Temporomandibular disorder (TMD) patients might present a number of concurrent clinical diagnoses that may be clustered according to their similarity. Profiling patients’ clinical presentations can be useful for better understanding the behavior of TMD and for providing appropriate treatment planning. The aim of this study was to simultaneously classify symptomatic patients diagnosed with a variety of subtypes of TMD into homogenous groups based on their clinical presentation and occurrence of comorbidities.Clinical records of 357 consecutive TMD patients seeking treatment in a private specialized clinic were included in the study sample. Patients presenting multiple subtypes of TMD diagnosed simultaneously were categorized according to the AAOP criteria. Descriptive statistics and two-step cluster analysis were used to characterize the clinical presentation of these patients based on the primary and secondary clinical diagnoses.The most common diagnoses were localized masticatory muscle pain (n = 125) and disc displacement without reduction (n = 104). Comorbidity was identified in 288 patients. The automatic selection of an optimal number of clusters included 100% of cases, generating an initial 6-cluster solution and a final 4-cluster solution. The interpretation of within-group ranking of the importance of variables in the clustering solutions resulted in the following characterization of clusters: chronic facial pain (n = 36), acute muscle pain (n = 125), acute articular pain (n = 75) and chronic articular impairment (n = 121).Subgroups of acute and chronic TMD patients seeking treatment can be identified using clustering methods to provide a better understanding of the clinical presentation of TMD when multiple diagnosis are present. Classifying patients into identifiable symptomatic profiles would help clinicians to estimate how common a disorder is within a population of TMD patients and understand the probability of certain pattern of clinical complaints. Temporomandibular disorders (TMD) are a group of painful conditions that typically involve the temporomandibular joint(s) (TMJ) and/or masticatory muscles . It is wIt is clear from clinical practice that TMD and orofacial pain patients share many common clinical features or symptoms. For instance, patients with chronic muscle pain associated with long-term parafunctional habits, such as clenching or bruxism, may develop secondary structural changes in the temporomandibular joints .A particular profile of patients seeking treatment for these conditions could be composed by reflecting the heterogeneity of the conditions involved into identifiable groups based on the clinical presentation of symptomatic patients. The classification of groups of patients who share properties in common might provide useful information for the diagnosis and initial management of TMD. The aim of this study was to classify the symptom presentation of patients who sought treatment and who were diagnosed with a variety of combined subtypes of TMD and to cluster them into homogenous groups based on their clinical condition and chief complaints.The study was a retrospective assessment of the clinical records of 357 consecutive symptomatic patients, 86.8% female, age ranging from 11 to 70 years old , referred to or seeking treatment for orofacial pain and/or TMD in a private clinic in Goiania, Goias, Brazil. Patients’ characteristics, inclusion and exclusion criteria and information about clinical examination and data collection were reported in a previous study . The stuAnamnesis and all clinical examination were performed by two trained dentists with a large amount of experience in dealing with patients with orofacial pain as part of the routine clinical practice of the private clinic. Both examiners were trained and certified in the same Orofacial Pain Center . Standardized criteria of the AAOP were used in all clinical assessment and diagnosis.“Do you think you sleep well?”, “How many hours do you sleep per night?”, “How long it takes to sleep?”, “How many times you wake during the night?”, “Your sleep restores your energy?”, “Do you feel rested when you wake in the morning?”. Some patients with suspect of severe sleep disorders were diagnosed by polissomnography.The information collected from patients during anamnesis included their chief complaint and other secondary complaints, if present, the patients’ reports of their perceptions about their pain status, and their dental and medical histories. It also included questions about pain characteristics , a description of the symptoms experienced since the onset of pain , headache and related characteristics, the presence of perceived joint noises, the history of locking and/or trauma in the orofacial region, the presence of conscious oral habits , the characteristics of sleep and diet, the type of professionals previously sought and any previous treatments. The questions for pain assessment were planned to get a comprehensive clinical evaluation for diagnostic and treatment purposes. It included opened questions about the features of the pain sensation, and the visual analogue scale was used to measure subjective characteristics or attitudes that cannot be directly measured, such as pain intensity , and to monitor the effectiveness of subsequent treatments. Sleep characteristics were assessed in the initial appointment using general opened questions such as The physical examination included cranial nerve functioning, cervical movement pain or limitation, palpation of masticatory and cervical muscles, a functional examination of the masticatory muscles with muscle stimulation tests and an evaluation of the range of mandibular motion. Additional exams and sectional images of the TMJ were requested and performed when needed, in cases where internal TMJ disorders were suspected.The American Academy of Orofacial Pain (AAOP) guidelines and diagnostic criteria  were adoThe diagnosis of internal TMJ disorders was based on clinical findings and conventional radiographs when indicated. Magnetic resonance images of the TMJ were requested for patients with persistent pain, significant limitations in mouth opening (< 30 mm) and suspected degenerative joint disease. Although bruxism is a contributor and might occasionally trigger TMD, it was considered a diagnostic group in cases when it was a chief complaint.When patients presented with more than one TMD, both the main and the secondary diagnosis were registered. The main diagnosis was based on the chief complaint reported by the patient and the secondary diagnosis was based on other relevant complaints or significant clinical findings elicited by clinical examination or the imaging methods. All other possible, additional diagnoses were registered but not considered for the characterization of the patients’ symptomatic profiles. Patients with tension-type headache, migraine, neuropathic pain and sleep disorder identified as the only diagnosis were excluded from the sample, except when primary headache was caused by a TMD or was triggered by muscle function or TMJ disorders. In such cases, for the purpose of the cluster analysis, only the TMD was considered for analysis. A complete description of the frequencies of patients’ diagnoses was published elsewhere .n numbers of clusters based on the primary and secondary diagnoses using an auto-clustering algorithm to reach an initial clustering solution. All TMDs were inserted in the cluster analysis as yes/no dichotomous variables. The relative importance of variables (diagnoses) with statistical significance in the formation of clusters (chi-square test) helped to identify the occurrence of yes/no responses to the different diagnoses. The frequencies of both positive (presence) and negative (absence) diagnoses with their statistical significance were considered for the identification of variables that contributed most to the differentiation of clusters.Data were analysed using a descriptive analysis and the non-hierarchical two-step cluster analysis procedure as an exploratory tool intended to reveal natural groupings (or clusters) within the data set that would otherwise not be apparent. The frequency analysis included the primary and secondary diagnoses and a cross-tabulation of the combined diagnoses. In the next stage, the two-step cluster analysis was used to divide samples into The initial cluster solution was used to identify relevant variables for interpreting the groups. Alternative solutions, other than the default auto-clustering option, were tried to disclose fewer natural groupings using a specific and fixed number of clusters. The proposed clustering solutions were selected according to clinical interpretability and plausibility. Finally, all clusters were named using a term that best represented the patients’ symptomatic characteristics, according to the combination of the primary and secondary TMD diagnoses.The SPSS 17.0 software  was used for all statistical analyses.Table Following the frequency analysis, the two-step cluster analysis procedure was to disclose the natural groupings. An initial solution with six clusters was achieved using the auto-clustering algorithm. Table The combined interpretation of Table Patients with acute cervical and/or localized masticatory muscle pain, without any articular complaints, comprised cluster n#4 (n = 46). Conversely, cluster n#5 (n = 72) was mainly composed of patients with acute articular pain (capsulitis/synovitis) and secondary DDWOR. Cluster n#6 included patients with cervical pain, non-painful chronic articular impairment (DDWOR) and a history of TMJ subluxation.Figure The results of this study present different symptomatic profiles of patients seeking treatment in a TMD clinic, who were classified by cluster analysis into four to six homogenous groups based on their clinical presentation.It is important to note that the cluster names were intuitively defined considering the time of onset, the location, the presence of pain and extent of the symptoms. Patients’ profiles may help clinicians to quickly recognize patient characteristics and provide a reasonable treatment approach. After clustering procedures, data also illustrate the prevalence of symptomatic profiles, which is helpful for identification of symptomatic profiles, would help clinicians to estimate how common a disorder is within a population of TMD patients and understand the probability of certain pattern of clinical complaints.Although internal validity of the diagnostic criteria and the efficacy of the examiners’ performance were not tested, standardized criteria of the AAOP were used and both examiners were trained and certified in the same Orofacial Pain