Genetic polymorphisms in genes involved in pain modulation have been reported to be associated to opioid efficacy and safety in different clinical settings.The association between COMT Val158Met polymorphism (rs4680) and the inter-individual differences in the response to opioid analgesic therapy was investigated in a cohort of 87 Italian paediatric patients receiving opioids for cancer pain (STOP Pain study). Furthermore, a systematic review of the association between opioid response in cancer patients and the COMT polymorphism was performed in accordance with the Cochrane Handbook and the Prisma Statement.p-value = 0.042). In the 60 patients treated only with morphine, the mean of total dose to reach the same pain intensity was significantly higher for G/G than A/G and A/A carriers . Systematic review identified five studies on adults, reporting that opioid dose (mg after 24 h of treatment from the first pain measurement) was higher for G/G compared to A/G and A/A carriers.In the 87 paediatric patients, pain intensity  was significantly higher for G/G than A/G and A/A carriers , as well as in adults (Systematic Review), indicating that the polymorphism impact could be not age-dependent in the cancer pain context.CRD42017057831.Registration number: The online version of this article (10.1186/s12885-019-5310-4) contains supplementary material, which is available to authorized users. Opioid analgesics are the treatment of choice for moderate-severe pain both in adults and in children , 2. A siIn particular, the common (50% frequency in Caucasian population) 472G > A single nucleotide polymorphism (SNP) in exon 4 of the COMT gene, Val158Met (rs4680), leading to a three- to four-fold reduced activity of the enzyme .Malignancy- or chemotherapy-induced pain therapy is a challenge for paediatric oncologists. Available information on the impact of genetic variability in COMT on the effect of opioids in cancer pain remains limited, especially in children . In EuroWhile pharmacogenetic data on opioids in adult cancer patients are limited, those in paediatric subjects are completely missing. Thus, the aim of Suitable Treatment for Oncologic Pediatric Pain (STOP Pain) study was to investigate the association between the most studied COMT polymorphism, rs4680, and the inter-individual differences in response to opioid analgesic therapy in a cohort of paediatric cancer patients receiving opioids. The opioid dose employed and the modifications in pain intensity were evaluated as efficacy outcomes, and the number of central and gastrointestinal adverse effects as safety outcomes.Furthermore, to evaluate whether the impact of this COMT polymorphism is age-dependent, data obtained in paediatric patients were compared to existing data in adult subjects. To this aim, a systematic review of published studies was conducted separately for three different outcomes: opioid dosing, pain intensity, and side effects.Materials and methods of the present study have been already published in part by Lucenteforte et al. 2018 . BrieflyStandard opioid conversion to intravenous (IV) morphine equivalents (ME) was performed , 14. The24h); total dose (mg/kg) of IV ME from Day 1 to the last day of pain therapy (Dosetot); mean dose (mg/kg) required to achieve maximal total pain relief reported by the patient (DoseVAS = 0). Pain relief evaluation was also assessed using pain intensity scores. Children pain was measured using three different scales: visual analog scale (VAS) was compiled by 58 subjects over six years of age; Wong & Baker FACES Pain Rating Scale was administered to 5 children between the ages of four and six years of age; Face, Legs, Activity, Cry and Consolability (FLACC) scale was used by nurses to assess pain in 24 children (less than four years old) unable to communicate their pain. These measures were performed at time 0 (before treatment) and defined as PIto. Then, two parameters for pain intensity were considered: difference between the pain intensity after 24 h-treatment and PIto (∆ VAS); time to reach the lowest pain intensity reported by the patient (Time tot). The number of side effects was analyzed using three categorical (presence/absence) variables: onset of any adverse drug reactions (ADRs) and onset of gastrointestinal or CNS effects. Each patient could experience more than one ADR. ADRs were recorded every eight hours for each patient.Three indicators of dose were used for pain relief evaluation: cumulative dose (mg/kg) of IV ME administered during the first 24 h of treatment or titration phase  and safety parameters (presence of side effects versus no side effects) and COMT rs4680 polymorphism by calculating odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression models adjusted for gender, age, body mass index (BMI), diagnosis, metastasis, pain location, and pain intensity at baseline. We considered a The software STATA 14.2  was used for all analyses.Cochrane Handbook and the Prisma Statement for Systematic Reviews  were useStudies were systematically searched in PUBMED and EMBASE databases up to November 24, 2016 . Full seIndependent investigators (AP and GC) selected articles reviewing titles and abstracts. Two other independent reviewers (EL and VM) resolved through discussion and consensus any disagreements.Then, AP and GC independently read the full texts selecting the original articles when patients were cancer patients, involved drugs were opioids, outcomes were related to opioid non-response and safety, and one or more genes were studied.Mean age and gender of the sample, study type and size, location, year of publication, drugs used and genetic information  were collected for each study. By study design, only results reported in papers investigating COMT gene as factor associated to therapy outcome were taken into consideration. “Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies”  was usedn = 8), end of life patients (n = 12), early discharge , hospitalization in sterile room (n = 8). Table One hundred thirty-three patients were evaluated from June 2011 to December 2014. Forty-six children were not included in the study for the following reasons: refusals of consent . Genotype frequencies agreed with the Hardy–Weinberg equilibrium  and consistent with 1000 Genome Project Data for European population (EUR) [None of the above characteristics was different among the three genotype groups (on (EUR) .tot significantly differed across the three groups . In particular, the mean for AG and AA groups was lower than GG . No difference was observed for all the other considered variables .Table tot and Timetot. In particular, A/G subjects needed a lower total amount of drugs compared to G/G individuals , and patients heterozygous or homozygous for the A allele reached the lowest pain intensity faster compared to G/G individuals . No significance was found for the association of safety parameters and COMT genotype.Table Systematic literature search produced 350 records. After an initial screening of titles and abstracts, 239 studies were excluded for the following reasons: not relevant 137); reviews (39); not human studies (36 studies); case reports (17); full text not available (10). We obtained the full text of 45 articles. Of them, 11 studies were defined not relevant because they did not focus on genotype effects on our clinical outcomes (pain relief and adverse events), and four focused on cancer patients’ postoperative pain and postoperative adverse events, thus they were excluded. Characteristics of studies excluded after full-text reading are shown in Additional file 37; revieOf the 31 selected papers, nine investigated COMT and were analyzed in the present review –26; noneTable COMT rs4680 polymorphism. Two studies included in the systematic review agreed on the finding that opioid Dose24h was lower among subjects with the A (158 Met) allele [tot of oral morphine and dose escalation, without reaching statistical significance. Otherwise, no clear associations emerged with pain intensity (measured with Brief Pain Inventory) or with side effects, with the exception of the EPOS study in which the intensity of nausea and vomiting (EORTC score) was significantly lower among the subjects with A/G genotype .Tables ) allele , 23. Onl) allele  reportedPrisma checklist validation is reported in Additional file Figure This is the first paediatric study addressing the role of COMT polymorphism rs4680 in opioid treatment of cancer patients as well as the inter-individual differences in the response to opioid analgesic therapy. Furthermore, we also compared the obtained evidences to existing data in adults retrieved by means of a systematic review of medical literature. The main result of the STOP Pain study was that paediatric cancer patients with the GG genotype needed a longer time to reach the lowest possible pain intensity compared with the A-containing genotypes. However, this association can be due to chance, given the many interaction tests carried out. The systematic review regarding adult cancer patients showed that the Dose24h was lower among subjects presenting the A allele , 23, 27,Focusing on investigations into the role of COMT rs4680 polymorphism in cancer pain, the G/G genotype was shown to require higher morphine daily doses as compared to G/A and A/A ones , 23, 27.On the other hand, the first study showed an association of this polymorphism with opioid-induced nausea . In anotCOMT polymorphisms associated with lower COMT activity have been studied in several painful conditions, such as postoperative surgery, cancer pain, neuropathic pain, and migraine or headache , not onlCOMT polymorphism was found using the total dose requested for maximal possible pain reduction, whereas the 24-h dose that correlated in adult cancer patients only showed a slight tendency towards association. The reasons for this discrepancy may reside in differences between adults and children in both pharmacokinetics and pharmacotherapy regimens. In fact, while pharmacological therapy in adults is based on fixed-dose increments, treatment in children needs to be personalized based on age and weight (or body surface), considering incomplete organ maturation, differences in body composition and plasma proteins, in receptor density and type. For example, children younger than 11 years show faster clearance of morphine and morphine metabolites than older subjects [In our sample of paediatric patients, the association with rs4680 subjects . Furthersubjects .For these patients, analgesics are the drug class most commonly used in hospital , with moOverall, results obtained for adults and children in both the total amount of opioids administered and in the dose administered during the first 24 h, could be primarily related to the factors mentioned above: developmental pharmacokinetic, medications’ differences, and the use of conversion tables. These variables could have influenced