Background and Objectives: Orthopedic surgeons commonly prescribe opioids, surpassing all medical specialties. Our objective was to develop a pain management scale that captures medication use, patient-reported pain scores, and helps orthopedic surgeons evaluate their post-operative prescribing practice. Materials and Methods: An IRB-approved prospective study followed 502 post-operative orthopedic surgery patients over a six-month period. All patients were surveyed in an orthopedic clinic at a Level 1 US Trauma Center, during a routine follow-up. Patient pain satisfaction was assessed using the validated Interventional Pain Assessment (IPA) scale, which uses three categories: 0 (no pain), 1 (tolerable pain), and 2 (intolerable pain). Daily narcotic use was translated to morphine milligram equivalents (MMEs) using the Michigan Automated Prescription System (MAPS) narcotics registry. When patient pain satisfaction and narcotic usage were combined, this scale was called the Detroit Interventional Pain Assessment (DIPA) scale. Results: The five classes based on common prescription and usage of narcotics in this cohort include the following: A (no pain medication), B (over-the-counter medication), C , D (consistent/regular use of short-acting narcotics 31–79 MMEs), and E (long-duration or stronger short-acting narcotics 80+ MMEs). Patients were most satisfied with their pain management at six weeks (80.5%) and three months (75.65%), and least satisfied at two weeks (62.5%) and six months (60.9%). Additional information displayed on the DIPA graph revealed there was a significant decrease in the percentage of patients on narcotics at two weeks (65.2%) to six months (32.6%) at p < 0.001. Conclusions: The DIPA pain scale shows the relationship between patient pain perception and opioid prescription/usage, while also tracking prescriber tendencies. Providers were able to visualize their post-operative pain management progression at each designated clinic visit with corresponding alphabetical daily MME categories. In this study, results suggest that surgeons were not effective at managing the pain of patients at two weeks post-operative, which is attributed to an inadequate number of pain pills prescribed upon discharge. Overall, the DIPA graph signaled that better pain management interventions are necessitated in periods with lower efficiency scores. The opioid crisis has become endemic to the United States since its inception two decades ago, and opioid overuse is a major problem for orthopedic providers . A recenThe Interventional Pain Assessment (IPA) scale was developed using only three descriptive categories: no pain, tolerable pain, and intolerable pain . The IPAGiven an increase in narcotic abuse, the CDC has taken precautions to increase awareness of opioid addiction by using morphine milligram equivalents (MMEs) . This nuAn IRB-approved prospective study for post-operative care was conducted at a Level 1 US Trauma Center over a period of six months. This study enrolled patients at an orthopedic clinic for routine follow-up after operative treatment of fractures, spine pathology, total joint replacement, and other general orthopedic procedures  . Additionally, they were asked about their daily narcotic consumption. Information was collected on all patients’ recent controlled substance prescriptions, as reported by the Michigan Automated Prescription System (MAPS) narcotics registry, to establish their daily narcotic usage in MMEs ,17. TheiPatients were further subdivided based on the following post-operative periods: two weeks, six weeks, three months, and six months. The IPA scale associated with each post-operative encounter was incorporated. For example, a patient taking occasional short-acting narcotics and reporting their pain as tolerable with this regimen at two weeks was rated a C1 . Finally, the percentage of patients with no or tolerable pain at each post-operative stage was calculated to provide the physician with an overview of how well they are managing their patients’ pain. The IPA scale combined with the ABCDE MAPS classification and post-operative stage graph was called the Detroit Interventional Pain Assessment, or DIPA. This study was funded by the Rehab Institute of Michigan Foundation .All statistical analyses were conducted using the Statistical Package for the Social Sciences  set at a significance level of 0.05. A hierarchical cluster analysis was initially used to identify the number of clusters or narcotic classes . This waPrior to pain assessment interviews, all patients’ consent was verbally recorded, and they were briefed about this study. Patients had the option to opt out at any time. There were minimal risks associated with this study.p = 0.163) between pain tolerability and gender   .p < 0.001). Class C patients had a daily MME average of 16.34 ± 0.08 (range 2.3–30) and corresponded to the use of schedule II and IV drugs  on occasion, as needed. Class D included patients who had a daily MME average of 45.39 ± 0.22 (range 33.75–67.5) and represented patients using schedule II drugs (hydrocodone or oxycodone) at regular intervals consistently each day. Occasional use was defined as those who ingested medication as needed or infrequently during post-operative care. Consistent use was defined as patients who consumed narcotics routinely every day during post-operative care. Class E included patients with a daily MME average of 94.09 ± 17.48 (range 80–135) and corresponded to patients using long-acting schedule II narcotics, such as hydromorphone, methadone, morphine, and Oxycontin with breakthrough short-acting medication  was more likely to have a larger MME value (p < 0.001), discriminating variables when determining the different grouping memberships of narcotics.According to the statistical analysis and after daily MME conversions, the narcotic classes corresponded to three MME numerical ranges . Again, dication  Boxplot.ME value . SimilarIn addition, we wanted to provide a feedback mechanism for providers to evaluate the efficacy of their post-operative pain protocol. Thus, we created a scoring system based on IPA responses which grouped together all treated patients experiencing no pain (0) or tolerable pain (1) and assigned them a value of 1. Patients who rated their pain as intolerable were assigned a value of 0. Next, we added them all up, effectively counting all adequately treated patients, divided the number by the total number of patients, and then multiplied by 100. This represented a percentage of patients who felt they had satisfactory pain management. The percentages were calculated at every post-operative time period. This new IPA pain management score categorized by medication class was represented graphically .p < 0.001.The results of the new IPA pain management score categorized by medication class (DIPA) displayed that the percentage of cases with no pain and tolerable pain was greater than the percentage of cases with intolerable pain in almost every class for each post-operative period. Patients were most satisfied with their pain management at six weeks (80.5%) and three months (75.65%). Lower patient satisfaction scores were represented at two weeks (62.5%) and six months (60.9%). The lower pain scores at two weeks reflected that many patients had run out of their pain medication before their visit at the clinic. Moreover, after reviewing the data, this was attributed to an inadequate number of pain pills prescribed as patients were discharged. New state prescribing rules maintained that a maximum of one week of pain medications can be prescribed at discharge. However, patients were not seen until two weeks post-operative. Additional information displayed on the DIPA graph revealed there was a significant decrease in the percentage of patients on narcotics at two weeks (65.2%) to six months (32.6%) at Pain is a complex patient experience that is frequently assessed and used as an objective piece of data along with other vital signs . As healIn order to study any metric, there must be a way to measure it. In a previous work, the patient-preferred IPA scale has been validated and exhibited a statistically significant correlation with the NRS . Next, wPrevious efforts to create a more meaningful use of MME values have been published. Fulton-Kehoe et al. created a medication classification system with meaningful definitions in conjunction with MME daily values using six categories . Within The statistical analyses demonstrate that the DIPA scale is reliable, valid, and applicable to our orthopedic clinic population. Additionally, any orthopedic practitioner can implement this scale in their clinic by asking their patients the following three questions: (1) Do you have no pain, tolerable pain, or intolerable pain? (2) What pain medication are you taking? (3) Do you take it occasionally as needed or consistently on a daily basis? From there, providers can group patients according to the DIPA scale. For example, if a patient reports their pain as tolerable, taking Norco 5 mg occasionally (as needed), then they are rated as a C1. Without having to refer to MAPS, the provider knows the patient’s daily MME value lies between 1–30 MMEs. Therefore, physicians can use this as a reference guide to longitudinally track their pain management efficacy and prescribe tendencies across post-operative periods.Limitations of this study include the cohort of patients. The surveys were conducted on all adult patients. Therefore, the IPA scale should be tested against a pediatric group to assess its validity in a vulnerable population. We did not assess for the use of other pain modalities, such as marijuana or illicit drugs, which would provide a broader understanding of pain perception. There were patients who used narcotics prior to surgery and may be using them for other diagnoses. This could include patients with chronic diseases that tend to increase the amount of pain experienced by patients. This study did not take this into account, and a review of intake histories and medication reconciliation data for those people could be performed in a future study. This is where fracture patients may differ from degenerative diseases, such as arthritis and back pain. We did not question why patients were taking pain medications at six months, which may solve these questions and could discover risk factors for continued use. Another limitation is the applicability of the DIPA scale. This study proves that the DIPA scale is only applicable to orthopedic providers. While its intended use is for it to eventually be applied to all cohorts of patients, more studies need to be performed within different patient populations for it to be validated. Lastly, this is a single-center study. Including a more diverse patient participant pool by surveying patients with the DIPA scale at other hospitals and clinics is a valuable future effort.The purpose of including a wide range of orthopedic patients was to show that the DIPA scale can be broadly applied across all orthopedic specialties. However, the next step should be to apply the DIPA scale to a specific population of orthopedic patients, such as those receiving fracture care, to determine providers’ prescription tendencies and patient pain satisfaction.Overall, the simplistic versatility and multidimensionality of the DIPA scale promote its usage in different pain management scenarios as well as its application as a longitudinal assessment tool. Once a problem can be measured, as in the case of patient pain satisfaction and narcotic usage, physicians can then study the problem more effectively in a way that produces better outcomes.The DIPA scale and assessment tool demonstrates the ability to evaluate pain perception, medication usage, and can track pain management efficacy. Providers were able to visualize their post-operative pain management progression at each designated clinic visit with corresponding alphabetical daily MME categories. In this study, results suggest that surgeons were not effective at managing patients’ pain at two weeks post-operative, which was attributed to an inadequate number of pain pills being prescribed upon discharge. However, in subsequent clinic visits at six weeks and three months, providers’ pain management practice improved, and was evidenced by a significant decrease in the percentage of patients on narcotics and corresponding higher efficiency scores. Overall, the DIPA graph signaled that better pain management interventions are necessitated in periods with lower efficiency scores.


