Burn is the worst tragedy among modern societies that individuals may experience. One of the most important problems of burns is pain; particularly at the time of treatment including burn dressings, debridement, surgical incisions and physiotherapy. The aim of this study was to determine the effect of rhythmic breathing on pain of dressing change in patients with burns.This semi-experimental clinical trial study with a control group was conducted on 60 eligible burn patients who were selected using convenient sampling method and allocated randomly in two groups of test and control (each n=30). Data collection tools included demographic data and pain observation questionnaires. The rhythmic breathing was individually and orally trained to the patients of test group in a room separated by dividers for a 20-minute session. The pain intensity in test and control groups before and after dressing was investigated for three consecutive days. Friedman test results showed that pain intensity in both control and test groups had statistically significant differences. The pain intensity after rhythmic breathing reduced more in the test group, and this reduction was more significant during 3 days.Rhythmic breathing is an effective method on pain reduction of dressing change in patients with burn injuries. It is estimated that 270,000 deaths per year are caused by burns that the vast majority of them occurs in low- and middle-income countries.4Burn is among the worst tragedies in modern society that people may experience5 The number of burning in Iran, with a population of 75 millions, is 150 thousand people annually, of which 25 to 30 thousand are hospitalized. Burn rate in our country was shown to be very high too.6 People suffering from burns also tolerate physical, psychological, and economic problems that pain is one of physical problems.7 Pain is so important that the American Pain Society has recognized pain as the fifth life sign in order to increase the importance of effective pain management among health care professionals.8According to the latest studies in Iran, accidents, poisonings, suicides and fires have caused the highest fatality after circulatory diseases and the second cause of death after motor vehicle accidents is burns.9 The studies also have shown that acute levels of pain are related to the long-term negative psychological impacts such as depression, thoughts of suicide and post-traumatic stress syndrome for two years after the initial burn injury.10 Accordingly, decisive pain management during and after interventions such as physiotherapy and dressing is of particular importance.11 That’s why some healthcare centers use drugs as the standard treatment during this phase; unless there is a prohibition.12 Surprisingly, despite pharmacological interventions, 35% of people reported persistent pain, 75% pain interference with sleep, 56% interference with work, and 67% interference with their social function.13Among the large group of patients experiencing severe pain, there are people who have suffered from burns.14 Since according to the gate control theory of Malzak and Wall, pain is not only a sensory experience, but also an emotional and cognitive experience.15 This theory encompasses physiological, psychological, cognitive and emotional aspects of pain and explains how to control pain by thoughts, feelings and behavioral practices and also directs the studies toward cognitive behavioral approaches to pain management.8Also, high doses of medications containing morphine increase the risk of complications such as respiratory failure, nausea, encephalopathy and constipation. These people also can show a degree of tolerance to painkillers.16 Non-pharmacological interventions used to treat burn pain include hypnotism, art therapy and play therapy, distraction, music therapy and relaxation techniques.17 In the meantime, relaxation techniques are the most important non-pharmacological methods used for pain control.17 Relaxation by creating balance between the posterior and anterior hypothalamus, reducing the activity of the sympathetic system and catecholamine secretion can reduce muscle tension and physiological adverse effects such as lowering blood pressure, heart rate and muscle spasms caused by stress.18It is important to use non-pharmacological methods including alternative medicine to reduce patients’ discomfort and pain, in addition to pharmacological effects.16 A simple relaxation technique is rhythmic abdominal breathing that is one of the simplest and most ancient relaxation techniques. In addition to relaxation advantages, this technique leads to cognitive distraction and a change in harmful stimulus structure like pain and stress.19Another advantage of relaxation in clinical environments is that the patients can apply it independently. Therefore, the use of relaxation in combination with painkillers provides a comprehensive approach of pain relief for patients. Relaxation is done in various ways, including the Progressive Muscular Relaxation (PMR), jaw relaxation, meditation, rhythmic breathing and so on.20 such as abdominal breathing, variable breathing from the nasal passages, breathing against the resistance of respiratory tracts, breathing at different physical postures, holding breath. This technique can have palliative effects on anxiety, depression, stress disorders after accidents, chronic pain and stress caused by the disease.21 The aim of this study was to determine the effect of rhythmic breathing on pain of dressing change in patients with burns.There is a variety of these techniques,The present study is a semi-experimental clinical trial with a control group in which the effect of rhythmic breathing on pain of dressing change in people with burns was investigated. For doing so, researcher referred to Ayat Allah Mousavi Education and Treatment Center in Zanjan, Iran after getting certification from Ethics Committee and research certification. By the permission of Hospital Manager and Supervisor of Burn Ward and also introducing himself and explaining the objectives and procedure of the research, researcher invited the subjects who met inclusion criteria.The inclusion criteria were the fourth day of hospitalization, daily dressing, older than 18 years, no inhalation and electric burns or self-immolation, burning level between 10% to 45% with some degree of 1, 2, 3, ability to communicate verbally and understanding Farsi, ability to read and write, ability to carry out co-breathing, lack of drug addiction, lack of mental illness, absence of severe hearing and vision problems. Sampling was in available way and subjects were enrolled after getting written consent. The patients were randomly divided into the test (n=30) and control (n=30) groups. To prevent bias, first the control group and then the intervention group entered the study.22 This tool has been widely used to measure pain in Iran.16Data collection tools included two questionnaires of demographic information and numeric pain scale. The scale included a 10 cm horizontal line graded based on the numerical pain scale from 1 to 10. Zero at this scale means no pain, 1 to 3 for mild pain, 4 to 6 for moderate pain, and 7 to 10 for severe pain. The subjects were asked to mark the point matched with their pain or tell its number to researcher. Pain Observation Scale was first designed in 1990 by Wewers and Lowe. This scale has been widely used in numerous empirical and clinical pain researches, and its validity and reliability are approved.At baseline, demographic data form was completed by the participants with the help of researcher. Then, in addition to routine care (including the use of drug before dressing), the rhythmic breathing method was individually and orally trained to the test group patients using in a private room separated by divisions. Training was done as follows: (i) Close your eyes, (ii) Relax the body muscles, (iii) Breath slowly and regularly and uniformly , so that breath in the air from your nose and then breathe out slowly through your mouth, and (iv) At all times of breathing, pay attention to the increased size of the chest, the movement of your abdomen and shoulders.The training was carried out for at least 20 minutes, but training will continue to ensure learning and doing right by patient, and in the end, the participants were asked to complete this procedure for 20 times till the researcher will ensure the patient’s mastery by exact observation. After training the patients, they were asked to do this in practice in order to get mastery. And at the end, the test group was given a written guide. In addition, they were taught how to use the tools on the day of training. The control group received only routine care which contains painkiller medication at the beginning of dressing and it was conducted for patients in both groups depending on the severity of pain.While the inclusion list of patients in the dressing room is available in the ward and arrangements have been made with the dressing room in this case, the pain numerical tool marked with code A was completed by the patient at the admission to the dressing room. Then the test group patients were asked to do rhythmic breathing during the dressing change that usually takes 10 minutes. Then a maximum of 5 minutes after leaving the dressing room, the pain numerical tool with code B was completed by the patient. This work was continued for 3 days. It is worth noting that the researcher was present at all stages of the study monitoring the patients. Ethical considerations After obtaining the required permit from the Ethics Committee of the university and officials of the selected hospital, data collection was carried out. In order to start sampling, the researcher introduced himself to the director of the burns unit of the hospital and identified the eligible subjects. Objectives and procedures of the study were explained to the participants, and informed consent was obtained from all the patients prior to participation. Moreover, participants were allowed to withdraw from the study at any time with no impact on their treatment process. After collecting the data and importing them into SPSS software , the data were analyzed using descriptive and inferential statistical methods. In connection with demographic characteristics, Chi-square, Wilcoxon and Mann-Whitney tests were used. A p value less than 0.05 was considered statistically significant.p=0.942), sex (p=0.436), education level (p=0.585), marital status (p=0.249), employment status (p=0.969), economic status (p=0.947), degree of burn (p=0. 154), cause of burn (p=0. 