The patients with FM had increased pain sensitivity and reduced EIH compared with healthy controls. None of the polymorphisms had an effect on EIH on their own. We found significant gene-to-gene interactions between OPRM1 x 5-HTT and OPRM1 x 5-HT1a regarding activation of EIH, with no statistically significant difference between groups. Better EIH was found in individuals with genetically inferred strong endogenous opioid signaling (OPRM1 G) in combination with weak 5-HT tone (5-HTT low/5-HT1a G), compared with strong 5-HT tone (5-HTT high/5-HT1a CC). Based on the proposed mechanisms of these genetic variants, the findings indicate antagonistic interactions between opioid and serotonergic mechanisms during EIH. Moreover, despite different baseline pain level, similar results were detected in FM and controls, not supporting an altered interaction between opioid and 5-HT mechanisms as the basis for dysfunction of EIH in patients with FM. In summary, our results suggest that, by genetic association, the mu-opioid receptor interacts with 2 major serotonergic structures involved in 5-HT reuptake and release, to modulate EIH.Chronic pain is associated with dysfunctional endogenous pain modulation, involving both central opioid and serotonergic (5-HT) signaling. Fibromyalgia (FM) is a chronic pain syndrome, characterized by widespread musculoskeletal pain and reduced exercise-induced hypoalgesia (EIH). In this study, we assessed the effects of 3 functional genetic polymorphisms on EIH in 130 patients with FM and 132 healthy controls. Subjects were genotyped regarding the mu-opioid receptor (OPRM1) gene ( Patients with FM also have a dysregulation of central serotonergic (5-HT) metabolism, with reports of reduced 5-HT metabolites in the cerebrospinal fluid.36 Moreover, there is evidence of an antagonistic relationship between opioid and serotonergic mechanisms in regard to pain regulation. The bimodal pain response of opioid agonists with initial analgesia followed by a delayed onset of hyperalgesic effects13 has also been attributed to 5-HT1a agonists but with a converse effect—initial hyperalgesia followed by a delayed long-term analgesic effect. Interestingly, 5-HT1a agonists have been shown to prevent and reverse opioid-induced hyperalgesia.9Chronic pain is associated with an aberrant cerebral response to painful stimuli and dysfunctional pain modulation in particular, which is well characterized in the chronic pain disease fibromyalgia (FM).1 we set out to investigate the interactions between functional polymorphisms of genes coding for key structures involved in opioid and serotonergic signalling. First, the single-nucleotide polymorphism (SNP) rs1799971 in the OPRM1 gene, regulating the activation of the mu-opioid receptor,15 where the presence of the G-allele is proposed to increase the tone of the endogenous opioid system compared with the homozygous AA-genotype.33 Second, 2 functional polymorphisms (5-HTTLPR and rs25531) in the serotonin transporter (5-HTT) gene SLC6A4 have jointly been shown to alter the degree of gene expression into high, intermediate, and low expression of 5-HTT.44 Third, the SNP rs6295 in the HTR1A gene, regulating the expression of the 5-HT1a receptor, where the G-allele, has been linked to reduce the overall 5-HT tone compared with the homozygous CC-genotype.46 The 5-HTT low-expression genotype has been associated with downregulation of 5-HT1a receptors,30 indicating that the 5-HTT low expression and 5-HT1a-G genotypes both mediate pain modulation comparably.29Genetic association studies offer an intriguing way to study pain-related behavior in vivo in a noninvasive and noninterfering manner in humans. As FM has demonstrated a clear genetic component,34 We hypothesized that individuals with genetically inferred strong endogenous opioid mechanisms would have better EIH if they also had weak 5-HT mechanisms (OPRM1 G and 5-HTT low/5-HT1a G) and vice versa (OPRM1 AA and 5-HTT-high/5-HT1a CC). Given our hypothesis that patients with FM have overactivated endogenous opioid mechanisms in combination with 5-HT dysfunction, we hypothesized that FM patients with genetically inferred weaker opioid mechanisms in combination with stronger 5-HT mechanisms (OPRM1-AA and 5-HTT-high/5-HT1a CC) would have more pronounced EIH function.The aim of this study was to investigate the interactions between genetically inferred opioid and serotonergic mechanisms on a pain assessment in patients with FM and in healthy controls (HC). We chose exercise-induced hypoalgesia (EIH) as pain induction because it often exacerbates pain and has previously been reported to be dysfunctional in patients with FM.ClinicalTrials.gov identification number: NCT01226784).25 Baseline data from this trial are used in this study. Only women were recruited for the study to represent the patient population.39 A total of 415 women with FM were screened by telephone for possible eligibility and information about the study. Out of these, 177 women were referred to a medical examination by experienced physicians who performed a standardized interview and palpation of tender points to verify the American College of Rheumatology 1990 criteria for FM.45 A total of 52 women were found not eligible because of not meeting the inclusion criteria (n = 32) or declining participation (n = 15). Exclusion criteria were high blood pressure (>160/90 mm Hg), osteoarthritis in hip or knee, other severe somatic or psychiatric disorders, other primary causes of pain than FM, high consumption of alcohol (Audit >6), participation in a rehabilitation program within the past year, regular resistance exercise or relaxation exercise twice a week or more, inability to understand or speak Swedish, and not being able to refrain from analgesics, nonsteroidal anti-inflammatory drugs, or hypnotics for 48 hours before examinations. For HC, 189 women were recruited by telephone screening to complete the baseline assessment, of which 55 women were excluded because of not meeting the inclusion criteria or declining participation. A total of 130 patients with FM and 134 HC, all white women, were eligible and included in the study. Because of inaccurate genotyping  and incomplete assessment of EIH , the analysed cohort consisted of 122 patients with FM and 129 HC. The study was conducted in accordance with the Declaration of Helsinki, with approval from the regional ethics committee in Stockholm (2010/1121-31/3). All participants were given written and oral information and written consent was obtained.Female patients with FM and HC of 20 to 65 years were recruited, by newspaper advertisement in the local newspapers of 3 cities in Sweden , to participate in a 15-week resistance exercise intervention trial ,10 and subjects with FM also completed the Fibromyalgia Impact Questionnaire (FIQ).5 HADS is a self-reported scale designed to screen for the presence of anxiety and depression in nonpsychiatric patients. It consists of 2 subscales assessing anxiety (HAD-A) and depression (HAD-D) independently. Each subscale includes 7 assertions with accumulated scores between 0 and 21, where cut-off scores of above 8 can be regarded as the presence of anxiety and depressive disease.6 The SF-36 BP is a subscale of the Short-Form 36 (SF-36), a generic health survey for the evaluation of perceived health and functional status. The subscale is a validated instrument to assess pain severity and its interference with working activities over a longer period of time (4 weeks).17 The raw scores are transformed into a 0 to 100 scale, where lower scores reflect more pain symptoms. This questionnaire was chosen to reflect the physical aspect of pain and over time. The FIQ is a 20-item self-reporting questionnaire that assesses symptoms and disability related to FM. The total score ranges from 0 to 100, where a higher score indicates a greater severity of symptoms, ie, lower health status due to FM.5The study took place at 3 sites , and 4 different investigators performed the test procedures. The investigators had been jointly trained to ensure consistent procedures across the sites. All participants completed standardized questionnaires regarding health status, namely, Hospital Anxiety and Depression Scale (HADS),2 and a pressure increase rate of 50 kPa/s. The subjects were instructed to press a button when the pressure caused the slightest perception of pain. Before the experiment, a few test assessments were conducted in order for the subjects to familiarize with the algometer. Pressure pain thresholds were assessed once at 8 different target sites: bilaterally on m. supraspinatus, the lateral epicondyle of the humerus, the gluteal area, and the inside of the knee (corresponding to the tender points used in the ACR 1990 criteria for FM classification). The average PPT was used for assessment of pain sensitivity.Pressure pain thresholds (PPTs) were assessed with a hand-held algometer , with a probe area of 1 cm7 The subjects were instructed to perform an isometric knee extension by pushing against the cuff with as much force as possible. The MVC was measured 3 times in both legs during a period of 15 seconds with 1 minute of rest between each period. Before the EIH session, the subjects rested for 10 to 15 minutes while doing other noneffort tests (not included in this study). For the experimental part, the subjects were seated in the same position and were instructed to perform a right leg isometric knee extension by pushing against the cuff with the force of 30% of MVC for as long as possible until exhaustion or for a maximum of 5 minutes. The subjects could adjust the force using visual feedback according to the display of Steve Strong. During the experiment, the investigator encouraged the participant to keep the force for as long as possible. Pressure pain thresholds were assessed at the right m. deltoideus (MD) and the contracting MQ first twice ahead of the contraction , and then continuously during static contraction. One PPT assessment was performed approximately every 20 to 25 seconds depending on how fast the pain threshold was reached, alternating between MD and MQ. Only PPTs assessed at MD were used for the assessment of EIH in this study because they assess the activation of central pain regulatory mechanisms. The values at start, middle , and end of contraction were used for statistics regardless of the total contraction time  in m. quadriceps (MQ) was recorded using Steve Strong , a dynamometer assessing isometric muscle force in the knee extensors.rs1799971 of OPRM1 and the C(-1019)G 5-HT1a promoter polymorphism of HTR1a gene were dichotomized into major allele homozygotes and minor allele carriers.43 The 5-HTT gene (SLC6A4) comprises the functional polymorphism 5-HTTLPR, which consists of an L allele and an S allele. The SNP (rs25531) containing an A-allele and a G-allele has been shown to further modulate the efficacy of 5-HTTLPR. The minor G-allele, which almost always coexists with the L-allele, reduces gene expression to S-allele levels. Thus, the functional division of individuals results in a high 5-HTT-expressing group (LA/LA), an intermediate 5-HTT-expressing group (LA/LG or LA/SA), and a low 5-HTT-expressing group (SA/SA or SA/LG). Studying the 2 polymorphisms jointly, referred to as the triallelic 5-HTTLPR, is proposed to be more accurate for studying the functionality of the 5-HTT gene.44 This has also been confirmed in clinical studies22 and was therefore used in this study.Saliva samples (Oragene G500) were collected from all subjects and were used for genotyping. All genotyping was performed blind to phenotypic information. The SNPs in this study were chosen based on a priori hypotheses based on existing literature. To be consistent with previous research, the genotypes of the 118A<G SNP rs1799971 (OPRM1) and rs6296 (5-HT1a), genotyping was performed using TaqMan SNP genotyping assays and ABI 7900 HT instrument (Applied Biosystems (ABI), Foster City, CA). Polymerase chain reactions (PCRs), with a total volume of 5 μL, were performed in 384-well plates containing 2.5 µL Universal Master Mix (UMM) and 5 ng dried-down genomic DNA per well. The PCR amplification protocol includes 2 holds, 50°C for 2 minutes and denaturation at 95°C for 10 minutes, followed by 45 cycles for rs6296 and 50 cycles for rs1799971 at 92°C for 15 