Opioids are frequently used in the postoperative period due to their analgesic properties. While these drugs reduce nociceptive somatic, visceral, and neuropathic pain, they may also lead to undesirable effects such as respiratory depression, urinary retention, nausea and vomiting, constipation, itching, opioid-induced hyperalgesia, tolerance, addiction, and immune system disorders. Anesthesiologists are in the critical position of finding balance between using opioids when they are necessary and implementing opioid-sparing strategies to avoid the known harmful effects. This article aims to give an overview of opioid-free anesthesia.This paper presents an overview of opioid-free anesthesia and opioid-sparing anesthetic techniques. Pharmacological and non-pharmacological strategies are discussed, highlighting the possible advantages and drawbacks of each approach.Choosing the best anesthetic protocol for a patient undergoing cancer surgery is not an easy task and the available literature provides no definitive answers. In our opinion, opioid-sparing strategies should always be implemented in routine practice and opioid-free anesthesia should be considered whenever possible. Non-pharmacological strategies such as patient education, while generally underrepresented in scientific literature, may warrant consideration in clinical practice. Moderate to severe pain is reported to occur in 30–80% of patients on the first postoperative day . If postAnesthesiologists are therefore in the critical position of balancing the judicious use of opioids when they are indicated while avoiding opioid-related harm and effectively managing pain. There are a number of methods or approaches that can be used to reduce opioid use before, during, and after surgery. These include identifying and optimizing individuals at risk of long-term opioid dependence and using a multimodal non-opioid analgesic regimen perioperatively , 9. In tCancer is one of the most common causes of mortality worldwide leading to an estimated 10 million deaths in 2020 . OpioidsOFA technique is feasible following the basic concept of multimodal analgesia that one drug alone cannot completely replace opioids. An adequate association of drugs, possibly with the concurrent use of regional anesthesia techniques, permits a good quality of anesthesia without using opioids. The multimodal approach blocks or mitigates the transmission of pain and inflammatory pathways at different levels, reducing or eliminating (in the case of OFA) opioid requirements .OFA has been shown to be feasible but only few well-designed studies have been published so far and very little data is available on long-term outcomes . The overall literature remains scarce and whether OFA is clinically advantageous or not in the different fields of application and with different modalities is yet to be established.The use of OFA techniques may be appropriate in certain surgeries for cancer patients, especially if regional anesthesia and more generally opioid-sparing strategies can be employed. Preclinical trials have suggested that opioids inhibit the function of natural killer cells and increase cancer recurrence by affecting angiogenesis and tumor cell signaling pathways. On the other hand, regional anesthesia is thought to contribute positively to outcomes in cancer patients by reducing surgical stress response and thus reducing the need for volatile anesthetics and opioids . HoweverHowever, differences in definitions have led to conflicting results. Its benefits, limitations, and applicability have been questioned, with some studies reporting that it does not provide any benefits . HoweverDexmedetomidine is a potent and highly selective α-2 adrenoreceptor agonist with sedative, anxiolytic, sympatholytic, and opioid-sparing properties. It reduces the need for anesthetics and opioids without causing respiratory depression but existing literature has reported conflicting results . Many std-aspartate (NMDA) receptor antagonist, is widely known as a dissociative anesthetic and phencyclidine derivative. It has complex hypnotic, analgesic, antidepressant and psychotomimetic effects that cannot be explained only by NMDA and receptor antagonism. Ketamine has also been shown to bind to all types of opioid receptors with the highest affinity for mu, kappa, and delta receptors [Ketamine, an N-methyl-eceptors . Ketamineceptors . Ketamineceptors . Howevereceptors . Ketamineceptors . There ieceptors .. Becauseceptors –32. Perieceptors . In patieceptors . Additioeceptors , 35–37.The use of regional anesthesia applications provides many essential benefits such as lower pain scores in the postoperative period, early hospital discharge, reduction in the incidence of PONV, and reduction in the use of additional analgesics. In addition, regional anesthesia is not only an important component of pain management: evidence suggests that it may also play a role in inhibiting cancer progression , 39.The importance of regional anesthesia in accepting an opioid-free modality was demonstrated in a prospective study of 2382 upper and lower extremity peripheral nerve blocks, with 90% of patients not requiring opioids in the PACU postoperatively . TherefoEpidural analgesia, thoracic paravertebral block, intercostal block, local infiltration analgesia, and transversus abdominis plane block are the most known and effective opioid-free regional anesthesia techniques . NeuraxiIn the setting of opioid-free analgesia, optimizing perioperative care with non-pharmacological strategies to mitigate nociception is a potentially understudied strategy, with literature currently dominated by studies on pharmacological interventions. Fiore et al., in a scoping review conducted in 2019, identified only 13 studies addressing specifically non-pharmacological interventions in opioid-free analgesia .(TENS) is one of the most studied non-pharmacologic strategies to improve analgesia in surgical patients and is used for pain management of both acute and chronic pain irrespective of cause. Though its role in postoperative analgesia may be yet controversial [Transcutaneous electrical nerve stimulation oversial , TENS waoversial  and was oversial .Acupuncture is another potential strategy to reduce pain in the postoperative period and was effective against controls in a randomized control trial on inguinal hernia repair . Recent Among other non-pharmacological interventions, sitz baths and moxibustion have been used after hemorrhoidectomy,  while arAnother potentially underestimated non-pharmacological strategy may involve the use of focussed preoperative patient education programs. A recent systematic review in orthopedic surgery concludes that multimodal preoperative education programs hold promise as an effective strategy to limit opioid consumption in the postoperative period . In gyneCurrently, a growing body of scientific evidence suggests that non-pharmacological strategies may have substantial effects in the treatment of both acute and chronic pain, though more large and well-designed studies are needed to reach a consensus regarding opioid-sparing analgesia in cancer surgery. Furthermore, among non-pharmacological strategies, other potential treatment modalities, such as relaxation, imagery/hypnosis, cognitive behavioral therapy/coping skills training, and meditation have not been studied extensively in the post-surgical setting and may also warrant future investigation .As a reflexive response to the opioid epidemic, there have been a number of “opioid-free anesthesia” protocols shared within the anesthesia community . In geneAs anesthesiologists and acute pain medicine specialists, it is critical to acknowledge the important role of opioids in perioperative pain management, especially in the context of treating visceral pain . While aThe deliberate restriction of opioids when they may be indicated, limiting them to the time when patients are in the operating room, may have unintended consequences. In a study of patients who underwent major non-cardiac surgery, patients assigned to an intraoperative opioid-free anesthesia protocol featuring dexmedetomidine experienced more postoperative side effects such as bradycardia, hypoxemia, and prolonged recovery than the opioid-exposed group . NumerouAn appropriate opioid stewardship plan must extend beyond the immediate intraoperative period , 67, 72.Over the past two decades, opioids have increasingly been prescribed for the treatment of various chronic pain conditions and during the perioperative period. Opioids have multiple side effects, especially in elderly patients. Recent studies have also shown that the use of opioids in patients undergoing surgery is responsible for worse outcomes, an increase in the length of hospital stay, and an increase in healthcare costs .OFA has gained in popularity as a way to enhance early recovery and to spare opioids for the postoperative period. While opioid-sparing strategies are recommended, little data exists on the feasibility of OFA in routine practice. However, promising results were obtained with OFA strategies, as described above. In the era of ERAS protocols, the use of multimodal analgesia with combinations of analgesic drugs and local regional anesthesia techniques is imperative , 78. AllChoosing the best anesthesia protocol for a patient undergoing surgery for cancer is not an easy task and the literature provides no definitive answers. However, in cancer patients, a pragmatic approach can be suggested considering the available options and the feasibility in the different settings. When possible, OFA strategies should be considered while ensuring that optimal pain management is achieved. Opioid administration may be needed but should be used in the lowest effective doses as part of multimodal analgesia. Considering the benefits and low risks, comprehensive patient education programs should be considered, as well as other non-pharmacological interventions when applicable. More well-designed studies are needed to reach a definitive conclusion on OFA in cancer surgery.


