Physical therapy (PT) methods applied in dentistry are increasingly discussed nowadays. Taking into account a rapidly growing number of temporomandibular disorders (TMDs) and orofacial pain patients, it is reasonable to determine which of the available physiotherapeutic (PT) methods are more effective than others, especially in terms of their possible analgesic and myorelaxant effects.To assess manual and physical factors influencing pain reduction or elimination and increased muscle tension in patients with TMD; yet the influence of the applied forms of PT on the range of motion (ROM) of temporomandibular joints (TMJ).A randomized, parallel-group, RCT, single-blind, equi-randomized (1:1) study was conducted in DC/TMD Group Ib patients (20–45 years of age). An experimental group  and a control group without TMD  were created according to CONSORT guidelines. Diagnostic measurements were performed in both groups . Group G1 was randomly divided (envelope method) into 4 therapeutic groups, in which therapy was carried out for 10 days: magnetostimulation (MS), magnetoledotherapy (MLE), magnetolaserotherapy (MLA), manual therapy (MT). Each time after the therapy, ROM and NRS measurements were performed, and after the 5th and 10th day sEMG.Statistically significant differences were found in the sEMG values of the masseter muscles, TMJ ROM and the pain intensity in G1 and G2 (p < 0.00). The largest decrease in sEMG (% MVC) of the masseter muscle occurred in the subgroup in which the manual therapy (MT) procedures were applied, p < 0.000. There was no clinically significant difference in and between other subgroups. There was a distinct mandible ROM increase noted in the MT group, with minimal changes in the MLA and MLE groups and no changes in the MS group. There was a clear increase in the lateral mobility of both right and left TMJ in the MT group. There were no differences in the course of the study in the MS group, and slight increases in the MLA and MLE groups. In the case of pain measurements, the greatest decrease in pain intensity was observed in the MT subgroup.According to our results manual therapy is an effective form of treatment in patients with pain, increased masticatory muscle tension and limitation in mandible ROM. Dental physiotherapy should become an integral part of multimodal TMD patients’ treatment. Each component of the masticatory system is characterized by a specific structural tolerance, the exceeding of which may lead to tissue damage. Potentially aggravated zones include: masticatory muscles, temporomandibular joints (TMJ), periodontal ligaments and teeth hard tissue , 2. If tTherapy of temporomandibular disorders (TMD) involves a complex healing process mainly due to the multifactorial etiology of the disease. The etiological factors include genetic conditions, factors located inside the oral cavity and environmental determinants, with particular emphasis on psychoemotional factors that were proven to have a decisive influence on the elevated muscle activity in the masticatory organ –7.The key in the treatment of TMDis to provide the patient with specialist dental care in order to restore intra-oral homeostasis, counselling in order to diagnose and treat psycho-emotional disorders and physiotherapeutic care, orofacial pain treatment focused on pain elimination, as well as the improvement or restoration of the regular movement pattern within TMJ and adjacent tissues .Due to the type of the therapeutic method used for TMD, procedures applied in the process can be divided into: dental  , 10 locaIn medical literature, the role of physiotherapy for the recovery of patients with TMD is emphasized . Modern According to the current definition provided by IFOMPT , MT should be understood as: ‘a specialized area of physiotherapy, devoted to the management of neuromuscular-skeletal diseases, based on clinical conclusions and the use of highly specialized methods of treatment, including manual techniques and therapeutic exercises’ . MT has Articular techniques dominated in MT until recently. Currently, it is believed that this way of management is only acceptable in the acute phase, therefore not used for chronic pain . Taking Modern physical therapy makes it possible to apply two physical factors simultaneously . Hence, The effectiveness of TMD treatment largely depends on the proper problem assessment and initial diagnosis. Orofacial pain specialist integrates patients’ medical history, physical examination and imaging prior to treatment plan implementation.In order to standardize the diagnostic criteria for TMD, a standardized tool, the Diagnostic Criteria for Temporomandibular Joint Disorders (DC-TMD), was established in 2014. Based on the patient’s signs and symptoms, DC/TMD defines two axes: (i) Axis I, dividing TMD into muscular (Group I) and atherogenic TMD (Groups II and III); Axis II, assessing behavioral and psychological status .Skeletal muscle palpation in standard diagnostic methods allows only for subjective, operator-biased assessment of elevated muscle tension and tenderness to palpation. Currently, thanks to the development of medical physics and biomedical engineering, it is possible to use additional functional diagnostic methods into our advantage, which is considered by many a valuable addition to clinical judgment process and proper patient management. One of the quantitative tools that significantly complement the examination of the masticatory muscle function is surface electromyography - sEMG , less inThe sEMG assessment of masticatory muscle function in people with TMD forms the basis for diagnosing the disease, monitoring its progression and measuring the effectiveness of treatment. Numerous studies have shown that, in patients with TMD, changes in masticatory muscle EMG activity are either due to the disease itself or to a compensatory mechanism related to symptoms –30. It hIn most up-to-date literature, there are just a few randomized controlled trials (RCTs) comparing the effectiveness of treatment with MT and physical therapy in TMD pain. This prompted the authors to investigate the topic of the analgesic application of manual therapy, magnetostimulation and synergism of physical factors in patients with TMD. Due to the wide variety of symptoms experienced by patients with TMJ disorders, the studies focused on three commonly reported conditions. These include: chronic pain in the masseter muscles (over 3 months), limited mobility of the mandible and a feeling of increased tension in the masseter muscle.We hypothesized that physical and manual therapeutic factors alter the bioelectrical activity of the masseter muscle, which could contribute to the improvement of TMJ mobility. Reducing muscle tension reduces the intensity of the perceived pain.The aim of the study is to test the effectiveness of the manual factors used.and physical exercises in the elimination of pain and increased muscle tension in patients.with TMD. Additionally, the assessment of the influence of the applied forms of therapy on the TMJ range of motion (ROM).This parallel randomized clinical trial (RCT), four-arm with equal allocation ratio 1:1), controlled study followed the Standards of Study Reporting (CONSORT) . The stu:1, contrwww.ClinicalTrials.gov database (NCT05021874).The research project was approved by the Bioethics Committee of the Pomeranian Medical University in Szczecin (no. KB – 0012/102/13). Trial was registered (date 19/08/2021) at The study included 104 women aged 20 to 45 years who, based on DC/TMD criteria, were diagnosed with myofascial pain with mouth opening restriction, for longer than 3 months (Ib). Patients were randomly assigned (simple randomization) to the experimental four therapeutic group i.e.: magnetostimulation , magnetoledotherapy , magnetolaserotherapy , manual therapy . None of the respondents refused to participate in the study.Study exclusion criteria were as follows: inflammation in the oral cavity that emerged as myospasm or preventive muscle contraction, earlier splint therapy, pharmacotherapy , systemic diseases , mental illness, lack of mandible orthopedic stability, masticatory organ or whiplash injury, pregnancy, patients undergoing orthodontic treatment, other types of inflammation in the oral cavity , and fibromyalgia;dermatology disease, contraindications to the use of physical treatments in the field of magneto-stimulation, light therapy or manual therapy.All women underwent an intra-oral and extra-oral dental examination performed by an Orofacial Pain trained dentist. The aim was to exclude odontogenic, periodontal and intracapsular origins of TMD pain.The control group (G2) consisted of 104 healthy women, aged 20 to 45, without claimed TMD and pain disorders .The determination of whether the patient met the inclusion criteria on the basis of the subject and physical examination was made by a dentist. Afterwards, another dentist participated to randomize the patients.The patients qualified for the study underwent instrumental diagnostics  and the level of pain intensity was assessed on the NRS numerical scale. Then, in G1, ROM and NRS measurements were performed each time after treatment, and sEMG after 5 and 10 days of treatment.The study was conducted from January 2022 to February 2023 on patients of the University Dental Clinic of the Pomeranian Medical University in Szczecin.The activities undertaken by the investigators during the trial are presented in Table In group G1, masseter muscles physiotherapy was performed for 10 days (excluding Saturdays and Sundays). The division into groups was as follows:MS (magnetostimulation).A pulsating, heterogeneous magnetic field generated by the apparatus using an elliptical applicator with a beam width of approx. 