To describe the 5 years’ trajectories in functionality and pain of patients with hip or knee osteoarthritis and arthroplasty and analyze the association of these with long-term patients survival. Patients with OA receiving total hip or knee arthroplasty were recruited and completed two sets of standardized questionnaires for functionality and pain 6, 12, and 60 months postoperatively. Multivariate mixed models were conducted to assess trajectories over time and the resulting improvement per month during the last time period was included in a landmark-model to estimate adjusted hazard ratios for mortality. In total 809 patients with joint replacement were included , 407 patients died (median follow-up 18.4 years). Both instruments of functionality and pain showed extensive improvement during the first 6 months. Baseline and change in functionality (both p < 0.001) and pain (p = 0.02) during the first 6 months were associated with mortality. Better values in functionality corresponded with improved survival whereas the association with the pain scores was inverse. In patients with hip and knee OA, an explicit improvement in function is seen within the first 6 months after arthroplasty. In addition, especially the functionality scores at baseline as well as their improvement showed an association with long-term patient survival. Arthroplasty is an established treatment in symptomatic patients in order to restore functionality, relief pain, and increase overall quality of life. It prevents disability and also enables a renewed physically active lifestyle, which is an important component of health3.Osteoarthritis (OA) is a very common musculoskeletal disorder. Prevalence of OA is increasing with age and OA leads to functional disability and pain in the joints4. A recent meta-analysis which investigated the association of symptomatic or radiological OA and all-cause mortality came to the conclusion that so far no reliable evidence exists for an association of OA with general and all-cause mortality5. We came to a similar conclusion when analyzing the 20 years’ mortality after the first hip or knee joint replacement in our study population6. However, as impaired function and chronic pain associated with OA may result in disability as well as in decreased physical activity, these patients may also have long-term consequences on a variety of health-related endpoints, and finally on long-term survival. However, studies that investigated the trajectories of functionality and pain after arthroplasty and the association with long-term health consequences are scarce yet. Additionally, the difference in association with long-term mortality between generic and osteoarthritis-specific instruments has not been investigated so far.Overall, patients with OA seem to have no increased all-cause mortality compared to the general population, also previous studies revealed inconsistent resultsTherefore, the aim of this investigation was to describe the 5 years’ trajectories in functionality and pain of patients from the Ulm Osteoarthritis Study cohort, who underwent a hip or knee replacement due to osteoarthritis and were characterized with different measurement instruments of pain and functionality. The resulting trajectories have then been analyzed to investigate the association with long-term patient survival after adjustment for multiple covariates.8), as well as the current follow-up, was approved by the Ethics Committee of Ulm University (No. 164/14). The study was conducted according to the relevant guidelines and regulations and the Declaration of Helsinki.For this prospective cohort study patients for unilateral total hip or knee arthroplasty due to advanced OA were recruited consecutively between January 1995 and December 1996 in four hospitals in the South-West of Germany. The inclusion criteria  were fulfilled by N = 809 patients who also gave written informed consent. The initial study  and the functionality sub-scale of the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) were applied. The basic version of FFbH (including 18 single questions regarding the last seven days) was used to assess general function. WOMAC (including 17 single questions) was used to specifically describe function in the operated joint at the time point of assessment.To measure pain, the Visual Analogue Scale (VAS) and the pain sub-scale of the WOMAC were applied. Both measures describe pain in the operated joint at the moment of assessment, the WOMAC pain sub-scale, however, concentrates on typical OA-associated circumstances. For comparability, each score was transformed onto a scale from 0 to 100 with higher values being positive for a patient . The measurements of these instruments were applied at baseline as well as at 6 months, 12 months, and at 60 months. Missing values in assessments occurred due to loss to follow-up of patients or missed follow-up visits during the study course. The exact number of observations is displayed in Fig. 6.Mortality was assessed during the follow-up time up to 20 years via residents' registration office. In case of death, the exact date of death was obtained from the respective residents' registration office. Information was gathered up until 31st August 2015. Further details can be found elsewhere6. The selected characteristics were age, gender, diabetes, cholesterol, uric acid, heart insufficiency, hypertension, overweight, smoking status, localization of OA, and secondary OA as covariates for overall survival (details of variable selection see6).The main characteristics of the study population at baseline were described. The selection of characteristics included in these analyses was based on a previous investigation of the same datasetTwo different approaches were used to analyze both, a functionality value and a pain value in one statistical model. Approach 1 combined the FFbH functionality score with the VAS pain score. Approach 2 combined the two sub-scales for functionality and pain of the WOMAC. To assess the course of functionality and pain, the mean values of all assessments with corresponding standard errors were computed for baseline and follow-up time points. The resulting mean courses of all four assessments were plotted. Correlations between measured baseline values and trajectories (changes within specific time periods) were assessed by Pearson’s correlation coefficients for descriptive purposes.13. Due to the follow-up times, landmark times were chosen to be 6, 12 and 60 months after follow-up and the previously described Cox model was calculated for each landmark time. For further information concerning the exact statistical methods see the Supplementary Material. Hazard ratios (HR) were estimated for the improvement in functionality or pain. The HRs with 95% confidence intervals (CI) and additional p values are shown for all 6 resulting sub-models (3 time points for 2 approaches). No adjustment for multiple testing was performed. All analyses were performed using SAS 9.4 .The statistical analysis was conducted via a landmark Cox model combined with a prior, two-dimensional linear mixed effects model. We excluded observations with missing baseline measurements in pain or functionality for this analysis. The linear mixed effects model was used to estimate the partwise-linear trajectories of pain and functionality in the corresponding landmark dataset. The linear mixed effects model was calculated including no covariates other than time as predictor, using the breakpoints 6 and 12 months after follow-up. Then, the estimated current slopes as well as baseline functionality, pain and other baseline characteristics were included in the landmark Cox modelIn the baseline investigation, 809 patients with OA were included; of these, 389 patients had arthroplasty of the knee, and 420 patients had arthroplasty of the hip, respectively. As displayed in Table Score values over time of functionality  and of pain  are displayed in Fig. Functionality measured by FFbH was in general lower  in knee OA compared to hip OA and in females compared to males at baseline Fig. , panel AThe WOMAC functionality sub-scale showed a strong increase up to month 6 and less steep to month 12, and was also reaching higher levels in patients with hip OA compared to knee OA  per point increase]. This association remained statistically significant also in landmark times 12 and 60 months ].The analyses using the osteoarthritis-specific WOMAC sub-scales to quantify functionality and pain yielded no associations with overall mortality  and approximately constant levels in later years. Our results are in line with the findings of these studies and expand them in several important respects.Previous studies already showed an increase in functionality as well as a relief in pain after hip or knee arthroplasty with more pronounced effect in the hip19. Hawker et al. confirmed this observation in patients with hip or knee OA who were followed over 13 years and reported an association of all-cause mortality with the WOMAC function sub-scale and walking disability but not with pain20. Interestingly, in the subgroup which received joint arthroplasty a reduced risk for cardiovascular events and improved patient survival was identified going in line with improved physical function. Joint arthroplasty also reduces chronic pain which may carry itself an increased risk for mortality. In a large cohort study from Denmark, patients with chronic pain had a 39% increased risk of death compared to the general population21. Management of peri- and postoperative pain is an important issue in patients with arthroplasty of the hip or knee. Several studies that investigated the effect of different strategies emphasized the importance of adequate pain management to prevent persistent postoperative pain23. Dumenci et al.24 estimated that among adults after knee arthroplasty about 18% had persistent pain, poor function, or both after 12 months. Interestingly, a recent review and meta-analysis suggested an overall modest risk of chronic pain in general with high heterogeneity between studies25. This variation was partly attributed to different pain phenotypes included. More recent studies on pain and mortality in adults above 50 years of age indicated that mainly pain which compromises daily life activities is associated with an increased risk of mortality26 and that functional limitation, as well as physical inactivity, may represent relevant mediators27.Looking on specific factors Nüesch et al. reported that mortality in patients with hip or knee OA is linked to walking disability28, an accepted predictor for all-cause mortality and cardiovascular events29. Interestingly, disability but not OA itself has recently been claimed to predict cardiovascular disease in a population-based cohort30.Arthroplasty of hip or knee usually improved cardiovascular fitness in patients after hip arthroplasty investigated up to 2 years postoperatively31. A study conducted with sensor-based measurements in 63 patients awaiting hip or knee arthroplasty from Australia showed no change to measurements 6 months later32, also 6 months measurements may still be influenced by post-operative pain and complications. In another study from Australia including 51 patients with total hip arthroplasty also no improvement in sensor-measured 24-h activity profiles at six months was seen33. A review including eight studies with patients with hip or knee arthroplasty and also sensor-based measurements showed negligible changes at 6 months follow-up, but larger changes at 12 months, which were especially evident for hip OA34. Still existing studies are based on relatively small