Substance Use Disorder (SUD) is a major public health concern affecting an estimated 22.5 million individuals in the United States. The primary aim of this study was to characterize psychological pain in a cohort of patients participating in outpatient treatment for SUD. A secondary aim was to determine the relationships between pre-treatment assessments of psychological pain, depression, anxiety and hopelessness with treatment retention time and completion rates. Data was analyzed from 289 patients enrolled in an outpatient community drug treatment clinic in Southern California, U.S. A previously determined threshold score on the Mee-Bunney Psychological Pain Assessment Scale (MBP) was utilized to group patients into high and low-moderate scoring subgroups. The higher pain group scored higher on measures of anxiety, hopelessness and depression compared to those in the low-moderate pain group. Additionally, patients scoring in the higher psychological pain group exhibited reduced retention times in treatment and more than two-fold increased odds of dropout relative to patients with lower pre-treatment levels of psychological pain. Among all assessments, the correlation between psychological pain and treatment retention time was strongest. To our knowledge, this is the first study to demonstrate that psychological pain is an important construct which correlates with relevant clinical outcomes in SUD. Furthermore, pre-treatment screening for psychological pain may help target higher-risk patients for clinical interventions aimed at improving treatment retention and completion rates. Substance Use Disorder (SUD) is a major public health concern affecting an estimated 22.5 million individuals in the United States . In 2017Psychological pain has emerged as an important clinical psychometric construct. Attempts to measure and characterize psychological pain began with early investigations into its impact on suicidality and more recently in populations suffering from Major Depression , 12,13––13–21. IThere is very little data characterizing psychological pain in SUD. Guimaraes et al. assessed psychological pain in a population undergoing treatment for SUD using a translated (English to Portuguese) abbreviated version (24 items) of the Orbach & Mikulincer Mental Pain Scale (OMMP), finding a small to moderate positive correlation between mental pain and the severity of addiction . A NorweThis study was undertaken to characterize psychological pain in a population undergoing treatment for SUD. We hypothesized that psychological pain scores would be correlated with assessments of depression and anxiety as we observed in previously studied depressed and suicidal clinical populations , 12. TheIn this study, we evaluated pretreatment assessments of psychological pain, depression, anxiety and hopelessness in a substance addicted outpatient treatment population. We hypothesized that psychological pain would correlate with ratings of co-administered symptom assessments as we observed in previous findings from depressed, suicidal and healthy control populations. In addition, we tested whether a subgroup of highest scoring SUD patients in terms of pre-treatment psychological pain would be associated with greater severity of co-assessed symptoms and elevated risk for poorer treatment outcomes (treatment retention times and completion rates) relative to lower scoring patients.http://orange.networkofcare.org/mh/services/agency.aspx?pid=TheGaryCenterSACS_348_2_0). The Institutional Review Board (IRB) of the County of Orange Healthcare Agency approved the study and waived informed consent due to the minimal risk associated with a retrospective chart review. We carefully protected the identity of the patients by assigning each patient chart record a numerical code to ensure privacy. Research personnel conducting chart reviews were blind to the study protocol.A retrospective analysis of medical records was conducted for patients enrolled between 2011–2013 in the Substance Abuse Counseling Systems of The Gary Center ; a community-based outpatient SUD treatment program. Data collected included demographics, standardized clinical assessments and outcome variables including completion/dropout status and length of stay (LOS). Patients were referred to the SACS program by medical providers, regional non-profit centers, Orange County (OC) courts, legal agencies and the OC Healthcare Agency. In addition, the SACS treatment program was advertised on the internet  from January 2011 to December 2013 for male and female patients ≥18 years of age and meeting the DSM-IV criteria for Substance Dependence or Substance Abuse were screened for inclusion in the study. Patients with incomplete medical records or who did not meet admission requirements were excluded from the study so that a total of 289 patient clinical charts were entered into the analyses. Successful program completion was defined as fulfilling all required elements of the clinical protocol. Data collected in the retrospective chart review included demographics, program length of stay (LOS), completion status and data from clinical rating scales. Detailed socioeconomic variables such as employment, education and marital status were not available. All patients entering the program underwent drug screening at admission and during the course of treatment for alcohol, tetrahydrocannabinol (THC), methamphetamine, cocaine, opiates and benzodiazepines.Subjects under age 18 and those who had not agreed to each required random drug screening as well as clinical assessment were excluded from the retrospective analyses as were those chart records with missing assessment and/or data relevant to completion status.Data collected from the intake assessment upon admission included ratings from the Mee-Bunney Psychological Pain Assessment Scale (MBP) , 12 the Completion was task dependent and determined by successfully completing the core programmatic components as designed by the SACS treatment team. Primary required elements included: attendance in the program >90 days, participation in 24 group sessions (16 process groups and 8 relapse prevention groups); four individual psychotherapy sessions, evidence of weekly attendance at community-based 12-step programs; two psycho-educational classes; and six random, observed drug tests. In order to maximize the opportunity to complete the treatment program and to accommodate relatively brief diversions from treatment , there was no predetermined maximum time for completion.Non-completion status was defined as not completing the tasks necessary for program completion (described above) and/or non-attendance for greater than 30 days.t-tests were conducted to compare the differences between two groups with respect to continuous variables, such as testing for a gender difference in Length of Stay (LOS). Pearson correlations were calculated to determine the linear relationship between two continuous variables. A logistic regression was conducted to examine the effect of psychological pain (high vs low-to-moderate) on dropout. A Kaplan-Meier Survival (Retention) analysis was conducted to examine the effect of psychological pain (high vs low-to-moderate) on LOS, with the null hypothesis assuming that psychological pain had no impact on LOS.Various statistical analyses were performed with IBM SPSS software. The type I error rate was set at .05 for all analyses. Chi-square analyses were conducted to study the association between whether patients withdrew from treatment  and gender, and between dropout and whether patients experienced high or low-to-moderate psychological pain . Between-group Data from 289 patients  were included in the analyses . PatientAs described in The correlations among the clinical assessments are described in Program completion was defined as satisfying all clinical requirements of the SACS program. Dropouts participated in the program but failed to complete.Χ2 = 12.75, df = 1, p < .001.68 patients (23.5%) completed the treatment program, whereas 221 (76.5%) did not. Significantly fewer patients with higher MBP scores completed the treatment (11.3%) than patients with lower scores did (26.3%). The association between dropout rate and gender was statistically significant, with the dropout rate being higher for males (82.1%) than for females (61.0%), SD = _79.4; range from 7 to 397 days; median number of days spent in treatment was 98 days).The mean number of days in treatment for all patients (completers and dropouts) was 117.1 days  and male  patients was not statistically significant, t(287) = 1.71, p = .09.The difference in LOS between female (t(287) = 11.52, p < .001. The earliest a patient completed the treatment was in 94 days, whereas the longest a patient required was more than a year (397 days).Completers stayed in treatment for an average of 197.4 days compared to 92.3 days for dropouts, and the difference was statistically significant, M = 24.4, SD = 9.09) were statistically significantly higher on psychological pain than completers were , t(287) = -2.82, p = .005. MBP scores were also significantly higher for dropouts with briefer length of stays (LOS < 65 days) than for dropouts with longer LOS  = 3.34, p < .001).Although overall MBP scores were in the low moderate range for the total patient population , patientr = –.20, p = .001), then with BDI  and with BAI . LOS was not correlated with hopelessness .LOS was negatively correlated with psychological pain (MBP), depression (BDI), and anxiety (BAI), with the correlations being statistically significant (see Fifty-three patients (18.3%) met the criterion for high psychological pain—the threshold to consider patients as experiencing high psychological pain (MBP≥32) was established in 2011 and shown to be applicable in two separate clinical populations of 72 and 57 patients . As illustrated