Established conventional treatments for postherpetic neuralgia (PHN) and postherpetic itch (PHI) are difficult and often disappointing. In this study, the authors investigated the effect and mechanisms of extracorporeal shockwave therapy (ESWT) on pain and itch associated with PHN and PHI.2, Richard Wolf GmbH, Knittlingen, Germany) to skin areas affected by pain or itch. An energy flux density of 0.09 to 0.16 mJ/mm2 at a frequency of 5 Hz and 2000 impulses was administered at 3-day intervals for 6 sessions. The NRS, 5D-Itch Scale, and Patients Global Impression of Change (PGIC) scale were used to evaluate the efficacy of ESWT.Thirteen patients, 50 to 80 years of age, with symptoms associated with PHN or PHI (duration of persistent pain >3 months) and complaints of pain or itch rated >4 on a numerical rating scale (NRS), were included. ESWT was administered using a shockwave device . There was a statistically significant difference between PGIC scores, which were checked every 2 sessions (P < .0001).NRS scores of pain and itch and 5D-Itch Scale scores decreased significantly compared with before treatment and at the end of the treatment sessions (ESWT is a noninvasive modality that significantly reduced PHN-associated pain and itch. The response to HZ virus-induced nerve inflammation results in anatomical and functional injury to neural tissue in the peripheral nerves, dorsal root ganglion, and spinal cord, resulting in the onset of neuropathic pain and sensory abnormalities in the affected dermatome.–6 Patients affected by PHN pain also experience itch, termed postherpetic itch (PHI). The prevalence of PHI is considerable, and affects 9% of patients in the acute stage; moreover, the prevalence of PHI is 30% to 58% at the chronic stage in those who develop PHN.,8 PHI is clinically defined as itching concomitant with pain or a sensation of itching that increases as pain subsides. Furthermore, only the itch sensation remains without pain. In such cases, the itching becomes troublesome. PHI also has 2 causes, peripheral and central, similar to PHN.The most common neurological complications associated with herpes zoster (HZ) is postherpetic neuralgia (PHN), defined as pain lasting for 90 days after the onset of rash. PHN is characterized by neuropathic pain, including a persistent spontaneous sharp or paroxysmal burning sensation, allodynia, and/or hyperesthesia, that affects patient quality of life. Of patients >50 years of age, approximately 10% to 15% with HZ develop PHN, and this complication occurs more often in older patients.,10 The principle of shockwave therapy is the production of mechanical energy using pressurized air. This energy is transmitted in the tissues as a longitudinal wave. It contributes to regeneration and revascularization by causing microfunctional and microstructural changes. Low and medium energy levels involve intercell and cell–matrix interactions and modify the cell membrane, and functional changes in cytoplasmic organelles.–13 Based on these mechanisms, ESWT can be considered a method of mechanotherapy for analgesia, regeneration, and reduction of neuroinflammation. ESWT can be applied to treat PHN and PHI that are refractory to medication based on their pathophysiology. In other words, ESWT is a safe and noninvasive treatment mainly used in musculoskeletal system, but its application can be extended to PHN expecting to induce pain relief and tissue regeneration.Extracorporeal shockwave therapy (ESWT) is usually used to treat musculoskeletal diseases such as nonunion fractures, plantar fasciitis, and epicondylitis, among others.,15 The main objective of the present study, therefore, was to evaluate the effect of focused ESWT on patients with PHN or PHI.To our knowledge, no previous studies have applied ESWT to PHN and/or PHI, although several previous investigations have described the efficacy of ESWT in burn pruritus and pain similar to PHI and PHN in terms of sharing a similar neuropathic mechanism.22.1 and with complaints of pain or itch with a rating >4 on an numerical rating scale (NRS) were included. Of patients who complained of itch, only those who complained of accompanying pain were included. Patients with contraindications to ESWT, including malignancy or acute infections, or inflammation of the affected area, history of epilepsy, coagulopathies, or cardiac pacemaker, were excluded from this study.This open-label, retrospective pilot study was conducted according to the tenets of the Declaration of Helsinki. The research protocol was approved by the local Institutional Review Board of Kangbuk Samsung Hospital, Seoul, Korea. All subjects were outpatients at a pain clinic of the hospital. Patients 50 to 80 years of age with symptoms appropriate for PHN or PHI (duration of persistent pain >3 months) undergoing classic conservative therapy such as combination medication treatment  and nerve block2.22, Richard Wolf GmbH, Knittlingen, Germany) equipped with piezo ceramic crystals for the focused shockwave. Accordingly, treatment was continued by moving the probe to tender areas in a sequential manner at a distance of 40 to 50 mm, which was set considering focal zone (46 mm × 4 mm) of linear, focused, piezo source after ESWT at 100 impulses/cm2 on the primary treatment site. The energy flux density was 0.09 to 0.16 mJ/mm2; with a frequency of 5 Hz and 2000 impulses were administered at 3-day intervals for 6 sessions.Among the affected skin areas with pain or itching, the primary treatment site where the symptoms were reproduced when the probe was placed and impulse and shockwaves were being delivered was selected. ESWT was conducted using a shockwave device , a patient rated instrument measuring change in overall patient status on a scale from 1 (very much improved) to 7 (very much worse) at weekly intervals, every 2 sessions.,18To evaluate the effect of ESWT on PHI, the NRS was used to evaluate the degree of subjective pruritus before treatment and immediately after every 2 sessions: 0 represented no pruritus and 10 represented the worst possible itching. The 5-D Itch Scale, consisting of 5 dimensions, was used. Each item was rated from 1 to 5 points according to the degree of pruritus, and the total score was calculated to quantify pruritus. 5-D scores can potentially range from 5 (no pruritus) to 25 (most severe pruritus).2.4t test and Bonferroni post hoc tests. All statistical tests were 2-tailed and P < .05 was considered to be statistically significant.Data are expressed as mean ± standard error of the mean. Statistical analyses were performed using GraphPad Prism version 5.0 . Repeated measures analysis of variance was used to compare NRS scores of pain, pruritus before treatment, and after every session (first session to the sixth session), followed by Bonferroni post hoc tests. PGIC and 5-D scores also were analyzed using repeated measures analysis of variance with the factor time (after 1–3 weeks). Comparisons between NRS before treatment and NRS at every session value were performed at each time point using the Student 3P < .0001) . There was statistically significant difference in NRS scores at the 2 points when comparing the third session of ESWT and sixth session (P = .010). There was a statistically significant difference between PGIC scores, which were checked every 2 sessions   . Differences in 5-D Itch Scale scores were statistically significant  .Thirteen patients participated in the present study. Patient demographic information  is summarized in Table sions , central sensitization , loss of descending control in the spinal cord, and neuroimmune and neuroglial interactions have been suggested as possibilities.,23,24 Considering these mechanisms, treatment of PHN and PHI is required to suppress various neurotransmitters associated with central sensitization to promote regeneration of damaged tissues.This study demonstrated that ESWT significantly reduced pain and severity of pruritus in patients with PHN. Patients with PHN complain of decreased quality of life and disturbances with the activities of daily living. PHN is difficult to treat due to its complex pathophysiology, which remains to be clarified. The concomitant inflammatory reaction of the dorsal root ganglion, peripheral nerve, and nerve endings on skin damage presumably lead to HZ-associated pain. This tissue damage and cascading inflammation stimulates nociceptors, causing excitatory and repetitive painful stimuli resulting in central sensitization of the nociceptive system. Initially, replicating HZ particle in infected neurons can be result to direct neurolytic lesions to the cell bodies or their axons, and indirect injury by the endoneurial inflammatory response and hemorrhage. Damage in axonal membrane and cell body can generate continue episodes of injury discharge. Injury discharge from afferent C fiber endings in the affected skin will release the various neurotransmitters onto spinal cord dorsal horn neurons which initiate and develop central sensitization in associated spinal segments. These processes are considered to be the most important mechanism underlying the chronic pain associated with PHN.,26 The effects of shockwaves on wound healing, bone regeneration, and skin grafts have also been extensively studied. However, no studies have yet applied ESWT to neuropathic symptoms in PHN or PHI. Several studies have investigated the effect of ESWT on burn scar itch and pain with aspects of neuropathic symptoms. These studies have noted that ESWT can cause alterations in the target cells. These interactions involve intracell and cell–matrix interactions. The production of proteins, nitric oxide, and specific growth factors contribute to the activation of the biological process, which results in achieving tissue regeneration. ESWT applied to peripheral nerve injury induced analgesia accompanied by removal of the degenerated axons and increases the capacity of the injured axons to regenerate. ESWT revealed an important role in the neural regeneration through increasing the myelin sheath proliferation, axons regeneration consequently significant enhancement of the nerve functional recovery.–29 In a similar context, ESWT can be considered for the treatment of PHN and PHI.Shockwaves were originally introduced in medicine for kidney stone treatment as extracorporeal shockwave lithotripsy, and clinical applications have since spread. ESWT has significantly expanded, first to musculoskeletal diseases and, later, to regenerative medicine. Shockwaves are mechanical in nature, and consist of an initial positive very rapid phase, exhibiting high amplitude, followed a few microseconds later, by a sudden phase of mild negative pressure, afterward returning to basic values. Shockwaves are mechanical waves, which act as the physical stimulus to correlate the interactions of physical energies with various tissues and cellular elements. In previous studies, ESWT as mechanotherapy, was demonstrated to positively influence some cellular functions and local homeostasis, therefore leading to tissue building and self-healing capabilities.5The present investigation included only a limited number of subjects in the preliminary study and no control group. In addition, there was no precedent study and, as such, there is a lack of evidence regarding how many sessions are needed. Nevertheless, the present study demonstrated improvement in symptoms after ≥3 sessions, and revealed that the effect increased as the number of treatment sessions increased to 6. However, because it is targeted at a small number, comparative studies are also needed to determine the optimal number of treatments for larger subjects. There is also a limit to how long the therapeutic effects of ESWT will remain in this study because of short-term follow-up.6To our knowledge, this is the first report to describe the use of ESWT in PHN patients with or without PHI. We found that ESWT was clinically useful as a noninvasive therapy for pain and itch associated with PHN, and can be considered an effective alternative modality for the treatment of PHN and PHI.Conceptualization: Sung Hyun Lee, Eun-Ah Cho, Kyung Seung Yang.Data curation: Sung Hyun Lee, Hyo-Won Lee, Pyoung On Kim.Writing–original draft: Sung Hyun Lee, Jin-Hee Ahn.Writing–review & editing: Sung Hyun Lee, Kyoung-Ho Ryu.Supervision: Kyoung-Ho Ryu.Formal analysis: Eun-Ah Cho.Validation: Inyoung Youn.Investigation: Jin-Hee Ahn.Sung Hyun Lee orcid: 0000-0001-5616-6649.


