This quality improvement study compares patient-reported pain and satisfaction scores within 6 months of a tooth extraction among patients who used vs did not use opioids. Are patient-reported pain and satisfaction scores similar between opioid users and nonopioid users after routine or surgical dental extractions?In this quality improvement study of 329 patients who underwent either surgical or routine extractions, patients who used opioids after the procedure reported higher levels of pain compared with nonopioid users. Those who did not use opioids reported similar satisfaction levels as the opioid users.These findings suggest that nonopioid analgesics, instead of opioids, should be the first-line medication for dental extraction. Dentists commonly prescribe opioids to relieve pain after tooth extraction. Understanding the differences in patient-reported outcomes between opioid users and nonusers could encourage the adoption of more conservative and appropriate prescribing practices in dental medicine.To evaluate whether pain and satisfaction scores reported by patients who used opioids after tooth extraction were similar to the levels reported by patients with no opioid use.This quality improvement study was conducted in the 14 dental clinics of the University of Michigan School of Dentistry. Eligible adult patients of these clinics who underwent routine or surgical extractions between June 1, 2017, and December 31, 2017, were contacted by telephone within 6 months of the procedure. Patients were surveyed about the type of extraction, use of prescription opioid (if given), use of nonopioid analgesics, pain levels, and satisfaction with care after the procedure. Data analysis was conducted from February 1, 2018, to July 31, 2018.The primary outcome was self-reported pain as assessed by the question, “Thinking back, how would you rate your pain in the first week after your dental procedure?” with a 4-point pain scale of no pain, minimal pain, moderate pain, or severe pain. Secondary outcomes included self-reported satisfaction with care as assessed by a Likert scale ranging from 1 to 10, in which 1 was extremely dissatisfied and 10 was extremely satisfied.P < .001; routine extraction group: 44 [64.7%] vs 35 [33.0%], P < .001). No statistically significant difference in satisfaction was found between groups after surgical extraction (median [interquartile range] scores: 9 [7-10] for nonopioid group vs 9 [8-10] for opioid group) and routine extraction (median [interquartile range] scores: 10 [8-10] for nonopioid group vs 9 [7-10] for opioid group).The final cohort comprised 329 patients, of whom 155 (47.1%) underwent surgical extraction  and 174 (52.9%) underwent routine extraction . Eighty patients (51.6%) with surgical extraction and 68 (39.1%) with routine extraction used opioids after their procedure. In both extraction groups, patients who used opioids reported higher levels of pain compared with those who did not use opioids (surgical extraction group: 51 [63.8%] vs 34 [45.3%], This study found that patients who used opioids after tooth extraction reported significantly higher levels of pain compared with nonusers, but no difference in satisfaction was observed. Largely owing to opioid-related overdoses, life expectancy in the United States dropped for the third consecutive year since World War I.2In 2017, the number of opioid-related deaths in the United States reached 49 068, an approximately 16% increase from the 2016 rate.4; however, dentists and oral surgeons have received more attention in recent years. Between 2010 and 2016, new dental procedure–associated opioid prescriptions to opioid-naive adult patients increased by 68%.5 Furthermore, dentists are among the most common prescribers for minor patients, and for many individuals, dental opioid prescriptions represent their first exposure to opioids.6 Previous studies of surgical cohorts have shown that opioid prescribing after a surgical procedure is not associated with patient satisfaction or the likelihood for refill requests.7 However, recent research has identified, for the first time, that dentists have an important role in the transition of opioid-naive users to persistent opioid users after a wisdom tooth extraction.9The Centers for Disease Control and Prevention and other national efforts have largely focused on the prescribing practices of primary care and pain physicians11 dental and oral surgical data are lacking. Randomized clinical trials in dentistry have shown that acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) are equivalent or even superior to opioids for dental pain.12 However, concerns remain from the dental community about the clinical relevance of the selected participants in these trials, and opioid prescribing after extractions remains common.13 Currently, knowledge is scarce about patient use (or nonuse) of the opioids prescribed by dentists. This quality improvement study was designed to test the hypothesis that patients who did not use opioids after routine or surgical dental extraction would report similar pain and satisfaction scores as patients who used opioids.Although a growing body of data is available that demonstrates that meaningful reduction, or even elimination, of opioids after a surgical procedure is appropriate,STROBE) reporting guideline.14The study protocol was not considered to be regulated quality improvement research by the institutional review board of the University of Michigan, Ann Arbor; therefore, informed consent was not obtained. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology  by searching the electronic dental records at the University of Michigan School of Dentistry, the first public university–affiliated dental school in the United States. The school was the ideal site for a study of opioid prescribing. Not only does it serve a large patient population, but it also has dental students, hygiene students, dental residents, and a private practice in which the dental faculty members treat patients. This study was conducted in the 14 clinics run by the University of Michigan School of Dentistry.Routine extraction was defined as requiring no conjunctive removal of bone or extraction of soft tissue because the teeth were visible and above the gum line. Surgical extraction was defined as requiring an incision into the connective tissue to gain access to the tooth. Following a similar structure used in previous surgical quality improvement studies,15 we contacted patients by telephone within 6 months after their procedure. We asked them whether they received an opioid prescription and, if so, to describe the number of opioid pills they used, the instructions for opioid consumption they followed, their opioid storage practices, their use of nonopioid analgesics, their pain before and after the procedure, and their satisfaction with their pain management. A 6-month postextraction window was used to ensure an adequate sample size while maintaining a time frame in which patients could recall their opioid use and patient experience. This process aligned with previous quality improvement efforts for surgical opioid prescribing as well as for perioperative pain and satisfaction.16 Exclusion criteria were patients who reported use of opioids before their procedure, an opioid fill that was not consistent with the dental record, extractions outside of the study time frame, and being younger than 18 years.Patients were surveyed if they had undergone a routine or surgical extraction procedure at the University of Michigan School of Dentistry between June 1, 2017, and December 31, 2017. The primary outcome was self-reported pain as assessed by the question, “Thinking back, how would you rate your pain in the first week after your dental procedure?” with a 4-point pain scale of no pain, minimal pain, moderate pain, or severe pain. Secondary outcomes included self-reported satisfaction with care as assessed by a Likert scale ranging from 1 to 10, in which 1 was extremely dissatisfied and 10 was extremely satisfied. For the cohort who received opioid prescriptions, patient-reported opioid consumption was converted into oral morphine equivalents (OMEs) and standardized to 5-mg–equivalent hydrocodone bitartrate pills.2 tests or unpaired, 2-tailed t tests. Among those who received an opioid prescription, the distributions of OMEs prescribed and OMEs consumed were compared using the Wilcoxon signed-rank test. Differences in pain level and satisfaction with pain management among those who used an opioid and those who did not were compared using the Wilcoxon Mann-Whitney test. In addition, we assessed for differences in these outcomes after stratifying patients by age group  and sex. The primary outcome compared those who reported any postprocedural opioid use with those who did not report use (0 pills) regardless of whether they received an opioid prescription.Both routine extraction and surgical extraction were each selected by a sufficient sample size of surveyed respondents and were evaluated separately. Both cohorts had patients who received an opioid prescription but did not fill the prescription and thus were considered nonopioid users. Descriptive statistics were calculated for patient demographic characteristics and postprocedure behavior. Univariate differences between patients who used an opioid (opioid group) and those who did not (nonopioid group) were assessed with χP < .05 was considered statistically significant. Because we did not have available data for postextraction pain before the study, a formal power analysis was not conducted. Data analysis was conducted from February 1, 2018, to July 31, 2018.All analyses were conducted with SAS, version 9.4 (SAS Institute Inc). Two-sided The patient flow diagram is shown in P < .001; routine extraction group: 44 [64.7%] vs 35 [33.0%], P < .001) (P < .001). The routine extraction opioid group had a median (IQR) of 3 (1-3) compared with the nonopioid group median (IQR) of 2 (1-3) (P < .001). The percentage of patients in the routine extraction opioid group who reported pain concerns was higher than those in the nonopioid group, but the difference was not statistically significant  . The opinificant . LikewisSatisfaction was high in both routine and surgical extraction groups. No differences in satisfaction scores were found between the nonopioid group and opioid group after surgical extraction (median [IQR] scores: 9 [7-10] vs 9 [8-10]) and after routine extraction (median [IQR] scores: 10 [8-10] vs 9 [7-10]) , nor werP < .001) (P < .001)  who underwent surgical extraction and 86 patients (49.4%) who underwent routine extraction received an opioid prescription after their procedure. Among those in the surgical extraction group, the median (IQR) OME prescribed was 60 (40-94.5). When standardized to hydrocodone, 5 mg, the median (IQR) was 12 (8-18.9) pills. Consumption of these opioids was significantly less, with a median (IQR) OME of 25 (0-60) with a median (IQR) number of pills consumed of 5 (0-12) ( < .001) A. Among  < .001) B. The toP = .57) and surgical extractions  (P = .71) and the routine procedure  cohorts. Approximately 12% of patients in both the routine and surgical extraction cohorts reported contacting the dental clinic for pain associated with the extraction. Although a higher percentage of patients in the routine extraction opioid group reported making telephone calls compared with the nonopioid group, this difference was not significant . Rates of telephone calls were similar in the surgical extraction cohort .No statistically significant differences in the number of patients who used NSAIDs or acetaminophen were found between the opioid group and nonopioid group for both routine extractions  . A smallP = .03] and routine extraction group ; second sensitivity analysis of pain in the surgical extraction group  and routine extraction group ). Likewise, no differences in median (IQR) satisfaction levels were observed between the 2 groups  vs 9 (7-10), P = .66] and routine extraction group  and routine extraction group )  vs 20 (43.5%), 12 Moreover, opioids have been associated with nausea, vomiting, and constipation, and recent studies have demonstrated that use of an opioid after a wisdom tooth extraction was independently associated with new chronic opioid use.17 Although randomized clinical trials generally recruit well-selected cohorts who may not represent the patients seen in clinical practice, data from these trials generally demonstrate the lack of effectiveness of opioids. These data also suggest that opioid prescribing is not needed to achieve high patient satisfaction. Although we do not suggest the routine prescribing of opioids for dental extractions, we acknowledge the rare cases in which opioid use is warranted.In this quality improvement study, patients who underwent routine or surgical extractions reported more pain  and simi20 Furthermore, some genes have been implicated in opioid responsiveness, including the OPRM1 gene.22 These patient covariates were not measured in the present study and may account for some of the differences in the cohorts.Previous studies have demonstrated that patient factors, like centralized pain and anxiety, are associated with increased pain and opioid consumption after