Chronic pain is common in multimorbid patients. However, little is known about the implications of chronic pain and analgesic treatment on multimorbid patients. This study aimed to assess chronic pain therapy with regard to the interaction potential in a sample of inpatients with multiple chronic conditions.We conducted a retrospective study with all multimorbid inpatients aged ≥18 years admitted to the Department of Internal Medicine of University Hospital Zurich in 2011 . Data were extracted from the electronic health records and reviewed. We identified 433 hospitalizations of patients with chronic pain and analyzed their combinations of chronic conditions (multimorbidity). We then classified all analgesic prescriptions according to the World Health Organization (WHO) analgesic ladder. Furthermore, we used a Swiss drug-drug interactions knowledge base to identify potential interactions between opioids and other drug classes, in particular coanalgesics and other concomitant drugs. Chronic pain was present in 38% of patients with multimorbidity. On average, patients with chronic pain were aged 65.7 years and had a mean number of 6.6 diagnoses. Hypertension was the most common chronic condition. Chronic back pain was the most common painful condition. Almost 90% of patients were exposed to polypharmacotherapy. Of the chronic pain patients, 71.1% received opioids for moderate to severe pain, 43.4% received coanalgesics. We identified 3,186 potential drug-drug interactions, with 17% classified between analgesics .Analgesic drugs-related DDIs, in particular opioids, in multimorbid patients are often complex and difficult to assess by using DDI knowledge bases alone. Drug-multimorbidity interactions are not sufficiently investigated and understood. Today, the scientific literature is scarce for chronic pain in combination with multiple coexisting medical conditions and medication regimens. Our work may provide useful information to enable further investigations in multimorbidity research within the scope of potential interactions and chronic pain. Pain is a medical condition listed among the most common diseases worldwide. The most common causes of chronic pain relate to musculoskeletal disorders . PrevaleThe WHO scheme also introduced the term “adjuvant drugs”; originally, a small number of drugs  was described as adjuvants, to enhance the analgesic “three-step” sequence from non-opioids, to weak opioids, and finally to strong opioids . Later, Today, adjuvant or coanalgesic drugs have become established in the treatment of cancer pain and non-cancer pain. As a consequence, the broad range of alternative analgesic strategies increases the risk of polypharmacotherapy. From this perspective, chronic pain therapy in patients with multiple chronic conditions can be challenging . Little The primary aim of this study was to assess drugs used to treat pain in multimorbid patients at a tertiary teaching hospital. The secondary aim was to examine the potential of DDIs by using an electronic DDI knowledge base.We undertook the following steps:We explored the current literature on common chronic conditions and their potential to modify chronic pain.We identified and characterized the target population from patients’ electronic medical chart reviews;We examined and described analgesic prescriptions corresponding to the WHO analgesic pain ladder;We examined and described coanalgesic and concomitant drugs of the target population;We reviewed the potential for DDIs; andThe University Hospital Zurich is a tertiary teaching hospital with 850 beds and about 38,000 inpatient admissions per year. We used a retrospective data set of all multimorbid inpatients admitted to the Department of Internal Medicine in 2011 . We included all adult inpatients discharged between January 1 and December 31, 2011, aged 18 years and older, and with more than one chronic medical condition. Patients in a methadone program, pregnant women, and palliative care patients were excluded. This study was conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines .www.microsoft.com): date of admission, gender, age (years), length of hospital stay (days), all chronic pain diagnoses, all diagnoses of other chronic conditions, and all medications prescribed during hospitalization. Two physicians reviewed each case with regard to the inclusion and exclusion criteria and completed a list of diagnoses, using the patient’s care and discharge report. Patients were categorized as ‘with’ or ‘without’ a painful chronic condition. The diagnoses identified were marked as active if the painful condition required the prescription of analgesics during the patient’s hospital stay. In addition, all analgesic prescriptions were assessed in accordance with the WHO analgesic ladder approach [Data were extracted from the hospital’s electronic health records by the hospital’s Research Center for Medical Informatics. The following variables were extracted and transferred to a spreadsheet , The knowledge base is used at the University Hospital Zurich (at present hospINDEX 2016–05). This knMultimorbidity was defined as the co-occurrence of two or more chronic medical conditions , 22. ChrThe International Association for the Study of Pain defined chronic pain as “pain that persists beyond the normal time of healing” . We defiThe terms ‘adjuvant drugs,’ ‘adjuvants,’ ‘adjuvant analgesics’ –26, ‘coaPatients’ pain medications were specified by trade name, using the Anatomical Therapeutic Chemical Classification System code; the duration (in days) of the prescription was also determined. Analgesic prescriptions were assigned to the steps of the WHO analgesic ladder : non-opiwww.stata.com). Continuous data were presented as means with standard deviations, categorical data as counts and proportions. We used t-tests to compare continuous data and chi square tests to compare categorical data. The significance level was set at 0.05.For the statistical analyses, we used Stata® statistical software . On average, these patients were 66 years old, with no significant difference in age between multimorbid patients with and without chronic pain . When only patients with chronic pain diagnoses were considered , the mosOf all patients with CP, 60% had one, 27% had two, and 13% had three or more pain diagnoses, respectively. The most common chronic pain diagnosis was chronic back pain 38.6%; , followeThe most frequent mode of prescription in terms of assignment to the WHO analgesic ladder was a combination of step I analgesics (non-opioids) with step III analgesics (strong opioids) in 35% of all CP hospitalizations with no step II analgesics (weak opioids). The second most frequent mode was a prescription of step I analgesics only (29%), followed by (third) concurrent prescription of all three steps (19%). Step I analgesics were prescribed to 98.6% of all inpatients with CP, with paracetamol (acetaminophen) or metamizole (novaminsulfone) the most often prescribed . In totaOverall, 43.4% (188) of all patients with chronic pain received drugs prescribed as coanalgesics. In addition, quite a number of these patients received drugs that were not primarily prescribed as analgesics but that have analgesic properties in some painful conditions (concomitant drugs) .Antidepressants were assigned to both categories . Potentially, antidepressants could be considered for the treatment of chronic pain and for the treatment of depressive disorders (66 cases). Alpha-2 adrenergic agonists, antidepressants, and corticosteroids have been categorized as multipurpose analgesics (multipurpose drugs have a various range of indications). Almost all patients received laxatives and antiemetic drugs. Most laxative agents were those that predominantly soften the stool (liquid paraffin). In addition to prokinetic agents/anti-emetics (domperidone and metoclopramide), other drugs ‒for example, corticosteroids ‒may enhance an antiemetic strategy. Pregabalin has been identified as a coanalgesic in the management of neuropathic pain (32 cases). All other antiepileptic drugs should be considered in patients with epilepsy or pain relief.ified most potential interactions with opioids in our inpatients as severity level 3 (“monitoring or adaption required”); the only exception were the DDIs between buprenorphine and opioid agonists, as severity level 2 (“contraindicated as a precaution”) (With an average mean of 10.4 medications (SD = 4.9) prescribed per inpatient hospitalization with chronic pain, the amount of polypharmacotherapy (five or more drugs) was high, at 89% of all cases. We identified 3,186 potential DDIs (overlapping drug orders of drug pairs listed as interacting in the drug-drug interaction knowledge base), with 551 (17%) potential interactions between analgesics ; 175 (5.5%) were with opioids. None of the interactions were classified as severity level 1 interactions (“contraindicated”). The DDIs knowledge base classaution”) . In a laThis study provides a general overview of the most common chronic pain diagnoses and combinations of chronic diseases (triplets) and the prescribed medications, respectively, in the multimorbid population under study. We discuss possible consequences of these data in regard to the impact of pain treatment on different multiple disease combinations found and vice versa. Furthermore, we discuss potential DDIs related to pain treatment with a focus on opioids and some selected coanalgesic or concomitant drugs.ified most DDIs for these multimorbid patients with CP as severity level 3 (“monitoring or adaption required”).In our study, 38% of all multimorbid inpatients had chronic pain. On average, these CP patients were 65.7 years old, had 6.6 chronic diagnoses, and were exposed to a high degree of polypharmacotherapy (10.4 drugs). The most common chronic pain diagnoses were musculoskeletal diseases see . The mosAccording to the WHO analgesic ladder, non-opioids should be combined with opioids, but opioids should not necessarily be combined with other opioids. Some experts , 33 haveTramadol in combination with other analgesics  was one of the most frequently prescribed analgesics. Tramadol has a specific dual mode of action relating to its affinities to the opioid receptors  and/or the inhibition of the uptake of noradrenaline and serotonin . AccordiThe common use of NSAIDs has been identified as critical, especially in terms of adverse drug events in elderly patients , 39. NSATo date, the potential interaction risk of metamizole has not been sufficiently addressed in research . The samHypericum perforatum extracts are usually not considered to be of clinical relevance as inducers [In our study, 17% of total potential DDIs were identified as DDIs with analgesic prescriptions by galdat/hospINDEX®. In particular, this knowledge base put the main focus on drugs involved in the opioid-cytochrome P450 isoenzymes metabolism and multiple drug transporters . These well-known DDIs are classified as inhibitors, inducers, or substrate accordingly . Still, for the use of the knowledge base a daily review of current medications is recommended , as well as an individual risk assessment to enhance patient safety. However, the risk of interactions and adverse events may increase with every additional medical condition and every additional drug prescribed (polypharmacotherapy) , 49. TabPain management is usually multimodal and in the first instance aims at reducing pain sufficiently and quickly. Beyond the desired effects of opioids, exogenous opioids can affect a number of the body’s own regulation systems, especially cardiac and vascular regulation .Intensified research is needed on relevant interactions in clinical practice , which simultaneously includes multimorbid patients with polypharmacotherapy receiving analgesics, coanalgesics, and a substantial number of concomitant drugs. Research of this kind is scarce, and precise data on the interplay of interactions and polypharmacotherapy  are lacking. Furthermore, it is unclear how the interaction potential changes in the case of polypharmacotherapy and a reduction of drugs (deprescribing) . A greatThe implementation of a comprehensive tool for the assessment of potential DDIs and drug-disease interactions in multimorbidity, with a multimorbidity score to estimate the severity of potential interactions, is probably essential for well-structured, evidence-based clinical decision making. More research is needed to gain insights into harmful and beneficial effects of various interactions. In the context of this study, future research could shed light on the (positive and negative) effects of pain management on the body’s regulation systems—for example, in terms of possible drug-endogenous opioid activity interactions . Critically, the present findings indicate that multimorbidity is insufficiently well-managed by exclusively considering and treating the individual diseases of a patient with multiple chronic conditions. The potential interactions  have yet to be investigated.Our study provides the basis for a deeper understanding of important interaction potential of patients with chronic pain. As a next step, frequent disease- and drug-combinations in multimorbidity should be investigated in pragmatic clinical trials.Our study has several limitations. First, we examined a highly specific study population at a tertiary hospital. Our results are based on a retrospective medical chart review; with potential underreporting. Second, owing to the retrospective study design, chronic pain diagnoses had to be taken from medical health records without accompanying self-reports from patients—for example, by using the Visual Analog Scale for Pain , 61. ThiOur study explored retrospective data of multimorbid patients with chronic pain at a tertiary teaching hospital. To our knowledge this is the first study examining complex treatment situations in multimorbid patients with chronic pain. The following conclusions can be drawn:Analgesics and analgesia-related drugs are often prescribed in combination with a large variety of other drugs, accompanied by a great potential of risks for multimorbid patients. Analgesic-related DDIs, in particular opioids, in multimorbid patients are often complex and difficult to assess by using DDI knowledge bases alone. Drug-multimorbidity interactions are not sufficiently investigated and understood. Currently, the scientific literature is scarce for chronic pain in combination with multiple coexisting medical conditions and medication regimens. Our work may provide useful information to enable further investigations in multimorbidity research within the scope of potential interactions and chronic pain.


