Persistent pain after inguinal herniorrhaphy is a disabling condition with a lack of evidence-based pharmacological treatment options. This randomized placebo-controlled trial investigated the efficacy of a capsaicin 8% cutaneous patch in the treatment of severe persistent inguinal postherniorrhaphy pain.P<0.01).Forty-six patients with persistent inguinal postherniorrhaphy pain were randomized to receive either a capsaicin 8% patch or a placebo patch. Pain intensity  was evaluated under standardized conditions  at baseline and at 1, 2 and 3 months after patch application. Skin punch biopsies for intraepidermal nerve fiber density (IENFD) measurements were taken at baseline and 1 month after patch application. Quantitative sensory testing was performed at baseline and at 1, 2, and 3 months after patch application. The primary outcome was comparisons of summed pain intensity differences (SPIDs) between capsaicin and placebo treatments at 1, 2 and 3 months after patch application (significance level P = 0.046). No differences in SPID between treatments were observed at 2 and 3 months after patch application. Changes in IENFD on the pain side, from baseline to 1 month after patch application, did not differ between capsaicin and placebo treatment: 1.9 [−0.1 to 3.9] and 0.6 [−1.2 to 2.5] fibers/mm, respectively (P = 0.32). No significant changes in sensory function, sleep quality or psychological factors were associated with capsaicin patch treatment.The maximum difference in SPID, between capsaicin and placebo treatments, was observed at 1 month after patch application, but the pain reduction was not significant (NRS, mean difference [95% CI]: 5.0 [0.09 to 9.9]; The study did not demonstrate significant differences in pain relief between capsaicin and placebo treatment, although a trend toward pain improvement in capsaicin treated patients was observed 1 month after patch application.2012-001540-22 ClinicalTrials.gov NCT01699854Clinicaltrialsregister.eu  Inguinal herniorrhaphy is a common surgical procedure with more than 800.000 repairs annually in the United States The capsaicin 8% cutaneous patch is used in the treatment of peripheral neuropathic pain and significant pain-relief for up to 12 weeks has been observed in randomized, controlled trials in post-herpetic neuralgia and HIV-related distal neuropathy In the present study we tested the hypothesis that capsaicin 8% patch treatment would be associated with a higher analgesic efficacy compared to placebo in patients suffering from severe persistent inguinal postherniorrhaphy pain.Since changes in intraepidermal nerve fiber density (IENFD) have been observed following capsaicin 8% patch application in healthy volunteers A randomized, double-blind, placebo-controlled, parallel-group study was conducted at the Multidisciplinary Pain Center, Rigshospitalet, Copenhagen with patients recruitment from August 2012 to May 2013 and follow-up from September 2012 to September 2013. Study approval was obtained from the Committee on Health Research Ethics of the Capital Region of Denmark (H-4-2012-055), the Danish Data Protection Agency, the Danish Medicines Agency (EudraCT-Nr. 2012-001540-22) and the study was registered at ClinicalTrials.gov (NCT01699854). The study was conducted in accordance with Good Clinical Practice (GCP) Guidelines and was monitored by the Copenhagen University Hospital GCP Unit. The protocol for this trial and supporting CONSORT checklist are available as supporting information; see Patients eligible in the study were referred to the Multidisciplinary Pain Center by a surgeon or a general practitioner and written informed consent was obtained from all patients. Patients were ≥18 years with severe unilateral persistent inguinal postherniorrhaphy pain  for more than 6 months. Concomitant analgesic medication was allowed if patients had maintained a stable regimen for at least 4 weeks prior to study entry and stayed on stable doses throughout the study period. Exclusion criteria were allergy to capsaicin or vehicle-ingredients in the patch, skin lesions or inflamed skin at the application site, bilateral groin pain, severe cardiac impairment, known diseases impairing nervous system function, alcohol or drug abuse, inability to understand Danish, and in female patients lactation or pregnancy .http://randomization.com/) and a block-size of four was used.Randomization was done by Herning Hospital Pharmacy according to a computer-generated randomization list  every morning and evening, at rest in the supine position, during transition from supine to standing position, and during the patient’s palpation of the point of maximum pain in the groin. Assessments were made in the 3 days preceding the patch treatment (baseline) and in the 3 days preceding the clinical visits at 1, 2 and 3 months after patch application.Questionnaires were completed at baseline and at 1, 2 and 3 months after patch application. Anxiety and depression were evaluated with the Hospital Anxiety and Depression Scale (HADS) 2). The baseline temperature was 32°C and thermal stimuli were delivered with a ramp rate of ±1°C/s with cut-off values of 50°C for heat, and 5°C for cold stimuli. The pressure pain threshold (PPT) was assessed at the point of maximum pain using a handheld pressure algometer  applied perpendicularly to the skin, until the pressure was perceived as painful or exceeded the cut-off value of 350 kPa. A heat stimulus  was delivered at the point of maximum pain to evaluate the suprathreshold heat pain perception (STH) rated by the patient (NRS). All QST parameters were assessed three times and the median values were used. The QST was performed at baseline and at the clinical visits: at 1 month (day 30–36), 2 months (day 60–66), and 3 months (day 90–96) after patch application . The QST assessments were performed in accordance with previous studies in persistent inguinal postherniorrhaphy pain lication .At baseline and at the clinical visit at 1 month after patch application two 3-mm skin punch biopsies  were performed, using a sterile technique, at the point of maximum pain in the groin and on the contralateral control side. Prior to biopsies, the skin areas were anesthetized with 1–2 ml of mepivacaine . The IENFD was estimated in agreement with previously described methods The research nurse and the physician responsible for the intervention did only meet the patient on the day of treatment and were not further involved in the study. The research nurse delineated the patch area corresponding to the inguinal pain distribution including the point of maximum pain. Patients were pre-treated with a topical local anesthetic cream  60 min before patch application. The patch application, patch removal, and skin cleansing were done by a physician. During this procedure the research nurse was not allowed presence in the treatment room since minute quantities of aerosolized capsaicin-particles during patch handling could have led to accidental un-blinding of the research nurse.2, 8% w/w; Astellas Pharma Europe B.V., Leiderdorp, The Netherlands) and the inactive placebo patches were identical in appearance and composition (in regard to vehicle substances). An inactive placebo patch was used since an active placebo patch was not obtainable from the manufacturer of the capsaicin patch. The patients were informed that they might experience pain during and after the patch application. The patches were applied in the groin area for 60 min. After patch removal a cleansing gel  was applied in order to remove capsaicin residues. In order to decrease local irritation of the skin cool packs  were administered for 45–60 minutes after patch removal. Patients were told to use oral acetaminophen 1 g every 6 h and ibuprofen 400 mg every 6 h for up to 3 days as needed after patch application. The patients and investigators were blinded to the treatment allocation throughout the study. At the clinical visit 1 month after patch application patients were asked to report if they had experienced application site skin reactions  or any other adverse events. To evaluate patient blinding we asked patients at the clinical visit 1 month after patch application to verbally report which treatment they had received.The capsaicin patches , a power of 0.9 (β = 0.1), an estimated standard deviation for the SPI assessments of 3.1 (NRS), and a minimal relevant difference for the six SPI assessments of 4.5 (NRS), the estimated number of patients needed in each group were 24 . In order to compensate for dropouts the number of patients was set to 50. Due to uncertainties in the power calculation an interim analysis by an independent statistician was planned a priori following completion of the first 32 patients.The pain intensities during the 3 standardized conditions , were evaluated twice daily in the 3 days preceding patch treatment (baseline) and in the 3 days preceding the clinical visit at 1, 2 and 3 months after patch application. The median value of the 3 standardized pain assessments was used to calculate the summed pain intensity (SPI) values  in accordance with a previously described method Linear regression analyses for repeated measures (a mixed model method) were used to evaluate the treatment effects over time. The summed pain intensity difference (SPID) was the outcome variable and treatment group (capsaicin or placebo) and time  were explanatory variables. While measurements taken at different time points were expected to correlate, we also assumed that measurements taken at adjacent time points were more correlated than measurements further apart, and therefore we used an unstructured covariance structure . We used the PROC MIXED procedure and the repeated statement in SAS software  to estimate the model. We included the interaction because we were interested in testing whether potential group differences changed over time. The mixed model is dealing with missing longitudinal measures and the analysis included all patients with at least one SPID-value. For secondary outcomes, including QST variables and questionnaire scores , differences (Δ) between post-treatment follow-up and baseline values were used to compare capsaicin and placebo patch treatments. The numbers of patients included in the data analyses vary for different outcome measures and are indicated in the tables for each analysis.P<0.01 (two-tailed).The normality of data was assessed with the Kolmogorov-Smirnov test and visual estimation of relevant residual distribution plots. Comparisons between treatment groups were performed with unpaired t-tests  and the Mann-Whitney tests . Fischer’s exact test was used to compare proportions. Statistical analyses were conducted using SPSS software  and MedCalc Software . The linear regression analyses for repeated measures were performed with SAS software. Due to the three statistical tests performed  and the planned interim