numbers and partly suffer a high risk of bias. Therefore larger and better designed studies are still needed to make firm conclusions.However, currently there is no good evidence to support the association between joint replacement and increased physical activity. Patient self-reported physical activity seems neither accurate nor reproducible as assessed in a group of patients pre-operatively and 6–8 weeks post-operatively35. Therefore, joint replacement should not be performed too late. Further investigations should look especially into the primary determinants and long-term consequences of different functional and pain trajectories especially visible in the first 6 months after OA. It seems plausible that the time shortly after OA is an important time slot for long-term prognosis, still with the possibility to eventually modifying treatment and rehabilitation efforts.Our results indicate that long-term mortality of OA patients after joint replacement is more associated with the general health status, physical activity, and comorbidities than with joint-specific impairmentThe study has the following strength: the study population with more than 800 patients with OA and arthroplasty of hip and knee was very well characterized at baseline and had a well-defined disease status. In addition, different measurements for functionality and pain were available during follow-up: on the one side a more general assessment of functionality by the FFbH score and of pain by the VAS, on the other side, an OA-specific assessment with the two WOMAC sub-scales.39.The advanced landmark analyses used in this investigation extend standard landmark approaches due to the inclusion of a previous mixed model. By prior estimation of the trajectories, we were able to account for missing values occurring over the course of time as well as for a time-dependent bias . A limitation of this technique is the disregard towards the joint distribution between survival process and trajectoryAnother advantage is based on the design of landmarking itself. We were able to gain estimators, evaluating the association of the trajectory slopes at certain landmark times with survival. This is important because patients undergo greater changes during the first period after an arthroplasty. This period is therefore much more likely associated with survival than later ones. Another strength is that we were able to mutually adjust for functionality and pain. A limitation in our advanced approach arises due to the created linear dependencies between different estimations in our trajectory. Therefore, we cannot conclude with certainty, that the borderline significant results in a change of functionality included in the 12 months’ model for FFbH are due to an existing association or the dependency to the change at landmark time 6. A landmarking sensitivity analysis without mixed modeling did not find such an effect (results not shown). As an additional limitation, we did not have data from all patients for all the follow-up time points. In addition, we had a limited sample size especially in the subgroups and we were not able to assess the specific cause of death. Furthermore, it has to be considered that especially fitter patients may have benefitted more from arthroplasty and eventually survived longer.Our final results suggest that in patients with hip and knee OA, arthroplasty leads to a clear improvement in both functionality measurements within the first 6 months, which seems to persist, although less steep, until month 12. The more pronounced improvement of the more generic VAS-pain score at the landmark time of 6 months showed an inverse association with long-term survival, pointing to a higher importance of general health status compared to joint-specific impairment for long-term patient survival.Supplementary file1Supplementary file2


When compared to the PS group, participants in the SS group showed a significant reduction of oxidant/antioxidant ratio  at a 3-month follow-up. A stabilization splint provides advantages over PS in the treatment of depressive symptoms and pain-related disability. Furthermore, clinical success in terms of reduction of depressive symptoms, which correlates with the reduction of oxidative stress markers in the SS group, indicates that oxidative stress is related to psychological factors in chronic TMD patients.Temporomandibular disorders (TMD), when progress to a chronic state, might contribute to psychosocial or psychological distress. This study aimed to evaluate the effect of stabilization splint (SS) therapy on pain, pain-related disability and psychological traits of chronic TMD patients, as well as to assess selected oxidative stress (OS) biomarkers during 6-month treatment and associate them with the symptoms of anxiety and depression. Thirty-four participants were randomly assigned into two treatment groups [SS and placebo splint (PS)]. Primary outcomes were pain intensity and pain-related disability while secondary outcomes included depressive and anxiety symptoms. The influence of the treatment type was analyzed with regards to the levels of OS biomarkers in saliva. Participants treated with SS demonstrated significantly greater improvement in pain-related disability (Pain-free mouth opening: p = 0.018, η Chronic craniofacial pain, similar to other chronic pain conditions, may be approached from the perspective of the biopsychosocial model that views the pain as a dynamic interaction among and within the biological, psychological, behavioral and social factors unique to each individual3. The goal of such an approach to both assessment and management of pain is to tailor the treatment to the specific needs of the individual as standard treatment protocols may lack efficiency if any of these components are ignored5.Temporomandibular disorders (TMD) encompass the group of disorders affecting jaw joints and masticatory muscles. With the exclusion of pain originating from teeth, TMD is the most common cause of orofacial pain. Their etiology is not clear; however, is considered to be multifactorial: genetic/biologic, behavioral, environmental, socioemotional, and cognitive factors seem to play a role10. Positive correlations were also shown between scores on measures of psychological distress and reported TMD pain and pain-related disability12. Thereby, pain may be a direct cause of emotional distress and lowered quality of life and aid in the development or deterioration of certain psychopathological conditions; on the other hand, individual's pre-existing psychological, behavioral and emotional characteristics may predispose for altered or even enhanced response to painful stimuli5. Psychological traits, such as depression and anxiety, have been shown to predict new-onset TMD pain13 as well as long-term persistence of TMD pain in patients with existing TMD15. Expectedly, initial treatment of patients with TMD may include psychosocial interventions targeted towards changing thoughts, behaviors and/or feelings that may exacerbate pain symptoms which have shown some benefit in treating chronic orofacial pain16. Costa et al.17 reported that the use of occlusal splints, alongside counseling, may provide an additional effect on the improvement in anxiety and depression symptoms in patients with TMD pain as well as reduce pain catastrophizing. Even though intraoral stabilization appliances for managing TMD are widely used, there is still controversy regarding their efficacy in reducing pain18. Therefore, one of the aims of our study was to evaluate the effect of a stabilization splint (SS) in comparison to a placebo splint (PS) on the characteristics of TMD pain and the psychological traits of an individual (anxiety and depression).Studies implicated higher occurrence of affective and psychosocial distress, somatic awareness, and pain catastrophizing in patients affected with TMD than in controls20. It has also been proposed that increased OS may be associated with the pathogenesis of depression21 and anxiety disorders22. Although OS has been implicated in the pathophysiology of many diseases due to the observed associations between OS and clinical symptoms23, whether OS is the cause or consequence of a disease (or perhaps both) remains elusive. Another aim of our study was to assess selected OS biomarkers during treatment with a stabilization splint in comparison to a placebo appliance and to correlate OS markers with the symptoms of anxiety and depression.It has been suggested that oxidative stress (OS) plays a role in TMD and the experience of pain related to TMDWe recruited participants between October 2016 to January 2019, and the final assessment session took place in July 2019. In that period 262 patients seeking treatment for orofacial pain were referred to our research team at the School of Dental Medicine, University of Zagreb. During the recruitment 198 of them did not fully meet the inclusion criteria, 25 of them refused to take part in the study due to travel difficulties and obligations that prevented them from participating, and 5 dropped out due to other reasons. Finally, 34 patients were randomized. The demographic data of participants who were referred but did not fully meet the inclusion criteria were not collected. The flow of participants through each stage of the trial is presented in a CONSORT diagram  with either myofascial pain or arthralgia, had average pain in the last 10 days > 30 mm on a Visual Analogue Scale (VAS), with pain duration of at least 6 months. They had to have their natural teeth and maintain good oral hygiene. Participants were not suitable if they were experiencing (1) inflammatory joint disease, (2) orofacial pain unrelated to TMD, (3) chronic systemic diseases , (4) causes of headache, unrelated to TMD, listed in the International Classification of Headache Disorders (ICDH II), (5) periodontitis, oral lesions and gum swelling. Individuals who had already been under treatment for TMD were excluded. Finally, participants who use supplements and medication known to affect the oxidative status, and smoke were not able to take part in the study.To reduce the waiting time and potential withdrawal until a sufficient number of participants are involved, we have chosen a randomization procedure based on our experience of enrolling 6–8 participants in 2 months. The patients were assigned into two treatment groups utilizing random block randomization with a block size of 8 and 6. Randomization was computer-generated, and participants were randomly assigned to two treatment arms, SS or PS. The allocation was prepared by the study's statistician prior to enrollment of the participants.Participants were unaware of the differences of each intervention. The principal investigator (IZA), who conducted the baseline evaluations, was the only person aware of the participants’ treatment conditions. All follow-up assessments were performed by the investigator (EV), blinded to the group allocation.Ten randomly selected subjects, different from the ones included in the investigation, underwent repeated clinical examinations by two experienced examiners to assess signs and symptoms of TMD (according to DC/TMD). No significant differences were recognized between the first and the second measurements . The weighted kappa statistics showed adequate agreement between the observers (κ = 0.86–0.88).Full-coverage hard acrylic upper stabilization appliance  was made on stone cast mounted in ARTEX articulator in the referent position of centric relation, with a thickness of 1.5 mm at the level of the first molar. Coverage of the approximately 1/3 of the labial and buccal surfaces of the maxillary