5 cm. In this subgroup, a therapeutic program was prescribed of increasing intensity from “3” to “7”, increasing by one level, every other day. The elliptical applicator remained stationary in the same place during the treatment .b) MLE (magnetoledotherapy).Synergic action of a slow-changing magnetic field and LEDs with a wavelength of 860 nm. An elliptical magnetic - light (IR) applicator with a diameter of 5 cm containing 47 infrared diodes was used. The method of applying the applicator, the type of program, its application and the duration of the procedure were the same as in the MS subgroup .c) MLA (magnetolaserotherapy).2 to 5.0 J/cm2 . The total dose of laser radiation administered to each patient was 40 J/cm2  = RLX [µV]/ MVC [µV] x 100% .Sample size was determined for Anova repated measurements model with within-between interaction at effect size 0.25, alpfa equal to 0.05 and power equal 0.80 total size requred was equal to 24 .Patients were randomly assigned (simple randomization) to the study group using the closed envelope method. In order to conceal the allocation (1:1), consecutively numbered, opaque, sealed envelopes were used, and care was taken to ensure that they were undamaged and not see-through when held against a light source. Randomisation was carried out by an investigator who was not involved in patient eligibility, intervention delivery or data collection.Outcome assessors were blind to group allocation, and were not involved in providing the interventions (single-blind). The statisticians conducting the statistical analyses were blind to group allocation until after the analyses were completed. It was not necessary to unblind any of the participants at any time during the study.The data were presented as a median with a quartile range due to significant deviations from the normal distribution assessed using the graphical method with the analysis of the histogram and the Q-Q plot. Due to significant deviations from the normal distribution, the dependence of the studied variables on time and between groups was performed based on the nparLD test, which is a non-parametric equivalent of the analysis of variance for repeated measurements. The Kruskall Wallis test with the post-Hoc multiple comparison test was used to compare the baseline values of the parameters studied for the control group. Comparisons between the control group and the total study group were made using the U-Mann Whitney test. The values of p < 0.05 were considered significant. The analysis was performed in the R language in the RStudio software using the NparLD, ggplot2, ggpubr libraries .The flow of patients through the study, according to CONSORT criteria, is reported below Fig. . One hunFigure Participants meeting the inclusion criteria were recruited between August 2021 and January 2022. Patients attended clinic visits at the time of randomization (baseline) and at 5-day and 10-day intervals from the baseline day.The results of the preliminary study in the test and control groups are presented in Table As shown in Table The primary analysis was intention-to-treat and included all patients who were randomly assigned. Patients in groups G1(n = 104) and G2 (n = 104) were analyzed according to the protocol.Fig. Significantly higher results were observed in all sEMG measurements in each therapeutic subgroup compared to the control group G2). The range of mandibular abduction and lateral mandibular movements in the control group were significantly higher than in the study groups. Similarly, in the case of the pain intensity scale, where in the control group all respondents scored ‘0’ on the NRS scale, while among the respondents from the study group, the pain intensity values were significantly higher in each subgroup  before the start of physiotherapy. On the other hand, all assessed ranges of mandibular mobility  were significantly smaller in the study group (p < 0.00). When characterizing pain intensity in the study group, its mean value was 6 NRS (moderate pain). As shown by other authors, increased muscle tension affects the range of mobility of the temporomandibular joints and contributes to the occurrence of pain [According to the studies conducted by the authors, MT turned out to be the most effective therapeutic method in terms of analgesic and myorelaxation. In patients who underwent physical therapy procedures, no clinically significant difference in the assessed parameters was found. This data may indicate the superiority of manual methods over physical methods in patients with TMD disorders. Hence, in the opinion of the authors, physical methods should only complement the therapy in manual work with TMD patients. Particularly noteworthy is the fact that after the 6th MT treatment the patients had complete pain relief (0 NRS) or the pain remained at the level of 1 on the NRS scale. For comparison, in patients who underwent physical procedures, the intensity of pain on the 6th day of therapy was: MS (NRS 7), MLA (NRS 6), and MLE (NRS 5), respectively. According to studies by Urbański et al., the use of MT treatments  in patients with TMD contributes to a decrease in the bioelectric activity of the masticatory muscles and a decrease in the intensity of pain in the VAS scale . ManzottAnalyzing the above data and our own results, it can be stated with great caution that treatments in the field of physical therapy reduce the intensity of the perceived pain, and thus improve the range of mandibular mobility, but their effect does not affect the bioelectrical activity of the muscle. On the other hand, the effect of MT, due to its deeper impact on soft tissues, in addition to improving the TMJ function and analgesic effect, leads to changes in the sEMG parameters.The lack of systematic knowledge about the effectiveness of MT in people with TMD prompted Calixtre et al.  to conduA very valuable meta-analysis was performed by Zangh et al. in which they compared the impact of therapeutic exercises and bite-bar therapy on pain and mobility in people with painful TMJ disorders. The conducted analysis did not show high-quality evidence to distinguish clinical efficacy between occlusal splint therapy and exercise therapy in patients with painful TMD and limited mandibular mobility. Hence, it seems necessary to implement more randomized, controlled trials comparing the effects of TMJ exercise and treatment of occlusal splints .When analyzing the TMJ mobility parameter in the conducted studies, also in this case the most effective form of therapy turned out to be the MT. The statistical analysis shows that 10 MT treatments lead to a significant improvement in TMD function, which is confirmed by the obtained parameters of MMO  and lateral movements of the mandible . In patients undergoing physical procedures after 10 days of treatment, no clinically significant therapeutic effects were observed, i.e. MS  MLE  MLA . Similar results were obtained by Tuncer et al., who showed that a more effective therapeutic effect in the treatment of TMJ dysfunction is achieved through MT, combined with home physical therapy than through monotherapy  .From the clinical point of view, the research conducted by the authors shows the legitimacy of implementing manual therapy treatments into everyday physiotherapeutic practice in patients with TMD. As can be seen from the analysis of the change in the values of the parameters studied during the study, obtained by subtracting the result after the 10th treatment from the result before the first procedure, from a clinical point of view, there was a significant saucer of pain intensity (-6NRS) and bioelectrical function of the masseter muscle (%MVC P=-6.4/L=-9.76) and an increase in the extent of mandibular visitation (7 mm) in the TM group. No clinically significant differences in the parameters studied were observed in any group where physical treatments were applied.Comparing the duration of therapy in our study with those of other authors, we can observe that there are large differences in the literature on this variable. In addition, there is often no information as to whether the therapy was conducted at the weekend. However, we saw two similar studies on physiotherapy in TMD patients that were similar to ours in terms of the duration of treatments. In the study by Urbanski et al. , this tiTherefore, when continuing future research, particular emphasis should be placed on assessing the effect of treatment duration on the therapeutic effect of physiotherapy treatments.The randomized control study conducted by the authors clearly shows the significant impact of manual therapy procedures on the improvement of the mobility of the temporomandibular joints, reduction of muscle tension and pain in people with TMD. In everyday physiotherapeutic practice, it can be observed more and more often that manual therapy procedures have started to replace physiotherapeutic procedures to a large extent. Despite the higher cost of manual procedures, both therapists and patients observe better therapeutic effects after using MT compared to physical therapy. Therefore, it seems reasonable to implement manual therapy supplemented with physiotherapy treatments in patients with TMD. The conducted studies additionally highlighted the need to continue research on this subject, as the available scientific literature contains a small number of randomized, control studies comparing the effectiveness of physical and manual therapies in patients with TMD. Summing up, as shown by the authors’ clinical experience, the cooperation between the TMD treatment team  and a dental physiotherapist should become the ‘gold standard’ in modern dentistry.As it results from the studies presented above, physiotherapy should be an integral part of the interdisciplinary treatment of patients with painful TMD. While assessing the effectiveness of physical treatments and manual therapy, it was observed that MT is definitely more effective. Manual therapy compared to physical therapy showed a more favourable analgesic (average pain intensity level after the 6th treatment was NRS 0) and myorelaxant effect, thus contributing to the improvement of the mobility of the temporomandibular joints’.