322), taking painkiller (p=0.739) and having an underlying illness (p=1); in other words, the two groups were homogeneous in terms of these characteristics. However, due to the homogeneity of demographic variables in the two groups, the results can be considered more reliably as a result of intervention.In connection with demographic characteristics, statistical anaysis showed that subjects in the two groups had no significant difference in terms of age (According to In the test group, over 70% had second- and third-degree burn. In terms of economic status, 95% of people were in moderate to low financial status. In connection with cause of burns, the results showed that the most frequent burns cause is direct heat with 52 percent of all people with burns. The other causes are boiling water and steam with 41% and chemicals with 7% of all causes of burns. In other resources, most of patients were burned by direct contact with flame or boiling water. Like this study, 95% of the cases were related to burning with direct flame.Concerning the place of burns, 75% of the patients in this study burned their hands. After that, burning body and face constituted respectively 31.4 and 30% of people with burns . The preComparing the mean pain change score in the test and control group shows that both groups have experienced reduction in pain, but the pain changes in the test group was greater than the control. There was a significant difference in reduction of pain in the test group from the first to the third day, so that the mean reduction of pain in the test group increases over time. In other words, the test group subjects show a greater reduction of pain compared with the first day of rhythmic breathing . With re23 Considering the cause of burns, the most frequent burn cause was direct heat among 52% of all patients with burn. The other causes were boiling water and steam with 41% and chemicals with 7% of all causes. In another report, most of patients were burned by direct contact with flame or boiling water. Like this study, 95% of the cases were related to burning with direct flame.24In our study, in the test group, 70% of burns were second- and third-degree injuries, while 95% of patients were in moderate to low financial status. These findings have been reported before.25 There was a significant difference in reduction of pain in the test group of our study, from the first to the third day, so that the mean reduction of pain in the test group increaseds over time. In other words, the test group subjects showed a greater reduction of pain compared with the first day of rhythmic breathing that is consistent with other studies in this area.26Concerning the place of burns, 75% of the patients in this study had hand burns. After that, burning body and face constituted respectively 31.4 and 30% of people with burns, respectively. In another report, burning of hands had the highest frequency too.et al. who assessed the effect of breathing relaxation on burns dressing pain and anxiety26 and Gani et al. who evaluated the effect of breathing techniques on burns dressing pain: a randomized clinical trial27 and also Borzou et al. who studied the effect of rhythmic breathing on vascular needles pain intensity in patients undergoing hemodialysis.28The results showed that the test group had less pain intensity after dressing when compared with the control group and the rhythmic breathing was effective on pain intensity of burn dressing. The results are consistent with the results of previous studies including Park According to the results of this study, use of rhythmic breathing technique was effective as a non-pharmacological method to reduce pain of change dressing. According to gate control theory, it can be explained this way when the input from descending and inhibitory fibers of brain was more than stimulus input of small fibers, the gate is closed and the pain data cannot be Accordingly, relaxation can reduce or complete remove the pain through inhibitory impulses of the cerebral cortex and thalamus and thus closing the gate.16In addition, based on gate control theory, feeling out of control conditions can cause opening the gate through the cerebral cortex and increase different aspects of pain. As a result, burns patients need to feel they have control over their position. For this purpose, learning relaxation methods can create increasing feeling of personal control on pain and hence patients can play active role in learning and implementing pain management skills instead of being passive receiver of medical interventions. Relaxation reduces pain and consequently anxiety by releasing endorphins.Therefore, given the positive impact of rhythmic breathing on burns pain reduction and due to its easy learning, burned people can be encouraged to use this method when they feel suffering from pain and tension. Since nurses are mostly dealing with the phenomenon of dressing change pain among all professionals involved in the care of burns, and also because nurses are the initial defense of these people to reduce or relief of pain, it is suggested to train rhythmic breathing by nurses to the burned people so that patients may experience less pain before and after the dressing.


Objective: Craving for substance abuse is a usual and complicated problem in patients, with opioid addiction who are in opioid detoxifying process. Craving has been added as one of the diagnostic criteria of substance use disorders in DSM-5. The present trial aimed at comparing the effects of celecoxib versus ibuprofen in reducing pain and decreasing the desire to use opiates in patients undergoing opiate detoxification (n = 32). Method: A total of 32 patients (both inpatients and outpatients), who were undergoing opiate detoxification procedure and met the inclusion criteria entered this 4- week study. Participants who suffered from pain due to opiate withdrawal were randomized into 2 groups: Group 1 received celecoxib 200 milligrams once per day and group 2 received ibuprofen 400 milligrams 4 times per day. Self-reported Desire for Drug Questionnaire (DDQ) and 0-10 numeric pain scale were used at baseline and at the end of the study to evaluate changes in opiate craving and pain, respectively. Data analysis was done by SPSS-21 statistical software.Results: In this study, 16 patients received celecoxib 200 milligrams once daily, and 16 received ibuprofen 400 milligrams 4 times daily. After 4 weeks of treatment with both ibuprofen and celecoxib, the results revealed that celecoxib and ibuprofen equally reduced the pain symptoms. After 4 weeks of treatment, with either ibuprofen or celecoxib, significant improvement was observed in decreasing the craving in the celecoxib group, but not in the ibuprofen group.Conclusion: The study revealed a significant difference between the celecoxib and ibuprofen group in reducing craving in patients with opiate craving after 4 weeks of treatment. However there were no significant differences between these two groups in reducing pain. Craving is very common in patients who undergo opiate detoxifying procedure. Although drug craving has been defined in numerous ways, it has generally been regarded as a compelling urge to use a substance . CravingSeveral mechanisms are involved in drug craving, some of which are as follow: Dopamine system , decisioResearchers have long posited a relationship between craving and addiction . AbstineNon-steroidal anti-inflammatory drugs are inhibitors of the cyclooxygenase enzyme family, which catalyzes the metabolism of arachidonic acid to prostaglandins, prostacyclin, and thromboxane. The cyclooxygenase-1 isoform is constitutively expressed in most tissues. The cyclooxygenase-2 is usually specific to inflamed tissue .Celecoxib is a COX-2 inhibitor that has been used in many psychiatric problems such as major depression by inhibiting prostaglandin E2, which may be raised in MDD  and reduIn our practice, we noted that many psychiatrists believe that celecoxib causes more craving inhibitory effect when compared with other nonsteroidal anti-inflammatory drugs (NSAIDs)and when being used as an analgesic in patients who have craving during their opiate cessation procedure. The researches reflect the action on celecoxib on some parts of the brain involving craving . To our The present study tested the theory that celecoxib would differ from ibuprofen in measuring the desire to use opioids because of its positive effects on brain, and also it was expected to lower the pain in the 2 groups of the study .In summary, this study aimed at testing whether the inhibition of craving effect, assessed terms of increased desire to use opioid for their rewarding effects, would be greater in the celecoxib group than the ibuprofen group, following administration of the 4-week therapy using both medicines.ParticipantsIn this study, 32 opiate addicts, who met DSM-5 criteria for opioid use disorder, participated. Patients were under a detoxification protocol at addiction clinics in Tehran, Iran. They were randomly allocated into 2 groups and they received a 30-day celecoxib treatment or a 30-day ibuprofen treatment for their pain during their detoxifying period. The inclusion criteria included patients aged 18 and 65 who were admitted to Roozbeh hospital clinic and a private clinic to receive opioid cessation regimens.The exclusion criteria included pregnancy and lactation, suffering from severe medical conditions , or neurological illnesses including epilepsy and Parkinsonism, having received NSAIDs within the week prior to the initiation of the study as well as having intellectual disability.There were no significant differences in the demographic variables or drug history between the participants of the 2 groups. All participants were identical in environment and lifestyle during the trial; for instance, they were received similar diet and drug regimen and the same psychiatric counseling during their therapy. Moreover, they were asked not to change their usual lifestyle during the trial. The detoxifying procedure was done by standard psychiatric counselling of psychiatrists and psychologists. No other routine detoxifying medications (such as methadone) were used.ProcedureEach patient participating in this study was assessed for pain and craving for opiates at baseline. The patients were assigned to receive either celecoxib or ibuprofen randomly for 4 weeks. Patients in celecoxib group received celecoxib capsule 200 milligrams orally once daily at 12 PM. Ibuprofen was administered in a soft gel form and in an equal dose of celecoxib, which is 1600 milligrams in 4 divided doses at 08:00 AM, 02:00 PM, 08:00 PM and 12:00 midnight . The dosA psychiatry resident randomly assigned the patients to receive treatment with either celecoxib or ibuprofen under single-blind conditions and allocated them to parallel groups, which was determined by simple randomization. He kept the randomization list secure during the study.After being provided with a full explanation of the protocol design, all patients provided written informed consent. This trial was approved by the Ethics Committee of the Faculty of Pharmacy at Tehran University of Medical Sciences and registered in the Iranian Registry of Clinical Trials . All phases of this study were performed according to the declaration of Helsinki on ethical principles for medical research involving human subjects.Questionnaires and MeasuresThe 14-item Desire for Drug Questionnaire (DDQ) is an effective tool for subjective assessment, showing how strong the desire is to use opiates  . It is athis study to assess the intensity of the patients’ pain. It is a numeric scale, ranging from 0-10, with zero indicating no pain and 10 the worst possible