Postoperative pain is a major cause of delayed recovery following inguinal hernia repair. Transcutaneous electrical nerve stimulation (TENS) is a simple, low-cost method of noninvasive analgesia. This study aimed to assess the efficacy and safety of TENS for pain management following inguinal hernia repair.We searched nine electronic databases and trial registries to identify randomized controlled trials (RCTs). The primary outcomes were postoperative pain and the use of rescue analgesics. The Risk of Bias 2 tool was used to evaluate the risk of bias in the included trials. The certainty of the evidence was assessed using Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). Subgroup analyses were conducted based on the anesthesia type or TENS dose and frequency. This study is registered with PROSPERO (CRD42022353932).P < 0.05). TENS may result in little-to-no difference in rescue analgesic use . No serious adverse events occurred (moderate certainty of the evidence).Eleven RCTs, with a total of 559 patients, were included. The overall risk of bias was concerning due to the lack of information about concealment or published protocols. TENS may reduce pain on postoperative day (POD) 0 , POD 1 , and POD 2 . According to the subgroup analyses, postoperative pain was reduced, particularly with local anesthesia or repetitive and frequent TENS (TENS may reduce pain in patients who have undergone inguinal hernia repair. Further trials are warranted to confirm our findings. Recovery time following hernia repair surgery is a major socioeconomic issue due to residual pain that interferes with the patient’s daily life and employment; this pain occurs in approximately 6% of patients following hernia repair surgery (2). Moderate or severe pain after hernia repair surgery is common and peaks on postoperative day (POD) 1 (3). It is hypothesized that active analgesia can avoid central sensitization from incisional and inflammatory stimuli during the early postoperative period (4). As a result, the risk of developing chronic pain may be reduced (5). Nonsteroidal anti-inflammatory drugs and opioids are often used for postoperative pain; however, opioids for postoperative pain exert many undesirable side effects, including nausea, vomiting, urinary retention, sedation, respiratory depression, drug dependence, dizziness, and dry month (6). Therefore, it is important to reduce pain and analgesic consumption after hernia repair surgery to achieve rapid recovery and enable return to normal activities (8).Inguinal hernia repair surgery is one of the most frequent general surgeries and is performed in more than 20 million patients annually worldwide, accounting for approximately one-third of all surgical interventions (9) and is also portable and inexpensive; furthermore, the device used produces a mild pulsed current that is delivered across the skin surface to stimulate peripheral nerves via electrode pads (10). Conventional TENS is applied at high frequencies (50-130 Hz), at a low intensity (comfortable and painless), and with short pulse durations (50-200 μs) (11). It selectively activates nonpainful, low-threshold afferent nerve fibers (Aβ fibers) in the skin, thus inhibiting the transmission of nociceptive information at the level of the spinal cord to provide analgesia (12). A previous Cochrane review evaluated the analgesic effects of TENS on acute pain in adults; however, these effects could not be confirmed due to the clinical heterogeneity caused by the integration of various acute pain conditions (13). No comprehensive systematic reviews of TENS have focused on inguinal hernia repair.Transcutaneous electrical nerve stimulation (TENS) is a noninvasive, transcutaneous method of electrical stimulation that produces analgesia Therefore, we aimed to assess the efficacy and safety of TENS in patients who have undergone inguinal hernia repair.(14). This study is registered with PROSPERO (CRD42022353932), and the protocol is registered in OSF (https://osf.io/6qctw/).We followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) 2020 Institutional review board approval was not required for this study as all data were retrieved from published articles.We included individual randomized controlled trials (RCTs) and excluded crossover, cluster, and nonrandomized trials. Furthermore, we included trials that compared adults older than 18 years who underwent hernia repair surgery. We excluded participants who had not undergone inguinal hernia repair when they were included in the study population and those with electronic implants, such as cardiac pacemakers and implantable cardioverter defibrillators. We included trials that compared TENS with placebo or usual care. In addition, we included the following cointerventions if they were not part of the randomized treatment: antibiotics, analgesics, and antiemetics.(8). When pain was measured several times, the last score was used. When pain at rest and pain during activities were measured, the former was used. The proportion of patients requiring rescue analgesics was defined as the number of patients requiring rescue analgesics divided by the total number of patients during postoperative hospitalization. Quality of life was evaluated using the Short Form (SF)-36 total score.The primary outcomes were pain on POD 1 and the use of rescue analgesics, whereas the secondary outcomes were pain on PODs 0 and 2, quality of life, and all adverse events. Pain following hernia repair surgery was defined using the mean visual analog scale (VAS) or numeric rating scale (NRS) regardless of whether the pain occurred at rest or when performing activity via PubMed (1966 to present), EMBASE (1988 to present), CINAHL (1982 to present), AMED (1985 to present), PsycINFO (1806 to present), and Web of Science (1956 to present) ((15). Furthermore, we contacted the authors of the identified trials and asked them to confirm any missing data.We performed a literature search to find all published and unpublished RCTs regardless of language on the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE present) . We checpresent) . We chec(16). We resolved any disagreement through discussion or consultation with a third review author (AM).Two review authors (JW and NI) independently screened the titles and abstracts for inclusion, screened the full text, and extracted the study characteristics and outcomes. We resolved any disagreement through discussion or consultation with a third author (FK or AM). Two of the three review authors (JW and FK or NI) independently evaluated the risk of bias using the Risk of Bias 2 tool (17). We evaluated the quality of evidence based on the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach for each table (18).A table containing summary of findings was created for the outcomes based on the Cochrane handbook (17). We summarized adverse events based on the definition in the original article; however, we did not conduct meta-analyses. We asked the original authors regarding any unreported data. We conducted an intention-to-treat analysis of all dichotomous data when possible. In accordance with the recommendation of the Cochrane handbook, we did not impute missing continuous data (17). We conducted a meta-analysis of the available data presented in the original study using the Review Manager software (RevMan 5.4.2). We used a random-effects model by default.We analyzed the relative risk ratios and 95% confidence intervals (CIs) of the rescue analgesics and the continuous data of pain using the standardized mean difference (SMD) and quality of life using the mean difference. We decided to use the SMD for pain as pain was measured using different scales, such as VAS and NRS, according to the Cochrane handbook 2I statistics  based on the Cochrane handbook (17). We assessed the cause of heterogeneity when it was substantial (2I > 50%). The Cochrane χ2 test (Q-test) was performed for 2I statistics, and P < 0.10 was considered statistically significant.We evaluated the statistical heterogeneity by visual inspection of the forest plots and calculation of the (17). We used the Egger test to determine the statistical significance of the reporting bias. P < 0.05 was considered to indicate statistical significance for reporting bias.We performed an extensive literature search on ClinicalTrials.gov and ICTRP for unpublished trials. When we pooled more than 10 trials, we created and examined a funnel plot to explore possible publication bias (13). We modified our protocol to add subgroup analyses of the anesthesia type and TENS dose and frequency.We conducted subgroup analyses of the surgical approach (anterior approach vs. laparoscopy) and TENS type  We conducted a sensitivity analysis to evaluate the robustness of our conclusions. Studies using imputed statistics and those with incomplete data were excluded. However, we could not conduct a sensitivity analysis of the excluded studies using imputed statistics as there were none.(30).We identified 585 citations, including 544 unique reports. Of these, we screened 18 full-text articles after excluding 527 reports based on the titles and abstracts. After the full-text screening, three articles were excluded, one because of its study design, the other because of its population (IRCT138706101061N2), and another one because of its comparisons. We included 11 RCTs (12 reports) involving 559 patients  (19), (2The eligibility criteria are presented in The evidence related to each outcome is summarized in (30). Among them, 10 used the VAS, whereas 1 used the NRS. TENS likely resulted in a large reduction of postoperative pain on POD 1  (P > 0.05); however, differences were found in the anesthesia type and TENS dose and frequency (P < 0.05). For patients who had undergone local anesthesia, TENS reduced postoperative pain on POD 1  but it did not reduce the postoperative pain of patients who underwent general anesthesia  or spinal anesthesia  on POD 1. Repetitive TENS reduced postoperative pain on POD 1 ; however, single TENS did not . High-frequency TENS reduced postoperative pain on POD 1 ; however, low TENS did not . Funnel plots were visualized as symmetrical, thus indicating minimal publication bias for pain on POD 1 (Egger test = 0.84)  . In the vidence) , no diff = 0.84) .(26). TENS may result in little to no difference in the proportion of patients requiring rescue analgesics  (P > 0.05). Subgroup analyses of the surgical approach and TENS type and frequency could not be conducted.A total of 5 studies with 252 patients reported the proportion of patients administered rescue analgesics vidence) . In the vidence) , no diff(27). TENS may result in a large reduction of postoperative pain on POD 0  (P > 0.05); however, differences were found in the TENS dose (P < 0.05). Subgroup analyses of the surgical approach could not be conducted. Repetitive TENS reduced postoperative pain on POD 0 , but single TENS administration did not .A total of 6 studies with 307 patients reported pain on POD 0 vidence) . In the vidence) , no diff(28). TENS may reduce postoperative pain on POD 2  (P > 0.05); however, there were differences in the anesthesia type and TENS dose (P < 0.05). Subgroup analyses of the surgical approach and TENS frequency could not be conducted. TENS reduced postoperative pain on POD 2 for patients who received local anesthesia  but not for those who received general anesthesia  or spinal anesthesia . Repetitive TENS may reduce postoperative pain on POD 2 , but single TENS did not . The results of the sensitivity analyses were consistent with those of the primary analyses  . In the vidence) , no diffanalyses .(30). The evidence of the effect of TENS on the quality of life is uncertain   .(29). One patient in the TENS group and two in the sham group had skin irritation (redness and itching). No serious adverse events occurred. The certainty of the evidence was moderate.Three studies reported adverse events This review of 11 RCTs that included 559 patients demonstrated that TENS may reduce pain until day 2 following inguinal hernia repair; however, TENS may result in little to no difference in the use of rescue analgesics. Differences were observed in the ability of TENS to reduce pain; such differences were dependent on the anesthesia type or TENS dose and frequency. No serious adverse events were observed. Furthermore, the current evidence indicates that the effect of TENS on the quality of life is uncertain. This is the first systematic review to demonstrate that TENS is useful for relieving pain following inguinal hernia repair.