To evaluate the impact of an opioid-sparing pain management protocol on overall opioid consumption and clinical outcomes.This was a single-center, quasi-experimental, retrospective, before and after cohort study. We used an interrupted time series to analyze changes in the levels and trends of the utilization of different analgesics. We used bivariate comparisons in the before and after cohorts as well as logistic regression and quantile regression for adjusted estimates.th percentile difference: -0.78; 95%CI -1.51 - -0.05; p = 0.036; 75th percentile difference: -2.23; 95%CI -3.47 - -0.98; p < 0.001).We included 988 patients in the preintervention period and 1,838 in the postintervention period. Fentanyl consumption was slightly increasing before the intervention  but substantially decreased in level with the intervention  and then progressively decreased . There was an increasing trend in the utilization of dipyrone. The mechanical ventilation duration was significantly lower , especially for patients who were mechanically ventilated for a longer time (50A pain management protocol could reduce the intensive care unit consumption of fentanyl. This strategy was associated with a shorter mechanical ventilation duration. The Society of Critical Care Medicine (SCCM) guidelines on pain recommend a proactive approach to pain management that includes (1) pain evaluation with validated scales; (2) opioids as a first line therapy for pain; and (3) multimodal analgesia to spare opioids in some scenarios.Unpleasant sensations are common in patients admitted to intensive care units (ICUs). Pain accounts for a substantial burden of symptoms, and its effects may be detrimental not only in the short term patients also frequently experience hemodynamic instability. This leads to the choice of fentanyl rather than morphine as the usual first-line opioid used in critical care due to its pharmacokinetic properties and hemodynamic stability.,6Pain management in the ICU may be difficult for some reasons. The pharmacokinetics of opioid and nonopioid analgesics are altered due to organ dysfunction;,6 Some adverse effects may negatively impact mechanical ventilation (MV) weaning: (1) respiratory drive dysregulation leading to high tidal volumes and low respiratory rates; and (2) a reduced level of consciousness.However, the use of opioids - and fentanyl in particular - is not without drawbacks. Excessive opioid use may lead to intoxication-like symptoms because fentanyl is subject to a high context-sensitive half-life when infused for prolonged periods. which could lead to a higher benefit of boluses of drugs instead of high-dose continuous infusions.Pain in critical care has further characteristics that may not benefit from the high-dose continuous infusions of opioids. Pain and discomfort are frequently related to mechanical reasons, such as fecal impaction, urinary retention, device traction and the patient's position on the bed, which are not treated adequately with and may even be worsened by opioids. Pain is also more intense during procedures,Therefore, our primary objective was, in a single intensive care unit, to implement a pain management routine and to assess its impact on overall fentanyl consumption. Furthermore, we evaluated routinely measured clinical outcomes to assess the potential benefits of an opioid-sparing strategy for pain management and the potential reduction in costs related to opioid consumption.This was a single-center, quasi-experimental, retrospective, before and after cohort study. Consent to participate was waived by the Institutional Review Board (IRB) given the retrospective nature of the study . This manuscript adheres to the STROBE guidelines.Hospital da Luz is a mixed ICU comprised of 20 beds. Unit staffing includes the following: one physician for five beds during the morning and one physician for every 10 beds during the afternoon, nightshifts and weekends; one nurse for every seven beds during the day and every 10 beds during night shifts; one nurse assistant for every two beds; and one physical/respiratory therapist for every 10 beds. Daily multidisciplinary rounds are performed to set daily goals of care.The ICU at Until September 2014, the pain management strategy for mechanically ventilated patients was based on high-concentration fentanyl infusions (50µg/mL), which is a common practice in Brazil. On October 2014, one of the authors implemented a new pain management protocol, which consisted of the following:,11Systematic evaluation of pain with validated and standardized pain scales: a numerical rating scale for patients who were able to communicate and a Behavioral Pain Scale (BPS) for patients who could not be assessed otherwise.Regular use of dipyrone as an adjuvant for analgesia.Use of diluted solutions of fentanyl (10µg/mL), starting at 10 - 20µg/hour when necessary, and using boluses (10 - 50µg) before painful procedures as necessary, such as tracheal suctioning.Staff training about the equianalgesic doses of fentanyl and morphine (10µg fentanyl = 1mg morphine).The study population used to evaluate the clinical outcomes comprised all patients admitted in the study period. We defined the "before" cohort as those patients admitted to the ICU from January 1, 2014, until September 30, 2014. We defined the "after" cohort as those patients admitted to the ICU from November 1, 2014, until December 31, 2015. We excluded patients admitted during October 2014 from the clinical outcomes analysis because it was the month of implementation of this ICU culture change, which could have had carry-over effects on the "after" cohort. We also excluded patients who were readmitted to the ICU from the clinical outcomes analysis. Given the retrospective nature of the study, there was no formal sample size calculation.The primary outcome was the consumption of analgesics, which was analyzed in aggregate. The secondary outcomes were individually measured clinical outcomes and aggregated analgesic-related costs.We retrieved variables related to monthly consumption of both opioid and nonopioid analgesics from the hospital database: intravenous (IV) morphine (2 and 10mg ampules), fentanyl , tramadol , dipyrone  and ketoprofen . We built monthly rates with patient-days in the ICU and MV days as denominators. For this analysis, we did not exclude any ICU admissions and considered all patients to create the denominators (ICU and MV patient-days). Furthermore, we measured the costs related to each unit to grossly evaluate monthly costs related to analgesic consumption. We did not measure costs related to drug preparation, such as syringes, needles and dilution fluids.®), which was recorded by a trained nurse during the study period and routinely audited for its accuracy, and it has been described previously. The measured baseline variables included age, sex, (Simplified Acute Physiology score 3 (SAPS 3), Sequential Organ Failure Assessment (SOFA) score, premorbid functional status, Charlson comorbidity score and type of admission. Use of vasopressors, MV and renal replacement therapy were retrieved from the database (at 24 hours or any time during the ICU stay). The measured outcomes were ICU mortality, hospital mortality, ICU length-of-stay (LOS), hospital LOS, MV duration, use of parenteral nutrition at any time during the ICU stay  and renal replacement therapy after 24 hours of ICU stay . Moreover, we retrieved the number of self-extubations from the adverse event reporting database.We retrieved variables of all patients during the study periods from the ICU quality database ; where:y = β1 = slope of the trend of utilization before the intervention (from January through October 2014).- β2 = change in the level of utilization of analgesics when the intervention was implemented (October 2014).- β3 = slope of the trend of utilization after the intervention (from November 2014 through December 2015).- βst order autocorrelation in the primary analysis. Durbin-Watson statistics, Durbin's alternative tests and adjusted R2 were evaluated to assess model adequacy.We used the Prais-Winsten method to account for 1 Standard errors were estimated using 1,000 bootstrap replications, and we adjusted only for the SAPS 3 and performance status to allow convergence of the model. All adjusted analyses were complete cases since we had < 1% missing data. All analyses were performed at the 0.05 alpha level. We used Stata SE 14.2 to run all analyses.Clinical variables were first analyzed with a Fisher's exact test for categorical variables. Continuous variables were assessed for normality with the Shapiro-Wilk test and analyzed with unpaired t-tests or the Wilcoxon rank-sum test, as appropriate. To obtain a meaningful interpretation of variables with a skewed distribution, we calculated median differences with 95% confidence intervals (95%CI) obtained from the Hodges-Lehmann estimator. Second, to provide adjusted estimates, we evaluated binary outcomes  through a multivariable logistic regression model adjusted for confounders at baseline. We built all models with available clinically relevant variables at baseline to adjust for confounding . We used quantile regression  to assess the impact of the intervention period on the duration of MV because it was a highly skewed variable precluding linear regression analysis.During the study period, 3,257 patients were admitted. We excluded 134 patients who were admitted on October and 286 patients who were readmissions . We inclFigures 1S and 2S - Supplementary material) showed two major trends: an increase in the use of dipyrone and a reduction in the consumption of fentanyl. In the segmented regression analysis by ICU patient-days, fentanyl presented with an increasing trend in use before the intervention , which decreased in level  and then in slope for a decreasing trend   . In the Dipyrone had no significant trend before the intervention, and the level did not change during the month of the intervention, but the slope after the intervention was significant and showed an increasing trend of utilization of this analgesic .Table 1S - Supplementary material). Other analgesics had no difference in their consumption rates . The results of equianalgesic doses of morphine (1mg) were driven mainly by fentanyl consumption, and the results were in line with this . This was driven mainly by reductions in fentanyl-related costs .There was a significant reduction in the costs of measured analgesic consumption per 100 ICU patient-days, from R$ 844,00 before the intervention to R$ 664,00 after the intervention . This occurred in parallel to increases in the use of dipyrone, without any detrimental effects observed in clinical outcome analyses in the before and after cohorts. The intervention also significantly reduced analgesic-related monthly costs and was associated with a median reduction in MV duration of 1 day: this effect was more prominent in patients who spent a larger number of days under artificial ventilation. its widespread adoption is not universal. In a recent cross-sectional study of 45 ICUs in the United Kingdom, physicians did not document pain assessment in almost two-thirds of the patients; nurses did not document pain assessment in 28.6% of the patients. Luetz et al. found better results in a European multinational survey: 81 out of 101 ICUs reported assessing pain, but only 24 used a scale validated for patients who were unable to communicate. A nationwide Dutch study confirmed these findings: a wide adoption of pain scales for patients able to communicate and a low use of behavioral pain scales.Although pain assessment is strongly recommended in guidelines, Before and after studies have confirmed these findings.