seconds and 60°C for 1 minute. For the genotyping of the triallelic 5-HTTLPR, 2 fragments, 487 bp (short) and 530 bp (long), were amplified by PCRs. Each PCR reaction contained 50 ng DNA, 0.2 mM deoxynucleotide triphosphate (dNTP), 0.4 µM of primer 17P-3F (5′-ggcgttgccgctctgaatgc-3′), 0.4 µM primer 17P-3R (5′-gagggactgagctggacaaccac-3′), 0.05 µL Qiagen HotStar Polymerase, 1 M Q-solution, and finally 1x buffer. Samples were amplified on Biorad Tetrade  with an initial denaturation for 10 minutes at 95°C followed by 33 cycles consisting of denaturation for 30 seconds at 95°C, annealing for 30 seconds at 57°C and elongation for 5 minutes at 72°C, and finally followed by another elongation step for 5 minutes at 72°C. Eight microliters of the PCR reactions were separated for 2 hours at 100 V by gel electrophoresis in TBE buffer on a 2.5% agarose gel containing GelRed and visualized using ultraviolet light. To determine the rs25531, 10 µL of the PCR product was digested with 0.1 μL MSP1  and 1 μL buffer per sample for 12 hours at 37°C. The MSP1 restriction enzyme breaks the 5′-C/CGG′ sequence that gives a fragment of 342 base pairs, one of 127 and finally one of 62 base pairs which constitutes the LA allele, whereas the 298, 127, and 62 base pairs is the SA allele, the 173, 166, 127, and 62 base pairs for the LG allele, and finally the 166, 130, 127, and 62 for the SA allele. Fragments were run on a 4% agarose gel  containing GelRed initially for 15 minutes at 70 V followed by 2 more hours at 100 V. The gels were then visualized with ultraviolet light.For the polymorphisms P-value of <0.05 was considered significant. Data were reported as mean ± SD and graphs as mean with error bars of ± 1 SEM. Genotype frequencies were analyzed with the Fisher exact test, and χ2 tests were used to assess deviations from Hardy–Weinberg equilibrium. The Shapiro–Wilk test was used to assess the assumption of normality, and when appropriate to use nonparametric tests. To assess differences in pain sensitivity, contraction time, and number of PPT assessments, the Mann–Whitney U test was used. Exercise-induced hypoalgesia was analyzed by repeated measures analysis of variance (ANOVA) with the within-subject factor TIME  and the between subject factor GROUP (FM or controls) and age as a covariate. The same analysis was also performed with the number of PPT assessments as an additional covariate. Greenhouse–Geisser correction was applied if the assumption of sphericity was violated. All post hoc differences in EIH were analyzed with the Mann–Whitney U test, except for group difference over time where the Wilcoxon signed-rank test was used. To assess whether the different genotypes affected symptom parameters, a multivariate ANOVA was performed separately for patients with FM and the HC group. The dependent variables were FIQ, HAD-D, HAD-A, average PPT, and SF-36 BP, the independent variables were the genes OPRM1, 5-HTT, and 5-HT1a, and age was used as a covariate. The overall effects of gene × gene interactions were analyzed by univariate ANOVAs, with a pain modulation score as the dependent variable, group and genotypes as independent variables, and age, HAD-A, and HAD-D as covariates. In addition, the same analysis was performed separately in HC and FM patients with the additional covariates of antidepressants , FM duration, and FIQ in the FM group. This was done to control for more covariates in patients with FM and because the groups differed significantly in the function of EIH and pain modulation scores. Post hoc analyses were performed with univariate ANOVAs and Student t test for further analysis of gene interactions.All analyses were performed using SPSS Statistics, version 22.0 . For all inferences, 2-tailed tests were used and a 21; the range of the values at rest in this study was 29 to 583 kPa. Thus, it was natural to consider the effect on EIH by assessing the relative change in PPTs during contraction, which is fairly constant for each individual.23 Therefore, all PPT values were divided by the individual's very first baseline PPT value and are referred to as the normalized PPTs. The normalized PPTs at MD were calculated at baseline, start, middle, and end of each individual's contraction and were used for the analysis of EIH. Furthermore, for genotype effects, the pain modulation score is a quantification of the amount of pain modulation that occurs during the EIH assessment, with zero being no modulation, positive values indicating pain inhibition, and negative values indicating pain facilitation. The pain modulation score was calculated for each individual as the PPT value at the end of contraction minus the mean PPT value at baseline, divided by the mean PPT value at baseline.28 The reason for this is to control for individual variation in baseline measures. The score represents the relative difference from baseline PPT value rather than the absolute difference in kPa. However, the pain modulation score was strongly correlated with the absolute change in PPT during contraction .The interindividual variability in PPTs is pronounced6 Genotype frequencies were similar for all genes for FM patients and HC .Patient characteristics grouped by FM patients and HC are presented in Table HC Table , and allP = 0.001) and HC (P = 0.049), and SF-36 BP scores were increasing with age (P = 0.010), indicating decreasing reports of pain severity with age in patients with FM.Assessments of gene effects on symptoms were performed separately for FM patients and HC because of their different baseline pain level. The ANOVAs revealed no effect of the genetic polymorphisms of OPRM1, 5-HT1a, and 5-HTT on assessed symptom severity  in either FM patients or HC . No significant gene x gene interactions were found regarding symptom severity. Pain sensitivity (average PPT) was increasing with age in both FM , group , and a significant time x group interaction . Because there was a significant difference in the number of PPT assessment, this was assessed as a covariate. The time × group interaction turned out more significant after controlling for the number of PPT assessments , indicating that the difference is not explained by the difference in the number of PPT assessments. Post hoc analysis revealed that normalized PPTs at MD increased significantly at the end of contraction compared with baseline in patients with FM and controls (both groups P < 0.001), indicating functioning pain inhibition in both groups during EIH. Post hoc analysis of group differences during contraction revealed no significant difference at start (P = 0.17); however, normalized PPTs were significantly lower in patients with FM at the middle (P = 0.001) and the end (P = 0.003) of contraction, indicating significantly reduced EIH in patients with FM than controls , showing reduced pain inhibitory mechanisms in FM.Regarding the EIH assessment, there was a statistically significant effect of time , and a significant effect for the covariate anxiety (HAD-A) . Post hoc analysis showed that individuals with OPRM1 G-genotype in combination with genetically inferred 5-HTT low expression had higher pain modulation scores compared with 5-HTT high expression , indicating better central pain inhibition , but no significant effects of covariates were found. Post hoc analyses revealed that in individuals with OPRM1 G-genotype, also having the 5-HT1a G-genotype, yielded significantly higher pain modulation scores compared with 5-HT1a CC-genotypes , indicating better central pain inhibition with the genetic setup of OPRM1 G-genotype and 5-HT1a G-genotype . In the 5-HT1a G-genotype group, the pain modulation score was higher for OPRM1 G-genotypes compared with OPRM1 AA-genotypes (P = 0.097). No significant interaction between 5-HTT and 5-HT1a was found, and thus, no post hoc analyses were performed.There were no statistically significant effects on the pain modulation score and no group differences when each polymorphism was tested separately. Neither were there any significant group differences found when analyzing the effects of gene-to-gene interactions on the pain modulation score. There was a statistically significant interaction between OPRM1 and 5-HTT . This analysis demonstrated an effect of the covariate HAD-A in patients with FM , but there was no effect of FM duration, FM severity, or the use of antidepressant medication.To control for additional relevant covariates in the FM group, such as antidepressant medication , FM duration, and FM severity (FIQ), the analyses were performed separately for FM and HC. No statistically significant main effects on the pain modulation score were found for the individual genetic polymorphisms when tested separately in patients with FM. The analysis showed a statistically significant gene-to-gene interaction between OPRM1 and 5-HTT in patients with FM (P = 0.008). Furthermore, a trend was found in carriers of the 5-HTT low genotype where the OPRM1 G-genotype had a higher pain modulation score than AA-genotype   Fig. A. No sig10) Fig. B.df = 1, F = 4.33, P = 0.040). Post hoc analysis revealed that the significance was specific for the OPRM1 AA-genotype, with a higher pain modulation score in individuals with the 5-HT1a CC-genotype compared with 5-HT1a G . There was a trend that HC with 5HT1a CC-genotype had a higher pain modulation score if they were carriers of the OPRM1 AA-genotype compared with G-genotype   while at the same time reducing serotonergic signaling . Thus, the joint genetic effect of OPRM1 x 5-HTT and OPRM1 x 5-HT1a on the pain inhibitory pathways tends to be working antagonistically, as our hypothesis stated. The fact that both serotonergic genotypes that mechanistically are proposed to reduce 5-HT transmission (5-HTT low and 5-HT1a G) independently interacted with OPRM1 in a similar direction (OPRM1 G) further validates the hypothesis of antagonistic opioid x 5-HT interactions on pain modulatory mechanisms.This study examined the role of specific functional genetic polymorphisms, acting on opioid and serotonergic signaling, on EIH in healthy subjects and patients with FM. None of the polymorphisms of OPRM1, 5-HTT, or 5-HT1a had an effect on EIH on their own. The major findings in both groups were the significant interactions between functional polymorphisms in the genes OPRM1 x 5-HTT and OPRM1 x 5-HT1a, suggesting joint effects of opioid and serotonergic mechanisms regulating central pain inhibitory signaling. Individuals with OPRM1 G-genotype in combination with either low expression of 5-HTT or the 5-HT1a G-genotype seemed to be helped by their genetic setup so that they had a better functioning endogenous pain inhibition compared with other serotonergic genotypes (5-HTT high or 5-HT1a CC). Although it has been shown that opioids, via disinhibition, engage inhibitory 5-HT projections to produce antinociception,35 However, few studies have examined the association between polymorphisms in opioid and serotonin-related genes and endogenous pain modulation. We found no significant associations between the studied polymorphisms of OPRM1, 5-HTT or 5-HT1a, and EIH when they were studied separately. Previous studies showed that healthy individuals with 5-HTT low expression had decreased conditioned pain modulation28 and decreased sensory modulation.40 However, conditioned pain modulation and EIH are 2 different paradigms to study pain modulatory processes and they do not seem to be correlated.41 Thus, the genetic associations related to alterations in EIH seem to be only noticeable when considering the interaction of more than 1 polymorphism, stressing the importance of studying joint gene effects on pain modulation.That both opioids and serotonin are involved in the endogenous pain modulatory system interactions is generally accepted.In this study, we found significant interactions between the OPRM1 G-allele and both serotonergic gene variants proposed to reduce 5-HT signaling. Whereas the results were clear in this direction the contrary, meaning that genetically inferred reduced opioid tone combined with increased serotonergic signaling  jointly yields better functioning EIH, was less consistent. The only statistically significant finding in this direction was that healthy individuals with OPRM1 AA had higher pain modulation scores if they had the 5-HT1a CC compared with the 5-HT1a