Center .Masticatory muscle pain is recognized as the most common complaint in patients in general practice, and perhaps only a few patients will present for treatment in private practice with a chronic stage. This could be explained by the fact that many patients might have previously searched for treatments that turned out to be ineffective and then began to give up on seeking new alternatives, leading to an even more chronic problem , or it cIn particular, this could occur with some internal derangement of the TMJ, which will eventually become a chronic condition quite easily. Kalaykova et al.  studied These could be some of the reasons why patients with acute muscle pain and chronic joint impairments were more frequent in this sample. Many patients do not know what to do in these situations or which professionals they should look for: an orthodontist, a maxillofacial surgeon, a prosthodontist or an otolaryngologist, for example. Moreover, many professionals are unsure about what to say to patients with this distressing disorder, when (or whether) to refer them to specialists and even which experts to refer them to .Another explanation for the high frequency of acute problems could be the fact that most of the TMDs are cyclical. Patients with a chronic condition that they had already been adapted, for some reason or event, may have worsened and make them seek for treatment ,9.A strong relationship between sore muscles  and bruxism (patients from cluster 2), myofascial masticatory muscle pain and bruxism (patients from cluster 1) and the need to seek for treatment was revealed by our results. A similar finding was found by Lobbezzo-Scholte et al. , whose rThe significance of dealing with bruxism and masticatory muscle pain early on and the importance of recognizing these conditions in everyday practice are highlighted, since myalgia, being a deep pain stimulus, can yield central excitatory effects and referred pain. Therefore, this statement may explain the fact that when a muscle pain is maintained, more muscle pain may be restarted, keeping the patient in a cycle of pain . This enA treatment plan could be outlined for patients with similar characteristics as for those comprising clusters 1 and 2 with muscle dysfunctions and bruxism. A more conservative management should be carried out since such disorders are related to multiple factors, and often, if not always, there is a strong role of emotional factors ,12,15-18A combination of capsulitis/synovitis and disc dislocation without reduction (DDWOR) was found in patients from cluster 3. Regarding the concept that internal TMJ derangement is significantly involved in the production of TMJ pain and dysfunction, these results corroborate findings from other authors . These fPatients presenting with non-painful articular impairment from cluster 4 were the second most frequent group of patients who were referred for or who sought treatment for TMD. Despite the fact that this cluster was named TMJ impairments, due to the main disorders clustered, perhaps we can infer that treatment seeking was mainly guided by dysfunctions associated with muscle disorders or DDWR, as shown in Table As discussed above for clusters 1 to 3, a combination of treatment modalities can also be outlined for the management of patients who have a similar presentation to those of cluster 4, due to the many associated muscle and joint disorders. Each particular case should be evaluated in order to define appropriate treatment planning. As there are many therapeutic options, if the selected treatment does not eliminate the patient’s pain complaint, the next more complex condition or chronic muscle condition should be considered by the clinician . Due to Velly et al.  clustereDespite some limitations regarding the generalization of results , we believe that the most interesting aspects that deserve particular attention from the results of our study are the large sample size, the large number of patients presenting with more than one TMD condition simultaneously diagnosed and the strong homogeneous relationship between patients in the formation of clusters. The clustering method may depend on the choice of classification variables and how they were collected . HoweverIn summary, the great homogeneity of patients with multiple conditions of TMD being diagnosed while seeking treatment allowed the recognition of subgroups of conditions. Determining the profile of patients with such characteristics is of paramount importance for understanding their clinical presentation and thus delineating the most appropriate treatment for them. The identification of these patients’ profiles and estimation of their prevalence within TMD symptomatic patients seeking treatment may be useful for the management of patients seeking treatment and for reducing misleading clinical decisions due to the large heterogeneity of TMD diagnostic subgroups.The authors declare that they have no competing interests.LPSM performed all data collection, created the database and drafted the manuscript, MBMN and CGN performed all clinical examinations, and CRL was the head of the study, performed the statistical analysis and collaborated in manuscript design and writing. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6831/12/26/prepub


Introduction: In trigeminal neuralgia, when drug treatment proves ineffective, other management options must be considered. In this context, conventional radiofrequency of Gasser’s ganglion is a safe and effective alternative.Material and Methods: We describe 5 patients with long-evolving trigeminal neuralgia subjected to conventional radiofrequency according to the Sweet technique, with a follow-up of two years.Results: Pain relief was complete after two months in all cases. One patient suffered an unexpected episode of nausea, vomiting and foul odor sensation that subsided after three days of rest and drug treatment. Three patients described non-painful hypoesthesia in the region of the treated nerve branch that subsided within three months. The patients remained free of symptoms over long-term follow-up. In one case the same radiofrequency technique had to be repeated after 21 months because of the reappearance of symptoms in the same zone, followed by immediate pain relief.Conclusions: In our series of patients trigeminal neuralgia was not controlled by drug treatment, and conventional radiofrequency targeted to Gasser’s ganglion proved very effective, with no major complications. Key words:Trigeminal neuralgia, conventional radiofrequency, trigeminal ganglion. Primary trigeminal neuralgia is one of the most painful conditions seen in human clinical practice, and while many treatments have been developed to afford pain relief, none of them are uniformly effective . RadiofrThe present study describes a series of patients with long-evolving trigeminal neuralgia subjected to conventional radiofrequency.Between January 2006 and December 2007, we reviewed 13 patients with trigeminal neuralgia seen in a medical-surgical unit of a University clinic; of these 5, complied with the following criteria for treatment with conventional radiofrequency:a. Typical or atypical primary trigeminal neuralgia with a duration of over two years.b. Inefficacy of drug treatment.c. A pain visual analog scale (VAS) score of over 7/10, with poor quality of life because of the pain.d. Absence of concomitant disorders capable of accounting for the symptoms.e. Normal brain magnetic resonance imaging findings.The inclusion criteria were the obtainment of informed consent to participation in the study and a clinical follow-up of two years. The treated patients had a mean age of 64.8 years (range 55-76); there were three women and two men. The distribution according to the affected trigeminal nerve branch was as follows: four patients suffered pain in the territory of the third branch (V3)(3 right side and 1 left side), and one patient suffered pain in the region of the second branch. Two subjects had undergone extraction of a premolar in the painful quadrant before the actual onset of pain. However, in both cases the clinical manifestations of neuralgia were typical . Only onAll of the patients received an explanation of the different treatment options, and accepted radiofrequency treatment of Gasser’s ganglion.Conventional radiofrequency targeted to Gasser’s ganglion is carried out under radioscopic control, following the technique described by Sweet . The patThe technique was carried out without problems in all patients, with positive sensitivity tests (at < 0.3 volts) and a positive motor test in the case of the third branch. Three lesions were made in the described temperature interval (60-65-75ºC). Following each lesion we checked the corneal reflex and the existence of hypoesthesia of the second and third trigeminal branches (consistent with the lesions made). The immediate postoperative course proved excellent in all cases.Thirty hours after RF treatment, one patient suffered an unexpected episode of nausea, vomiting and foul odor sensation that subsided after three days of rest and drug treatment with ondansetron  and corticosteroids . The olfactory symptoms slowly subsided, leaving persistent dull pain that dis-appeared after two months. In the rest of the patients pain relief was immediate and lasting.Three patients described non-painful hypoesthesia in the region of the treated nerve branch that subsided within three months . As regaPrimary trigeminal neuralgia most often manifests between 50 and 70 years of age. In 90% of the cases, the symptoms first appear after age 40. The prevalence is higher in women than in men (1.5:1 proportion). In our series the women were within the established age range . In our Regarding treatment, the initial approach always consists of drug therapy. Carbamazepine is usually able to reduce the pain by 70% . Other dThe development of foul odor sensation following radio-frequency has not been described in the literature. We are unable to find a physiopathological explanation for this condition, recorded in one of our patients, not even when treatment is targeted to the second trigeminal branch, which conducts sensitivity from the nasal portion.Despite the few complications of conventional radiofrequency, pulsed radiofrequency appears to be a reasonable alternative in the treatment of trigeminal neuralgia, given its non-ablative nature. However, the results obtained in the only randomized study published to date have been disappointing .In our series of patients trigeminal neuralgia was not controlled by drug treatment, and conventional radio-frequency targeted to Gasser’s ganglion proved very effective, with no major complications.