the relationship between COMT polymorphism and the opioids doses.In light of these considerations, the secondary aim of the present study (whether the impact of rs4680 polymorphism is age-dependent) is not completely pointed out. Our results suggest that, independently from age, rs4680 could actively influence the efficacy of pain therapy also in children. Future studies, with large number of paediatric patients, are needed to fully ascertain the trend towards association shown also by our observational data.Current guidelines encourage accurate monitoring of pain in children and its treatment  in orderi.v. infusion, reduces the effect of this shortcoming. Future studies should prospect a multi-center collaborative setting to address this point. Moreover, regarding pharmacological treatment, we could not establish whether any non-opioid analgesics used in our sample may have affected pain ratings and side effects. This information would be very important, since some agents may synergize with opioids and/or have similar genetic influences on metabolism and/or drug sensitivity.The number of enrolled patients in the STOP Pain study was relatively small. However, the uniform treatment regimen, with 69% of patients receiving titration of morphine by continuous Another limitation is represented by the mixed nature of pain in cancer patients. In fact, paediatric cancer pain can vary from acute, procedure-related pain to progressive chronic and breakthrough pain, associated to disease progression and/or treatment. Moreover, due to the relatively small sample size when considering the wide variability of cancer diagnoses, it was difficult to state whether the type and location of the primary cancer or metastases influenced the pain measurements independent of genetic influences on opioid metabolism and receptor activity. Thus, whether cancer-associated pain may represent an additional bias, it may only be determined through a large study including comparison of patients with pain of different origins. Finally, an additional obvious limitation is that the present results in children can only be compared with those reported in studies conducted on adults, simply due to the lack of similar studies in paediatric subjects. On the other hand, comparison of paediatric data with those obtained in adults, collected in a systematic review, has shown differences in the relevant parameters  providing useful information for future studies in children.The results of this research show that paediatric cancer patients with the GG genotype, compared with the A-containing genotypes, received a higher mean dose of morphine equivalents and needed a longer time to reach the lowest possible pain intensity. These results suggest that the presence of A allele in COMT rs4680 SNP could represent an evaluable marker of opioid sensitivity in paediatric cancer patients, as well as in adults. Although further studies are needed to confirm these findings, to date these evidences are still not sufficient to support a previous expensive evaluation of COMT SNPs before starting an opioid therapy in children suffering for cancer pain.Additional file 1:BMC Cancer.doc, Full Search Strategy. (DOCX 26 kb)Additional file 2:BMC Cancer.doc, Criteria for the quality assessment of the included studies in the review. (DOCX 272 kb)Additional file 3:BMC Cancer.doc, Characteristics of 8 missing subjects in the STOP Pain Project. (DOCX 24 kb)Additional file 4:BMC Cancer.doc, Efficacy and safety parameters of 8 missing subjects in the STOP Pain Project. (DOCX 25 kb)Additional file 5:BMC Cancer.doc, Characteristics of studies excluded after full-text reading. (DOCX 26 kb)Additional file 6:BMC Cancer.doc, PRISMA Checklist for the current review. (DOCX 30 kb)


To evaluate the association between opioid use and treatment outcome  after a brief interdisciplinary fibromyalgia treatment program (FTP).Subjects (n = 971) with fibromyalgia participated in the FTP. They filled out the Fibromyalgia Impact Questionnaire (FIQ) and the Short Form-36 Health Status Questionnaire (SF-36) at baseline and 6 to 12 months after the FTP. Post-treatment changes in FIQ and SF-36 scores were compared after stratifying the participants into opioid user and non-opioid user groups.p < .001) and all subscales at baseline and post treatment, as well as worse QOL measured using all SF-36 subscales and physical and mental components. Comparison of least-square means of mean change of QOL between opioid users and non-opioid users after analysis of covariance adjusted patient characteristics and baseline scores showed that the FIQ subscale scores of physical impairment (p < .05), job ability (p < .05), and fatigue (p < .05) were significantly less improved in the opioid users compared with the non-opioid users. Moreover, the SF-36 subscale score of general health perception (p < .05) was significantly less improved in the opioid users compared with non-opioid users. However, post-treatment changes in mean scores for QOL subscale generally did not significantly differ in both groups.A total of 236 patients (24.3%) were opioid users. Compared with non-opioid users, the opioid users had worse symptom severity measured using FIQ total score (Opioid use did not affect response to the FTP, as measured using the FIQ total score or SF-36 physical and mental component summary scores. Furthermore, the opioid user group showed less improvement in the FIQ subscale scores of physical impairment, job ability, and fatigue and in the SF-36 subscale scores of general health perception. These symptoms include headache, bowel and bladder symptoms, fatigue, sleep disturbance, cognitive dysfunction, headache, and depression. Extensive research has revealed that central sensitization is the main pathophysiologic feature of fibromyalgia. Central sensitization is characterized by augmented processing of pain stimulation that is managed partially through peripheral mechanisms. Therefore, evidence-based pharmacological therapy for fibromyalgia focuses on alterations in descending inhibitory pathways and other pain-processing pathways. Despite little evidence supporting the long-term effect of opioid treatment for fibromyalgia, opioid therapy in this population ranges from 24% to 30%.–7Fibromyalgia is a condition characterized by chronic, widespread, musculoskeletal pain with decreased pain threshold to pressure or other stimuli. However, further knowledge on the effect of opioids in fibromyalgia is crucial because previous studies suggested that patients who use opioids have worse outcomes in pain-related physical and emotional function. Consequently, this study aimed to investigate the effect of opioid use on outcome of fibromyalgia treatment, specifically interdisciplinary fibromyalgia treatment program (FTP).Currently, the use of opioids for the treatment of chronic pain is widespread.22.1 Each patient had a confirmed diagnosis of fibromyalgia according to the American College of Rheumatology 1990 criteria for fibromyalgia classification. Patients underwent the FTP from May 1, 2001, to April 30, 2004. All patients agreed to participate in the study. The study was approved by the Mayo Clinic Institutional Review Board, and informed consent was obtained from each patient before participating in the study. The patients were not self-referred nor externally referred. This study population consisted of 917 patients who agreed to complete the Fibromyalgia Impact Questionnaire (FIQ) and the Short Form-36 Health Status Questionnaire (SF-36) at baseline and 6 to 12 months after participating in the FTP.The study population was part of the earlier study report by our group, regarding 6 to 12-month treatment outcome after our FTP.2.2At the first visit for the FTP, a patient was evaluated by a registered nurse (RN) who would use “shorthand” computer software to collect standardized information while the evaluation was being conducted. This comprehensive assessment included current symptoms, impact of pain, medical history, and other symptoms on physical and emotional functioning. The nurse also performed a tender point examination.,12 and hence has been included in treatment recommendations and guidelines for fibromyalgia.–15 The pain control effects of tramadol in fibromyalgia are speculated to be mainly from inhibition of norepinephrine and serotonin and reuptake.All patients participating in the FTP during this time period were internally referred within the institution, which used the same computer operating software. A complete list of medication was organized by former providers before referral to the FTP. The RN reconducted a medication recognition process, confirming with the patient and updating any details related to medication use, to ensure an accurate medication list. Meanwhile, the RN asked in a nonjudgmental, matter-of-fact manner if the patient used any nonprescribed material to assist them in symptom management. Substances, such as cocaine, heroin, marijuana, and opioids, were provided as examples that were prescribed for another person. Finally, if the patient had any records from the local physician, the RN would review and remark them as prior medications in the patients’ current medical record. Opioid user was defined as patients who were active users at the time of the FTP evaluation. Participants who used opioids before but were not using at the time of the evaluation were included in the nonopioid user group. Patients who had stopped using opioids the day before the evaluation were also considered in the nonopioid group. Moreover, patients using tramadol were included in the nonopioid user group. Despite the weak μ-receptor agonist property of tramadol, several studies have shown some positive effects in fibromyalgia management2.3 This self-administered questionnaire evaluates multiple components of symptoms and functional impairment related to fibromyalgia through 20 questions. The included 10 items are as follows: physical functioning, fatigue, symptoms of pain, morning tiredness, job difficulty, stiffness, depression, anxiety, days of work missed, and overall well-being in the previous week. Result score ranges from 0 to 100, with 100 demonstrating maximum impairment. The FIQ was performed according to the directions specified by Bennett.The FIQ and SF-36 were used to measure treatment outcome. The FIQ, developed in 1991, is a validated, practical tool used to assess the health status of patients with fibromyalgia. The self-administered questionnaire measures 8 health concepts, namely, role limitation due to physical health, physical functioning, bodily pain, general health perception, social role functioning, vitality score, role limitations due to emotional health and mental health, and physical and mental composite scores. The SF-36 score ranges from 0 to 100, with higher score indicating better health status.The SF-36 assesses health-related quality of life (QOL). It was developed as a tool for evaluating patient outcomes in a busy clinical setting.Patients completed the FIQ and SF-36 at the initial visit. The same questionnaires were mailed 6 and 12 months after FTP completion. If no response was received within 1 month after mailing, the questionnaires were remailed. We did not communicate with the patients through phone or otherwise persuade them to complete the follow-up questionnaires. Both returned questionnaires were used for our analysis.2.4t test. For non-normally distributed variables, Mann–Whitney U test was used. For categorical variables, data were expressed as sample number and percentage, N (%). Chi-squared test or Fisher exact test was performed to compare proportions of sample number as appropriate.R language version 3.3.3 , T&F program ver. 2.5 , and IBM SPSS Statistics for Windows version 22  were used for all statistical analyses. Data were expressed as mean ± SD for continuous variables. When variables were normally distributed, mean difference test between 2 sample groups was performed using Student t test was used to test if the mean difference between paired sets of observations was zero. For non-normally distributed variables, Wilcoxon signed-rank test was performed. The paired sets are FIQ and SF-36 scores measured at baseline and post-treatment.When variables were normally distributed, paired sample Analysis of covariance (ANCOVA) was performed to evaluate whether population means of response were equal across sublevels of group variable (opioid users vs nonusers) while statistically controlling for the effects of confounding covariates such as age, sex, body mass index (BMI), tobacco use, alcohol use, employment status, benzodiazepine use, and FIQ or SF-36 scores measured at baseline. Response consisted of FIQ and SF-36 scores measured at baseline and post-treatment. Mean change of FIQ and SF-36 scores were also used as response.33.1Our study population consisted of 971 patients (917 women and 54 men), with a mean (SD) age of 49 (12.92) years and a mean (SD) duration of symptoms of 132.45 (134.52) months in the nonopioid users. In the opioid users, a mean (SD) age was 47.55 (12.33) years and mean duration of symptoms was 123.21 (135.55) months. Among these patients, 236 (24.3%) were opioid users and 735 (75.7%) were nonopioid users. The patient characteristics of opioid and nonopioid users are outlined in Table 3.2The opioid users showed a higher severity of symptoms measured using the FIQ total score and all subgroups at baseline and post-treatment Table  than the3.2.1P = .017), job ability (P = .038), and fatigue (P = .04) were significantly less improved in the opioid users compared with the nonopioid users. The SF-36 subscale score of general health perception (P = .013) was also significantly less improved in the opioid users compared with the nonopioid users. However, post-treatment changes in mean scores for QOL subscale generally did not significantly differ in both groups. The changes in FIQ and SF-36 scores in both groups are summarized in Tables After ANCOVA was used to adjust for patient characteristics  and baseline scores, the FIQ subscale scores of physical impairment (ue P = .0 were sig4The important finding of this study was that the use of opioids in fibromyalgia does not improve the outcome of the treatment program. Improvements were noted for the total measures of function, pain, and mood, regardless of opioid status. However, the opioid user group constantly scored higher than the nonopioid user group in all measures of symptom severity, with significance prominent for higher pain scores and worse functional impairment. The results suggest that despite improvements in pain, function, and psychological variables during a multidisciplinary pain clinic care, these measures were irrespective of opioid use. The use of opioids was not associated with improvement of disease status beyond what was observed from previous standard multidisciplinary treatment setting. Furthermore, work status of opioid users was less favorable with more disability payments noted and unemployment for the opioid user group. These findings raise questions regarding the rational use of opioids in patients with fibromyalgia. However, the efficacy of any treatment method in fibromyalgia should reflect both improvement in the target symptoms and functional status. Opioid therapy has been established in the management of chronic pain. Our findings of 20% prevalence of opioid use in patients with fibromyalgia are consistent with studies of opioid use in patients with chronic nonmalignant painful conditions. In fact, treatment with any analgesic other than nonsteroidal anti-inflammatory drugs was reported by more than half of patients with fibromyalgia in a survey conducted in the United States. Patients with fibromyalgia evidently consider opioids as the best symptom reliever. According to an Internet survey of people with fibromyalgia, opioids were reported to be the most helpful treatment of pain.Pain response is presently used as a significant outcome measurement for treatment assessment in clinical trials of fibromyalgia.,25 However, opioid use is not supported by any guidelines for the management of fibromyalgia.,26,27While the use of opioids in the management of fibromyalgia pain remains controversial, their known analgesic properties should encourage further investigation in fibromyalgia treatment. Only tramadol has been formally studied in fibromyalgia management to date, with a positive effect on pain and QOL. Whereas demographic variables did not differ between patients stratified according to opioid use, the opioid group evidently showed more functional impairment, pain, and mood disorder at baseline compared with the nonopioid group. This may suggest that the opioid users were more symptomatic from the beginning.A number of factors need to be considered with regard to the worse outcome in patients on opioid treatment. Opioid users possibly had more severe disease course or had more comorbidities resulting in continuous opioid use as has been previously mentioned. This suggestion is conceivable, as symptoms of fibromyalgia and adverse effects of opioid use are markedly similar, such as deteriorated physical and mental performance, fatigue, and even worse pain. In accordance with this observation, our result suggests that opioid use is somewhat common but is associated with worse fibromyalgia-associated symptoms and poorer QOL measures. A recent 1-year observational study on patients with fibromyalgia showed worse outcomes in opioid users in functioning, depression, daily activities, and insomnia compared with nonopioid users and tramadol users. However, the mechanisms mediating the adverse effects of opioids in this particular patient population are poorly understood. In a previous study, patients with fibromyalgia showed a decreased central μ opioid receptor availability. This alteration in the endogenous opioid system has been suggested to negatively influence the efficacy of opioids and worsen the sensitization of pain-associated neural pathways.,32 In another report, patients with fibromyalgia had an increased level of endogenous enkephalins in cerebrospinal fluid.Despite the expectation of showing a better clinical outcome related to opioid use, we have observed that the opioid group, even when longitudinally followed by a multidisciplinary team, was more functionally impaired and symptomatic. This raised the question whether opioids per se may have contributed to our results due to the effects of higher pain associated with central sensitization.Despite vigorous studies concerning the mechanism of opioids in fibromyalgia, without definite evidence which supports the effect of opioids on patients with fibromyalgia, their use should be considered with caution.The present study had several limitations. First, the patients in this study cohort were treated at a tertiary medical center. Therefore, they may not be representative of all patients with fibromyalgia. Second, most patients who participated in this study already had symptoms for more than 10 years. Therefore, we could not determine the severity of symptoms neither at onset of disease nor in the absence of treatments. Third, data collection had no accurate assessment of opioid dose or duration of opioid use. Fourth, we did not use the updated American College of Rheumatology criteria for fibromyalgia, as our study participants were assessed from 2001 to 2004. However, the previous version of the criteria has more strict standards than the updated version. Therefore, no controversy exists with regard to patient recruitment.5Both opioid and nonopioid groups showed improvement in QOL and functional ability based on FIQ and SF-36 scores. However, opioid use did not affect response to the FTP, as measured using the FIQ total score or SF-36 physical and mental component summary scores. Furthermore, the opioid user group showed less improvement in the FIQ subscale scores of physical impairment, job ability, fatigue, and SF-36 subscale scores of general health perception. While opioids remain a treatment choice for fibromyalgia, physicians should consider these study results and be more attentive with regard to the need for opioid prescription.Conceptualization: Jong-moon Hwang, Terry H. Oh, Donghwi Park, Chul-hyun Kim.Data curation: Jong-moon Hwang, Terry H. Oh.Supervision: Donghwi Park.Writing – original draft: Jong-moon Hwang, Chul-hyun Kim.Writing – review & editing: Jong-moon Hwang, Byung-joo Lee, Chul-hyun Kim.


