Introduction: In 2014, New York (NY) became the 23rd state to legalize medical marijuana (MMJ). The purpose of this survey was to collect data about practicing NY physicians' comfort level, opinions, and experience in recommending or supporting patient use of MMJ.Materials and Methods: An anonymous web-based survey was distributed to medical societies and to academic departments in medical schools within NY.Results: A total of 164 responses were analyzed. Physician participants were primarily located in New York City and surrounding areas. The majority (71%) agreed that MMJ should be an option available to patients. Most respondents were not registered to certify MMJ in NY, but were willing to refer patients to registered physicians. Common reasons for not registering included specialty and federal status of cannabis. More than 75% reported having patients who used cannabis for symptom control, and 50% reported having patients who inquired about MMJ within the past year. Most respondents are willing to discuss MMJ with their patients, but had little familiarity with the state program and a modest knowledge of the endocannabinoid system. Pain was a common symptom for which cannabis was recommended by registered physicians (69%) and purportedly used by patients (83%). Most respondents would consider MMJ as an adjuvant to opioids, and 84% believed opioids have greater risks than MMJ.Conclusion: Given that the majority of surveyed physicians support MMJ as an option for patients, few are registered and have adequate knowledge of MMJ. Although our study sample is small and geographically limited, our survey results highlight key physician issues that are likely applicable to practitioners in other states. Concerted efforts are needed at the federal, state, and academic levels to provide practitioners with evidence-based guidelines for the safe use of MMJ. They are classified as Schedule I under the Controlled Substances Act—substances considered to be the most harmful and conferring no medical benefits.4 With the exception of three Food and Drug Administration (FDA)-approved synthetic cannabinoid drugs, botanical cannabis and its constituents cannot be prescribed or legally dispensed outside of a federally approved research program. Physicians residing in states with MMJ laws, including NY, can only “certify” that patients have a qualifying condition and may “recommend” MMJ use, but cannot issue a prescription.6On July 7th, 2014, the Compassionate Care Act was signed into law, making New York (NY) the 23rd state to legalize medical marijuana (MMJ).8 Only 10 medical conditions were approved and a patient had to present with at least one of five qualifying symptoms. The qualifying conditions were as follows: amyotrophic lateral sclerosis, cancer, epilepsy, HIV/AIDS, Huntington's disease, inflammatory bowel disease, multiple sclerosis, neuropathy, Parkinson's disease, and spinal cord injury with spasticity. At least one of the following qualifying symptoms must have been present with a qualifying condition: severe or chronic pain, severe or persistent muscle spasms, seizures, cachexia, or nausea.8 Physicians who registered to certify patients must complete a 4-h course that provides an overview of the endocannabinoid (eCB) system, physiological and adverse effects of cannabinoids, and guidelines for dosing and administration. The NY-MMP combined several safeguards to mitigate potential diversion and MMJ abuse, and to ensure product safety.10 No smoking or possession of raw plant material was allowed; only oils, liquids, or pills that were either ingested or vaporized were permitted. There was a 30-day supply limit, no individual dose contained >10 mg of Δ9-tetrahydrocannabinol (THC), the major psychoactive compound found in cannabis, and dispensaries are required to report data to the Prescription Drug Monitoring Program Registry (PDMP). NY has since amended these laws to include two new qualifying conditions, to allow both nurse practitioners and physician assistants to register as practitioners, to reduce the educational requirement from 4 to 2 hours, and to expand the types of MMJ available to patients.11In the original law, the New York State Medical Marijuana Program (NY-MMP) had strict regulations for patients, providers, caregivers and dispensaries.12 To date, no physician survey about the NY-MMP has been published. The purpose of this survey was to probe NY physicians' knowledge and perspectives of the MMP and cannabinoids in patient care. As a large proportion of patients in other states with MMPs are purportedly certified to use MMJ for chronic or severe pain,13–15 there was a particular interest to assess physicians' opinions regarding MMJ for the management of pain.Physicians began registering with the NY-MMP in October 2015, and began certifying patients on December 23rd, 2015. Patients began obtaining MMJ on January 7th, 2016.This study was reviewed and approved by the New York University School of Medicine Institutional Review Board.17 but adapted to NY-specific needs  Health Commissioner, to the organization “Compassionate Care NY,” and to department chairs in academic medical centers in NY to disseminate to their faculty members. A total of 37 medical specialty societies, 60 county societies of the Medical Society of NY, and 12 academic medical centers were contacted across NY to participate in the study .Study data were collected and stored in a password-protected account using the online survey service company Survey Monkey. To further protect anonymity of participants to stop IP address tracking, “Anonymous Responses” was turned on in the survey settings. Only the principal investigator and actively involved researchers had access to the survey results. Strict control of data was maintained and no personal identifiers were collected or reported in the findings. Data were collected between August 3rd, 2016, and July 11th, 2017.Survey responses from close-ended questions were sorted and analyzed using Survey Monkey and Excel, and Prism statistical software. Responses from open-ended questions were analyzed through thematic categorization and frequency analysis.A total of 4 medical specialty societies, 11 county societies, and 6 academic departments from 3 medical schools agreed to participate in the study. All specialty societies had state-wide members; two were related to the pain specialty, one was anesthesiology, and the other was a family medicine society. Of the county societies that agreed to participate, one was a borough in NYC, three were surrounding counties, and seven counties were from Upstate. Of the medical schools that participated, one was located in Upstate NY and the others in NYC. The six academic departments were anesthesiology (2), physical medicine and rehabilitation (1), psychiatry (1), ophthalmology (1), and oncology (1).n=142) of respondents were not registered; only 8% were planning to register within the next year, but 73% were willing to recommend patients to registered physicians. Twenty-one (∼13%) of the respondents were registered with the MMP. Of these, 85% were in primary care, pain medicine, or palliative medicine and 75% were in private practice. Nonregistered physicians fell equally into academic/university and private practice settings , and were in practice for over 25 years (37%) . Of thessettings . Medicalsettings . Respondsettings .Among registered physicians, neuropathy (93%) and cancer (77%) were the most common conditions, while pain (69%) was the most common symptom for which MMJ was recommended . With reWhen participants were asked to rate their knowledge of the eCB system on a 5-point rating scale , 60% were somewhat or not well-informed (1–3) and 26% were informed (4), but only 14% were very well informed (5). The majority of respondents (71.2%) believed that MMJ should be an option available to patients . Regardin=88), anxiety , nausea , depression , cachexia , and 17.9% (n=19) for other indications, including for spasticity, sleep issues, and seizures.Approximately 95% of registered physicians and 49% of nonregistered physicians had patients who inquired about MMJ within the past year. All pain physicians (23/23) and almost all primary care physicians who answered this question (23/25) had patients who inquired. Most respondents  reported a willingness to discuss MMJ with patients, regardless of their registration status or specialty, if they felt their patient could benefit. Greater than 75% (118/156) reported having patients who used cannabis for symptom control: pain  reported prescribing them strictly for the FDA-approved conditions , 54% (n=21) reported prescribing them for pain as well. When asked to consider cannabinoids in a patient's treatment regimen, overall, 32.9% (48/146) would first opt for FDA-approved cannabinoids, while 30% (43/146) would choose NY MMJ as a first option. The other 38% (55/146) reported that choosing cannabinoids in their treatment regimen is not applicable to them.Approximately 25% of respondents (39/155) previously prescribed the FDA-approved cannabinoids. While 44%  prescribe opioids for their patients; 27% of the opioid prescribers would not consider MMJ as an adjuvant to opioids, 25% would consider it only for cancer pain or palliative care, and 48% would consider adjuvant MMJ for both nonmalignant and cancer pain. Compared to primary care physicians, pain physicians were less likely to consider MMJ as an adjuvant to opioids for both nonmalignant and cancer pain (56% vs. 35%), and were less likely to continue opioid therapy if, for an otherwise expected urine drug screen (UDS), THC was detected (63% vs. 19%) . Overall18 A May 2014 poll indicated that 88% of NY registered voters supported legalizing MMJ.19 Greater than 70% of physicians who took this survey believed that MMJ should be an option available to patients. Many have patients who inquired about or already used cannabis for symptom control; however, the respondents' familiarity with the NY program and the eCB system was modest. Evidence-based guidelines for practitioners are lacking. Given the increasing trend in MMJ use, research to address the safety, tolerability, and efficacy of various cannabis formulations alone and with other medications is an urgent public health need.Despite the fact that more than half of the United States has MMJ laws, little is known about physicians' attitudes toward these programs or their experiences with them. This survey study assessed the experience of practicing NY physicians with the state's MMP. Although the response rate was low, the survey results provide insight into future MMJ educational and research needs. MMJ is emerging as an option for many patients across the country, and there is an increasing trend for its demand.12 The most common