Hysterosalpingography (HSG) is an accepted radiologic diagnostic modality for initial infertility workup, and is generally considered uncomfortable and painful. However, the management of pain related to HSG remains inefficient. As an emerging nonpharmacologic and noninvasive pain control strategy, virtual reality (VR) distraction has been successfully used in areas such as burns, blunt force trauma, hospital-based needle procedures, dental/periodontal procedures, and urological endoscopy patients. This study aims to evaluate the analgesic effect of VR during HSG.A single-center, parallel-group, randomized controlled trial will be carried out in the Radiology Department of Yinchuan Women and Children Healthcare Hospital, Yinchuan. A total of 200 participants who are scheduled for HSG will be enrolled in this study. The participants will be randomized (1:1) into two groups: a VR group and a blank control group. The VR group will receive routine care plus immersive VR intervention and the blank control group will receive routine care. Outcomes will be monitored at baseline, immediately after HSG and 15 min after HSG for each group. The primary outcome is the worst pain score during HSG by a visual analog scale (VAS). The secondary outcomes include: affective pain, cognitive pain, and anxiety during the HSG procedure; worst pain within 15 min after HSG; patient satisfaction and acceptance with pain management; physiological parameters; adverse effects; HSG results; and immersion perception score of the VR system (for the VR condition only).This study will focus on exploring a simply operated, noninvasive and low-cost analgesia during the HSG procedure. The results of this trial will provide data on the feasibility and safety of VR distraction therapy during HSG.ChiCTR1900021342. Registered on 16 February 2019.Chinese Clinical Trial Register,  Infertility is clinically defined as 1 year of attempted conception that has not resulted in pregnancy; it is one of the most prevalent chronic health defects impacting young couples  of couplHSG is a minimally invasive gynecological procedure performed in the outpatient department which is generally considered to be uncomfortable and painful. It has been reported that 85% of women suffer operation pain, with half complaining of moderate to severe pain . CurrentVarious interventions have been assessed to decrease pain and increase patient compliance during HSG, including paracetamol , nonsterNonpharmaceutical therapy, including music therapy, hypnosis, massage and distraction, can significantly improve the patient experience while undergoing painful medical procedures , 14. ResTo date, and to the best of our knowledge, no study has examined the effect of VR intervention on women undergoing HSG. This clinical randomized controlled trial aims to evaluate whether VR intervention, when compared with a blank control group, could decrease pain and to evaluate the effects of pain relief on the ease of performing HSG for infertility diagnosis.The primary objective of this single-center, parallel-group, randomized controlled trial is to find out the clinical analgesic effect of VR intervention in patients during HSG compared with a blank control group. The secondary objectives of this trial include comparing the anxiety level during HSG between the two groups, evaluating the safety of clinical use of VR by recording adverse effects and physiological indexes, assessing patient acceptance for the nonpharmaceutical analgesia therapy and investigating the satisfaction of patients with VR.The trial has been approved by the Institutional Ethics Committee of Ningxia Medical University (reference no. 2018–233). This randomized controlled trial has been registered in the Chinese Clinical Trial Registry (ChiCTR1900021342). The whole study design is illustrated in Fig. This study will be conducted in the HSG room of the Radiology Department of Yinchuan Women and Children Healthcare Hospital in Ningxia province. This institution is an urban, public, tertiary-care teaching hospital, specializing in maternal care and childcare in Ningxia Hui Autonomous Region located in Northwest China. Annually 50,000 patients undergo treatment at the fertility clinic and approximately 1000 HSG are performed every year in this institution. It is therefore feasible to reach the target sample size in this selected clinical setting. We expect to complete recruitment within 10 months.Women will be recruited into the study according to the following inclusion criteria: 1) indications for HSG including infertility, recurrent miscarriage, and other miscellaneous reasons ; 2) agedThe exclusion criteria are: 1) use of antidepressants or sedatives; 2) presence of psychiatric disorders; 3) recent receipt of analgesics within 6 h; 4) allergy to contrast medium or iodine; 5) a recent history of acute pelvic inflammatory disease; 6) visual acuity <1.0 or hearing abnormity; 7) susceptible to motion sickness; 8) operator difficulty due to cervical adhesion or congenital variation, or completing the examination after multiple operations.In the Radiology Department, the HSG procedure will be carried out on each weekday by two gynecology assistants . The results of the HSG will be analyzed by a Chief Radiologist (who has worked in the HSG room for >10 years). These two gynecology assistants will receive training from the protocol conceiver.Recruitment will take place in the Radiology Department of Yinchuan Women and Children Healthcare Hospital. Participants for the study will be recruited through WeChat advertising and posters in the infertility clinic. After patients arrive at the Radiology Department they will be screened with a free preliminary physical examination and a check against the inclusion/exclusion criteria. The potential participants will receive information about the aims, benefits, and latent risks of the study from the protocol designer. If the patients wish to participate, they will be asked to sign an informed consent form that they agree to participate in the study and are willing to let the protocol designer publicize the research results, including pictures. Participants are entitled to withdraw from the study at any time and this will not prejudice their subsequent treatment. The whole process of recruitment follows the principle of respect for autonomy.A simple random sampling method will be used in our study. Patients who are scheduled for HSG and meet the eligibility criteria will be randomly allocated into either the blank control group or the VR group at a 1:1 ratio. The randomization sequences will be generated in advance with a computerized random number generator (random.org). This is performed by a statistical expert who is not involved in this trial. A sealed opaque envelope will be used to store the randomization sequences of all allocations. The random number table will be kept confidential by the full-time secretary of this project. Baseline data will be recorded as close to immediately before the HSG procedure as possible. After baseline data collection, the allocation will be revealed. Blinding is not feasible.www.zamertech.com). Under VR treatment, participants can travel on a canoe slowly through three magic virtual scenes  with Steam VR software. The VR environment comes from Zamer which is a software platform to distribute VR content  will be administered intramuscularly approximately 30 min before HSG to prevent fallopian tube spasm which could lead to false obstruction during the imaging examination during HSG.After placing the patients in the lithotomy position on the fluoroscopic table, the gynecology assistants help them to flex and separate the thighs to fully expose the vulva and then perform vaginal irrigation for local cleaning with antiseptic 1% chlorhexidine solution. After disinfecting the vulva with a standard 2000 mg/L iodophor solution, a sterile bivalve speculum is introduced into the vagina to visualize the uterine cervix. A 4-mm sterile uterus radiography balloon catheter is inserted through the cervical canal and a tenaculum used to hold the cervix only if it is difficult to insert. The gynecology assistant injects 2 mL air into the aerocyst in the uterus radiography balloon catheter. After filling the balloon, it is gently pulled back to fix the catheter in the internal cervical orifice to prevent contrast leakage. A water-based iodine contrast medium  in volumes of 5–15 ml is instilled through the uterus radiography catheter with fluoroscopic x-ray images obtained intermittently to assess the uterus and fallopian tubes. The whole procedure lasts about 20 min. At the end of the operation, the cannula and instruments are removed and the patient remains under observation for 15 min in the Radiology Department before discharge.In the blank control arm, gynecology assistants will perform the whole procedure as they usually would. In the VR group, the immersive VR system will be provided Fig. . After pDemographic data  and physiological parameters, including pulse rate, blood pressure and oxygen saturation, will be recorded by the investigator. In order to evaluate gynecologic and pelvic pain-associated histories, patients will be examined and their relevant medical history will be collected . Other indexes regarding pain score, baseline anxiety level, anxiety level during HSG, adverse effects, patient satisfaction and acceptance of pain management, as well as the immersion perception of the VR system, will be recorded by the researcher.Cognition and emotion are important factors known to regulate pain perception in clinical settings and laboratories . SensoryAny observed adverse effects will be carefully evaluated and recorded by the investigators. The expected adverse effects include gastrointestinal adverse reactions , adverse effects on the cardiovascular system  and any other discomfort . If any adverse effects take place, health care givers will administer corresponding treatment or nursing care. All severe adverse reactions and solutions during the procedure will also be noted. HSG results  should be recorded and compared. The physiological indexes will