in 2 (2) = 5.02, p = .025, odds ratio 2.79, relative risk = 1.21. Regarding treatment retention times, patients scoring higher on psychological pain pre-treatment (M = 90 days) had a lower LOS than patients scoring lower on psychological pain did (M = 123 days), and the trend was statistically significant, t (287) = 2.75, p = .006. In addition, for only the patients who dropped out of treatment, LOS was statistically significantly shorter for those with high psychological pain (M = 73.1 days) than for patients with lower psychological pain (M = 97.5 days), t(219) = 2.31, p = .02. Although patients high in psychological pain exhibited diminished LOS and lower subsequent completion rates, robust increases in both of these variables for patients who remained in treatment for more than 100 days were observed. Specifically, when LOS was greater than 100 days, completion rates for the patients high in psychological pain increased from 11.3% to 35.3% and the low-moderate pain group increased from 26.3% to 48.3%. Overall, 96.8% of all completions for both groups occurred after 100 days of treatment.A logistic regression analysis was conducted to determine the effect of the dichotomized pre-treatment MBP scores  on treatment dropout. The results showed that patients scoring high on MBP pre-treatment were more likely to dropout of treatment than patients scoring low on MBP pre-treatment were to, χp = .011). Sixty-six percent (n = 35) of high scoring MBP patients had dropped out before the first patient completed the treatment program (day 94), and by day 129, 75% of high-category psychological pain patients had dropped out. Patients high on psychological pain reached 50% attrition after just 53 days compared to 108 days for patients lower on psychological pain.Kaplan-Meier survival analyses and retention curves were estimated to further compare the high (n = 53) and low-to-moderate (n = 236) psychological pain subgroups and to provide a visualization of LOS and dropout patterns. These analyses revealed significant differences between the patient curves (Log Rank p = 0.001) in terms of retention rates and patterns . Even atχ2 = 11.1, p = .001). (+) indicates individual patient-program completion event. There is a notable clustering of patient completions on the low-moderate pain curve while relatively absent on the high pain curve at similar time points.Program retention curves for High and Low-moderate pain categories. Log Rank analysis showed that the curves significantly differed between the high pain and low-moderate pain patient groups  and reduced likelihood for program completion. We chose program completion as a proximal indicator of overall treatment outcome as follow-up data for maintain abstinence were not available.Dropout was the most frequent treatment outcome for the SACS patients. This observation agrees with data from the Treatment Episode Data Set (TEDS) published by SAMHSA . Our patPre-treatment levels of anxiety, depression and hopelessness for the total treatment population indicated minimal comorbid psychopathology. A simple binary risk stratification method based on psychological pain (MBP scores), previously developed and applied to depressed and suicidal psychiatric populations , 12 re-gThere are a number of limitations to this modestly sized, retrospective observational study. Caution is warranted in generalizing our results pending replication in larger populations. Future studies would benefit from a prospective design, however, retrospective designs can be appropriately used in the context of multiple outcome measures . Chart dIn this study, we present evidence that elevated pre-treatment psychological pain may negatively impact program completion and LOS in outpatient substance treatment. The highest scoring patients on psychological pain assessment were ultimately 1.21 times more likely to drop out and to participate in treatment significantly fewer days compared with lower pain scoring peers. Whether this reduction in completion rates is a direct or indirect consequence of decreased LOS remains unanswered and further work in larger populations is needed to better understand these relationships. The survival curve analysis demonstrated a preferential clustering of completions on the lower pain group curve and relative lack of completions on the higher pain curve at identical time points. This suggests that a factor involving high psychological pain, apart from reduced LOS, may also negatively influence completion likelihood. Regardless, the study of psychological pain represents a novel area to further our understanding of the unpredictable outcomes in substance use disorders treatment. The subset of patients experiencing very high levels of psychological pain at treatment initiation may be inherently poorer candidates for outpatient substance treatment and early identification could allow for prompt referral to accessing higher levels of care. Efforts to further our understanding on the negative influence of high pre-treatment levels of psychological pain on completion rates and LOS offer additional opportunities for improving substance treatment outcomes.S1 File(XLSX)Click here for additional data file.


Factors associated with post-surgical pain are not fully explored. The aim of this study was to identify determinants of postoperative pain after arthroscopic surgery of the knee. Synovial tissue metabolism was analysed by microdialysis and the association with individual and peri-surgical factors to identify determinants important for pain management and thus patient satisfaction.2 (PGE2), glucose, and glycerol were measured by microdialysis in the knee synovium. Patients reporting VAS ≥ 4 received rescue pain medication with systemic opioids.Cross-sectional study of 57 patients (22 women) with median age of 39 years. All patients were operated on with arthroscopic surgery of the knee and monitored postoperatively with synovial microdialysis. The cross-sectional cohort was investigated to determine local tissue levels of inflammatory and metabolic compounds along with postoperative pain experience. Measurements: pain was determined by visual analogue scale (VAS). Postoperative synovial tissue levels of prostaglandin Ep = 0.04), lower body weight (p = 0.02), had a lower BMI (p = 0.04) and/or were smokers (p = 0.02). A closer analysis using multinomial logistic regression showed a significantly higher amount of pain in smokers (p = 0.01) and patients of a younger age (p = 0.02). A significant correlation was also found between VAS and duration of surgery (p = 0.007). No significant correlation could be found between VAS and synovial levels of PGE2, glycerol and glucose, but a statistically significant decline with time of PGE2 in both groups.Initial results indicated that patients with pain (interpreted as having VAS ≥ 4), i.e. those receiving rescue medication with systemic opioids, were of a younger age (p = 0.02) and smokers (p = 0.01), as well as an association between pain and length of surgery (p = 0.007). These findings point out individual factors useful for the prediction of postoperative pain after arthroscopic surgery and are clinically important for personalized pain management.The results from this study show a significantly higher frequency of pain, post-surgery among younger patients (II. In the c states –13. The The study design was observational cross-sectional cohort with surgery performed on eligible patients when operating room and laboratory personnel were available for performing microdialysis. The study period was between 2004 and 2013. The protocols for perioperative treatment, anaesthesia and the surgical procedures remained the same during the study. The study was conducted at the Department of Orthopaedic Surgery at Karolinska University Hospital in Huddinge, Sweden, with a catchment area representative of the general population.57 patients (22 women), healthy, apart from knee problems, were eligible for inclusion in the study. Informed written consent was obtained from each patient before inclusion.The inclusion criteria were indication for arthroscopic surgery of the knee due to intra-articular pathology  using the International Statistical Classification of Diseases and Related Health Problems (ICD-10). Patients with the following diagnoses were included in the study. patients undergoing arthroscopic surgery: derangement of meniscus due to old tear or injury (23), tear of meniscus, current injury (5), unilateral primary osteoarthritis of knee (2), other unilateral secondary osteoarthritis of knee (1), tear of articular cartilage of knee, current (3), damage to multiple structures of the knee joint (2), sprain of the superior tibiofibular joint and ligament (2), late-onset pain and discomfort after injury to the lower extremity (1), late-onset pain and discomfort after injury to tendon or muscle in the lower extremity (1), and sprain of cruciate ligament of knee (1).Performed type of arthroscopic surgery: arthroscopic partial excision of a meniscus in the knee joint (26), Arthroscopic partial excision of cartilage in the knee joint (2), arthroscopic synovectomy in the knee joint (1), arthroscopic exploration of the knee joint (8), arthroscopic or endoscopic reimplantation of a meniscus in the knee joint (3), other arthroscopic or endoscopic surgery on synovia or articulating surface (1).Diagnoses of patients with a cruciate ligament injury: sprain of cruciate ligament of knee 15) and damage to multiple structures of the knee joint (1). Performed surgery: arthroscopic reconstruction of a ligament in the knee joint without using a foreign material (16). ACL reconstructive surgery was done using the ipsilateral semitendinosus tendon as autograft. Exclusion criteria were known systemic inflammatory/metabolic diseases, or a regular intake of anti-inflammatory or other