(31). In addition, the duration of the effect of TENS on acute pain was inconclusive. Previous systematic reviews reported that the efficacy of TENS for specific types of acute pain, such as labor pain (33) and dysmenorrhea, has not been proven (34). Our study corroborated the results of these previous reviews and extended them by focusing on patients who underwent inguinal hernia repair and showing that TENS reduced pain on POD 2. According to Cohen’s interpretation, pain reduction following inguinal hernia repair was considered significant at −0.8 or less (35). It is noteworthy that even though local anesthesia is superior to general anesthesia for pain reduction following inguinal hernia repair (36), our subgroup analysis revealed that TENS may be more effective for patients who have undergone local anesthesia. Similar to the results of a previous review of TENS for knee osteoarthritis (37), our subgroup analysis revealed that repetitive TENS was more effective than single TENS. Comparable with the results of a previous review of TENS for acute pain (13), our subgroup analysis showed that high-frequency TENS was more effective than low-frequency TENS. Although internal guidelines suggest that laparoscopy reduces postoperative pain better than the anterior approach (1), our subgroup analysis found no significant difference in postoperative pain on POD 1 between the two approaches. Because our review included only one trial with laparoscopy, additional trials are warranted to help elucidate the role of TENS in pain management for patients undergoing laparoscopic procedures and possibly lead to improved postoperative outcomes.TENS should be used in clinical practice if desired by patients after inguinal hernia repair, particularly those administered local anesthesia or repetitive and frequent TENS, as it reduces pain for up to POD 2 without increasing adverse events. Previous systematic reviews have demonstrated that TENS reduced the pain intensity of adults with acute pain but that acute pain conditions varied and clinical heterogeneity existed (38). Further studies should use the NRS after determining the timing of rescue analgesic use indicated by the protocol.In this review, TENS did not reduce the proportion of patients requiring rescue analgesics. The reason for the absence of differences is unclear; however, it may have been caused by the different postoperative analgesic regimens. Although protocols should predetermine when rescue analgesics is crucial, the outcomes of rescue analgesics use and doses were predetermined by the protocols reported by one of the five studies. In this review, 10 studies used the VAS and 1 used the NRS. In a previous systematic review, the NRS was more sensitive than the VAS for pain assessment (39). However, as TENS is designed to improve acute postoperative pain, the Carolinas Comfort Scale allows better assessment of the quality of life and satisfaction of patients who have undergone surgical hernia repair compared with the generic SF-36 (40). More studies should evaluate the effect of TENS on the quality of life using the Carolinas Comfort Scale.In this review, the evidence of the effect of TENS on the quality of life was uncertain as only one included study reported the quality of life. Severe chronic pain following inguinal hernia repair affects the SF-36 score, a valid indicator of overall health, social life, daily activities, and overall quality of life (41). A previous systematic review of TENS for acute and chronic pain has obtained similar results (33). This supports the notion that TENS is generally a safe intervention for pain management, with only minor adverse effects that can be easily managed. Patients with electronic implants, such as cardiac pacemakers or implantable cardioverter defibrillators, are contraindicated for TENS. In the present review, it is noteworthy that the use of TENS is indicated for patients following inguinal hernia repair. This is because TENS is generally contraindicated to “patients with abdominal or inguinal hernias” prior to surgery. TENS should be used only in patients deemed appropriate by the surgeon, considering their specific condition and potential risks.No serious adverse events of TENS following inguinal hernia repair were observed in this study (moderate certainty of the evidence). Our finding that adverse events were mild, primarily involving erythema and itching at the electrode site, corresponds to safety assessments conducted by professional organizations (43). Considering that the main cause of postoperative pain following inguinal hernia repair is damage to the pubic groin, iliopsoas, and femoropopliteal nerves, this may explain why local anesthesia was particularly effective in the present study. Furthermore, this effect may not last longer than the duration of the stimulation (43), consistent with the finding that repetitive TENS was more effective than single TENS in the present study. The physiological intent of administering conventional TENS is to selectively activate nonnociceptive low-threshold afferent nerve fibers (Aβ fibers) in the skin, which are believed to inhibit the transmission of nociceptive information at the level of the spinal cord (44). The physiological purpose of acupuncture-like-TENS is to increase the activity of small afferent nerve fibers (Aδ) in the muscle, leading to muscle contractions that are thought to activate the descending pain suppression pathway (45). In this study, no significant differences were observed between conventional TENS and acupuncture-like-TENS. High-frequency TENS has been demonstrated to influence the pharmacological effects on the central nervous system in animal studies (46). In the present study, high-frequency TENS was more effective than low-frequency TENS, supporting the notion that higher frequencies may have a more significant impact on pain relief.The exact mechanism of TENS on postoperative pain relief following inguinal hernia repair is unclear. One possible mechanism is that TENS selectively activates low-threshold somatosensory peripheral afferents, which has been demonstrated to decrease the activity and excitability of sensitized and nonsensitized central nociceptive transmitter cells (14). Second, the included studies used different doses and types of TENS; however, we investigated subgroup analyses of the TENS doses, types, and frequency. Third, we could not evaluate chronic pain, but one RCT found no occurrence of chronic pain in either the placebo or TENS group (30). A previous Cochrane review on chronic pain did not provide conclusive evidence to determine whether TENS is harmful or beneficial for chronic pain control. This highlights the need for further high-quality research to better understand the efficacy of TENS in managing chronic pain and its potential impact on various aspects of patients’ lives.This study had several limitations. First, it included only 11 RCTs, and the sample size was small. However, we employed a rigorous methodology based on the PRISMA statement https://osf.io/) to improve transparency. Second, we searched nine electronic databases and two trial registries and carefully and rigorously designed the screening, extraction, and scoring processes according to the Cochrane handbook (17). Third, we evaluated and summarized the outcomes of interest with the certainty of the evidence using the GRADE approach (18).Nonetheless, this review had several strengths. First, the protocol was registered with PROSPERO (CRD42022353932) and published in OSF  1 by A) surgical approach (anterior approach vs. laparoscopy), B) transcutaneous electrical nerve stimulation types , C) anesthesia types , D) dose of transcutaneous electrical nerve stimulation (single vs. twice vs. repetitive), E) frequency of transcutaneous electrical nerve stimulation (high vs. low)Supplementary Figure 2: Funnel plot of pain on POD 1Supplementary Figure 3: Forest plot of the use of rescue analgesics by A) anesthesia types , B) dose of transcutaneous electrical nerve stimulation (single vs. repetitive)Supplementary Figure 4: Forest plot of pain on POD 0 by A) transcutaneous electrical nerve stimulation types , B) anesthesia types , C) dose of transcutaneous electrical nerve stimulation (single vs. twice vs. repetitive), D) frequency of transcutaneous electrical nerve stimulation (high vs. low)Supplementary Figure 5: Forest plot of pain on POD 2 by A) transcutaneous electrical nerve stimulation types , B) anesthesia types , C) dose of transcutaneous electrical nerve stimulation (single vs. twice vs. repetitive)Supplementary Figure 6: Forest plot of pain on A) POD 1, B) POD 0, and C) POD 2, excluding studies with incomplete dataClick here for additional data file.


Neurostimulation is a highly effective therapy for the treatment of chronic Intractable pain, however, due to the complexity of pain, measuring a subject’s long-term response to the therapy remains difficult. Frequent measurement of patient-reported outcomes (PROs) to reflect multiple aspects of subjects’ pain is a crucial step in determining therapy outcomes. However, collecting full-length PROs is burdensome for both patients and clinicians. The objective of this work is to identify the reduced set of questions from multiple validated PROs that can accurately characterize chronic pain patients’ responses to neurostimulation therapies.Validated PROs were used to capture pain, physical function and disability, as well as psychometric, satisfaction, and global health metrics. PROs were collected from 509 patients implanted with Spinal Cord Stimulation (SCS) or Dorsal Root Ganglia (DRG) neurostimulators enrolled in the prospective, international, post-market REALITY study . A combination of linear regression, Pearson’s correlation, and factor analysis were used to eliminate highly correlated questions and find the minimal meaningful set of questions within the predefined domains of each scale.The shortened versions of the questionnaires presented almost identical accuracy for classifying the therapy outcomes as compared to the validated full-length versions. In addition, principal component analysis was performed on all the PROs and showed a robust clustering of pain intensity, psychological factors, physical function, and sleep across multiple PROs. A selected set of questions captured from multiple PROs can provide adequate information for measuring neurostimulation therapy outcomes.PROs are important subjective measures to evaluate the physiological and psychological aspects of pain. However, these measures are cumbersome to collect. These shorter and more targeted PROs could result in better patient engagement, and enhanced and more frequent data collection processes for digital health platforms that minimize patient burden while increasing therapeutic benefits for chronic pain patients.The online version contains supplementary material available at 10.1186/s12955-023-02158-2. The individual and social burdens associated with chronic pain have been escalating globally. Chronic pain affects approximately one in five adults worldwide and estimates of chronic pain among U.S. adults range from 11 to 40% . In addiThe intensity of pain is usually evaluated in clinical settings by subjective unidimensional scales such as the Numeric Rating Scale (NRS) and the Visual Analog Scale (VAS). These pain scales can be useful in assessing a person’s acute or sudden pain intensity. However, these tools can sometimes oversimplify the pain assessment process. Nonetheless, chronic pain often affects other dimensions of a patient’s life such as sleep, physical function, psychological health, and quality of life. Accurate pain measurement facilitates early diagnosis, disease progression monitoring, and therapeutic efficacy evaluation; thus, it is key to the management of chronic pain. Appropriately selected patient-reported outcomes (PROs) are effective tools to measure treatment efficacy using patients’ pain intensity, psychological metrics, disability and physical function metrics, and health-related quality of life scores . ValidatNeurostimulation therapy, in this paper referred to as both Spinal Cord Stimulation (SCS) or Dorsal Root Ganglia (DRG) stimulation, has been very effective in treating chronic pain –12. ReceIn the digital health era, easily obtaining frequent information updates regarding a patient’s health condition, with minimal patient and clinician effort, is of paramount importance. Collecting multiple PROs to accurately measure the impact of pain on