a surgical procedure and with poor opioid efficacy.23 Research has demonstrated that convenience of a dental practice,24 cost of care,25 and even facility factors (such as availability of current magazines)26 seem to have implications for patient satisfaction. Dentists are health care professionals; however, most dentists must also run a small business, that is, their practice. More than 50% of dentists still run a solo practice27 and only approximately 3% of practices have 20 or more dentists.28 Any small business must optimize client satisfaction to protect and grow its brand; therefore, dentists must be cognizant of patient satisfaction. The current study showed that satisfaction was high in both routine and surgical extraction groups for opioid and nonopioid users. In many ways, this finding was not surprising given that multiple studies showed that interpersonal factors were the most important factors in patient satisfaction.31 Evidence has suggested that historical measures of technical skill  are more associated with interpersonal factors than with skill.32 Evidence has also shown that communication about cost is more important in satisfaction than the cost itself.33Patient satisfaction with dental care is a complex metric given that the dentist’s technical competence is difficult for a patient to recognize.35 and it is possible that this finding is associated with the intermingling of these highly variable factors rather than a true difference in analgesia effectiveness of opioids. Thoughtful preoperative discussion between clinician and patient about reasonable expectations may reduce the need for an opioid prescription after an extraction. Much is known about pain after dental extractions, and knowledge of pain intensity and duration can help the patient to feel more prepared to endure the discomfort for a limited time without opioids. The rates of acetaminophen and NSAIDs use were similar between the opioid group and nonopioid group, a finding that presents a quality improvement and patient education opportunity (the former group may not need an opioid prescription). Compelling evidence is also mounting for nonpharmacological methods for managing dental pain, such as acupuncture36 and behavioral techniques.The current study demonstrated that patients who used opioids actually reported worse pain compared with those who did not in both surgical and routine extraction groups. However, the decision to prescribe an opioid is not based on universally recognized standards of practice in dentistry, and thus individual clinician-level variability in prescribing exists. In addition, patient pain perception is highly variable,37No significant difference in the number of calls to the dental clinic about extraction-associated pain was found between the opioid group and the nonopioid group. For a small office that performs a high volume of extractions, this concern may lead to reducing opioid prescribing given that an increase in the number of calls and pain concerns could overburden the staff and the dentist and could serve as a barrier to practicing more conservative opioid prescribing; however, no such difference was revealed in this study. Previous studies of surgical cohorts demonstrated a lack of association between the amount of opioid prescribed and refills.38 The small cohort in that study generated 1010 unused opioid pills. In the United States, no regulation has been established that requires dentists to educate their patients on the safe storage and disposal of their opioids. Unfortunately, unused drugs can enter a drug reservoir and play a role in opioid dependence, addiction, and mortality. In the current study, we found that 1146 pills went unused among 195 patients who underwent extractions.Previous research involving 79 participants demonstrated that approximately 54% of opioids prescribed by dentists for surgical procedures went unused.12 and which demonstrated morbidity after dental prescribing17), nonopioid analgesics be prescribed and used instead of opioids after dental extractions for most patients. Future studies may better identify those patients who are at risk for severe pain and ascertain whether opioids are efficacious in that cohort.Despite the potential for unmeasured confounding variables that can affect opioid prescribing, we recommend that, when considering these findings together with those of previous studies (which reported a lack of efficacy for opioids after dental extractionThis study has several limitations that should be considered when reviewing the findings. First, this study had a retrospective design, which required participants to recall their opioid use, patient satisfaction, and pain perception regarding their past dental experience. The potential recall bias could be greater in patients who completed the survey 6 months after the extraction compared with those with a shorter window between the extraction and the survey. This potential bias would, however, be expected in both the opioid users and nonusers. Second, opioid prescribing was not randomized, and potential unmeasured confounding of patient and clinician characteristics could affect opioid prescribing and use. Third, the data were from a single academic medical center and may not be generalizable to other institutions or clinics. Although the total number of patients included was large for a study with patient-reported outcomes, we were unable to reach many patients, and a small number refused to participate. We did not find a statistical difference in sex between survey respondents and nonrespondents. A statistical difference in age was found, with respondents being approximately 5 years older on average. The surgical extraction group also had a substantially lower number of respondents who received an opioid prescription compared with nonrespondents.This study found that after routine or surgical extractions, patients who used opioids reported greater pain compared with those who did not use opioids. Moreover, opioid use was not associated with differences in patient satisfaction or telephone calls to report concerns about extraction-associated pain. We recommend the use of nonopioid analgesics instead of opioids for most patients undergoing dental procedures.


In the field of pain, virtual reality (VR) technology has been increasingly common in the context of procedural pain management. As an interactive technology tool, VR has the potential to be extended beyond acute pain management to chronic pain rehabilitation with a focus on increasing engagement with painful or avoided movements.We outline the development and initial implementation of a VR program in pain rehabilitation intervention to enhance function in youth with chronic pain.We present the development, acceptability, feasibility, and utility of an innovative VR program (Fruity Feet) for pediatric pain rehabilitation to facilitate increased upper and lower extremity engagement. The development team was an interdisciplinary group of pediatric experts, including physical therapists, occupational therapists, pain psychologists, anesthesiologists, pain researchers, and a VR software developer. We used a 4-phase iterative development process that engaged clinicians, parents, and patients via interviews and standardized questionnaires.P<.001), fear (P=.003), avoidance (P=.004), and functional limitations (P=.01) significantly decreased. Qualitative analysis revealed (1) a positive experience with VR ; (2) feeling distracted from pain while engaged in VR; (3) greater perceived mobility; and (4) fewer clinician-observed pain behaviors during VR. Movement data support the targeted impact of the Fruity Feet compared to other available VR programs.This study included 17 pediatric patients  enrolled in an intensive interdisciplinary pain treatment (IIPT) program, with mean age of 13.24 (range 7-17) years, completing a total of 63 VR sessions. Overall reports of presence were high , suggestive of a high level of immersion. Among those with multisession data (n=8), reports of pain (The iterative development process yielded a highly engaging and feasible VR program based on qualitative feedback, questionnaires, and movement data. We discuss next steps for the refinement, implementation, and assessment of impact of VR on chronic pain rehabilitation. VR holds great promise as a tool to facilitate therapeutic gains in chronic pain rehabilitation in a manner that is highly reinforcing and fun. Virtual reality (VR) is a newly emerging and promising intervention tool for chronic pain treatment to both distract individuals from their pain and facilitate otherwise painful or feared movements ,2. For aMoreover, few studies have applied VR tools for pediatric chronic pain . In a reBeyond pain treatment, VR programs that target physical rehabilitation in children are emerging. Meyns and colleagues  developeThe goal of this project was to develop a VR intervention to enhance mobility in the presence of chronic pain. Fruity Feet is a VR program created with input from a multidisciplinary team of pediatric pain rehabilitation clinicians, pediatric pain researchers, and VR technology developers. Fruity Feet responds to the growing need for VR applications that specifically target pediatric chronic pain populations who experience limited mobility due to fear and activity avoidance. In this paper, we first describe the development, acceptability, feasibility, and utility of Fruity Feet using a 4-phase iterative development process to facilitate increased upper and lower extremity engagement. We then discuss next steps for the refinement, implementation, and impact assessment of Fruity Feet.Youth admitted to an intensive interdisciplinary pain treatment (IIPT) program were specifically targeted as these individuals typically present with fear of movement and significant physical limitations due to pain. IIPT teams include physical therapists (PTs), occupational therapists (OTs), pain psychologists, pain medicine physicians, and pain medicine nurse practitioners ,20. TreaEligibility criteria for enrollment in the VR in pain rehabilitation pilot feasibility study included the following: (1) English speaking, (2) aged 7-21 with (3) a diagnosis of chronic pain and the need for physical rehabilitation, and (4) on stable medication/therapy for 2 weeks prior to the initial session. Patients were deemed ineligible if they had (1) diagnoses of neurological conditions  or (2) severe psychiatric symptoms (severe depression/anxiety).The IIPT pediatric pain rehabilitation team worked collaboratively with the CHARIOT technology software design team and Mighty Immersion, Inc. to develop Fruity Feet, a unique VR experience for youth undergoing chronic pain treatment and rehabilitation. This team incorporated an iterative process to develop this VR intervention, building upon patient and clinician feedback to improve acceptability and utility. The development of Fruity Feet consisted of 4 phases: Needs Assessment, Prototyping, Iteration and Refinement, and Feasibility and Acceptability. The Needs Assessment phase involved gathering information from the IIPT team to determine the scope of clinical needs and establish parameters for the VR intervention, hardware, and space. The Prototyping phase involved designing the initial functionality for lower extremity movement. The Iteration and Refinement phase involved a cyclical process of (1) testing the program with clinicians and test case patients, (2) gathering feedback, and (3) adjusting the software design, space, and hardware needs accordingly.The Feasibility and Acceptability phase ran in parallel to the Iteration and Refinement phase. Following Institutional Review Board approval, eligible patients that were enrolled in the IIPT at Stanford Children’s Health were invited to participate in feasibility testing. After consent from parent and assent from child were obtained, VR sessions were incorporated into the patient’s IIPT schedule. VR sessions occurred once weekly for approximately 30 minutes. After each session, patients were asked to complete the following questionnaires related to their experience while in VR.Patients were asked to provide a rating, ranging from 0  to 4 (very strongly) to 10 questions, assessing the patient’s perception of how real the virtual world seemed and whether they felt their virtual body (avatar) was an extension of their own. Higher scores are suggestive of greater presence in the virtual environment .The Child Daily Questionnaire was developed for repeated administration in the context of pediatric pain clinical trials . The ChiAfter each VR session, patients, parents, and clinicians were also asked to provide feedback in an open-ended interview format .Descriptive statistics for all questionnaires were run and repeated measures mixed models were run for the multisession Child Daily Questionnaire data using SPSS 25 (IBM). For interview data, NVivo qualitative statistical software was utilized to analyze participant  responses provided following VR sessions. Interview responses were imported into NVivo and case nodes were set up for each participant. The material was explored and emerging themes were coded. Text was searched and word frequency queries were placed into those coded themes. Themes