Opioids are associated with wide inter-individual variability in the analgesic response and a narrow therapeutic index. This may be partly explained by the presence of single nucleotide polymorphisms (SNPs) in genes encoding molecular entities involved in opioid metabolism and receptor activation. This paper describes the investigation of SNPs in three genes that have a functional impact on the opioid response: OPRM1, which codes for the μ-opioid receptor; ABCB1 for the ATP-binding cassette B1 transporter enzyme; and the calcium channel complex subunit CACNA2D2. The genotyping was combined with an analysis of plasma levels of the opioid peptide β-endorphin in 80 well-defined patients with chronic low back pain scheduled for spinal fusion surgery, and with differential sensitivity to the opioid analgesic remifentanil. This patient group was compared with 56 healthy controls.The plasma β-endorphin levels were significantly higher in controls than in pain patients.A higher incidence of opioid-related side effects and sex differences was found in patients with the minor allele of the ABCB1 gene. Further, a correlation between increased opioid sensitivity and the major CACNA2D2 allele was confirmed. A tendency of a relationship between opioid sensitivity and the minor allele of OPRM1 was also found.Although the sample cohort in this study was limited to 80 patients it appears that it was possible to observe significant correlations between polymorphism in relevant genes and various items related to pain sensitivity and opioid response. Of particular interest is the new finding of a correlation between increased opioid sensitivity and the major CACNA2D2 allele. These observations may open for improved strategies in the clinical treatment of chronic pain with opioids. The treatment of moderate to severe pain is largely dependent on the use of opioids . OpioidsNew molecular and genetic techniques have now made it possible to identify specific genes coding for pain-relevant proteins, genes that contain mutations that could explain the variations in pain response ,7 as welOPRM1) gene [ABCB1) gene [CACNA2D2) gene [Since pain is a complex bio-psychosocial phenomenon, the task of searching for and finding single gene variations to explain individual differences could be seen as futile. However, in this study, the focus is on three genes, all of which encode proteins related to the pain-relieving effects of opioids, and on the endogenous opioid peptide β-endorphin. The search for candidate genes containing SNPs possibly associated with pain and opioid sensitivity resulted in the choice of the μ-opioid peptide receptor (M1) gene -12, the B1) gene ,14 and tD2) gene . In the OPMR1 receptor, since this has been shown in earlier studies to alter the response to opioids [OPMR1 amino acid sequence. As this change occurs on the extracellular part of the receptor, it results in an additional net charge with loss of a putative glucosylation site in the area of the ligand-receptor interaction. This can result in differences in opioid sensitivity, clinically manifested as altered analgesic requirements [We chose to analyze an SNP at position 118 (A118G or 118A>G) of the gene for the  opioids . The 118irements -17, variirements . The majABCB1 gene is composed of 28 exons ranging in size from 49 to 209 base pairs, encoding an mRNA of 4.5 kb. The most common polymorphisms found in ABCB1 are 1236C>T, 2677 G>T/A/C, and 3435C>T. The transport protein P-glycoprotein, a product of the ABCB1 gene, plays an important role in the absorption and distribution of many drugs. P-glycoprotein is an ATPase-powered enzyme that transports substances, including opioids, across cell membranes and the blood–brain barrier [ABCB1 could be a cause of inter-individual differences in drug response [ABCB1, where C>T. Thus, the major allele is CC, the heterozygous minor allele is CT and the homozygous minor allele is TT.The  barrier ,20, whicresponse . In thisCACNA2D2 gene encodes a member of the alpha-2/delta subunit family, a protein in the voltage-dependent calcium channel complex [The  complex . Calcium complex . It has  complex , with po complex . The α2δ complex . The maj complex .β-endorphin is an opioid peptide produced primarily in the anterior lobe of the pituitary gland . FollowiOPRM1, the ABCB1 gene for the drug transporter P-glycoprotein and the calcium channel fragment gene α2δ CACNAD2, as well as the endogenous ligand for the μ-opioid receptor β-endorphin. These three candidate genes, all associated with pain processing and opioid analgesia, were analyzed in blood samples collected from 80 patients with chronic low back pain and 56 healthy controls. We also collected plasma samples for assessment of β-endorphin levels. The patients were classified as high responders (N=16), normal responders (N=44) or non-responders (N= 20) to the opioid remifentanil. All the study participants filled out an EORTC QLQ-30 Quality of Life (QoL) form for pain, function and symptom scoring.Thus, in order to move the issue of the genetic aspects of chronic pain and opioid sensitivity a step forward, we investigated the influence of SNPs in the μ-receptor gene OPRM1, ABCB1 and CACNA2D2 are presented in Table The genotype frequencies of the minor allele of β-endorphin plasma levels were determined by radioimmunoassay (RIA) in patients and healthy controls Table . The opiOPRM1 were distributed as presented in Table The major and minor alleles of OPRM1 had higher concentrations of β-endorphin (26.8 ± 3.25 fmol/ml) than male patients with the minor allele . There were no differences in that respect among female patients or in the control groups (Table 2 = 0.035 p = 0.106).Male patients with the major allele of ABCB1 allelic distribution was similar in all groups  than men with the major allele CC (25.8 ± 3.20 fmol/L). Similarly, women with the major allele CC tended to have higher β-endorphin levels (26.4 ± 3.30 fmol/L) than women with the minor TT allele , while 12/44 (27%) of the normal responder group, 6/20 (30%) of the non-responders, and 15/56 (25%) of the control group had this allele . There was also a trend for men with the major CACNA2D2 allele to respond better to opioids than men with the minor allele (p = 0.087). In a multivariate model adjusted for age and sex there was a significant association between CACNA2D2 genotype and opioid sensitivity .The OPRM1 118 G variant [The use of opioids for the treatment of chronic pain has increased dramatically over the past decade ,33. Howe variant .This study focused on the genes for the μ-opioid peptide (MOP) receptor, which mediates opioid effects, the ABCB1 transporter of opioids, and the calcium channel gene fragment α2δ, which affects the G-protein of the opioid receptor. The effects of these gene variants were in the present study measured in a group of patients with chronic pain and the effects were correlated with the perception of pain, the incidence of opioid side effects, plasma levels of β-endorphin and opioid sensitivity.An important finding in the present study is that the plasma levels of β-endorphin the endogenous ligand for the MOP receptor were significantly lower in the chronic pain patients compared to control subjects. This observation agrees with previous reported findings showing that plasma levels of β-endorphin correlate inversely with pain levels in patients with various pain syndromes -42, i.e.OPRM1 than normal responders, non-responders or controls. However, there were too few patients to confirm any statistical significance in this regard. The study reported by Landau et al. [OPMR1 allele required less intrathecal fentanyl than those with the major allele is in accordance with our results. Similarly, Janicki and co-workers [OPRM1 receptor gene SNP IVS2+31 G>A have a higher pressure pain threshold than women with the major allele. Taken together, all these findings indicate that the minor alleles of the OPRM1 gene could offer some protection from pain and subsequently have decreased requirement for opioids in chronic pain conditions.Our results also demonstrate that high responders to remifentanil tended to be more likely to have the minor allele of u et al.  indicati-workers  demonstr-workers . Similar-workers  women wiOPRM1 require more morphine than those with the major allele, and that patients who are undergoing abdominal hysterectomy [OPRM1 require more morphine than those with the major allele. However, the results of our study suggest that the situation could be different in patients with a phenotype of chronic pain from that in patients with postoperative or cancer pain and healthy subjects.In contrast, recent studies have indicated that patients with malignant disease who have the minor allele of erectomy  or totalerectomy  who haveerectomy . Other serectomy ,49. ThusThe consequence of the mutation A>G in the OPMR1 gene is an additional net charge with loss of a putative glucosylation