For patients with chronic pain, the heterogeneity of clinical presentations makes it difficult to identify patients who would benefit from multimodal rehabilitation programs (MMRP). Yet, there is limited knowledge regarding the predictors of MMRP’s outcomes. This study identifies predictors of outcome of MMRPs at a 12-month follow-up (FU-12) based on data from the Swedish Quality Registry for Pain Rehabilitation (SQRP).n = 227). During the FU-12, the patients also retrospectively reported their global impressions of any changes in their perception of pain and their ability to handle their life situation in general.Patients with chronic pain from two clinical departments in Sweden completed the SQRP questionnaires—background, pain characteristics, psychological symptoms, function, activity/participation, health and quality of life—on three occasions: 1) during their first visit; 2) immediately after the completion of their MMRP; and 3) 12 months after completing the MMRP . At the FU-12, 53.6% of the patients reported that their pain had decreased and 80.1% reported that their life situation in general had improved. These improvements were associated with high education, low pain intensity, high health level, and work importance (only pain perception). The explained variations were low (9–11%).Representing patients in real-world clinical settings, this study confirmed systematic reviews that outcomes of MMRP are associated with broad positive effects. A mix of background and baseline variables influenced the outcomes investigated, but the explained variations in outcomes were low. There is still a need to develop standardized and relatively simple outcomes that can be used to evaluate MMRP in trials, in clinical evaluations at group level, and for individual patients.The online version of this article (doi:10.1186/s12891-016-1346-7) contains supplementary material, which is available to authorized users. Patientnic pain . Accordinic pain . The fivAcute and chronic pain are influenced by and interact with physical, psychological, social, and contextual factors –10, thuspractice based evidence (PBE)—is based on prospective observational cohort study designs and has also been applied in rehabilitation research [MMRPs represent important evidence-based progress in treatment for patients with chronic pain –21. Althresearch .Patients with chronic pain exhibit heterogeneous clinical presentations and the question arises if certain patient characteristics are indicative of outcomes after MMRP. Answering these questions are important as MMRPs are time consuming and expensive even when most of the activities for the patients are group based. Little is known about outcome predictors of MMRPs , 25–30. www.ucr.uu.se/nrs/) for two multidisciplinary pain centres in Sweden. Six outcome domains were identified  mainly according to the recommendations of the IMMPACT-group [This PBE study identifies predictors of outcome of MMRPs for patients with chronic pain based on data from the Swedish Quality Registry for Pain Rehabilitation (SQRP) .This study collected data using the SQRP on 464 patients between 18 and 65 years old who had chronic mainly musculoskeletal pain. These patients were referred to the Pain and Rehabilitation Centre at University Hospital of Linköping or the Pain Rehabilitation Clinic at University Hospital of Umeå between 2008 and 2012. In total, 464 patients with chronic pain were referred to these two facilities to participate in a MMRP. The present study is primarily based on patients who answered the SQRP both at baseline (before the MMRP) and at the 12-month follow-up  they were accepted to participate in the program. The MMRP was conducted in groups of six to nine participants and was based on CBT principles and included physiotherapy, ergonomics, training in coping strategies, and education in pain management. The patients were encouraged to take an active part in goal setting. At the Linköping site, medical assessments were performed by senior physicians, primarily from specialists in rehabilitation medicine or similar specialities, or by specialists in training under the supervision of a senior colleague. The majority of the participants were also assessed by a psychologist, an occupational therapist, and a physiotherapist. The Linköping program followed the same main principles as the Umeå program—group treatment from a CBT perspective, group physiotherapy, interventions targeting improved ergonomics, and occupational therapy. At both sites the MMRPs lasted between 6 and 8 weeks for at least 20 h per week of group-based activities. In addition, lectures in basic pain science and pain management were offered for both patients (both sites) as well as for relatives, friends, and colleagues (only Linköping). Both programs included work related advice and support, and individually tailored sessions with team members were available. Further individual sessions might also be required for a few weeks following the program.The following inclusion criteria for the MMRP were used: (i) disabling chronic pain (on sick leave or experiencing major interference in daily life due to chronic pain); (ii) age between 18 and 65 years; (iii) no further medical investigations needed; (iv) written consent to participate and attend to the MMRP;(v) and agreement not to participate in other parallel treatments. The following exclusion criteria were used: (i) ongoing major somatic or psychiatric disease; (ii) a history of significant substance abuse; and (iii) state of acute crisis. General exclusion criteria included severe psychiatric morbidity, abuse of alcohol and/or drugs, diseases that did not allow physical exercise, and specific pain conditions with other treatments options available (red flags).pre-MMRP or baseline); 2) immediately after MMRP (post-MMRP); and 3) at the 12-month follow-up (FU-12). Demographic data are only collected before MMRP. In the present study, the predictions concerned the FU-12.The SQRP is recognized as a national registry by the Swedish Association of Local Authorities and Regions. The SQRP is mainly based on questionnaires. The patients completed the SQRP questionnaires on three occasions: 1) at the assessment during the first visit to the clinical department GenderEducation . This variable was dichotomized into University vs the other alternatives.Country of birth . This variable was dichotomized into Nordic countries vs. outside Nordic countries.Work/study-now.Currently working/studying (Yes or No) denoted Own prognosis-RTW.○ What do you think it will be like to return to work/studies or to extend working hours if you are not working full time?  to 5 (very difficult). This variable was denoted as RTW-when.○ When do you expect to be able to return to work or studies or to work longer if you are not working full time?  to 5 (never). This variable was denoted as Chances-restored.○ How confident are you about your chances to be fully restored? Likert scale: 1  to 5 . This variable is denoted as Three items concerned the attitude about the future. Those working/studying full time were instructed to skip the first two items below; subjects who were seeking a job were instructed to imagine being employed when answering the following items:Work-importance.What significance does the work have for you in addition to the importance of income?  Very important, 2) Important, 3) Partially important, 4) Hardly no importance, or 5) No importance). This variable was denoted as Dr-visits.How many times have you visited a physician for your pain complaints the previous year? 0–1 times; 2–3 times; or ≥4 times). This variable was dichotomized into ≥4 times vs. the other alternatives and is denoted as Pain-duration.When did you first experience the pain you are currently troubled by? (days). This variable was denoted as Pain-duration-persistent.If persistent pain exists, how long? (days). This variable was denoted as NRS-7days.Average pain intensity the last week . This is denoted as PRI).Using 36 predefined anatomical areas (18 on the front and 18 on the back of the body), the subjects marked where they experienced pain: 1) head/face, 2) neck, 3) shoulder, 4) upper arm, 5) elbow, 6) forearm, 7) hand, 8) anterior aspect of chest, 9) lateral aspect of chest, 10) belly, 11) sexual organs, 12) upper back, 13) low back, 14) hip/gluteal area, 15) thigh, 16) knee, 17) shank, and 18) foot. The number of areas associated with pain were counted (between 0 and 36) and this variable was labelled the Pain Region Index  MPI—is a 61-item self-report questionnaire that measures psychosocial, cognitive, and behavioural effects of chronic pain , 37. ParThe HADS is a self-assessment questionnaire that measures anxiety and depression using 14 items . HADS coCPAQ measures acceptance behaviours and attitudes towards pain. The process of acceptance refers to the concept of coping with pain; this process changes the focus from controlling pain and related psychological experiences to a wider focus that includes being open to pain without trying to alter the experience. Acceptance includes flexible engagement in goal-directed activities, which include pain as a part of the engagement, without struggling to control pain. CPAQ is a 20-item scale with two subscales: activity engagement  and pain willingness  . All iteTampa measures fear of movement . The iteLISAT-11 captures the patient’s estimations of satisfaction with life as a whole (LISAT-life) as well as satisfaction in ten specific domains . Each itSF36 intends to represent multidimensional health concepts and measurements of the full range of health states, including levels of well-being and personal evaluations of health . The insEQ-5D captures a patient’s perceived state of health –51. The Retro-pain) and their ability to handle life situation in general (labelled Retro-life situation). The Retro-pain item was rated on a five-point Likert scale from markedly increased pain (0) to markedly decreased pain (4). The other item was rated on a five-point Likert scale from markedly worsened (0) to markedly improved (4). In the regressions, these two items were dichotomized  vs. improved (1).The patients retrospectively at FU-12 reported their global evaluations of change in pain (labelled Average pain intensity the last week (NRS-7days)Pain severity according to the Multidimensional Pain Inventory (MPI-Pain severity)Pain intensity aspectsPain interference according to MPI (MPI-PainInterfer)Physical functioning according to Short form Health Survey (SF36-PF)Physical functioningDepression according to Hospital Anxiety and Depression Scale (HAD-D)Anxiety according to HADS (HAD-A)Distress according to MPI (MPI-Distress)Emotional functioningLife control according to MPI (MPI-LifeCon)Activity engagement according to Chronic Acceptance Questionnaire (CPAQ-AE)Pain willingness according to CPAQ (CPAQ-PW)Tampa Scale for Kinesiophobia (Tampa)Copingperceived state of health (single item) according to European Quality of Life Instrument (EQ5D-VAS)perceived state of health (index) according to EQ (EQ5D-index)Satisfaction with life in general (LISAT-life)HealthRetrospective rating of global