be monitored in terms of treatment safety with an electronic manometer  and oximeter (PC-60B).Participants’ demographic data, relevant medical history and baseline anxiety level, as well as pulse rate, digital monitoring of oxygen saturation and noninvasive monitoring of blood pressure, will be collected at baseline (T0) before the procedure. Patients will complete a series of assessment including three pain dimensions, physiological parameters , anxiety level during HSG, satisfaction and acceptance of pain management and adverse reactions along with the immersion perception of the VR system (for the VR group only) immediately after the procedure (T1). HSG results and worst pain will be recorded 15 min (T2) after the procedure. To promote participant retention, every woman who completes all data collections will receive a free overall analysis of the HSG results by an experienced gynecologist.The primary outcome measure will be the worst pain score experienced during HSG (by VAS). It will be collected by asking patients to rate “Your WORST pain intensity during HSG?”, ranging from no pain at all to worst pain possible.Secondary outcome measures include: 1) pain score of the cognitive component (by VAS), collected by asking patients to rate “How much time did you spend thinking about your pain during HSG?”, ranging from none of the time to all of the time; 2) pain score of the affective component (by VAS), collected by asking patients to rate “How UNPLEASANT was your pain during HSG?”, ranging from not unpleasant at all to excruciatingly unpleasant; 3) worst pain score within 15 min after HSG (by VAS); 4) anxiety score before/during HSG (by GRS), collected by asking patients to rate “How much ANXIETY did you have before/during HSG?”, ranging from none at all to extremely anxious; 5) patient satisfaction score with pain management (by GRS), collected by answering the question: “How satisfied were you with the holistic pain management during HSG?”, ranging from not satisfied at all to completely satisfied; 6) patient acceptance score of pain management (by GRS), collected by answering the question: “How receptive were you to overall pain management during HSG?”, ranging from not receptive at all to completely receptive; 7) immersion perception score of the VR system (by GRS), collected by answering the question: “To what extent did you feel like that you went into the virtual reality environment while experiencing VR?”, ranging from “I did not feel like I went into the virtual reality environment at all” to “I went completely into the virtual reality environment” (for the VR group only); 8) physiological parameters; 9) adverse effects; and 10) HSG results.A Data Monitoring Committee, which is independent of any competing interests, will be established immediately after the project launch. Members consist of one pain management specialist, one chief radiologist, two gynecology assistants working in the Radiology Department, and a senior academic statistician who will serve as the committee’s chair. Regular Data Monitoring Committee meetings will be held to discuss project issues, modify the protocol and monitor the progress of the study. No audit or interim analyses are planned.Collected paper-based materials will be stored in locked filing cabinets in a locked office in Ningxia Medical University. All data will be collected in password-protected digital files on a password-protected computer in a locked office. Data entry will be performed continually throughout the study using the double-entry method. When the investigator inputs the information into the computer, each participant will be given a unique numeric code (ID number). As a result, the data acquired from patients are individually identifiable by the research team members only. Only deidentified information will be presented or published. To guarantee data quality, an independent clinical research assistant will verify the completeness and accuracy of the data by review of medical records once a month. Authorship will follow guidelines recommended by the International Committee of Medical Journal Editors (ICMJE).n represents the total sample size of the whole study, σc represents the standard deviation, δ represents the between-group difference with clinical significance, and q1 and q2 are the sample size ratio of the two groups (q1 = q2 = 0.5). According to the preliminary test, the worst pain score experienced during HSG reported by all blank control group participants (n = 7) revealed a mean (standard deviation (SD)) of 6.50 (2.26) out of 10. Participants (n = 7) in VR group reported a mean (SD) of 5.61 (0.93). The standard deviation of the whole sample (n = 14) was 1.72. At an α value of 0.05, a power of 90% (β = 0.10), and given a two-tailed test, we obtained σc = 1.72, δ =  ∣ μ1 − μ2∣ = 0.89. These data were used to calculate the value of the overall parameter to enter into the formula, and an n value of 157.02 was obtained. Thus, the rounded total sample size of the two groups was 158 (79 participants in each group). Allowing for a 20% dropout rate and withdrawals before study completion, we decided to enroll a total of 190 participants (95 participants in each group).The worst pain severity as the primary end-point measure is employed to estimate sample size in the current research according to previous studies on physical therapy for pediatric burn injury pain and dentalgia pain , 24. AccP values <0.05 to be statistically significant.In this study, all data will be collected by a specialized researcher. A blinded statistician who is not involved in this trial will perform statistical analysis using SPSS version 22.0 . A complete statistical analysis plan will be generated in advance by the trial statistician. All randomized participants should be included in the analysis, and missing data will be handled using multiple imputation. Data will be analyzed initially on an intention-to-treat basis. For comparing the primary outcome between the two parallel groups, additional per-protocol analysis will be performed, and reasons for any protocol violations will be reported. We will consider all t test will be applied to determine the differences between the primary outcome. Secondary outcomes such as the amount of time spent thinking about pain, pain unpleasantness, worst pain within 15 min after HSG, anxiety, satisfaction, and acceptance with pain management will use t tests or Mann–Whitney tests. Chi-squared tests or Fisher’s exact test will be used for HSG results and adverse reactions. When comparing the physiological parameters, the repeated measures analysis of variance will be used. Pearson correlation analysis will be used to analyze the relationship between immersion perception score of the VR system and the three pain dimensions.Descriptive statistics will be used to describe the demographic features by means (SD), medians , and proportions . A P < 0.01). Although none of the study participants reported side effects, the risk of inhibition of respiration after opioid administration necessitates continuous monitoring. The ideal analgesic for outpatient operations would have the characteristic of providing adequate pain control with an absence of significant adverse effects. For safety reasons, opioids are effective for pain management during HSG but cannot be used in outpatient settings.HSG is routinely performed on an outpatient basis in most settings as an initial diagnostic tool for assessing infertility in women. The mechanism of pain related to HSG is complex, and there are many influencing factors. Although the main causes of HSG pain are not known, researchers have considered different methods to reduce pain during the HSG procedure, such as replacing the metal cannula with a balloon catheter and replacing oil-based media with iodinated hydro-soluble contrast media , 28. VarWith a deeper recognition of pain mechanisms, multimodal analgesia will tend to be used for pain management. Compared to traditional treatment, multimodal analgesia is a multidisciplinary approach to pain management that can maximize the positive effects of the treatment while decreasing the associated adverse effects . The effVR distraction is an emerging nonpharmacologic and noninvasive analgesic. It is commonly used for procedural pain management with few adverse effects. Pain perception requires attention , 32. TheIn the above studies, VR was used as an adjuvant to pharmacologic analgesic. We realize that it is necessary to provide a direct comparison between VR intervention and a blank control. Patients can benefit if the simply operated, noninvasive and low-cost VR application is proven to be effective during HSG procedure. Furthermore, the use of VR can have the potential to improve the safety of invasive outpatient checkups and to benefit patients from a cost-effectiveness perspective. Therefore, our study will evaluate the reliability of VR by providing data regarding the efficacy and safety of VR application in comparison with a blank control in a randomized controlled trial.There are several limitations to this trial. The treatment condition will not be blinded, which may cause the participants to under-report their VAS pain scores after the VR intervention. Additionally, the questionnaire data from the participants on their three pain dimension scores, anxiety and side effects during HSG will not be collected during the procedure. Relying on recalled pain is not accurately reflecting the degree of pain in the prevailing circumstance. Nevertheless, during the distraction activity, asking patients questions will impact the efficacy of the intervention. The study will be conducted in one setting only. A multicenter study would be more representative and, in the future, we will perform a multicenter study.At the time of manuscript submission recruitment for this study is ongoing. It is anticipated that the enrollment will be completed by the end of February 2020. At present, the trial has already recruited 22 participants.Additional file 1. SPIRIT 2013 checklist: recommended items to address in a clinical trial protocol and related documents.