from interview feedback responses with the most frequency were summarized into visual charts for patients and clinicians.Patient questionsWhat was it like to be in VR?How did it feel to be in VR?Tell me about any of the feelings you are experiencing now after being in VR.Tell me about what happened when you were in VR. Tell me about the parts that you expected? Tell me about the parts that you did NOT expect?Now that you have tried VR, how do you think VR can help other kids?How do you think we could improve the VR experience for other kids?If you could change anything about this, how would you make it better?Questions about the process of learning to use the avatar: eg, “How did you learn to use the VR character?” “Which bits were easy to learn?” “Which bits were hard to learn?”Feelings of ownership and control of the avatar: eg, “How did you feel you could control your virtual character?” “How was it difficult to control? How was it easy to control?”Feelings of presence or immersion: eg, “How ‘real’ did it feel to you?” “When you were in the virtual world, what did you notice was happening around you in the real world?” “What else did you think about?” “Where did you have your attention focused?”What they consider to be the biggest benefits and failures of VR therapy eg, “What are the best things about the virtual reality?” “What are the things you don’t like about it?” “What would you do differently?”Would they consider doing VR therapy often as a more intensive treatment program? eg, “How often would you be willing to come back to the clinic to do more VR?” “How much do you think doing VR regularly would help with your pain?” “How would you compare VR to other treatments for pain?”Parent questionsWhat do you think or how do you feel about your child’s VR session today?Is there anything that could be improved in the VR sessions?Clinician questionsHow did the VR session go today?Is there anything that could be improved in the VR sessions?Seventeen, predominantly female  youth with a mean age of 13.24 (ranging from 7 to 17 years) being treated in an IIPT from January 2019 to March 2020 participated in this feasibility pilot . PatientAcross 17 patients, 63 VR sessions were completed. All sessions were conducted with a clinician  present in a dedicated VR room with flooring for physical activity use, such as floor mats typically used in a rehabilitation gym for safety. VR sessions were typically 30 minutes in duration . The clinician determined the appropriate treatment and chose the duration as well as the mode that was needed for each patient while engaged in VR. Clinicians ensured safety parameters within the space and considering patient ability and function.The first phase of the project was dedicated to program start-up, which included identifying needs for the VR intervention, obtaining Institutional Review Board approval, outfitting a permanent testing room for VR use, and training clinicians on how to administer a VR session. The team initially met to establish the parameters for the intervention, following an extensive exploration of existing VR programs for rehabilitation purposes. The team found that existing rehabilitation programs focused solely on upper extremity involvement. The team deemed these existing programs inadequate for the pediatric pain rehabilitation population, which presents with a greater need for lower extremity interventions within a more age-appropriate and engaging platform. The needs assessments with pediatric clinicians  further defined the goals and recommendations for VR interventions in pediatric pain rehabilitation. PTs requested activities targeting functional goals to strengthen muscles and increase range of motion. OTs requested movements targeting activities of daily living. Pain psychologists provided insights into fears about pain related to movement during OT and PT sessions. Pain psychologists also requested options for modifying the delivery format for youth who may be distressed by wearing a headset or too anxious to begin lower extremity VR in a standing position. Pain medicine physicians requested options for patients who were sitting, standing, or otherwise limited in their physical abilities.Following clinician needs assessments, the software design team shadowed each clinician to observe youth with chronic pain during typical IIPT sessions. This process provided the software design team with use cases and insight into the tasks youth were attempting to master in physical therapy, occupational therapy, and pain psychology sessions . Understanding these tasks, as well as the process and protocols within each therapy session allowed the software design team to further define an optimal VR tool for IIPT—an immersive VR world that would promote engagement in gamified pain rehabilitation tasks that scale to meet treatment demands based on a patient’s current ability.Following the clinician needs assessment and initial program software design, the technical team was able make decisions about the VR hardware and room setup. The team chose to use an HTC VIVE VR System, which tracks a user’s head in a 10′ × 10′ play space with 6 degrees of freedom. The VIVE VR System also includes 4 additional 6 degrees of freedom trackers, which track the position and rotation of the player’s hands and feet. Using this system, users can fully immerse themselves in a virtual world, with the ability to walk around and touch virtual objects with their hands and feet. The VIVE VR System requires a VR-ready computer and 2 external trackers (lighthouses) positioned in opposite corners of the play area. In order to house this system, the program used a dedicated VR room with adequate space for the hardware setup, which included a 10′ × 10′ play area, a locked cabinet for storing the computer and other VR equipment, 2 permanently mounted VR lighthouses for quick session setup, a retractable cable management system to help keep the VR headset’s cable out of the way during a session, and rubber gym flooring for safe, active VR usage.The software design team began by focusing on a single game, Fruity Feet, to prototype and test with patients. Fruity Feet gamifies lower extremity PT, helping patients increase their range of motion and become more comfortable with moving their feet and legs. Gameplay mechanics were built around the following lower extremity PT movement goals: multiplanar stepping , stomping, marching, kicking, raising leg to different heights, and active ankle range of motion tasks . Importantly, the module was also built to scale to a patient’s mobility, ensuring that patients of all abilities could play the game and benefit from the VR intervention.The team designed Fruity Feet to be developmentally appropriate for children and adolescents. The game is fun, light-hearted, and often silly, while employing stylized graphics, in-game feedback, and sound design to offer immersive and engaging game play. During play, users are placed on a farm and instructed to stomp and kick as many virtual fruits and vegetables as possible in order make juice and gain points before a timer runs out. Player step/stomp quality is measured by the VIVE sensors, scoring players based on how high they raise their legs and whether they land their feet in the center of the fruit. As players stomp and kick at the fruit appearing beneath their feet, virtual fruit juice splatters the world and a cartoon farmer yells encouraging phrases such as “Nice job!” and “That’s some juicy fruit!” . CliniciFollowing the initial development of Fruity Feet, the team began a cyclical process of testing the program with clinicians/patients, gathering feedback, and iterating on the software design. This feedback loop was critical in building a VR module that was easy to use, fun to play, and met the appropriate therapy goals for patients and clinicians. During this process, both Fruity Feet and commercially available VR programs were used to obtain feedback to further develop Fruity Feet and the VR environment. Providers noted the importance of including both upper and lower extremity engagement during Fruity Feet tasks. For example, an OT on the team provided feedback about neck discomfort while constantly looking downward when the task was initially solely focused on lower extremity movements. One of the first patient test cases initially presented with mobility limitations, using one crutch to ambulate. The patient was a 12-year-old Caucasian female with a diagnosis of CRPS of the lower right extremity. She struggled with tasks such as standing, walking, and other movements that required her to bear weight on her right foot. She regularly participated in VR sessions during her rehabilitation process, and as her pain and function began improving, she requested more challenges and further gamification of Fruity Feet. As an avid gamer herself, she requested a competitive element for the game, and even went so far as to suggest an “alien invasion” component when players got to a certain level. With this patient’s feedback, the team developed a new game add-on in which unknown flying objects (UFOs) appeared, challenging advanced users with faster-flying fruits.Fruity Feet was eventually expanded to include new game modes. These modes were designed as a modification to allow the use of VR for lower extremities from a seated position. This prompted the development of a graded process for increasing lower extremity active range of motion and weight bearing by transitioning from seated tasks  to standing tasks . Game modes also included the use of upper extremities, creating an active and dynamic experience for patients pursuing both upper and lower extremity goals , all at once. Beyond specific movement goals, these new game modes provided variety and choice for patients using VR, which made for a more engaging and less repetitive session.Modifications helped to simulate activities of daily living, play, and leisure activities while downregulating the sensory system. The movements within Fruity Feet helped to promote increased function for daily living tasks. Fruity Feet engaged participants in leisure activity that required movement, balance, and endurance, which could be generalized to age-appropriate occupations including the act of raising one’s arms above the head in order to don a shirt , weight shifting, and standing balance skills necessary for showering  and functional endurance activities important for school, sports, and other active recreational tasks . Each change and addition to Fruity Feet went through multiple iterations and feedback sessions with clinicians and patients. As the tasks became more dynamic, clinicians continued to identify and ensure safety measures were considered through each iteration of Fruity Feet . Many patients in the IIPT program were able to see their suggestions and feedback come to life in VR as requests for additions, such as farm animals and aliens, were incorporated into the software.One example of how Fruity Feet was improved during the iteration and refinement phase for wheelchair-bound patients involves a 12-year-old Caucasian female patient who was nonweight bearing yet eager to participate in the VR in pain rehabilitation platform. The patient was diagnosed with CRPS in both of her lower extremities. She initially struggled with tasks of standing or stepping but seemed to benefit from active ankle range of motion tasks conducted while seated in a chair. This patient provided feedback to include rewards in addition to points, such as being able to add animals to the virtual farm in exchange for a certain amount of points earned. This addition improved motivation to remain engaged in the game for longer periods and allowed the patient to progress to more dynamic standing and stepping goals. The patient struggled to achieve these movement goals during her typical PT sessions in the IIPT program without VR in pain rehabilitation; however, once VR was added, she was able to attain such goals more effectively. The patient was able to increase use of her lower extremities, resulting in an improved ability to ambulate without assistive devices. She noted that Fruity Feet improved her motivation to engage in standing/walking IIPT goals with the PT.F4,27.7=9.27, P<.001), fear , avoidance , and functional limitations  across VR sessions. Activity engagement and pain reactivity reports did not significantly change across VR sessions.After each VR session, patients were surveyed on their perception of the virtual character (avatar) as well as the virtual environment. Patients were asked about how real the virtual world seemed , and whether they felt the avatar’s body was an extension of their own body . Overall reports of presence were high , with scores ranging from 0 to 40, with higher scores suggestive of greater presence. As the child daily questionnaire began after the feasibility pilot started, we provide data on those who completed it more than once n=8; . The repThere were a total of 63 child interview responses from 17 patients completed after VR sessions. Feedback was obtained for the first 45 sessions (n=13), as part of the iterative process, following each VR session. These 45 responses were entered into the NVivo qualitative analysis software system. An