To determine if the Charlson comorbidity index (CCI) is an accurate predictor of unplanned readmissions for patients using outpatient parenteral antimicrobial therapy (OPAT) services.Retrospective analysis of patients >16 years of age who had received OPAT at Lancashire Teaching Hospitals between 2019 and 2021. The number of unplanned hospitalizations was measured and categorized as OPAT related or non-OPAT related. The CCI for each patient group was calculated using an online tool, and logistic regression was used to assess the association between risk factors and risk of being readmitted.The cohort consisted of 741 patients. Unplanned readmission was seen in 112 patients (15.1%). The mean CCI score for patients with OPAT-related readmissions was 4.22, 0.92 higher than the mean for patients who were not readmitted (3.30). The mean CCI score for patients with non-OPAT-related readmissions was higher still at 4.89. The logistic regression showed that increased CCI, age, male gender and home location compared with clinic were associated with increased odds of readmission, although these effects did not meet statistical significance.These results suggest that a higher CCI score is associated with a non-statistically significant increased risk of unplanned hospitalization. We concluded that the CCI may therefore be used in future decision-making regarding the acceptance of patients to OPAT and requires further investigation. Gilchrist et al.5 summarized findings from the UK National OPAT Registry. This revealed considerable variation between OPAT services in the proportions of episodes classed as infection failure and OPAT success. Overall, 90.8% of patients had OPAT outcomes classed as success/partial success. However, there was an increased risk of OPAT failure for patients with urinary/genitourinary tract infections and bronchiectasis. There is limited published literature on the predictors of readmission for OPAT patients. Two US studies have attempted to evaluate risk factors for unplanned hospitalizations.7 Schmidt et al.6 showed that the location of OPAT administration was associated with unplanned hospitalization. They also demonstrated that there was a significant difference between the Charlson comorbidity index (CCI) scores for patients who were readmitted and those who were not. However, Allison et al.7 found that CCI did not have a statistically significant effect on 30 day readmissions for OPAT.Outpatient parenteral antimicrobial therapy (OPAT)—providing IV antimicrobial therapy to patients in a clinic or home-based setting—is now a standard aspect of UK healthcare.8 Each comorbidity increases the score, and the higher the score, the lower the estimated chance of survival in the next 10 years.8The CCI was developed in 1987 as a weighted index to predict 10 year survival in patients with multiple comorbidities.This service improvement project was undertaken to determine if there was an association between CCI and risk of readmission for our UK teaching hospital OPAT patients, as increased readmission rates had been noted in our home OPAT cohort, who are generally older/frailer and with more comorbidities than the clinic OPAT patients. We also explored whether additional factors including indication for OPAT, antibiotic used, treatment duration and line complications were linked to increased risk of readmission. Using this information, we hope to be able to improve patient selection and risk assessment for OPAT.This study took place at Lancashire Teaching Hospitals NHS Foundation Trust (LTH), a large secondary care trust in the Northwest of England, which provides tertiary services including vascular surgery, neurosurgery and oncology. It offers both home and clinic-based OPAT. The clinic OPAT service was piloted in 2012 using an ambulatory model with patients attending a day unit on the hospital site for daily treatment and OPAT team review. The home OPAT service was established in 2017 and is run in conjunction with the local district nursing teams who visit to provide IV antibiotic administration, line care and blood sampling with oversight from the OPAT team/multidisciplinary team (MDT).All referrals to the OPAT service must be approved by a consultant microbiologist/infection specialist. Patients are then holistically reviewed by the OPAT team to determine suitability for the service and the most appropriate form of OPAT. The key factors that lead to a patient being treated via home OPAT include frailty, poor mobility and difficulty reaching the hospital site .9 OPAT-related readmissions were defined as those associated with the infection or antimicrobial therapy, such as treatment failure, drug reactions or line complications. Readmissions for unrelated reasons were classed as non-OPAT related.Retrospective analysis of data routinely collected for clinical care and outcome monitoring of patients receiving OPAT at LTH between 2019 and 2021 was undertaken. Demographic data, indication for antimicrobial therapy, antimicrobial agent(s) prescribed, duration of therapy (from initiation of OPAT to either completion of IV therapy or readmission) and OPAT location were recorded. Adverse events, reason for readmission, OPAT and patient outcomes were also recorded in accordance with the BSAC Good Practice Recommendations.10The CCI was calculated using MDCalc from conditions that the patient had been diagnosed with at the time of acceptance to the OPAT service.ANOVA was used to compare the difference between all three categories  for continuous variables such as mean CCI. A chi-squared test was used to compare binary/nominal variables such as antibiotic used and infusion location. The Kruskal–Wallis test was used for ordinal variables such as age and treatment duration. The significance level was set at 0.05, and each was performed as a two-tailed test.P values.We also developed a logistic regression model to estimate the strength and direction of the associations between a set of demographic and clinical variables and the odds of being readmitted. In particular, the model included OPAT location, gender, age, OPAT indication, antibiotic to be given, OPAT bed-days and PICC line complication as independent variables, with the statistical significance set at the 5% level for This study was determined to be a local service evaluation project and ethics approval was not required.Seven hundred and forty-one patients received OPAT during 2019–21 and none were excluded from analysis. Most patients were over 60 years of age  and had a treatment duration of 42 days or less . Median treatment duration for the whole cohort was 13 days (IQR 6–21), for home OPAT was 14 days (IQR 5–24) and for clinic OPAT was 10 days (IQR 7–19). The most common single indication for OPAT was intra-abdominal abscess . More patients received clinic OPAT than home OPAT . The most frequently prescribed antibiotic was ceftriaxone . The most common CCI score was 2–3 . Of the 112 readmissions, 63  were non-OPAT related, 49  were OPAT related. Readmission was more frequent in patients aged over 69 years. The lowest rates of readmission were seen in patients aged 17–39 years (Table P  ≤  0.001) (Table The CCI was lower on average for those who were not readmitted (3.28). Mean CCI score for patients with OPAT-related readmissions was higher at 4.22, and patients experiencing non-OPAT-related readmissions had the highest mean CCI at 4.89 . Those with endocarditis, empyema, discitis, native joint septic arthritis or prosthetic joint infections had the lowest rates of OPAT-related readmissions. For non-OPAT-related readmissions, patients with intra-abdominal abscess and bronchiectasis were most likely to be readmitted, whilst those with cellulitis and native joint septic arthritis were least likely to be affected.Receiving OPAT at home was significantly associated with a higher rate of readmission. There was a total of 58 readmissions from home OPAT (23.8% of home OPAT patients), whereas for clinic OPAT there were 54 readmissions (10.9% of clinic OPAT patients). Even though home OPAT patients comprised only 32.9% of the total cases, they contributed to 51.8% of the total readmissions, giving a risk ratio of 1.57. Further analysis of the relationship between home and clinic OPAT was performed and showed that the mean CCI was significantly different between the two groups: clinic OPAT 2.9, home OPAT 4.63, cohort mean 3.48. Comparison of age profiles demonstrated that home OPAT patients were generally more elderly, with 83.2% aged 60 years or older, compared with 48.9% of clinic OPAT patients. It was also found that a larger proportion of patients with intra-abdominal abscess received treatment in clinic .Ceftriaxone was the most frequently used antibiotic in readmitted patients (45/112) and for both OPAT- and non-OPAT-related reasons . However, when considering the chance of readmission by antimicrobial used, patients receiving ceftriaxone had the lowest risk . Patients receiving ertapenem and piperacillin/tazobactam had a higher chance of being readmitted for non-OPAT-related reasons. Patients administered teicoplanin and tigecycline had higher rates of OPAT-related readmission.Ceftriaxone was used more frequently for clinic OPAT patients, making up 61.4% of antibiotic usage for clinic OPAT, in comparison with 43.4% in home OPAT.The results from the logistic regression are presented in Table This study has demonstrated factors associated with an increased risk of unplanned readmission in our setting. It has provided insight into the use of the CCI when assessing the risks of referring a patient to OPAT. To our knowledge, this is the first UK study to investigate the relationship between CCI and readmission rates.Multivariate analysis showed that increased CCI, age, male gender and home location compared with clinic were associated with increased odds of readmission, although these effects did not meet statistical significance.et al.11 and Schmidt et al.6 Schmidt et al.6 found lower rates of readmission in patients treated at home compared with skilled nursing facilities, but this study was conducted in the USA, where healthcare models differ. This contrasts with the work of Allison et al.,7 who reported that CCI did not affect 30 day OPAT readmissions.The finding of an association between CCI and risk of readmission has previously been demonstrated by Luu Multivariate analysis showed that patients with cellulitis had statistically significant decreased chance of readmission compared with other infections, and this warrants further investigation.Calculating CCI is straightforward and could be used as part of the patient assessment and selection process for OPAT. CCI may help to guide and inform discussions involving the parent medical team, OPAT team and patient regarding the risks/benefits/suitability of alternative infection management options and to manage expectations regarding their relative outcomes. It may also open useful dialogue concerning optimization for comorbid conditions prior to commencement of OPAT. A prospective evaluation of CCI in the OPAT service is now underway.


