Postoperative pain cannot be measured accurately among many children with intellectual and developmental disabilities, resulting in underrecognition or delay in recognition of pain. The Critical-Care Pain Observation Tool (CPOT) is a pain assessment tool that has been widely validated in critically ill and postoperative adults.The objective of this study was to validate the CPOT for use with pediatric patients able to self-report and undergoing posterior spinal fusion surgery.Twenty-four patients (10–18 years old) scheduled to undergo surgery were consented to this repeated-measure, within-subject study. To examine discriminative and criterion validation, CPOT scores and patients’ self-reports of pain intensity were collected prospectively by a bedside rater before, during, and after a nonnociceptive and nociceptive procedure on the day following surgery. Patients’ behavioral reactions were video recorded at the bedside and retrospectively viewed by two independent video raters to examine interrater and intrarater reliability of CPOT scores.Discriminative validation was supported with higher CPOT scores during the nociceptive procedure than during the nonnociceptive procedure. Criterion validation was supported with a moderate positive correlation between the CPOT scores and the patients’ self-reported pain intensity during the nociceptive procedure. A CPOT cutoff score of ≥2 was associated with the maximum sensitivity (61.3%) and specificity (94.1%). Reliability analyses revealed poor to moderate agreement between bedside and video raters and moderate to excellent consistency within video raters.These findings suggest that the CPOT may be a valid tool to detect pain in pediatric patients in the acute postoperative inpatient care unit after posterior spinal fusion. Children and adolescents with CP who undergo major orthopedic surgery experience more complicated and costly hospitalizations than normally developing patients undergoing similar orthopedic surgeries, such as patients with adolescent idiopathic scoliosis.2 Patients with CP or adolescent idiopathic scoliosis, a three-dimensional deformity of the spine with pronounced single or double curving of the spine,3 may undergo spinal fusion surgery with instrumentation, which is an invasive and extensive surgery such that persistent pain is a common postoperative complication.4 Resolution of pain and pain management are of paramount importance in the success of any surgical intervention in these patient populations because pain can lead to negative consequences such as prolonged emotional distress, long-term pain medication usage, and delayed recovery from surgery.4–7 A case–control analysis revealed that patients able to self-report pain after spinal fusion surgery received more than twice the amount of opioids compared to a matched group of patients with neuromuscular scoliosis.8 This suggests that patients with IDDs may be undertreated postoperatively compared with patients able to self-report their pain.The clinical challenge of assessing pain of children and adolescents with neuromuscular diseases, such as patients with cerebral palsy (CP), is their inability to effectively report their pain because of intellectual and developmental disabilities (IDDs). Nevertheless, there is no reason to believe that pain is any less frequent or intense in these patients than in normally developing patients. Patients with CP often require major orthopedic surgeries due to motor impairments secondary to anomalies in the brain leading to muscle imbalance and resulting in severe musculoskeletal complications such as hip dislocation and spinal deformities.9–11 the multiple levels of cognitive functioning and verbal abilities encountered increase the challenges of providing high-quality pain management, and no single approach for pain assessment fits all children with limited communication skills. Because of the elusive nature of pediatric pain in nonverbal children, therapeutic decisions are frequently based on proxy measures of pain  and revert to a series of trial and error.12 The Non-Communicating Children’s Pain Checklist–Postoperative Version,9 the revised Face, Legs, Activity, Consolability, Cry Scale,13 the Pediatric Pain Profile (PPP),10 and the Individualized Numeric Rating Scale (INRS)14 are available, reliable, and validated pain assessment tools for use in patients with IDDs. However, factors that may limit their clinical utility and their ability to inform effective pain management practices include the complexity of the tool and the interpretation of its score, the time required to perform a pain assessment using such a tool, and the individualization of the tool with input from parents or caregivers.15 For example, though the revised Face, Legs, Activity, Consolability, Cry Scale and INRS have a score range that is common in pain measurement , the score range of the Non-Communicating Children’s Pain Checklist–Postoperative Version (0–81) and PPP (0–60) is wide and less intuitive. These broader score ranges may hinder the interpretation of pain intensity.16 Moreover, some of the presented tools require considerable preparation time, which may be disadvantageous in an acute postoperative setting. The PPP is several pages long, demands ongoing pain assessments, and requires an interview with the parents to personalize the assessment criteria. Some of the presented tools can be utilized rapidly, such as the INRS with its 1-min observation period and 11-point scale. However, the time required to prepare this fully individualized tool may impede its implementation. Furthermore, there are a few important factors that limit the reliability of individualized tools, notably the possibility of parent or caregiver bias. Relying on parental input assumes that parents or caregivers are able to accurately describe their child’s pain behavior. There are instances where an objective observer is better suited than a parent or caregiver to evaluate a child, such as in cases of Munchausen by proxy or situations in which the parent or caregiver is impaired by mental health or addiction issues.14Even though there has been great improvement over the past years with the validation of pain assessment tools designed for children with IDDs,17 This pain assessment tool has been validated in adult postoperative, medical, and trauma intensive care unit patients18–26 and healthy adults.27 The CPOT is recommended by many experts in pain in this vulnerable population because of its well-established psychometric properties29 and because it has been validated in different languages.30 Moreover, the CPOT has a recommended observation period of 1 min, excludes family input and their potential bias, and has simple scoring, which may require less training.30 However, there is still a need to explore its utility in other contexts and populations, such as children and adolescents. To our knowledge, only one study has validated a pediatric version of the CPOT, which made adaptations to existing items and added a fifth one , resulting in a score range from 0 to 10.31Taking into account the drawbacks of other observational tools, a promising tool that merits investigation in our population of interest is the Critical-Care Pain Observation Tool (CPOT), which is a behavioral scale initially developed to assess pain in critically ill adults unable to self-report.17 in pediatric patients able to self-report who were undergoing major orthopedic surgery such as spinal fusion surgery prior to its validation in patients with CP undergoing a similar surgery. This study aimed to examine (1) discriminative validation of CPOT scores when exposed to common nonnociceptive and nociceptive procedures, (2) criterion validation of CPOT scores with the patients’ self-reports of pain intensity, and (3) interrater and intrarater reliability of CPOT scores by trained bedside and video raters.The objective of this study was to perform an initial validation of the original CPOTWe conducted a repeated-measure, within-subject study at the Shriners Hospitals for Children–Canada between October 2018 and February 2019, between July 2019 and March 2020, and between October 2020 and January 2021. This study was part of a larger prospective study assessing perioperative pain in children undergoing orthopedic surgery and received ethics approval from the Research Ethics Board of McGill University (A08-M71-14B). Patients were screened in an outpatient spine clinic when the decision to undergo surgery was made. Those eligible were invited to participate in the research study and written informed consent was obtained by a trained research assistant. For patients under the age of 14, written informed assent was obtained and written informed consent was obtained from a parent or legal guardian. The study was conducted in accordance with the Declaration of Helsinki. Inclusion criteria included (1) diagnosed with adolescent idiopathic scoliosis between the ages of 10 and 18 years, (2) scheduled to undergo posterior spinal fusion surgery with instrumentation, (3) able to understand either English or French, and (4) able to self-report. Exclusion criteria included (1) previous major surgery, (2) diagnosis of a major chronic medical condition (American Society of Anesthesiology status III or higher), (3) diagnosis of an intellectual disability that would interfere with the ability to understand questions asked, and (4) diagnosis of a condition that may confound behavior assessment, namely, paralysis or neurological and neuromuscular disorders.no pain) to 10 (worst pain imaginable) using the Faces Pain Scale–Revised32 for criterion validation. This order was established to minimize the first rater’s bias.A total of six assessments of the main study variables (CPOT scores and patients’ self-reports of pain intensity) were completed by trained research assistant at the patient’s bedside on the day following surgery. Pain assessments were done before, during, and within 15 min after a nonnociceptive procedure (gentle touch on the forearm) and a nociceptive procedure part of routine nursing care (turning from back to side). These two procedures were selected for the examination of discriminative validation; that is, the ability of the CPOT scores to discriminate between a painful and a nonpainful procedure. Therefore, for each patient, six 1-min assessments were made. First, at each assessment, CPOT scores were obtained by the research assistant based on real-time observations of the patient’s behavioral responses. Then, the research assistant asked patients to self-report pain intensity from 0  to examine interrater reliability of the CPOT scores. Intrarater reliability was also examined by having the same second and third raters view the videos 1 month after completion of their initial rating. All raters underwent a 60-min training session by the tool developer to describe the items and scoring of the CPOT, including practice of rating patient videos created for educational purposes.17 The CPOT cannot be used if the patient is unresponsive . Because the assessments were conducted on the day following surgery when patients were no longer intubated, the behavioral item of vocalization was used. Each behavior was rated on a 0 to 2 scale, resulting in a total score ranging