Previous studies indicated that addition of the antihistaminic chlorpheniramine to the usual combination of acetylsalicylic acid, acetaminophen, and caffeine further increases their synergism both in terms of anti-inflammatory and analgesic effect. The present non-interventional study tested the superiority of two Algopirin® tablets, containing a total of 250 mg acetylsalicylic acid (ASA), 150 mg acetaminophen , 30 mg caffeine (CAF) and 4 mg chlorpheniramine (CLF) vs. a combination containing 250 mg ASA, 250 mg PAR, and 65 mg CAF recognized as “safe and effective” by FDA in treating migraine. Patients evaluated their pain intensity on the Visual Analog Scale—VAS(PI) before and 30, 60, 120, 180, and 240 min after drug intake. Interpretation of the pain curves as “survival pain curves” was considered as a method for direct comparison of the pain curves. This interpretation permitted the application of the log rank test for comparison of pain hazards. The results of the applied parametric and non-parametric statistical tests indicated significant differences between the main endpoints: both Areas Under Pain Curves and time to decrease of the pain intensity to less than 50% of the initial value comparisons highlighted that Algopirin® was more efficient in spite of smaller doses of PAR and CAF. Comparison of “survival of pain” led to the same conclusion concerning the superiority of Algopririn. Consequently, the addition of CLF permitted decreasing of ASA, PAR, and CAF doses as well as their potential side effects, without a loss of analgesic effect. Migraine is a high prevalence primary headache form, associated with a high socio-economic burden. The majority of people affected will treat their condition with medication. About 41% use prescription medications, either alone or in combination with over-the-counter (OTC) drugs  potentiated analgesic action of morphine and fentanyl Malec, . ClorpheAlthough CLF does not have antiinflammatory or analgesic effects, our studies highlighted, using the rat paw model and a clinical study a supplementary potentiation of the both anti-inflammatory  The study was conducted according to International Conference on Harmonization (ICH) Good Clinical Practices, to the Guidelines for Controlled Trials of Drugs in Migraine , were recruited by general practitioners or internal medicine specialists at the clinical facility. Diagnosis of headache was based on a structured questionnaire. The enrolled subjects fulfilled the criteria of the International Headache Society for episodic tension headaches and/or migraines with or without aura ., Male and female subjects, aged between 18 and 65 years , acetaminophen or caffeine containing drugs as well any other prescription or non-prescription analgesics. Patients receiving treatment with antidepressants or antipsychotics 1 month prior to the study, patients receiving anti-rheumatic or anti-inflammatory drugs in the last 4 days as well as the ones under ongoing treatment with anticoagulants were also excluded. Other exclusion criteria also included special physiological conditions , alcohol or drug abuse, hypersensitivity to ASA, acetaminophen or caffeine, different diseases .Headache lasting over 10 days/month or headache that left untreated lasts over 4 h as well as prolonged (over 10 days/month) analgesic treatment were also considered exclusion criteria.Excedrin®  was purchased from a community pharmacy, whereas Algopirin® was provided by LaborMed Pharma, Romania.During the first 4 h after study medication, no other drug intake was allowed. Rescue medication was allowed only 4 h after the administration of the study medication. Two hours before and after intake of the study medication, the patients were not allowed to drink coffee or caffeine containing beverages.The study was designed as an open-label trial, extension of a randomized, two-sequences, two periods double-blind cross-over non-inferiority study previously described  were called at the clinical site in case of a new migraine episode and received two Algopirin® tablets, containing a total of 250 mg ASA, 150 mg PAR, 30 mg CAF and 4 mg CLF.From the 46 patients who received one tablet of Excedrin® in the non-inferiority study, 24 came to the extension phase, receiving two tablets of Algopirin®.Pain Intensity was measured on a horizontal 100-mm Visual Analog Pain Intensity Scale [VAS(PI)] scale labeled: No Pain (0 mm) as the left anchor and Worst Pain Imaginable (100 mm) as the right anchor. During the screening visit, the investigator gave to all study participants a standardized explanation on how to record the VAS (PI) score, using a written explanatory text.Patients were required to record in a headache diary the date and time of drug administration, baseline (immediately before treatment) pain intensity on the VAS (PI) scale, and pain intensity after treatment recorded at 30, 60, 120, 180, and 240 min, if the pain persisted 4 h after the administration of the study medication, if rescue medication was used (the drug and dose).Clinically, with no absolute reference standard for pain measurement, individuals vary in the subjective rating of the pain intensity they indicate on the VAS (PI) scale. Thus, the actual value of the VAS (PI) score has no intrinsic meaning from a clinical perspective. Two different approaches were used in order to account for the differences in baseline pain intensity among patients. The first one was to normalize VAS (PI) scores, by expressing the values at intermediate time points as percent of the pain score taken at the predose baseline (considered as 100%). The second method, more common in literature . The parameter was estimated as time corresponding to intersection of the 50% gridline of pain intensity curves, and its value was calculated for each subject by linear interpolation between adjacent observation time points.The primary endpoint of the trial was time to 50% pain relief (T20) and to 10% (Time to 90% pain relief -T10) on the VAS(PI) scale, as well as the percentage of patients with at least 50% pain relief after 1 h and percentage of patients pain free 4 h after treatment were considered.As secondary endpoints, time until reduction of pain intensity to 20%  is a natural global parameter useful in comparison of curves. For instance, area under plasma levels curves of active substances is the most significant parameter in defining bioavailability of a drug. Different statistical methods are used in order to assess AUC, of which the most common is the trapezoid rule:f(ti−1) and f(ti) correspond to consecutive measurement time points. For the present study, by assimilating the time course of pain score with a “pain curve,” the Area Under Pain Curve (AUPC) can be evaluated and used as comparison tool.where AUPC was calculated using a similar formula:ti) and PI(ti−1) correspond to two pain intensity measurements at consecutive time points, expressed as normalized VAS(PI) scores.where PI can be obtained  software.For continuous variables, descriptive statistics  were calculated. In order to apply the parametrical tests, the normal distribution of the results was verified both visual and using D'Agostino-Pearson normality test.50, T20, T10, AUPC0−2h, AUPC0−4h, SPID0−2h, SPID0−4h) were performed using Student's T-test. When only testing the superiority hypothesis one-tailed T-test was applied, whereas for general comparison purposes two-tailed T-test was used. The results were considered statistically significant when P-values were < 0.05.Statistical comparisons of different numerical data sets  for categorical variables.Comparisons using Chi-square test were performed  evaluation , gender repartition , weight , body mass index , as well as clinical aspects: number of migraine episodes in the last month , and mean pain intensity of the untreated migraine expressed as VAS(PI) score .Details on the demographic characteristics of patients enrolled in the study are presented in Table P > 0.5)  Table .The visual analysis of the entire set of individual curves Figure  allowed The global evaluation of the clusters of pain curves revealed a shifting toward lower VAS(PI) score values in case of the Algopirin® treatment in comparison with the Excedrin® treatment. In the Excedrin® cluster most of the pain curves are placed in the middle and lower region of the graph, whereas in the Algopirin® cluster the highest density of curves is in the lower part of the scale. Therefore, at a direct visual analysis, it appears that Algopirin® is more effective in reducing pain.The mean pain curves for Algopirin®, and Excedrin® respectively, calculated based on normalized individual VAS(PI) data are depicted in Figure 50 distribution clearly appears bimodal, phenomenon absent in the case of Algopirin®. A possible explanation for the obtained could be the occurrence of some allergic reactions after Excedrin® treatment, which were countered by the clorpheniramine component of Algopirin®.For the Excedrin® set, T50 was 30 min for Algopirin® and 45 min for Excedrin®  was calculated by linear interpolation or extrapolation and the mean experimental values were found to be 180 min for Algopirin® and 240 min for Excedrin® respectively.Time to 90% pain relief (T20) was considered as alternative to T10. In the present study, T20 was 80 min for Algopirin® and 130 min for Excedrin®, suggesting that Algopirin® is more efficient than Excedrin®  and patients receiving Algopirin® (n = 24), and the other one taking into consideration only the patients receiving both treatments (n = 24).Two different types of comparisons between treatments were performed: one comparison between all the patients who received Excedrin®  AUPC values at 2 h, respectively at 4 h were calculated . Converting in percentages of the maximum possible value  was attempted. A technical problem in calculating this parameter is the calculation of the extrapolated area from the last measured point to infinity. This extrapolation is common in pharmacokinetics, based on the observation that, on the terminal elimination phase data points follow an exponential decay. Applicability of this method for the present study can be verified simply by logarithmic scale representation of the pain score data. If the terminal phase data can be fitted by a linear regression with slope k, monoexponential decay can be considered, and the extrapolated area will consequently be:Since it is common to discuss about time to total pain relief (TOTPAR), an extrapolation of the pain intensity curves in order to compute the total AUPC .Each individual pain curve can be reduced to a series of points, corresponding to the VAS(PI) scores measured at each of the measuring times. In the timeframe between two consecutive measuring times, some of the points may disappear, following the effect of drug or a physiological evolution independent of drug. Therefore, it is possible to associate the disappearance of some points due to the two above mechanisms  and death of the patients in the classical survival analysis. Hence, it is suitable to treat the pain curves by means of the survival analysis, and to apply the Cox-Mantel method for comparison of means of “pain survival curves” and, if differences are the same at all measuring times the sum For the explanation of the symbols