teeth provided retention for the splints.All appliances were fabricated in a dental laboratory by the same dental technician. The occlusal surface was smooth and flat, with a canine guidance occlusal scheme. The appliances were adjusted by the clinician (IZA) so that the antagonistic teeth occluded simultaneously with the splint surface, and if necessary, further adjusted at follow-up appointments.25. Therefore, a thin transparent foil with a thickness of 0.5 mm (Erkodent) was used as a placebo splint. The increase in vertical dimension was less than 0.5 mm, therefore thought to provide a negligible influence on occlusion and condylar position. Contacts that interfered with maximal intercuspation were removed.The success of stabilization splint is attributed to various factors such as changes in condylar position, changes in neuromuscular activity, and increase in the vertical dimension of occlusion which probably contributes to the relaxation of the musculature and the relief of temporomandibular jointsPatients were instructed to wear their splints only at night while sleeping. During the entire study, participants did not receive other forms of treatment.Patients were monitored for new symptoms or exacerbation of symptoms related to TMD throughout the study. None of the participants experienced any treatment-related adverse effects or pain unrelated to TMD. If this had occurred, we would have considered excluding the participant from the study.26. We expected changes in oxidative status during the day due to environmental effects and extrinsic stressful events. Also, when validating the method in our previous study, some of the markers (i.e. afternoon MDA) showed better repeatability at a certain time of a day27.After the patients had been provided with a stabilization splint or a placebo splint, they were followed for 6 months. Primary and secondary outcome data, as well as saliva samples, were collected at baseline, 3-month follow up and post-treatment (6-month follow up). Saliva samples were collected at the same time of the day, at 7 AM and 5 PM. The morning and afternoon sampling was conducted because some of the studies urge to take into consideration the circadian rhythm of markersParticipants were strongly advised to follow detailed sampling instructions provided by the researcher (EV) in person and received those same instructions in writing. The morning samples were collected at home before tooth brushing. Participants were instructed not to eat or drink before morning saliva sampling and not to consume food or drink anything but water 2 h before afternoon sampling. Samples were collected after rinsing the mouth with water. Participants were instructed not to brush or floss their teeth before sampling to avoid blood contamination. Five mL whole, unstimulated saliva was collected into a calibrated tube while the patient was in a normal sitting position. Saliva aliquots (1 mL) were stored at − 80 °C before analysis.27.The sample collection and storage principles used in the study are described in detail by Alajbeg et al. 29.To assess the average pain, participants marked their average facial pain intensity in the last 30 days on an 11-point scale, where 0 indicated no pain and 10 indicated pain as bad as could be29.To assess the worst pain, participants filled an 11-point scale indicating the worst intensity of facial pain experienced in the last 30 days The number of disability days is defined as the number of days of pain that is serious enough to keep the participant from doing normal  activities such as work, school or housework within 1 month.29.All three items are part of the Graded Chronic Pain Scale. The instrument was validated based on a 6-month and 1-month time frame and has been extensively used across multiple disorders, languages, and settings30.A maximum comfortable mouth opening (pain-free mouth opening) is defined as the maximum distance the participant could open their mouth without feeling additional pain or discomfort. It was measured as the maximum distance between the incisal edges of maxillary and mandibular central incisors32. Cronbach’s α in our sample was 0.81 indicating good reliability.Generalized Anxiety Disorder (GAD-7) was used for measuring the severity of anxiety symptoms of the participants. The questionnaire consists of 7 statements assessing anxious mood and behavior. Participants selected one of four response choices ranging from 0  to 3 (nearly every day), with a total score being the sum of responses on the 7 items on how often they have been bothered by the specified problems. Scores range from 0 to 21, with cut-points 5, 10, and 15 represent mild, moderate, and severe anxiety respectively. The internal consistency of the GAD-7 is excellent (Cronbach α = 0.92)33. In the present study, Cronbach's α was 0.75, indicating acceptable internal consistency.The Patient Health Questionnaire-9 (PHQ-9) was used for measuring the severity of depressive symptoms. The questionnaire comprises 9 items assessing depressed mood, and participants had to indicate on a scale from 0  to 3 (nearly every day) how often they have been bothered by the specified problems. Scores range from 0 to 27, with cut-points 5, 10, 15, and 20 represent mild, moderate, moderately severe and severe depression, respectively. The questionnaire has excellent internal reliability with a Cronbach's α of 0.89Uric acid (UA) was determined using an automated enzymatic two-step colorimetric assay by Roche Diagnostics, Mannheim, Germany. Firstly, uric acid is cleaved by uricase to allantoin and hydrogen peroxide. In the presence of peroxidase, hydrogen peroxide oxidizes the chromogen 4-aminophenazone to form a quinone-diimine dye which increases absorbance that is measured at 293 nm. Within-run and between-run coefficients of variation are 1.4% and 1.8%, respectively, as determined during method verification following the Clinical and Laboratory Standards Institute EP15-A3 protocol . UA was measured on the Cobas c501 automated biochemistry analyzer .Superoxide dismutase (SOD) and total antioxidant capacity (TAC) were measured using commercially available reagent kits RANSOD and TAS  which were used according to instrument-tailored applications defined by the manufacturer, on Cobas c501 biochemistry analyzer .The RANSOD assay utilizes xanthine and xanthine oxidase that generates superoxide radicals which react with 2-(4-iodophenyl)-3-(4-nitrophenol)-5-phenyltetrazolium chloride to form a red formazan dye. The activity of SOD is measured by the degree of inhibition of this reaction, where one unit of SOD corresponds to a 50% inhibition of the reaction rate which is measured at 505 nm. According to the manufacturer, within-run and between-run CVs are 4.6% and 7.1%, respectively.TAS assay is based on simultaneous incubation of a radical generating system consisting of metmyoglobin and hydrogen peroxide, which oxidizes the ABTS substrate and subsequently produces ABTS cation radicals, which are measured photometrically at 600 nm. The presence of antioxidants in the sample cause suppression of this reaction to a degree that is proportional to their concentration. Within-run CV was determined by 10 replicate measurements of a saliva sample and was 2.8% at 1.5 mmol/L TAC.Malondialdehyde (MDA) was determined using the MDA Adduct competitive ELISA kit  that quantifies MDA-stable hybrid protein adducts (MDA-adducts), formed during lipid peroxidation. The ELISA microplate is precoated with an MDA conjugate. The anti-MDA polyclonal antibody competes for binding between MDA adducts in the sample and MDA conjugate bound on the wells of the ELISA microplate. The addition of HRP-conjugated secondary antibody produces a color reaction that is measured spectrophotometrically at 450 nm. The content of MDA adducts in the sample is inversely proportional to the intensity of the colorimetric reaction and is determined from a calibration curve. The content of MDA adduct in the calibrators is predetermined by a Thiobarbituric Acid Reactive Substances (TBARS) kit. A within-run CV of 16.6% at the concentration of 134 pmol/mL was obtained by 10 repeated analyses of one saliva sample in a single batch.All measured OS markers were normalized to the concentration of total protein.Total proteins (TP) in saliva were quantified using the commercially available turbidimetric assay TPUC3  for measurement of total proteins in urine and cerebrospinal fluid that exhibits satisfactory measuring range for saliva samples, i.e. from 0.02 to 2 g/L. Proteins in the sample react with benzethonium chloride in a basic medium producing turbidity that is measured photometrically at 505 nm. Within-run and between-run CVs are 0.9% and 1.0%, respectively, and were also obtained during method verification. TP were measured on the Cobas c501 automated biochemistry analyzer .The salivary oxidative index ratio was used to reflect the changes in oxidative balance. It was calculated by dividing the concentration of pro-oxidant MDA by the concentration of the antioxidant SOD (MDA/SOD ratio).34. The mean changes in the salivary MDA level at a 3-month follow-up were estimated to be 0.13 µM and 0.08 µM, respectively (SD 0.05 µM). A sample size calculation for a repeated measurement within-between analysis of variance with two groups showed that 26 participants (13 per group) were required to obtain a power of 0.80 at an alpha level of 0.05.Since there are no similar published studies on the effect of stabilization splint compared to placebo splint on the level of oxidative stress markers, the sample size calculation was based on the studies that compared the effect of a stabilization splint on biochemical markers with no-treatment group17, a-priori power analyses based upon 5-month reduction in pain catastrophizing  revealed that 24 participants (12 per group) were necessary to achieve 80% power with a significance level of 0.05.Modeled from previous studies which compared stabilization splint with other types of treatment (only counseling)If these calculations can be generalized and applied to our sample and design, the size of our sample (n = 34) provided acceptable power to identify moderate treatment effect size differences.Data on all patients who were randomly assigned were analyzed on an intention to treat (ITT) basis. Once enrolled, retention at follow-up assessments or the post-treatment was 89% . We substituted missing data employing the K-Nearest Neighbour imputation algorithm.All analyses were performed using Statistica 13.4.0 software package (1984–2018 TIBCO Software Inc.). The distribution of data was tested using the Shapiro–Wilk test. Before performing the statistical analyses, a log transformation was performed for all data that were not normally distributed (OS markers). We first performed a series of Student's t-tests and chi-square tests to determine whether there were any differences at baseline on demographic and pain variables as well as on oral behaviors between the two randomized groups .Additional analyses were carried out to evaluate whether: (1) treatment groups differed significantly at baseline, (2) outcome variables were correlated significantly at baseline.Analyses of differences between groups at 3-month follow-up and post-treatment were tested using ANCOVA to determine whether the follow-up and post-test means, adjusted for pre-test scores, differ between the two groups. Baseline variables  were included as covariates.2) was calculated for analyses as an indication of the effect sizes.Within-group changes for SS and PS on primary and secondary treatment outcomes at both 3-month follow-up and post-treatment were analyzed