from 0 to 8.17 A recent systematic review and meta-analysis revealed that the CPOT has been validated in different adult groups and showed good psychometric properties.34 Good (Cronbach’s α >0.70) and acceptable (0.50–0.70) internal consistency was found in most adult studies. Interrater reliability reported with weighted κ and/or intraclass correlation coefficients (ICCs) was observed to be greater than 0.60 in half of the adult studies, with lower values (<0.40) mainly observed at rest. Moreover, the CPOT had a moderate diagnostic accuracy when a cutoff score >2 was used for the presence of pain .34 It is important to note that the CPOT is intended to support the detection of the presence of pain by the number and intensity of exhibited behaviors and does not give an indication of pain intensity.The CPOT includes four behavioral items: (1) facial expressions, (2) body movements, (3) muscle tension, and (4) vocalization (in nonintubated patients) or compliance with the ventilator (in intubated patients).no pain) to 10 (worst pain imaginable).32Participants were asked to rate their pain intensity after each assessment with the Faces Pain Scale–Revised along with a numeric rating scale  that ranges from 0 (Demographic information (age and sex) and clinical data  were collected from patients’ electronic medical charts.36 Sample size calculation was based on a G*Power 3.1 procedure using exact tests for bivariate normal model correlation.37 Based on moderate correlations of r = 0.50 obtained in previous studies between CPOT scores and self-reports of pain22 with an alpha of 0.05 and a power of 80%, a sample size of 29 participants was required. Analyses were based on available data, with no imputation for missing data. Descriptive statistics are presented as means and standard deviations unless otherwise specified. Prior to data analysis, the distributions of total CPOT scores were examined via normal probability plots and by the Shapiro-Wilk test for normality. All total CPOT scores, except for the scores from the bedside rater during the nociceptive procedure, were not normally distributed . Nonparametric tests were used because it was assumed that most of the study data were not normally distributed. To address the first aim, the CPOT scores of all raters were analyzed separately by Friedman tests for the assessments before, during, and after the nonnociceptive and nociceptive procedures followed by post hoc Wilcoxon signed rank tests. The second aim was addressed by performing Mann-Whitney tests and bivariate Spearman correlations for CPOT scores of the bedside rater and patients’ self-reports of pain intensity during the nonnociceptive and nociceptive procedures. In the case of significant tests between the CPOT score and the participant’s self-report, receiver operating characteristic curve analysis was used to evaluate the ability of the scale to classify patients who reported moderate to severe pain (≥4/10) or no to mild pain (0–3/10). An area under the curve of 0.5 suggests that the CPOT is unable to detect moderate to severe pain, 0.70 to 0.80 is considered acceptable, 0.80 to 0.90 is excellent, and 0.90 to 1.00 is outstanding.38 The third aim was addressed by calculating two-way random effects model ICCs of the CPOT scores obtained by all three raters at each assessment through the viewing of video recordings for each patient. ICCs <0.5, between 0.5 and 0.75, between 0.75 and 0.9, and >0.9 suggested poor, moderate, good, and excellent reliability, respectively, between and within raters.40Data were analyzed using R Studio and plotted using Prism v9.n = 4), overwhelmed by the study (n = 3), or not interested in the study (n = 5). Thirty patients consented to participate in the study. However, 1 patient dropped out prior to the assessment due to unanticipated severe pain and 5 patients were excluded due to missing video recordings. Because the clinical utility of the CPOT relies also on its validity and reliability, only the data for 24 patients were analyzed, and their demographic characteristics are presented in P > 0.05). Moreover, no correlation was observed between the CPOT scores and patient age, surgical variables, and analgesic intake 4 h prior to the assessment (P > 0.05).Forty-two eligible patients were approached and 12 declined the study because they were uncomfortable with an observer or video recording  but not for video rater 1  and video rater 2 . However, post hoc Wilcoxon signed ranked tests with Bonferroni correction (α = 0.017) did not show any significant differences between CPOT scores before, during, and after touching for the bedside rater. Friedman test analyses revealed a significant change in CPOT scores before, during, and after turning for the bedside rater , video rater 1 , and video rater 2 . Post hoc Wilcoxon signed rank tests showed a significant difference only between CPOT scores before and during the turning procedure (P < 0.05) and during and postprocedure (P < 0.05) but not between pre- and postprocedure  and turning  procedures (P = 0.001), which suggests acceptable discriminate properties. The cutoff point associated with the maximum sensitivity (61.3%) and specificity (94.1%) was observed to be ≥2.Patients’ self-reports of pain were obtained and are described in ocedures . ReceiveICC was calculated for the CPOT scores collected at each assessment by three trained raters via bedside collection (rater 1) and the viewing of video recordings (raters 2 and 3) for each participant. ICCs ranged from 0.41 to 0.74 , indicatICC was also calculated for the CPOT scores collected at each assessment for two trained raters via the viewing of video recordings at least 1 month after the first viewing. This procedure was conducted to avoid raters’ close recall of their initial CPOT scorings. For rater 2, ICCs ranged from 0.65 to 0.93 , indicat18–26 and healthy adults.27 During a common nociceptive procedure  for patients after spinal fusion surgical, patients displayed significant changes in their behavioral CPOT scores compared to a common nonnociceptive procedure , therefore supporting discriminative validation in this postoperative pediatric patient group. Criterion validation was also supported through the observation of a moderate correlation between the CPOT scores of the bedside rater and the patients’ self-reported pain intensity. Reliability analyses revealed poor to moderate agreement between the bedside and video raters and moderate to excellent consistency within the video raters. Based on these findings, the CPOT may be valid for use in this specific postoperative pediatric group.To our knowledge, this study was the first to examine whether the CPOT could successfully capture pain-related behaviors in adolescents with idiopathic scoliosis the day after undergoing posterior spinal fusion surgery. Our findings are consistent with those obtained from previous studies in critically ill adult patientsIn the current study, despite patients displaying an overall increase in their behavioral CPOT scores during the turning procedure, which is known to cause pain after spinal fusion surgery, wide ranges of CPOT scores and self-reported pain intensity were observed. Seven patients demonstrated behavioral CPOT scores <2, and six patients self-reported no to mild pain intensity . It is important to note that the patients still had access to their patient-controlled analgesia morphine pump the day following their surgery, which may have caused some of them to display fewer behavioral changes and self-report mild pain. Nevertheless, the surgical incision was on the back of the patients, which caused the majority of them (79.2%) to self-report moderate to severe pain intensity during turning. It is possible that another common recovery mobilization procedure such as standing would have been more painful in these patients due to the activation of spinal muscles, unlike turning, which only involves moving patients from one side to another while in bed.17–26 Our results suggest that the CPOT can potentially be used in postoperative adolescent patients. The high specificity could help clinicians adequately identify patients in pain and avoid administering analgesics to patients without pain who do not need any. However, half of the patients reported moderate to severe pain during the touch procedure but did not exhibit pain behaviors (median CPOT score = 0). Therefore, although the CPOT may be used to detect pain during painful procedures, it may be difficult to identify pain in patients at rest or during routine care procedures that may not be painful. Further testing and validation are needed to determine whether the CPOT can be used in nonverbal postoperative pediatric patients.Our findings indicate that a CPOT cutoff of ≥2 showed acceptable sensitivity and excellent specificity, which is similar to cutoff thresholds observed in adult postoperative patients in the intensive care unit.41 Previous studies in adult populations have shown good to excellent interrater reliability before, during, and after nonnociceptive and nociceptive procedures.22 Knowing that cognitive biases may change in pain observation over time and that there was gap in patient recruitment and testing due to the global pandemic, revision training sessions may have been beneficial to decrease interrater variability. However, moderate to excellent intrarater reliability was observed for two independent video raters during all assessments when video recordings were viewed 1 month after the initial viewing. In the current study, with minimal standardized training,33 the CPOT was shown to have moderate to excellent reliability within and between raters and thus could be consistently used.Our results demonstrated moderate interrater reliability during all assessments except for postturning, which demonstrated poor reliability despite a standardized training session for all raters. Poor interrater reliability may have been because the video recordings captured only a window of time lacking contextual data, unlike real-time observations.Our study examined discriminative and criterion validation and inter- and intrarater reliability of the CPOT for the detection of acute postoperative pain in adolescents with idiopathic scoliosis who underwent posterior spinal fusion surgery. Although acceptable results of sensitivity and specificity were obtained, the generalizability of our findings to all pediatric orthopedic surgery patients should be interpreted considering certain limitations. This study had a relatively small sample size with a specific subpopulation of pediatric patients undergoing orthopedic surgery. Moreover, due to unforeseen circumstances, the final sample size was less than required to achieve a power of 80%. Another limitation of the study is the study design, including a nonnociceptive procedure and a nociceptive procedure that consisted of the passive turning of the patient. It is unknown whether the CPOT tool can detect evoked pain through active movement or whether it is sensitive to analgesia administration. Further research with larger sample sizes and in various pediatric contexts, such as evoked nociceptive procedures, after postoperative analgesia administration, and nonverbal children and adolescents, is still needed.