-21 Our study, with a similar design, also showed a reduced duration of MV, especially for those patients who received MV for longer durations, suggesting a dose-response effect plausibly explained by the high context-sensitive half-life of fentanyl.Previous studies have shown the efficacy of the systematic assessment of pain in critically ill patients. In a large cohort study, pain assessment was associated with a shorter duration of MV and reduced ICU length of stay. others showed opposite results.,20 Our findings are in accordance with the latter. Although it would be counterintuitive to make an association between better pain assessment and decreased use of opioids, there are some possible reasons for this result. First, routine pain management strategies focus on pain assessment. Therefore, as opportunities for assessment increase, dose reevaluation also increases. In the period before our strategy implementation, physicians and nurses were initiating fentanyl infusion in high doses, as recommended in previous guidelines, and without standardized periodic reevaluations. This approach could mean using fentanyl as a sedative, which could only potentiate fentanyl prolonged effects.,8 Previous studies on "analgesia first" strategies used very low doses of opioids. For example, in a landmark study of "no sedation" in patients undergoing MV, analgesia was maintained with 2.5 - 5mg of morphine as needed. In a Brazilian study comparing daily interruption of sedatives and a sedation protocol in critically ill patients on MV, patients used only a median of 300mcg of fentanyl per day in the sedation protocol group. Second, a multimodal analgesia approach could spare opioid consumption. Dipyrone use increased after the implementation of our pain management approach. In the previously mentioned cohort study, Payen et al. demonstrated that nonopioids were used more frequently when pain was systematically assessed. Many studies in critically ill patients show that the use of nonopioid analgesics decreases the use of opioids without differences in pain scores; enables lighter sedation levels; and reduces the time to extubation. Our study is the first to show that dipyrone may be a reasonable nonopioid to be used in critically ill patients. At the very least, it seems to be as good as paracetamol for use in a multimodal approach to spare opioids. A third reason that we believe may have had a role in reduced opioid consumption is the use of a diluted solution of fentanyl: a continuous infusion of 10mL/h of this dilution represents 100µg/h of fentanyl, while the previous infusion represents 500µg/h of fentanyl. Although physicians and nurses may know the actual concentration of fentanyl in each solution, cognitive biases regarding the infusion speed may lead to unwanted 2- to 3-fold higher doses of the drug.The reduction in opioid use can be considered unexpected. While a study showed that better pain assessment increased fentanyl use per patient,This study has some limitations. First, although we performed adjusted analyses to compare the two periods, we could not adjust for all possible confounders; other variations in care and secular trends may also have contributed to the observed results - especially MV duration and ICU length of stay - since the ICU medical team had changed at the time of the implementation of the protocol, although nurses and physical therapy teams remained unchanged throughout the study period. Nevertheless, the substantial reduction in opioid consumption is a clinically significant result that leads to a substantial reduction in unnecessary spending and may have an impact on clinical outcomes. Second, we do not have pain measurements available for the purposes of this study, and therefore, we cannot prove that patients had adequate pain control. However, all the ICU staff were trained to evaluate and treat pain properly, with special attention given to mechanical causes of pain  and to preprocedural analgesia. Furthermore, this does not invalidate the findings of the intervention in the aggregate measures. Third, our results are from a single-center study and may not be generalizable, although these findings could help others scrutinize their pain management protocols, which can have an impact on clinical outcomes. Fourth, one major side effect of opioids that we could not address with our methodology was the development of paralytic ileum, constipation and reduced tolerance to enteral nutrition; further studies will be necessary to address these issues.An intensive care unit pain management protocol characterized by routine pain assessment, increased use of dipyrone and use of a diluted solution of fentanyl substantially reduced the intensive care unit consumption of fentanyl. This strategy was also associated with a shorter mechanical ventilation duration.Click here for additional data file.


They were evaluated with the Foot Function Index (FFI) and a visual analog scale (VAS) for pain. At a median follow up period of 47 months (range 36–54 months), all five patients reported marked pain relief with improvements in their daily activities. In particular, the median FFI decreased from 77% (range 71.0%–84.5%) pre-treatment, to 0.5% (range 0%–6%) after treatment. The median VAS score decreased from 4 (range 3–7) to 0 (range 0–1), respectively. Throughout the follow-up period, there were no major complications regarding either therapeutic intervention . Based on these results, it can be concluded that adjuvant RSO with 169Er following surgical excision is effective and safe in the treatment of PVNS of the ankle.Pigmented villonodular synovitis (PVNS) of the ankle is a very rare, locally aggressive, proliferative disorder. Although surgical excision represents the standard curative treatment, the PVNS relapse rate is high. We present our study of five young athletes (range 20–36 years) with a histopathological diagnosis of PVNS of the ankle, who were treated by surgery and adjuvant radiosynoviorthesis (RSO). The operation involved either arthroscopic (four patients) or open (one patient) debridement, followed by intraarticular RSO with the radiopharmaceutical erbium-169 ( Pigmented villonodular synovitis (PVNS) is a rare, idiopathic, locally aggressive, proliferative disorder of unknown etiology that may focally or diffusely involve the synovial tissue of the joint . Most caSurgical excision represents the standard curative treatment for both localized and diffuse PVNS of the foot and ankle ,5. Howev90Y), which is characterized by a tissue penetration of 3 to 11 mm. Currently, this agent is indicated primarily for knee joints and not for joints with a narrow joint space and a thin soft tissue envelope, such as the ankle [Radiosynoviorthesis (RSO) is another adjuvant therapy that has only rarely been applied in the treatment of ankle joint PVNS, with conflicting results ,13. Howehe ankle .169Er).In this case series, we present our study of five young athletes suffering from PVNS of the ankle joint who were treated with synovectomy followed by adjuvant intraarticular RSO with the radiopharmaceutical erbium-169 (Five young amateur athletes suffering from diffuse PVNS of the ankle joint underwent arthroscopic (four patients) or open (one patient) synovectomy between 01/2015 and 01/2017. There were three female and two male patients, aged from 20 to 36 years (mean age: 28.2 years). All the patients had at least one preoperative contrast-enhanced MRI. In all cases, the diagnosis was confirmed by histopathology. The present study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and all subsequent revisions. All persons gave their informed consent prior to their inclusion in the study.An arthroscopic debridement of the synovium was performed under tourniquet with the use of an anterior or posterior ankle arthroscopy or a combination of the above .In the case of a combined anterior and posterior arthroscopy, the operation was performed in two stages. In another case, the procedure was combined with a mini open approach, with an extension of the arthroscopic portal approach. Finally, in one case, the anterior tibial tendon was also involved and an anterior tendon tendoscopy was performed, followed by open debridement. The choice of the arthroscopic approach depended on the location of the affected synovium, as shown by the imaging studies. All arthroscopies were performed with a regular 3.5 mm 30° angle arthroscope and debridement was performed with a combination of 3.5 and 4.0 mm shavers. In cases where the synovium extended to the medial and lateral ankle gutters, a 2.7 or 2.9 mm shaver was also utilized. Depending on the duration of the procedure and the type of anaesthesia, the patients were treated either as a day case or with a one-night hospitalization. A regular postoperative protocol with two weeks protected weight-bearing on crutches was implemented in all cases.99mTc-MDP) uptake in the blood pool phase  was performed to demonstrate the distribution of the radiopharmaceutical in the joint and exclude potential extraarticular leakage  and a visual analog scale (VAS). In particular, FFI is a self-administered index consisting of 23 self-reported items divided into 3 subcategories on the basis of patient values: pain, disability, and activity limitation. The patients had to describe their foot by scoring each question on a scale from 0 (no pain or difficulty) to 10 (worst pain imaginable or so difficult it requires help). Finally, scores ranged from 0 to 100, with higher scores indicating worse pain ,16. FFI The VAS score is a unidimensional measure of pain intensity, consisting of a straight line with the endpoints defining extreme limits such as ‘no pain at all’ and ‘pain as bad as it could be’ . The VAS99mTc  immediately after 169Er application confirmed the intraarticular administration of the radiopharmaceutical in the joint and excluded extraarticular leakage in all patients  before treatment to a median of 0.5% (range 0%–6%), as assessed after communication with all patients at a median follow up of 47 months (range 36–54 months) .Moreover, the median pre-treatment VAS score was 4 (range 3–7) and decreased after two months to 1 (range 0–2), after six months to 1 (range 0–1), and after twelve months to 0 (range 0–1). Further, at a median of 47 months after therapy (range 36–54 months) the median VAS score was further reduced to 0 (range 0–1) . Apart fThroughout the follow-up period, no major complications regarding either therapeutic intervention  were recorded. Only one patient reported pain and edema three weeks after RSO, which subsided after a week of oral non-steroid anti-inflammatory drugs (NSAIDs).RSO has been used for more than 60 years in the treatment of a range of refractory painful synovitis . The mod90Y [169Er in the ankle joint. The reasons for the usage of 169Er lie in the post-surgical, adjuvant setting of the treatment. All patients had already undergone synovectomy, thus a large—but not whole—proportion of the hypertrophic synovium had been surgically removed. Since the main objective of adjuvant RSO was to complete the resection of the affected tissues, which were no longer markedly hyperthrophic, we chose to use a radiopharmaceutical with a maximum tissue penetration of up to 1 mm like 169Er and not the recommended isotope 168Re, which emitts β-particles that have ranges of up to 4.5 mm in tissue. Another reason for the application of 169Er in this patient cohort is that, during the operation (either arthroscopic or open debridement), the integrity of the joint capsule is inevitably compromised. In the postoperative period where RSO is applied, this is only partially repaired with interrupted sutures. Especially in the case of ankle arthroscopy, only the skin is repaired, with sutures leaving the joint capsule to heal by itself. This does not provide a true sealant to microleakage. In the case of posterior involvement in particular, additional facts need to be considered. Firstly, the posterior joint capsule is located deep to the retrocalcaneal fat pad, with a broad and rather loose attachment to the distal tibia. This