The objective of this prospective cross-sectional study was to analyze the differences between patients with fibromyalgia and non-pain controls in terms of EEG power in the eyes-closed resting state. This study also aims to evaluate potential correlations between EEG power and subjective pain. The fibromyalgia patients were recruited by the Extremadura Association of Fibromyalgia (AFIBROEX) in Cáceres, Spain. Age- and sex-matched healthy controls (1:1 ratio) were recruited from university facilities and people close to the AFIBROEX by public calls. All underwent EEG during a 1-minute resting period with their eyes closed. The theta, alpha-1, alpha-2, beta-1, beta-2, and beta-3 frequency bands were analyzed by using EEGLAB. Self-reported visual analog scale pain scores were determined just prior to EEG. A total of 62 women participated in the study, 31 of them diagnosed with fibromyalgia and 31 healthy controls. Fibromyalgia group exhibited a significantly lower alpha-2 in C4, T3, P4, Pz, and O2 compared to the healthy controls. Interestingly, pain correlated negatively with alpha-2 in Cz, P4, and Pz only in the fibromyalgia group. The fibromyalgia group exhibited decrease alpha-2 power in central, temporoparietal, and occipital brain areas. Furthermore, higher values of pain correlated with lower level of alpha-2 power in Cz, P4, and Pz. These findings may point the importance of alpha-2 power in pain in women with fibromyalgia. Fibromyalgia is a chronic syndrome that is characterized by widespread pain. Fatigue, stiffness, sleep disturbance, and affective and cognitive problems  are the  et al. (2015) proposed that the lower alpha EEG power band of fibromyalgia patients compared to healthy people during the closed-eye state may associate with diminished sensorimotor integration in brain processing and could, therefore, be an indicator of the need of fibromyalgia patients to make extra efforts to attenuate the chronic pain sensation [Electroencephalography (EEG) power provides information about brain activity dynamics with excellent temporal resolution , 5. Seveensation .This prospective cross-sectional study aims to contribute further to our understanding of the EEG power differences between fibromyalgia patients and healthy controls. Thus, EEG power spectrum analyses of FM patients and healthy controls in the eyes-closed resting state were conducted. Furthermore, this study also aims to investigate potential correlations between pain and EEG power spectrum. It was hypothesized that, in line with the studies discussed above, fibromyalgia patients would exhibit altered EEG patterns in this condition.i.e., major depression with suicidal ideation, schizophrenia, or substance abuse), and/or autoimmune or inflammatory diseases that can cause pain were excluded. In addition, healthy controls, who did not suffer from both localized or generalized chronic pain in the last six months, who were matched in terms of sex and age to the fibromyalgia participants (1:1 ratio) were also selected.The Extremadura Association of Fibromyalgia (AFIBROEX) in Cáceres recruited the participants with fibromyalgia by telephone calls. All had been diagnosed with FM according to American College of Rheumatology criteria . ParticiAll participants were verbally informed about the details of the study and gave written informed consent to participate. All participants underwent EEG in July, 2017. All procedures were approved by the research ethics committee of the University of Extremadura  and were conducted in accordance with the tenets of the updated Declaration of Helsinki.All participants underwent a semi-standardized interview that assessed their medication intake. The pain intensity was also measured by using the visual analog scale (VAS) . This isμV2/Hz per channel and frequency band to an excel file, being easy to correlate the EEG data with the behavioral variables such as VAS pain.The participants were instructed to rest on a chair in a quiet room with their eyes closed. The EEG signals were assessed during a 1-minute period by using the Enobio device, which is a wireless electrode system  . The relThe SPSS statistical package  was used to analyze the data. Parametric tests were conducted based on the results of Shapiro-Wilk and Kolmogorov-Smirnov normality tests. t-tests were conducted to explore differences between groups in the six different frequency bands at each of the 19 channels. In addition, correlation in the fibromyalgia group between VAS pain scores and the power in the alpha-2 frequency band at each of the 19 channels was determined by Pearson's correlation coefficient analyses.Independent t-tests were respectively conducted.Furthermore, in order to examine the possible influence of age or use of medication  in the frequency bands, at each of the 19 channels, Pearson's correlation coefficient analyses and independentThe alpha-level of significance was set at 0.05. t-tests showed that the fibromyalgia and control groups differed significantly in terms of VAS pain scores (p<0.001) and frequency of antidepressant or analgesic/relaxant medication but did not differ significantly in terms of age  and 31 healthy controls (50.84 ± 8.51 years). Independents of age . t-tests comparing the fibromyalgia and the healthy controls, in terms of their EEG data, showed that the fibromyalgia patients had decreased alpha-2 power in C4 (p=0.049), T3 (p=0.018), P4 (p=0.043), Pz (p=0.028), and O2 (p=0.047)  see . Other iPearson's correlation coefficient analyses of the fibromyalgia group showed that their VAS pain scores correlated significantly and negatively with Alpha-2 at Cz, P4, and Pz . Other s t-tests also showed that the fibromyalgia patients who were treated with antidepressant and/or analgesic/relaxant medication did not differ from the fibromyalgia patients who were not being treated with these medications in terms of the theta, alpha-1, alpha-2, beta-1, beta-2, and beta-3 band signals at the 19 scalp locations.Interestingly, Pearson's correlation coefficient analyses of the 31 fibromyalgia women showed that age did not correlate with the theta, alpha-1, alpha-2, beta-1, beta-2, and beta-3 band signals at the 19 scalp locations. Moreover, independent et al. (2010) [The present study examined the differences between fibromyalgia patients and non-pain controls in terms of their EEG power spectrum frequency bands  at rest with their eyes closed. We found that the fibromyalgia patients had lower alpha-2 power in the central, temporoparietal, and occipital areas than the non-pain controls. Some of these results are in line with those reported in previous studies that focused on brain dynamics differences between fibromyalgia patients and non-pain controls. Specifically, these studies show that fibromyalgia patients have greater beta activity over the right middle frontal lobe and the midcingulate gyrus  and mark. (2010)  for the  et al. (2017) [Alpha synchronization or coherence is believed to be a communication mechanism in the brain. Specifically, alpha-2 oscillations associate with tonic alertness in a network that includes the dorsal anterior cingulate cortex, the anterior insula, and the anterior prefrontal cortex . Vannest. 2017)  suggest . (2017) . This me17  sugge. (2017) . Allosta. (2017) , namely,. (2017) , the amy. (2017) , and the. (2017) , 26. The. (2017) . In this. (2017) –31. ThesOur findings support the use of therapies that could putatively remodel the brain dynamics of fibromyalgia patients. These therapies include neurofeedback, transcranial direct current stimulation (tDCS), and repetitive transcranial magnetic stimulation (rTMS). In relation to neurofeedback, however, a meta-analysis  suggests et al. showed that, compared to the resting condition, healthy people placed in a noxious condition also exhibit decreases in the alpha-1 and alpha-2 bands. Moreover, like us, they showed that the parietal scalp channels correlated with pain levels [ et al. [Our study also showed that there was a negative correlation between the pain levels of the fibromyalgia patients and their alpha-2 power in the Cz, P4, and Pz EEG channels. In this regard, Nirn levels . This sun levels , our res[ et al.  reinforc t-tests comparing the fibromyalgia patients who were or were not taking medication  showed that the two subgroups did not differ significantly in terms of EEG results. Another limitation was that our sample was only composed of women. Thus, the results of this study cannot be generalized to male patients with fibromyalgia.One potential limitation of our study design was the possible effect of pharmacological treatment on the results. However, independentIn summary, compared to non-pain control subjects, the fibromyalgia group exhibited a significant decrease in alpha-2 power in the central, temporoparietal, and occipital areas. The fibromyalgia group also exhibited negative correlations between their pain level and the alpha-2 frequency band in Cz, P4, and Pz. These findings indicate the importance of the alpha-2 frequency band in pain and the impact of fibromyalgia. Age did not relate significantly with the EEG data of the participants with fibromyalgia.