different aspects of patient’s lives can be burdensome for patients, research staff, and clinicians. The lengthy list of questions is time-consuming and subsequently reduces the likelihood that all the questions will be appropriately and accurately answered. This manuscript aims to identify a subset of questions selected from the commonly collected PROs for chronic pain that can be used to accurately model and characterize a patient’s response to neurostimulation therapies.Data for our analysis were extracted from the ongoing prospective, multicenter, international REALITY  study (NCT03876054). Before initiating the study, an Institutional Review Board or Ethics Committee approval was received at each site and all patients were provided with written informed consent. The devices used in this study are FDA-approved or approved by a corresponding national agency for this indication. Study enrollment is still ongoing, and subjects will be followed for five years from the time of permanent implant. Study visits occur at enrollment, at baseline, peri-operatively, and at six months, one year, and yearly thereafter until the subject has been followed for five years post-implantation.The eligibility criteria included a baseline pain score ≥ 6 on the 0–10 Numerical Rating Scale (NRS) and scheduled for implantation of an Abbott SCS or DRG neurostimulation system  within 60 days of the baseline visit. The study inclusion criteria for REALITY were designed with few restrictions on the pain indication as allowed by the regulatory bodies in each geographical region and according to standard clinical practice to replicate the range of complex patients that would be seen in everyday medical practice.Demographics, chronic pain history, and pain etiologies were collected at baseline. Various patient-reported outcome measures, as described in detail below, were collected at baseline and each follow-up study visit per the IMMPACT recommendations  to captuWe implemented the principal component analysis (PCA) dimensionality reduction as an exploratory way to identify similarities across multiple PROs. PCA is a statistical method used for large datasets to reduce the dimensionality of the data while increasing interpretability with minimal data loss. Survey questions from all scales were treated as unique entries. Data points from various scales were standardized using the z-score (standard score) prior to this analysis. The z-score describes the fractional distance between a data point and the population means in terms of standard deviation units. We performed linear regression analysis to assess the relationship across multiple PROs such as ODI and PROMIS-29 where PCA identified clusters with common questions.To further examine the questions selected by the PCA within each PRO, we ran Pearson’s correlation  to selecLastly, we evaluated the patient’s response to neurostimulation therapy using both the original long-form and selected short-from questions using Receiver Operating Characteristics (ROC) analysis on the changes of all PRO values at each follow-up visit from baseline. Subject response to neurostimulation therapy was evaluated based on PGIC categories. Subjects who selected “No change (or the condition has gotten worse)”, “Almost the same, or hardly any change at all”, “A little better, but no noticeable change”, and “Somewhat better, but the change has not made a real difference” were considered non-responders. Subjects who selected “Moderately better, and a slight but noticeable change”, “Better and a definite improvement that has made a real and worthwhile difference”, and “A great deal better and a considerable improvement that has made all the difference” were considered responders. The classification accuracies between the original long-form and selected short-form questions were then compared using the Area Under the Curve (AUC) from the ROC analysis. Figure p-values < 0.001) is presented as a Supplementary Table SAt the time of data collection, 538 patients at 53 investigational sites  had completed at least one follow-up visit. Of those, 391 subjects were implanted with an SCS, and 118 subjects were implanted with a DRG neurostimulator system. Baseline characteristics and pain etiologies for all subjects are summarized in Table The PCA analysis on all domains of PROMIS 29, PCS, ODI, NRS, and PGIC revealed clustering of meaningful questions. The top five principal components explained 85% of the data: 55.4%, 10.8%, 7.8%, 6.1%, 4.4%, and 3.9% for each principal component, respectively. As a measure of domain proximity, the 3-dimensional PCA loading plot shown in Fig. R = 0.78), Social Roles (R = -0.72), and Physical Function (R = -0.73). Supplementary, Figure SAs also highlighted in the largest cluster in Fig.  R = -0.7, and PhyPearson’s correlation analysis exposed several highly correlated clusters R ≥ 0.65) within each domain of PROMIS-29 and PCS. Each PROMIS-29 domain includes four questions. A single question within each domain was selected apart from the sleep domain, where two questions were selected Fig. . The pai within eThe ROC analyses showed almost identical classification accuracy for modeling patient response to neurostimulation therapy on the PGIC scale using both long and short versions of PROMIS-29 and PCS scales. The classification accuracy was quantified with the area under the curve (AUC) for both questionnaires. Table In this work, we used statistical models and dimensionality reduction techniques, such as CFA, PCA, and Pearson’s correlation to identify the reduced set of questions from the validated PROs to model subjects’ response to neurostimulation therapy. Our results suggest that selected questions from multi-dimensional PROs that cover different aspects of pain combined into a short-form survey questions are sufficiently good at quantifying overall meaningful improvement in chronic pain populations as the long-form versions of the surveys. There are many highly correlated questions within different domains of PROs such as PCS, PROMIS, and ODI. Although these questions are important factors to provide comprehensive details on subjects’ functioning, psychological health, and pain, they do not necessarily provide additional information on how well a subject is responding to neurostimulation therapy. Our analysis shows the shorter version of the questions proposed here has just as much predictive power as the original longer versions for classifying patient response to neurostimulation therapy using the PGIC scale. In addition, in consideration of the IMMPACT clinical guidelines for the measurement of pain, we kept all the domains of the PROMIS-29 and PCS scales and selected the questions within each domain to make sure we were not neglecting crucial information due to the nature of our data set. Although there are several validated questionnaires for characterizing patients’ emotional distress, PCS was used as the main surrogate for measuring emotional distress. This was due to previous studies that showed pain catastrophizing is the most consistent psychosocial factor predictor of chronic pain and a higher level of catastrophizing is often associated with the intensity of chronic pain intensity and disability .The short form comprising questions selected from the PROMIS-29 and PCS proposed in this study have many overlaps with the already validated shorter versions of PCS  , 35 and R = -0.73; P < 0.001) and social roles , and a strong positive correlation with pain interference . These findings strongly suggest the possibility of characterizing subjects’ physical function and disability measures in response to neurostimulation therapy without collecting the ODI. In addition, the choice of the PROs we used in this work was from our post-market REALITY study. These PROs were selected to capture different aspects of pain for patients with very broad pain etiologies in as close to real-world scenarios as possible. The study results suggest, even with a broad selection of chronic pain patients included in our analysis, a limited set of questions captured from multiple PROs can provide adequate information for measuring therapy success.Our principal component analysis (PCA) suggests that there is overlap across questions obtained from multiple PROs that can be reduced to optimize the process. PCA results showed a clear representation of different aspects of chronic pain such as physical function and disability, psychological affects, sleep and fatigue, and pain intensity that can be captured using different overlapping questions from multiple PROs. The ODI score and its sub-questions are strongly correlated with multiple domains of the PROMIS-29. Prior research established similar correlations between PROMIS physical function and ODI in patients with back or neck pain  as well Our study has limitations. The data used for training and testing the classifications of PGIC were both from a post-market study and was limited to a single intervention. Despite this, the study included patients from 53 international sites and the study was designed with very few exclusion criteria for patient selection in order to replicate the range of complex patients that would be seen in everyday clinical practice. This makes our dataset more heterogenous and less prone to common overfitting issues. Additionally, the conclusions made here have not been tested in all neuromodulation designs or other commercially available programming waveforms; the majority of the subjects in this study were programmed with paresthesia-free DeRidder Burst  with thePROs are important subject measures to evaluate physiological and psychological aspects of pain, but these measures are cumbersome to collect and are sometimes redundant. Reducing the number of questions collected through the surveys likely would increase patient engagement and could help create patient-centric digital health products. Furthermore, the validated long-form and short-form PROs measuring subjective data are limited in distinctiveness. Current subjective measures (using both short and long versions of PROs) have limitations in quantifying subject responses to therapy. Different variables in both models showed AUC around (0.55 to 0.75), demonstrating moderate classification power. Future work will be focused on integrating objective measures gleaned from wearable technologies with subjective data derived from the short form of PROs. Adding objective measurements could improve the accuracy of classification models and enable us to move toward a more personalized therapy with a limited burden on both patients and clinicians.PROs are important subjective measures to evaluate the physiological and psychological aspects of pain. However, these measures are cumbersome to collect. The reduced number of questions selected using our mathematical algorithms demonstrated almost identical accuracy for predicting chronic pain outcomes when compared with using longer validated questionnaires. The shorter and more targeted PROs could potentially result in better patient engagement, enhanced data collection processes, and ultimately increase patient satisfaction with neurostimulation therapy. Testing our approach on independent and more heterogenous data sets and combining meaningful outcomes with objective measures will be the next step in validating our approach and moving away from solely relying on the more subjective NRS/VAS score. This work highlights the potential to move toward a digital health platform that minimizes patient burden while increasing therapeutic benefits for chronic pain patients.Data for our analysis were extracted from the ongoing the prospective, multicenter, international, post-market REALITY  study .Additional file 1: Table Supplementary 1. Summary of all collected PROs  and comparison of the mean of each PRO at all study visits and their corresponding significant differences.Additional file 2: Figure Supplementary 1. Two-dimensional (2D) projection of the top 5 principal components used to cluster the questionnaires. Only ODI total score is included in the 2D projection of the principal components.Additional file 3: Figure Supplementary 2. Regression analysis of the ODI total score versus the PROMIS-29 domains of Physical Function, Social Roles, and Pain Interference. Each blue dot shows an individual subject data point for these two scales. The box and whisker plots show the variation of both scales; the minimum, the maximum, the first and third quartiles, and the median are illustrated with a solid black line.