used see also the An estimation of the ratios of hazard functions and the confidence interval for it will be: The results for the present study are presented in Figure where 2 = χ2 = 2, 71 and the obtained value is greater than the threshold, the conclusion is that the pain curves are significantly different and the analgesic effect of two Algopirin® tablets is superior to the effect of one Excedrin® tablet (p < 0.001).Since decision threshold is χik, could be described by Weibull distribution in the form:Weibull model is one of the most general model in science, being applicable to processes running in several steps with constant rate of transfer Weibull, . In casenik(t)/100)vs. ln t describes a linear dependency, we can conclude that Weibull model is applicable.Consequently, if ln ; central analgesia (PAR); local antihistaminic and decongestant effect (the antihistaminic component); decreased vascular permeability and increased peripheral vascular tone, both leading to inflammation decrease through central mechanism (CAF)—the composition acts at different functional levels and through different ways. This complex action represents the complex pharmacodynamic background of the four associated components potentiating synergism.In other words, while the literature presents mostly cases of synergism by addition , our compositions present a pharmacodynamic potentiation synergism, where the sum of the combined results is higher than the sum of the results of each ingredient taken individually. This is possible following the action of each ingredient through different mechanisms and different targets, allowing the incentive obtained result, that is: the smaller dose with the lower side effects, and better tolerability.Different clinical trial data reports that the acetaminophen, acetylsalicylic acid and caffeine combinations are generally well-tolerated  is preferable to the usual SPID parameter, being more sensitive in detecting the global difference between pain curves. Supplementary, the concept permits an analogy with areas under plasma levels of active compounds which are responsible for the therapeutic effect.Interpretation of pain curves as “survival pain curves” brings a new approach in the methods of statistical analysis of the pain phenomenon, allowing application of more sophisticated methods from cancer analysis. Since no pain comparison method can be considered a “gold standard”, these approaches, in conjunction with the conventional ones, offer a mosaic of complementary methods in quantification and comparison of therapeutic effects.The results were practically similar whatever the applied statistical test: two tablets of Algopirin® were more efficient than one tablet of Excedrin®. Addition of CLF increased the analgesic effect of ASA-PAR-CAF combination. Therefore, Algopirin®, in spite of lower doses of ASA, PAR and CAF has a greater analgesic effect and potentially lower adverse effects than the ASA-PAR-CAF alone.VV was the Principal Investigator of the clinical trial and coordinated the entire Algopirin® project, IM, BV, VA, and CP performed pharmacological and clinical experiments, RS and CM performed the mathematical and statistical analysis of the data, CM and VA prepared the manuscript. All authors approved the manuscript.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.


Since few studies have characterized painful diabetic peripheral neuropathy (pDPN) symptoms in multicultural populations, this study fielded a survey to better understand pDPN and its impact in African-American, Caucasian, and Hispanic populations.Kelton fielded a survey by phone or Internet, in English or Spanish, among adults with pDPN symptoms in the United States between August and October 2015; African-Americans and Hispanics were oversampled to achieve at least 500 subjects for each group. Patients were required to have been diagnosed with pDPN or score ≥ 3 on ID Pain validated screening tool. The survey elicited information on pDPN symptoms and interactions with healthcare providers (HCPs), and included the Brief Pain Inventory and pain-specific Work Productivity and Assessment Questionnaire (WPAI:SHP).p < 0.05). African-Americans and Hispanics were less likely than Caucasians to report experiencing specific pDPN sensory symptoms. Significantly fewer African-Americans and Hispanics reported receiving a pDPN diagnosis relative to Caucasians (p < 0.05), and higher proportions of African-Americans and Hispanics reported difficulty communicating with their HCP (p < 0.05). WPAI:SHP activity impairment was lower in Hispanics (43%) relative to African-Americans (53%) and Caucasian .Respondents included 823 Caucasians, 525 African-Americans, and 537 Hispanics; approximately half of African-Americans and Hispanics were <40 years of age, vs 12% of Caucasians. Pain was less likely to be rated moderate or severe by African-Americans (65%) and Hispanics (49%) relative to Caucasians  contains supplementary material, which is available to authorized users. Diabetic peripheral neuropathy (DPN) is a common complication of Type 1 and Type 2 diabetes that is characterized by nerve damage. When DPN presents with painful symptoms the condition is known as painful diabetic peripheral neuropathy (pDPN). While the epidemiology of pDPN has not been well-characterized, an overall prevalence of 15% has been estimated in the diabetic population , and a sThe substantial patient and economic burdens associated with pDPN are well-recognized and include reductions in patient function, quality of life, and productivity , 6, as wDespite studies evaluating quality of life and other patient-reported outcomes in pDPN, there are limited data on the severity and impact of painful pDPN symptoms from the patient’s perspective. A survey in patients and clinicians who treat patients with diabetes not only showed that misperceptions on the cause and management of pDPN were common in both stakeholder groups but also indicated additional disparities between patient and clinician perspectives regarding communication, severity, and treatment . Howeverand either self-reported having received a diagnosis of pDPN by an HCP or had a score ≥ 3 on ID Pain [Kelton fielded a survey among pDPN patients in the United States between August and October 2015. For inclusion, patients were required to be adults (≥ 18 years old) who self-reported being diagnosed with either Type 1 or Type 2 diabetes  ID Pain    and the t-tests, respectively. The impact of ethnicity was explored based on the combined main sample and oversample and controlled for effects of age, education, and household income using layered cross-tabulations (chi-square tests) and stepwise linear regression [Survey results reflect an unweighted sample. The margin of error was ±3.1% for the total patient sample and 4.0% for the oversampled groups. Analyses for categorical data and continuous data were conducted using chi-square tests and gression . The croStepwise linear regression was also performed among the main sample, using pain severity as the dependent variable and 10 items related to the patients’ experience with symptoms as independent variables . All analyses were performed using IBM® SPSS® Statistics 23.p < 0.05) among Caucasians than African-Americans and Hispanics, and differences were also observed in the age distribution. Almost half of the African-Americans (49%) and more than half of the Hispanics (59%) were under 40 years of age, compared with only 12% of Caucasians. Caucasians had the lowest rate of employment and the highest rate of retirees among the three cultural groups, and annual income was highest in Hispanics, lowest among Caucasians. Consistent with the older demographic, a significantly greater proportion of Caucasians relative to the other groups had health insurance through Medicare, and a significantly lower proportion were uninsured (both p < 0.05) (Table Table p < 0.05), the medians were similar across ethnicities, 8 years, 8 years, and 9 years, respectively.While mean time since diabetes diagnosis was slightly but significantly higher among Caucasians (10.9 years) relative to African-Americans (9.4 years) and Hispanics (9.4 years) (both p < 0.05); shooting pain, which was significant for 11 strata p < 0.05); and electric shock pain (p < 0.05: for 9 strata) (Table p < 0.05) by ethnicity were limited for pain and discomfort at night (only 4 strata showed a significant effect of ethnicity), and burning pain and sensitivity to touch (each with 6 strata that showed an ethnicity effect).African-American and Hispanic patients were less likely than Caucasians to experience a range of sensory symptoms Fig.  that area) Table . Howeverexplained variance in overall pain scores. The second strongest predictor was shooting pain (17%), followed by electric shock-like pain (10%). The overall model was significant (p < 0.05), with R2 = 0.29 and F = 59.077.A stepwise regression analysis with average pain severity in the past year as dependent variable and the 10 pain symptoms as independent variables showed that sensitivity to touch is the strongest predictor of pain, being responsible for 20% of the total p < 0.05)  and Hispanics (4.7) relative to Caucasians (5.8), the differences were not significant Fig. . However05) Fig. . This fip < 0.05) . Similar patterns were observed when stratified by pain severity; consistently and significantly higher proportions of Caucasians reported a pDPN diagnosis relative to the other two populations across severity levels , and Hispanics generally reported the lowest rate of diagnosis, although the differences were not significant vs African-Americans.The proportion of Caucasians who reported receiving a diagnosis of pDPN (87%) was significantly higher than that of African-Americans (51%) and Hispanics 36%)   Fig. . Additio05) Fig. , as indip < 0.05). Activity impairment was significantly (p < 0.05) higher among Caucasians (56%) relative to African-Americans (53%) and Hispanics (43%) (Fig. Overall work impairment due to pain was substantial among employed patients in the three populations Fig. . While CThis study suggests not only that there are significant disparities across cultural groups in their interaction with HCPs regarding pDPN and its symptoms, but that presentation of pDPN itself is also significantly different across these groups, with lower pain severity and fewer number of pDPN symptoms reported among African-Americans and Hispanics relative to Caucasians. In particular, among the types of symptoms, only for pins and needles was there concordance among all three cultural groups for the percentage of patients reporting this symptom. For the other symptoms, the percent of patients reporting the symptoms was generally lowest among Hispanics and highest among Caucasians.While it has previously been reported that there are differences in how ethnic groups perceive and report types and severity of experimental pain , 15, whiThe robustness of these results was demonstrated by additional analyses that adjusted for demographic and socioeconomic factors, since age, education level, and income may be potential confounding factors that contribute to pain perceptions or HCP interactions. These additional analyses suggest that regardless of socioeconomic status, ethnicity is a