interferes with its healing process, as the effect of tamponade from the postoperative bandages is minimized. Secondly, the Achilles tendon is unique in that it lacks a true synovial sheath. It is covered only by a thin layer of paratenon, which makes it more vulnerable to toxicity due to leakage of the RSO agent. The above reasons reinforce the choice of 169Er citrate, as it offers a good balance between efficacy and the minimum possible penetration.PVNS is treated by surgical excision. However, simple resection of the lesion is associated with local recurrence rates as high as 50% . RSO has90Y ,21,22,23169Er RSO as an effective adjuvant to the surgical excision of PVNS in the ankle. All five patients responded to the combined treatment satisfactorily, with significant pain reduction and return to daily activities early after administration of a single dose of 169Er. Patient follow-up showed an essential reduction in pain intensity as early as two months after treatment and, more importantly, a lasting effect of the treatment regarding pain alleviation and ability to perform daily activities, as estimated at a median of 47 months after RSO. This result is of great importance given the young age (20–36 years) and the strenuous, everyday activity—as athletes—of the herein treated cohort.The findings of this small case series support the use of 90Y 6–8 weeks after the last surgery. The reported results were very satisfying regarding both safety and efficacy [90Y. In that paper, the authors reported extensive complications following intraarticular injection of the radiopharmaceutical, with all patients suffering from pain associated with redness and swelling of the involved ankle. More importantly, two patients developed full-thickness skin necrosis around the injection site, necessitating free muscle flap transfer, while a third patient developed a draining sinus associated with chronic severe pain [90Y have a longer penetration in tissue than 169Er, leading to the irradiation of neighboring tissues, mostly the skin, thus causing radiation-induced erythema or skin necrosis. In fact, this penetration length is the main reason that 90Y is nowadays indicated for large joints, like the knee, and not for medium-sized joints. Moreover, the doses applied in that study were much larger in comparison to the ones administered in our study (555 MBq vs. 74 MBq), which could also contribute to the unacceptable toxicity of the 90Y-RSO. Finally, following the injection of the isotope, we also administered corticosteroids into the ankle joint in order to reduce inflammation, which was not reported in the study by Bickels et al.Reports on RSO in the ankle joint with PVNS are scarce ,13. Shabefficacy . However169Er in PVNS of the ankle following surgical synovectomy. Secondly, although all patients followed the same protocol regarding the timing and the dose of the RSO, there are certain variations in the operative management, as dictated by the different manifestations of the disease itself, leading to the use of an anterior or posterior ankle arthroscopy or a combination of the above. Nevertheless, all patients responded more than satisfyingly to treatment without variations.There are certain limitations in this study. Firstly, it is a relatively small case series. However, PVNS of the ankle is a very rare disorder, rendering the design of prospective large cohort studies extremely difficult. To our knowledge, this is the first published report of intraarticular RSO with the radiopharmaceutical 169Er following arthroscopic or open excision is effective and safe in the treatment of PVNS of the ankle. Long-term follow-up is required to confirm the very encouraging results presented herein.Adjuvant intraarticular RSO with


Pain is a common symptom in patients who survive cancer and in those who live with progressive advanced disease. Evidence from meta‐analyses suggests that pain remains poorly controlled for a large proportion of patients; barriers to good management include poor assessment of pain, inadequate support for patient self‐management and late or inadequate access to strong opioid analgesia in those with advanced disease.The European Pain Federation (EFIC) established a Task Force in 2017 which convened a European group of experts, drawn from a diverse range of relevant clinical disciplines, to prepare a position paper on appropriate standards for the management of cancer‐related pain. The expert panel reviewed the available literature and made recommendations using the GRADE system to combine quality of evidence with strength of recommendation. The panel took into account the desirable and undesirable effects of the management recommendation, including the cost and inconvenience of each when deciding the recommendation.The 10 standards presented are aimed to improve cancer pain management and reduce variation in practice across Europe. The Task Force believes that adoption of these standards by all 37 countries will promote the quality of care of patients with cancer‐related pain and reduce unnecessary suffering.Pain affects up to 40% of cancer survivors and affects at least 66% of patients with advanced progressive disease, many of whom experience poor pain control. These 10 standards are aimed to improve cancer pain management, promote the quality of care of patients and reduce variation across Europe. In line with other standards development groups, a panel of international experts was instituted, chaired by EE and MB. Experts from European countries were invited by email to participate, explaining the rationale for the process, and aiming for broad geographical representation within Europe.EFIC recognizes that improving the experience of patients with cancer‐related pain requires actions that focus on patients, clinicians and healthcare providers or systems. The EFIC Task Force on cancer‐related pain reviewed existing evidence‐based guidelines and reached a consensus on the standards for the management of cancer‐related pain across all 37 European countries that are members of the European Pain Federation (EFIC). This paper describes 10 standards that EFIC member countries should institute or be working towards. The standards do not specify which healthcare professional(s) should conduct assessments, agree management plans, provide tailored treatment and support, or refer for more specialized advice and treatment. The Task Force considered that all services involved in the care of patients with cancer should consider how best to meet these standards considering local expertise and resources. These standards may also prompt greater collaboration between clinicians in pain medicine, palliative care and oncology to meet the needs of patients with cancer‐related pain.The GRADE  system was used to determine recommendations for each standard based on quality of evidence and strength of recommendation  and cancer treatments, particularly surgery, chemotherapy  and radiotherapy Bennett, . It can Pain may also be caused by comorbid conditions unrelated to cancer, and this aetiology accounts for around 10%–20% of pains in cancer patients . However, most patients can be adequately treated at a nonspecialized care level and on an outpatient basis. Proper coordination is required between the different healthcare professionals to ensure consistent and quality care.2.4Patients must have access to drugs and other interventions which are tailored to them. This means that the treatments are believed to be effective in their type of cancer‐related pain, and that they are consistent with the patient’s preferences and goals for treatment.Analgesic medication that is appropriate for the patient and their pain should be available within 24 hr of a pain assessment where indicated; this must include access to a prescriber as well as access to a dispensed prescription Table .Prescribers should adhere to regional or national protocols or evidence‐based guidelines for cancer‐related pain  in the context of disease that has been cured or is in remission (Boland and Ahmedzai, Access to oncological and surgical management options to control pain should be available regionally within each country. For example, radiotherapy for bone metastases, spinal stabilization, surgical fixation of pathological fractures, vertebroplasty or palliative debulking of tumour.2.5Self‐management is the capability of a patient to manage their pain, their analgesic treatments and the physical and psychological consequences of living with cancer‐related pain (Johnston et al, Addressing concerns about pain and strong opioids, and providing strategies that help patients though provision of educational materials, improve patient outcomes and should be routine practice (Bennett et al, 2.6Although patients understandably express that they want to be pain free, in general, they do not actually expect their pain to go completely (Gibbins et al, Patients should know who is responsible for reviewing their pain management plan, when this review is expected to take place and whether this can be done face‐to‐face, by telephone or digital technology (Adam et al., 2.7Patients should be referred for specialist support if pain is not well controlled despite initial management or the pain has been identified as complex. Specialist support must be available regionally within each country in the form of specialist multidisciplinary pain services, oncology services including radiotherapy and palliative care services. Access to specialist services for pain that is insufficiently responding to standard care should be readily available regionally within one week IASP, . This inPatients who present with severe uncontrolled pain, significant drug related adverse events or extreme psychological distress should also be referred urgently to a specialized care facility IASP, . HealthcWith improved early cancer diagnosis and enhanced treatments, many patients are now living with cancer as a chronic disease. Increasing numbers of patients experience cure or prolonged remission and are regarded as cancer survivors. Some of these patients will continue to experience pain which negatively affects their quality of life (Glare et al, 2.8Significant gaps in knowledge on cancer pain diagnosis and management by healthcare professionals are well documented in the medical literature, leading to inadequate relief in a substantial number of patients with cancer pain (Oldenmenger et al, 2.9Regular review of outcomes for patients enables services to identify areas for improvement, focusing on safety and efficacy data of various methods of pain control. Novel methods for supporting patients to complete outcome measures are needed, for example using electronic or digital technology (Adam et al., 2.10Many international and national guidelines on cancer pain assessment and treatment are available but they may not be suitable for all countries (Piano et al, We recommend that each country will develop a mechanism, by either professional organizations or through regulatory authorities, to monitor and assess the implementation and usage of national guidelines and European standards.3The 10 standards presented are aimed to improve cancer pain management and reduce variation across Europe. We believe that adoption of these standards by all 37 countries will promote the quality of care of patients with cancer‐related pain and reduce unnecessary suffering. EFIC will continuously support enhancing the quality of cancer pain management through its pain schools, special sessions in conferences and reviewing and when necessary revising this document in the future.Each of the authors made a substantial contribution to the development of the paper by informing its content, collaborating in the drafting of the various sections and reviewing the final draft. MB and EE served as chairs of the group, wrote the first draft and coordinated the editing of the final draft.