improvement in life situation (Retro-pain)Retrospective rating of global improvement in life situation (Retro-life situation)Ratings of global improvementIn order to predict changes in outcomes, we, as far as possible, chose to adopt the recommendations of the IMMPACT group with regard to output domains and core outcome measures for chronic pain trials , 34 and All statistics were performed using the statistical package IBM SPSS Statistics (version 20.0) and SIMCA-P+ ; in all tests, a probability of <0.05 (two-tailed) was accepted as the criteria for significance. In the tables and text, the mean value ± one standard deviation (±1SD) of the investigated variables are given.av was seen as the most appropriate way to present the effects as this uses the average standard deviation of the two measurement points [d = 0.2 is small, d = 0.5 is medium, and d = 0.8 is large [p = 0.00083 level.Effect sizes of the rehabilitation program were calculated using the template developed by Lakens . In thist points . Roughlyis large . BonferrPrincipal Component Analysis, PCA) for the multivariate correlation analyses of all investigated variables and Partial Least Square Regression (PLS) for the multivariate regressions using SIMCA-P+. These techniques do not require normal distribution [Advanced multivariate analyses (MVDA) are essential in PBE studies. Classical statistical methods such as multiple linear regression (MLR) and logistic regression (LR) can quantify the level of relations of individual factors but disregard interrelationships among different factors and thereby ignore system-wide aspects  . Classicribution .2 describes the goodness of fit—the fraction of sum of squares of all the variables explained by a principal component [2 describes the goodness of prediction—the fraction of the total variation of the variables that can be predicted by a principal component using cross validation methods [2 and 2) distance to model in X-space. No extreme outliers were detected.PCA was used to extract and display systematic variation in a data matrix. All variables were log transformed before the statistical analyses if necessary. A cross validation technique was used to identify nontrivial components (p). Variables loading on the same component p were correlated, and variables with high loadings but with opposing signs were negatively correlated. Variables with high absolute loadings—i.e., 95% jack-knife uncertainty confidence interval non equal to zero—were considered significant. Hence, the most important variables were those with high absolute loadings. The obtained components are per definition not correlated and are arranged in decreasing order with respect to explained variation. Romponent . Q2 desc methods . OutlierPLS was used for the multivariate regression analyses [analyses . The VIPMLR or LR could have been an alternative, but they assume that the regressor (X) variables are independent. If multicollinearity  occurs among the X-variables, the regression coefficients become unstable and their interpretability breaks down. MLR and LR also assumes that a high subject-to-variables ratio is present , an assumption not required for PLS. In fact, PLS can handle subject-to-variables ratios < 1. Moreover, PLS, in contrast to MLR and LR, can handle several Y-variables simultaneously.t(437) = 2.09, p = 0.04). Hence, no statistically significant differences were found for demographic variables, psychological well-being, quality of life, acceptance, kinesiophobia, general health, or psychological functioning as measured by the SF-36.When comparing those who did not and who did complete the questionnaire at FU-12, only one just barely significant difference was found—the pain intensity variable NRS-7days. Those who did not complete the questionnaire had a mean score of 7.02 (SD 1.06) in comparison to those who did   was 14.7 ± 7.9 out of 36 anatomical regions. Mean pain duration was 2550 ± 2609 days; corresponding figures for persistent pain were 1856 ± 2218 days. Health care seeking was prevalent; 58.9% had visited a physician four or more times during the previous year.For the selected outcomes and domains, significant improvements were found, except for LISAT-life Table . The effThe difference  between pre and FU-12 values for the selected outcomes were calculated and transformed if necessary so that an improvement had a positive value.R2 = 0.25, Q2 = 0.16), the strongest regressors among the background and baseline variables were NRS-7days, MPI-Pain-severity, MPI-SocSupp, Work/study-now, and LISAT-psychhealth , the strongest regressors of the background and baseline variables were HAD-A, HAD-D, MPI-Distress, and SF36-MCS  , the three significant regressors were SF36-PF, RTW-when, and Own prognosis-RTW  using the background and baseline variables as regressors.R2 = 0.19, Q2 = 0.09), the two significant regressors were EQ5D-VAS and EQ5D-index : Education (VIP = 1.84 +), MPI-Pain severity (VIP = 1.42-), EQ5D-index (VIP = 1.07+), and Work-importance (VIP = 1.07-). Hence, improvements were associated with relatively high education, low pain intensity (MPI-pain-severity), high health (EQ-5D-index), and perceiving work as important for reasons other than economic (i.e. Work- importance). For Retro-life situation, the important variables at baseline  were MPI-Pain severity (VIP = 1.77-), EQ5D-index (VIP = 1.72+), NRS-7days (VIP = 1.25-), and education (VIP = 1.20+). Hence, improvements in life situation were associated with low pain intensities (NRS-7days and MPI-Pain-severity), high health (EQ5D-index), and relatively high education at baseline.At FU-12, 53.6% retrospectively reported improvements for pain and 80.1% for general life situation  was achieved according to the cross-validation rules in SIMCA-P+. The four most important variables – i.e., highest absolute loadings—were changes in MPI-PainInterfer (loading = 0.33), MPI-LifeCon (loading = 0.31), MPI-Pain severity (loading = 0.30), and MPI-Distress (loading = 0.29). Hence, these four variables showed the most prominent variability across subjects.To understand to what extent the changes in outcomes of the different domains together with the two retrospective items above were independent, a PCA was made for the situation at FU-12. Only one significant component . Hence, improvements in these four MPI variables were associated at baseline with low life control, high psychological distress, and perceiving work as important for reasons other than economic.When regressing the changes in the four most important MPI variables according to the PCA, the most important background/baseline variables were MPI-LifeCon (VIP = 2.05-), MPI-Distress (VIP = 1.46+), and Work–importance (VIP = 1.08-) and to the retrospective evaluations.Pain intensity and emotional aspects showed the strongest improvements  according to the repeated measurements.The analyses of the repeated measurements showed that the largest improvements in outcomes were significantly associated with poor situations according to their respective baseline scores.Although significant regressors of the investigated domains of outcomes were found, the significant predictors were weak and only explained a small part of the variation in outcomes.Major results of the present study are listed below.This PBE study confirms the generally positive results for MMRPs according to SRs –18, healThe majority of patients retrospectively reported improvements according to both pain and in their ability to handle their life situation in general Table . FortunaA mix of background and baseline factors were important regressors. The two retrospective items had several regressors in common. That is, low pain intensity, high education, and high health perception were related to improvements. Similar results have been reported in other studies using retrospective evaluations , 61. In In the repeated measurements , the most prominent effects according to Cohen’s d were for emotional and pain aspects  were low (15–25%). Similar results have been reported by other researchers [Based on the regressions of the changes in the repeated measurements Table , model 1earchers . Hence, high pain intensity at baseline  can be majority of outcomes had to be significantly better than for the control intervention [primary and secondary outcomes and what was necessary to classify an intervention as positive before reviewing the RCTs [There is a need to develop clinically applicable and standardized ways to evaluate multiple outcomes of MMPRs in individual patients in trials and in PBE studies. This involves both the statistical methods (cf. Statistics) and strategies for handling multiple outcomes. This study used different approaches for evaluation of outcomes. The number of outcomes in MMRPs are generally high; one SR including 46 RCTs found in median nine outcomes and that these generally were not divided into primary and secondary outcomes . In a rervention , 17. Thethe RCTs .independent comparisons [The analysis of several outcomes may raise an issue of multiple comparisons and Bonferroni corrections are frequently applied  and recoparisons . The latparisons  but a naparisons , but thiparisons .Multivariate methods that are able to handle non-commensurate outcomes in one analysis have been presented . The preThere are several limitations to consider. No control group was included and outcomes can be due both to the effects of MMRP and to other factors such as natural course. On the other hand, these patients on average had their pain for a considerable period (on average more than 2500 days), a period that reduces but does not eliminate the risk that effects are related to the natural course. Patients participating in MMRPs have often tried different unimodal treatments with little or no effects and thus represent a selection of patients. The present cohort of patients also represents a selection of patients with the most complicated clinical pictures as they were referred to a university hospital. Hence, the generalizability of the present results is limited and the results of MMRP in primary care may be different. Not all the MMRP participants answered the questionnaire at FU-12. The only significant difference at baseline was a small difference in pain intensity. But bias cannot be ruled out since the non-responders may have had worse effects of MMRP than the responders. It was not possible to analyse our results in relation to the contents and it was not possible to control for small changes in content over time. There are no internationally accepted definitions of MMRP , 81 and This study—representing the consecutive non-selected flow of patients in real-world clinical practice settings using SQRP—confirmed systematic reviews that outcomes of MMRP are associated with broad positive effects. A mix of background and baseline variables affected the outcomes investigated, but the explained variations in outcomes were low. In the future there is a need to develop a standardized and relatively simple outcome that can be used to evaluate a complex intervention such as MMRP in trials, in clinical evaluations at group level, and for individual patients.