site in the area of the ligand-receptor interaction and this feature may have consequences for the sensitivity to opioids of pain patients, although the phenotype of the pain seems to be essential.OPRM1 A118G SNP has also been associated with higher heroin doses in addicted individuals [Interestingly, the ividuals . In one ividuals , which cividuals . The menOPRM1 A118G allele in our study population compared many other studies on the Caucasian population. However, calculation of the allele frequency in our material yields values that are in good agreement with those reported from other laboratories [It should be noted that in the present study we present data from the gene analysis as expressed in genotype frequency  years. The inclusion criteria were patients with chronic low back pain for more than 6 months on the waiting list for spinal fusion surgery. Age over 18 and ability to understand written and spoken Swedish was required. The patients were all scheduled for lumbar spinal fusion surgery after having performed diagnostic MR indicating degenerative disc disease, identification of diseased lumbar segment with discography and a clinical and neurological investigation by the orthopedic surgeon. At the time for the remifentanil study the pain of the patient was graded by visual analogue scale 0–100 mm. To be included in this study the patients were required to grade a minimum of 40 mm on this scale. The exclusion criteria were significant comorbidity that would preclude the planned operation. The control group consisted of 25 men and 31 women with a mean age of 40.5 27–61) years. The ethnicity of the patients and the control population were mainly North European with the exception of 2 persons from each group that were of Middle Eastern heritage. Blood samples from the patients and healthy volunteers were collected and centrifuged. The red blood cells and plasma were used for DNA-analyses and for β-endorphin, respectively. Pain, QoL and opioid side effects and symptoms were measured in both patients and controls using the EORTC-OLQ-30 form. The rationale for using this instrument was that it is validated for opioid treated chronic pain and cancer patients  years. T. Opioid All patients had received opioids, but none was receiving daily doses of strong opioids at the time of opioid testing and blood sampling. The results obtained from the patients were compared with those from the control population of 56 healthy volunteers without pain.2 and a rate of pressure increase of 50 kPa/s was applied to the area of maximal pain in the lumbar area and the patient indicated the point when pressure was experienced as pain; i.e. the pressure pain threshold. The target levels of remifentanil that were measured for 50% pain relief were 1–7 ng/ml. High responders to remifentanil had blood levels of the opioid in the range of 0.5–1.5 ng/ml, while normal responders required 2–7 ng/ml. In non-responders to remifentanil, the infusion had to be stopped because of sedation or side effects before any pain relief was obtained. There were 16 high responders, 44 normal responders and 20 non-responders.The patients were investigated for opioid sensitivity using a target-controlled infusion of remifentanil, as described by Schraag et al. . This waThe Magtration 12GC system  and the Magazorb® DNA Common Kit-200  were used for the total genomic DNA preparation from the whole blood samples. The DNA-fragments containing the SNP site was amplified in a reaction mixture on Mastercycler Ep Gradient S .OPRM1 A118G were conducted using the TaKaRa LA Taq  at 95°C for 3 min, then 30 cycles of 95°C for 30 s, 60°C for 30s and 72 for 1 min and hold at 4°C. PCR primers were forward 5’-CTGACGCTCCTCTCTGTCTCA-3’ and reverse 5’CAACATTGAGCCTTGGGAGT-3’. The second PCR were conducted with the identical program but using the HotGoldStar DNA polymerase , using the primers forward 5’GAAAAGTCTCGGTGCTCCTG 3’ and reverse 5’ GCACACGATGGAGTAGAGGG 3’.The first PCR for CACNA2D2 was conducted with TaKaRa LA Taq polymerase  by touch-down PCR: 94°C for 3 min, then 10 cycles of 94°C for 20 s, 60°C down to 50°C (−1°C/cycle) for 30s, 72°C for 1 min, then 25 cycles of 94°C for 20 s, 50°C for 30 s, 72°C for 1 min, then 72°C for 10 min and hold at 4°C. Primers used were forward 5’-AAGACGGATGGCCTCGTTA-3’ and reverse 5’-ACATATGGATGGCCAGTTGAA-3’. The second PCR was conducted using the HotGoldStar DNA polymerase  at 94°C for 3 min, then 40 cycles of 94°C for 30 s, 65°C for 30 s, 72°C for 1 min and ending with 72°C for 1 min and hold at 4°C, using primers forward 5’-TCCAACATCACTCGGGCCAACT-3’ and reverse 5’-TTGTTGGCACAGGCCATCCACT-3’.PCR for ABCB1 was conducted with one PCR at 94°C, 2 min, 94°C 30 sec, 60°C 30 sec, 68°C 1 min 30 cycles, 4°C hold using the AccuPrime Taq DNA polymerase . Primers used were forward 5’-GAGCCCATCCTGTTTGACTG-3’ and reverse 5’-ACTATAGGCCAGAGAGGCTGC-3´.Amplification of The PCR product was purified with the PCR Clean-Up Kit  using the Magtration 12GC system and the concentration were determined using NanoDrop .OPRM1 A118G (rs1799971), as described earlier [OPRM1 A118G by ASOCH, were as follows: 5’ GTCGGACAGGTTGCCATC TAAGT 3’ (AA), 5’ GTCGGACAGGTCGCCATCTAAGT 3’ (GG). Hybridization was conducted automatically in room temperature using the Magtration 12GC System. The Bio-Strand Tip was first pre-hybridized by incubation in 450 μl of a solution containing 2xSSC (1xSSC is 150 mM NaCl and 15 mM sodium citrate), 0.1% SDS and 200 μl/ml salmon sperm DNA , then incubated 5 min in 450 μl of the hybridization solution containing 2xSSC, 0.1% SDS, 200 μl/ml salmon sperm DNA and 10nM Cy5 probes. The Bio-strand Tip was washed for 2 min each in 450 μl washing buffer 1 (2xSSC and 0.1% SDS) washing buffer 2 (1xSSC and 0.1 %SDS), washing buffer 3 (0.1xSSC and 0.1% SDS) and then soaked in 450 μl of 2xSSC. The Cy5 probes for ASOCH were: 5’-ATGGCGACCTG 3’ (G), 5’ Cy5-ATGGCAACCTG 3’ (A). Two non-labeled oligonucleotides were used as competitor to the Cy5-probes, (5’-ATGG CAACCTG-3’) for G and (5’-ATGGCGACCTG-3’) for A. The Cy5 fluorescent signal was scanned with the Handy Bio-Strand scanner  and the results were analyzed with Hy-Soft software . In addition, all OPRM1 SNP were confirmed by PCR direct sequencing.The Handy Bio-Strand method was used for the SNP genotyping of  earlier . BrieflyCACNA2D2 G>A (rs5030977) and ABCB1 C3435T (rs1045642) SNP genotypes. Briefly, the PCR-product was mixed with Exo-SAP-IT , diluted 1:20 with H2O and incubated in 37°C, 30 min. Exo-SAP-IT was inactivated by heating at 80°C for 20 min. Direct DNA sequencing were performed at Macrogen .PCR direct sequencing was used to analyse The frozen plasma samples were thawed on ice and centrifuged at 4°C for 10 min at 3000 × g. The supernatants were collected, diluted (1:5) with 0.1 M formic acid and 0.018 M pyridine (buffer I) and separated on minicolumns (1 ml) packed with SP-Sephadex C-25 gel according to a previously outlined procedure . The colThe EURIA-β-Endorphin kit  was used for the β-endorphin radioimmunoassay (RIA). This RIA is based on the principle of double-antibody precipitation. The evaporated samples were diluted with 220 μl diluent  and incubated with 100 μl of anti-β-endorphin antiserum for 24 h at 4°C. After incubation, the labeled peptide was added to each sample and incubated for an additional 24 h, at 4°C. Thereafter, the double antibody PEG was added, and the test tubes were incubated for 60 min and then centrifuged for 15 min at 3000 × g at 4°C. Finally, the supernatants were decanted and the radioactivity of the precipitates was counted in a gamma counter.The material was analyzed with SPSS 14 quantitative data using Student’s t-tests. Ordinal data and variables not normally distributed were analyzed by the Mann–Whitney U-test, the Kruskal Wallis test and the z-test for comparison of population proportions. Hardy-Weinberg equilibrium was assessed for each SNP by χ2 analyses. The findings in univariate analyses were furthermore investigated in multivariate models adjusted for age and sex.Harumi Ginya, working as a guest researcher at Uppsala University  when this project was conducted, is employed at PSS, Tokyo, Japan, from where the Magtration 12GC system was bought. The remaining authors declare no competing interests.AR participated in the contact with the patients, collected samples, analyzed the data and drafted the manuscript. AG participated in the SNP genotyping, the radioimmunoassay and helped to draft the manuscript. HG carried out the SNP analysis. KWN and AR performed the statistical analysis. QZ carried out the radioimmunoassay. ME participated in opioid sensitivity testing and analysis. MH participated in the design of the study. TG participated in the design and coordination of the study and helped to draft the manuscript. FN conceived of the study, participated in the design and coordination and drafted the manuscript. All authors read and approved the final manuscript.