utilizing Within subjects repeated measures ANOVA. Bonferroni corrected post hoc tests were used to evaluate the difference between the time points. Partial eta squared (ηIf the sphericity assumption was violated (Mauchly’s test of sphericity p < 0.05), Greenhouse–Geisser corrections were performed.Associations between changes in treatment outcomes were tested using Pearson's correlation.A total of 64 participants met initial criteria, and 34 agreed to participate in the study (mean age 36.1 ± 11.95). They were randomized to one of the two treatment groups . All participants were female and Caucasian (n = 34) .As expected, several variables were significantly correlated at baseline. Number of disability days was significantly correlated with anxiety , worst pain  and average pain . Anxiety was positively correlated with depressive symptoms . A significant positive correlation was found between log TAC and log UA values , while morning log MDA and log SOD were negatively correlated . Both anxiety and depression were negatively correlated with afternoon antioxidants levels (r2 = 0.101). When controlling for baseline values, at post-treatment, participants treated with SS exhibited significantly stronger improvement in pain-free mouth opening than participants who received PS    and worst pain levels  at post-treatment, relative to those recorded at baseline, were noted in SS group compared to placebo . When comparing treatment effects at post-treatment to baseline values stronger improvements for depressive symptoms again were present in subjects treated with SS   was found only in the SS group The results of post hoc analyses showing differences from baseline to 3rd and 6th month are presented in Table Although participants treated with SS demonstrated stronger improvement than participants treated with PS for anxiety symptoms, the differences between the groups were not statistically significant Table . In examWhen comparing changes in secondary outcomes between groups, participants in the SS group presented a significantly greater reduction in anxiety  and depression  at post-treatment relative to values obtained at baseline, compared to placebo  and log UA  while those in the PS group did not change from baseline to post-treatment follow up (p > 0.05). The results of post hoc analyses showing differences from baseline to 3rd and 6th month are presented in Table However, according to within-group analyses, participants in SS group showed a significant decrease in the levels of log TAC   in participants treated with SS. No significant associations were found between a decrease of secondary outcomes and TAC decrease in participants treated with PS Table .Table 4CThis study aimed to assess if a 6 months long treatment of patients with TMD with a stabilization splint would lead to a greater reduction in pain, pain-related disability  and the expression of depressive and anxiety symptoms in comparison to a placebo splint. The influence of the treatment type was also analyzed with regards to the levels of several OS biomarkers in saliva. Also, levels of salivary OS markers were associated with the psychological characteristics of patients with TMD, which is, to the best of our knowledge, the novelty of this study.18. In the present study, between-group comparisons did not confirm the superiority of SS over PS in TMD pain experience. Within-group analyses showed a decrease in average pain for both groups, while decrease in worst pain was present only in the SS group. The absence of statistically significant differences for painful symptoms between groups supports the theory that the placebo has the same therapeutic efficacy as SS. However, given that within-group analysis showed significant changes for the worst pain only in the SS group, we would prefer not to disregard the possibility that the SS could have a superior therapeutic effect over the PS. Studies with a larger sample could clarify this ambiguity regarding our results.Results of previous studies assessing the effects of hard stabilization appliances on self-reported pain as a measure of TMD severity are inconsistent. However, a meta-analysis demonstrated that there is evidence that hard stabilization splints may offer improvement in TMD pain symptoms in comparison to both control appliances and no treatment35, PS in our study may have provided some pain relief even though these splints were constructed to have as little effect as possible on changes in both vertical dimension and the position of the lower jaw. It is important to have in mind that the pain-relieving effect of both placebo and stabilization splint may be attributed to other factors rather than merely the change in the vertical dimension and changes in the positioning of the condyle which were the main difference between SS and PS in our study. Those factors  might also lead to pain reduction, thus must be taken into consideration when interpreting our results.A significant difference between groups was found for pain-free mouth opening and a number of disability days at post-treatment follow up (after 6 months), however with a small effect size. Our results thus indicate that SS may offer slightly greater benefits in reducing pain and pain-related disability. Taking into account that hypotheses proposed to explain biological mechanisms by which oral appliances influence experience of both myofascial pain and arthralgia have not been substantiated by sufficient evidence36. Thereby, certain signs of psychological distress that relate to these conditions have been found to be more prominent among pain patients  than others 37. Average GAD-7 and PHQ-9 scores revealed the presence of, on average, mild anxiety and depressive symptoms in our study sample. These symptoms may be partly related to pain caused by TMD (rated of medium average intensity), but also to other factors such as personality traits and interindividual differences in coping profiles 38. Different factors influencing participants' responses to GAD-7 and PHQ-9 might explain why we found a significant difference in depressive symptoms scores between groups, while the difference in anxiety scores was not statistically significant. Taken into account that both SS and PS group expressed similar levels of anxiety and depressive symptoms at baseline (due to randomization) and, thereby, participants were evenly distributed between the groups with regards to their level of adaptation to their long-lasting painful condition, alleviation of pain caused by SS therapy could be expected to influence answers to PHQ-9 and reflect itself in increased pleasure or interest in doing things, better mood, better sleep, better concentration and/or a feeling of having more energy. On the other hand, the same influence of SS therapy would not need to be reflected in the GAD-7 scores in individuals who, as a personality trait, tend to worry too much, who are always in fear that something could go wrong (out of their control) and/or are easily annoyed.Treatment with SS has led to a greater improvement in depressive symptoms scores than the use of PS, but again with a small effect size. This finding could be suggestive of some beneficial biological effects of SS that might alleviate pain and, consequently, lead to an improvement in patients’ psychological characteristics as no additional form of treatment was used in our study . It must be pointed out that the participants of our study were not patients with diagnosed depression or anxiety disorder. However, it may be expected that individuals suffering from chronic pain express depressive symptoms and more anxious behavior in comparison to pain-free individuals34 reported the successful use of stabilization splints in relieving clinical symptoms of TMD but found no effect on the markers of OS  in synovial fluid in a 3-month follow up period. A previous study of our research group39 demonstrated a significant reduction in afternoon TAC in TMD patients treated with occlusal splints after a 3-month follow up. In addition, a significant decrease in afternoon MDA and MDA/SOD ratio was found in the subgroup of patients with high pain intensity whose pain, expressed through VAS scores, decreased over time. In the present study, statistically insignificant differences between SS and PS group in the levels of all measured OS biomarkers at baseline (except for the afternoon MDA) remained such during the whole treatment period except for the afternoon MDA/SOD ratio that was significantly lower in the SS group at 3-month follow up. Within-group analyses showed a significant decrease in TAC and UA in the SS group. Our previous study on OS indicators in chronic TMD40 showed that TAC was significantly higher in TMD patients than in healthy controls. We suggested that higher TAC in patients with TMD pain lasting more than 6 months might imply a compensatory increase of the antioxidant enzymes in response to changing levels of OS as a prerequisite for efficient defense. Based on this explanation, and taken into account that, in the present study, a positive correlation was found between TAC decrease and a decrease in depressive symptoms scores in the SS group, a reduction in TAC levels in patients who used SS could be seen as an indicator of improvement.Studies assessing the influence of splint therapy for TMD on OS are scarce. Baş et al.The finding that both anxiety and depressive symptoms scores were negatively correlated with afternoon antioxidant levels (TAC and UA) at baseline could be considered as an expected finding. In light of this result, a positive correlation between TAC decrease and a decrease in depressive symptoms scores in the SS group seems difficult to explain. A possible explanation could be in the observed reduction in the MDA/SOD ratio indicating lower oxidative stress and a possible decrease in the activity of other substances that may cause oxidative damage but were not measured in our study. In this way, the reduction of TAC during the course of the therapy might reflect a changing balance between oxidative and antioxidative systems.39 found that higher TAC levels were related to higher pain intensity so the results of the correlation analyses in the present study could possibly be different if the patients had been stratified according to pain intensity.In this study, no association between OS markers and pain was found. Our previous studyThe present study has limitations. Regardless of power analysis, we consider that for research on such a delicate and variable matter as OS markers, a larger sample size would provide stronger evidence. The additional benefit in the interpretation of the results could have been achieved by including an additional control group that would receive no treatment. However, it seems unlikely that the participants would readily agree not to receive any help in dealing with their pain  for 6 months.The results of our study gave evidence that the SS provides some additional advantages over PS in the treatment of chronic TMD, especially in reducing symptoms of depression and improving pain-related disability. The efficacy of SS could be reflected in a significant decrease in oxidant/antioxidant ratio which was not present for PS. Furthermore, clinical success, in terms of reduction of depressive symptoms, which correlates with the reduction of oxidative stress markers in the SS group, indicates that oxidative stress might be related to psychological factors in TMD patients. If our results could be supported with randomized studies that are larger in the sample, the treatment for these common orofacial pain disorders could be understood better and, thus improved.