Secondary endpoint data on fertility and pain development were collected during 12-month follow-ups. Methods: This RCT comprised 50 patients. Preoperatively and after 1, 6 and 12 months, pain scores for cycle-independent pelvic pain, dysmenorrhea, dyspareunia, dyschezia, and dysuria, as well as the number of pregnancies, were recorded,. Results: The pregnancy rate in the intervention group was significantly higher (p < 0.05). Pain development was also improved: after 12 months, all 5 subscores were lower in the intervention group and improvements were more pronounced, most prominently concerning cycle-independent pelvic pain and dysmenorrhea, the two subcategories with the highest preoperative scores and, therefore, the highest relevance for the patients. Cycle-independent pelvic pain even recurred in the control group, while barrier application prevented this. Conclusions: Considering the known causal link between adhesions and pain, it is apparent that the favourable outcomes in the intervention group are linked to effective adhesion prevention. The significant increase in pregnancies is remarkable.Background: Adhesions after endometriosis resection are frequent and the most common causes for chronic pain and secondary infertility. Primary results of our randomized controlled trial (RCT) on adhesion prevention after deep infiltrating endometriosis (DIE) resection using the gel barrier 4DryField Endometriosis affects about 10% of reproductive-age females ,3, and cTreatment options for endometriosis include medication and/or surgical resection, depending on the symptoms, lesions, desired outcome and patient’s choice . ExcisioWhen endometriosis is surgically resected, adhesion formation is a common complication. Even with a minimally invasive approach, more than 80% of patients develop adhesions after resection of deep infiltrating endometriosis (DIE) . Two mecAdhesion formation is also a leading cause for acquired female infertility . In addi® PH as a gel.This randomized controlled trial (RCT) is a follow-up of our study on adhesion prevention after endometriosis resection and adhesion prophylaxis with a barrier: we now compare the outcome pain and fertility to the control group, testing the hypothesis that pregnancy rate and pain development are improved by using the adhesion barrier 4DryFieldThis monocentric RCT was conducted at the University Hospital for Women, Tübingen, between July 2018 and November 2019, with follow-up continuing during the subsequent 12 months. The study was approved by the Ethics Committee of the Medical Faculty at our institution (no. 217/2018BO1). It is registered in the German Clinical Trial Register (DRKS) and the International Clinical Trials Registry Platform of the World Health Organization .® PH exists, the operating surgeon automatically knew the group assignment of each patient when carrying out the treatment, thus preventing full double blinding. Additionally, the application of the analysed agent (4DryField® PH vs. control) in the first surgery had to be repeated in the second intervention according to the study protocol to enable the evaluation of long-term outcomes after the second surgery. The rationale for this design is that possible adhesions formed after the second intervention would have interfered with the adhesion prevention effects after the first intervention and therefore misled the interpretation of follow-up results. Despite the general advantages of full double blinding, trials that are not fully double-blinded should not automatically be deemed inferior, and proper reporting of the blinding efforts should be considered crucial [A total of 50 women undergoing laparoscopic resection of endometriosis in a two-step approach were randomized into two groups. The trial was designed as a parallel study with an allocation ratio of 1. Randomization was performed using simple randomization utilizing a randomization list generated using the RAND function of Microsoft Excel. The randomization list was generated by the study nurse, who was the only person unblinded to randomization. She was present at all first surgeries, as randomization was performed during surgery. Participants were only enrolled by surgeons participating in the study, and the interventions were only carried by a small group of surgeons extensively trained in the procedures carried out in this study, who also complied with ISO 14155 . Patients were blinded to the group assignment as recommended by Probst et al. . As both crucial . In the  crucial . Such a ® PH at the end of both surgeries, while the control group received irrigation with saline solution for adhesion prevention. 4DryField® PH is a starch-based powder that forms a gel after irrigation with saline solution, separating surgical sites as a physical barrier for adhesion prevention. During the second intervention, the adhesion development was scored (primary endpoint). In the second intervention, the same treatment as in the first intervention was applied following the respective study arm to ensure integrity of follow-up data. All surgeries and follow-up visits were conducted at the Department for Women’s Health at the University Hospital for Women, Tübingen. Only patients with histological diagnosis of DIE or extensive peritoneal and/or ovarian endometriosis upon diagnostic first-look laparoscopy, with the indication for a definite subsequent therapeutic procedure according to our centre’s practice (second-look laparoscopy), were included. In these patients, endometriosis was excised locally for histological confirmation and a second surgery for definite treatment was planned. The study nurse only announced group assignments afterwards, and an anti-adhesive treatment at the excision sites was carried out according to the randomization. This two-stage concept for advanced endometriosis represents the practical routine in our centre and allows optimized interdisciplinary planning concerning the extent of the condition, as well as the patient’s leading symptoms . Pregnant and/or breastfeeding patients, patients with known intolerance to starch-containing substances, and patients who did not undergo resection of endometrial tissue for histological confirmation during the first laparoscopy, and therefore did not require any adhesion-prevention treatment, were excluded. The patients were blinded during the whole study, including the follow-up.The intervention group received 4DryField® PH treated group  and the incidence of adhesion formation based on the number of affected sites was significantly reduced, by 53% . No complications occurred in any of the patients during either hospital stay. Adhesions were assessed during both interventions using the same detailed adhesion score [Patient collectives and primary endpoint results of our trial are published elsewhere . In summon score . In bothDuring the first surgery, the extent of possible adhesion formation sites (predilection sites) resulting from the planned endometriosis resection and/or from intended adhesiolysis was rated on a scale from 0 to 4 , 2: moderate (between 1/4 and 2/4 of the area affected), 3: pronounced (between 2/4 and 3/4 of the area affected), 4: extensive (more than 3/4 of the area affected)) .During the second surgery, the same sixteen regions were assessed for postoperative adhesions and their extent was scored in accordance with the first surgery. Additionally, the severity was scored as either 0, 1, or 4 , 4: severe ). Corresponding to the AFS score, severity and extent were then multiplied to yield a site score. The sum of all site scores added up to the total score .There were three time points at which follow-up data was collected via telephone interviews: 1 month, 6 months and 12 months after the second surgery. In each interview, patients had to assess their pain levels with respect to cycle-independent pelvic pain, dysmenorrhea, dyspareunia, dyschezia and dysuria on a numeric rating scale (NRS) from 0 (no pain) to 10 (worst pain), with decimals also being possible. Additionally, they were asked if an adhesiolysis surgery had been recommended  and if any other complications occurred. During the interview after 12 months, they were also asked if they still had the wish to conceive (if that had been their pre-surgery status) and if they had become pregnant . In addition to the pain scores collected during follow-up, pain scores were also taken in hospital before both surgeries for all five subcategories, and for cycle-independent pelvic pain on a daily basis after the second surgery.In total, 45 of the 50 patients (90%) completed the whole 12-month follow-up, 22 (88%) in the control and 23 (92%) in the intervention group. For patients lost at different time points during follow-up, data available from previous time points were included in the analysis .p-value of 0.05, a statistical power of 0.8 and an allocation rate of 1, the calculation led to a required sample size of 50.Sample size determination was performed based on the primary endpoint (scoring of adhesion development) using G*Power 3.1 . Resultst-tests were employed, and if not, Mann-Whitney tests were employed . To compare data within a group, paired t-test and Wilcoxon matched-pairs signed rank tests were used, respectively. Categorical variables were evaluated using Fisher’s exact test and time-to-event variables using the Mantel-Cox test. The level of significance was always 0.05.The statistical evaluation was performed using Prism 9 for Windows (GraphPad Software Inc.). Continuous variables were tested for normality of distribution. If normally distributed, unpaired A total of 45 of the 50 patients completed the follow-up (90%). In the 4DryField group, two patients were lost during follow-up (92% completed) but were available for the interviews after one and six months. In the control group, three patients were lost (88% completed). One of these was not available for any of the telephone interviews, and the other two only for the interview after one month. All available data from these patients were included for the respective evaluations, leading to somewhat varying group sizes.p-value of 0.049. A comparison of the pregnancy rates between the two groups can be found in In the intervention group, 11 patients declared and retained their wish to conceive, and 7 of these became pregnant. This corresponds to a ratio of 64%. In the control group, 14 declared and retained their wish to have a child, and 3 of these became pregnant. This corresponds to a ratio of 21%. The difference is statistically significant, with a An overview of all mean pain scores is included in p-values for the comparison of the pain scores before the first and at twelve months after the second, within the group as well as between groups for the two time points.p-value > 0.9999.In the intervention group, 2 of 23 patients (8.7%) and in the control group, 3 of 23 patients (13.0%) reported having received a recommendation for adhesiolysis surgery. This difference is not statistically significant, with a None of the patients reported any complication due to study-related treatment .In the present study, adhesion prevention treatment led to a significantly higher pregnancy rate. The general trend was expected, as adhesions are the leading cause for acquired female infertility  and a diPain development was improved through the application of the adhesion barrier. After 12 months, all 5 subscores were lower in the treatment group, and the respective improvements were also higher. The effect was most prominent for cycle-independent pelvic pain and dysmenorrhea, which are the two subcategories in which the preoperative scores were highest. For cycle-independent pelvic pain, a recurrence of pain was observed in the control group, while barrier application prevented this effect . A direcAs the rate of patients with a recommended indication for adhesiolysis surgery was also lower in the treatment group, adhesion barrier application led to better results regarding all secondary endpoints. Although statistical significance could only be reached in terms of fertility and singular pain subscores, the general trend is unambiguous and in line with the results for the primary endpoint.It should be considered that initially the study was not powered to find significant differences concerning any of the secondary endpoints discussed here.The perseverance of patients was rather high, with 90% of patients completing the whole follow-up of 12 months with 3 telephone interviews. This allowed substantial data collection.The endpoint “indication for adhesiolysis surgery” has limited explanatory power, as neither the reason for the indication nor the performance and outcome of the intervention were ascertained. The physicians responsible for the subsequent care might have very different reasons for this recommendation, and data on the performance of an adhesiolysis surgery, as well as the adhesion burden observed, are not available.Although the follow-up time of 12 months was rather short, significant improvement was found in the intervention group with respect to both fertility and pain. Although no third-look surgery was performed to assess adhesion formation after the second intervention, considering the significantly lower adhesion scores in the intervention group during the second look as compared to the control group and the generally high reformation rates of postsurgical adhesions, it is conceivable that the higher fertility rate in the intervention group is also linked to reduced adhesion formation. In general, the formation of adhesions is considered the main cause of secondary female infertility ,32,33. AThe literature on anti-adhesive agents lacks data and comparisons on immediate clinical outcomes such as pain relief and improved fertility, which are of paramount importance for endometriosis management. Previously published randomized controlled trials on adhesion prevention after endometriosis resection and second look did not include a follow-up or endpoints other than adhesion scores ,29,39,40Crosignani et al.  investigHealey et al.  includedThe improvements achieved in our control group are nearly identical (dysmenorrhea and dysuria) or smaller. This might be due to only patients with DIE being included in the present study, whereas Healey et al.  also incIn a study by Abbot et al., a group of 19 women underwent laparoscopic excision of endometriosis and a re-intervention six months later, in which residual and/or recurred lesions were excised. Pain scores  