Laparoscopic gastrectomy could reduce pain and opioid consumption, compared to open gastrectomy. However, it is difficult to judge the clinical relevance of this reduction, since these outcomes are reported in few randomized trials and in limited detail.This secondary analysis of a multicenter randomized trial compared laparoscopic versus open gastrectomy for resectable gastric adenocarcinoma (cT1-4aN0-3bM0). Postoperative pain was analyzed by opioid consumption in oral morphine equivalents  at postoperative day (POD) 1–5, WHO analgesic steps, and Numeric Rating Scales  at POD 1–10 and discharge. Regression and mixed model analyses were performed, with and without correction for epidural analgesia.p < 0.001). After correcting for epidural analgesia, these differences remained significant at POD 1–2 . At discharge, 27% of patients in the laparoscopic group and 43% patients in the open group used oral opioids (p = 0.006). Mean highest daily pain scores were between 2 and 4 at all PODs, < 2 at discharge, and did not relevantly differ between treatment arms.Between 2015 and 2018, 115 patients in the laparoscopic group and 110 in the open group underwent surgery. Some 16 patients (14%) in the laparoscopic group and 73 patients (66%) in the open group received epidural analgesia. At POD 1–3, mean opioid consumption was 131, 118, and 53 mg OME lower in the laparoscopic group, compared to the open group, respectively (all In this multicenter randomized trial, postoperative pain was comparable between laparoscopic and open gastrectomy. After laparoscopic gastrectomy, this was generally achieved without epidural analgesia and with fewer opioids.NCT02248519.The online version contains supplementary material available at 10.1007/s11605-023-05728-3. However, laparoscopic gastrectomy for advanced gastric cancer is rapidly being adopted.5 Laparoscopic surgery has the potential to reduce pain and thus postoperative opioid consumption.7 This could be highly relevant since postoperative opioid usage is a potential important contributor to the current opioid epidemic.13Gastric cancer is the sixth most prevalent cancer and the third most common cause of cancer-related death worldwide.18 However, detailed pain and analgesic results from randomized trials on laparoscopic versus open gastrectomy are limited. Three Eastern trials on distal gastrectomy indicated a reduction in pain and/or use of analgesics after laparoscopic compared to open gastrectomy.20 However, these trials provided limited details, since analgesic consumption was generally expressed as one composite endpoint . Hence, it is difficult to judge the clinical relevance of these results for the patient. Furthermore, these trials did not include total gastrectomy.The Dutch LOGICA-trial on laparoscopic versus open gastrectomy for gastric cancer has reported similar safety and oncological efficacy for laparoscopic and open gastrectomy, in concordance with previous trials from the East.22 However, it was not yet reported since data on analgesics and opioid consumption were still lacking, rendering it impossible to present the data in a meaningful manner. The current study aims to provide a detailed secondary analysis, comparing postoperative pain and opioid consumption between laparoscopic and open gastrectomy in the multicenter randomized LOGICA-trial.14 It was hypothesized that laparoscopic gastrectomy would lead to reduced pain and/or reduced opioid consumption.Postoperative pain was a prespecified outcome measurement during the LOGICA-trial.21 Briefly, between 2015 and 2018, 227 patients with surgically resectable (cT1-4aN0-3bM0) gastric cancer were included and randomized to laparoscopic (n = 115) or open gastrectomy (n = 112). Both groups did not differ regarding median initial hospital stay , postoperative complication rate , and all other postoperative outcome parameters.All patients who participated in the LOGICA-trial were included in this secondary analysis. The LOGICA-trial was a multicenter randomized controlled, open-label, superiority trial comparing laparoscopic with open gastrectomy in 10 Dutch hospitals. The study protocol was approved by the institutional review board at each participating hospital, and all patients signed written informed consent. The protocol and main results were published previously .23As previously described, multiple quality control measures were included in the trial, and the treatment protocols were in accordance with the guidelines for Enhanced Recovery After Surgery (ERAS).24 The type of opioid and infusion rates varied between hospitals. All hospitals administrated paracetamol 1000 mg/6 h, but nonsteroidal anti-inflammatory drug (NSAID) usage was limited. Between hospitals, different opioids were used orally and intravenously, and intravenous opioids were administered in different ways . Some hospitals added esketamine as part of a multimodal analgesic protocol in patients with insufficient pain control from opioids.Postoperative pain protocols were left to the discretion of each participating hospital and did not differ between treatment arms, except for epidural analgesia. For open gastrectomy, epidural analgesia was the standard unless there were (relative) contraindications. For laparoscopic gastrectomy, epidural analgesia was not allowed according to the trial protocol, and pain control was achieved via intravenous opioids, oral opioids, or paracetamol only. Patients that received epidural analgesia anyway were regarded protocol-violations but analyzed according to the intention-to-treat principle nonetheless. Epidurals were placed between intervertebral levels T5–T10. All infusions contained local anesthetics  and an opioid, since the combination of local anesthetics with opioids provides superior analgesia and is thus recommended in recognized guidelines.Standardly, pain scores (NRS) were assessed by the ward nurse once every 8 h and after each intervention for pain. Additionally, a dedicated pain team evaluated pain control at POD 1 in all patients and hereafter daily in patients receiving epidural analgesia, intravenous opioids, or patients in whom pain control was difficult. This pain team evaluated pain scores in combination with opioid consumption, side effects, and complications, and in case of epidural analgesia, the epidural sensory block range was tested. An NRS < 4 in rest and < 6 while mobilizing was generally considered to be acceptable. In case of insufficient pain control with opioids, analgesics daily opioid dose was increased, or non-opioids were added . In case of epidural analgesia with an inadequate sensory block, an epidural top-up was performed, and continuous infusion was increased if a top-up was successful. If a top-up was unsuccessful, the epidural was removed and the patient switched to intravenous or oral opioids. Opioids were removed from the epidural mixture in patients who received opioids parallel to epidural analgesia. In case of sufficient pain control, intravenous opioids or epidural analgesia was gradually switched to oral opioids and then to paracetamol only.27The primary outcomes of the current study included daily postoperative pain scores, daily analgesic steps of the WHO pain ladder as an indicator of pain severity, and daily opioid consumption.22 The mean of the highest collected NRS pain scores of the day were used for the main analyses.Pain scores were assessed in admitted patients at POD 1–10 and at the morning of discharge. Pain was assessed on a 0–10 NRS.27 For illustrative purposes, step III was split by route of administration: orally or intravenously.Analgesic steps were assessed in admitted patients at POD 1–10 and at the day of discharge. Analgesic steps were based on the WHO analgesic ladder: (I) no analgesics or paracetamol ± NSAID, (II) addition of weak opioids , (III) addition of strong opioids, and (IV) addition of epidural or esketamine.29 for example, 1 mg intravenous (IV) morphine = 3 mg OME.Data on all administered analgetics, administration routes, and dosages were collected for postoperative day (POD) 1–5. For optimal comparison, opioids were converted into daily oral morphine equivalents (OME),Secondary outcomes included quality and efficacy of epidural analgesia: quality of sensory block, incidence of top-ups, replacements, need for additional analgesia, day of removal, and occurrence of minor or major epidural-related complications  or esketamine, opioid intoxications, use of an enema, and mobilization milestones .Analgesic steps and pain severity scores at POD 1–5 were registered prospectively in the LOGICA electronic case report forms (eCRF). An additional retrospective data collection was performed in each participating hospital’s patient files and medication dispense registries, to collect the data regarding opioid consumption (including dosages) at POD 1–5, analgesic steps, and pain severity scores at POD 6–10 and at discharge and all secondary outcomes. Opioid consumption was not collected after POD 5, since this retrospective data collection was time-consuming.21 Analyses were according to intention-to-treat.21 Primary outcomes were displayed descriptively in bar and line charts. Additionally, comparative statistics were performed between treatment arms. Differences in pain scores and daily opioid consumption at POD 1–5 were analyzed with linear mixed-effects models. In these longitudinal analyses, between group differences were reported for each of the dependent time points at POD 1–5. Pain at discharge was analyzed with linear regression, and analgesic step at discharge was analyzed with Poisson regression with robust error variances for binary outcomes.31 Length of stay until discharge did not vary between the laparoscopic and open group, but did vary within both groups; hence, it was mathematically not feasible to analyze these endpoints in a mixed model. The study protocol caused an inherent difference between treatment arms in epidural analgesia and consequently analgesic steps at the first PODs.21 Hence, comparative statistics were performed only for the analgesic step at discharge and not at POD 1–10. For optimal transparency and to evaluate possible bias by epidural, all models were performed with and without correction for initiation of epidural analgesia. Secondary outcomes were compared with chi-squared tests, Fisher’s exact tests, or Mann–Whitney U tests,32 depending on the type of data and distribution. p < 0.05 was considered statistically significant. Supplementary material This was a secondary analysis of the LOGICA-trial. NRS pain scores were a prespecified outcome measurement, whereas opioid consumption was not.Between 2015 and 2018, 115 patients in the laparoscopic group and 110 in the open group underwent surgery Table .Table 1Tp = 0.008). After correcting for epidural analgesia, the highest daily pain score at POD 1 did no longer differ between the laparoscopic versus the open group . At POD 2–10 and at discharge, there were no significant differences between treatment arms, regardless of correction for epidural analgesia  .The analgesia use, as WHO pain ladder steps during admission at POD 1–10 and at discharge, is displayed descriptively in Fig. 05) Fig. . This dip < 0.001; 