pain .Prior to the beginning of the study, sample size was calculated to detect a 20% difference in improvement between celecoxib and ibuprofen. Under the assumption of a significant level of 0.05 with a power of 0.80, a minimal sample size of 32 with 16 cases in each group was determined. Estimating a dropout rate of 20%, we decided to recruit 20 participants for each group.Data AnalysisData analysis was done by SPSS-21 statistical software. The changes in pain and craving were detected at Weeks 0 and 4 between the 2 groups. Statistical significance was set at p < 0.05.Demographic CharacteristicsDemographic characteristics of the patients in both groups are demonstrated in The 0-10 numeric pain scale  was also used inParticipants who were assigned into the 2 groups did not differ in their gender, age, marital, job or educational status . AnalysiPain SeverityAt first for analyzing the scores the outlier test was passed. To analyze pain severity, independent samples Mann-Whitney U test, a non-parametric test, was used because the shapiro-wilk test showed a significant difference (p<0.05). The result of pain score is presented in Inhibitory Effects on Craving=0.004). The results did not indicate a significant difference at the pretest point for craving symptoms. So to compare the 2 groups of treatment, analysis of covariance (ANCOVA) was used with pretest score as the covariant. The ANCOVA results and the means and standard deviation of the outcome measures at the pretest and posttest are presented in  = 12.94, p = 0.001)  was used to determine the equivalences of the treatment conditions on outcome measures at the pretest point and the pre-hypothesis tests were done before analysis. The general linear model test also was not significantly different at the pretest  has proposed that the biological basis for drug ‘craving’ reflects 2 independent processes: one in which the primary objective is to alleviate an aversive state , and the other in which appetitive motivational processes are involved .Frolov’s trial shows that celecoxib as a COX-2 Inhibitor, can act in several parts of the brain and in those parts responsible for craving .In another study, Dembo et al. found that celecoxib penetration into the CNS is indicated by the CSF plasma concentration ratio .Ciceri et al. showed that celecoxib reduced the elevated PGE2 levels in the brain of kainate-treated rats and inhibited induced COX activity, demonstrating the ability of this compound to act on COX-2 in CNS .Beiche et al. found that mRNA of both COX isoforms is expressed continuously in the spinal cord with COX-2 as the predominant isoform .Celecoxib administration produces a decrease in the subjective desire to use opiates for their pleasant effects. There was no overall significant difference on this measure between the 2 groups at baseline so these results reflected no pre-existing differences prior to drug administration day. However, the pattern of results obtained revealed significant differences between the ibuprofen and celecoxib group on craving. However, no significant difference was obtained between the 2 groups of treatment on reducing pain.The author suggests considering high risk patients such as patients who have GI diseases, cardiac diseases and etc., before starting celecoxib or ibuprofen for them. Furthermore, regular monitoring of the patients after initiating NSAIDs may prevent further complications. It is also important to consider any drug-drug interactions before initiating celecoxib or ibuprofen. In general, celecoxib or ibuprofen may be used for pain in opiate addict patients during their detoxifying procedure. Further studies are needed to assess the effects of chronic use of celecoxib and other NSAIDs in opiate addict patients.The study suggests that both celecoxib and ibuprofen improved pain related to opioid withdrawal in the studied patients. Furthermore, no significant difference was observed between the 2 groups in the assessment of alteration of pain perception. On the other hand, the trial revealed a significant difference between celecoxib and ibuprofen on craving for opiates, suggesting a positive evidence for consumption of celecoxib rather than ibuprofen for opiate craving in clinical settings. More randomized controlled trials with larger sample sizes and longer duration of follow- ups are needed to confirm the findings of this study.


Persistent pain is a challenging clinical problem after breast cancer treatment. After surgery, inflammatory pain and nociceptive input from nerve injury induce central sensitization which may play a role in the genesis of persistent pain. Using quantitative sensory testing, we tested the hypothesis that adding COX-2 inhibition to standard treatment reduces hyperalgesia after breast cancer surgery. A secondary hypothesis was that patients developing persistent pain would exhibit more postoperative hyperalgesia.138 women scheduled for lumpectomy/mastectomy under general anesthesia with paravertebral block were randomized to COX-2 inhibition  or placebo. Preoperatively and 1, 5, 15 days and 1, 3, 6, 12 months postoperatively, we determined electric and pressure pain tolerance thresholds in dermatomes C6/T4/L1 and a 100mm VAS score for pain. We calculated the sum of pain tolerance thresholds and analyzed change in these versus preoperatively using mixed models analysis with factor medication. To assess hyperalgesia in persistent pain patients we performed an additional analysis on patients reporting VAS>30 at 12 months.48 COX-2 inhibition and 46 placebo patients were analyzed in a modified intention to treat analysis. Contrary to our primary hypothesis, change in the sum of tolerance thresholds in the COX-2 inhibition group was not different versus placebo. COX-2 inhibition had an effect on pain on movement at postoperative day 5 (p<0.01). Consistent with our secondary hypothesis, change in sum of pressure pain tolerance thresholds in 11 patients that developed persistent pain was negative versus patients without pain (p<0.01) from day 5 to 1 year postoperatively.Perioperative COX-2 inhibition has limited value in preventing sensitization and persistent pain after breast cancer surgery. Central sensitization may play a role in the genesis of persistent postsurgical pain. Persistent pain after surgery is a significant clinical problem which affects 10 to 50 percent of patients . In breaA key insight from fundamental pain research is that ongoing nociceptive input alters subsequent sensory processing by the nervous system . SurgicaRegional anesthesia is currently the best therapy to block surgical nociceptive input and may protect partially against persistent pain development after surgery –21. HoweThe primary aim of this study was to assess the value of perioperatively inhibiting the inflammatory component of sensitization added to block of neuronal nociceptive input on central sensitization after surgery. A secondary aim was to assess the relationship between hyperalgesia and persistent pain development at 12 months postoperatively. We studied these aims in a randomized prospective controlled trial in women undergoing breast cancer surgery under paravertebral blockade combined with perioperative COX-2 inhibition or placebo. We hypothesized that:Adding COX-2 inhibition to standard maximal antinociceptive treatment  perioperatively would result in less widespread hyperalgesia as a sign of central sensitization–and therefore less persistent pain–following surgery compared to a placebo-supplemented group.Patients who complained of persistent pain 12 months postoperatively would exhibit more widespread hyperalgesia following surgery, than patients not complaining of persisting pain.We conducted a prospective, randomized, double blind, placebo-controlled, clinical trial at the Bernhoven Hospital in Uden, the Netherlands, approved by the Ethical Committee on March 16th 2005 . All participants provided written informed consent; the trial was registered with the Netherlands Trial Register (NTR1793). Trial registration was not complete when subject recruitment had begun. However, this was rectified and our trial was registered on May 3rd 2009. The authors confirm that all ongoing and related trials for this drug/intervention are registered. The protocol for this trial and supporting CONSORT checklist are available as supporting information; see S1 Protocol.We included women scheduled for breast cancer surgery. Two dedicated breast surgeons performed all surgeries. Surgery was by lumpectomy, total simple mastectomy or modified radical mastectomy. Exclusion criteria were: previous breast surgery, planned immediate breast reconstruction, chronic pain syndromes , regular analgesic medication for 2 weeks preceding surgery, pre-existing central nervous system pathology , conditions predisposing to neuropathy , inability to comply with testing procedures or to give informed consent, presence of contra-indications to COX-2 therapy  and contraindications to paravertebral blockade.After obtaining informed consent during an outpatient anesthesia visit, eligible patients were randomized in a one-to-one ratio to receive perioperative COX-2 inhibition or placebo. A pseudo-random code was computer generated for the randomization blocks that had a size of six. Stratified random sampling ensured equal distribution of axillary lymph node dissections over groups. The hospital pharmacy held the randomization scheme for the trial and supplied parecoxib and celecoxib (active treatment) or placebo in blinded packages. Parecoxib is currently not FDA approved, but is widely available worldwide, including in the European Union as the only injectable COX-2 specific inhibitor. The morning of surgery, patients received oral midazolam premedication (7.5 mg). In the operating theatre, COX-2 inhibition group patients received parecoxib 40 mg i.v. 30 minutes before surgery start. This injection was repeated 6 hours later. The postoperative morning, patients started celecoxib 200mg, continued to the morning of day five postoperatively. The placebo group received placebo injections and tablets according to the same regime. Medication was blinded, neither observers nor persons involved in patient management were aware of patient assignment.Paravertebral blockade was by standard technique (20 ml ropivacaine 0.75%). Before surgery, local anaesthetic blockade was tested using pin-prick. Unsuccessful block, as defined by no hypoalgesia to pinprick, led to patient exclusion. Patients received standardized general anaesthesia ,  and on movement (immediately after sitting up on bed). For all postoperative pain scores, the patient was explicitly asked to report pain associated with surgery at that moment. At several time points patients were asked to complete a quality of life questionnaire assessing surgery-related symptoms and functional impairment.Postoperative changes in pain sensitivity  were quantified using electric and pressure pain tolerance thresholds. Electricity stimulates mainly cutaneous nerve endings , bypassiBaseline demographic data, electric pain tolerance thresholds, pressure pain tolerance thresholds and CPM were collected the