qualifying condition was neuropathy (34.09%), and the most common associated condition or complication was severe or chronic pain (53.53%).12 These statistics align with the survey responses of the registered physicians regarding the reasons for certifying patients. As of July 2017, the number of certified patients in the MMP exceeded 20,000.1 With the addition of “chronic pain” as an approved qualifying condition in March 2017, ∼7500 new patients were certified by the end of June—a 50% increase in 3 months , while nabilone is approved for CINV.25–27 Of the survey respondents who prescribed FDA-approved cannabinoids, >50% indicated doing so, in part, for the management of pain. When given the scenario of choosing between FDA-approved cannabinoids or NY MMJ formulations as a first option in a patient's treatment plan, respondents were equally divided between the two. It is not clear why respondents would opt for one over the other, but it is intriguing that FDA-approved cannabinoids are not necessarily favored.During our study, the MMP only allowed the production and dispensing of mixed cannabinoid formulations (THC and CBD) as capsules or as liquid or oil preparations intended for metered oromucosal, sublingual administration or vaporization.15 Some patients substitute cannabis for opioids.28–34 Evidence suggests that cannabinoids may be effective adjuvants and can affect tolerance to opioids.35–42 Although cannabis does not lead to overdose deaths, its use can lead to cannabis use disorder and cognitive impairments,44 which could lead to risky behavior.45–50 Importantly, there is limited information on the risks associated with the use of MMJ alone or in combination with opioids. To our knowledge, this is the first physician survey to assess attitudes toward opioids and MMJ for the management of pain. Most physicians surveyed believe MMJ is safer than opioids. Approximately 75% of the opioid-prescribing respondents would consider recommending adjuvant MMJ, and almost half would do so for either malignant or non-cancer pain. Even if THC was found in their patients' UDS, most primary care respondents would continue with opioid therapy; pain physicians were divided in their approaches. In the 2016 Pain Treatment Guidelines from Oregon, another MMJ state, providers may ask their patients to choose between opioids or MMJ, adopt a “don't ask, don't tell” policy, or recommend CBD-rich MMJ as an adjuvant to opioids.51 In the CDC Guideline for Prescribing Opioids for Chronic Pain, UDS for THC is not advocated, stating that the clinical implications of doing so are not clear.52 Our survey results reflect that there is no consensus for how to manage opioid and cannabis use, underscoring the crucial importance of addressing their concurrent use in pain management.53The current opioid epidemic necessitates alternatives for pain control. Associations between the presence of state MMJ laws and decreases in opioid overdose deaths have been noted.54–57 Although MMJ state laws vary widely, common concerns among healthcare practitioners are legal uncertainties, inadequate knowledge, questionable efficacy, and abuse potential of cannabis. At the base of these concerns is the Schedule I status of cannabis, which creates legal ambiguity for recommending practitioners and imposes regulatory burden in the study of cannabis and its extracts. While the federal government supports therapeutic cannabinoid research and provides cannabis plant material,58 the current cannabis strains available from the National Institute on Drug Abuse do not reflect what is available in state legal markets.59 Well-controlled studies with cannabis products used in state MMPs are needed to address research gaps. With regard to abuse potential, recent national data indicate that up to 30% of cannabis users may develop cannabis use disorder.43 Furthermore, numerous reports link cannabis use with exacerbated or emergent psychotic symptoms, particularly in patients with a predisposition.50 Additional research is needed to harness the therapeutic potential of cannabis and to minimize potential risks to individuals.Physician surveys on cannabis have been conducted in several states and nationwide.There are several limitations in this study. The response rate was low, not all specialties were represented, and respondents were primarily located in two NY counties. Moreover, we cannot rule out the possibility of self-selection bias of survey participants. Societies and individuals who decided to participate in the study may already hold strong viewpoints regarding MMJ in patient care. Thus, the findings of the study may not be generalizable to all NY physicians. Furthermore, after the survey was disseminated, the MMP was expanded to allow nurse practitioners and physician assistants to register, and approved two more qualifying conditions. As the MMP evolves, future surveys to assess the perspectives of a broader group of practitioners may lead to a better understanding of education and policy needs.61 This survey study emphasizes that concerted efforts are needed to address the safety and efficacy of cannabinoids, particularly in pain management, so that practitioners are better able to inform and care for their patients.In accordance with recommendations made in the state's 2-year report, NY continues to enhance its MMP to provide additional educational resources and streamline the registration process.63 These states are uniquely poised to elucidate opioid-MMJ dispensing patterns. Interrogations of these patterns should yield novel insights into practitioners' regimens, patients' needs, and health outcomes at the state level.From a patient's perspective, it is not clear if cannabis helps control symptoms and if state certification is a desirable option. Future surveys to understand cannabis use from patients' perspectives are needed. NY, Connecticut, and Ohio are the only MMJ states requiring dispensaries to report data to their PDMP registries.Policies regarding recreational and MMJ continue to change rapidly. The potential future sanctioned use of MMJ from a federal perspective will depend on a more complex interplay between several stakeholders, including the FDA, Drug Enforcement Administration, and the National Institutes of Health. Ultimately, more research is needed to drive policy and guide the safe use of cannabinoids.


Triage is used to prioritize the patients in the emergency department. The majority of the triage systems include the patients’ pain score to assess their level of acuity by using a combination of patient reported pain and observer-perceived pain; the latter therefore requires a certain degree of inter-observer agreement.The aim of the present study was to assess the inter-observer agreement of perceived pain among emergency department nurses and to evaluate if it was influenced by predetermined factors like age and gender.A project assistant randomly recruited two nurses, who were not allowed to interact with each other, to assess patient pain intensity on the numeric ranking scale. The project assistant afterwards entered the pain scores in a predesigned electronic questionnaire.We used weighted Fleiss-Cohen (quadratic) kappa statistics, Bland-Altman statistics and logistic regression analysis to assess the inter-observer agreement.One hundred and sixty-two patients were included. They had a median age of 38 years and 45% were females. 30% of the patients were acute surgical patients and 70% acute orthopedic patients. The average time between the pain assessments were 1,7 min. The Bland Altman analysis found a mean difference in pain score of 0.2 and 95% limits of agreement of +/− 3 point. When the NRS scores were translated to commonly used pain categories  we found a 70% agreement with a mean difference in categories of 0.05 and 95% limits of agreement of +/− 1 category. Patient age, gender, localization of pain, examination room or presence of a significant other did not affect the inter-observer agreement.We found 70% agreement on pain category between the nurses and it is justified that nurse-perceived pain assessment is used for triage in the emergency department. Pain is one of the most common complaints in the emergency department (ED) . PrimariPain assessment is an integrated part of many triage systems, which determine the patient’s level of acuity and, thus, their treatment priority. Using patient-reported pain assessments creates risks of misclassification, either as over-triage, which binds resources unnecessarily, or under-triage, where a serious condition risks going unrecognized.Some triage systems have tried to compensate for this risk of misclassification by using observer-perceived pain assessment, either instead of or in combination with the patient-reported pain assessment. In the Danish Emergency Process Triage (DEPT), which has been implemented in most Danish EDs , patientHowever, observer-perceived pain assessments in the triage process require a certain level of agreement between ED nurses when rating patient pain. Thus far, no studies have examined the inter-observer agreement of perceived pain among nurses in an ED setting, which is the primary aim of this study. As a secondary aim we assessed whether patient location (emergency room or a ward room), type of pain or the presence of a significant other would affect this inter-observer agreement.This was a cross-sectional, single-center study conducted at the ED in the Hospital of Southern Jutland, Denmark, between October 23 and November 26, 2013. The ED consisted of “emergency rooms” equipped with facilities for resuscitations and surgical procedures and “ward rooms” with only a hospital bed and facilities for monitoring.All of the patients with musculoskeletal pain or abdominal pain assessed in the ED were invited to participate in the study if they were able to speak Danish, German, or English. Patients with obvious life- or limb-threatening conditions and patients who were unable to provide informed consent were excluded, as were patients with no pain complaint. We did not include patients with chest pain, as this group always receives high-level triage according to most triage systems, including the DEPT.Two project assistants identified the patients who met the inclusion criteria and received the informed consent to participate. All of the ED nurses participated in the study. Among the staff on duty, two available nurses were recruited to assess patient pain intensity on the numeric ranking scale (NRS) in the same way that they would normally according to the DEPT instructions. The first nurse went to the patient, secured privacy, and asked them to assess their pain on a 10-point NRS scale. The nurse then assessed the patient’s pain on the same scale without informing the