95% CI [− 144 to − 92], p < 0.001; and 95% CI [− 80 to − 27], p < 0.001, respectively) , whereas POD 3–5 did not significantly differ between treatment arms . However, median POD and interquartile ranges (IQR) were low in both arms for first time sitting in a chair (median 1 [IQR 1–1] versus 1 [IQR 1–2]) and walking in the hallway (median 2 [IQR 1–3] versus 2 [IQR 2–3]).The probabilities of earlier first time sitting in a chair and walking in the hallway were higher in the laparoscopic group, compared to the open group . Mobilization milestones were quickly reached in both treatment arms and only modestly quicker in the laparoscopic group. In the laparoscopic group, mean daily opioid consumption was significantly lower, and significantly fewer patients used oral opioids at discharge. Hence, laparoscopic gastrectomy led to adequate pain control, generally without epidural analgesia and with a clinically relevantly lower consumption of opioids, compared to open gastrectomy.33 Nevertheless, even after correcting for epidural analgesia, mean daily opioid consumption at POD 1–2 was still up to 69 mg OME lower in the laparoscopic group, which likely reflects lower analgesic requirements due to reduced pain from the smaller incisions of the laparoscopic surgery itself. Furthermore, usage of oral opioids at POD 1–7 and discharge (27% versus 43%) was lower in the laparoscopic group, compared to the open group.The higher opioid consumptions in the open group were partly due to the majority of this group receiving epidural analgesia, through which local anesthetics and opioids are administered. Epidural administered opioids also reach the systemic circulation and were therefore converted into daily oral morphine equivalents  and added to the daily opioid consumption.34 In the USA, approximately 76 million adults reported to have used prescribed opioid drugs in 2015–2016, and prescription opioid deaths have increased from 3442 deaths in 1999 to 17,029 in 2017.34 In Europe and more specifically the Netherlands, prescription opioid users nearly doubled from 4109 per 100,000 inhabitants in 2008 to 7489 in 2017.8 Oxycodone use almost quadrupled in this period, and opioid prescribing after surgery, especially in the context of increasingly short hospital stays due to ERAS protocols, has been recognized as an important potential contributor to opioid misuse and related harm.10 Hence, the lower opioid consumption at discharge in the laparoscopic surgery group could be a relevant benefit.These opioid reductions are deemed especially relevant in light of the current opioid epidemic.9 Indeed, 3 recent non-randomized studies evaluated laparoscopic versus open colectomy, and 2 of these studies associated laparoscopic surgery with both reduced short-term and long-term opioid usage.35 Unfortunately, the current trial only had data up to 1-year postoperatively regarding patient-reported pain scores (showing no differences between treatment arms), but no data on opioid consumption up to 1-year postoperatively.14 Future research is required to examine how many short-term opioid users become long-term users after gastrectomy and whether this differs between laparoscopic and open gastrectomy.It would be especially relevant if this would also result in reduced long-term opioid users after laparoscopic gastrectomy. Chronic opioid use often begins with treatment of acute pain, and approximately 3.3% of patients exposed to chronic use become addicted.20 However, none of these trials reported detailed descriptions of the postoperative pain protocols. Importantly, opioid dosages in morphine equivalents per postoperative day were not reported. Instead, one or two composite outcomes were included with limited details . Although this makes it hard to judge the clinical relevance of these outcomes for the patient, these composite outcomes did indicate reduced pain and/or analgesics after laparoscopic gastrectomy, which is in line with the current study results. An advantage of the current study is that the pain and analgesic-related data were reported in a high level of detail and that total gastrectomy was also included.Three trials on distal gastrectomy briefly reported on pain or analgesic consumption upon publishing the main trial results.36 Fortunately, complications such as hypotension were only reported in a minority of patients in the current trial, though this might be an underrepresentation due to the retrospective data collection of epidural details.37 Importantly, 29% of patients in the open group with epidural analgesia also received intravenous opioids sometime during the first 5 PODs, indicating that the epidural analgesia itself often was insufficient. Nevertheless, adequate pain control was achieved in both treatment arms.Epidural analgesia is an invasive procedure, and complications can occur, such as hypotension and not adequately functioning epidural catheters in up to one-third of patients.23 In the laparoscopic group, it was hypothesized that adequate pain control could be achieved without epidural analgesia. To address possible bias by epidural, analyses were performed with and without correction for epidural analgesia. Furthermore, we reported oral opioid consumption at discharge Supplementary file2 (PDF 1511 KB)Below is the link to the electronic supplementary material.


Current pharmacologic treatments may provide limited analgesia in fibromyalgia and other chronic pain disorders. Low-dose naltrexone (LDN) has emerged as a potential analgesic option that has been minimally explored. This study aims to describe current real-world prescribing practices of LDN, to investigate if patients have a perceived benefit of LDN in treating pain symptoms and to identify predictors associated with a perceived benefit or discontinuation of LDN. We evaluated all outpatient prescriptions for LDN prescribed for any pain indication in the Mayo Clinic Enterprise from 1 January 2009 to 10 September 2022. A total of 115 patients were included in the final analysis. The patients were 86% female, had a mean age of 48 ± 16 years, and 61% of prescriptions were for fibromyalgia-related pain. The final daily dose of oral LDN ranged from 0.8 to 9.0 mg, while the most common dose was 4.5 mg once daily. Of patients who reported follow-up data, 65% reported benefit in their pain symptoms while taking LDN. Adverse effects were reported in 11 (11%) patients and 36% discontinued taking LDN by the most recent follow-up. Concomitant analgesic medications were used by 60% of patients and were not associated with perceived benefit nor discontinuation of LDN, including concomitant opioids. LDN is a relatively safe pharmacologic option that may benefit patients with chronic pain conditions and warrants further investigation in a prospective, controlled, and well-powered randomized clinical trial. Fibromyalgia is a prevalent musculoskeletal disorder affecting approximately 2–6.4% of people in the United States ,2. FurthAlthough the etiology of fibromyalgia is likely multifactorial , there is growing evidence for both central and peripheral biological immune-mediated mechanisms to explain these phenomena , which mPharmacologic therapies for the treatment of fibromyalgia are limited in efficacy and are often associated with intolerable side effects. Analgesics that are currently approved by the Food and Drug Administration (FDA) for treatment of fibromyalgia include pregabalin, a gabapentinoid which acts at the alpha-2 voltage-dependent calcium channels, and duloxetine and milnacipran, two serotonin-norepinephrine reuptake inhibitors . ConservNaltrexone is another off-label pharmacologic option for chronic pain disorders that has been used sparsely in this population. Naltrexone is well-known as a non-selective opioid receptor antagonist used to treat opioid use disorder and alcohol use disorder. It has also been shown to have anti-inflammatory effects; it inhibits central nervous system proinflammatory cytokine activity via TLR-4 antagonism in microglia  and moduLow-dose naltrexone (LDN) is commonly defined as oral dosages ranging from 1–5 mg daily but can go up to 4.5 mg twice per day ,17,18,19Despite growing evidence, data on the efficacy of LDN are limited to several small clinical trials and case reports. It is a generic, compounded medication with a lack of commercial interest among vendors in pursuing large clinical trials . In thisThis study was given exempt status by the Mayo Clinic Institutional Review Board . The electronic medical records (EMR) from the Mayo Clinic Enterprise including three academic tertiary care centers  and all upper midwest community health systems were queried. All facilities use a common EMR . All outpatient prescriptions containing the word “naltrexone” and oral dosages up to 10 mg daily from 1 January 2009 to 10 September 2022 were queried from the EMR and data on eligible patients were extracted. Patients were included if they were prescribed LDN for any pain indication . Patients were excluded from further data extraction if they were prescribed LDN for non-pain indications such as obesity, autoimmune processes, and chronic fatigue. There were more prescriptions than corresponding patients due to duplications in the prescription data or refills.The resulting patient charts were manually reviewed for data extraction. The following variables were collected: date of birth, gender, diagnosis associated with naltrexone prescription, first naltrexone order date, starting dose and frequency, titration interval, final dose and frequency, pain scores at time of and within 6 months of the prescription, reported adverse effects, discontinuation date, specialty of prescriber, concomitant analgesic medications, and patient report of the medication being beneficial or leading to moderate or substantial improvement in pain intensity. All records were queried for follow-up data up through the date of chart review in October 2022.Concomitant analgesic medications were extracted according to the following definitions. Gabapentinoids included gabapentin and pregabalin. Serotonin-norepinephrine reuptake inhibitors (SNRI) included desvenlafaxine, duloxetine, milnacipran, and venlafaxine. Muscle relaxants included baclofen, cyclobenzaprine, and tizanidine. Opioids included hydrocodone, morphine, oxycodone, hydrocodone-acetaminophen, and oxycodone-acetaminophen combination products. No patients were prescribed codeine, fentanyl, methadone, or buprenorphine but these medications were also queried. Tramadol was considered separately from other opioids and SNRIs due to multiple mechanisms of action including µ-opioid agonism, serotonin reuptake antagonism, and norepinephrine reuptake antagonism, as well as other targets. Tricyclic antidepressants included amitriptyline and nortriptyline. Data on acetaminophen, non-steroidal antiinflammatory medication, and topical medication use were not recorded. Additionally, data on historical or concomitant interventional pain procedures or injections such as botulinum toxin, local anesthetics or steroids were not recorded.For descriptive characteristics, continuous variables were summarized by the mean, standard deviation, and range. Categorical variables were