G-genotype. It is worth noticing that all analyses that reached significance did so in the direction in line with our hypothesis regarding HC; strong opioids together with weak 5-HT or weak opioids together with strong 5-HT seemed to provide better pain inhibition during exercise.11 Thus, the total synergistic effect of 5-HT1a G has decreased 5-HT transmission both in raphe nuclei and its peripheral projection areas.37 Interestingly, the 5-HTT low-expressing genotype has been proposed to downregulate 5-HT1a receptors.30 Thus, in the raphe nuclei 5-HT-synthesizing neurons, the 5-HT1a G-genotype upregulates 5-HT1a receptors, reducing 5-HT transmission, whereas the 5-HTT low genotype conversely downregulates 5-HT1a receptors, increasing 5-HT transmission. On the contrary, in the postsynaptic neurons, both the 5-HT1a G and 5-HTT low would be expected to downregulate 5-HT1a receptors, reducing 5-HT1a-mediated 5-HT effects. Thus, 5-HTT low and 5-HT1a G should have the same physiological effect in postsynaptic nonserotonergic neurons but opposing effects in the serotonergic neurons of raphe nuclei. Therefore, our results showing similar OPRM1 x 5-HTT low and OPRM1 G x 5-HT1a G interactions regarding EIH would indicate that the effect is mediated by postsynaptic nonserotonergic neurons in the projection areas rather than by the 5-HT-synthesizing neurons in the raphe. Interestingly, greater availability of 5-HT1a receptors in brain areas associated with pain processing, including dorsal raphe nuclei and its projection areas, has been related to greater ability to suppress pain.32 If greater availability indicates more 5-HT1a-mediated 5-HT inhibition, and thus reduced 5-HT transmission, then this corresponds to the proposed mechanism of the 5-HT1a G variant and is accordingly in line with our results.The 5-HT1a G variant exerts dual effects on 5-HT1a receptor expression depending on where the receptor is situated. It yields upregulation of inhibitory autoreceptors in the raphe nuclei but downregulation of postsynaptic 5-HT1a receptors in the projection areas.38 Despite this, we found no overall significant differences between the groups regarding the gene-to-gene interactions on EIH. Patients with FM showed interactions in the same direction as HC—individuals with genetically inferred stronger endogenous opioid signaling (OPRM1 G) and weaker serotonergic signaling (5-HTT low/5-HT1 G) had better pain modulation scores compared with serotonin strong signaling (5-HTT high/5-HT1a CC). In addition, several trends support that FM and HC exhibit opioid x 5-HTT and opioid x 5-HT1a interactions in the same direction. Thus, we found no support for our hypothesis of different opioid x 5-HT interaction patterns as the basis for the reduced function of EIH in patients with FM. The results are in accordance with the absence of gene-to-gene interactions to explain the difference in FM symptoms between patients and HC, ie, average PPT and questionnaires FIQ, HAD-A, and HAD-D.In accordance with previous research, patients with FM had reduced function of EIH compared with HC.First, there was a minimal, yet statistically significant difference in age, which likely does not affect the results. Moreover, although all subjects were whites, a few in each group had ethnicities outside Europe. These subjects did not differ in allelic frequencies from the whole group; thus, it is not likely that population stratification has a significant effect on the results. Also, the functions of the mu-opioid receptor, the serotonin transporter, and the 5-HT1a receptor were inferred from genotypes and not assessed directly. However, the method is well established in the literature and allows us to study the effects on behavior under normal conditions, ie, without pharmacological manipulation. Furthermore, based on previous studies, we examined the effects of 4 polymorphisms within 3 genes. This does not exclude that other genetic polymorphisms are in linkage and influence gene expression and transcription, nor are epigenetic changes taken into account. However, the polymorphisms studied were thoroughly chosen based on previous research demonstrating their involvement in pain regulation.Our results suggest that, by genetic association, the mu-opioid receptor interacts with 2 major serotonergic structures involved in 5-HT reuptake and release, to modulate EIH. Furthermore, we found that the interaction worked in an antagonistic manner, ie, genetically inferred increased opioid signaling combined with decreased serotonergic signaling produced better pain inhibition during exercise. Lastly, in contrast to our a priori hypothesis, the opioid x 5-HT interactions on pain modulation existed regardless of baseline function of endogenous pain modulatory mechanisms, with similar effects in patients with FM and HC. Thus, our results do not support an altered interaction between opioid and 5-HT mechanisms as the basis for dysfunction of EIH in FM. Instead, we were able to reproduce similar findings of interactions between opioid x serotonergic signaling in 2 different human cohorts.As no effect of a singular genetic polymorphism was found, the present results indicate the importance of assessing joint gene effects when studying behavioral traits with complex modulatory mechanisms, such as pain modulation. To our knowledge, no previous reports have been made on genetic interactions between the opioid and the serotonergic systems on pain mechanisms in humans. Many current pain medications target either the opioid system or the serotonergic system; therefore, increased understanding of the interactions between the systems could help develop new combined treatment options of pain syndromes.The authors have no conflicts of interest to declare.


To examine race/ethnicity differences in pain management outcomes following inpatient palliative care consultation.We conducted a retrospective study based on data from a community-based teaching hospital in Fresno, CA, USA, from April 2014 to July 2015. One hundred sixty-one patients with life-limiting diagnoses and palliative care pain-related consultations were included. The patients were categorized into four racial groups: Caucasians, African-Americans, Hispanics, and Asians/Others. Demographics and baseline pain scores using the Visual Analogue Scale (VAS) were obtained. The outcome measures included the length of stay, time to consult, and pain scores at admission, 24 hours before the consultation, 24–48 hours after consultation, and at discharge.The initial median pain scores were not significantly different between the groups, however, the Asians had slightly higher pain scores compared to the other groups. African-Americans, Caucasians, and Hispanics had significant differences in pain outcomes after consultation compared to 24 hours prior to consultation . Caucasians and Hispanics had significant differences in pain outcomes after palliative consultation compared to initial admission assessment (p < 0.01). The differences between discharge and admission pain scores were significant only for Asians, Caucasians, and Hispanics  but not African-Americans. There were no significant pain score differences across the racial groups following consultations.There were no significant differences in pain reduction amongst the racial groups, suggesting that pain can adequately be managed in individual racial groups after inpatient palliative care consultations. Pain has been described as the fifth vital sign. Since this advent, nurses and physicians have increasingly focused on treating pain in the inpatient setting. Sixty-two percent of patients with a cancer diagnosis experience pain. This percentage increases to almost all patients as they reach the terminal stages of their diagnoses -2. PalliLikewise, patients with increased pain in the inpatient setting may have longer lengths of stay due to inadequate pain control. The patients referred to palliative care services within the first week of admission proved to have a shorter length of stay and lower in-hospital mortality compared to the patients who received consults after the first week of stay .Despite diverse studies on the benefit of inpatient palliative care consultations, there have been mixed findings with regards to the effect of race on pain outcomes. A study by Ng, et al. demonstrated that Caucasians were more likely to require more morphine compared to Asians and Hispanics following limb fractures . FurtherThis study examines racial differences in pain management outcomes following inpatient palliative care consultations.A retrospective study was conducted following Community Medical Centers institutional review board (IRB) approval. The study was based on chart review of data drawn from a community-based teaching hospital, Community Regional Medical Center (CRMC), in Fresno, CA from April 2014 to July 2015. The patients were identified from the records kept by the palliative care nurse manager. The following data were extracted: medical record number (MRN), date of admission, date/time of consult, date palliative consult completed, primary diagnoses, and date of discharge.Further information was obtained from CRMC EPIC™ electronic medical records . This information included: date of birth, gender, race/ethnicity, insurance, disposition, and pain scores. Palliative care consultations with pain measures were included using the Visual Analog Score . Excluded were patients who did not have pain-related palliative care consultations or did not have reported pain scores at the established time points examined in the study.The patients were categorized into four racial groups: Caucasians, African-Americans, Hispanics, and Asians/Others. Four pain scores were created by averaging all pain scores over the following specific 24-hour periods: first 24-hour period in the hospital (including admission), pain scores from the 24-hour period before the date/time of consult, pain scores 24-48 hours after consults were completed, and finally pain scores 24 hours prior to discharge. Age at time of admission, days from admission to time of initial consult, and total days in the hospital were also calculated.Of the 1,671 palliative care consults, 197 pain consults were completed on 161 patients with life-limiting diagnoses of cancer or non-cancer (chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), liver failure and another end-organ failure). Of the 161 patients that met inclusion criteria, 15 were African-American, 15 were Asians/Others, 78 were Caucasian, and 53 were Hispanic. There was a higher percentage of males compared to females in the African-American, Caucasian, and Hispanic groups. The mean age was significantly different with Asians and Caucasians slightly older (p < 0.001). Furthermore, significant differences in the insurance status were observed, with a preponderance of the groups having Medicaid as a primary insurance (p = 0.003). The majority of patients had cancer compared to non-cancer diagnoses. The initial median pain score, although not statistically significant across the groups did show Asians had a slightly higher pain score (6.1) on the VAS compared to other groups. The majority of patients within all groups were discharged to home after hospitalization. A greater percentage of Asians and Caucasians was discharged either to home or skilled nursing facility with hospice. Higher percentages of deaths were seen in African-Americans and Caucasians compared to other groups. Significant differences in the length of stay were observed amongst the groups, with Hispanics having the longest length of stay, followed by Caucasians, Asians, and African-Americans (p = 0.02). There were no significant differences amongst the groups in days of admission to consult [See Table Note Table African-Americans, Caucasians, and Hispanics had significant reduction in pain scores after consultation compared to 24 hours before . Caucasians and Hispanics also had significant differences in pain reduction after palliative consultation compared to initial admission assessment (p < 0.01). Differences between discharge and admission pain scores were significant for Asians, Caucasians, and Hispanics . Although there were significant pain score differences within certain racial groups, there were overall no significant pain score differences