It is theorized that neck pain may cause reduced postural control due to the known physiological connection between the receptors in the cervical spine and the vestibular system. The purpose of this study was to examine whether the pressure pain threshold in the neck is associated with postural sway in patients with dizziness or neck pain.n = 243) and neck pain (n = 129) were recruited from an otorhinolaryngological department and an outpatient spine clinic, respectively. All subjects underwent static posturography. Pressure pain thresholds were measured at four standardized points in the neck, and generalized pain was assessed using the American College of Rheumatology tender points. The relationship between postural sway and pressure pain threshold was analyzed by linear regression, and the covariates included age, sex, and generalized pain.Consecutive patients with dizziness . The same inverse relationship was found between pressure pain thresholds in the neck and the Romberg ratio on a bare platform after adjusting for age, sex and generalized pain . Neither of these relationships were present in the neck pain group.In the dizzy group, there was a small, inverse relationship between pressure pain thresholds and sway area with eyes closed, after adjusting for age, sex, and generalized pain (bare platform; lower neck, Our findings indicate that the pressure pain threshold in the neck is associated with postural sway in patients suffering from dizziness after adjusting for age, sex, and generalized pain, but only with closed eyes. The association was small and should be interpreted with caution.NCT03531619. Retrospectively registered 22 May 2018.Trial registration: Clinicaltrial.gov  Postural control is a complex system  and to mSelf-reported pain intensity has been the most common approach to pain measurement. While self-reported pain is indeed important, it is mediated by biopsychosocial aspects  that canThe main aim of this study is to examine whether there is an association between PPT and postural sway in patients with dizziness and in patients with neck pain. As patients with pain syndromes, such as Fibromyalgia, have been shown to have reduced balance , 27 and We conducted a prospective cross-sectional study of consecutive outpatients examined at two clinical centers at a university hospital in Norway. The first center was an ear-nose-throat (ENT) clinic that receives referrals from general practitioners and specialists, both nationally and locally, concerning dizziness of suspected vestibular origin. The second center was an outpatient spine clinic that admits patients from primary care physicians concerning long-lasting musculoskeletal pain either causing or threatening to cause work disability.n = 243) were recruited from the ENT clinic. The ENT clinic also receives tertiary referrals nationally and is a quaternary referral center for vestibular schwannomas and for divers suffering from vestibular problems. As we wanted the study population to be representative of secondary referrals, persons having the latter conditions were not invited to participate  and only locally referred patients from western Norway were included. They were diagnosed by an otorhinolaryngologist, and the examination included pure-tone audiometry, dynamic posturography, videonystagmography with measurements of ocular smooth pursuit, saccades and bithermal caloric tests, a standard ENT examination including otomicroscopy, examination of cranial nerves and cerebellar function as well as clinical tests of postural sway, gait, and nystagmus. In addition, hospitalized patients with acute vertigo were also excluded.During a one-year period 2017–2018), we included consecutive patients examined in both clinics. The recruitment is illustrated in Fig. 7–2018, wn = 129) as their primary complaint were recruited from the outpatient spine clinic where they were examined by a multidisciplinary team and diagnosed by a physician. In both groups, the participants had to be between 18 and 67 years old. Exclusion criteria included language barriers associated with filling in patient questionnaires and neurological or orthopedic disorders known to interfere with postural control . The project was approved by the Regional Committee for Health and Medical Research Ethics of South-Eastern Norway (REK 2017/783). The participants signed a written consent prior to testing.Patients with long-lasting (> 3 months) neck pain (2 round rubber tip was used to apply pressure to the upper four standardized and defined American College of Rheumatology (ACR) tender points [Neck PPT were used to quantify the mechanical pain sensitivity of the cervical region using a pressure algometer. This threshold has previously been found to predict shoulder/neck pain  and to cr points : bilaterr points . Prior tr points , we usedPressure testing at the 18 ACR tender points was used to measure the level of generalized pain. The test assesses nine defined points on each side of the body as illustrated in Wolfe et al. (1990) . The tes2 described by the center of pressure during each test lasting 2 × 20 s. The patients were instructed to stand quietly on the force platform with their arms hanging freely along their body and their feet aligned with markings corresponding to their foot size. To evaluate the different contributions of proprioceptive and visual inputs, the patients were tested under four different conditions: eyes open or eyes closed while standing on the bare platform and eyes open or closed while standing on a foam rubber mat placed on top of the platform. Additionally, as an indicator of the proprioceptive contribution to postural stability the Romberg ratio [Postural control was evaluated by static posturography using a commercially available force platform . The center of pressure under the feet was sampled at a rate of 100 Hz. The evaluated parameter was the sway area in mmrg ratio  was calcA study nurse at each clinic recruited the patients the same day as their appointment at their respective clinic. Four experienced physiotherapists conducted subsequent testing on the day of their appointment. To ensure consistent examination techniques, the examiners had two practice sessions before the study and one more after 5 months. Before testing, the participants filled in medical chart data such as age, sex, and symptom characteristics. The examination was carried out in the following sequence: PPT, ACR tender points, and posturography. At the ENT clinic, the patients were examined before or after their physician appointment, and at the outpatient spine clinic the patients were tested as a part of the physiotherapy examination and after they were examined by a physician.m where m is the number of predictors; thus, resulting in a sample size of at least 105 patients for each regression analysis. Sway area and Romberg ratio were positively skewed and were logarithmically transformed prior to regression analysis. PPT in the upper and lower neck was highly correlated and thus assessed in separate analyses to avoid multicollinearity. To facilitate interpretation of the coefficients, they were back transformed after analysis. Statistical analysis was performed using Stata® version 15 .Linear regression was used to estimate the relationship between postural sway (sway area and Romberg ratio) and PPT after adjusting for age, sex, and generalized pain (number of ACR tender points). Sway area was used as the dependent variable and PPT as the predictor variable. Three regression models were generated, including the unadjusted model (Model 1), the age and sex-adjusted model (Model 2), and the age, sex, and generalized pain-adjusted model (Model 3). The alpha level was set to 0.05. Descriptive statistics included means and standard deviations for normally distributed data or median and interquartile range for skewed data. Categorical data were presented as percentages. The sample size was estimated based on recommendations by Green , which sThis study included 243 patients from the ENT clinic with dizziness and 129 patients from the spine clinic with neck pain. Due to technical issues, three patients from the ENT clinic and four patients from the spine clinic had to be excluded because of missing posturography data. In addition, five patients from the ENT clinic were excluded due to neurological or orthopedic disorders that were not uncovered prior to participation in the study. Diagnoses of the different populations are shown in Additional file p = 0.002) and a 1.8% reduction of sway in the eyes closed on foam condition . In the upper neck, there was an inverse relationship between PPT and sway area in the third model, when standing with eyes closed on bare platform and an increase of 10 kPa was associated with a 1.6% reduction of sway in the eyes closed condition . In the patients with neck pain, PPT was not associated with postural sway in any of the models  in the lower neck in the dizziness group. An increase of 10 kPa was associated with a 3.1% reduction of sway in the eyes closed condition  and a 1.8% decrease in PPT in the lower neck . On foam rubber, the PPT was only associated with the Romberg ratio in the age and sex-adjusted model. No relationship was found in the neck pain group in either of the conditions  was associated with better performance (lower sway area and lower Romberg ratio) on the platform, and thus, a lower PPT (higher pain sensitivity) was associated with worse performance (higher sway area and higher Romberg ratio). The associations tended to remain significant after adjustment for age, sex, and generalized pain.Previous studies have demonstrated impairments of postural control in patients with assumed cervicogenic dizziness –18 and iAn association between postural sway and PPT was found in patients examined for dizziness at the ENT clinic. This is an interesting finding. Postural control relies on several sensory systems, and a deficit in one of these may be compensated for by the others. In the ENT clinic, approximately 50% were diagnosed with a vestibular problem. A possible explanation for our findings in this group may be that there was a synergistic interaction between neck pathology and vestibular deficit. Neck pain alone may not be sufficient to cause an association between neck pain and postural imbalance. However, 45% in the neck pain group reported dizziness. It may be speculated that dizziness in most of these patients was non-vestibular, possibly related to their neck pain.After adjusting for age, sex, and generalized pain, the association with PPT in the neck was only present with eyes closed, i.e. when the patients were deprived of visual feedback. In the eyes closed condition, the central nervous system has to rely on accurate vestibular and somatosensory feedback, including important information about head-on-body position from proprioceptive afferents in the neck . This isThe relationship between sway area and PPT was most consistent in the lower neck. This was somewhat contradictory to the fact that the mechanoreceptors are more concentrated in the upper region of the cervical spine . The PPT2) shows that the PPT has small effects on sway. Although a small significant association was found, there is no consensus on normative values for the sway area; thus, making an interpretation of the importance of the percentage change difficult. However, the aim of this paper was merely to determine whether an association exists between PPT and sway area. The relationship between neck pain and reduced postural control is founded on basic research and experimental evidence showing that the activity of primary vestibular neurons is modulated by proprioceptive afferents in the neck [This study has several limitations. First, the coefficients of the association were small with small changes in percentage of sway. In addition, the small explanatory power . In addition, the Romberg ratio was associated with PPT. However, altered postural control has a myriad of possible causes and the effect of PPT on sway was small and needs to be corroborated in future studies.Additional file 1: Table S1. Frequency of diagnosis of 231 patients referred to the ENT clinic and the 125 patients referred to the outpatient spine clinic.