emergent coding approach was utilized, with 2 coders (AG and AF) creating the same themes, to demonstrate accuracy, as responses could be coded in various ways. Multiple responses informed the 4 derived themes with sample responses detailed in These emergent patient response themes included (1) positive experience or response to the VR session ; (2) feeling distracted from pain while engaged in the VR task ; (3) VR increased physical function/mobility ; and (4) reduced pain behaviors/symptoms  during VR .We highlight responses from 1 participant who demonstrated progress over 3 weekly sessions. This patient identified initially not liking the immersive experience, but agreed to continue exploring the VR platform. Over the subsequent 2 sessions, the patient’s responses improved to conclude that Fruity Feet was acceptable and noted improvements in function without noticing pain with movement . The patMost patients reported a positive response to the VR experience. Patients reported that it felt real, and that they felt immersed in the VR world, even while speaking with the clinician in the room during the session. Nearly all patients, in at least one of their sessions, reported feeling distracted from their pain:Painless. It's ... kind of like a coping thing where you're distracted and ... you don’t feel like you have pain. You’re just trying to focus on whatever game you're doingID 1, Session 1It was really neat! It made me forget about the pain a little because I was in a world where the pain didn’t existID 6, Sessions 1 and 2Patients also reported experiencing ownership and control over their avatar during the VR sessions, and for some this increased over subsequent sessions. All patients responded in at least one session that VR would help other youth with chronic pain. All patients responded that they would use VR in the IIPT program, with several commenting that it was more “fun” or “distracting” than alternatives such as physical therapy sessions without VR. Many patients also responded with increased functional gains during the VR task, reporting:When I was in VR I was able to move my foot around much more in order to squash all of the fruitID 6, Session 1An emergent coding approach in NVivo was also utilized with clinician responses, with 2 coders (AG and AF) creating the same themes, demonstrating accuracy. Qualitative results generated frequency scores, resulting in 4 primary themes for clinicians derived from 32 responses from 5 clinicians . Clinician response themes about observations of their patients included the following: (1) increased function/mobility , (2) enjoyment of the VR experience , (3) VR extended or lengthened patient’s ability to engage in physical activity , and (4) VR increased patient’s distraction from pain symptoms during the VR sessions .Clinician feedback suggested that VR helped their patients achieve pain rehabilitation goals. Some credited VR with helping to progress patients to no longer need assistive devices.He really comes to life when he's doing VR. So, it's nice to see him so active, animated ... the point where he's singing and he's dancing, and he's really blossomed with what he can do with the gameID 1, Session 4She didn't even mention a concern about the fact that she was standing for nearly 40 minutes ... didn't complain, didn't say anything, and she was shifting her weight onto the affected limb ... standing equally or even on the right leg, pretty frequentlyID 2, Session 5Some clinicians commented that VR was a useful environment for overcoming psychological barriers.It's kind of like nice to be able to tie in some of the things we're working with in psychology, with what he was doing in VR ... and (it) was sort of the perfect kind of concrete example of being able to put that into actionID 1, Session 5When available, parents were interviewed about their child’s VR experience. Derived from 4 responses from 3 parents, parents remarked on the immersive quality of VR at their child’s level of engagement while playing the games.I love it... And the most impressive thing was that she can walk around without help and without complaining about her pain.ID 8, Session 1It gets her moving a lot more than she thinks she canID 2, Session 7One parent suggested that it would benefit their child to watch footage of their own motion after the session, to “change her mind” about how much she can do .Based on clinician observation and interviews, areas for improvement or modifications were identified to attenuate any adverse effects from VR engagement. For example, there was 1 patient (ID 5) that reported feeling “trapped” and “out of control” during her first session, which was discontinued. Rather than engaging in VR with the headset, a projector was utilized to illuminate the gaming images on the wall, because the patient was interested in finding a way to comfortably participate in the VR intervention. She returned for additional sessions with this modification, and during her third session, the patient commented that she “loved it.” The patient and clinician both suggested that more games be made available in projector mode for patients who do not feel comfortable with the immersive VR experience. Furthermore, 2 patients reported feeling “dizzy” or “weird” after sessions, with 1 patient noting that it was difficult to become accustomed to light and other sensory stimuli in VR . This patient later reported having a headache prior to participating in the session, which may have been exacerbated by the light in VR. One patient reported that the headset was heavy .Clinically, clinicians noted that patients moved their lower extremities more frequently with Fruity Feet in comparison to other VR programs. The VR team then compared Fruity Feet to other commercially available VR games and programs . In order to capture differences in movement across these programs, the software developers created a novel method to compare movement while using different VR programs called the VR Clinical Comparison Research Tool. The VR Clinical Comparison Research Tool tracks the movements of each extremity simultaneously in real time with advanced analytic capabilities for range of motion across VR programs. Clinicians can create custom play lists, leveraging existing content with custom modules, while tracking progress within each session and longitudinally throughout the course of therapy. This allows for comparison across VR programs for VR in pain rehabilitation. Preliminary data for 1 sample case demonstrated that Fruity Feet tracked increased movement for a patient with CRPS in the patient’s affected left lower extremity .This paper describes the development and implementation of a novel VR intervention for youth with chronic pain participating in an intensive IIPT program. Existing game-based VR programs as well as rehabilitation-centered VR programs do not currently meet the physical rehabilitative needs of pediatric patients with pain, particularly due to the preponderance of those suffering from lower extremity pain and mobility limitations. To address this opportunity for meaningful VR engagement in rehabilitation, we implemented a multistep and iterative process of treatment development with a cohort of individuals admitted to an IIPT. The intervention described in this paper, Fruity Feet, was born out of a collaboration between pediatric pain researchers, clinicians on the front line with patients , and software developers interested in designing a VR program specifically to meet the needs of pediatric patients with chronic pain participating in functional rehabilitation. The result is a gamified VR program that has unique lower extremity capabilities and that is adaptable to each individual’s mobility.To develop Fruity Feet, a needs assessment with rehabilitation clinicians was critical to understand the unique ways that youth struggle to engage in therapies, and potential ways in which VR could not only enhance their participation in therapy, but also benefit their progress. Furthermore, understanding specific movements that are often avoided due to pain and fear provided targets for Fruity Feet optimization . After the prototyping phase, patient involvement was critical to the iteration and refinement of the Fruity Feet game developed. In this initial phase, feasibility was high, particularly with a captive audience of youth participating in an IIPT 5 days per week with multiple therapy sessions per day. Patients often preferred and even requested that their therapy session include VR, demonstrating high acceptability as well. Qualitative data from patients and parents reflected engagement in activities not previously perceived possible , distraction produced by VR, and therapies with VR described at times as “fun.”The Fruity Feet program yielded results consistent with prior VR therapies in the treatment of pediatric pain, as it was both tolerable and safe . MoreoveThere are several limitations with regard to the implementation and generalizability of our VR program. Equipment setup for sessions using VR was typically more time-consuming than typical PT or OT sessions. A dedicated VR room with specifications for optimizing safety  was needed for administering sessions due to space required for conducting the physically active VR sessions. Although technical issues were uncommon, our clinicians did have a dedicated technology expert available for assistance during all sessions. Expense of equipment, staffing, and space constraints may limit adoptability by other institutions. The clinical team also reported difficulty with patients generalizing their progress outside of VR sessions at times . This suggests the importance of potentially implementing VR in pain rehabilitation over the course of several sessions to examine the cumulative impact of VR on skill generalization. In addition, it was not possible for patients to utilize the VR equipment outside of session which limited their abilities to emulate their therapy sessions when completing their home exercises. Interestingly, some families with resources to purchase VR headsets and gaming consoles requested guidance on purchasing their own; however, Fruity Feet is not yet commercially available, limiting their ability to continue with the therapy-inspired modules after participation in the IIPT. A further limitation and caution arises in terms of sanitary reuse of equipment. Although our team disinfected the headsets and controllers prior to each patient’s participation, additional health and safety concerns must now be considered in a time even more focused on infectious disease prevention. Consideration should be made for also utilizing a UV sanitizing device along with the standard disinfecting process. Lastly, applying a single-case experimental design approach in future studies would allow for a more sensitive analysis of change processes as the current data collected limited the conclusions we could draw about the impact of VR in pain rehabilitation on functional outcomes.mirror therapy and exaggerated movement modules. In addition, a clinical protocol for the exposure therapy and range of motion exercises is underway. We have continued to develop tools for pain psychology interventions with the addition of a heart rate variability biofeedback component connected to VR (currently in the prototype phase). This tool will include the use of pain management coping skills with the benefits of heart rate variability to explore an immersive and interactive VR task, while fostering relaxation and self-regulation for downregulation of the nervous system. Furthermore, we have also been testing the use of VR with pedaling for increasing a variety of seated tasks. It will be critical to also assess sustained benefits from VR after active treatment across domains of function. Finally, we have begun expansion of VR in pain rehabilitation to multiple sites in the United States and Canada to examine the feasibility of dissemination and the effectiveness of this VR intervention across a large, diverse population of youth with chronic pain.Future developments of VR in this context will focus on testing with additional samples, as well as further testing of The VR application Fruity Feet has the potential to make a tremendous impact on the rehabilitative treatment of youth with chronic pain. The iterative process has helped to improve and refine this resource, with customized settings for a specific extremity, mirror therapy, exaggerated movement capabilities, and a VR Clinical Comparison Research Tool that tracks the movements of each extremity in real-time with advanced analytic capabilities across VR programs. Preliminary data suggest improvements in movement with decreased focus on pain symptoms while immersed in the VR world. VR in pain rehabilitation helped youth with chronic pain in an IIPT program to increase distraction from pain and helped to improve function to achieve rehabilitation goals. Furthermore, VR in pain rehabilitation successfully incorporated the use of lower extremities, in addition to upper extremities, which allowed both sitting and standing tasks for improved patient accessibility and generalizability. Youth with chronic pain found VR in pain rehabilitation to be acceptable, feasible, and engaging.