amongst the racial groups [See figures One of the goals of this study was to determine if racial disparities existed in pain outcomes for patients with life-limiting illnesses. A thorough review of the literature by Anderson, et al. determined that ethnic minorities tend to have lower quality pain management in acute, chronic, cancer, and palliative care settings . OverallAsians in our study had non-significant higher initial pain scores compared to the other race/ethnicities. This was in contrast to the findings of Bell, et al. that being of an Asian race increases the likelihood of having lower pain scores when controlling for age, gender, Karnofsky score, and pre-consultation length of stay. Furthermore, the study found better pain outcomes in the non-Caucasian compared to Caucasian groups. It should be noted that the study by Bell, et al. also included surgical patients in addition to patients with cancer and non-cancer diagnoses.Our study underscores findings of a prior study conducted by Casarett, et al. noting higher overall patient satisfaction scores in the realm of pain and symptom management after palliative care consultation . AlthougHowever, our study had several limitations. First, it was conducted at a single community hospital with potential sample bias reducing generalizability. We only included patients with life-limiting illnesses. Furthermore, our study population was primarily Caucasian and Hispanic; both the African-American and Asian groups together accounted for less than 20% of our population. In addition, male preponderance and age differences could also contribute to the non-homogeneity of the population.There was wide variability in pain scores, but because of the smaller sample size, we lacked the power to find the statistical differences. Cultural influences, different validated pain scales, patient comorbidities, and functional status were not included and could potentially influence the results.The present study provides insights into the clinical utility of palliative care services in the inpatient setting. Palliative care consultations have a positive impact on pain reduction. Although there were no significant differences in pain outcomes across the four racial groups, our data showed that pain can be adequately managed regardless of race/ethnicity.


Anaesthetic technique for open surgery of acute distal for arm fracture in adults/elderly is not well defined. Regional anaesthesia, general anaesthesia or a combined general and regional block may be considered. General anaesthetic technique, the timing and drug/drug combination for the regional block must also be considered. This is a study around published studies assessing anaesthtic technique for wrist surgery. A systematic database search was performed and papers describing the effect of anaesthetic techniques were included. We found sparse evidence for what anaesthetic technique is optimal for open wrist fracture repair. In total only six studies were found using our inclusion criteria, which all supported the short term, early recovery benefits of regional anaesthesia as part of multi-modal analgesia. More protracted outcomes and putting the type of block into context of quality of recovery and patients’ satisfaction is lacking in the literature. The risk for a pain rebound when the block vanishes should also be acknowledged. Therefore, further high quality studies are warranted concerning the anaesthetic technique for this type of surgery. The incidence is increasing among adults and elderly in Sweden3. There are certainly several factors contributing to the increased risk; the fact that individuals are becoming more active at later stages of life and osteoporosis is prevalent in older individuals are both likely to have importance. In addition, there is seasonal variation of distal wrist fracture with high risk during winter months5.Fracture on the upper limb is common, and fracture on the distal forearm, wrist fracture, is one of most common upper limb fractures. Whether the incident increases or declines at least among women is a matter of discussion6 shows that approximately 20% of acute wrist fractures undergo open surgery. In 2009, Smektalaet al.7 conducted a cohort study around surgical wrist fracture care in Germany. They found that most patients were elderly females, and the predominant fracture management procedure was percutaneous K-wire osteosynthesis (56% of cases), followed by plate osteosynthesis (44%) and more than half of patients had general anaesthesia (55%).The best treatment of wrist fracture is debated. Data from the Swedish fracture registerSurgical repair of wrist fracture can be performed under various anaesthetic techniques. Studies assessing anaesthetic technique, whether regional anaesthesia, general anaesthesia or a combined general and regional anaesthetic approach provides the best perioperative care are not well defined. Currently, there is no firm evidence to support a best technique and no clear consensus guidance is available.The aim of this study was to identify the currently available data regarding anaesthetic technique, general, regional or combined general and regional anaesthesia, and postoperative pain course for open surgical repair of wrist fracture in adults and elderly.A systematic database search was performed on PubMed, Scopus and Cochrane databases, searching for articles in the period from 2007 to October 2017 (the last 10 year period), to identify studies regarding the impact of anaesthesia method on pain and long term outcomes after open radius fracture repair. Quantitative as well as qualitative English language studies limited to adults were searched.The search strategy used the following text words or Medical Subject Headings (MeSH): “Radius fractures, Wrist injuries, Surgery, Anaesthesia, Regional anaesthesia, Pain, Postoperative, Clinical outcome”, combined search for the last 10 years; (radius fractures OR wrist injuries OR wrist fractures) AND anesthesia. The result was further analysed by two of the authors and secondary papers searched from the initial studies retrieved.Observational studies and case series were excluded, as it was considered that these could be associated with major bias. Study selection was based on an initial screen of titles and abstracts, and then reading the final identified articles. Papers with at least two different techniques assessing clinical peroperative effects were included.Selection of papers and subsequent extraction was performed independently by two of the authors (MWS and JGJ). Consensus was reached for final article inclusion and data extraction through discussion between all authors.A standard data extraction matrix was conducted manually, to gather study information including: references/year of publication/author, anaesthesia method, postoperative pain before and after discharge from hospital.In total, 6 studies, 4 prospective randomised and 2 retrospective studies of various designs, were identified, which altogether included 619 participants  see.Overall, it could be seen that there is little information around anaesthetic techniques used, and base pain medications is sparsely addressed. The focus has been on early and intermediate pain and opioid consumption. Pain was assessed with different scales in each study.et al.Hadzic8 performed a study in 2004 comparing general anaesthesia to infraclavicular plexus block with short-acting local anaesthesia for hand and wrist surgery. They included 52 patients; however 2 were excluded from analysis, resulting in 50 patients; 25 each in general and regional anaesthesia were evaluated. The focus was on early recovery during the stay in hospital, but patients were also called on the telephone once daily for days 1, 2 and 3 and interviewed about pain felt. In addition, 2 weeks later the patients were asked about satisfaction and willingness to have the same anaesthesia. They found that the block group needed approximately 5 minutes longer time for preparation prior to surgery, but more patients in the block group were eligible for early recovery room bypass. The block group also experienced less pain, nausea, sore throat and fatigue. The block group were eligible for discharge at a significantly faster rate that the anaesthesia group. Pain at follow-up did not differ at day 1 and 3 between the two groups, but was found in favour, lower pain, for block group of patient at day 3. Satisfaction with anaesthesia at 2 weeks was found to be the same, but willingness to have same anaesthesia favoured the block technique.et al.Galos9 randomized patients to general anaesthesia (n=18) or plexus block (n=18) and followed postoperative pain 2, 4, 6, 12, 24, 48 and 72 hours after surgery. They found that the general anaesthesia group had more pain 2 hours postoperatively, but regional anaesthesia experienced more pain 12 and 24 hours after surgery, termed “rebound pain”, as compared to the general anaesthesia patients. There were no differences in pain ratings at 48 and 72 hours or at 2 weeks. Follow-up of function at 2 and 6 weeks did not show any differences.et al.O’ Neil10 studied 98 patients, 45 receiving general anaesthesia and 53 regional anaesthesia, a single shot peripheral block, for preoperative management. They had a questionnaire follow-up at a 2-week follow-up visit where the amount of pain medication used was requested. They did not find any difference in opioid need between general and regional anaesthesia groups. Opioid need decreased, however, with age and increased in relation to the severity of the fracture.et al.Holmberg11 studied 52 patients with fractured radius. The study compared pre- and post-operative block, in both groups combined with general anaesthesia total intravenous anaesthesia (TIVA). The patients were randomized to a preoperative (n=25) or a postoperative (n=26) infraclavicular plexus block. Time to the first rescue analgesic, as well as pain score evaluation, was at 1, 2, 4, 8 and 24 hours after surgery. Patients were further called for phone interview on day 7 and 6 months postoperatively, and asked about pain, rescue analgesia daily function and side effects. The time for needing first rescue opioid analgesic was significantly longer for the pre-operative block group (544 vs 343 minutes). There was also a significantly lower mean VAS pain score at 30 minutes, 1, 2 and 4 hours. Pain was, however, not different after 4 hours and beyond. At day 7 more patients in the postoperative block group needed oral paracetamol as compared to the preoperative group; however, the total opioid need was the same. During the first postoperative night, most patients from both groups experienced severe pain. Follow-up at 6 months showed no difference in pain; median pain score in the pre-operative group was 2 as compared to the postoperative group median of 1.et al.Egol12 published a retrospective register study in 2012 assessing pain after wrist surgery. Included in the analysis were 122 patients that had surgery under general anaesthesia and 65 under a regional block. Patients were followed up for analysis at 3, 6 and 12 months after surgery; pain and function was assessed. At 3 and 6 months, patient that had regional anaesthesia showed significantly less pain and better function; however, at 12 months groups were equal in pain assessment, and function measured by the test were similar and normalised, back to normal range.et al.Sunderland13 conducted a retrospective review, for a retrospective quality improvement project, to assess the need for unplanned medical visits caused by pain in the first 48 hours after wrist surgery and the impact of anaesthetic technique, general anaesthesia or regional block. All 77 patients who had general and 118 patients who had regional anaesthesia were reached for follow-up interview within 6 weeks, which posed the question “In the first 24 to 48 hours after surgery, did you need to seek medical attention for pain?”