summarized as frequency count and percentages.p-values for gender, age, concomitant medications, and final LDN dose on these two outcomes. p-values were determined by Wald tests and values < 0.05 were considered to be significant. Due to small sample size, the primary focus was on univariate analyses. Any variables with significant p-values in the univariate models were included in multivariate binomial regression models for the same outcome variables. All analyses were performed in R v.4.0.5.Univariate analyses were conducted to assess factors associated with (1) LDN being perceived as beneficial for pain-related symptoms, and (2) discontinuation of LDN among patients for whom these data were available. Binomial regression models were performed to determine the odds ratios, 95% confidence intervals and Additional analysis was performed on patients subgrouped into those prescribed LDN who were not on any concomitant analgesic medications versus those prescribed LDN plus concomitant analgesic medications. For descriptive characteristics, continuous variables were summarized by the mean, standard deviation, and range. Categorical variables were summarized as frequency count and percentages.2 tests for categorical variables. p-values < 0.05 were considered to be significant differences between groups.Descriptive statistics were compared between these two groups by t-tests for continuous variables and ΧAmong 32.5 million total outpatient prescriptions in the EMR database (accessed on 20 August 2022), 203 prescriptions were for naltrexone at doses less than or equal to 10 mg daily between 1 January 2009 and 15 October 2022. This corresponded to a total of 104 patients. These 104 patients were combined with an additional 30 patients previously extracted by the senior author (RSD) with prescriptions for LDN. Complete chart review for the variables mentioned above was performed on these 134 patients. After 19 patients were removed due to naltrexone prescriptions for non-pain indications , there was a final total sample of 115 patients .Pain scores at the time and within six months of the initial LDN prescription were queried and recorded. However, these data were sparse and if they were recorded, they were associated with other encounters such as a visit to an emergency department or pre-/post-procedures. They did not represent average daily pain scores and thus were not included in further analysis.Only 11 patients reported adverse effects of LDN  which prn for each model represents the number of patients with complete data for each pair of variables. None of these models showed significant associations and thus no multivariate models were performed. Due to small sample size, these results are likely underpowered if true associations exist.Univariate logistic regression models were used assess whether age, gender, concomitant analgesic medications, or final LDN dose were predictive of (1) LDN being reported as beneficial and (2) LDN discontinuation . Each li2 tests. Although not statistically significant, it is interesting to note a larger percentage of patients on concomitant analgesics reported side effects compared to the LDN-only group . This may reflect pharmacologic interactions.A subgroup analysis was performed on the 45 patients prescribed LDN who were not on any concomitant analgesic medications versus the 67 patients prescribed LDN with concomitant analgesics . There wThis study identified that a majority of patients (65%) who took LDN for any pain indication reported a benefit in their pain symptoms. A significant portion of our cohort comprised patients with fibromyalgia, which is an often challenging condition to diagnose and treat. Potential mechanisms that may explain the analgesic benefit from naltrexone at low doses ranging from 1–5 mg include glial modulation and antagonism of TLR-4 that is implicated in generating inflammatory end-products . SubsequThe current study also analyzed for predictors of treatment benefit and predictors of treatment discontinuation, including gender, age, and administration of certain analgesics , and LDN dose. Although the analysis did not identify statistical significance for any predictor variable, future studies are warranted to validate these data. Future studies may also explore other predictor variables such as smoking status, alcohol use, history of substance abuse, and other potential negative predictors.In our current study, only 11 (11%) patients reported side effects from LDN, none of which were severe or life-threatening. Previous research has suggested side effects of LDN treatment are uncommon and mild, including vivid dreams, headaches, anxiety, and tachycardia . No serip = 0.38). Evidence from animal models suggests that LDN administered with oxycodone attenuates neuropathic pain and reduces tolerance to the oxycodone alone [It should be noted that 11% of patients in our cohort were on concomitant chronic opioid medications. Many clinicians are hesitant to deliver LDN in those with opioids due to concern that LDN is a µ-opioid receptor antagonist. Our regression analysis suggests that concomitant opioids and LDN is not predictive of discontinuation of LDN therapy , primary care (19%), and neurology (19%). Pain medicine physicians comprised only a small portion of prescribing physicians (13%). There may be several potential reasons for this finding. Firstly, pain medicine physicians are trained in performing a variety of interventional procedures. These include ultrasound-guided injections, fluoroscopic-guided injections, and neuromodulation interventions such as spinal cord stimulation and peripheral nerve stimulation. Therefore, pain medicine physicians may be inclined to offer these interventional modalities before trialing analgesic medications with limited evidence. Secondly, many specialties may be unfamiliar with LDN as an analgesic due to its limited evidence base in chronic pain treatment. Finally, there may also be concerns for its side effect profile and its potential interaction with opioids medications.The authors query possible explanations for the high rate of discontinuation (36%) of LDN in the current study. In most cases, a specific reason for discontinuation was not provided or clarified in the patient’s EMR. Although most of these patients likely did not experience meaningful analgesia from LDN, it is plausible that a portion may have obtained pain relief and may have discontinued the medication after achieving analgesia and attenuation of central sensitization.This study is limited by the constraints of retrospective EMR data. Average daily pain scores at baseline and within 6 months trial of LDN would have provided valuable efficacy data. Because pain scores were unavailable or unreliable, we chose to focus on evidence via follow-up notes or patient communication with explicit mention of benefit. However, many patients had no follow-up data and thus our estimates may include selection or reporting bias. Long-term effects of LDN could not be ascertained from this limited review and duration of concomitant medications likewise could not be extracted from the EMR as it was unclear when patients may have discontinued them.We additionally were underpowered to assess associations of patient factors with perceived LDN benefit or discontinuation in the binomial models. Since there was no comparative arm present , conclusions from the study are limited and the authors can not exclude the possibility of a placebo effect . Our samWith the favorable LDN efficacy and safety data we have thus far, and in the setting of limited non-addictive pharmacologic options for treatment of chronic pain, LDN can be considered for a trial in patients with fibromyalgia and other chronic pain conditions. Future randomized, placebo-controlled trials are warranted to better assess patient-related factors associated with efficacy. The current study was focused on treatment success or change in pain intensity. Other patient-reported outcomes such as physical function, disability, pain interference, quality of life, mental health outcomes, and satisfaction rates should also be explored in formal surveys. Studies should also explore the mechanisms of action of LDN that may explain its therapeutic attenuation of central sensitization and chronic pain. Additional analgesics such as methadone ,42 and kLDN may provide meaningful pain relief in most patients with fibromyalgia and other refractory chronic pain syndromes. This study did not identify predictors of treatment success or discontinuation. Generally, adverse effects from LDN are mild and infrequently reported. Other analgesic medications, including opioids, may be co-administered concomitantly with LDN. Further investigation in a prospective, controlled, and well-powered randomized clinical trial is warranted.


Therefore, there was a significant difference in opioid consumption (p < 0.0001) and functional recovery (p < 0.0001). Also, NLR and PLR levels 12 h (p < 0.0001) and 24 h (24 h) after surgery (p < 0.0001) were much lower in the iPACK + ACB group. Conclusion: After total knee arthroplasty, the iPACK combined with ACB block group improved pain management, functional recovery, and stress response. Therefore, we strongly recommend this technique as a part of a multimodal analgesia protocol in knee surgery.Introduction: This study aimed to investigate pain management, functional recovery, and stress response expressed by the neutrophile-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) after the popliteal artery and posterior knee capsule infiltration (iPACK) block combined with adductor canal block (ACB) in total knee arthroplasty (TKA). Patients and Methods: This was a prospective, double-blinded, randomised, controlled trial in a tertiary referral hospital. Three hundred and sixty-six patients were randomly allocated into the sham block group and iPACK combined with the ACB group. The primary outcome was postoperative pain scores. The secondary outcomes were opioid consumption, functional recovery expressed by a range of motion, and quadriceps strength. Also, the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were calculated. Results: There were significant differences between the sham block and iPACK + ACB group in pain scores  Total knee arthroplasty (TKA) is one of the most frequent and most painful procedures in orthopaedic surgery, and extreme pain immediately after surgery has been reported in half of TKA patients . OptimalAdductor canal block (ACB) is an alternative to femoral nerve block (FNB) after TKA. ACB provides analgesia to intra-articular and anteromedial parts of the knee. In contrast to FNB, ACB preserves quadriceps muscle strength, thus facilitating functional recovery . HoweverThe neuroendocrine hormones and cytokines are released during surgery and anaesthesia. Also, postoperative pain during TKA represents inflammatory, nociceptive, and neuropathic pain and matches surgical stress response. Leukocytosis, lymphopenia, and neutrophilia develop in return for surgery. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are extensively used in many branches of medicine as prompt markers of immune replay to different noninfectious stimuli ,12. ReceThis study intended to evaluate the accoutrements of iPACK and ACB on TKA by comparing postoperative pain, opioid consumption, functional recovery, and NLR and PLR levels between the sham block and iPACK combined with ACB. Therefore, this is the first trial that investigates the effects of peripheral nerve block on NLR and PLR in patients undergoing TKA. clinicaltrails.gov (NCT06086483). Written informed consent was collected from all patients for this research program.The prospect of this trial was conducted by the Declaration of Helsinki at the Independent Public Health Care Institution of the Ministry of the Interior and Administration in Poznan, Poland. The Institutional Review Board of the Poznan University of Medical Sciences approved the study policy on 17 June 2020, protocol 495/20, and it was registered with Enrolment was introduced before surgery for adults undergoing elective primary unilateral total knee arthroplasty under spinal anaesthesia, American Society of Anesthesiologists physical status 1, 2, or 3, and aged >18 years.2), had pre-existing anatomical or neurological disorders in the lower limbs, or had severe psychiatric illness or intellectual problems in pain evaluation. Also, patients with blood transfusions during the perioperative period and whose estimated blood loss during surgery was over 30% of the total blood volume were excluded from the study.Patients were not admitted to this study if they denied participating, had an adverse reaction to any of the drugs used in the study, had an infection of the site of needle puncture, had a history of opioid abuse, had ASA > 3, were less than 18 years of age, had known or suspected coagulopathy, had a liver failure or renal failure . The randomisation list was given to an impartial investigator who camouflaged group assignments in serially numbered, closed, blurred boxes. An expert specialist tracked management to disclose the envelopes before the nerve block administration to announce the group allotment and execute the procedure. The anaesthesia team, surgeons, operating room staff, and patients were unaware of the study group assignment. Group unblinding and uncovering appeared once the statistical investigation was finished.All the patients underwent routine spinal anaesthetic management as commonly practised in our hospital. Patients in both groups were given 7.5 mg of midazolam orally and 8 mg of dexamethasone intravenously half an hour before the surgery as a part of pre-emptive multimodal analgesia. Then, 100 mg of fentanyl and 2 mg of midazolam for mild sedation were administered intravenously before induction of anaesthesia. Additionally, all patients underwent spinal anaesthesia while the patient was seated, and 20 mg of 0.5% ropivacaine was injected into the L3–L4 space with a 27G Whitacre needle. After spinal anaesthesia and before surgery, 1 g of tranexamic acid and 1 g of cefazolin were injected intravenously. No periarticular infiltration occurred by the surgeon during the surgery.The transducer was placed transversely over the medial aspect of the knee, 2–3 cm above the patella. The transducer was slid proximally to identify the distal femoral shaft and popliteal artery. The needle was inserted in-plane, from the anteromedial facet of the knee, into the space between the femur and popliteal artery. When the posterior part of the popliteal artery was reached, 2 mL of the 0.5% ropivacaine was injected to confirm the proper needle position. Additionally, 20 mL of 0.5% ropivacaine was injected into the space between the popliteal artery and the posterior knee capsule.The transducer was located in a transverse orientation at the middle level of the middle third of the thigh. The femoral artery, sartorius muscle, and adductor longus muscle were identified. The needle was inserted in-plane in a lateral to a medial direction and advanced toward the femoral artery and saphenous nerve. After the negative aspiration, 1 mL of local anaesthetic was injected to confirm the proper injection site. A total of 10 mL of 0.5% ropivacaine was administered. All TKA procedures were performed by two surgical teams using a standard medial parapatellar approach without a tourniquet. Both measured gap-balancing and resection techniques were utilised. Cemented, fixed bearings and posterior-stabilised implants from the Stryker Triathlon knee system were implanted. One gram of intravenous tranexamic acid was given before surgery to reduce the blood loss.After the total knee arthroplasty ended, the patients were transmitted to the post-anaesthesia care unit (PACU). Postoperatively, a cold pack reduced pain for twelve hours after surgery. The same multimodal postoperative analgesia was applied in the PACU in both groups, which was consistent with ketorolac 50 mg every twelve hours. Also, metamizole 1 g i.v. and acetaminophen 1 g i.v. were both applied every six hours. If the NRS score was higher than 4, 5 mg morphine was administered as rescue analgesia. The 8 mg of ondansentrone was given when severe nausea or vomiting occurred. Enoxaparin for four weeks postoperatively was given as a thromboembolism prophylaxis. Finally, patients were ambulated with the help of the walker after the first ten postoperative hours.The primary outcome quota was pain scores at rest and during active flexion 45° to 5 days following surgery. At all postoperative time points , patients were asked to rate perceived pain using an 11-point Numeric Pain Rating Scale (NRS: 0 indicating no pain and 10 indicating the worst pain imaginable) experienced at rest and during active flexion 45°. The secondary outcomes included time to first opioid use obtained from the postoperative and orthopaedic wards. Also, total opioid consumption was recorded 0–24, 24–48, and 48–72 h after surgery. The expenditure of the different types of postoperative opioid administration was converted to intravenous morphine equivalents according to The range of motion and quadriceps strength was measured to grade the functional recovery of the knee joint after surgery. The protractor was used for the range of motion. The interval of activities was three times a day, 6 h apart, and we used the best value as the day’s value. The quadriceps strength was measured by asking the patient to flex the hip and knee and the complete knee extension. The outcome assessor used resistance to knee extension and palpated the thigh muscles to measure muscle strength. No muscle movement scored 0 points, no joint movement with muscle contraction scored 1 point, no gravity resistance with joint movement scored 2 points, gravity resistance scored 3 points, partial counterforce resistance with gravity resistance scored 4 points, and normal joint function scored 5 points. The resulting judgement was accompanied by a group of two clinicians (GK and TR) who were satisfied with the group allotment.Also, blood samples for NRL and PLR were collected 12 and 24 h after surgery.We studied our primary hypothesis that the iPACK block with ACB improves postoperative analgesia to calculate the sample size. Based on the published data on total knee arthroplasty using the iPACK block with ACB , we estit test resolved the deviations between groups. The analysis of contingency was correlated with Fisher’s exact test. Categorical variables were compared with the Mann–Whitney U test. Values are given as the mean (standard deviation), the median (interquartile range), or the number of patients (proportion). The equity of inpatient and operation eccentricity between the randomised groups was resolved by judging the standardised difference, which was corrected as the alteration in means or ratios prorated by the pooled standard deviation. Individually measured variables were delayed using a linear mixed exemplary with the patient mark as a random effect and group, time, and group-by-time cooperation as fixed effects, balancing for volatiles of operation and patient characteristics . An unstructured covariance structure was practised. The Bonferroni correction was imposed to adapt for multiple resemblances. All analyses were adjusted using GraphPad Prism 8 software . A p-value of <0.05 was studied as statistically significant.We used the Kołomogorov–Smirnov normality test to evaluate the parametric distribution of numerical variables. The Mann–Whitney U or Student’s Of 403 patients postponed for eligibility, 19 did not fit the inclusion criteria, and 16 chose general anaesthesia. The remaining 366 were randomly assigned to both groups. Another five were lost to follow-up as a result of surgical complications. Overall, 361 patients were inspected, as shown in p < 0.0001; 3.7 vs. 2.9 at 48 h, p < 0.0001; 2.0 vs. 1.2 at 72 h, p < 0.0001; 1.1 vs. 0.7 > 72 h, p = 0.0001, compared to the sham block.Postoperative pain scores are demonstrated in p < 0.0001. Also, the NRS scores during active flexion 45° were decreased in the iPACK + ACB group at all time points. 5.1 vs. 2.9 at 48 h; 3.1 vs. 1.2 at 72 h; 1.1 vs. 0.6 >72 h, all Every patient in the sham group needed opioid pain medication for pain relief. In contrast, 74 (41%) in the iPACK + ACB group received none. p < 0.0001  are the standard analgesic option for pain management following TKA . The druThe iPACK block is a relatively novel ultrasound-guided regional anaesthesia technique designed to block the small articular sensory branches of the popliteal plexus and the obturator nerve, resulting in analgesia of the posterior knee capsule. iPACK blockade targets the pain sensation below the knee and can relieve pain behind the knee without causing muscle weakness ,23. TherThe iPACK block with ACB has been documented to provide significant analgesia and early mobilisation following knee surgery due to its quadriceps strength-sparing effect ,19,26. HPeripheral nerve block suppresses the formation of proinflammatory cytokines related to the stress response . Also, pProsthetic joint infection (PJI) is one of the most severe complications after TKA . SeveralOn the other hand, Tirumala et al.  revealedAlso, NLR levels correlate with venous thromboembolism (VTE), which is a severe complication after TKA . Seo et To date, no studies have characterised the influence of peripheral nerve blocks on NLR and PLR levels following knee surgery. Our analysis indicates that iPACK with ACB reduces the surgical stress response expressed by NLR and PLR. Therefore, iPACK with ACB lowers the risk of PJI and VTE following TKA.However, this study has limitations. The large volume of the local anaesthetic used for the iPACK block and the ACB is a single-shot injection rather than a catheter. We did not obtain the dermatome levels, the duration of the block, and the hospital discharge times. Also, we only calculated NLR and PLR 12 and 24 h after surgery.Based on our findings, ultrasound-guided iPACK with ACB lowers the pain scores and reduces opioid consumption. Due to its motor-sparing mechanism of action, iPACK with ACB enhances functional recovery in patients undergoing TKA.Also, iPACK combined with ACB lowers NRS and PLR levels, thus reducing the stress response.Thus, we firmly advocate for this approach as part of a multimodal analgesia agreement in knee surgery.