Evidence for the effectiveness of splinting in thumb carpometacarpal osteoarthritis is limited. We aimed to evaluate the effects of a prefabricated carpometacarpal metacarpophalangeal immobilization splint on pain, hand function, and hand strength in patients with early-stage thumb carpometacarpal osteoarthritis.Sixty-three hands with stage 1 or 2 thumb carpometacarpal osteoarthritis were enrolled in the study. The nonsplint group received oral information about how to accommodate daily activities. The splint group was given a prefabricated carpometacarpal metacarpophalangeal immobilization splint for 6 weeks. Pain was evaluated using the Australian/Canadian Osteoarthritis Hand Index (AUSCAN). Hand functions were evaluated using the AUSCAN and the Quick Disabilities of Arm, Shoulder and Hand (Q-DASH) questionnaire. Grip and pinch strengths were measured using a hydraulic dynamometer and a hydraulic pinch gauge.The AUSCAN pain, stiffness, function, total scores, and Q-DASH scores were significantly decreased in the splint group compared to the nonsplint group. Significant increments in grip and pinch strengths were detected in the splint group compared to the nonsplint group.The prefabricated carpometacarpal metacarpophalangeal immobilization splint is effective in improving pain, hand function, and hand strength in patients with thumb carpometacarpal osteoarthritis. Thumb carpometacarpal (CMC) joint osteoarthritis (OA) is the second most common hand OA. Patients with thumb CMC OA often present with pain, instability, and functional limitations. Pain and instability in the thumb may cause a reduction in the ability to perform activities of daily living such as grasping, pinching, and turning. The stability of the thumb CMC joint is essential to reduce pain and difficulty in daily living activities [1].Treatment of thumb CMC OA consists of conservative therapeutic interventions and surgical interventions. Conservative therapy includes joint protection principles, splinting, pain control, exercise, nonsteroidal antiinflammatory drugs, corticosteroid injections, and physical therapy. Splinting is the mainstay of conservative therapy. The aims of splinting are to improve the stability of the thumb CMC joint by providing external support, to increase hand function, and to reduce pain. Increased stabilization of the first CMC joint prevents dorsal subluxation and further joint deformity, provides pain control, and maintains hand function [1–5].The choice of splint design depends on which joint needs to be immobilized, the degree of OA, coexisting hand conditions, patient’s functional status, and patient preference . Static splints are the most commonly used splints in thumb CMC OA [1]. The types of static splints are the wrist-CMC-MCP  immobilization splint (long opponens splint), the CMC-MCP immobilization splint (short opponens splint), and the CMC immobilization splint [2].Evidence for the effectiveness of different types of splints in thumb CMC OA is limited [6–10]. The European League Against Rheumatism (EULAR) reported that placebo-controlled or nonsplint-controlled research evidence is required [11]. To our knowledge, there is only one randomized controlled trial with a nonsplint control in the literature. In this study, Rannou et al. studied the effects of a custom-made rigid CMC-MCP splint in patients with both early and advanced thumb CMC OA [10]. There is no study to assess the prefabricated CMC-MCP splint in the treatment of early-stage thumb CMC OA. The prefabricated CMC-MCP splint is readily available in varying sizes and more inexpensive than the custom-made CMC-MCP splint. Therefore, we aimed to evaluate the effects of a prefabricated CMC-MCP immobilization splint on pain, hand function, hand strength, and quality of life in patients with stage 1 or 2 thumb CMC OA.In previous studies, stabilization of the thumb CMC joint in palmar abduction and the MCP joint in flexion with the short opponens splint was recommended in both early and advanced stage thumb CMC OA [12–14]. According to these studies, we preferred the prefabricated CMC-MCP immobilization splint in patients with early-stage OA. This type of splint provides adequate support to the CMC and MCP joints while allowing functional use of the hand. In addition, the prefabricated CMC-MCP splint is readily available in varying sizes and is less expensive than custom-made splints. To our knowledge, there is no study to assess the prefabricated CMC-MCP splint in the treatment of early-stage thumb CMC OA. Therefore, we aimed to evaluate the effects of the prefabricated CMC-MCP immobilization splint on pain, hand function, hand strength, and quality of life in patients with stages 1 or 2 thumb CMC OA.Sixty-six patients with 80 hands affected with stage 1 or 2 thumb CMC OA who were admitted to an outpatient hand clinic between July 2017 and January 2018 were enrolled in the study. The diagnosis of thumb CMC OA was made by a hand surgeon based on history, physical examination, and X-ray. Patients with thumb CMC OA were staged according to the Eaton-Littler-Burton classification system based on radiographic findings. The exclusion criteria were: 1) prior treatment for thumb CMC OA within the previous 6 months; 2) posttraumatic OA; 3) previous hand surgery; 4) inflammatory hand involvement; 5) neurologic hand involvement; 6) clinical signs of carpal tunnel syndrome, Dupuytren’s contracture, de Quervain tenosynovitis, and trigger finger; 7) peripheral vascular disease; 8) cognitive dysfunction; 9) skin disease interfering with wearing a splint; 10) pregnancy.This study was performed with the approval of the local ethics committee in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and all subsequent revisions. All patients provided written informed consent to participate.Eighty hands were randomly assigned following a simple randomization procedure (computed random numbers) to a splint group (n = 40) and a nonsplint control group (n = 40). Seventeen hands were excluded from the study analysis. The remaining 63 hands were analysed. The flow chart of the study design is shown in Figure 1.The splint group was given a prefabricated splint program and oral information about how to accommodate activities of daily living  throughout the study period. A prefabricated CMC-MCP immobilization splint (short opponens splint) was recommended for the patients in the splint group. This splint was made from neoprene with a removable metal stay. The metal stay extended along the thumb to support the first CMC joint in 30° palmar abduction and the MCP joint in 15° flexion . We assessed the suitability of the splint before starting usage. The patients were instructed to wear their splints all the time (daytime and night-time) as much as possible for the first 3 weeks and then only during painful activities for another 3 weeks. A maximum of 1500 mg of paracetamol per day was allowed to be taken for pain throughout the study.The nonsplint control group received only oral information about how to accommodate activities of daily living throughout the study period. Paracetamol was allowed to be taken for pain throughout the study.The demographic and clinical characteristics of the patients at baseline were recorded. We used the Kapandji finger opposition test to assess the opposition of the thumb. The patients were instructed to touch the affected thumb to 10 points on the same hand.Wrist/hand pain and functions were evaluated using the Australian/Canadian Osteoarthritis Hand Index (AUSCAN). It is a self-report assessment of pain (5 items), stiffness (1 item), and hand function (9 items) in OA of the hand. Each item is scored on a 5-point scale  [15]. Higher scores indicate worse symptoms and function. The AUSCAN has been shown to be valid and reliable in measuring symptoms and hand function in hand OA [16].We also used the Quick Disabilities of Arm, Shoulder and Hand (Q-DASH) questionnaire to assess hand functions. It has 11 items and each item is scored from 1 to 5. Higher scores indicate lower functional levels. The validity and reliability of the Turkish version of the Q-DASH have been done by Düger et al. [17].Grip strength was measured using a Jamar hydraulic hand dynamometer. Lateral pinch, 2- point pinch, and 3-point pinch strengths were measured using a Jamar hydraulic pinch gauge . Patients were seated with shoulder adducted, elbow 90° flexed, forearm and wrist in neutral position. Patients were encouraged to press as firmly as possible. Three consecutive measurements were performed. The average of the three measurements was recorded in kilograms (kg) [18].Patients’ quality of life was measured using the Nottingham Health Profile (NHP). It is a self-report questionnaire with 6 dimensions of health: physical mobility (8 items), pain (8 items), sleep (8 items), energy (8 items), social isolation (5 items), and emotional reaction (9 items). Patients were asked whether or not each item applied to them. Positive answers were given the appropriate weight according to their relative severity. Each dimension score ranges from 0 to 100. Lower scores indicate better quality of life. The Turkish validity and reliability study of the scale was performed by Kucukdeveci et al. [19].All patients were asked to rate their overall satisfaction with the splint using a 10 cm visual analogue scale (VAS) at the end of the intervention.  