To investigate the effect of neck-specific exercise with (NSEB) or without (NSE) a behavioural approach and prescribed physical activity (PPA) on general pain disability and psychological factors in chronic whiplash-associated disorders (WAD), grade 2 and 3, with a 2-year follow-up.A randomized controlled multi-centre study of 3 exercise interventions  including a 2-year follow-up. A total of 216 volunteers with chronic WAD were recruited and 194 were analyzed, mean age 40.4 (Standard Deviation [SD] 11.4). Measures of general pain disability, pain catastrophizing, anxiety and depression, and kinesiophobia were evaluated at baseline, and 3, 6, 12 and 24 months with linear mixed models.P < 0.001) and the improvements in disability were maintained over time  compared to the NSE (P > 0.42) and PPA groups (P > 0.43). Pain catastrophizing decreased in the NSE group from baseline to 6 and 12 months (P < 0.01) and in the NSEB group from baseline to 3 and 24 months (P < 0.01) compared to the PPA group (P > 0.82) that showed no change over time. The NSE group improved in kinesiophobia over time from baseline to12 months (P < 0.01) compared to the NSEB (P = 0.052) and the PPA groups (P > 0.74). Anxiety decreased over time from baseline to 12 and 24 months in the NSE group (P > 0.02), but not in the NSEB (P > 0.25) or the PPA (P > 0.50) groups. The PPA had no effect on general disability or any of the measured psychological factors.General pain disability decreased by 28% in the NSEB group from baseline to 3 months (This randomised controlled trial with a 2-year follow-up shows that physiotherapist-led neck-specific exercise with or without the addition of a behavioural approach had superior outcome on general disability and most psychological factors compared to the mere prescription of physical activity. Patients remaining symptomatic or showing residual disability after 6 months are considered to have chronic WAD and is a challenging condition for clinicians. Similar to other chronic pain conditions, central pain processing is likely to play a crucial role in the transition from acute toward chronic WAD. Consistent with other chronic pain conditions, a number of psychological factors, together with high initial pain and disability, have been found to play a role in the central pain processing in WAD.–13 Pain-related catastrophizing, broadly defined as an exaggerated negative orientation toward pain stimuli and pain experience, has shown to lead to a 3.8 times greater risk for chronicity and was associated with lower perceived health and quality of life. Pain-related catastrophizing is believed to play an important role in the complaints of patients with chronic WAD when referred to a physical therapist. Fear avoidance was found to be predictive for the development of chronic WAD, and it is advocated to be a promising model for understanding the development of persistent complaints after an acute whiplash injury. Depression also appears to predict WAD recovery, and persistent depression is seen in patients 5 years after a whiplash injury. In order to adequately address these psychological factors, cognitive behavioral components in physiotherapy management of chronic WAD have been recommended.,16,17 Moreover, based on the available research, exercise programs are suggested to be the most effective noninvasive treatment for patients with chronic WAD.,19 Commonly recommended in Sweden is to advise WAD patients to perform general physical activity.Whiplash is an acceleration–deceleration mechanism of energy transfer to the neck and head from indirect neck trauma. Symptoms following whiplash trauma can be for example, neck pain, headache, dizziness, and cognitive symptoms, leading to disability, illness, and reduced work ability. However, if this is true also for patients’ self-rated general disability from pain and psychological factors is unknown.Pain intensity and neck-specific disability have earlier shown to be superiorly treated with neck-specific exercises (NSEs) alone or combined with behavioral components compared with prescribed general physical activity.The aim of the study was to investigate the effect of NSE with or without a behavioral approach and prescribed physical activity (PPA) on general pain disability and psychological factors in chronic WADs, grades 2 and 3, with a 2-year follow-up.22.1This study was a planned analysis of secondary outcomes of a randomized controlled multicenter study with assessor and group allocation blinding including a 2-year follow-up. Participants were randomized to 1 of 3 alternative physiotherapy treatments: NSE followed by PPA, NSE with a behavioral approach (NSEB) followed by PPA, and PPA by a physiotherapist without NSE. The Regional Ethical Committee at Linköping University, Sweden, approved the study.2.2 participants were individuals with chronic WAD grade 2 or 3. A total of 216 participants were included and 194 were analyzed. Inclusion criteria were age between 18 and 63 years, WAD grades 2 to 3 after a whiplash injury at least 6 months but not more than 3 years ago, pain intensity >20 mm on a 100-mm Visual Analog Scale, and/or >20% on the Neck Disability Index . Exclusion criteria were known or suspected serious physical pathology, including myelopathy, spinal tumor, spinal infection, or ongoing malignancy, earlier fracture or luxation of the cervical column; neck trauma with persistent symptoms from previous injury, surgery in the cervical column, neck pain that caused >1-month absence from work in the year before the whiplash incident, signs of traumatic brain injury at the time of the trauma , generalized or a more dominant pain elsewhere in the body, diseases or other injuries that might prevent full participation in the study, diagnosis of a severe psychiatric disorder, known drug abuse, insufficient knowledge of the Swedish language (inability to answer the questionnaires). For a detailed description of the participants, see Table In accordance with the study protocol ,Several participants reported use of analgesic drugs due to neck pain at baseline. This was distributed over the groups as follows: use of analgesic drugs yes/no (%), NSE 40/35 (53/47), NSEB 44/27 (62/38), and PPA 45/22 (67/33).The vast majority of the patients were born in Sweden (n = 186), 13 were born in another Nordic country, 5 in the rest of Europe, and 12 were born outside Europe.Physiotherapists in primary care centers or private outpatient clinics in 6 different counties in Sweden performed the treatment. They were experienced in managing patients with neck pain disorders, and the treatment was conducted within the publicly funded reimbursement system. The physiotherapists participated in a 1-day educational session and practiced the different interventions.2.3,21 Participants were recruited between February 2011 and May 2012, and all participants received written and verbal information about the study. Informed consent and baseline data were collected before allocation.Healthcare registers of 6 Swedish counties, including primary health care, specialist orthopedic clinics, and hospital outpatient services, were examined for potential participants. Participants were screened for eligibility by a 4-step process. A detailed description of the procedure is described in earlier articles on this trial.2.4An independent researcher made a computerized randomization list and put the individual results in sealed completely opaque envelopes to be distributed to the treating physiotherapists. The study was assessor and group allocation blinded. Due to the nature of the intervention, blinding of the participants and physiotherapists was not possible.2.5 Exercise pain provocation was avoided in this group. Toward the end of the 12-week exercise period, participants were encouraged to engage in general physical activity and to continue NSE at home. In the NSEB group, the exercise protocol was the same as that undertaken by the NSE group, but with the addition of a behavioral approach. According to the concept of graded exercise, patients were encouraged not to focus on temporary increases in neck pain. They also received behavioral interventions including education and introduction to activities aimed at pain management and problem-solving, guided by a physiotherapist. Participants in the PPA group initially received a physical examination and a short motivational interview conducted by a physiotherapist. They were then prescribed individualized physical activity to be performed independently based on the interview and the physical examination. NSEs including any form of head resistance were not prescribed in this group. Further details about the intervention protocols have been published previously.The 3 interventions were physiotherapist-led NSE, NSE with the addition of an NSEB, or PPA. All 3 interventions were provided by physiotherapists in primary care and were undertaken over a 12-week period. In the NSE group, participants received supervised NSE twice weekly. Progressive resistance training was introduced in the gym with a focus on low-load endurance training. A detailed description of the exercises can be found at the Academic Archive On-line.2.6All outcome measures were self-administered and filled in by the patients at their homes. The Pain Disability Index (PDI) and the Pain Catastrophizing Scale (PCS) were collected at baseline, and 3, 6, 12, and 24 months after inclusion. The Hospital Anxiety and Depression Scale (HAD) and the Tampa Scale of Kinesiophobia (TSK) short version were collected at baseline, 6, 12, and 24 months after inclusion.2.6.1 It is a 7-item inventory designed to measure the degree to which pain interferes with functioning across a range of activities. Each item score can range from 0 (no interference) to 10 . Thus, the total PDI score can range from 0 to 70. The PDI has shown good reliability and validity.–25The PDI was used to measure domain-specific and general disability related to chronic pain.2.6.2 The PCS is a 13-item scale in which participants are asked to reflect on past painful experiences and indicate the degree to which they experienced thoughts or feelings during pain on a 5-point scale, ranging from 0  to 4 . The scale has been shown to have good reliability and validity in pain outpatient samples.,27The PCS was used to measure the extent of pain catastrophizing in participants. HAD is a 14-item scale with 2 subscales—1 subscale of 7 items for anxiety and 1 subscale of 7 items for depression. It was designed to measure both anxiety and depression. It has a 4-point scale for each question, ranging from 0  to 3 (very often). It has shown to be a valid clinical indicator of the possibility of depression and clinical anxiety in a Swedish population.The HAD was used to measure anxiety and depression.The TSK short version (TSK-11) was used to measure fear of movement and (re)injury. The 11-item scale (score range 11–44) is a short version of the original TSK. It evaluates fear of movement with higher scores indicating greater fear of movement, and each item is scored on a 4-point scale. Scoring possibilities range from “strongly disagree” (score = 1) to “strongly agree” (score = 4). The TSK-11 possesses similar psychometric properties to the original TSK.2.7 A total of 216 patients were recruited. One hundred ninety four patients were analyzed using linear mixed models. This method requires at least 2 measures besides baseline. Data were analyzed by using SPSS . All participants, who completed each measurement, were included in the analysis on an intention-to-treat basis. An α level of <0.05 was used for statistical significance. Background data were analyzed with one-way analyses of variance or the Kruskal–Wallis test for nonnormally distributed data. The chi-square test was used for binary outcomes.The sample size for the whole randomized controlled trial was based on the primary outcome NDI. For all models, exercise group , time , gender , and the interaction between group and time were included as fixed factors. The linear mixed model P values were reported for the within-group differences over time (Pt); differences between groups, estimated marginal means (Pg); differences between sex (Ps); interaction between time and group; if significant means that one or more of the groups are changing over time but the groups are changing in different ways (Pt × g) and interaction between time, group, and sex (Pt × g × s).Pain disability (PDI), pain catastrophizing (PCS), anxiety and depression (HAD), and kinesiophobia (TSK-11) were analyzed with linear mixed model.2.8This study was supported by funding from the Swedish government through the REHSAM Foundation (RS2010/009), the Swedish Research Council (521-2014-2982), the regional Center for Clinical Research and the County Council