Severe pain from oral mucositis in cancer patients affects oral intake, thus disrupting the quality of life. This pathology is thus far not well managed with standard approaches. Although the biggest challenge in clinical practice is pain control, many efforts have unsuccessfully concentrated on prevention. Methylene blue oral rinse is a safe treatment for refractory oral pain in this population. The low cost of MB makes it potentially accessible to patients of all socioeconomic backgrounds.p < 0.0001) and oral function burden . Eleven patients (19%) had percutaneous endoscopic gastrostomy tubes placed before using methylene blue oral rinse; subsequently, four (36%) resumed oral alimentation after methylene blue oral rinse. Two patients (3%) required percutaneous endoscopic gastrostomy tubes despite methylene blue oral rinse. Minimal adverse events were reported . Our study showed that methylene blue oral rinse was an effective and safe topical treatment for opioid-refractory oral pain from oral mucositis associated with radiation therapy for head-neck cancer.Pain from radiation-therapy-induced oral mucositis during head-neck cancer treatment is aggravated by concurrent chemotherapy and commonly fails traditional treatments. To explore safe and sustainable alternatives, we investigated methylene blue oral rinse to reduce radiation-therapy-related oral mucositis pain. For this, we conducted a retrospective observational cohort study in a tertiary-care academic care cancer center including 85 patients with refractory oral mucositis pain during radiation therapy for head-neck cancer. Changes in pain , oral function burden  and requirement for percutaneous endoscopic gastrostomy tube placement were measured. Among 58 patients, 60% received radiation therapy alone and 40% received concurrent chemotherapy-radiation therapy. Methylene blue oral rinse (MBOR) significantly decreased oral mucositis pain for at least 6.2 h (median + SD 8 ± 1.68 before vs. 2 ± 2.20 after;  Oral mucositis (OM) is a common toxic adverse effect of cancer therapy for the oral, pharyngeal, and esophageal mucosa . The incThe clinical manifestations of OM include progressive oral pain, dysphagia, and odynophagia. Patients may develop intolerance for oral fluids and caloric intake leading to dehydration, sarcopenia, weight loss, and general debilitation. The burden together with the costs of unplanned admissions, along with the need for enteral hydration and nutrition via gastric feeding tubes, increases costs of care and may interrupt cancer treatment, leading to worse oncologic outcomes .While some strategies to prevent OM have shown promise, they have had limited clinical success and scopes of application ,6. PalliBased on its structural composition, topical methylene blue solution has been used to treat a variety of tegument pain syndromes, including anal fissures and genital herpes. When used as a mouth rinse, it has been shown to lower pain scores and lower opioid requirements when compared with patients who received conventional therapy alone for oropharyngeal pain secondary to mucositis because of different cancer therapies . This paOur current study endeavored to further substantiate the claim that methylene blue mouthwash is an effective and safe adjunct for the treatment of OM-associated pain in patients with head and neck cancer (HNC) receiving RT with or without concurrent chemotherapy.This retrospective cohort study was performed at The University of Texas MD Anderson Cancer Center, a tertiary care academic care center, and was approved by the institutional review board with a waiver of consent.Utilizing billing codes in our electronic medical records, we identified, and retrospectively reviewed study candidates seen in our pain department with OM-associated pain. We selected only those whose symptoms were related to RT for the treatment of HNC. We included patients treated between 1 December 2019 and 1 December 2020.Patients of any age, sex, HNC diagnosis, and stage of disease were included. In addition to RT alone, we included RT combination treatment modalities . Completion of follow-up was defined as an adequate medical records documentation from the initial use of methylene blue oral rinse (MBOR) to its discontinuation.Patients with head and neck malignancy undergoing therapy are frequently seen at the pain service for management of OM-related uncontrolled pain. In our practice, those patients are encouraged to continue other modalities of pain management, including systemic analgesics and coating and anesthetic agents in oral rinses, if needed or beneficial. Patients are instructed to swish and gargle 10 milliliters of the MBOR  for five minutes, then to spit, and this is to be done every 6 h until pain control is achieved. Detailed instructions are given about safety, toxicity, side effects and precautions. The MBOR dilution is compounded by either our institutional pharmacy or outside pharmacies, per availability. When MBOR is prescribed, patients are advised to keep a diary of pain levels before and after oral rinsing, medications used, and their effect on their ability to eat and talk.We used validated patient-reported numerical rating scale (NRS) scores for oral pain using a 11-point Likert scale from 0 (no pain) to 10 (worst possible pain). Pain reduction was classified into 3 groups: >5, 2–5, and <2, termed severe, moderate, and mild, respectively. We also documented changes in oral function burden (OFB) based on the modified Harris mucositis-related pain assessment tool measured on a 7-point validated scale from 0  to 6 . If documented, both the NRS and OFB scores were tabulated before starting MBOR, immediately after the first use, and until pain control was achieved. Information was obtained from the medical records of patients’ encounters at their scheduled follow-up appointments or at their bedside if hospitalized. Notes from patients’ diaries were frequently documented on the medical records.The incidence, indication and timing of the placement of a percutaneous endoscopic gastrostomy (PEG) feeding tube was also recorded. Other information collected included the location and duration of the pain before MBOR treatment, as well as the duration of the analgesic effect and the time to maximal pain relief. We also reviewed any adverse effects reported and changes in the use of opioids by calculating the morphine-equivalent daily dose (MEDD).Summary statistics, including the mean, standard deviation, median, and range, are provided for continuous variables such as age, NRS, and OF, and frequency counts and percentages are provided for categorical variables such as gender. The chi-square test was used to evaluate the association between categorical variables. The Wilcoxon signed-rank test was used to evaluate the change in pain scores from before to after treatment. The Wilcoxon rank sum test was used to evaluate the difference in continuous variables. A boxplot was generated as a visual aid to show the changes of continuous variable between patient groups. Statistical software SAS 9.4  and Splus 8.2  were used for all the analyses.The dataset, SAS program file, and Splus program files are stored in “Y:\proj\PainMedicine\RoldanCarlos\2019-1143_MethyleneBlueOralRinseForPainCausedByOralMucositisSecondaryToCancerTreatment0819\AnalysisRadiationPts0222”.We identified 85 adult patients who were seen in our pain clinic between 1 December 2019 and 1 December 2020 for OM-associated pain related to RT for the treatment of HNC . Among tn = 26, 45%) and squamous cell carcinoma of the tonsil . The most common combination of cancer therapy used was chemotherapy plus radiation , and the least common cancer therapy was RT alone , while others had surgery as well  and the oral mucosa  , and other descriptions of the pain included “ache”, “sore”, “cutting blades”, “scraping”, “needles”, “raw”, and “sharp”.All patients had multi-site National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 mucositis of the oropharyngeal epithelium, and most patients had painful mucosal lesions of the lingual oral area  . Most con = 42, 72%); 11 had a pain reduction of 2–5 (19%), and 5 had a pain reduction of <2 (9%). The mean NRS pain score was 7.59  before MBOR therapy and 2.05  after MBOR therapy. The mean NRS pain score reduction was 5.53  (NRS pain scores were reported both before and after MBOR therapy. Most patients had a pain reduction of >5 ( 0.0001) .n = 49, 84%) reported maximum pain relief within the first two doses (within 12 h), and five patients reported maximum pain relief after three–four doses (within 24 h). Four patients claimed a lack of improvement even after several doses of the MBOR. Although most patients reported pain control within the first day, while undergoing RT, most patients had pain recurrence or reported a mean duration of the analgesic effect of MBOR of 6.18 h .Most patients (p < 0.0001)  before MBOR therapy was 3.55 , and after therapy it was 0.52 . The mean OFB score reduction was 3.03  .p = 0.17). However, because of inadequate documentation, overall conclusions regarding the effect of MBOR on the morphine-equivalent daily dose could not be drawn.The morphine-equivalent daily dose at baseline was documented as a mean of 70.53 . Only 22 patients (38%) who reported pain control in the first 24 h of using MBOR continued their systemic opioid regimens at lower doses. Those patients had documented multi-site pain . Interestingly, the median morphine-equivalent daily dose was 50 for patients younger than 60 years and 30 for patients 60 years old or older . One of these patients had a PEG tube placed because of a poor nutritional condition.Among the 58 included patients, and for different indications, 11 (19%) had therapeutic PEG feeding tubes placed before using MBOR. Of these patients, 4 (36%) were soon able to ingest nutrition orally after their pain was controlled using MBOR. Only 2 patients (3.44%) had PEG tubes inserted despite receiving MBOR treatment  reported adverse events. Three patients experienced an oral burning sensation during their first MBOR treatment. One patient discontinued use of the MBOR because of the pharmacy’s compounding cost (A few patients (ing cost .p < 0.0001) after using MBOR reflects its analgesic properties, not achieved with the use of other rinses and systemic analgesics. Whereas NRS pain scores are self-reported, the OFB scores are of more objective clinical relevance . Therefore, a mean OFB score reduction of 3.03  objectively supports its clinical efficacy.This study shows that 0.05% MBOR is a safe and effective treatment of OM pain associated with RT or combined chemotherapy and RT for HNC. The mean NRS pain score reduction of 5.53 (SD, ±2.44; median, 6; Although the clinical indications for therapeutic PEG tubes are multifactorial, not only including odynophagia, the requirement for and dependence on feeding tubes are significant markers of RT or chemo-RT toxicity . Prior sThere were no major MBOR toxicities, and compliance in use was high. As the most common toxicity was a transient oral burning sensation, this was tolerated by most who experienced it, and the therapy was continued because the benefit was greater. As this mix is not commercially available, it must be compounded individually, which in some cases led to costs.Topical methylene blue solutions have been used to treat different tegument pain syndromes, such as anal fissures and pain from genital herpes-simplex infections ,14. MultIn a recently published trial of MBOR for OM-related pain, patients undergoing RT were excluded from the study because of the unknown ionization effect of MBOR on radiating tissue . HoweverIf swallowed, methylene blue is absorbed from the gastrointestinal tract, reaching a peak plasma concentration in less than 2 h . HoweverUnlike other coating agents containing topical anesthetics, MBOR does not cause local anesthesia, which manifests as intraoral numbness. Thus, methylene blue does not inhibit the gag reflex or alter the taste of ingested meals if patients have a residual taste sensation during RT for HNC. Additionally, methylene blue appears to have an accumulative analgesic effect, as opposed to the short-lasting pain relief provided by other oral rinses.As the analgesic effect of methylene blue is based on direct contact with the painful sites, a large limitation to its effectiveness is its inability to reach the compromised mucosa of the esophagus and the larynx unless swallowed. In this study, as in previously reported studies, our patients are instructed to swish and spit without swallowing, so posterior and lower pharyngeal and cervical esophageal analgesic effects could not be evaluated.Although the use of other preventive therapies, such laser and other light therapy, have shown effectiveness, as supported in at least 24 studies , the posInadequacies in data acquisition could not be addressed owing to the retrospective nature of the study. The discrepancy in the size of the comparison groups could not be reconciled. In addition, we could not objectively address patient compliance with the recommendations given.Our report demonstrates that MBOR is a safe, low-risk, efficient, and easy-to-use treatment for refractory pain from OM during RT for HNC. In our data, it provided at least 6 h of relief. This therapeutic agent is potentially accessible to patients of all socioeconomic backgrounds in the absence of compounding charges. Larger randomized controlled trials are warranted to evaluate in more detail the pain, functional and nutrition benefits, compliance, reduction in opioid and other systemic analgesic use, reduction in therapeutic PEG requirement, and reduction in costs for unplanned emergency department visits and hospitalizations.


