The aim of this study was to assess safety and efficacy of fixed combination oxycodone prolonged release (PR)/naloxone PR in terms of both analgesia and improving opioid-induced bowel dysfunction (OIBD) and associated symptoms, such as opioid-induced constipation (OIC), in adults with chronic non-cancer pain.These were open-label extension studies in which patients who had previously completed a 12-week, double-blind study received oxycodone PR/naloxone PR for up to 52 weeks. The analgesia study assessed pain using the modified Brief Pain Inventory-Short Form (BPI-SF). The bowel function study assessed improvements in constipation using the Bowel Function Index (BFI).n = 379), mean score [± standard deviation (SD)] for the BPI-SF item ‘average pain over the last 24 h’ was 3.9 ± 1.52, and this remained low at 6 months (3.7 ± 1.59) and 12 months (3.8 ± 1.72). Mean scores for BPI-SF item ‘sleep interference’, and the BPI-SF ‘pain’ and ‘interference with activities’ subscales also remained low throughout the 52-week study. In the bowel function study (n = 258), mean BFI score (± SD) decreased from 35.6 ± 27.74 at the start of the extension study to 20.6 ± 24.01 after 12 months of treatment with oxycodone PR/naloxone PR. Pain scores also remained low and stable during this study. Adverse events in both extension phases were consistent with those associated with opioid therapy; no additional safety concerns were observed.At open-label baseline in the analgesia study (Results from these two open-label extension studies demonstrate the long-term efficacy and tolerability of fixed combination oxycodone PR/naloxone PR in the treatment of chronic pain. Patients experienced clinically relevant improvements in OIBD while receiving effective analgesic therapy. The fixed combination of oxycodone PR/ naloxone PR was shown to be tolerable and effective in providing analgesia and improving bowel function in a 12 weeek randomised, controlled study setting.The fixed combination of oxycodone PR and naloxone PR is a safe and efficacious agent also for the long-term treatment of chronic pain.Almost one in five adults within the European Union suffers from chronic pain , imposinAs recommended by the World Health Organization, opioids have become the established treatment for moderate-to-severe chronic cancer pain  and, in Opioid-induced bowel dysfunction is a consequence of the action of opioids on receptors within the gastrointestinal (GI) tract, which reduce GI motility, inhibit secretion, increase absorption, affect blood flow and increase anal sphincter tone . As a reCurrent management strategies for OIC are non-specific and often ineffective . LaxativPrevention of OIC, and bowel dysfunction in general, is considered to be a more effective therapeutic strategy than merely treating the symptoms as they occur . One appNaloxone is an opioid-receptor antagonist that, when administered orally, has a very low systemic bioavailability of < 3%  because The efficacy and tolerability of the fixed combination of oxycodone PR/naloxone PR has been shown in two Phase III, double-blind, randomised controlled clinical trials, one focusing on analgesic efficacy and the other focusing on bowel function. The first showed oxycodone PR/naloxone PR to be superior to placebo in terms of analgesic efficacy while also providing significant benefits in terms of bowel function . FurtherThis report presents the results of the open-label extensions of the aforementioned two Phase III studies ,23, one These were uncontrolled, open-label, extension phase studies in patients with non-cancer pain, who had completed one of two previous randomised, controlled, 12-week studies ,23, perfAll patients who completed one of the previous double-blind studies ,23, who At the start of the double-blind phase of the bowel function study, patients had to be experiencing constipation caused or aggravated by opioids, be willing to discontinue their current laxative regimen and comply with the use of oral bisacodyl as a laxative rescue medication. Laxative rescue medication was permitted no sooner than 72 h after the patient’s most recent bowel movement; however, if patients experienced discomfort during this period, they could take bisacodyl 5 mg as a laxative earlier than 72 h after their most recent bowel movement, as required, to treat constipation. The maximum total amount of oral bisacodyl permitted was five doses within seven consecutive days. Patients taking daily fibre supplementation or bulking agents were eligible for inclusion if they could be maintained on a stable dose and regimen throughout the study and were considered able to maintain adequate hydration.In the extension phase of both studies, patients’ pain was treated with open-label study medication  for up to 12 months . In the The extension studies were conducted primarily to assess the long-term safety of the fixed combination of oxycodone PR/naloxone PR in the treatment of chronic non-cancer pain. No defined primary end-point was set; however, analgesic efficacy and bowel function were assessed.The objective of the analgesia study was to assess pain and interference of pain with activities during treatment with oxycodone PR/naloxone PR, based on the modified Brief Pain Inventory–Short Form (BPI-SF) . The modThe objective of this study was to assess whether patients with moderate-to-severe non-cancer pain taking oxycodone PR/naloxone PR had improvements in bowel function, as measured by the validated Bowel Function Index (BFI) , 32 at eSafety assessments consisted of monitoring all adverse events (AEs), including serious adverse events (SAEs); monitoring haematology, blood chemistry and urine values; periodic measurement of vital signs and electrocardiograms (ECGs); and physical examinations. In the bowel function study, symptoms of opioid withdrawal were also assessed using the Subjective Opiate Withdrawal Scale (SOWS) .post hoc, consisting of patients who received oxycodone PR/naloxone PR > 40 mg/20 mg per day on > 7 days consecutively. In the bowel function study, a post hoc analysis was conducted to examine changes in BFI score according to treatment received in the double-blind phase.The extension study population consisted of all patients who received at least one dose of oxycodone PR/naloxone PR in the extension phase. In the analgesia study, a subpopulation was defined Summary statistics were provided for each single item and each subscale of the BPI-SF using the last observation carried forward (LOCF) method for missing values. Summary statistics of average pain over 24 h, the pain subscale, the sleep interference and the interference subscale were also displayed for observed values without any missing values. Changes in dose were assessed using a shift table with numbers of changes from the dose at the start of the double-blind phase to the oxycodone PR/naloxone PR dose at the end of the extension phase, as well as the oxycodone PR/naloxone PR dose after 2 weeks of the extension phase. Changes in dose after 2 weeks of the extension phase were grouped according to double-blind phase treatment.n , mean (i.e. arithmetic average) and standard deviation (SD), whereas number and percentage were used to summarise categorical efficacy variables.Continuous efficacy variables were summarised by n , mean (i.e. arithmetic average) and SD. The number and percentage of observed levels were reported for all categorical measures. AEs were classified by system organ class and Medical Dictionary for Regulatory Activities (MedDRA)-preferred term. The incidence of AEs considered as having a causal relationship to study medication  was also recorded. In the analgesia study, the incidence of GI AEs and nervous system disorders was recorded for 0–3 months, 3–6 months, 6–9 months, 9–12 months, > 12 months and follow up.For the safety data analyses, all continuous variables were summarised by Of the 464 patients who were initially randomised, 463 received study medication and entered the double-blind phase. Of these patients, 380 (81.9%) continued to the extension phase and 379 received study medication. The majority of patients (78%) completed the 12-month study, with 86% remaining in the study at 6 months. Only 83 patients (22%) had discontinued the study by 12 months; the majority of these discontinuations were resulting from the patients’ choice , administrative error  or patients being lost to follow up  . AEs werPatients were 56.2 years in average, with 39% male and 61% female; all were Caucasian . The aveThe objective of the extension study was to assess the long-term analgesic efficacy of oxycodone PR/naloxone PR for up to 12 months. After