. The block group was found to have significantly more unplanned visits (20% vs 5%), and self-reported severe pain was also more common in this group of patients (41% vs 10%), as compared to the general anaesthesia group of patients. Patients were also asked about persistent post-operative pain and if they had been diagnosed with a “complex regional pain syndrome” (CRPS). No difference in development of chronic pain or diagnosis of CRPS was found between the two groups.Most wrist fractures in adults and the elderly can be managed by close reposition. However, certain fractures require open reposition and fixation at initial examination, and others fail close reposition and fixation therapy and thus require an open procedure. Wrist surgery is not uncommonly performed as day or over-night stay surgery and is common in elderly patients. Thus, it is of importance to consider various outcomes when comparing anaesthetic techniques used in these procedures and on these patients.We found only six papers explicitly addressing anaesthetic technique for open acute distal arm surgery. The pharmacological effect of blocking nociceptive influx is clear; preoperative block seems better than post-surgery block. The effect beyond the early period and duration of the pharmacological blockade was more diverse between studies, and it seems that the risk for “rebound” pain should be acknowledged.14. The importance of multi-modal analgesia is well-accepted, and today this standard of care is especially important in ambulatory surgery15. The application of local anaesthetics in the wound area, site for incision, or as a peripheral block, is a basic part of the multi-modal analgesia concept. The effects of peripheral block on early pain, reducing the need for opioid analgesics are well-known16. The effects beyond the early period and the duration of the pharmacological local block is less well documented17. There are several options to improve the duration by the addition of adjuncts e.g. alf-2-blocking agents, such as clonidine or dexmedetomidine; however, the prolongation of the block resolution by liposomal bupivacaine preparation needs further studies18.The benefits of prevention of pain and the concept of multi modal analgesia have been known for decadeset al. used propofol followed by desflurane and Holberget al. describes general anaesthesia as TIVA for all patients, the general anaesthetic techniques used were not further addressed. Awakening/emergence from anaesthesia is faster when inhaled anaesthesia has been used, shown by many previous studies20. The benefits of the use of nitrous oxide to quicken emergence is also well documented22. The impact of low blood gas solubility on awakening is also shown with xenon as the main anaesthetic23. Xenon does promote stable intraoperative haemodynamic and rapid recovery, as compared to traditional halogenated inhaled anaesthetics24. The classic study by Apfelet al. verified the importance of multi-modal PostOperative Nausea and Vomiting - PONV prophylaxis25. Appropriate risk based PONV prophylaxis should be administered reducing its occurrence26. The benefits of propofol-based anaesthesia to reduce early PONV is well known27.Hadzicet al., Egolet al., Galoset al. and Holmberget al. used sole infraclavicular block technique, while Sunderlandet al. used mixed infra- and supraclavicular block technique and O’Neilet al. used sole supraclavicular blocks. The local anaesthetics used differed as well: Hadzicet al, chloroprocaine; Galoset al, mixed lidocaine and bupivacaine; O’Neilet al., ropivacaine and dexamethasone; Holmberg, ropivacaine. Adding adjuncts to increase the analgesic block duration is of interest, but generally is off-label use, and there is no firm consensus about what drug and concentration should be usedxiii. There is a recent review suggesting dexmedetomidine is superior to clonidine as adjunct for supraclavicular block, but there is also a risk of side effects28.From the six studies identified, the blocks were done with different techniques and solutions. The studies by Hadzic29. Pain associated with the performance of local anaesthetic blockade was not evaluated in this study but may be further taken into consideration in the patient´s participation in anaesthetic decision.We did not address anaesthesia/analgesia/sedation for closed reduction; there is a Cochrane review around anaesthesia for the close reposition from 200230. The long-term outcome and the risk for chronic pain is dependent on several factors and the impact on anaesthetic technique may not have major impact. Long term outcomes are of importance, but the impact on training, rehabilitation surgical technique and even osteoporosis must be acknowledged when assessing long-term results. Similarly, considerations must be taken that wrist fracture may initiate complex regional pain syndrome type I. For instance, severe fractures and women are at high risk for development this syndrome after surgical treatment of distal radius fractures 31.It is obvious that further high quality studies are warranted; studies assessing not only early but more protracted outcome variables. For example, effect on logistics, theatre time, patients eligible for fast-track, bypassing recovery area and time to discharge should all be included. Effects beyond discharge need to also be assessed in a standardised fashion, pain and analgesic requirement at least up to a week post-surgery and quality of recovery should be assessed by a standardised tool. There are today at least two well-accepted tools for the assessment of quality of recovery, the PostopQRS and the Quality of Recovery scaleIn conclusion, there is sparse evidence for what anaesthetic technique is superior for open wrist repair. The short term, early recovery benefits of regional anaesthesia as part of multi-modal analgesia is well documented; however, more protracted outcomes and putting the type of block into context of quality of recovery and patients’ satisfaction is lacking. The risk for pain rebound when the block finishes should also be acknowledged. Further high quality studies are warranted.1https://stratum.registercentrum.se/#!page?id=1094 The authors have conducted a systematic review to identify if regional versus general anaesthesia is superior for post-operative pain for distal wrist fractures. They correctly show that there is an evidence gap in the literature, and cannot provide recommendation from their data. The study is well conducted, but the contributing trials are all small and have sufficient heterogeneity that it is simply not possible to draw any conclusions, other than more trials need to be done.I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. The article’s title suggests focusing on the elderly but the studies mentioned do not refer especially to the elderly. Although the authors are right in saying that wrist fractures are more common in the elderly it is not clear in the studies mentioned; I suggest to remove “elderly” from the title. In the text it is rightly mentioned. It is interesting that the article shows a relative lack of information in the literature on this specific wrist fracture treatment. I agree with all the conclusions drawn by the authors about desired further studies; important that is noted that rebound pain in the aftercare phase is higher in the regional group than the multimodal group of patients; this provides us an important “mirror” to our daily practice!I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.


Dear Editor,Perceived heart risk factors including psychological and non-psychological factors  are as part of the mental representation of illnesses that arise from patients' health knowledge and independently can predict their health behavior -2. CausaBased on these considerations, a study was conducted to compare the chest pain severity and discomfort in heart patients with and without perceived psychological risk factors. From May to July 2015, 219 cardiac patients (23- 79 years with the mean [SD] = 58.5±9.4) after cardiac surgery were invited to participate in the study in Imam Ali Hospital of Kermanshah City (Western part of Iran). After obtaining a written informed consent to participate in the study, demographic data and medical histories of the patients were evaluated and recorded by an expert cardiologist. Then, a brief pain inventory , and opeAccording to descriptive data, 63% of patients were males, 89.4% married, 34.7% housekeepers, 32.2% self-employed, 8.2% employees, and 21.9% retires. In terms of level of education, 70.3% were below high school level 18.3% high school graduate and 11.4% with a college degree. In addition, the results show that 118 and 110 people respectively are with the perceived non-psychological and psychological risk factors. The means (SD) of pain intensity respectively were 3.751.94 and 4.321.86 for the patients with perceived non-psychological and psychological risk factors. Also, the means (SD) of pain discomfort respectively were 9.486.52 and 12.307.58 for patients with the perceived non-psychological and psychological risk factors. In relation to the main analysis, the independent t-test results show that there is a significant difference between the two groups in term of pain intensity (P=0.030) and discomfort (P=0.004) and the patients with perceived psychological risk factors indicate more pain severity and discomfort compared with the patients with perceived non-psychological risk factors. Our results showed that the severity of pain and pain discomfort are more in patients with perceived psychological risk factors compared with those patients with perceived non-psychological risk factors. In this regard, the results of the two studies showed that the patients with perceived psychological risk factors experience more anxiety and depression compared to others (


Evidence is lacking on the prognosis and prognostic factors of back-related leg pain and sciatica in patients seeing their primary care physicians. This evidence could guide timely appropriate treatment and referral decisions.The present study aims to describe the prognosis and prognostic factors in primary care patients with low back-related leg pain and sciatica.This is a prospective cohort study.The present study included adults visiting their family doctor with back-related leg pain in the United Kingdom.Information about pain, function, psychological, and clinical variables, was collected. Good outcome was defined as 30% or more reduction in disability (Roland-Morris Disability Questionnaire).Participants completed the questionnaires, underwent clinical assessments, received a magnetic resonance imaging scan, and were followed-up 12 months later. Mixed-effects logistic regression evaluated the prognostic value of six a priori defined variable sets . A combined model, including variables from all models, examined independent effects. The National Institute for Health Research funded the study. There are no conflicts of interest.A total of 609 patients were included. At 12 months, 55% of patients improved in both the total sample and the sciatica group. For the whole cohort, longer leg pain duration , higher identity score , and patient's belief that the problem will last a long time  were the strongest independent prognostic factors negatively associated with improvement. These last two factors were similarly negatively associated with improvement in the sciatica subgroup.The present study provides new evidence on the prognosis and prognostic factors of back-related leg pain and sciatica in primary care. Just over half of patients improved at 12 months. Patient's belief of recovery timescale and number of other symptoms attributed to the pain are independent prognostic factors. These factors can be used to inform and direct decisions about timing and intensity of available therapeutic options. Low back pain (LBP) is the leading cause of years lived with disability worldwide Given the high probability of long-standing pain and disability in nonspecific LBP, and limited potential for diagnostic information to guide clinical decision-making, much research has focused on describing prognosis and identifying prognostic factors Systematic reviews of predominantly secondary care cohorts indicate that factors such as age, gender, smoking, occupational workload, and neurological deficits are unlikely to be associated with outcome in sciatica The aims of this study were (1) to describe the overall prognosis, (2) better understand the associations between potentially important prognostic factors and disability, and (3) identify the strongest factors independently associated with disability.This is a prospective cohort study including patients