Specific IgE (sIgE) is merely a sensitization marker that cannot be used for allergy diagnosis if there are no associated clinical symptoms. As of 2023, there is still no evidence regarding the quantity of sIgE necessary to confirm or exclude clinical disease. Therefore, this study aimed to calculate cut-offs for sIgE, allowing us to effectively diagnose olive or grass pollen allergy and select allergenic immunotherapy (AIT) candidate patients in a region under high olive and grass allergenic pressure.An observational retrospective study consisting of the review of electronic medical records from 1,172 patients diagnosed with seasonal rhino-conjunctivitis and suspected allergy to olive or grass pollen. Symptoms correlated with sIgE to Poaceae and Oleaceae whole extracts and sIgE to genuine allergenic components were evaluated. Optimal cut-off values were calculated using receiver operating characteristic curves. Relevant clinical symptoms and AIT indications were taken into consideration when determining the clinical allergy diagnosis.sIgE to Lolium showed the best area under the curve (AUC) for both diagnosis (0.957) and an indication of AIT (0.872). The optimal cut-off values for grass diagnosis and AIT indication were 1.79 kUA/L and 8.83 kUA/L, respectively. A value of 5.62 kUA/L was associated with a positive likelihood ratio (LR) of 10.08 set for grass allergy. Olea sIgE showed the best AUC for the diagnosis (0.950). The optimal cut-off for diagnosis was 2.41 kUA/L. A value of 6.49 kUA/L was associated with a positive LR of 9.98 to confirm olive pollen allergy. In regard to immunotherapy, Ole e 1 sIgE showed the best AUC (0.860). The optimal cut-off was 14.05 kUA/L. Ole e 1 sIgE value of 4.8 kUA/L was associated with a 0.09 negative LR to exclude olive AIT indication.The sIgE cut-offs found in this population under high olive and grass allergenic pressure reduce the gap between sensitization and clinical allergy, providing a new tool for the diagnosis of seasonal allergic rhinitis/asthma and helping to discriminate patients who will benefit from AIT. According to the World Health Organization (WHO), 500 million people worldwide suffer from rhinitis and 262 million have asthma. These two diseases significantly impair the quality of life of the inflicted individuals and their relatives .in vitro testing , and severity assessment are key to determining the need and appropriateness of therapies aimed to modify the course of the disease, such as allergen-specific immunotherapy.For an accurate diagnosis, quantification of sIgE is a decisive factor. However, the current criteria for determining positive/negative or clinically relevant/non-relevant sensitization/non-sensitization are influenced by a lack of evidence-based cut-offs .The “clinically relevant sensitization” concept, generally considered as sIgE detectable loads in the context of consistent symptoms, is a must to discriminate which patients would benefit from allergen immunotherapy. Besides the traditional optimal cut-off based on sensitivity/specificity balance, a new diagnostics strategy based on the ratios of whole extract-specific IgE/total IgE and component-specific IgE/whole-extract specific IgE has recently been proposed to define the relevance of sensitization in the patient symptoms .Olea europaea) is one of the most important respiratory allergy triggers in the Mediterranean area and in regions of America, South Africa, Japan, and Australia   , 10–13.In conclusion, our aim was to establish effective and efficient cut-off points for sIgE to genuine allergenic components and to the whole allergens (Poaceae and Oleaceae). By establishing these cut-off points, we could identify genuine sensitizers and ultimately predict the clinical reactivity to these pollens while increasing the probability of AIT success in highly exposed patients.2.2.1Retrospective study carried out in Hospital Reina Sofía, Córdoba, . The study population included all consecutive patients referred for allergy evaluation to our hospital from January 2015 to April 2018. Inclusion criteria were established as suspicion of olive and/or grass pollen allergy according to general practitioner anamnesis.At the first visit, all included patients were subjected to skin prick testing with grass/olive pollen extracts. Patients with negative results for both pollens were then excluded. For patients displaying a positive result or negative result , specific IgE (sIgE) tests were requested as detailed in the diagnostic algorithms .Lolium perenne whole extract) and Oleaceae (Olea europea whole extract) pollen antibody loads. Then, if the result was positive (>0.35 kUA/L), the sIgE levels for olive  and grass  allergen genuine sensitization components were tested. For those sera testing negative, sIgE levels to highly cross-reactive allergens  and profilins (rPhl p 12)) were determined  was collected from the patient's electronic medical records. Based on this information, the allergy specialists evaluated the appropriateness of allergen-specific immunotherapy according to standard guidelines for AIT prescription.A total of 1,205 cases were initially included. However, 33 of them were excluded, and therefore a total of 1,172 cases were finally considered for the statistical analysis.2.2Clinical data and laboratory marker values were obtained from electronic medical records corresponding to the clinical episode at the inclusion visit.2.2.1.A/L), final diagnosis , and consideration of immunotherapy (yes/no) were also recorded.The collection form included demographic, epidemiological, and clinical data such as age at diagnosis, gender, symptoms , skin tests, laboratory data, clinical diagnosis, and immunotherapy details. Patients with rhino-conjunctivitis were classified following ARIA guidelines  as mild Outcome variables were the final diagnosis and AIT indication.2.2.2.Olea europaea, Lolium perenne, and profilin . Polcalcin extract was supplied by ALK Abelló as no commercial extract. A positive result was established for a mean diameter wheal of ≥3 mm (Skin prick tests (SPTs) were performed following the routine diagnostic procedure, using available commercial extracts: of ≥3 mm . The res2.2.3.Serum total IgE (tIgE), sIgE to the whole extracts, and species-specific components from olive and grass pollen were tested. Total serum IgE levels were measured by sandwich immunoassay on an Advia Centaur analyser ; sIgE load to Lolium, Olea, rPhl p 1,5, rPhl p 7 + 12, Ole e 1, Ole e 7, and Ole e 9 were measured by fluoroenzymeimmunoassay with ImmunoCAP  on a Phadia 250 system, according to the manufacturer's specifications.2.2.4.The allergological diagnosis was established through the integration of clinical data, SPT results, and sIgE values, according to allergy specialist criteria for clinical routine. Patients with clinically relevant symptoms of rhinitis/rhinoconjunctivitis/bronchial asthma during the olive or grass pollen pollination period (April to June) and positive sIgE (Prick-test or ImmunoCAP) were considered allergic .2.2.5.Immunotherapy indication was considered for allergic patients with moderate-severe or poorly controlled rhinitis. In the case of bronchial asthma, it was indicated when the disease was well controlled with low or medium levels of treatment [therapeutic steps 2–4 from GEMA ]. The co2.3.The Kolmogorov-Smirnov test was used to assess the normal data distribution. Demographic and clinical characteristics of patients were expressed as mean and standard deviation (SD); If not adjusting for a normal distribution, the median was used to represent non-parametric data for continuous variables, and frequency distributions represented categorical variables.The Mann–Witney test or Kruskal–Wallis test was used to analyse the relationship between continuous and categorical variables. Spearman's correlation coefficient was used to evaluate the correlation between quantitative variables.1.Grass allergy or both vs. non-allergic or Olive allergy.2.Olive allergy or both vs. non-allergic or Grass allergyFinally, the maximum value of the Youden Index (YI) was used as a criterion for selecting the optimal cut-off value for each variable , negative predictive value (NPV), the receiver operating curve (ROC), and the area under the curve (AUC) were calculated with the following comparisons:variable . Moreovevariable .3.3.1.A/L for Olea-sIgE, and 3.5 kUA/L for Lolium sIgE. 70.5% of the included subjects were positive for olive extract and 58.4% positive for grass extract using SPT. According to the final diagnosis made by the Allergy specialist, patients were classified into four groups: 17.8% (209) were diagnosed with grass allergy, 24% (281) with olive allergy and 29.2% (341) were allergic to both pollens; moreover, allergy to olive/grass pollen was ruled out in 29.1% (341) of the individuals. AIT was indicated in 29.6% of the patients. The final percentage of patients who received AIT was 22.3%.A total of 1,172 individuals with suspected allergy to olive or grasses were included. Descriptive baseline characteristics of the total population and stratified according to final allergy diagnosis are shown in 3.2.A/L), 84% were positive to Ole e 1, 56.4% were positive to Ole e 7, and, 33.4% were positive to Ole e 9. p < 0.001), 0.818 (p < 0.001) and 0.636 (p < 0.001) respectively. For Ole e 1 and Ole e 9, the correlation was 0.628 (p < 0.001). Ole e 1 and Ole e 7 showed a correlation of 0.585 (p < 0.001). Finally, the correlation between Ole e 7 and Ole e 9 was 0.496 (p < 0.001). Moreover, the correlation coefficient for Ole e 1 and Ole e 9 in patients Ole e 9 positive was 0.706. Regarding grasses, Lolium sIgE and rPhl p 1,5-sIgE showed an overall Spearmańs correlation coefficient of 0.904 (p < 0.001).sIgE values to the whole olive and grass extracts and their respective molecular components are shown in Tables 3.2.85 from 209 (40.7%), 118 from 281 (42%), and 58 from 341 (17%), grass pollen allergic patients, olive or both respectively, received AIT . None of3.3.A/L with 98.47% sensitivity and 82.77% specificity. Moreover, a value of 5.62 kUA/L showed a positive likelihood ratio (+LR) of 10.08, corresponding to 92.27% specificity 92.27%. Considering the grass allergy indications as the result variable, once again, Lolium showed the best AUC (0.872: 95% CI 0.849–0.896). Nevertheless, considering rPhl p 1,5-sIgE as final variables showed also relevant results. The optimal Lolium cut-off for grass AIT indication was 8.83 kUA/L with 93.98% sensitivity and 71.94% specificity , Lolium sIgE showed the best area under the curve . Thus, the optimal Lolium-sIgE cut-off was 1.79 kUcificity .A/L, with 95.34% sensitivity and 83.70% specificity . Considering the AIT indication for olive allergy as the result variable, Ole e 1-sIgE showed the best AUC . The optimal Ole e 1 cut-off for olive AIT was 14.05 kUA/L, with 83.33% sensitivity and 76.5% specificity. Ole e 1 load of 4.8 kUA/L showed a -LR of 0.09 to exclude olive AIT (sensitivity 94.25%). The diagnostic accuracy threshold for each allergen is shown in Univariate ROC analysis considering olive pollen allergy final diagnosis , Olea sIgE showed the best area under the curve . The optimal Olea sIgE cut-off was 2.41 kUcificity . Moreove3.4.A/L) with the best cut-off values obtained with our analysis, where 2.4 kUA/L for Olea-sIgE and 1.79 kUA/L for Lolium-sIgE for clinical diagnostic purposes. Likewise, we compared the performance of the standard cut-off (0.35 kUA/L) with the best cut-off for Ole e 1-sIgE (14.05 0.35 kUA/L) and Lolium-sIgE (8.83 0.35 kUA/L) obtained from our analysis for indication of AIT. The statistical parameters, sensitivity, specificity, and positive and negative predictive values are shown in We compared -in our population- the performance of the standard cut-off  and its severity  were analysed. Higher loads of sIgE to Olea, Ole e 1, Ole e 7, Ole e 9, and Lolium were associated with the presence or severity of rhino-conjunctivitis and/or asthma –5. Howev4.A/L as the cut-off. Thus, revealing the lack of real validated cut-offs to assess the sensitization clinical relevance. The sIgE cut-off has been generally set to 0.35 kUA/L, without considering other factors that could influence the immunogenicity of the allergen and the characteristics of the disease presentation. For the same reason, values below this cut-off have been shown to be relevant  and much better specificity (82.55%) were obtained compared to those obtained with the 0.35 kUA/L cut-off (A/L NPV was similar for both methods (close to 100%), the PPV was very low for the in vitro assay. Increasing ImmunoCAP cut-off to 1.5 kUA/L paired PPV from both methods  for specific IgE >3.5 kUA/L  and an increased specificity (83.7%)  were obtThe fact that we were unable to settle a cut-off value for Olea AIT indication reinforces the concept that this is a multiple factor-dependent decision that must be made on a