of Östergötland, Centre for Clinical Research Sörmland at Uppsala University, the Medical Research Council of Southeast Sweden, and the Uppsala-Örebro Regional Research Council.3P > 29) or baseline characteristics (P > 0.10), except for visits to physician. Dropouts had sought physicians significantly fewer times  compared to those included in the mixed model analyses . Tables One hundred ninety four individuals with chronic WAD were analyzed in this study, 126 women and 68 men, with a mean age of 40.4 years (Standard Deviation [SD] 11.4). There were no differences between groups at baseline except for significantly more women and younger participants in the NSE group compared to the PPA group (Table 3.1P < 0.01) and main group by time interaction effect . Pain disability decreased in the NSEB group from baseline to 3 months, and the improvements in disability were maintained over time  compared to the NSE and PPA groups. There was no change over time in the NSE  or the PPA groups . There were no gender differences  or interaction between group, time, and sex . For a detailed description of the results, see Table There was a significant change over time effect  and main group by time interaction effect  in pain catastrophizing. Pain catastrophizing decreased in the NSE group from baseline to 6 and 12 months  and in the NSEB group from baseline to 3 and 24 months  compared to the PPA group  that showed no change over time. There were no group differences between gender  or interaction between group, time, and sex . For a detailed description of the results, see Table There was a significant change over time effect  but no significant group by time interaction effect . Anxiety decreased over time from baseline to 12 and 24 months in the NSE group , but not in the NSEB  or the PPA  groups. There were no gender differences  or interaction between group, time, and sex .Regarding anxiety, there was a significant change over time effect , group by time interaction effect , differences between groups , gender differences , or interaction between group, time, and sex . For a detailed description of the results, see Tables Regarding depression, there was no significant change over time effect  and main group by time interaction effect  in kinesiophobia. The NSE group improved over time from baseline to12 months  compared to the NSEB  and the PPA groups .There was a significant change over time effect  and in the PPA group at 6 months . They were also close to significant gender difference in the NSEB group at baseline  where men had tendency to higher kinesiophobia. For a detailed description of the results, see Table There was a significant effect of gender. In the NSE group, men showed significant higher kinesiophobia at baseline and 6 months compared to women in the NSE group  principles, and a recent review of CBT treatment on chronic pain patients calculated a reference value for general disability, measured by the PDI, for WAD patients  to a mean of 37.6 points. The patients in the different treatment groups in our study had 18.8 to 23.1 as means, indicating considerably lower disability than Soers’ WAD patients at baseline. Moreover, if we compare the means of our patients (WAD grades 2 and 3) concerning pain catastrophizing with Sullivan et al, it shows that the patients in Sullivan's study of WAD patients (grades 1 and 2) had a mean of 27 points on the PCS, while our groups scored 17.1 to 19.2 at baseline, indicating again a considerably lower score for the patients in the present study. If we continue to look at anxiety and depression, our participants presented a mean score of 4.5 to 6.3 on HAD, which is below the cutoff score of 8 for low mood or low anxiety. Taken together, there are clear indications that the present study population at baseline had low disability, pain catastrophizing, depression, and anxiety. This leaves less room for improvement compared to patients from rehabilitation or pain clinics with higher baseline scores.A first reason for modest difference in the outcome between the physiotherapist-led NSE leg and the intervention with the addition of a behavioral approach on psychological factors may lay in the study population. In a recent study, Soer et al–38 For adaptive coopers, there is little room for improvement, and the behavioral approach might have had little impact on outcome contributing to the similar results for psychological factors for both active treatment arms. In concordance with this, Sullivan et al showed in a study of chronic WAD patients using a psychosocial risk-factor-targeting intervention that this treatment was only successful for patients displaying many psychosocial factors, whilst the intervention was superfluous for patients without these factors. So the patients in our study with a low degree of psychological factors that were randomized to the behavioral treatment arm might not have benefited much from the addition of the behavioral component. Yet, a 28% reduction in general disability was accomplished with the active treatment incorporating the behavioral component and was sustained over a 2-year period. The Minimal clinical important change (MCIC) for the PDI scale for chronic back pain patients, including neck pain patients, has been calculated to be 8.5 to 9.5 points. This was calculated from a mean of 34.6 corresponding to a 26% reduction. Participants in our study reduced their disability with 6 points but from a substantially lower starting point, 23.1 to 18.8 points, resulting in a similar MCIC of 26% reduction on general disability.Furthermore, more than 50% of the patients in the present study worked full-time and around 80% had employment at treatment start, suggesting a relatively high percentage of adaptive coopers. Adaptive coopers are patients dealing well with the psychological and emotional problems incorporated in chronic pain and characterized by lower interference with everyday activities, lower affective distress, and higher life control.Participants in our study were identified through healthcare registers of 6 Swedish counties, including primary health care, specialist orthopedic clinics, and hospital outpatient services. They were contacted by mail and invited to participate in a study for WAD patients that included a form of exercise. Given the low baseline scores on disability, pain catastrophizing, anxiety, and depression in comparison with other studies, the data suggest that we might have encountered a selection bias. It seems reasonable to assume that patients with lower levels of distress and other psychological discomfort would be more inclined to submitting themselves to training and therefore probably chose to participate, while those with more prominent psychological factors may have chosen not to respond to the invitation. advocated in his review to take central sensitization into account when prescribing exercise and to avoid time contingent exercise for patients with signs of central sensitization. This would mean that time contingent behavioral approach would be suitable for patients without sensitization and exercise with pain contingent approach would be more suitable for patients with signs of sensitization. Because our patients were randomly allocated to the different treatment arms instead of allocated based on sign of sensitization, and assuming that patients with central sensitization were equally distributed between the active treatment arms, the effect of the intervention may have been partially washed out.The second reason for modest difference in the outcome may have to do with the patients’ characteristics in combination with treatment allocation. In our study, patients were allocated to the treatment arms irrespectively of their characteristics. Patients receiving the specific neck exercises without the behavioral approach were treated according to a pain contingent approach, and exercise pain provocation was avoided in this group. In accordance with the concept of graded exercise, patients who received the behavioral approach were encouraged not to focus on temporary increases in neck pain and were treated according to a time contingent regime. This may have increased the risk of augmenting nociceptive barrage toward the central nervous system during and following treatment in patients with signs of central sensitization, which in turn is likely to sustain the process of central sensitization. Nijs et al,41 show that physiotherapists working with pain patients only partially recognized cognitive, psychological, and social factors, we have no reason to believe that this played a major role in the outcome. Treatment with a behavioral approach has been advocated and tried before, but to our knowledge, the present study is the only study that shows a positive outcome of a physiotherapist-led behavioral approach on chronic WAD patients grades 2 and 3.Great care was taken into recruiting the physiotherapists administering the behavioral treatment. The vast majority had an interest in behavioral medicine and many had attended postgraduate courses in this field before participating in the study. They all received an additional 1-day training on how to deliver the behavioral treatment before treatment start. Although 2 recent systematic reviews using the same NSE treatment as in the present study showed NSE to be superior to staying on a waiting list.The strength of this study is that it has a 2-year follow-up, which enables us to investigate if the results are stable and sustained over time. It also has a relatively large number of participants, which makes the findings robust. It includes individuals with WAD grade 3, often excluded in other studies and was assessor blinded and conducted at multiple primary care centers. Although the study had a strict treatment protocol, a weakness of this study is that we do not have any data on actual practice behavior and therefore cannot be completely certain that the treatment was given in the way it was intended. Although all participating physiotherapists were experienced in managing patients with neck pain disorders, we cannot be sure of the specific competency of the physiotherapists in delivering a behavioral approach. Another limitation was the lack of no-intervention control group. However recently, Peolsson et al as well as challenging and changing inappropriate pain beliefs. It is often administered in a time contingent fashion. A new cognitive approach addressing the educational and cognitive aspect but administered on a pain contingent basis might be more appropriate for patients with signs of central sensitization and psychosocial risk factors. A behavioral approach on a time contingent basis is probably more appropriate for patients without signs of central sensitization but with potential psychosocial barriers for recovery. Instead of a one-size-fits-all strategy that ignores the heterogeneity in chronic WAD patients, predetermined patient characteristics will decide to what type of intervention they will be assigned, with a nonstratified group as control for the results. This type of stratified approach has been successfully tested before on other pain patients and in physiotherapy settings.,47For future research, given these modest results and the uncertainty of the impact of the possible other explanations, maybe a new line of research should be opened. Instead of submitting all patients irrespective of their characteristics to the same kind of treatment, like in traditional randomized controlled trials, tailoring the treatment to patient characteristics could be a more successful approach. In this kind of study, both central sensitization and potential psychosocial barriers for recovery could be taken into account as potential modifiers. A behavioral approach can consist of different components. It should include oral education regarding physiological and psychological aspects of painIn summary, the results of this randomized controlled trial with a 2-year follow-up show that physiotherapist-led NSEB or NSE had better outcome on general disability and most psychological factors compared to the mere PPA. The PPA had no effect on general disability or any of the measured psychological factors. More specifically, neck-specific training with the addition of a behavioral component significantly decreased general pain disability by 26% in the first 3 months and sustained this over 2 years. The active physiotherapy-led treatment with or without the behavioral component also decreased pain catastrophizing, while PPA did not. Moreover, NSEs significantly diminished kinesiophobia the first year and anxiety over 2 years. To our knowledge, the present study is the only study that shows a positive outcome of a physiotherapist-led behavioral approach on chronic WAD patients grades 2 and 3.