patient of the result, went out, and immediately reported the patient’s score and the nurse score to the project assistant.The second nurse then went to the patient and performed the same procedure. The nurses were not allowed at any time to discuss or compare their results with each other. The project assistants entered the scores into a predesigned electronic questionnaire together with the time, patient age, gender, main complaint, the presence of a significant other, if the patients had received analgesics, and if the pain assessment was in an emergency room or a ward room.The data was collected on random days, including weekends, from 9 am to 6 pm, which was the time with the highest patient flow.The study was powered to detect a mean difference of 2 NRS points between observers, giving a sample size of 44 paired observations, based on a power of 90% and a confidence interval of 95%. For the kappa statistics, a kappa value of 0.60 was expected and the study was powered to detect a difference in positive proportion in a dichotomous test between observers of 10% with a 95% confidence interval not larger than kappa +/− 0.11, resulting in a sample size of 164 patients.The data from the electronic questionnaire was transferred to Stata 14 for statistical analysis.We used weighted Fleiss-Cohen (quadratic) kappa statistics, which accounts for a situation where there were constantly two raters but their identity varied and the rating was in ordered categories. We also calculated the Bland-Altman statistics to assess the agreement between the two rating nurses. We then transferred the NRS assessment to four categories of pain in accordance with the definitions in the DEPT: No pain 0, mild pain as NRS 1–3; moderate pain as 4–6 and severe pain as 7–10  and repeSince the study only involved an assessment of the patients’ pain, no acceptance from an ethical committee was required according to Danish legislation. The study was registered with the Danish Data Protection Agency.A total of 163 patients participated in the study. One patient received analgesics between the nurses’ respective assessments and was therefore excluded. The remaining 162 patients had a median age of 38 years (p25–p75: 20–61 years) and 73 were females (45%), 48 of the patients (30%) had abdominal pain and 114 (70%) musculoskeletal pain. The mean time between the two pain assessments was 1.7 min (95% CI: 1.2–2.3 min). The data was primarily collected during working days (76%). The inclusion time was from 9 am to 6 pm, with 57% of the inclusions performed before 2 pm.The mean NRS scores between Nurse 1  and Nurse 2  did not differ significantly (p: 0.18), with a Kappa-value of 0.55 (95% CI: 0.48–0.57), i.e. a moderate agreement . The BlaTable Table We found that when two nurses independently assessed the same patient, the inter-observer agreement had a kappa value of 0.55, which correlates to a moderate agreement.Transferred to commonly used pain categories of no, mild, moderate or severe pain, a 70% agreement among the nurses was found, with a 95% prediction interval of +/− 1 pain category. This was independent of age, gender, presence or absence of a significant other, whether the patient was assessed in an emergency room or ward room, or if the patient complained of abdominal or musculoskeletal pain. The nurses were disagreeing more than one out of four pain categories in only 1% of the assessments.Few studies have compared the inter-observer variation of pain assessment among nurses, and none of these studies have been in emergency departments. We are thus unable to compare our results directly with others in similar work environments. Studies based on theoretical pain cases revealed that there was a certain variation between nurses’ assessments, which could be attributed to the patient’s age, type and stage of illness, as well as the nurses’ professional experience and personal experiences of pain , 14. FurOur results have some clinical implications. The inter-observer agreement was lower than we had expected in a group of experienced ED nurses, who were well trained in using the NRS scale, but we found high inter-observer agreement when pain scores were transferred to commonly used pain categories. Also, the assessment of patient pain intensity where not influenced by different patient groups, age, gender, or other circumstances. Thus, our results justifies that nurse-perceived pain assessment is used for triage in the emergency department.The advantage of our study was that it is the first to evaluate the inter-observer agreement of perceived pain of patients in an ED setting and the study has a reasonable size. However, the study is weakened by a number of factors. It was performed in an ED where all of the nurses had been trained in the use of NRS scales and had a considerable clinical ED experience, on average more than 2 years. A more heterogeneous nursing staff might have produced different results. Furthermore, we did not include patients with chest pain, and our results should not be extended to this group of patients. Moreover, we did not include patients who did not complain about pain. This might be considered as a bias, but for the evaluation of the clinical use of a triage system, which uses pain as a variable, it does not make sense to assess patients who were not complaining of pain or had no pain-associated reason for referral to the ED. Finally, since the nurses first asked the patients for their own pain assessment and first made their own assessment thereafter, the pain score was not absolutely independent. As this is how the currently used DEPT and other triage systems are used, our study reflects the pragmatic usage of the triage.This is the first study to validate inter-observer pain agreement in an emergency department. We found 70% agreement on pain category between the nurses, and the pain assessment was unaffected by age, gender, localization of pain, examination room, or whether or not a significant other was present. This justifies that nurse-perceived pain assessment is used for triage in the emergency department.


The purpose of the current study was to examine the effect of a non-invasive, home-based biomechanical treatment program for patients with spontaneous osteonecrosis of the knee (SONK).Seventeen patients with SONK, confirmed by MRI, participated in this retrospective analysis. Patients underwent a spatiotemporal gait analysis and completed the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) and the Short-Form-36 (SF-36). Following an initial assessment, patients commenced the biomechanical treatment (AposTherapy). All patients were reassessed after 3 and 6 months of treatment.A significant reduction in pain and improvement in function was seen after 3 months of therapy with additional improvement after 6 months of therapy. Pain was reduced by 53% and functional limitation reduced by 43%. Furthermore, a significant improvement was also found in the SF-36 subscales, including the summary of physical and mental scores. Significant improvements were found in most of the gait parameters including a 41% increase in gait velocity and a 22% increase in step length. Patients also demonstrated improvement in limb symmetry, especially by increasing the single limb support of the involved limb.Applying this therapy allowed patients to be active, while walking more symmetrically and with less pain. With time, the natural course of the disease alongside the activity of the patients with the unique biomechanical device led to a significant reduction in pain and improved gait patterns. Therefore, we believe AposTherapy should be considered as a treatment option for patients with SONK.NCT00767780.Assaf Harofeh Medical Center Institutional Helsinki Committee Registry, 141/08; ClinicalTrials.gov  The knee, after the hip, is the second most common site for osteonecrosis (ON) . SpontanSONK is classically described as a focal, superficial subchondral lesion, affecting the medial femoral condyle in up to 94% of the time , 6. The Non-operative management of SONK includes treatment with non-steroidal anti-inflammatory drugs (NSAIDs), protected weight-bearing, analgesics, high-dose of vitamin D supplementation, and bisphosphonate . SurgicaIn the last half decade, several publications have described the effect of treatment with a unique non-invasive, home-based biomechanical therapy on clinical symptoms and gait patterns of patients with different musculoskeletal conditions including knee pathologies, such as knee OA –22, degeThis was a retrospective analysis based on a private clinic’s database. The protocol of the current study was similar to previous publications of our research group , 24, henA search for eligible patients diagnosed with SONK and confirmed by MRI was done on the clinic’s database from January 2010 to August 2015. Inclusion criteria for the study were SONK confirmed by MRI and having gait data and questionnaires at pre-treatment assessment and after 3 and 6 months of therapy. Exclusion criteria included a history of major trauma, predisposing factors of osteonecrosis, previous surgery to the knee excluding arthroscopy, and knee arthroscopy in the 3 months prior to the first assessment. Eighty-seven patients diagnosed with SONK commenced therapy during the abovementioned period. Seventy patients were excluded since they did not meet the inclusion criteria and/or had one or more of the exclusion criteria. A total of 17 patients were included in the analysis; their characteristics are presented in Table All patients underwent a spatiotemporal gait assessment and completed clinical questionnaires to assess pain, function, and quality of life at pre-treatment assessment and following 3 and 6 months of therapy.Anamnesis. During their first visit to the therapy center, patients underwent systematic assessment including a physical examination by a certified physical therapist and anthropometric measurements of height and weight.Spatiotemporal gait assessment. Using a computerized mat  [ont, PA) , patientClinical outcomes. Patients completed the Western Ontario and McMaster Osteoarthritis Index (WOMAC) to assess pain and function. This questionnaire contains 24 questions using a visual analogue scale (VAS). Results may range from 0 to 100 mm, with 0 mm indicating no pain, stiffness, or limitation in function and 100 mm indicating the most severe pain, stiffness, or limitation in function. The mean average of the 24 questions creates an overall score. In addition, three subscales are calculated: 5 questions to assess pain, 2 questions to assess joint stiffness, and 17 questions to assess function.Patients also completed the Short-Form (SF)-36 Health Survey to assess the quality of life (QoL). This questionnaire contains 36 Likert scale