drugs known to or suspected of altering the metabolism of the knee joint. Patient characteristics are shown in Table 5 and damAll patients received a standardized premedication of paracetamol (2000 mg) and codeine (60 mg). The patients were not allowed glucose infusion, NSAID, or cortisone perioperatively. Anaesthesia was introduced and maintained using atropine 0.5 mg/ml, propofol 10 mg/ml, fentanyl 0.05 mg/ml and sevoflurane. The duration of the knee arthroscopic surgical procedure was 13–160 min.The method works by inserting a catheter with a tubular semipermeable membrane at its tip. When inserted, the catheter mimics the function of a capillary vessel by causing an equilibration across the semipermeable membrane between the interstitial fluid and dialysis fluid streaming through the probe. The equilibrated dialysis fluid is thereafter collected in a vial, and later analysed.2 using enzyme-linked immunosorbent assay ELISA  along with ethanol escape percentage measuring local blood flow. This was repeated five times. Microdialysis was done for a duration of 240 min (4 h) post-surgery. A total of six vials were collected from each patient  was injected into the knee joint, and a microdialysis catheter with a pore size of 20 kD  was introduced into the synovial membrane on the medial side of the knee under arthroscopic control. All catheters were perfused with a perfusion fluid  and the perfusion speed was 2.0 µl/min. The equilibration of the system started when a flush period of 40 min was finished. The first dialysate was collected after another 40 min. The samples were quickly frozen to minus 80 °C, and were later analysed together in the same assay for concentrations of glucose and glycerol with the CAM 600 , and PGEBlood flow was measured due to its regulating effect on cellular and extracellular substances through microcirculation. It was measured with the ethanol escape method (EtOH) , 15. TheMeasuring pain is commonly done using the visual analogue scale (VAS) , which is a subjective grading tool. The patients were asked to assess their VAS score every 40 min as the vials were collected. The patients who estimated their pain to be severe (VAS ≥ 4) postoperatively were offered pain medication (systemic ketobemidone). The patients were then divided into two groups depending on if they requested rescue medication (RM) or not (NRM). 47 of the patients had no need of rescue medication postoperatively. Ten patients had a higher degree of pain and required rescue medication. The first dose of pain medication was given at an average time point of 47 min post-surgery: a median of 2 mg of ketobemidone (1.5–3) iv. Four of the ten patients received a second dose on request: median 2 mg (1.5–3) iv. at average time 121 min post-surgery. One of the ten patients received a third dose of 2 mg iv. at 240 min post-surgery  and random effects . Variables showing significant univariate associations with pain were selected for a logistic regression analysis. Statistical analyses were performed using statistical software SAS version 9.4 .Continuous variables are expressed as median (10–90 percentile) and nominal and ordinal variables as percentage. The continuous variables were not normally distributed hence we expressed these variables as one standard deviation increase from the mean. Significance was set at the level of p = 0.04), with a lower body weight (p = 0.02), a lower BMI (p = 0.04) and a higher frequency of smoking (p = 0.02). There was a significant correlation between pain (VAS) and duration of surgery (p = 0.007) , based at study start Table . We foun07) Fig. . There wVAS Fig. .p = 0.02), gender (p = 0.15), smoking (p = 0.01) and 1-SD increase of BMI (p = 0.38) , with the RM group experiencing a higher degree of subjective pain. The curves differed significantly (< 0.0001).Factors that were associated with variability of VAS were evaluated using a multivariate mixed model. VAS showed a significant difference in subjective pain between the RM and NRM at 40 and 80 min (2. However, we found a statistically significant difference between the PGE2 levels at 40 min and the PGE2 levels between 120 and 240 min (Fig. Although a visual difference between curves, there was no statistically significant difference between the RM and NRM groups when using multivariate mixed model for the levels of PGEThe multivariate mixed models of glucose, glycerol and EtOH showed no statistically significant differences in or between groups. Overall the synovial tissue blood flow was stable.2, a mediator of central and peripheral pain sensitization [2, known as a pain mediator and a marker of inflammation, showed a visual difference between the NRM and the NRM group (Fig. 2 in patients requiring opioids [2 was significant in both groups post-surgery. This suggests a primary elevation associated with the initial pain and/or surgical trauma. Glucose levels showed no statistical difference between RM and NRM groups which is in contrast with other studies that demonstrate an increased consumption of glucose in the synovial membrane after minor arthroscopic surgery, but no change after ACL reconstruction [The most important finding of this study was that patients requiring rescue medication after arthroscopic knee surgery differed significantly in age, weight, BMI and smoking compared to those not requiring rescue medication. Multinomial logistic regression, showed a higher frequency of pain among young patients and smokers. These findings are in accordance with earlier studies , 5. The tization . The resoup Fig. . However opioids . The dectruction , 13, 19.The results of the present study show a higher degree of pain in younger patients, smokers, and after long-lasting arthroscopic surgery of the knee. This should be taken into consideration during planning and management of arthroscopic surgery to create a more effective and personalized pain management.


Thymus daenensis has been used since old times for the treatment of bone and joint deformities and pain in traditional medicine.Background: Osteoarthritis is a syndrome characterized by joint pain and reduced performance and efficien- cy in patient. T. daen- ensis with respect to the effect of the plant in patients with osteoarthritis.Purpose: This study was conducted to examine traditional usages and pharmacological features of Thymus daenensis gel, 1% diclofenac gel, or placebo for 6 weeks, along with oral celecoxib capsules. Patients were assessed in different intervals, based on the VAS score for assessment of pain in the joint and different dimensions of WOMAC questionnaire.Methods: 120 patients with osteoarthritis were divided into 3 groups. Patients in each group were treated by 5% P < 0.005), stiffness during the day (P < 0.05), morning stiffness (P < 0.05) and physi- cal performance (P < 0.05) were significantly different among the groups.Results: Pain level (Thymus daenensis gel improves the symptoms in patients equal and without significant difference than diclofenac group. It can be argued that its use can produce a satisfactory effect on patients with osteoarthritis due to its low cost, easy access, the plant’s natively occurring in Iran.Conclusions:  OAOsteoarthritisVASVisual Analogue ScaleWOMACWestern Ontario and McMasterThymus daenensis is one of the effective plants for treatment of osteoarthritis in traditional medicine. Thy- mus daenensis fresh leaves and stems have a pleasant smell that results from a combination of compounds in oils and extracts of this plant. In vegetative organs of thyme, a compound such as phenols, tannins, flavonoids, saponins, and bitter substances are found . Another study by Singh et al. on cancerous cells confirmed the effect of isoquino- line alkaloid on the decreased expression of cyclooxygenase-2 and reduced production of prostaglandin E2 and prostaglandin E2 receptors [57]. In the case of physical performance of patients, physical activity significantly improved in both groups received diclofenac and Thymus daenensis that significant difference was not found between two groups to end of the study. This can be due to a reduction in knee pain of patients during daily activities and improvement in other symptoms of the disease by reducing inflammation.The results obtained in the case of morning stiffness and stiff- ness of knee joint of patients during the day also indicated that there is of thyme , 21, 55.Although the effectiveness of the thyme gel was approved in this study, there are some limitations to generalize these results to the entire population, including the small size of the population used in this study. Lack of objective criteria for estimating the perfor- mance of the patients, despite validity and reliability of WOMAC questionnaire was another important limitation of the study. In addition, since the osteoarthritis is a disease with chronic nature, the study of variables at an interval after the intervention could be a limitation of our study. With increasing the period of study, we can have a better estimate of the impact and acceptability and safety of the gel. In addition, it determines side effects and topi- cal and general effects resulting from continuous using of the considered drug well.Based on the results of this study, the medicinal plant thyme could effectively reduce knee pain, morning stiffness and daily stiffness in the knees and improve physical performance of patients. In our study, no side effect for this plant was reported, so it can be ar- gued that its use can produce a satisfactory effect on patients with osteoarthritis due to its low cost, easy access, the plant’s natively occurring in Iran and no problem caused by the consumption of chemical drugs. It is suggested that be done further studies with different doses of the plant to be conducted to find the dose that has the highest impact and lowest side effect.