entering the extension phase, the mean pain score (± SD) for the BPI-SF item ‘average pain over the last 24 h’ was 3.9 ± 1.52 (Week 1), which was comparable with the mean score at the end of the double-blind phase . Mean paThe mean score (±SD) for the BPI-SF item ‘sleep interference’ was 2.9 ± 2.52 after switching to the extension phase (Week 1), which was comparable with the mean score at the end of the double-blind phase . Mean slIn the subgroup of patients using daily oxycodone PR/naloxone PR doses greater than 40/20 mg, the mean average pain score (±SD) at the end of the double-blind phase was 4.2 ± 1.4; this remained stable throughout the study (varying between 4.1 and 4.3), being 4.2 ± 1.74 at 12 months. These pain scores were comparable with those of the total extension population, and no clinically relevant differences could be observed throughout the 12-month extension phase.After the first 2 weeks of the extension phase, the majority of patients remained on a dose of oxycodone PR/naloxone PR that was comparable with the dose they had received in the double-blind phase. A total of 53.8% of patients remained on the same dose as they received in the double-blind phase. The percentage of patients who had a decrease or increase in dose was comparable between, and independent of, the different double-blind phase treatment groups from which the patients had been switched . The meaOverall, the incidence of AEs in the extension phase (68%) was comparable with that in the double-blind phase , taking into account the longer observation period. Most AEs were mild or moderate, and the incidence of severe AEs was low (13%). For the majority of AEs (62%), no action was taken regarding the study drug. In the subgroup of patients using oxycodone PR/naloxone PR doses greater than 40/20 mg daily, the incidence of AEs was slightly higher than in the overall population, during the extension phase (71.6 vs. 68.0% respectively).The incidence of AEs considered as having a causal relationship to study medication was 38% and the number of AEs leading to treatment discontinuation was 6.3%. Constipation (9.2%), nausea (7.7%), back pain (6.3%) and depression (6.3%) were the most frequently reported AEs . The incThe overall incidence of nervous system disorders was 14% , being tOverall, 48 patients (13%) experienced 88 SAEs. Of these, 27 events in 12 patients were considered to have a causal relationship to study medication, but only six events in three patients were considered by the investigators to have a possible relationship to the study medication, and included confusional state, urge incontinence and depression in one patient, cholecystitis acute and cholelithiasis in one patient, and dyspepsia in one patient. No remedial action was deemed necessary in these three patients who recovered from these AEs. The sponsor also assessed the causality of the SAEs. In this regard, four SAEs were considered to have a stronger relationship to the study drug compared with the assessment of the investigator. A hypertensive crisis and epilepsy attack in two patients were assessed as possibly related, whereas arterial hypertension and abdominal pain in two other patients were assessed as unlikely related to the study drug. As a result, 30 events in 14 patients were considered by the sponsor to have a possible relationship with study medication. Overall, treatment was discontinued for four patients with SAEs that were considered causally related to the study drug.After 6 and 12 months, the majority of the clinical laboratory values were normal. No clinically relevant changes in vital signs were observed during the study and ECG abnormalities were isolated.A total of 258 patients (80.1%) of the 322 who were randomised in the double-blind phase entered the extension study and received the fixed combination oxycodone PR/naloxone PR. The majority of these patients  completed the study. Of the 31 patients (12%) who discontinued the study, 9 (3.5%) did so through choice, 4 (1.6%) did so because of administrative error and 3 (1.2%) were lost to follow up . The cauPatients were 58.4 years in average, with 102 (39.5%) male and 156 (60.5%) female patients . The aven = 258), the mean BFI score (±SD) fell from 35.6 ± 27.74 at baseline (end of the double-blind study) to 20.6 ± 24.01 by 12 months, which represents an average 15-point reduction in BFI score (n = 250), in which the mean BFI score (±SD) fell from 35.6 ± 27.74 at baseline to 20.4 ± 23.68 at 12 months.The BFI score decreased throughout the extension phase. After 12 months of treatment with oxycodone PR/naloxone PR, in the LOCF analysis  fell from 42.7 ± 28.61 at the start of the extension phase to 26.1 ± 23.31 after 1 week of treatment (Visit 10), compared with only a slight reduction from 28.7 ± 25.15 to 26.2 ± 25.09 respectively, for those who had received oxycodone PR/naloxone PR in the double-blind phase. From Week 1 onwards, the BFI fell at similar rates in the two groups  for the item ‘average pain over the last 24 h’ was 3.3 ± 1.77, which was similar to the combined mean pain score for the two treatment arms at the end of the double-blind phase (3.5 ± 1.87). The mean average pain scores (±SD) were similar at all visits in the extension phase, being 3.1 ± 1.94 at 12 months. During the first 7 days of treatment, 75.3% of patient days were free from use of analgesic rescue medication, and the mean (±SD) daily rescue dose was low (2.51 ± 4.60 mg). The mean (±SD) daily supplemental analgesic use was also low (0.4 ± 0.64) during Days 1–7 of the extension phase. For the remainder of the study, requirement for other opioid analgesic medication (at the investigator’s discretion) was reported by 83 patients (32.2%). During the first 7 days of the study, 24 patients (9.3%) received laxatives on a regular basis and after the first week, only 22 patients (8.5%) reported regular laxative intake.A total of 211 patients (81.8%) experienced an AE during the extension phase . Fewer tGastrointestinal AEs occurred in 94 patients (36.4%), with 40 (15.5%) experiencing constipation and 18 (7.0%) experiencing diarrhoea. There was one serious GI AE, although this case of abdominal pain was considered as unlikely to be related to treatment with oxycodone PR/naloxone PR. For patients who experienced constipation or diarrhoea, only 29 (11.2%) and 7 (2.7%), respectively, were classed as possibly, probably or definitely being related to treatment. Only three patients (1.2%) experienced an episode of severe diarrhoea. Treatment for constipation was given to 28 (10.9%) subjects but in no case did constipation result in treatment discontinuation, dose interruption or dose reduction.One patient died during the study, but this was because of necrotising faciitis and was not related to treatment. A further 26 patients (10.1%) experienced 35 SAEs. Overall, 11 events in eight patients were considered by the investigators to have a possible relationship to the study medication and included cardiovascular disorder, ECG and angina pectoris in one patient, haematuria and bladder disorder in one patient, and atrial fibrillation, amnesia, non-cardiac chest pain, myocardial infarction, abdominal pain and cerebrovascular accident (one patient each). Only one SAE (amnesia) was considered possibly related to the study drug, for which treatment was discontinued. Treatment was also discontinued in the patient with the cerebrovascular accident. All eight patients recovered from the AE, although the patient with bladder disorder recovered with sequelae.post hoc by means of two-sided TOST analyses on difference in  for basophils, eosinophils, total bilirubin and direct bilirubin, or ratio in . Abnormal blood pressure or liver enzyme levels were isolated. Changes in ECG were infrequent and isolated.Subjective Opiate Withdrawal Scale score remained stable in the extension study, with the mean (SD) score being 4.7 (5.68) after 1 week of treatment and 6.0 (6.36) at the end of the study (12 months). End-of-study results for haematology, blood chemistry and vital sign parameters were statistically equivalent to their respective start-of-study values, as shown In the study focusing on analgesic efficacy, the mean score for the item ‘average pain over the last 24 h scores and BPI-SF pain subscores were low and stable over 6 and 12 months, indicating that oxycodone PR/naloxone PR provides effective long-term analgesic efficacy. These results were supported by the BPI-SF sleep quality item and interference subscores, which correlated with the low pain scores, indicating the positive effect of oxycodone PR/naloxone PR on sleep and activities – an effect that was maintained throughout