gathered before and 6 and 12 months after the first surgery were: CIPP = 62 (baseline), 44 (6 months), 17 (12 months); dysmenorrhea = 78, 52, 29; dyschezia = 45; 30; 25; and dyspareunia: 65, 49, 22. This demonstrates a steady decline over time, while our data mostly show constant or even increasing values from 6 to 12 months. Abbot et al. report that at 6 months, 43% of patients had biopsy-proven endometriotic lesions, which were excised and which might be causative for the steady decline observed. This could mean that the increase we saw was (at least in part) due to endometriosis recurrence and progression, although we intended to completely excise all endometriotic tissue. However, it remains unclear if the higher pain scores in the control group were primarily due to adhesions or whether they were possibly due to endometriosis recurrences [® PH.Pain after endometriosis surgery is commonly linked to adhesion formation ,36,37,38Previous studies have shown direct correlations between different types of pelvic pain and adhesions ,44,45. IIn a study by Steege and Stout , patientConsidering that a correlation between adhesion formation and pain has been shown in many studies, it is conceivable that the more favourable pain development in the intervention group is linked to an effective prevention of the adhesion development in this group as compared to the control group. In our control group, pain scores increased during the later course of the follow-up period. This observation might be explained by the general presence of adhesions, combined with the fact that the severity of adhesions increases over time . AccordiThe negative influence of endometriosis and adhesions on fertility is much clearer than their impact on pain: chronic inflammation, tuboperitoneal distortion, hormonal changes on implantation, and decrease in ovarian reserve are relevant factors . The inf® PH significantly reduced adhesion formation. The follow-up results indicate that this adhesion reduction is clinically relevant in terms of fertility and pain. So far, only a few studies on adhesion barriers have presented follow-up results, and data related to patient-reported outcomes is mostly not included. This manuscript describes data on pain relief and pregnancy rates, which can be considered as the most relevant patient-reported outcomes after endometriosis surgery.The primary endpoint results showed that adhesion prevention with 4DryFieldTo date, only few guidelines address adhesion prevention at all ,63. This® PH gel led to an 85% reduction in adhesion scores. The clinical follow-up of this significant adhesion prevention demonstrated favourable results for the secondary endpoints of fertility and pain after endometriosis surgery. Subsequent studies with larger cohorts and a similar design are warranted to confirm our results, which could then lead to clearer recommendations regarding adhesion prophylaxis in this set of patients.Primarily, the application of 4DryField


Postoperative patients who were previously engaged in the live musical intervention Meaningful Music in Healthcare reported significantly reduced perception of pain than patients without the intervention. This encouraging finding indicates a potential for postsurgical musical interventions to have a place in standard care as therapeutic pain relief. However, live music is logistically complex in hospital settings, and previous studies have reported the more cost-effective recorded music to serve as a similar pain-reducing function in postsurgical patients. Moreover, little is known about the potential underlying physiological mechanisms that may be responsible for the reduced pain perceived by patients after the live music intervention.The primary objective is to see whether a live music intervention can significantly lower perceived postoperative pain compared to a recorded music intervention and do-nothing control. The secondary objective is to explore the neuroinflammatory underpinnings of postoperative pain and the potential role of a music intervention in mitigating neuroinflammation.This intervention study will compare subjective postsurgical pain ratings among 3 groups: live music intervention, recorded music intervention, and standard care control. The design will take the form of an on-off nonrandomized controlled trial. Adult patients undergoing elective surgery will be invited to participate. The intervention is a daily music session of up to 30 minutes for a maximum of 5 days. The live music intervention group is visited by professional musicians once a day for 15 minutes and will be asked to interact. The recorded music active control intervention group receives 15 minutes of preselected music over headphones. The do-nothing group receives typical postsurgical care that does not include music.At study completion, we will have an empirical indication of whether live music or recorded music has a significant impact on postoperative perceived pain. We hypothesize that the live music intervention will have more impact than recorded music but that both will reduce the perceived pain more than care-as-usual. We will moreover have the preliminary evidence of the physiological underpinnings responsible for reducing the perceived pain during a music intervention, from which hypotheses for future research may be derived.Live music can provide relief from pain experienced by patients recovering from surgery; however, it is not known to what degree live music improves the patients’ pain experience than the logistically simpler alternative of recorded music. Upon completion, this study will be able to statistically compare live versus recorded music. This study will moreover be able to provide insight into the neurophysiological mechanisms involved in reduced pain perception as a result of postoperative music listening.The Netherlands Central Commission on Human Research NL76900.042.21; https://www.toetsingonline.nl/to/ccmo_search.nsf/fABRpop?readform&unids=F2CA4A88E6040A45C1258791001AEA44PRR1-10.2196/40034 An on-oIn contrast, the NCT relies on the randomness of who is scheduled for surgery during a given intervention week but does not exclude any patient from the activity being conducted (listening to live or recorded music). Therefore, the treatment schedule  will be predetermined months in advance, and the patients included will be offered whichever treatment is occurring during their hospital stay. The patients will, however, be asked for their consent before they are informed which treatment will be offered during their surgery recovery. This will attempt to prevent patients who are initially biased for inclusion based on their affinity to music or not.After patients are recruited to the study, they will be allotted to the treatment occurring during the scheduled postoperative hospital stay. Noninvasive procedures include preoperative cognitive testing (6CIT), postoperative VAS pain ratings, HR, blood pressure, respiration rate, and EEG recording. Invasive procedures include obtaining blood samples, after which the serum will be analyzed in a laboratory for neuroinflammatory markers IL6, NGAL, CRP, and serum TPSO. An example schedule of procedures can be found in The main end point, VAS pain ratings, requires patients to subjectively rate their pain on a plastic VAS where they move a tick mark to the desired location on a 0-10 scale [The secondary end points, HR and blood pressure, will be collected from standard equipment on the ward at the time of obtaining VAS pain ratings.Respiration rate and tidal volume have been linked to subjective pain experience in the literature . TherefoOne 10-ml vial of blood will be collected per day resulting in a maximum of 5 vials of blood over 5 days. The first sample must be taken before the first assigned intervention. Blood samples will be collected together with standard care insofar as possible. Serum extracted from blood samples will be processed by the Haemoscan lab and evaluated for the presence of 4 markers associated with neuroinflammation .As opposed to typical electrode setup with, for example, a cap, the face electrode grids for EEG recording require minimal preparation of skin and are quickly applied. Each morning, the patient’s face will be cleaned and prepared with exfoliating gel, and electrodes will be applied with adhesive tape. The face electrode grid for EEG recordings will remain on the patient from morning until evening, spanning the first and last pain VAS ratings. Actual recordings will occur 4 times a day, in 15-minute increments, coinciding roughly with the times that pain VAS ratings are collected . During the 15-minute EEG recording windows, the patients will be instructed to remain seated or lying doing a consistent activity of their choice, or otherwise as instructed during the assigned treatment.After 30 days postsurgery, patient medical dossiers will be consulted, and any incidence of delirium and POCD will be recorded.A short, 6-item questionnaire ,28 will F test is described immediately below. Statistics will be conducted with SPSS (IBM Corp) or equivalent software [The primary outcomes of this study are VAS subject pain ratings. The software .P values for Kolmogorov-Smirnov tests will be evaluated for normality of distribution. A univariate, one-way repeated measures (RM) ANOVA will be conducted with factors group  by time points . The α significance threshold will be .05. The result of interest is the significance of the training×time point interaction, that is, whether the course of the data across time points was altered by the training type. Data are planned with 4 time points; in case of up to 2 missing time points, data will be interpolated [Pain ratings will be collected 4 times a day with a VAS. VAS mean and SD will be reported, and box plots, histograms as well as rpolated . Cases wF test described for the VAS ratings (as well as correlated with other baseline parameters as described in the “Other Parameters” section). For blood marker metrics that have 2 data collection points, a similar RM ANOVA will be conducted, but with 2 as opposed to 4 measures, and a significant interaction between treatment and time point would indicate whether treatment significantly impacted the amount of the neuroinflammatory blood marker. Categorical incidence metrics (delirium and POCD) will be evaluated with a one-way ANOVA to determine whether treatment impacted these neuroinflammatory-related complications. Delirium and signs of delirium will be perceived using the DOSS. The DOSS is a screening instrument for delirium, consisting of 13 items, and will be filled by a registered nurse during hospital admission until discharge. Nurses have frequent contact with the patients and are in a good position to observe behavior changes 24 hours a day when patients are admitted. The DOSS is already part of a routine in the surgical wards and all registered nurses are already trained. Likewise, scalar pain medication dosage will be averaged over 24-hour periods per patient and entered into a chi-square test to determine whether the dosage was significantly different across the 3 treatment groups. As this is exploratory and serves to inform future hypothesis-directed testing, we will not correct for multiple comparisons.For metrics that are collected on the same schedule as the VAS , the values per participant will be entered into the same Posthoc analyses will be conducted to inform recommendations for participant grouping in future studies. Continuous baseline parameters  will be treated as covariates in an ANOVA in order to see whether the addition of these elements improves the model for each outcome. Similarly, categorical baseline parameters  will be coded and entered as an additional factor (two-way RM ANOVA: treatment×baseline×time point) to see whether the additional factor can explain more variance than in the primary analysis model.The sample size was calculated using G*Power 3.1 , an indu2=0.051, converted to f=0.2318206) was determined from a retrospective RM ANOVA with published data [The effect size  for each participant.P=.07); therefore, no correction (1) was entered in the G*Power calculation.Nonsphericity correction: As mentioned earlier, retrospective analyses were conducted with the data published in . The ANOSample size: The sample size n=327,  outputteThe medical ethics committee of the UMCG approved the study in April 2022. This study began recruiting its participants in June 2022 and upon submission had recruited and collected data from 5 participants. Preliminary data analysis will commence once enough data have been collected to reach 0.8 power. Data collection is expected to be finished in 2026. The study results will be available within 1 year of completed data collection and shared in local, national, and international meetings within the medical, scientific, hospital administrative, and medical professional communities as well as the general public.Previous studies have shown that postoperative pain management can be supplemented with music intervention. Yet, little is known about the benefits of live versus recorded music, or what physiological mechanisms may be mitigating pain perception as a response to listening to music. This NCT will compare the MiMiC live music intervention with listening to recorded music and care-as-usual. The primary objective is to see whether pain VAS ratings differ across the 3 conditions, and the secondary objective is to see whether postoperative neuroinflammation is reduced as a response to listening to music.The strength of this study is the inclusion of preoperative assessments to establish some baseline characteristics of patients. First, the preoperative musical background questionnaire (selected items from ) assesseWhile postoperative pain is common to most patients undergoing surgical intervention in hospital, other characteristics surrounding the surgery  are widely varied across patients. Thus, a limitation of the study is that we will have a heterogeneous patient group. Considering that reduced pain VAS among patients experiencing MiMiC live music intervention compared to care-as-usual was previously a robust finding in a heterogeneous patient group , we do nUpon completing this study, we will contribute a systematic comparison of the effects of live versus recorded music on postoperative pain. This study can ultimately inform policy makers as to the benefits to patient pain outcomes when incorporating live versus recorded music in postoperative recovery settings.