preoperative afternoon. Pain scores, electric pain tolerance thresholds and pressure pain tolerance thresholds were collected 1, 5 and 15 days after surgery and at 1, 3, 6 and 12 months after surgery.Electric pain tolerance threshold testing was performed using an electric stimulation device , delivering electrical tetanic stimulation  via self-adhesive skin electrodes 3 cm apart. A trained research assistant operated the device and documented the value at which stimulation became intolerable and was discontinued. Pain tolerance thresholds were determined three times and the mean value was used. Pressure pain tolerance thresholds were assessed using a pressure algometer  with a 1.0 cm2 probe and a ramping rate of 50 kPa/s until thThe condition pain modulation paradigm tests the ability to generate descending inhibitory modulation . An elecAt baseline and 1, 3, 6, and 12 months post surgery patients filled out a quality of life questionnaire . The EORTC QLQ-C30 is internationally validated for evaluating quality of life in daily living and symptoms and side effects related to different treatment modalities . The indThe primary study outcomes are change in electric and pressure SOT after surgery vs. baseline values. Secondary outcomes are VAS pain and EORTC symptom, functional and QOL sum scores.Based on data from previous postoperative quantitative sensory testing studies by our group , 34 we cData were analyzed with Statistica , p<0.05 was considered significant. Results are expressed as mean ± 95% confidence interval. Postoperative sums of thresholds were expressed as percentage change compared to preoperative baseline. Chi-squared tests and t-tests were used to assess differences between the treatment groups regarding axillary lymph node dissection, type of surgery, duration of surgery, surgical complications, size of specimen removed, baseline electric SOT, baseline pressure SOT, baseline CPM, baseline QOL-score, baseline functioning score and baseline symptom score.Our main analysis was aimed at testing our primary hypothesis that perioperative COX-2 inhibition would result in less hyperalgesia as a sign of central sensitization following surgery compared to a placebo-supplemented group. We performed mixed model analyses on change in electric and pressure SOT, and on secondary outcomes VAS scores and EORTC sum scores with fixed factors medication (COX-2 inhibition vs. placebo) and time, and subjects were included as random factor. Preoperative CPM is reported in the literature as a predictor for persistent postsurgical pain development and was included as covariate . We perfTo test our secondary hypothesis that patients developing persistent pain 12 months postoperatively would exhibit more hyperalgesia following surgery than patients not complaining of persisting pain two groups were formed post hoc: patients with persistent pain 12 months postoperatively  or those without persistent pain. The chosen cutoff score >30 mm VAS is widely used in the pain literature , 41, corFrom October 2006 to December 2010 a total of 327 patients were screened for eligibility and 138 patients were randomized . There w©, Minneapolis, MN, USA) in the year following the initial breast cancer surgery. There were no harmful or unintended effects associated with COX-2 inhibition.There were no differences in baseline and demographic data between the placebo and COX-2 inhibition group . SurgicaPerioperative treatment with COX-2 inhibition was not associated with postoperative differences in tolerance to electric or pressure stimulation .COX-2 inhibition did not affect VAS scores at rest but influenced VAS scores on movement (Time x Medication: p = 0.02)–Covariate preoperative CPM significantly affected electric SOT (p = 0.04), and showed a trend towards significance on pressure SOT (p = 0.06)–EORTC functioning, symptom and QOL score were comparable between treatment groups .Twelve months postoperatively 11 patients (13%) complained of persistent pain with VAS>30 mm. Characteristics of patients that eventually would develop persistent pain and patients free of pain are displayed in Patients in the persistent postsurgical pain group did not exhibit postoperative hyperalgesia to electric stimulation, but were significantly more hyperalgesic postoperatively to pressure stimulation (Persistent pain: p<0.01)–Persistent pain patients had significantly higher postoperative pain VAS scores at rest  and on movement –Covariate preoperative CPM significantly affected electric SOT (p = 0.03) and showed a trend towards significance on pressure SOT (p = 0.07)–Patients in the persistent postsurgical pain group reported lower functioning score (Persistent pain: p<0.01) and total QOL (Persistent pain: p<0.01), and higher symptom score –We assessed the value of inhibiting the inflammatory component of sensitization added to blockade of neuronal nociceptive input  on central sensitization  and persistent pain after surgery in women undergoing surgery for breast malignancy. Adding perioperative COX-2 inhibition to maximal anti-nociceptive therapy had no impact on change in electric or pressure pain tolerance thresholds as a measure of central sensitization after breast cancer surgery. COX-2 inhibition did lead to lower pain scores on movement at postoperative day 5, but had no effect on later time points and did not affect quality of life scores. Thus, our primary hypothesis was rejected.We found that patients developing persistent postsurgical pain were significantly more hyperalgesic to pressure both early after surgery (5 days) and throughout the rest of the year (15 days to 12 months). Thus, our secondary hypothesis was confirmed. There was no difference in sensitivity to electric quantitative sensory testing. Patients with persisting pain 12 months postoperatively had more pain in the acute postoperative period  and the rest of the year . Total QOL and functioning scores were lower in persistent pain patients and symptom score was higher vs. patients not developing persisting pain.Our study describes the effects of perioperative COX-2 inhibition on postoperative sensitization of pain processing in a long-term prospective and longitudinal trial. Regarding persistent pain  after breast surgery some data are available regarding perioperative COX-2 inhibition. Romundstad et al.  found noSurgical tissue damage is associated with prostanoid production . This reThe generalized pressure hyperalgesia detected in this study suggests that persistent central sensitization is an important process in persisting pain development after surgery. Other quantitative sensory testing studies have assessed pain processing in women with persistent pain at single time-points after breast cancer surgery. These studies confirm the widespread mechanical hyperalgesia we observed , 52. OthWe observed a relatively low incidence of persistent postsurgical pain following surgery (13%) compared to other less recent studies (25 to 60%). MaximalOur results indicate that the role of COX-2 and inflammation in the genesis of postoperative hyperalgesia may be less important than that of neuronally mediated nociceptive input. Adding perioperative COX-2 inhibition to maximal neuronal anti-nociceptive therapy  appears of limited clinical value in preventing postoperative hyperalgesia or persistent pain.Despite all patients receiving maximal neuronal anti-nociceptive therapy in the form of paravertebral blockade, 13% of patients still developed persistent pain postoperatively. These patients showed widespread hyperalgesia to pressure in the acute postoperative period and the rest of the year and would seem to be relatively resistant to current therapeutic interventions. Future studies should further explore causes of developing early and persistent postoperative hyperalgesia, possibly an important process during persistent pain development.Clinically, the fact that persistent pain patients showed more widespread hyperalgesia to pressure in the acute postoperative period means that peri-operative monitoring using quantitative sensory testing should be able to identify patients at risk of developing persistent postsurgical pain, possibly allowing for targeted antihyperalgesic treatment.There is increasing interest in the potential for perioperative quantitative sensory testing to predict persistent postsurgical pain. A relationship between peri-operative quantitative sensory testing measures and persistent pain has thus far been shown in only a limited number of studies. These studies demonstrated an association between persistent postsurgical pain and preoperative measures of widespread pain sensitization, such as pressure pain thresholds –63. HowePrediction and possible interventions targeting persistent pain after breast cancer surgery are especially relevant given the poorer function scores and QOL we found with persistent pain after breast cancer surgery. Furthermore, persistent pain after breast cancer surgery is increasing in prevalence due to increased survival after breast cancer .We chose quantitative sensory testing measures as the main outcome measures because we intended to conduct a study investigating relations between COX-2 inhibition, hyperalgesia development and persistent pain after surgery. Pressure quantitative sensory testing detects hyperalgesia of deep tissues such as muscle as a manifestation of central sensitization , and is We measured electric and pressure pain tolerance thresholds at multiple topographic sites. Others have advocated extensive multimodal quantitative sensory testing protocols . These pTwo limitations pertain to this study. First, we were unable to include some patients in the modified intention to treat analysis due to treatment failure, and had to exclude some patients due to an incorrect initial diagnosis. However, we achieved the group size we calculated beforehand to deliver sufficient power to detect a 30% difference from baseline and the analyzed treatment groups were comparable for baseline characteristics. A second limitation was the small number of patients developing pain 12 months postoperatively. A larger study population and thus a larger group of pain patients might have provided more insight into the deferential characteristics of persistent pain patients vs. patients not suffering from pain, even though we were able to detect several significant differences between the groups that we analyzed.In conclusion, we found that adding perioperative COX-2 inhibition to current maximal anti-nociceptive therapy  has no significant impact on central sensitization, persistent pain and QOL in the year following breast cancer surgery. Patients that developed persistent pain after breast cancer surgery were significantly more hyperalgesic, had higher pain scores and lower QOL throughout the year following surgery. Sensitization early after surgery may play a role in the genesis of persistent pain after breast cancer surgery and perioperative monitoring using quantitative sensory testing may be able to identify patients at risk of developing persistent pain.S1 Checklist(DOC)Click here for additional data file.S1 Protocol(DOC)Click here for additional data file.