general factor in how symptoms associated with pDPN are manifested or perceived.Additionally, and of potential greater clinical relevance, was the large proportion of African-American and Hispanic populations who were <40 years of age. While it is well-recognized that diabetes disproportionally affects African-Americans and Hispanics , to our The differences in symptoms and severity were paralleled by the impact of pain on daily activities on the WPAI:SHP reported by the three populations; the least impairment was consistently reported by Hispanics, and this was significant for Activity impairment vs both other populations, and for Presenteeism vs Caucasians. It should again be noted that the WPAI:SHP responses on work productivity were obtained only from employed respondents, while the activity impairment question was answered by all respondents and was limited to activities other than employment. These observations on the WPAI:SHP are consistent with a recent review suggesting lower rates of activity limitation among Hispanics with pain relative to other cultural groups despite greater pain sensitivity . Among tDespite the presence of these symptoms and pain of moderate or severe severity in substantial proportions of African-Americans and Hispanics, fewer of these patients reported receiving a pDPN diagnosis than Caucasians. This lower rate of diagnosis may potentially be due, at least in part, to the observations related to interactions of these populations with their HCPs: Fewer African-American and Hispanic patients reported discussing their pain symptoms with their HCP, and there was consistently less comfort with their HCPs in these groups.These interactions with HCPs are consistent with the disparities in healthcare resource availability and use that have been reported among minority populations and that contribute to the challenge of diagnosis and management of these patients . In partAs with any survey dependent upon respondents, an important limitation is potential selection bias, since patients who agreed to participate may have characteristics and perceptions different from those who refused. A related limitation is that the patient-level data on diagnosis, pain, and symptoms were based on self-report and, as such, may be subject to misunderstanding or misinterpretation of the questions that may result, at least in part, from cultural differences across the populations.It should also be noted that this study did not capture other factors that may have contributed to patients’ perceptions of their pain experience, such as mood, negative emotions and thoughts, poor pain control, or construals. These factors, as well as others not collected, could be a potential missing source of information that may have contributed to how subjects reported their painful symptoms or interactions with their HCPs, and warrant further evaluation in future studies.While use of both internet and phone as survey modalities could be criticized, such a design was necessary to reach the target populations, and the inability to disentangle the administration modality from the results across the populations represents another limitation. Lastly, the survey results reflect an unweighted sample, and thus may not necessarily be reflective or representative of the entire general population in the United States. However, the findings provide directional insights that can be used to optimize patient care.Significant differences in patient experiences of pDPN symptoms and pain severity were reported across cultural groups including African-Americans, Hispanics, and Caucasians; African-Americans and Hispanics were less likely to experience the same sensations as Caucasian patients and reported lower pain ratings. Further evaluation is needed to determine what may account for these observed differences. Differential rates of pDPN diagnosis and comfort levels with HCPs were also reported in this multicultural population, with the differences providing support for barriers that contribute to disparities in healthcare among specific populations.These results suggest a need to broaden pDPN educational initiatives among both patients and clinicians. While patient intiatives should especially target multicultural populations, the goals of clinician initiatives should be to increase attention that symptoms may differ among individuals with different cultural backgrounds and to improve patient-HCP dialogue by encouraging discussion of pDPN symptoms and their impact in multicultural settings.


Approximately 80% of patients presenting to emergency departments (ED) with chest pain do not have any true cardiopulmonary emergency such as acute coronary syndrome (ACS). However, psychological contributors such as anxiety are thought to be present in up to 58%, but often remain undiagnosed leading to chronic chest pain and ED recidivism.To evaluate ED provider beliefs and their usual practices regarding the approach and disposition of patients with low risk chest pain associated with anxiety, we constructed a 22-item survey using a modified Delphi technique. The survey was administered to a convenience sample of ED providers attending the 2016 American College of Emergency Physicians Scientific Assembly in Las Vegas.p = 0.015). Most providers (82%) indicated that they wanted to have referral resources available to a specific clinic for further outpatient evaluation.Surveys were completed by 409 emergency medicine providers from 46 states and 7 countries with a wide range of years of experience and primary practice environment (academic versus community centers). Respondents estimated that 30% of patients presenting to the ED with chest pain thought to be low risk for ACS have anxiety or panic as the primary cause but they directly communicate this belief to only 42% of these patients and provide discharge instructions to 48%. Only 39% of respondents reported adequate hospital resources to ensure follow-up. Community-based providers reported more adequate follow-up for these patients than their academic center colleagues  contains supplementary material, which is available to authorized users. Chest pain is one of the most common chief complaints evaluated in the Emergency Department (ED), accounting for approximately 20% of all annual ED visits nationwide . A smallWe sought to evaluate ED provider beliefs regarding patients with low risk chest pain thought to be secondary to anxiety symptoms. Further, we wanted to evaluate if there was a discrepancy between these beliefs and their management practices.This work was a hypothesis generating survey, conducted in accordance with guidelines by Mello et al., including both expert consensus and a modified Delphi technique , 6. ThisThe survey was then administered to a convenience sample of Emergency Medicine (EM) providers visiting the exhibitor hall at the 2016 American College of Emergency Physicians Scientific Assembly (ACEP16) in Las Vegas, Nevada from October 16–19, 2016. This forum was chosen because it represents the largest annual gathering of EM providers . EligiblParticipants first viewed a description and purpose of the survey prior to starting, and then completed the survey using either a laptop computer or electronic tablet. Study data were collected and managed using REDCap electronic data capture tools hosted at Indiana University . ExporteFour-hundred-and-nine surveys were completed, representing approximately 5% of ACEP16 conference attendees. There was diversity in respondent geographic location  or 1–2% (44%) with only 4% of respondents willing to accept an ACS miss rate of 3–5% illustrated in Fig. % or 1–2%Thirty-nine percent 161/407) of respondents reported adequate hospital resources to ensure follow-up for patients with low risk chest pain they suspect is secondary to anxiety. Community-based providers reported more adequate follow-up for these patients than their academic center colleagues , Additional file 2.Table S1. Hypothetical Patient Scenario. Responses to questions regarding a hypothetical presentation of a patient with chest pain and suspected anxiety or panic. (DOC 224 kb)


Ongoing pain after surgery is a major problem and influences recovery and the quality of life of the patient. Associations between anxiety and their impact on postoperative pain after herniated disc surgery have been reported, but the results are inconsistent. The aim of the present longitudinal study was to evaluate the predictive value of preoperative anxiety for postoperative ongoing pain and prolonged analgesic intake after herniated disc surgery.106 patients with lumbar disc herniation were evaluated in the study. Anxiety was measured with the Generalized Anxiety Disorder 7-Item Scale (GAD-7) before surgery. Pain intensity was assessed on a numeric rating scale (NRS) at baseline, 6-weeks and 6-months after surgery. Regression analysis was performed to identify independent predictors of pain and regular utilization of analgesics up to 6 months after surgery while controlling for confounding variables.p < 0.001). With binary logistic regression analyses, preoperative pain intensity, but neither demographic factors nor preoperative anxiety, was identified as predictor for postoperative pain and need for analgesic medication up to 6 months after lumbar disc surgery.42.5% of the patients were rated as anxiety cases (sum scores GAD-7 > 5), mean scores of anxiety showed mild to moderate symptom severity, and 43% suffered from chronic pain before surgery. Six months after surgery, 55.6% of the patients indicated pain levels of 4/10 (NRS) or higher and about 40% still took pain medication on a regular basis, regardless of their preoperative classification as anxiety-case (37.7% and 41.5%). The preoperative pain level was statistically significant for ongoing postsurgical pain in all four analyses  contains supplementary material, which is available to authorized users. Low back pain is a common medical condition, often recurring, and a major cause for sick leave and activity limitation . In mostAssociations between psychological factors such as anxiety and depression and musculoskeletal disorders and their impact on postoperative results after herniated disc surgery have been reported –13. In aThe aim of the present longitudinal study was to investigate the role of preoperative anxiety as a potential influencing factor for postoperative ongoing pain and predictor for prolonged analgesic intake after herniated disc surgery.clinicaltrials.gov (Identifier: NCT01488617) before patient enrolment. All patients gave their written informed consent.This single center cohort study was conducted at the Department of Anesthesiology of the University Medical Center of the Johannes Gutenberg University Mainz, Germany. Data were extracted from a data set evaluating the influence of psychological variables on pain-related outcome after major neurological (spine), orthopaedic (hip or knee) or urological surgery (Mainz Outcome Predictor Study). Ethical approval for this study [Ethical Committee N° 837.519.11 (8061)] was provided on 3rd January 2012 by the Regional Ethics Committee of Rhineland-Palatinate, Mainz, Germany. The study was registered in Data of 143 patients undergoing spine surgery were evaluated , 6-weeks after surgery, and 6-months