The Electronic Chronic Pain Questions (eCPQ) has been developed to help healthcare providers systematically capture chronic pain data. This study evaluated the impact of using the eCPQ on patient-reported outcomes (PROs) and healthcare resource utilization (HCRU) in a primary care setting, and patient and physician perceptions regarding use of, and satisfaction with, the eCPQ.This was a prospective pragmatic study conducted at the Internal Medicine clinic within the Henry Ford Health (HFH) Detroit campus between June 2017 and April 2020. Patients (aged ≥18 years) attending the clinic for chronic pain were allocated to an Intervention Group to complete the eCPQ in addition to regular care, or a control group to receive regular care only. The Patient Health Questionnaire-2 and a Patient Global Assessment were assessed at baseline, 6-months, and 12-months study visits. HCRU data were extracted from the HFH database. Telephone qualitative interviews were conducted with randomly selected patients and physicians who used the eCPQ.p > 0.05) were found in PROs and HCRU between the 2 groups. In qualitative interviews, physicians and patients reported the eCPQ as useful, and using the eCPQ improved patient-clinician interactions.Two hundred patients were enrolled, 79 in each treatment group completed all 3 study visits. No significant differences (Adding the eCPQ to regular care for patients with chronic pain did not significantly impact the PROs assessed in this study. However, qualitative interviews suggested that the eCPQ was a well-accepted and potentially useful tool from a patient and physician perspective. By using the eCPQ, patients were better prepared when they attended a primary care visit for their chronic pain and the quality of patient-physician communication was increased. Chronic pain is a worldwide health problem . In the Pain is a sensory and emotional experience; biological, psychological, and social factors can influence pain reporting . Based o® Screener and the sensory hypersensitivity pain questions are part of the eCPQ to assist the provider in determining pain quality and type. A cross-sectional study in adults with a physician-confirmed diagnosis of either a neuropathic pain or sensory hypersensitivity condition found that a paper version of the CPQ was able to help differentiate between patients with neuropathic pain and those with sensory hypersensitivity (The Electronic Chronic Pain Questions (eCPQ)sitivity , and psysitivity .Consistent, systematic electronic capture of data for chronic pain, such as the Collaborative Health Outcomes Information Registry (CHOIR), allows physicians to assess and monitor patients more easily with improved guidance on treatment decisions. These data will also allow healthcare organizations to more accurately estimate the prevalence impact of chronic pain on healthcare resource utilization (HCRU) trends. Meanwhile, systematically obtaining pain-related data could enhance the interaction between the patient and the clinician, leading to a good patient-clinician relationship that can result in effective pain management. The current study aimed to determine if using the eCPQ in a primary care practice setting within a large integrated delivery network  can lead to improved PROs. The impact of the implementation of the eCPQ on HCRU was assessed. The patients’ and the physicians’ perceptions about the use, feasibility, and satisfaction with the eCPQ were evaluated.This was a prospective pragmatic study conducted at the Internal Medicine clinic within the HFH Detroit campus. The study protocol was approved by the Institutional Review Board at HFH. The study was conducted in compliance with the Declaration of Helsinki. All participating patients provided written informed consent.Eligible patients were men and women aged ≥18 years who were attending a primary care visit for their chronic pain. A diagnosis of “chronic pain” (non-cancer) made by physicians in the patient Problem List was required  and availability of appointments. Patients in the Intervention Group self-completed a paper version of the eCPQ in the waiting room before seeing the physician at each visit. The physician seeing the patient reviewed the eCPQ answers with the patient during their appointment, and the clinical research personnel input the data into the electronic medical records. At Visits 2 and 3, patients in the Intervention Group were asked to complete all the questions of the eCPQ regardless of their answers to Question 1.The Patient Health Questionnaire-2 (PHQ-2) was completed routinely as part of the standard of care in the usual (non-study) visits to screen for depression. For those who had PHQ-2 scores indicative of a need for further assessment, the PHQ-9 was also completed. As part of the regular care, patients in both groups completed the Patient Global Assessment (PGA) following their appointment at each visit .To capture the clinician and patient perspectives of the eCPQ, approximately 15 patients in the Intervention Group were randomly assigned to a qualitative interview using a 1:5 randomized block design; approximately 10 clinicians were randomly selected among those who used the eCPQ and interviewed as well. The patient interview was scheduled after Visit 2 to obtain any insights regarding the use of eCPQ from the patient-perspective in a timely manner. The physicians’ interviews were scheduled after the last study patient was enrolled and approximately 50% of study participants had completed Visit 2.Changes in eCPQ pain intensity and pain interference with mood, sleep, and usual activities from baseline to 6 and 12 months were assessed. Percentage of the patients who had neuropathic, nociceptive, or sensory hypersensitivity type of pain (based solely on patient responses to the eCPQ) at baseline, 6 months, and 12 months were summarized.a priori coding dictionary was developed based on themes and concepts that emerged during the interviews. ATLAS.ti software version 8.4.20.0. was used to facilitate the systematic coding and analysis of the data. The findings of the interviews were summarized.The qualitative interviews were conducted by telephone by a trained independent interviewer . Patients and physicians were asked a series of open-ended questions  about thChanges in PGA score and PHQ-2 and PHQ-9 scores from baseline to 6 and 12 months were evaluated for the Intervention vs. the Control Group.Administrative data regarding all-cause HCRU were downloaded from the electronic data warehouse of HFH. Assessment of HCRU included inpatient admissions, inpatient days, emergency department visits, total outpatient visits, outpatient visit–primary care, outpatient visit–specialty care, outpatient visit–pain management, and total billing charges. HCRU specific to comorbidities was not assessed separately but included in all-cause HCRU. The assessments for HCRU  were performed at 6 and 12 months from the baseline visit.No previous research on the primary endpoint of PGA score had been published or documented at the time of the study with respect to the presence versus the absence of the eCPQ intervention. Therefore, a general benchmark on treatment effect size and sample size determination was applied . For a tt-test or chi-square test. The statistical software used was SPSS version 26. p values <0.05 were considered as significantly different.Descriptive statistics were used. The means, SDs, medians, and sample sizes were reported for continuous outcomes . For categorical outcomes, proportion, counts, and sample sizes were provided. Differences between the 2 groups were assessed by In total, 200 patients were enrolled between June 2017 and March 2019 . Five patients were excluded from the Intervention Group ; one patient in the Control Group died before Visit 3 and was excluded . TherefoThe study was completed in April 2020, 79 patients in both the Intervention  and the Control Group  completed all 3 visits.Baseline demographic characteristics were comparable between the 2 groups, the mean age was over 60 years, most (>60%) patients were female, and over 85% were Black . There were no significant differences in the percentages of patients using commercial insurance, Medicaid, or Medicare between the 2 groups .At baseline, Visit 2, and Visit 3, 97, 77, and 79 patients in the Intervention Group completed the eCPQ form, respectively . At eachFor item 10  and item 11 (assessing the impact of pain on sleep), a small increase was reported from baseline to Visit 2, but a small decrease was seen at Visit 3. For item 12 (assessing the impact of pain on mood), a small decrease was seen from baseline to both Visits 2 and 3. An increase in the scores of items 13 and 14  was seen from baseline to Visit 2; at Visit 3, a decrease in the score of item 13 and a small increase in score of item 14 were reported .At baseline, nociceptive pain and neuropathic pain was considered for 42  and 55  patients, respectively; hardly any changes were found at Visit 2 . At Visit 3, 47  patients had nociceptive pain and 32  patients had neuropathic pain.Fourteen patients in the Intervention Group and 9 clinicians who used the eCPQ in this study took part in the qualitative interviews exploring the feasibility of the eCPQ  of patients in the Intervention and 42.7% (41/96) in the Control Groups had positive PHQ-2 results, indicating that the patient may be experiencing depressive symptoms. The percentage of patients with positive PHQ-2 results decreased in Visits 2 and 3 for both groups . At baseNo significant difference was found between the Intervention Group and the Control Group for any of the HCRU measures at any of the study visits .In addition, HCRU was also analyzed according to pain intensity categorized using the eCPQ data for the intervention group. At both 6 and 12 months from the baseline visit, patients with severe pain had the highest total billing charges. However, patients with moderate pain had the highest total outpatient visits, primary care visits, and pain management visits at both visits .Using the eCPQ as part of the primary care for patients with chronic pain who had visited the clinics every 6 months showed limited overall impact of pain on normal daily activities as measured by the PGA. Management of chronic pain is often a long-term process with multimodal and multidisciplinary interventions as it is difficult to change treatment outcomes once the patient has long-standing chronic pain. For a subgroup of patients with chronic pain, an intractable pain syndrome or disease has been reported . Pain maQualitative interviews with patients and clinicians who were in the Intervention Group and used the eCPQ supported the content of the eCPQ. Overall, the eCPQ was a well-accepted and potentially useful tool from the patient and the clinician’s perspective, which is similar to the qualitative feedback received previously . Most paIt has been observed that in the follow-up visits, the percentage of patients with positive PHQ-2 showed a decrease from baseline. Since there are only 2 items in PHQ-2 and the patients might have guessed the relationship between their response and the positive results after the baseline visit, it was possible that the patients deliberately chose their response in Visits 2 and 3 to avoid a positive result indicating depression, since a positive result would lead to unwanted additional follow-up for a possible diagnosis of depression. Further, there is no clear trend in the PHQ-9 categories between the Intervention Group and the Control Group across the study period. No definite conclusion could be made on the effect of eCPQ on PHQ-9 due to the small sample size.For patients with osteoarthritis, increased pain severity is associated with increased HCRU, such as increased number of imaging tests used to monitor osteoarthritis progression, more healthcare provider visits, higher hospitalization rates, and more prior and planned surgeries . In the This study was carried out in an urban clinic. The participating patients were predominantly (>85%) Black/African American, which mirrored the demographic of the population served by these urban clinics. Baseline demographic characteristics, findings in PROs, and assessments of HCRU were similar between the two groups; no other analysis was performed. There are limitations of the current study. Patients who completed the eCPQ reported many body areas affected by chronic pain with back pain and pain in the lower extremity as the most common and no details to differentiate joint pain from soft tissue pain. Therefore, it might not be possible to extrapolate the results to patients with other types of chronic pain. Further, patients included in the current study were likely to have long-standing pain conditions (at least lasting for more than 3 months), and it is not clear whether implementing the eCPQ upon diagnosis of chronic pain versus an entrenched patient population would make a difference in clinical outcomes. Also, this study did not capture data to describe clinical decisions for treatment changes based on the provider having access to eCPQ. For instance, no data were collected that could show whether patients with neuropathic pain as identified by the eCPQ had received appropriate medication choices and doses, or whether