Introduction. Most spinal-cord-injured patients have constipation. One-third develop chronic abdominal pain 10 years or more after injury. Nevertheless, very little is known about the nature of abdominal pain after spinal cord injury (SCI). It may be neuropathic or caused by constipation. Aim. To compare characteristics of abdominal pain in SCI with able-bodied with chronic idiopathic constipation (CIC). Subjects and Methods. 21 SCI and 15 CIC patients were referred for treatment of bowel symptoms. Constipation-related symptoms were assessed with the Cleveland Constipation Scoring System and the International Spinal Cord Injury Basic Bowel Function Data Set. Characteristics of abdominal pain were described using the Brief Danish Pain Questionnaire. Total gastrointestinal transit times (GITT) were measured by radiopaque markers. Results. Seventeen (81%) SCI and 14 (93%) CIC patients reported abdominal pain or discomfort within the last month (P = 0.38). Pain was considered more intense by CIC than by SCI patients (P < 0.05). Only minor differences were found in patient's qualitative description of abdominal pain or in the location of pain. In neither SCI nor CIC was pain associated with GITT. Conclusion. Most characteristics of abdominal pain among SCI patients resemble those of CIC. This indicates that constipation is a major cause of pain after SCI. Spinal cord injury (SCI) has severe consequences for colorectal and anal sphincter function. The term neurogenic bowel dysfunction (NBD) has been introduced and includes constipation, faecal incontinence, and abdominal pain . It is w The nature of abdominal pain in NBD is unknown. This is unfortunate as the choice of treatment should reflect the underlying cause. We have previously described an association between infrequent defecation and abdominal pain suggesting a relation to constipation . This is We hypothesised that abdominal pain in NBD is both neuropathic and visceral. Accordingly, we further hypothesised that characteristics of abdominal pain in NBD are different from those of chronic idiopathic constipation (CIC) and only weakly associated with prolonged gastrointestinal transit time.  The aims of the present study were threefold: to describe the characteristics of abdominal pain in patients with SCI, to compare the characteristics of colorectal function and abdominal pain in patients with SCI and patients with CIC, and, finally, to investigate the association between abdominal pain and gastrointestinal transit time in patients with SCI.Between September 2009 and February 2012, 21 adult SCI patients with NBD and 15 able-bodied patients with CIC were consecutively included from the Anorectal Physiology Unit at Aarhus University Hospital, Denmark. International standards for the classification of spinal cord injury  were useConstipation was assessed with the Cleveland Constipation Scoring System  consistiBoth patient groups filled in a questionnaire composed of 18 questions describing pain or discomfort in the abdomen within the last month. Items included were location of pain/discomfort on a body chart, pain descriptors from a Brief Danish Pain Questionnaire (list of 18 descriptors) , temporaM is the total number of markers left, D is the number of markers ingested each day, and f is the fraction of the daily markers selected for the provision of transit. In this case f = 0.5.Total gastrointestinal transit time (GITT) was determined as part of the standard clinical evaluation of patients and performed as described by Abrahamsson et al. , At 12 aU test, whenever appropriate. Correlation between nonparametric variables was assessed using Spearman's correlation. P < 0.05 was considered statistically significant.Differences between the two patient groups were compared using Fisher's exact test or Mann-Whitney Clinical and basic characteristics of patients are shown in P = 0.01). Furthermore, the clinical presentation of constipation was fundamentally different in the two groups   than in patients with SCI    and 5 (24%) of SCI patients. Six (29%) had incontinence more than once a week, and two (10%) had daily faecal incontinence using a pad all the time. No patients with CIC had perianal disease or faecal incontinence. P = 0.38). Pain was, however, considered more intense and unpleasant by those with CIC . Further characteristics are presented in Seventeen out of 21 (81%) with SCI and 14 out of 15 (93%) patients with CIC reported abdominal pain or discomfort within the last month  did not fill in the body chart.P = 0.95, r = 0.015 and P = 0.53, r = −0.15) nor those with CIC . Likewise, there was no association between the Cleveland Constipation Score and total GITT in neither SCI  nor in CIC patients . There was no association between total GITT and average intensity of pain or unpleasantness in neither patients with SCI , and low SCI, n = 7 (lumbar SCI). There was no association between neurological level of SCI and abdominal pain or discomfort as 11 of 14 (79%) with high SCI and 6 of 7 (86%) with low SCI had pain, P = 0.70. Likewise, there was no association between neurological level of SCI and the Cleveland Constipation Score as the high SCI group had a median constipation score of 11 (range 4–16) and the low SCI group had a median constipation score of 11 (range 4–16) (P = 91).The SCI group were subdivided into two: high SCI, In the present study abdominal pain and discomfort were highly prevalent in subjects with SCI and NBD as well as those with CIC. In both groups pain had significant impact on daily functions, mood, and, in patients with CIC, also sleep. Abdominal pain in CIC is common and well described in the literature. Based on the present data, we find that abdominal pain is important among patients with NBD too. Even though many similarities were found between abdominal pain in CIC and NBD, there were differences. Specifically, abdominal pain was considered significantly more intense and unpleasant by patients with CIC, and, accordingly, it affected their mood and sleep more. We can only speculate to what degree these differences reflect different referral patterns of the two patient groups for treatment at our unit, reduced visceral sensation in SCI, or real differences in the underlying pathophysiology. Neuropathic pain in SCI is often described by patients as “pricking,” “stinging,” “warm,” and “burning” , 16. In  Speaking against constipation as the main cause of pain in NBD, we found no association between the severity of abdominal pain and GITT assessed by radiopaque markers. This may not be surprising, as no association has been found between GITT and other symptoms of NBD . Likewis The pathophysiology of constipation in NBD is poorly understood. Patients with conal or cauda equina lesions have reduced tone and reflex activity of the distal colorectum , 21. Thi In light of the fundamental differences between NBD and CIC the choice of methods for evaluation of bowel function is questionable. We choose the Cleveland Constipation Scoring System, often termed the Wexner Constipation Score . The sco Selection of patients may have had significant effects on the results of the present study. Patients with SCI are referred to our unit for various reasons, mainly including faecal incontinence and constipation. Therefore, constipation needed not be the main complaint of all SCI patients. In contrast, most patients with CIC are treated in primary care or in regional hospitals. Only a minority with severe symptoms are referred for evaluation at our unit. These would probably include those with most severe pain. Based on the present study we conclude that, even though abdominal pain in some patients with SCI has characteristics of neuropathic pain, most characteristics resemble those reported by patients with CIC. Therefore, we find it likely that constipation is a major cause of abdominal pain in NBD. However, intervention studies including assessment of abdominal pain in NBD patients successfully treated for constipation and studies of abdominal pain and small intestinal dysmotility in NBD should be performed before firm conclusions can be made.


Post-operative pain and the administration of opioids to relieve it, is considered to be one of the important issues in surgery wards. This issue is even more significant in obese patients, because of the side effects of opioids. Pregabalin is an analog of gamma aminobutyric acid (GABA) which can be effective in dealing with post-operative pain.This study will consider the effect of oral pregabalin in relieving the pain of obese patients after gastric bypass surgery.In a double blind clinical trial, 60 candidates for laparoscopic gastric bypass surgery were enrolled in the study through convenience and non-random sequential sampling, into two groups; pregabalin group and control group. Inclusion criteria consisted of: morbid obesity with a body mass index (BMI) > 35, age 18–50, American Society of Anesthesiologists (ASA) status I or II, and willingness to take part in the study. Patients in the pregabalin group received 300 mg of oral pregabalin on the morning of the surgery. Post-operative pain was controlled by the patient-controlled intravenous analgesia (PCIA) method, an AutoMed infusion pump containing 20 mg of morphine and normal saline  was administered to all patients after surgery. Patients’ level of pain were compared by considering their pain intensity on a visual analog scale (VAS), and the occurrence of nausea/vomiting from recovery, until 24 hours after surgery.P < 0.001). Incidence of nausea/vomiting was greater in the control group than in the pregabalin group (P < 0.001).A total of 60 patients were compared; 30 patients in each of the pregabalin and control groups. Both groups were similar in age and sex distribution. Mean pain intensity levels during the whole follow up were lower in the pregabalin group than in the control group, up to a maximum of 24 hours after the operation  can alleviate patients’ pain and nausea/vomiting and notably reduce adverse effects. Nowadays, the number of people undergoing surgery in order to lose weight and control the complications of morbid obesity is increasing. As a result of the administration of opioids to relieve