questions regarding different aspects of QoL. The SF-36 is scored between 0 and 100, with 0 indicating the worst quality of life and 100 indicating the best quality of life. An overall score is calculated from the results of all questions. Furthermore, eight subscales can also be calculated including physical functioning, pain, limitation due to physical health, vitality, emotional well-being, limitation due to mental health, social functioning, and general health. Two summarizing scores are also available: a physical component summary (PCS) which is the average score of the following four categories: physical functioning, pain, limitation due to physical health, and general health; and a mental component summary (MCS) which is the average score of the following four categories: vitality, emotional well-being, limitation due to mental health, and social functioning.The biomechanical device  utilized in the study and the treatment modality have been previously described , 26, 27.All spatiotemporal gait parameters and self-evaluation questionnaires scores were presented as mean and standard deviation, followed by 95% confidence interval for all time periods. Non-parametric one-sample Kolmogorov-Smirnov tests were calculated to compare the observed cumulative distribution function for the continuous variables with the normal theoretical distribution. The GLM Repeated Measures procedures and Friedman non-parametric tests were used to provide level of improvement for gait parameters and self-evaluation questionnaires when the same measurement was made three times on each subject.t tests.The comparison between the involved and uninvolved limb was conducted where applicable using paired The correlations between the changes in gait velocity (from pre-treatment assessment to 6 months’ follow-up) and the changes in pain and function (from pre-treatment assessment to 6 months’ follow-up) were assessed using Spearman correlations.Data were analyzed with IBM SPSS software version 23.0, and the significant level was set at 0.05.p < 0.001), stance (p < 0.001), and SLS (p < 0.001). After 3 months of treatment, significant differences between limbs were found in swing (p = 0.028), stance (p = 0.028), and SLS (p = 0.009). After 6 months of treatment, significant differences between limbs were found in swing (p = 0.011), stance (p = 0.011), and SLS (p = 0.009).All patients complied with the treatment and completed the study protocol with no adverse events reported. Significant improvement was found in all gait measures except for the base of support, stance phase of the involved limb, swing phase of the involved limb, and SLS phase of the uninvolved limb Table . FurtherSignificant improvements were also found in the clinical outcomes of pain, function, and QoL. Changes in WOMAC subscales are presented in Fig. r = −0.535, p = 0.027). The correlation between changes in gait velocity and changes in function was −0.553 (p = 0.021).The correlations between the changes in gait velocity (from pre-treatment assessment to 6 months’ follow-up) and the changes in pain and function (from pre-treatment assessment to 6 months’ follow-up) were calculated. A significant moderate correlation was found between the changes in gait velocity and the changes in pain , function (43%), PCS 44%), and MCS (28%), meeting the criteria for clinical significance , 37. Fur%, and MCTo the best of our knowledge, this is the first time a non-pharmacological, non-invasive treatment is offered to patients with SONK. This treatment is based on walking with a biomechanical device and allows patients to be active. The unique structure of the device, which can change the center of pressure and thereby change the loads at the knee joint, enables patients to walk with reduced pain while improving neuromuscular control. The current study showed positive results for patients with SONK, adding support to the positive effect of treatment for other knee conditions including degenerative meniscal tear , ACL teaSome limitations should be acknowledged. First, this was a single cohort study with no control group. The lack of a control group makes it difficult to conclude that the treatment is better than other alternatives. However, this study presents a positive trend and should be considered as an additional non-invasive treatment option for patients with SONK. It should be emphasized that none of the patients required any surgical intervention during the follow-up period. We acknowledge that further research is necessary and recommend that a future study should examine the effect of treatment for patients with SONK in a randomized controlled trial. This will support the preliminary results of the current study. Second, this was a retrospective analysis of patients seeking treatment at a private clinic. As such, the study population may have been biased to those who were exposed to this clinic rather than the entire population. We postulate that this had a minor effect on the results and that the group’s characteristics are good representatives of the population. Third, this study monitored the changes in objective gait patterns and clinical outcomes. Having a randomized controlled trial with an additional MRI assessment of the involved knee after 6 months would have given a clearer picture of the changes in the knee joint over time.Following 6 months of therapy, patients presented a significant improvement in gait and gained a more symmetrical gait pattern. Patients also reported a significant reduction in pain and improvement in function and QoL, meeting the gold standard criteria for clinical significance.


A patient’s recovery expectations prior to knee arthroplasty influence postsurgical outcome and satisfaction but a unidimensional measure of expectation has not been reported in the literature. Our primary purpose was to determine the extent to which a patient expectations scale reflects a unidimensional construct. Our second purpose was to identify pre-operative variables associated with patients’ expectations. We hypothesized that previously identified predictors of the latent expectation scale score would be associated with expectations and that previously unexplored variables of pain catastrophizing, depressive and anxiety symptoms, self-efficacy and number of painful body regions would also associate with pre-operative expectations.Our randomized clinical trial had 384 patients assessed prior to knee replacement surgery. The expectations scale along with several predictor variables including WOMAC, psychological distress, and sociodemographic variables were obtained. Confirmatory factor analysis tested the unidimensionality of the measure and structural equation modeling identified predictors of the latent expectations measure.p = 0.224; RMSEA = 0.035; 90% CI = [0–0.146]; CFI = 0.999; TLI = 0.993). The only variable significantly associated with expectations in the multivariate model was self-efficacy.The expectations scale was found to be unidimensional with superior model fit (χ2 = 1.481; df = 2; The expectations scale used in our study demonstrated unidimensionality and has strong potential for clinical application. Poor self-efficacy is a potential target for intervention given its independent association with expectation. Addressing expectations directly and indirectly through self-efficacy assessment may assist in better aligning patient’s expectations with likely outcome.NCT01620983.ClinicalTrials.gov  Patients’ expectations of post-surgical recovery, assessed prior to knee replacement surgery have been extensively studied . BecauseAs a construct, expectation may be conceptualized as a latent variable. As such, it can only be indirectly measured via the use of indicator variables. For example, the extent of pain relief and functional improvement a patient might expect following surgery are commonly used indicator variables in expectation scales developed for knee replacement surgery , 4, 8–14The most extensively developed and commonly referenced preoperative expectation scale for knee arthroplasty (KA) recovery is the Hospital for Special Surgery Knee Replacement Expectations Survey (HHSKR) , 11. TheWe recently recruited a multi-site sample of 384 persons with moderate to high levels of pain catastrophizing, an indicator of poor pain coping , for a rOne purpose of our study was to determine the extent to which the patient expectations scale reflects a unidimensional construct. We hypothesized that the scale would reflect a single construct. Our second purpose was to identify pre-operative variables associated with expectations of postsurgical recovery. We hypothesized that previously identified evidence-based predictors of preoperative expectations scale score , 17  conducted at 5 sites . Patients were recruited and signed an IRB approved consent form between January, 2013 and June, 2016. The current study was cross-sectional. Only the pre-operative baseline data were used to test the study hypotheses.n = 3641 were excluded, with n = 1694 not meeting inclusion criteria, n = 748 declined participation and n = 1199 excluded for a variety of other reasons. A total of 18 subjects who consented to participate had their surgeries cancelled for medical reasons after consent, leaving 384 subjects who underwent KA surgery subsequent to study admission.Patients were considered eligible for consenting to the study if they: (1) were aged 45 years or older; (2) had a diagnosis of knee osteoarthritis; (3) had KA surgery scheduled within 8 weeks following consent; (4) scored a 16 or greater on the Pain Catastrophizing Scale a score that was found to associate with poor WOMAC Pain outcome , and (5)n = 367) or partial knee arthroplasty (n = 17). A total of 32 surgeons performed KA surgeries across the 5 sites and the total number of patients seen by each surgeon ranged from 1 to 54.Patients were approached by a site coordinator within eight weeks prior to surgery and were informed about the purpose of the clinical trial. If patients expressed a willingness to participate, they read and signed an Institutional Review Board (IRB) approved consent form and then completed all required baseline data collection via an in-person interview. All patients underwent either total knee arthroplasty  Pain scores ranged from 0 to 20 with higher scores indicating greater pain with activity. Because greater preoperative pain is associated with worse outcome , we suspRace was dichotomized to African American subjects or all other subjects. African Americans are less likely to undergo KA and are less trusting of healthcare recommendations regarding KA surgery . We usedTo account for other variables that may be associated with both expectation and our predictors or interest, we also adjusted for patient age, sex, opioid