there were changes in treatment regime based on the type of pain identified by the eCPQ. Considering that any changes in clinical decision making and its potential causal factors would be of significant interest to clinicians, obtaining such data should be evaluated and included, if at all feasible, in the design of future studies. All of these might have limited the interpretation of the results. In this study, patients completed a paper version of the eCPQ and the research team entered the results into the electronic medical records; such a process may limit the generalizability and utility of the eCPQ in a busy clinical settings without a research team. The qualitative interview was only conducted on a proportion of the participants in the eCPQ group. Nevertheless, even though the sample size was small, results of the qualitative interviews performed in patients with chronic pain and physicians who used the eCPQ indicated that it was beneficial using the eCPQ in clinical practice for chronic pain management, as these patients who completed the eCPQ were better prepared for their visits and the quality of patient-physician communication was increased compared with those who received regular care only.In summary, adding eCPQ to the regular care for patients with chronic pain attending a primary care practice did not significantly impact PROs. However, qualitative interviews suggested that the eCPQ was a well-accepted and potentially useful tool from the patient and physician perspective. More detailed investigation is warranted to determine the usefulness of the eCPQ.https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Institutional Review Board at the Henry Ford Health (HFH). The study was conducted in compliance with the Declaration of Helsinki. The patients/participants provided their written informed consent to participate in this study.LL, VS, LA, JC, BD, SE, RH-D, and PP contributed to research idea, study design, data analysis, data interpretation, manuscript development, manuscript review, and approval for manuscript submission. LL, VS, and SE contributed to data acquisition. LL contributed to statistical analysis. All authors contributed to the article and approved the submitted version.This study was sponsored by Pfizer. The qualitative substudy in patients and physicians was conducted by Evidera and was sponsored by Pfizer. Employees of the funding source, Pfizer, who contributed to the design of the study, the collection, management, analysis, and interpretation of the data, and reviewed the manuscript, are named authors of this manuscript.LL, VS, and SE are employees of the Henry Ford Health, which received funding from Pfizer for this study. LA, JC, BD, RH-D, and PP are employees of Pfizer with stock and/or stock options.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


No significant differences were noted in non-opioid analgesia prescriptions (p = 0.507). A higher frequency of anti-depressants/anti-psychotic prescriptions and alcohol use was recorded amongst the non-Hispanic patients . Conclusions: Rates of opioid prescriptions for abdominal pain patients were substantially lower for the Hispanic patients compared with the non-Hispanic patients, despite having a decreased rate of high-risk features, such as alcohol use and depression. The root cause of this disparity needs further research to ensure equitable access to pain management.Background: Disparities in pain control have been extensively studied in the hospital setting, but less is known regarding the racial/ethnic disparities in opioid prescriptions for patients with abdominal pain in ambulatory clinics. Methods: We examined opioid prescriptions during visits by patients presenting with abdominal pain between the years of 2006 and 2015, respectively, in the National Ambulatory Medical Care Survey database. Data weights for national-level estimates were applied. Results: We identified 4006 outpatient visits, equivalent to 114 million weighted visits. Rates of opioid use was highest among non-Hispanic White patients (12%), and then non-Hispanic Black patients (11%), and was the lowest in Hispanic patients (6%). Hispanic patients had lower odds of receiving opioid prescriptions compared to non-Hispanic White patients (OR = 0.49; 95% CI, 0.31–0.77,  Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care” examined the extent and causes of racial and ethnic disparities in healthcare across the United States (US) [The US Institute of Medicine’s report in 2003 titled “tes (US) . It concOne area in which these disparities have been particularly pronounced is the prescribing practices of opioids for pain control . OpioidsLess is known about the racial and ethnic disparities in opioid prescription patterns in the ambulatory setting. A small number of older studies have reported that ethnic minority patients, especially Hispanics, are less likely to receive opioid medication by primary care physicians for acute and chronic pain of various etiologies ,11. ReasAbdominal pain is one of the most common causes of healthcare visits in the US, for which there has been an increase in opioid prescribing patterns for its treatment ,14. HencIdentifying and understanding the factors contributing to outpatient opioid prescription disparities is crucial to ensure equitable access to appropriate pain management for patients, regardless of their race or ethnicity. To that end, we elected to analyze data from the National Ambulatory Medical Care Survey (NAMCS). The NAMCS dataset is ideal for researching outpatient prescription disparities as it is built on a thorough, annual, and nationally representative survey of ambulatory care visits in the US. With a focus on care provided by generalist clinicians, the NAMCS dataset provides a unique insight into abdominal pain management with opioids outside specialty care settings. Our paper aimed to examine the extent of racial–ethnic disparities in opioid prescriptions in the outpatient treatment of abdominal pain using NAMCS data from the period of 2006–2015.International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM); NCHS Reason for Visit Classification for Ambulatory Care codes (of up to three), and medications (of up to thirty) listed using the Cerner Multum Lexicon Plus drug database.Data were extracted from the 2006 to 2015 editions of the National Ambulatory Medical Care Survey (NAMCS), an annual National Center for Health Statistics (NCHS) survey. This survey was distributed to achieve a nationally representative sample of ambulatory care appointments with non-federally employed clinicians using a multi-stage probability sampling design based on geography, physician specialty, and individual patient visits. Within participating medical offices, a systematic random sample of patient visits over a 1 week period were selected for data collection. Information provided from these patients via a standardized patient record form included patient demographics; diagnosis codes (of up to five) using the We identified visits made by adult patients (age ≥ 18) presenting for abdominal pain with general internists based on the NCHS Reason for Visit Classification code 1545 . We limited our analysis to patients with abdominal pain as the primary reason for their visit.The primary outcome of interest was new or continued opioid analgesic prescription. Narcotic analgesic and narcotic analgesic combination prescriptions were identified using the Multum Therapeutic Classification categories . To identify the specific opioid analgesic medications, we used the NCHS five-digit drug codes.Covariables included sex , age, and race/ethnicity . In addition, we identified non-opioid analgesia prescriptions, including non-steroidal anti-inflammatory drugs, salicylates, analgesic combinations, and cox-2 inhibitors . Available data for comorbid conditions, such as smoking, alcohol use, depression, addiction (available from 2014 onwards), as well as insurance status, were also collected. Data on anxiety history was not available in this dataset. The major reason for visit (variable MAJOR), as determined by the provider at the visit, was used to compare the nature of the visits themselves .t-test, adjusted Wald test, chi-square analysis, and bivariate and multivariate logistic regression, as appropriate, to compare the outcomes between these racial–ethnic groups. Visits by female patients or non-Hispanic White patients were used as the reference group. Odds ratios (OR) were expressed with 95% confidence intervals (CI), and p values less than 0.05 were considered to be statistically significant.Statistical tests included the We applied standardized NCHS-provided data weights to achieve nationally representative estimates. For weighted analysis, we followed the NAMCS guidelines requiring a minimum of 30 unweighted visits per subgroup and a relative standard error of 30% or less. Analysis was conducted using Stata version 14 . No institutional review board approval was required for this publicly available, and de-identified database analysis.Between the years of 2006 and 2015, respectively, we identified 4814 ambulatory general/primary care visits with abdominal pain as the primary reason for visit. Excluding 808 visits that were made by pediatric patients, we identified a total of 4006 visits, corresponding to 114.0 million weighted visits. The majority of visits involved non-Hispanic White patients (74.3 million), followed by Hispanic (21.0 million), non-Hispanic Black (11.7 million), and non-Hispanic other patients (7.0 million). More visits involved female patients (74.2 million) compared to male patients (39.7 million).Opioid prescriptions were recorded in 13% of unweighted visits and 11% of weighted visits, respectively . The typp = 0.002) (p = 0.002). There was no significant difference observed in the opioid prescription rates for abdominal pain visits by sex .Opioid prescription rates were the highest at visits for abdominal pain made by non-Hispanic White patients (12%), followed by visits from non-Hispanic Black patients (11%), and were lowest among visits by Hispanic patients (6%). Multivariate logistic regression demonstrated that only visits made by Hispanic patients were less likely to record opioid prescriptions than those of non-Hispanic White patients  . Bivariap = 0.833). The average patient age was similar among visits by all racial–ethnic groups . The rates of depression diagnosis were found to be similar at visits by non-Hispanic and Hispanic patients ; however, there was a higher number of anti-depressants/anti-psychotic prescriptions reported amongst the non-Hispanic patients (p = 0.027).There was no significant difference noted in non-opioid analgesia prescriptions . Conversely, there was a similar prevalence of smoking  and substance abuse history  across visits that were made by all racial–ethnic groups.Data on alcohol and substance abuse was available from the year of 2014 onwards. Among the 22.3 million weighted visits in 2014 and 2015, there was a higher reported level of alcohol abuse amongst visits by non-Hispanic patients compared to Hispanic patients . This difference persisted between visits by Hispanic patients, non-Hispanic Black patients, and other minority patients . A similar trend was noted in workers’ compensation visits for Hispanic vs. non-Hispanic patients . Insurance visits covered by private insurance, Medicare, and Medicaid were found to be similar across all groups.Stratifying insurance types revealed that visits made by Hispanic patients were significantly more likely to be self-pay visits (or no recorded insurance) compared to visits made by non-Hispanic patients .The most common diagnoses of abdominal pain among those prescribed opioids were unspecified abdominal pain, right upper quadrant pain, esophageal reflux, calculus of gallbladder, chronic pain, right lower quadrant pain, and constipation. The major reason for visit was similar among visits by all racial–ethnic groups, with acute concerns accounting for approximately two-thirds of visits by each racial–ethnic group  extrapolated a large representative population to study outcomes. The ability to isolate exact diagnoses based on ICD coding, demographics, and co-variates allows for curating a clean cohort of patients to study, which included adjusting for pain chronicity, mental health, alcohol use, tobacco use, substance abuse, and insurance carriers.However, there are certain limitations as well. Firstly, the subjective discussions of the provider–patient relationship, which go into shared decision making, has not been accounted for in this analysis. For example, cultural differences in the perception and management of pain varies significantly between ethnicities. Hispanics and other minorities may favor non-opioid analgesia and self-care over opioid use ,32. FurtIn conclusion, racial and ethnic disparities in pain management persists in the treatment of abdominal pain, with lower rates of opioid-based analgesia among Hispanics. The reason for this disparity remains challenging to identify, and is a complex issue with numerous causes, including provider biases. Understanding and addressing these disparities is crucial in improving healthcare equity and in providing appropriate pain management for all patients.