Pain is one of cancer patients’ most frequent and distressing symptoms; however, analgesics’ side effects often increase symptom burden. Further, with the home rapidly becoming the primary cancer care setting, family caregivers (FCs) commonly play central roles in patients’ pain self-management, but with little or no preparation. One US-tested intervention, the PRO-SELF© Plus Pain Control Program (PCP), designed to support cancer outpatients and their FCs in pain self-management, is currently being tested in the Swiss multi-centre PEINCA study. The current PEINCA-FAM study is a sub-study of PEINCA. The aims of PEINCA-FAM are: a) to test the efficacy of the adapted German PRO-SELF © Plus PCP to reduce side effects of analgesics; b) to enhance patients’/FCs’ knowledge regarding cancer pain; and c) to explore FCs’ involvement in patients’ pain self-management.N = 42–60) will be interviewed regarding their pain management experiences. Data collection will take place from April 2016 until December 2018. An intent-to-treat analysis and generalized linear mixed models will be applied. Qualitative data will be analysed by using interpretive description. Quantitative and qualitative results will be combined within a mixed method matrix.This mixed methods project combines a multi-centre randomized controlled clinical trial with qualitative data collection techniques and includes 210 patients recruited from three oncology outpatient clinics. FCs involved in patients’ pain self-management are also invited to participate. After baseline evaluation, eligible participants are randomized to a 6-week intervention group and a control group. Both groups complete a daily pain and symptom diary. Intervention group patients/FCs receive the weekly psychoeducational PRO-SELF© Plus PCP interventions; control group patients receive usual care. After completing the six-week study procedures, a subsample of 7–10 patients/FCs per group and hospital .The PEINCA study is registered in the Clinical Trials.gov site (code:  Pain is one of cancer patients’ most frequent and distressing symptoms. However, analgesics’ side effects often increase symptom burden , 2. The Although pain is a treatable symptom, up to 40% of cancer patients experience inadequate pain management. System-level barriers include limited access to pain specialists or opioids  and miscWith the home becoming the primary setting for many aspects of cancer care, a key goal is to improve patients’ pain and side effect self-management . Self-maThree recent meta-analyses focusing on the effects of psychosocial interventions to support cancer pain management from 1983 to 2012 found that, while gaining attention, the psychosocial approach to pain management remains understudied –26. The To date, little research has focused on interventions supporting FCs in patients’ cancer pain self-management. First, Keefe et al.  tested tHowever, no studies have evaluated the effectiveness of interventions focusing on analgesic side effect management to improve self-management in cancer patients and their FCs. Similarly, no study has yet investigated correlations between FCs’ cancer pain management knowledge and self-efficacy related to pain management and patients’ pain intensity.N = 174) . At an alpha error level of 0.05, a sample size of 32 FCs should be sufficient to achieve a statistical power of 80%.The results of the above-mentioned pilot study  includeWith respect to the sample size for the qualitative part, a sample of 42–60 patients and FCs should supply sufficiently redundant data to discover patterns, commonalities and differences among the groups.Specifically trained nurses from the outpatient clinics work as research assistants (RAs) for the study. All RAs are experienced registered nurses or graduate students in nursing who have received study-specific training by the study coordinator (HR). RAs screen potential participants and verify inclusion criteria via patient files and discussions  with their treating physicians. If the initial inclusion criteria are met, the RAs contact the patients directly during their outpatient appointment to check whether they have experienced repeated pain that they would rate on an NRS as ≥3 over the last week, are able to understand, read and write German, and have access to a telephone. The RAs then inform patients about the study and invite them to participate. Each patient is also asked if an FC is involved in their daily pain self-management. If yes, the FC is also invited to participate in the study. Written information and consent forms  are then given to the patient. After at least 24 h, an RA contacts each patient (or patient/FC dyad) again to provide verbal information to the FC as needed, ask about their decision regarding participation, and collect the signed written consent form. In all settings, these written informed consent forms are stored safely in the Investigator Site File (ISF) by the RAs. Only afterwards are participants randomized to the IG or CG. Patients and FCs have the right to withdraw from the study at any time without consequences.Concerning the recruitment of participants for qualitative data collection, all patients (and FCs) are asked at the beginning of the main study whether they are willing to participate in an interview following completion of the study’s 6 weeks of procedures. At the end of the final home visit, the intervention nurse (IN) or an RA asks selected patients (and FCs) whether they are still willing to participate in the interview. They then provide verbal and written information and obtain written consent from those who agree. Purposive sampling is applied to ensure approximately equal sample sizes per study site, as well as variation regarding pain intensity, intervention adherence, age, gender, education, living situation, and tumour entity.As shown in Fig. Blinding is not possible because the INs use collected data directly for the intervention ). And while treating physicians are not informed, they may still become aware of group allocation if participants ask questions or take their diary to an appointment.The intervention is performed by four specially trained oncology nurses. These INs have completed a Master’s degree in nursing and are experienced clinicians in this field of study. A two-day training segment provided by the primary investigator (ES) included a review of current pain management guidelines and detailed teaching and training for each intervention component of the adapted German PRO-SELF © Plus PCP.The intervention is intended to implement structured and tailored components of the German PRO-SELF© Plus PCP and is based on three key strategies: nurse coaching, skill building, and provision of information via academic detailing , 41. AcaTo identify patients’ and FCs’ pain management knowledge deficits, the INs check their baseline knowledge of cancer pain and side effect management based on the results of the PPQ. To reinforce their education and enhance knowledge of cancer pain and side effects, patients and FCs receive the PRO-SELF © Pain Control Booklet, as well as individualized information.Concerning the tailored intervention components, the IN reviews each pain diary with the associated patient/FC, assesses the appropriateness of the analgesic prescription and the side effect management, and teaches the patient/FC how to adjust the prescribed analgesics in response to changing pain conditions and side effects. Adherence to analgesic medication instructions and the IN’s recommendations is assessed and discussed with the patient/FC at each subsequent visit, after which modifications to the pain and side effect management plan are made as needed. The intervention is provided during in-home visits , followed by weekly in-home or telephone visits. The number, type  and frequency of visits are determined by defined criteria as follows: pain score > 3 on an NRS, patient is dissatisfied with pain management, patient adherence with pain medication or recommendations < 50%. If one or more of these criteria apply, the IN schedules an in-home visit; if none apply, she schedules a phone call. In addition, a reinforcement phone call is scheduled after major changes to the pain management plan.For quality assurance and analysis, all intervention sessions and phone calls are audio recorded. The primary investigator and the study coordinator review audio recordings of visits and report their observations using an audit checklist based on the intervention protocol. In order to enhance the intervention’s implementation, they and the INs promptly discuss any deviations. They continue to monitor audiotapes until a 95% protocol adherence rate is achieved. Afterwards, audio-recordings are reviewed at random.The CG participants receive usual care regarding pain management by participating centres. The treating physicians assess pain and prescribe analgesics. However, if participants raise concerns to RAs about pain or side effects, they are encouraged to contact their physicians. No specific counselling is provided.Both quantitative and qualitative data will be collected from March 2016 until December 2018. Patients in both groups complete a daily pain and symptom diary; patients and FCs fill in questionnaires. The same 6-week data collection protocol is applied via in-home visits at baseline and during weeks 1 and 6. In the IG, data are collected by the IN. In order to minimize diffusion of the intervention to CG participants, an RA collects data in the control group. Between in-home visits at baseline and weeks 1 and 6, patients/FCs receive brief telephone calls every second week, during which the RA ensures that the pain diary is being completed on a daily basis.Table Questionnaires employed in this study are applied in their German versions, for which validity and reliability have been established. The primary patient outcomes are selected analgesics’ side effects , self-efficacy, and knowledge of cancer pain management. Primary FC outcomes are self-efficacy and knowledge of cancer pain management. The secondary outcomes are patients’ average and worst-pain intensity. Anxiety, depression, functional status, and