It has been suggested that oxycodone is effective in relieving acute postoperative pain. The aim of this study was to investigate the efficacy and tolerability of oxycodone (O) versus fentanyl (F), and the adequate potency ratio of oxycodone and fentanyl in patients with intravenous patient-controlled analgesia after gastric laparotomy.In this double-blinded, randomized, controlled study, 60 patients undergoing elective gastric laparotomy were allocated to receive either oxycodone or fentanyl for postoperative intravenous patient-controlled analgesia (potency ratio 60:1). The patients received ketorolac 60 mg before the end of anesthesia and then continued with patient-controlled analgesia for 48 hours postsurgery. Pain severity, side effects and respiration rate were recorded 30 minutes, 3, 6, 12, 24, and 48 hours after the surgery. Cumulative opioid requirements and patient satisfaction were also measured.P < 0.05). Whereas the incidences of adverse events were similar between the groups , a significant higher sedation scores were found in patients given fentanyl at 30 minutes after the surgery (P = 0.04).The median consumption more than 48 hours after operation of oxycodone was 50 mg (range: 40.0–62.4 mg) and fentanyl was 0.8 mg (range: 0.6–1.1 mg), and the percentage of patients requiring rescue medication was not statistically significant. Numeric rating scores at rest and upon movement were significantly lower in group O than in F (Oxycodone was comparable to fentanyl in the relief of postoperative pain following gastric laparotomy. Oxycodone not only provides better postoperative pain relief and less sedation, but also there was a tendency toward more side effects with oxycodone. Increasing evidence shows that undertreated acute pain may not only increase the need for hospitalization after surgery,–6 Patient-controlled analgesia (PCA) with intravenous an opioid is a more efficient method for achieving improved postoperative analgesia and high patient satisfaction with minimal sedation and complications, has become the most common regimen for pain relief after major surgery.Opioids are considered to be the standard analgesic for relieving moderate to severe acute postoperative pain. After surgery, however, many patients are unable to ingest oral medication and instead receive intravenous an opioid. Patient-controlled techniques allow patients to self-administer small boluses of analgesic, providing better titration and enhancing responsiveness in analgesic requirement.–11 is superior in the treatment of visceral pain.,13 Oxycodone is highly effective and well tolerated in different types of surgical procedure and in patients with renal or hepatic failure, and age is no contraindication for oxycodone, is replacing morphine as a first-choice opioid in several countries. In china, the utility of oxycodone is increasingly frequently in patients after major abdominal surgery. To the best of our knowledge, no comprehensive data exist regarding the analgesic efficacy of intravenous oxycodone versus fentanyl in patients after gastric laparotomy.Fentanyl is widely used for the control of postoperative pain, but there is a trend toward the use of oxycodone. Oxycodone, a semisynthetic opioid that may be an agonist of the central and peripheral kappa- as well as mu-opioid receptors,In this prospectively, randomized, double-blind study, we compared the analgesic efficacy, adverse events, and patient satisfaction ratings of fentanyl and oxycodone in patients experiencing moderate to severe pain after gastric laparotomy. In addition, this study also evaluated the conversion dose rate of intravenous PCA (IV-PCA) oxycodone and fentanyl for postoperative analgesia on the basis of adequacy pain control.22. The following patients were excluded: pregnant and lactation women; allergy, sensitivity, or contraindication to study medications; history of chronic opioid usage within 8 weeks of surgery; had bleeding disorders; history of severe hepatic, renal, pulmonary, or cardiac disease; history of underlying psychological disorders or communication disability.The study protocol was approved by the Institutional Review Board at Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, China. Written informed consent was obtained from each patient or a legal representative. We collected patients in our institute from July 2015 to December 2015. Patients of age between 40 and 70 years who scheduled to undergo elective gastric laparotomy with general anesthesia were eligible if they were considered as American Society of Anesthesiologists’ (ASA) Class I to III classification and with a body mass index (BMI) 18–25 kg/mAll patients were assigned randomly to receive either oxycodone (group O) or fentanyl (group F) by blinded researchers, according to a computer-generated simple randomization code. Group allocation was controlled and concealed by our institution's pharmacy and released only after completion of the study, thus ensuring blinding of patients, researchers, and observers. Double-blinding was achieved by labeling the PCA reservoir bags with consecutive patient numbers. For reasons of patient safety, a sealed envelope containing the treatment assignment was kept with the patient in the ward.®, Smiths Medical, St. Paul, Minnesota, USA) and a numeric rating scale , the purpose of the study, side effects and cautions were also explained to the patients.In the morning before the operation, the patients were instructed about the use of PCA system  were used for all patients. After connecting the monitoring devices, general anesthesia was induced with propofol 1.5 to 2.0 mg/kg, fentanyl 2 to 4 μg/kg, cisatracurium 0.15 to 0.20 mg/kg, and endotracheal intubation was performed later. Anesthesia was maintained with sevoflurane 0.8% to 2.0% in 50% nitrous oxide and 30% oxygen, and a sufentanil injection of 0.2 to 0.4 μg/kg was used for analgesia as necessary. All patients were given 30 mg lansoprazole i.v. (at induction of anesthesia) and 0.125 mg of palonosetron i.v. (during operation) as prophylaxis of intraoperative regurgitation and postoperative nausea and vomiting.At the skin suturing stage, the patients were attached to an IV-PCA pump, and 60 mg ketorolac i.v. was administered to all patients for postoperative pain relief. Neostigmine 0.2 to 0.5 mg and atropine 0.015 mg/kg were given to reverse residual neuromuscular block at the end of surgery. Tracheal extubation was performed after recovery of response to verbal commands and spontaneous respiration.According to reviewing previous research and conducting a few pilot trials, the potency ratio of oxycodone and fentanyl were determined at 60:1. Patients in group O were administered a 100-mL mixture of oxycodone 0.7 mg/kg, 180 mg of ketorolac, and 0.125 mg of palonosetron with a normal saline solution. On the other hand, patients in group F were administered fentanyl 12 μg/kg, 180 mg of ketorolac, and 0.125 mg of palonosetron with a normal saline solution. The setting for PCA was 1 mL bolus with a 15-minutes lockout and a background continuous infusion of 1 to 2 mL/h. As soon as the patients were awake, their pain was assessed using the Numeric rating scores (NRS). If the patient reported a NRS at rest more than 3, an anesthetist monitoring and interviewing of the patients titrated PCA solution i.v. 2 mL at 5 minutes of intervals until the NRS was 3 or less. Then, the patients were encouraged to self-administer small boluses with their own PCA medications. To optimize analgesia while minimizing adverse event and hemodynamic instability, the patient-controlled setting could be further adjusted by the observer during the 48 hours of postoperative period, nurses also received extensive training regarding the studied techniques. When the patient had received the maximum number of bolus, but the NRS was higher than 3, bucinnazine 100 mg intramuscular (i.m.) were additionally administered.Intensity of pain, level of sedation, the amount of analgesics consumed, administration of additional analgesics, side effects, and RR were evaluated and recorded at 30 minutes, 3, 6, 12, 24, and 48 hours after operation. The cumulative consumption of opioid and the overall satisfaction of patients were measured at 48 hours after the surgery.Pain scores were evaluated with NRS in 2 categories, at rest and upon movement. Patients were asked to score their worst NRS since the previous assessment. NRS at rest was assessed with the patient lying supine and NRS upon movement was assessed with the patient were in activities including lifting limbs, sitting, rolling, or coughing.Adverse events such as nausea, vomiting, and dizziness were investigated by incidence and severity. The severity of an adverse effects judged by observer as unrelated, possibly related, or defined related to the study drug was classified as mild , moderate , or severe . When adverse events occurred, metoclopramide 10 mg i.m. were available once the patients requested. Persistent nausea, vomiting, or dizziness would warrant PCA termination with the patient then being switched to an alternate analgesic modality. PCA-related bradycardia (heart rate < 50 beat/min), respiratory depression (ventilatory frequency < 8 bpm lasting for more than 10 min) were considered as severe adverse events. If severe adverse events occurred, the use of PCA was interrupted immediately and the adverse events were treated with appropriate medication. All medications administered were recorded and this information was maintained as part of the study data.Level of sedation was assessed with Ramsay sedation score scale .The overall satisfaction