This study aimed to assess the effectiveness of Chinese medicine warm compress (CMWC) on back meridians in relieving cancer pain, reducing adjuvant analgesic doses and adverse reactions, and improving the quality of life (QOL).A total of 62 patients (age range 39–82 years) diagnosed with a malignant tumor and suffering from cancer-related pain were randomly divided into a treatment group (group A) and a control group (group B) (n = 31 for each). The patients in both groups were administered appropriate drugs for 2 cycles of 7-day treatments according to the World Health Organization (WHO) 3-step ladder for cancer pain relief in adults. In addition, a CMWC was given to patients in group A. Pain relief was assessed using the visual analogue scale (VAS) at various time points before and after interventions in each group. Alteration of analgesic doses, adverse reactions, performance status (PS), and QOL were evaluated and any differences between groups A and B evaluated.P < .001). Significant differences in clinical pain relief efficacy in various locations were found in group A after treatment vs before treatment (P < .05). Adjuvant analgesic doses were significantly changed in the control group compared to the treatment group after 1 cycle of 7-day treatment . QOL were improved more in group A than in group B . Significantly reduced adverse reactions were observed after treatment of group A compared with group B in terms of the overall incidence  or incidence of constipation .VAS scores at various time points after treatment were significantly decreased compared with the baseline level in group A. Overall response rate was significantly improved in group A compared with group B (70.97% vs 29.03%, The application of CMWC on back meridians combined with WHO 3-step analgesic ladder treatment was effective in relieving cancer-related pain with reduced doses, less adverse reactions, and improved QOL. Pain can be caused by inflammatory mediators , which are released from tumor-associated macrophages, mast cells, neutrophils and T lymphocytes. In addition, cancer patients often have disorders of the blood microcirculation and pain can be triggered by vasodilatation, induced by free chemicals and local blood stasis. The endothelin-B receptor (ETBR) is believed to mediate inflammatory pain and vasodilatation.,9 The characteristics of cancer pain vary depending on the duration, location, and type of cancer. Even with the broad availability of analgesics, more than 50% of cancer patients were undertreated for the relief of moderate and severe pain symptoms.,10Cancer is the leading cause of death in China. In 2015, it was estimated that about 4,292,000 patients with invasive cancer would be newly diagnosed and about 2,814,000 were expected to die. which suggested that prompt oral administration of nonopioid analgesics with or without adjuvants, low-potency opioids plus nonopioid analgesics with/without adjuvants, and potent opioids plus nonopioid analgesics with/without adjuvants should be used to treat mild pain (Step 1), medium pain (Step 2) and intense pain (Step 3), respectively. Long-term use of analgesics for cancer pain should consider concerns about side effects. Nonopioid analgesics may produce gastrointestinal bleeding, kidney and liver dysfunction, cardiovascular toxicity and allergic reactions. The adverse effects of opioids include constipation, itchiness, urinary retention, nausea, and dizziness. Serious consequences may be coma and respiratory depression. In addition, opioid analgesics may lead to addiction or acute toxicity, affect physiological and psychological well-being, cause social phobia and also a reduced QOL.,13One common approach to cancer pain management employs the guideline of the 3-step pain ladder introduced by the World Health Organization (WHO),qi) and stasis of blood are thought to result in “pain due to impediment” and “pain due to lack of nourishment.” TCM treatment for cancer pain involves the use of traditional Chinese medication to restore the balance of the internal environment by reinforcing and adjusting qi to circulate through meridians, which connect various internal organs and functions. Studies have shown that the application of Chinese herbal medicine (CHM) and acupuncture increase the peripheral release of endogenous analgesic agents, reduce pain mediator secretion and induce central nervous system (CNS) analgesia.–18 These studies demonstrated that the use of TCM to treat pain triggered by cancer is effective and economical and furthermore produces fewer side effects.Traditional Chinese medicine (TCM) has a long history in the treatment malignancies and believes that impediment of collaterals and meridians is the origin of pathogenic of cancer pain. Long-term stagnation of vital energy (evodia rutaecarpa (Wuzhuyu), semen sinapis (Baijiezi), ephedra sinica (Mahuang), and asarum sieboldii (Xixin). It is designed for cancer pain relief through dredging healthy qi to warm and activated blood and by promoting the circulation through the back meridians, which is considered to be the source of yang qi  and have broad connections with the viscera. In the present study, we investigated the efficacy and safety of a CMWC on cancer pain treatment combined with the WHO 3-step analgesic ladder treatment.According to the statement of Wu Shiji, a great master of external treatment in the Qing Dynasty, the external treatment is the same as the endotherapy in theory; CHM for external treatment is also the same as endotherapy. CHM for external treatment can be absorbed through the skin, infiltrate the skin and reach the target meridians for its actions. Wen Jing Zhi Tong Fang, a CMWC, is a CHM and composed of 22.1The current study was carried out in the Department of Medical Oncology of the Guangdong Provincial Hospital of Chinese Medicine between December 2016 and January 2017. Patients were enrolled if they were diagnosed with a malignant tumor, suffered from mild to severe cancer-related pain and agreed to take part in the study. Patients were excluded if they had grave skin lesions, drug allergy, dysfunction of vital organs , mental disorders, severe idiopathic disease, or bad compliance. As a result, a total of 62 patients (32 men and 30 women) aged 39 to 82 years were recruited and randomly allocated into the treatment group (group A) or the control group (group B) (n = 31 for each group). The WHO 3-step analgesic ladder for the relief of cancer pain with and without CMWC, named as “Wen Jing Zhi Tong Fang” in Chinese, were given to patients in the treatment and control groups, respectively. Written informed consent was obtained from every patient before enrolment and approval for the study was granted by the Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine (no. B2016-131-01).2.2The number of samples to study the effect of Chinese medicine in cancer pain patients has been estimated to be at least 30 by preliminary treatments. The participants were randomly divided into the research group and the control group, using unbiased systematic sampling. The patients in the 2 groups were tested individually before intervention and 12-, 24-, 48-, and 72 hours, as well as 7- and 14 days after intervention initiation and the cancer pain assessment, analgesic doses the types of drugs administered, adverse events, performance status as well as QOL for each participant was recorded. Comparison of before versus 14-days after treatment initiation between the treatment and control groups served as data for clinical efficacy of treatment and safety evaluations.2.3All participants in both the treatment and control groups were given drugs for cancer pain relief for 2 cycles (7-day per cycle) according to the following guideline of the WHO 3-step analgesic ladder: step 1 for minor pain with a nonopioid analgesic  with/without an adjuvant analgesic; step 2 for moderate pain with a low-potency opioid  with or without a nonopioid or adjuvant drug; step 3 for severe pain with a strong opioid , Semen sinapis , Ephedra sinica  and Asarum sieboldii . The herbs were packed in a warm packet of size 40 × 20 cm2, heated and deposited on the back meridians of patients  in the supine position for approximately 30 minutes, once daily for 2 weeks.In addition to the WHO 3-step analgesic ladder medication regime, patients in the treatment group were also given a CMWC, ‘Wen Jing Zhi Tong Fang’, which was composed of 2.42.4.1 and numeric rating scale (NRS) VAS: The patients marked their pain on a 100 mm line, with 0 mm at the left side and 100 mm at the right side, indicating no pain and the most excruciating pain, respectively. The intensity of the pain score was calculated by measuring the distance in mm between the “no pain” mark and the patient's mark, producing scores ranging from 0 to 100. VAS scores have been recommended as the following grades (in mm): no pain (0–4), mild pain (5–44), moderate pain (45–74), and severe pain (75–100). NRS: The patients rated their pain from 0 to 10 and the pain level was divided into the following 4 grades: 0 for no pain (grade 0), 1 to 3 for mild pain , 4 to 6 for moderate pain  and 7 to 10 for excruciating pain .The pain intensity was assessed using the visual analogue scale (VAS)2.4.2Pain relief was compared before versus 14 days after treatment initiation by using VAS scores to determine the clinical efficacy of treatment. The clinical efficacy of treatment in each group was described as follows: Complete relief (CR): no pain experienced (VAS = 0); partial relief (PR): the pain was significantly alleviated (>50%), sleep disturbance was not detected and the patients lived normally; minimal relief (MR): the pain was obvious but significantly reduced (30%–50%) and sleep disturbance was detected; no effect (NR): the pain level was unchanged (<30%) or was more serious than before. PR and CR were taken as effective responses to the treatment of cancer pain .2.4.3 In addition, QOL was measured by a health form survey comprised of 12 items (SF-12) that measured 8 health domains, including general well-being, physical functions, physical role, body pain, vitality, social functioning, emotional role and the mental state of the patient. The scores of QOL with a maximum at 60 points were divided and interpreted as the following: <20 very poor; 21 to 30 poor; 31 to 40 fair; 41 to 50 good; and 51 to 60 very good.Performance status and quality of life (QOL) was measured before and 14 days after treatment initiation for each participant. PS was used to quantify patients’ general well-being and ADLs. The Zubrod score or Eastern Cooperative Oncology Group (ECOG) score was scored from 0 to 5, with 0 denoting normal health and a score of 5 death.2.4.4Analgesic doses and the types of drugs administered were compared between 7 and 14 days after treatment initiation with before treatment in each group and recorded as follows: no change; dose reduced; dose increased; medication changed.2.4.5 with a detailed clinical