Pain is one of the predominant and troublesome symptoms that burden cancer patients during their whole disease trajectory: adequate pain management is a fundamental component of cancer care. Opioid are the cornerstone of cancer pain relief therapy and their skillful management must be owned by physicians approaching cancer pain patients. In light of the increased survival of cancer patients due to advances in therapy, deprescription should be considered as a part of the opioid prescribing regime, from therapy initiation, dose titration, and changing or adding drugs, to switching or ceasing. In clinical practice, opioid tapering after pain remission could be challenging due to withdrawal symptoms’ onset. Animal models and observations in patients with opioid addiction suggested that somatic and motivational symptoms accompanying opioid withdrawal are secondary to the activation of stress-related process (mainly cortisol and catecholamines mediated). In this narrative review, we highlight how the lack of validated guidelines and tools for cancer patients can lead to a lower diagnostic awareness of opioid-related disorders, increasing the risk of developing withdrawal symptoms. We also described an experience-based approach to opioid withdrawal, starting from a case-report of a symptomatic patient with a history of metastatic pheochromocytoma-paraganglioma. HoweverMost of patients with cancer experience pain as the predominant symptom during their illness and cancer treatment, thus affecting the quality of life (QoL). More than half of patients report the presence of moderate-severe pain since cancer diagnosis: its prevalence increases up to 80% in the advanced stage of the disease , 3. CancThe correct assessment and quantification of pain are essential in the management of cancer patients. Cancer pain treatment is based on the expert use of non-steroidal anti-inflammatory drugs (NSAIDs), opioid, and adjuvant drugs. NSAIDs are indicated for mild to moderate pain, and their side effects are common and relevant in clinical practice. The use of opioid drugs is indicated in the treatment of patients with moderate to severe pain. At each step, the use of adjuvant drugs should be considered –7. When As World Health Organization (WHO) suggests, a tiered and personalized approach is needed. The use of non-pharmacological pain management techniques is of utmost importance, to optimize the clinical response. The psychologist should be involved as an active part of the treatment, concurrent with the start of pharmacological therapy. Patients on opioid therapy should be adequately screened for the risk of developing Opioid Use Disorders (OUD). It is of utmost importance to differentiate physical dependence from addiction because psychological vulnerability is relevant in patient with cancer. The onset of withdrawal symptoms after a rapid reduction in opioid dosage, or because of the administration of an antagonist, defines physical dependence. As a precaution, patients should always be considered physically dependent after regular treatment with an opioid drug. Contrariwise, addiction is a syndrome characterized by the loss of control over the use of drugs and by compulsive and continuous use. This is not a pharmacological property of opioid and must be distinguished from physical dependence –7.Although the literature shows a clear increase in the survival of cancer patients, there are still very few studies that have investigated the risk of OUD and withdrawal syndrome in patients with cancer, in which it is possible to plan a tapering or even a cessation of the relief-pain therapy. While there are many studies and clear guidelines on the choice and management of pain therapy in patients with cancer, to date there are no defined guidelines on the tapering of therapy in these patients and on the management of withdrawal symptoms in patients who do not develop addiction.The clinical case presented allowed us to reflect on the thin red line between the symptoms that may indicate a disease recurrence and those related to opioid tapering, focusing our attention on the need for adequate tools to monitor patients during the deprescribing process. Therefore, the purposes of the article are to highlight the clinical skills and challenges related to opioid therapy in cancer pain, and to suggest how the lack of validated tools for the cancer patient represents a limitation in the process of prescription and deprescription.2.In April 2010, a 38-year-old female underwent left trans-parotid cervicotomy after the discovery of a left parapharyngeal neoformation. Histology confirmed the diagnosis of vagal paraganglioma. Oncological staging with total body computed tomography (CT) scan and 18F-FDG positron emission tomography did not show distant metastases, urinary catecholamine levels were normal. Therefore, the patient started a clinical and radiological follow-up. Pheochromocytomas and paragangliomas are rare endocrine neoplasms, composed of chromaffin cells, characterized by particular clinical manifestations (due to often catecholamines secretion), and often with a benign outcome after surgery. They are grouped together in the same pheochromocytoma and paraganglioma syndrome (PPGL) , therefore she underwent a total spine CT scan with evidence of an osteolytic lesion of the posterior portion of D10  excluded pathogenic mutations. The back pain due to osteolytic lesion was unresponsive to NSAIDs, therefore she started oxycodone 10 mg BID and gabapentin 300 mg BID from May 2019 . Therefore, therapy with doxazosin 2 mg TID was started, and oxycodone therapy was re-boosted at 15 + 15 + 10 mg.After the increase of the oxycodone dosage and the introduction of doxazosin, the symptoms rapidly disappeared, with a return to normal blood pressure values after a week , without palpitations and sweating, allowing the suspension of the antihypertensive therapy already after about 15 days.CT scan and 18F-FDG positron emission tomography were performed and excluded a paraganglioma recurrence. The radiological features, combined with clinical data and endocrine evaluation, allowed us to conclude that the symptomatology reported by the patient could be attributed to opioid withdrawal which mimicked a recurrence of secreting paraganglioma.α2 agonists (Clonidine).The rapid disappearance of symptoms with the resumption of oxycodone therapy, the tests performed and the overall clinical picture of the patient led us to exclude other possible causes of hypertension, palpitations and sweating, such as peri-menopausal hormonal variations. After the excluding of recurrent disease, it was agreed with the patient to maintain the dosage of oxycodone until now. A new tapering effort will be planned using a premedication with 3.Opioid are the cornerstone of cancer pain relief therapy. Opioid therapy should be administered at different stages of the disease, according to the clinical presentation . In choo•weak opioids, such as codeine and tramadol, are recommended if pain is reported as mild to moderate, there are no substantial differences in the choice of drug to start with.•strong opioids  are recommended when the pain intensity is moderate to severe.For many years, morphine was considered the first-choice opioid for the treatment of moderate to severe cancer pain. The availability of new molecules and different routes of administration has raised the question of opioid choice. In 2007, a Cochrane Review  and their most recent revisions, pain-relief therapy and opioid prescribing is based on the WHO steps scale, since 1986 –16. In pe Review  investige Review , oxycodoe Review . Only a e Review .The choice of the most appropriate opioid for the treatment of moderate or severe cancer pain should balance pharmacokinetic properties (first bioavailability) and the route of administration. Furthermore, in cases of organ failure or renal/kidney impairment, clinicians should try to avoid complications and toxicities. Unless there are no alternatives, morphine should be avoided in case of moderate to severe renal impairment. Oxycodone, fentanyl, and hydromorphone should be carefully monitored because they are primarily excreted in urine . A systeAccording to guidelines, opioid therapy should be initiated as immediate-release formulations and used first on demand for symptom control, at the lowest dose to achieve acceptable analgesia, that can be shared with the patient’s expectations , 24. AftFor better pain relief, patients who have been taking other analgesics, such as NSAIDs, may continue these analgesics for a limited time after opioid initiation, if these agents provide additional analgesia and are not contraindicated . In addi3.1.The most common side effects of long-term opioid administration are constipation, nausea and vomiting, sedation and dizziness, physical tolerance and/or dependence, and respiratory depression. Less common adverse events are delayed gastric emptying, immunologic and hormonal dysfunction , muscle rigidity and myoclonus, and opioid-induced hyperalgesia. Among them, opioid-induced constipation and nausea are challenging symptoms: they often persist because tolerance does not develop, especially the former. Opioid-induced side effects may be severe enough to require a dose reduction or drug discontinuation .•Innate: the predisposition genetically determined, that starts from the first opioid dose;•Acquired: the consequence of repeated drug exposure and linked to pharmacokinetics and pharmacodynamics .Moreover, physical dependence and addiction could prevent proper prescribing and inadequate pain management  is a paradoxical opioid effect and should not be forgotten: OIH often leads to the need to reduce or modify the therapy . OIH is Treating OIH is often a time-consuming clinical challenge. The main available options include opioid treatment discontinuation or switch to a different opioid, or a low-dose start due to incomplete cross-tolerance, allowing an overall dose reduction. Improved analgesia after opioid rotation has been reported in several clinical situations . The use4.μ-opioid agonists for analgesia, untreated underlying psychiatric disorders, young-er age, and social/familial background  ,•Clinical Opioid Withdrawal Scale (COWS) ,•Slubjective Opioid Withdrawal Scale (SOWS) .None of these tools has been specifically validated for the patient with cancer pain.There are many scales, tools, and questionnaires that could be useful in the diagnosis and during follow-up of opioid withdrawal syndrome, such as:5.2.Evidence-based recommendations are lacking: randomized controlled trials are not available to establish which drug is the most suitable for the management of withdrawal symptoms during opioid reduction or withdrawal, particularly in cancer patients .