There is a growing body of literature implicating angiotensin II in the modulation of tumour-associated inflammation and pain. However, the impact of angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) on pain and inflammation has not yet been studied in oral cancers. The objective is to investigate the role of ACEi and ARB pharmacotherapy on preoperative pain and inflammatory biomarkers, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and monocyte-to-lymphocyte ratio (MLR), in patients with oral cancer.We performed a retrospective study on patients who underwent oral cancer surgery. The Wilcoxon rank-sum test or Kruskal–Wallis analysis was used to evaluate differences in demographic, tumour-related and preoperative characteristics and amongst patients using ARBs, ACEis and no treatment. Multivariable analysis was fitted to estimate the effects of important covariates on severe preoperative pain.p = 0.0278). Similarly, patients taking ARBs were found to have lower levels of perineural invasion (p = 0.035). The analysis did not demonstrate a significant difference in pain levels when comparing ARBs or ACEis to the no treatment group (p = 0.250). Furthermore, the use of ARB or ACEi did not significantly alter preoperative NLR (p = 0.701) or MLR (p = 0.869).A total of 162 patients with oral malignancies were included in the study. After adjusting for significant covariates, patients with perineural invasion were found to have higher levels of pain . Oral and lip cancers rank amongst the 15th most common malignancies worldwide . This paPrevious studies indicate that ACEis and ARBs modulate important signalling mechanisms involved in inflammatory and neuropathic pain –7. Pain et al [et al [Multiple mechanisms appear to mediate pain in oral cancer including inflammation and nerve invasion. Preclinical studies by Scheff et al  indicateet al , 12. Baket al [In addition, other nociceptive mediators such as nerve growth factor (NGF) also promote nociception in mice bearing oral cancers. Ye et al  demonstret al . Moreoveet al , 14, 15.The study was designed to evaluate a possible modulation role of ARBs and ACEis in pain associated with oral cancers. Due to the neuropathic and the inflammatory components of pain associated with this pathology, we hypothesised that patients actively taking ARBs and ACEis would present with lower pain intensity before surgery. Second, we also investigated whether the use of ARBs or ACEis had any impact on inflammatory markers. Since AT2 is a known inflammatory mediator via CD3+ T cells and macrophages, we hypothesised that patients taking ARBs and ACEis would present with lower levels of inflammation and decreased leucocyte proliferation, which we assessed via the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and monocyte-to-lymphocyte ratio (MLR).After approval from the University of Texas MD Anderson Cancer Centre Institutional Review Board (#PA16-1033), we performed a retrospective study that included a cohort of patients with oral cancers who underwent surgical treatment between January 2004 and January 2018. Patients of 18 years of age or older were included, whereas patients with positive HPV status and those with missing information regarding demographics, tumour pathology, preoperative pain, preoperative pharmacotherapy and living status were excluded.Information collected from the electronic medical records included age, gender, body mass index (BMI), the American Society of Anaesthesiologist’s (ASA) physical classification, stage of disease, history of smoking, tumour location, presence of perineural invasion, neoadjuvant chemotherapy, preoperative analgesics, preoperative analgesic use (any) and preoperative blood pressure pharmacotherapy . Recorded dependent variables included self-reported preoperative orofacial pain intensity using a verbal numeric rating scale  at the time of anaesthesia assessment, preoperative NLR, PLR and preoperative MLR.On analysing the effects of ARBs and ACEis on inflammation and nociception, the primary outcomes of this study were (1) preoperative oral cancer pain scores as rated by the VNRS and (2) level of inflammation as indicated by biomarkers, NLR, PLR and MLR. Preoperative NLR was defined as the ratio between the absolute neutrophil count and absolute lymphocyte count of routine blood samples drawn within 14 days prior to the date of surgery, closest to time of surgery. Preoperative MLR was defined as the ratio between the absolute monocyte count and absolute lymphocyte count of blood samples drawn within 14 days prior to the date of surgery, closest to time of surgery. The same strategy was applied to calculate NLR and PLR.p-value < 0.05 was considered to be statistically significant. The statistical software SAS 9.4  and S-Plus 8.2  were used for all the analyses.Summary statistics including mean, standard deviation, median and range for continuous variables such as age, BMI, preoperative haemoglobin, NLR, PLR and MLR and frequency counts and percentages for categorical variables such as ASA, T stage, N stage, severe preoperative oral cancer pain and recurrence/death status are provided. The Chi-square test or Fisher’s exact test was used to evaluate the association between two categorical variables. The Wilcoxon rank-sum test or Kruskal–Wallis test was used to evaluate the difference in a continuous variable between/amongst patient groups. A multivariable logistic regression model was fitted to estimate the effects of important covariates on severe preoperative pain. A n = 118) were not actively taking ARB or ACEi pharmacotherapy. Amongst the others, 20.4% were taking ACEis (n = 33), and 6.8% of patients were taking ARBs (n = 11).Of the 589 patients who underwent surgical resection for oral cancer, 162 patients met inclusion criteria . The demp = 0.015). The most common ARBs used were losartan (72.7%), followed by valsartan (18.18%) and irbesartan (9.09%). Amongst patients taking ACEIs, lisinopril was the most frequently used (84.8%) followed by enalapril (9.09%) and benazepril (6.06%). Interestingly, patients taking ARBs also had the lowest rate of perineural invasion , as well as the lowest percentage of tumoural location at the tongue . We did not detect a significant difference in the rate of neoadjuvant chemotherapy, analgesics or non-steroidal analgesic drug (NSAID) use amongst different treatment groups.From the Kruskal–Wallis test or Fisher’s exact test, we observed statistically significant differences in age, tumour location and perineural invasion amongst treatment groups . Patientn = 117) experienced mild levels of preoperative pain (VNRS: 0–3), whereas 16.3% of patients (n = 26) reported moderate levels of preoperative pain (VNRS: 4–6), and only 10.6% (n = 17) reported severe pain (VNRS ≥ 7). More than half  of the patients were taking analgesics at the time of surgery. The rate of moderate-to-severe preoperative pain was higher for patients with stage N1–N4 tumours compared to patients presenting in stage N0 . Furthermore, the univariate analysis indicated that individuals with tumours with perineural invasion more commonly reported severe pain (p = 0.017). Patients taking ARBs were found to have the lowest level of perineural invasion   .p = 0.251) (n = 90), the analysis indicated that the proportion of subjects reporting moderate-to-severe pain was higher in the ARB (37%) group than in the two other cohorts of patients . Due to the small sample of patients reporting severe pain , the multivariable logistic regression model was limited to two covariates. With the adjustment of tumour location, the odds of severe preoperative pain for patients with perineural invasion was 3.938 times higher  than patients without perineural invasion  . After einvasion .p = 0.701), PLR (p = 0.482) or MLR (p = 0.869) amongst treatment groups, even after excluding analgesic use. Similarly, the preoperative NLR (p = 0.231), PLR (p = 0.852) and MLR (p = 0.933) were not found to be significantly different amongst patients with severe preoperative pain when compared to patients with mild-to-moderate preoperative pain. Interestingly, patients taking ARBs had the highest mean preoperative NLR (3.187) and preoperative MLR (0.529) when compared to the ACEi and no treatment group, but this was not observed for PLR values  and angiotensin II type II receptors (AT2R2) should be considered. With the exception of losartan, all ARBs are highly selective for the AT2R1 and show 10,000–30,000 times greater affinity for this receptor than for AT2R2. As a result of ARBs’ high selectivity, the AT2R2 can be exposed to a higher concentration of ATII counteracting the effects of AT2R1 . In addiet al [Third, patients in this cohort taking ARBs were less likely to have perineural invasion, and tumours without perineural invasion were less likely to report severe pain. However, we did not find a significant reduction in severe pain amongst patients taking ARBs. It is important to consider that perineural invasion is a complex process highly regulated by multiple nociceptive mediators which are predominantly inflammatory cytokines, chemokines and growth factors . Althouget al  demonstret al . Other iet al , 25. In Finally, previous data suggest that angiotensin-converting enzyme inhibitors inhibit the enzyme dipeptidyl carboxypeptidase, thus blocking the degradation of nociceptive kinins such as bradykinin and substance P , 27. In This work has several limitations including the retrospective design and the small number of patients receiving ARBs and ACEis which may have affected the statistical analysis. Furthermore, due to the small number of patients receiving those medications, dose-response studies or any investigation to underpin their effect on the primary outcome was not possible. Another limitation of this study is that we did not account for differences in baseline levels of plasma AT2 between treatment and control groups. AT2 is known to be elevated in patients with hypertension . HoweverIn conclusion, this study suggests that the use of ACEis or ARBs is not associated with a significant effect on pain in patients with oral cancers. However, patients taking ARBs were shown to have lower levels of perineural invasion. Additional studies should be performed to establish whether ARB-induced reduction in perineural invasion is due to direct effect on cancer cells or via an indirect effect on infiltration leucocytes.The author(s) declare that they have no conflicts of interest.This study was supported by internal departmental funds and NIH P30CA016672 (MD Anderson Cancer Center).