use (yes or no), and education .Confirmatory factor analysis was used to test the measurement structure and baseline variables associated with the expectancy scale. We tested two measurement models: a one-factor model with and without the method factor and compared them during the model selection process. The best fitting model was subsequently used in the validation of the instrument using structural equation modeling. The measurement model specification with and without the method factor was motivated by the difference in item stems (“how likely” versus “how painful/limited”) as well as the response format difference between two sets of items (0–3 versus 0–10) that might potentially yield larger covariances between items with the same item characteristics. We used the M-1 method factor specification with unit factor loadings as suggested by Eid . Trait aTo account for clustered sampling design (patients nested within surgeons), we used the random intercept model to account for correlated data. Items with a 0 to 3 scoring format  were fitted as ordinal categories in all models because categorical outcome variables (factor indicators) violate the multivariate normality assumption.Using the appropriate measurement model selected using confirmatory factor analysis, a measurement invariance test was conducted between the gender groups followed by a structural model to identify predictors of the latent expectation construct. Potential predictors included demographic characteristics, preoperative pain, assistance at home, pain catastrophizing, depressive symptoms, anxiety, and number of pain sites, self-efficacy, and opioid use. Each predictor was testing using an alpha level of 0.05. Mplus software (version 7.4) was used in model fitting.We consented a total of 384 patients who underwent KA surgery. The average age of the sample was 63.18 (standard deviation/sd = 8.03) years, 34.9% were African American and 66.9% were female. The average pain catastrophizing score was 29.95 (sd = 9.27) and is indicative of persons with moderate to high levels of pain catastrophizing . The cha2 = 24.962; df = 2; p < 0.001; RMSEA = 0.173; 90% CI = [0.116–0.236]; CFI = 0.942; TLI = 0.826). A method factor had a superior model fit . The statistical difference between the two models was significant  indicating that the unidimensional expectation scale with a method factor was the best fitting model. Incorporating the method factor assures that the unidimensional Expectancy factor is not confounded with this source of systematic error (bias).Descriptive statistics along with skewness and kurtosis estimates for the four items of the expectations scale appear in Table The graphical representation of the measurement model with standardized factor loadings appear in Fig. p = .399; RMSEA (90% CI): .015 (0–.091); CFI = .999; TLI = .998. Based on the rule of parsimony, the results support the measurement invariance between males and females.Measurement invariance for sex based differences was assessed. The model with scalar invariance restriction  fit the model as well as the configural invariance model (factor loadings are freely estimated in both groups): χ2 = 7.29; df = 7; p < 0.01) with expectations such that higher (worse) scores in each of these predictors were associated with higher (worse) expectations. Opioid use was the only covariate associated with expectations (p = 0.043). Self-efficacy was negatively associated (p < 0.001) with expectations such that higher self-efficacy scores were associated with lower (better) expectations. Only one variable, self-efficacy, was associated with expectation after adjustment for all other variables in the model. Persons who scored higher on self-efficacy tended to score lower (better) on the Patient Expectation latent construct, as hypothesized. No other variable was associated with the latent construct of expectation after adjusting for all other variables in the model. A correlation matrix of all 13 predictors of the expectation latent variable appears in Table Structural equation modeling was used to predict the latent expectation variable using all predictor and covariate variables see Fig. . Standars p = 0.03. Self-eExpectations of postsurgical recovery, assessed preoperatively, are considered by orthopaedic surgeons to be an important and commonly used prognostic indicator of patient outcome and patient satisfaction after KA , 3, 6. IWe evaluated the measurement structure of the expectation scale  collecteOur findings related to correlates of expectations were unexpected. Only self-efficacy associated with expectation scale scores in our multivariate model. Several other baseline variables shown to associate with expectations in other studies  were associated with expectations in our study but not when adjusted for other variables in the model. Additionally, we hypothesized that pain catastrophizing, depressive symptoms and number of painful body regions would be positively associated with expectations in our sample, and all were associated but only in univariate analyses. We suspect the truncated range of scores for the PCS may have limited our ability to detect an association between pain catastrophizing and expectations. We specifically recruited persons with moderate to high catastrophizing and excluded persons with either a score of 0 or only mild catastrophizing.Prior work , 17 onlyHypothesized associations between expectations and potential correlates were obtained in prior studies using a variety of expectations measures on a broad spectrum of patients undergoing KA , 10, 17.The only hypothesized association we found in our multivariate model was between expectation and patient self-efficacy. The higher a patient’s self-efficacy, the better the preoperative expectation. Our data suggests that self-efficacy is an independent correlate and is moderately associated with expectations. Self-efficacy, the belief that one can control both pain and functional challenges associated with arthritis and KA can affect expectations negatively if the patient’s self-efficacy is poor. Addressing reasons for poor self-efficacy may assist in better aligning expectations with expected outcome leading to better results and potentially improving patient satisfaction, given substantial evidence indicating that about 20% of patients are dissatisfied with their outcome and a similar proportion have only slight or mild pain following recovery , 38. AltOur study had some important limitations. Our study design was cross sectional and the patients we studied had moderate to severe pain catastrophizing. This population may respond differently to expectations scales as compared to the general total knee arthroplasty population. Interestingly, the expectations scores in our sample suggested very high expectations, with mean scores of 5.05 (sd = 5.31) on a 0 to 40 scale with lower scores indicating higher expectations. Given the elevated risk of poor outcome for persons with moderate to high catastrophizing , 27, 36,We found that the patient expectation scale  is unidi


Alterations in muscle milieu are suggested as important activity of peripheral drive in patients with chronic musculoskeletal pain (CMP). Microdialysis (MD) has been used in monitoring altered metabolic response pattern in muscles. However, the insertion of MD probe causes a local tissue trauma. Whether and how metabolites in trapezius muscle are affected by acute tissue trauma is unknown. Hence, this study investigated the metabolic response and nociceptive reaction of the tissue following MD probe insertion in patients with CMP and healthy individuals. Fifty-nine patients and forty pain-free volunteers were recruited. Pressure pain thresholds (PPTs) were obtained at the trapezius and tibialis muscles. Pain questionnaires determined the levels of pain related aspects. MD (20 kDa cut-off) was performed in the trapezius and samples were collected within 40 min. Interstitial concentration of the metabolites was analyzed by a two-way-mixed-ANOVA. The metabolic response pattern changed over time and alterations in the level of metabolites could be seen in both CMP and healthy controls. Pain questionnaires and pain intensities manifested clinical aspects of pain closely to what CMP patients describe. Analyzing metabolites due to acute tissue trauma by aid of MD may be a useful model to investigate altered metabolic response effect in CMP. CMP is characterized as either regional, localized or widespread pain and severe states affect approximately 20% of the adult population in Europe with higher prevalence in women3. The majority of this population experience negative consequences related to the chronic pain problem affecting their socio-economic status and work-related activities. Hence, a reduced quality of life is reported3. Often the pain is a symptom driven by sensory inflammatory disturbances or tissue injury as a result of repetitive strain or work-related conditions4. On consensus, a complex network including biochemical pathways and psychological factors play a fundamental role. However, potential underlying mechanisms maintaining the ongoing pain are not well achieved but alteration in muscle milieu has been suggested as an important activity of peripheral drive in patients with CMP7. The Microdialysis (MD) technique has been used to provide important information on release of pain related substances and metabolic alterations in the trapezius muscle of chronic pain patients10. Higher interstitial concentrations of lactate and pyruvate have been found in patients with fibromyalgia and localized chronic myalgia10. In addition, increased levels of glutamate and lactate in muscles have been identified in patients with chronic widespread pain compared to healthy controls8. Since insertion of a MD probe causes local tissue trauma, a recovery period has been introduced before sampling in prior studies investigating muscle characterization and metabolism11 as the release of substances from the injured tissue may influence the findings12. A trauma phase period within 2 hours is normally considered to allow tissue normalization12. It is unclear however, if such inflammatory response would act on nociceptors and sensitize those13. This is in particular important feature as sensitization of nociceptors may last longer than the actual release time when it is initiated, and if such peripheral activity drive continues or become recurrent, it may lead to central sensitization that can be manifested as hypersensitivity in chronic pain patients. Whether metabolic alterations occur during this acute trauma phase are currently unknown. Initial steps have been taken by Gerdle et al.14 comparing levels of metabolites in the muscle collected during trauma phase of MD in women with neck-shoulder