after surgery. At baseline, all patients provided demographic, anxiety, clinical, and pain data. Pain data were additionally collected 6-weeks and 6-months after surgery and data on analgesic intake 6-months after surgery. Demographic data included age, gender, marital status, and education level. Clinical data included body mass index (BMI), physical status, and duration of surgery.Demographic data were collected with a questionnaire. Anxiety was assessed with the Generalized Anxiety Disorder 7-Item Scale GAD-7  and relative frequencies (%) for categorical parameters and means and SD for continuous parameters. Pain was additionally described by one bar chart per measurement time point.The association between preoperative anxiety (independent variable) and postoperative pain intensity during movement (dependent variable) was analyzed graphically and in four linear regression models.Graphical analysis included medians and interquartile ranges by presence versus absence of preoperative anxiety on the GAD-7 . ParticiThe association between preoperative anxiety (independent variable) and 6-months postoperative analgesic intake (dependent variable) was analyzed graphically and in two binary logistic regression models. Graphical analysis included bar charts of analgesic consumption by presence versus absence of preoperative anxiety as defined above. One regression model of postoperative analgesic intake by preoperative anxiety was performed for binary and for continuous anxiety, respectively. Transformations of continuous anxiety and adjustment for potential confounders were performed as described above.P-values < 0.05 were considered statistically significant.All analyses were performed using IBM SPSS Statistics for Windows, Version 22 . Start of enrolment of patients was in January 2012. Of 199 eligible patients, 156 patients underwent spine surgery , and 51 (48.1%) were female  suffered from chronic pain prior to surgery, which was defined as pain lasting for at least 6 months. Generally, patients’ mean pain ratings before surgery were higher than postoperatively. Mean NRS scores preoperatively were 6.8 (SD 2.6), and decreased to 2.9 (SD 2.4) 6-weeks after surgery. After 6 months, the mean NRS score was 3.7 (SD 2.7). While only five patients (4.7%) reported absence of preoperative movement pain, 23 patients (21.7%) indicated to be pain-free during movement after 6-weeks and 21 patients (19.8%) after 6-months .6-weeks after surgery, data concerning pain medication were obtained from 101 patients. 40 (39.6%) of the patients reported a regular use of pain medication, 10 (9.9%) still took opioids. At 6-months 37 patients (39.4%) reported to take pain medication on a regular basis, and 9 (9.6%) took opioids, respectively .However, preoperative pain levels were statistically significant for ongoing postsurgical pain in all four analyses  indicated preoperatively  [p > 0.2) in a small sample of 53 patients [The role of psychological factors such as anxiety, depression or catastrophizing for the outcome of patients  undergoing herniated disc surgery is considered as relevant, as shown in several review articles , 13, 24.< .0001) . Howeverpatients .Although we identified a considerable percentage of patients experiencing anxiety , the presence of anxiety prior to surgery does not represent a valid prognostic factor for persistent pain and analgesic intake 6 weeks or 6 months after nucleotomy due to herniated lumbar disc.These conflicting results may be due to small sample sizes in all three studies, including ours, differences in socio-demographic patient characteristics, duration of follow-up and instruments to measure preoperative anxiety. Questionnaires to assess anxiety differ with regards to their sensitivity and specificity to measure state or trait anxiety. Compared to other self-assessment instruments such as APAIS  or STAI Our results also suggest that a higher BMI is predictive for increased postoperative pain 6-months after lumbar disc surgery. However, in two retrospective cohort studies of patients undergoing lumbar spine surgery, obesity was associated with higher complication rates, but body mass index did not have an effect on the pain-related clinical outcome , 28. DifWhile we found no influence of demographic factors such as female gender and younger age as risk factors for persistent postoperative pain, their effect was inconsistent in other studies , 30. In In the present study we could demonstrate that preoperative pain was the strongest predictor for persistent postoperative pain. Although the majority of our patients indicated a decrease in pain of about 3 points on a NRS after surgery, the benefit was significantly lower in patients with a higher preoperative pain level. The fact that stronger preoperative pain is associated with increased postsurgical pain is supported in a review article by Kehlet et al. .Prediction of the severity of early postoperative pain with a combined scoring system, based on age, sex, type of surgery, extent of preoperative pain, and level of anxiety has been proposed by Kalkman et al. . HoweverDespite overall pain reduction in the entire sample 6-months after surgery more than half of the patients (55.6%) still reported pain levels above 4/10 NRS 6 months postoperatively. Furthermore, we found that 30% of all patients still reported the intake of non-opioid analgesics 6 months after surgery, and additional 10% even indicated the intake of opioids. These aspects show that the analysis of factors contributing to the development and the persistence of pain symptoms to weigh up the potential benefit of a surgical intervention against a conservative therapeutic approach should be considered before decision-making for surgery. In addition, it is important to identify and treat psychological comorbidities related to the genesis of ongoing pain. A better identification of patients at risk to develop chronic postoperative pain would be helpful to find preventive approaches, including e.g. preemptive multimodal analgesia or psychological therapeutic attempts, e.g. behavior therapy.The major limitation of the present study is lack of power for the secondary outcome , while the power was sufficient for the primary outcome (pain). Thus, the large association between preoperative anxiety and medication use at follow-up was not statistically significant. A further limitation is the lack of information on pain-related patient disability beyond 6-months of follow-up, as well as an associated interference with daily life activities and work. A longer follow-up period would have been helpful to better adjust for clinical risk factors of postoperative pain and to assess their impact on disability and return to work.In conclusion, in patients with nucleotomy due to lumbar disc herniation the intensity of the preoperative pain was identified as an influencing factor for the persistence of postoperative pain up to 6 months after surgery. The influence of preoperative anxiety, measured with the GAD-7, on postoperative pain and analgesic intake during the first 6-months after disc surgery could not be confirmed in this relatively small sample of patients. Considering the number of patients without benefit in terms of long-lasting pain relief after disc surgery, further research on psychological prognostic factors is needed.Additional file 1:Attachtment A GAD-7. (DOC 24 kb)


Methods. 25 patients with type 2 diabetes (13 F and 12 M) were admitted in the study. The evaluation of the analgesic efficacy of tapentadol PR was based on both the assessment of the intensity of the pain  and the nature of the pain (DN4 questionnaire) and on assessment of the patient's quality of life and state of health . Study duration was 3 months: a baseline visit and follow-up included visits after 1 week, 1 month, 2 months, and 3 months. Results. At the beginning of the study, the mean intensity of the pain was 7.88 ± 1.17 on the NRS scale and at visit 2 it reduced in a statistically significant way; at the end of the treatment with tapentadol PR, the mean intensity was 2.84 points on the NRS scale. Conclusion. In type 2 diabetic patients with chronic severe pain due to PAD, tapentadol PR reduced pain intensity, improving the quality of life.This study has been performed in diabetic type 2 patients with pain due to peripheral artery disease (PAD) in order to evaluate the efficacy and tolerability of tapentadol prolonged release (PR).  According to WHO definition, diabetes mellitus is a chronic disease that appears when a deficit in the secretion of insulin by the pancreatic cells or an insulin resistance occurs . In 2035According to the International Diabetic Foot study group, a diabetic foot is defined as a foot with anatomical-functional alterations caused by peripheral artery disease (PAD) and/or distal symmetrical neuropathy.Neuropathy and arteriopathy often appear in the same patient and are capable of generating not only a significant worsening of the patient's prognosis and quality of life but also chronic complex pain –5.Diabetic neuropathy is frequent and affects up to 50% of patients with types 1 and 2 diabetes , 4; it iDiabetic PAD affects medium and small arteries , with relatively less involvement of the aorto-iliac arteries than in atherosclerotic arteriopathies .Clinically, a pain presented during the march is less prevalent than in nondiabetic patients due to the possible simultaneous presence of polyneuropathy, so it is not rare that the first clinical manifestation of the disease is skin ulceration .The pain that accompanies arteriopathy is often intense, with a complex pathogenesis, due to the presence of both a nociceptive and a neuropathic component, initially triggered by walking and then also present at rest, as the vascular damage progresses –9.μ receptor agonism (MOR), synergic with a noradrenergic action due to the inhibition of noradrenalin reuptake  )This is the first published information collected on a group of patients with a severe complication of diabetes mellitus such as PAD; in fact, to date, the analgesic efficacy of tapentadol PR has been demonstrated in diabetic polyneuropathic pain ; in partHowever, it is noteworthy that the sample examined is limited and it will be important to confirm these preliminary data in a greater number of diabetic patients. Moreover, the duration of treatment is quite short and can certainly be prolonged in order to verify the efficacy of the treatment in a longer period of time. The analgesic role of tapentadol PR was evaluated in patients treated with other drugs for other pathologies, and, as an observational study, we did not modify the concomitant therapy. The variable of concurrent therapies should therefore be considered in the interpretation of the results.These preliminary data seem to demonstrate the efficacy of tapentadol PR in the treatment of ischaemic pain and not just of neuropathic pain. However, this result needs to be confirmed in a larger sample of diabetic patients who would need to be observed for a longer period of time.Moreover, in our patients, tapentadol PR seems to be well tolerated and no adverse events have been reported, thus making this drug particularly interesting in the treatment not only of neuropathic pain but also of ischaemic pain.