the extension phase.Following titration to an effective analgesic dose during the first 2 weeks of the extension study, the majority of patients remained on an oxycodone PR/naloxone PR dose comparable with that which they received in the double-blind study. There was no indication that the treatment that patients had received in the double-blind study influenced the dose increase after the first 2 weeks. Some patients did require an increase in dose; however, it is important to note that this increase in mean daily dose of oxycodone may reflect the natural progression of the underlying pain-causing condition, which is supported by the slight increase in dose observed during the 12-month extension phase. In addition, rescue medication intake was low, which could also represent an additional factor affecting the increase in study medication dose. A similar analgesic effect to that observed in the total study population was seen in the subpopulation of patients who received doses > 40/20 mg oxycodone PR/naloxone PR per day on > 7 days consecutively – mean pain scores were stable and comparable at all study visits throughout the extension phase. This also suggests that the long-term analgesic efficacy of oxycodone PR/naloxone PR was maintained at higher doses.In this study focusing on bowel function as the main efficacy measure, the mean BFI scores continued to improve over 52 weeks of treatment with oxycodone PR/naloxone PR. Interestingly, patients who had previously received oxycodone PR in the double-blind phase experienced a rapid reduction in BFI score during the first week of treatment with the fixed combination of oxycodone PR/naloxone PR. Following this, BFI scores decreased at a similar rate to those in patients who had received oxycodone PR/naloxone PR in the double-blind study. The improvement in OIC was achieved without negatively affecting the analgesic efficacy of the oxycodone PR component, as mean pain scores remained low and stable, and use of rescue medication was low throughout the study. This supports the results from the extension study focusing on analgesic efficacy.The results of these two extension studies show that the efficacy of the fixed combination of oxycodone PR/naloxone PR observed in the previous 12-week studies ,23, in tIn the analgesia study, the incidence of AEs in the extension phase (68%) was comparable with that in the double-blind study  when the longer observation period was taken into account . The mosThe incidence of GI AEs and nervous system disorders was the highest in the first 3 months of the analgesia study. In this sensitive phase, all subjects restarted opioid treatment with 20 mg oxycodone/naloxone, were uptitrated to their effective analgesic dose and started new analgesic co-medication (oxycodone IR as rescue medication). Throughout the next 9 months, the incidence of constipation consistently decreased, dropping from six subjects at 3 to 6 months to one subject at greater than 12 months. The incidence of constipation increased again to 12 subjects within 7 days after the end of oxycodone/naloxone treatment and the switch to a marketed product. In 11 subjects, constipation was assessed by the investigator as not related to study medication (2.9%). Therefore, the incidence of constipation related to study medication is reduced to 6.3%.n = 18) experienced SAEs that were not related to study medication. Of the eight SAEs considered to have a possible relationship with the study medication, only one was considered possibly related to the study medication (amnesia), and for which the treatment was discontinued and the patient recovered. Importantly, the incidence of diarrhoea was low, and SOWS sum scores were not exacerbated with oxycodone PR/naloxone PR.While 81.8% of patients experienced AEs in the bowel function study, only 48.4% of these events had a positive causal relationship to study medication; only 26 patients experienced SAEs, the majority of whom (Based on the AEs, clinical laboratory reports, and vital sign and ECG data, the long-term use of oxycodone PR/naloxone PR has a favourable tolerability profile. Furthermore, there was no indication of an increased risk of AEs in patients taking doses > 40/20 mg/day oxycodone PR/naloxone PR for > 7 days consecutively, compared with the total extension phase population.The study design allowed patients to be up-titrated to 80/40 mg oxycodone PR/naloxone PR per day and to take rescue medication. This ensured that patients received adequate pain relief similar to the usual practice of prescribing a dose of IR oxycodone, as needed, for pain. The efficacy measurements were those commonly used to evaluate pain in patients with chronic non-cancer pain and were consistent with other studies in this development programme. Moreover, the BFI ,32 and tOpioid-induced constipation is the most frequently reported AE experienced by patients receiving long-term opioid therapy, and can cause significant pain and discomfort. In many cases, this can be sufficiently severe to undermine the effectiveness of pain management and, therefore, negatively impact on patients’ QoL. The results from these studies provide evidence that the fixed combination of oxycodone PR/naloxone PR is a safe and efficacious agent for the long-term treatment of chronic pain. Mean scores for the item ‘average pain over the last 24 h’ and BPI-SF pain subscores remained low and stable throughout the 52-week study and were comparable with those observed at the end of the double-blind study , indicat


The aim of this study was to explore the intensity of post-arthroscopy knee pain during the first 24 hours, and to study the influence of pre-operative pain, tourniquet time and amount of surgical trauma on post-arthroscopy pain. In 78 male patients that underwent elective arthroscopic menisectomy or diagnostic arthroscopy of the knee, preoperative and post-operative pain were registered using the Visual Analogue Scale. Variance for repeated measures and for independent observations was analysed. Supplementary analgesia was required for 23% of the patients, more often in the recovery room and between 2 and 8 hours postoperatively. Of all factors analyzed, only time was statistically significant in determining the level of post-operative pain. Supplementary analgesia was required only in patients that underwent operative arthroscopy, and more often in patients with tourniquet time of more than 40 minutes. In conclusions, post-operative time is the most significant factor related to the post-arthroscopy knee pain. Knee arthroscopy is a very common procedure and very often is performed as day-case surgery. It seems that ambulatory arthroscopic surgery of the knee is preferred by the majority of properly selected and well informed patients . It has In an effort to provide an effective, safe and long lasting post-arthroscopy analgesia, several studies using different drugs and regimes have been published during the last two decades. Intra-articular administration of local anaesthetics has been widely used but some studies have questioned their efficacy -11. The Several clinical trials reported the effects on post-operative analgesia of various drugs or regimes and numerous factors have been implicated to influence post-arthroscopy pain: anaesthetic technique, residual effects of peri-operative analgesia, sensitivity of the methods for postoperative pain registration, pre-operative pain level, the amount of surgical trauma (i.e. diagnostic arthroscopy or arthroscopic surgery), the use and duration of tourniquet ex-sanguination, the experience of the surgeons, the sex of the patient and the post-operative activity level of the patients ,  22-26.The aim of this prospective study was to explore the true incidence and intensity of post-arthroscopy pain and the influencing factors without a specific regime for post-arthroscopy analgesia.In an effort to reduce confounding factors it was decided to include only male patients, treated by one surgeon, using one anaesthetic technique, the same post-operative activity level of the patients and no pre-emptive or intra-operative analgesia apart from Remifentanil. Therefore the variables in this study were the pre-operative pain level, the amount of surgical trauma and the tourniquet time.Male patients scheduled for elective knee arthroscopy, with normal knee radiographs, ASA I, that underwent diagnostic arthroscopy or arthroscopic meniscectomy participated in this study. The exclusion criteria were (a) previous knee surgery (b) chronic knee pain, or history of arthritis (c) daily intake of steroids (d) recent intake of non-steroidal anti-inflammatory drugs or