cancer-related symptoms are measured as covariates. Our analytical models will also control for age, education, time since diagnosis and current disease status.Clinical data from patients’ medical records include the date of the initial diagnosis, type of tumour, existence of any metastases , comorbidities, and completed or current tumour therapy.These questionnaires assess socio-demographic data including age, sex, living alone (yes/no), employment status and educational level.A pain management diary is used to assess analgesics’ side effects for each 7-day period. Patients are asked to rate 12 side effect items on an 11-point NRS . Our analysis will focus on constipation, nausea, emesis, and concentration difficulties. On a second 11-point NRS  patients also rate their daily average and worst pain intensity.Pain intensity, i.e., average and worst pain, is measured on 0–10-point NRSs, which are part of the German version of the BPI. Daily pain scores will be averaged for each week of the study. The BPI is a pain measurement tool with reliability and validity established as excellent , 45.The CAS, an 8-item self-report tool, is completed weekly to measure the presence and severity of constipation . The total possible score ranges from 0 (no constipation) to 16 (severe constipation). A score of ≥2 will trigger the use of a constipation management plan. This scale’s validity and reliability have been established , 47.The nine-item PPQ measures individuals’ knowledge of cancer pain. In cases of patient/FC dyads, a similar tool, the FPQ, is used for the FC . Each itThe Self-Efficacy Questionnaire includes 15 items measuring perceived ability to manage specific aspects of pain on a scale ranging from 10 (very uncertain) to 100 (very certain). The questionnaire is separated in three subscales: one for pain management, one for physical function and one for other symptoms. A total score is calculated by summing the scores for each of the subscales. To assess caregivers’ confidence regarding their ability to support cancer pain management, a caregiver version of the self-efficacy scale was used. This version is identical to that applied in cancer patients except that caregivers are asked to rate how confident they are that they can support the control of patients’ cancer pain . ConstruThe HADS, a non-diagnostic self-report screening instrument, is used to assess anxiety and depression symptomatology. Based on two 7-item subscales, each using a 4-point (0–3) Likert-type scale, a score of 11 or more (of a possible 21) on either subscale indicates significant psychological morbidity  .The ECOG-PS measures functional status, i.e., the capacity to perform a variety of activities considered normal for most people. Developed in 1960, the scale has been widely used in clinical trials and oncology practice . It consAll intervention sessions are audio recorded by the IN who provides the intervention. The PhD student (SV) then listens to these audio-recordings and transcribes all relevant passages, that is, all that concern side effect management, learning processes, or FC involvement. Additionally, field notes serve as qualitative data.Selected patients and FCs are interviewed by specially trained nurses who are not yet involved in the study procedures. These nurses are experienced in conducting individual interviews and have been trained by the primary investigator and the study coordinator. Following an interview guide, they ask open-ended questions to explore patients’ and FCs’ experiences with pain management and related interactions with clinicians. To better understand the degree to which the intervention meets individual needs and to identify remaining difficulties regarding pain management, participants in the IG are also asked to discuss their perceptions of the study intervention’s burdens and benefits.Focusing on PEINCA-FAM, we hope to identify remaining difficulties concerning side effect management, to explore patients’ and FCs’ learning processes during the intervention, and to explore the FCs’ involvement and self-efficacy. Interviews, which last approximately 60 min, are audio recorded and transcribed in standard German. So that relevant new topics can be integrated in the interview guide, analyses are performed in parallel with data collection.Quantitative data will be compiled and analysed using SPSS 24.0. Data will be retrieved from the SecuTrial® database. Data will be systematically examined for out of range values and data inconsistencies. As appropriate, descriptive statistics will be calculated, including means and standard deviations for interval variables and frequencies, as well as percentages for categorical variables. An intent-to-treat analysis will be applied, using a significance level of .05 . AlthougGeneralized linear mixed models will be applied to determine differences between the IG and the CG analgesic side effect developments throughout the intervention. This approach allows calculation of the main group and time effects, and of group-by-time interaction. The influence of missing data on the model results will be examined using sensitivity analysis . Change Our quantitative analysis will use descriptive statistics to summarize PPQ/FPQ items’ distribution characteristics. Generalized linear mixed models will be applied to determine differences between the IG’s and the CG’s knowledge of cancer pain management throughout the intervention. The influence of missing data on the model results will be examined using sensitivity analysis . Change For qualitative data analysis, transcript data will be stored and analysed in ATLAS.ti 7. Field notes and audiotapes of telephone calls, home visits and interviews will serve as qualitative data to explore both the IG’s and the CG’s the learning processes concerning knowledge of cancer pain and pain self-management. Data will be analysed via interpretive description–an approach using stepwise, systematic and iterative processing of data to arrive at a meaningful description and interpretation .Information from quantitative and qualitative data collection will be combined within a mixed method matrix. Qualitative and quantitative results related to each German PPQ/FPQ item will be integrated in a final synthesis , 58.For the quantitative analysis, to determine associations between FCs’ pre- and post-intervention score changes regarding self-efficacy, knowledge of cancer pain and patients’ average and worst-pain intensity between the two groups, we will calculate Pearson correlation coefficients.Qualitative data will be generated in the same way as for aim 2 via field notes, recordings of telephone calls, home visits and interviews. Data will be analysed by applying interpretive description .Information from quantitative and qualitative data collection will be combined within a mixed method matrix and integrated in a final synthesis , 58.Data are handled confidentially and stored in a locked cabinet for 10 years. Data are anonymized by applying numerical IDs. The master file with patient names and associated ID numbers is kept secure. Only the study team has access to the written and electronic data. With regard to the final trial data set, only the primary investigator, the study coordinator, the PhD student and the person who enters the data will have access. In order to communicate trial results to participants, health care professionals and the public, we plan to publish results of primary and secondary outcomes. Furthermore, the study team and nurse managers of participating university hospitals will be informed about study results via scientific presentations in various settings.This study is the first to evaluate the effects of a psychoeducational intervention to reduce analgesics’ side effects and to explore the involvement of FCs in pain management in a sample of Swiss cancer outpatients and their FCs. As with other chronic illnesses, cancer places new demands on patients and their FCs to manage their care; however, to do so effectively requires specialized skills. Therefore, to achieve adequate pain and side effect self-management, cancer patients and their FCs require educational interventions. Their self-management support should focus on enhancing patients’ and FCs’ pain management knowledge and self-efficacy, while improving their use of pain and side effect relief strategies , 59, 60.This RCT involves the evaluation of a multicomponent self-management support intervention that combines monitoring of pain, side effects and medication based on nurse coaching via weekly in-home or telephone visits, skill building, and information provision. Compared to usual care, self-management support is expected to result in improved control of pain and analgesics’ side effects, as well as enhanced self-efficacy and knowledge .Previous qualitative studies on home cancer pain management have showed that cancer patients have to manage diverse analgesics’ side effects, which is an ongoing multidimensional process , 32. TheThe proposed psychoeducational intervention, the PRO-SELF © Plus PCP, differs from previous attempts in its interactive, multicomponent approach: (1) Following evidence-based guidelines, a comprehensive pain assessment–including rating scales alongside patient reports of pain qualities, side effects, treatments and satisfaction with pain relief–is performed first at baseline, then at each contact . (2) BecPrevious evidence indicates that, while the recruitment of oncology patients is rarely easy, it can be especially challenging for studies involving symptom management , 66. ObsFurther, previous research experiences have taught us that, in this already strained population, minimizing participation burden will likely increase enrolment while remaining efficacious , 69. TheThis study’s results will contribute to the understanding of interventions designed to improve side effect self-management, knowledge and self-efficacy in cancer outpatients and their FCs. If efficacious, the proposed intervention could be implemented in clinical practice to reduce pain and analgesics’ side effects, while enhancing patients’ and their FCs’ pain management skills and knowledge.