of patients with the postoperative analgesia were evaluated on a 5-point scale  at 48 hours postsurgery.2.1The primary outcome measure was the NRS scores (0–10). To detect a difference of 1 in NRS scores with a standard deviation of 1.2 for each group based on the previous studies, 23 subjects per group would be needed for a study with α level was 0.5 (two-tailed) and β level was 0.2 (80% power).t test. Cumulative opioid consumptions, pain and sedation scores were analyzed using the Mann–Whitney U test. Sex, ASA classification, incidence of adverse events, use of rescue medication, and patient satisfaction were analyzed using the chi-square (X2) test or Fisher exact test. A P value less than 0.05 was considered to be statistically significant.SPSS 17.0, Chicago, IL was used to perform statistical analyses. Patient characteristics  and RR were analyzed using Student 3A total of 60 patients were enrolled and were randomized to treatment, with 30 patients were allocated to each of the 2 groups. Four patients (6.67%) withdrew from the study: 1 patient in group O required reoperation within 24 hours of surgery for postoperative anastomotic errhysis; 2 patients in group O and F discontinued treatment because of adverse events ; and 1 patient in group O discontinued the study due to hypotension that was judged more likely to be caused by anaemiae. Therefore, 56 patients completed the study: 27 in group O and 29 in group F. There were no statistically significant between-group differences with regard to patient clinical characteristics and intraoperative data including age, sex, BMI, ASA physical status, and duration of surgery (Table The median consumption over 48 hours after operation of oxycodone was 50 mg (range: 40.0–62.4 mg) and fentanyl was 0.8 mg (range: 0.6–1.1 mg), with a potency ratio of 62.5:1.P < 0.05, respectively)  .NRS at rest was significantly lower in the group O at 30 min, 12, 24, and 48 hours after operation (P = 0.64). Three subjects in group O (11.1%) and 9 subjects in group F (31.0%) had a sedation score of 4 after 30 minutes of surgery, and the sedation scores 30 minutes after the surgery was significantly higher in group F than in group O (P = 0.04). There were no statistically significant intergroup differences regarding the incidence and severity of dizziness, nausea and vomiting. In group O, however, 1 patient experienced moderate vomiting and was administered 2 doses of metoclopramide 10 mg i.m., and 1 patient experienced severe vomiting and requested terminating PCA use.Main adverse events are reported in Table . The perRR at each time point were presented in Fig. . No statP = 0.15)  Table .4This study shows that oxycodone at a cumulative median dosage of 50 mg (range: 40.0–62.4 mg) provided better analgesia than fentanyl at a cumulative median dosage of 0.8 mg (range: 0.6–1.1 mg) over 48 hours after gastric laparotomy.–17 In this study, we planned to evaluate the analgesic efficacy and tolerability of intravenous oxycodone and fentanyl using PCA in patients after gastric surgery.Oxycodone is a potent opioid, which may make it useful in the postsurgical pain control. The onset time of i.v. oxycodone is 2 to 3 minutes after injection and duration of action is 4 hours 52 minutes after a single dose of i.v. Oxycodone. Many studies have suggested that intravenous oxycodone is an effective treatment for acute postoperative pain. 78 laparoscopic cholecystectomy patients were randomized to receive IV oxycodone or IV fentanyl for pain control at the end of anesthesia and in the postanesthetic care unit, the median intraoperative and postoperative opioid consumption was 15 mg oxycodone (range 10–40 mg) and 200 μg fentanyl (range 100–500 μg), respectively. The oxycodone patients experienced better analgesia but also more side effects. In a subsequent study in patients scheduled for laparoscopic cholecystectomy, IV-PCA oxycodone provided comparable effects for pain relief compared to IV-PCA fentanyl in a potency ratio of 1:75. In a study of 60 laparoscopic hysterectomy, patients were randomized to receive PCA oxycodone or PCA fentanyl (potency ratio 100:1) following surgery find that oxycodone presented a better analgesic effect, also resulted in a higher occurrence of postoperative nausea and vomiting. In another recent similar study, the potency ratio was 60:1, and both agents were found to provide similar analgesic efficacy and similar rates of adverse events. Overall, the potency ratio of fentanyl to morphine has a range of 60–100:1. After conducting a series of pilot study, we originally performed this study under the hypothesis that the potency ratio of oxycodone to fentanyl was 60:1.However, the safe dose conversion ratio of oxycodone to fentanyl is yet to be established. In the koch et al Study,,17 However, IV oxycodone and IV morphine were thought to be equipotent, that is, had a potency ratio of 1:1 in many studies.,16 The pain mechanism might make the difference. Gastric laparotomy is often accompanied by severe visceral pain. Traditional μ-opioid agonists, such as fentanyl, however, may not be optimal in the treatment of visceral pain. Oxycodone is a semisynthetic derivative of thebaine. The main mechanism of action of oxycodone is associated with stimulation of the peripheral and central opioid receptors of the μ and κ type. It has been suggested that κ receptors constitute an essential part in the analgesic mechanism of action of oxycodone. Opioid receptors of the κ type on peripheral nerves may be an important feature for antinociception in the visceral pain system, and hence oxycodone has high therapeutic efficacy, especially in visceral pain, but this may not be the case for other types of pain. Therefore, Oxycodone may have more of an advantage over other opioids at equianalgesic dosages such as morphine after surgeries in which the visceral pain component is a large contributor to a patient's overall postoperative pain.,22It has been suggested that the most effective method to determine adequate doses in relation to the present pain is titrating the dose, and IV titrating has been used for rapid opioid titration in many clinical situations. Patient-controlled techniques allow patients to self-administer small boluses of analgesic, and thus providing better titration. Overall, in our study the potency ratio of fentanyl and oxycodone was 62.5:1, the results from the present study compare favorably with those from the fentanyl/oxycodone study after laparoscopic gynecological surgery for the potency ratio of 60:1, and was lower with all other previous studies. This seems to suggest that oxycodone is more potent than morphine. Our finding is in line with previous studies that have also suggested that the potency ratio of oxycodone to morphine is more on the order of 1:1.3–1.5.,24 In addition, some reports have suggested that the administration of cyclooxygenase (COX)-2 inhibitors can be effective in reducing movement-evoked pain by preventing central sensitization. Furthermore, the addition of ketorolac in intravenous PCA opioid could shorten the recovery duration of postoperative bowel movement and passage of fatus in patients who received major colorectal surgeries.,24Opioids are the most effective drugs for the management of moderate-to-severe perioperative pain in the major abdominal surgeries. However, their adverse effects have limited the use of them as analgesic agents. Therefore, ketorolac was added to the opioid IV-PCA in an effort to maintain the analgesic efficacy of opioids while reducing their adverse effects. Ketorolac have been shown to reduce postoperative opioid consumption while maintaining pain control and did not increase the incidence of non-steroidal anti-inflammatory drugs (NSAIDs)-related side effects.,20,21Our results showed that although the difference was statistically insignificant, the oxycodone group experienced more side effects, and one patient in group O alone requested additional antiemetics, this result was consistent with the report that oxycodone had a tendency toward more side effects than fentanyl.,20,21 In addition, median doses of opioid consumed 30 minutes postsurgery was oxycodone 3.5 mg (range: 2.4–5.4 mg) and fentanyl 64 μg (range: 49–120 μg), this meant to be relatively few oxycodone consumption during this time period.In this study, we also found that the sedation scores 30 minutes after the surgery was significantly higher in group F than in group O. There are possible explanations to this finding. First, it has been demonstrated that oxycodone produced similar or less sedation compared to fentanyl in several recent studies.There was no statistically significant difference between the 2 groups in terms of satisfaction with the IV-PCA 48 hours after the surgery. However, 2 subjects in group O against five subjects in group F reported disappointment with the pain control. These results may indicate that although the oxycodone group experienced more side effects, patient's satisfaction with the good analgesic effect presented by oxycodone make up this defect.In conclusion, this study demonstrated that by PCA-based drug administration, oxycodone was comparable to fentanyl when used with a conversion ratio of 62.5:1 in patients following gastric laparotomy. However, clinical data indicate that not only the type of surgery but also the extent of surgery may affect the comparison of different opioid analgesics. Future studies in various clinical settings are warranted to investigate the efficacy and tolerability of IV oxycodone versus IV fentanyl, and the appropriate equianalgesic dose ratio of IV oxycodone and IV fentanyl.