post-operative pain, respiratory and cardiovascular side effects in laparoscopic gastric bypass patients, are the most important issues to be addressed. Therefore, establishing analgesia and at the same time preserving respiratory and cardiovascular stability, have significant roles to play in the treatment of these patients. Administering non-opioid drugs to alleviate pain in these patients and reducing the dose of intravenous opioids, are among the most effective methods in controlling post-operative pain and its side effects –3.Pain during and after surgery can lead to sensitization and consequently over-sensitivity to pain, it can also transform post-operative acute pain into chronic pain . RelieviAt present, patient-controlled intravenous analgesia (PCIA) is extensively employed in surgery wards as a way to deal with post-operative pain. In this method infusion pumps are used, these tools allow patients to receive a prescribed dose of analgesic substance intravenously. Opioids are commonly used in this method. A number of limitations accompany the benefits of this practice; the cost is high and administering opioids increases the side effects and risks of abdominal surgeries –7.A solution for acute post-operative pain is utilizing compounds pre-emptively, which alleviates pain by reducing sensitivity and lowering the chances of acute post-operative pain turning into chronic pain.Among these compounds are anti-epileptic drugs. Anti-epileptic drugs like carbamazepine have been utilized as an adjuvant treatment for chronic pain complications for years. Therefore, it was no surprise that pregabalin (derivatives similar to gabapentin) can be used to relieve pain in a range of different diseases, including pain syndromes –10.Pregabalin is an anticonvulsant drug that reduces calcium entry to the nerve terminals of the central nervous system and lowers substance P, glutamate and noradrenalin levels, which play roles in creating a sense of pain .Pregabalin is also utilized in the reduction of neuropathic and even inflammatory pain, tissue irritation and fibromyalgia –16. InitStudies also suggest that gabapentin has a satisfactory effect in alleviating post-operative pain , 19. PreThe aim of this study was to evaluate the effects of 300 mg oral pregabalin, before laparoscopic gastric bypass surgery, on pain intensity measured by a visual analog scale (VAS), and the incidence of post operative nausea/vomiting.This study was designed and carried out as a double blind, non-randomized clinical trial. After approval by the center’s medical ethics committee and obtaining informed consent from all of the candidates for laparoscopic gastric bypass surgery, patients in the pregabalin group received 300 mg of pregabalin before entering the operation room. Sampling was in convenience and non-random sequential form. The control group was an historical control, which was adapted from another study that was conducted almost at the same time, with the same criteria as this study and the method of data collection was also the same. Inclusion criteria consisted of; morbid obesity with a body mass index (BMI) > 35, age 18–50, an American Society of Anesthesiologists (ASA) status of I or II and a willingness to take part in the study. Exclusion criteria consisted of; history of hypersensitivity to pregabalin or derivative, hereditary problems with galactose and glucose, lactation, blood pressure less than 90 mm Hg, history of addiction, or moderate to severe respiratory disorder.In the pregabalin group 300 mg of pregabalin was given to the patients an hour before their operation. The PCIA method with morphine content was utilized to control the pain following surgery in both groups.After establishing an intravenous line and monitoring, 3 cc/kg of Ringer’s lactate solution was administered, and 2 mg of midazolam and 2 μg/kg of fentanyl were used as a premedication. The patients were given 5 mg/kg of sodium thiopental and 0.15 mg/kg of cisatracurium for induction and then they were intubated. For maintenance of anesthesia, isoflurane (1%) and remifentanil (0.2 μ/kg/min) were administered. During the operation cisatracurium (2 mg) was given every 30 minutes. Twenty minutes before the end of the operation, remifentanil administration was stopped and 2 cc of fentanyl was injected.If the patient’s blood pressure exceeded 180/100 mm Hg during the operation, trinitroglycerin (TNG) was administered in 5 μg/min incremental doses to lower the blood pressure below 160/90 mm Hg.The anesthesiologist had no information concerning the drugs given to the patients before the operation. Patients were checked against a VAS upon recovery and 4, 12 and 24 hours after the operation. They were also checked in regard to side effects of nausea and vomiting until the end of the first 24-hour period. Pain control in the pregabalin and control groups was according to the acute pain protocol and through PCIA  containing 20 mg of morphine in normal saline with a total volume of 100 cc which was administered continuously in 5 cc per hour and 2 cc bolus injection with a 30 minute lockout interval.t-test for quantitative variables. In cases of non-adherence, non-parametric equivalent assessment was employed. Significance level was considered as P < 0.05 in this study.The data were collected by questionnaires and analyzed through statistical analysis software (SPSS 17). Quantitative data was presented as mean and standard deviation, and qualitative data was presented as frequency. In order to compare quantitative and qualitative data between the two groups  K-2 assessment was utilized for the qualitative variables and P = 0.70). Considering sex distribution, it is noted that women comprised the majority of the patients. In the pregabalin group 25 patients (84%) and in the control group 23 patients (76.7%) were female. The difference in sex distribution between the two groups was not statistically significant (P = 0.432).A total of 60 patients were divided into two groups of 30; pregabalin group and control group. The mean age of the patients was 33.8 ± 7.6 in the pregabalin group and 37 ± 5.2 in the control group. Although the mean patient age was slightly higher in the pregabalin group, the difference was not statistically significant . That is, the pain intensity in the patients of the pregabalin group was significantly lower than in the control group at the time of recovery. Based on figure, the mean pain intensity 4, 12 and 24 hours after the operation was lower on average in the pregabalin group (P < 0.001). In order to compare the mean variance in the pain intensity between the two groups, frequent measurements taken at different times were carried out and the variance analysis of the frequent measurements was considered to eliminate differing factors such as time, age and sex. According to the analysis significant changes which occurred during the effective period, stemmed from the treatment pack type (administered drugs) (P < 0.001) and the time factor. Patients’ age (P = 0.545) and sex (P = 0.136) had no effect on the changes.Pain intensity on VAS in the pregabalin and control group at the time of recovery is presented in Table 2. All patients in the control group complained about nausea/vomiting. Nausea occurred in 17 people (56.7%) and vomiting occurred in 13 people (43.3%). In the pregabalin group only 6 people (20%) complained about nausea/vomiting, 4 patients (13.3%) suffered nausea, and 2 patients (6.7%) vomiting. Statistically, nausea/vomiting were significantly more frequent in the control group than in the pregabalin group (P < 0.001).Incidence of nausea/vomiting in the two groups is given in The findings of this study indicate that a single 300 mg dose of pregabalin before the operation can significantly alleviate the pain intensity of laparoscopic gastric bypass patients, who are treated with morphine analgesia by PCIA. It also reduces the incidence of nausea/vomiting after the operation.Parallel to the increasing growth of obesity, surgical interventions have progressed to control weight, and reduce the side effects of obesity such as; diabetes, blood pressure, cardio and respiratory diseases, arthritis, etc. , 3. ThisThe usual practice for alleviating post-operative pain is the administration of long acting opioids, especially morphine. As well as advantages such as; an extended analgesic period and lower costs for the patient, this practice can also lead to side effects such as; a reduced level of consciousness, depression of the respiratory system, nausea/vomiting, constipation and even a prolonged period of hospitalization –7.Patient-controlled analgesia has been employed in clinical wards to effectively relieve pain following operations; however, since opioids are still administered by this method, to lower the dose of opioids delivered, other methods need to be considered as well. In recent years the administration of pregabalin to relieve post-operative pain has been favored. Like gabalin, pregabalin has anticonvulsant, analgesic and anti-anxiety characteristics, but it differs from gabalin in possessing better pharmacokinetics such as dose-independent absorption which results in its preference over gabalin in clinical practice , 14.et al. gave patients a 150 mg dose of pregabalin per hour, before a laparoscopic cholecystectomy under general anesthesia to relieve pain. Although in this clinical trial intravenous fentanyl was injected in both groups, the pain intensity was significantly lower in the group receiving pregabalin, than in the control group   , 21. Theo groups . Looking placebo , 23.A meta-analysis in 2011 indicated that administering pregabalin does not result in less pain during the first 24 hours following surgery (Non-random selection, and an insufficient number of patients volunteering at the treatment center that was surveyed, are among the limitations of this present study. Nevertheless, the remarkable efficacy of pregabalin made our study strong enough to demonstrate differences between the two groups. Therefore, it appears necessary for further research with simultaneous random groups and a larger number of patients to be conducted and the exact efficacy level of pregabalin needs to be investigated.