Therapeutic virtual reality (VR) has emerged as an effective, drug-free tool for pain management, but there is a lack of randomized, controlled data evaluating its effectiveness in hospitalized patients. We sought to measure the impact of on-demand VR versus “health and wellness” television programming for pain in hospitalized patients.We performed a prospective, randomized, comparative effectiveness trial in hospitalized patients with an average pain score of ≥3 out of 10 points. Patients in the experimental group received a library of 21 VR experiences administered using the Samsung Gear Oculus headset; control patients viewed specialized television programming to promote health and wellness. Clinical staff followed usual care; study interventions were not protocolized. The primary outcome was patient-reported pain using a numeric rating scale, as recorded by nursing staff during usual care. Pre- and post-intervention pain scores were compared immediately after initial treatment and after 48- and 72-hours.There were 120 subjects . The mean within-subject difference in immediate pre- and post-intervention pain scores was larger in the VR group  than in the control group ; this difference was significant in favor of VR (P < .04). When limited to the subgroup of patients with severe baseline pain (≥7 points), the effect of VR was more pronounced vs. control . In regression analyses adjusting for pre-intervention pain, time, age, gender, and type of pain, VR yielded a .59 (P = .03) and .56 (P = .04) point incremental reduction in pain versus control during the 48- and 72-hour post-intervention periods, respectively.VR significantly reduces pain versus an active control condition in hospitalized patients. VR is most effective for severe pain. Future trials should evaluate standardized order sets that interpose VR as an early non-drug option for analgesia. Effective and safe pain management is an important challenge in the acute-care setting. Nearly half of hospitalized patients experience pain, of which one quarter is considered “unbearable.” Pain treFig 1). A proposed mechanistic theory of VR suggests that by stimulating the visual cortex while engaging other senses, VR acts as a distraction to limit the user’s processing of nociceptive stimuli.[Therapeutic virtual reality (VR) has emerged as an effective, non-pharmacological treatment modality for pain., 5 Users stimuli. The ubiq stimuli., 7–11 Fo stimuli. Similarl stimuli. and dent stimuli.Our group has previously investigated the role of VR in hospitalized patients. After demonstrating initial feasibility of using VR in the inpatient setting, we conduIn this study, we performed a comparative effectiveness study evaluating a scalable VR intervention vs. “health and wellness” television programming in a diverse group of hospitalized patients with pain.We conducted a prospective, randomized comparative effectiveness study between November 2016 and July 2017 to compare pain scores of hospitalized patients exposed to either an on-demand, immersive video experience consisting of VR and 360-videos, or an active control consisting of an in-room television tuned to the “Health and Wellness Channel”. We recruited adults aged 18 years or over admitted to the hospitalist, orthopedic, gastrointestinal, or psychiatric consultative services at Cedars-Sinai Medical Center, a large, urban, tertiary care hospital. the CONSORT diagram for patient flow through the study.Patients with an average pain score of ≥3 out of 10 points during the 24 hours preceding patient screening were eligible for inclusion. We chose this pain score cutoff because past studies have found it corresponds to the boundary between mild and moderate pain-related interference with mood and activity. We excluUpon providing written informed consent, eligible patients were randomized one-to-one between groups using the Microsoft Excel random number generator. Patients in both groups were informed that researchers were testing the effect of “two types of audiovisual experiences” on the perception of pain. Because it was important for research staff to exhibit equipoise when describing the competing interventions, we prepared a script that used neutral language regarding both interventions. In both arms, we minimized investigator interactions with the study participants, relying on non-study nursing staff to collect pain scores and allowing patients to use their assigned audiovisual experience on their own terms without a formal protocol or order set. In this manner, we designed the study to be a pragmatic assessment of VR compared to an inherent, active control condition already found in the treatment environment, described below.Fig 1). We selected the Samsung Gear because it is commercially available, widely used, relatively inexpensive, has minimal visual latency, and offers an acceptable patient experience based on our previous research.[S1 Fig), and a partial list is included in Fig 3.We administered VR using the Samsung  Gear Oculus headset fitted with a Samsung Galaxy S7 phone , discussions about health and wellness topics, and poetry readings. We selected the programming as a control condition because there is evidence that offering in-room relaxation programming can reduce pain and psychosocial distress in hospitalized patients.–23 FolloThe primary outcome was pain intensity collected via repeated measures in the course of usual care by hospital staff. At three-to-four hour intervals during waking hours, subjects were asked by their assigned nurse to rate their pain using a standard 11-point numeric rating scale (NRS), where 0 is “no pain” and 10 is “worst imaginable pain.” The 11-level pain NRS is supported by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) as a valAt the conclusion of their participation in the study, subjects were asked “Would you recommend the audiovisual experience you received here in the hospital to your family and friends?” Responses were collected on a 5-point Likert-type scale ranging from “Definitely Not” to “Definitely Yes”.We measured relevant aspects of global patient satisfaction using four selected items from HCAHPS collected from participants 5-weeks post discharge. Two of these items are conceptually related to pain: item 13 of HCAHPS, which reads “During this hospital stay, how often was your pain well controlled?’; and item 14, which reads, “During this hospital stay, how often did the hospital staff do everything they could to help you with your pain?”. Two other HCAHPS questions measured general satisfaction: item 21, which reads, “Using any number from 0 to 10, where 0 is the worst hospital possible and 10 is the best hospital possible, what number would you use to rate this hospital during your stay?”; and item 22, which reads, “Would you recommend this hospital to your friends and family?”Opioid usage was defined as mean total milligrams of morphine equivalent (MME), calculated by first multiplying the quantity of each prescribed medication by the strength of that medication (milligrams of given opioid per unit dispensed), and then multiplying this quantity-strength product by conversion factors derived from published sources to estimate the milligrams of morphine equivalent to the opioids dispensed in the prescription. The mean pre-intervention MME for subjects in each arm was calculated by adding the morphine equivalents for each prescription dispensed during the 48 hours before intervention, while the post-intervention MME for subjects in each arm was calculated by adding the morphine equivalents for each prescription dispensed during the 48 hours after intervention.We calculated descriptive statistics for demographic and clinical characteristics of the sample including age, sex, race, ethnicity, primary reason for hospitalization, and baseline pain scores. We performed bivariate analyses to evaluate for significant differences between groups, using two-sample t-tests for continuous variables and chi-square tests for categorical variables.identity covariance structure. The control variables  were time-invariant and therefore included in the fixed-effects portion of the model only. To test the appropriateness of using mixed models for these data, we performed likelihood ratio tests comparing ordinary least square and mixed models.For the primary outcome, we first compared within-subject differences in immediate pre- and post-intervention pain scores between groups to evaluate the initial impact of the first treatment session, similar to our previous non-randomized trial, using twWe compared satisfaction with audiovisual experiences between groups using t-tests. We compared HCAHPS item scores between groups using chi-square tests for four-level responses and t-tests for responses collected on the 