aged 18 years and older, visiting their family doctor  with symptoms of low back-related leg pain, including sciatica, of any severity and duration. The project was approved in accordance with the agreed procedure with the South Birmingham Research Ethics Committee (REC Ref. 10/H1207/82). The study protocol, baseline assessments, and patients' characteristics are reported in detail elsewhere The Roland-Morris Disability Questionnaire (RMDQ) leg pain version  was the primary outcome measure Prognostic factors to be examined were a priori selected based on evidence of their association with long-term outcome, building on exploratory evidence from existing studies in LBP and sciatica, and expertise within the study team. The self-reported and clinical assessment variables investigated in the study are summarized in Participants were managed according to one of three care pathways: (1) up to two physiotherapy sessions for those patients with improving or mild symptoms, (2) a course of physiotherapy treatment (three and more) for those patients with more troublesome pain, and (3) referral to secondary care; most patients in this pathway initially received a course of physiotherapy treatment. Secondary care options included referral to pain clinic for consideration of specialist analgesia review and/or injections, or to spinal orthopaedics for consideration of surgery and/or injections, or to chronic pain management services. Choice of pathway was based on clinician's judgment and patients' preferences.The following analyses were conducted for the whole cohort, and separately for the subgroup clinically diagnosed with sciatica.Descriptive analysis was performed to describe the course of patients' disability and pain using mean (standard deviation [SD]) scores for RMDQ and pain intensity (LBP and leg pain) at baseline and each month, with 4 and 12 months being the main follow-up points. The percentage of patients defined as improved on the RMDQ was calculated.A mixed-effects logistic regression model, which allows all available outcome data at all three time points to be used, accounts for autocorrelation due to repeated measures, and gives valid inferences when data are assumed missing at random, was used to estimate odds ratios (OR) and 95% confidence interval (CI) for the association between each of the potential prognostic factors and the binary outcome of improvement in disability. The model included an interaction term between each predictor and time to obtain estimates (and 95% CI) for each point of follow-up (4 and 12 months).Univariable associations were described, followed by a series of models evaluating the prognostic value of the six sets of variables relating to the six domains described in Previous research and expertise has highlighted these six domains as important, although it is unclear which factors specifically are most strongly associated with outcome within and between domains. Univariable analysis was first used to examine associations between each factor and outcome. Each model was then adjusted for (1) variables in the model only (for models with more than 1 factor); (2) age, gender, body mass index, smoking, and comorbidities; and (3) care pathways. Correlations between individual prognostic factors were investigated using bivariate associations and variance inflation factor, and if this was the case (variance inflation factor≥5), then only one of the variables (with higher OR) was included in analyses.Finally, a combined model comprising all variables in the six models was fitted to identify the strongest factors from the six domains predicting long-term outcome. This was performed with a backwards approach by removing nonsignificant variables from the model one by one, until remaining variables had p<.05 (using the likelihood ratio test).As a sensitivity analysis for addressing missing data, multiple imputation was employed by combining results from 40 multiply imputed datasets. Additional sensitivity analysis using linear mixed model was also performed using numerical RMDQ, with adjustment for baseline RMDQ score as the outcome, as opposed to the binary classification. In a further sensitivity analysis, a combined model using the subsample of participants with sciatica and confirmed nerve root compression on MRI was fitted.In this study, the total number of factors considered complied with the rule of at least 10 events per variable in the logistic regression analysis For primary follow-up time points (4 and 12 months), we compared the key patient baseline characteristics  for those followed up and those lost to follow-up.Data were analyzed using Stata 13 .Six hundred nine patients were included in the study. Response rates were 402 (66.0%) at 4 months and 450 (73.9%) at 12 months; 74.2% (n=452) were clinically diagnosed as having sciatica. The Participants who did not respond to the 12-month questionnaire were more often male, younger, and had higher baseline disability score compared with responders ; this had decreased to means of 8.2 (6.7) and 7.8 (7.0) at 4 and 12 months, respectively. Baseline mean back pain intensity was 5.6 (2.2); this decreased to 3.4 (2.6) and 3.3 (2.7) at 4 and 12 months, respectively. For leg pain, mean baseline pain intensity was 5.2 (2.4), falling to 2.8 (2.9) and 2.4 (2.7) at 4 and 12 months, respectively.Adjustment for demographics and care pathways did not have a large impact on associations for most variables for all domains , Table 5For the whole cohort, the combined multivariable model incorporating all variables from the six sets or domains showed that longer leg pain duration , higher identity score , and patient's belief that the problem will last a long time  were the strongest independent prognostic factors negatively associated with improvement. These last two factors were similarly negatively associated with improvement in the sciatica subgroup . The senTo our knowledge, this is the first comprehensive study to describe prognosis and prognostic factors in patients seeking care in primary care for back-related leg pain, including sciatica, of any duration and severity. The prognosis of low back-related leg pain is similar in those with and without a clinical diagnosis of sciatica, with 55% meeting the study's criterion for improvement in disability. The improvements in disability from baseline in our cohort were similar, but mostly higher , compared with some LBP cohorts (UK) with or without leg pain, receiving primary care including physiotherapy interventions ((4.3) In this study, we set out to specifically investigate prognostic factors thought to be associated with long-term outcome in low back-related leg pain and in sciatica and also examine their independent effect.The factors associated with improvement in disability in this cohort were shorter pain duration, lower leg pain intensity, fewer other symptoms associated with the back and leg pain (lower identity score), patient's belief that the problem will be short-lived, and initially having myotomal weakness. Symptom duration and pain levels are similarly reported to be associated with better outcomes in nonspecific LBP For the sciatica subgroup, pain intensity was not statistically significant after adjustment for care pathways, which perhaps indicates that treatment modifies its effect . This contrasts with the current secondary care literature which points to leg pain severity in sciatica as likely associated with subsequent surgery (proxy of poor outcome with conservative management) Depression was not found to be a significant factor when included with other psychological variables in the model. This is consistent with results from other studies, where factors of “timeline” and “identity” are independent and stronger prognostic factors in nonspecific LBP when compared to depression We found that having myotomal weakness at baseline was associated with improvement in disability at 12 months. All patients with myotomal weakness had additional neurologic signs . One recent study in secondary care As the majority of patients with back-related leg pain and sciatica are managed in primary care, one major strength of our study is the primary care setting, thereby providing important new evidence in a sample that is more representative of people with sciatica consulting healthcare than previously reported secondary care cohorts. The inclusion of consecutive eligible patients with any degree of pain severity and duration of symptoms further strengthens the generalizability of our findings, as these are applicable across the spectrum of patient presentations and not only for those populations with the most severe symptoms. The choice of potential prognostic factors was comprehensive and underpinned by previous research and clinical experience. The sensitivity analysis using the RMDQ continuous scales produced similar results to the primary analysis using the dichotomous outcome increasing confidence in the results.A potential limitation is the higher than expected attrition; however, the multiple imputation sensitivity analysis showed similar estimates. Another limitation is that, because of small numbers in the referred leg pain subgroup, we were unable to do separate analyses as we did in the sciatica subgroup. We therefore cannot confirm that similar factors are associated with outcome in patients with referred leg pain.Another issue is the potential confounding by treatment, where beneficial effects of treatment may influence the association between prognostic factors and outcome Lastly, it is important to consider the issue of uncertainty when diagnosing sciatica versus referred leg pain, and the potential for misclassification. In the absence of a “gold standard” for the diagnosis of sciatica, diagnosis in this study was based on clinical opinion based on the clinical assessment findings, which reflects normal primary care practice. Extensive discussion of these points is presented elsewhere Of the prognostic factors we investigated, independent predictors of improvement were similar in the whole sample and in the sciatica subgroup (which was the largest), with clinical characteristics more weakly associated with outcome and no longer significant in the combined model. This suggests that long-term outcome may be more strongly influenced by factors indicative of overall impact of the condition as indicated by the “identity” variable; therefore, this should influence early management and treatment intensity. Although we included most factors currently considered potentially important, it is possible that there are still unknown characteristics especially relevant to sciatica that we are not capturing, and which may better guide choice of intensity and timing of different care pathways. More specific MRI findings  were not included as prognostic variables, mainly because of the primary care setting, which does not include routine MRI for this population. However, MRI characteristics can be investigated in further analysis to assess their contribution to the generic factors identified in this study.We could not disentangle whether the prognostic factors mediate or moderate treatment effect. Further research investigating different models of care , and incorporating the prognostic factors this study identified, may elucidate which factors are prognostic and which are predictive of treatment outcome.At 1 year, 55.0% of primary care patients with low back-related leg pain and sciatica receiving current best care reported a 30% or more improvement in disability. In the long term, patients' belief that they will get better soon, and not having many other complaints attributed to the back and leg pain, were independent prognostic factors associated with improvement. These prognostic factors can be used to inform and direct management decisions about timing and intensity of available therapeutic options for symptoms relief, especially in sciatica patients with corroborative MRI findings, for whom there are potentially appropriate therapeutic interventions that are not applicable for patients with nonspecific low back and leg symptoms. Exploration and appropriate handling of patient's expectations about their pain trajectory, both in referred leg pain and in sciatica cases, is considered relevant, similarly to most health problems presentations.