analysis, thus increasing the probability of a type I error, all results were considered significant at A total of 46 patients were randomized . BaselinAs previously mentioned, an interim analysis was planned for the first 32 patients, but due to a lower patient-recruitment rate than anticipated and a premature expiry date of the placebo patches (May 2013) an interim analysis could not be performed. The interim analysis would have impeded study progression and prolonged the study for an estimated period of at least three months . The analysis showed that the maximum difference in SPID between capsaicin and placebo treated patients was observed at 1 month after patch application, although statistical significance at the 0.01 level was not achieved. The mean difference [95% CI] in SPID at 1 month after patch application was . Similarly, there were no significant differences in SPID between capsaicin and placebo patch treatments at 2 months after patch application  or at 3 months after patch application .The summed pain intensity (SPI) values (NRS) at baseline and at 1, 2 and 3 months after patch application are presented in . A lineaAnalyses of changes in QST assessments from baseline to 1 month after treatment are presented in P<0.0001, Wilcoxon signed rank test). Changes in IENFD, from baseline to 1 month after patch application on the pain side, did not differ between capsaicin and placebo treated patients  IENFD at baseline was significantly lower on the pain side, i.e. 4.3 (1.5 to 6.8) fibers/mm compared with the non-pain side 8.6 (7.4 to 11.0) fibers/mm, (At baseline the median (95% CI) S-LANSS score was 15 (10 to 17) and 26 of 42 patients (62%) reported a S-LANSS score of ≥12 indicating pain components of predominantly neuropathic origin P = 0.006, Fischer’s exact test, Seventeen of 23 (74%) capsaicin treated patients and 6 of 20 (30%) placebo treated patients reported one or more skin reactions on the application site .Sixteen of 23 patients (70%) treated with the capsaicin patch and 17 of 21 patients (81%) treated with the placebo patch correctly identified their treatment allocation , or anxiety and depression (HADS) scores associated with capsaicin patch treatment.a priori assigned significance level of 0.01. The authors regarded this conservative statistical measure a precaution against the introduction of type I errors due to the use of multiple comparisons and interim analysis. However, the statistical comparisons of SPID-scores, one month after patch application, yielding P-values of 0.024 and 0.046, indicated a trend of an improved pain relief in capsaicin treated patients. A potential contributing factor to the non-significant findings is obviously the premature discontinuation of the study after 46 randomized patients compared to the a priori estimated sample size of 50 patients. This circumstance may have introduced a type II error. A post hoc power calculation could be considered but is generally not recommended Interpretation of the study’s main finding should consider the The study corroborates our previous findings of a reduced IENFD on the pain side compared to the contralateral side in persistent inguinal postherniorrhaphy pain patients, most likely caused by surgical nerve injury The QST assessment did not demonstrate any differences in cutaneous  or deep tissue  sensory function between capsaicin and placebo treatment. A possible explanation is the previously mentioned lack of a significant reduction in IENFD after capsaicin treatment. In addition, sensory nerve endings not expressing TRPV1 receptors, i.e. Aβ-fibers, the majority of Aδ-fibers, and a subgroup of C-fibers, remain intact after capsaicin treatment and are thus still capable of transmitting sensory stimuli A confounding factor for the study is the patient-blinding. The higher incidence of local side effects experienced by patients in the capsaicin group (74%) compared to the placebo group (30%), and the correspondingly high proportion of patients who correctly identified their treatment allocation, indicate an insufficient blinding-technique. Therefore, it cannot be excluded that the potential analgesic effect experienced by the capsaicin treatment may in fact represent a placebo effect. The short duration of the potential analgesic effect (i.e. one month) also may connote to a placebo effect. The study thus supports the use of an active placebo (e.g. low-dose of capsaicin) in order to ensure adequate blinding in future studies assessing the effects of topical capsaicin.Pain relief up to 12 weeks after capsaicin patch application has been observed in previous randomized, controlled trials in post-herpetic neuralgia and HIV-related distal neuropathy In conclusion capsaicin patch 8% did not significantly reduce combined static and dynamic pain components compared to placebo in persistent inguinal postherniorrhaphy pain, albeit a trend towards pain relief was observed 1 month after capsaicin patch application.Checklist S1CONSORT Checklist.(DOC)Click here for additional data file.Protocol S1Trial Protocol.(PDF)Click here for additional data file.


Previous studies have shown that electroacupuncture (EA) has a significant effect on acute pain, but it has not solved the clinical problem of the chronification of acute pain. Diffuse noxious inhibitory controls (DNIC) function as a reliable indicator to predict the risk of chronic pain events. DNIC function in knee osteoarthritis (KOA) patients has been demonstrated to gradually decrease during the development of chronic pain. The purpose of this study is to conduct a randomized, controlled clinical trial to determine if EA can repair impaired DNIC function and thus prevent chronification of the acute pain of KOA.This is a multicenter, single blind, randomized, controlled, three-arm, large-scale clinical trial. A total of 450 KOA patients will be randomly assigned to three groups. The strong EA group will receive EA with high-intensity current (2 mA < current < 5 mA) at the ipsilateral ‘Neixiyan’ (EX-LE5), ‘Dubi’(ST35), ‘Liangqiu’(ST34) and ‘Xuehai’ (SP10). The weak EA group will receive EA with low-intensity current (0 mA < current < 0.5 mA) on the same acupoints. The sham EA group will receive EA with low-intensity current (0 mA < current < 0.5 mA) with fine needles inserted superficially into the sites 2 cm lateral to the above acupoints. The patients will be treated with EA once a day, 30 minutes per session, in 5 sessions per week, for 2 weeks. In order to determine the best stage of KOA for effective EA intervention, patients within the treatment groups also will be divided into four stages. The primary outcomes are Visual Analog Scale (VAS), DNIC function and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Clinical assessments will be evaluated at baseline (before treatment) and after 5 to 10 sessions of treatment.This trial will be helpful in identifying whether strong EA is more effective than weak EA in reversing chronification of acute pain through repairing the impaired DNIC function and in screening for the best stage of KOA for effective EA intervention.ChiCTR-ICR-14005411. The date of registration is 31 October 2014.Chinese Clinical Trial Registry Number:  Knee osteoarthritis (KOA) is one of the most common types of osteoarthritis and often occurs in older adults . PatientThe concept of diffuse noxious inhibitory controls (DNIC) has attracted particular attention in the past decades, which means under normal conditions, pain can be attenuated by a conditioning noxious stimulus to a remote body region . DNIC fuThe aim of this study is to explore whether EA can reverse impaired DNIC function by reducing the pain of KOA during the process of chronification of acute pain. Moreover, we will screen for the best EA therapeutic regimen, which will include optimizing the intensity of the current used in the EA stimulation and determining the best stage for effective EA intervention using a randomized controlled clinical trial.The study is in accordance with the Declaration of Helsinki, it has been approved by the Chinese Ethics Committee of Registering Clinical Trials (reference: ChiECRCT-20140035), and it also has been registered with Chinese Clinical Trial Registry (ChiCTR-ICR-14005411). Before randomization, all patients will be expected to sign a written informed consent.A randomized, controlled, three-arm, large-scale trial to compare two true EA groups (strong EA and weak EA) with a sham EA group will be undertaken in this study . Four huPatients who meet the inclusion criteria will be randomly assigned to one of three groups  in a ratio of 1:1:1 using a computer-generated random allocation sequence through the stratified block randomization method of SAS version 9.1.3 . The randomization will be performed by an independent research assistant, who will inform the acupuncturists of the treatment assignments by mobile message. Allocation concealment will not be exposed until the final data analysis report is completed.To maintain blinding, each patient will have needles (true or sham) inserted into his/her ipsilateral leg. The needles are connected to an EA apparatus, and the patients can feel electric stimulation. Strong and weak EA groups will be acupunctured on four acupoints. The sham EA group will be acupunctured on four non-acupoints without ‘De-qi’.In this clinical trial process, the patients, statisticians and the evaluators for the statistical data and outcomes are blind to the treatment allocation. However, the blind method is not used by acupuncturists in the implementation of EA manipulation because it is not feasible to conceal allocation from them.Patients will be recruited from among acupuncture inpatients and clinics of six hospitals with a target sample size of 450 subjects. The trial will be ongoing from September 2014 to September 2016.Patients who meet the clinical criteria for KOA formulated by the American College of Rheumatology (ACR) will be considered for inclusion . AccordiPatient has had an adverse reaction to acupuncture or is unwilling to accept acupuncture treatment.Patient conforms to the inclusion criteria, but does not follow prescribed treatment, which decreases the curative effects of EA so that it cannot be judged, or patient has incomplete information that may interfere with his/her ability to accurately judge the effects of his/her treatment.Patient has accompanying severe cardiovascular, cerebral, hepatic, renal, or hemopoietic diseases .etcetera or other diseases that may affect the condition of the knees [Patient has inflammatory arthritis such as rheumatoid arthritis, gouty arthritis, he knees .Patient is pregnant, attempting to become pregnant or lactating .Patient has a mental disease .The exclusion criteria are as follows:Two schemes will be used to recruit patients with KOA. The first is to recruit patients in the outpatient and inpatient departments from