However, there are currently no evidence-based recommendations about drug selection, drug administration, drug interactions, and use in special populations or other pharmacology-related content of such medications. To this end, the Chinese Pharmaceutical Association Hospital Pharmacy Professional Committee developed multidisciplinary guidelines on using topical NSAIDs to treat musculoskeletal pain. (2) Methods: The guidelines development process followed the World Health Organization guideline development handbook, the GRADE methodology, and the statement of Reporting Items for Practice Guidelines in Healthcare. The guideline panel used the Delphi method to identify six clinical questions to be addressed in the guidelines. An independent systematic review team conducted a systematic search and integration of evidence. (3) Results: Based on the balance between the benefits and harms of an intervention, the quality of the evidence, patient preferences and values, and resource utilization, the guideline panel developed 11 recommendations and nine expert consensuses on using topical NSAIDs to treat acute and chronic musculoskeletal pain. (4) Conclusions: Based on the effectiveness and overall safety of topical NSAIDs, we recommend patients with musculoskeletal pain use topical NSAIDs and suggest high-risk patients use topical NSAIDs, such as those with other diseases or receiving other concurrent treatments. The evidenced-based guidelines on topical NSAIDs for musculoskeletal pain incorporated a pharmacist perspective. The guidelines have the potential to facilitate the rational use of topical NSAIDs. The guideline panel will monitor the relevant evidence and update the recommendations accordingly. Musculoskeletal diseases are one of the leading causes of disability globally. According to data in 2019, about 1.71 billion people worldwide have musculoskeletal disorders . MusculoNon-steroidal anti-inflammatory drugs (NSAIDs) are widely used for musculoskeletal pain. NSAIDs can block prostaglandin synthesis by inhibiting cyclooxygenase (COX) enzyme activity, thus alleviating pain and reducing inflammation associated with musculoskeletal diseases . In the Although topical NSAIDs have been recommended in several management guidelines for musculoskeletal diseases, these guidelines ,18,19,20The guidelines apply to all levels of healthcare settings. The target patient population is those with acute and chronic musculoskeletal pain. The target healthcare professionals are clinicians , pharmacists, nurses, and other healthcare professionals and policymakers involved in musculoskeletal pain management.The detailed guideline development process has been published elsewhere . GuideliThe guidelines panel comprised experts from the following disciplines: clinical pharmacy, pharmacoeconomics, pharmaceutics, orthopedic surgery, rheumatology and immunology, pain management, and guidelines development methodology. Members were divided into a steering group, a development group, a secretary group, and an external review group according to their responsibilities. The member composition and responsibility details are shown in Preliminary clinical questions were proposed according to the PICO principles: P (Patient), I (Intervention), C (Control), and O (Outcome). The steering group selected the initial clinical questions and outcomes based on relevant literature, their clinical experience, and communication with other healthcare providers. Subsequently, the development group assessed the importance of research questions  and outcomes  using Likert-like scales through three rounds of Delphi questionnaire consultation ,18,19,20An independent systematic review group completed systematic reviews for all PICO questions . The selTwo reviewers independently screened the title, abstract, and full-text records for potentially relevant studies and then extracted data from included studies using a standardized data extraction form. Two reviewers cross-checked the screening results and data extraction forms, and disagreements were resolved through group discussions led by another senior researcher. After the evidence retrieval was completed, the corresponding assessment tool ,30,31,32A systematic review was adopted when it was relevant and of high quality . OtherwThe guideline panel conducted a questionnaire-based survey to assess patients’ values and preferences in pain management. The questionnaire included questions about the effectiveness, safety, and prognosis of treatment. We recruited 318 patients (or caregivers) with musculoskeletal pain. The results of this survey were submitted to the guideline panel to provide references to make recommendations.For each clinical question, the development group proposed recommendations based on the balance of benefits and harms suggested by the best available evidence, evidence quality, patient values and preferences, cost and cost-effectiveness, feasibility, and acceptability. The levels of recommendations are a “strong recommendation (recommend … for or against use)” and a “weak recommendation (suggest … for or against use)” based on the GRADE recommendation table ,36. WhenAfter the guideline panel drafted the guidelines following the RIGHT checklist , the guiThe dosage forms of topical NSAIDs include, but are not limited to, solutions, gels, creams, ointments, sprays, aerosols, cataplasms, and patches. Topical preparations usually contain three components: active ingredients, excipients, and transdermal absorption enhancers. These components significantly influence the preparation’s characteristics and clinical features .An ideal topical preparation should have a low molecular weight (<500 Da), be potent, and be both hydrophilic and hydrophobic . UnfortuVarious topical NSAIDs have been approved worldwide, including ten dosage forms and more than ten pharmaceutical ingredients . IndicatDue to the low systemic absorption, compared to oral formulations, the incidence of systemic adverse events of topical NSAIDs is very low. Adverse events are mainly local skin irritation or reaction at the application site, manifested as redness, rash, and itching ,47. ThesA Cochrane systematic review on topical NSAIDs for acute musculoskeletal pain published in 2015 was included ,57,58,59(1) compared to the placebop < 0.00001). The number needed to treat (NNT) was 5 (95% CI 3.67–4.89). Compared to placebo, topical NSAIDs did not increase the risk of local adverse events   compared to placebo (relative risk (RR) 1.55, 95% confidence interval (95% CI) 1.48–1.64, = 0.93)  .(2) compared to oral NSAIDsThree RCTs found that topical and oral NSAIDs  had similar treatment success rates ,67,68. T(3) compared to other topical medicationsFour RCTs compared topical NSAIDs and other topical medications for acute musculoskeletal pain ,65,66,69A 2016 Cochrane systematic review on topical NSAIDs for chronic musculoskeletal pain was included ,81,82,83(1) compared to the placebop < 0.00001) when taken for two to six weeks for chronic musculoskeletal pain. When taken for more than six weeks, a high treatment success rate was maintained . The NNT was 11 (95% CI 7.56–18.27). Differences in local adverse event risks were not statistically significant , and so was the difference for gastrointestinal adverse events . However, topical diclofenac had a higher risk of discontinuation due to adverse events  ( p = 0.03). The NNT was 25 (95% CI 12.90–219.27). The risks of local adverse events , gastrointestinal adverse events , and drug discontinuation  for ketoprofen were comparable to those of placebo  than placebo   . Compare placebo .