Clonazepam significantly improved burning pain in BMS patients who had taste disturbances.Burning mouth syndrome (BMS) is frequently accompanied by dysgeusia and xerostomia. Clonazepam has been widely prescribed and is effective, but it is unclear whether clonazepam also affects the symptoms that accompany BMS, or whether such symptoms affect treatment outcomes. Here, we investigated the therapeutic outcomes in BMS patients with various symptoms or comorbidities. We retrospectively reviewed 41 patients diagnosed with BMS between June 2010 and June 2021 at a single institution. Patients were instructed to take clonazepam for 6 weeks. Before the first dose, burning pain intensity was measured using a visual analog scale (VAS); the unstimulated salivary flow rate (USFR), psychologic characteristics, site(s) of pain, and any taste disturbance were evaluated. Burning pain intensity was measured again after 6 weeks. Thirty-one of the 41 patents (75.7%) exhibited a depressed mood, whereas more than 67.8% of the patients exhibited anxiety. Subjective xerostomia was reported by ten patients (24.3%). The mean salivary flow rate was 0.69 mL/min and hyposalivation  was apparent in ten patients (24.3%). Dysgeusia was present in 20 patients (48.7%); a bitter taste  was reported by the largest proportion of patients. Patients who reported a bitter taste responded best in terms of burning pain reduction after 6 weeks . Overall, 32 patients (78%) reported decreased oral burning pain after clonazepam (mean VAS score changed from 6.56 to 5.34) use. Patients who reported taste disturbances exhibited a significantly greater decrease in burning pain, compared with other patients (mean VAS score changed from 6.41 to 4.58) ( The principal symptom is pain, often accompanied by oral dryness (xerostomia) and dysgeusia. Further, BMS is often associated with psychological issues (depression or anxiety)3, hormonal changes, local effects (lichen planus or candidiasis), and systemic dysfunctions. Although many authors have studied BMS pathogenesis, the etiology remains unclear but is probably multifactorial, involving complex interactions between local, systemic, and/or psychogenic factors. BMS has been divided into two types: spontaneous (or primary) BMS, and Secondary BMS may be caused by complex interactions between local factors  or systemic/psychogenic factors, but a clear definition of secondary BMS remains elusive6. Based on recent findings, primary BMS is now believed to be a form of neuropathic pain8. With respect to secondary BMS, there are findings for local or systemic factors11. Among them, many studies have focused on psychologic issues, hyposalivation, and disturbance of the taste sensory pathway as causes of BMS13. Depressive mood (in up to 35% of patients) or anxiety trait (in up to 50% of patients) have been reported frequently in BMS patients14. In addition, approximately 25% of BMS patients exhibit xerostomia, and two-thirds of patients report taste disturbances11. However, the exact cause has not been proven to date6. Thus, diagnosis and management remain challenging, and the responses to various treatments have been inconsistent and limited. In the meantime, several studies have been conducted on the treatment of BMS; representative examples include clonazepam therapy, which has demonstrated relatively consistent therapeutic effects18. However, compared to the frequent accompaniment of xerostomia and taste change or psychogenic factors in BMS patients, studies on the therapeutic effect of clonazepam in the presence of these medical conditions or comorbidities have not been well studied. Here, we investigated the effects of clonazepam on xerostomia, taste disturbances, dysgeusia, and psychogenic conditions.Burning mouth syndrome (BMS) is a complex disorder, usually present in older women (1.5–5.5% of older women), and is characterized by pain and a burning sensation in the mouth but no visible mucosal abnormality19. The exclusion criteria were: current usage of benzodiazepines; allergy to benzodiazepines; and any serious disease of the central nervous system. At the first visit, an oral examination, Beck Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI) questionnaire, and the comprehensive questionnaire were provided to the patients. Patients were then interviewed by one doctor and received an explanation regarding the possible etiology and management strategies for BMS. At the second visit, scheduled in the morning, the salivary flow rate was measured, the BDI and STAI was recollected, and the comprehensive questionnaire was checked by the staff to ensure the completion of any omitted sections. Then, patients were instructed to take 0.75 mg clonazepam  three times daily for the first 2 weeks (2.25 mg daily). If no severe drowsiness and/or dizziness developed, the dose was increased to 1.5 mg (one full tablet) three times daily for the remaining 4 weeks (4.5 mg daily). Patients were instructed to place clonazepam tablets sublingually, allow them to dissolve, and then swallow. Questionnaires were completed before treatment and after 6 weeks of treatment. All patients completed treatment without side effects.From June 2020 to June 2021, we retrospectively enrolled consecutive patients with BMS. This study included 41 patients who visited our otorhinolaryngology outpatient department for treatment of intraoral burning or dysesthesia and were then diagnosed with BMS. The inclusion criteria were established in accordance with the 2013 International Classification of Headache: intraoral burning or dysesthesia daily for > 2 h/day for > 3 months, without any clinically evident causative lesion. Pain has both of the following characteristics: (1) burning quality, (2) felt superficially in the oral mucosaThis study was carried out in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All study procedures were approved by the Institutional Review Board of the Inje university (IRB No. 2022-08-005-001). All the participants gave their informed written consent and all methods were performed in accordance with the relevant guidelines and regulations.The questionnaire used to evaluate subjective symptoms included questions about duration of suffering, area of symptoms, type of discomfort. Burning sensation was assessed using a visual analog scale (VAS) that ranged from 0 to 10, with 0 indicating no pain and 10 indicating the worst possible pain. Additionally, the following items were explored in the questionnaire. Before treatment items were pain location; time of day when pain was most severe; pain duration; factors affecting pain ; any change in taste (and the extent of such a change); dry mouth intensity; time since onset of burning; and whether dry mouth was worst before or after burning symptom onset. After treatment (6 weeks) items were burning sensation improvement (VAS score); region of improvement; and any change in taste.21. We measured unstimulated salivary flow rates (uSFRs) in patients at rest in a quiet room. Samples from the subjects were collected between 9:00 and 11:00 a.m., to minimize diurnal variability. All subjects abstained from smoking, eating, and drinking for 2 h prior to the measurement of salivary flow rate. The collection of unstimulated saliva started with the instruction to void the mouth of saliva by swallowing. Subsequently, saliva was allowed to ac cumulate in the floor of the mouth, without stimulation of saliva secretion by means of orofacial movements. After 5 min, participants were told to expectorate residual saliva into the container and unstimulated saliva flow rates were read. Then, patients were asked to collect saliva and spit it into a test tube for 5 min. The flow rate of whole saliva was expressed as mL/min. Hyposalivation was defined as a uSFR ≤ 0.1 mL/min22.Saliva was collected by a standardized method as described elsewhere23. The 21-item BDI measures the extent of depression . State-Trait Anxiety Inventory (STAI) actually classifies patients who have anxiety as a trait, i.e. personality characteristic while anxiety as a state reflects current anxious state of the person. STAI questionnaire is used to diagnose and measure state and trait anxiety and also to distinguish it from depressive syndromes24. The STAI includes two 20-item subscales: the State Anxiety Scale (S-Anxiety) evaluates state anxiety , whereas the Trait Anxiety Scale (T-Anxiety) evaluates longer-term “anxiety proneness”. A score of 20–37 indicates no or low anxiety, while scores of 38–44 and 45–80 indicate moderate anxiety and high anxiety, respectively.We used the Beck Depression Inventory (BDI) and State-Trait Anxiety Inventory (STAI). Beck Depression Inventory (BDI) is a self-reported instrument that measures attitudes and symptoms characteristic of depressionData were compared using the chi-square, Fisher’s exact, paired-t, or Wilcoxon-signed rank test, as appropriate. In comparing demographic and clinical data, the authors used Student’s t-test for continuous data and Chi-square tests or Fisher’s exact tests for discrete data. All calculations were performed using IBM SPSS Statistics for Windows ver. 25 . The level of statistical significance was set to P < 0.05.Forty-one patients (four men and 37 women) were included. Table The BDI showed that 19 patients (46.3%) had mild-to-moderate depression, six patients (14.6%) had moderate-to-severe depression, and six patients (14.6%) had severe depression. The STAI-S showed that 12 patients (29.2%) exhibited moderate state anxiety and 18 patients (43.9%) exhibited severe anxiety. The STAI-T showed that 12 patients (29.2%) exhibited moderate trait anxiety and 18 patients (43.9%) exhibited severe anxiety  reported that clonazepam was effective (mean VAS score changed from 6.56 to 5.34). The changes in pain severity in the tongue, palate, lip, buccal area, gingiva, mouth floor, and teeth are listed in Table Patients were divided into subgroups according to the BDI, STAI-T, and STAI-S scores Table . Nine paPatients were divided into subgroups according to the USFR Table . In the The effects of clonazepam on taste are listed in Table p = 0.02) , burning pain with taste disturbance n = 17), and burning pain with xerostomia (n = 10). Patients who reported concurrent burning pain, taste disturbance, and xerostomia (n = 5) were excluded. After treatment, all three subgroups responded, but only the second subgroup reported significant improvement in burning pain  and secondary 11. Primary BMS is idiopathic, in that the organic local/systemic causes cannot be identified; however, peripheral and central neuropathological pathways are potentially involved9. Secondary BMS may feature a local or systemic condition such as a mucosal disease ; a hormonal disturbance; a psychosocial stressor; a vitamin or nutritional deficiency; diabetes; dry mouth; a contact allergy; a parafunctional habit; a cranial nerve injury; or a side-effect of medication, but this remains unclear26. Primary BMS treatments seek to alleviate symptoms; secondary BMS requires diagnosis and treatment of the underlying condition11. There were substantial differences in burning symptom cessation with treatment; the patients who had secondary BMS improved if the underlying clinical abnormality was treated, whereas the primary BMS group rarely reported such positive results11. Meanwhile, the main accompanying medical conditions or