pain (CNSP), chronic widespread pain (CWP) and healthy controls. Although results indicate that different type of chronic pain conditions show different metabolic response pattern compared to healthy controls, questions remain whether this could feature a distinct response based on the type of chronic pain condition.Chronic Musculoskeletal Pain (CMP) is referred to a variety of different pain conditions affecting deep tissue structures in human body. The clinical description is often presented by diffuse pain localization, referrals, and deep tissue hyperalgesia or allodyniaTherefore, this study aimed at investigating the metabolic response pattern and nociceptive reaction of the tissue in the trapezius muscle of patients with CMP and healthy controls during 40 min of acute trauma introduced by a MD probe. In addition, we examined if any differences in metabolic concentrations would be related to sex and specific sub-population of patients in CMP.All participants completed the study without any detection or reports of safety issues. Four patients and one control subject were excluded from data analysis of the questionnaires due to lack of response. No significant differences in background data were seen between CMP  and CON  except for the BMI  were included in the analysis. No differences were found between the two groups in relation to age (P = 0.244) or BMI (P = 0.121). However, significant differences were found in the depression subscale of HADS , anxiety subscale of HADS , and in the Pain Catastrophizing Scale . A decrease in the concentration of glutamate was found from 20 min to 40 min in both groups; . However, at 20 min, Fcmp showed higher levels of glutamate (143.60 ± 13.54 µmol/L) compared to the female controls . No difference was found between the groups after 40 min of sampling (P = 0.985). An effect of time was found in the concentration of glycerol (P ≤ 0.000) with a decrease of 34.43 (18.59–50.28) mmol/L after 40 min. At group level, Fcmp had 0.41 (0.12–0.70) mmol/L higher concentration of lactate than the controls  were included in the analysis. No significant difference in age (P = 0.068) or BMI (P = 0.051) was found between the two groups , but no difference was found in the reference muscle between Mcmp and Mcon  and glycerol  respectively  µmol/L in the concentration of glutamate was found after 40 min (P ≤ 0.000). At group level, Mcmp had 32.01 (18.4–45.6) µmol/L lower concentration of pyruvate compared to the male controls. Interstitial blood flow was unchanged between the two male groups (P = 0.697) at both time points , Reg (n = 35) and Gen (n = 24). One control and two patients were excluded from the analysis of the pain questionnaires due to lack of response. A significant difference in weight was found between the two patient groups P = 0.016) as well as a difference in BMI was found between Con vs. Gen (P = 0.001), and between Reg vs. Gen (P = 0.006) respectively. Furthermore, both subgroups of patients showed higher scores in the pain aspects of HADS-D, HADS-A, and PCS compared to CON (P ≤ 0.05), but no difference was found between Reg and Gen. Gen showed the highest score within both subscales of HADS, however all scores were within normal ranges6 as wellComparing PPTs over the trapezius and tibialis anterior muscles, lower PPTs were found in Reg and Gen in comparison to CON on both sides of the trapezius muscle and in the reference muscle, tibialis anterior , glycerol , and Glutamate  in the trapezius muscle in patients with CMP and healthy individuals. The study was approved by The Regional Ethical Committee of Linköping University (project number: 2013/151-31) and was carried out at the PAINOMICS® Laboratory, Rehabilitation Medicine, Department of Medicine and health science, Linköping University, Sweden, within the period of 2014 to 2016. The study consisted of one session lasting approximately 2 hours and was conducted following the GCP guidelines and the declaration of Helsinki was taken into account.Fifty-nine patients  with chronic musculoskeletal pain (CMP) and mean age (SD) of 43.7 (10.6) years were recruited through review of medical reports of former patients and from the Pain and Rehabilitation Center, University Hospital, Linköping. Forty  healthy and pain free controls (CON) with a mean age (SD) of 39.6 (8.9) were recruited via local advertisement. Both groups of participants were assessed for eligibility through a routine medical examination at the clinic, which included information on weight, height, blood pressure and use of medications. The examination of pain patients also included current pain status, possible diagnosis, palpation of tender points and the localization of the pain marked on a standardized drawing of a body chart. Exclusion criteria in both groups were diabetes mellitus, inflammatory disease, neurological disease, systemic diseases, thyroid disease, heart and/or lung diseases or psychiatric disorders. Prior to the clinical session the participants were instructed not to take any non-steroidal anti-inflammatory drugs (NSAIDs) and to refrain from any strenuous exercise 48 hours before the examination. On the actual test day, the participants were not allowed to drink any caffeine-containing beverage, smoke or use any analgesics before the MD was performed. Additionally, any deviations from the instructions were noted. Upon meeting the eligibility criteria, baseline assessments for pressure pain thresholds (PPTs) over the trapezius muscle and the tibialis anterior muscles were determined for all participants. Subsequently, the MD was conducted in the trapezius muscle on the dominant side (CON) or the most painful side (CMP) of the participants and all subjects rated their pain intensity on a numerical rating scale  before insertion of the MD probe, after 20 and 40 min, and once upon the completion of MD. After examination, the participants were given a set of questionnaires characterizing different aspects of pain. All participants gave their written informed consent before the clinical examination was initiated.36,  were included in this study. The HADS is divided into two subcategories including 7 items. Each item is rated on a 4-point scale (0–3) resulting in a sum score ranging from 0–21. A score of 0–7 for either subcategory indicate normal ranges, score of 8–10 indicate suggestive presence, and score above 11 indicate potential presence of anxiety and/or depression. The PCS is rated on a 5-point scale , resulting in a total sum score ranging from 0–52.The following instruments; Hospital Anxiety and depression Scale (HADS) and Pain Catastrophizing Scale (PCS)Mechanical stimulation of the trapezius and tibialis anterior muscles were performed by a handheld electronic pressure algometer  with a standard flat-ended probe of 10 mm in diameter. Pressure was applied perpendicularly on the skin overlaying the region of interest with an increase rate of 30 kPa/s and a maximum of 600 kPa/s. The participants were instructed to report their PPTs by pressing a stop button when the sensation of the increasing pressure changed to the first sensation of pain. The stimulus intensity was then noted. PPT was determined on both sides of the trapezius muscle and conducted at two time points with a reference measure of PPT obtained over the tibialis anterior muscle on both legs. The average of two readings was calculated and used for further analysis and comparisons.37. Briefly, prior to insertion of the MD probe, the skin and subcutaneous tissue were anaesthetized with a local injection (0.5 mL) of Xylocaine (20 mL/mg). Two MD catheters  were inserted into the upper descending part of the muscle positioned halfway between the lateral border of acromion and pros. spinosus C7 with an inter-catheter distance of 2 cm. To reduce resistance from upper layers, a guided cannula was used to facilitate the entrance of the catheters into the muscle. A high-precision syringe pump  with a flow rate of 5 µL/min was used to perfuse the catheters with a Ringer acetate solution  containing 3 mM glucose and 0.5 mM lactate, 0.3 µL/m [14C]-lactate  and 0.3 µl/mL 3H2O (specific activity 37 MBq/gram). Glucose and lactate were used to mimic the component of biofluid presented in the intramuscular space38, and radioactive [14C]-lactate and trihydrate were added to calculate relative recovery (RR)39 and nutritive muscle blood flow (BF)40. After the MD probe insertion, samples were collected every 20 min during a period of 40 min. Each MD vial to collect the obtained samples was weighted on electronic scale before and after the procedure in order to verify consistent sampling to the actual flow rate set. All vials were placed on ice throughout the experiment and subsequently, the dialysate were transferred to Eppendorf tubes and stored at −70 °C until analysis.The MD technique in the trapezius muscle was conducted as previously described41 and further used to determine the true concentration of each analyte in the extracellular fluid. Nutritive trapezius muscle blood flow (BF) was estimated by the MD ethanol technique, using 3H2O instead of ethanol40 as the ratio of 3H2O in the dialysate and perfusate (outflow-to-inflow ratio of 3H20) inversely depends on the local blood flow in the muscle42. RR and BF were calculated as previously described in details by Olausson et al.41.3 mL of scintillation fluid  was mixed with 5 µL of the dialysate or 5 µL of the perfusate into a counting vial and vortexed. Secondly, β-counting was performed by the use of a liquid scintillation counter . RR was calculated as the extraction efficiencyDialysates were analyzed for concentrations of glucose (Gluc), lactate (Lac), pyruvate (Pyr), glycerol (Gly) and glutamate (Glu) by the use of ISCUSSflex Analyzer . The MD analyzer measures the concentrations using enzymatic degradation and colorimetric measurements and is calibrated against a standard concentration of each metabolite. Ranges of detection levels were presented as; [Gluc]: 0.1 to 25 mmol/L, [Lac]: 0.1 to 12 mmol/L, [Pyr]: 10 to 1500 µmol/L, [Gly]: 10 to 1500 mmol/L, [Glu]: 1.0 to 150 µmol/L.The statistical analysis was performed using SPSS (IBM SPSS version 23). Normality was checked by Shapiro-Wilk test and a P ≤ 0.05 was considered statistically significant. Descriptive statistics are presented as mean (SD). To evaluate demographic and clinical data, One-Way ANOVA (two-tailed) were used for group comparisons. The Bonferroni post hoc test was used in cases of significant differences between the groups. For analysis of interstitial concentration of each metabolite and muscle blood flow at the different time points respectively, a repeated analysis of variance (Two-way mixed-model ANOVA) was used with the factors time (20 min and 40 min) and group (patients and controls).