(2) compared to oral NSAIDsp = 0.26). However, topical NSAIDs had a higher risk of treatment discontinuation due to poor efficacy  and a higher risk of local adverse events . Compared to oral NSAIDs, topical NSAIDs had better gastrointestinal safety . The risk of treatment discontinuation due to adverse events was comparable between topical and oral NSAIDs .In addition, we evaluated the efficacy and safety of topical and oral NSAIDs in patients with chronic musculoskeletal pain  compared to other topical medicationsTwenty-two RCTs compared the efficacy and safety of topical NSAIDs with complementary and alternative topical medications or capsaicin creams to treat chronic musculoskeletal pain. Due to the significant comparative heterogeneity among the included studies, data synthesis could not be performed.In surveys, patients with musculoskeletal pain preferred topical NSAIDs, with an average willingness score of 4.23 or more  . More paRationale: In conclusion, our evidence review found that topical NSAIDs are superior to placebo. While comparing topical versus oral NSAIDs, topical NSAIDs lead to comparable pain relief, and higher risk of local adverse events, but they are generally safer in systemic adverse events. In addition, patients had preferences for topical administration over oral administration. Therefore, the guideline panel made the following recommendations for using topical NSAIDs.Recommendation 1: Compared to no treatment, given the safety and efficacy of topical NSAIDs, we recommend that patients use topical NSAIDs for acute musculoskeletal pain (1A).Recommendation 2: Topical NSAIDs are as effective as oral NSAIDs in treating acute musculoskeletal pain but with greater safety. We suggest patients choose topical or oral NSAIDs for acute musculoskeletal pain (2D).Recommendation 3: Compared to no treatment, given the safety and efficacy of topical NSAIDs, we recommend that patients use topical NSAIDs for chronic musculoskeletal pain (1B).Recommendation 4: The efficacy of topical NSAIDs in treating chronic musculoskeletal pain is similar to oral NSAIDs but with greater safety. We suggest patients choose topical or oral NSAIDs for chronic musculoskeletal pain (2B).Two high-quality Cochrane systematic reviews ,16, one Compared to placebo, the following topical NSAIDs with different gradients all had higher treatment success rates: diclofenac , ibuprofen , ketoprofen , piroxicam , indomethacin , benzydamine  .p < 0.00001). The therapeutic effects of the ibuprofen gel  and plaster  were better than those of the cream formulation . Among the ketoprofen formulations, the gel formulation was relatively effective .Among the different topical diclofenac formulations, the gel formulation had the highest treatment success rate . The flurbiprofen cataplasm provided better pain relief than the indomethacin cataplasm in treating acute and chronic orthopedic pain in an RCT .Among the different dosage forms, patients with musculoskeletal pain preferred cataplasms and patches, with an average of >4 points (relatively willing), which was followed by sprays and gel. Creams were the least preferred (3.64 points) .Rationale: In conclusion, the quality of evidence comparing different topical NSAIDs was low or very low. The guideline panel found that the evidence was not sufficient to support recommendations. However, with limited evidence and patient preference considerations, the panel made the following statements on the rational use of topical NSAIDs.Expert Consensus 5: When topical NSAIDs are used for musculoskeletal pain, topical NSAIDs with different ingredients have a relatively high possibility of treatment success compared to placebo. There is relatively sufficient evidence to support the use of diclofenac, flurbiprofen, ibuprofen, ketoprofen, and piroxicam (3C).Expert Consensus 6: When topical NSAIDs are used for musculoskeletal pain, the quality of evidence on the therapeutic effects of different formulations of topical NSAIDs is very low. Physicians and patients are suggested to choose appropriate dosage forms based on the underlying diseases, the etiology and location of pain, and individual preferences (3C).After comprehensive evidence collection and screening, no RCTs or non-RCTs met the inclusion criteria. To form guiding recommendations and standardize clinical practice, expert clinical experience on the fixed-dose or on-demand use of topical NSAIDs was collected through an online questionnaire. The survey found that the composition and dosage forms used in these therapies were not fixed in clinical practice. On-demand treatment depends on the pain area or pain relief from the previous administration. Fixed-dose treatment generally followed the drug instructions with the scheduled number of daily uses and duration of therapy and was typically for patients with chronic musculoskeletal pain. If tissue damage was minor, the therapeutic effect between the two modalities was not significantly different. No significant differences in safety were observed between the two methods.Rationale: In conclusion, there was no direct applicable evidence for comparing the use of fixed-dose or on-demand topical NSAIDs. The guideline panel made the following statements based on expert evidence to guide the rational use of topical NSAIDs.Expert Consensus 7: Clinicians or pharmacists can choose fixed-dose or on-demand topical NSAIDs for musculoskeletal pain according to pain severity, etiology, patient’s conditions and preferences, and therapeutic response to topical NSAIDs. Fixed-dose therapy may be more advantageous in patients with chronic polyarticular musculoskeletal pain or combined muscle and joint pain. Medication orders for fixed-dose topical NSAIDs can follow drug instructions. The fixed dose and duration of use are convenient for patients to adhere to the medication order (3E).A post hoc RCT analysis analyzed the safety of topical diclofenac and other drug interactions. The risk of adverse events was 62.6% in patients taking other drugs known to interact with NSAIDs (n = 171). In contrast, the risk of adverse events was 55.4% in patients who did not use medications known to interact with NSAIDs (n = 83) . These rThe efficacy and safety between oral and topical diclofenac combination therapy and topical or oral diclofenac monotherapies were compared in an RCT . There wAn RCT compared ketoprofen patches combined with acetaminophen and acetaminophen monotherapy in patients with osteoarthritis. More significant analgesia was observed in the combination group . MeanwhiFive adverse events with an enhanced anticoagulant effect of warfarin were reported in the literature, one of which resulted in gastrointestinal bleeding  Supplem. Since tThere was no evidence for the combined use of ACEI, ARB, or β-receptor blockers with topical NSAIDs. Drug metabolism studies of oral and topical NSAIDs suggest that compared to oral administration, topical NSAIDs had lower blood drug concentrations and less impact on organ systems. Taburet et al. studied the drug metabolism of topical and oral flurbiprofen in healthy subjects. They found that topical flurbiprofen had a lower Cmax and a more delayed Tmax than oral flurbiprofen .Rationale: In conclusion, there was limited evidence for using topical NSAIDs in combination with other medications. Considering the metabolism characteristics, topical NSAIDs may be safer than oral NSAIDs. The guideline panel made recommendations on the combined use of topical NSAIDs with other drugs based on limited evidence and the pharmacokinetic characteristics of topical NSAIDs.Recommendation 8: We suggest that topical or oral NSAIDs be used alone to treat musculoskeletal pain. We suggest topical NSAIDs as the first-line choice for patients with mild musculoskeletal pain. If symptoms persist or for moderate to severe pain, oral NSAIDs or analgesics with other mechanisms of action can be used after a comprehensive evaluation (2D).Recommendation 9: We suggest oral acetaminophen as short-term rescue therapy if necessary when using topical NSAIDs in patients with musculoskeletal pain (2D).Recommendation 10: There are case reports that topical NSAIDs can enhance the anticoagulant effect of warfarin. We suggest that patients with musculoskeletal pain monitor the international normalized ratio (INR) value when using a combination of topical NSAIDs and warfarin (2D).Expert consensus 11: There is no evidence that the combination of topical NSAIDs and ACEI, ARB, β-blockers, or other cardiovascular drugs will increase the risk of adverse events.For pregnant patients, there is currently no evidence to evaluate the efficacy and safety of topical NSAIDs in the treatment of musculoskeletal pain. The US FDA recommends avoiding NSAIDs after 20 weeks of pregnancy to prevent fetal kidney damage . HoweverCurrently, there is no evidence to evaluate the efficacy and safety of topical NSAIDs in treating musculoskeletal pain in lactating patients. Studies have shown that except for aspirin, most NSAIDs are less excreted in breast milk after oral administration . TherefoThere is no evidence to evaluate the efficacy and safety of topical NSAIDs in patients with liver disease or liver dysfunction. NSAIDs have a low risk of liver injury, with an incidence rate of 0.29–9/100,000. Nimesulide and diclofenac have a relatively high risk of liver injury ,128. TheAlthough there is indirect evidence comparing kidney injury in patients with osteoarthritis and back pain treated with topical and oral NSAIDs in the Japanese National Health Insurance database, topical NSAIDs had a similar risk of kidney injury compared to oral NSAIDs . No seriTopical NSAIDs can be safe and effective in pediatric patients. An RCT of 112 children with acute sprains found that ketoprofen gel provided short-term pain relief without an increased risk of adverse