The authors called the patients weekly to assess adherence to wearing the splint. Patients were evaluated before the intervention and at the end of 6 weeks. All assessments were performed by the same clinician who was blind to the treatment.The sample size was determined based on a previous study. To achieve a 2 cm reduction on a 10 cm VAS pain scale in the splint group, we calculated at least 23 patients per group using the 5% significance level and 80% statistical power [20]. The Kolmogorov–Smirnov test was used to evaluate the distribution of normality. We performed the unpaired t-test for normally distributed data and the Mann–Whitney U test for nonnormally distributed data to compare the demographic characteristics, baseline measurements, and change scores between the groups. We used the paired samples t-test for normally distributed data and the Wilcoxon sign rank test for nonnormally distributed data to compare the difference between the baseline and posttreatment values within the groups. The Pearson Chi-square test was used to analyse categorical data. SPSS version 17  was used for all statistical analyses. P values less than 0.05 were considered to represent a significant difference.There was no significant difference in baseline demographic and clinical characteristics of the patients between groups. The baseline demographic and clinical characteristics of the patients are shown in Table 1. A total of 11% of patients in the splint group and 14% of patients in the nonsplint group used paracetamol for pain relief throughout the study. There was no significant difference between the groups (P = 0.04).The AUSCAN pain, stiffness, function, and total scores were significantly decreased in the splint group at the end of the treatment (P < 0.05). In the nonsplint group, there were no statistically significant differences in the AUSCAN pain, stiffness, function, and total scores at the end of treatment. The Q-DASH scores were also decreased in the splint group after treatment (P < 0.05), whereas no significant changes occurred in the nonsplint group. We did not find a significant change in Kapandji scores of patients after treatment in both groups. The AUSCAN, Q-DASH, and Kapandji scores of the groups are shown in Table 2.In the splint group, we detected significant increments in grip strength, lateral pinch, 2-point pinch, and 3-point pinch strengths at the end of the treatment (P < 0.05). However, no significant increments in grip strength and pinch strength were detected in the nonsplint group after treatment. Grip strength and pinch strength of the groups are shown in Table 2.The NHP pain, energy level, emotional reaction, sleep, social isolation, physical mobility, and total scores of the splint group decreased significantly after the treatment (P < 0.05). Only the NHP total score decreased significantly in the nonsplint group after the treatment (P < 0.05). The change in NHP total score for the splint group was significantly better than that for the nonsplint group . The NHP scores of the groups are shown in Table 2.The mean satisfaction score of patients withsplint usage was 7.3 ± 1.7 (0–10 cm VAS).Scores greater than or equal to 5 were accepted as high satisfaction with the splint. According to this, 77% of the patients in the splint group had a high satisfaction level. A total of 23% of the patients in the splint group reported that the splint was uncomfortable and restricted their daily activities.Although different types of splints were evaluated in the previous studies, what is the optimal splint type in the treatment of thumb CMC OA is controversial . To the best of our knowledge, this is the first study to compare the effects of a prefabricated CMC-MCP immobilization splint for a duration of 6 weeks with no splinting in patients with early-stage thumb CMC OA. In the present study, we detected that the prefabricated CMC-MCP immobilization splint is an effective treatment intervention for improving pain, hand function, and quality of life in patients with early-stage thumb CMC OA.There is no evidence on which type of splint was more effective in pain relief and enhancing the function of the thumb CMC OA. Bongi et al. splinted 13 patients with thumb CMC OA in a custom-made short opponens splint for 1 month and detected significant pain relief at the end of the intervention [9]. Weiss at al. evaluated the effects of rigid custom-made CMC immobilization splint and prefabricated CMC-MCP immobilization splint in 25 hands with stage 1 or 2 thumb CMC OA. Both pain and function were improved more with the prefabricated CMC-MCP immobilization splint [7]. These findings are consistent with the results of the present study, in which the prefabricated CMC-MCP immobilization splint provided significant pain relief and functional improvement compared with no splint. On the contrary, Sillem et al. showed that custom-made CMC immobilization splint was significantly better than prefabricated CMC-MCP immobilization splint to reduce pain. They showed no improvement in hand function after wearing the splints for 4 weeks [3]. Rannou et al. found no significant differences in pain and disability between the custom-made rigid CMC-MCP immobilization splint group and the nonsplint group at 4 weeks [10]. The different results were attributed to the differences in sample size, splint materials, splint wearing schedule, stage of thumb CMC OA, and measured variables.The evidence regarding the use of splinting to improve hand strength is insufficient . We found significant increments in grip strength, lateral pinch strength, 2-point pinch strength, and 3-point pinch strength in the splint group compared to the nonsplint group at the end of the sixth week. We believe the increase in grip and pinch strengths observed in the splint group was due to a reduction in pain and an improvement in thumb CMC joint stabilization. Our results differ from the previous studies in regard to the effect of splinting on the grip and pinch strengths. Weiss et al. found that both custom-made CMC immobilization and prefabricated CMC-MCP immobilization splints did not significantly alter the pinch strengths as compared with pretreatment values [7]. Sillem et al. reported no improvement in grip and pinch strengths after wearing the prefabricated CMC-MCP immobilization splint in patients with thumb CMC OA [3]. Rannou et al. did not detect a significant difference in pinch strength between the custom-made rigid CMC-MCP immobilization splint group and the nonsplint group [10]. It was difficult to compare the results of previous studies with the present study because of differences in study samples, splint materials, and duration of splint use.Besides pain, physical function, and strength, it is also important to assess the quality of life of the patients with hand and thumb OA. Hand and thumb OA has a high impact on the quality of life of patients [21]. To our knowledge, there is no study in the literature to evaluate the effects of splinting on the quality of life of patients with thumb CMC OA. We assessed the effects of splinting on the quality of life of patients using NHP and detected that splinting is effective in improving the quality of life of patients due to pain relief and increased hand function.In the present study, the patients rated their splint satisfaction using a 10-cm VAS. The mean satisfaction score of the patients was 7.3. When a score of 5.0 or more was accepted as high satisfaction, 77% of patients had high satisfaction with the prefabricated CMC-MCP immobilization splint. Seventy-seven percent of patients reported that daily activities were easier to perform while wearing the splint, whereas 23% of patients reported difficulty in performing daily activities. This result is in line with those reported by other studies . Weiss et al. reported that three-quarters of patients with thumb CMC OA preferred the prefabricated CMC-MCP immobilization splint [7]. In another study, 63% of patients preferred the prefabricated CMC-MCP immobilization splint to the custom-made CMC immobilization splint due to its comfortable usage [3].The information about wearing splint schedules for thumb CMC OA in the literature is contradictory . Swigart et al. offered to wear the splint continuously for 3 weeks and then only during the heaviest activities for 3 weeks [8]. Bongi et al. instructed to wear the splint for 5–6 h per day and at night during 4 weeks, then during heavy activities only [9]. Glickel recommended the splint only during the day for pain relief [13]. In the present study, patients were instructed to wear the splint all the time as much as possible during the first 3 weeks for immediate reduction of pain. After this period, the splint was recommended only during activities of daily living that cause pain to support the hand functions and to reduce pain. We found that splinting is a well-tolerated conservative treatment in patients with thumb CMC OA.The study has some limitations. First, the follow-up time of the study (6 weeks) was short. Longer-term follow-up of patients after the end of the scheduled treatment period will provide more important information on the persistent effects. Second, we did not evaluate the effects of another type of splint in patients with thumb CMC OA. A comparison of the effects of different types of splints with no splinting will provide a more valuable contribution to the literature.In conclusion, we evaluated the effects of a prefabricated CMC-MCP immobilization splint in patients with thumb CMC OA. We detected that this type of splint is effective in improving pain, hand function, grip strength, pinch strength, and quality of life at the end of a 6-week usage period. Future randomized controlled studies with larger sample sizes and longer follow-up periods are needed to confirm the effects of splinting in the treatment of thumb CMC OA.The study protocol received institutional review board approval. All participants provided informed consent in the format required by the relevant authorities.