The optimal postoperative analgesia after cesarean section (CS) remains to be determined. The primary objective of this study was to assess whether oral oxycodone provides the same or better pain control and satisfaction with pain relief as oxycodone given intravenously using a patient-controlled analgesia (PCA) infusion device. The secondary objectives were to compare the gastrointestinal symptoms and postsurgical recovery of the two groups.n = 133) or orally (n = 137). Pain control and satisfaction with pain treatment were assessed by a numeric rating scale (NRS) at 2, 4, 8, and 24 h postoperatively.This prospective randomized trial was conducted at a University Hospital between February 2015 and June 2017. Altogether 270 CS patients were randomly assigned to receive postoperative oxycodone pain relief by IV PCA (p = 0.006). In the IV PCA group, the patients experienced more nausea at 4 h (p = 0.001) and more vomiting at 8 h (p = 0.010). Otherwise, postoperative recovery was similar in both groups. The equianalgesic dose of oxycodone was significantly smaller in the oral group (p = 0.003).No differences were found in NRS pain scores or satisfaction between the groups except at 24 h pain when coughing; there was a statistically significant difference favoring the IV PCA group (This study indicates that oral oxycodone provides pain control and satisfaction with pain relief equal to IV oxycodone PCA for postoperative analgesia after cesarean section. Satisfaction with pain treatment was high in both groups, and both methods were well tolerated. Early nausea was less common with oral medication. Cesarean section (CS) is one of the most common surgical operations in the world . In someAfter CS, patients usually need opioid analgesia for 1–2 days. Intrathecal, epidural, intravenous (IV), intramuscular (IM), subcutaneous, or oral routes and a continuous or intermittent manner of dosing can be used . In addiNeuraxial or IV morphine is considered the standard choice of opioid for post-CS pain . IV oxycIn our institution, both oral and IV patient-controlled analgesia (PCA)-based pain relief are used. Our primary goal was to investigate by randomized controlled trial whether orally administered oxycodone provides pain control that is equal to or better than IV PCA oxycodone in CS patients. Our secondary objectives were to compare gastrointestinal symptoms and postsurgical recovery between the groups.This prospective randomized study was conducted at the Department of Obstetrics and Gynaecology at Tampere University Hospital, Finland, between February 2015 and June 2017. During the study period, 1637 cesarean sections were conducted at the study hospital. The study protocol was approved by Pirkanmaa Hospital District’s ethics committee .We sought to recruit women scheduled for elective or acute CS. Patients who underwent emergency CS or were unable to understand the Finnish language were excluded. Overall, 270 patients were randomized, 133 into the PCA group and 137 into the oral analgesia group. A flowchart of the recruitment process is shown in Fig. Patients were recruited to the study either in the outpatient clinic when the elective CS was arranged or in the delivery room when the decision for the acute CS was made. A written information letter and an oral explanation were given to the patients, and written consent was requested. A research nurse not participating in the treatment of the patients prepared envelopes including the information that assigned the patient to the IV PCA or oral group. A sealed opaque envelope was opened in the operating room by the operative nurse.All patients were operated on under spinal anaesthesia. Spinal anaesthesia was performed using a 27-gauge BD™ Quincke spinal needle at the L3–4 level. The patients were given intrathecal 0.5% hyperbaric bupivacaine 11 mg and fentanyl 10 µg. Non-invasive arterial blood pressure was maintained above − 10% of the preoperative value using an intravenous crystalloid fluid infusion and boluses of intravenous phenylepinephrine 0.05 mg.The patients had either a Pfannenstiel incision (263 patients) or a lower midline incision .Patients in both groups received extended-release oxycodone/naloxone 10/5 mg (OX/NAL) , ibuprofen 600 mg, and paracetamol 1 g orally 1 h after surgery. Thereafter, an OX/NAL dose was given every 12 h, and ibuprofen and paracetamol were given every 8 h.In the IV PCA group, the patients received an intravenous PCA device  with oxycodone 1 mg/ml, using oxycodone bolus doses of 2 mg and a lockout time of 10 min. Patients were taught to use the pump in the operating theatre, and they were recommended to use it for at least 24 h.In the oral analgesia group, patients were given an oxycodone 5 mg capsule upon request, the maximum dose being 60 mg in 24 h. The postoperative medication protocol is shown in Fig. Maternal pain scores and satisfaction with pain relief were asked and documented on the maternity ward. A numeric rating scale (NRS) was used. Pain and satisfaction were rated at 2, 4, 8, and 24 h after surgery. The pain scale ranged from 0 (= no pain) to 10 (= worst pain imaginable), and the satisfaction scale ranged from 0 (= completely dissatisfied) to 10 (= completely satisfied). Furthermore, the patient’s subjective perception about gastrointestinal symptoms—such as nausea, vomiting, and abdominal distension—was asked at 4, 8, and 24 h after surgery and categorized into two groups: patients with no symptoms and patients with symptoms. The time point for mobilization, the first meal, and defecation was recorded as well.The equianalgesic dose ratio between intravenous and oral oxycodone has been reported to be 1:2 , 14; thiBased on previous studies , the samt test in cases of normality and by the Mann–Whitney U test in cases of skewed distribution. Categorical data are presented as percentages. They were compared using the Chi-square test or Fisher’s exact test, where appropriate. Intention to treat analyses was made by groups.Statistics were analysed using SPSS for Windows, version 22.0 . Variables were tested for normality using the Shapiro–Wilk and Kolmogorov–Smirnov tests. Differences in continuous variables were studied using Student's In total, 221 patients after elective CS and 49 patients after acute CS were enrolled in the study. The groups did not differ by characteristics regarding maternal background or the type of operation . No other differences were found between the groups either in the experience of severe pain or in dissatisfaction with pain treatment  and dissatisfaction with pain treatment (NRS ≤ 3) were defined. At 24 h after CS, five patients suffered severe pain at rest in the IV PCA group, compared to none in the oral group (p = 0.001) and vomited more often at 8 h (p = 0.010). Otherwise, the groups did not differ in terms of gastrointestinal symptoms (Table Patients in the IV PCA group had more nausea at 4 h (ms Table . There wp = 0.003).In the IV PCA group, the mean consumption of iv oxycodone was 58.2 mg (SD 23.5), while in the oral group, the mean counted equianalgesic dose was 48.3 mg (SD 11.8) during the first 24 h . However, nausea and vomiting were slightly more common in patients receiving IV PCA. Regarding postoperative pain scores and general satisfaction with pain relief, both methods were equally accepted by the patients. The results of our study are in line with those of Dieterich et al., who randomized 239 patients to receive either intravenous opioid piritramide (PCA) or oral oxycodone . They usAlthough alternative drugs, new combinations of existing drugs, and new applications of local anesthetics have been studied intensively, opioids are still required for post-cesarean analgesia . IntraveIt is challenging to treat postoperative pain efficiently without side effects. Especially after CS, one must consider not only the pain relief and wellbeing of the mother, but also active mother–child bonding and breast-feeding. It is also crucial to take into account the high risk of thromboembolism after CS . Since dSelf-administration with an IV PCA is the standard treatment in some hospitals, whereas oral administration is considered easier and practical in others. Compared to per oral administration, patients with an IV PCA can receive a drug therapy that is more individualized . They reAs part of our study protocol, all patients received oral ibuprofen and paracetamol regularly every eight hours. Combined with the opioid, their safety and opioid-sparing effect have been documented in many studies. In the IV PCA group, patients used more oxycodone compared to the patients in the oral group. Regardless, there were no major differences between the groups in terms of the NRS, postoperative recovery, or satisfaction. The protocol of this study included per oral postoperative extended-release oxycodone, which entailed constant oxycodone content for all patients. By combining this with a non-steroidal anti-inflammatory drug and paracetamol regularly, the need for short-acting extra oxycodone is considerably lower after surgery. This may be the reason why oxycodone administrated either by an IV PCA or orally ensured equal pain relief in our results. As is generally known, all patients usually benefit from participating in a clinical trial, regardless of the randomization.n = 155/216) reported abdominal distension 24 h after surgery (no difference between study groups). Patients in the PCA group experienced more nausea at the 4-hour time point. Postoperative recovery was equal in both groups. The mean time of mobilization was 17 h, which is an exceptionally long time compared to our 6-h recommendation. Postoperatively, the patients were given meals depending on the schedule of the ward, i.e., the time of operation determined the time that the meal was offered. The mean delay was 7 h postoperatively. The Cochrane review in 2014 found early postoperative feeding after major gynecological surgery to be safe and to enable the faster recovery of bowel function, a shorter hospital stay, and higher satisfaction [When using an IV PCA, patients may have more nausea and drowsiness than with per oral analgesia , and thiThe strengths of this study include the large, randomized, non-selected material, and the comparison of two treatments that are normal in clinical use. A potential weakness of this study was the relatively low recruitment percentage of acute CS patients, which was 19.5% (26/133) in the IV PCA group and 16.8% (23/137) in the oral group. The difference between pain relief and postoperative recovery between the elective and acute CS could not be reliably estimated.In conclusion, the results of this study show that oral oxycodone is an effective and satisfactory method for postoperative analgesia after cesarean section. IV oxycodone administered with the use of a PCA did not offer clinically significant benefits. Both methods were generally well tolerated, and pain relief was good with both methods. Early nausea was less common with oral medication. Therefore, our findings do not support the routine use of a IV oxycodone PCA in this patient group.