Diabetic retinopathy is one of most common and threatening ocular diseases. Many of these patients need to be submitted to panretinal photocoagulation (PRP), experiencing a significant level of pain. The purpose of this study is to evaluate the effectiveness of oral metamizole in reducing pain during PRP in patients with proliferative diabetic retinopathy (PDR) and very severe non-proliferative diabetic retinopathy (VSNDR).p < 0.05.Patients from a single center with PDR or VSNDR and indication of bilateral PRP were recruited for a double-masked, controlled, prospective study. The treated eyes were randomly assigned in two groups, and each patient had one eye assigned per group. Group A received 1000 mg of metamizole and group B received a placebo pill 40 min before the laser treatment. The groups were switched for the treatment of the fellow eye. Each patient scored the pain sensation immediately after each PRP section using Scott’s visual analogue scale (VAS). The paired Student t test was used to measure the significance between the two groups VAS scores, with significance level adopted of Twenty-one patients were recruited. The level of pain was significantly lower when submitted to PRP after oral metamizole treatment compared to placebo (p = 0.002). The mean pain scores for groups A and B were 4.72 ± 1.708 and 5.89 ± 1.967, respectively. The minimum/maximum scores within groups A and B were 1/8 and 1/10, respectively.The use of 1000 mg of metamizole 40 min before PRP significantly reduces the pain associated with the procedure in patients with PDR or VSNDR. Diabetic retinopathy is one of the most important causes of visual impairment in adult population. The standard treatment in the last few decades for eyes with high risk of visual loss, with very severe nonproliferative diabetic retinopathy (VSNDR) or proliferative diabetic retinopathy (PDR), has been the administration of laser panretinal photocoagulation (PRP) –4. The DMost of the patients undergoing PRP treatment complain about moderate to severe pain sensation. Previous studies show that 73 % of the patients submitted to PRP report painful sensation during the laser treatment –8. DiffeMetamizole, also known as dipyrone, is widely used as an analgesic in many countries  . AlthougThe purpose of our study is to analyze if metamizole, a common oral analgesic widely used in South America, is effective in reducing painful sensation during retinal laser treatment in patients with PDR or VSNDR , 11.We performed a randomized, double-masked clinical trial to evaluate the efficacy of metamizole as a pre-emptive analgesic agent during PRP. Patients with bilateral PDR or VSNRD from the Ophthalmology Service of the Hospital das Clínicas—University of São Paulo Medical School that were recruited over a 2-year period were included. All patients signed an informed consent form and the ethics committee approval was obtained before the beginning of the study.Inclusion criteria were: bilateral proliferative diabetic retinopathy or very severe non-proliferative diabetic retinopathy, no previous laser treatment, best corrected visual acuity of 20/200 or better, intraocular pressure under 21 mmHg, spherical equivalent of ±5.00 diopters, clear media and vitreous, diabetes diagnosed after 30 years of age. The exclusion criteria were: previous photocoagulation treatment, media opacity such as cataracts, corneal diseases or vitreous hemorrhage, unilateral PDR, chronic use of analgesics or history of any side-effects related to metamizole use.All patients were submitted to PRP, divided in two sessions per eye. PRP was performed by two specific authors (RBA and BMSA) who were blind to the pre-emptive treatment in all sessions. A third professional (BSG) was responsible for administering the drug or the placebo to the patient. The eyes of each patient were randomized into groups A and B. Randomization tables were sent to the pharmacist who allocated each pill in a randomized sequence. Group A eyes received 1000 mg of metamizole 40 min before the laser session and group B eyes were medicated with a placebo pill. Each patient had one eye on group A and one eye on group B. Therefore, a group of patients took metamizole before any PRP, and had PRP with placebo at the fellow eye, while a group of patients started PRP with placebo pills, and had PRP with metamizole when treating the second eye.Before the laser treatment sessions, each patient was submitted to a complete ophthalmological examination, that consisted of best-corrected visual acuity (BCVA) measurement, biomicroscopy, gonioscopy, tonometry and fundoscopy. Each patient had his or her pupils dilated with topical 1 % tropicamide. The laser treatment was performed with green argon double-frequency laser with a panretinal contact lens. Each session consisted in approximately 500 spots, with laser energy adjusted to achieve moderate white burns, spots size of 250 micrometers and exposure time of 0.2 s. The inferior and nasal retina was treated in the first session, and superior and temporal retina in the second session.The painful sensation scores were evaluated immediately after finishing each session with the Scott’s Visual Analogue Scale (VAS), that ranges from 0  to 10 (the worst pain imaginable).p < 0.05.Statistical analysis was expressed in mean, maximum, minimum scores obtained, and standard deviation. Sample size was calculated considering a pain score difference of 2 points between both groups, with Alfa error of 5 % and beta error of 20 %. All data was processed with SPSS version 20.0. The paired Student t test was used to measure the significance between the two groups, with significance level adopted of A total of 21 patients (42 eyes) were recruited and their characteristics are summarized in Table All patients took their appropriate pretreatment medications , underwent their first PRP session, and answered the pain questionnaire. At the very next visit (1 week later), patients were submitted to the same PRP procedure at the fellow eye and therefore took a different pill .Laser parameters delivered to the patients were similar between the groups and there was no statistical difference between groups regarding the number of spots delivered, as shown in Table The mean VAS pain scores for groups A and B were 4.72 ± 1.71 and 5.89 ± 1.97 (p < 0.01), respectively. The minimum/maximum scores within groups A and B were 1/8 and 1/10, respectively Table . There wPatients referred a significant lower level of pain during PRP when submitted to previous oral metamizole treatment when compared to placebo (p = 0.002). No serious adverse events or drug allergy related to metamizole were reported.Most patients undergoing PRP typically experience pain during the procedure, which may be so uncomfortable that there is a risk of inadequate treatment being applied or perhaps the patient may even default from attendance .There are numerous options available to reduce or prevent it. Retrobulbar, peribulbar, or subtenon anesthesia are effective pain-relieving procedures, but are invasive for patients and possess risk of potential complications and therefore are not feasible for in-office daily routine , 26. On This study sought to find an inexpensive, safe and easy-to-administer method to reduce the pain intensity felt during PRP. It would make the treatment more comfortable for patients, would likely decrease the need for rescue injection anesthesia, and could potentially improve compliance with follow-up PRP treatments .Metamizole is a non-opioid analgesic and one of the most frequently used analgesics around the world, therefore it was chosen for this study to evaluate its analgesic effects. However, in some countries, the drug has been avoided since the 1970s because of what was thought to be an unacceptable risk of agranulocytosis. Recent scientific data do not justify this reasoning .Its mechanism of action is still under discussion, but the main pathway is attributed to an inhibition of prostaglandin synthesis in both peripheral tissues and the central nervous system .The results of this study show a positive effect of metamizole in reducing pain caused by PRP. It is known that pain perception is a personal experience to each individual. Many factors can influence this perception, including gender, cultural differences, past experiences, and anxiety levels .In order to avoid any kind of bias, we selected bilateral cases that had never experienced laser before. Moreover, the same patient was submitted to PRP after either placebo or metamizole (only the order of it was randomized). Our intention was to create the best scenario in order to make unbiased comparison.The main limitations of our study are the lack of assessment of differences regarding the pain report between first and second laser session or between different retinal areas, which should be aim of further studies. Despite the significant results, this is a small trial and our results should be confirmed by other future studies.Furthermore, an important observation in this study was the similar laser parameters applied to bot. The occurrence of pain in PRP may be influenced by many parameters, such as duration, intensity, spot size and obviously the number of spots delivered in each session. Recent literature evaluates the pain response with reduced exposure laser times and micropulse technology, with good pain score outcomes , 18, 19.In conclusion, PRP is a painful treatment for most patients. According to our study, the use of 1000 mg of metamizole 40 min before PRP significantly reduces the pain associated with the procedure in patients with proliferative diabetic retinopathy or VSNDR. Therefore, metamizole is a safe and cheap option that can be applied before the procedure, especially in patients with no history of drug allergy, resulting in more comfort to patients with PDR or VSNDR.