Temporal summation of pain, which is defined as the perception of greater pain evoked by repetitive painful stimuli, varies among individuals. This study aimed at determining the impact of the timing of rocuronium after induction with propofol on the temporal summation of pain.  One hundred patients aged 19–60 years underwent gynecologic laparoscopic surgery. Patients were randomly assigned to one of the two groups: group PRi received immediate injections of rocuronium after propofol administration and group PRd received rocuronium injections when the bispectral index score (BIS) decreased to <60 after propofol administration. The grade of rocuronium-induced withdrawal movement (RIWM) according to the timing of propofol injection, the incidence and severity of propofol injection pain (PIP), rescue analgesics, visual analog scale (VAS) score after surgery for postoperative pain, patient-controlled analgesia (PCA) opioid consumption, association between PIP and the grade of RIWM, and associations between PIP, the grade of RIWM, and postoperative pain outcomes were measured.  The differences between the incidence and severity of PIP in the two groups were not significant. The grade of the RIWM in the PRd group was significantly reduced compared with the PRi group. Rescue analgesics, severity for postoperative pain, and PCA opioid consumption were not significant. Correlations between the incidence and severity of PIP and the grade of RIWM were weakly negative. Correlations between the grade of RIWM and pain outcomes were moderately positive, but correlations between the severity for PIP and the postoperative pain outcomes were negligible.  The timing of rocuronium administration after propofol injection played a role in reducing RIWM. The grade of RIWM was significantly related to pain outcomes compared with the severity of PIP. Therefore, delayed rocuronium injection after induction with propofol reduced temporal summation of pain. Temporal summation of pain is an increase in pain perception in response to repeated exposure to painful stimuli. Individuals with increased pain processing and/or reduced pain-modulatory capabilities are regarded as pronociceptive, whereas those with reduced pain processing capacity are characterized as antinociceptive. The perceptions of a noxious stimulus may differ among individuals .Propofol and rocuronium, which are used as anesthetic induction agents during general anesthesia, are often associated with pain or withdrawal movement (25%–100% for propofol and 22%–84% for rocuronium) in most patients . The chaSeveral studies have reported the incidence or the severity of injection pain or withdrawal movement induced by the two anesthetic agents individually –8. A fewWe hypothesized that the timing of rocuronium administration after propofol injection may affect the rocuronium-induced withdrawal movement (RIWM), which was termed as the temporal summation of pain in this study. The timing of rocuronium administration after propofol injection was as follows: rocuronium was administered immediately after propofol injection or when the BIS decreased to less than 60 after propofol administration. Therefore, we investigated the frequency and severity of propofol injection pain (PIP), RIWM, and the associations between PIP, grade of RIWM, and postoperative pain outcomes .clinicaltrials.gov (NCT04547608) .Ethical approval for this prospective, randomized, and controlled study (registration no. 2020-04-033-002) was provided by the Wonkwang University Hospital Institutional Review Board (IRB) in April 2020. Written informed consent was obtained from all participants. The study was performed at the University Hospital from May 2020 to October 2020. Patients who were scheduled for laparoscopic gynecological surgery were enrolled in this study. The trial was registered at The following patients were excluded: menopausal patients to exclude the hormonal effect on pain , those wn = 50), which received an immediate injection of rocuronium after propofol administration, and (b) group PRd (n = 50), which received rocuronium injection when BIS decreased to less than 60 after propofol administration.Randomization was performed using Stata 9.0  statistical software. The patients were stratified using a 1 : 1 allocation and random block sizes of 4. All patients were assigned using simple randomization procedures (computerized random numbers) to 1 of 2 treatment groups: (a) group PRi  measurement, and pulse oximetry.Anesthesia was induced using 2 mg/kg of 1% propofol over 15 s (when considering arm brain circulation time (15–20 s)), and 0.6 mg/kg of 1% rocuronium was injected over 10 s.An attending anesthesiologist observed patient movement during and after propofol and rocuronium administration. The patients were assessed using the VAS, with the scores ranging from 0 to 100 for pain severity after half-dose and full-dose propofol injection. If a patient could not respond to verbal questions after full-dose administration, the VAS score after half-dose administration was recorded.The responses to rocuronium administration were graded on the following scale: 1 (none) = no response; 2 (mild) = movement at the wrist only; 3 (moderate) = movement involving the upper arm or shoulder; and 4 (severe) = movement in more than one extremity or a generalized response.We adjusted the sevoflurane concentration using the mean arterial blood pressure (MBP) ± 20% and heart rate ± 20% and maintained BIS between 40 and 60. Neuromuscular blockade was reversed using pyridostigmine and glycopyrrolate when surgery was completed, and the train-of-four ratio (TOF) had returned to 25%. When patients started spontaneous breathing and BIS values reached 80, they were extubated.μg), ketorolac (150 mg), and ramosetron (0.6 mg) in 150 mL of saline was prepared to deliver a basal infusion of 2 mL/h and bolus doses of 0.5 mL, with a 15 min lockout period for postoperative analgesia. The pain severity after propofol injection and during the postoperative period was measured using a 100 mm linear VAS. The VAS score for pain during the postoperative period was measured during movement at 1, 24, and 48 h after surgery. When patients complained, pain corresponding to 50 mm or more on the VAS was treated with intravenous 100 μg fentanyl. Ketorolac 30 mg was administered if the pain score was less than 40 mm on the VAS or the patient asked for analgesia.A PCA pump containing fentanyl  was used for statistical analysis. The data are presented as mean ± SD or number (%) of patients. The groups were compared using the independent t-test or the Mann–Whitney U test for continuous variables depending on the normality of their distributions and the χ2 test or Fisher's exact test for categorical variables, as appropriate. The correlation between parameters was analyzed using Kendall's tau-b correlation test.The sample size was calculated using PASS 2008 . A preliminary investigation showed that the proportions of patients with no withdrawal movement induced by rocuronium administration after propofol injection in the two treatment groups were 0.312 and 0.590, respectively. Thus, a sample size of 47 patients per group would enable the detection of a significant difference with a power of 80% and an A total of 135 patients were assessed for eligibility, and 35 patients were excluded; 20 did not meet the inclusion criteria and 15 refused to participate. A hundred patients received medication after randomization. Five patients were withdrawn after enrolment due to conversion to open surgery, loss of follow-up, and reexploration for postoperative bleeding .The differences between the ages, heights, weights, ASA classification, duration of anesthesia, duration of surgery, and the types of surgery of the two groups were not significant .P=0.00). The incidence and severity of PIP of the two groups assessed with VAS were not significant. The grade of the RIWM was significantly reduced in the PRd group than in the PRi group (P=0.019). The VAS scores for pain at 1, 24, and 48 h after surgery, PCA opioid consumption at 24 and 48 h after surgery, and total opioid consumption for 48 h after surgery of the two groups were not significantly different. Rescue analgesia (with ketorolac or fentanyl), tenderness/redness/hardness of the vein, tenderness and hardness of the vein, and recall (pain or respiratory difficulty) after surgery were not significantly different between the two groups  and severity  of PIP, assessed with VAS, and the grade of RIWM were weakly negative and significant , VAS score for pain at 24 h after surgery , VAS scores for pain at 48 h after surgery , or total opioid consumption for 48 h after surgery were moderately positive and significant, but the relationship between the VAS score of PIP and postoperative pain outcomes was negligible (The correlations between the incidence (nificant . The corgligible .The main findings of our study demonstrated that the grade of RIWM was significantly lower in patients who received delayed rocuronium injection (BIS < 60) than in those who received immediate rocuronium injection after propofol administration. The incidence of RIWM and the incidence and severity of PIP, assessed with VAS, were consistent with those reported by previous studies –5.The perceptions of pain may vary with age and sex, owing to biological or psychosocial mechanisms; they may even differ for individuals of the same age or sex because of their experience of pain –12. ThisThe duration to obtain a BIS of <60 was significantly shorter in patients who received an immediate injection of rocuronium than in patients who received a delayed injection of rocuronium after propofol administration. This may have been an effect of electromyographic activity on the calculation of BIS . This stThis study showed that the correlations between the grade of RIWM and the VAS score for pain at 1 h after surgery, VAS score for pain at 24 h after surgery, VAS score for pain at 48 h after surgery, and total opioid consumption for 48 h after surgery were moderately positive and significant, but the relationship between the VAS score for PIP and postoperative pain outcomes was negligible. Although the two anesthetic agents caused pain or withdrawal movement, preoperative pain perception of rocuronium may be related to pain outcomes after surgery.There were some limitations to this study. First, the sample may be small for evaluating the impact of the timing of rocuronium injection after propofol administration on the temporal summation of pain, although the sample size was determined by the proportion of patients with no withdrawal movement after rocuronium administration following propofol injection in the two treatment groups. A small sample may point the researcher to different directions during clinical decision making. Second, age and sex can affect pain perception. We performed gynecologic surgery in women without menopause to reduce selection bias. We did not consider the hormonal state of the women or the stages of their menstrual cycles, and this may have affected the results.Finally, this study was not blinded to minimize observer bias. One attending anesthesiologist assessed the severity of injection pain after propofol administration, and the grading of RIWM was open, but other attending anesthesiologists who evaluated postoperative pain outcomes and complications were blinded to it.In conclusion, the timing of rocuronium administration after propofol injection facilitated the reduction of RIWM. The grade of RIWM was significantly related to postoperative pain outcomes; the severity of PIP was not. Therefore, delayed rocuronium injection after induction with propofol reduced temporal summation of pain. Further studies are required to elucidate the temporal summation of pain for drugs used during anesthetic induction.