Radiation therapy (RT) results in pain relief for about 6 of 10 patients with cancer induced bone pain (CIBP) caused by bone metastases. The high number of non-responders, the long median time from RT to pain response and the risk of adverse effects, makes it important to determine predictors of treatment response. Clinical features such as cancer type, performance status and pain intensity, and biomarkers for osteoclast activity are proposed as predictors of response to RT. However, results are inconsistent and there is a need for better predictors of RT response. A similar argument can be stated for the development of cachexia; there are currently no predictors that can identify patients who will develop cachexia later in the cancer disease trajectory. Experimental and preclinical studies show that pain, depression and cachexia are related to inflammation. However, it is not known if inflammatory biomarkers can predict CIBP, depression or development of cachexia.This multicenter, multinational longitudinal observational study will include 600 adult patients receiving RT for CIBP. Demographic data, clinical variables, osteoclast and inflammatory biomarkers will be assessed before start of RT, and 3, 8, 16, 24 and 52 weeks after last course of RT. The primary aim of the study is to identify potential predictors for pain relief from RT. Secondary aims are to explore potential predictors for development of cachexia, the longitudinal relationship between pain intensity and depression, and if inflammatory biomarkers are associated with changes in pain intensity, cachexia and depression during one-year follow up.The immediate clinical implication of the PRAIS study is to identify potential predictive factors for a RT response on CIBP, and thereby reduce non-efficacious RT. Patient benefits are fewer hospital visits, reduced risk of adverse effects and more individualized pain treatment. The long-term clinical implication of the PRAIS study is to improve the knowledge about inflammation in relation to CIBP, cachexia and depression and potentially identify associations and mechanisms that can be targeted for treatment.NCT02107664, date of registration April 8, 2014 (retrospectively registered).ClinicalTrials.gov The European Palliative Care Research Centre (PRC), Department of Clinical and Molecular Medicine, NTNU, Faculty of medicine and Health Sciences, Trondheim, N-7491, Norway. Pain is one of the most frequent symptoms among cancer patients . About hCancer induced bone pain (CIBP) often present as a combination of somatic and neuropathic pain . When tuPalliative radiation therapy (RT) is a major treatment modality for cancer induced bone pain (CIBP), often together with opioids and co-analgesics . UnfortuBased on a relative high number of patients not responding to RT, time to treatment effect and the risk of potential side effects it is important to identify potential predictors for RT response. Former RT trials have used different pain assessments and different definitions for RT response. An international consensus on endpoints in RT trials were first published by Chow et al. in 2002 and updated in 2012 and have resulted in more comparable RT trials , 18. TwoImaging techniques may also be helpful to predict RT response. Two studies have demonstrated that low uptake on FDG PET-CT before RT predicted better RT response , 22. MRIThus, there is still not enough information to predict which patients who are likely to respond poorly, and consequently should not receive RT. To identify patients who have increased likelihood of successful analgesia from palliative RT would improve cancer pain management.In recent years there has been an increased interest among researchers to understand the correlation between the immune system and development of cancer and cancer-related symptoms. Inflammation is present in the majority of patients with advanced cancer , and it Based on results from pre-clinical studies several inflammatory mediators are proposed to play an important role in CIBP. The pro-inflammatory interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α are associated with nociception in animal models of bone cancer , 32. OthUp to 80% of patients with advanced metastatic cancer develop cachexia, and approximately 20 % of cancer deaths are attributed to cancer cachexia . Cancer The complete pathophysiology behind cachexia is still unclear. Most studies on molecular mechanisms have been performed on different animal models; studies in humans are scarce. Anemia, low serum albumin and increased inflammatory biomarkers such as CRP, TNF-α, soluble TNF-receptor 1 (sTNF-R1), IL-1, IL-6 and interferon (IFN)-gamma are observed in patients with cachexia . InflammDepression disorder contribute to reduced quality of life in patients with advanced cancer . DepressIn a cross-sectional study that also controlled for disease load, we demonstrated that by only using the 5 psychological depression symptoms for defining depression disorder, we could circumvent the challenge of the overlap between the somatic depression symptoms and symptoms of the cancer  45]. Ho. Ho45]. Patients with advanced cancer and depression disorder have more somatic symptoms including pain compared to non-depressed patients, but no appropriately designed studies to examine a possible causal relationship have to our knowledge been published. Clinically, a common observation is that long-lasting pain is associated with increased levels of depression symptoms. Still the direction of causality is not established and might be bidirectional. The relation between pain and depression has to be studied in a longitudinal design in order to better understand how they are related.Behavior corresponding to the depression symptoms, such as lowered mood, anhedonia, fatigue, sleep and appetite alterations, are also observed as a response to infections in mammals and then termed sickness behavior. Sickness behavior has been recognized as a symptom cluster that is associated with pro-inflammatory cytokine activation . In non-As cancer treatment develops, a wider range of treatment options are available to each patient, and the need for tools to determine treatment response arises to select the right individual treatment. The primary aim of the PRAIS study is to combine clinical and biomarker predictors to predict the response to RT for patients with CIBP.The availability and indications for new cancer therapeutics that modulates the immune system in order to delay development and even cure cancer have increased the last years, and a better understanding of the role of systemic inflammation in relation to cancer and cancer associated symptoms are of interest when the field of immunotherapy develops. To better understand complexity of systemic inflammation one need to extrapolate knowledge from pre-clinical studies to clinical studies with a robust study design. Secondary aims of the PRAIS study are, therefore, in a longitudinal study to explore the relationship between cancer related symptoms and inflammatory biomarkers during a one-year follow up.A multicenter, international longitudinal observational study of patients commencing palliative RT for CIBP.The primary aim of the PRAIS study is to investigate clinical and biomarker predictors of pain response after palliative RT for CIBP. In the secondary analyses of this longitudinal study we will explore association between inflammation and pain intensity, cachexia, and depression in patients with CIBP that undergo palliative RT, factors associated with development of cachexia in one-year follow up and correlation between pain intensity and depression Fig. .Fig. 1StAll patients admitted to palliative RT for bone cancer pain is eligible for screening.Verified cancer diagnosis, including hematological malignancies Bone metastases verified either by x-ray, bone scan, computer tomography (CT) or magnetic resonance imaging (MRI)Patients that are about to undergo RT with palliative intent for painful bone metastasesRT to be administered within 1 week after baseline observations are obtainedAge ≥ 18 yearsPatient able to comply with trial proceduresPathological fracture in long bonesPatients not consenting to participate in the studyOn-going RT or RT administered within the last 4 weeksPatients who are not able to follow the trial proceduresPrevious participation in this studyThe patients will be assessed at baseline and 3, 8, 16, 24 and 52 weeks after RT.*, gender*, ethnicity, height, comorbidity* (Charlson Comorbidity Index) [* [*, type of department , oncological history related to the current cancer disease *), planned RT  for the primary analyses*, re-irradiation, previous pain treatments  and medications and doses for the previous 24 h . In addition, an objective measurement of lean body mass, measured by CT scan of L3 and/or Th4 vertebrae will be performed at baseline.At inclusion the following information will be collected : Agey Index) , Karnofsndex) [* , living *, nausea* and constipation* will be included as variables), nutritional status (PG-SGA) [*), pain at rest and at movement from each planned irradiated site [*) and depression* (PHQ9) [* and self-report neuropathic symptoms and signs* (LANSS) [At both baseline and at all follow-up visits the following self-reports will be collected: Health related quality of life (EORTC QLQ-C15 PAL)  (for the(PG-SGA) , weight,(PG-SGA)  (for theted site  (for the* (PHQ9) . Specifi (LANSS)  will be Data on history of hospitalizations, changes in medications, new cancer treatment, treatment for hypercalcemia, new pathological fractures or spinal cord compression since last visit will be obtained at all follow-up visits Table .Table 1Fultiplex cytokine assay  will be carried out to analyse inflammatory biomarkers. Cytokines involved in bone remodelling will be analysed by EIAs using matched antibodies from R&D Systems. High-sensitivity CRP will be analysed on a MODULAR platform  For patients where collection of blood samples at follow-up is not possible (i.e. due to travelling distance from study center), the clinical data are obtained, and participation is allowed without the collection of follow-up blood samples , Meldola (FC), Italy; Hospital Universitari Arnau de Vilanova, Lleida, Spain; Castle Hill Hospital, Cottingham, United Kingdom.For all planned analyses baseline data will be presented with descriptive statistics; continuous variables as mean with standard deviation and categorical variables as frequency with percentages. A detailed overview of research questions and statistical analyses are described in the following section. All analyses will be performed using SPSS v 23  and STATA v 16 .Research question 1: Which are the clinical predictors and biomarkers predictors of pain response to palliative RT for CIBP?Objective: To obtain demographic, clinical data and biomarkers before start of RT and compare with RT response for pain in order to develop a classification system relevant for predicting RT response.Outcome: Primary endpoint is response to RT defined as at pain reduction of worst pain score of two or more at the treated site on the 11-point NRS together with no increase in analgesic intake, or a reduction in opioid intake of at least 25% from baseline without an increase in worst pain score at the treated site [ted site . PatientStatistical method: Clinical variables (see previous chapter) and CRP will be included in a multivariate logistic regression model to predict potential factors for response to RT. The model will be adjusted by study centre. Regression diagnostics will be performed for all analyses adding interactions terms if necessary. Significant variables from the multivariable model will be presented as a response-score to determine the likelihood of response to RT. Second, we will perform analyses on inflammatory biomarkers and bone biomarkers correlated with response to RT. Only inflammatory biomarkers and bone biomarkers with levels of serum concentrations above the detection threshold and which have a variability between measurements will be analysed with a multivariate logistic regression model with response to RT as the dependant variable. Finally, an integrated regression model with response to RT including both the significant clinical variables and significant biological biomarkers will be conducted if appropriate based on results from the previous analyses.Research question 2: Which inflammatory biomarkers are associated with change in pain intensity in patients with CIBP?Objective: To investigate the correlation between pain intensity and inflammation. Patients included in the PRAIS study all have CIBP and will receive a standardized intervention expected to give pain relief in about 60% of the patients. This study can explore if there is a longitudinal relationship between changes in pain intensity and the detected level of inflammatory biomarkers.Outcome: Serum concentrations of inflammatory biomarkers as described above associated with changes in pain intensity as measured by average pain intensity and worst pain intensity last 24 h (NRS 0–11) for a maximum of 1 year follow-up.Statistical method: Longitudinal data analysis with repeated measurements using a liner mixed effect model or generalized estimating equation (GEE).Research question 3: Which inflammatory substances are associated with cancer cachexia?Objective: To gain insight into the role of inflammation in cancer cachexia.Outcome: Cachexia is defined as a) weight loss > 5% over past 6 months (in absence of simple starvation); or b) body mass index (BMI) < 20 and any degree of weight loss > 2%; or c) appendicular skeletal muscle index consistent with sarcopenia  and any degree of weight loss > 2% [oss > 2% . CachexiStatistical method: Fist, we will perform a cross-sectional analysis in the baseline parameters using a logistic regression with cachexia as outcome, and the various inflammatory markers as explanatory variables. Second, we will investigate the association between changes in inflammatory markers over time and cachexia severity using mixed linear modelling.Research question 4: Which inflammatory substances are associated with depression in cancer patients?Objective: To explore the associations between serum concentrations of inflammatory substances and depression.Outcome: Depression is measured by the PHQ-9 questionnaire [ionnaire . The PHQStatistical method: We will use repeated measurements and a linear mixed effect model to perform the analyses.Research question 5: Which are the clinical predictors and biomarker predictors of development of cachexia in patients with metastatic cancer disease?Objective: To obtain demographic and clinical data and biomarkers in a homogenous population of patients with metastatic cancer, and within a prospective, longitudinal follow-up study observe which factors predicting the development of severe cachexia during one-year follow-up.Outcome: Cachexia is defined as for research question 3.Statistical method: As the purpose is to evaluate development of cachexia, only patients without cachexia at baseline will be included in this analysis. A Cox regression will be used to evaluate baseline predictors of cachexia development.Research question 6: What is the relationship between pain reduction and depression in patients receiving RT for CIBP?Objective: RT is expected to reduce pain in a substantial number of patients. This creates a possibility to study the relationship between depression and pain longitudinally in an experimental-like design in which one variable (pain) is manipulated and the effect on another related variable (depression) is studied.Outcome: Depression is measured as for Research question 4.Statistical method: Longitudinal analyses with repeated measurements analyzed with a linear mixed effect model.A signed consent will be obtained from all participants by an investigator at each site. The study will be carried out in accordance with ICH GCP and the World Medical Association Declaration of Helsinki (1964) and its’ revisions . The study is approved by The Regional Committee for Medical and Health Research Ethics, REC Central Norway, and by the regulatory authorities at each trial site. If modifications to the protocol, amendments will be applied for to the regional ethics committee and after approval distributed to all local study investigators.RT is indicated and will be given regardless of whether the patients choose to participate in the study or not. Thus, study participation means that patients consent to report symptoms and have their blood drawn. The volumes of blood samples are limited (less than 50 ml) and give no extra risk for anemia. Thus, the study includes no interventions that increase the risk for the patients. Data are handled anonymously. The database used for analyses only identify each patient by a study number. The linkage between study number and patient identity is in a document and / or memory stick stored in a safe at each study center.A Trial Steering Group will oversee the running of the trial. Members of the trial steering group include the chief principal Investigator, the principal Investigators of each centre, the Clinical Trial coordinator, and the trial statistician. After completion of the inclusions the Trial Steering Group will consists of the chief principal investigator, the principal investigators at all sites including 100 patients or more, and the trial statistician.The coordinating centre will administer the study. This includes development and administration of Case report forms (CRFs), monitoring of data quality and preparation of the final study report. (CRFs) will be supplied by the coordinating centre. Specific queries about data will be addressed to the clinical trial coordinator at each study centre.The results will be published in peer-reviewed journals. Authorship is based upon the Vancouver rules. All manuscript will be prepared by the researchers. The trial steering group will make decision related to use of data for publication. The principal investigator has access to all data. Access to researchers will be decided based upon the actual need for access relevant for analyses. Access to anonymously participant-level data set will be supplied depending on the journal policies.Clinical trials in cancer are mostly carried out to evaluate and compare different treatment strategies, medications and interventions. Whiles the effect of RT to treat CIBP is well documented, there is limited information about which characteristics that differs among responders versus non-responders. To achieve reliable predictors for treatment response, studies with large patient materials that obtain follow-up visits are needed. In this study, detailed clinical information, inflammatory and bone biomarkers will be collected before RT. These are all data and analyses that could be included in routine clinical practice to better select patients likely to have RT response. This can reduce the administration of non-efficacious RT. Patients will benefit from not spending time on futile treatment and not risking adverse effects related to RT as well as not delaying alternative pain treatments.Our research group has in the last decade published several papers on cancer pain and the relationship between pain and other cancer symptoms to improve cancer pain classification –61. InteThe investigation of the role of inflammation in respect to RT response for patients with CIBP and other cancer related symptoms like pain intensity, depression and cachexia is of a more explorative character. Current literature is mostly based on pre-clinical studies that needs to be investigated further in human studies. This study will include patients who all have on-going CIBP, which is a more homogenous population than usually seen in cancer pain studies. The patients will receive a standardized intervention expected to give pain relief in about 60% of the patients, and the study is therefore a unique possibility to identify which inflammatory substances that are associated with changes in cancer pain intensity. Improved knowledge about the pathophysiology of bone cancer pain and the role of inflammation can identify potential targets for therapy. The longitudinal design of the study also makes it possible to study the relationship between inflammation and symptoms of depression and development of cachexia. If biological factors are detected they could be used to identify which patients who could benefit from therapy directed towards hindering or delaying the development of severe cachexia or treatment of depression in cancer patients.As for all studies on palliative cancer patients we expect the number of drop-outs and missing data to be relatively high. A reason for drop-out before evaluation of treatment response may be that the patients are too sick or because of high symptom burden. These patients cannot be included in the predictive analyses as they are not missing at random and may bias the results. The patient inclusion is also for practical reasons not consecutive and the sample size of 600 do not allow for a validation sample analyses. Also, in order to assess the adverse effects from RT, a day-to-day evaluation of symptoms after RT would have given important information but were not performed in order to simplify data collection for the patient population.