the six hospitals. The chief physicians of the acupuncture and rehabilitation department in each hospital will screen eligible patients according to the inclusion/exclusion criteria with the help of research assistants. Moreover, potential patients in local communities and out-hospital clinics will be recruited by advertisements through posters, leaflets, newspapers, and so on. After being screened and found to meet the inclusion criteria, the patients will be included only if they agree to join in every procedure of the trial willingly and provide written informed consent.According to the Traditional Chinese Medicine meridian theory of treating pain of KOA ,12, patiAfter the local area has been disinfected, the needles (30-gauge with an outer diameter of 0.32 mm and a length of 50 mm) will be inserted at a depth of 25 to 40 mm vertically and ‘De-qi’  sensation will be achieved in the strong and weak EA groups through lifting and thrusting combined with twirling and rotating the needles. Direct current and continuous wave will be delivered with a medical EA apparatus , at 2 Hz frequency and 0.5 ms pulse width for 30 minutes. EX-LE5 will be connected to ST35, and SP10 will be connected to ST34 with a pair of electrodes . DiffereIn the sham EA group, a sterile, disposable, fine and short needle (35-gauge needle with an outer diameter of 0.20 mm and a length of 25 mm) will be used and inserted superficially (to an approximate depth of 5 to 10 mm) into the sites of the non-acupoints 2 cm lateral to the above four acupoints , DNIC function and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC).VAS is an internationally recognized pain scale. It is a 100-mm line ranging from 0 (no pain) to 100 (pain as bad as it could be) .The prediction of chronification of acute pain can be indicated by DNIC function, which means that pain elicited by a noxious stimulus applied to a given body site can be attenuated by application of a conditioning noxious stimulation to another, even distant body region . DNIC fuWOMAC can be used as an initial assessment of the intensity of pain and functional disability of KOA . It is aThe secondary outcome measurements are Numerical Rating Scale (NRS), Emotional Scale (ES), Present Pain Intensity (PPI) and range of motion (ROM).The NRS of pain is a scale containing the numbers from 1 to 10 on a straight line to measure the magnitude or intensity of pain . It has Pain, whether acute or chronic, can affect a patient’s emotions. Under normal circumstances, emotion can be distinguished according to four levels, measured as ES: Excellent , Good , General , and Poor .PPI is also one of the clinical tools most commonly used to help patients express the intensity of pain. It moves from 0 to 5, indicating the following levels of pain according to number: no pain, mild discomfort, discomfort, terrible pain and extreme pain.ROM indicates the maximum range of joint activities. Determination of ROM is a basic step in assessing muscle, bone and neurological damage. It is one of the indicators used to evaluate the scope of damage and degree of joint movement function, and it can be measured with the help of protractor whose axis is placed on the fibular capitulum, with the fixed arm parallel to the long axis of the femur and with the moving arm parallel to the long axis of the fibula while in a prone position. The normal range of motion of the knee is ‘0 to 135°’.According to a previous study and our pilot data, the sample size calculation assumed an average DNIC increase percentage of 30% for the strong EA group . The DNIP value of less than 0.05 will be considered statistically significant. Data showing an abnormal distribution will be analyzed by the Wilcoxon signed-rank test.Data with normal distribution will be presented as means ± SEM. We will use a one-way analysis of variance (ANOVA) or a two-way ANOVA to determine the overall effect of EA. The Post hoc test (Newman Keuls test) will then be used to determine the statistical differences among individual groups. A The acute pain stage group. The pain of KOA has been ongoing for less than 6 months.The early chronic pain stage group. The pain of KOA has been ongoing for 6 months to 3 years.The medium-term chronic pain stage group. The pain of KOA has been ongoing for 3 to 5 years.The advanced chronic pain stage group. The pain of KOA has been ongoing for more than 5 years Figure A.Figure In order to determine which EA intervention is the best for each of the different stages of KOA, patients in the three EA groups will be further divided according to four different stages of KOA:The effect of EA on the different stages of KOA will be observed, and the stage with the best response to EA intervention will be discussed. Furthermore, in yet another comparison, we will divide all patients into the four stages and then compare the effects of the strong, weak and sham EA groups within the different stages separately Figure B.The aim of this trial is to use EA intervention to inhibit chronification of the acute pain of KOA by reversing the damage to the DNIC function. Completion of this trial will help to identify whether EA with high-intensity current (strong EA) is more effective than EA with low-intensity current (weak EA) and whether EA applied at an early stage of KOA will be more effective than that at a later stage of KOA.We will establish two treatment groups and one control group in this randomized controlled trial. Since the primary consideration of this trial is to clarify whether EA is effective in preventing chronification of the acute pain of KOA, we will use sham EA as a control to rule out the placebo effect. In the sham EA group, acupuncture needles are shallowly inserted into non-acupoint locations to rule out the effect of acupoint. Because most of the KOA patients are familiar with the sensation of EA, they could realize that it is the sham EA if they cannot feel any current from the apparatus. Therefore, we will use a low intensity of electrostimulation to exclude a placebo effect.Acupoints of EX-LE5, ST34, ST35, and SP10 are located around the knees, which have been regarded as the most common and effective acupoints for use in treating KOA in many high-quality trials ,21. SincDNIC involves supraspinal structures, modulates the transmission of nociceptive signals and is another pain perception methodology recently used to study pathophysiology of various pain disorders because it reflects the function of the endogenous pain system ,24. ThisTo screen for the optimal intensity of EA for improving DNIC function, the effect of strong EA and weak EA will be compared. EA with low-intensity current (less than 1 mA) has been demonstrated to mainly excite large fibers (Aβ fiber), which may not activate the DNIC function . InsteadMoreover, we also will try to determine the best stage of KOA for EA intervention. DNIC function is the function of the endogenous analgesic system . In otheThis project will not only increase knowledge on the effects of treating KOA with EA, but also may contribute a solution to the difficult problem of the chronification of acute pain, and promote the clinical application of EA analgesia.This trial is currently recruiting patients.


The aim of the present study was to investigate the factors associated withchronic post-sternotomy pain in heart surgery patients. Between January 2013 and February 2014, we evaluated 453 patients with >6months post-sternotomy for cardiac surgery at a surgical outpatient clinic.The patients were allocated into a group with chronic post-sternotomy pain(n=178) and a control group without pain (n=275). The groups were comparedfor potential predictors of chronic post-sternotomy pain. We used Coxproportional hazards regression to determine which independent variableswere associated with the development of chronic post-sternotomy pain.P=0.009; HR=1.39; 95% CI, 1.08 to 1.80); (b) a historyof antidepressant use ; (c) hypothyroidism ; (d) surgical wound complication , and (e) patients on disability benefits or scheduledfor a consultative medical examination for retirement. In total, 39.29% of the patients had chronic poststernotomy pain. Thefollowing factors were significantly associated with chronic post-sternotomypain: (a) use of the internal thoracic artery in coronary bypass grafting( The factors associated with chronic poststernotomy pain were: use of theinternal thoracic artery; use of antidepressants; hypothyroidism; surgicalwound complication, and patients on disability benefits or scheduled for aconsultative examination. Median sternotomy is the most widely usedapproach in cardiac surgery and, despite all the advances in this field, a largenumber of patients report postoperative chest pain. The incidence of chronicpost-sternotomy pain (CPSP) varies between 17% and 56%-; in approximately one-thirdof these patients, CPSP can compromise quality of life, affecting their sleeppatterns and impairing their working ability.The concept of CPOP was first proposed by Crombie, in 1998. Other psychosocial factors such as depression, anxiety,low education level and fear of surgery are established risk factors forCPOP,.In addition to the diverse characteristics of pain in the various body tissues,sensitivity to pain varies between individuals depending on age, gender, and theunderlying disease itselfEven though CPOP is frequently regarded as expected or irrelevant, it should be seenas a major clinical - and even social - issue. Chronic pain is often responsible fordelayed return to work, which entails greater burden on the public health system andsocial security.The aim of the present study was to determine some factors associated with CPSP inpatients who underwent cardiac surgery at the Santa Casa de MisericórdiaHospital in Ponta Grossa, Paraná, Brazil.After approval by the Human Research Ethics Committee of the Universidade Estadual dePonta Grossa (Ponta Grossa State University) under Formal Opinion 159.531, weperformed an observational analytical case-control study to examine the influence ofa number of factors on the development of CPSP following heart surgery.We evaluated 453 consecutive patients with more than 6 months post-sternotomy forcardiac surgery assisted at the Heart Surgery and Cardiology Outpatient Clinicand private practice office of the Heart Surgery Service of the Santa Casa deMisericórdia Hospital of Ponta Grossa in the years 2013 through 2014. Thetime from surgery to evaluation ranged from 6 to 279 months, mean 58 months. Allof these patients agreed to complete a pain questionnaire. Clinical and surgicaldata were complemented with data from the patients' medical records. Patientswere included if they had undergone valve surgery, coronary artery bypasssurgery, interatrial communication closure, aortic surgery, left ventricleaneurysm repair, myxoma resection or combined procedures in which sternotomy wasthe selected