Si guan xue (the four points) have been widely used in clinical practice, and has shown that it is highly effective, effective in obtaining qi, shows strong acupuncture stimulation, and is simple to manipulate and safe to use. Therefore, the aim of this study is to test the protocol and safety of acupuncture at the si guan xue in the management of cancer pain.Pain is a common symptom in cancer patients. Acupuncture is a suggested treatment for a wide range of clinical conditions, usually for its beneficial effects on pain control. si guan xue arm, n = 14), treatment arm 2  and the control arm (the commonly used acupoints arm n = 14). Primary outcomes included acupuncture relieving cancer pain, and patients’ subjective improvement as measured by the Patient Global Impression of Change (PGIC). Secondary outcomes included the scores of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and Karnofsky’s Performance Status (KPS).This is a single-blind, randomized controlled pilot trial. 42 patients with moderate to severe cancer pain were randomly assigned to three different arms with seven sessions of treatment; that is, treatment arm 1 (the P<0.05). There was no difference in the scores of PGIC, EORTC QLQ-C30 or KPS among the three groups (P>0.05). Furthermore, no serious adverse events were observed.The analysis showed that the cancer pain reduction in treatment arm 2 was most prominent on day 5 when compared with the control arm  Cancer is one of the world’s leading causes of death. According to recent reports, 12.7 million people diagnosed with cancer in 2008, and 7.6 million people died of it, accounting for 13% of all the deaths. It has been predicted that the total number of cancer deaths worldwide will increase from 13% in 2007 to 45% in 2030. For newly developed countries, the number is expected to increase from 11.3 million in 2007 to 15.5 million in 2030 [Pain is a common cancer symptom. According to the World Health Organization (WHO) in 1995, there are 24.6 million cancer patients worldwide, 20% to 30% of whom suffer from various levels of pain. Although the three-step analgesic ladder of the WHO has been widely used, there is still a paucity of effective pain controls for many cancer patients, especially those in advanced stages of the disease. Many of these patients need to use analgesics such as opioids which act on the central nervous system. However, they may cause serious side effects, including nausea, vomiting, constipation, dryness of mouth, urinary retention, sleep disturbance, confusion, hallucinations, or even respiratory distress. They can give rise to intolerance among patients and coping difficulty for their families [Acupuncture is recommended for a wide range of clinical conditions. In particular, it has beneficial effects on pain control, and more importantly is safe to use. The benefits of acupuncture include rapid onset of analgesic effect, long sustained remission, ease of application, no risk of drug dependence or addiction, and by and large the absence of serious side effects .Si guan xue is a unique combination of acupoints for acupuncture. It was first described in the "Twelve of the original nine-pin, Lingshu." It pointed out that "there are five zang and six fu. The six fu come from twelve original fu. The original twelve come from the si (four) guan. The si guan treat the five zang." Then Yang Jizhou, a famous Chinese Medicine Practitioner of the Ming Dynasty added that, "the si guan are Taichong (LR3) and Hegu (LI4)" [yin and yang, zang and fu, superior and inferior parts of the human body, and the qi and blood, and thus complementing each other. The si guan xue are widely used clinically. They have high treatment efficacy, easily get to the qi, are simple to manipulate, and safe to use [si guan xue in the management of cancer pain and informing the protocol for a larger study.u (LI4)" . The come to use , 7. TheiA pilot randomized clinical trial was conducted in the Department of Oncology at the First Affiliated Hospital of Guangzhou University of Chinese Medicine and at the OncWell Integrated Cancer Centre in Hong Kong. The trial lasted from May 2012 to February 2014. The study protocol was approved by the Ethics Committee of Hong Kong East Cluster (Reference no.: HKEC-2012-024) before the start of the study. The reporting of the study complied with the requirements of the CONSORT 2010 statement .Patients who fulfilled the following criteria were recruited into this study: (1) having advanced cancer with cancer pain as the chief complaint; (2) no chemotherapy or radiotherapy within one month before the study; (3) men or women aged 18 years or above; (4) levels of conscious to the extent that he/she could evaluate and report on their pain; (5) life expectancy of three months or above; and (6) capability of giving informed consent. Those with the following conditions were excluded: (1) pain was unrelated to cancer; (2) inability to report his/her pain accurately; (3) mental illness or lack capacity; (4) children or pregnant/lactating women; (5) other serious diseases; (6) unwillingness to cooperate or give informed consent –13.A computer program was used to randomize the participants . The stuThe Chinese Medicine style of acupuncture was used. Acupuncture was conducted by two qualified Chinese Medicine Practitioners with nine and twelve years of experience in clinical practice, and three and ten years of acupuncture experience respectively. Both have bachelor’s and master’s degrees in Chinese Medicine related fields (one of whose master’s degrees is in acupuncture), and are well trained in acupuncture. A course of acupuncture with seven treatment sessions, delivered either daily or on alternating days, was given to the patients in the three arms. The standards of the study complied with the requirements of the Checklist for items in the Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) 2010 .qi and blood, ying and yang, zang fu etc., whereas the latter implies a surplus of qi and blood. The normal circulation of qi and blood in the meridians requires warming by yang, moisturizing by yin, promotion by qi and the nourishment by blood. Deficiency of these elements leads to the malnutrition of zang fu, and then the pain. Deficiency is more prominent in advanced cancer patients [si guan xue have been considered to have an important effect on communicating the yin and yang, zang and fu, superior and inferior parts of the human body, as well as the qi and blood. They thus complement each other. Hence, we hypothesized that si guan xue would enhance the treatment effects of the commonly used acupoints.The design of our acupuncture treatment protocol was based on traditional Chinese Medicine theory. Pathophysiology of cancer pain, based on Western Medicine, did not affect the formulation of acupuncture interventions in this study. According to the Chinese medical diagnosis, diseases can be conceptualized as conditions of deficiency or strength. The former refers to the insufficiency of patients , 17. Thesi guan xue, whereas treatment arm 2 used the si guan xue in combination with a set of commonly used acupoints. This set of commonly used acupoints, including Neiguan (PC6), Zusanli (ST36) and Sanyinjiao (SP6), were chosen according to a previous extensive literature review [There were two treatment arms in the study. Treatment arm 1 used only the e review –32. Theyqi until the sensation of the arrival of qi  was reported by patients. Patients were maintained in supine positions with the needles left in situ for 30 min. A course of acupuncture treatment consisted of seven sessions in total, performed either daily or on alternating days. Safety precautions were conducted for the patients before each treatment session to prevent acupuncture related adverse events such as fainting, hematoma, curved needles and broken needles.Single-use acupuncture needles (0.25 x 25 mm or 0.30 x 40 mm) manufactured by MOCM International Development Limited were inserted under the skin at 10-20 mm vertical depth. Then, a reinforcing-reducing method was used to activate the The primary outcome of the study, the change in pain, was evaluated by two methods. Firstly, it was measured by the pain assessment form with a numeric rating scale (NRS) from 0 to 10  . SecondlSecondary outcomes included the scores determined by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)  and the χ2) or Fisher Exact test. Statistical significance was defined as a two-tailed P < 0.05. Statistical analysis was performed by SPSS 20.0  and SAS 9.2 software .The analyses were performed on the intention-to-treat population, defined as the participants who had completed baseline assessment and at least one evaluation after treatment. A repeated measures design approach was adopted to compare the treatment outcomes  over time between the three groups. A model was established for performing longitudinal data analysis to explore the intervention effect and the time effect. Among-group differences at each measure time point were further examined using Analysis of Variance (ANOVA). Categorical variables, including categorical baseline variables and incidence of adverse events, were analyzed using a Chi-square  were randomly assigned to the three study arms with 14 in each of them , while it was in the head or neck for those in Hong Kong (n = 4). Most of the patients had stage IV cancer (n = 37), and some had been suffering from another chronic disease as well (n = 26) (Table P > 0.05)   Table . The ave0) Table . The aveP<0.05). There was no difference among the three groups observed in a repeated measures design approach.According to analysis of the seven treatment sessions, the magnitude of pain score reduction tended to decrease in both treatment arm 1 and control arm, while it increased in treatment arm 2 Fig.  (P<0.05)P > 0.05)  Table .Table 7PP > 0.05). Additionally, no difference between the three groups was observed in a repeated measures design approach.Both the Global Health Scale and the Functional Scale increased during the treatment course Tables , whereasP>0.05)  Table .Table 11The safety of acupuncture, including acupuncture related fainting, hematoma, curved and broken needles was also examined in the pilot study. Throughout the study period, no serious acupuncture-related adverse events occurred. There was only one reported episode of mild local bruising, at one acupuncture site, which was successfully managed with direct digital pressure administered by the practitioner.Acupuncture may be useful in controlling the pain experienced by many cancer patients. It is a complementary and conservative therapy that balances the flow of vital energy, and in turn helps to relieve pain. It is an analgesic adjunctive method for cancer patients that is worthy of additional high quality studies –39.si guan xue for cancer pain management for a larger study and its safety. The primary outcomes were the trend of acupuncture in relieving cancer pain and patients’ subjective improvement as measured by the PGIC. Secondary outcomes were patients’ well-being as determined by the EORTC QLQ-C30 and the KPS. According to the data analysis, the effect of pain relief tended to decrease in treatment arm 1 (si guan xue only) and the control arm (commonly used acupoints only). However, it increased in treatment arm 2 (a combination of si guan xue and commonly used acupoints), especially on the fifth day of treatment. This phenomenon reflects the fact that acupuncture treatment takes time to accumulate and exert its analgesic effect, which is consistent with the clinical experience of our routine practice [Because of the small sample size, this pilot study mainly intends to examine the preliminary effects of the acupuncture protocol using the practice . On the si guan xue or commonly used acupoints are effective in reducing cancer pain, but that the combination of these two appears to further enhance pain reduction. Thus, this seemed to be a better acupuncture protocol for cancer pain management. There are several possible explanations for this enhanced effect. Firstly, a special technique of acupuncture was used in treatment arm 2. The si guan xue was opened first before regulating the commonly used acupoints. It had been recognized that this technique could produce a stronger clinical effect [si guan xue could activate the qi, replenish the vital substances of the body and strengthen the visceral organs [si guan xue could give rise to sedative, antispasmodic and analgesic effects. Thus, the use of the si guan xue would be more effective in controlling cancer pain [si guan xue. It enrolled 86 patients and revealed that acupuncture achieved a better control on cancer pain than codeine treatment [Also, it revealed that either the acupuncture at l effect , 42. Secl organs , 7. Thircer pain , 44. Thoreatment . The resP>0.05). A possible explanation is that the treatment and evaluation period was too short to reveal the full effect of the acupuncture. However, these clinical outcomes might require longer observation times to see improvement, as documented by these scores. Therefore, the clinicians should contemplate the appropriate duration of acupuncture treatment for cancer pain. A course of 14 acupuncture sessions, or at least 2 weeks of treatment is needed for better management of this problem [There was no statistically significant difference found across the three arms in the PGIC, EORTC QLQ-C30, and KPS scores ( problem , 46. In si guan xue helps to control their cancer pain and improve their quality of life, but a longer treatment course remains more desirable.As mentioned above, the main limitation of this study was the small sample size, which was inadequate to confirm the efficacy of acupuncture in the management of cancer pain. Moreover, the treatment and observation time were too short to reveal the full effect of the acupuncture. Seven patients even requested to continue their acupuncture treatment upon completion of the study. This may reflect the fact that acupuncture at the si guan xue plus commonly used acupoints tends to be effective in reducing cancer pain. It may also be beneficial in controlling cancer pain in advanced cancer patients. The use and addition of the si guan xue in acupuncture for cancer pain has also been found to be feasible and manageable. Although no firm conclusions can be drawn from such an under-powered study, it did show a trend towards an improvement in cancer pain scores. Therefore, further large scale and multi-centre randomized controlled trials of the si guan xue plus commonly used acupoints are warranted to confirm its treatment efficacy.The results of this pilot study indicate that acupuncture at the


Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is the most common urologic morbidity in men younger than 50 years and is characterized by a diverse range of pain and inflammatory symptoms, both in type and severity, that involve the region of the pelvis, perineum, scrotum, rectum, testes, penis, and lower back. In most patients, pain is accompanied by inflammation in the absence of an invading infectious agent. Since CP/CPPS etiology is still not well established, available therapeutic options for patients are far from satisfactory for either physicians or patients. During the past two decades, chronic inflammation has been deeply explored as the cause of CP/CPPS. In this review article, we summarize the current knowledge regarding immunological mechanisms underlying chronic pelvic pain and prostate inflammation in CP/CPPS. Cumulative evidence obtained from both human disease and animal models indicate that several factors may trigger chronic inflammation in the form of autoimmunity against prostate, fostering chronic prostate recruitment of Th1 cells, and different other leukocytes, including mast cells, which might be the main actors in the consequent development of chronic pelvic pain. Thus, the local inflammatory milieu and the secretion of inflammatory mediators may induce neural sensitization leading to chronic pelvic pain development. Although scientific advances are encouraging, additional studies are urgently needed to establish the relationship between prostatitis development, mast cell recruitment to the prostate, and the precise mechanisms by which they would induce pelvic pain. Lower urinary tract symptoms may include obstructive and/or irritative voiding symptoms. Erectile dysfunction is a major concern for CP/CPPS patients, which is defined as the persistent inability to attain and maintain a penile erection that is sufficient for satisfactory sexual performance . All theThe term prostatitis defines as a state of inflammation of the prostate gland. The currently used classification of prostatitis was proposed by the National Institutes of Health (NIH) in 1999 . ProstatChronic prostatitis/chronic pelvic pain syndrome is a syndrome, thus patients may be very heterogeneous and present a widely variable array of symptoms. In response to that, two multimodal approach systems are currently used to assess CP/CPPS symptom severity and to help physicians to manage patients: the CP Symptom Index from the NIH (NIH-CPSI) and the urinary, psychosocial, organ specificity, infection, neurologic, and tenderness (UPOINT) system , 19. On Available therapeutic options for CP/CPPS are far from satisfactory for either physicians or patients. A novel, effective therapeutic approach is urgently needed , 25, 26.Burkholderia cenocepacia overexpressed in CP/CPPS patients. In contrast, midstream or postprostatic massage samples were not significantly different . Indeed, an autoimmune basis for CP/CPPS is a very prominent theory based on substantial evidence from studies in patients and animal models Table  10, 36––36–38.Evidence from studies in patients is summarized in Table ex vivo when prostate-draining lymph node T cells from these mice were in vitro stimulated  condition to reduce tissue damage . HoweverAlthough thalamic and brain cortical levels may be involved in pelvic pain in CP/CPPS, most attention has focused on the dorsal horn of the spinal cord. Central sensitization is caused by chemical and anatomical changes leading to hyperexcitability in the dorsal horn cells from persistent afferent C fiber bombardment by painful stimuli . ChronicW-sh/KitW-sh mice have significantly decreased intraprostatic NGF levels and attenuated pain responses upon EAP induction (The presence of markedly increased numbers of mast cells in prostate cell infiltrates was already reported in animal models of autoimmune prostatitis several years ago –129. Mornduction . Cytokinnduction . In thisnduction . Authorsnduction . In ordenduction . Our resnduction . Therefonduction . In summnduction . Once thnduction , 68, 69.Chronic prostatitis/chronic pelvic pain syndrome is a complex and frustrating syndrome because of the unknown underlying pathophysiological mechanisms and the lack of appropriate and effective therapies. The emergence of interest and new research on the field has allowed a significant improvement in the understanding of this syndrome. Data obtained from studies in patients and animal models have confirmed the involvement of immune mechanisms in the etiology, pathogenesis, and chronic pelvic pain development. Several factors may trigger chronic inflammation in the form of autoimmunity directed against PAg and foster chronic prostate inflammation with the recruitment of different leukocytes including mast cells. The local inflammatory milieu and the secretion of inflammatory mediators may induce neural sensitization leading to chronic pelvic pain development Figure . FurtherAll authors have contributed to the conception, design, drafting, and revision of the work, provided important intellectual content; and carefully reviewed and approved the final version of the manuscript. Authors agree to be accountable for all aspects of the work, in terms of accuracy or integrity and other related aspects.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.