Immediate breast reconstruction with an expander is a reasonable option for properly selected patients. After reconstruction, patients have severe postoperative pain, which responds poorly to opioids. Our aim was to evaluate if continuous wound infusion of a local anaesthetic into the surgical wound reduces postoperative pain, consumption of opioids and incidence of chronic pain compared to standard intravenous piritramide after primary breast reconstruction in breast carcinoma patients.Altogether, 60 patients were enrolled in our study; one half in the group with wound infusion of a local anaesthetic, and the other half in the standard (piritramide) group. Parameters measured included: pain intensity , drug requirements, alertness, hospitalisation, side-effects and late complications. A p-value of < 0.05 was considered statistically significant.P = 0.03) and at activity (P = 0.01), and on the day of the surgical procedure they reported less pain at activity (P = 0.003). Consumption of piritramide and metoclopramide was lower in this group (P < 0.0001), but their alertness after the surgical procedure was higher compared to the standard group (P < 0.001). After three months, the test group reported less chronic pain (P = 0.01).In the recovery room, the test group reported less acute pain at rest (After primary tissue expander breast reconstruction, wound infusion of a local anaesthetic significantly reduces acute pain and enables reduced opioid consumption, resulting in less postoperative sedation and reduced need for antiemetic drugs. Wound infusion of a local anaesthetic reduces chronic pain. Breast cancer is the most common cancer in women both in the developed and the developing countries. AlthougAs a reconstruction method, an expander or an implant provides a reasonable option in properly selected patients. Patients with small, minimally ptotic breasts are good candidates. The advantages of this method are simple operation, no morbidity at a distant donor site, use of tissue of similar colour, texture and sensation, reduced operating time, and faster postoperative recovery. AlthougUse of local anaesthetics is one of the possible methods for the treatment of acute postoperative pain. To our knowledge, only three studies have been published on the use of local anaesthetics for the treatment of acute postoperative pain after breast reconstruction-10. Use et al., a bolus application of local anaesthetic was not a successful pain treatment after mastectomy[We decided to conduct study because of the good results obtained in previous studies on axillary lymph node dissection and mastectomy due to breast carcinoma-14. Levostectomy, so we dAltogether, 60 breast carcinoma patients were enrolled in the study protocol between January 2011 and May 2012: 72 patients who were eligible for inclusion were offered the opportunity to participate in our study during the recruitment period; 12 of them declined participation, and the remaining 60 were included in the study. Patients listed for mastectomy and primary reconstruction with a tissue expander because of the presence of breast carcinoma or for prophylactic mastectomy, were randomized during the routine preoperative anaesthetic assessment. Anaesthesia for the procedure was the same for all study subjects. We used the same protocol as already reported for patients with axillary dissection. The firAfter informed consent was obtained the randomization was made by research nurses from the Clinical Research Unit of the Institute of Oncology Ljubljana. The research nurse performed randomization using random numbers generated by a computer and then informed the principal investigator about the treatment allocation of the patient.Surgical procedures were performed by ten experienced oncology surgeons and ten plastic surgeons. Sentinel lymph node biopsy was performed in 55 patients. In one patient with positive imprint cytology of the sentinel lymph node, axillary lymphadenectomy was performed immediately.The study was reviewed by the The National Medical Ethics Committee of the Republic of Slovenia and performed in accordance with the ethical standards laid down in the appropriate version of the 1964 Declaration of Helsinki. Our study was approved by the Institutional Review Board of the Institute of Oncology Ljubljana and conducted with the understanding and consent of all subjects involved. Study was entirely financed by the Institute of Oncology as a part of public service.Before wound closure, a fenestrated wound catheter was placed by a plastic surgeon into the wound cavity under the musculus pectoralis major and upon the entire length over the upper side of the wound. The wound catheter was fenestrated along 15 cm in the distal part. Nine patients undergoing bilateral reconstruction received a catheter into the wound on both sides. A bolus of 15 mL of 0.25% levobupivacaine was injected into the wound through the catheter immediately after wound closure. Surgical drains and the fenestrated catheter were clamped for 5 minutes after the administration of levobupivacaine to enable its absorption. After the administration of the bolus, the elastomeric pump was connected to the wound catheter. Clamps on the surgical drains were released after 5 minutes, and the clamp on the fenestrated catheter was released after 20 minutes, enabling a continuous infusion of 0.25% levobupivacaine. The elastomeric pump contained 100 mL of 0.25% levobupivacaine, and the flow rate was 2 mL per h. The catheter was removed after 50 h.The control patients, that is, those who received the standard intravenous piritramide treatment, were on a continuous intravenous infusion with piritramide (30 mg), metoclopramide (20 mg) and metamizole (2.5 g) in 100 mL of 0.9% sodium chloride (3 mL/h - 6 mL/h) until the next morning. The nursing staff were instructed to maintain the lowest drip rate of infusion, which relieved the pain. Our experience is that after the first postoperative day the severity of pain decreases and becomes bearable. In order to avoid the side effects of opioids the patients from our control group were treated with continuous intravenous infusion only during the first 24 h as is the standard of care in our department.Patient-controlled analgesia was not used in our patients. A rescue dose of analgesics was administered by nursing stuff on the demand of a patient. Whenever needed, patients from both groups could get an intravenous bolus of a rescue analgesic (3 mg of piritramide) and/or an antiemetic drug. In the case of nausea or vomiting, the patient received a bolus of an antiemetic drug, the first one being metoclopramide. If no relief was achieved, 1 mg of granisetron or, with persistent nausea 1.25 mg of droperidol, was administered intravenously.From the first postoperative day, all patients received analgesics in the form of tablets. They were administered one tablet of 100 mg of diclofenac and a combination of paracetamol 2,600 mg per day and tramadol 300 mg per day. The consumption of drugs  during hospitalisation was registered.Data about pain  score) were collected by nursing staff, that is, by an independent observer. Pain was measured using the standard VAS score, ranging from 0 to 10. The first measurement was made in the recovery room. Pain was also measured 3, 6 and 9 h after the surgical procedure. Thereafter, pain was measured every 8 h over the next 4 days. All VAS measurements were performed twice, at rest and on activity of an upper extremity. Median VAS score was calculated on the day of surgery and on the first postoperative day from all eight and six measurements, respectively.Three months after the surgical procedure, that is, before the tissue expander was replaced by an implant, the patients were asked about pain in the postoperative area or upper extremities. Chronic pain after 3 months was defined as pain that bothered patients during normal daytime activities or during rest or sleep. In the majority of patients with persistent pain it occurred during movement of an upper extremity or in a specific position of the extremity. Pain was permanently present when at rest in only a minority of patients. Six hours after the surgical procedure, we measured patients' alertness using the observer’s assessment of alertness/sedation (OAA/S) scale in a comAfter the surgical procedure, the patients received adjuvant therapy according to the tumour stage and guidelines. Adjuvant chemotherapy, external irradiation and/or hormone therapy was used in 38%, 20% and/or 60% of the patients, respectively. The occurrence of complications  was recorded.In order to estimate the probability (power) to reject the null hypothesis, PS: Power and Sample Size Calculations Software  was used. Prior data indicated that the failure rate among controls was 0.5. If the true failure rate for experimental subjects is 0.15, 27 experimental subjects and 27 control subjects are needed to be able to reject the null hypothesis that the failure rates for experimental and control subjects are equal, with probability (power) of 0.8. The type-I error probability associated with this test of the null hypothesis is 0.05.t-test or the Mann–Whitney U-test was used according to data distribution. The association between categorical variables was tested by the chi-square test or Fisher's exact test, as appropriate. All comparisons were two-sided and a P-value <0.05 was considered statistically significant. The statistical packages PASW 18  and R 2.11.1  were used for the analysis.The Student The mean age of patients was 47.8 years range 25 to 64 y), height was 166 cm (range 153 to 178 cm), weight was 61.7 kg (range 45 to 85 kg), and the body mass index (BMI) was 22.4 (range 17 to 31.2). There were no significant differences between the study groups in BMI, American Society of Anesthesiology (ASA) score, comorbidities (Table 5 to 64 yData on postoperative pain are presented in Table P <0.0001) (Table P <0.001).Consumption of piritramide during the first 24 h after the surgical procedure was lower in the test group compared to the control group (P <0.0001).Patients in the test group reported less nausea than patients in the standard group. Consumption of metoclopramide during the first 24 h after the surgical procedure was also lower in the test group compared to the standard group  underwent another surgical procedure because of haematoma, one from the test group and one from the standard group. Inflammation after the surgical procedure occurred in four patients, one in the test group and three in the standard group. After antibiotic therapy, all patients recovered, and the tissue expander stayed in place.The average postoperative hospital stay was 5.3 days. There was no significant difference in the duration of the hospital stay between the two groups.P <0.05).In order to collect a sufficient number of patients all cases with a unilateral or bilateral tissue expander were included in our study. As a result of randomization the number of the patients with a bilateral and unilateral tissue expander reconstruction in the local anaesthetic and control group was nine and ten, respectively. Patients with bilateral tissue expander reconstruction received 2 mL/hour of 0.25% levobupivacaine on each side. Thus, the total daily amount of levobupivacaine was 240 mg, which is within the