Postoperative incisional pain, dysesthesia scores, and overall satisfaction with postoperative pain management were evaluated. The severity of dysesthesia within 12 and 24 h in the nefopam group was significantly lower than that in the control group . Satisfaction scores for postoperative pain management were significantly higher in the nefopam group . The administration of nefopam effectively reduced the severity of dysesthesia within 24 h of surgery in geriatric patients undergoing spine surgery and increased patient satisfaction with postoperative pain management.Postoperative residual pain and dysesthesia in patients with lumbar spinal stenosis (LSS) can reduce patient satisfaction. We investigated the effects of nefopam on dysesthesia, postoperative pain, and satisfaction in patients with LSS who underwent spine surgery. A total of 73 patients were randomly assigned to two groups: the nefopam group ( Lumbar spinal stenosis (LSS) is a degenerative lumbar disease characterized by compression of the spine’s neural structure through ligamentum flavum hypertrophy, facet joint hypertrophy, disk extrusion, or spondylolisthesis ,2. PatieA decompressive laminectomy, with or without posterior fusion, is performed when symptoms are uncontrollable with conservative treatment ,2. Most Nefopam is a centrally acting, non-opioid analgesic . NefopamSeveral studies investigating various types of surgeries, including abdominal, thoracic, and orthopedic procedures, have documented that nefopam reduces acute postoperative pain and exhibits an opioid-sparing effect ,10,11,12Insufficient relief of dysesthesia following surgery in patients with LSS can reduce patient satisfaction with the procedure ,7. Howevhttps://cris.nih.go.kr, accessed on 7 April 2021, KCT0006067). Written informed consent was obtained from all participants before enrollment.This study was a prospective, double-blind, randomized controlled trial conducted at the Korea University Ansan Hospital. The study protocol was approved by the Institutional Review Board of Korea University Ansan Hospital (2019AS0165) and registered at the Clinical Research Information Service . An anesthesia nurse who was not involved in this study administered normal saline or nefopam according to the assigned group with the same drug labeling to ensure double blindness.Eligible participants for this study included patients scheduled for decompressive laminectomy, with or without posterior fusion, with a diagnosis of chronic degenerative LSS with neurogenic claudication. Only adult patients aged 20–75 years with an American Society of Anesthesiologists Physical Status Classification of 1 or 2 were included in the study. The exclusion criteria were as follows: lumbar disc herniation or other spinal disorders, polyneuropathy or peripheral arterial disease, severe pain or disability in other joints (including rheumatoid arthritis or gout), psychiatric disease, sensitivity to test drugs, epilepsy or history of seizure, use of irreversible monoamine oxidase inhibitors, history of myocardial infarction, closed-angle glaucoma, and high risk of urinary retention. All participants were randomly divided into two groups (control and nefopam) in a 1:1 ratio using computer-generated randomization , capnography, and neuromuscular monitoring, and an esophageal stethoscope was applied to the patients throughout the procedure. Total intravenous anesthesia using propofol and remifentanil was performed to induce and maintain general anesthesia. The doses of propofol and remifentanil were adjusted to maintain a BIS between 40–60 and blood pressure and heart rate within 20% of the preoperative values. Rocuronium 0.6 mg/kg was administered initially, and additional rocuronium 0.15 mg/kg was administered when the train-of-four count was 2 or more. Mechanical ventilation was controlled to maintain the end-tidal carbon dioxide partial pressure at 35–40 mmHg with an inhaled oxygen fraction of 40%. Body temperature was monitored using an esophageal stethoscope and maintained above 35 °C with a forced air warmer. Sugammadex (2 mg/kg) was used to reverse muscle relaxation at the end of surgery.The unlabeled interventional drug solution was administered one hour before the end of surgery. In the nefopam group, a 20 mL solution containing nefopam  20 mg diluted with normal saline was infused over 20 min. In the control group, 20 mL of normal saline was infused over 20 min for the purpose of blinding. At the end of surgery, a patient-controlled analgesia (PCA) device containing a 20 µg/mL fentanyl solution was connected via intravenous access. The PCA device provided a continuous infusion of 10 µg of fentanyl per hour with additional bolus injections of 10 µg of fentanyl every 15 min as needed by the patient. Pethidine (50 mg) was provided as a rescue analgesic upon the patient’s request when the postoperative pain score exceeded 3.The primary outcome was the severity of dysesthesia in the lower extremities at 12, 24, 48, and 72 h postoperatively, evaluated using an 11-point visual analogue scale ranging from 0 (no discomfort) to 10 points (most extreme discomfort). Dysesthesia was defined as voluntary or involuntary abnormal unpleasant sensations in the lower extremities, including numbness, burning sensation, and tingling.The secondary outcomes were the severity of postoperative incisional pain in the lumbar area, evaluated using an 11-point visual analogue scale ranging from 0 (no discomfort) to 10 points (most extreme discomfort), incidence of rescue analgesic use, use of PCA, incidence of postoperative nausea and vomiting (PONV), and side effects of nefopam  at 12, 24, 48, and 72 h postoperatively. Overall satisfaction with postoperative pain management was measured at 72 h postoperatively using the 5-point Likert scale: (1) very unsatisfied, (2) unsatisfied, (3) neutral, (4) satisfied, and (5) very satisfied.Based on a previous study of leg numbness following lumbar surgery, the severity of leg numbness was 5.9 ± 2.6 preoperatively [t-test. All statistical analyses were performed using SPSS Statistics ver. 21.0 . A p-value of <0.05 was considered statistically significant.Data are expressed as means ± standard deviation or numbers (percent). The Chi-squared test was performed for comparing categorical data. Continuous variables were compared using the independent A total of 78 patients were enrolled and randomly allocated to two groups. One patient in the control group  and four patients in the nefopam group  were excluded. Therefore, 38 and 35 patients in the control and nefopam groups, respectively, were analyzed .Demographic and operative data are presented in The scores for dysesthesia in the lower extremities, preoperative back pain, and postoperative incisional pain in the lumbar area are shown in There was no difference in the amount of PCA (fentanyl-based) or additional use of rescue analgesics (pethidine) between the two groups . After 2There were no significant differences in the incidence of PONV or nefopam side effects between the two groups .The results of this study indicate that, in geriatric patients who underwent spine surgery, dysesthesia in the lower extremities was reduced for 24 h post-operation without any additional severe side effects following the intraoperative administration of nefopam (20 mg) before the end of surgery. In addition, nefopam (20 mg) reduced postoperative pain for 48 h after surgery, although this was not statistically significant. Additionally, nefopam (20 mg) administration increased patient satisfaction with postoperative pain control, without any side effects.Nefopam, a non-opioid analgesic derived from the non-sedative benzoxazocine, acts centrally to alleviate pain through an unconventional mechanism. Operating on the brain and spinal cord, its primary analgesic mechanisms involve elevating serotonin, norepinephrine, and dopamine activity ,23, and Previous studies investigating the effectiveness of nefopam in patients undergoing spine surgery have yielded mixed results. Some studies have reported that nefopam did not reduce PCA or opioid consumption during the first 3 d post-operation ,32,33. IConversely, nefopam demonstrated a significant effect in reducing postoperative dysesthesia for up to 1 d, unlike postoperative pain. As postoperative dysesthesia is considered a part of neuropathic pain , this reIn our study, a single bolus of 20 mg nefopam was administered immediately after surgery. Previous studies have indicated that the median effective dose of nefopam in minor-to-moderate surgeries ranges from 18 to 28 mg ,38,39. TAccording to a previous study on the clinical course of pain and disability following surgery for spinal stenosis, most patients experienced a 50% reduction in pain three months after surgery; however, mild-to-moderate pain and disability persisted even after 60 months . In partThis study had several limitations. First, patients were observed for only 3 d, providing short-term information. Previous studies have suggested that nefopam may have beneficial effects on chronic pain even after three months . NotablyThis study highlights the potential pivotal role of nefopam in postoperative pain management, specifically in the alleviation of postoperative neuropathic pain. These findings hold significant value, as they contribute to the development of a suitable PCA regimen that aligns with patient expectations. This alignment is a crucial factor in enhancing postoperative satisfaction among patients while minimizing the risk of severe side effects. Further research and long-term follow-up studies are warranted to validate these findings and provide a more comprehensive understanding of nefopam’s role in postoperative pain management.In this study, the nefopam-treated group exhibited a reduction of up to 30% in dysesthesia in the lower extremities compared to the control group for up to 24 h postoperatively. Additionally, they reported a 16% higher satisfaction with overall pain control until 72 h postoperative. However, there were no significant differences observed in incisional pain or the usage of analgesics. Consequently, the administration of nefopam appears to be effective in reducing postoperative dysesthesia and satisfaction in patients with LSS undergoing spine surgery.