opioids.All patients were instructed preoperatively in the use of the 10-cm Visual Analogue Scale (VAS) for pain, 0=no pain to10=the worst pain . Pre-opeAll operations were performed by the same surgeon (GID), under general anaesthesia using the same anaesthetic protocol. No pre-medication was used. General anesthesia was induced with Propofol 2 mg/kg, Remifentanil 0.1 μg/kg and Vecuronium 0.1 mg/kg, and maintained with Propofol 0.06 mg/kg/h and Remifentanil infusion as needed, with the patients breathing N2O 70% and O2 30% through endotracheal intubation. A pneumatic tourniquet was inflated at a pressure of 300 mm Hg in all patients, after leg elevation for 3 minutes.The patients were evaluated by VAS at 2,4,6,8,12,16,24 hours after surgery. In the recovery room patients received morphine 20 mg intravenously when the VAS exceeded 3 and this was registered. Postoperatively the patients commenced isometric quadriceps exercises as soon as they returned to the ward and mobilised on crutches when they felt comfortable. Supplementary analgesia - pethidine 0.5 mg/kg intramuscularly- was given at patients request and the time of administration was registered. All the patients stayed in the hospital for at least 24 hrs before discharge.Pain scores at 2, 4, 6, 8, 12, 16, 20 and 24 hours were analyzed in relation to type of arthroscopy (diagnostic or therapeutic), pre-operative pain level (POPL): Low (average VAS: < 3) / Middle (average VAS: 3-6) / High (average VAS: > 6), tourniquet time: Low (< 40 minutes) / High ( > 40 minutes) and supplementary analgesia.The statistical methodology included analysis of variance for repeated measures and for independent observations ,  29. St1).Seventy-eight male patients were included in the study. Sixty-five underwent arthroscopic meniscectomy and 13 had a diagnostic procedure (Table 1A).The average pain was higher during the first 2 hours, followed by a plateau until the 8th hour, decreased until the 16th hour and then reached again a plateau up to the 24th hour . It is worth noting that all patients were mobilized between the 6th and 8th hours post-operatively.Eighteen patients (23.1%) required supplementary analgesia, and seven of them received this analgesia twice. The supplementary analgesia was required more often in the recovery room, followed by the 8th and the 2nd postoperative hour . Supplementary analgesia was required more often in patients with middle POPL .Patients with middle pre-operative pain level (POPL) exhibit on average more post-operative pain than patients in the low POPL, and this difference was significant during the first 6 post-operative hours, while the ones belonging to the high POPL have a mixed post-operative pain behaviour (Table 3A). Supplementary analgesia was required only for the patients who underwent arthroscopic meniscectomy .Diagnostic arthroscopy caused on average less post-operative pain than arthroscopic meniscectomy, but the difference was not significant , . Supplementary analgesia was required more often in patients with long tourniquet time than in patients with short tourniquet time .Patients with low tourniquet time exhibit on average less post-operative pain compared to patients with high tourniquet time but again the difference was not significant , .The effect of time elapsed since the procedure is statistically significant in determining the level of post-operative pain . More specifically, the average pain demonstrates a downward trend as time passes  pre-operative pain level , (b) the type of procedure , and (c) tourniquet time .Furthermore, the interaction of time with supplementary analgesia and the three-way interaction among time, POPL and tourniquet time is statistically significant .Regarding the three-way interaction, we observe that within each POPL, the post-operative pain level is almost always higher when the tourniquet time is high. However, this difference varies according to time. The worsening effect of a prolonged tourniquet time on post-operative pain is experienced in the early period (up to the 8th hour) by patients with a low POPL, later (after the 16th hour) by those with middle POPL and between the 8th and the 24th hour by those with a high POPL.The mean post-operative pain is significantly affected by the fact that supplementary analgesia was given to some patients . More specifically, it is estimated that patients that were administered supplementary pethidine analgesia had a higher post-operative pain by 1.39 units provided that the other factors  remain the same.The primary aim of this study was to explore the true incidence and intensity of post-arthroscopy pain for 24 hours. The fact that the patients stayed in the hospital during the entire period of the study has the benefit of a more accurate registration of the pain scores and the required supplementary analgesia, and allows a better control of a similar postoperative level of patient activity .Our patients were not just instructed preoperatively in the use of the 10-cm VAS for pain as in most studies, but actually learned how to use this scale as they assessed their pre-operative pain. It has been suggested that patients who learn to assess their pain and communicate their analgesic needs will have more control over the dose and delivery of analgesic agents regardless of the route of administration .The anaesthetic technique and analgesics or NSAIDs used peri-operatively in particular, may affect the post-operative pain by residual analgesic effect ,  26. InThe influence of some factors that may affect the post-arthroscopy pain, such as the experience of the surgeons, the sex of the patient, and the post-operative activity level of the patients, was the same in this study. All operations were performed by the same surgeon, only male patients were included in the study, and by having the patients in the hospital the entire study period the patient’s postoperative level activity was similar.Only 23.1% of the patients in this study required supplementary analgesia. This is in agreement with recent studies where it was found that a significant proportion of patients have only very mild or mild after knee arthroscopic procedures ,  33-35.The post-arthroscopy pain intensity may be an important factor when the analgesic effect of various drugs or regimes is studied in clinical trials. The post-arthroscopy pain intensity may influence the sensitivity of methods for postoperative pain registration . It has The results of this study showed that the effect of time is the only statistically significant factor in determining the level of post-operative pain.The post-arthroscopy pain was found to be more pronounced during the first 8 post-operative hours. These findings should be expected since postoperative pain is at its peak immediately after surgery and becomes less severe with time .Although the need for supplementary analgesia was greater in the recovery room, and during the first 8 post-operative hours, our patients continued to experience some pain during the rest of the 24 hours period, indicating the need for analgesia for at least 24 hours.Some authors found that the pre-operative level of discomfort was the most significant predictor or determinant of post-operative discomfort ,  17. AlIn this study it was found that the post-operative pain was on average higher in patients with a middle pre-operative pain level (POPL) than in patients with a low POPL, and this difference was significant during the first 6 post-operative hours, while the ones belonging to the high POPL have a mixed post-operative pain behaviour. Nevertheless supplementary analgesia was required more often in patients in the middle POPL than in the other two groups.et al. (1992) [Joshi . (1992)  stated t. (1992) ,  8,  20. (1992) .Although the difference was not statistical, patients who underwent arthroscopic meniscectomy exhibit on average more post-operative pain than those in the diagnostic arthroscopy group, and supplementary analgesia was required only in patients that underwent arthroscopic meniscectomy.Previous studies have found that post-arthroscopy pain is not related to the use of a tourniquet ,  22 or In conclusion, according to the results of this study, the only significant factor related to the level of post-arthroscopy pain was the postoperative time elapsed since surgery. Statistical analysis of the post-operative scores did not show significant difference for the other factors, but supplementary analgesia was required (a) only in patients that underwent arthroscopic meniscectomy, (b) mostly when the tourniquet time exceeded 40 minutes and (c) the preoperative pain level was in the middle range.


Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended for multimodal postoperative pain management. We evaluated opioid-sparing effects and rehabilitative results after perioperative celecoxib administration for total knee arthroplasty.This was a prospective, randomized, observer-blind control study. Eighty patients that underwent total knee arthroplasty were randomized into two groups of 40 each. The study group received a single 400 mg dose of celecoxib, one hour before surgery, and 200 mg of celecoxib every 12 hours for five days, along with patient-controlled analgesic (PCA) morphine. The control group received only PCA morphine for postoperative pain management. Visual analog scale (VAS) pain scores, active range of motion (ROM), total opioid use and postoperative nausea/vomiting were analyzed.Groups were comparable for age, pre-operative ROM, operation duration and intraoperative blood loss. Resting VAS pain scores improved significantly in the celecoxib group, compared with controls, at 48 hrs  and 72 hrs  after surgery. Active ROM also increased significantly in the patients that received celecoxib, especially in the first 72 hrs . Opioid requirements decreased about 40% (p = 0.03) in the celecoxib group. Although patients suffering from post-operative nausea/vomiting decreased from 43% in control group to 28% in celecoxib group, this was not significant (p = 0.57). There were no differences in blood loss (intra- and postoperative) between the groups. Celecoxib resulted in no significant increase in the need for blood transfusions.Perioperative celecoxib significantly improved postoperative resting pain scores at 48 and 72 hrs, opioid consumption, and active ROM in the first three days after total knee arthroplasty, without increasing the risks of bleeding.Clinicaltrials.gov NCT00598234 Surgical trauma induces the synthesis of prostaglandins, which sensitize the peripheral nociceptors . Non-steCelecoxib is a selective cyclooxygenase (COX)-2 inhibitor and an effective analgesic for acute postoperative pain . AlthougThis study was performed (from September 2006 to March 2007) after institutional IRB approval. All TKA surgeries were performed by one surgeon (Ching-Chuan Jiang). Under a randomized, prospective, observer-blind study design, subjects were sorted by random numbers into two groups. Inclusion criteria for this study were primary osteoarthritis and an age over sixty. Exclusion criteria for this study were rheumatoid arthritis, end-stage renal disease , previous cerebral vascular accident history, peptic ulcers, recent myocardial infarction (within 1 year), and allergy to sulf, NSAIDs, or morphine. The National Taiwan University Hospital and National Institutes of Health have approved the study and all participants will provide written informed consent.The study group (n = 40) received 400 mg oral celecoxib at about 1 hr prior to surgery, and 200 mg every 12 hrs, along with PCA morphine, over the first five post-operative days. The control group (n = 40) received PCA morphine over the same postoperative period.All patients had spinal anesthesia and hemovac drain tubes inserted for postoperative blood loss evaluation. Patient data included gender, age, range of motion (ROM), pain scores, blood loss and procedure duration. Pain scores were measured using a visual analog scale (VAS), with 0 indicating no pain and 10 indicating the worst imaginable pain . Pain scThe primary endpoint was VAS pain reduction through perioperative celecoxib administration. Group sample sizes of 40 and 40 can achieve 85% power in the detection of a difference of one point on a 10-point VAS scale, which is equivalent to the minimal clinical significant difference on the VAS scale , in a dePatient demographics were analyzed by ANOVA or Chi-squared test. Postoperative pain scores, postoperative ROM, morphine doses, blood loss, and PONV rates were analyzed by Mann-Whitney test. Group differences in pain intensity and ROM were also analyzed by repeated measures ANOVA test. Significance was defined as p < 0.05.From Sep 2006 to March 2007, ninety-seven patients that fulfilled inclusion criteria received elective TKA surgery by the senior author (Ching-Chuan Jiang) at the author's institute. Fifteen patients were excluded . Two patients suffered from epigastralgia, without tarry stool, during the study and were also excluded, leaving a total of eighty patients. They were randomized into two groups. There were no significant differences between them in age, preoperative ROM, preoperative pain scores, operation duration, and intraoperative blood loss Table .The celecoxib group showed less postoperative VAS pain at rest than the control group at 48 hrs (p = 0.03) and 72 hrs (p = 0.02) after TKA surgery Fig . The celCelecoxib significantly improved postoperative knee ROM, especially during the first three days  , postoperative blood loss through Hemovac drain tubes (544 vs 511 ml), and postoperative blood transfusions (3.85 vs 3.93 units) between the celecoxib group and controls.In our study, we found that perioperative administration of celecoxib, a selective COX-2 inhibitor, reduced postoperative VAS pain scores at rest and decreased morphine usage while providing better ROM rehabilitation results. Perioperative administration of celecoxib did not increase perioperative bleeding or blood transfusion amounts.Coxibs are effective analgesics for post-operative pain -22. To tNSAIDs are known to decrease opioid consumption by 30–50% ,7,24. InPrevious studies have shown that conventional preoperative non-selective NSAIDs increase bleeding risks ,25. Conv2 [Selective COX-2 inhibitors may be a better choice for multimodal analgesia than conventional non-selective NSAID. Selective COX-2 inhibitors may have better gastrointestinal tolerance and less risk for cardiovascular events. It's suggested that selective COX-2 inhibitors have less gastrointestinal toxicity than conventional non-selective NSAIDs ,29. It's2 . It has 2 . TherefoOne limitation of this study is the lack of a true placebo group. Placebo response has been observed in up to 30% of patients that undergo surgery. However, placebo usage may present ethical concerns in the postoperative care of TKA surgery; we therefore adopted an active-control trial design that compared celebrex treatment to the standard therapy (PCA morphine) at our institute. Another limitation was the limited research period. We recorded data for only the first seven days. Although we demonstrated that celecoxib had better rehabilitative results in the first week than PCA morphine, long-term efficacy is still in question. There may be many reasons for the resting VAS scores to not have reached significance until 48 hours after surgery. One possibility is that the true difference does exist and that a larger sample size is needed to draw out the difference, despite that we had shown that the sample size in our study had adequate power.Perioperative celecoxib, combined with opioids, is an effective and safe regimen for pain control in TKA patients. Perioperative celecoxib can significantly decrease postoperative pain scores at rest and opioid use, while improving postoperative ROM results for TKA surgeries. Considering the benefits, we suggest celecoxib for multimodal analgesia.The authors declare that they have no competing interests.Y–MH, C–MW, W–PL, and C–CJ were responsible for the design of this study. L–CH was the study evaluator and recorder. C–TW provided analytical support. Y–MH, C–TW and C–CJ prepared the writing of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


The objective of this study (DO-118X) was to characterise the pain control achieved with long-term repeated dosing of OROS® hydromorphone in patients with chronic cancer pain.Opioid analgesics have proven efficacy in the short-term management of chronic cancer pain, but data on their long-term use is more limited. OROS® hydromorphone was administered to 68 patients with moderate-to-severe chronic cancer pain, who had successfully completed a short-term equivalence study, and whose pain was controlled with a stable dose of medication . Patients were started on the dose of OROS® hydromorphone equivalent to the opioid dose on which they achieved dose-stable pain control in the equivalence study; dose adjustments were made as necessary and breakthrough pain medication was permitted. Efficacy was assessed with the Brief Pain Inventory (BPI) and patient and investigator global evaluations of treatment effectiveness. No formal statistical analysis was done.In this multicentre, phase III, open-label, single treatment, 1-year extension study, OROS® hydromorphone was 43.7 (28.14) mg/day. All scores were maintained at a mild to moderate severity throughout the study; however, BPI scores for pain at its worst, pain at its least, pain on average, pain right now, and pain relief were slightly worsened at end point compared with baseline. Mean BPI pain interference with daily activities and patient and investigator global evaluation scores also remained generally stable. Treatment effectiveness was rated as fair to good throughout the study. The most frequently reported adverse events were nausea , constipation , and vomiting .The mean (standard deviation) duration of exposure to study medication was 139 (129.9) days and the mean (standard deviation) average daily consumption of OROS® hydromorphone can be beneficial in the continuing management of persistent, moderate-to-severe cancer pain.The results of this extension study suggest that long-term repeated dosing with once-daily OROS Chronic severe pain is a common complication of cancer . Opioid ® hydromorphone  is a novel, once-daily, CR formulation of oral hydromorphone which uses a patented Push-Pull™ osmotically-controlled pump system  to release hydromorphone in a continuous monophasic manner for up to 24 hours. It is an important treatment option for patients with chronic pain as it provides consistent pain relief, convenient once-daily dosing, and can reduce opioid-related adverse effects and breakthrough pain associated with peak and trough fluctuations in plasma concentrations typically seen with IR formulations ) duration of exposure to study medication was 139 (129.9) days . The mean (SD) average daily consumption of OROSAt the beginning of the study, 8 patients received doses of ≥ 64 mg ; at end point, this increased to 20 patients .