events . AnotherA subgroup analysis of five RCTs ,136,137 Only indirect evidence comparing cardiovascular adverse events was found in patients with rheumatoid arthritis treated with topical and oral NSAIDs in a Taiwanese healthcare database. Topical NSAIDs were associated with a lower risk of cardiovascular events than oral NSAIDs  . In genep < 0.00001) and possibly a lower risk of treatment discontinuation   .Drug metabolism studies of oral and topical NSAIDs have shown a lower Cmax and a delayed Tmax for topical NSAIDs compared to oral administration . FurtherRationale: In conclusion, there was limited evidence on using topical NSAIDs in high-risk patient populations. Considering the pharmacokinetic characteristics, topical NSAIDs may be safer than oral NSAIDs. The low or very low quality of evidence suggests that topical NSAIDs are generally safe to use. The guideline panel made recommendations in high-risk populations based on limited evidence and the pharmacokinetic characteristics of topical NSAIDs.Expert Consensus 12: For patients with musculoskeletal pain during pregnancy, we recommend that women in the third trimester do not use topical NSAIDs. Very low-quality evidence suggests that the short-term use of topical NSAIDs may be safe for women in the second trimester. There is no evidence for topical NSAIDs for women in the first trimester .Expert Consensus 13: For breastfeeding patients with musculoskeletal pain, there is currently no relevant evidence for topical NSAIDs. Therefore, we suggest breastfeeding patients with musculoskeletal pain use topical NSAIDs with caution, start NSAID treatment with higher safety ratings, and monitor adverse events .Expert Consensus 14: Topical NSAIDs are safer than oral NSAIDs due to their lower systemic exposure. Systemic exposure to topical NSAIDs may increase in patients with hepatic insufficiency. We suggest that patients with hepatic insufficiency use topical NSAIDs with caution and monitor adverse events .Expert Consensus 15: Topical NSAIDs are safer than oral NSAIDs due to their lower systemic exposure. Systemic exposure to topical NSAIDs can increase in patients with renal insufficiency. We suggest that patients with renal insufficiency use topical NSAIDs with caution and monitor adverse events .Recommendation 16: We suggest that children with musculoskeletal pain use topical NSAIDs and monitor adverse events (2C).Recommendation 17: We suggest that older patients with musculoskeletal pain use topical NSAIDs and monitor adverse events (2C).Expert Consensus 18: There is currently no direct evidence of using topical NSAIDs in patients with musculoskeletal pain who have cardiovascular disease.Recommendation 19: For patients with musculoskeletal pain combined with gastrointestinal diseases, we suggest using topical NSAIDs, and adverse events must be monitored (2D).After comprehensive evidence retrieval and screening, only three non-RCTs were included as indirect evidence. At the same time, expert experience in clinical practice was collected through online questionnaires to form guiding opinions and standardize clinical practice. Indirect evidence shows that pharmacist intervention can improve the rational use of analgesic drugs, improve short-term pain relief, and help identify and manage adverse events in different settings, such as primary care and clinics ,144,145.Expert experience shows that patients receiving pharmacist services are mostly older, with musculoskeletal pain involving multiple joints and other underlying diseases, or taking concomitant medications. Pharmacist services include medication education, prescription review, medication consultation, etc. The participation of dedicated pharmacists in pain management helps optimize medication regimens, reduce adverse effects and medical costs, and improve patient satisfaction. Pharmacy services enhance patient awareness of drugs and medication adherence and avoid wrong medication behaviors. Furthermore, pharmaceutical care helps identify high-risk groups and early signs of severe adverse events, prevent them as soon as possible, and protect patient safety.Rationale: In conclusion, there was no directly relevant evidence on the pharmacist intervention and service. The guideline panel made the following recommendation based on clinical experience to guide the optimal use of topical NSAIDs and lower the risk of adverse events.Recommendation 20: We recommend the pharmacist service for patients with musculoskeletal pain who use topical NSAIDs (1C).These are the first clinical practice guidelines for treating musculoskeletal pain with topical NSAIDs, focusing on drug choice, drug interaction and safety, and pharmacist service. The approach focuses more on issues related to the rational use of topical NSAIDs, and the recommendations are patient-centered. Given the effectiveness and safety of topical NSAIDs and their broad application in musculoskeletal pain, the rational use of topical NSAIDs is critical. We formulated 11 recommendations and nine expert consensuses on the use of topical NSAIDs based on the evidence from the systematic review, patient preferences, and expert experience. Overall, the curative effect of topical NSAIDs in treating musculoskeletal pain is similar to that of oral NSAIDs. However, the risk of systemic adverse events is lower, and the risk of interaction with other drugs is lower, which has certain advantages in patient populations who have comorbidities or who take concomitant medication. Furthermore, pharmacist interventions can play an active role in musculoskeletal pain management.There are several limitations. First, most recommendations on topical NSAIDs, interactions with other drugs, use in special populations, and pharmacist intervention are based on indirect evidence or expert evidence due to limited clinical evidence. There were only studies with a high risk of bias, which further led to low-quality evidence or not enough evidence to form a recommendation. More RCTs should be conducted to clarify these clinical issues. Second, the outcomes included in the research evaluations often focus only on pain relief and the risk of adverse events. Some critical outcomes, such as treatment satisfaction, ability to return to work, medication adherence, and incremental cost-effectiveness ratio, have not been systematically evaluated. Future RCTs should assess a broader range of outcomes to better understand the full impact of interventions. Third, the focus of experts on the safety of NSAIDs may have influenced the recommendations for the use of topical NSAIDs in special populations. Fourth, the guidelines do not clearly define the exact conditions and characteristics of a special population, such as liver or kidney insufficiency and cardiovascular or gastrointestinal diseases, to maintain a broad representation and increase the applicability of recommendations.The guideline panel aims to distribute and promote the guideline in various ways to ensure that clinicians, pharmacists, and nurses fully understand and apply the guidelines correctly. We will monitor and evaluate the implementation of the guideline recommendations, the acceptance of the guideline recommendations in clinical practice, and their impact on treatment decisions and patient outcomes. Meanwhile, we will monitor the evidence on the topical NSAIDs, and when possible, the guideline recommendations and the strength of the recommendation will be updated.The guidelines summarized the relevant evidence on topical NSAIDs and recommended using topical NSAIDs in treating musculoskeletal pain based on high-quality evidence. Considering the route of administration and the metabolic characteristics of topical NSAIDs, topical NSAIDs may be safer than oral NSAIDs. Using topical NSAIDs in high-risk groups, such as those with comorbidities, or receiving concurrent medications is recommended. Due to the increasing popularity of topical NSAIDs in musculoskeletal pain, the rational use of these drugs deserves attention. The guidelines focus on the most concerning issues for healthcare personnel, including clinicians and pharmacists, and patients with musculoskeletal pain when using topical NSAIDs. The guideline development process was rigorous. These are the first standard guidelines for treating musculoskeletal pain with topical NSAIDs, focusing on drug selection, drug interaction, and safety from a pharmaceutical perspective. Therefore, the guidelines can support decision making for healthcare personnel and patients and facilitate the rational use of topical NSAIDs in clinical practice. The guideline panel will continuously monitor the relevant evidence on topical NSAIDs and update pertinent recommendations in due course.