description as follows: grade 1, intermittent or occasional symptoms, occasional use of laxatives or stool softeners, modification of diet, or enema use; grade 2, persistent symptoms with routine use of enemas or laxatives, inhibition of the ADLs; grade 3, constipation with manual evacuation required, inhibition of self-caring ADLs; grade 4, life-threatening circumstances requiring urgent interventions; and grade 5, the patient died.The safety evaluation was based on adverse events, which were recorded during the treatment with analgesics with or without the CMWC. The degrees of constipation was rated as grade 1 to 52.5t test were used for comparative analysis of VAS scores and QOL before and after treatment between the 2 groups, respectively. A P < .05 was considered to be statistically significant.All statistical analyses were carried out using SPSS ver. 17.0 . The continuous and categorical data are shown as the mean ± standard deviation and percentages, respectively. The chi-squared analysis was applied to compare clinical efficacy between the treatment and control groups. Comparison of changes in analgesic doses between the treatment and control groups were measured using a Fisher exact test. A Wilcoxon rank-sum test was employed to compare PS and the incidence of constipation between the 2 groups. A paired repeated-measures analysis of variance (ANOVA) and a 33.1P > .05)  were eligible for the study. The mean age of patients was 58.85 ± 11.38 years (range 39–82). The patients pain was located in various regions including the chest and rib (n = 6), abdomen (n = 15), lower back (n = 3), chest and back (n = 9), upper and lower back (n = 3), upper back (n = 3), abdominal and lower back (n = 8) and >2 locations (n = 15). There were 19, 22 and 21 patients who suffered from mild, moderate and severe pain, respectively. The patients were divided at random into 2 groups  using a stratified sampling method and according to the registration sequence. No significant differences were found between the 2 study groups with regard to sex, age, pain location or its intensity (3.2P = .000), especially at 12-, 24-, 48- and 72 hours, 7 days and 14 days after treatment initiation between the treatment and control groups  , suggesting less medication adjustment in the treatment group compared with the control group. However, no significant difference of alterations in analgesic doses and medication were found between the control and treatment groups after 14 days treatment (P = .287).The changes of analgesic doses and medication between control and treatment group 7- and 14-day after treatment initiation were compared and are summarized in Table 3.4P = .000).Comparison of the PS scores 14-day after treatment initiation in both groups was measured and the results are shown in Table P = .000).As summarized in Table The results suggested that the use of integrated modern medicine and CMWC on back meridians improved PS and QOL.3.5Adverse events (AEs) were recorded before and during the period of analgesic treatment. By 14-day treatment, there was only events of mild constipation reported in the treatment group, in contrast to events of mild-to-severe constipation, nausea and vomiting, urinary retention and other symptoms reported in the control group.P = .065). There were 25 cases of constipation  in the control group after 7-day treatment, whereas there were only 9 cases of mild constipation in the treatment group. The difference of incidence of constipation after 1-week treatment was statistically significant between the control group and the treatment group . A total of 24 cases of constipation  were found in the control group after 14-day treatment compared with only 1 case of mild constipation in the treatment group. The difference of incidence of constipation after 2-week treatment was statistically significant between the control group and the treatment group . These data suggested that CMV compress combined with analgesic treatment significantly reduce incidence and level of adverse events.Table 4 Regardless of the effectiveness of the 3-step analgesic ladder treatment, some patients fail to achieve pain relief due to intolerable side effects and the prevention of drug addiction. Recent research has reported that TCM treatment has good efficacy in alleviating cancer pain and improving the overall QOL of cancer patients. In the present study, cancer patients were treated with a 3-step analgesic ladder with or without CMWC, and the effect of the CMWC on pain relief, analgesic doses, adverse events and QOL of patients were assessed.Pain is a commonly reported symptom and a primary concern for patients with cancer. Although the etiology of cancer has not been completely illustrated, cancer pain relief can be achieved through various strategies, including the 3-step analgesic ladder management and biological and nerve block treatment. Approximately 50% of patients however, do not have their pain effectively controlled for various reasons.qi, invasion of pathogens (evil qi), obstruction of channels of healthy qi and blood stasis, which results in the accumulation of pain-producing chemicals. Therefore, the principles of TCM for cancer pain focus on strengthening healthy qi, expelling evil qi and activating and warming blood to treat both the symptoms and pathogens. Previous studies showed TCM together with the 3-step analgesic ladder achieved a total response rate of cancer pain relief greater than 80%.,28 Our study also showed a significant difference in alleviating cancer pain using “Wen Jing Zhi Tong Fang” combined with the 3-step analgesic ladder treatment compared with the 3-step ladder alone  can decrease blood pressure, improve the microcirculation, regulate body temperature and has anti-thrombotic, anti-allergic, anti-cancer, analgesic and anti-inflammatory effects.Semen sinapis (Baijiezi) has anti-tussive, expectorant, anti-asthmatic, anti-radiation and anti-inflammatory effects and is attributive to the lung and stomach meridians. Ephedra sinica (Mahuang) can promote sweating, ventilate lungs to relieve dyspnea, and induce diuresis to disperse swelling. It is attributive to the lung, large intestine, and urinary bladder meridians. Asarum sieboldii (Xixin) is attributive to the lung and kidney meridians. It has been reported that Xinxin can expel heat, relieve pain and dyspnea, strengthen cardiac function, eliminate phlegm, improve the body's metabolism and immune system, and have anti-inflammatory and anti-convulsive effects. A combination of these herbs in appropriate proportions is expected to relieve cancer pain by stimulating healthy qi, dredging the meridians and collaterals, regulating qi and blood, and restoring the internal physiological functions of vital organs in the body.From the perspective of TCM, the etiology and mechanism of cancer pain involves a deficiency of healthy qi and blood flow, controlling the functions of internal organs (zang fu), improving the body's immune system and relieving pain.–35 The back of the body is considered to be the region where qi from the individual internal organs converges and from where the qi and blood return to the targeted viscera. There are several important meridians located on the back of the body including: 1) the urinary bladder (UB) meridian on the first (back shu) and second line (shu point), which has close and broad connections with internal organs; 2) Du meridian, starting from the midpoint between the coccyx and the anus. It ascends along the spinal column of the body up to the top of the head and connects with the Ren meridian. The Du meridian enters the spine and brain and has associations with the kidneys, spine and brain. It also connects UB, Yang Wei and Yang Qiao meridians as well as several individual internal organs; 3) Hua Tuo Jia Ji acupoints located bilaterally in a row alongside the spine, is part of the CNS responsible for consciousness and has a close relationship with individual internal organs, limbs and connective tissues. In addition, the heated CMWC was deposited on the back meridian from T1-T12 vertebrae at the Du, Back Shu and Jiaji points. The role of the CMWC in pain relief was likely to be similar to that of ‘dermatomes’ associated with the T1-T12 vertebrae, which could activate the sympathetic nervous system and lead to autonomic neuropathy, resulting in disorders pertaining to internal organs, blood flow, alterations in nutrition supply and producing local symptoms in the case of thoracic vertebrae, spinal cord or nerve root damage. Conversely, a lesion of an internal organ could cause the local transmission of pain to the cerebral cortex and into spinal cord, resulting in referred pain.,37 Therefore, the combined use of the 3-step analgesic ladder treatment with CMWC on the back meridians was expected to function in dredging qi of internal organs, regulating yin/yang and qi/blood, unblocking meridians/collaterals, resolving pain and easing the mind. Moreover, our study showed improved ORR of pain relief with the CMWC treatment in different locations  and the incidence of constipation was significantly decreased in the treatment group compared with the control group . Moreover, analgesic doses were significantly reduced after 1 week of CMWC treatment, suggesting the potentiality of using CMWC instead of western medicine in appropriate cancer patients to treat pain at an early stage of cancer. In agreement with other studies, our study showed improved QOL of cancer patients due to less side effects and decreased adverse events using CMWC combined with the 3-step analgesic ladder for cancer pain treatment.Currently the WHO 3-step analgesic ladder strategy is the internationally recognized and widely accepted management strategy for cancer pain. However, various side effects related to non-opioid and opioid analgesics, such as nausea and vomiting, urinary retention, constipation, dizziness, respiratory inhibition and even coma, have been reported.Wen Jing Zhi Tong Fang” compress deposited on back meridians was combined with the 3-step analgesic ladder treatment. Further study is needed to address whether “Wen Jing Zhi Tong Fang” alone is effective in relieving cancer pain in appropriate cancer patients.A limitation of the study was that although the application of CMWCs on back meridians combined with WHO 3-step analgesic ladder treatment was effective in relieving cancer-related pain with reduced doses, less adverse reactions, and improved QOL, the research findings of this study were limited by a small sample size and short duration. It should be noted that in our study the CHW “5Wen Jing Zhi Tong Fang”, a CMWC, was effective in alleviating cancer pain, reduced side effects of adjuvant analgesics and improved QOL of cancer patients in combination with the WHO 3-step analgesic ladder treatment.The current study demonstrated that “