comorbidities of BMS are xerostomia, dysgeusia, or psychological issues such as depression and anxiety3. Thus, clinicians have attempted to manage BMS along with xerostomia, taste disturbance, and psychogenic issues. In general, clonazepam has been recognized as the most effective standard treatment, regardless of the accompanying symptoms or type of BMS18; its therapeutic effect is mediated by the inhibition of pain signaling16. Clonazepam is known as an agent for the inhibitory neurotransmitter gamma-amino butyric acid (GABA), and GABA receptors are distributed in the oral pain and taste signaling pathways27. Therefore, clonazepam may have the effect of reducing burning pain in the oral cavity.Due to its complex nature, the definition of BMS has been changed over time. A recent international study using the Delphi method found that experts are of the view that the ICD-11 term, disease description, and diagnostic criteria for BMS should be revised and the condition termed burning mouth disorder (BMD)30. Rodriguez et al. gave detailed data and analysis of all 66 patients, including a gradual increase in number of pills used in the placebo group compared to that of the treatment group, and affirmed the benefit of the medication29. Some other studies investigated the systemic effect of clonazepam31. Heckmann et al. demonstrated ingested clonazepam showed a significant decrease in pain scores, but reanalysis of the data failed to show a significant change between the initial and final stages of the therapy18. On the other hand, Grushka’s study presented a consistent pain reduction in systemic clonazepam treatment31. To see topical as well as systemic effects, Amos et al. explored combined administration methods32. This study found that intraoral clonazepam was superior to oral ingestion; pain was much more rapidly alleviated but the duration of action was reduced32. As such, there have been several studies on the effect of clonazepam according to the route of administration, but there is no consensus as to which is the optimal method, with a large-scale study yet to take place. Under this circumstance, clonazepam tablets were placed sublingually to see both local and systemic effects in this study.Optimal administration route for clonazepam in BMS patients has been explored by many studies. A few studies on topical clonazepam demonstrated both significantly decreased pain scores and improvement of pain/burning symptoms in BMS patients33. Scala et al. reported that 46–67% of BMS patients claim to be experiencing xerostomia, regardless of whether the salivary flow rate is decreased; notably, dry mouth is often subjective, as opposed to any real decrease in salivary gland function26. However, the response to clonazepam treatment for BMS in those with xerostomia is not clear, as only a few studies have examined this. In one of them, Silva reported that the therapeutic response of topical urea treatment  was 60% in patients with xerostomia, which was similar to the results obtained with the control group34. In our present work, ten patients (24.3%) out of 41 reported subjective xerostomia, and all ten of these patients exhibited objective hyposalivation. Among the hyposalivation patients, seven out of ten (17%) responded to clonazepam in terms of a reduced BMS visual analogue score (VAS) score (mean VAS changed from 7.6 to 5.9); however, the response rate was lower than that (80%) of the normal group, which was not statistically significant. Previous studies have presented evidence suggesting that changes in the salivary flow rate may be associated with mucosal atrophy and/or subclinical inflammation, which may be accompanied by oral neuropathy in BMS patients36. Lauria et al. also demonstrated oral neuropathy by examining the tongue epithelium of BMS patients and found fewer small-diameter nerve fibers, which may explain the thermal hypoesthesia symptoms and change in the pain thresholds. Considering the above, it is thought that dry mouth is closely related to BMS onset. In addition, it can be hypothesized that the effect of clonazepam may be reduced as chronic neural degeneration occurs extensively as the duration of dry mouth is extended. Therefore, we think that this study can provide some insight into predicting the treatment effects of BMS patients with xerostomia.BMS is often accompanied by complaints of xerostomia, as reported by 25–40% of BMS patients in recent studies39. Depressive mood, anxiety, somatization, and aberrant personality traits have frequently been reported in BMS patients, and much of the research has been devoted to the role of psychological factors in BMS38, in which psychosocial disorders with a principal focus on anxiety and/or depression were examined. Several studies reported that up to 35% of BMS patients showed depressive mood and up to 50% of patients complained of anxiety38. On the other hand, some controversy remains as to whether psychogenic pathological conditions occur primarily or are secondary to BMS. In general, psychological disorders may be associated with the modulation of pain perception, increasing nerve transmission by peripheral pain receptors, and altering of an individual’s perception of pain. Based on this, with the belief that the treatment effect for each BMS patient may differ depending on the accompanying psychogenic problem, some studies have shown that psychological problems are associated with worse prognoses40. According to Ko's study, the reduction in burning pain caused by clonazepam was smaller in the psychologic disease group than the control group 26. Among our patients, depressive mood and anxiety trait were reported by 75.7% and 65.9%, respectively. Like other studies, our study found that the response rate with clonazepam therapy on burning pain was less in patients with psychologic problems than in those without . However, there was no significant improvement in the BMS VAS score, regardless of the Beck Depression Inventory or State Trait Anxiety Inventory (T/S) score. The small degree of pain reduction in patients with psychogenic problems may be explained by emotional and cognitive factors for chronic pain. Forssell et al. demonstrated that BMS patients with more intensive and interfering pain report more depressive and pain-related anxiety symptoms, compared to patients with less severe pain intensity41; he explained this using a biopsychosocial model of chronic pain, showing that emotional and cognitive factors play a role in pain experience. Forssell also claimed that BMS patients with more intensive pain reported more depressive- and pain-related anxiety symptoms, and more hypervigilance to pain, compared to patients with less severe pain intensity41. Excessive attention to pain or pain hypervigilance has been reported in association with a higher pain intensity, disability, and emotional distress in different pain patient populations42. Such patients usually exaggerate their pain, thus they are likely to express a poor response to clonazepam26. Also, patients with psychogenic symptoms are likely to take psychologic medications. According to Ko's study, 23% of BMS patients had been taking psychologic medications; these patients showed significantly reduced salivary flow rates because psychologic medications may decrease salivary gland function and may result in a reduction of saliva’s protective capacity in the mouth26. As described above, the treatment effect of clonazepam may be influenced by a change in salivary components and xerostomia induced by psychologic medication.From the aspect of psychogenic factors, several studies have suggested that psychological factors cause BMS13, and suggested that changes in the female sex hormone levels may predispose women to BMS. As both BMS and vulvodynia are far more common in postmenopausal than menstruating women, estrogen deficiency may be a shared etiological mechanism; estrogen receptors have been identified in the tongue, salivary gland, and vaginal mucosae43. Some reports stated that hormone replacement therapy in postmenopausal patients with oral discomfort was useful44; however, more research is needed.Especially, menopause has been suggested to be a major cause of BMS. Earlier reports found that BMS affected primarily postmenopausal women13. Repetitive nociceptive inputs against a background of peripheral neuropathy eventually elicit central sensitization and other changes. Grushka proposed that BMS reflects the persistent breakdown of an intrinsic equilibrium caused by a reduction in corda tympani function; subsequently, lingual nerve inhibition and central sensitization tend to occur1. Multiple studies have revealed damage to the innervation areas of the corda tympani and glossopharyngeal nerves in BMS patients; these areas control bitter taste. Such selective inhibition may reflect the loss of central pain inhibition45. Among our patients with taste disturbances, most of them showed changes in bitter taste; these patients responded best to treatment, supporting the selective inhibition hypothesis described above. Although the role of taste in terms of oral burning syndrome is complex, clonazepam is an agonist of the inhibitory neurotransmitter GABA, which is active in the oral mucosa, mandible, palate, and salivary gland. Above all, it can be noted that it also acts on the taste pathway12. If burning causes taste disturbances that result in the loss of normal inhibition of a central structure that mediates oral pain, GABA-specific agents may relieve such pain. We found that the pain VAS scores improved significantly after treatment in patients with taste disturbances. Based on the contents described above, we assume that when taste change accompanies the treatment response, there is a better effect on pain improvement.A loss of taste inhibition by central structures that mediate oral pain has been proposed to explain BMS development29. However, studies on the therapeutic effect of clonazepam in the presence of these concomitant symptoms or comorbidities have been insufficient. Thus, we assessed the therapeutic effects according to psychological, dysgeusia, and hyposalivation status. We found no correlation of psychological or hyposalivation status with the therapeutic effect of clonazepam; however, taste disturbance was associated with a higher response rate and greater improvement in relieving the burning pain. Our work had several limitations. First, it was questionnaire-based and retrospective. Second, the sample size was small. Third, it was a single-center study. Finally, we could not confirm that clonazepam had been appropriately taken; nevertheless, we found that clonazepam significantly improved the burning sensations of BMS patients with taste disturbances. Such information can be employed during patient counseling and to predict therapeutic outcomes.There have been many studies reporting the prevalence of psychogenic conditions, and taste disturbance in patients with BMSA large proportion of BMS patients also experience xerostomia, psychogenic symptoms, and taste change. Clonazepam significantly reduced burning pain in BMS patients with taste disturbances, but no significant reduction in burning pain was found in BMS patients with xerostomia or psychogenic traits only. Such information can be used in BMS patient counseling and the prediction of therapeutic outcomes with clonazepam treatment.