α2 agonists. However, buprenorphine alone does not control withdrawal symptoms, and α2 agonists can be combined with adjuvant drugs.Drug choice strongly depends on the expected goal. Buprenorphine is probably the treatment of choice if the target is the discontinuation of opioid therapy in patients still complaining of pain, given its superiority in terms of pain control over Methadone and buprenorphine are both recommended for the management of opioid withdrawal, their reduction of withdrawal symptoms and improvement of opioid abstinence are similar. Methadone is contraindicated in case of acute bronchial asthma or hypercapnia, and in known or suspected paralytic ileus. Methadone use should be carefully balanced with adverse events in patients with psychiatric disorders, decompensated liver disease, respiratory insufficiency, or concomitant use of sedative, hypnotic, anxiolytic or other QT-interval affecting drugs. Attention should be paid to the substances that interfere with this cytochrome P450 enzyme, such as anticonvulsants, antiretrovirals, and alcohol .µ opioid receptor agonist available in different formulations, most of which have been approved by the Food and Drug Administration (FDA) since 2015. Buprenorphine is recommended for the pharmacological treatment of OUD and opioid withdrawal: results are similar to methadone, and superior to lofexidine or clonidine . Clonidine is often combined with other non-narcotic medications targeting specific opioid withdrawal symptoms  .n = 14), buprenorphine with methadone (n = 6), or buprenorphine tapering (n = 7). Buprenorphine was associated with a lower withdrawal score than α2 agonists , longer retention in treatment , and increased likelihood of withdrawal treatment completion . A direct comparison among studies was not feasible because each author used a different scale. In such scenario, an effort of the scientific community is to homogenize the scale used. Buprenorphine was similar to methadone in terms of treatment duration or completion rate. Clonidine reduces noradrenergic hyperactivity in locus coeruleus neurons that cause opioid withdrawal symptoms, and therefore is effective in patients  in the treatment of opioid withdrawal. α2 agonist treatment  was more effective than placebo and more likely to result in the completion of treatment, withdrawal signs and symptoms occurred and resolved earlier than methadone, and treatment duration was shorter. Also in this case measures of withdrawal severity differed between studies  , 67. It patients , 56, 69.patients  investig studies .6.Several drugs (not only opioid) are able to modulate the activity of the hypothalamic–pituitary–adrenal (HPA) axis or the sympathetic nervous system, leading to an impaired secretion or activity of respectively cortisol or catechol-amines. Moreover, somatic and motivational symptoms accompanying opioid withdrawal are secondary to the activation of stress-related processes (either cortisol or catecholamines).α1-adrenergic and the β-adrenergic receptor, respectively), or with spironolactone  decreased somatic symptoms of morphine withdrawal , allowing to measure somatic and affective/motivational aspects of physical morphine dependence. The withdrawal symptoms assessed in the study were jumps, rearing, paw tremors, body tremors, wet-dog shakes, teeth chattering, defecations, and urinations. Moreover, in the same model, only propranolol pretreatment attenuated the dysphoric affective state accompanying opioid withdrawal  responses to CRH and ACTH were not related to morphine tolerance . In micethdrawal . Lateralthdrawal . The locthdrawal . Depletethdrawal . C1 neurthdrawal .in vivo. It is suggested to occur in addition to the acute conversion into their known metabolites, and can play a role in abuse and dependence. Not only analgesic opioid (morphine and oxycodone) but also their antagonists  may be converted to catecholamines through a series of currently unidentified reactions. From a chemical point-of-view, the molecule of morphine and oxycodone contain some domains : the formation of dopamine or epinephrine is possible if these methyl groups are enzymatically removed , or with methadone (30 patients). CRH concentration during acute abstinence was lower in patients treated with benzodiazepines and clonidine or methadone; CRH levels then normalized 30 and 90 days after withdrawal in the former group. Contrariwise, ACTH levels were similar to controls. Cortisol levels during acute abstinence were higher in patients treated with benzodiazepines and clonidine and lower in those treated with methadone (both with respect to controls) . Metyrapα2-adrenoceptor agonist clonidine decreases the muscle sympathetic activity and catecholamine plasma concentrations  but also the adrenal medulla (with catecholamines) is involved in stress response and may be affected by opioid use and its withdrawal. Plasmatic adrenaline concentrations in-crease up to 30-fold  after the initial injection of naloxone during ultra-rapid opioid detoxification, leading to increased heart rate and stroke volume . In the trations . Howevertrations .Some case reports support the evidence that opioid withdrawal leads to sympathetic hyperactivity and increased catecholamine release, which may trigger catecholamine-induced cardiomyopathy, resulting in heart failure and fatal arrhythmias . Takotsuα2-adrenoreceptors agonist, it reduces sympathetic outflow and noradrenaline release from sympathetic nerve endings. Obviously, autonomous catecholamine secretion from pheochromocytoma-paraganglioma (PPGL) is not affected by clonidine: suppression test with clonidine is used in patients with suspected PPGL and moderate endocrine excess  should be used in the withdrawal phase in patients treated with opioid with cancer pain, not only in those with addiction.In this narrative review, we summarized some aspects that are relevant to the medical management of opioid treatment for cancer pain. First, opioid withdrawal syndrome can mimic several symptoms that are very common in cancer patients. We used a scholarly case presentation of a patient with a history of metastatic sporadic paraganglioma, to underline the endocrine aspects of opioid withdrawal syndrome. Moreover, in cancer patients, a high psychological burden leads patients and physicians to underestimate some distinctive symptoms of abstinence as asthenia and nausea.The clinical case also allowed us also to highlight the lack of guidelines on opioid tapering in cancer patients. Patients with cancer pain clearly represent a different population from those with chronic non-cancer pain, due to the evolutionary characteristics of the underlying disease, which often lead to long-term therapy. One of the fundamental reflections that emerge from our experience is that the correct timing for reducing therapy must be identified according to the patient, who has to be correctly informed about the symptoms that may appear in this process. As is often done in titration, even in the deprescribing it could be useful to create a “therapeutic diary” for the patient, to report withdrawal symptoms. Follow-up by the pain specialist should also be strictly timed.In clinical practice, there are several tools that can help physicians to unmask opioid withdrawal; nonetheless, none of them is tailored to the patient that uses opioid to relief cancer pain: an effort in this regard is suggested to the scientific community of palliative specialists. These tools should be validated not only for inpatients, but their use is “out” of the hospitalization, at home, and pain management should be shared with caregivers, nurses, and general practitioners: the awareness of the pain and opioid use  should be enriched in all clinical settings.ad hoc guidelines for opioid deprescribing, we deem it useful to suggest the creation of a self-completion questionnaire for daily administration that allows the patient to promptly identify the onset of withdrawal symptoms. It is also essential to illustrate, share and agree from the beginning of opioid tapering on the therapeutic attitude to maintain in the event of the onset of symptoms: return to the previous dosage vs use of drugs for symptom management vs. multimodal non-pharmacological approach. The keyword must therefore be the sharing of decisions. Furthermore, the presence of a multidisciplinary team is the added factor to optimize the patient management, integrating moreover the outpatient approach with home service.The most relevant food for thought that emerges with respect to the management of this clinical case is the frequent lack of education of the patient to promptly recognize withdrawal symptoms. Patients with cancer are used to experiencing negative symptoms related to life-prolonging treatments and therefore resilient towards the appearance of even disturbing symptoms. In developing


FSFI, V-Q, and muscle-strength measures also improved but were not statistically significant. Conclusions: Our findings showed the potential of TENS in the treatment of VBD.Background: Vestibulodynia (VBD) is the most common form of vulvodynia. Because VBD is a pain disorder, transcutaneous electrical nerve stimulation (TENS) can be used as treatment. This study aims to evaluate the effects of two-parameter combinations (frequency and pulse duration) of TENS in reducing pain intensity and dyspareunia in VBD. Methods: A randomized, double-blind, controlled trial was conducted to study the effect of two different electrical stimulation treatment regimens on women with VBD receiving domiciliary TENS. Outcomes were the mean change from baseline at 60 and 120 days of burning/pain and dyspareunia (VAS), Vulvar Pain Functional Questionnaire (V-Q), Female Sexual Functioning Index (FSFI) and vaginal electromyography measurements. Results: A total of 78 subjects, 39 in each group, completed the trial. Patients in Groups 1 and 2 received a mean of 46.9 and 48.4 TENS sessions. By day 120, there was a 38.2% reduction in the burning/pain and a 52.1% reduction in the dyspareunia VAS scores in Group 1, as compared to 21.3% ( A recent consensus statement has been made on the difference between persistent vulvar pain of at least three months triggered by a specific disease  and vulvodynia, which is vulvar pain without an identifiable reason . VulvodyThis hyperinnervation correlates with allodynia (pain from light contact) and hyperalgesia (enhanced pain perception) ,8. FurthTranscutaneous electrical nerve stimulation (TENS) involves delivering an electrical current through the skin to treat pain and is effective in many clinical areas, including inflammatory, neurological, and non-inflammatory conditions . ClinicaAccording to studies, TENS yielded a significant improvement in pain and sexual function in patients with VBD ,13,14. Thttp://www.isrctn.com . Subjects were eligible for enrollment if they were at least 18 years of age and were not yet in menopause (absence of menstruation for 12 months), were diagnosed with VBD for at least six months, and underwent a standardized gynecological examination by one of our staff gynecologists.This was a randomized, single-blind, controlled trial performed between January 2019 and December 2019. Institutional Review Board approval for the study was obtained and registered at The exclusion criteria were an active vulvovaginal infection at the time of their gynecological examination, genital bleeding of unknown origin, a cardiac pacemaker, or pregnancy. Patients enrolled in the trial signed an informed consent form and were randomly and blindly assigned to one of two groups with different