Although long term pain and mobility outcomes in total knee arthroplasties (TKA) are successful, many patients experience significant amount of debilitating pain during the immediate post-operative period that necessitates narcotic use. Percutaneous cryoneurolysis to the infrapatellar saphenous and anterior femoral cutaneous nerves may help to better restore function and rehabilitation after surgery while limiting narcotic consumption. A retrospective chart review of primary TKA patients receiving pre-operative cryoneurolysis from 2019 to 2020 was performed to assess total opioid morphine milligram equivalents (MME) consumed inpatient and at interval follow-up. Demographics and medical comorbidities were compared between cryoneurolysis and age-matched control patients to assess baseline characteristics. Functional rehabilitation outcomes, including knee range of motion (ROM), ambulation distance, and Boston AM-PAC scores, as well as patient reported outcomes using the KOOS JR and SF-12 scores were analyzed using STATA 17 Software. The analysis included 29 cryoneurolysis and 28 age-matched control TKA patients. Baseline demographics and operative technique were not significant between groups. Although not statistically significant, cryoneurolysis patients had a shorter length of stay (2.5 vs. 3.5 days) and overall less inpatient and outpatient MME requirements. Cryoneurolysis patients had statistically significant improved 6-week ROM and 1-year follow-up KOOS JR and SF-12 mental scores compared to the control. There were no differences in complication rates. Cryoneurolysis is a safe, effective treatment modality to improve active functional recovery and patient satisfaction after TKA by reducing MME requirements. Patients who underwent cryoneurolysis had on average fewer MME prescribed during the perioperative period, improved active ROM, and improved patient-reported outcomes with no associated increased risk of infections, deep vein thrombosis, or neurologic complications. Total knee arthroplasty (TKA) is a highly successful and cost-effective procedure for chronic knee osteoarthritis, with a 10-year survival of 94% and 20-year survival of 71% according to recent literature ,4,5,6,7.One of the most significant predictors of postoperative dissatisfaction following TKA is a painful total knee replacement . FactorsCryoanalgesia (cryoneurolysis) has emerged as one such method to manage knee pain and reduce persistent postoperative pain in patients undergoing TKA. This procedure entails the induction of neuronal degeneration through exposure of nerve endings to temperatures below −20 °C and functions similar to a long-active nerve block ,19,20. IIn this study, we sought to validate these findings through assessing the efficacy and safety of cryoneurolysis treatment prior to TKA, with a specific focus on evaluation of postoperative knee range of motion and opioid consumption. Our hypothesis was that preoperative cryoneurolysis would result in increased postoperative knee range of motion and decreased stiffness as well as decreased postoperative opioid consumption.This study is a retrospective cohort analysis comparing patients receiving cryoneurolysis prior to TKA against controls undergoing TKA without cryoneurolysis. All information was abstracted from patients undergoing standard of care TKA. Data from patients’ care was obtained from the pre-operative course through completion of follow up. The primary outcomes of the study were range of motion improvement and opioid analgesics use reported in milligram morphine equivalents (MME). The secondary outcomes were any kind of complication after surgery. The study was performed according to the strengthening the reporting of observational studies in epidemiology (STROBE) guidelines .A retrospective chart review of 57 patients, with diagnosed knee osteoarthritis, who underwent TKA by a fellowship-trained orthopaedic surgeon (DS) between 2019 and 2020 was performed. Twenty-nine patients had undergone cryoneurolysis 1 week prior to TKA. Twenty-eight age-matched patients who were not treated with cryoneurolysis before TKA were used as a control group. Patients who presented any additional knee pathology, below the age of 18, and pregnant were excluded from our study. The study protocol was reviewed and approved by the University of California, Irvine Institutional Review Board, and patient informed consent was waived due to the retrospective design of the study.Demographic variables included age, sex, body mass index [BMI], diabetes, smoking, ASA status, preoperative lab values, history of prior knee surgery or chronic pain, and opioid use before surgery. Perioperative variables obtained included tourniquet time, adductor canal block, use of a continuous nerve catheter, blood loss, inpatient MME intake, length of hospital stay, distance walked on discharge, and Boston AM-PAC scores. Inpatient MME was calculated using the total dose of opioid analgesics administered normalized to MME. Total distance walked was a summation of the reported patient distance traveled with physical therapy teams on postoperative day 1. The postoperative outcomes variables collected were 4–6-week MME prescribed, clinical complications, and range of motion as reported by the treating providers. Patient reported outcome variables (PROM) included subjective pain and functional outcome scores as outlined in Knee Injury and Osteoarthritis Scores (KOOS JR) and Short Form Survey (SF 12), which have been validated by previous studies ,21,24. OCryoneurolysis was administered using the Iovera device by a fellowship trained sports medicine physician 1 week before planned TKA. The AFCN and ISN were targeted using the technique as previously described by Dasa et al. Treatment lines for each corresponding nerve consisted of 6 treatment cycles, each lasting about 60 s, and a 90 mm SmartTip probe was used to administer the cryoneurolysis with direct patient feedback.p < 0.05 was considered statistically significant. Stata 17  was used as statistical software for all analyses.Continuous variables were described with mean ± standard deviation or mean and range, whereas categorical variables were reported with absolute and relative frequency . The Wilp = 0.0463), there was no difference in infections, deep vein thrombosis, discharge destination, cardiac complications, or length of stay between groups . 6-week ROM improvements relative to pre-operative measurements in the treatment group reached statistical significance (12 ± 9 vs. 3 ± 12 p = 0.042), although earlier interval measurements were not significant  (p = 0.01). All other patient reported outcomes, including VAS inpatient pain scores and earlier interval KOOS JR and SF 12 mental and physical scores, failed to reach significance.Patient reported outcomes demonstrated a statistically significant increase in the improvement in KOOS scores from pre-op to 12 months (38.8 (11.2) vs. 11.1 (9.6) = 0.007) . There wCryoneurolysis is a safe, effective preoperative modality that can be incorporated into an integrated multimodal pain management pathway to reduce opioid consumption and improve knee functional outcomes. Management of pain is an important part of patient care and satisfaction, and identifying techniques to reduce postoperative opioid dependence improves the physician-patient communication on expected outcomes and discharge planning. Previous studies have found prolonged postoperative use of opioids after TKA to be associated with increased rates of stiffness, poor functional outcomes, and limitations on quality of life . ImplemeDespite not reaching statistical significance, cryoneurolysis patients required on average less MMEs compared to the control group both in the acute inpatient stay and postoperative discharge period. The decreased MME requirement is clinically significant since fewer opioids overall decreases the risk of respiratory complications, falls, nausea, vomiting, constipation, urinary retention, and cognitive impairment, which are side effects that can significantly increase the length of stay, prolong the rehabilitation process, and increase hospital costs . In factProlonged opioid use after TKA has been associated with increased rates of stiffness, infection, and poor satisfaction scores, and our cryoneurolysis patients at the 4–6 weeks clinic visit had nearly half the prescribed amount of opioids compared to the control group . While nIn terms of active recovery and return to independence, patients in the cryoneurolysis group ambulated on average 100 feet farther than the control group on postoperative day 1 despite not reaching statistical significance. The improvement in ambulation on postoperative day 1 may reflect the improved endurance and strength to participate in physical therapy, which oftentimes may be limited by confounding effects of nausea, vomiting, and sedation from high opioid intake. Overall reduced opioid intake combined with improved pain control may contribute to greater participation during therapy sessions that lead to earlier and safer discharge to home . AlthougIn fact, regaining knee ROM is an important postoperative outcome that has been shown in the literature to affect ability to return to activities of daily living, such as going up and down stairs and getting up from a chair . At the With the emphasis on pay for performance measures to evaluate TKA outcomes, PROMs, such as the KOOS Jr. and SF-12, have become widely used in the literature to gauge patient satisfaction and knee function . SimilarHowever, there are limitations to consider in this study, including its retrospective design, nonrandomized nature, and lack of blinding of patients which may limit the generalizability of our results. Due to the relatively new implementation of the technique performed in a single surgeon cohort, there were limited number of patients in the analysis and many patient-reported outcome measures were not fully completed. It is possible that many outcomes deemed not statistically significant may not have been powered to elucidate associations due to the small sample size. As there was no phone call or recorded measurement of pain scores one day prior to surgery, we were unable to assess the interval change in patient’s symptoms from time between undergoing cryoneurolysis and surgery. In addition, although outpatient opioids prescribed may have been used for other sources of pain and may not truly reflect the actual use of the narcotic, prescribed amounts of MME at clinic visits were used in this study as reflective of opioid requirements.Overall, cryoneurolysis is a safe treatment with no evidence of dyesthesias or numbness complications reported to interfere with patient rehabilitation in this study. While other studies report neuropathic pain, deep vein thrombosis, and wound infections associated with the surgical incision to be possible limitations to cryoneurolysis, this study found no increased risk compared to the control group . AlthougCryoneurolysis is a safe, effective treatment modality for patients undergoing TKA to reduce opioid consumption, improve knee ROM, and improve patient satisfaction. Although there was no statistically significant reduction in MME consumed between groups, there was a trend towards reduced MME prescribed at follow-up visits. The improved knee ROM at 6-week follow up evaluations in the cryoneurolysis group may reflect a more active recovery process and faster return to activities of daily living.