Two patients, a woman aged 34 and a man aged 56, were included in the study. They reported the existence of pain in the areas of the infraorbital nerve, which, over the last four to five years, aggravated by the stimuli of eating, laughing, and being touched. 2 ml of 0.5% lidocaine was administered to these patients six times percutaneously. It was observed that the ease of pain lasted until the local anesthesia lost its effect, and the pain resumed its original intensity. Neurolysis with 0.5 ml of 50% ethanol was applied to the infraorbital nerve. This procedure was applied to the first patient twice and three times to the second. Thereafter, the patients were cured completely. For the treatment of idiopathic chronic infraorbital neuropathy, the neurolysis of the infraorbital nerve using 50% ethanol could be considered as an effective treatment alternative. Infraorbital nerve neuralgia is an uncommon element for facial pain. It is essential to manage facial pain appropriately as it often causes pain, and the stimuli of eating, laughing, and being touched result in irritation. Among a number of management options present for facial pain, intervention at the branches of the trigeminal nerve has been proved to be clinically useful , 2. BlocA woman aged 34 complained about brief stabbing pain in the innervated right areas of the infraorbital nerve that lasted for four years. The pain was aggravated by the stimuli of eating, laughing, and being touched. The intensity of the pain was 5 out of 10 on the visual analog scale . She also suffered from infrequent exacerbations which lasted about an hour and the pain intensity of which was 9/10 on the VAS.A man aged 56 was included in the study. He complained about brief stabbing pain in the innervated right areas of the infraorbital nerve that had lasted for five years, and the pain was defined to be aggravated by the stimuli of eating, laughing, and being touched. The intensity of the pain was 5 out of 10 on the visual analog scale . He also suffered from infrequent exacerbations which lasted about half an hour and the pain intensity of which was 9/10 on the VAS.Before consulting our pain service, both patients had also been assessed by the departments of neurology, otorhinolaryngology, and maxillofacial surgery. The patients had first consulted to the department of neurology, where they were clinically examined and their diagnostic tests were performed. Magnetic resonance imaging and facial computed tomography scans had also been performed, yielding no pathological findings. Both of them stated that they had never previously experienced any trauma and undergone any face or tooth operation. Then, consultation was asked from the departments of otorhinolaryngology and maxillofacial surgery. These departments were also not able to identify any pathology. Thereupon, the neurology clinic diagnosed these patients with idiopathic infraorbital neuropathy and pharmacological treatment was started, from which neither patient could benefit.When both these patients presented to our pain clinic, the case was as follows: the patients reported that they could not get rid of their pain although they received carbamazepine, diphenylhydantoin, and baclofen therapy. They also stated that it was confirmed by a dentist that they did not have any dental problems. The neurological examination of both patients revealed that the pain could be caused by the palpation of the nerve in the infraorbital notch. During the examination, no other concomitant data of interest were observed. It was concluded that, as the pains were in the region innervated by the infraorbital nerve, the patients had idiopathic infraorbital neuropathy. Consequently, by taking the condition of the patients into consideration, we had the same diagnosis with the neurology clinic. However, the patients had not benefited from the pharmacological treatment, which was the first option in such cases. Therefore, based on our previous experience with such patients , we deciWe administered 2 ml of 0.5% lidocaine hydrochloride over six times percutaneously to these patients. It was seen that the patients were free from pain until the local anesthesia lost its efficiency, but then the pain resumed at its usual intensity. Thus, in order to ease the pain definitely, the patients were recommended the application of neurolysis and informed on the side effects and complications that might occur. Then, upon the receipt of confirmations of the patients, application of neurolysis was started. After identifying the location of infraorbital foramen on the patient's face using thumb nail, a 22-gauge needle was forwarded down to the point where it touched the periost. In the infraorbital foramen, nerve, artery, and vein are found together. In order not to destroy the perfusion of this area, the needle was withdrawn 1 mm immediately after it touched the periost. After the negative result of the aspiration test, 2 ml of 0.5% lidocaine was injected. The needle was held up still for a whole minute until when the patient confirmed that the pain was gone, and then 0.5 ml of 50% ethanol was injected.For the first patient, the same procedure was repeated 8 months after the first time, when the patient suffered from mild pain. For the second patient, however, the same procedure was repeated twice: one after six months and the other after a year as he still suffered from moderate pain. During the patients' clinical follow-up, they were scheduled for an evaluation once in six months for the following two years. Besides, they were advised to call in immediately in the event of any pain. At the end of the clinical follow-up, these two patients reported that they did not experience such pain any longer.By virtue of its ophthalmic, maxillary, and mandibular divisions, the trigeminal nerve supplies the face and anterior portions of the scalp. The maxillary nerve is wholly sensory. The maxillary nerve gives seven branches within the pterygopalatine fossa, and it passes through the infraorbital canal as it continues. It exits onto the front of the maxilla through the infraorbital foramen. At this very point, the maxillary division is now known as the infraorbital nerve. The terminal branches of the infraorbital nerves on the face are the inferior palpebral, lateral nasal, and superior labial branches , 5.When infraorbital neuralgia is in question, other symptomatic causes should be eliminated to be able to assign a specific diagnosis. The presence or absence of any history of any traumatic episode should be determined. If such a history is not in question, other secondary causes, mainly neoplasms that can cause these symptoms due to haematogenous, lymphatic, or perineural spread, should be ruled out. Therefore, imaging studies are essential for all these patients. Upon the elimination of all the above-mentioned possible causes, primary neuralgia can be considered , 6.Medical treatment for infraorbital neuralgia generally includes analgesic, anti-inflammatory, anti-epileptic, or antidepressant drugs; however, it may be unmanageable by medical treatment . Among oCases where terminal branch neuralgia of the trigeminal nerve is in question are quite rare, and they frequently appear in the form of continuous pain. However, cases where the trigeminal nerve is centrally involved are generally connected to painful paroxysms . ConsideWhen the presence of peripheral nerve injury is obvious, a direct treatment on this area would be appropriate. If trauma or amputation of a body part is in question, the cut ends of the neurons search desperately for the nerve trunk which is missing, and in the end, they may curl around themselves in a whirl-like fashion or become nested in either a scar or some other soft tissues. These bulbous collections of nonmyelinated neurons are called neuromas. Neuromas do not act like normal sensory receptors. They often cause an excessive response with sharp lancinating pain along the affected nerve when they are stimulated. In the meantime, both mechanosensitivity and thermosensitivity may be observed , 10.In the treatment of pain secondary to peripheral nerve lesions, many treatment methods have been reported to be useful. Despite the fact that it is far from being a routine procedure, the neurolytic block (neurolysis) has been reported to provide patients with secure and effective relief for pain that does not respond to conventional treatments. In order to achieve neurolysis, the neurolytic agent is injected to intentionally destroy a nerve or nerves and thus interrupt nociceptive pathways for weeks or months. The use of different agents for chemical neurolysis is suggested in literature. Alcohol is one of the agents used in this procedure .Neurolysis is a medical surgery method performed by the injection of a neurolytic agent on the nerve. It other words, it is the chemical destruction of the nerve without incision in order to interrupt the transmission of nerve signals. The side effects or complications depend on the nerve on which neurolysis is performed. Therefore, prior to neurolysis, whether the nerve in question is a motor nerve or a sensorial nerve or both should be known, and the formations it innerves should be well understood. The procedure is performed according to the topographical anatomy of the nerve that will be neurolysed. Before neurolysis, the patient should be informed regarding the senses that will disappear, and the functions that will be lost following neurolysis and consent should be received.In these cases, the infraorbital nerve on which we performed neurolysis was one of the sensorial branches of the maxillary branch of trigeminal nerve, which performs innervation following exit from the infraorbital canal. The infraorbital nerve is found within the canal with vein and artery. When neurolysing this nerve, entry into the infraorbital canal should strictly be avoided. Thus, the complications that may occur will be prevented. The patient should be informed that following the neurolysis procedure, there will be numbness or tingling at the region innervated by the nerve.Both these patients who applied to our pain clinic suffering from facial pain had previously been given proper standard pharmacological treatment; yet neither of them benefited from it even though the time passed was sufficient for such treatment. Therefore, based on our previous experience, we decided to perform alcohol neurolysis of the infraorbital nerve procedure on these patients. Prior to the decision for the performance of neurolysis procedure on the patient, it is necessary to make sure that all steps regarding standard pain treatment are taken and yet the patient does not benefit from any of those steps. It is recommended that for the treatment of head and face neuralgia, the conventional treatment involves carbamazepine, diphenylhydantoin, or baclofen. However, it is stated that if medical measures fail, radiofrequency treatment of the ganglion or microsurgical decompression of the trigeminal root is appropriate . For paiTo our knowledge, our study is the first one to report on neurolysis of the infraorbital nerve by using a closed method. For our patients, in order to cure infraorbital neuropathy, we administered 2 ml of 0.5% lidocaine six times over three-day intervals . However, it was observed that after a few hours, the patients' pain resumed to its initial intensity. Therefore, for the treatment of the pain for good, we decided to perform neurolysis using alcohol. The patients were given information on the procedure to be made, and then, 0.5 ml of 50% ethanol neurolysis was applied to the infraorbital nerve. We repeated the procedure for a second time for the first patient, and for the second patient, we had to repeat the procedure two more times. Then, the pain went for good.In cases where conservative methods do not work to eliminate pain within six months, and if a damage occurring on the infraorbital nerve is in question, we recommend the application of neurolysis to the infraorbital nerve. For the treatment of idiopathic chronic infraorbital neuropathy, the neurolysis of the infraorbital nerve using 50% ethanol could be considered as an effective and safe treatment.