Pain can have a significantly negative impact on the quality of life of patients. Therefore, patients may resort to analgesics to relieve the pain. The struggle to manage pain in cancer patients effectively and safely has long been an issue in medicine. Analgesics are the mainstay treatment for pain management as they act through various methods on the peripheral and central pain pathways. However, the variability in the patient genotypes may influence a drug response and adverse drug effects that follow through. This review summarizes the observed effects of analgesics on UDP-glucuronosyl (UGT) 2B7 isoenzyme, cytochrome P450 (CYP) 2D6, μ-opioid receptor μ 1 (OPRM1), efflux transporter P-glycoprotein (P-gp) and ATP-binding cassette B1 ABCB1/multiple drug resistance 1 (MDR1) polymorphisms on the mechanism of action of these drugs in managing pain in cancer. Furthermore, this review article also discusses the responses and adverse effects caused by analgesic drugs in cancer pain management, due to the inter-individual variability in their genomes. Pain is often experienced by cancer patients, particularly those in the advanced stage of disease where the prevalence is estimated to be more than 70% . More thHowever, some patients with advanced cancer have inadequate control of pain with systemic analgesics. These patients may alternatively benefit from the invasive techniques such as neuraxial analgesia for vertebral pain, peripheral nerve blocks, sympathetic blocks for abdominal cancer pain and percutaneous cordotomy .CYP2D6, CYP3A4/5, ABCB1 and UGTs,) and pharmacodynamics (OPRM1 and COMT) of opioids [Non-opioids, co-analgesics , and non-pharmacological measures, are frequently used to enhance analgesic control and lessen opioid requirements. In addition, they are also used to reduce adverse events related to opioid use . A myriaThis review focuses on the different types of drugs that are used in cancer pain therapy and the various enzymes, which are involved in the metabolism of these drugs.According to the World Health Organization (WHO) in 1986, the analgesic ladder is the main reference for cancer pain management . MorphinThe first step the of analgesic ladder is used for treating mild pain and includes non-opioids analgesics, such as acetaminophen (paracetamol), and non-steroidal anti-inflammatory drugs (NSAIDs) with or without adjuvant analgesics ,8,9,10. Chronic pain remains a disturbingly common consequence of cancer and its treatment. Several studies have found that more than 50% of cancer patients experience moderate to severe pain throughout their lifetime . Opioid Morphine was first isolated from the opium poppy plant by a German pharmacist, Friedrich Sertürner, between 1803 and 1805. It is still one of the most commonly used drugs to achieve analgesia in cancer pain relief. Morphine acts on μ and κ receptors but its analgesic effect is mediated primarily by the μ receptors. This is confirmed by loss of morphine analgesia in μ receptor knockout mice . The maiCodeine is known as a pro-drug: An inactive metabolite that is converted to its active counterpart. Codeine is a weak opioid that is generally administered after surgery and is used alongside certain drugs to manage acute and chronic pain . The anaHydrocodone is often used in patients with advanced cancer. It is metabolized by CYP2D6 to form the active metabolite hydromorphone, which has a 10× to 33× greater affinity for μ-opioid receptors than hydrocodone . AlthougHydromorphone has a similar structure to morphine and is available as parenteral and oral products . Its potOPRM1 were present in various Asian cohorts’ post-surgery and revealed lower fentanyl requirements in A118G-homozygous individuals [ABCB1 could lead to significant changes in fentanyl plasma concentrations, with the ABCB1 1236TT variant being associated with a lower need for rescue medication. To date there have been no statistically significant findings for fentanyl-related adverse effects, in the previous study or current body of literature [Fentanyl is a highly lipophilic opioid and is used for relieving cancer pain in transdermal and transmucosal immediate-release formulations . It is mividuals . The useividuals . Compariividuals , Radbrucividuals  and Greiividuals , respectividuals . In one terature ,32.Sufentanyl is often used as a replacement to fentanyl when the volume of fentanyl needed for treatment is above the range which can be administered through an injection ,34,35. SThe pharmacokinetics of methadone is highly variable. Methadone is a synthetic opioid, which is commonly used as a second-line option in the presence of neuropathic pain in cancer and recognized for its use in the treatment of opioid dependency . Its aveLevorphanol is a potent opioid and is similar to methadone and morphine. Levorphanol has a strong affinity for μ, κ and δ opioid receptors . StudiesBuprenorphine has a high affinity for the μ receptor. Transdermal buprenorphine is available at a higher dosage formulation in other countries compared to the United States and is used for managing cancer pain . BuprenoOxycodone is an oral opioid treatment choice for chronic cancer pain, and it is a semi-synthetic opioid prescribed for moderate to severe pain . OxycodoTramadol is recommended for patients with moderate, severe nociceptive or neuropathic pain. It is used widely in certain countries, particularly amongst cancer patients who are opioid naive or have limited opioid exposure . It consTapentadol is structurally similar to tramadol and is approved for use in the treatment of severe chronic pain in cancer patients . TapentaNSAIDs are a group of non-opioid analgesics, which are commonly used for the treatment of acute pain, following surgery or chronic pain . NSAIDs N-acetyl-p-benzoquinoneimine (NAPQI) is produced from cytochrome P450 2E1 and 3A4 metabolism of paracetamol [Paracetamol (N-(4-hydroxyphenyl)-acetamide) is one of the most widely used over-the-counter analgesics . Paracetacetamol . NAPQI iNefopam is a common postoperative non-opioid, non-steroidal analgesia. The main mechanism of analgesic action of nefopam is through the inhibition of serotonin, norepinephrine and dopamine reuptake ,53,54,55Metamizole is a widely used non-opioid analgesics for the treatment of cancer pain however it is banned in several countries due to its toxicity towards patients who have agranulocytosis ,59. GaerAdjuvant analgesic refers to drugs that are marketed for indications other than pain but with analgesic properties in some painful conditions . Drugs sAntidepressants are a mainstay treatment for neuropathic pain. Antidepressants are most commonly used to treat patients with a history of depression cases. Tricyclic antidepressants (TCA) and the selective serotonin reuptake inhibitors (SSRIs) are common antidepressants used in pain management among patients ,63. SeroCorticosteroids are usually used for cancer pain management. Studies have shown that corticosteroid treatment improves the patient’s appetite and reduces nausea ,63. BoneThe most common anticonvulsant drugs used for managing cancer induced neuropathic pain are gabapentin and pregabalin . GabapenLidocaine may be administered through the oral, subcutaneous, parenteral and transdermal route . Cancer The use of ketamine in the management of cancer related neuropathic pain produced opioid-sparing effect ,49,74. PPatients administered with olanzapine was shown to have reduced pain scores and improved cognitive function besides also reduced anxiety . ConsumpBisphosphonates are used in adjunction during treatment of cancer due to the high occurrence of cancer induced bone pain. Patients under palliative care often experience bone pain. Bisphosphonates have been shown to improve pain management among patients with breast, prostate or lung cancer . One bisThere are limited studies on cannabinoids use in cancer pain management as of now. Tetrahydrocannabinol (THC) and cannabidiol are the two most abundant compounds found in the cannabis plant. Some studies have suggested that the use of cannabinoids as adjunct to opioid, provided significant pain relief ,79. CannDexmedetomidine is sedative drug that is usually used in the intensive care units or for patients who are under hospice or palliative care. Based on a case study reported by Hilliard and colleagues , the druOne of the most common CYPs involved in drug metabolism is cytochrome P450 family 2, subfamily D, polypeptide 6 (CYP2D6). In this enzyme in which the metabolic rate can fluctuate by over 100× between the allelic variants expressed in different ethnic groups ,91. The CYP2C9 is the most abundant P450 cytochrome in the liver. Almost 15% of clinically useful drugs, including various NSAIDs is metabolized by this enzyme in the first phase of drug metabolism . Phase 1OPRM1 gene need a higher morphine dose than patients with 118AA . Other genes, such as CREB1, GIRK2 and CACNA1E, have similar consequences on the pain-relieving effects of opioids. Genotypes related to morphine’s ability to treat pain, such as the GG genotype for OPRM1, may help inform appropriate dose selection. In one study, patients with the GG genotype often require higher daily doses of morphine to achieve appropriate levels of analgesia, in comparison to the wild-type A allele  [OPRM1) have been identified [Opioid receptors belong to a family of G-protein-coupled receptors (GPCRs), which are located in the brain and spinal cord ,48. Ther= 0.006) ,32,93. Mentified .MDR1) encodes for P-glycoprotein [Adenosine triphosphate (ATP)-binding cassette subfamily B or multi-drug resistance gene (oprotein . P-glycooprotein . These poprotein . Decreasoprotein .The catechol-O-methyltransferase (COMT) enzyme is one of the enzymes that metabolizes the catecholamines, norepinephrine, epinephrine and dopamine. Therefore, the COMT enzyme acts as the main modulator of dopaminergic and adrenergic/noradrenergic neurotransmission . Patient−1 in EMs and 16 (10–24) μg·h·L−1 in UMs relative to individuals with the PM phenotype  [The uridine diphosphate glucuronosyltransferases (UGTs) family serves a major role in the conjugation of potentially toxic drugs and endogenous compounds. UGTs catalyze the glucuronidation reaction, resulting in the addition of glucuronic acid to several lipophilic compounds . Althoug = 0.02) ,32.MC1R gene indicated the potential for highly targeted analgesia on gender and other differences. There is evidence that women, respond to κ-induced analgesia more than men [Variation in the than men . Women wthan men ,41. Womethan men .Pain management regimes are established to care for post-operative and palliative patients to improve their quality of life. Patients suffering from cancer are usually subjected to chemotherapy treatment, which can be painful and cause uneasiness. Therefore, patients will resort to analgesics. The human genome is highly complex and consists of various types of polymorphisms that differ from one individual to another. A plethora of drugs are discovered and introduced into the market to counter this issue because there is not a specific drug that is suitable for every patient. Administering an incorrect drug to a patient can be life threatening. Hence, it is crucial to have the correct information on individual patient pharmacogenomics at the time of a care decision so that the data can be used to guide therapeutic decision-making. Pharmacogenomics can be employed as the future of analgesic administration to investigate the drug metabolizing enzymes or disease genes, RNA expression or protein translation of genes affecting drug response, inter-individual genetic variability in DNA sequence of drug targets and drug safety . SeriousThe limitation to this review is that the data and information collected are from low or moderate quality articles. In addition, more studies need to be carried out to fully understand the interactions of cancer drugs and painkillers that may affect therapeutic outcome. Hence, this article should only serve as a baseline and reference for future research to be carried out.