Objective: Many pieces of research have focused on pain within individuals, but little attention has been paid to whether pain can change an individual’s empathic ability and affect social relationships. The purpose of this study is to explore how chronic low back pain changes empathy.Methods: Twenty-four chronic low back pain patients and 22 healthy controls were recruited. We set up an experimental pain-exposed model for each healthy subject. All subjects received a painful-empathic magnetic resonance scan. After the scan, all subjects rated the pain intensity and multiple empathy-related indicators. The clinical assessment scale was the 20-item Basic Empathy Scale in Adults.Result: The chronic low back pain patients reported lower scores on the total scores of BES-A, the subscale scores of emotional disconnection and cognitive empathy, and the discomfort rating. The fMRI results in the chronic low back pain patients showed that there were multiple abnormal brain pathways centered on the anterior insula. The DTI results in the chronic low back pain patients showed that there were reduced fractional anisotropy values in the corpus callosum, bilateral anterior thalamic radiation (ATR), right posterior thalamic radiation (PTR), right superior longitudinal fasciculus (SLF), and left anterior corona radiate (ACR).Conclusion: Our study found that patients with chronic low back pain have impaired empathy ability. The abnormal functional connectivity of multiple brain networks, multiple damaged white matter tracts, and the lower behavioral scores in chronic low back pain patients supported our findings. Imagine that your hand was accidentally scratched. This experience can lead to nociceptive pain, which originates in the peripheral nociceptors. This stimulus eventually leads to cerebral cortex, causing changes in brain network activity. Now imagine that you saw someone else’s hand accidentally being scratched. This experience typically produces empathy for pain, a phenomenon that, despite differences in origin, has the same characteristics of nociceptive pain and changes in brain network activity.Briefly speaking, empathy can be generated by directly observing or imagining the emotions of the target. The occurrence of empathy can lead individuals to altruistic and prosocial behaviors towards the plight of others, and this ability to perceive the distress of others also keeps individuals alert to dangerous stimuli , may be a good method to explore empathy. Previous studies have explored the neural brain network mechanism of empathy in healthy adults through fMRI technology and have gotten some excellent results  group  and experimental pain group (EP group), fMRI and DTI technology will be jointly used in this study to explore the brain structural abnormalities and the functional brain changes during empathy state in patients with chronic pain. Diffusion tensor imaging is a magnetic resonance technique that reflects the random diffusion of water molecules in the brain. The Basic Empathy Scale in Adults (BES-A) will be used to quantify the empathy ability of all subjects  clinically diagnosed as cLBP  saline was inserted into the lower back muscles, 2 cm to the right of the 4th lumbar vertebra. The time that was taken for the pain caused by the needle puncture to subside ranged from 10 to 30 s in all subjects. After the pain resolved, subjects turned from the lateral decubitus to the supine position, and the hypertonic saline was injected into the lower back muscles of the subjects through the indwelling needle at a speed of 0.15 ml/min, maintaining pain until all scans were completed.The best bottom-up input to produce emotional resonance may be to observe the facial expression of the target directly , and the intensity of pain suffered by the individual in each photo (“How painful do you think the person in the photo is?”). The assessment of pain intensity of oneself and others can be used to measure the cognitive-evaluative dimension of subjects. The evaluation of the degree of discomfort after receiving stimulation can be used to measure the emotional dimension of empathy  and 1 non-diffusion-weighted image (b = 0 s/mm2).All image data were collected by a Philips 3.0 T Achieva magnetic resonance imager in Zhujiang Hospital, Southern Medical University, and scanned in a standard radio-frequency head coil. T1 data were acquired with a T1-weighted rapid spin echo sequence: repetition time (TR)/echo time (TE) = 25/3 ms; flip angle = 90°; field of view (FOV) = 220 mm × 220 mm; matrix size = 256 × 256; 0.859 mm × 0.859 mm in-plane resolution; slice thickness = 5 mm; 24 slices; slice gap = 0.7 mm. Functional MRI data were acquired using a T2*-weighted, single-shot, gradient-recalled echo planar imaging (EPI) sequence, TR/TE = 2,000/35 ms; field of view (FOV) = 230 mm × 230 mm; matrix size = 64 × 64; flip angle = 90°; 3.4 mm × 3.4 mm in-plane resolution; slice thickness = 5 mm; 24 slices; slice gap = 0.7 mm; number of signals averaged (NSA) = 1. DTI data were acquired using a single-shot EPI sequence: TR/TE = 12,500/112 ms; FOV = 256 mm × 256 mm; matrix = 128 × 128; 2 mm × 2 mm in-plane resolution; number of slices = 75; slice thickness of 2 mm and no gap. There were 33 images acquired for each scan: 32 diffusion-weighted images  was based on our DTI data analysis  plays an important role in the emotion-cognitive empathy network. Therefore, locating the ROI in the AI is an important means to explore the joint nodes of the brain network of empathy for pain. In our study, the specific ROI coordinate of AI  correction , and the minimum voxel threshold was set to 20. Finally, each subject’s brain Z-score image was acquired  function in the rest toolkitacquired .n × n FC matrix (n is the number of ROI). Finally, the statistical analysis of the inter-group FC matrix was carried out.Based on the results of voxel-wise analysis, each brain region with abnormal functional connectivity to ROI in patients with cLBP was included in the ROI–ROI analysis. These brain regions were set to spherical ROIs with a radius of 3 mm centered on the MNI coordinate point, and the time series of each ROI  was extracted and incorporated into the ROI-Wise analysis module in the rest toolkit. We then calculated the correlation coefficient based on time series between the ROIs, and generated an t-tests were used for comparing the data between groups. Non-parametric tests were used for data that were not normally distributed. Pearson correlation analysis was used to calculate the correlation between the FC correlation coefficient with the behavioral results . Chi-square test was used for comparing the dichotomous variables between groups. All statistical assessments were two-tailed, and the significance threshold was p < 0.05. The results satisfying normal distribution were expressed as means ± standard deviations; otherwise, they were expressed as median (InterQuartile Range). The effect of age on behavioral data is shown in the The SPSS22.0  software package was used to conduct statistical analysis on the demographic characteristics, BES-A scores, and behavior data of subjects in both groups. Two independent sample p < 0.05 [family-wise error (FWE) corrected for multiple comparisons performed by permutation test with threshold-free cluster enhancement (TFCE)], and the number of permutations was set to 5,000. The rest toolkit was used for statistical analysis of fMRI data, and the significance threshold for intergroup differences was also p < 0.05. The resulting images were shown by the rest toolkit, and the FC correlation coefficient between the brain areas was shown by Circlize  and the discomfort rating (p = 0.014) distribution between the groups were significantly different (p = 0.005), the subscale scores of emotional disconnection (p = 0.017), and cognitive empathy (p = 0.015) between the groups were significantly different , the functional connectivity between the AI and left dorsolateral prefrontal cortex (DLPFC) showed a significant correlation with the cognitive empathy scores , the functional connectivity between the left superior parietal lobule (SPL) and right precuneus showed a significant correlation with the emotional disconnection scores , but no correlation was found between the SPL-DLPFC functional connectivity and the emotional disconnection scores  showed a significant correlation with the discomfort ratings , bilateral anterior thalamic radiation (ATR), right posterior thalamic radiation (PTR), right superior longitudinal fasciculus (SLF), and left anterior corona radiata ACR; .Compared with the EP group, the cLBP group showed increased AI functional connectivity to the left DLPFC, left fusiform gyrus, left SPL, right precuneus, left postcentral gyrus, right PHP, and bilateral cerebellum. The left caudate demonstrated a noticeably decreased connectivity to the AI. The left SPL showed increased functional connectivity to the left fusiform gyrus, left DLPFC, and right precuneus. The left fusiform gyrus showed increased functional connectivity to the left DLPFC. The left caudate showed increased functional connectivity to the right parahippocampal gyrus .The empathy for pain has long been a focus of social psychology research. With the progress of research methods and technologies, the study of empathy for pain has developed into a multi-disciplinary and dynamic field, attracting great interest from disciplines such as cognitive psychology, and emotional and cognitive neuroscience. However, as a complex physiological and psychological experience involving multiple dimensions, the exploration of the neurogenesis and development mechanisms of empathy for pain is still in its infancy. At present, there is still a lack of research on whether the progress of some diseases will affect a patients’ ability for pain empathy and then foster social prejudice. In our study, the protocol was specially designed for neuroimaging the change of pain empathy in patients with chronic lower back pain. The behavior measure results showed that there was a significant difference in self-experienced negative emotions (as defined by “discomfort” rating) between the two groups, which is considered to be one of the most specific assessment methods of affective sharing . As a result, we can still assume that the cLBP reduced the resource distribution of external attention and allocated more attention resources to self-regulation, which is one of the reasons for the decreased scores of emotional disconnection in cLBP. For structural MRI analysis, the DTI results showed a decreased FA value of the right SLF in cLBP. Research has found that the white matter tract of SLF underlying the temporoparietal cortex and the right temporoparietal junction are considered to be a component of the ventral attention network, a right-lateralized supervisory system (Kucyi et al., The current study also found that the cLBP had lower scores of emotional disconnection subscale in BES-A. Emotional disconnection is considered to be self-protection regulation mechanism. When witnessing others being hurt, emotional disconnection enables individuals to correctly distinguish the boundaries between themselves and others and to protect individuals against injury and emotional impact (Carré et al., A study has proposed that the discomfort ratings of watching photos may be the most appropriate index to evaluate the ability of affective sharing (Singer and Lamm, However, a large number of studies have reported that the FA value of the white matter tracts related to somatosensory in patients with chronic pain is decreased (DeSouza et al., Although the results of this study demonstrate the impaired empathy ability of cLBP patients, we still need to pay attention to some shortcomings in this study. First, the sample size was small. The sample size of each group in this study is about 23 cases, which may decrease generalizability. It is necessary to increase the sample size in future experiments. Second, the covariate effect of the age gap on behavior data did not reach statistical significance. However, the significant difference in age distribution between the groups should be avoided in future studies. Third, voxel-based morphometry is useful for studying the damage of chronic pain to the volume of cerebral gray matter, and it could be employed in future experiments. Fourth, selecting multiple ROIs in the same brain area can detect the changes of functional connectivity more thoroughly. Therefore, multiple ROIs and even symmetrical ROIs in brain regions of interest need to be considered in future studies.In conclusion, we found that patients with cLBP have impaired empathy ability, which involves cognitive empathy and emotional empathy. We found that the impairment of cognitive empathy is mainly related to the impairment of attention network in patients with cLBP, while the damage of emotional empathy is related to the pain emotional memory. The lower behavioral scores, the abnormal functional connectivity of multiple brain networks, the correlation between behavioral scores and functional connectivity of brain regions, and multiple damaged white matter tracts in chronic pain patients supported our findings. These findings enrich the neural theory of the change of empathy in patients with cLBP. Moreover, we hope that these findings will call attention to the impairment of prosocial behavior in patients with chronic pain.