recommended range and does not exceed the maximum tolerated dose. Patients from the control group with a bilateral reconstruction had more severe pain than patients with a unilateral reconstruction, whereas pain in the local anaesthetic group was not different after a bilateral or unilateral reconstruction. In the control group the mean VAS score in the recovery room after a bilateral and unilateral reconstruction was 6.45 and 4.09, whereas on the day of surgery it was 5.36 and 3.13, respectively (P = 0.01), respectively. Unilateral lymphoedema of the arm was present in two patients, one from the control group and one from the test group. The patient with oedema from the test group underwent a dissection of the axilla; the patient from the control group underwent a bilateral sentinel lymph node biopsy.Three months after primary reconstruction, the patients completed a questionnaire on pain. In the test and the control groups of patients, pain was reported in 16.7% and 50%  in the early postoperative period[et al. used an epidural catheter with only a few holes at its tip and instilled local anaesthetic every 3 h. They probably did not establish an equal distribution of the local anaesthetic along the entire length of the muscle and the wound. On the other hand, we used quality wound-catheters that were perforated 15 cm at the distal end, which enabled a better distribution of the local anaesthetic. Furthermore, we used an elastomeric pump, which enabled a continuous infusion of the local anaesthetic. That is probably the reason why only seven patients (23.1%) in the test group reported pain above a VAS score of 5.0, whereas in the control group, such pain levels were reported by thirteen patients (42.9%).The most positive result of our study is the observation that 77% of patients treated with local anaesthetics did not experience severe pain. To our knowledge, there are no reports in the literature about similarly effective early postoperative analgesia after the implantation of a breast-tissue expander. Legeby e period. Legeby et al. found that the use of opioids was about three times higher after the implantation of a tissue expander compared to other breast surgical procedures[Legeby ocedures. After tocedures. Our patocedures. Local aocedures,13,14 anocedures. Our stuocedures,21,25-30ocedures-33.There was no difference in pain on the first postoperative day between the study and control group of patients. It means that local anaesthesia was no longer as effective as it was on the day of surgery. A possible explanation is that muscle overstretching caused by a tissue expander is no longer as painful as it was. Other explanations are that in some patients the position of the wound catheter might have changed during movement or that there was a different perfusion region in the erect, prone or supine position, or that continuous infusion was flawed because of the wound drainage. Unfortunately, in our study we did not test a rescue bolus-injection of levobupivacaine in the case of severe pain. However, we have good experience with application of a rescue bolus of levobupivacaine in patients with neuropathic pain after axillary lymphadenectomy. Many times we have observed that injection of a bolus of 15 mL of 0.25% levobupivacaine into a drain and clamping of wound drainage inhibited neuropathic pain for a couple of hours.Memory of severe postoperative pain is the most important risk factor for the development of chronic pain. PatientOur current prospective randomized study shows that a continuous local anaesthetic infusion with the use of analgesic catheters inserted into the surgical wound after primary breast reconstruction with a tissue expander reduces acute pain immediately after the surgical procedure and also on the operative day. Because of that, it represents an effective postoperative pain treatment without side effects. It enables lower opioid consumption in the first 24 h after the surgical procedure, higher alertness and less nausea. We observed that patients treated with a local anaesthetic experienced a lower frequency of chronic pain compared to patients treated with standard analgesia.BMI: body mass index; ASA: American Society of Anesthesiology; VAS: visual analogue scale; OAA/S: observer’s assessment of alertness/sedation.The authors declare that they have no competing interests.BS - made the study design, carried out the study and drafted the manuscript, NB - co author of the study design and co drafted the manuscript, UA - consultant and co drafted the manuscript in the part of Synopsis. All authors read and approved the final manuscript.


There is a circadian and circaseptal (weekly) variation in the onset of acute coronary syndrome (ACS). The aim of this study was to elucidate whether the likelihood of ACS among emergency department (ED) chest pain patients varies with the time of presentation.All patients presenting to the Lund ED at Skåne University Hospital with chest pain or discomfort during 2006 and 2007 were retrospectively included. Age, sex, arrival time at the ED and discharge diagnose (ACS or not) were obtained from the electronic medical records.There was a clear but moderate circadian variation in the likelihood of ACS among presenting chest pain patients, the likelihood between 8 and 10 am being almost twice as high as between 6 and 8 pm. This was mainly explained by a variation in the ACS likelihood in females and patients under 65 years, with no significant variation in males and patients over 65 years. There was no significant circaseptal variation in the ACS likelihood.Our results indicate that there is a circadian variation in the likelihood of ACS among ED chest pain patients, and suggest that physicians should consider the time of presentation to the ED when determining the likelihood of ACS. Despite tremendous progress in the treatment of acute coronary syndrome , our ability to diagnose or rule out ACS in emergency department (ED) chest pain patients remains relatively poor. “Rule-out” admissions to inhospital care are common, and some 7 of 10 patients admitted with a suspicion of ACS prove not to have it. BecauseIt is well known that there are circadian, circaseptal (weekly) and seasonal variations in the onset of ACS-17, and The aim of this study was to explore the impact of the time of arrival at the ED and the weekday on the likelihood of ACS in ED chest pain patients.The Lund ED at Skåne University Hospital has a catchment area of some 300,000 inhabitants and receives a total of 65,000 patients per year with problems related to Internal Medicine, Neurology, Surgery, Orthopedics and Urology. In the hospital, there is a cardiac intensive care unit with 19 beds and an intermediate care ward with ECG monitoring for cardiac patients at 19 beds. Percutaneous coronary intervention and coronary bypass surgery are available 24 hours/day. During the patient inclusion period, there was no systematic diagnostic protocol for patients with suspected ACS, and no dedicated chest pain unit.st 2006 to December 31st 2007. Data for each patient regarding age and sex, arrival time at the ED, admission to in-hospital care or not, and discharge diagnosis (ACS or not) were retrieved from the electronic patient records.We retrospectively included all patients presenting with non-traumatic chest pain or discomfort as chief complaint, as identified by the triage nurse and/or the responsible physician, at the Lund ED from January 1During the study period, diagnostic criteria for ACS  at the hospital were those recommended by the European Society of Cardiology, the American College of Cardiology and the American Heart Association-21. DiscWe used SPSS for Windows version 18 (IBM Corp.) for the statistical analyses. The circadian and circaseptal variation in the probability of ACS was modeled using multiple logistic regression with time (12 different groups) and weekday as categorical independent variables. Sex and age (9 groups) were also included in the regression models to control for potential differences in sex and age distribution in the patient inflow at different times of the day and at different days of the week. The analyses of circadian and circaseptal variation were conducted for the entire data set, but also stratified for sex and for age (below/at least 65 years old).This study was approved (dnr 384/2007) by the Regional Ethics Committee at Lund.As can be seen in FigureAs can be seen in FigureThe circaseptal variation of chest pain patient inflow was modest with Monday as the busiest day (18% of weekly patients) and Friday as the least busy day (12%). There was no significant circaseptal variation in the likelihood of ACS (p>0.3).Among chest pain patients admitted from the ED to inhospital care (n = 5233), the average ACS likelihood was higher for men than for women, and also higher for older than for younger patients Table. The likThis study indicates that there is a diurnal variation in the likelihood of ACS among chest pain patients presenting at the ED. To our knowledge, this variation has not been described before. The diurnal variation was more marked among females and younger patients, and was not explained by differences in sex and age distribution in the patient inflow at different times of the day.The circadian variation in the ACS likelihood was clear but moderate, with a higher likelihood midnight-10 am Figure, a peak The ED physician often determines the ACS likelihood using Bayesian reasoning and diagThe demonstration of a diurnal variation of the ACS likelihood may have at least two clinical implications. First, knowledge of this variation might influence the ED physician’s decision-making. Patients presenting at 9 am had almost twice the ACS risk of those presenting at 7 pm Figure, and in The present inflow pattern of chest pain patients was very similar to the overall patient inflow at our and other-26 EDs, In patients with acute myocardial infarction (AMI), the average delay from symptom onset to presentation at the hospital is 2–4 h. If the This study was performed in a single university hospital ED and did not include data on chest pain duration or characteristics, prehospital delay or comorbidities in the patients. Although the diurnal presentation pattern and the age and sex distribution suggest that our patients were similar to those in other EDs-27, the These results indicate that there is a circadian variation in the likelihood of ACS among chest pain patients presenting to the ED. The causes of the variation are likely multiple, and probably include the well-known diurnal variation in ACS symptom onset. The results suggest that physicians should consider the time of arrival at the ED when assessing the likelihood of ACS in ED chest pain patients, but additional studies are needed to confirm this in other populations and health care settings.The authors declare that they have no competing interests.UE conceived and designed the study, interpreted the data and wrote the manuscript. MA and AK collected and interpreted the data and critically revised the manuscript. JB provided expert statistical advice in the design and presentation in the study and critically revised the manuscript. MO collected and organized the electronic data, and critically revised the manuscript. All authors read and approved the final manuscript.