case-by-case basis. A real-life example is represented by Ole e 9, which does not seem to influence the indication for olive AIT in our population. Nevertheless, the evidence of variability in Ole e 9 content from one immunotherapy batch to another requires an accurate characterization of Ole e 9 sensitized patients and only commercial immunotherapy extracts containing considerable amounts of the protein are valid for them .Moreover, the Ole e 7 cut-offs for AIT prescription that we have calculated are biased by a particular prescribing habit in our group, which in clinical practice reduces the prescription of olive pollen AIT to patients exhibiting much higher levels of sIgE Ole e 7 than sIgE Ole e 1. The main reason is that a higher incidence of AIT systemic reactions in olive-allergic patients with exclusive or predominant sensitisation to Ole e 7 has been described . In factAs also described by Moreno et al. , it shouThe main limitation of this study is the retrospective nature of data from clinical practice without a specific previous design. For this reason, there are notable data gaps, such as tIgE in some included patients. The analysis of the so-called ratios and the determination of cut-off values for these ratios could also have been of interest to complete our studies . AnotherAllergic profiles are local, so when talking about the generalization of the results , we must consider that this study was carried out in a single center in a specific geographical area; therefore, the safety of the data obtained when applied in other regions, still has to be determined. Nevertheless, the value of the differences in the variables between groups has been obtained with an explicitly stated confidence interval of 95%.in vitro test results using a Bayesian approach has recently gained interest. In contrast to the dichotomy of a single, often arbitrary cut-off point, the use of LRs helps to determine to what extent a test result changes the probability of a particular diagnosis or treatment indication  that shorten the gap between sensitization and clinical relevance in the diagnosis of seasonal allergic rhinitis to olive or grass pollen, or both. It also provides cut-offs that, together with the clinical history and the sensitization profile, could help in clinical decision-making, such as the AIT prescription. Additionally, it suggests that simplified diagnostic algorithms would save analytical determinations while improving patient diagnosis and healthcare system efficiency.Further prospective studies are needed in which the predictive value of sIgE for diagnosis could be compared with the expert's diagnosis, blinded to this factor and based on clinical and skin prick test results. Likewise, it could be helpful to include the evaluation of the response to immunotherapy and not exclusively the indication for immunotherapy.


One of the current choices of treatment for Trapeziometacarpal (TMC) joint arthritis is trapeziectomy with ligament reconstruction and tendon interposition arthroplasty. The Ceruso’s technique consists of complete trapezial excision and abductor pollicis longus (APL) tendon suspension. The APL tendon is tied to the flexor carpi radialis (FCR) tendon with two loops, one around it and one inside, and then used as interposition tissue. The purpose of the present study was to compare two different techniques of a trapeziectomy with ligament reconstruction and tendon interposition arthroplasty using the Abductor Pollicis Longus (APL) tendon, which is only Once Looped Around (OLA) versus Once Looped Inside (OLI) the Flexor Carpi Radialis (FCR) tendon.A single-center, retrospective study (Level of evidence: III) has been conducted on sixty-seven patients older than 55 years , assessing clinical outcomes for at least 2 years of post-surgery follow-up. The outcomes were to assess and compare surgical outcomes comparing the two groups, in terms of subjective and objective evaluation for both groups at the last follow-up (primary outcome), and at the intermediate follow-ups (three and six months). Complications were also assessed.The authors found an improvement in pain, range of motion, and function, with equivalent results for both techniques. No subsidence was observed. FCR tendinitis was significantly reduced with OLI, as well as the need of post-operative physiotherapy.The one-loop technique allows for reduced surgical exposure, providing excellent suspension and clinical outcomes. Intra FCR loop should be preferred to improve post-surgical recovery.Level III study. This is a retrospective cohort study (written according to STROBE guidelines). Osteoarthritis of the trapeziometacarpal joint of the thumb is a painful and debilitating condition of the hand with a reported age-adjusted prevalence of 7% in men and 15% in women . ConservIn advanced stages, , –4 reconsIn our center, for several years we routinely performed a simplified version of this technique with a single-loop passage around the FCR , hereinafter called the OLA (one-loop around) technique Fig. B. Our beTherefore in 2015, we made a further adjustment to the technique. The external weaving of the APL tendon around the FRC tendon was avoided, and the slip of the APL was passed through the FCR tendon and fixed without additional maneuvers. We have called this further modification “one-loop inside” (OLI) technique  joint arthritis who underwent surgery from January 2015 to April 2018 were considered. A written consent was obtained from all patients before surgery.Patients older than 55 years;Stage III-IV disease of Eaton and Littler .At least 2 years of post-surgery follow-up.A retrospective study has been conducted on 201 consecutive patients affected by TMC joint arthritis who have been treated at our center between January 2015 and April 2018. The inclusion criteria were:The exclusion criteria were the presence of hand polyarthritis (confirmed by the preoperative X-ray), rheumatic diseases, neuromuscular disease, scaphoid-trapezial-trapezoidal arthritis, previous corticosteroid injection in TMC joint and the simultaneous presence of other hand diseases  with or without indication to surgery. Patients with severe metacarpo-phalangeal (MP) hyperextension (> 20°) were also excluded from the study. In the event of hyperuricemia, patients were prescribed treatment and then required to repeat blood tests, to confirm the normalization before surgery. Furthermore, patients with a follow-up period shorter than 2 years, or who had undergone reoperation, or who had suffered fractures to the hand and wrist before the last follow-up were excluded from the study. Finally, patients with incomplete pre- or post-operative data set were excluded from the study.Pre-operative dataset included general demographic, clinical history, Charlson Comorbidity Index (CCI) score, X-rays of both hands , thumb opposition score of Kapandji, strength measured through dynamometers , Michigan Hand Outcome (MHQ)  and DASHGroup A: patients operated on with the OLA technique;Group B: patients who underwent OLI technique.Given the retrospective evaluation no randomization was performed and eligible patients were divided into two groups as below considering the description of the surgery:All patients were operated on by three authors and signed an informed consent before surgery.Surgery is performed under peripheral anesthesia and transient ischemia (pneumatic cuff) by two expert hand surgeons (R.D.V. and G.T.). The skin is incised longitudinally (approximately 40–45 mm) along the course of the APL, centered on the TMC joint. The sensory branches of the radial nerve and the radial artery are identified and protected, the joint capsule is Y-incised to preserve a large distal triangular flap, the basis of which is inserted on the first metacarpal bone. Trapeziectomy is performed. The FCR tendon is exposed at the bottom of the surgical field. The APL tendon is commonly composed of several distinct subunits; the most dorsal subunit should be used to perform the arthroplasty and tendon interposition, after ensuring that it inserts at the base of the first metacarpal bone. The selected portion is then isolated and dissected proximally about 6 cm from its distal insertion. The skin at that point is very elastic. Excellent exposure is achieved by lifting the proximal end of the skin incision. Furthermore, the tendon is harvested without opening the pulley of the first dorsal compartment.OLA: the APL subunit is looped around the FCR from palmar to dorsal at the bottom of the surgical field.OLI: the APL subunit is looped inside the FCR from palmar to dorsal at the bottom of the surgical field perforating the tendon with a curved and blunt instrument Fig. .Now the technique is continued in two different ways:Regardless of the variant (OLA or OLI), APL is anchored on the capsule through a hole in the triangular capsular flap using a nonresorbable woven 2.0 suture. The suture is performed to give stability to the first metacarpal bone, by exerting adequate traction on the tendon, to ensure sufficient hold of the suspension, with the first metacarpal bone in a neutral position . HemostaA plaster splint is made, to block the wrist, with thumb in anteposition and abduction, and free thumb IP joint, to be maintained for four weeks.Any patient, who has a normal course that meets our expectations, gradually resumes his or her usual activities two months after surgery, with full recovery from the sixth month post-surgery.Pain is managed by pain killer therapy with NSAIDs, based on the needs of the individual patient. After surgery, patients underwent a month of physical therapy with a physical therapist specializing in the hand. We consider one month of physiotherapy assisted by the specialized physiotherapist as the standard to achieve a good recovery of hand function for all patients. At the end of the month, the therapist decides in agreement with the patient whether it is appropriate to continue physiotherapy, depending on the functional recovery achieved.However, the need for physiotherapy lasting more than one month is considered not attributable to a normal post-operative course, even if the result obtained is very good. For this reason, in our opinion, the need for further physiotherapy is to be considered as a complication.Flexor carpi radialis (FCR) tendinitis is characterized by swelling and pain of volar radial wrist and is a frequent complication of this type of arthroplasty. This complication appears soon after plaster removal and is described by several patients as disturbing and life-dampening. Flexor carpi radialis (FCR) tendinitis could be resolved spontaneously, with splints and drugs, with spontaneous rupture of the FCR tendon or with surgical release of the tendon , 19.Each patient was assessed pre-operatively and post-operatively at 3-month, 6-month and 2-year follow-ups at our outpatient clinic. Pain was investigated using a visual analogue scale (VAS), where zero indicates no pain and 10 the maximum unbearable pain, and overall satisfaction using a ten-point scale, where zero is totally dissatisfied and 10 is completely satisfied. Impact of disability was assessed with the Quick DASH questionnaire and MHQ questionnaire. The range of opposition was classified with the Kapandji score. Grip strength, tip and lateral pinch strength by using a dynamometer.The primary outcome was to assess and compare surgical outcomes comparing the two groups, in terms of subjective and objective evaluation for both groups at the last follow-up. The secondary outcome was to analyze any significant difference in terms of pain, DASH and MHQ score during the post-operative recovery, at 3 months (T1) and 6 months (T2) after surgery, and to outline any difference in complication rates.All data were analyzed using IBM SPSS Statistics for Macintosh, Version 26.0 . For numerical data, mean ± SD were assessed.The Wilk-Shapiro test was used to check for normal distribution for continuous variables.t test was used for parametric data. The Wilcoxon test for two dependent continuous non-parametric variables, the Mann–Whitney U-test for two independent continuous was used for non-parametric variables. For nominal data, the Chi-square test was applied to evaluate the p values associated. Statistical significance was expressed as p < 0.05.The Among 201 consecutive patients, 68 were identified by applying the inclusion and exclusion criteria. Group A (OLA) consisted of 35 patients (4 men and 31 women), with an average age of 64.4 (± 4.3) years. Group B (OLI) consisted of 33 patients (3 men and 30 women), with an average age of 62.8 (± 4.9) years.Clinical and demographical features of participants are resumed in Table p > 0.05), as resumed in Table About the primary outcome: no differences have been revealed in terms of clinical and functional results comparing the two techniques. At the last follow-up, patients obtained excellent results in both