11-point scale. We compared mean pre- and post-intervention MME between groups using t-tests.Using power calculations based on a predicted mean VAS pain score of 5.4 (SD 2.7), assuming a change in pain score of 1.5, and targeting a power of 80% , we calculated a total study sample required of 104 using the Stata .power twomeans command. We expanThe Cedars-Sinai Institutional Review Board approved this study (IRB Pro00045641) and it was registered with ClincialTrials.gov (NCT02887989).Table 1 provides baseline demographic and clinical characteristics for the two groups. There were no significant differences between groups for age, sex, race, ethnicity, or pre-intervention pain scores. The reasons for admission were similar between groups. The mean cumulative pre-intervention pain scores were not significantly different between the groups, nor was the mean of the last pain measurement taken pre-intervention. Mean pain-scores for each group at 12-hour intervals during the 72-hours before and after the intervention are displayed in Fig 4. We report usage data for the intervention period in the supplement .One hundred twenty eligible patients completed the protocol, with 61 patients in the VR arm and 59 patients in the control arm. Table 2), exposure to VR conferred a 1.17-point incremental reduction in pain vs. controls (P = 0.048). Age was also a significant predictor in this multivariable model, with each additional 10-years of age predicting a 0.6-point reduction in pain (P = .001).The distribution of the within-subject differences in immediate pre- and post-intervention pain scores was tested for normality using the Shapiro-Wilk test (P = 0.19). A T-test showed the mean difference significant in favor of VR (P < .04). When limited to the subgroup of patients with the most severe baseline pain , the effect of VR was more pronounced vs. control . After adjusting for age, gender, and type of pain using linear regression analysis (Table 3) found VR was associated with significant drops in pain for each period when adjusting for time, study group, age, gender, and type of pain. Models describing the 48- and 72-hour post-intervention periods found .59 (P = .03) and .56 (P = .04) incremental reductions in pain versus controls, respectively.When extending the analysis to include pain scores collected in the 48- and 72-hour periods before and after the intervention, the multilevel mixed model regression analyses .Global measures of patient satisfaction, as recorded with selected HCAHPS items administered after discharge, exhibited a ceiling effect in both groups. Patients across the trial were broadly satisfied with their hospital stay upon 5-week reflection, rendering it difficult to identify incremental differences between the experimental groups. Specifically, there were no differences in perceived pain control (P = .48), efforts of the staff to manage pain (P = .42), overall perception of the hospital (P = .69), and willingness to recommend the hospital to a friend (P = .31); scores across all these HCAHPS items were high in both groups.There was no difference in the quantity of opioids consumed between groups in either pre-intervention or post-intervention periods. The mean MME in the VR vs. control groups pre-intervention was 80.83 (SD 51.82) and 75.07 (SD 52.78), respectively (P = .57), and the mean MME in the VR vs. control groups post-intervention was 81.04 (SD 45.09) and 77.08 (SD 43.94), respectively (P = .66).There were no significant treatment-related adverse events reported in either group. Three patients in the VR group (4.9%) reported transient dizziness at some point during their VR therapy, and all these individuals reported symptomatic resolution upon removing the headset without lasting effects.Although previous research has demonstrated therapeutic benefits of VR for pain, there has been no prospective, randomized, adequately powered, pragmatic trial of VR versus an active control in hospitalized patients. In this study, we found that on-demand use of VR in a diverse group of hospitalized patients was well tolerated and resulted in statistically significant improvements in pain versus a control group exposed to an in-room “health and wellness” television channel. These results build upon earlier studies and further indicate that VR is an effective adjunctive therapy to complement traditional pain management protocols in hospitalized patients.Notably, the VR group achieved improved pain scores despite the pragmatic and comparative effectiveness design of the study. Specifically, the trial minimized investigator interactions, did not enforce a VR usage protocol beyond initial patient instructions, relied solely on non-study nursing staff to collect the primary outcome measure, and utilized a control intervention with potential for therapeutic benefits. Moreover, the trial enrolled hospitalized patients with all forms of somatic and visceral pain, including oncologic, neurological, orthopedic, and gastrointestinal pain, among other types. Many of the patients suffered from complex, multi-factorial causes of biopsychosocial distress and received multi-modal treatments, making it difficult for any single intervention to offer consistent pain benefits across this diverse, hospitalized patient population. Nonetheless, the VR intervention achieved statistically significant benefits both initially and after 48-hours and 72-hours of use. Patients also reported higher satisfaction with the VR experience than watching television, indicating an improvement over the current standard of care for in-room audiovisual engagement.Although the effect of VR was statistically significant, the absolute reduction in pain scores was relatively small. After multivariable adjustment, VR accounted for an incremental 1.17-point drop in pain compared to the control group after the initial treatment; the incremental benefit dropped to 0.59 points when evaluating cumulative pain scores over the subsequent 48-hours. These differences fall below the 2-point threshold for a minimal clinical important difference (MCID) on the NRS, as reported by Farrar and colleagues. However,We did not observe a difference in opioid prescribing between the study groups. This is not altogether surprising, as treating physicians were free to manage pain according to usual practice and the protocol did not specify whether or how VR should impact clinical decision-making. Pain medications are typically ordered upon admission, and nurses work with their patients to dispense analgesics according to on-demand need within the constraints of physician orders. Our pragmatic study did not instruct nurses on whether to substitute VR for opioids or any other analgesic. Nonetheless, it is notable that patients in the VR group had lower pain scores despite receiving an equivalent MME as the control group. Future research should evaluate structured and standardized order sets that explicitly interpose VR as an early option prior to initiating or escalating opioids; this may promote earlier and more frequent use of VR and has potential to reduce subsequent use of opioids and other analgesics.It is notable that despite evaluating 591 patients for participation, only 120 enrolled and completed the protocol. Although this study is, to our knowledge, the largest randomized trial of inpatient VR for pain management, it is important to emphasize the drop-off between patient identification and study completion. This result is consistent with our previous research using VR in hospitalized patients, 14 and It remains unknown exactly how VR works to reduce pain perception and experience or whether different forms of VR have varying efficacy. Most proposed mechanisms attribute the benefit to simple distraction. When theNonetheless, important unanswered clinical questions include: (1) does enhanced VR that applies principles of Acceptance and Commitment Therapy (ACT) such as mindful meditation and/or physiologic biofeedback outperform conventional VR that employs simple distraction? (2) Are there patient characteristics that predict enhanced response to VR beyond baseline pain severity? (3) Are there usage patterns or engagement characteristics that predict enhanced response to VR? (4) Can VR reduce pain while also reducing opioid requirements? Although the current study further supports the effectiveness of VR for managing inpatient pain, it also raises additional questions that deserve inquiry as the field of therapeutic VR broadens and evolves.S1 FigRepublished under a CC BY license, with permission from AppliedVR, original copyright 2016.(PDF)Click here for additional data file.S2 Fig(PDF)Click here for additional data file.S1 Doc(DOC)Click here for additional data file.S2 Doc(PDF)Click here for additional data file.