approach to the thoracic cavity.Patients with less than 6 months of surgery and patients with connective tissuedisorders were excluded. There weren't other exclusion criteria. defined CPOP as painoriginated after a surgical procedure and lasting at least 2 months. In thepresent study, as a factor of safety, we only included patients with apostoperative period > 6 months. Any sternal or anterior chest pain,regardless of its intensity, was taken into account and provided that the painwas present at the time of evaluation.The patients were inquired with respect to the presence of chest pain, itscharacteristics, and intensity ranging from 1 to 10. For the aim of our study,only the binary variable "presence or absence of pain" was taken into account.Chronic pain was defined as new-onset pain that arose postoperatively,persisting for more than 6 months after the surgery. MacraeThe patients were allocated into a group with chronic pain and a control groupwithout pain (dependent variable). The following independent variables wereincluded in the Cox regression model: (a) age; (b) gender; (c) foreign descent(patients whose parents were not born in Brazil. There are a lot of Europeandescents in the study and it was intended to assess whether this population hasdifferent sensitivity to pain); (d) use of internal thoracic artery (ITA) graftsin coronary artery bypass surgery; (e) depression or anxiety that needed use ofantidepressant medication at any point in time for treatment to exclude anyminor episode of depression or anxiety that did not need use of medications; (f)diabetes mellitus ; (g) chronic obstructive pulmonary disease (COPD) clinicallyconfirmed by patient history, physical examination, and use of COPD medication;(h) systemic arterial hypertension (SAH)  hypothyroidism (patients with confirmeddisease by TSH level and on thyroid hormone replacement therapy); (j)dyslipidemia (patients with history of dyslipidemia and using lipid-loweringagents); (k) surgical wound complication , and (l)patient on disability benefits or scheduled for a consultative medicalexamination for retirement purposes.The clinical criteria were based on history, laboratorial exams and diseasetreatment, since the patients were receiving optimized medical treatment and inthe late postoperative period with multiple medications.P<0.05 wereconsidered statistically significant.The data were analyzed using the Cox proportional hazards model. The Cox modelmakes it possible to determine which independent variables have an intensifyingeffect when analyzed as a set, and computes their statistical significancewithin a confidence interval (CI) 95%. Thus, we were able to estimate the hazardratio (HR) of each of these variables. Values of We evaluated 453 patients; 178 (39.29%) of these had CPSP . The prevs.62±12.6 years for the control patients. In all, 94 (52.8 %) patients weremale and 84 (47.2%), female.The mean age of CPSP patients was 58±10.9 years Of the patients who developed CPSP, 120 (67.4%) received internal mammary arterygrafts; 116 (65.2%) patients had depression or anxiety disorders at some point intheir lives; 29 (16.3%) had hypothyroidism, and 25 (14%) underwent postoperativesternotomy wound complications. With regard to work status, 92 (51.6%) patients wereretired; 43 (24.1%) were receiving disability benefits or scheduled for aconsultative medical exam; 13 (7.3%) were working; 4 (2.2%) patients wereunemployed, and 26 (14.6%) were self-employed.The results of the statistical analysis by Cox regression are presented in P=0.009; HR=1.39; 95% CI, 1.08 to1.80); history of use of depression or anxiety medication ; hypothyroidism ; surgicalwound complication , and patients ondisability benefits or scheduled for a consultative medical examination forretirement .The following variables were statistically significant according to Cox model oflogistic regression: ITA grafts , values that areclose to those of our study . Because OR and HRare effect size measures, both resulting from a regression study, OR and HR valuesare comparable.Intraoperative nerve injury is a major cause of pain manifest postoperatively ashyperalgesia and allodynia, both typical symptoms of neuropathicpainperformed a study that provided evidence of the association of chronic pain withdepression. Ohayon & Schatzberg, in a 2010 study with 3243 patients, informed that66.3% of the patients with depression reported chronic pain in the most diverselocations. In the present study, 65.2% of the patients with CPSP had depression oranxiety disorder. If analyzed separately, 59.4% among the patients diagnosed withdepression or anxiety disorder had chronic pain, which is close to the percentagefound in the Ohayon & Schatzberg study. Nevertheless, data are still lacking in theliterature correlating CPSP to depression or anxiety disorder.The proportional hazards regression of Cox made it possible to demonstrate therelationship between CPSP and depression or anxiety disorder. Romano &Turner stated that, on account of the action ofneurotransmitters, pain conduction can in fact be altered by depression in the sameway as a nociceptive impulse is capable of inducing or exacerbating a given mood. Ithas been hypothesized that, psychologically, chronic pain is a particular form ofsomatization in which negative emotions are expressed through physical complaints -including pain. Somatosensory amplification is a related concept that has beendefined as a person's increased propensity to feel and express pain. Based on theexplanation for these complex mechanisms, Von Korff & Simon. were able to prove therelationship between pain and depression, which was also found in the present studysample.The origin of this type of pain can be explained by a number of theories, withdepression or anxiety disorder and pain being related on the most diverse levels,such as the psychological, behavioral, and neurobiological. Neurotransmitters suchas serotonin and noradrenaline, both implicated in depressive or anxiety disorders,act on the neurobiological level and play an important role in the modulation ofpain. Osterweis et al..About dyslipidemia, all of the patients were using statin. Although statin can causemuscle pain there wasn't statistical differences in this variable. Hypothyroidismwas also more common in the group of patients with CPSP. Many reports can be foundin the literature concerning thyroid hormones and their functions; however, studiesof their connection with pain are scarce. The thyroid gland has a prominent role intissue metabolism and development; in addition, the hypothalamic-pituitary-thyroidaxis is central to the modulation and neurotransmission processes in the centralnervous system, ina pilot study with a group of 200 women with chronic pain - whose medical historywas investigated - found that 19% of them had some degree of thyroid dysfunction.That rate is similar to the overall value of 16.3% found in our analysis.Aloisi et al.. Aminoglycan deposits surrounding nerves,primary axonal degeneration, and segmental demyelination mechanisms have beenproposed for the peripheral nerve dysfunction in hypothyroidism, as demonstrated inrodents.Another piece of evidence is the low oxygen consumption and high blood pressurefrequently found among hypothyroid individuals, leading to regional hypoxia andeventually to muscle spasms due to the inadequate supply of blood and nutrients forthe muscles.This could explain some of the mechanisms involving hypothyroidism and pain.Despite the number of existing studies, the hypothesized relationship betweenhypothyroidism and chronic pain is still far from understood. The origin of paincould be neuropathic; this is one of the key points to be elucidated, as neuropathicpain is prominent in somatosensory system injury. Marques et al. pointed out that although woundcomplications following sternotomy are rare, infection is a threatening occurrencebecause it could extend to other areas, thus causing future complications.As evidenced by Cox regression, sternal surgical wound complications are associatedwith the outcome under study. Sternal wound complications increase the risk of CPSP,ranging from superficial infections to sternal instability andmediastinitissuggested that sternal surgical wound infection is one of the likely causes of CPSP.This had already been indicated by Ottino et al. in 1987. Although there are reports on therelationship between surgical wound complications and chronic pain, concrete data toevidence this association were still lacking.Einsenberg et al.studied the relationship between the perception of chronic pain by patients whoderived some form of secondary gain from their complaint of pain and those who didnot have such gain. Even though those authors suggested that there could be a linkbetween altered perception of pain and the benefits obtained, they also stated thatthey were not able to demonstrate a difference between the group receiving benefitsand the group without benefits.Another risk factor for CPSP was identified in the patients who were receivingdisability benefits or were scheduled for a consultative medical examination toapply for early retirement by the National Social Security Institute. Although noreports can be found in the literature addressing this specific variable and itsrelationship to CPSP, similar studies have been developed. In 1995, Rosomoff etal., in a 1997 retrospective study with 24 patients whohad chronic low back pain, found that 11 out of the 13 patients who had applied forworker's compensation showed poor outcomes in the management of their chronic painwhile 9 of the 11 patients in the group of non-claimants had excellent results.Those authors concluded that although the sample size was small and the study wasretrospective, worker's compensation and litigation claims were strongly associatedwith worse outcomes in the management of chronic pain.Along these lines, Vaccaro et al.Our clinical experience shows that the patients who have not yet retired and are notworking complain of chronic pain more often, which was evidenced in the present casepopulation. Psychological and behavioral mechanisms may be implicated in theenhanced pain of patients who expect to be granted social security benefits or whofear losing those benefits, since these beneficiaries have to undergo frequentconsultative medical exams for years. On the other hand, given that patients withpain are more likely to seek disability benefits, CPSP may be either the cause orthe effect in the case of patients on disability benefits.In the case patients of the present study, the factors associated with increasedincidence of chronic post-sternotomy pain were: (a) use of ITA grafts; (b) historyof depression or anxiety that needed use of antidepressant medication; (c)hypothyroidism; (d) surgical wound complications, and (e) patients on disabilitybenefits or scheduled for a consultative examination.