Music listening may reduce the physiological, emotional, and mental effects of distress and anxiety. It is unclear whether music listening may reduce the amount of opioids used for pain management in critical care, postoperative patients or whether music may improve patient experience in the intensive care unit (ICU).A total of 41 surgical patients were randomized to either music listening or controlled non-music listening groups on ICU admission. Approximately 50-minute music listening interventions were offered 4 times per day (every 4-6 hours) during the 48 hours of patients’ ICU stays. Pain, distress, and anxiety scores were measured immediately before and after music listening or controlled resting periods. Total opioid intake was recorded every 24 hours and during each intervention.P = .037). The Numeric Rating Score decreased in the music group but remained stable in the control group. Following discharge from the ICU, the music group’s interviews were analyzed for themes.There was no significant difference in pain, opioid intake, distress, or anxiety scores between the control and music listening groups during the first 4 time points of the study. However, a mixed modeling analysis examining the pre- and post-intervention scores at the first time point revealed a significant interaction in the Numeric Rating Scale (NRS) for pain between the music and the control groups (Despite the limited sample size, this study identified music listening as an appropriate intervention that improved patients’ post-intervention experience, according to patients’ self-report. Future mixed methods studies are needed to examine both qualitative patient perspectives and methodology to improve music listening in critical care units. This fear is intensified by the unfamiliar environment of critical care units which is often described as less than “patient-friendly.” The result, coined “intensive care unit (ICU) anxiety,” is often attributed to higher levels of noise and light pollution in critical care settings3; however, this ICU anxiety is truly multifactorial,4 often affected by postoperative pain. Clinical practice guidelines have recommended nonpharmacological interventions such as music therapy for the management of pain in critical care patients.5 Critical care nurses are in a unique position to investigate the efficacy of complementary, nonpharmacological interventions for reducing the burden of acute, postoperative pain and to examine methods for creating an ICU environment more conducive to healing.Music listening is a common, frequent, and universally enjoyed human endeavor. Listening to music, whether it is the classical notes of a Bach concerto or the hard beat of rap, produces powerful emotional, mental, and perhaps even spiritual feelings. These complex qualities and attributes of music are not easily explained.69 and has many advantages including its low cost, high feasibility, and low risk of adverse effects. Music is believed to be part of the neurological reward pathway, and stimulation of the mesolimbic system by music has been demonstrated by Menon and Levitin10 using functional magnetic resonance imaging (fMRI). Music may divert the listener’s attention away from an unpleasant episode, such as pain, and instead focus attention on the music listening experience.1 In a Cochrane Review, music listening experiences were reported to provide peacefulness and tranquility to hospitalized patients during a time of great distress; for example, patients undergoing treatment for coronary heart disease.11 The purpose of this randomized, controlled trial was to determine the efficacy of music listening as a means of reducing pain, anxiety, distress, and opioid use in patients admitted to a critical care unit following surgery.Music has been used as a means of reducing patient anxiety before, during, and after surgeryThis study was a randomized, controlled trial that evaluated the effects of music listening on eligible surgical patients’ opioid use and self-reported pain, distress, and anxiety. Participants were consented preoperatively, but randomized postoperatively to either a music listening or a control group. The control group received standard postoperative care supplemented by an approximately 50-minute period of rest instituted to match the 50-minute music listening period of the experimental group.ClinicalTrials.gov). The principal investigator screened and evaluated lists of surgical patients admitted to the NIH Clinical Center (CC) on a weekly basis, contacted eligible patients preoperatively, and invited them to participate. Adult (18 years of age or older) surgical patients at the NIH CC who understood and spoke English or Spanish, with an anticipated postoperative ICU stay of 24 to 48 hours, and anticipated use of a patient-controlled analgesia (PCA) device for postoperative pain management were considered eligible. Eligible patients were consented prior to surgery and data collection by the principal investigator or a trained associate investigator. Patients were not eligible for enrollment if they were scheduled for a neurological procedure, were visually or hearing impaired, or met criteria for severe anxiety. The General Anxiety Disorder (GAD-7) questionnaire was used to screen for severe anxiety,12 as music listening was not anticipated to mitigate its effects.13 Therefore, patients with a GAD-7 score of 15 or higher (15-21 = severe anxiety) were excluded.This study was conducted over a period of 18 months (August 2011 to February 2013). Study approval was obtained from the National Cancer Institute’s intramural Institutional Review Board  and Numerical Rating Scale (NRS).21 In completing the VAS, patients indicated the severity of their pain on a scale with markings from 0 to 100 mm.20 A marking of 0 mm represented no pain and 100 mm represented the most severe pain.20 Patients verbally reported their pain on a scale from 0 to 10 to complete the NRS.21 The ETs score anxiety and distress on a scale of 0 to 10.22 All of these measures were previously validated in many other patient populations and are provided in the supplementary appendix.2326 Opiates, benzodiazepines, and other drugs that could effect patients’ tolerance to pain medication were recorded 24 hours before surgery and during the postoperative period.Participant demographic data were recorded and patients were educated on the use of the PCA device. In addition to the GAD-7, preoperative anxiety was measured using the State-Trait Anxiety Inventory (STAI) and the Emotional Thermometers (ETs) with permission from both authors.The critical care unit at the NIH CC is a multidisciplinary, 18-bed medical-surgical unit that admits patients requiring intensive monitoring because of critical illness; all admitted patients are participants in a research-related protocol, directly related to their illness. The critical care unit is staffed by critical care nurses, respiratory therapists, and intensivists. The surgical patients are jointly managed by surgeons and intensivists. Acute pain management techniques involve intravenous opioids and/or peripheral or epidural PCA. Postoperative management commonly involves epidural catheters and PCA devices. Nurses usually care for a maximum of 2 patients. On ICU admission post-surgery, subjects were randomized to either music listening or control groups. Randomization criteria included the ability to verbally answer questions regarding pain and anxiety. Patients who were intubated were not randomized. In addition, an active order for pain medication using a PCA device was required. Randomization was conducted using opaque, sealed envelopes with group designations that had been prepared previously by the statistician using a computer-generated, permuted block randomization schema. The research staff was blind to the contents of the envelopes. Once the patient was randomized, the appropriate bedside booklet was provided that listed all the measures and time points for ease of documentation by the nurses in the ICU. Prior to beginning the study, this booklet and all the study measures were reviewed by the ICU staff.27 Patients were instructed to listen to the entire selection. The music from this company was selected for use in medical settings and had been used in similarly designed studies.29 The control group participants experienced approximately 50-minute quiet resting periods at the same frequency as music listening participants. No restrictions were placed on nursing care or medical care during interventions. However, each nurse was asked to perform a “settling routine” before the intervention to prepare the surgical patient. Repositioninng, mouth care and dimming lights were part of this routine. Both groups received this settling routine. Initially, music listening patients received a maximum of 3 sessions each day, at approximately 8-hour intervals. Music intervention periods did not occur more often than within 4 hours of the previous session. Other than these limitations, patients could ask to listen to the music at any time during their 48-hour ICU stay. After enrolling the first 3 patients to the protocol, music interventions were increased to every 4 to 6 hours to maximize the frequency of interventions among patients who were discharged earlier than 48 hours. The control group also followed these guidelines.The music listening group was exposed to the MusiCure Dreams album  using noise-canceling headphones for approximately 50-minute intervention(s) during their ICU stay.Supplementary Appendix B).30Before and after each resting period or music intervention, anxiety and distress were measured using the ETs, and postoperative pain was determined using both the NRS and VAS. Opioid intake was measured using PCA devices  during the entire ICU stay. Study participants were categorized by PCA opioid administration route, with epidural and intravenous PCA routes measured separately, in units of micrograms of fentanyl or milligrams of morphine. All opioids were calculated for each patient, including both PCA-delivered and additional doses of analgesia. All nonepidural opioids were converted to milligrams of morphine using a standard equianalgesic table calculation (Opioid administration was recorded during each intervention. Music or resting interventions were conducted for a maximum of 48 hours. Patients received a variable number of interventions (1-8 sessions) depending on the length of their ICU stay and their compliance. Interviews were conducted by the study team after ICU discharge to assess ICU and music study experiences.t test, 1-way analysis of variance, and the Mann-Whitney U test were used to examine the differences in demographic, clinical variables, and the main outcomes between groups. Unless otherwise noted, data are presented as mean values and their standard deviations.The study is a randomized, controlled trial with 2 groups: music listening and quiet resting control group. Descriptive statistics were performed on all study variables at each time point. Bivariate relationships of the main outcomes  were examined by correlations (Spearman correlation coefficient) for all cases. The Fisher exact test, 31 In linear mixed models, the response depends on both population-level parameters (fixed effects) and subject-specific random effects. Linear mixed modeling does not require the same number of observations in each subject. It also does not require that all the measurements be taken at the same time. In this repeated measures study, missing data can be predicted by the model. For mixed models, the estimates (“least square means”) and the associated standard error of the estimates with the P value are reported. All data analyses were done using IBM SPSS statistics version 21  and SAS version 9.3 . A P value of .05 or less was considered statistically significant.Linear mixed models were used to examine whether there was a change in pain, anxiety, or distress between groups during the first 4 interventions. The difference scores were calculated by subtracting the pre-intervention score from the post-intervention score for each intervention. A separate set of mixed models examined whether a statistical difference existed between the 2 groups, prior to and following the first intervention. Intravenous and epidural PCA opioid intakes were compared between music and control groups in the first and second 24-hour periods. A restricted maximum likelihood procedure was used for model parameter estimation. Akaike information criterion (AIC) and Bayesian information criterion (BIC) were used to compare models.Supplementary Appendix C). Independent thematic analysis was conducted by 3 research team members. This was followed by 2 consensus building meetings on the initial themes generated. These themes were placed in NVivo  to better visualize theme patterns and understand the prevalence of each theme. These themes were reverified by a team member (N.A.) with clinical ICU experience to further establish credibility and reproducibility of the generated themes.Qualitative analysis was performed from the transcribed interviews of the music group. A semi-structured interview guide was used with each participant . There were no significant differences in any of the characteristics among the music and the control group nor was there any significant difference among those 2 study groups and the participants who failed to randomize. Participants ranged from 27 to 83 years of age, with an average age of 54 