Enhanced recovery after surgery (ERAS) programs typically utilizes multi-modal analgesia to reduce perioperative opioid consumption. Systemic lidocaine is used in several of these ERAS algorithms and has been shown to reduce opioid use after colorectal surgery. However it is unclear how much the other components of an ERAS protocol contribute to the final outcome. Using a noninferiority analysis we sought to assess the role of perioperative lidocaine in an ERAS program for colorectal surgery, using pain and opioid consumption as outcomes.We conducted a retrospective review of patients who had received intravenous lidocaine perioperatively during colorectal surgery. We matched them with patients who were managed using a multi-component ERAS protocol, which included perioperative lidocaine. We tested a joint hypothesis of noninferiority of lidocaine infusion to ERAS protocol in postoperative pain scores and opioid consumption. We assigned a noninferiority margin of 1 point  difference in pain and a ratio [mean (lidocaine) / mean (ERAS)] of 1.2 in opioid consumption, respectively.Fifty-two patients in the lidocaine group were matched with patients in the ERAS group. With regards to opioid consumption, in the overall [1.68 (1.43–1.98)] [odds ratio ] analysis and on postoperative day (POD) 1 [2.38 (1.74–3.31)] lidocaine alone was inferior to multi-modal analgesia. On POD 2 and beyond, although the mean odds ratio for opioid consumption was 1.43 [1.43 (1.17–1.73)], the lower limit extended beyond the pre-defined cut-off of 1.2, rendering the outcome inconclusive. For pain scores lidocaine is non-inferior to ERAS [-0.17 (-1.08–0.74)] on POD 2 and beyond. Pain scores on POD 1 and in the overall cohort were inconclusive based on the noninferiority analysis.The addition of a multi-component ERAS protocol to intravenous lidocaine incrementally reduces opioid consumption, most evident on POD 1. For pain scores the data is inconclusive on POD 1, however on POD 2 and beyond lidocaine alone is non-inferior to an ERAS program with lidocaine. Opioid-related complications, including return of bowel function, were not different between the groups despite reduced opioid use in the ERAS group.The online version of this article (doi:10.1186/s12871-017-0306-6) contains supplementary material, which is available to authorized users. Enhanced Recovery After Surgery (ERAS) protocols are evidence-based algorithms first described by Kehlet almost two decades ago  ERAS proEnhanced recovery protocols typically utilize multi-modal analgesia to reduce perioperative opioid use. Whereas the benefits of multi-modal analgesic approaches are well demonstrated, it is less clear which components are essential and which have little effect on outcome. As each component adds some degree of work, cost and potential risk, it is important to define how each component contributes to pain management.Intravenous lidocaine has gained increasing popularity over the last decade –6. SysteGiven these effects, it can be hypothesized that intravenous lidocaine provides the majority of the analgesic benefits of any ERAS protocol, even if the protocol contains many additional interventions. If so, those other components could be eliminated without affecting outcome, which would likely reduce cost and improves safety. At our institution we utilized perioperative lidocaine with opioid-based analgesia for colorectal surgery, and then implemented an ERAS program that included perioperative lidocaine but added multi-modal analgesia, opioid restriction and fluid and activity interventions. This practice change allowed a comparison between the two approaches as to pain scores, opioid consumption and side effects.We hypothesized that in colorectal surgery perioperative systemic lidocaine with opioid analgesia is non-inferior to a full ERAS protocol with regards to the endpoints of postoperative pain scores and opioid consumption.This study was initially performed as a quality improvement project with approval from our local departmental quality improvement committee. Subsequent approval for publication of the data was obtained from the University of Virginia institutional review board (HSR #10712) and the need to obtain consent was waived. The study period was from January 2013 to June 2015 and included all patients who underwent colorectal surgery. The two cohorts identified were patients who received perioperative lidocaine with opioid-based postoperative analgesia (LIDO group) and those who were part of an ERAS program that included multi-modal analgesia and perioperative lidocaine, as well as restriction of intravenous fluids and encouragement of oral fluid intake and ambulation (ERAS group). Patients were matched by age (within 5 years), gender and chronic opioid use (>1 month).As described in our previous study, we assigned a noninferiority margin of 1-point  difference in pain and a ratio [mean (LIDO) / mean (ERAS)] of 1.2 in opioid consumption , 11. NonThe primary outcome was patient-reported pain scores at rest and opioid consumption for the first four postoperative days or discharge if earlier. Secondary outcomes include hypotension , patient-reported nausea and documented vomiting, pruritus, urinary retention requiring catheterization, duration of indwelling urinary catheterization, time to first ambulation, time to first bowel movement and duration of hospital stay. The regional anesthesia team monitored the lidocaine infusion and collected data on patient satisfaction and mental status.The anesthetic regimen in both groups included general anesthesia with endotracheal intubation. The typical induction agent was propofol with muscle relaxation achieved with either succinylcholine or rocuronium. Anesthesia was maintained with either sevoflurane or desflurane. If reversal of neuromuscular blockade was required, neostigmine and glycopyrrolate were administered.In the LIDO group, intraoperative opioid administration was at the discretion of the anesthesiology provider. A lidocaine infusion was started following induction of general anesthesia at a rate of 2–3 mg/min, based on previous reported dosing regimens , 14. PriPostoperatively, hydromorphone patient-controlled analgesia (PCA) was commenced at a dose of 0.1 to 0.2 mg hydromorphone per bolus, and opioid-tolerant patients received 0.3 to 0.4 mg hydromorphone per bolus; both groups had an 8-min lockout. Patients who did not receive a PCA were given 0.5 to 1.0 mg intravenous hydromorphone every hour as needed. Acetaminophen was administered intravenously initially with a total dose that did not exceed 4 gram/day. Acetaminophen was changed to an oral formulation when oral intake resumed. Oxycodone was started when oral intake permitted to facilitate transitioning off the PCA. At this time the lidocaine infusion was typically discontinued.In the ERAS group, prior to surgery, patients received an oral regimen of celecoxib 200 mg (not given to patient with coronary artery disease), acetaminophen 975 mg and gabapentin 600 mg Table .Table 1PThe components of the intraoperative multi-modal analgesia included: 1) Prior to induction of anesthesia, a single intrathecal dose of preservative free morphine (100 mcg), (2) ketamine 0.5 mg/kg IV at induction followed by an infusion at 0.6 mg/kg/h (stopped 45-min before closure for laparoscopic cases and decreased to 0.3 mg/kg/h in open cases until completion of the case (3) magnesium 30 mg/kg intravenously at induction, (4) dexamethasone 4 mg at induction  is a function of the  results . In addi results .Normality of data was established using the Shapiro-Wilk test. Normally distributed data are reported as mean and SD while non-normally distributed data are reported as median and 25th-75th interquartile range.The two primary outcomes (postoperative pain and opioid consumption) were assessed postoperatively in the recovery room, and every 12 h for up to 4 days. Mixed-effects models were used to examine the changes in the primary outcomes over time, taking into account the within-individual correlations between assessments.The mixed-effects model found to be best fit the changes in the overall postoperative pain scores is:Yij is the postoperative pain score for observation j in patient i; xij1 refers to the linear time (number of days), and xij2 refers to the analgesia group (ERAS vs. LIDO) fixed effects for observation j in patient i; β0 is the random intercept for patient i, zij1 is the random slope for time; and εij is the error for observation j in patient i. This model indicates that the change in postoperative pain scores follows a linear trend over time, with between-patient heterogeneity in initial postoperative pain scores (in recovery room) and the rate of changes in pain scores across time. The same model was fitted to the changes in postoperative pain scores POD1 only, and POD2 to POD4.where The mixed-effects model found to be best fit the changes in the overall postoperative morphine consumption is:Yij is the postoperative morphine consumption for observation j in patient i; xij1 refers to the linear time (number of days), xij2 refers to the quadratic (non-linear) time, and xij3 refers to the analgesia group (ERAS vs. LIDO) fixed effects for observation j in patient i; β0 is the random intercept for patient i, zij1 is the random slope for time; and εij is the error for observation j in patient i. This model indicates that the change in morphine consumption follows a non-linear trend over time, with between-patient heterogeneity in initial postoperative pain scores (in recovery room) and the rate of changes in pain scores across time. The same model was fitted to the changes in postoperative morphine consumption POD1 only. However, the model without the quadratic time fixed effects was fitted to the changes in postoperative morphine consumption on POD2 to POD4, meaning that the changes in postoperative morphine consumption POD2 to POD4 follows a linear trend over time.where U test was used to compare the incidences of each secondary outcome. All statistical analyses were conducted using the statistical program R version 3.2 (R Core Team (2015). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/).Fisher’s exact test or Mann-Whitney p = 0.14), however significantly more intravenous opioids were administered in the lidocaine group while there was more intrathecal opioid use in the ERAS group. This was primarily related to the ERAS protocol limiting intravenous administration of opioids. All patients in the ERAS group received oral acetaminophen, gabapentin and celecoxib prior to surgery. No patient in the standard group received oral acetaminophen, gabapentin and celecoxib prior to surgery. Total lidocaine dose was higher in the LIDO group , primarily due to the earlier discharge in the ERAS group. An additional supplementary file titled ‘Database’ reports the raw data in more detail  on POD 1.A single dose of intrathecal morphine prior to surgery reduces postoperative enteral and parenteral opioid requirements after abdominal surgery. The duration of opioid-sparing depends on the type of opioid and the dose administered. Reported benefits of a single dose of intrathecal morphine are evident up to 24 h after administration , 19. TheThe inclusion of ketamine also likely played a role in reducing postoperative opioid use. In abdominal surgery sub-anesthetic doses of ketamine modulate opioid-induced hyperalgesia via the NMDA receptor reducing postoperative pain and opioid consumption , 21. Thep = 0.63) between the two groups.Although our data demonstrates reduction in opioid use in the ERAS group, opioid-related complications were not significantly different between the two groups. Somewhat surprisingly, return of bowel function, a major side effect of opioids, was not different (LIDO: 40  h vs. ERAS 41.3 h, The opioid consumption and pain scores profile reported here are similar to findings presented in our previous study comparing lidocaine to epidural analgesia for major abdominal surgery . In thatThere are several limitations of this study. In the LIDO group no pre-defined algorithm for opioid administration was utilized with opioid administration solely determined by the clinical team managing the patient. This variability may have influenced our results. We had a small study size, which reduces the chance of detecting a true effect or reduces the likelihood that a statistically significant result reflects a true effect. This was a single-center study investigating an institutional specific ERAS program, therefore our results may not be translatable to other institutions using different ERAS programs. Finally this was retrospective chart review and the possibility of misclassification bias or incorrectly coded data in the electronic medical record cannot be excluded.a priori power analysis in the current study; however, power analysis for future studies can be performed with the current data.As reported in our previous study, there are no standardized criteria for non-inferiority analysis . We utilIn conclusion, our data suggest that ERAS protocols that include intraoperative intrathecal opioids and non-opioid analgesics have a distinct opioid-sparing effect within the first 24 h compared to lidocaine alone. We suggest that a combination of intraoperative protocolized pain management with postoperative continuation of intravenous lidocaine has distinct benefits on pain scores and opioid use for colorectal surgery.