The use of manometry, i.e. the recording of pressures within hollow viscera, after being successfully applied to the study of esophageal and anorectal motor dysfunctions, has also been used to investigate physiological and pathological conditions of the small bowel. By means of this technique, it has been possible to understand better the normal motor functions of the small intestine, and their relationship and variations following physiologic events, such as food ingestion. Moreover, intestinal manometry has proved useful to document motor abnormalities of the small bowel, although recognition of altered patterns specific for a determinate pathologic condition is still unavailable. However, this technique often permits the detection of abnormal gut motility in patients with abdominal symptoms such as unexplained vomiting and diarrhea, and it is sometimes also useful to address therapeutic targeting.  Manometric techniques are methods that detect pressure events within hollow viscera. After being successfully employed to study upper  and lower  motility, manometry has also been applied to investigate the small  and the Physiological aspectsIn humans, the motor activity of the upper parts  features specific patterns that mostly depend from individuals in the fasted or fed state . In factThe three phases recur on average every 90 minutes, with phase III being relatively short (10% or less of the MMC), as well as phase I and phase II occupying each about 30%-80% of the cycle ; this acPerforming intestinal motility studies: when and in whom?The first important point to be stressed is that manometric studies of gastrointestinal motility should be preceded by an accurate exclusion of other organic and/or metabolic disorders by means of radiologic and endoscopic studies. The availability of less invasive radioisotopic techniques in some centers  may reprUpper gastrointestinal manometry is chiefly used to investigate complaints of unexplained nausea, vomiting, abdominal pain and distention. in patients with an abnormal gastric emptying test in the absence of an etiological diagnosis , 17. HowManometric investigations may also help to identify the presence of abnormalities reconductable to neuropathic or myopathic disorders that affect the small bowel in both adult and pediatric patients -27. The Also, manometric techniques may reveal postsurgical motor abnormalities , 31. TheMore recently, intestinal manometry has been used to study patients with small bowel bacterial overgrowth. These studies have consistently shown the presence of small bowel motor abnormalities, suggesting that altered gut motility might likely predispose to the pathological growth of bacteria -37Can intestinal manometry identify pathophysiological processes? Manometry is often able to provide evidence of a pathophysiological process; at the same time it is not usually diagnostic of a specific disease per se , 39. Whe1) Patterns suggesting mechanical obstruction. These are represented by two events: a) a sustained (>30 minutes) postprandial pattern of "minute" clustered contractions separated by brief periods of motor quiescence ; b) repe2) Generally low amplitude contractions, documented at several intestinal levels, and thought to be suggestive of a myopathic process. These low amplitudes  are mainly recorded in patients with hollow visceral myopathies or progressive systemic sclerosis , 44 Fig.3) Normal amplitude, but “uncoordinated”  contractile activity in the gastric antrum and the small bowel, suggesting a neuropathic process. These motor abnormalities are usually present during phases II and III of the MMC  Figure ; in addi4) Postprandial antral hypomotility . This pattern is frequently found in patients with diabetes mellitus, post-vagotomy, and postviral or idiopathic gastroparesis , 48.5) Minute clustered contractions associated with abdominal pain firstly reported in patients with irritable bowel syndrome , 50. ThiLimits of intestinal manometryEven though in selected subgroups of patients, neuropathic and myopathic motility patterns have been described , their pIntestinal manometry: useful to establish therapeutic programs?Treating subgroups of patients with intestinal motor abnormalities may be complex, unsuccessful, and not infrequently frustrating . HoweverFinally, intestinal manometry may help to explain the gut motor responses to different food formulas , 69, thu


Revision knee arthroplasty is assumed to be even more painful than primary knee arthroplasty and predominantly performed in chronic pain patients, which challenges postoperative pain treatment. We hypothesized that the adductor canal block, effective for pain relief after primary total knee arthroplasty, may reduce pain during knee flexion (primary endpoint: at 4 h) compared with placebo after revision total knee arthroplasty. Secondary endpoints were pain at rest, morphine consumption and morphine-related side effects.NCT01191593.We included patients scheduled for revision knee arthroplasty in general anesthesia into this blinded, placebo-controlled, randomized trial. Patients were allocated to an adductor canal block via a catheter with either ropivacaine or placebo; bolus of 0.75% ropivacaine/saline, followed by infusion of 0.2% ropivacaine/saline. Clinicaltrials.gov ID: We enrolled 36 patients, of which 30 were analyzed. Mean pain scores during knee flexion at 4 h (primary endpoint) were: 52±22 versus 71±25 mm , ropivacaine and placebo group respectively. When calculated as area under the curve (1–8 h/7 h) pain scores were 55±21 versus 69±21 mm during knee flexion (P = 0.11) and 39±18 versus 45±23 mm at rest (P = 0.43), ropivacaine and placebo group respectively. Groups were similar regarding morphine consumption and morphine-related side effects (P>0.05).The only statistically significant difference found between groups was in the primary endpoint: pain during knee flexion at 4 h. However, due to a larger than anticipated dropout rate and heterogeneous study population, the study was underpowered.NCT01191593Clinicaltrials.gov  Revision total knee arthroplasty (TKA) is a challenge, both for surgeons and anesthesiologists. For the surgeon the procedure is technically more difficult, takes longer time, and has a higher rate of complications than primary TKA The femoral nerve block has been the mainstay for postoperative pain treatment following knee replacement for decades. Current trends however, focus on providing analgesia with minimal motor block. Contrary to the femoral nerve block, the adductor canal block (ACB) is predominantly a sensory nerve block, preserving quadriceps muscle strength and mobilization ability We hypothesized that the adductor canal block would also reduce postoperative pain following revision TKA. Hence the primary aim of this study was to examine the effect of adductor canal block on pain during knee flexion after revision TKA compared with placebo. Secondary endpoints were pain at rest, morphine consumption and morphine-related side effects.This prospective, randomized, blinded, placebo-controlled trial was approved by the local Regional Ethics Committee (H-3-2010-063), the Danish Medicines Agency (2010-021161-71), the Danish Data Protection Agency and registered at clinicaltrials.gov (NCT01191593). After obtaining written informed consent, we recruited patients scheduled for revision TKA from August 2010–March 2013. The study was conducted at the Centre of Head and Orthopaedics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark and monitored by the Copenhagen University Hospital GCP  unit. Data are presented in accordance with the CONSORT  statement. The protocol for this trial and supporting CONSORT checklist are available as supporting information; see 2. Exclusion criteria were inability to cooperate, allergy to any drug used in the study, alcohol or drug abuse.Eligible patients were Danish speaking adults, scheduled for revision TKA in general anesthesia, aged 40–85 years, with American Society of Anesthesiologists physical status I–III, and body mass index of 18–40 kg/mPremedication, consisting of 1 g acetaminophen, was given orally one hour before surgery. General anesthesia was induced with propofol, and maintained with propofol (variable rate) and remifentanil 30 µg/kg/h (fixed rate). Thirty minutes prior to the end of surgery, patients were given morphine 0.2 mg/kg intravenously. A femoral tourniquet was applied peri-operatively and intraoperative fluids were administered at the discretion of the anesthetist.The adductor canal block was performed after the end of surgery, while maintaining general anesthesia until completion of block procedure. A 12L-SC linear ultrasound transducer  was placed on the medial part of the thigh, halfway between the superior anterior iliac spine and the patella with the leg slightly externally rotated. The femoral artery was identified in short axis in the adductor canal, underneath the sartorius muscle. After skin disinfection with chlorhexidine gluconate and isopropyl alcohol an 18-gauge, Contiplex Tuohy needle  was inserted in-plane from the lateral side of the transducer. The needle tip was placed underneath the sartorius muscle, just lateral to the artery and saphenous nerve, using 2–3 ml of saline to ensure correct placement . A 20-gauge catheter was then advanced 2 cm beyond the tip of the needle, and 30 ml of study medication was slowly injected via the catheter, with repeated aspiration. The position of the catheter tip was adjusted during injection to obtain a semicircular expansion between the sartorius fascia and the artery.In a double masked fashion patients were allocated to ACB with ropivacaine or placebo  for 24 hours. We administered study medication as an initial bolus of 30 ml 0.75% ropivacaine or saline, followed by another bolus of 15 ml 6 hours later. Immediately after the second bolus, we started infusion of study medication  at a rate of 8 ml/h.Postoperatively, all patients received oral acetaminophen (1 g) and ibuprofen (400 mg) every six hours and a patient-controlled analgesia (PCA) pump with morphine intravenously . If analgesia was inadequate patients received an additional bolus of 2.5 mg morphine and/or 0.05 mg fentanyl intravenously until adequate analgesia was obtained (0.1 mg of fentanyl was considered equipotent with 10 mg of morphine). Patients with a daily intake of strong opioids  received their habitual analgesics during the study period. These doses were not included in the cumulative morphine consumption. In case of moderate to severe postoperative nausea or vomiting (PONV), patients received 4 mg of ondansetron intravenously, with supplemental doses of 1 mg, when needed.The primary endpoint was pain during 45 degrees flexion of the knee at 4 hours postoperatively.Secondary endpoints were pain at rest and during flexion of the knee , cumulative morphine consumption , number of vomiting episodes, ondansetron consumption and degree of nausea and sedation .We assessed all outcomes at 1, 2, 4, 6, 8 and 24 h postoperatively. Pain intensity was assessed on a visual analogue scale (VAS) with 0 mm  =  no pain, and 100 mm  =  worst imaginable pain. Patients