Nonspecific acute low back pain (LBP) is a common reason for accessing primary care. German guidelines recommend non-steroidal anti-inflammatory drugs and physical activity as evidence-based treatments. Manual Therapy (MT) remains controversial. To increase evidence-based treatment options for general practitioners (GPs), a Pilot-Study was set up to gather information about the required conditions and setting for an RCT.The open pilot-study assesses recruitment methods for GPs and patients, timelines, data collection and outcomes of treatment immediately (T0) and 1, 6 and 12 weeks after consultation . Inclusion criteria for GPs were: no experience of MT; for patients: adults between 18 and 50 suffering from LBP for less than 14 days.Study process: Patients’ control-group (CG) was consecutively recruited first and received standard care. After GPs received a single training session in MT lasting two and a half hours, they consecutively recruited patients with LBP to the intervention group (IG). These patients received add-on MT.Primary outcomes: (A): timelines and recruitment success, (B): assessment tools and sample size evaluation, (C) clinical findings: pain intensity change from baseline to day 3 and time till (a) analgesic use stopped and (b) 2-point pain reduction on an 11-point scale occurred.Secondary outcomes: functional capacity, referral rate, use of other therapies, sick leave, patient satisfaction.14 GPs participated, recruiting 42 patients for the CG and 45 for the IG; 49% (56%) of patients were women. Average baseline pain was 5.98 points, SD: ±2.3 .For an RCT an extended timeline and enhanced recruitment procedures are required. The assessment tools seem appropriate and provided relevant findings: additional MT led to faster pain reduction. IG showed reduced analgesic use and reduced pain at T1 and improved functional capacity by T2.Before verifying the encouraging findings that additional MT may lead to faster pain reduction and reduced analgesic use via an RCT, the setting, patients’ structure, and inclusion criteria should be considered more closely.https://www.drks.de/drks_web/. Registration date: 14.11.2011. First patient: March 2012. Funding: the Rut and Klaus Bahlsen Stiftung, Hannover.Number: DRKS00003240 Registry: German Clinical Trials Registry (DRKS) URL:  Acute nonspecific low back pain (LBP) with a one-year prevalence of up to 76% is a major health problem and a common reason for consulting a general practitioner (GP) , 2. The Are the intended recruitment procedures and proposed supporting strategies sufficient?Are the tools chosen for the GPs’ examinations and treatment and the patients’ feedback appropriate for use in this field of research?Is there evidence, such as would support running an RCT, that the MT-techniques used here and provided by MT naïve general practitioners to patients with nonspecific LBP lead to faster pain reduction compared to standard care?An American study focusing on MT provided by GPs, however, showed some small but encouraging results, particularly on the improvement of patients’ physical function . The GPsThe ManRück pilot trial is a non-blinded, multicentre intervention study to assess the feasibility of a randomized control trial (RCT) which will quantify the impact of standardized MT on patients with LBP. The rationale for the study design is detailed in the study protocol and has been described in depth elsewhere .The study progress is shown in Fig. These patients received MT and usual additional care if it was required. The treatment process and the study end-points were documented by questionnaires and pain diaries at T0 (baseline), and after 1, 6 and 12 weeks (T1-T3)  change in patients’ self-reported pain perception from T0 to day 3, measured by an 11-point combined visual analogue and numeric rating scale designed and recommended by the German Pain Society (VAS-NRS) and (2) a combined outcome of (a) time from T0 until a reduction of 2 points on the VAS-NRS occurred and b) time till patients stopped using analgesic drugs.B.For the ManRück pilot: (1) time till 20 GPs consented to participate, (2) number of enrolled CG and IG patients over a 2 week time period, (3) completeness of pain diary and questionnaires compared to the data gathered by phone interviews and (4) number of returned diaries and questionnaires.A.Combined for ManRück pilot and the intended RCT: (1) change in value of pain intensity on the VAS-NRS from T0 to day 7 (T1), (2) self-reported amount of analgesic use (prescribed or over the counter), (3) functional capacity assessed by the Funktionsfragebogen-Rücken , (4) referral by the GP for further treatment (yes/no), (5) use of other forms of therapy, (6) duration of sick leave (days) and (7) patient satisfaction with their treatment recorded at T0 using a Likert scale (0–10).B.For the ManRück pilot: assess the feasibility of teaching specific MT techniques to MT naïve GPs during a single 2 ½ hour training session.The FFbH-R questionnaire consists of 12 items describing activities of daily life and the patients’ ability to perform these on a three-point scale , with a higher score indicating a better functional capacity.The timetable of the data collection and the content of the distributed questionnaires Q1-Q4 are shown in Fig. The training for the GPs in standardized MT suitable for the treatment of LBP was planned and agreed upon by an expert panel drawn from the different German MT schools , 18. DuePracticing GPs from teaching practices associated with the Hannover Medical School and from the registry of the Association of Statutory Health Insurance of Lower Saxony were invited by telephone to participate in the study. The lists of both groups were sequentially followed until 20 GPs gave their written informed consent to participation. Exclusion criteria were: previous training in chiropractic or experience in osteopathy or physical therapy. An incentive of 100€ was not advertised during recruitment but assigned during the trial at the end of the CG treatment phase.All patients meeting the inclusion criteria Table  were invPatients younger than 18 were excluded as their inclusion would require additional parental approval. We limited the participants’ age to 50 and below, as the risk of LBP caused by specific illnesses increases with age .Participating GPs were required to carefully examine the patients and to use the appropriate documentation provided and the predefined expert-approved approach for clinical examination and history taking , as summAnalgesics and other forms of therapy  were prescribed by the GPs according to their usual treatment methods. There were no restrictions on their usual criteria for referral of patients to other professionals as they found appropriate.An expert panel discussed, selected and agreed on techniques to be taught to the MT-inexperienced GPs. High-velocity, low-amplitude (HVLA) thrusts were excluded for safety reasons. Moreover, only techniques that could be taught within 2.5 h were eligible. Two diagnostic tests and three therapeutic techniques focusing on the sacroiliac joint (SIJ) and the lumbar spine were chosen: see Table Due to the high prevalence of LBP, we expected 20 GPs to be able to successfully recruit at least 10 patients to the CG during a period of 2 weeks.At the baseline visit (T0) patients completed the first part of Q1 (incl. 12 items of the FFbH-R) before seeing the GP. The second part of Q1, including general health-related and pain-specific questions as well as items referring to patient satisfaction regarding the quality of care provided by the GP, was answered in the practice immediately after the consultation. Although some of these questions could have been addressed before seeing the doctor, we tried to keep the first part short to minimize disturbance of the consultation proceedings.Intensity and perception of pain and its consequences (sick leave) during the previous week were documented using selected questions from the Örebro Musculoskeletal Pain Screening Questionnaire (OMPSQ) . This alQ1 was sent by post to the study center by the patients in a sealed, prepared envelope. Questionnaires Q2-Q4 and patient diaries were completed at home and also sent by post to the study center. To validate the answers and minimize data loss, patients’ answers were additionally collected by phone interviews at T2-T4 during the evening hours on the respective days. If the participant could not be reached, the call was repeated the following day. In case of discrepancies, results of the telephone interview were used to analyze the clinical outcomes.The diaries documented self-assessed pain severity (using an 11-point combined VAS-NRS) and analgesic intake from T0-T1. The patients marked their pain intensity on a continuum between a sad and a smiling face. An 11-point NRS was printed on the reverse, and after indicating the appropriate level, the patients turned the scale over to read off the numerical value corresponding to their mark. A change of 2 points on the NRS was accepted as the minimal clinically relevant difference . The comThe FFbH-R (distributed at T0-T3) assesses the subjective functional ability to perform daily activities on a 0–100% scale using 12 questions. The minimal clinically relevant difference is estimated to be 12% .The sample size of patients was estimated according to the requirements of the clinical primary and secondary outcomes. The intervention was considered globally superior if (a) the change in numeric pain scale on day 3 is non-inferior compared to the change that is achieved by standard therapy and (b) the second composite end point (time until pain perception is reduced by 2 points on the NRS and painkiller use is stopped) is improved after the intervention. Our non-inferiority margin was defined as an improvement of 1 visual analog scale point.For the first primary outcome, a sample size of 86 patients per group was necessary to show the non-inferiority of additional MT compared to usual care with a power of 90% . Due to the lack of published appropriate and defined assumptions, the same sample size was also used for the second primary endpoint. We, therefore, expected that sufficient patients would be recruited if around 10 GPs each enrolled approximately 10 patients in each group .The primary analysis was performed using the intention to treat population (ITT). The results were compared with those of the per protocol population (PP). When data for a patient in the ITT population was incomplete, the last known VAS-NRS value was carried forward. Missing values in the PP population were not replaced.First, analysis of covariance for the change in VAS-NRS score from T0 to day 3 was carried out, adjusted by baseline value, GP’s practice and treatment group as independent variables. Then time taken to achieve the combined outcome of VAS-NRS-reduction of at least 2 points and cessation of analgesic use was determined. We used a common Wilcoxon/Breslow-test to compare the spread of times for both groups. A sensitivity analysis adjusted for IG and GP’s practice was carried out by a Cox-regression. The median event-times and their 95%-CI were reported.2-Test, Fisher’s exact test or Student’s t-test. Descriptive p-values were reported. Duration of sick leave and results of the FFbH-R questionnaire are presented in an explorative manner. For the FFBH-R a covariance analysis was used with treatment group, GP’s practice and baseline-value as independent variables and the changes from T0 to T1 and T2 as dependent variables.A secondary analysis used PP population with no input of missing data. The frequencies of secondary outcomes were compared for both groups by χFurther details of the tests employed were previously published in the study protocol . StatistOverall, 124 GPs from the combined list of teaching practices associated with the Hannover Medical School and from the registry of the Association of Statutory Health Insurance of Lower Saxony practicing within the city of Hannover were eligible to participate in the study. Seventy-eight of these GPs were contacted by telephone, 50 of whom wished to receive further information. Twenty