parameter combinations of TENS therapy in a self-administered domiciliary protocol. Before randomization, patients were asked to stop any topical, systemic, or physical therapy at least 30 days before starting TENS therapy. Women with VBD completed questionnaires and underwent a gynecological examination, including a vulvo- and colposcopy. The International Society for the Study of Vulvovaginal Disease vulvodynia questionnaire was used in this study . Women wAll subjects underwent vaginal surface electromyography (EMG). Vaginal EMG measurements were taken at rest and during several exercises of the pelvic floor, through an EMG device with a vaginal sensor (Myotonus plus©-London-UK). Pelvic floor muscle (PFM) activity at rest was measured as the mean muscle tone value at rest after six maximum contractions separated by a rest period of at least 12 s, while the PFM peak activity was calculated as the mean of six maximum voluntary contractions separated by a rest period of at least 12 s. The assessments also included the PFM strength obtained by subtracting the maximal value from the resting values .The primary efficacy endpoint for this study included the mean change from baseline to 60 and 120 days of pain and dyspareunia. The secondary endpoints were variations in the vestibular cotton swab sensitivity and vaginal EMG measurements.A dual-channel portable TENS unit  was used. The stimulation was delivered through a plastic vaginal probe connected to the device  that was 20 mm in diameter and 110 mm in length with two gold metallic transversal rings as electrodes. The tube was inserted 20 mm into the vagina. The participants were randomized into two groups with different electrical stimulation treatment regimens. Two customized programs were set for each group according to our previous studies ,13 and sGroup 1: 15 min of 100 Hz frequency, a pulse width of 50 µs, and time on:off 20:10 s (first program) followed by 15 min of 5 Hz frequency, a pulse width of 100 µs, and time on:off 20:10 s (second program).Group 2: 15 min of 60 Hz frequency, a pulse width of 50 µs, and time on:off 20:10 s (first program) followed by 15 min of 5 Hz frequency, a pulse width of 200 µs, and time on:off 20:10 s (second program).The electric parameters used in both treatments were:Each patient underwent two to three assessments designed to familiarize them with the use of TENS while allowing the therapist to check if the patient was using the device properly. In the TENS treatment protocol, the pulse was increased rapidly until the patient reported any sensation under the electrodes. The intensity was then increased slowly until this sensation reached a level described as the maximum tolerable sensation without experiencing pain. After completing the trial, the patient obtained their TENS unit after verbal and written instructions, with a recommendation to perform home treatment three times per week.Randomization was generated by a computer program, and the concealed allocation was achieved by varying the number of self-adhesive labels attached to the TENS unit according to the information provided in the envelope sent to the company representative. The envelope sent to the clinic contained information on which of the number-coded units should be handed out to the participants of the first and second groups. The data were all blinded from the commencement of the analysis until after the completion of study protocols.p < 0.05. Statistical analyses were performed using SPSS Statistics V21.0 .The sample size was calculated based on averages and standard deviations of a mean pain reduction of 3.5 points based on the results of available studies regarding the use of TENS in a woman with VBD ,13,14. BA total of 85 patients were recruited in this study. Five patients did not meet the inclusion criteria. Two participants, one for each group, dropped out at the 8th week for personal reasons unrelated to the study; thus, 78 subjects, 39 in each group, completed the trial .No significant difference in any characteristic was found at baseline between the groups . After 1p = 0.003). Similarly, there was a 52.1% cumulative reduction in the dyspareunia VAS scores for Group 1, as compared to 23.1% in Group 2 (p = 0.01) (The between-group difference in VAS scores for burning/pain and dyspareunia was significantly lower after TENS treatment . By day  = 0.01) . For V-Q = 0.01) . The res = 0.01) .p = 0.003). Conversely, in Group 2, the decrease 60- and 120-days post-treatment was not statistically significant  (p = 0.03), while Group 2 exhibited a small difference between 60- and 120-days post-treatment  (p = 0.01)  . Similarificant) . Both gr = 0.01) . The int = 0.01) . No adveOur results showed the effectiveness of self-applied TENS in the treatment of VBD, with a significant reduction in burning/pain and dyspareunia. In addition, the average FSFI total and V-Q questionnaire scores were significantly lower after treatment. Furthermore, the improvement was more pronounced in the group of patients who underwent specific parameters of stimulation (frequency and pulse duration), according to our previous studies ,13 and cAs a non-invasive and non-pharmacological treatment, TENS has been used to treat many types of neuropathic pain . The anaA different pulse duration in high- and low-frequency TENS could be a decisive factor for efficacy. Several studies involving TENS in neuropathic pain reported that the combination of high frequency (100 Hz or more) and short pulse duration (50–60 µs) works through a spinal effect that is related to ‘pain gate’ mechanisms, in which the stimulation of large-diameter Aβ non-noxious afferent fibers  inhibits central nociceptive transmission, consequently decreasing pain perception . In contFurthermore, there was an increase in β-endorphins in the bloodstream and cerebrospinal fluid in healthy subjects after administration of either high- or low-frequency TENS . High- aIt has been reported that repeated use of TENS at equal parameters (frequency and pulse duration) can produce analgesic tolerance, which may decrease its positive effects. In contrast, a modulated TENS that applies stimulation across a range of frequencies may prevent the development of tolerance to electrical stimulation . As withMost women with VBD described their pain as “hot”, “burning”, or “pricking”, that the vestibular area was sensitive to touch , and that the pain would be aggravated by rubbing .The pattern of VBD responses suggests sensory abnormalities in the form of evoked pain , suggesting sensitization as a manifestation of neuropathic pain . FurtherA limitation of this study is the lack of a placebo and control group and follow-up without treatment, although placebo TENS was already compared with functional TENS in our previous randomized controlled trial on women with VBD with three months follow-up . Our finIt is becoming increasingly apparent that VBD is a summation and overlap of various trigger factors  with weight and predominance varying from patient to patient, in which the common endpoint is vestibular hypersensitivity and pelvic floor hypertonic dysfunction. As a result, any single-approach management strategy may not be adequate for all women. TENS is usually administered to patients as an adjunct treatment for pain reduction and is not given as a sole treatment.Our findings confirm that TENS therapy is effective for reducing pain and sexual problems in patients with VBD. Therefore, we recommend that TENS be administered not as a single therapy but as an important part of multidisciplinary therapy, in order to maximize its effectiveness in the treatment of VBD. However, proper stimulation parameters must be identified.


Four studies found comparable pain scores between these groups. PCEA use reduced epidural medication  in four studies. One study found a 23% reduction (p < 0.001) of top-ups in PCEA; intravenous morphine use by PCEA patients was reduced  in one study. PCEA patients were more satisfied with analgesia (p < 0.001) in two studies. Nausea and vomiting were reduced in PCEA (p = 0.01). Conclusions: Regarding the reduction in pain scores, the effects of PCEA were not significant or clinically not relevant. However, regarding the amount of epidural drug use, the amount of required rescue systemic analgesics, patient satisfaction, and the number of required top-ups, PCEA had advantages over CEA in surgical patients.Background: The advantages of PCEA over CEA have been demonstrated in obstetric patients. Whether a similar benefit applies to surgical patients is unclear. Methods: Embase, PubMed, and Cochrane Library were searched, enabling a systematic review of studies comparing PCEA and CEA in adult surgical patients (PROSPERO: CRD42018106644). The study quality was assessed using the Cochrane risk-of-bias tool (RoB2). The primary outcome was pain scores on postoperative day one (POD1). Secondary outcomes were 24 or 48 h epidural or intravenous total analgesic dose, systemic analgesics, manual top-ups, side effects, and patient satisfaction. Results: Six randomized controlled trials with high heterogeneity of study characteristics were identified with a moderate risk of bias. Two studies showed significantly reduced resting pain scores on POD1 in PCEA compared with CEA patients (36–44%,  Epidural analgesia is still considered the standard of care for major upper abdominal or thoracic surgery ,2,3,4. HDuring labor, the superiority of patient-controlled epidural analgesia (PCEA) compared with continuous epidural analgesia (CEA) has been proven in numerous clinical studies and has been confirmed in systematic reviews with meta-analyses. The more novel method of PCEA used programmed intermittent mandatory bolus (PIEB) ,7,8,9. AOur hypothesis, based on evidence in the obstetric population, was that the use of PCEA leads to reduced pain scores in rest and movement compared with CEA. Furthermore, we expected a reduction in the use of epidural medication, a reduction in top-ups, and a reduction in the use of systemic analgesics, with improved patient satisfaction in the PCEA group. Our aim was to investigate and compare the existing methods of epidural analgesia in non-obstetric patients undergoing surgery. Our secondary aim was to ascertain which method offers the best analgesic benefit and fewest side effects.The review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with registration number CRD42018106644. The guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) were followed . Embase Adult surgical patients receiving perioperative epidural analgesia were included. The intervention involved patient-controlled epidural analgesia , and for comparison, conventional CEA was considered. Our primary outcome was postoperative pain during rest on day 1 . The secondary outcomes were (1) postoperative pain during movement on day 1; (2) the amount of epidural medication used; (3) the number of top-ups required; (4) the use of systemic analgesics; and (5) patient satisfaction. To enable a better comparison with obstetric studies that have a relatively short duration of epidural treatment, we chose day 1 pain scores as the primary endpoint. Furthermore, the first