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the ethics committee of Zhujiang Hospital of Southern Medical University. The patients/participants provided their written informed consent to participate in this study.All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. JM and WW: conceptualization, methodology and writing—review and editing. JM and XW: investigation. JM: formal analysis, data curation and writing—original draft. JM, XW, QQ, and HZ: resources. WW: supervision and funding acquisition.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Chronic postsurgical pain (CPSP) after hernia repair research has mainly relied on unconfirmed self-reporting. We aimed to describe confirmed CPSP incidence, management, and quality of life (QoL) in a 2-year prospective study.Multicenter study (GENDOLCAT) of 3890 patients undergoing 4 common surgical procedures in 23 hospitals to develop a risk model for CPSP; 2352 men underwent open hernia repair. Patients with pain were identified by telephone at 1 and 3 months and referred to the hospital 4 months after surgery for a physical examination to confirm CPSP. Three validated tools were used: the Brief Pain Inventory (BPI) for severity, analgesic use, and interference with activities; the SF-12 questionnaire for QoL , and the Douleur Neuropathique 4 (DN4). Patients with CPSP were called again at 1 and 2 years.In 1761 patients who underwent hernia repair and were eligible for physical examination for CPSP, the incidence of confirmed pain at 4 months was 13.6% . Neuropathic pain was diagnosed in 38.5% of the CPSP patients at 4 months. The incidences of neuropathic CPSP in patients with mesh or non-mesh repairs were similar . SF-12 physical component scores changed little in all patients, whether or not they developed CPSP. The SF-12 mental component decreased significantly in all patients, but the decrease was clinically significant only in CPSP patients. CPSP interfered with activities (18%), work (15.6%), walking (15%) and mood (10.2%). At 2 years 52.1% of CPSP patients had moderate/intense pain and 28.2% took analgesics.CPSP affects QoL-related activities, and although it diminishes over the course of 2 years after surgery, many patients continue to have moderate/intense pain and take analgesics. CPSP and neuropathic pain rates seem to be similar after mesh and non-mesh repair. BPI and SF-12 mental component scores detect effects on QoL.ClinicalTrials.gov NCT01510496. Chronic postsurgical pain (CPSP) is a frequent complication in the general surgical population , 2. AfteThe features and persistence of CPSP and its impact on quality of life (QoL) have been reported after studies seeking to establish risk factors –3, 11–13The aim of the present analysis of the GENDOLCAT data for physician-confirmed diagnoses of CPSP after hernia repair was to include full descriptive information on clinical features and management of pain not reported earlier, with particular focus on neuropathic pain. We discuss pain features in the context of incidence rates, interference with QoL at 4 months (the main GENDOLCAT outcomes), and the course of pain over the full 2-year period.ClinicalTrials.gov NCT01510496).The prospective, multicentre, population-based GENDOLCAT study of clinical and genetic risk factors for CPSP in 23 hospitals in Catalonia and Valencia between 2009 and 2010 [Patients who might have CPSP were identified in two preliminary telephone interviews between the first and third months after surgery. If pain was reported, they were given appointments for a physical examination and clinical interview. CPSP was defined by a modified version of the diagnostic criteria of Macrae and Davies : 1) painEach hospital centre recruited a researcher or research team. One anaesthesiologist from each team was designated to attend training sessions on how to gather data before surgery and during hospitalisation, and to diagnose CPSP and neuropathic pain at 4 months. The data manager (J. Cantillo) conducted all the follow-up telephone interviews. , opioid use, and intraoperative complications. Postoperative pain on the two scales and analgesia used were recorded for 24 h after wound closure.The next phase of data collection involved the standardised telephone questionnaire  or the Wilcoxon test . The CPSP incidence was calculated for the population of included patients, after removing early exclusions , withdrawals, deaths, and patients not located after 2 phone calls. Patients lost during telephone screening before the 4-month physical examination were counted as having no CPSP. This decision was made in order to avoid overestimating the percentage of chronification. Cases were classified as CPSP on the basis of confirmed presence of pain related to surgery in the follow-up visit at the patient’s hospital.We compiled descriptive statistics for all demographic and clinical variables. Clinical variables included a finding of neuropathic pain (DN4), use of postoperative analgesics, use or non-use of nerve-sparing techniques, BPI results and scores on physical and mental components of the SF-12. Continuous variables were presented as mean (SD). Categorical variables were presented as number of observations and percentage of the relevant number of cases with available data. SF-12 results at 4 months were compared with the . Of the 1522 patients who reported no pain in the first and second telephone interviews and who were sent the postal questionnaire (SF-12), 471 (30.9%) responded.Of the 2352 patients recruited, 1761 were located and eligible for assessment for CPSP at 4 months, after 591 losses (25.1%) as shown in the flow chart Figure Neuropathic pain was diagnosed in 92 (38.5% of the 239 of the patients with confirmed CPSP). The difference in the rates of neuropathic pain between patients with mesh  and non-mesh repairs  was not significant. Table Table Four months after surgery 32 patients with CPSP (18.9%) reported taking nonsteroidal anti-inflammatory drugs or paracetamol, 2 (1.2%) took weak or strong opioids, and 5 (3.0%) took adjuvant treatments (anticonvulsant agents or antidepressants) Table . These fThe incidence of CPSP Table  decreaseThis prospective population-based study found that 13.6% of the cohort of 1761 patients had firmly diagnosed CPSP at 4 months after groin hernia repair. The incidence of CPSP fell substantially by about two-thirds (to 4.0%) after 2 years. This study also provides exhaustive information on the location and characteristics of pain, particularly for the 38.5% of CPSP patients with neuropathic pain. We found that the interference of pain with QoL could be detected mainly by the mental component of the SF-12. Finally, even though the incidence of CPSP fell substantially over 2 years, the proportion of patients who continued to take analgesics remained stable at about a quarter of the CPSP patients. Nonetheless, only 30% of those still on analgesics reported they were effective.The proportion of CPSP patients we diagnosed with neuropathic pain after hernia repair was higher than the 28.7% other authors identified by means of neuropathic pain descriptors in the short-form McGill Pain Questionnaire  but loweWe assessed the interference of pain with QoL with two instruments, the SF-12 and the BPI. A decrease of 3.08 points was detected in the SF-12 mental component score at 4 months in patients with CPSP, an effect that was just over the threshold considered clinically important. The decrease in this measure in patients without CPSP, while statistically significant at 1.65 points, was well below that threshold. However, it is important to remember that the response rate in non-CPSP patients was only 30.9%, whereas all patients with CPSP responded to the SF-12. Physical component scores changed little after surgery in all patients, regardless of the presence or absence of diagnosed CPSP. We think that the presence of a mental, but not a physical, effect on QoL can be attributed to the unexpected nature of long-term pain. In other words, the physical impact of pain might be relatively minor but the fact that it takes a considerable number of patients by surprise exacerbates the emotional impact. If our interpretation is right, these results suggest that patients undergoing hernia repair procedures should be informed of the possibility of CPSP and given discharge instructions on how and when to seek care if pain persists beyond 3 months. Of the three other studies that used used the SF-12 to assess QoL after hernia repair –25, one A large number of validated instruments are available to assess QoL and function: the Activities Assessment Scale, Activity Restriction Questionnaire, Carolinas Comfort Scale , Core Ou7 reported a much lower rate of analgesic use (2%), but they they did not look at how much time had passed since the patients’ operations. It is striking, however, that our review of the literature on recovery from groin hernia repair found that analgesic use is not systematically reported or analyzed in detail. The drugs most often taken by our patients with CPSP were nonsteroidal anti-inflammatory drugs, and there was little use of opiods or coadjutants. This last finding was particularly interesting given the proportion of CPSP patients with neuropathic pain (38.5%). We also observed that the percentages of patients with moderate/intense pain  and those taking analgesics (only 24.9 to 28.2%) were quite different. Moreover, only 30% of treated patients felt their analgesic regimens were effective. These data suggest that CPSP seems to be under-diagnosed and under-treated in routine clinical practice, at least in our mixed urban-rural area of eastern Spain. The incidence of CPSP we detected (13.6% at 4 months) was similar to results reported elsewhere [,[Our finding that 24.9% of patients with CPSP were taking some type of analgesic 4 months after surgery, and that the proportion had changed little after 2 years, is noteworthy. Kailliomaki et al. pain 38.%. We alslsewhere , but mucewhere [,, which iThe CPSP rates associated with mesh 13.8%) and non-mesh (4.4%) were dissimilar in our cohort but not significantly different, although we note that the number of non-mesh repairs was low (68 cases) and the number of confirmed CPSP cases was fewer than expected (3 rather than the 9 cases we expected). Still, this observation of nonsignificance and the similar rates of neuropathic pain after mesh and non-mesh repair suggest that using a mesh seems not to play a role in neuropathic CPSP. Rather, our observations suggest that the patient-related factors that form part of the GENDOLCAT group’s risk model  are the main predictors of both neuropathic and non-neuropathic CPSP after hernia repair, as they are after other procedures 3.8% and . The relAn important strength of this study, which is the largest prospective long-term analysis of CPSP after groin hernia repair thus far, was its reliance on a trained, expert physical examination to confirm the CPSP diagnosis. Although one other recent study did include physical examination , the autOne limitation is that the questionnaires we used to identify QoL issues (the BPI and SF-12) were not specific to hernia repair. We did not use the Inguinal Pain Questionnaire  or the CIn conclusion, we have provided prospectively gathered data detailing the clinical features and management of CPSP at 4 months in the 13.6% of patients the GENDOLCAT [Additional file 1. Online Resource 1: Data collection, variables, definitionsand telephone questionnaires.