To compare efficacy and safety of intravenous continuous infusion of oxycodone with morphine in patients with cancer pain.  A 5-day, randomized, open-label, exploratory study at 6 sites in the Republic of Korea. Sixty-six adults aged ≥19 years with moderate-to-severe cancer pain  were enrolled. The study group received intravenous (IV) oxycodone, and the comparator group received IV morphine which were titrated depending on pain intensity. The efficacy endpoint is change in average NRS score from baseline to Day 5. Other assessments included worst, current, and average pain intensity; patient satisfaction; medication dose; and adverse events. P value = 0.562), oxycodone achieved faster pain relief  on Day 2 and significant NRS reductions for worst pain on Day 2  and current pain on Day 2  and Day 5  compared to morphine. Patient satisfaction, adverse events, and adverse drug reactions were similar for both groups.  Both groups achieved >50% reduction in average pain intensity: from “moderate” at baseline (oxycodone versus morphine: 6.0 ± 1.8 versus 5.9 ± 1.4) to “mild” at Day 5 (2.5 ± 1.8 versus 2.8 ± 1.6). While this reduction was similar between groups (3.5 ± 2.2 versus 3.1 ± 1.8, NCT02660229. For Asian patients with cancer pain, IV oxycodone is faster acting and showed similar analgesic efficacy and safety profiles as IV morphine. This trial is registered with Clinicaltrials.gov  Patients with cancer can suffer from excruciating pain especially in cases with metastatic, advanced, or terminal disease. The prevalence of pain in patients with cancer exceeds 50% for all cancer types , 2. CancAmong the administration methods for analgesics, IV infusion is widely used for the management of cancer pain in Korea. IV administration has particular advantages in the form of faster onset of pain relief and more predictable pharmacokinetics compared to other routes of drug administration . Strong Morphine has been the treatment of choice for moderate-to-severe cancer pain. However, its use is often hindered by its unpredictable onset of action, interindividual variability in dose requirements and response , and phyStudies on pain management using IV administration methods in patients with cancer are somewhat lacking unlike the postsurgical pain management, which have been actively researched. The earliest double-blinded, crossover study comparing oxycodone and morphine as analgesics for cancer pain reported that their analgesic effects were equivalent when administered orally, and when administered intravenously, the IV dose of oxycodone was 30% higher than that of morphine . More naNCT02660229). It was conducted in accordance with Korean Good Clinical Practice (KGCP)  + bolus injection (mg).On Day 3 and Day 5 (end of the study), overall analgesic treatment satisfaction regarding pain was assessed by investigators using a 7-point Clinical Global Impression of Change (CGIC) scale (1 = very much improved to 7 = very much worse) , 29 and Physical examination was performed, and all vital signs were measured each day. Clinical laboratory tests and ECG were conducted at baseline and at Day 5. Patients were asked to report all adverse events (AEs), and these were confirmed through interview and history taking. A list of possible AEs was provided to the investigators to assist them in this process. The severity of the AE was assessed using a 3-point grade system, that is, (1) mild (causes mild discomfort but does not interfere with daily activities), (2) moderate (causes significant discomfort and interferes with daily activities), and (3) severe . The information on AEs included onset and resolution dates, severity and outcome, action taken and causal relationship to the study drugs, and name of suspected drug other than the study drugs. Safety was assessed based on AEs, vital signs, physical examination, clinical laboratory tests, and ECGs. All safety data were collected and documented in the case report form (CRF).t-test or Wilcoxon rank sum test , and for categorical data, for example, sex and cancer history, the analysis was conducted using the chi-square test or Fisher's exact test.As this was an exploratory study, we targeted to enrol a total of 66 patients (33 in each group). This number sufficiently allowed for an estimated 10% dropout rate and normality assumptions on the data and is also used in a number of similar studies , 31. Dest-test or Wilcoxon rank sum test was conducted to test for differences between groups. A paired t-test or Wilcoxon signed rank test was used to analyze within-group differences in the change of NRS scores at each time point. Additional analyses on the cumulative proportion of subjects in each group who achieved at least 30% and 50% reduction in pain levels on each day of study were computed. A chi-square test was used to analyze the between-group difference in proportions.The mean, SD, and percent change at each time point from baseline were computed for the study and comparator groups for the NRS score, change in NRS scores, and cumulative administered dose. A two-sample The frequency and proportion for the CGI-C and PGI-C scores on Day 3 and Day 5 were summarized for each group, and Fisher's exact test was conducted to test the difference between groups. All analyses were performed using the SAS™ statistical analysis software , and statistical significance was evaluated at 0.05 levels.The study was conducted from 3 September 2015 to 24 July 2016 at 6 sites. A total of 68 patients were screened. Of these, 2 failed the screening, and the remaining 66 patients, that is, safety set (SS) consisting of 34 patients for the oxycodone group and 32 in the morphine group, were randomized for treatment . One patP value = 0.042); pancreatic and gastric cancers were most common in the oxycodone group while gastric, lung, and colorectal cancers were more represented in the morphine group. Most (83.1%) patients had concurrent illnesses. Almost half (49.2%) of the patients had chemotherapy from 14 days before screening till end of study, but none had radiation therapy. Nearly all patients had prior medication (other than anticancer therapy), and all of them had concomitant medication.Patients' demographic and cancer characteristics are shown in P value = 0.963) and, similarly, at the end of the study . However, on Day 2, there is a significant difference in the average pain scores . Patients who were given IV oxycodone reported average NRS scores of 3 or lower from Day 2 onwards compared to Day 4 for the morphine group. Similar observations were also recorded for the current pain scores.P value < 0.001) from Day 1 onwards with the oxycodone group having the largest one-day decrease in worst, current, and average pain scores of 1.8, 2.0, and 2.1 points, respectively, from baseline to Day 1. On Day 5, both groups achieved >50% reductions in average NRS pain scores, that is, from “moderate” to “mild” pain as compared to baseline. There was no difference in this reduction between the two groups . The PP set also showed similar results. The worst pain scores, at baseline, were 8.0 ± 1.8 and 7.6 ± 1.7  for the oxycodone and morphine groups, respectively. These decreased to 4.5 ± 2.1 and 5.1 ± 2.3  on Day 5. Between the two groups, oxycodone achieved significantly better pain relief for the worst pain recorded on Day 2 (−2.9 ± 2.7 (oxycodone) versus −1.7 ± 2.2 (morphine); P value = 0.045) and current pain on Day 2 (−2.7 ± 2.7 (oxycodone) versus −1.2 ± 2.0 (morphine); P value = 0.035) and Day 5 (−3.4 ± 2.6 (oxycodone) versus −1.9 ± 1.6 (morphine); P value = 0.020) (= 0.020) .at least 30% reduction in pain for the oxycodone group compared to the morphine group on Day 2 .There were no differences in the treatment satisfaction scores reported by patients (PGIC) and investigators (CGIC) for both drugs on Day 3 and Day 5. By Day 3, most patients (≥95.3%) reported some improvement in pain relief regardless of the pain medication. The investigators also reported similar observations. Similar results were also observed in the PP set.P value = 0.996), respectively. There were no differences in the cumulative medication doses given to each group on a daily basis during the study period.The mean cumulative doses of oxycodone and morphine groups of the FA set at the end of the study (Day 5) were 226.8 ± 110.4 mg and 226.6 ± 135.1 mg . This was also the case for the incidence of serious AEs: 8.8%  and 6.3%  in the oxycodone and morphine groups, respectively.P value = 0.049). The nature of these disorders (by system-order-class) is shown in P value = 0.569).The most commonly reported AE in both groups was gastrointestinal disorders . The influx rate across the BBB is much more rapid for oxycodone compared to morphine, and the extent of this difference has been estimated to be sixfold faster , 35. ThiThe cumulative doses of drug administered intravenously were similar in both our study groups, demonstrating that a 1 : 1 potency for oxycodone to morphine can be achieved in Asian patients with cancer pain. This potency ratio has previously been estimated for oral administration to range from 1 : 1 to 1 : 2.2, with the consensus that oral oxycodone is about 1.5–2 times as potent as oral morphine . Oral opPain is a personal and subjective experience, and a number of measures have been developed to describe the level of pain, for example, pain intensity difference, pain relief, % of maximum total pain relief (TOTPAR), and sum of pain intensity difference (SPID) . The timThe incidence of AEs is >80% for both groups. However, there were no significant differences between oxycodone and morphine groups in the incidence of AEs, or associated adverse drug reactions. A meta-analysis of studies on the use of strong opioids for cancer pain management reported similarly high incidences regardless of the opioid used . The anaWe are aware that this small sample size and the short duration of our exploratory study did not allow a formal evaluation of efficacy of the study drugs due to potential statistical bias and the limited time for the full effects of the drugs to be realized. An open-label study design was chosen as the study aimed to evaluate the two drugs under conditions approximating normal clinical use. This may cause some bias in the subjective assessments especially from the investigators as an active comparator was used. We recognized this to be a limitation of a nonblinded design. However, the route of administration for both drugs was similar, that is, IV, and together with the randomization, may minimize some of the bias.While there are some negative effects on the use of strong opioids such as tolerance and abuse , achieviOur study showed that oxycodone and morphine, administered by IV infusion for patients with moderate-to-severe cancer pain in an Asian population, have similar efficacy and safety profiles. Oxycodone was found to be faster acting and can be a good alternative to morphine.