We report on two critically ill pediatric patients, aged 16 and 18 years, presenting with acute myopericarditis at a tertiary-care center in New Jersey, United States. Both patients had their severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinations, tested negative for SARS-CoV-2, and shared only significant history of asthma. Clinical presentations were similar to acute onset chest pain that worsened with deep inspiration. One patient reported a history of vaping and escalating marijuana use several hours preceding presentation. Both patients had elevated troponin on admission and had ST-segment elevation on electrocardiogram (EKG), thus prompting admission to the pediatric intensive care unit (PICU) for cardiac monitoring. Myopericarditis has multiple etiologies and is a newly described rare complication of the SARS-CoV-2 vaccine. It can also occur as a complication of vaping and frequent marijuana drug use. Our paper highlights the importance of a detailed social and drug history in adolescents presenting with chest pain. The clinical characterization is necessary to promote better case definitions and the design of targeted interventions for this vulnerable group.  In response to the global pandemic of coronavirus, COVID-19 vaccinations were developed and produced as a primary preventive measure to help mitigate the spread and severity of those affected. Vaccinations have been monumental in preventing the transmission of infections in both the school and community . EtiologCase 1An 18-year-old previously healthy male with a past medical history of asthma presented to the emergency room for a sudden onset of chest pain. The chest pain started 30 minutes before arrival while he was vaping marijuana. He reported using increasing amounts of cannabis and vaping in the preceding few days. The pain was moderate to severe, pleuritic on the anterior chest wall, worsened with deep breaths, and was non-radiating and non-exertional in nature. He took an aspirin without any relief. He had no known sick contacts or recent foreign travels. In the emergency department (ED), vitals were temperature of 36.6°C, heart rate of 68 beats per minute (pm), respiratory rate of 20 breaths pm, blood pressure 120/85 mmHg, and oxygen saturation of 94%. Laboratory workup showed elevated troponin 1,070 pg/mL at 12:15 pm, and two hours later, it increased to 3,362 pg/mL, and ST-segment elevation was appreciated on the EKG  with complaints of chest pain. He stated the pain started in the early morning hours and was mild, intermittent, and non-radiating in nature. It was aggravated by deep breaths and was alleviated with time and rest. The symptoms initially resolved but returned in the late morning, which prompted his mother to bring him to the emergency room. There was no active chest pain in the ED. Of note, the patient received a second dose of his Pfizer COVID-19 vaccine four days prior. There were no known sick contacts or recent foreign travels. The patient denied any extremity pain or swelling, any previous chest pain, or other associated symptoms at this time. In the ED, the vitals were: temperature 36.5°C, heart rate 79 beats pm, respiratory rate 20 breaths pm, blood pressure 125/62 mmHg, and oxygen saturation 99%. Pertinent lab findings included elevated troponin 7,367 pg/mL at presentation. EKG revealed ST-segment elevations in V3-V6 anteriorly, and T-wave inversions in the inferior leads , a part of the Centers for Disease Control and Prevention (CDC), which tracks adverse events due to vaccinations. It remains a rare side effect in young adolescents and is more likely to occur after the second dose . Many caMyopericarditis is a constellation of symptoms, including high troponins and chest pain with an inflammation of the myocardium and pericardium, usually as a complication of acute pericarditis. It is interchangeably used with perimyocarditis ,3. The pBoth patients presented with chest pain, the most common presenting complaint. Both patients had recently received their second dose of the COVID-19 vaccine, similar to the findings in a detailed cross-sectional study . The patBoth patients were admitted to the pediatric intensive care unit for continuous cardiopulmonary monitoring, including trending troponin, brain natriuretic peptide, erythrocyte sedimentation rate, and C-reactive protein every eight hours. They were supportively managed with acetaminophen, Ibuprofen, famotidine, lidocaine, and intravenous fluids . Both paMarijuana is one of the most frequently used illicit substances in adolescence . Vaping Though there are limited research studies on time to heart disease presentation with cannabis use, one study showed a decreased time of onset for chest pain after cannabis use . MyoperiCOVID-19 vaccine has undoubtedly reduced the worldwide disease burden. Together with other preventive measures, vaccines have helped curb the ever-evolving COVID-19 pandemic. Myopericarditis is a rare side effect in adolescents with typically good outcomes. Our study highlights the essence of good history taking, which helps broaden differentials and understanding of other synergistic factors with the goal of promoting targeted interventions in this vulnerable group. For an adolescent presenting with chest pain attributable to myopericarditis, a detailed history taking is crucial to developing a comprehensive differential diagnosis. It is imperative to inquire about a thorough history of drug abuse, especially marijuana use.


Myofascial pain syndrome (MPS) and fibromyalgia (FM) are underestimated painful musculoskeletal conditions that could impact function and quality of life. A consensus about the most appropriate therapeutic approach is still not reached. Considering the long course of the diseases, prolonged assumption of drugs, such as NSAIDs and pain killers, could increase the risk of adverse events, often leading affected patients and physicians to prefer non-pharmacological approaches. Among these, radial and focused extracorporeal shock waves therapies (ESWT) are widely used in the management of painful musculoskeletal conditions, despite the fact that the mechanisms of action in the context of pain modulation should be further clarified. We performed a scoping review on PubMed using Mesh terms for analyzing the current evidence about the efficacy and effectiveness of ESWT for patients with MPS or FM. We included 19 clinical studies ; 12 used radial ESWT, and 7 used focused ESWT for MPS. Qualitative analysis suggests a beneficial role of ESWT for improving clinical and functional outcomes in people with MPS, whereas no evidence was found for FM. Considering this research gap, we finally suggested a therapeutic protocol for this latter condition according to the most recent diagnostic criteria. Myofascial pain syndrome (MPS) and fibromyalgia (FM) are musculoskeletal (MSK) conditions that significantly affect function and quality of life (QoL). Myofascial pain syndrome has been defined as a regional pain characterized by the presence of one or more myofascial trigger points (MTrPs), or ‘taut bands’, that are a limited number of hyperirritable muscle fibers organized in nodules that can cause spontaneous and referred pain on palpation . The patFibromyalgia is a chronic disease characterized by widespread MSK pain with specific limited soft tissue areas of hyperalgesia and/or allodynia . Moreover, affected patients complain of fatigue, sleep disorders, and other somatic and cognitive symptoms . It shouSeveral interventions have been proposed to treat FM and MPS, such as drug therapy, exercise, physical therapy, acupuncture, and needling . However, the most appropriate and effective approach for these conditions is still debated . ExtracoThe aim of this scoping review is to summarize current evidence about the efficacy and effectiveness of ESWT in patients with FM or MPS.In performing this scoping review, we followed the PRISMA-ScR  guidelines .We planned a search on PubMed  with ad hoc search strings with selected keywords for FM, MPS, and ESWT .According to the study objective, we defined the characteristics of the sources of evidence, considering for eligibility any research published in the medical literature until 31 December 2021 and including only those in the English language and conducted on humans .Clinical research, including interventional  and observational studies, were selected. Research findings from each included study were qualitatively analyzed.Seventy-six items were initially found. After duplicate removal, 35 records remained. We screened them on the basis of titles and abstracts for inclusion/exclusion criteria, and 14 studies were excluded. After full-text reading, we excluded another two articles because the authors did not specify the type of ESWT used. Finally, we included in this review 19 studies published between 2012 and 2021. None of the trials involving people with FM met the eligibility criteria. Among those including people with MPS, 12 used radial ESWT (rESWT), and 7 used focused ESWT (fESWT). Of the 12 studies investigating the effectiveness of rESWT for the management of patients with MPS, 10 are RCTs (1 pilot) ,20,21,22Of the seven studies investigating the efficacy and effectiveness of fESWT, five were RCT ,27,28,29Two observational studies investigated the effectiveness of fESWT in the treatment of MPS in the low back (quadratus lumborum)  and the To our knowledge, this is the first PRISMA-driven scoping review aiming to investigate the efficacy and effectiveness of ESWT in the treatment of patients with MPS or FM.First of all, we must stress that although there are numerous studies dealing with the efficacy of ESWT in patients with MPS in the literature, no paper has aimed to evaluate this intervention in people with FM.2. Considering the number of sessions, authors generally performed one session per week for 3 weeks .Of note, starting from an overview of included studies, a substantial issue concerned the heterogeneity of treatment protocols, particularly in terms of the number of sessions, intervals between sessions, number of SW administered per TrP, and intensity. About rESWT, shock waves number ranged from 1000 to 4500 . This intervention was usually provided once a week for 3 weeks or sometimes for four sessions, while only Gezginaslan et al. carried out seven sessions with 3-day intervals. For fESWT, the number of SW used ranged from 1000 to 3000, while the intensity ranged from 0.056 to 0.25 mJ/mmAmong studies included in our review , 16 compared ESWT to other interventions, while two studies compared this intervention to sham ESWT. Moreover, in an observational retrospective study, no treatment was administered to the control group.Observational studies comparing ESWT to another