rated nausea and sedation on a four-point scale , and reported the number of vomiting episodes (volume greater than 10 ml).To counter the problem of tolerance in patients treated with opioids, we decided that patients with a daily intake of strong opioids should continue with their habitual analgesics during the study period, and that these doses should not be included in the cumulative morphine consumption.The pharmacy prepared the study medication in identical pre-packed boxes, consecutively numbered according to a computer generated block randomization list . Subjects were assigned consecutive numbers upon inclusion to the study and received the study medication from the corresponding boxes. A research fellow neither involved in the study nor in the care of the patient administered the study medication in unlabeled syringes for injection and unmarked drug bags for infusion, before handing it over to the investigators. Ropivacaine and saline are identical in appearance.All investigators, staff and patients were blinded to the treatment groups. The randomization key was first broken after all patients were enrolled, data computed and statistical analyses performed.We considered a difference of 20 mm in VAS pain scores to be clinically relevant. Assuming a SD of 20, with α = 0.05 and power  = 0.80; 17 patients in each group were required to detect a difference of 20 mm in VAS pain scores. We planned for an inclusion of 36 subjects to compensate for dropouts.Statistical analyses were conducted using SPSS 19 . Continuous variables are presented as mean ±SD or with medians and 10th–90th percentiles, as appropriate, and ordinal and nominal variables as n (%). The Kolmogorov-Smirnov test was used to assess whether data were normally distributed. If the assumption of normality was met, comparisons between the groups were performed using independent samples t-test; if the assumption of normality was rejected, comparisons were made using Mann-Whitney U test for unpaired data. Nausea and sedation scale scores were compared at 24 h, and by using the mean score from each patient from 1–8 h. We calculated the area under the curve (AUC) for the interval 1–8 h, for VAS pain scores during knee flexion and at rest. Categorical data  were analyzed using the Chi-squared test or by Fischer exact test, as appropriate. The nature of the hypothesis testing was two-tailed, and P<0.05 was considered statistically significant.We performed a linear mixed model including pain scores at 1, 2, 4, 6 and 8 hours , where we included time as a repeated effect with a first order autoregressive covariance structure (AR(1)). Treatment, time and the interaction treatment*time were set as fixed effects, and preoperative pain scores were included as covariates to compensate for baseline differences. This analysis was performed as an intention to treat analysis.We enrolled and randomized 36 patients during a 31-month period, beginning August 2010; 6 patients were excluded prior to receiving any treatment, 2 patients were excluded between 4 and 6 h, and another 4 patients were excluded after completion of the first 8 h of the study protocol. This resulted in 30 patients with data for our primary endpoint : VAS during flexion of the knee at 4 h postoperatively. As for the secondary outcomes all available data were analyzed, although missing data for the final end point in cumulative morphine consumption and pain scores calculated as AUC will in practice render these analyses per protocol analyses. The details of patient flow through the study, including details on patient exclusions, are presented in VAS pain scores during flexion of the knee at 4 h postoperatively (primary endpoint) were 52±22 mm in the ropivacaine group and 71±25 mm in the placebo group . At 24 h, pain scores were 50±27 vs. 57±27 mm during knee flexion  and 21±19 vs. 37±24 mm at rest  at rest; ropivacaine and placebo group respectively. When calculated as AUC for the interval 1–8 h/7 h, VAS pain scores during flexion of the knee were 55±21 mm in the ropivacaine group compared with 69±21 mm in the placebo group , 43±34 vs. 44±28 mg at 0–8 h (P = 0.97) and 28±30 vs. 29±18 mg from 8–24 h (P = 0.95), ropivacaine and placebo group respectively . There wAll data used for analysis are available in the file: There were no adverse events in the study population.Daily intake of strong opioids was omitted from total morphine consumption to counter the problem of tolerance. By chance, more patients in the ropivacaine group had a daily intake of strong opioids  showed a tendency of lower pain scores in the ropivacaine group during knee flexion for the repeated measurements at 1, 2, 4, 6 and 8 hours  but not for pain at rest .a priori considered to be clinically relevant (20 mm), and what can be expected in a multimodal analgesic setting with patients receiving acetaminophen, ibuprofen and morphine. Pain scores were consistently lower in the ropivacaine group, but mean differences varied between 6–19 mm.The ACB reduces pain scores and morphine consumption compared with placebo after primary TKA To our knowledge, this is the first postoperative pain study performed exclusively in patients undergoing revision knee arthroplasty. In most studies revision TKA is an exclusion criteria, probably because this group of patients are assumed to have a more complex pathology, and more complex pain problems. As the number of revision TKAs is steadily increasing, we believe it is necessary to perform specific studies in this subgroup of patients.a priori calculated sample size of n = 17 in each group. Although the exclusion of these first six patients is not likely to have biased our results, additional six patients were excluded after obtaining our primary endpoint at 4 h postoperatively  versus 2/16 (12.5%) had a daily intake of strong opioids . IncludiAs the ACB is a novel technique, we believed it was important to compare the block with a placebo control. If we had compared two active treatments, and had found no significant difference, we would have risked concluding equal efficiency, while on the contrary neither might have been effective Previous reports of the ACB state that intermittent boluses are preferable, in order to ensure spread throughout the aponeurotic canal Two previous studies reported a success rate of 95 and 98% for the ACB, assessed by temperature discrimination in the saphenous innervation area Pain scores were consistently lower in the ropivacaine group including clinically relevant differences between groups. However, the mean differences varied and the only statistically significant difference between our groups was seen for pain during knee flexion at 4 hours postoperatively (primary endpoint). Due to a larger than anticipated dropout rate and considerate heterogeneity in the study population , more studies are needed before any recommendations regarding ACB for pain relief after revision TKA can be made. Future studies should include a large enough sample size to balance the distribution of confounders, or alternatively minimize heterogeneity by in- and exclusion criteria.Checklist S1Supporting CONSORT checklist .(DOC)Click here for additional data file.Protocol S1The protocol for this trial is available in the supplementary information file.(DOC)Click here for additional data file.Data S1All data used for analysis are available in the supplementary information file.(XLSX)Click here for additional data file.


Ibuprofen is an effective analgesic treatment with a ceiling effect at doses above 400 mg. This study compared the combination of ibuprofen 400 mg and caffeine 100 mg with ibuprofen 400 mg monotherapy, caffeine and placebo in the analgesic treatment of moderate to severe acute dental pain following third molar extraction.III, active‐/placebo‐controlled, double‐blind, single‐centre, two‐stage, parallel‐group study in adult patients with at least moderate baseline pain intensity. Primary endpoint was defined as the time‐weighted sum of pain relief and pain intensity difference over 8 h (SPRID0–8 h), secondary endpoints included duration of pain relief, time to meaningful pain relief and more.Phase N = 748 patients were enrolled and N = 562 treated. Mean baseline pain intensity was 7.7 on a 0–10 numerical rating scale. Analysis of SPRID0–8 h demonstrated superior analgesic effects for a single dose of ibuprofen/caffeine versus ibuprofen, caffeine and placebo over 8 h, rescue medication in this stage was requested by more patients on ibuprofen (32.5%) than on ibuprofen/caffeine (16.0%). Median time to meaningful pain relief was shorter for ibuprofen/caffeine (1.13 h) compared with ibuprofen . More patients on ibuprofen/caffeine than on ibuprofen reported meaningful pain relief. Adverse events were infrequent and mostly mild or moderate across treatment groups. Tolerability was rated as ‘very good’ or ‘excellent’ by most patients in both treatment groups.This study demonstrated clinically relevant superiority of ibuprofen/caffeine over monotherapy with ibuprofen in patients with acute dental pain. All treatments were well tolerated.This trial showed superior efficacy of 400/100 mg ibuprofen/caffeine, compared to 400 mg ibuprofen alone, for treating acute pain, reflecting that caffeine is an effective analgesic adjuvant. Data on efficacy of 400 mg ibuprofen combined with caffeine for the treatment of acute pain were not available yet. After oral administration of a single dose analgesia is achieved rapidly and maintained for up to 8 h. Its well‐proven efficacy and the beneficial safety profile – especially for the short‐term treatment of acute pain – make ibuprofen one of the most popular analgesics.At single doses exceeding 400 mg, ibuprofen has pronounced anti‐inflammatory effects, which are used for, e.g. long‐term treatment of chronic inflammatory diseases  increases efficacy, compared to ibuprofen alone.This double‐blind clinical study was conducted to assess the acute effect of the combination of ibuprofen (acid) 400 mg and caffeine 100 mg in patients with post‐surgical dental pain. The primary objective was to demonstrate superior efficacy of a single dose of ibuprofen/caffeine versus either ingredient alone as well as placebo. The dental impaction pain model is validated, reproducible and widely recognized and utilized as acute pain model for testing efficacy of analgesic treatments in clinical trials  of ibuprofen (acid) 400 mg and caffeine 100 mg versus ibuprofen (acid) 400 mg, caffeine 100 mg, and placebo in patients aged between 18 and 55 with postoperative dental pain. The study was conducted and reported in accordance with the Declaration of Helsinki, the ICH‐GCP guidelines, local regulations and Boehringer Ingelheim standard operating procedures (SOP)s, and in compliance with the clinical trial protocol. The study received prior ethics‐committee approval by the Institutional Review Board (IRB) of the participating centre .Electronic case report forms (eCRFs) were used for all patients. All clinical data were captured using the Oracle Clinical™ remote data capture (RDC) system, a web‐based tool. Data entered in the eCRFs had to be consistent with the