Pain on injection is a well-recognized adverse event of propofol administration for the stimulation of general anesthesia. Pre-treatment with lidocaine or flurbiprofen axetil has proven to be effectual in the reduction propofol-induced pain in adults. Nonetheless, only few studies have evaluated the clinical therapeutic effects of lidocaine combination with flurbiprofen axetil to prevent pain on injection of propofol. The current study aims to evaluate the clinical therapeutic effects of lidocaine combination with flurbiprofen axetil to reduce pain on injection of propofol among adult patients.The literature search will be conducted from their inception to November 2020 from MEDLINE, EMBASE, Web of Science, and Cochrane Library databases without date or geographical restrictions. However, language will be restricted to publications in English and Chinese. Two authors will independently screen abstracts and titles of all papers to determine whether to include or exclude them. The authors will also study characteristic and outcomes of data extraction and carry out risk of bias assessment. We plan to use either a fixed-effects or random-effects model to estimate the risk ratios (RR) or mean difference (MD) or standardized mean difference (SMD) together with 95% confidence interval (CI).This study will provide high-quality evidence for the clinical therapeutic effects of lidocaine combination with flurbiprofen axetil for reducing pain on injection of propofol in adult patients.This study will summarize current evidence for the management of pain on injection of propofol in adult patients and provide guidance for both intervention and future research.Since no data collection will be involved, there is no need for an ethics approval.https://osf.io/72tpj/)November 17, 2020.osf.io/72tpj/. ( Therefore, flurbiprofen, which is a non-selective cyclooxygenase inhibitor can be used clinically as non-steroidal anti-inflammatory drugs (NSAID). In particular, flurbiprofen axetil is regarded as an injectable product of flurbiprofen for post-operative pain control.,9 However, no studies have evaluated the clinical therapeutic effects of lidocaine combination with flurbiprofen axetil to prevent pain on injection of propofol. Thus, the current study will explore the best available evidence, focusing on clinical therapeutic effects of lidocaine combination with flurbiprofen axetil to reduce pain on injection of propofol among adult patients.Propofol is usually utilized in painless endoscopy anesthesia due to its benefits, such as the rapid onset and its relation with early recovery. Pain on injection, however, is a well-known adverse even usually associated with administration of propofol for the stimulation of general anesthesia.2http://osf.io/), and the registration number was 10.17605/OSF.IO/72TPJ. The study will be reported in accordance with guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol (PRISMA-P) statement.We have registered this protocol on the Open Science Framework  evaluating the clinical therapeutic effects of lidocaine combination with flurbiprofen axetil will be included to ascertain their impact to prevent pain on injection of propofol.2.1.2Participants to be considered for this study will include adult patients aged above 18 years who were administered propofol intravenously.2.1.31.The experimental groupsIn the experimental groups, any RCTs study that utilize lidocaine combination with flurbiprofen axetil as intervention will be included in the present study.2.The control groupsIn the control groups, any RCTs study that utilize any treatments with lidocaine alone or flurbiprofen axetil alone or any another treatment.2.1.4The primary outcomes will include incidences of propofol-induced injection pain. The secondary outcomes will include the gravity of propofol-induced injection pain, adverse outcomes, including thrombophlebitis, cardiac arrhythmia, hypoxemia, hypotension, allergic reaction, vital signs, and patient satisfaction.2.22.2.1We intend to perform a literature review from inception to November 2020 in MEDLINE, EMBASE, Web of Science, and Cochrane Library database without date or geographical restrictions. However, language will be restricted to publications in English and Chinese. The following search terms: propofol∗, lidocaine∗, flurbiprofen∗, adult∗, “injection pain”, “RCT∗”, “randomized controlled trial”, “randomised controlled trial”, and randomly∗ will be combined using “AND” or “OR” to identify relevant studies.2.2.2https://clinicaltrials.gov/) will be searched and the reference lists of all the main articles will be checked to obtain extra references.ClinicalTrials.gov  together with 95% confidence intervals (CI) for all dichotomous results of the included studies. We will express results as mean difference (MD) or standardized mean difference (SMD) together with 95% CI for all continuous outcomes.2.3.5I2 statistic to evaluate heterogeneity. We will plan to regard a level of heterogeneity above 50% as substantial heterogeneity, and then the random-effects model will be utilized to estimate the results.We will use the 2.3.6We intend to establish and explore the funnel plots to determine potential publication bias where we can pool over 10 trials.2.3.7We plan to perform a sensitivity analysis to evaluate the robustness of our findings if we identify sufficient studies.3This study will provide an up-to-date assessment of the clinical therapeutic effects of lidocaine combination with flurbiprofen axetil to reduce pain on injection of propofol in adult patients. We consider that this study will focus on examining the clinical therapeutic effects of lidocaine combination with flurbiprofen axetil to treat adult patients with propofol-induced pain. Although several studies have proved the efficiency of lidocaine in prevention of pain on injection of propofol in adult patients, the use of lidocaine combination with flurbiprofen axetil to treat adult patients with pain on injection of propofol remains undiscovered. Therefore, the present study will systematically explore the clinical therapeutic effects of lidocaine combination with flurbiprofen axetil to prevent pain on injection of propofol in adult patients. The expected findings will provide recommendation for the treatment of adult patients with pain on injection of propofol.Conceptualization: Weiqiang Sun, Xiaofeng Ye, Jun Fu.Data curation: Weiqiang Sun, Jinfen Yu, Gang Lu.Formal analysis: Weiqiang Sun, Jun Fu.Funding acquisition: Jinfen Yu, Xiaofeng Ye.Investigation: Jinfen Yu, Jun Fu.Methodology: Gang Lu.Project administration: Jinfen Yu, Gang Lu.Resources: Jinfen Yu, Gang Lu.Software: Weiqiang Sun, Jinfen Yu.Supervision: Gang Lu, Xiaofeng Ye.Validation: Weiqiang Sun, Xiaofeng Ye.Visualization: Jinfen Yu, Gang Lu, Jun Fu.Writing – original draft: Weiqiang Sun, Xiaofeng Ye, Jun Fu.Writing – review & editing: Weiqiang Sun, Xiaofeng Ye, Jun Fu.