The evaluation of chronic pain is challenging because of the lack of specific biomarkers. We identified the Mu opioid receptor-positive (Mu+) B cell percentage of expression, named Mu-Lympho-Marker (MLM), as a candidate marker for chronic pain in fibromyalgia (FM) and osteoarthritis (OA) patients. Here, we investigate the role of MLM on natural killer (NK) cells in the same patients. Twenty-nine FM and twelve OA patients were analyzed, and twenty-three pain-free subjects were considered as the control group. Blood samples were collected to perform immunophenotyping and Western blot analysis. Biological and clinical data were statistically analyzed. The final results showed that the percentage of NK cells expressing Mu was statistically lower in FM and OA patients than in pain-free subjects, as already demonstrated for B cells. A Western blot analysis was performed in order to detect NK cells’ functional status. Moreover, the correlation analysis of MLM expression with pharmacological therapy did not show any significant results. In conclusion, here, we confirm the role of MLM as a suitable marker for chronic pain and underline NK cells as a new possible immune cell type involved in the “Mu opioid receptor reserve theory”. Chronic pain represents a significant social, clinical, and economic problem in communities worldwide. In recent years, there has been an enormous interest in improving the diagnostic processes for pain, in order to meliorate the therapeutic approach . HoweverMore than in other scientific scenarios, much attention is paid on biomarker identification in the pain field. The need of an objective and unequivocal tool for pain diagnosis or prognosis is pivotal. In definition, a biomarker is an indicator of a biological or pathological process or even a symbol of a pharmacological response . It is uAs other immune cells, natural killer (NK) cells express opioid receptors on their surfaces. It is well known that NK cells play a central role in innate immunity, as they mediate early defenses through innate cytotoxicity against microbial-infected cells and malignant-transformed cells ,10,11,12The indirect pathway consists of antibody-dependent cytotoxicity involving the CD16 receptor. Moreover, the NK killing mechanism of target cells can occur by both the exocytosis of granules, containing cytotoxic enzymes, or by receptor-mediated apoptosis .In the context of pain research, several studies focused their attention on Mu opioid receptors expressed on NK cell surfaces ,15. In tThis is an observational, cross-sectional single-blinded diagnostic trial. The protocol has been designed by the ISAL Foundation, the IRC-FSH, Department of Health Science of University of Catanzaro, the Rheumatology Unit of Sapienza—University of Rome, and IRCCS San Raffaele Roma (Rome). The current study is approved by the institutional independent ethics committee of Sapienza University of Rome, with the name of “I markers Bio-Psico-Sociali nella sindrome fibromialgica” , on 8 March 2018 (Ref. 4937), and the trial is registered in the ISRCTN registry, ID: ISRCTN24645566, 10 December 2018.All the patients enrolled were female. Twenty-nine 29) FM patients, twelve 12) OA patients, and twenty-three (23) pain-free healthy people (Ctrl (-)) were analyzed. FM patients, following both the 1990 and 2010 ACR criteria [2 OA pati9 FM patiClinicians of Rheumatology Unit, Sapienza University of Rome, assessed the clinical characteristics. The day of enrolment, clinical data were collected in a specific CFR following the numerical code for single patients. The pain score was reported using the Numerical Rating Scale (NRS), where zero represents “no pain” and ten “the worst possible pain”.Fifteen milliliters of peripheral blood were collected during the clinical examination in order to be analyzed within the next 24 h. Research biologists, receiving samples with the numerical code, were blind to the patients’ personal information and therapy.Peripheral blood samples were stained with the following antibodies: APC-conjugated anti-Mu , BUV395-conjugated anti-CD45 , PE-Cy7-conjugated anti-CD16 (BD), BB515-conjugated anti-CD-56 (BD), and BV480-conjugated anti-CD3 (BD) for 20 min at 4 °C. Stained samples were incubated at room temperature for 15 min with BD FACS Lysing Solution (BD) and then centrifuged for 5 min at 1500 RPM. After washing, samples were suspended in PBS and then acquired on a LSR Fortessa X20 flow cytometer (BD). Analyses were performed using Diva software in order to detect the percentage of Mu+ NK cells in FM and OA patients and the pain-free control group.Peripheral blood mononuclear cells (PBMCs) were isolated using a Ficoll  density centrifugation gradient. Fifteen milliliters of whole blood sample were diluted with PBS (1:1 dilution) and carefully layered over a Ficoll medium. Layered whole blood was centrifuged at 2200 RPM for 20 min at 20 °C at the acceleration max without a break. The resulting PBMCs were washed with PBS and centrifuged at 1800 RPM for 5 min at the acceleration and deceleration max; then, the pellet was collected, suspended with PBS, and centrifuged at 800 PRM for 10 min . The obtained PBMCs were used for protein extraction and the Western blot analysis.w/v ratio. Solubilized extracts were centrifuged at 14,000 rpm for 20 min at 4 °C. The resulting supernatants were used for immunoprecipitation and the Western blot analysis to evaluate NK cell activity.PBMCs were homogenized with lysis buffer  in a 1:3 For immunoprecipitation, 50 μL of protein A–sepharose 4B  resin was washed four times in PBS. In each wash, the resin was mixed with fresh PBS and collected after centrifugation at 14,000 rpm at 4 °C for 1 min. The cleaned resin was suspended in lysis buffer, coated with anti-phosphotyrosine antibodies , and mixed overnight at 4 °C. The beads were washed four times in PBS and added to each 300 μg of homogenate cell supernatant, then incubated overnight at 4 °C. After sample centrifugation at 14,000 rpm for 20 min at 4 °C, each pellet was collected. The protein concentration was determined using the Pierce BCA protein assay . Immunoprecipitated proteins were resolved in 10% SDS-PAGE mini-gels and transferred to nitrocellulose membranes. Membranes were blocked for 1 h at room temperature in 1% BSA/0.1% thimerosal in 50 mM Tris-HCl (pH 7.4)/150 mM NaCl/0.01% Tween-20 (TBS/T). After blocking, membranes were incubated overnight at 4 °C with anti-KIR  Italy) and anti-actin  antibodies. Membranes were then washed with TBST and incubated with secondary monoclonal antibodies  conjugated to horseradish peroxidase for one hour at room temperature. After washes, the proteins were visualized by enhanced chemiluminescence . No differences were observed between actin lanes. The quantification of the protein bands of interest was determined by densitometry using Molecular Dynamics ImageQuant 5.2 software .p) in the two-group comparison. A p threshold of 0.05 was considered for statistical significance.We used one-way ANOVA both for group comparisons and for intra-group homogeneity assessments. All data were expressed as the mean ± S.E.M. Tukey’s least significant difference multiple comparisons was used for the post hoc analysis following one-way ANOVA to compute the probability values , linear regression was used. The nonparametric analysis, corrected for multiple comparisons using Dunn’s test, was performed for the comparisons between therapy before enrollment and Mu+ NK cell percentage. For all the analyses, Patients’ clinical data were collected in a specific Case Report Form (CRF) based on the exclusion and inclusion criteria see . The CRFn = 29), 19% were OA patients (n = 12), and 36% (n = 23) were pain-free people (Ctrl (-)) ) .All the patients were following a pharmacological therapy, stable for three months before enrollment: 8% antidepressants, 11% myorelaxants, 8% paracetamol, 4% benzodiazepines, 12% NSAIDs, 12% nutritional supplements and 45% previous drug combinations . None usAll of the FM and OA patients ranked between moderate and severe NRS scores .p < 0.0001) and between Ctrl (-) and OA (p < 0.0001)  mean: 30.18 ± 2.8), and we registered differences in the percentage of expression of Mu+ NK cells between Ctrl (-) and FM ( 0.0001) .NK cells are directly involved in immune diseases, participating in immune responses with innate cytotoxicity, cytokines production, and crosstalk activity with dendritic cells and lymphocytes. The study of HLA class I has been crucial to understanding NK cell functions ,10,11. HOur preliminary data show a significant reduction in expression of the KIR phosphorylation domains in OA and FM patients compared to the Ctrl (-). Probably, these events could lead to a different functionality/activation of KIR, which would compromise NK cell functions .p value = 0.05). At a higher level of Mu+ NK cell percentage is a correspondingly lower level of NRS.Following our previous published data  showing Considering pain as the main disabling symptom for FM and OA patients, all the participants at the trial followed a pharmacological pain therapy before their enrollment.OA patients, who usually suffer inflammatory pain, took paracetamol as the first medication. On the other hand, FM patients usually need a combination of different drugs, considering pain and psychiatric comorbidities. Here, we analyzed the following pharmacological subgroups in order to detect the percentage of expression of Mu+ NK cells in comparison with a specific therapy: antidepressants, myorelaxants, paracetamol, benzodiazepines, NSAIDs, nutritional supplement/none, and previous drug combinations. We found that, despite the different pharmacological medications, the percentage of Mu receptor on the NK cell surfaces was almost identical across the subgroups (mean 6) .We correlated Mu+ NK cell percentages with the ages of all the participants. We did not find any statistically significant correlations .The lack of specific diagnostic tools in chronic pain influences the choice of the right therapy for a single patient. Thus, in the last decades, scientists have focused their attention on the identification of pain biomarkers in order to obviate a possible misdiagnosis, delayed clinical results and useless therapies ,26. ConsRecently, we hypothesized Mu+ B cell percentages of expression as candidate markers (MLM) of the pain intensity in OA and FM patients. Our previous data have already demonstrated the modulation of Mu+ B cells in these groups of people. In particular, Mu+ B cell percentages in pain-free subjects were significantly higher than the same percentage of expression in OA and FM patients. Moreover, Mu+ B cell percentages were related to the intensity of the pain. Patients with moderate/severe NRS pain scores showed lower Mu+ B cell percentages of expression than mild pain patients and pain-free people. We explained this result as a deficit of Mu opioid receptor reserve in pain patients. A low expression of MLM seems to correspond to a low threshold of pain perception and to a modified endogenous opioid analgesic activity. In the same study, we did not identify any association between the percentage of expression of Mu+ B cells and depression, anxiety, stress symptoms, pain acceptance, and illness representation .The role of NK cells in the pain pathway has been analyzed in clinical studies , but theThese results lead us to deep down the relation between NK and B cells in chronic pain patients. In the last decades, the interplay between NK and B cells has been demonstrated . InteresIn 2009, Jennings and co-workers  presenteFurther studies are needed to understand the interplay between NK and B cells in chronic pain patients. Moreover, it could be interesting to extend the study of the Mu-Lympho-Marker to a larger cellular contest in order to analyze whether different cellular types could be involved in Mu opioid receptor modulation in chronic pain conditions. Further studies should also be directed to understand whether the modulation of B and NK cells presenting Mu could also be a common mechanism for other, different chronic pain conditions.At the end, the utilization of a specific diagnostic biomarker could lead to an accurate recognition of the pain intensity, facilitating the prescription of the most suitable drug for the best patient management ,31. FM pThe complexity of pain pathophysiology strongly requires new therapeutic approaches in order to improve patients’ and caregivers’ quality of life. Pain biomarker availability could open the way for personalized therapies and more effective and safer rehabilitation programs ,31. MoreIn conclusion, the discovery of unique and objective diagnostic biomarkers seems to remain the most intriguing challenge in chronic pain medicine.