not a mediator of the effect neither in and upper extremity physical function directly, as well uncontrolled nor in controlled models. Path a2 was as indirectly through increased depression, anxiety, and significant in the uncontrolled model, yet after control- pain catastrophizing. ling for depression and other covariates, it became Results of this study support prior research on the 1,44,45,46 11,12 nonsignificant (P < 0.001 vs. P = 0.064). Path b2, the association of pain-specific and general effect of anxiety on physical function, was not significant psychological inflexibility with pain intensity and phys- in both models (uncontrolled; b = 0.020, P = 0.856 and ical function and expand it by providing support for controlled; b = 0.101, P = 0.502). The 95% BCa CI of these relationships to pain intensity and upper extremity the unstandardized coefficient of the indirect effect (path physical function in patients with musculoskeletal pain a2 9 path b2) also contained the 0, which further in an orthopedic surgical practice. The level of psycho- confirmed that there is no significant indirect effect path logical inflexibility, which entails the inability to inte- through anxiety (uncontrolled; b = 0.009, 95% BCa CI grate and manipulate new information, defuse from [0.110, 0.117] and controlled; b = 0.014, 95% BCa thoughts and act consistent with values rather than CI [0.107, 0.024]). Normal theory approach did not based on pain sensations or pain-related thoughts, also demonstrate any significant indirect effect through appears to be a driving force toward negative pain anxiety (uncontrolled; z = 0.178, P = 0.859 and con- outcomes.1,11,44 Further, this study broadens our under- trolled; z = 0.566, P = 0.572). standing of the mechanism through which psychological 10 TALAEI-KHOEI ET AL.

inflexibility may lead to pain intensity and physical presenting to an orthopedic surgical practice. Our study function. Although a prior study showed an association suggests that a general tendency toward psychological of cognitive fusion, a component of psychological inflexibility is a risk factor for increased pain intensity inflexibility, to pain catastrophizing, to our knowledge and decreased physical function when patients experi- this is the first study supporting the mediating role of ence an upper extremity illness. This is of great pain catastrophizing in the relationship between psy- significance and suggests that those who measure high chological inflexibility and both pain intensity and on psychological inflexibility may be at risk of not only upper extremity physical function. We found that chronic pain when experiencing an upper extremity psychological inflexibility impacts pain intensity and illness, but also other negative health outcomes when upper extremity physical function both directly and experiencing other health concerns. indirectly through pain catastrophizing. There are some caveats that should be considered A large body of research has documented the asso- when interpreting the results of this study. The cross- ciation of pain catastrophizing to pain intensity and sectional design of the study limits any conclusion about – physical function.15 17 However, what leads to pain the causation or direction of the effects. The relationships catastrophizing when patients encounter pain is not could go the other way as well, although both the good known. We hypothesized and found support that the model fit parameters and theory go against that. For level of psychological inflexibility influences the degree example, it may be that pain catastrophizing triggered by to which patients engage in pain catastrophizing when an orthopedic condition increases psychological inflex- encountering pain sensations, and this impacts their pain ibility, which in turn decreases physical function. A and physical function. Possessing greater psychological longitudinal study is warranted to provide more defini- flexibility (eg, low psychological inflexibility) may allow tive evidence for the direct and indirect effects of patients who experience pain to become aware of the psychological inflexibility on pain intensity and physical initial, automatic, protective worry when a novel pain function. Pain patients were limited to upper extremity symptom develops, defuse such cognitions, and engage conditions, and results may not necessarily generalize to in value-driven behaviors, which lead to better out- patients with pain complaints in other body locations. comes. On the contrary, those high in psychological Despite our expectations based on literature, a correla- inflexibility may get stuck in the pain–thought fusion tion between depression and upper extremity physical and become unable to accept pain sensations, leading to function was not shown. This may be a function of our rumination on pain experiences, magnification of pain sample being relatively healthy as depicted by the scores experiences, and a sense of helplessness in the face of on the PROMIS measures, as well as due to our choice of pain (ie, pain catastrophizing), leading further to higher assessing upper extremity-specific rather than general pain intensity and disability. physical function. Results may be different with patients Our study also confirms prior research on the with higher symptoms of depression and lower levels of relationship of psychological inflexibility to both depres- physical function, and with a general physical function sion and anxiety,8,10,11 of depression and anxiety to pain measure. As pain catastrophizing mediates the effect of intensity, and of anxiety to upper extremity physical psychological inflexibility on pain intensity and upper – function.3,16,18 20 However, neither depression nor extremity physical function, there might be other medi- anxiety were supported as mediators when entered ators that this study did not address. together with pain catastrophizing in the mediation Despite these limitations, this study advances our models, suggesting that only pain catastrophizing carries understanding of the mechanisms through which the the effect of psychological inflexibility on pain and general construct of psychological inflexibility impacts upper extremity physical function in patients with pain and upper extremity physical function in patients musculoskeletal pain. with musculoskeletal pain presenting to an orthopedic We found support that the general psychological surgical practice. The fact that a general rather than a inflexibility construct leads to pain catastrophizing, pain-specific psychological inflexibility scale predicts increased pain intensity, and decreased physical func- pain intensity and physical function supports the con- tion, while prior studies in adults generally used a pain- tention that the general rather than symptom-specific specific inflexibility measure.1,44 To our knowledge, this cognitive fusion and subsequent experiential avoidance is the first study that assessed general psychological are the root problems that may impact not only pain and inflexibility in adult patients with musculoskeletal pain pain outcomes, but also other health outcomes. In other Effect of Psychological Inflexibility on Pain 11

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