groups , with better results with OLI technique. This clinical difference was not found to be statistically significant at further follow-ups (Table p = 0.01). Almost half of the patients in group A underwent postoperative physiotherapy (16/35) compared to an eighth (4/33) of patients in group B (p = 0.006). No one underwent reoperation.TMC subluxation, subsidence or loss in suspension were checked through X-rays at the last follow-up. In accordance with Andrew J. Miller  et al. uAim of the surgical treatment of thumb carpometacarpal osteoarthritis is to eliminate pain, to provide stabilization and to standardize the modalities of surgical treatment , 21–28.Simple trapezial excision, initially performed in 1948 , is commMultiple procedures of trapezial excision with soft tissue arthroplasty were described and are distinguished between trapeziectomy + LRTI and Hemi-resection interposition arthroplasty.Hemi-resection interposition arthroplasty provides similar benefits to trapeziectomy + LRTI in cases with no or mild joint subluxation and can be considered in younger, active patients .LRTI is the most frequently surgical treatment performed for thumb carpometacarpal osteoarthritis and one option for a failed hemi-resection interposition arthroplasty or failed total joint prosthesis replacement. The most common complications are metacarpal subsidence and FCR tendinitis , 19, 20.Different techniques are often performed, but limited comparative evidence exists between these techniques. The interposition material and suspension tenoplasty are considered essential surgical procedures to give more support to the thumb and to reduce the metacarpal subsidence.Many anchor passages and many sutures are commonly performed to reinforce the suspension but there are no precise references regarding tension and filling in suspension teno-arthroplasty because is difficult to prove , 13, 14.Catalano F. simplified the technique performing a single loop thinking that this procedure, together with careful capsuloplasty hourglass-like and intra-capsular fibrosis that occur in the 4 weeks of immobilization, was enough to stabilize the joint and to reinforce the suspension.These modifications produced a reduction of surgical exposure because the tendon to be prepared is much smaller. A reduction of surgical times guaranteeing excellent results in terms of pain reduction, maintenance of strength and global function. Compared to a simple trapeziectomy, the modified technique promotes rapid functional recovery with excellent patient satisfaction. , 13, 14In this work, we perform a comparison between trapeziectomy + LRTI/OLA and trapeziectomy + LRTI/OLI. The risk of adhesion in both OLA and OLI LRTI is lower than in other LRTI because the incision and dissection is shorter resulting in a hemi-resection of the APL and due to there being only one loop rather than Ceruso’s double loop technique.No differences have been revealed in terms of clinical and functional results comparing the two techniques. We did not find any metacarpal subsidence at the final follow-up.However, significant differences have been revealed in terms of pain, MHQ and DASH scores with better results with OLI technique due to the lower incidence of FCR tendinitis.The common techniques of LRTI could cause FCR tendinitis by overload on synovial of the FCR tendon . OLI tecIn the case of FCR tendinitis, a spontaneous resolution often occurs in a few months. Corticosteroid injection or physiotherapy is rarely needed.There have been no ruptures of the FCR tendon, but if it occurs after the end of the fibrosis stabilization, we think that the metacarpal subsidence is not a complication to be considered and no treatments are necessary. However, a longer follow-up might lead to different findings.The further modification made to Catalano’s technique maintains the improvement of the original technique and represents a further improvement in post-operative management.


Thoracic myofascial pain syndrome is a clinical problem arising from the muscles and soft tissues of thoracic region, which include the mid and upper back area. Risk factors associated with myofascial pain syndrome are muscle overuse and repetitive strain, poor posture, trauma or injury, emotional and psychological stresses. The management of myofascial pain syndrome (MPS) typically involves a multidimensional approach that focuses on relieving pain, reducing muscle tension, and improving muscle function. Bowen therapy and tennis ball technique are also recommended for treating myofascial pain syndrome.The objective of this study was to compare the effects of Bowen therapy and tennis ball technique on pain and functional disability in patients with thoracic myofascial pain syndrome.It was a randomized clinical trial conducted on thirty patients. It was carried out in physiotherapy outpatient department of D.H.Q Hospital, Kasur. Non-probability convenience sampling technique was used. Data collection was done from the patients of thoracic myofascial pain syndrome by using Numeric Pain Rating Scale (NPRS) for pain and Pain Disability Questionnaire (PDQ) for functional disability. Participants were randomly allocated into two groups using computer generated random number method. Group A received Bowen therapy, and group B received tennis ball technique. Outcome measures were measured at baseline, after second week treatment session and after fourth week with three sessions in a week on alternate days. Data analysis was done by using Statistical Package for the Social Sciences (SPSS) version 26.p value < 0.05. The results indicated that both treatments were significant but Bowen therapy is more effective treatment than tennis ball technique. Within-group difference calculated with repeated-measure ANOVA indicated that there was significant difference from pre- to post-values of both groups.There was significant difference between the mean values of NPRS and PDQ in both groups at baseline, second week and fourth week with Trial registration. (IRCT20190717044238N7).This study concluded that Bowen therapy produced statistically significant and clinically relavant results for all the outcome measures.  Myofascial pain syndrome (MPS) is a disorder that causes pain and discomfort in the muscles and surrounding soft tissue. It is caused by the existence of trigger points, which are sore areas in the muscle that become painful when pressure is applied . These tOne commonly used set of criteria is the "Diagnostic Criteria for Myofascial Trigger Points" developed by Simons et al. They proposed five major and three minor criteria. Here are the diagnostic criteria for MTrPs according to Simons et al. The major criteria include (a) regional and impulsive pain; (b) palpable taut band in accessible muscle; (c) within the taut band, there should be a tender point, exquisite localized tenderness; (d) the palpation of tender point should reproduce or intensify the patients typical complaint of pain; and (e) decreased range of motion, when measurable. The minor criteria include (a) altered sensation or propagation of pain complaint due to tender points; (b) local twitch response by inserting needle into the taut band; and (c) pain is diminished or decreased by muscular therapy (stretching of muscles or injection of the MTrPs).Presence of five major and one out of three minor criteria is necessary for diagnosing myofascial pain syndrome .The manaThe study was randomized clinical trial. Trial was registered in IRCT with IRCT reference number: IRCT20190717044238N7.Data were collected from the physiotherapy department of D.H.Q Hospital, Kasur.A single blinded, randomized clinical trial was used in this investigation, which was lasted for ten months. In this study, 30 patients with thoracic myofascial pain syndrome were selected after meeting the inclusion and exclusion criteria. According to inclusion criteria, participants were included on the basis of diagnostic criteria explained by Simon and Travell et al. for MPS: the existence of five major  and at least one out of three minor signs   and age This scale is used for assessing pain. English version of NPRS was used in this study. Total score is 0–10. With 0 representing ‘no pain’ and 10 representing ‘pain at its extreme,’ the patients were requested to select a number between 0 and 10 that best described their pain before and after treatment. NPRS declared the good test-retest reliability is r = 0.79–0.96  .The Pain Disability Questionnaire (PDQ) is tool for assessing disability caused by pain. English version of this scale was used. The total score of PDQ is 0–150. The following ranges are used to examine the score: mild/moderate (0–70), severe (71–100), extreme (101–150) . PDQ exhhttps://www.randomizer.org/), subjects were divided into two groups at random. The allocation list was created using the approach of sealed, opaque envelops, labeled 1 for group A and 2 for group B. Thirty participants were divided into two groups fifteen in each group. Group A participants received Bowen therapy, and group B participants received tennis ball technique. The CONSORT flow diagram represented the process of participants’ assignment to these groups.Using computer software  .Version 26 of SPSS for Windows was used to analyze the data. The statistical significance was set at p ≤ 0.05. The tests utilized were as follows:p = 0.054–2.00). Analysis of variance (ANOVA) was performed to assess the differences within group after adjusting for pre-test scores in order to determine whether group had the more successful intervention. The 95% confidence interval was kept when the p-value was less than 0.05, indicating that the result was significant. Between the two groups, the difference in effect size was assessed by Cohen’s d. Effect sizes of 0.2, > 0.5, and > 0.8, respectively, were categorized as small, medium, and large.Frequency tables were utilized to display an overview of the group measures taken throughout time. For each variable, the mean and standard deviation were computed. The Shapiro–Wilk test was used to examine the assumptions of normality, and the results showed no obvious violations ; therefore, parametric test was applied.Table Table p-value < 0.05. Although both the therapies were found to be effective, Bowen therapy showed better results as compared to tennis ball technique. Mechanism of action of Bowen therapy is that it stimulates the sensory fibers of nervous system which in turn helps to restore body’s health [The recent study was conducted to campare the effects of Bowen therapy and tennis ball technique on pain and functional disabillity in patients with myofascial pain syndrome. Thirty participants were selected randomly after meeting the inclusion and exclusion criteria. Within-group analysis indicated that participants receiving Bowen therapy and tennis ball technique showed a statistically significant reduction in pain, and improvements in functional disability with s health . Tennis s health . The fins health . Anothers health .The outcomes of this study are consistent with earlier investigations of patients with dyspraxia, a developmental problem. Boys with dyspraxia aged 8 to 11 were the subjects of this study. An eight-week treatment period was followed by a post-treatment evaluation. The study's findings demonstrated the positive effects of Bowen therapy on motor function. Following the fascia treatment with Bowen therapy, motor function significantly improved . In contThe outcomes of previous studies are consistent with the results of the recent investigation. These studies' conclusions concur with one another. Bowen treatment is a special method for enhancing functionality and reducing pain. For patients with myofascial pain syndrome, it can be used as an extra therapeutic option to enhance functional outcomes.In 2020, Fariba Eslamian et al. studied the effects of electroacupuncture and biofeedback on neck and upper back myofascial pain syndrome. This randomized clinical trial showed that both treatment protocols were equally effective. Intergroup comparison showed that electroacupuncture was more effective in some parameters over biofeedback treatment . In MalaThis study concluded that Bowen therapy produced statistically significant and clinically relevant results for all the outcome measures. Bowen therapy was proved to be more effective in reducing pain and improving functional disability as compared to tennis ball technique.There was lack of considering the other factors like depression and anxiety and the results cannot be generalized to all age groups. It is recommended that future research should conduct larger sclae randomized controlled trials to confirm the effectiveness of Bowen therapy and consider long-term follow-up to assess the sustained effects of Bowen therapy beyond the immediate intervention and study should also be conducted to see the effects of Bowen therapy on aged population.