source documents which were filed at the investigator's site. The investigator was responsible for retaining all records pertaining to the trial. Concomitant diagnoses and AEs were coded using the Medical Dictionary for Regulatory.Activities (MedDRA) version 17.0 and concomitant medications were coded according to the World Health Organisation Drug Dictionary version 14.MAR.A physical examination, ECG and laboratory tests were conducted at the screening visit to evaluate whether the patients were in good general health and thus suitable for study participation. Laboratory analyses were performed by Quest Diagnostics Clinical Trials, Valencia, California, USA. The investigator assessed the clinical significance of screening safety laboratory results to determine if the patient was healthy enough for study participation. Parameters included clinical chemistry, complete blood cell count, drug abuse test (urine dipstick), urinalysis and urine dipstick‐pregnancy test.2.2Before the start of the study, the clinical trial protocol (CTP), the patient information leaflet, the informed consent form and other locally required documents were reviewed by the Institutional Review Board (IRB) of the participating centre. The IRB  of the principal investigator of the trial  granted approval of the study on 02 Aug 2013. The IRB met the requirements of the International Conference on Harmonisation (ICH) Harmonised Tripartite Guideline for Good Clinical Practice (GCP), local legislation, and the requirements of 21 CFR 312.120. There was one global amendment to the CTP which required approval of the IRB.2.3This trial was performed in male or female outpatients who were eligible for participation in the study if they were between 18 and 55 years of age and scheduled to undergo surgical extraction of 3–4 impacted third molars, with a minimum of two mandibular extractions, were in good general health, with a body mass index (BMI) ≤30, had no contraindications to any of the study medications or anaesthetic drugs, and gave written informed consent before any pre‐screening, screening or study‐specific procedures were performed.Patients qualified for the study if after the dental surgical procedure they presented a baseline pain severity assessment of either ‘moderate’ or ‘severe’ pain on a 4‐point verbal rating scale (VRS) which was based on a written selection of options of ‘no pain’, ‘slight pain’, ‘moderate pain’, or ‘severe pain’ and a baseline score of ≥5 on the 0–10 numerical pain rating scale (NPRS) ranging from 0 = ‘no pain’ to 10 = ‘worst possible pain’. Patients were periodically asked to verbally rate their pain using the NPRS, beginning about 30 min following completion of the surgical procedure, until the patient qualified with a NPRS pain intensity (PI) score of ≥5 or until 5 h had elapsed. The first dose of trial medication was administered no later than 5 min after the qualifying pain score assessment. Patients with ‘no pain’ or ‘slight pain’ on the VRS or with a score of <5 on the NPRS were not eligible for randomization. If the patient failed to qualify by 5 h post‐surgery, the patient was not randomized and considered a screening failure.Patients were excluded from the study if they met any exclusion criteria, i.e. had a history of hypersensitivity to the study medications, any significant disease or gastrointestinal disorder, impaired liver function, clinically significant abnormal electrocardiogram (ECG) at screening, in case of alcohol or substance abuse, habituation to and abuse of other analgesic or psychotropic drugs, or ingested any caffeine‐containing beverages, chocolate, or alcohol 6 h or less before surgery. Women were excluded if pregnancy or breastfeeding could not be ruled out.Trial medication  was supplied as identically appearing film‐coated tablets. It was produced by Delpharm SAS, Reims, France and provided by the Clinical Trial Supplies Unit, BI Pharmaceuticals, Inc., Ridgefield, CT, USA. The batch release of trial kits was performed by the Department of Pharmaceutical R&D, Clinical Trial Supplies Unit, BI Pharma GmbH & Co. KG, Biberach, Germany.The randomization list was generated using a validated system, which involved a pseudo‐random number generator so that the resulting treatment was both reproducible and non‐predictable. Patients were randomized in blocks to ensure that equal numbers of patients were allocated to each treatment sequence. A block size of 16 was used. Patients and investigators remained blinded with regard to the randomized treatment assignments until after database lock. Access to the codes was controlled and documented.At the time of randomization, to stratify the randomization regarding the baseline pain intensity, eligible patients having reported ‘moderate’ were assigned the lowest available medication number, whereas patients having recorded ‘severe’ were assigned the highest available medication number. Interactive Voice Response (IVR) system was not utilized. After a screening evaluation Visit 1), eligible patients underwent dental surgery at Visit 2 and were randomized to one of the six treatment sequences of the double‐blind treatment phase consisting of two study stages in a 6:6:1:1:1:1 ratio  and paracetamol 500 mg plus hydrocodone 5 mg (1–2 tablets). After Study Stage 1, patients continued treatment with either ibuprofen/caffeine or ibuprofen on an outpatient basis for 5 days in Study Stage 2, with up to 3 doses per day every 6–8 h.The study included three visits: Screening Visit (Visit 1), Dental Surgery/Study Stage 1 (Visit 2) and End‐of‐trial Visit (Visit 3). Participation in the trial started with the Screening Visit and ended with the End‐of‐trial Visit. Adverse events were to be recorded further during a follow‐up period, which comprised 7 days after the last administration of trial medication.2.4All assessments concerning the primary and secondary efficacy endpoints were completed in Study Stage 1 after single dosing of ibuprofen/caffeine, ibuprofen, caffeine or placebo over an 8‐h postoperative period on an inpatient basis. The primary endpoint of this trial was the outcome measure SPRID0–8 h: the time‐weighted sum of pain relief and pain intensity difference from pre‐dose baseline pain intensity – summed up for all assessment times from 0 to 8 h after administration of the first dose of study medication.Pain relief from starting pain was assessed in a patient diary using a 5‐point VRS  at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7 and 8 h after the first dose of study medication. Pain intensity was assessed using a 0–10 NPRS ranging from 0 = ‘no pain’ to 10 = ‘worst possible pain’. Patients assessed their dental pain intensity in a diary pre‐dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7 and 8 h after the first dose of study medication. As soon as the patient required rescue medication or a second dose of study medication before 8 h post‐dose (whichever was first) pain intensity and pain relief were assessed before use of rescue/second intake of study medication. Subsequent pain intensity assessments after rescue/second intake of study medication were still performed.Secondary endpoints comprised SPRID0–2 h , duration of pain relief and time to meaningful pain relief. Duration of pain relief was defined by the time to first dose of rescue medication or second dose of study medication (whichever was first) within the first 8 h after the first study drug intake.Time to meaningful pain relief was captured by a stopwatch started immediately after the first dose of study medication and stopped as soon as a meaningful pain relief was felt by the patient.Other endpoints included time to first perceptible pain relief, pain intensity difference (PID) and pain relief (PAR) at individual time points and number of rescue medication doses in Stage 1.Time to first perceptible pain relief was captured by a stopwatch stopped as soon as the patient first began to feel any pain relief.Safety was assessed based on the incidence and intensity of adverse events (AEs and SAEs) which were recorded from the time of consent until 7 days after completion of the study treatment course as well as on laboratory assessments, physical examinations and patients’ final global assessment of tolerability. This final global assessment of tolerability was performed by the patient at the end of the study by answering the question: ‘How would you rate your ability to tolerate the study medication’  in the diary.2.5For SPRID0–8 h, the treatment difference of the FDC versus the single components and placebo were tested using two‐sided tests and a significance level of 0.05. Secondary endpoints were considered as supportive and other endpoints as explorative endpoints, respectively.The sample size calculation was based on SPRID0–8 h evaluated in Study Stage 1, in which the treatment groups FDC, ibuprofen, caffeine and placebo were allocated in a 3:3:1:1 ratio. A total of 560 evaluable patients (210:210:70:70) had 90% power to detect a standardized mean difference (SMD) of 0.45 when the sample sizes in the two groups were 70 and 210, respectively , and 94% power to detect an effect size of 0.35, when the sample sizes in the two groups were 210 each. Therefore, a total planned number of 560 patients had to be randomized to one of the six treatment sequences as outlined in Fig. In total, three analysis datasets were defined: the treated set (TS), the full analysis set (FAS) and the per‐protocol set (PPS). The TS comprised all randomized patients who took at least one dose of study medication. The FAS included all patients in the TS who provided any post‐treatment data for the primary efficacy endpoint. The PPS was based on all patients in the FAS who had no important protocol violations.SPRID0–8 h and SPRID0–2 h were tested for the FAS using an analysis of covariance (ANCOVA) including treatment as fixed effect and the pre‐dose baseline pain intensity measured on the 4‐point VRS as a categorical covariate. In these analyses, assessments of pain relief and pain intensity were considered as missing if completed after the patient had taken rescue medication or the second dose of study medication (whichever was first) before hour 8 after study drug intake. The last assessment completed before to rescue/second study medication was then carried forward to replace the observations up to 8 h.The Kaplan–Meier estimator was presented for the endpoints ‘time to perceptible pain relief’, ‘time to meaningful pain relief’ and ‘duration of pain relief’ with the log rank test used to evaluate the difference between the treatment groups.The analysis of PID at each time point utilized a restricted maximum likelihood‐based repeated measures approach, using all available longitudinal pain intensity observations or replaced‐by‐missing observations after the patient had taken rescue medication or the second dose of study medication (no LOCF procedure was applied in this repeated measures model) at each post‐baseline time up to 8 h. PID means were adjusted for the continuous covariate of baseline PI (NPRS).An ordinal logistic regression model including the factors treatment, time and treatment‐by‐time