Patients using opioids to treat chronic non-cancer pain often experience side effects that may affect health-related quality of life (HRQOL). These side effects include opioid-induced constipation (OIC), sedation, dizziness, and nausea. OIC can significantly affect HRQOL for patients on a daily basis. However, it is not well understood whether patients and clinicians view OIC management similarly.In this study, we sought to elucidate the decision-making process around managing OIC by assessing patient and provider treatment preferences, experiences, and communication regarding this condition.We conducted semi-structured interviews with 33 clinicians, and held three focus groups with patients who were currently using or had used opioids for chronic non-cancer pain. We then analyzed transcribed interviews using descriptive qualitative methods based on grounded theory methodology.Clinicians recognized OIC as a concern but prioritized pain management over constipation. They focused on medication-based treatments for OIC, but also recommended lifestyle changes  and reducing opioids to relieve symptoms. Patients reported using over-the-counter treatments, but the majority focused on diet-related constipation management. Patients reported not receiving adequate information from clinicians about OIC and relevant treatments. Cost of treatment was a major concern for both patients and clinicians.Assessing experiences with and preferences for OIC treatment, including cost, ease of access, and side effects, could improve patient-provider communication and HRQOL. Quality improvement efforts can target uncovered misalignments between patients and clinicians to improve communication about opioid medication adverse effects and relevant treatment options, which may help improve quality of life for patients with chronic pain. Opioid-induced constipation (OIC) is one of many potential adverse effects resulting from chronic opioid use. OIC can have a significant adverse impact on health-related quality of life given that individuals develop little to no tolerance to OIC. A systematic review of patients receiving opioid therapy for chronic non-cancer pain found that constipation was the most frequently reported adverse effect . In addiRecommended strategies to reduce OIC severity include lifestyle changes, such as increasing dietary fiber and fluid intake as well as physical activity, decreasing opioid dose or frequency, switching to another type of opioid, and using over-the-counter stool softeners, bulking agents, or laxatives , 4. OtheSeveral studies have examined patient preferences for and satisfaction with OIC treatments. One survey found that only 46% of patients on daily opioid therapy taking medications for constipation achieved desired results . Our groGiven increased concerns around opioid misuse, abuse, overdose, and death , 11, it We employed a qualitative descriptive study design and used inductive coding to ground the codes in data , 15. TheWe recruited patients for this qualitative study using flyers placed around the ambulatory care clinics, including primary care, rheumatology, neurology, and pain management clinics. Patients were screened by a study coordinator and were deemed eligible to participate if (1) they were 18 years of age or older; (2) used English as their primary language; and (3); were taking or had previously taken opioid medications to treat chronic non-cancer pain. Participants were not required to be taking opioids regularly for chronic pain treatment to be included in the study, as we wanted to capture different experiences with opioid use. We accepted all eligible patients in the focus groups and did not recruit based on any demographic characteristics. Patients were paid $50 for their participation.Clinicians were recruited via e-mails sent to all eligible healthcare providers affiliated with the academic medical center, including internal medicine and family practice physicians, primary care nurse practitioners, neurologists, rheumatologists, and pain specialists, including dentists specializing in orofacial and neck pain. Clinicians were eligible if they prescribed opioid medications for chronic non-cancer pain. Clinicians were paid $250 for their participation. As a member of the Department of Medicine at the institution where the interviews were conducted, B.S. was familiar with some of the physicians interviewed in the study; A.J. and M.S.K., who conducted the interviews, knew only one study participant prior to the interviews.We developed two semi-structured interview guides to elicit experiences with taking/prescribing opioid medications, side effects, and communication around medications and side effects (Appendix 1). The patient focus group guide concentrated on overall experiences with chronic pain, decisions to take opioid medications, side effects, and communication with clinicians about pain management and treatment options, both pharmacological and non-pharmacological. The clinician interview guide focused on the decision-making behind prescribing opioids, experiences prescribing opioid medications with different types of patients, and decision-making around side effect treatment. We refined the interview guide as we identified preliminary themes from the first few interviews .M.S.K. and A.J. co-led the focus groups and interviews. At the time of the study, M.S.K. was a doctoral student at the UCLA Fielding School of Public Health, had a Masters in Public Health (MPH), and was working at the medical center where the clinicians were employed as a clinical research coordinator. M.S.K. is trained in ethnographic methods and Constructivist Grounded Theory research and had previously conducted qualitative research. A.J. was completing her MPH at UCLA and served as both an intern and a research coordinator at the medical center. M.S.K. and A.J. are both women. The majority of the interviews were conducted in the clinicians’ offices, two were conducted in a private office in the researchers’ offices. M.S.K. and A.J. wrote field notes and memos following each interview. We received written informed consent from all study participants. The focus groups were conducted in a conference room in the researchers’ office space. Only the researchers and study participants were present during the interviews and focus groups. Study participants were informed that the research study was aimed at examining opioid prescribing, chronic pain care, and opioid use broadly. We did not send the transcripts or findings to study participants for review.M.S.K. is a health services researcher whose research is focused on patient-provider relationships, chronic pain treatment, and the prescribing of controlled substances. A.J. is a health services researcher and medical student interested in chronic pain. B.S. is a health services researcher and gastroenterologist whose research is focused on improving patient-provider relationships through mobile technologies.Interviews were audio-recorded, professionally transcribed, and verified for accuracy. A.J. and M.S.K. analyzed the interviews and performed line-by-line coding using Atlas.ti  and Dedoose . Using descriptive qualitative methods based on grounded theory methodology, we did not create a codebook prior to coding. Codes were created by reading through the transcripts and highlighting concepts that were recurring or significant . The anaA total of 13 individuals with chronic non-cancer pain were recruited and participated in three focus groups. Nearly all patients 12/13) were currently taking opioid medications for pain management. All patients were being managed by a clinician at the time of the study for their chronic pain condition. Four to five patients participated in each focus group, each of which lasted approximately 90–120 min. A total of 33 clinicians were recruited to participate in the individual interviews, which lasted 45–90 min. One clinician was interviewed twice to obtain further clarification on the first interview. Tables /13 were After creating approximately 46 codes, we organized the codes into two main categories: 1) general approaches to treating and managing OIC and (2) patient-clinician communication around OIC. Each of these main categories had several sub-categories, which we describe in depth below and also illustrate in Fig.  general Clinician PerspectivesI’m just - my impression is that I’m more reluctant than many physicians to use opioids, just because I’m concerned about the adverse effects and also in the older people … All you’ve got to do is give them severe constipation, and you can have a problem that’s as bad as, what you, what you used the narcotic for in the first place.” However, in contrast, one internist emphasized that the opioids “allow [patients] to function. They may get some side effects, the constipation and those type of issues too and sedation, but for a lot of people, they need it function.”Nearly all of the clinicians interviewed brought up constipation as a potential significant side effect of opioid medications. Several clinicians discussed being particularly cognizant of special populations who might be at higher risk for constipation, including elderly individuals, hospitalized patients, people taking other medications known to cause constipation, and those with limited mobility and muscle function diagnosed with conditions such as Parkinson’s and Amyotrophic Lateral Sclerosis. Balancing pain relief, function, and side effects, including OIC, was an important decision that clinicians raised when thinking about prescribing opioid medications. Two providers voiced concerns that for certain populations, the constipation from opioid medications could be worse than the benefit of the narcotics. Dr. V, a neurologist, noted, “Patient Perspectives“They say, ‘I cannot deal with that. [I’m] too constipated and I have to do something else.’” One patient with several chronic pain conditions described his concerns about using pain medications and his strategy to mitigate these concerns, saying, “When I started to have some pain I said, ‘Gee. You know isn’t there something I can take without too many side effects that will give me some relief?’ But as it turns out, there wasn’t … You get the lecture when you’re prescribed and you hear about all the abuse and I’m not a pill taker so I’ve always under-taken the prescribed amount and I’ve been told that that’s not good for me either because I’m not getting any pain relief. But it’s a balance that I look for.” Another patient experiencing temporomandibular joint dysfunction commented on the dose-dependent nature of side effects such as OIC. She explained her side effect management strategy by saying, “If I’m in one of those phases where things aren’t so flared up and I’m taking less than, you know, even what my supply is, then I don’t really have constipation.”Some patients also expressed concerns about balancing pain relief, function, and side effects, and several providers described conversations where a patient expressed wanting to avoid side effects such as constipation, nausea, vomiting, and drowsiness. One pain specialist, Dr. X, explained that patients would often stop taking opioid medications due to dizziness and constipation: Clinician Perspectives“then they call us and then we talk about more, like starting with over-the-counter things that they could try, like MiraLAX, stool softeners, those kinds of things.”Patients and clinicians differed slightly in their approaches to treating side effects, particularly constipation. Most clinicians emphasized over-the-counter medications, such as stool softeners and laxatives, and lifestyle changes, while patients mostly focused on dietary solutions. One primary care clinician noted that patients typically tried to problem-solve on their own by trying “prune juice” or “fiber” and if that wasn’t sufficient, “then you don’t make any other suggestions. Why rock their boat? But if they are having problems then there’s - you can make suggestions or prescribe things to help with it.” This strategy allowed her to reduce