A long-acting κreceptor agonist parenteral analgesic may theoretically improve acute pain and reduce incidence of chronic postsurgical pain (CPSP) after laparoscopic cholecystectomy with minimal drug-related side effects of the traditional μreceptor opioids.n = 40) or placebo (n = 40) after anesthesia induction. Standard multimodal analgesia (MMA) was administered for postoperative pain control. The primary endpoint was pain intensity within 7 days after surgery. The secondary endpoints were incidence CPSP at 3 months and adverse reactions up to 7 days after surgery.Eighty adult patients undergoing elective laparoscopic cholecystectomy were randomly assigned to receive single intramuscular injection of an extended-release sebacoyl dinalbuphine ester . Significantly higher incidence of drug-related adverse events, including dizziness, nausea and injection site reactions, were recorded in the SDE group.The highest visual analogue scale (VAS) and area under the curve of VAS 0 to 48 hours after operation were not different between the two groups and a similar proportion of patients requested rescue parenteral analgesics. Average pain intensities were also not different at 72 hours and 7 days after surgery. Incidence of CPSP was 22.5% and 13.1% in patients who received placebo and SDE treatment, respectively (A single dose of extended-release analgesic SDE given intraoperatively did not provide sufficient add-on effect for acute and chronic pain management after laparoscopic cholecystectomies in patients who received standard postoperative MMA. Intramuscular injection of 150 mg SDE in patients with average body mass causes adverse events that could have been overlooked. More clinical studies are warranted to determine the target populations who may benefit from SDE injections for improvement of acute and chronic postsurgical pain management. Patients may still suffer from acute postoperative surgical-related pain even with the minimally invasive laparoscopic operations. It has been found that up to 80% of patients undergoing laparoscopic cholecystectomies complained of moderate-to-severe pain within the first day after the operation. Most importantly, 20% of the patients may develop persisting chronic postsurgical pain (CPSP) within 1 year postoperatively and they require prolonged use of opioid analgesics to control the CPSP. Several important clinical observational studies have suggested that inadequate control of surgical-related pain at the initial week after cholecystectomy is one of the major risk factors for developing CPSP. Since the length of hospital stays after uncomplicated laparoscopic cholecystectomies are relatively short ,,6 postoperative pain is inevitably managed by repeated doses of oral form analgesics, including opioids. Management of postoperative pain using a multimodal analgesia (MMA) approach is widely recommended by the international scientific societies by administration of drugs with differing mechanisms of actions target pain pathways resulting in additive and/or synergistic effects to opioids. Therefore, a long-acting parental analgesic in addition to the standard MMA could be a viable strategy to achieve optimal control of acute postoperative pain after laparoscopic cholecystectomies in patients who are discharged early (within 24 hours). This strategy could also reduce the incidence of CPSP as plasma therapeutic levels of the parental analgesic can be maintained for several days after injection.Cholecystectomies are a common procedure for the surgical removal of inflammed or otherwise pathological gall bladders and most cholecystectomies are performed laparoscopically in Taiwan (>85%). Sebacoyl dinalbuphine ester  is the prodrug of nalbuphine, and was approved by the Taiwan FDA in 2017. After intramuscular injection, SDE is hydrolyzed by tissue esterase to release the active compound nalbuphine. The systemic bioavailability of nalbuphine is 85.4% with a mean absorption time of up to 145 hours. Therefore, a single parenteral injection of SDE may provide a prolonged analgesic effect for 6 days. Currently, there have been 3 prospective randomized double-blind trials investigating the efficacy and safety of SDE for pain management after hemorrhoidectomy, laparotomy and laparoscopic bariatric surgery. The clinical outcomes of these previous studies show that SDE is superior to the conventional or patient-controlled analgesia for the management of acute postoperative pain with less need for rescue analgesics and more tolerable adverse drug reactions. However, patients who were assigned to control groups in the first 2 studies did not receive the standard MMA treatment, and periods of observation for adverse events were not specified in the study protocols. Furthermore, SDE was administered at least 12 hours before surgical intervention in these studies, which can be a major limitation for the application of SDE in the day-case surgeries, such as laparoscopic cholecystectomy. Therefore, this clinical study was designed to determine the extended analgesic effect of SDE administered after anesthesia induction as a component of MMA for laparoscopic cholecystectomy and evaluate the drug-related adverse events up to 7 days after administration.Nalbuphine is a semi-synthetic opioid that acts as a mixed κreceptor agonist and μreceptor antagonist, but its clinical applications for acute postoperative pain is limited by its relatively short duration of action of 3 to 6 hours.This phase II/III randomized, double-blind, placebo-controlled clinical trial was conducted in E-Da Hospital and E-Da Cancer Hospital  from August 2021 to April 2022. Adult patients aged 20 to 65 years with American Society for Anesthesiologist physical statuses ≤ III who were scheduled for laparoscopic cholecystectomies. This study included patients who were anticipated to stay in the hospital for > 72 hours after operation for feasibility to observe the analgesic effect and potential drug-related adverse events following administration of study drugs. The study was approved by the institutional review board of the E-Da Hospital, Kaohsiung, Taiwan . The trial was registered in March 2021 with Clinicaltrials.gov registration: NCT04808544. All participants provided written informed consent before the commencement of the study.Patients who were scheduled for laparotomies or urgent operations and patients with chronic opioid use, with allergies to Nalbuphine, benzyl benzoate, or sesame oil were excluded from the study. Patients who might require ventilator support after surgery and those who were not able for assessment of pain intensity or refused to participate in questionnaire surveys were also excluded. and other clinical trials.–13 Patient’s treatment allocation was concealed in an opaque envelope and the envelope was opened after the patient was admitted to the holding area of the operating room by the research assistant.Participants were randomly assigned to receive SDE  or vehicle solution (2 mL of mixture of benzyl benzoate and sesame oil) in permuted blocks of 10 using a computer-generated list. Dose of SDE used in this study was derived from the previous pharmacokinetic study,14 Parenteral opioids, including morphine and fentanyl, were individually prescribed by the anesthesiologist according to the patient’s hemodynamic changes and nociceptive responses during operation. At the end of operation, the endotracheal tube was extubated in the operating room. Patients were transferred back to the original wards from the post-anesthetic care unit. Patients were commenced on regular oral analgesics after resumption of normal oral intake, including acetaminophen and non-steroidal anti-inflammatory drugs (NSAID). Rescue parenteral analgesics, including opioids, parecoxib and NSAIDs were prescribed by the anesthesiologists or surgeons when visual analog scale (VAS) remained > 4 after regular oral analgesics were administered. The intraoperative MMA regimen, including SDE, parecoxib and propacetamol were supported by the research funds. The vehicle solutions were generously provided by the Lumosa Therapeutics Co. Ltd. .SDE  and the vehicle solution (solvent containing benzyl benzoate and sesame oil) was prepared in an identical injection syringe within 30 minutes before injection. The research drugs were prepared by a research nurse who did not involve in the clinical care. The surgical procedure was performed under endotracheal intubation general anesthesia and controlled ventilation. Anesthesia was maintained by inhalational anesthetics (desflurane or sevoflurane) at optimal minimal alveolar concentrations and bispectral index levels. After anesthesia induction, SDE or the vehicle solution was injected into the gluteus muscles by the in-charge anesthesiologist under ultrasound guidance. Since study drugs were prepared by the research nurse, the patients, anesthesiologists, surgeons, and research team members who assessed the study outcomes were blinded to the treatment groups. Dexamethasone (5 mg) was given intravenously after induction of anesthesia and intravenous Palonosetron (0.25 mg) was administered in patients who had high risk of developing postoperative nausea and vomiting. Parecoxib (40 mg) and propacetamol (2 g) were administered intravenously at the end of the operation as the standard postoperative MMA. Areas under the curve (AUC) of the VAS were calculated by plotting the individual VAS score as curves in which the x-axis represented measurement time points from baseline  to 48 hours after surgery, and the y-axis represented the VAS score. The secondary endpoints included total doses of rescue parenteral analgesics administered during hospital stay period, length of stay after operation, incidence of CPSP and patient’s quality of life (QoL). CPSP was defined as the newly developed pain at the surgical site or incisional wounds within 3 months after surgery, as other etiologies of pain were excluded. QoL was evaluated by the 12-item short form (SF-12) questionnaire on hospital admission, and at 7 and 90 days after surgery. The scores of SF-12 questionnaire range from 0 to 100, and lower scores indicate more impaired health-related QoL. Systemic and focal drug-related adverse reactions were recorded up to 7 days after surgery.The primary endpoint of this study was the intensity of surgical pain from post-anesthetic care unit to 7 days postoperatively. Pain intensity was assessed by ward nurses using the visual analog scale  in 4-hours intervals from 0 to 48 hours after operation. The numeric rating scale (0 represents “no pain” and 10 represents “worst pain”) was used to evaluate the pain intensity at 72 hours and 7 days postoperatively by the outcome assessors who did not participate in the clinical care. Acute postsurgical pain was defined as unpleasant sensation related to tissue injury during the acute phase after surgical intervention. In comparison to laparotomies, the intensity of postoperative pain is generally reduced in laparoscopic procedures. Therefore, our study proposed that SDE injection might reduce surgical related pain by 20% after laparoscopic cholecystectomies. With a pre-defined 20% standard