The medical community is beginning to recognize the contribution of prescription opioids in the growing national opioid crisis. Many studies have compared the safety and efficacy of alternative analgesics to opioids, but none utilizing a completely opioid-free perioperative protocol in orthopedics.We developed and tested an opioid-free perioperative analgesic pathway (from preoperative to postoperative period) among patients undergoing common elective orthopedic procedures. Patients will be randomized to receive either traditional opioid-including or completely opioid-free perioperative medications. This study is being conducted across multiple orthopedic subspecialties in patients undergoing the following common elective orthopedic procedures: single-level or two-level ACDF/ACDA, 1st CMC arthroplasty, Hallux Valgus/Rigidus corrections, diagnostic knee arthroscopies, total hip arthroplasty (THA), and total shoulder arthroplasty/reverse total shoulder arthroplasty (TSA/RTSA). The primary outcome measure is pain score at 24 h postoperatively. Secondary outcome measures include pain scores at additional time points, medication side effects, and several patient-reported variables such as patient satisfaction, quality of life, and functional status.We describe the methods for a feasibility randomized controlled trial comparing opioid-free perioperative analgesics to traditional opioid-including protocols. We present this study so that it may be replicated and incorporated into future studies at other institutions, as well as disseminated to additional orthopedic and/or non-orthopedic surgical procedures. The ultimate goal of presenting this protocol is to aid recent efforts in reducing the impact of prescription opioids on the national opioid crisis.clinicaltrials.gov (Identifier: NCT04176783) on November 25, 2019, retrospectively registeredThe protocol was approved by the local institutional review board and registered with  Opioids have long been used in various forms for pain control in the medical field. While there is demonstrated analgesic effect of these compounds , they arThe existing literature on opioid prescribing for musculoskeletal conditions has consistently demonstrated frequent over-prescribing, leading to unused pills available for nonmedical use or diversion –12. ThesThis decrease in prescription-opioid death rates can largely be attributed to widespread efforts to reduce provider reliance on opioids. The scientific community now has an improved understanding of the risks and benefits of various forms of pain medication. Efforts have been made to identify synergistic compounds to use for acute pain management in the perioperative time period, all of which report some degree of opioid-sparing effects. These studies have focused on the safety and efficacy of gabapentinoids –16, locaThe most robust adjuvant effects have been reported with NSAIDs and acetaminophen. Some studies indicate that there may be a synergistic effect between these two to reduce postoperative opioid intake : oxycodoAt this time, no study has examined the possibility of utilizing a multi-modal perioperative analgesic pathway that does not include some form of opioid medication in orthopedic patients. We report an ongoing feasibility randomized controlled trial (RCT) designed with the objective to investigate the safety and efficacy of opioid-free pain management in elective orthopedic procedures and determine if opioid-based analgesia is needed in orthopedic surgery. This is, to our knowledge, the first investigation of its kind. Patients in the opioid-free analgesia arm did not receive any opioid medications in the pre-, intra-, and postoperative phases through the time they followed up in clinic . This article describes our opioid-free clinical pathway in detail with review of the existing literature to justify each component. The ultimate goal is that this protocol may be replicated for future studies and potentially incorporated into a perioperative clinical pathway. Should this study demonstrate equivalent efficacy of opioid-free and opioid-based analgesic protocols, then its findings may also help reduce the amount of prescribed opioid medications for patients undergoing elective orthopedic surgery.clinicaltrials.gov , retrospectively registered . Figure This parallel group RCT was performed at a single institution, which is a large private orthopedic practice with an affiliated research institute, across 6 subspecialties . Specifically, surgeons from this one practice enrolled their patients; patients had surgery across six facilities that were either hospital-affiliated or private ambulatory surgery centers . The study also included an observational arm for those patients who did not wish to be randomized. The protocol was approved by the local institutional review board and registered with A draft medication protocol was developed for each subspecialty, covering preoperative, intraoperative, post-anesthesia care unit (PACU), postoperative, and discharge settings based on the literature. A steering committee consisting of physicians, anesthesiologists, nurses, and the research team was created to develop these protocols. Specifically, one orthopaedic surgeon was included from each of the following subspecialties: Shoulder & Elbow, Spine, Foot & Ankle, Hand, Sports, and Hip & Knee. One orthopaedic surgery resident was included. Finally, four anesthesiologists to represent both hospital systems were on the steering committee. These steering committee members are experts in their respective fields and utilized existing literature (summarized in the background section) to inform the inclusion of various non-opioid analgesics in the protocols. Pilot testing was performed on a group of shoulder arthroplasty patients (data published previously in a case series ). The fiPatients were randomized to one of two arms. The treatment group included treatment without the use of opioids. The control group included a traditional opioid-based pain protocol, agreed upon by the treating surgeons. The observational group consisted of patients who were eligible for the study but were not willing to be randomized to a postoperative pain management pathway. They were treated based on patient/surgeon preference and included in an associated cohort study.> 18 undergoing the following routine elective orthopedic surgical procedures: single-level or two-level Anterior cervical discectomy and fusion/Anterior cervical disc arthroplasty (ACDF/ACDA), 1st carpometacarpal (CMC) arthroplasty, Hallux Valgus/Rigidus corrections, diagnostic knee arthroscopies, total hip arthroplasty (THA), and total shoulder arthroplasty/reverse total shoulder arthroplasty (TSA/RTSA). Eligible patients who provided informed consent were randomized to one of the two study arms. Outcomes were assessed at multiple time points – 6, 12, and 24 h postoperatively, then 2 weeks, 6 weeks, and 1 year postoperatively.The study population consisted of patients aged A key element of the clinical protocol was providing physicians and clinical/research staff with education on opioid medications and their role in perioperative pain-relief. Studies have identified knowledge gaps in providers managing chronic  and acutEligibility was determined based on the inclusion and exclusion criteria listed in Table Participants underwent an initial screening visit that included a series of questionnaires (dependent upon the type of surgery being performed) and physical exam. The questionnaires, described in the outcomes section below, asked about level of pain, function, and satisfaction with pain control. The exam included an assessment of range of motion, when applicable. All patients were asked to complete a Resilience Questionnaire  at thisAll patients underwent a blood draw (5 ml) to confirm eligibility based on creatinine clearance (CrCl), which was calculated with the Cockcroft-Gault Formula. Patients with a CrCl < 30 mL/min were excluded from the study. Patients with CrCl between 30 and 60 mL/min received a half-dose of NSAIDs if enrolled in the intervention arm of the study. Patients with reported liver disease received a second blood draw to evaluate hepatic liver enzymes and ensure safe dosing of acetaminophen.Patients were randomized in a 1:1 fashion to one of the treatment groups – Control (with opioids) or Intervention (opioid-free). Randomization occurred within 1 week prior to surgery and was performed with a random number generator in REDCap by research staff . This raOnce randomized to an arm, the treating team of surgeon, anesthesiologist, and clinical staff were notified of the result. There was no blinding involved in this study. Patients were identified as being a part of the study, and the corresponding treatment arm was listed in their hospital chart. Reminders of each patient’s treatment designation were provided to the anesthesiology team in the preoperative holding area on the day of surgery.Estimated sample size was calculated using data from a previous study comparing the pain numeric rating scale (NRS) at 24 h between patients receiving opioid medications or not . This waPatients in the opioid-free treatment arm did not receive any opioid medications from the preoperative period to the postoperative period. The control arm included traditional opioid-based analgesia. Medications in the treatment arm were selected based on findings from current literature on opioid-alternatives. Medications in the control arm were included as usual perioperative analgesic options. Some variations to the treatment pathways existed by procedure type. Tables We employed several strategies to improve adherence to study protocols. First, we took measures to ensure that medical staff were clearly aware of which study arm each patient was enrolled in. The treating surgeon and key staff contacts at the surgery location’s preoperative, anesthesia, post anesthesia care, and postoperative units received an email notification with the patient’s assigned study arm at the time of randomization (1 week prior to surgery) and 2 days prior to the surgery. This email also contained a reminder of the medication protocol specific to that case. A notification sheet and copy of the medication protocol was placed on the front of the patients’ hospital charts along with an opioid-free wristband if the patient was randomized into the opioid-free arm of the study. Secondly, all patients received a diary after their surgery to record medication usage in the first 2 weeks of the postoperative period. This diary helped monitor protocol adherence, at least in self-reported form.Importantly, patients and care team members were also free to communicate with the treating physician any levels of discomfort found to be unsatisfactory to the patient. If a patient had exhausted all options in the opioid-free pathway, they were given the option to receive opioids. Upon discharge, patients were given instructions to contact their physician for unacceptable levels of pain to receive an outpatient prescription of an opioid. However, no “rescue” or “just in case” prescriptions were given to patients upon discharge to avoid prescription diversion