® hydromorphone. Table Pain control was maintained during the year with repeated once-daily dosing of OROS® hydromorphone and CR morphine.Mean BPI pain interference scores remained stable during the study, increasing only slightly from baseline to end point for each of the QoL items . BPI pain interference scores at baseline and end point for all patients are shown in Figure Mean patient and investigator global evaluation scores of overall treatment effectiveness also remained generally stable from baseline to end point Figure . Treatme® hydromorphone in the previous equivalence study and 29 patients (87.9%) who had received CR morphine. The most commonly reported AEs, with at least a 10% incidence, were nausea, constipation, vomiting, anaemia, peripheral oedema, dyspnoea, asthenia, disease progression, somnolence, and urinary tract infection. AEs reported in at least 5% of patients are shown in Table Overall, 63 patients (92.6%) reported AEs during the study, 34 patients (97.1%) who had received OROS® hydromorphone in the previous equivalence study and 16 patients [48.5%] who had received CR morphine). Of the most common AEs (= 10% incidence in a treatment group), some cases of nausea (11/24), constipation (18/22), vomiting (7/15), and somnolence (6/8) were considered related to study treatment. In addition, all cases of dry mouth were considered related to study treatment as well as several cases of confusional state, anxiety, and insomnia. None of the reports of diarrhoea or headache was considered related to study treatment.Most AEs were considered mild or moderate in severity, approximately 25% of all reported AEs were considered severe. Severe AEs were reported by 43 patients (63.2%), and severe AEs considered related to study treatment were reported by 11 patients (16.2%). 36 patients (52.9%) reported AEs that were considered related to study treatment  were reported by 32 patients, the majority of which were considered unrelated or unlikely to be related to study medication. 8 patients (11.8%) had SAEs that were considered to be possibly, probably, or definitely related to study treatment; these were: nausea and vomiting in 2 patients; dehydration, malaise, nausea (2 episodes), pain, and vomiting (2 episodes) in 1 patient; faecaloma in 1 patient; dizziness and nausea in 1 patient; restlessness in 1 patient; suicide attempt in 1 patient; and confusional state, hallucination, and pain in 1 patient. The faecaloma and suicide attempt events were considered to have a definite relationship to study treatment.9 patients (13.2%) had at least 1 AE that led to early discontinuation of the patient from the study; the majority of these were considered probably related to study medication.No clinically significant changes in any of the other safety measures occurred during the study. The most commonly used concomitant medications were the anti-inflammatory dexamethasone , the antiemetic metoclopramide , and the diuretic furosemide .Chronic cancer pain is a highly prevalent condition. Although opioid analgesics are known to be effective for chronic moderate-to-severe pain in the short-term, data on their long-term use is more limited. Understanding the effects of long-term exposure to opioids has become particularly important in recent years as the life expectancy of cancer patients increases owing to improved oncological treatments.® hydromorphone may be particularly well suited to the long-term management of cancer pain because it provides consistent plasma concentrations, sustained analgesia, and convenient once-daily dosing. In this open-label, single treatment extension study, OROS® hydromorphone was administered to patients with moderate-to-severe chronic cancer pain who had successfully completed a previous short-term equivalence study and whose pain was controlled with a stable dose of medication. Prior opioid therapy in the previous equivalence study (OROS® hydromorphone versus CR morphine) did not affect clinical outcomes such as efficacy or safety in this study.CR opioid formulations are advocated for the management of chronic cancer pain because they can provide more consistent, around-the-clock pain relief with decreased dosing frequency (once- or twice-daily). OROS® hydromorphone is maintained for up to 1 year with repeated once-daily dosing in patients with chronic cancer pain. This was shown using a variety of measures, including the BPI items pain at its worst, pain at its least, pain on average, current pain, and pain relief, and patient and investigator global evaluations of overall treatment effectiveness. Throughout the study, pain scores were maintained at mild to moderate levels. These results support short-term studies of OROS® hydromorphone for chronic cancer pain [® hydromorphone or CR morphine in the previous equivalence study. Although most efficacy measures were maintained at similar levels throughout the study, for most measures, the mean scores were slightly worsened at end point compared with baseline. However, owing to the progressive nature of the disease, some deterioration is to be expected.The results demonstrate that pain control achieved with OROScer pain -22,34. Icer pain ,48. Ther® hydromorphone compared with CR morphine in the equivalence study; however, the clinical significance of this difference is questionable because of the degree and nature of AEs expected in an advanced cancer population. In addition, the majority of AEs were mild or moderate in severity. 19 patients died either during or after the study. There were slightly more deaths in patients treated with OROS® hydromorphone compared with morphine in the previous equivalence study; however, all deaths were considered unrelated or unlikely to be related to study treatment. The occurrence of these deaths was not unexpected given the severity of patients' conditions and the progressive nature of the disease. Of the 32 patients who reported other SAEs, the majority of the events were considered unrelated or unlikely to be related to study treatment. 8 patients had SAEs that were considered to have a possible, probable, or definite relationship to study treatment. 9 patients reported AEs that led to early discontinuation from the study, and most of these AEs were considered probably related to study treatment. In conclusion, OROS® hydromorphone was found to be safe and reasonably well tolerated in this extension study.The most commonly reported AEs, with an incidence of at least 10%, were nausea, constipation, vomiting, anaemia, peripheral oedema, dyspnoea, asthenia, disease progression, somnolence, and urinary tract infection. These are events typically seen with the use of strong opioids or in a chronic cancer pain population. Slightly more AEs overall and AEs considered related to study treatment were reported in patients who had previously received OROSThere are a number of limitations of this study, which may affect the interpretation of the results. This was an open-label, uncontrolled study, so the results cannot be directly compared to either no therapy or other opioid therapies. A large number of patients  did not complete the study. However, this is not unexpected given the severity and progressive nature of the disease; in fact, a large number of patients did not complete the study owing to death (n = 15) and progression of disease (n = 14). Dropouts due to lack of efficacy were uncommon (n = 8), but were to be expected given the progression of cancer. A further limitation was that no formal statistical analyses were done on the data. This was an open-label, single treatment arm trial mainly assessing the safety of long-term usage and secondary maintenance of efficacy; therefore, all analyses were done descriptively. End point was calculated using the LOCF method, a method that involves extrapolating the last observed measurement for the patient. This method was necessary because the study involved multiple visits and a critically ill patient population, and therefore a high number of dropouts was expected.® hydromorphone for relief of cancer pain, which may be applicable to clinical practice. It also suggests that conversion from previous opioid therapy to OROS® hydromorphone is feasible without loss of pain control. The effective morphine to hydromorphone conversion ratio varies from 4:1 to 8:1 in different publications [® hydromorphone is maintained to some extent for up to a year, and the study will be useful in the development of other long-term studies of OROS® hydromorphone.In spite of these limitations, this study has provided useful insights into the effectiveness of the long-term use of OROSications ,33,49-53ications ,34,43-46® hydromorphone is beneficial in the management of persistent, moderate-to-severe pain in patients with cancer.The results of this open-label, single treatment, extension study shows that long-term treatment with OROSALZA Corporation, that manufactures the drug, funded the current study; Johnson and Johnson Pharmaceuticals also contributed some funds for the editing of the current manuscript. MH was a paid advisor for Janssen-Cilag.MH and AT were investigators in this study and were involved in revising this manuscript for important intellectual content. JT contributed to the analysis of the study and reviewed the manuscript.The pre-publication history for this paper can be accessed here:


The neurovascular conflict in trigeminal neuralgia is an intractable condition; medical treatment is usually of long duration and can be annoying for both patients and clinicians.This prospective study was designed to assess the outcome of microvascular decompression (MVD) in patients with more than 3 years' history of intractable idiopathic trigeminal neuralgia (TN) and poor response to drugs.Twenty-one patients  with intractable idiopathic TN (group 1) underwent MVD and were followed up for 2 years. Group 2 (n = 15), which included 6 females and 9 males, received pharmacotherapy. The outcome responses of pain relief were evaluated using a 10-cm visual analog scale (VAS) and the Barrow Neurological Institute (BNI) scoring system. The patients' morbidity was recorded as well.P>0.5), while 53.3% (n = 8) of the subjects in group 2 showed poor response with pharmacotherapy over the same period of time and many patients experienced drug intolerance that had statistical significance (P<0.01).All patients fulfilling the inclusion criteria were offered MVD surgery. Freedom from pain was achieved immediately after surgery in 95.2% (n = 20) of patients in group 1, and 90.5% (n = 19) had sustained relief over the follow-up period. There were no statistical significance recurrences or surgical complications in group 1 (Early MVD in TN can help patients avoid the side effects of drugs and the adverse psychological effects of long-term pharmacotherapy and prolonged morbidity. Idiopathic trigeminal neuralgia (TN), or tic douloureux, is a painful condition affecting the face. It is commonly unilateral and is characterized by brief attacks of lancinating neuropathic pain over the face that lasts from several seconds up to 2 min; it may either be provoked or may occur spontaneously. TN pain is limited to the distribution of one or more of the divisions of the trigeminal nerve, with the maxillary division being involved in 17% of cases, the mandibular in 15%, and both branches in 32%. TN never spreads across the midline nor does it ever present on both sides of the face simultaneously.[et al. the annual incidence of TN is 4.3/100,000 and the prevalence is 15.5/100,000. There is no significant sex difference, the female/male ratio being 1.5/1. The familial type of TN presents earlier in successive generations and behaves like a disease with autosomal dominant inheritance with variable penetrance.[The peak incidence of TN occurs in the fifth to seventh decades, with 90% of cases starting after the age of 40. It is almost never seen before the third decade unless it is associated with multiple sclerosis.[It is suggested that unrelieved vascular compression of the trigeminal nerve entry zone initiates a focal demyelination that causes firing in the trigeminal primary afferents, which is enhanced by impairment of the inhibitory systems in the trigeminal brainstem complex.7 It has This prospective study aimed to assess the long-term outcome of microvascular decompression (MVD) surgery and to compare it with pharmacotherapy in patients with idiopathic trigeminal neuralgia.This prospective study, a collaborative effort by Mansoura University Hospital in Egypt and Sebea Military Hospital in Libya, was conducted from June 2005 to September 2008 and enrolled 36 patients with a history of intractable idiopathic trigeminal neuralgia. The patients were divided into two groups: Group 1 included 21 patients who underwent MVD with 2 years' follow-up; group 2 included 15 patients who received drugs and refused MVD surgery.A detailed history was taken from all subjects, after which clinical examination and routine laboratory tests were done; the investigations included complete blood count, blood urea, serum creatinine, fasting blood sugar, serum potassium, serum sodium, serum calcium, serum phosphorous, liver function tests, ESR, and antinuclear antibody test .Magnetic resonance imaging (MRI) of the whole brain, with particular attention paid to the region of the pons, was done for all subjects in both groups to rule out any mass lesion that could explain the occurrence of the pain. An MRI of the brain was also done in the first postoperative week for group 1 patients to exclude any complications.All patients were followed up after surgery in the outpatient clinic for 2 years using a 10-cm visual analog scale (VAS) and the Barrow Neurological Institute (BNI) scoring system. The presence of residual pain and postoperative complications were documented. Symptom relief was assessed by comparison with the preoperative symptoms.We used the 10-cm VAS and the BNI scoring system for evaluating pre- and postoperative pain in all patients.–11Using the 10-cm VAS we classified response to treatment as follows[‘Excellent’ - if the patient indicated no pain‘Failure’ - if the patient indicated the worst pain‘Good’ - if the patient indicated improvement in painThe BNI scoring system was used to label the degree of pain relief as follows:Grade I - no pain and no medication requiredGrade II - occasional pain and no medication requiredGrade IIIa - no pain and continued use of medications requiredGrade IIIb - some pain, which was adequately controlled on medicationGrade IV - pain improved but not adequately controlled on medicationGrade V - no pain relief whatsoeverIf the patient had grade IV or V symptoms after surgery they were labeled as showing ‘poor response,’ those who had grade III pain relief were considered as showing ‘good response,’ and those who had grade I pain relief were considered as showing ‘excellent response.’On the basis of both scores, the clinical outcome was plotted as ‘excellent’ if there was total absence of symptoms, as ‘good’ if some improvement of the symptoms was observed, and as ‘failure’ if the preoperative clinical status was unaffected or had become worse.The surgical approaches were individualized for every patient according to the anatomic and pathological interactions identified on preoperative imaging. After induction of general anesthesia, the patient was positioned in the prone, lateral decubitus, sitting, or supine position, depending on the surgeons' preference. Then a retromastoid subocciptal craniotomy was performed. The trigeminal nerve was examined microsurgically for vascular compression at or near its brainstem entry zone. Complete decompression of the trigeminal nerve was achieved using Teflon, autologous muscle tissue, or a tentorial sling.–15P-value < 0.05 was considered statistically significant. All data were expressed as mean ± standard deviation (SD) or patients number (n) and percentage (%) as appropriate.The demographic, clinical, and technical data were collected using a ‘data collection form’ and entered into a computerized database before statistical analysis. Continuous variables were compared using analysis of variance for repeated measures. The 36 patients enrolled in this study were divided into two groups: group 1 included 21 subjects  with a mean age of 50.9 ± 7.75 years (range 40-70 years); group 2 included 15 patients  with a mean age of 53.3 ± 8.87 years .The pain scoring systems that we used identified ‘severe pain’ in 90.5% of the patients in this study. Subjects in both groups reported that the pain caused marked limitation in their daily activities and that they were dissatisfied because of the side effects associated with drug therapy.In 18 patients, the pain disappeared on the first postoperative day; the rest of the patients reported gradual reduction of pain within 4 days of surgery. There was no recurrence throughout the 2-year follow-up period, except in one patient in whom no definite aberrant vessels were identified. This patient developed mild to moderate recurrent facial pain 1 year after surgery but the symptoms improved with a low dose of carbamazepine (400 mg per day).Although the TN pain completely disappeared in all patients, six of them developed facial numbness after surgery; treatment was not required in any of the cases. Our final surgical results show that 17 patients had ‘excellent’ response and four had ‘good’ response; no ‘poor’ outcome was recorded. There were no major complications following surgery, apart postoperative surgical wound infection in two patients that improved without any residual consequences after an intensive course of antibiotics.n = 13), the anterior inferior cerebellar artery (AICA) in 9.5% (n = 2), and the transverse pontine vein in 19.1% (n = 4); no definite cause was identified in 9.5% (n = 2) of cases [In our series, the vessels identified during surgery as causing compression were the superior cerebellar artery in 61.9% .Regular follow-up was done using the VAS and BNI scales every 3 months and revealed that all patients had excellent or good response postoperatively. After 12 months, all but one patient continued to report excellent response, with no recurrence of pain; the lone exception was a patient who required treatment with carbamazepine (400 mg/day) for an additional 22 months; this patient's pain was well controlled with this low dose of carbamazepine. In this study, no major complications resulted from MVD, apart from temporary hearing loss in three patients; in all of them hearing returned to normal after 4–6 months without any statistical significance hearing loss (n = 8) reported poor response with pharmacotherapy over the same period of time; patients also experienced drug intolerance (P < 0.01) [In group 2, 53.3% ( < 0.01) .et al.