postoperative day is often the day with the highest pain score, and most studies include the pain score on day 1 in their analysis.Studies involving patients aged <18 years, obstetric patients during labor, language not native to at least two team members , conference abstracts or communications, comparisons using PCEA followed by CEA or vice versa in the same patient, the use of programmed intermittent epidural bolus instead of PCEA, and publications other than a randomized controlled trial (RCT) or cohort analysis were excluded from this study. We included cohort analyses to enable a more complete comparison in case there was an insufficient number of RCTs found in the search.Titles and/or abstracts of studies retrieved using the search strategy were independently screened on Rayyan.qcri.org by two review authors (G.v.S. and Y.R.T.) to identify studies that met the inclusion criteria. Conflicts in this stage were resolved by a third reviewer (M.F.S.). The full text of potentially eligible studies was retrieved and independently assessed for eligibility by two review authors (G.v.S. and Y.R.T.). Any disagreement between them over the eligibility of particular studies was resolved through discussion with a third reviewer (M.F.S.). After the final selection of studies to be included, a predefined data extraction form was used (by G.v.S. and Y.R.T.) to extract data from the respective studies for assessment of study quality and evidence synthesis . The risp < 0.05 considered significant) and expressed the quantity using the I2 statistic and 95% confidence interval (CI). We followed the Cochrane Handbook’s classification for the importance of I2. Between-study variance (Tau2) and the I2 statistic were computed to estimate the percentage of variability in effect sizes that cannot be explained by sampling errors. We defined statistical heterogeneity as high when I2 > 50. Forest plots were used to present the data when appropriate for specific outcomes.Meta-analysis of data was performed using Cochrane’s Review Manager 5.4 software when four or more RCTs were available for a specific outcome. Differences in primary and secondary outcome parameters were expressed as mean differences and standard deviations. We assessed statistical heterogeneity using Cochrane’s Q statistic  are described in p < 0.001) in pain scores during motion, compared with CEA-treated patients :,24:17,24patients . However < 0.01) . NightinWe found an insufficient number of studies investigating comparable types of surgery to perform a proper meta-analysis. We present the results in forest plots as 2 (0.03) and I2 (35%). The forest plot of resting pain scores  is arranp < 0.01) [Epidural medication: Four out of six studies found a significant reduction in epidural drug use by 28–40% in PCEA patients ( < 0.01) ,20,21,22p < 0.001) in epidural top-ups among PCEA patients [Top-ups: One study found a 23% reduction (patients .p < 0.001) [Patient satisfaction: In two studies, the percentage of good patient satisfaction was higher in PCEA patients  ,24. One < 0.001) .p < 0.05) in PCEA patients [Use of intravenous rescue opioid medication: One study found a reduced requirement of intravenous morphine  [Hypotension was described by two authors, but no significant differences between the groups were found ( = 0.78) ,22.p = 0.12) [Respiratory depression was described in one study, in 8/55 patients in the PCEA group versus 15/56 patients in the CEA group, but no significant differences between these groups were found ( = 0.12) .p = 0.11) [Systemic opioid use was described in three studies, but no significant differences between the groups were found in the pooled analysis ( = 0.11) ,22,24.Other side effects:p = 0.01 [Nausea and vomiting (PONV) were described in four studies. In PCEA, this was less frequent, with an odds ratio of 0.31 (95% CI 0.12–0.76), p = 0.01 ,17,21,22p = 0.70) [Itching was described in three studies, but no significant differences between the groups were found ( = 0.70) ,17,21.p = 0.10) [Urine retention was described in two studies without significant differences between the groups ( = 0.10) ,22.p = 0.90) [Motor block was described by Hering and Silvasti, without significant differences between the groups ( = 0.90) ,22. Forep = 0.08). Top-ups, described by Nightingale et al., were reduced in PCEA (p < 0.005). Epidural medication needs, described by Hering et al., were reduced in PCEA (p = 0.03). The pooled comparisons of patient satisfaction, systemic opioid use, itching, motor block, and nausea and vomiting did not reveal any significant differences between PCEA and CEA.Subanalysis of abdominal operations: Hering et al. and Nightingale et al. performed studies involving patients undergoing abdominal surgery ,24. We cThe funnel plot illustrates the extent of publication bias: It is not funnel-shaped but reasonably symmetrical. Thus, the low number of studies does not show detectable bias .A summary of findings is found in We set out to find evidence of the potential advantages of PCEA in surgical patients. Our findings were as follows:(1) PCEA significantly reduced resting pain scores in some studies, while other studies found no difference; (2) PCEA reduced the dose of epidural medication; (3) PCEA reduced the need for systemic medication; (4) PCEA reduced the requirement for additional top-ups; (5) PCEA increased patient satisfaction; (6) PCEA reduced the frequency of nausea and vomiting.The quality of recovery is measured using a multidimensional assessment, which includes pain, nausea and vomiting, sleep quality, and satisfaction ,26. We dRegarding the pain scores, it is noteworthy that Hering et al. found that patients receiving PCEA had higher pain scores during motion (3.4 in PCEA patients vs. 1.9 in CEA patients) . A possiAn important finding is the significant reduction in epidural medication among PCEA patients demonstrated in four studies. The reduction in the need for systemic opioid medication can be an important factor in enhancing safety. The guidelines and protocols by the Enhanced Recovery After Surgery group (ERAS), and the workgroup of Procedure-Specific Recommendations (PROSPECT) stress the importance of opioid-sparing anesthesia in surgery ,28. In lAnother current recommendation suggests the use of epidural analgesia in open surgeries involving gynecologic oncology, gastrectomy, radical cystectomy, pancreaticoduodenectomy, colonic surgery, rectal surgery, and esophagectomy ,32,33,34Reduction in additional, i.e., manual top-ups, may lead to cost savings depending on hospital logistics around epidural top-ups . This maA previous study revealed that PCEA procedures require more expensive devices than CEA procedures using standard pumps . An analAnalysis of the retrieved studies showed that PCEA can increase patient satisfaction. However, a difference could only be shown if the control (CEA) group did not already have a high level of patient satisfaction (>90%). Patients’ feeling of being able to self-administer the pain medication could have contributed to these findings. Our analysis results of safety profiles and side effects, including respiratory depression, hypotension, nausea and vomiting, itching, systemic opioid medication, urine retention, and motor block, are shown in forest plots in the A recent Cochrane review demonstrated the benefits of PCEA in obstetrical patients include a reduced amount of epidural medication, improved satisfaction, and a reduction in breakthrough pain . Since o2 35%). The number of studies and the number of included patients was limited, especially regarding patient satisfaction and top-ups. There was also heterogeneity in patient populations, type of surgery, epidural site, and medication used in the protocol. The specific PCEA regimen employed was heterogeneous, with the common factor being “local anesthetic in the epidural medication”.Limitations: The overall quality of the studies included was moderate. More importantly, there was heterogeneity in the primary outcome parameter (pain scores, I2 and Tau2 and warrants caution in the interpretation of the results. A proper meta-analysis is therefore not appropriate, as there are an insufficient number of studies concerning the same type of surgery to allow a good comparison. Our findings are presented in forest plots as There are 26 years between the first and the most recent study, adding to the heterogeneity of the study periods. This heterogeneity cannot properly be assessed using IThe differences in pain scores between PCEA and PCA were not clinically meaningful. PCEA in surgical patients had advantages over CEA in regard to the amount of epidural drug use, the amount of required rescue systemic analgesics, patient satisfaction, and the number of top-ups required. Further research should evaluate PCEA using more composite postoperative comfort scores instead of primarily focusing on pain scores.


This is a peer-review report submitted for the paper “Exercise-Induced Hypoalgesia Following Proprioceptive Neuromuscular Facilitation and Resistance Training Among Individuals With Shoulder Myofascial Pain: Randomized Controlled Trial”This paper  shows th1. Why was this sample size chosen?2. Regarding the first inclusion criteria, the patients must report their MPS for at least 4 weeks up to 3 months. In my opinion, the patients do not know whether they have MPS, and they commonly complain about their shoulder pain only. They will be informed about having MPS after being diagnosed by the physicians. Thus, it is not clear what the statement, “reported MPS” is referring to. In addition, I am not sure if patients with cardiovascular conditions, such as uncontrolled hypertension, are excluded from the study. Is it because of some risks of cardiovascular problems while performing accidental events during exercises such as holding the breath or due to resistant exercise–induced cardiovascular problems?3. I am not sure how 60% maximum voluntary contraction (MVC) or pain-free load is set for each exercise intervention. Can we set it with other intensities? Is it possible that the patients doing an exercise with 60% MVC or pain-free load show significant differences on the outcomes? Why does the proprioceptive neuromuscular facilitation (PNF) method use 60% MVC for designing the PNF training protocol? The PNF intensity is set as a maximal resistance of the patients to facilitate an optimal outcome. Some techniques, such as the hold-relax technique with maximal resistance but within subpain threshold, are effectively used for relaxing muscle spasm or guarding in patients with muscle pain conditions. The authors apply agonist reversal, combination of isotonic contraction, and rhythmic stabilization without providing details of start and end positions, thus making it difficult to follow.1. Please provide a specific name for a muscle affected by MPS, such as “patients with MPS of upper trapezius muscle.”2. Exercise-induced hypoalgesia should be defined in relation to what outcomes are included for it.3. Please specify specific area of pressure pain threshold of remote sites on the extensor carpus radialis and the peroneus longus.4. Is the visual analog scale one of the study's outcomes?