interaction as well as the categorical covariate of baseline PI [VRS] was used for the analysis of PAR at each time point. In this analysis, all pain relief assessments completed during the first 8 h, after the patient had taken rescue or the second study medication, were set missing. Odds ratios together with 95% CIs were used to quantify the effect of the FDC compared to ibuprofen, caffeine and placebo; odds ratios > 1 were to be interpreted as being in favour of the FDC.Post hoc responder analyses were performed with regard to SPRID0–8 h and the parameter SPRID0–6 h. A responder was defined as a patient who achieved 50% of the individual maximum achievable effect with regard to SPRID0–8 h/SPRID0–6 h, respectively. The maximum achievable SPRID0–8 h/SPRID0–6 h, respectively, was reached if PI was 0 on the 0–10 NPRS and PAR was 4 (=complete) at all assessment times under consideration.Proportions of responders were used to calculate the absolute risk reduction (ARR) and the number needed to treat (NNT) for the FDC group in comparison to the ibuprofen, caffeine and placebo groups; in addition 95% confidence intervals (CI) by Wald were calculated for ARRs and NNTs.All patients in the TS were evaluated for the safety of the study medication. Incidence, severity and causal relationship of any AEs were tabulated by system organ class (SOC) and preferred term (PT) coded according to MedDRA version 17.0. All AEs occurring between the time of the first drug intake and the drug discontinuation date as recorded in the eCRF plus 1 day (inclusive) were assigned to the respective treatment group. Adverse events occurring before the time of first drug intake were assigned to ‘screening’ and AEs occurring after the drug discontinuation date plus 1 day (inclusive) were assigned to ‘post‐treatment’. In addition, AEs with an onset date before the start of study drug but with worsening in intensity during treatment were assigned to the treatment period.33.1A total of 748 patients were enrolled in this trial, of whom 562 patients were randomized and treated. The proportion of patients who discontinued trial medication prematurely was low (9 patients 1.6%]). The most common reason for discontinuation was other AE, which was reported in five patients (of whom 3 were treated with ibuprofen/caffeine–ibuprofen/caffeine). Two patients (0.4%) discontinued trial medication due to non‐compliance with the clinical trial protocol. The disposition of patients is summarized in Fig. .6%). TheDemographic characteristics  and baseline pain intensities  were well balanced across treatment arms  were reported for <1% of the overall trial population and were balanced across treatment arms in Study Stage 1.3.2The adjusted mean SPRID0–8 h achieved with ibuprofen 400 mg/caffeine 100 mg was statistically significant higher when compared to all other treatment arms. The FDC provided approximately 30% higher pain reduction/pain relief than ibuprofen alone on average over 8 h. The SMDs for SPRID0–8 h were 1.4 and 1.2 for the comparisons FDC versus placebo and caffeine, respectively, and 0.4 for the comparison FDC versus ibuprofen alone.The results of the primary analysis were confirmed by a sensitivity analysis using the per‐protocol set (data not shown) and corroborated by the results for the secondary endpoint SPRID0–2 h, which demonstrated about 50% higher pain reduction/pain relief with the FDC than with ibuprofen alone on average over the first 2 h after intake of the first dose of trial medication, i.e. in the immediate post‐surgical phase characterized by peaking acute pain  and pain relief (as measured on the 5‐point VRS) at individual time points corroborated the findings of the primary and secondary endpoint analyses. Treatment with ibuprofen/caffeine showed maintained analgesic efficacy with a fast onset. For pain intensity difference, the comparison of adjusted means for ibuprofen/caffeine versus ibuprofen achieved fen Fig. . When coConcerning pain relief, the odds ratios for the comparison of ibuprofen/caffeine versus ibuprofen favoured the ibuprofen/caffeine arm already at the first time point after 0.25 h and up to 2 h of administration of trial medication  and remaining separated over the entire observation period see Fig. . The curThe median duration of pain relief  was almost as long as the observation period of Study Stage 1 in the ibuprofen/caffeine arm , and ibuprofen arm , and significantly shorter in the caffeine  and placebo arms , respectively.3.5The proportion of patients who took rescue medication in Study Stage 1 was more than twice as high in the ibuprofen arm (32.5%) compared with the ibuprofen/caffeine arm (16.0%) Table .3.6p < 0.0001) versus an NNT of 3.1  for treatment with ibuprofen versus placebo.An additional analysis was performed to derive responder rates from the results for SPRID0–8 h. The responder analysis for SPRID0–8 h confirmed the results of the primary endpoint analysis and the observation that more patients responded to treatment with ibuprofen/caffeine than to ibuprofen. Less than one quarter of patients in the placebo (17.3%) and caffeine (24.6%) arms achieved 50% of the maximum achievable SPRID0–8, whereas the 50% responder rates for ibuprofen and the FDC were 49.7% and 67.8%, respectively. Compared with placebo, treatment with ibuprofen/caffeine resulted in an ARR of 50.5% indicating an NNT of 2.0  in the ibuprofen arm compared with two‐thirds of patients (67.8%) in the ibuprofen/caffeine arm achieved at least the half‐maximum achievable SPRID0–8 h with a number needed to treat (NNT) of 5.5, compared to ibuprofen. This means that the addition of caffeine to ibuprofen increased the proportion of patients who achieved at least the half‐maximal SPRID0–8 h by almost 20%, and that for every six patients treated with ibuprofen/caffeine, one would achieve 50% response who would not achieve it with ibuprofen. Similar results were obtained for the responder analysis of SPRID0–6 h Table .3.7Exposure of patients to placebo and caffeine was limited to a single tablet during Study Stage 1 which lasted 6–8 h. Therefore, AE frequencies are provided separately for Study Stage 1 and Stage 2.n = 2 and headache, n = 1) which were considered drug‐related versus 1 subject with nausea in the ibuprofen group, none in the placebo group and 2 subjects with a total of 2 AEs  in the caffeine group. One patient in the ibuprofen group experienced an AE of severe intensity (vomiting). None of the AEs led to treatment discontinuation.The frequency of patients with any AE in Study Stage 1 was 6.1% for ibuprofen/caffeine, 2.4% for ibuprofen, 2.9% for caffeine and 4.3% for placebo. Most patients experienced mild AEs, none had a serious AE. In the ibuprofen/caffeine group 3 subjects had a total of 3 AEs  reported AEs on preferred term (PT) level in Study Stage 1 were nausea  and vomiting .In Study Stage 2, the patients allocated to placebo and caffeine received either ibuprofen/caffeine or ibuprofen 3 tablets daily up to 5 days. The frequency of patients with any AE in Study Stage 2 was 21.6% for ibuprofen/caffeine and 13.3% for ibuprofen. The majority of patients were reported with AEs of mild or moderate severity, severe AEs occurred in 2 patients (0.7%) in both treatment arms. AEs considered as drug‐related by the investigator were experienced by 11 patients of the ibuprofen/caffeine arm (3.9%) and two patients of the ibuprofen arm (0.7%). In one patient of the ibuprofen arm (0.4%) and four patients of the ibuprofen/caffeine arm (1.4%) AEs resulted in the discontinuation of study drug. One patient receiving ibuprofen discontinued due to a serious adverse event (SAE) requiring hospitalization. The SAE  was considered to be not related to study drug intake; the patient recovered. None of the drug‐related AEs were considered to be serious and all patients recovered from all drug related AEs, except for one patient who was lost to follow‐up. All AEs leading to discontinuation that were reported in the ibuprofen/caffeine arm were non‐serious and of mild or moderate intensity.The most frequently reported (>1% in at least one treatment group) AEs on preferred term (PT) level in Study Stage 2 were nausea , aphthous stomatitis , vomiting , alveolar osteitis , dizziness , headache  and insomnia .3.8At the end of Study Stage 2, patients rated the tolerability of the study medication as ‘very good’  or ‘excellent’ . A comparison of ibuprofen versus ibuprofen/caffeine resulted in an odds ratio of 1.2, slightly in favour of the FDC.4This phase III, randomized, active‐ and placebo‐controlled, double‐blind study demonstrated superior efficacy of the FDC 400 mg ibuprofen and 100 mg caffeine over either single compound and placebo in the dental impaction model, which is validated, reproducible and predictable for treatments of acute pain in general. The results confirm recent meta‐analyses which have shown that 100–130 mg caffeine used as analgesic adjuvant for decades increases the responder rate of WHO stage I analgesics  was slightly longer for the FDC compared to ibuprofen. It can be speculated that this might have been induced by the relative fast recovery of the patients (as seen in the placebo and caffeine arm), which in this trial was faster compared to other published data , following previously published clinical studies using such endpoints and their analyses. In acute pain, baseline observation carried forward was described to be more conservative than last observation carried forward, which was considered relevant for trials longer than 8 h  and a lower proportion of patients who took an additional dose of analgesic within the observation period  and ketoprofen 100 mg provided total pain relief over 0–6 h in 71–79% of patients (etoricoxib) and >72% (ketoprofen)  AEs nausea, vomiting, insomnia and dizziness were expected and are known side effects of ibuprofen or caffeine. Also insomnia is a common side effect of caffeine intake and alveolar osteitis is a common sequel after third molar extraction. The patients rating of overall tolerability was similar under treatment with ibuprofen and ibuprofen/caffeine slightly favouring the FDC, however, in both groups about 70% of the patients rated the tolerability as ‘very good’ or ‘excellent’.In summary, this study demonstrated that the FDC 400 mg ibuprofen/100 mg caffeine is an effective treatment for acute pain and is well tolerated and safe when administered over a period of five consecutive days, with superior efficacy compared to 400 mg ibuprofen alone.T.W., E.R., A.H., D.D.M. and R.L. substantially contributed to study concept, design and results interpretation. The manuscript was drafted by T.W., E.R., A.H. and R.L. All authors critically revised the manuscript for important intellectual content and approved it.ClinicalTrials.gov Identifier: NCT01929031.Table S1. Demographics and baseline pain intensities in Study Stage 1 – treated set (TS).Click here for additional data file.Table S2. Pain relief at individual time points compared with ibuprofen/caffeine– FAS.Click here for additional data file.Table S3. Responder analysis for SPID0–6 h, FAS.Click here for additional data file.