Short-segment pedicle-screw instrumentation is frequently used to stabilize thoracolumbar burst fractures. A recognized disadvantage of this procedure is recurrent kyphosis from intervertebral disc creep into the fractured central endplate. Balloon Assisted Endplate Reduction (BAER) using Tricalcium Phosphate bone cement (TCP) enables elevation of the centrally depressed endplate. Our objective was to evaluate the bone-tissue response to TCP and to analyse whether BAER using TCP can prevent recurrent kyphosis after removal of the instrumentation.Fourteen patients with traumatic thoracolumbar burst fractures were operated with BAER using TCP in combination with short-segment instrumentation. Nine months after surgery, instrumentation was removed and transpedicular biopsies were taken for histological and histochemical analysis. Roentgenograms pre- and postoperatively and at latest follow-up after removal of the instrumentation were evaluated.p < 0.001). After removal of the instrumentation no significant differences in wedge-angle or height ratios were seen (p = 0.12). The kyphosis-angle increased four degrees (p = 0.01).Average follow-up was 2.6 years. Analysis of the biopsies showed a variable degree of bone remodelling with incorporation of TCP into newly formed bone matrix. No extensive foreign body reactions, inflammation, granulomatous responses or tissue necrosis were observed. Wedge-angle, kyphosis-angle and both the anterior-posterior and central-posterior vertebral body height ratios improved significant postoperatively . The best treatment option for thoracic- and lumbar burst fractures without neurological deficits is unclear. Several operative methods exist, but none has proven to be superior in terms of patient outcome. Treatment objectives after thoracic- and lumbar burst fractures are to stabilize the spine, prevent neurological deterioration, restore sagittal balance, retain as much segmental mobility as possible with the least operative tissue trauma and to mobilize the patient as quickly as possible.Short-segment pedicle-screw instrumentation is widely used and can be done minimally invasive. However a recognized disadvantage of this procedure is early instrumentation failure , 2 and rPosterior spinal fusion has been used to augment the stability of posterior implants. Several studies recommend posterior fusion, , 10 but Several studies evaluated the use of transpedicular vertebral body fracture reduction with Balloon Assisted Endplate Reduction (BAER) using Tricalcium Phosphate bone cement (TCP) and short-segment pedicle-screw instrumentation in thoracic- or lumbar burst fractures –17. ThesTCP cement rather than polymethylmethacrylate cement (PMMA) was used in the previously mentioned studies –17, becaThe main objectives of this retrospective cohort study were to evaluate the bone-tissue response of TCP cement in the human spine and to analyse whether BAER using TCP in combination with short-segment instrumentation for traumatic thoracic- or lumbar burst fractures can prevent recurrent kyphosis after removal of the instrumentation.The current study was approved by the Zuyderland medical ethics committee 13 N31) and registered at the Dutch Trial Registry (NTR3498). Informed consent was acquired in all patients. Medical records of patients who sustained an acute traumatic thoracolumbar burst fracture. (AO-type A.3 or B.1) between 2003 and 2010 were reviewed. The fractures were classified on CT-scan according to the AO-Magerl classification  and the 3 N31 andN = 6), a traffic accident (N = 3) and domestic trauma (N = 5). The level of spinal involvement and type of fracture are listed in Table The study group included eight female and six male patients with an average age of 41 years (range 23 to 61 years). The mean follow up was 29 months (range 9 to 100 months). All patients were operated between 0 to 21 days post injury (average 5 days). The mechanisms of injury were a fall from a height . None of these patients had neurological deficits, pre-existing spinal deformity, spinal stenosis, osteoporosis (criteria WHO) or previous spinal surgery.All patients were operated on by the senior author (PT). Surgical procedures were performed with the patients under general anaesthesia with endotracheal intubation. Patients were placed in a prone position. Pedicle screws were placed into the non-fractured vertebrae one above and one below the fractured vertebrae. Consequently in the patients with 2 levels of spinal involvement, 3 instead of 2 segments were stabilised. Subsequently reduction of the kyphosis was achieved by inflation of the Kyphon® balloon-kyphoplasty in the fractured vertebrae . In the patient with a burst fracture in both L1 and L2, balloon-kyphoplasty was applied in both vertebrae. Stabilisation was achieved with an open procedure without fusion in the first 4 consecutive patients. Subsequently a percutaneous procedure was performed in the following 10 patients. The Monarch polyaxial spinal fixation device® and the Expedium Viper minimally invasive pedicle screw system®  were used  after the initial surgery. At that time-point consolidation of the fractured vertebra was expected based on radiological evaluation.Analysis of the biopsies was performed by a single pathologist (HP). The biopsies were fixated using 4% buffered formalin and subsequently decalcified with Ethylenediaminetetraacetic Acid. After paraffin embedding, histological slices were cut and stained with haematoxylin and eosin. Goldner, elastica von Gieson, Giemsa, periodic acid shift and/or reticulin stains were used to visualize the osteoid formation, the amount of fibrosis or to identify the cell population present in the biopsies. One additional sample consisting only of cement was processed in the same way as the biopsies for histological examination. The decalcified remnants of the cement were compared with the bone biopsies and used to identify the remnants of cement in the samples. The biopsies were scored for the presence of osteoid formation, woven bone, osteoclasts and osteoblasts using a score of one to three. One stands for a little amount or near absence of the features, two representing medium changes and three for a large amount or obvious features. The sum of these two results was made to determine the amount of bone remodeling (score of two to six). Finally, the amount of haematopoietic tissue present was measured (score of one to three).For study purposes standing anteroposterior and lateral roentgenograms pre- and approximately 9 months postoperatively and at latest follow-up after removal of the instrumentation were analysed . In eight out of the 12 patients with lumbar fractures, flexion-extension roentgenograms were available at latest follow-up. All roentgenograms were evaluated by two independent observers who were not involved in patient care . Mean values of their measurements were calculated. Interclass correlation coefficient was used to determine the conformity between the two observers. The wedge angle WA, Fig. , the segAfter removal of the instrumentation at latest follow-up, back pain intensity was recorded on the basis of a Pain Visual Analog Scale . Functional outcome after surgery was evaluated using the Short Form-36 survey  and the Roland Morris Disability Questionnaire score (RDQ). Younger patients might show better compensation mechanisms after thoracolumbar fractures. A comparison between patients older than 40 years was made.p < 0.05.Statistical analysis was performed with use of SPSS (Version 23.0). The non-parametric Wilcoxon Signed-Rank test was used for changes of each radiographic parameter. The level of significance was set at Twelve bone biopsies, taken 6 to 14 months after the initial surgery, were processed for histological examination. One sample was lost due to technical failure. In all of the 11 remaining biopsies, remnants of the cement were easily identified Table . The preAs shown in Table The hematopoietic tissue situated in between the bony trabeculae and between the trabeculae and the remnants of the cement showed no striking aberrations Table . No cellp < 0.001) after the initial surgery. No signs of spinal canal encroachment, cement leakage or malposition of the instrumentation were seen on CT-scan. Convection was similar among patients with a percutaneous- or open posterolateral procedure.The mean values for the reduction of the segmental kyphosis angle and restoration of the central endplates pre- and postoperatively and after removal of the instrumentation are displayed in Table p = 0.01) was maintained in comparison to the preoperative kyphosis angle.After removal of the instrumentation the wedge angle as well as both height ratios were preserved. The segmental kyphosis angle increased significantly with a mean of four degrees Table . HoweverOn roentgenograms at latest follow-up no spontaneous fusion was observed. However residual mobility Fig.  was obsen = 7) in our group were compared to those younger (n = 7) no significant changes in VAS- (p = 0.33), RDQ- (p = 0.36) and SF-36 score (p = 0.44) were seen. With the exception of screw breakage in one patient, no other complications occurred . The SF-36 score and the RDQ score were respectively 72 SD, 21) and 5.3 . When the patients older than 40 years ( and 5.3 In the current study the biocompatible properties of the TCP cement in the human spine were studied. In addition we evaluated if BAER using TCP cement in combination with short-segment instrumentation, could prevent recurrent kyphosis after removal of the instrumentation in patients with thoracic- or lumbar burst fractures.Recurrence of deformity after short-segment instrumentation for thoracic- or lumbar burst fractures may result from intervertebral disc creep into the fractured central endplate –8. A cadSeveral clinical studies evaluated the use of TCP for the reconstruction of osseous defects of the vertebral body, the distal part of the radius and the proximal part of the tibia and femur , 28–30. Our study demonstrates a significant reduction of the segmental kyphosis after restoration of the central endplates when, in addition to the short-segment instrumentation, BAER with TCP was performed. These findings are consistent with other recently conducted studies –17. A syNone of the previously mentioned studies report on the effects after removal of the instrumentation. A study by Öner et al. demonstrates a recurrent kyphosis of 10 degrees after removal of the instrumentation in patients with thoracolumbar fractures managed with posterior reduction and fusion . In our Although in 6 out of 8 patients residual mobility was clearly observed, it is difficult to draw definitive conclusions since in only eight out of the 12 patients with lumbar fractures, flexion-extension roentgenograms were available. However this may speak in favor for removal of the material especially when the recurrent kyphosis afterwards is not substantial.Based on the VAS scale, SF-36- and RDQ-score, functional outcome after removal of the instrumentation was good and comparable with the literature , 15. UnfTCP cement showed histological osseointegration without adverse histological findings. TCP can therefore be safely used in treatment of thoracolumbar burst fractures. In addition this study indicates that BAER with TCP cement in combination with short-segment instrumentation might reduce the recurrence of deformity of the fractured vertebrae even after removal of the instrumentation when compared to short-segment instrumentation alone.