Patients with persistent pain due to osteoarthritis (OA) complain of multiple symptoms that cannot be explained solely by structural changes. A poor correlation exists between structural and inflammatory changes in OA and pain levels. Central sensitization (CS) has been identified as a factor that induces chronic pain in patients with OA. Although it is important to identify osteoarthritis patients with CS components, the prevalence and characteristics of CS, especially those in patients with hip OA, are not well understood. Thus, we aimed to determine the prevalence and characteristics of CS in patients with hip OA, in this study.The CS Inventory (CSI), used as a non-invasive routine clinical tool to evaluate the presence of CS 1 month before surgery in 100 patients with hip OA, was measured at our outpatient clinic, and the data were retrospectively reviewed. We determined the number of patients with a CSI score of 40 points or higher and assessed the relationships between the CSI score and clinical factors  using the Spearman’s correlation coefficient.r = 0.348, P < 0.001).The mean age of participants was 63.9 ± 11.6 years, and there were 15 men and 85 women. All patients had hip OA, categorised as advanced and terminal stage (Tönnis grade 2–3) on preoperative plain radiography. The mean duration of hip pain was 4.2 ± 4.4 years. The mean CSI score was 19.5 ± 11.3 and 5 (5.0%) of the patients had a score of 40 or more points. CSI scores correlated significantly only with VAS pain at rest (In this study, 1 out of every 20 hip OA patients had CS components. CSI scores were significantly correlated with pain at rest in hip OApatients. CS approaches to hip OA may be one of the treatment options for pain at rest. Osteoarthritis (OA) is a heterogeneous disease, characterised by progressive cartilage loss, subchondral bone remodelling, osteophyte formation, and synovial inflammation, with resultant joint pain and increasing functional disability. Patients with persistent pain due to OA complain of multiple symptoms that cannot be explained solely by structural changes. It has been reported that there is a poor correlation between structural and inflammatory changes in OA and pain levels . AlthougIn 2011, the International Association for the Study of Pain defined central sensitization (CS) as increased responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold afferent input. CS results from persistent, intense nociceptor stimulation that triggers changes in the central pain transmitting neurons, leading to alterations in pain presentation and perception, and centrally mediated symptoms, such as fatigue and mood disorders . Over th, fibromyalgia, chronic fatigue syndrome, temporomandibular joint disorder, irritable bowel syndrome, migraine or tension headaches, multiple chemical sensitivities, and restless leg syndrome). CS involvement is strongly suggested in these seven disorders, and CSS was proposed as a comprehensive disease concept ) and clinical characteristics , data were collected preoperatively at an outpatient clinic 1 month before surgery.Radiographic OA was graded as 0 (no changes); 1 ; 2 ; and 3  using the Tönnis classification. The severity of OA-related hip pain at rest and on activity was assessed using an 11-point visual analogue scale . HHS, with a maximum of 100 points, is used to assesses the hip function [scores range from 0 (worse disability) to 100 (less disability)] and includes the following domains: pain, function, deformity, and motion.P values < 0.05 were considered to indicate statistical significance.Results are expressed as the mean and the standard deviation of the mean unless otherwise indicated. A sample size calculation was performed based on the study’s main objective, which was to evaluate the correlation between CSI scores and significant variables in all patients. The minimum power level was set at 0.80. It was determined that we needed to include 97 patients to satisfy the expected effect size. Therefore, our sample size of 100 patients was deemed adequate. Continuous variables were calculated using the Mann-Whitney U test and categorical variables were calculated using the chi-square test. Correlations between the CSI score and age, duration of hip pain, VAS pain at rest, VAS pain on activity, and HHS in all patients were evaluated using the Spearman’s correlation coefficient. Correlation coefficient is represented by r. All statistical analyses were performed using Statistical Package for the Social Sciences software . Patient demographics and clinical assessments are summarised in Table P = 0.063) in Table The CSI score did not differ significantly between patients with Tönnis grades 2 and 3  in all patients with hip OA  (Table Fifteen percent of the patients were diagnosed with one or more CSSs. The CSI score was significantly higher in patients with one or more CSSs (30.00 ± 12.50) than in patients without a CSS diagnosis (17.70 ± 10.00; A CSI score of 40 out of 100 was reported as the best distinguishing factor in patients with CSSs . Kim et Previous studies have reported that a relationship exists between radiographic hip OA and pain severity, but have found no evidence of an association between preoperative pain severity and hip OA grade . In our Recently, some treatments of OA pain related to CS components have been reported –11. DuloThis study has a limitation to acknowledge. This study used a cross-sectional study design. The relationship between preoperative CS components and postoperative clinical results remains unclear in patients with hip OA. Therefore, a prospective longitudinal study will be needed to evaluate these relationships.In this study, 1 out of every 20 hip OA patients had CS components. CSI scores were significantly correlated with pain at rest in hip OA patients. Our results suggest that CS approach to hip OA may be one of the treatment options for pain at rest.


To compare the subjective level of pain in patients who underwent an ultrasound-guided percutaneous liver biopsy (PLB) after either pericapsular anesthesia (PA) or subcapsular anesthesia (SA), based on the numeric rating scale (NRS).A total of 323 patients, mean age 51, range 21–82 years; 160 (49.5%) male, referred to the Interventional Radiology Clinic of Kocaeli University Faculty of Medicine for image-guided PLB, between June 2019 and May 2020 were included and randomized into two groups by anesthetic type; the first (n = 171) consisted of patients undergoing SA while the second (n = 152) included patients undergoing PA. The intensity of pain at 0, 1, and 6 h after PLB was evaluated between the groups using NRS.At hours 0, 1, and 6, the median [range] NRS scores in the subcapsular and pericapsular groups were 2 [1–2] versus 3 [2–4] (P < 0.001), 1 [0–1] versus 1 [1–2] (P < 0.001), and 0 [0–0] versus 1 [0–1] (P < 0.001), respectively. Subgroup analysis revealed that the patients who underwent the subcostal procedure with subcapsular anesthesia reported the lowest pain scores and intercostal procedure with pericapsular anesthesia reported the worst pain scores for each time point: 0 h 1 [1–2] versus 3 [3–4], P < 0.001; 1 h 1 [0–1] versus 1 [1–2], P < 0.001; and 6 h 0 [0–0] versus 0 [0–1], P < 0.001, respectively.Subcapsular anesthesia is a well-tolerated procedure compared to a pericapsular procedure. Furthermore, the application of a subcapsular anesthetic with a subcostal approach was reported to result in the lowest pain and greatest patient comfort.  Percutaneous liver biopsy (PLB) is a procedure that we obtain a small piece of liver tissue by a needle inserted into the liver through the skin, subcutaneous tissue, and muscles, either with or without the guidance by simultaneous imaging . PLB is an essential procedure in assessing chronic liver diseases and the differentiation of primary or metastatic liver malignancies .After the biopsy procedure, minor complications such as pain and significant complications such as pneumothorax, hemorrhage, and death may develop [5]. Although pain seems to be a minor complication, it may affect the diagnosis and treatment in liver diseases by affecting the patient’s willingness to have the procedure. Previous studies have demonstrated moderate to severe perception of pain after liver biopsy .Pain is a sophisticated subjective experience. Pain arising from the liver biopsy is believed to originate from skin and liver capsule innervation [5]. In previous reports, the patient’s age and sex, operator experience, route of biopsy, size of the needle, number of needle passes, and intravenous drug usage have been identified as factors that lead to pain from liver biopsy .Traditionally, pericapsular anesthesia is a commonly used approach as a part of liver biopsy [10]. In our institution, two techniques –subcapsular (SA) or pericapsular (PA)– are used for the administration of a local anesthetic. In the past, most of the liver biopsies in our center were performed with PA. However, anecdotal reports from patients indicated that the SA approach was associated with less pain. This study aimed to compare the levels of pain, as reported by patients undergoing PLB, after either SA or PA local anesthesia.The study was designed as a cross-sectional single-center study. All patients who were referred for liver parenchyma biopsy to the Interventional Radiology Clinic of Kocaeli University Faculty of Medicine between June 2019 and May 2020, and met the inclusion criteria were considered for the study. Patients were randomly assigned to one of the local anesthesia approaches, SA or PA.Adults over 18 years old and with normal coagulation parameters and agreeing to participate in the study were included. Patients under the age of 18 and those with abnormal coagulation test results , low platelet count (<70.000/mm³), dilatation of the biliary ducts, massive ascites, past liver transplantation, and pregnancy were excluded from the study.Patients were randomly assigned into two groups, liver biopsy performed after PA (n = 152) and SA (n = 171). A web-based randomization platform Urbaniak GC, Plous S (2021). Randomizer [online]. Website https://www.randomizer.org/ [accessed 01 July 2020]. was used, and randomization codes for either a PA or SA procedure were placed in sequentially numbered, sealed envelopes in the interventional radiology department. The radiologist who performed the biopsy procedure was aware of the approach, but the patients and the physician (CA) evaluating the pain were blinded to the method.All PLB procedures were guided by ultrasound (US) and were performed by a single experienced operator (OC) with more than ten years’ experience. The operator had achieved more than 100 PLBs