the number of drugs that patients were taking while still ensuring that patients were not suffering from severe OIC.Clinicians often heard stories from patients about managing constipation with “random teas,” foods such as “watermelon,” and other homespun remedies. One pain specialist, Dr. C, explained how she would ask patients about their strategies to deal with constipation and if they were satisfied, Patient Perspectives“I have to stay at home for an hour after my coffee and I have never had a constipation problem with that … The coffee seems to really take care of it.”Patients described different approaches to managing OIC, with a majority of patients turning to dietary strategies to manage their constipation. Dietary strategies included incorporating fiber capsules, fiber-rich cereal, prunes, figs, and fiber-rich vegetables into their meals and increasing fluid intake and coffee consumption. One patient, D, who had had several shoulder, neck, and back surgeries mentioned that he tried to take as little of his prescribed opioid medications as possible to avoid adverse effects, so he generally didn’t have major issues with constipation. He switched to a primarily vegetarian diet to increase his fiber intake and was confident that this alteration reduced his susceptibility to constipation. Another patient, K, who was diagnosed with osteoarthritis and back pain also described eating a high-fiber diet with a lot of salads. Several patients relied on black coffee in the morning to stimulate their bowel movements. One woman with severe arthritis who takes chronic pain medications said: Clinician Perspectives“you treat the dose of the medicine first. Okay. That’s number one. You treat the medicine first. So, you don’t ever want to add a medicine without taking down the dose.” Several primary care clinicians used a similar approach, using a “tapering and titrating” strategy. Noted one family practice clinician, “If you can taper the meds a little bit and titrate the fiber up, you might find a sweet spot because a lot of times the constipation can be more disconcerting than even the pain.” However, clinicians using this strategy noted that they sometimes faced resistance from patients when they attempted to taper down the medicine to reduce side effects. One internist noted that when trying to help an older female patient with severe OIC, the patient was resistant to decreasing the dose or tapering off the opioids: “They, they hate you when you want to – you know? I realized, I’m the evil messenger. I’m the one who’s telling her the emperor has no clothes.” He noted that after six months of working with the patient and bringing up tapering, the patient eventually left his practice.Clinicians, particularly specialists working in pain medicine, prioritized tapering down or switching medications to treat OIC. One clinician noted that before adding any sort of medication, even an over-the-counter medication, Patient PerspectivesPatients described taking fewer opioids than prescribed to avoid side effects such as OIC. Several patients were confident in their ability to manage OIC themselves by taking fewer opioids or increasing the time between doses. One patient with fibromyalgia and multiple musculoskeletal pain conditions expressed her interest in switching out her opioid prescription for medical marijuana, partly because “the constipation goes away after.”Clinician Perspectives“if the side effect is specifically constipation, I mean, there’s a lot of things that we can do and obviously now there’s medication specific to opioid constipation, which I think is just marketing, honestly. And not to say that it’s not effective, but I rarely need to use it.”Six of 33 clinicians interviewed brought up the use of prescription medications specifically used to treat OIC. Some clinicians considered using prescription medications used to treat general chronic constipation or their patients with OIC. However, in all cases, they reserved the use of prescription medications for severe constipation. Clinicians who used the drugs noted that they had only used them in rare cases for very severe intractable constipation. One internist, Dr. Q, noted that he didn’t buy the “hype” around these medications: I hate prescribing a drug to treat a side effect of a drug. So, if somebody has like end-stage [severe] constipation, I’ll really try to find a different [pain] medication.” They also expressed concern about adding additional medications to the long list of drugs that their patients were already taking. Explained Dr. C, “Oh, my God. It’s like the number of drugs people are on is unbelievable. And you look at it and you go, ‘Why are you taking that?’ Well, that’s to treat the side effect. If they’re on three drugs the fourth drug is to treat the side effect of one of the other three.”Several clinicians, including pain specialists and primary care clinicians, expressed reluctance to add another prescription medication to treat adverse effects and attempted to use other strategies to manage side effects, particularly constipation. These strategies included tapering down the medication or changing the medication. One pain specialist, Dr. C, noted, “I try to stay away from the, you know these expensive prescription drugs that have come out in the last five years for opiate induced constipation, I usually can avoid those with, hydration, fiber … They’re already, these people are also, tend to be on a lot of medication already so I’m not really looking to add something in. And in my experience, they’re not as effective as they make them seem, and they’re more expensive and they’re often not covered on their formulary and so it’s like a hassle all around.” Given the cost and access issues, clinicians explained that they preferred to recommend over-the-counter medications or lifestyle changes. Only one clinician, a primary care doctor, mentioned that patients specifically asked for an OIC medication by name, but said he often didn’t prescribe it because it was typically not covered by insurance.Cost and access to the medications was also an important issue with regards to prescribing drugs specifically used to treat OIC. Clinicians also noted that the prescription OIC medications were often not covered by insurance, making it challenging for them to prescribe these medications. One family practice clinician, Dr. H, who sees a large proportion of patients with chronic pain, explained: “Patient Perspectives“feel really uneasy in my stomach.” After one week of trying the medication, he switched back to Milk of Magnesia, which he described as his “medicine of choice. And it causes less gas etc. and it seems to work as long as I stay on it every other day.” Patients even expressed concerns about the cost of over-the-counter OIC medications such as MiraLAX or fiber-rich dietary items such as figs and prune juice, demonstrating that cost is an important issue to patients as well. One patient noted that he preferred when medications were prescription as opposed to over-the-counter, as the insurance would pay part of the cost of the medication.Patients also expressed issues with the prescription OIC medications. One patient with multiple chronic pain conditions noted that he tried one of the prescription OIC medications and it made him Clinician Perspectiveshave the discussion I just laid out, you know it’s tough for people to talk about their poop as it were, you know I mean what I’ll tell ‘em is things like, you know you don’t want to have to break up a log jam, you know so what you want to do is you want to get ahead of it, you want to be hydrated, and stool softeners.” Another clinician, a rheumatologist, worried that many of her patients were not aware that opioids can cause constipation and actively educated her patients on potential side effects when she prescribed narcotics. Constipation is “insidious because not everybody goes to the bathroom that has a bowel movement every day so they may not notice it for a few days and then – then it continues and then they think it’s because they didn’t eat something or whatever, so if you don’t educate the patients they don’t realize that the reason that they’re not having a bowel movement is because the amount of narcotics they’re taking.” One clinician noted that he specifically told his patients about all of the side effects because he didn’t want patients coming back to him and saying, “you know, you never told me,” so he spent a great deal of time explaining all of the potential adverse effects when he prescribed any medication, whether it be an antibiotic or a controlled substance. In contrast, other clinicians perceived that their patients were already aware of how to treat side effects, particularly constipation. One pain specialist perceived that most of his patients made dietary changes or increased fluid intake, explaining, “Most of the patients, for constipation they, they know how to do it. They drink more water, [are] more active, and eat more veggies, fiber.”Clinicians differed in their perceptions of whether patients were effectively managing OIC on their own. Several internists and family practice clinicians prophylactically prescribed or recommended stool softeners, laxatives, and lifestyle changes for their patients taking opioid medications. One internist, recognizing that patients are often too embarrassed to bring up constipation, noted that he will “Patient Perspectives“no one gave me a lecture on constipation. You know, they’ll say well, you know, you’ll have to take a laxative; you should take some laxatives, you know. But there wasn’t a prescribed laxative or this is better for you or not better for you.” She described how she wished her clinicians had brought up alternatives to treat constipation, including diet and lifestyle factors. Another patient mentioned that her pain specialist never brought up constipation and she experienced such severe constipation that she had to go to the emergency department. During her ED visit, she finally learned about stool softeners and stimulant laxatives.While many clinicians mentioned that they discussed OIC, some patients expressed that they didn’t receive enough information to manage the condition. One patient, a woman in her early 50’s with chronic jaw pain, discussed how Clinician PerspectivesI would leave that to the GI,” explained Dr. W, a family care practitioner who had been practicing for 11 years. Dr. K, a private practice internist noted that the medications “would probably be in the purview of people who manage cancer patients.”The question of who should treat OIC, particularly severe constipation, came up several times in the interviews, with clinicians of different specialties often looking to other clinicians to manage the condition. Several primary care providers noted that prescribing medications specific to treat OIC fell into the scope of practice of other specialties – anesthesiologists, palliative care experts, gastroenterologists – given that they see more severe pain and gastrointestinal cases. Several seasoned primary care clinicians acknowledged knowing little about the prescription medications and in some cases had never heard of the newer OIC medications. “I mean, I’m not a constipation expert, but if those type of things don’t work, then I’d say, you know what, see your physician, internist and see if they have some other recommendations.” Another clinician, a rheumatologist, noted that she ensures that patients have a good primary care clinician who can address more severe issues. She elaborates, “I will tell patients, ‘I’m like, listen, you know, this is, I don’t want to give you advise cause I’m probably gonna be wrong on this as to what the greatest and you know, latest things are,’ but I will say ‘look, you can try over-the-counter things and if you need something beyond that … talk to your internist about that’.” Practitioners who expressed these perceptions generally saw severe OIC and the prescription OIC medications as beyond the scope of their practice. As one rheumatologist explained, “If it was