GPs provided signed written informed consent and were enrolled in the study. The overall time for the GPs’ recruitment (from first phone contact to received informed consent) was 3 months.Starting on 16th of March 2012 the GPs recruited 42 patients to the CG. Despite their written commitment to participate and the offered encouragement, six out of the 20 GPs failed to recruit at least one patient for the CG during 1 year and therefore had to be excluded from the second recruitment phase (for IG-patients) due to the study design. Reasons given upon request were work overload and lack of time. To compensate for this high drop-out rate three further suitable GPs were contacted but finally only one participated in the study.The second phase of the study started on 18th of February 2013, during which the GPs recruited 45 patients to the IG , as they had suffered back pain for more than 14 days, were older than 50 years or were pregnant. Nevertheless, these patients showed no significant differences in baseline data concerning pain intensity, functional capacity and the overall superiority of the add-on MT-treatment. Following the ITT approach, data for these 11 patients were included in all analyses. T0 data for 3 patients went missing. The number of analyzed answers per question (denominator) differs as some of the returned questionnaires were incomplete.In total 11 patients were inaccurately included (IG N = 87) of returned FFbH-R questionnaires overall: 97% at baseline, 90% at T1, 86% at T2 and 83% at T3.There was a high rate  reported referrals to other doctors by their GP at T2. In all cases, these referrals during the previous 6 weeks were to orthopedic specialists.n = 84 to n = 72), although remaining at a high level, whereas the data collected by phone showed only two missing entries during the whole study period. Further nonclinical findings concerning the feasibility of an RCT and influencing the deployed study-design are summed up in Table Only 76 of the 87 patients returned their pain-diaries to the study center, and the return of questionnaires decreased slowly from T0 to T3 , PP: ]. The sensitivity analysis excluding the 11 patients who fulfilled the exclusion criteria showed similar results .p = 0.021)  cessation of analgesic use and (b) 2-point pain reduction on the 11-point VAS-NRS scale) earlier (see Table 21) Fig. , Table 7p = 0.036); the probability of reaching this outcome during the first week was twice as high for IG patients.Comparing the second combined primary outcome between the IG and CG during the first 7 days by Cox-regression, the hazard ratio was 1.961  According to our results, add-on-MT is not inferior in pain reduction from baseline to day three to usual care. (2) Moreover, add-on-MT is superior to usual care alone, as the second primary outcome  was reached faster by the IG. These two facts combined and considered together indicate a potential global superiority of add-on-MT in comparison to usual care alone.p = 0.023 and p = 0.009 respectively). As the sample size calculation focused on the power of the primary outcomes, however, this finding can only be interpreted as a tendency.From days 1 to 7, the IG patients reported less pain than patients in the CG Fig. . Moreovep = 0.129). The mean difference between the groups from T0 and T2 was: . However, this slight difference could not be observed after longer periods of time . The mean difference between IG and CG in the change in FFbH-R score from T1-T0 was:  of absence from work due to LBP was 3.6 (±9.2) for the CG and 4.0 (±9.5) for IG.Both groups of patients were equally satisfied with their GP and the quality of treatment they received.No adverse events were reported during the trial.The results of the ManRück trial support our hypothesis that MT- techniques in addition to the usual treatment for LBP lead to faster pain reduction and reduced analgesic intake. Moreover, the pain reduction was accompanied by a faster improvement in functional capacity values in the IG, a difference that lasted up to 6 weeks after treatment. Both observations encourage the pursuit of the question of whether MT is a useful option for treating acute non-specific LBP. In general, the ManRück findings confirm the feasibility of this kind of research, while simultaneously indicating improvements which need to be made in the main study. For example, the number of recruited GPs should be increased, and enhanced techniques developed to support their recruitment of patients. The ManRück results showed that the sample size of participating patients must be re-evaluated, as must the time needed for their recruitment. The inclusion and exclusion criteria for patients  should also be critically rethought. Data collection by telephone is preferable to using posted replies, although of course more time-consuming. It would also be beneficial to increase the frequency of the contacts between the study center and the study nurses in the GP’s practices. A further important consideration would be to raise awareness of the study by the use of more target-group adapted flyers, by a higher number of seasonally adapted posters and the use of “new communication channels” (such as electronic messaging on screens in practice waiting rooms) to inform eligible participants of the opportunity of participating in the study.Recently a randomized controlled trial assessed the effect of interferential current on chronic low back pain, but to our knowledge, only one previous trial involving GPs has considered the effect of MT on acute LBP , 22. CurTo anticipate and avoid expected criticisms concerning the self-limiting character of LBP  as raiseBecause specialists from many different professions performed MT with different approaches, it was difficult to directly compare the results of the MT treatments or the competence and efficiency of the physicians in the trials identified by a systematic literature review. Sometimes osteopaths, chiropractors, orthopedic surgeons, GPs, and physiotherapists applied MT during the same trial , 24. In There is no standardized, generally accepted tool to assess the impact of MT. Available diagnostic tests are controversial , 26, 27.The ManRück study was designed to investigate the feasibility of an RCT in the GP practice with the aim of reflecting the LBP-concerned population and the real-life practice as closely as possible. For this reason, all patients presenting to their GPs with acute non-specific low back pain were included. This reduced the risk of selection bias from the start and hopefully will maximize the transferability of the results into the daily practice routine. Despite our efforts concerning the study design, a performance bias could not be ruled out with complete certainty, but the successive recruitment of first the CG and then the IG and the positioning of the training sessions between the two recruitment phases ensured that the GPs had no knowledge of MT during CG recruitment and treatment. This minimized a potential source of influence on both the recruitment process and the outcomes of ManRück and will also be taken into account in the RCT.Due to the lack of randomization in the ManRück study, systematic differences between the CG and the IG group could potentially still occur, such as differences in sex and age. Investigation of the baseline values, however, showed no evidence of such differences between the two groups. To document any influences of potential differences in duration and intensity of the doctor-patient contact on the results of the investigation, both the IG and CG were questioned regarding their satisfaction with their treatment directly after the appointment. Analysis of the data showed no difference on average between the two groups.The use of a defined standardized MT that predominantly features mobilization techniques may be incompatible with current clinical beliefs that MT should be individualized according to the patient’s overall presentation , 30. MorThe time points at which the outcome parameters were measured were chosen deliberately in order to investigate the immediate effects of MT on acute LBP in the first week after treatment. A 12-week follow-up was used, as, according to the German guidelines, back pain lasting for longer than 12 weeks should be classified as chronic . In the GPs were asked to register all patients presenting with a backache in a table during the CG and IG recruitment phases, but unfortunately, these data were not collected as intended. The GPs explained that they did not have the time to note down all back-pain patients due to their high number and, instead, concentrated on those fulfilling the criteria for inclusion in the study. According to the GPs, most of the excluded patients had already received other forms of treatment, mostly by physiotherapists or chiropractors. The lacking documentation on excluded patients is an important point to be improved in an RCT to obtain a proper sample description and identify the subgroup population which will benefit most from this kind of intervention.Finally, we would like to highlight one of the ManRück findings: the reduced analgesic use in the IG. We found this particularly striking, although it had no immediate effect on improving function. It is of special interest for patients with known intolerances to commonly used analgesics such as NSAIDs or acetaminophen, or suffering from side-effects of these medications –35 and sManRück is a study that investigates the use of MT in a GP practice setting and offers a detailed description of the standardized MT technique used, thus ensuring that the study design and the training can be copied and used by any interested party. Moreover, the outcome of the treatments can be contrasted with that of future investigations.However, this study was not without limitations. Due to the strict inclusion and exclusion criteria, the final sample size was not as high as planned, although recruitment was extended to a total of 23 months, thus reducing the power of the trial. A reason for insufficient recruitment might be the limited financial resources for this preliminary feasibility study. Moreover, there was a change in the study-staff involved in the recruitment, which meant some time passed before an adequate replacement was found. Additionally, in spite of existing estimations of LBP prevalence (point prevalence up to 70% in Germany, including all back pain locations from thoracic- to sacrum spine segments  and a meTo verify the promising results of faster pain reduction, future study designs should preferably include a sham intervention. Considering the possibility that the findings of ManRück are due to additional attention, action and time attributed to the patients and not to specific MT-techniques, the assessed outcomes might turn out to be the result of a powerful placebo.Although the unbalanced distribution of participating patients between the practices was addressed by defining the practices as independent variables in the statistical models, wherever possible this problem should be solved beforehand in upcoming trials. Finally, the trial focused on GPs who were inexperienced in MT, a primary care setting and specifically on adults. For this reason, the effect of MT documented in the ManRück study cannot be generalized for other professionals and is not applicable to younger or older patients or those with specific LBP.The pilot ManRück trial explored the possibility of a convenient approach to improve treatment of LBP in a “real life” primary care setting. The employed techniques seemed to be suitable to enrich the usual treatment of LBP in primary care because they apparently reduce the burden of pain. Moreover they may potentially be of use in preventing chronification of LBP and reducing costs of illness and by this worthy of further investigation. The assessment of the effects of MT with a greater sample size, a longer follow-up and a measurement of the acquired competences of GPs in MT by a randomized controlled trial is needed to confirm the findings of the ManRück pilot and to investigate further the possibilities of MT techniques when treating LBP.