years. Most of the study participants were white (83%) and had approximately 16 or more years of education . Other comorbidities, including diabetes mellitus, chronic obstructive pulmonary disease/emphysema, fluid and electrolyte disturbances, and cardiac arrhythmias were rare in the sample. There were a variety of admitting diagnoses, the vast majority secondary to cancer. Von Hippel-Lindau disease (n = 12), Birt-Hogg-Dubé (n = 3), and renal cell carcinoma (n = 3) were the 2 most common diagnoses in the sample. Other forms of cancer including rectal, renal, bladder, and lung cancers were also present in this cohort. A nephrectomy was the most common type of surgery.P = .01). The other screening tools were all strongly correlated with both State and Trait Anxiety with a P value at the .01 level, the ET Distress , and ET Anxiety , as well as the GAD-7 .All 59 patients completed the STAI, baseline ETs, and pain scales. The mean score for the state anxiety inventory was 34.8 (11.0) and the trait was 30.6 (9.4). The mean score of the GAD (n = 59) was 4.1 (2.9). The ETs had low mean scores at baseline with mean ET Anxiety of 2.6 (2.3) and the mean ET Distress of 1.8 (2.0). The mean VAS was 5.2 (10.0) mm and the mean NRS was 0.63 (1.31). The preoperative VAS and NRS pain scales were found to be strongly correlated . Similarly, within the first 24-hour period, average intake of opioids administered intravenously again demonstrated little difference in the music group  mg as compared with control subjects  mg . The same trend was observed within the second 24-hour period of ICU admission for music  mg and control  mg groups .P = .557, independent sample t test). However, none of these values were statistically significant. In the first 24-hour period, average intake of opioids in epidural PCA was higher in the music group  as compared with control subjects , but not significant . The reverse was observed within the second 24-hour period, in which the music group had lower epidural opioid intake  as compared with control subjects . Again, this value was not significant .P = .037)  mean score of 5.05 (SE: 0.53) pre-intervention to 3.34 (SE: 0.56) post-intervention, whereas the control group mean remained relatively constant at 3.67 (SE: 0.52) pre-intervention to 3.29 (SE: 0.53) post-intervention. Linear mixed modeling showed no significant difference between the music and control groups in pain, distress, and anxiety difference scores in the first 4 interventions. The differences in the model-estimated mean values and standard errors are presented in  = .037) . The calPatient interviews were conducted after ICU discharge with study participants who completed either the music or standard care interventions to assess patients’ ICU and study experiences. Three patients in the music group were not interviewed either because they refused or had been taken off the study. Seventeen music interviews were completed and analyzed qualitatively for common themes. Two researcher assistants and a nurse very experienced in qualitative techniques (G.R.W.) independently reviewed the transcribed interviews. Most of the interviews were performed by the principal investigator (N.A.). None of these reviewers had participated in the original interviews. Besides the 3 participants in the music group who asked to discontinue study participation after starting the first intervention, 2 other participants did not wish to continue listening to the selection after 2 interventions. These participants cited dislike of “confining” headphones and refusal to listen to music as reasons for stopping. Two patients out of 5 had pain scores of 10 when they requested to stop the music listening. No participants in the control/quiet resting group requested to stop the interventions at any time. One patient in the control group inadvertently listened to music before the last intervention. This additional intervention was not entered into the analysis. Three patients were only offered the intervention 3 times a day when the protocol first started. One patient refused to listen after starting the first music listening period as reported above.Music listening had no significant effect on opioid use between control and experimental groups  and 3. AIn addition, the differences in pain, distress, and anxiety scores did not differ significantly between groups. 3236 Many other studies examining the effects of music listening during various procedures, such as colonoscopy, also demonstrate this positive effect of music on pain and/or anxiety.3739 It is important to note that the insignificant correlation between music listening and anxiety scores in this study might be attributed to our small sample size relative to similar studies. However, to date, the effect of music listening on pain is small, subjective, and inconsistent.13 In the Cochrane review of 51 studies examining the effect of music on pain, only 14 studies were included that examined postoperative pain. Among these 14 studies, only a small percentage examined the effect of music on pain in a critical care environment.13 Recently, a meta-analysis examining music in pediatric surgery patients (n = 196) recommended music as a useful intervention for clinical use.40 Although music demonstrated a significant effect in the abovementioned studies, there are other examples in the literature that conflict with these studies, demonstrating conflicting or no significant differences between music listening interventions and standard care in reducing sedative or opioid use.4143 Many studies used only a single intervention and shorter intervention lengths of only 20 or 30 minutes,44 whereas this study implemented approximately 50-minute music listening or quiet resting periods. One recent study that demonstrated a significant reduction in anxiety allowed the ventilated patient to listen to music as often as requested.45 This ventilator study demonstrated a significant decrease in anxiety in intubated patients. Interestingly, the mean minutes per day for the ventilated patients who listened to music were 79.8 (SD: 126) with a median time of 12 minutes and a range of 0 to 796 minutes.45 We chose a music selection that was approximately 50 minutes in an attempt to standardize the “dose” of music that was received by each participant. Many studies used 20 to 30 minutes of listening time at varying times during the day or study.4648 Although we attempted to maximize the music listening “dose” through 50-minute periods, we acknowledge the subjective nature of the music listening experience and recognize a variety of both genres and durations may yield the greatest potential benefit.Studies examining the effects of music have had conflicting results. Some studies in postoperative surgical patients have demonstrated significant reductions in pain and/or anxiety after music listening.The significant finding identified in this study was a significant interaction between the pre- and post-NRS at intervention time point 1 . Using l50 The identification and development of an integrative, alternative modality that could decrease patients’ pain and anxiety throughout their recovery from surgery would be important. We hypothesized that music listening would have an effect in reducing pain, distress, and anxiety scores over time. We identified a significant difference in self-reported pain scores before and after the first intervention. No other effect of music listening was identified.Postoperative pain is linked to numerous, negative health outcomes, including poor wound healing, decreased immune function, increased length of hospital stay, and a prolonged recovery period.A strong significant correlation was also found between State and Trait Anxiety Inventories, ETs, and GAD-7 questionnaires. The STAI is a validated tool that has been the first choice of many researchers for quantifying anxiety; however, both the shorter and less-intensive GAD-7 and the Distress and Anxiety ETs were better suited for critical care and other clinical environments. This finding supports the use of the ETs in the critical care setting based on less burden to respondent and provider alike.The major limitations of this study include not only decreased sample size, but also lack of choice of music type, duration of listening, and lack of an objective measure of pain. The most important limitation in this study was sample size. The study was stopped after a discovery that the PCA device could not accurately deliver 2 mL or fewer per hour in the continuous mode. Recognizing that this alert would significantly change prescribers’ practices, the study was ended. Prior to this alert, only 1 patient in this study had been ordered a 2 mL/h or fewer continuous infusion. This patient received that rate for approximately 3 hours. In addition, the sample size was decreased as many (18) failed the randomization criteria postoperatively. Despite this small sample size and the exploratory nature of the study, interesting trends were identified. In addition, the small sample size prevented the stratification of results to surgery type. It would be important in future work to examine either one type of surgery or to randomize on surgery type such as abdominal or thoracic.45 suggests that participants should be allowed to listen to music unobstructed by the study parameters. Another limitation became clear as more participants were interviewed after listening to the music selected by the study team. An alternative design may include querying patients prior to surgery to select music genre.There is little agreement in the literature on the optimum time adults should listen to music to have the greatest effect. However, the recent study by Chlan et al51 With more research, this might be a useful tool to measure pain.Vital signs including blood pressure and heart rate could be used as objective measures of pain. However, in this study, because of surgery and anesthesia, these signs would not be appropriate as many patients may experience complications such as hypovolemia. Recently, investigators have been examining skin conductance as an objective measure for pain.The 50-minute “quiet resting period” may have affected the control group as this was not part of the standard postoperative care. Furthermore, despite frequent education and reminders, the nursing staff did not always complete all study interventions. In addition, many of the patients transferred out of the ICU sooner than predicted.52 This study underscores the complexity of music’s effects and further emphasizes that additional research is needed to understand the influence of music on pain.Another important limitation was the subjective nature of music listening and its potentially small effect on opiate use. A modality such as music listening may be more appropriately measured in a qualitative way rather than through a single outcome measure such as opiate use. “Music-induced analgesia,” as it was termed in one recent study of the effects of music on MRI findings, explained the intricate neural physiologic response caused by listening to music while invoking a painful stimulus.53 Currently, many critical care environmental studies examine how to decrease ambient noise without taking into account the patient’s need to be able to hear what is happening in the immediate surroundings. These studies should consider that patients desire auditory awareness in this setting. Therefore, the use of headphones in the ICU requires further study. Another issue points to the subjectivity of music. It is possible that allowing patients to choose their own music from a library of instrumental music with slow tempo, major key tonality, and other soothing attributes, such as nature sounds, would have made patients’ opinions more universally positive toward the music listening experience. Additional studies focused on the ICU environment, music, and its effect on critical care patients should be planned.One of the more surprising qualitative findings of this study was that music listening interventions inspired polarizing opinions and subjective experiences. Some patients had positive responses to music listening, but many were bothered by the music and/or the headphones. Although patients reported that music was a distractor, some patients disliked feeling disconnected and unaware of ambient noises. This response to wearing headphones, increased anxiety due to a reduction in ambient noise, has not previously been described in the ICU environment. In fact, just the opposite has been reported. In a recent publication, ventilated patients expressed that noise-canceling headphones helped them sleep and block out the noise of the unit when they were awake, therefore, decreasing anxiety.Music is an integrative, complementary modality that could provide a safe and simple intervention to critical care patients. In this study, some patients really enjoyed the music and felt that it was able to assist them with remaining calm and comfortable after their surgery. Because music listening is such a subjective experience, a larger sample size would be important to demonstrate significance and would be important in planning future studies. At the present time, offering patients music as part of their standard postoperative care is not done in most critical care units. More work is needed to characterize music listening as an intervention. However, this study suggests that this nonmedicinal approach to symptom management could have a place in this environment.