using both the subcostal and intercostal approaches before conducting this study. No sedation procedure was administered before the process. All the biopsy procedures were performed under an aseptic field, using a 25-gauge needle and a total of 10 mL of 1% lidocaine for anesthesia. In the PA group, 5 mL of 1% lidocaine was injected into subcutaneous tissue and 5 mL of 1% lidocaine to the liver’s periscapular area. In the SA group, 5 mL of 1% lidocaine was injected into the subcutaneous tissue, and the remaining 5 mL of 1% was injected into the liver capsule. Both PA and SA lidocaine injections were performed under US-guidance, and vascular leakage was checked by applying negative aspiration, before giving the local anesthetic agent. The spread of the anesthetic agent delivered to the subcapsular liver area was observed by the US, as shown in Figures 1A and 1B. PLB was performed using either an intercostal or subcostal approach as appropriate for the intended biopsy site. We performed the intercostal method from the right lateral lower chest and the subcostal approach from the epigastrium. After a small incision of less than 5 mm, we performed freehand US-guided biopsy with an 18-gauge, automated, cutting, biopsy needle . The throw of the cutting needle was set at 22 mm, and if the specimen was judged inadequate in size (≤15 mm in length), we repeated the biopsy procedure at the same access site. After PLB, patients were observed on the ward for 12 h with control of vital signs.The numeric rating scale is a scale designed to help assess the extent of an individual’s pain and improve communication regarding pain with health care providers. In our study, we preferred NRS because of our experience in using and evaluating in previous studies in our clinic and ease of application. The level of pain was evaluated with the numerical rating scale (NRS) immediately after the procedure (pain score at 0 h), and after 1 h (pain score at 1 h) and after 6 h (pain score at 6 h). Patients were asked to rate their pain on a 10-point scale, where 0 represents no pain, and 10 represents the worst pain that the patient could imagine. NRS is a validated and reliable tool. The pain scores were subdivided to achieve final ratings of 0–3  as previously described [11]. A physician (CA) informed all the patients about NRS before the biopsy procedure and asked patients to mark the pain levels experienced at 0, 1, and 6 h by guiding them and providing as much information as necessary.Descriptive statistics for demographic characteristics of the patients and features related to the procedure were presented as frequency and percentage (%) for categorical variables and mean with standard deviation (mean ± SD) or median and interquartile range [median (IQR = Q3–Q1)] according to the distribution of the continuous variables. Demographic and clinical features were compared between the subgroups using the Mann–Whitney U test (Wilcoxon rank-sum test), independent sample t-test, or chi-square test as appropriate. We analyzed the relationship between the pain scores and the duration of the procedure by Spearman’s rank correlation coefficient. Kruskal–Wallis H test was used to assess the pain scores between the subgroup analysis of the type of anesthesia and the biopsy location. Dunn’s pairwise tests were carried out with post hoc analysis using Mann–Whitney U test. The p adjusted using the Bonferroni correction.The sample size was calculated to achieve 80% power to detect 0.6 of a standard deviation difference in NRS with an alpha of 0.05.All statistical analyses were performed using SPSS, version 20.0 software . Two-sided p values less than 0.05 were considered statistically significant (P < 0.05).Final numbers in the PA and SA groups exceeded the power calculation requirement at n = 152 and n = 171, respectively. The comparison of demographics of population and features of procedure between the SA and PA groups is summarized in Table 1.Based on the previous reports suggesting the subcostal approach was superior over intercostal, the pain scores were analyzed after subgrouping for both the anesthesia type and biopsy approach route. It resulted in there being four subgroups: SA with the subcostal procedure (SA+SC), SA with the intercostal procedure (SA+IC), PA with the subcostal procedure (PA-SC), and PA with the intercostal procedure (PA-IC). When the pain scores at 0, 1, and 6 h with subgroups were compared, there was a significant difference in terms of reported pain (Table 2). The pairwise comparison revealed that the PA-IC group reported the worst pain scores while the SA-SC subgroup reported the least pain at all time points, as shown in Figure 2.There was no correlation between patient age and pain scores in each anesthesia subgroup (data not shown). There was a significant and positive correlation between the duration of the procedure and pain scores at 0 h in patients who underwent pericapsular anesthesia (Table 3).Liver biopsy is an essential diagnostic tool for evaluating acute and chronic parenchymal liver diseases as well as mass lesions . As a result of therapeutic advances, histological assessment has become a central aspect of diagnosis and staging of the parenchymal liver diseases [12]. Although the typical imaging pattern enables the determination of liver metastasis and hepatocellular carcinoma (HCC) with noninvasive diagnostic techniques (CT or MRI), it can be a significant challenge to diagnose nodules smaller than one centimeter in diameter in cirrhotic liver parenchyma . If imaging modalities are not sufficient for diagnosis of HCC, histopathological assessment is recommended as a more definitive diagnostic tool but requires invasive procedures such as PLB [15].Pain is the most common complaint of patients after PLB [2]. It has been reported that 69% of the patients complained about the pain after PLB, with 1.5%–3% requiring hospitalization . Pain during and after the liver biopsy is a subjective clinical finding, and it is challenging to address because of its complex nature. The studies have shown a correlation between reported pain and an increased number of biopsies, a close relationship between complications and percutaneous intervention, or biopsy needle thickness [2]. However, the diagnostic accuracy of the histological assessment is closely linked to the number of biopsy samples and the adequacy of samples [18].We randomized the patients undergoing US-guided PLB into either the SA or the PA groups. Our results showed that the SA approach resulted in lower levels of pain immediately after the procedure, 1 and 6 h postoperatively. Although Pazeshki et al. reported no difference in reported pain between parenchymal PLB and PLB for focal mass lesion, it is not clear if either group of patients received more analgesics before the biopsy procedure because of anxiety [2]. More patients with PA had a history of previous liver biopsy, but a history of previous PLB has not been reported to be associated with higher reported pain in previous studies. Therefore, we suggest that a previous unpleasant biopsy experience may lead to more reported pain in these patients. Interestingly, the procedure duration was longer in the SA group than the PA group, and it may be expected to result in more pain due to several factors. This finding should be investigated further before concluding that a prolonged procedure duration for patients receiving SA may not affect the pain experienced by patients.We created four subgroups to evaluate the contribution of the intercostal and subcostal routes to the type of local anesthesia; subcapsular anesthesia + subcostal procedure, subcapsular anesthesia + intercostal procedure, pericapsular anesthesia + subcostal procedure and pericapsular anesthesia + intercostal procedure. Consistent with the results of previous reports, we found that the subcostal procedure was associated with less pain in addition to the effect of anesthesia type . SA with subcostal procedure resulted in the lowest pain scores for all three-time points, and PA with the intercostal procedure was associated with the worst NRS scores. Our study is the first, in terms of pain assessment, to investigate the combination of route and anesthesia type in PLB. We found no correlation between procedure duration and pain in the SA group. However, there was a weak but significant positive correlation between reported pain immediately after the biopsy and duration in the PA group. Age did not correlate with pain at three different points of evaluation in both groups. One of our study’s main finding was a significant difference between the pain scores in favour of the subcapsular anesthesia procedure. The critical point is that patients with hepatitis are usually young, asymptomatic, and need repeated biopsies for management [12]. Unfortunately, unpleasant experiences at the first biopsy may result in patients being lost to follow up and, thus, suboptimal treatment results. The second main finding was that the subcapsular anesthesia/subcostal approach combination resulted in significantly better pain scores. Although previous studies have evaluated many factors, our study is the first to evaluate the biopsy route and anesthesia technique together .A significant limitation of this study was that we did not assess the level of anxiety before and after the biopsy procedure. Anxiety level was associated with pain levels and also correlated with an increase in analgesia use after biopsy . There is a need for studies that evaluate pre-procedure anxiety and the effect of either SA or PA in PLB. Another limitation is the heterogeneity of the two anesthesia groups in terms of several factors, including needle type, needle thickness, biopsy indication, which may be confounding for pain, and homogenization of the groups may result in different results.In summary, the results of our study suggest that subcapsular anesthesia is superior to pericapsular anesthesia. The use of the combination of SA and subcostal liver biopsy route seems to be the best approach among the four subgroups and resulted in the lowest pain scores. Improving the patients’ experience of PLB by the type of anesthesia and route of intervention may ameliorate the negative effect of previous intolerable experiences for patients and result in a greater willingness to undergo further biopsies.The study was approved by the local ethics committee , as stated in the protocol of research number (GOKAEK 2019/229). All patients participating in the study were provided with detailed information, and informed consent was obtained for the study from all study participants in addition to consent routinely obtained for the procedure.