To evaluate various kinematic movements on postoperative pain using a Reciproc system.Fifty-six molar teeth were divided into four groups according to kinematics as follows: continuous rotation, 360° CCW – 30° CW, 270° CCW – 30° CW, and 150° CCW – 30° CW. Preoperative and postoperative pain levels using visual analogue scale (VAS), percussion pain, and analgesic intake were recorded for each subject. Postoperative pain levels at 1, 3, 5, and 7 d were evaluated. Data were analyzed statistically using the Kruskal-Walis, Mann-Whitney-U, one-way analysis of variance, and chi-square tests (p=0.05).Continuous rotation resulted in more pain at Day 1 when compared with the reciprocating groups (360° CCW – 30° CW and 270° CCW – 30° C) (p<0.05).Continuous rotation resulted in more postoperative pain at Day 1 than in reciprocating groups, and thereafter no significant pain was found among the groups. Postoperative pain can be affected by almost all of the procedures in root canal treatment, including anaesthesia administration6, introduction of glide path8, use of instrumentation systems5, and retreatment13.One of the most important matters in endodontic treatment is the prevention of pain. Postoperative pain after endodontic treatment is a frequent complication. According to a systematic review, the frequency of endodontic postoperative pain in patients is between 3% and 58%2. These instruments are produced with a special NiTi alloy (M wire) subjected to a special thermal treatment process, performed to provide higher flexibility to the instrument9.Reciproc system  is characterized by an S-shaped cross section. It has sharp cutting edges and a non-cutting tip. It shapes the canals with a reciprocal back-and-forward motion (150 degrees counterclockwise and then 30 degrees clockwise). This single file-system consists of three files; R25 (25/0.08), R40 (40/0.06), and R50 (50/0.05)5. Neelakantan and Sharma4 (2015) evaluated postoperative pain after instrumentation of root canals with a single-file reciprocating (Reciproc) and rotary  file systems, concluding that Reciproc showed significantly less intensity and duration of postoperative pain than One Shape. However, Nekoofar, et al.5 (2015) compared the intensity and duration of postoperative pain using WaveOne and ProTaper Universal, systems for root canal instrumentation, and found that postoperative pain was significantly lower in patients undergoing canal instrumentation with ProTaper Universal rotary instruments than with the WaveOne reciprocating single-file technique. These conflicting results could be a result of the use of instruments with different designs and/or the number of instruments used. We believe that there is nothing about the effect of different kinematics using the same instruments on postoperative pain in the literature. Therefore, the purpose of this study was to evaluate four (combinations of) kinematic movements  regarding postoperative pain using just one type of instrument, a Reciproc system. The null hypothesis was that there is no difference among the groups in postoperative pain.Previous studies have reported conflicting results on postoperative pain regarding the effect of instrumentation using reciprocating and rotationin vivo study. Study subjects were recruited from the pool of patients referred to the Department of Endodontics for root canal treatment from May 2015 to October 2015 (6 months). The protocol was approved by the Research Ethics Committee. Sample size was calculated as 56 with a power of 0.80 (effect size=0.46). A total of 56 patients were selected for this Healthy patients without any systematic diseases or allergic reactions;Tooth responsive to cold test;Patients with maxillary and mandibular molars;Patients with a preoperative pain level from 0 to 25 on the visual analogue scale (VAS) of 100 mm length.Palpation pain;Bruxism or clenching;Antibiotics or analgesics taken in the past 24 h;Previous root canal treatment;Swelling or sinus tract;Severe periodontal disease;Pocket depth greater than 5 mm;Mobility greater than grade 1;Periapical radiolucency;Severely damaged teeth;Absence of occlusal contact;Treatment with technical difficulty;Teeth with problems, such as over-instrumentation, broken files, and problems in determining working length.www.randomizer.org). Patient and group numbers were recorded on paper. After each patient signed the informed consent form, the tooth was anesthetized with a local anaesthetic solution containing 1.7 mL of 4% articaine with 1:100 000 epinephrine . A buccal infiltration anaesthesia and palatal injection were performed. The procedure was initiated 15 min later.The patients were randomly distributed into the groups using a web program , and the Reciproc instruments were used according to the manufacturer's instructions. A new Reciproc instrument was used for each patient. Palatine canals of maxillary molars and distal canals of mandibular molars were finished with R40, and the others were finished with R25. The patients were divided into four groups (n=14) according to the kinematic movements, as follows: counterclockwise continuous rotation, 360° CCW – 30° CW, 270° CCW – 30° CW, and 150° CCW −30° CW.For all groups, the speed of the motor was adjusted to 300 rpm. For the continuous rotation group, 200 g/cm torque was used. A size 10 K-file was used to maintain apical patency. For the irrigation, 2 mL of 1.25% NaOCl was used between in-and-out pecking motions with safety tip needle  approximately 4 mm short from working length, and a final rinse was performed using 1.25% NaOCl and 17% EDTA for 1 min to remove the smear layer.2.After root canal preparation, the root canals were dried with paper points and then filled using matched single cones and AH Plus sealer . The pulp chamber was filled with a flowable composite resin, and a nanohybrid composite resin was inserted into the cavity using an incremental technique and cured for 20 s using a LED light-curing unit  with an output of 1000 mW/cmThe patients were instructed to use 400 mg ibuprofen  if the pain was bearable and informed to record the analgesic intake on a customized form, which was also used by them to record any pain experience. The following variables were recorded:Age;Gender;Tooth number;Preoperative pain on the VAS;Preoperative and postoperative percussion pain levels on the VAS;st, 3rd, 5th, and 7th days;Pain level on the 1Analgesic intake after the procedure.Change in pain was calculated at the related day based on the preoperative pain.The Kolmogorov-Smirnov test for distribution of data for reduction in pain levels, according to the day, revealed non-normal distribution. Thus, data were analyzed using the Kruskal-Walis and Mann-Whitney-U tests for inter group analysis (p=0.05). The differences in age and preoperative and postoperative percussion pain levels were statistically analyzed using one-way ANOVA test (p=0.05). The differences in gender and analgesic intake were statistically analyzed using a chi-square test (p=0.05).The preoperative and postoperative percussion pain levels among the groups seven days after treatment were not statistically different (p>0.05).None of the patients were referred to the clinic with swelling or sinus track after the treatment. Also, none of the patients needed an unscheduled appointment. Three patients in the continuous rotation group, two patients in the 360° CCW – 30° CW group, one patient in the 270° CCW – 30° CW, and two patients in the 150° CCW – 30° CW group had taken analgesics, postoperatively. No significant differences were found in analgesic use among the groups (p=0.761).4 (2015) and Nekoofar, et al.5 (2015) evaluated postoperative pain after instrumentation of root canals with a single-file reciprocating or rotary file systems. However, one may argue that the different cross-sections, speed, kinematics, and systems may have had an impact on the postoperative pain. It is necessary, therefore, to evaluate the effect of pure reciprocating or continuous rotary motions using instruments with the same cross-sections on postoperative pain. Thus, the purpose of this study was to evaluate various kinematic movements on postoperative pain using just one type of instrument, a Reciproc system.Recently, Neelakantan and SharmaAccording to the results of this study, significant differences were found among the groups at Day 1 (p<0.05), but not at the other time periods (p>0.05) Thus, the null hypothesis was partially rejected.5 (2015) compared the intensity and duration of postoperative pain using WaveOne and ProTaper Universal systems, for instrumentation of root canals, and found that postoperative pain was significantly lower in the patients undergoing canal instrumentation with ProTaper Universal rotary instruments. Pasqualini, et al.7 (2015) evaluated the impact of rotary and reciprocating instrumentation on postoperative quality of life and concluded that reciprocating instrumentation affected postoperative quality of life to a greater extent than rotary instrumentation. Relvas, et al.10 (2015) and Kherlakian, et al.3 (2016) did not find significant difference between different reciprocating and rotary systems in terms of postoperative pain. These findings are not in concordance with our results. However, a recent report by Neelakantan and Sharma4 (2015) concluded that Reciproc showed significantly less intensity and duration of postoperative pain compared with One Shape. Shokraneh, et al.12 (2016) evaluated postoperative pain after using hand files, ProTaper Universal, and Wave-One instruments and concluded that postoperative pain was significantly lower in Wave-One group. The results of the latter two studies corroborate our results.An interesting finding was that continuous rotation resulted in more pain at Day 1 than in the reciprocating groups. Because there is no similar study in the literature, this finding cannot be compared with those of previous studies. Nekoofar, et al.1 (2015) on the amount of apically extruded debris, using different kinematics, also supports our findings. According to the results of the study by Arslan, et al.1 (2015), the 150° CCW – 30° CW and 270° CCW – 30° CW reciprocating motions extruded significantly less debris than continuous rotation (p<0.05). In this study, the continuous rotation resulted in more pain at Day 1 than in reciprocating groups (360° CCW – 30° CW and 270° CCW – 30° C). Although the 150° CCW – 30° CW reciprocating motions extruded significantly less debris than continuous rotation in the laboratory study, in this study no significant difference was found between the 150° CCW – 30° CW reciprocating motions and continuous rotation. There are several explanations for the differences in the results of the studies, the most likely being the different methodologies (in vivo and in vitro) employed.A laboratory study by Arslan, et al.Within the limitations of this study, continuous rotation resulted in more postoperative pain at Day 1 than in reciprocating groups (360° CCW – 30° CW and 270° CCW – 30° C), and, thereafter, no significant pain was found among the groups.