Chronic back and knee pain impairs health- related quality of life (HRQoL) and patient enablement can improve HRQoL.To determine whether enablement was a moderator of the effect of chronic back and knee pain on HRQoL.A cross-sectional study of Chinese patients with chronic back and knee problems in public primary care clinics in Hong Kong.Each participant completed the Chinese Patient Enablement Instrument-2 (PEI-2), the Chinese Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the Pain Rating Scale (PRS). Multivariable regression examined the effects of PRS score and PEI-2 score on WOMAC total score. A moderation regression model and simple slope analysis were used to evaluate whether the interaction between enablement (PEI-2) and pain (PRS) had a significant effect on HRQoL (WOMAC).P<0.001), whereas PEI-2 score was associated inversely with WOMAC total score  and PRS score. The effect of the interaction between PRS and PEI-2 (PRS × PEI-2) scores on WOMAC total score was significant  suggesting PEI-2 was a moderator. Simple slope analyses showed that the relationship between PRS and WOMAC was stronger for participants with a low level of PEI-2 (gradient 3.056) than for those with a high level of PEI-2 (gradient 1.746).Valid patient-reported outcome data from 1306 participants were analysed. PRS score was associated with WOMAC total score (β = 0.326, Patient enablement moderated the impact of pain on HRQoL. A higher level of enablement can lessen impairment in HRQoL associated with chronic back and knee pain. Illness perception focuses on how a patient experiences and mentally frames their life with illness,This study aimed to determine whether enablement was a moderator of the effect of chronic back and knee pain on HRQoL. The authors hypothesised that pain and enablement would affect HRQoL, and that the effect of pain on HRQoL could be moderated by enablement. The conceptual model is shown in Supplementary Figure S1.34 There are 73 GOPCs organised in seven clusters around Hong Kong. The care in GOPCs is standardised by evidence- based guidelines whereas care is more variable in the private sector. Participants of this study were recruited from six GOPCs in two clusters.The study was carried out in Hong Kong where the healthcare system is serviced by both the public and private sectors, and residents can freely choose where they receive care without means testing. As a result of the heavy financial subsidies, the public primary care clinics, called general outpatient clinics (GOPCs), are the main care providers for patients with chronic diseases.35 Participant inclusion criteria were adults aged ≥18 years, who had a doctor-diagnosed symptomatic back and/or knee problem that was expected to last for ≥1 month. The exclusion criteria were patients who had a life expectancy <12 months, had current cancers, were too ill, or were unable to communicate in Chinese. All eligible patients were recruited by their doctors or trained research assistants in the clinics between 1 June 2020 and 31 December 2021. After completion of a written consent form, participants’ sociodemographic and clinical data were collected by structured questionnaires and PROs by a telephone survey administered by an independent survey organisation. The participant flow chart is shown in Supplementary Figure S2. More details on participant recruitment and data collection are described in another article.35This cross-sectional study was part of a single-blinded cluster randomised controlled trial to evaluate the effectiveness of measuring and reporting HRQoL in routine clinical practice.36 showed a power of 0.95 for moderation analysis at a significance criteria of α = 0.05, 2F = 0.011.A total of 1221 participants who had complete PRO data were included in this moderation study. Post hoc power analysis, using G*Power version 3.1.9.7,Participants’ sociodemographic information, lifestyle factors, and self-reported comorbidities were collected by a questionnaire administered by a trained research assistant in the clinic. Another questionnaire was completed by the physician to collect data on the diagnosis and duration of musculoskeletal problems and to provide a global rating about the severity of the participant’s condition on a five-point Likert scale (GRS) from 1 (no problem) to 5 (very severe).et al15 and consists of six items: ability to cope with life; ability to understand one’s illness; ability to cope with one’s illness; ability to keep oneself healthy; confidence about one’s health; and ability to help oneself. Each item is rated on a 5-point Likert scale, ranging from 1  to 5 (extremely well). The item scores are summated to give a total PEI-2 score (range: 6–30), with higher scores indicating better enablement. Missing item values can be imputed with the average of the scores of answered items, up to three items. The Chinese PEI-2 is valid, reliable, and sensitive in a Chinese population.14The Chinese PEI-2 is a PRO measure that was adapted from the PEI originally developed by Howie 37 and back38 problems. It consists of 24 items in three domains: pain (five items); stiffness (two items); and physical function (17 items). Each item is rated on a 5-point Likert scale (0 to 4), with higher scores indicating more symptoms or greater impairment. The item scores in each domain are summated as the domain score. The total WOMAC score is the sum of the three domain scores, ranging from 0 to 96.39 For participants with completion of at least four of the five pain items, one of the two stiffness items, and 14 of the 17 function items, missing item values can be imputed with the average of the completed items in the relevant subscale.40 The Chinese version of WOMAC is valid, reliable, and sensitive in Chinese patients.41The WOMAC is a widely used HRQoL measure specific to musculoskeletal problems, which has been applied to patients with knee42 to assess the severity of pain. The validity and reliability of the Chinese version is established.43The PRS is a self- reported tool consisting of a scale with extreme anchors of ‘ no pain (0)’ to ‘ extreme pain (10)’Descriptive statistics were used to describe the patients’ sociodemographic information, lifestyle factors, disease characteristics, and PROs. One-way analysis of variance (ANOVA) was used to test the mean differences in the PROs between the groups of patients diagnosed with a back problem only, knee problem only, and both back and knee problems. Post hoc test (by Tukey’s honestly significant difference) was used to compare each group against the others. Pearson’s correlation between different PROs was examined. Multivariable regression was used to test the effect of disease characteristics, PRS score, and PEI-2 score on WOMAC total score, adjusted by sociodemographic characteristics.44 The PRS and PEI-2 scores were standardised (converted to a Z-score) to avoid multicollinearity in the moderation analysis. Other variables that had significant effects on WOMAC total score were included as confounders in the moderation regression model. The moderation analysis was carried out by Hayes’s PROCESS macro44 for SPSS Model 1. In addition, a simple slope analysis was used to show the moderation effect.45 The mean of the estimated WOMAC total score (Ŷ) was calculated according to the following equation:Moderation analysis was used to test if enablement (PEI-2 score as the moderator) would interact with pain level (PRS score as the predictor) to influence HRQoL . Moderation analysis hypothesises that a predictor and the interaction between a predictor and a moderator can predict the outcome if there is a ‘moderation effect’.A 5% statistical significance was used for all analyses. All the analyses were carried out with IBM SPSS Statistics (version 27).46 The mean and median GRS score was 2.45 (SD 0.64) and 2 (range 1 to 5), respectively.n = 13) (see Supplementary Table S1). Valid PEI-2 scores and PRS scores were available for 1258 and 1307 participants, respectively. Valid WOMAC scores (the primary outcome) were available from 1306 participants whose characteristics were similar to those with incomplete data  found that participants with both back and knee problems had significantly higher WOMAC scores than participants with back or knee problems only. Participants with back problems only had significantly higher PRS scores than those with knee problems only.r = 0.506, P<0.001) but negatively correlated with the PEI-2 score . The PEI-2 score was negatively correlated with the PRS score .Pearson correlation analysis  found thP<0.001), GRS score , and number of comorbidities  were positively associated with the WOMAC total score. A higher PEI-2 score was associated with a lower WOMAC total score .Multivariable regression analysis with adjustment for sociodemographic and lifestyle factors  showed tThe result of the moderation analysis is shown in Simple slope analysis  shows a As the WOMAC total score includes the pain domain that may bias the association with PRS, a sensitivity analysis was carried out on the moderation effect using the WOMAC stiffness domain and physical function domain summation score (excluding the pain domain score) as the outcome. It showed similar results , further substantiating that PEI-2 was a moderator between PRS and WOMAC total scores.This study examined the moderation of patient enablement on the negative impact of pain on HRQoL in the context of chronic back and knee problems. The results confirmed that patient self-reported pain and enablement were the most significant determinants of HRQoL. As hypothesised, a higher level of pain was associated with more impairment, and a higher level of enablement was associated with less impairment of HRQoL. This study has established that enablement was a significant moderator of the association between pain and HRQoL. Specifically, a high level of enablement weakens the effect of pain on HRQoL impairment.The strength of the study was the large number of participants recruited from multiple primary care clinics. The age and gender distribution of the participants was similar to that of the back and knee problem patient population found in the Hong Kong territory-wide primary care morbidity survey in 2021/2022. The results may be generalisable to the general Hong Kong population. The PRO data were measured with standard valid measures and they established patient enablement as a moderator of the association between pain and HRQoL. The sensitivity analyses showed consistent results, supporting reliability. There were a few limitations to this study. First, the analysis of cross-sectional data could not ascertain a causal relationship, and the correlations between PEI and WOMAC (−0.39) and PRS (−0.20) scores were relatively small. Second, the results from patients in public primary care clinics may not be applicable to those managed in the private sector. Third, self-report data are subject to bias from recall and a tendency to give socially acceptable answers. The authors believe these biases applied to all participants and should not have affected the moderation analysis results. Finally, the results from Chinese patients may not be generalisable to populations who are not Chinese.8–11,27,48–50 and the positive association between enablement and HRQoL.51 A significant, although weak, negative association was found between enablement and pain, which moderated the association between pain and HRQoL. Theoretically, enablement promotes the patient’s ability to control their health, life, and coping strategies, which can lessen pain, depression, and limitation in daily functioning; therefore, it can improve HRQoL.26,27,52 Another mechanism by which enablement helps is through improved health literacy.25 Studies in Australia have shown that patients with chronic diseases who were more enabled were more likely to have a higher level of health literacy and to actively manage their health.20 In addition, health literacy can influence an individual’s illness perception resulting in better coping ability.53The current study confirmed the findings from previous studies on the negative association between pain severity and HRQoL54,55 Education about the nature of the musculoskeletal problem and self- care strategies should be part of routine care for these patients.56 Exercise and self-care management programmes can reduce pain and improve function in patients with musculoskeletal problems.57,58 Appropriate referrals to other healthcare professionals can further enable patients to overcome specific environmental limitations. For instance, occupational therapists can advise on home modification so that patients can continue to live comfortably at home.The findings on the role of enablement as a moderator between pain and HRQoL has implications for a paradigm change in clinical practice. Most chronic musculoskeletal problems are progressive degenerative conditions with no cure. Primary care physicians should recognise patient enablement as a first-line intervention for chronic musculoskeletal problems. The scope of patient-centred care should be broadened to include an assessment of HRQoL and enablement so that management can be customised to enhance coping, health literacy, and self-care to maximise functioning. A reorientation of the treatment goal may help reduce the use of analgesics that can cause serious side effects and are subject to misuse.In conclusion, patient enablement moderated the negative impact of pain on HRQoL. Higher level of enablement can lessen the impairment of HRQoL related to chronic back and knee pain. Education, exercise, and self-care programmes that aim to enhance patients’ health literacy, functioning, and ability to cope with their illness should become routine treatments for chronic musculoskeletal problems. Future studies with more diverse populations are required to establish the interaction between enablement and pain on HRQoL, and how patient enablement can be effectively enhanced in patients with chronic musculoskeletal problems.