that bad, then they would be seeing their internist, or they’d be going to somebody somewhere to think about it.”On the other hand, several specialists in rheumatology and dentistry noted that while they gave some general advice, managing severe constipation fell into the realm of the primary care physician. If the over-the-counter medications and the lifestyle changes don’t work, one clinician said, “The surgeons never tell ‘em this stuff.” Several clinicians emphasized to patients that they should become advocates for themselves and bring up side effects such as constipation with their other providers. Dr. R, an internist who works primarily in the urgent care setting, explained that approximately once or twice a week, he saw a patient with severe constipation “because they were given a narcotic medication after a surgery or a procedure and they weren’t warned about the risks and given the appropriate medication to prevent that side effect, and aren’t even knowledgeable about it until we talk to them.” He discussed all of the potential side effects of opioid medications with patients and encouraged them to “make sure that the side effect is addressed, that you get a medication in case the constipation develops.”Clinicians also expressed frustration that other providers who prescribed opioid medications did not bring up constipation, especially in the context of post-operative opioid use, which several studies have found often progresses to long-term opioid use for chronic pain resulting from or aggravated by the procedure –18. Dr. Patient Perspectives“My doctor tells me about things that are not in his forte. They aren’t pain management. Like I had a problem with my bowels and he said go see a specialist for that … Constipation year after year after year …” She appreciated her provider’s forthcoming attitude and referral to gastroenterology to manager her OIC. Two other patients also described seeing a gastroenterologist after developing OIC during the course of their pain management therapy.Patients recognized that their prescribing clinician was not always comfortable treating opioid medication side effects. One patient with fibromyalgia noted, Clinician Perspectivese’ll get you down about twenty percent on this, it’ll help you be less constipated.” Another clinician, Dr. F, mentioned that he didn’t want to “buffer” patients’ side effects. He explained how when he gave patients an opioid prescription for a sore throat or for low back pain, he felt that the constipation and other side effects worked as “a nice built-in check to make sure that folks don’t overuse it … And that’s sneaky, but sorry, I do it anyway.” Dr. F made the distinction between using constipation as a strategy to discourage overuse for these two indications, but for patients who had come out of surgery, he would co-prescribe medications to reduce constipation. One nurse practitioner noted that when patients expressed concerns with side effects such as dizziness, sedation, or constipation and had stopped taking the narcotics, she actively supported the patient’s decision to stop taking the medications.Several clinicians used discussions about side effects, particularly constipation, as a strategy to ensure that patients didn’t become too comfortable using opioids or as a way to encourage tapering down doses. One provider, a family medicine practitioner, used constipation as a “motivation” to taper down his patients, explaining, “WClinician Perspectives“[it’s] the 75 year old who went in and you know fractured their pelvis and came out with narcotics is like, ‘My belly hurts so bad’,” but patients who have been taking opioids for a long time “don’t claim to have any side effects.” One clinician, Dr. A, an internist who had a lot of geriatric patients, explained that patients “probably won’t complain too much because they don’t want you to not give them [the medications].” Another clinician, Dr. J, a pain specialist, explained that she had “patients that come in and they’re begging for it so they’re not complaining of any side effects.” The burden of discussing things like constipation and other side effects thus fell upon the clinician who often had to probe in order to get patients to open up about potential side effects. Clinicians expressed different levels of proactivity with regards to discussing the issue, with some actively bringing it up during follow-up visits, while others assumed patients were likely to be managing the issue or not experiencing it since they did not bring it up. One internist who worked primarily in the urgent care setting noted that he thought patients who brought up side effects were more likely to be taking the medications for “legitimate pain” as opposed to patients who might be taking opioid analgesics for other reasons. In some cases, patients were actively managing their OIC but didn’t discuss it since it had become part of their daily routine. Dr. Z, the internist, explained that “some of them have been taking [opioid medications] for so long that they forget to tell you, ‘Oh yeah, I guess I do take you know a Docusate, you know, with it … ’ that became a normal part of my day-to-day thing.”Many clinicians chronicled how most patients who had been taking opioids for many years were reluctant to bring up side effects. Dr. Z, a primary care provider, recounted how patients who were new to opioid medications were more likely to bring up side effects: Yeah, and I’ll push you know and if I sense resistance I’ll say, ‘Look I’m not trying to embarrass you, though that’s fun too.’ [laughs] But no, I really do say it like that and people laugh and I say, ‘But you understand my job is, I have to pry, I have to push, I gotta get, for me to help you I’ve gotta get the information so if you don’t want to disclose it, it’s your right, but I can’t help you solve your problem.’” Dr. B and other clinicians described using verbal cues such as patients complaining of bloating, “belly pain,” gas, and nausea to try to understand whether the underlying issue was OIC.Embarrassment was another important reason that clinicians perceived patients did not bring up side effects such as constipation. One internist, Dr. B, used strategies such as humor to bring up sensitive topics. In his experience, patients usually made an appointment for one reason but were actually hoping to bring up issues such as constipation, impotence, or incontinence. When he sensed discomfort, he joked around with them or made it clear that they had to trust in him as a doctor, saying, “Patient PerspectivesHowever, in the focus groups, patients said they were not afraid to bring up side effects with their clinicians. Several patients appreciated that their doctors continually asked about side effects when refilling medications, including constipation, dizziness, and fatigue. However, many patients also wished their clinicians would bring up other concerns surrounding chronic pain, including mental health issues, sleep, and energy. A few patients mentioned that they had to bring up constipation with pain specialists and other clinicians, even when they were receiving monthly opioid prescriptions. A handful of focus group participants explained that they never experienced constipation severe enough to warrant a discussion with their prescribing clinician.In general, we found that patients relied more heavily on diet-related treatments, and while clinicians often recommended lifestyle changes — including increasing fiber, fluids, and exercise — many also heavily recommended over-the-counter medications or reduced the dose of a patient’s current opioid prescription. Although several clinicians were confident in patients’ ability to manage OIC on their own, many patients wished they had more information on OIC, other adverse effects, and treatment options. Additionally, despite recommendations that OIC treatment be prescribed or recommended prophylactically when opioids are initiated , we founWe also found that many clinicians viewed moderate-to-severe OIC as outside of their purview, preferring that the primary care provider or a gastroenterologist address these concerns. The provider interviews revealed that the perceived responsibility of managing OIC is dynamic and often falls between providers in lieu of a single provider taking control of OIC decision-making. However, if patients are relying on individual clinicians for their opioid medications, then the opioid prescriber may be the best person to address adverse effects directly rather than passing along the responsibility to other providers.In an oftentimes rushed primary care visit, patients may not always raise issues such as constipation, particularly if they are embarrassed or if they prefer not to mention their opioid use for fear of a discussion about tapering the medication. Clinicians who regularly prescribe opioid analgesics should be aware of the side effects and treatment recommendations for managing conditions such as OIC. With the increased scrutiny over opioid prescribing, many clinicians may be wary of co-prescribing medications that alleviate side effects, but for indications where opioid medications are considered appropriate, including certain chronic pain conditions, severe acute pain, post-operative pain, palliative care, cancer care, and end-of-life care, clinicians should regularly ask patients about constipation and other side effects to ensure that patients are well-informed about available treatment options. Regular clinical use of patient-reported outcome surveys such as the NIH Patient Reported Outcomes Measurement Information System (PROMIS®) GI questionnaires can help clinicians measure and address OIC symptoms consistently even when the clinician might perceive that a patient is hesitant to bring up the issue , 20.Our findings regarding clinician strategies to reduce opioid side effects are similar to those identified by previous research. Chancellor et al. interviewed clinicians from six European countries and found that clinicians often taper opioid doses to reduce the side effect burden, switch to other medications, advise patients to increase fiber intake, and then prescribe over-the-counter laxatives . Our finOur study has a few limitations. Our sample was limited to patients and clinicians in one geographic area , so the results may be less generalizable to other areas. Our study did not capture the socioeconomic status of the participants, so we were unable to assess whether socioeconomic status was associated with knowledge of OIC, OIC medication use, or concerns about cost of OIC treatments. Additionally, it is possible that patients not currently using opioid medications may have recall bias regarding their medication use and may not remember all side effects.We found that patients report being eager to discuss OIC and its potential remedies, despite clinician beliefs that patients rarely seek to raise these points during their consultation. For patients who are on chronic opioid therapy, regular discussions about OIC can help improve patients’ health-related quality of life. Patients also noted that they often do not receive enough information about treating constipation and other side effects. This lack of knowledge may lead to unnecessary provider visits that could be potentially avoided with more regular discussions about managing OIC. Offering patients educational handouts about OIC mitigation strategies when prescribing opioids may be a useful approach to initiating proactive conversations between patients and provider regarding this common opioid side effect. We also found that cost was a major concern for both patients and clinicians regarding treating OIC. Clinicians should discuss whether cost considerations are an issue for patients when treating OIC, as even some over-the-counter medications or dietary solutions might be too expensive for patients with lower incomes. Assessing patient preferences for treating OIC, including cost, ease of access, and side effects could improve patient-provider communication around this important and prevalent issue.