error, a total sample size of 80 patients (including a dropout rate of 10%) was desirable to detect a 20% difference in pain reduction with an α value 0.05 and statistical power 0.8. Categorical variables were compared using the Fisher’s exact test. Comparisons of the continuous variables between the 2 study groups were analyzed using the Student t test or Mann–Whitney U test, as appropriate. Two-way repeated measures ANOVA was used to compare SF-12 scores at baseline and after surgery. All analyses were carried out using the SAS software, version 9.1 .A recent study showed that SDE significantly reduced the VAS by 32% at 48 hours after elective laparotomy surgery.During the study period, a total of 163 patients were evaluated for inclusion and 83 patients were excluded due to ineligibility and patient refusal  (Table P = .893) , and fewer patients required rescue analgesics from 24 to 48 hours postoperatively in both groups  (Table P = .379)  and 26 (68.4%) patients in the placebo and SDE groups, respectively  and nausea (defined as feeling of retching or stomach distress with an urge to vomit) was found in patients who received SDE within 72 hours post-operatively  for acute pain up to 7 days after laparoscopic cholecystectomy. In comparison to the previous controlled studies,–13 there were 2 main differences in our study design. First, the study drug was injected after induction of anesthesia in this study rather than administered > 12 hours preoperatively. Administration of SDE after anesthesia induction may not only reduce the discomfort of deep intramuscular injection in conscious patients, but also allows the treatment for day-case surgeries or when preoperative admission is not mandatory. Although the onset of SDE therapeutic effects could be delayed for 12 hours, this study did not detect clinically significant beneficial responses in pain intensity reduction from 24 hours to 7 days after administration. Secondly, standard parenteral MMA was administered intraoperatively to all participants in this study and the previous trial reported by our research team, whereas the placebo groups in the 2 previous studies received only blank or suboptimal analgesics for postoperative pain control.,12 Nevertheless, our study results are consistent with a previous open-label study, which demonstrated that preoperative administration of SDE did not significantly improve pain intensity and requirement for rescue analgesics after laparoscopic cholecystectomy. The results of these 2 studies suggest that laparoscopic cholecystectomies only induce mild-to-moderate levels of pain in the acute post-operative stage. The postoperative pain could be adequately managed by the standard opioid-sparing MMA regimen, including NSAID, selective cyclooxygenase-2 inhibitors, and acetaminophen.Three previous randomized double-blind placebo-controlled trials have demonstrated that a single preoperative injection of 150 mg SDE provides significant clinical analgesic effects in the management of post-open surgery pain. The presence of CPSP after laparoscopic cholecystectomy is known to increase the risk of chronic opioid use . Therefore, the long-lasting analgesic effect of SDE could theoretically attenuate the development of CPSP. To our knowledge, this is the first study testing the potential beneficial effect of a long-lasting parenteral analgesic in the prevention of CPSP, as acute postoperative pain is more likely to transit into chronic pain if the acute pain is not adequately controlled and it persists beyond the usual tissue healing time of 1 week. Our results showed that the incidence of CPSP at 3 months after surgery in the placebo-controlled group was 22.5%, which is comparable with the findings of previous studies reported by other groups in the range of 3% to 59%.,22,23 The incidence of CPSP was reduced by 41% in the SDE-treated group (22.5% vs 13.1%), but the difference was not statistically significant.After intramuscular injection, SDE is hydrolyzed by tissue esterase and the active compound nalbuphine is constantly released over 145 hours to mediate a longer lasting analgesic effect.,12,20 and retrospective clinical studies. In general, the adverse drug reactions include systemic responses reacting to the active compound nalbuphine  and focal reactions following intramuscular injection (such as soreness and tissue reactions at the injection site). These studies also noted an increase in unexpected pyrexia in patients who received SDE injection.,20 It should also be noted that the plasma concentration of nalbuphine can be maintained at therapeutic levels for up to 6 days after administration, but onset and subsidence time frames of the drug-related adverse responses were not reported in these studies. In our study, the potential drug-related adverse events were recorded up to 7 days post-operatively. We did not record any cases of pyrexia while in hospital. Dizziness was the most common systemic adverse reaction in this study and was significantly higher in the SDE group through postoperative days 1 to 3. 39.5% of the patients in the SDE complained of dizziness on postoperative day 3 compared to only 5% in the placebo group. The incidence of nausea was similar between the placebo and SDE on the first day post-operatively, but significantly more patients in the SDE group remained nauseous on day 2 to day 3 postoperatively. At day 7, most of these systemic adverse events resolved spontaneously, except a small proportion (7.9%) of patients in the SDE group who reported ongoing dizziness. On the contrary, incidence and severity of SDE-related systemic adverse events were significantly reduced in overweight patients (body weight index > 38 kg/m2) who received laparoscopic bariatric surgery, suggesting that these adverse drug reactions might be dose-dependent and the therapeutic doses of SDE should be titrated according to the patient’s total body weight. Although injection site reaction seldom occurs following a single dose of intramuscular nalbuphine, our study and other study groups found that more than 20% of the patients receiving SDE injections experienced local erythema, swelling, and tenderness while only 6% to 12.5% of the patients who only received the vehicle solution injection developed focal reactions. In addition, we observed that injection site reactions  more often developed 48 hours after injections and could last for more than 5 days. However, these focal reactions at injection sites were usually mild and transient, and there were no participants who requested additional medical attention or management in this study. To avoid accidental administration into other subcutaneous tissues, such as the adipose layers, ultrasound-guided intramuscular injection of SDE is highly recommended.The drug-related adverse reactions of SDE were previously reported in the several prospectiveThis study also measured pre- and post-operative QoL using the SF-12 questionnaire, which includes physical and mental health composition domains. The average total SF-12 scores were found to be low both before and at 7 days post laparoscopic cholecystectomy in both groups (75–79). These scores increased significantly to > 90 at postoperative day 90, suggesting an improvement in physical and mental health after surgical removal of the pathological gall bladder. Since there were no differences in the SF-12 scores between the 2 groups at the 3 measurement time points, we suggest that the SDE-related adverse events were most likely tolerable and did not significantly affect the physical and mental recovery after laparoscopic cholecystectomy. Therefore, the preemptive analgesic benefit of SDE might not be available if SDE was administered just before surgical stimulation. Second, all patients were interviewed over telephone at postoperative days 7 and 90 and the development of CPSP at postoperative day 90 was surveyed using a standard questionnaire. Since most of the patients who claimed to develop CPSP were unwilling to return to our pain clinic for further assessment, this study could only confirm that there was newly developed pain at the surgical sites or on the incisional wounds in some of the participants, but the severity and nature of the chronic pain were not assessed by pain specialists. Since postoperative MMA was administered in the 2 treatment groups, the effects of MMA on relieving of injection site reaction were not determined. Nevertheless, QoL was improved similarly in both groups at postoperative day 90, and none of these patients required medical attention for CPSP during the telephone interview. This suggests that the degree of chronic pain was mild, and it did not significantly affect post-operative recovery. Third, although there were no significant differences in the number of patients who requested for rescue parenteral analgesics up to 48 hours after surgery, differences in the total dosage and types of analgesics could exist between the 2 groups. Forth, although the incidence of CPSP was reduced in patients received SDE injection, this study was underpowered to detect a statistically significant effect of SDE to prevent the development of CPSP after laparoscopic cholecystectomy. Lastly, the drug-related adverse reactions could be dose-dependent. Further dose-ranging or divided dosing studies is advised to determine the clinical pharmacodynamics of SDE.Several limitations of this study should be addressed. First, this study tested the postoperative analgesic effects of SDE that was administered after induction of anesthesia rather than > 12 hours before surgical intervention. According to the clinical pharmacokinetics of SDE, plasma therapeutic levels of nalbuphine are achieved at 12 hours after intramuscular injection.In conclusion, a single dose of the extended-release analgesic SDE administered intra-operatively did not provide a sufficient add-on effect to the standard MMA for acute and chronic postsurgical pain after laparoscopic cholecystectomy. On the contrary, intramuscular injection of 150 mg SDE in patients with average body mass can cause certain adverse events that may have been overlooked in previous reports. The adverse reaction profile and appropriate dosing of SDE should be more thoroughly investigated.The authors wish to appreciate Ms. Tzu-Shan Chen  for the advice in statistical analysis of the clinical data.Conceptualization: Ying-En Lee, Chen-Yu Fu, Jen-Lung Chen, Chen-Fuh Lam.Data curation: Ying-En Lee, Chen-Yu Fu.Formal analysis: Ying-En Lee, Chen-Yu Fu, Yow-Ling Shiue, Chu-Yun Lu, Jen-Lung Chen, Chen-Fuh Lam.Funding acquisition: Chen-Fuh Lam.Investigation: Ying-En Lee, Chen-Yu Fu, Chung-Yen Chen, Jian-Han Chen, Jen-Lung Chen, Chen-Fuh Lam.Methodology: Ying-En Lee, Yow-Ling Shiue, Chu-Yun Lu, Jen-Lung Chen, Chen-Fuh Lam.Project administration: Jen-Lung Chen, Chen-Fuh Lam.Resources: Jen-Lung Chen, Chen-Fuh Lam.Software: Yow-Ling Shiue, Chu-Yun Lu, Chen-Fuh Lam.Supervision: Jen-Lung Chen, Chen-Fuh Lam.Visualization: Jen-Lung Chen, Chen-Fuh Lam.Writing – original draft: Ying-En Lee, Chen-Yu Fu, Chung-Yen Chen, Jian-Han Chen.Writing – review & editing: Yow-Ling Shiue, Chu-Yun Lu, Jen-Lung Chen, Chen-Fuh Lam.