Most studies examined the effects of short-term intravenous opioid therapy. The incidence of OIRD varied between 0.13% and 4.6%; besides SNI, comorbidities, and polypharmacy were the most relevant risk factors. Additionally, three clinical cases of OIRD in PPC patients receiving oral or transdermal opioids are presented and discussed. The case reports indicate that the risk factors identified in the scoping review also apply to adolescents and young adults with SNI receiving low-dose oral or transdermal opioid therapy. However, the risk of OIRD should never be a barrier to adequate symptom relief. We recommend careful consideration and systematic observation of opioid therapy in this population of patients.Pediatric Palliative Care (PPC) addresses children, adolescents, and young adults with a broad spectrum of underlying diseases. A substantial proportion of these patients have irreversible conditions accompanied by Severe Neurological Impairment (SNI). For the treatment of pain and dyspnea, strong opioids are widely used in PPC. Nonetheless, there is considerable uncertainty regarding the opioid-related side effects in pediatric patients with SNI, particularly concerning Opioid-Induced Respiratory Depression (OIRD). Research on pain and OIRD in pediatric patients with SNI is limited. Using scoping review methodology, we performed a systematic literature search for OIRD in pediatric patients with SNI. Out of  Pediatric Palliative Care (PPC) accompanies children, adolescents, and young adults with a broad spectrum of life-threatening or life-limiting conditions (LTC/LLC) for many years or even decades ,2. In coPain is a frequent symptom in PPC patients with SNI and seems to be most prevalent in those with the most significant impairments ,8. In PPResearch on pain and OIRD in pediatric patients with SNI is scarce. While a considerable proportion of these patients experience chronic pain as well as postoperative pain due to frequent surgical procedures, they are often excluded from studies on pediatric pain management ,16,17. AThe pathophysiological process of Opioid-Induced Respiratory Depression is well understood. The respiratory drive is generated in the brainstem. It is influenced by inputs from the cortex, as well as by central and peripheral chemoreceptors. The clinically relevant analgesic effect of opioids is mediated mainly by the mu-receptor, with potential effects on delta-opioid and kappa-opioid receptors . Mu-receThis study aims to present a comprehensive summary of currently available research on OIRD in pediatric patients with SNI by means of a scoping review. We subsequently present three clinical cases of severe respiratory events in PPC patients with SNI who were treated with oral or transdermal opioids for pain management in a specialized PPC unit in Datteln, Germany. To our knowledge, these are the first reported cases of OIRD after oral and transdermal administration in pediatric patients with SNI.This study complies with the “Preferred Reporting Items for Systematic reviews and Meta-Analysis extension for Scoping Reviews (PRISMA-ScR)” guidelines . For theArticles eligible for inclusion were required to report on OIRD in children and adolescents with SNI. Exclusion criteria were defined as (1) age less than six months, (2) age over 21 years, (3) children with no SNI, and (4) no OIRD. Respiratory support or tracheostomy did not per se lead to patient exclusion. Patients with respiratory support or tracheostomy were not excluded. After excluding duplicate articles, the remaining articles’ titles and abstracts were blindly screened for inclusion by two authors (MM and PS). MM and PS also independently screened the full texts of all eligible articles. Any discrepancies in the assessment of inclusion and exclusion criteria were discussed until a consensus was achieved.The electronic database search yielded 440 articles. An additional 104 articles were identified through hand searching, and 521 articles remained after duplicates were removed. Based on the initial abstract screening, nine articles remained for further full-text assessment. Of these articles, a total of six met eligibility criteria and were included in the scoping review see .The reviewed literature reported adverse respiratory events with different severity levels. Opioid-Induced Critical Respiratory Events or OIRD were defined as an adverse event leading to the administration of naloxone , airway Five of the six studies examined the incidence and risk factors for OIRD during short-term intravenous PCA ,29, PatiAll included studies reported on the incidence of OIRD in children predominately receiving short-term postoperative opioid medication. The reported incidence of OIRD varied between 0.13% and 4.6% due to the different contexts of application. Only Jay et al.  named a Respiratory depression and somnolence, leading to the administration of naloxone occurred in 2.8% of all patients reported in the article by Czarnecki et al. . Voepel-Most authors identified SNI as an independent risk factor for OIRD ,28,29,30Monitto et al.  found noFive articles reviewed risk factors for respiratory depression after opioid administration ,29,30,31Morton et al.  similarlThe authors recommend some potential preventive strategies for avoiding OIRD in children. Four studies advised against co-administration of opioids and CNS depressants or, if this should not be possible, recommended a significant opioid dose reduction ,29,30,31n = 200 children with LTC/LLC and a mean age of 9.5 years are admitted to the unit. This first PPC unit in Europe opened in 2010. It is located in one of the three largest pediatric hospitals in Germany. The idea to conceptualize a specialized pediatric palliative care unit derived from ten years’ experience in specialized pediatric palliative home care in the most crowded are of Germany. The PPC home care team was often confronted with therapy refractory symptoms that required a more intensive bio-psycho-social assessment and treatment of a multidisciplinary team. The PPC unit consists of eight single bedrooms with garden access. Parents can accompany their children. They can sleep in the same bedroom or in a separate family apartment on the second floor. The professional team includes pediatricians of diverse medical backgrounds , nurses with various specialist trainings , psychologists, and other therapists . Patients mainly experience irreversible but non-progressive conditions originating in the perinatal or postnatal period, or progressive neurodegenerative or metabolic conditions. Pain is a common symptom at the time of admission, present in 47% of all patients [Three cases of OIRD in children with SNI treated in a specialized PPC unit are described hereinafter. The PPC unit is a self-reliant unit in a tertiary care children’s hospital, comprising eight patient beds in single rooms and offering intensive inpatient PPC. Annually, approximately patients ,32. In oDuring opioid titration, children were monitored by pulse oximetry and regular measurement of their respiratory rate. The patients’ characteristics are specified in The first case report refers to an 18-year-old young adult with hypoxic-ischemic encephalopathy and spastic cerebral palsy (GMFCS level V) following preterm birth and who received cardiopulmonary resuscitation due to severe sepsis at the age of 16 years. Owing to the presence of severe musculoskeletal pain caused by spasticity and hip luxation, opioid therapy with an ultra-low dose of 2 mg oral morphine four times a day was started via the patient’s gastric tube. On day two of treatment, he showed an oxygen desaturation  and a reduced respiratory rate of 7/min, requiring repeated stimulation. The daily oral Morphine Equivalent Dose (MED) was 0.241 mg/kg/d, equivalent to 16.87 mg/d in a 70 kg patient. At this time, the patient was severely underweight  and was concomitantly treated with 13 different substances, including levetiracetam, valproate, dronabinol, and chloral hydrate. As a result, the morphine therapy was discontinued. Two days post-incident, the patient developed pneumonia, necessitating antibiotic treatment. A second opioid-based pain therapy was attempted during the remainder of the inpatient course. We decided to attempt opioid treatment with levomethadone. Oral levomethadone was titrated up to 0.5 mg twice daily under close monitoring of pulse oximetry and respiratory rate until sufficient pain relief was achieved. The patient did not show any signs of respiratory depression under oral levomethadone therapy.The second patient is a 15-year-old adolescent with early infantile epileptic encephalopathy (Ohtahara syndrome) and spastic cerebral palsy (GMFCS level V). He was admitted to the PPC unit to evaluate and manage his severe neuroirritability associated with pain-like behavior and seizures. Because of a possible central, neuropathic pain component of the therapy-refractory agitation states, we started oral levomethadone therapy of 2.5 mg three times daily via the patient’s gastric tube. The treatment was paused after one day of treatment due to increased myoclonus, seizures, and oxygen desaturations requiring oxygen supply. At the time of the incident, the patient received a comedication of 10 substances, including lamotrigine, domperidone, and risperidone. A second attempt with 1 mg of levomethadone orally three times daily was conducted. On day 8 of therapy, the patient showed increased apnea phases and oxygen desaturations, requiring repeated stimulation and oxygen supply  having a cognitive developmental age of less than 12 months. The patient was severely underweight , was concomitantly treated with 12 different substances, including oxcarbazepine and valproate, and had severe obstructive sleep apnea. He was experiencing severe musculoskeletal pain secondary to spasticity as well as hip dysplasia refractory to oral therapy with the weak opioid tilidine, administered in a fixed combination with naloxone (this fixed combination is supposed to prevent the drug’s intravenous abuse). In the absence of a gastric tube, a therapeutic attempt was initiated with transdermal buprenorphine (5 µg/h patch) as a long-acting alternative to intensified oral opioid therapy. On the night of the first day of therapy, the patient showed oxygen desaturations  requiring repeated stimulations, oxygen supply, and the removal of the transdermal patch , which is mainly attributed to the R-isomer. Tilidine is available only in a few countries like Belgium, Germany, Spain, and South Africa . There iCase 3 showed oxygen desaturations under transdermal buprenorphine therapy. The obstructive sleep apnea and the CNS depressant effect of the patient’s anticonvulsive comedication may have contributed to the OIRD.In contrast to other opioids, buprenorphine has shown a ceiling effect regarding OIRD in healthy adult volunteers . InteresAnother potential cause of OIRD named by Jay et al.  is the fIncreased sensitivity to opioids in patients with recurrent hypoxemia before treatment can also result in respiratory depression . TreatinTwo patients of the reported cases were severely underweight. Nutrition is a widespread problem in pediatric patients with SNI . AccordiHowever, studies on cachectic adult cancer patients with low plasma albumin concentrations have reported a negative effect on transdermal absorption of fentanyl . Even ifSymptom control is a primary outcome domain for PPC patients . In the Children, adolescents, and young adults with SNI have an increased risk of OIRD. As our case reports show, this risk also seems applicable to the oral or transdermal administration of opioids preferred in PPC.Although the risk of OIRD is relatively low when starting opioid treatment, this vulnerable cohort of patients requires special attention. Inpatient care, if available in a specialized PPC unit, makes it possible to assess the effects and side effects of opioid therapy. These side effects must be anticipated and treated proactively. We recommend a careful titration, starting from a third of the starting dose of otherwise healthy opioid-naïve children.Dose determination includes close monitoring of the patient’s vigilance, respiratory rate, pulse oximetry, and a prepared emergency plan . It is highly recommended to become aware of the additional risk linked to disease-associated comorbidities and drug interactions, especially in the case of polypharmacy. The simultaneous treatment of opioids and CNS depressants should be initiated with utmost caution and only in conjunction with opioid dose reduction. Concerns about possible OIRDs should never be a barrier to adequate symptom relief in PPC patients. If feasible, a palliative expert should be consulted.The majority of patients described in the reviewed articles received short-term intravenous opioids for postoperative pain. However, the results should not simply be generalized to the population of pediatric patients with SNI suffering from chronic pain. Future research should focus on assessing and managing pain in pediatric patients with SNI and their risk of OIRD, especially in PPC. As a limitation of the study, concentration on the  database PubMed/Medline must be mentioned. Even if this is sufficient for the purpose of the scoping review, it cannot be excluded that relevant literature is available in other databases. Therefore, conducting a systematic review is worth considering in the future. Improvement of PPC through research and clinician education can reduce the risks of both symptom undertreatment and OIRD ,54,55,56