To evaluate the effectiveness of transforaminal lumbar epidural steroid injections (TFESI) in patients with unilateral radiculopathy due to lumbar intervertebral disc protrusion regarding pain intensity, functional disability, current opioid intake and patients’ satisfaction. The study is conducted in a pain management center , during 2018. Inclusion criteria were age ≥18 years, radiculopathy for more than 6 months due to imagine-proved lumbar intervertebral disc protrusion and no response to conservative treatments. Exclusion criteria were spinal canal stenosis, lumbar surgery, and inability to communicate in Persian language. During a phone call interview, cases were instructed to rate their pain intensity according to the visual analogue scale (VAS), functional ability, satisfaction according to the patient satisfaction score (PSQ) and report current opioid use and additional injection and/or surgery. p=0.002). Mean functional disability before intervention was 47.23 and after intervention was 37 (p<0.001). Mean patient satisfaction score was 3.07 while 18 cases reported a PSQ level ≥4.  10 cases reported using opioid for analgesia, 23 cases reported receiving additional TFESIs and 11 reported having undergone lumbar surgery.Forty-three (89.5%) of the 48 subjects were reachable for study with mean age of 59.14 years and 16 subjects were men (37.2 %). Mean VAS after intervention was 4.67 and before the intervention was 6.91 (Lumbar Epidural steroid injection is an effective non-surgical treatment option with regard to pain relief and improvement in functional ability with an average patients’ satisfaction during 2 years follow up although nearly 25% of patients may need additional injections and half of the patients may finally proceed to surgery.  Among the multiple presentations of back pain and lower extremity pain, lumbar radicular pain is a common condition which may be caused by a herniated intervertebral disc exerting pressure on the nerve root, resulting in pain, functional disability, opioid use for pain relief and consuming health resources. Multiple modalities of treatments are exploding in managing chronic back pain and radiculopathy along with increasing prevalence. Most patients will respond to conservative treatment. But after the failure of conservative treatment, either surgical or nonsurgical modalities such as epidural injections are considered in the management of lumbar radiculopathy -3.Epidural corticosteroid injections (ESIs) have been used for decades as a non-surgical therapeutic modality in controlling of spinal pain and radiculopathy syndromes attributed to intervertebral disc pathology . EpiduraThis study is designed to evaluate the effectiveness of transforaminal lumbar epidural steroid injections in patients with unilateral radiculopathy due to lumbar intervertebral disc protrusion. This report consists of the results of 43 patients with a 2-year follow-up, and is a continuation of a previously published randomized, double-blind clinical trial on the effects of corticosteroid after lumbar TFESIs. Outcome measures included pain Intensity and functional disability, assessed at baseline and at 24 months following the treatment. Patients’ satisfaction from the intervention and current opioid intake are also evaluated. Additional lumbar spine injection and progression to surgery during the past two years were secondary outcome measures. Study population   The present observational/analytical non-randomized prospective study is designed and conducted in an interventional pain management referral center , during 2018 in order to demonstrate the results from a two-year follow-up of a previously performed intervention of lumbar transforaminal steroid injection on patients with unilateral radicular pain due to lumbar intervertebral disc protrusions. Study protocol was approved by local ethics committee of the university and study was performed in accordance with the ethical standards of the 1964 Declaration of Helsinki.  Study population were all patients who had undergone lumbar TFESIs in our medical center during 2016. Inclusion criteria were age> 18 years, history of unilateral radicular pain for more than 6 months, lumbar intervertebral disc protrusion which was proved by diagnostic medical imaging, and no response to conservative treatments. Exclusion criteria were history of spinal canal stenosis, history of any lumbar surgery, and inability to communicate in Persian language. Sampling was done using convenience method and all the participants of the previous study who met the criteria were included in the present study.Study protocol   Baseline and demographic data for all patients were recorded in patient’s profile and each participant is called by an independent researcher. If any patient was unreachable after 3 calls in different times of a day and different days of a week, patient was excluded from the study. During the phone call interview, Study aim and objective were described to each patient and participants were instructed to respond to the questions or rate each scale independently. Pain intensity was evaluated based on verbal numerical rating scale (NRS). NRS is one of the most commonly used self-report scales for measuring pain, likely due to its ease of use  and because its 0 to 10 metric is preferred by health care professionals. Patients typically were asked, “How strong is your pain during the past 14 days, where 0 is no pain and 10 is the strongest or worst pain you can imagine?” Functional ability was evaluated based on Oswestry Disability Index (ODI). ODI is a self-administered questionnaire measuring “back-specific function” on a 10 item scale with six response categories each. Each item scores from 0 to 5, higher scores being worse, which is transformed into a 0–100 scale. The ten items include pain intensity, personal care, lifting, walking, sitting, standing, sleeping, work, social life and traveling. Patients with scores between 0 to 20 have Minimal Disability, between 21 and 40 have Moderate Disability, between 41–60 have Severe Disability, 61 to 80 are crippled and 81 to 100 are bed-bound or exaggerating their symptoms. Patient Satisfaction was evaluated based on Patient Satisfaction Questionnaire (PSQ). PSQ is a treatment-specific instrument for measuring satisfaction with treatments. Patients were asked to choose their overall rating of TFESI among five choices from excellent to poor. Patients were asked about their Opioid consumption for their presenting symptoms during the past 2 weeks. Additional lumbar spine injection and progression to surgery during the past two years were asked and the answers were documented in their profile.Due to the long duration of follow-up and for reasons such as death, migration, or change in the status of sample cases over time, the presence of cases with no follow up (loss-to-follow-up) is predictable. To minimize this bias, inclusion and exclusion criteria are limited, and therefore, the samples will be completely homogeneous from the pathological point of view. As a result, the sample population will represent the community studied. In order to avoid recall bias, the primary outcome measured concentrated on current condition of the patients .  In order to avoid response bias, patients were provided with adequate details and necessary clarifications about the questions and the correct way of responding to the questionnaires.Statistical analysis   Date were analyzed using SPSS . Continuous variables are presented as mean (± SD) or median (range) according to the normal or not-normal distribution of data. Ordinal data are presented as count (%). An independent-samples t-test (two-tailed) was used to compare the variables at baseline and at 2-year follow-up between patients. An alpha level <0.05 was considered to be statistically significant. During the past recruitment period (March 2018-December 2018), 48 subjects with unilateral radicular pain had undergone lumbar transforaminal epidural steroid injection in our tertiary medical center. Between 2 years after the procedure, 43 (89.5%) of the 48 subjects were reachable for follow up. Baseline and demographic characteristics of those reachable for follow-up were analyzed. Average age of participants was 59.14 years with 16 subjects being male (37.2 %) and 24 cases (55.8%) reporting no comorbidity. Of 19 cases who had reported comorbidity, 9 were known cases of hypertension (HTN), 4 were known cases of diabetes mellitus (DM) and 1 was known case of ischemic heart disease (IHD) while 2 reported being diagnosed with DM and HTN, 1 reported being diagnosed with IHD and HTN and 2 reported being diagnosed with IHD and HTN at the same time. Baseline data are demonstrated in Upon evaluating the entire results, all 43 cases reported a history of current pain since intervention  with mean VAS of 4.67. Mean VAS was 6.91 (ranged from 5-10) before the intervention. The difference in VAS before and after intervention was statistically significant. Mean functional disability (ODI score) before intervention was 47.23 (ranged from 33-64). After receiving the intervention and during 2 years follow up, mean ODI score was 37.35 (ranged from 15-68). This difference in ODI was before and after intervention statistically significant. Mean patient satisfaction score (PSQ) was 3.07 while 18 cases reported a PSQ level ≥4. Data are stated in The 2 year results of the present study evaluating the effectiveness of lumbar transforaminal epidural steroid injections in patients with unilateral radicular pain due to single-level lumbar intervertebral disc protrusion showed significant, clinically applicable results in interventional pain management settings. This study showed significant improvement in pain relief and functional ability of patients receiving transforaminal epidural steroid at the end of 2 years along with an average patient satisfaction rating (PSQ: 3/5).et al. in 2018 aimed to determine the long-term outcomes for a homogenous group of patients with acute unilateral lumbar radicular pain due to single-level herniated nucleus after lumbar epidural steroid injection at ≥5 years. They found that despite a high success rate at 6 months, the majority of subjects experienced a recurrence of symptoms at some time during the subsequent 5 years. Few reported current symptoms, and a small minority required additional injections, surgery, or opioid pain medications. They concluded that Lumbar disc herniation can be effectively treated in the short-term by TFESI or surgery, but long-term recurrence rates are high regardless of treatment received [ Although epidural steroid injections have been used for more than half a century in the management of lumbosacral radicular pain and numerous studies have evaluated the efficacy of caudal or lumbar administration of epidural steroids, but studies that have specifically assessed the follow-up outcomes regarding opioid consumption, need for additional injections and/or surgery  are still scarce -9. Kennereceived .et al. showed that Fluoroscopic transforaminal epidural steroid injections are an effective nonsurgical treatment option for patients with radiculopathy in whom more conservative treatments are not effective [et al. compared transforaminal epidural steroid injections with saline trigger-point injections used in the treatment of lumbosacral radiculopathy secondary to a herniated nucleus pulposus. After an average follow-up period of 1.4 years, the group receiving transforaminal epidural steroid injections had a success rate of 84%, as compared with 48% for the group receiving trigger-point injections. They concluded that fluoroscopically guided transforaminal injections can serve as an important tool in the nonsurgical management of lumbosacral radiculopathy secondary to a herniated nucleus pulposus [In a prospective case series that investigated the outcome of patients with lumbar herniated nucleus pulposus and radiculopathy who received fluoroscopic transforaminal epidural steroid injections, Lutz ffective . Vad et pulposus .et al. performed a prospective cohort study. From a total of 34 patients who were followed for 1 year, Seventy-five percent of patients had successful long-term outcome, reporting at least a >50% reduction between pre-injection and post-injection pain scores. Sixty-four percent of patients had improved walking tolerance, and 57% had improved standing tolerance at 12 months. They concluded that transforaminal epidural steroid injections may help reduce unilateral radicular pain and improve standing and walking tolerance in patients with degenerative lumbar spinal stenosis [To identify the short- and long-term therapeutic benefit of fluoroscopically guided lumbar transforaminal epidural steroid injections in patients with radicular leg pain from degenerative lumbar stenosis, Botwin stenosis .et al. 20 patients with chronic low back pain were followed for 3 months after lumbar ESI and pain relief, functional ability and opioid use were evaluated. Over a three month period, they realized that pain ratings improved and opioid use decreased initially after lumbar ESI for LBP but this effect tapered over time [et al. aiming to determine the efficacy of epidural steroid injection in the treatment of patients with lumbar herniated disc who were surgical candidates revealed that Epidural steroid injection was not as effective as discectomy with regard to reducing symptoms and disability associated with a large herniation of the lumbar disc. However they concluded that epidural steroid injection was effective for up to three years by nearly one-half of the patients who had not had improvement with six or more weeks of noninvasive care [Previous studies have reported pain reduction and improved activity after LESI. However, the data on opioid consumption after LESI is less clear.  In a pilot study performed by Sehgal ver time . In a stive care . In the et al. in 2008 conducted a 2-year study in which 13,741 different patients underwent an ESI for low back pain. Their aim was to evaluate whether the use of epidural steroid injections (ESIs) is associated with decreased subsequent opioid use in patients and to determine whether treatment with multiple injections are associated with decreased opioid use and lumbar surgery after ESIs. They found that Opioid use did not decrease in the 6 months after ESIs. Patients who received multiple injections were more likely to start taking opioids and to undergo lumbar surgery within the 6 months after treatment with ESIs. They came to the conclusion that ESIs are not reducing opioid use in this population [Friedly pulation . Findingpulation ,  it can We note some limitations to our study. The study was performed in a single pain intervention department and confirming the results by a relatively small number of patients examined in our study will require further prospective multi-central randomized trials with larger and clustered samples for accomplishing significant, clinically applicable results in interventional pain management settings. In conclusion, lumbar Epidural steroid injection is an effective non-surgical treatment option with regard to pain relief and improvement in functional ability with an average patients’ satisfaction during 2 years follow up although nearly 25% of patients may need additional injections and half of the patients may finally proceed to surgery. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are associated.None declared.