Behavioral and psychiatric problems are common in patients with Prader-Willi syndrome (PWS), while physical complaints such as pain, fever, and vomiting are rare due to a high pain threshold and dysregulation of temperature control. PWS patients have an increased mortality rate, some due to undiagnosed life-threatening diseases. We describe 2 patients with PWS whose behavioral changes, initially thought to be part of their behavioral phenotype, delayed the final diagnosis of a life-threatening underlying illness. A 13-year-old girl with PWS presented with a sudden change in behavior including aggression, scratching, and self-injury. She was seen by several health care providers, and after 5 months the diagnosis of pyosalpinx was made, for which laparoscopic resection of an infected tailgut cyst was performed, resolving the behavioral symptoms. A 38-year-old man with PWS presented with recurrent vague inguinal pain and nonepileptic seizures. After several years of consulting physicians and psychiatrists, including several hospital admissions, the diagnosis of bilateral inguinal hernia was made. After surgical correction, the pain and seizures ceased. In PWS patients presenting with unexplained behavioral changes and unusual somatic complaints, clinicians should perform an extensive clinical examination and consider underlying physical illness rather than attribute the problem to the behavioral phenotype. Prader-Willi syndrome (PWS) is a neurodevelopmental disorder, caused by lack of expression of genes inherited from the paternal chromosome 15q11-q13 region. PWS results from a paternally inherited deletion of the 15q11.2-q13 region, from uniparental maternal disomy, an imprinting defect (ID), or a translocation involving chromosome 15. Patients with PWS have dysmorphic features , hypogenitalism, axial hypotonia, and feeding difficulties (from poorly controlled sucking) in the neonatal period, with a gradual progression toward excessive eating and insatiability. If untreated, PWS patients develop morbid obesity and the consequences of associated metabolic syndrome [Furthermore, patients with PWS have altered pain tolerance and dysregulated temperature control. The changes in pain tolerance are attributed to an impaired peripheral somatosensory function and altered central processing of painful stimuli, possibly mediated by abnormal GABA-A receptor binding , 2. ThesTogether with the reduced occurrence of vomiting , it is nWe describe 2 patients with PWS, who consulted their health care provider because of behavioral changes and abdominal complaints initially attributed to the behavioral phenotype in PWS. The patients were ultimately diagnosed with severe intra-abdominal pathology for which surgical intervention was required. We urge caution if PWS patients present with newly onset abdominal symptoms or change in behavior, as these could be the only signs of life-threatening underlying illness.We present 2 patients with PWS, presenting with atypical symptoms of an underlying physical illness.A 13-year-old girl with PWS confirmed by genetic testing  and moderate intellectual disability  presented in May 2021 to the pediatric outpatient clinic. She demonstrated constipation and soiling paired with a change in behavior described as increasing episodes of self-harm, skin picking, and aggression toward other children. She was seen by multiple physicians and treated with laxatives for multiple months. A genital physical examination was not performed because of her lack of cooperation. Five months later in October 2021, when vaginal soiling was reported by the parents, abdominal computed tomography (CT) and magnetic resonance imaging (MRI) scans were performed showing a pyosalpinx and an intra-abdominal mass . Blood sA 38-year-old male with PWS confirmed by genetic testing (15q11-12 deletion) and mild intellectual disability  was seen in 2015 with complaints of vague inguinal and abdominal pain, leg and back pain, “tingling in the hands,” and headaches during the night. The general practitioner suspected an inguinal hernia. The man was referred to a physiotherapist who attributed the pain to inflammation of the adductor muscles. X-rays of the hip and pelvis and MRI of the spine were normal. Physiotherapy did not resolve the symptoms and there was a further increase in abdominal and leg pain, as well as tingling in the hands. He was seen by an internist who diagnosed swollen lymph glands and he referred him to the urologist. Ultrasound examination was normal. Amitriptyline was prescribed as a treatment for depression and pain.A first seizure occurred in 2016, described by the parents as “falling down, convulsions, growling, excessive salivation, grasping his head.” After the seizure he complained of muscle pain and headache. Electroencephalography (EEG) performed at the emergency department was normal. Corticosteroids were prescribed. In 2017, the seizures occurred more frequently and topiramate was prescribed. A repeat electroencephalography was normal. Polysomnography showed sleep apnea and he was started on continuous positive airway pressure (CPAP) therapy. Lormetazepam was prescribed for his anxiety. In January 2018, he had several severe and prolonged seizures episodes of reduced consciousness lasting more than 2 hours. After administration of diazepam at the emergency department, he was transferred to the intensive care unit. He was diagnosed with epilepsy and levetiracetam was prescribed by the neurologist. Because of severe behavioral problems and fugue behavior he was transferred to the isolation room, which induced a further increase in seizures and even more behavioral difficulties. During this admission, he was diagnosed with psychogenic nonepileptic seizures and transferred to a psychiatric inpatient unit for intellectually disabled persons with behavioral difficulties, where he was treated with eye movement desensitization and rehabilitation (EMDR) therapy for posttraumatic stress disorder.In the following months, his condition worsened with increasing seizures, abdominal pain, urinary incontinence, and irritability. He was seen by a general practitioner, pneumologist, endocrinologist, general internist, and neurologist. Finally, an abdominal CT scan was performed, which revealed a bilateral inguinal hernia with enclosed omental and intestinal loops in 2021 , for whiIn both patients, there was a major discrepancy between the preexisting behavioral phenotype and the newly emerging complaints, there was no fever, and abdominal symptoms were only very vague. The patients could not adequately describe their complaints, and no comprehensive physical examination with genital inspection was performed, delaying the diagnosis of the underlying illness. Immediately after the resolution of the physical illness, the behavioral changes stopped in both patients, establishing the causal link between the genitoabdominal problems and the behavioral change.Optimal management of patients with PWS involves both the management of several comorbidities that constitute the syndrome, as well as the ongoing assessment for the emergence of associated conditions and complications that evolve over the lifespan of these individuals. Butler et al  recentlyWe report 2 young adults with possible life-threatening genitoabdominal complications that remained undetected for a long time, presumably because of the atypical presentation. The girl was known with constipation, soiling, and a change in behavior. The man presented with longstanding vague inguinal pain, pain in the legs, general discomfort, behavioral changes, and nonepileptic seizures for multiple years. Only after repeated urging by the parents, additional physical and genital examinations were performed leading to the diagnosis of a genitoabdominal abscess in the girl and an inguinal hernia in the man. This late detection may be explained on one hand by the atypical symptoms, including vague abdominal complaints and a change in behavior, on the other hand by the difficult cooperation of PWS patients on physical examination.It is well known that PWS individuals have a high pain threshold, impaired thermoregulation, and lack of vomiting, and may therefore not respond normally to abdominal infection or painful stimuli, with behavioral changes and vague physical complaints as the only clinical signs . Severe In addition to the impaired somatosensory function, PWS patients have mild to moderate intellectual disability, possibly attributing to the difficulty expressing their health complaints. It has been proven that health problems are less likely to be diagnosed in patients with intellectual disability .We conclude that the increased mortality rate seen in PWS patients  may partOur 2 case reports emphasize the importance of a multidisciplinary approach to the care of PWS patients, including endocrinologists with an interest in behavior and child psychiatrists with interest in physical problems. There is a paucity of data supporting the use of medical approaches documented for PWS; however, standard recommendations for treatment have been published . The mulBehavioral problems, including temper tantrums, stubbornness, aggressive outbursts, and self-injuring behavior, as well as psychiatric comorbidities including autism spectrum disorder, anxiety, mood disorders, and psychosis are common in children and adults with Prader-Willi syndrome (PWS).Individuals with PWS have a high pain threshold, impaired temperature regulation, and a high threshold for vomiting leading to a risk of delay in the diagnosis of severe physical problems.PWS patients have difficulty expressing their health problems; therefore, information from caregivers and family can provide important clues in the diagnostic odyssey.A change in behavior can be the only presenting symptom of a serious physical illness in PWS patients and may be mistaken as part of their behavioral phenotype, causing diagnostic delay.Health care providers should be cautious about a possible underlying physical disease when a behavioral change occurs in patients with PWS.