It has been hypothesized that dexamethasone can inhibit persistent postoperative pain, but data on humans is lacking and results from animal studies are conflicting. We explored the effect of 16 mg dexamethasone IV administered preoperatively on persistent pain 1 year after lumbar discectomy.This is a prospective 1-year follow-up on a single-centre, randomized, and blinded trial exploring the analgesic effect of 16 mg IV dexamethasone or placebo after lumbar discectomy. One year follow-up was a written questionnaire including back and leg pain (VAS 0–100 mm), Short Form 36 survey (SF-36), EuroQol 5D (EQ-5D), OSWESTRY Low Back Pain Questionnaire, duration of sick leave, working capability, contentment with surgical result.P = 0.03). No difference regarding back pain. The placebo group reported significantly more improvement of leg pain and were significantly more satisfied with the surgical result. Patients in the dexamethasone group reported significantly higher pain levels in EQ-5D- and Oswestry questionnaires. No difference in the SF-36 survey or daily analgesic consumption.Response rate was 71% (55 patients) in the dexamethasone group, 58% (44 patients) in the placebo group. Leg pain (VAS) was significantly lower in the placebo group compared to the dexamethasone group: 17 (95% CI 10–26) vs 26 (95% CI 19–33) mm, respectively (mean difference 9 mm (95% CI −1 to 0), (We found significantly higher pain levels in the dexamethasone group compared to placebo 1 year after lumbar disc surgery.NCT01953978). Registered 26 Sep 2013.Clinicaltrials.gov ( An increasing number of studies have explored the role of glucocorticoids as a potential adjuvant in analgesic regimens for acute postoperative pain management , 2. ReviThe mechanisms that influence the transition from acute, adaptive postoperative pain to persistent, maladaptive pain are uncertain, but nerve injury and ongoing inflammation play important roles . PeriphePersistent postsurgical pain is a serious and widely unnoticed clinical problem, difficult to treat and often permanent , 11, 12.This is a prospective 1-year follow up trial on a single-centre, prospective, randomized, and blinded trial exploring the analgesic effect of 16 mg dexamethasone IV on acute postoperative pain after lumbar disc surgery as the main outcome . The triThe trial was performed at Glostrup Hospital, Copenhagen University Hospital, Glostrup, Denmark during the period December 7, 2012 to December 7, 2014, and was monitored by the Copenhagen University Hospital Good Clinical Practice Unit. The follow up period was from December 1, 2013 to September 20, 2015. The study fulfilled the guidelines for Good Clinical Practice and the Helsinki Declarations. The protocol, design and reporting of the study complied with the Standard Protocol Items, Recommendations for Interventional Trials (SPIRIT) statement , and theOne hundred-sixty patients undergoing one- or two-level primary lumbar discectomy during general anaesthesia were approached for inclusion in the original trial . InclusiIn the original trial, patients were randomly assigned to one of two groups: Oral paracetamol + oral ibuprofen + IV dexamethasone 16 mg; or oral paracetamol + oral ibuprofen + IV placebo. Randomization was performed by the pharmacy according to a computer-generated block randomization list (each block containing 10 numbers), in a 1:1 ratio. Study medication was pre-packed by the pharmacy in consecutively numbered boxes according to the computer generated randomization list, containing identical 1 ml ampules of either dexamethasone 4 mg/ml , or isotonic sodium chloride 9 mg/ml. The intervention was blinded to patients, investigators, surgeons, and clinical personnel .The randomization code was disclosed until a three months follow-up period had ended, exclusion of patients was decided, and statistical handling of the data was completed, but prior to the 1-year follow-up.The primary outcome of the original trial was pain during mobilization 2 to 24 h postoperatively calculated as a ‘weighted average level’ area under the curve (AUC) (in mm) .Secondary outcomes included pain at rest , total morphine consumption 0–24 h postoperatively, and 3- and 12-months follow-up .The 1-year follow-up was performed by a written questionnaire. The questionnaire was used with permission from Centre for Rheumatology and Spine Diseases, Glostrup University Hospital, Denmark, and the Danish Spine Database. This questionnaire was developed to construct a national database that systematically collects data on patients undergoing spine surgery. The questionnaire consists of demographic data, back and leg pain (VAS 0–100 mm), duration of sick leave, working capability and contentment with the results of the operation. Further it contains the following questionnaires: Short form 36 survey (SF-36), EuroQol 5D (EQ-5D) and OSWESTRY Low Back Pain Questionnaire.If patients had not returned the questionnaire after three weeks, they received one written reminder.We randomized 160 subjects in the original study, and data on acute pain were analysed in 77 and 76 patients in the dexamethasone and placebo groups, respectively .U-test was used for data that were not normally distributed. Categorical data were analyzed using the x2 test or Fisher’s exact test if any cells had expected counts less than five. Data are presented as mean (SD), mean , median (lower and upper quartiles) or frequencies , as appropriate. A sensitivity analysis was performed for missing data on the VAS pain scores with multiple, average, best case and worst case imputation.For the present data, we used SPSS version 22.0 for Windows  for statistical analysis. Variables were tested for normal distribution with the Kolmogorov-Smirnov test and visual inspection. Data that followed normal distribution were compared using the independent samples t test. The Mann–Whitney OSWESTRY Index Score is calculated using the following method: Questions are rated on a scale of 0–5 with zero recorded as no disability and five recorded as maximum disability. The scores from all questions are summed, and then multiplied by two to attain an index (range 0–100). Zero is then no disability and 100 is maximum disability.The SF-36 questionnaire is summarized as two sets of scores: A profile of eight section scores, and two summary scores, one for the physical component (PCS) and one for the mental component (MCS) summary scores. Scores are recalculated to normal zero-to-100 scores for the eight scales and all item scores are oriented so that high scores correspond to better health. All scores are calculated according to the formula described by McDowell . Using nThe nature of the hypothesis testing was 2-tailed. P values of less than 0.05 were considered statistically significant. As we consider the results of this 1-year-follow-up trial exploratory, outcomes were not statistically corrected for mass significance. The primary investigator carried out statistical analyses.All 153 patients included in the original data analysis, 77 and 76 subjects in the dexamethasone and placebo groups, respectively, received a follow-up questionnaire 1 year postoperatively. In the dexamethasone group 55 patients (71%) replied, and in the placebo group 44 patients replied (58%), resulting in an overall response rate of 65%   vs 20 (95% CI 14–28) mm in the dexamethasone and placebo groups, respectively (mean difference 2 mm (95% CI −1 to 0), P = 0.04)  vs 2 (0 – 5), respectively, (P = 0.01) in the original total study population and 32 (20) vs 41 (20) mm with a mean difference of 11 mm (95% CI 2 to 18), (P = 0.02) in the subgroup of one-year follow-up responders [A post hoc analysis of preoperative VAS pain scores and VAS pain during the trial period (weighted average AUC (wAUC) 2–24 h), showed that results from the subgroup of patients that completed the 1-year follow-up were similar to the results from the total study population. Only pain during mobilization was significantly different between groups: Dexamethasone compared to placebo, 33 (22) vs 43 (18) mm (wAUC 2–24 h) with a mean difference of 10 mm (95% CI 3 to 16), (sponders .P = 0.07).The relation between leg pain levels 3- and 12 months postoperatively are summarized in scatter plots  having a daily use of analgesics in both groups  (P = 0.02)  component summary score was mean 52 and 54 in the dexamethasone group and placebo group, respectively, P = 0.49.The SF-36 section scores are summarized in Table P = 0.03)  Fig. .Fig. 4EuP = 0.26).There was no significant difference between groups in self-reported health  with medians of 80 (4–100) vs 80 (14–100) mm in the dexamethasone and placebo groups, respectively, (P = 0.09), categorizing both groups with minimal disability. However, in the questionnaire, there was a significant difference regarding pain with more severe pain scores in the dexamethasone group: Median 1 (0–5) vs placebo median 1 (0–3), (P = 0.01).Results from OSWESTRY Low Back Pain Questionnaire are summarized as an Oswestry Index Score 0–100, with 0–20 being minimal disability and 81–100 being patients who are bed-bound. There was no significant difference between groups: Dexamethasone median 14 (0–60) vs placebo median 8 (0–56),  [In contrast we found increased pain levels in the dexamethasone group, specifically leg pain, indicating increased levels of neuropathic pain. In our original trial, 16% (95% CI 7–26) versus 8% 95% CI 0–17) reported new weakness and/or paralysis of the legs affecting the ability to walk in the dexamethasone and placebo groups, respectively, 3 months postoperatively . However, this should be similar in both groups. We found no differences in patient characteristics between responders and non-responders. Further our imputations of missing data did not contribute with new indications that dexamethasone can prevent persistent postoperative pain. Our study contains exploratory secondary outcomes from an original trial. Thus, the sample size calculation was not performed with regards to these secondary outcomes. Many of the questions in the questionnaires regard the same topic and we would therefore have to do multiple corrections introducing a greater risk of ignoring a relationship that is real and performing a type 2 error. As we consider these outcomes hypothesis generating, we chose not to correct for multiple comparisons and interpret the results with respect to the increased risk of type 1 errors.Further this study suffers from the well-known weaknesses of written questionnaires: Suboptimal response rates, a level of subjectivity, recall bias, interpretation of questions, and researcher imposition. The strength of the study is that very few investigators were involved in the trial, leading to few protocol violations, and very few original data missing.Future studies on possible effects and safety aspects of dexamethasone on sustained postoperative pain are warranted. We consider our results on back pain incidence after lumbar back surgery as a significant negative finding in this study. The exact dose of glucocorticoids at which potential harm outweighs benefit is still unknown.In conclusion, we found no inhibitory effect of dexamethasone on chronic pain 1 year after lumbar disc surgery. In contrast we observed significantly higher pain levels in the dexamethasone group compared to placebo, which may be of concern. Our results may be considered as hypothesis generating for future properly sized studies investigating long-term effects of perioperative glucocorticoids on human postoperative pain.