and unnecessary home stores of opioids. Additionally, if a patient deviated from the medication protocol assigned to them, they were not considered study failures. Instead, we continued to follow the patient through study completion and continued to track patient-reported outcomes and total opioid consumption.A full list of assessments obtained at each time point is summarized in Table We obtained baseline assessments during each patient’s screening visit. These measures included, but were not limited to, demographics, comorbidities, subjective pain ratings, constipation ratings, patient reported outcomes specific to the planned procedure, and resilience ratings.Initial follow-up assessments were obtained at 6, 12, and 24 h after surgery. Patients were asked to return for postoperative follow-up visits at 2 weeks, 6 weeks, and 1 year after surgery. These visits were scheduled to be at routine visits that were already a part of our investigators’ standard-of-care treatment time tables. Patients that were unable to attend any in-person visit were asked to completed all study patient-reported outcomes via phone call or REDCap electronic survey for that visit to facilitate retention and optimal follow-up. Pain level, medication usage, constipation level, complications, and patient reported outcomes were gathered during these visits.Each patient received a diary upon hospital discharge to record their pain levels, overall comfort/satisfaction levels, and medication usage. Patients who underwent ACDF/ACDA surgery were also asked to record their compliance with soft collar equipment. Information from the diaries was collected at the 2-week postoperative visit.The primary outcome measure was pain at 24-h postoperatively. If the patient was in-hospital, the pain rating was obtained by the nurse. If the patient had been discharged, they were called by research staff to obtain a pain rating. This outcome was measured on a 0-10 NRS, a reliable and valid measure of present-moment subjective pain .Secondary outcomes of interest included pain ratings (NRS) at the additional time points noted previously as well as other clinical and patient-reported variables.Basic clinical information was collected at time of surgery or hospitalization, including length of hospital stay, intraoperative complications, and length of surgery. Morphine milli-equivalents were recorded in-hospital, and post-operative opioid use was recorded after discharge. Medication side effects were recorded as episodes of delirium, number of falls, and patient reported nausea/constipation.Several patient-reported variables were collected throughout the duration of the study and included nausea/constipation, satisfaction with pain control and surgical experience, quality of life, resilience, and functional status specific to the surgery performed. Functional outcomes were assessed with validated, standardized questionnaires , BMI, alcohol or other non-prescribed medication use to help with comfort, tobacco use, and tourniquet time (when applicable). Basic demographic information was also noted.http://project-redcap.org/) [Data were collected by research staff and entered into REDCap (ap.org/)  on at leStudy information is de-identified by removing PHI and using coded subject identifiers. Study data is kept in locked cabinets/rooms only accessible by research staff. Electronic data is kept in an access-privileged, password-protected, encrypted database.Adverse events were collected as part of the surgical and follow-up source documents. They were collected via patient reporting, questionnaires, and chart review. Serious Adverse Events that were “related,” “probably related” or had an “unknown” relatedness to the study procedure were reported via secure email to the data safety monitoring board as they occurred. These occurrences were reviewed every other month or as needed by the data safety monitoring board, which is made up of members of the OrthoCarolina Research Institute (OCRI) Research Advisory Committee. At each meeting, the study was reviewed for adverse events, serious adverse events, and overall feasibility issues. Additionally, the board conducted internal audits for this clinical trial. Initial auditing occurred after surgery and data collection had been completed for one patient in each study group per subspecialty. After that point, auditing has occurred on an as-needed basis with an internal audit happening at least once per year.The primary outcome of pain at 24-h postoperatively will be assessed for normality using visualization methods, including QQ plots as well as statistical analysis tests including Shapiro-Wilk. If these data are normally distributed, an independent t-test will be used to compare pain at 24-h postoperatively. If these data are non-normal, a Mann-Whitney U test will be used to compare pain at 24-h postoperatively between treatment groups.Normality testing as previously described will be evaluated for all continuous secondary outcomes including pain at additional postoperative time points, length of stay, morphine milliequivalents, satisfaction, and scores from patient reported outcome measures. The appropriate statistical test, either independent t-tests or Mann-Whitney U tests, will be used to compare these outcomes between treatment groups. Categorical outcomes such as intraoperative complications, medication side-effects, and other postoperative complications, will be compared between treatment groups using a Chi-Square of Fishers Exact test.Statistical associations between covariates and outcomes will be evaluated using the appropriate statistical methodology as previously described. Multivariable linear regression models will be appropriately fitted to continuous data based on the distributions of that data. Multiple logistic regression models will be fitted for all dichotomous outcome variables. Appropriate variable selection methods and model fit statistics will be used to determine the best fitting model to determine the effects of the treatment after adjusting for significant effects of covariates.Finally, a per protocol analysis is planned. There is no plan to impute missing data and all statistical analyses will be conducted with the available data. We also plan to include sub-group analyses for the individual subspecialties.clinicaltrials.gov, then the study’s registration on clinicaltrials.gov was updated accordingly.Any protocol amendments were first submitted to the Institutional Review Boards. Upon their approval, the new protocols were disseminated to all research staff  via email with a summary of all changes. If the amendment required additional training for study procedures, training was conducted with the applicable study staff. If the amendment changed anything about what is reported on In the event that a subject was harmed as a result of their participation in this study, the clinical team provided or arranged for treatment as necessary. This treatment, as well as other medical expenses, were billed to the subject or the subject’s insurance company in the usual manner. Subjects did not waive any legal rights by signing the informed consent form for this study.clinicaltrials.gov as is required upon study completion. Final study results will be published in a peer-reviewed, PubMed-indexed journal to reach healthcare professionals. The authors will also seek to present the study findings at relevant orthopaedic subspecialty society meetings. A website exists on the OrthoCarolina Research Institute website describing this project. Final findings and results will be published on this website for the general public, as well as disseminated through the OCRI social networking channels.Once the study has entered the data reporting phase, the datasets used and/or analysed during the current study will be available from the corresponding author on reasonable request. The protocol and results will be released onto This study is, to our knowledge, the first to evaluate the safety and efficacy of utilizing a completely opioid-free perioperative analgesia protocol. Studies to date have combined opioid and non-opioid medications or pharmacologic alternatives in the same protocol. This study will be the first to try and distinguish the analgesic effects of opioid-including and opioid-free pain regimens. A particularly novel element of this protocol is the elimination of opioids during the surgical procedure. It is unknown what effect opioid administration during anesthesia has on patients with regards to known opioid-related side effects including post-operative delirium, nausea, and constipation. An early case-series study offers encouraging results. Leas et al. (2019)  reportedAnother strength of the present study is the randomized study design, which limits error and bias in the results. Conclusions gained from the RCT are also potentially bolstered by the addition of the prospective observational arm. Finally, the results from this study are generalizable, as we enrolled patients from multiple orthopedic subspecialties, allowing us to draw conclusions that may impact orthopedic surgery as a whole.The major limitation of this study is the inclusion of a select few orthopedic procedures. All surgeries were relatively straightforward (i.e. no revision surgeries) and commonly performed procedures. Patients who are optimal candidates for these elective surgeries may be healthier, less likely to experience post-operative complications, and/or more likely to be opioid-naïve than other orthopedic populations (e.g. trauma or oncology patients). Complicated procedures may also inherently be experienced as more painful. The orthopedic community will need to establish the efficacy of opioid-free multi-modal analgesic protocols in a broader range of patients and procedures, including complex operations and patients with significant medical comorbidities.We recognize that there are some substantial barriers to establishing completely opioid-free analgesic pathways in practice. When pain was introduced as the fifth vital sign in the 1990s, a cascade of events commenced that resulted in unintended consequences of overzealous treatment of pain. Clinicians started relying on opioid medication to eliminate patients’ pain, and public misconceptions about the efficacy of opioids for treating pain grew , 53. ParFinally, our immediate future plan is to complete enrollment for this present study. Once this single-institution investigation is complete, we will analyze our results. Provided this study demonstrates safety and efficacy, we will launch a population health study with protocol implementation across a large, state-wide healthcare system.We describe the detailed protocols used in the first multi-specialty orthopedic RCT comparing totally opioid-free perioperative pain management to traditional analgesic pathways. This represents an initial step towards demonstrating that non-opioid multimodal protocols can provide a safe and predictable pathway for patients undergoing elective surgery. Our goal in reporting these pathways is so that they may be implemented at other institutions and utilized in the nationwide fight against the opioid epidemic.