intervention reported that both focused and radial modalities were more effective than TPI, KT, and physical agents in MPS patients in terms of pain, mobility, and disability.On the other hand, results from clinical trials investigating the efficacy of ESWT in MPS people are conflicting. In the RCTs comparing ESWT versus placebo , both radial and focused modalities seem to significantly improve pain in people with MPS.Regarding evidence about rESWT in comparison with DN, laser therapy combined with stretching, and therapeutic exercise, no significant differences were reported in terms of pain relief and disability, while rESWT seemed significantly more effective than TPI or a combination of physical agents (HP + TENS + US therapy or US therapy + hot pack) in terms of improvements of pain, fatigue, depression, sleep quality, disability, and QoL in patients with MPS.RCTs investigating the efficacy of fESWT versus other interventions reported that this treatment modality was not better than TPI combined with TENS in terms of pain relief and mobility, while it was more effective than laser therapy in improving pain, disability, and QoL in patients with trapezius MPS. Moreover, the same intervention significantly improved pain and mobility compared to topical NSAIDs.It was hypothesized that several mechanisms involved in the pathogenesis of clinical manifestations of MPS and FM might be addressed by different ESWT modalities.Myofascial pain syndrome was described as muscle pain in different body regions reproduced by pressure on TrP, which are localized hardenings in skeletal muscle tissue. This condition may originate from muscular injury due to intense contractions or repetitive low-intensity overload, inducing an excessive release of acetylcholine by the neuromuscular endplate . This evOn the contrary, pathogenic mechanisms underlying FM are still unclear. The characteristic tender points are considered as areas of tenderness symmetrically located in specific body parts that do not cause referred pain after stimulation. Recent studies suggest that various agents acting on central  and peripheral nervous systems, including small nerve fibers (inflammatory mediators), can lead to neuromorphological modifications and pain dysperception . Small fConsidering that FM and MPS share some clinical and pathophysiological features, there might be a rationale for using physical agents, including ESWT, in the management of these conditions. Indeed, ESWT has documented effects on several MSK disorders, including the stimulation of angiogenesis with consequently improved perfusion of ischemic tissues.However, the biological effects of SW targeting pathogenic mechanisms of FM and MPS are still unclear. It is possible to speculate that ESWT may modulate ion influx, particularly of calcium, with consequent improvement of perfusion and promoting angiogenesis. These events might reduce local ischemia, enhancing tissue healing . MoreoveDespite our scoping review being the first comprehensive analysis of the role of both ESWT modalities in MPS and FM, some years ago, Ramon et al. already published an article dealing with this topic, proposing an ESWT protocol for a small cohort of FM patients . In partMyofascial pain syndrome and FM are two complex conditions requiring challenging management. By considering the hypothesized pathophysiological mechanisms, the administration of ESWT was proposed for improving pain and disability in patients affected by these conditions, particularly MPS. Indeed, our scoping review suggests that ESWT could have a role in relieving pain and improving functional outcomes by modulating biological mechanisms of pain, inflammation, and angiogenesis in MPS. However, our results show that a widely accepted therapeutic schedule for both radial and fESWT has not been defined so far. Finally, considering the lack of evidence about the use of ESWT in people with FM, we proposed a new treatment protocol, based on the most recent diagnostic criteria taking into account patients’ tolerability, that needs to be investigated in future trials.


Therapy decision for patients with metastatic renal cell carcinoma (mRCC) is highly dependent on disease monitoring based on radiological reports. The purpose of the study was to compare non-standardized, common practice free text reporting (FTR) on disease response with reporting based on response evaluation criteria in solid tumors modified for immune-based therapeutics (iRECIST).Fifty patients with advanced mRCC were included in the retrospective, single-center study. CT scans had been evaluated and FTR prepared in accordance with center’s routine practice. For study purposes, reports were re-evaluated using a dedicated computer program that applied iRECIST. Patients were followed up over a period of 22.8 ± 7.9 months in intervals of 2.7 ± 1.8 months.Weighted kappa statistics was run to assess strength of agreement. Logistic regression was used to identify predictors for different rating.Agreement between FTR and iRECIST-based reporting was moderate (kappa 0.38 [95% CI 0.2–0.6] to 0.70 [95% CI 0.5–0.9]). Tumor response or progression according to FTR were not confirmed with iRECIST in 19 (38%) or 11 (22%) patients, respectively, in at least one follow-up examination. With FTR, new lesions were frequently not recognized if they were already identified in the recent prior follow-up examination (odds ratio for too favorable rating of disease response compared to iRECIST: 5.4 [95% CI 2.9–10.1].Moderate agreement between disease response according to FTR or iRECIST in patients with mRCC suggests the need of standardized quantitative radiological assessment in daily clinical practice.The online version contains supplementary material available at 10.1007/s00432-022-03997-0. The incidence of renal cell carcinoma up to age 75 is 4.4/100 000 worldwide   is common, in clinical studies, consideration of standardized response evaluation criteria in solid tumors (RECIST) is required. With FTR, in general, no specific criteria for evaluation are defined. Radiologists routinely refer to the most previous finding. In contrast, RECIST based reporting refers either to baseline or to nadir. Moreover, with RECIST, selection of target lesions is specified. RECIST were updated in 2009  and are mainly to be applied in case of cytotoxic chemotherapy  with a detector width of 160 mm. After intravenous administration of a 1 ml/kg body weight bolus of contrast agent  followed by a 50 ml saline flush, the imaging started with a bolus-triggered technique . For CT scans, parameters were as follows: 120 kVp, automatically set mAs values, reconstructed to a slice thickness of 3 mm and a pitch of 53.Based on morphological evaluation of CT scans, FTRs had been prepared as part of daily clinical practice by two radiologists in agreement. At least one of them had more than 5 years of experience concerning assessment of tumor burden. Overall, 58 radiologists had participated in preparation of the considered FTRs. FTRs covered both description of pathologies and clinical interpretation including indication of tumor development. Assessment criteria had not been specified. Tumor burden after a given treatment had usually been compared to the recent prior CT examination, however, reference CT was not mentioned explicitly. For study purposes, if not already done by the examiner, a resident physician of the radiology department retrospectively assigned interpretation of FTRs to one of the following four disease response categories: complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD).In parallel, we imported the same image datasets into a commercially available semi-automatic software   . Analysis was performed using StatsDirect statistical software version 2.8.0. (StatsDirect Ltd.) and XLSTAT version 2015.6.01.24026 (Addinsoft).Categorical variables are presented as counts and percentages and continuous variables as means and standard deviations. Agreement was assessed with Cohen’s kappa statistics. Amount of difference in rating was considered using weighted kappa. Strength of agreement was interpreted according to Landis and Koch ,  with mRCC were included in the study. Prognostic risk according to international metastatic renal cell carcinoma database consortium (IMDC) assessment was poor in 20% of patients. Average number of target lesions per patient was 2.4 ± 1.4. The most common sites of target and non-target lesions were lung (33.0%), lymph nodes (30.0%), kidney (7.1%), and liver (6.6%)  or two (0–6% of patients) categories ,  to 0.70 (95% CI 0.5–0.9). There was no trend in the series of weighted kappa over subsequent follow-ups , Fig. b. WeightWith FTR, disease was preferably reported as SD at all follow-ups. Assessment of PR was 8–22 and PD was 10–32 percentage points less with FTR compared to iRECIST-based reports from the 3rd follow-up on. In contrast, with iRECIST, proportion of SD ratings declined from 76% at the 1st to 18% at the 10th follow-up. Overall, FTR on response or progression was not confirmed by iRECIST-based reports in 22%  or 16% , respectively  to 1.0 (95% CI 0.81–1.19), Online Resource: ESM Fig. 2. Different assessment was caused by pseudoprogression in 5 patients (identified with iRECIST at 11 follow-ups) representing 10% of the total study cohort. Pseudoprogression was observed in lymph nodes (3 lesions), lung (3 lesions), and pleura (1 lesion). In 4 of 11 (36%) examinations, pseudoprogression was also covered by FTR. Examples for assessment of progression with iRECIST are provided in Fig. Univariable analysis revealed that first occurrence of new lesions decreased the odds of different assessment according to FTR compared to iRECIST (odds ratio [OR] 0.02 (95% CI 0.001–0.4). In contrast, the presence of already existing new lesions raised the odds that disease response was assessed as better according to FTR than to iRECIST by more than fivefold (OR 5.4 (95% CI 2.9–10.1). Both an increase in the sum of target lesion diameters and in the number of target lesions decreased the odds of disease response of being assessed as lower according to FTR compared to iRECIST . Involvement of lymph nodes nearly doubled the odds of different assessment (OR 1.77 (95% CI 1.1–2.7). Every month from baseline increased the odds that disease response was assessed as better according to FTR than to iRECIST (OR 1.0 per 30 days from baseline [95% CI 1.0–1.1])  or show stable disease (iSD), partial response (iPR), or complete response (iCR) compared to baseline. This new assessment should prevent patients to be withdrawn from immunotherapy in case of pseudoprogression. An earlier study found that continued immunotherapy beyond iUPD can prolong survival Below is the link to the electronic supplementary material.