[MVD, in posterior fossa compression syndromes, has high safety and a low morbidity rate. In this study, the vascular loop compression at the root entry zone was the commonest cause of TN. Compression in this area initiates focal irritation, demyelination, and consequent devastating pain. Similar findings have also been reported by Tomasello et al.et al.[In nineteen (90.5%) MVD patients vessel compression of the trigeminal nerve was documented either pre- or intraoperatively. Two cases who were clinically suspected to be idiopathic TN had good response postoperatively. These results are comparable to that reported by Kabatas et al.On the basis anatomic studies, the transverse pontine vein is hypothesized to be the vein that is most frequently aberrant. This vein, which drains into Meckel's cave from the medial side, is usually close to the superior or inferior surface of the trigeminal nerve, just facing Meckel's cave. Missing the venous compression site might lead to a poor surgical outcome. A meticulous understanding of the venous anatomy around the trigeminal nerve and Meckel's cave may help surgeons to recognize offending veins or arteries accurately.–23In two cases, there was no definite vascular compression. This could be explained by the patients' head position, which may have separated the blood vessels from the nerve during the operative procedure. We therefore preferred to use Teflon for nerve protection.We do not recommend surgical re-exploration in cases that do not respond satisfactorily. Such re-exploration carries a 30% risk of complications such as hearing loss and facial weakness. In the cP > 0.05). The short duration of the conductive-type hearing loss was due to avoidance of cerebellar retraction during surgery. This finding is consistent with the results from other studies on MVD, which have reported death due to cerebellar hemorrhage or infarction in 1%, intracranial hemorrhage in 2%, permanent hearing loss in 3–8%, temporary hearing loss in 21%, and sensory loss in 5–31% patients.[In three cases, there was short-term hearing loss secondary to accumulation of fluid in the mastoid air cells (as detected by postoperative MRI); these patients regained their hearing after 4–6 months without any statistical significance residual patients.20P > 0.05.The current study revealed favorable outcomes that may be due to the stringent selection criteria  that werOur results  are simiPatients in whom MRI/MRA could demonstrate an abnormal vascular loop around the trigeminal nerve at the root entry zone usually benefitted from MVD, and this can be considered the ‘gold standard’ surgical procedure in such cases as it offers the best long-term cure rates. Outcome of MVD has also been reported to vary with the case load of the operating surgeon.23Other therapy modalities, such as acupuncture, extracranial peripheral denervation, percutaneous radiofrequency thermocoagulation, glycerol trigeminal rhizotomy, balloon compression, and gamma knife radiosurgery, show high rates of recurrence and only short-lasting freedom from pain. These modalities are therefore suitable only for those who are medically unfit for surgery or those patients who, for some reason, have a short life expectancy.25et al. and Lee et al. mentioned that evidence from intraoperative documentation reveal that 80.8% of cases of compression are due to arterial compression and mostly due to the superior cerebellar artery, while 19.1% are venous compressions;[Matsushima ressions;23 these ressions;.et al. in 1981 who used carbamazepine for 16 years and found that the drug was effective in 56% of patients, though 19% experienced carbamazepine intolerance. Phenytoin's effectiveness decreases with time and less than 30% of patients continue to respond to treatment after 2 years.[et al.[In group 2, 46.7% of subjects had good response to drug therapy over the same period of time, though with the expected adverse effects of drug therapy . This is 2 years. Baclofens.[et al.28The cost of medical care for each patient was $500 a year. It was very difficult to assess the costs due to impairment of the activities of daily living and the number of working days lost. In comparison, the total cost of surgical treatment was almost $2500, with freedom from pain at least for the follow-up period in this study.In conclusion, although TN can be managed both medically and surgically, MVD is an option that can be considered for avoiding the side effects of drugs, the adverse psychological effects of long-term pharmacotherapy, and the problems posed by comorbid conditions.We accept that our study is underpowered. We tried to highlight the significance of early MVD in management of idiopathic TN. So, further adequately powered, multicenter trials are recommended.


Surrogate pain models have been extensively tested in Normal Human Volunteers (NHV). There are few studies that examined pain models in chronic pain patients. Patients are likely to have altered pain mechanisms. It is of interest to test patient pain responses to selective pain stimuli under controlled laboratory conditions.The Institutional Ethic Committee approved the study. 16 patients with chronic neuropathic radiculopathy and 16 healthy volunteers were enrolled to the study after obtaining informed consent. During electrical stimulation (150 minutes for volunteers and 75 minutes for patients) the following parameters were measured every 10 minutes:Ongoing pain: Visual Analogue Scale (VAS) and Numeric Rate Scale (NRS)Allodynia (soft foam brush)Hyperalgesia (von Frey monofilament 20 g)Flareth edition.For each endpoint, the area under the curve (AUC) was estimated from the start of stimulation to the end of stimulation by the trapezoidal rule. The individual AUC values for both periods were plotted to show the inter- and intra-subject variability. For each endpoint a mixed effect model was fitted with random effect subject and fixed effect visit. The estimate of intra-subject variance and the mean value were then used to estimate the sample size of a crossover study required to have a probability of 0.80 to detect a 25% change in the mean value. Analysis was done using GenStat 8Each endpoint achieved very good reproducibility for patients and NHV. Comparison between groups revealed trends towards:Faster habituation to painful stimuli in patientsBigger areas of hyperalgesia in patientsSimilar area of allodynia and flare The differences demonstrated between patients and NHVs suggest that the electrical stimulation device used here may stimulate pathways that are affected in the pathological state. Experimental pain models are key tools for improving our understanding of pain mechanisms and play an increasingly important role in providing early evidence of clinical efficacy, evaluating new analgesic compounds and establishing a link between preclinical and clinical pain research. Assessment of clinical pain presents a unique challenge compared to other major health conditions, such as heart disease or cancer, which can be detected by objective biological measurements, where the diagnosis of chronic pain depends upon subjective reports by patients on the presence and intensity of pain. However, comparable reports on sensory attributes cannot be obtained from laboratory animals without language skills .The need for increased translational research in the field of pain research was highlighted recently following the development of the 'selective substance P receptor antagonist class' which was efficacious in a wide range of animal models, but failed to alleviate pain in patients ,3. UltimThe ultimate goal of modern pain assessment is to obtain a better understanding of mechanisms involved in pain transduction, transmission and perception under normal and pathophysiological conditions . SurrogaThere is a long and well-documented history of electrically induced pain, sensitization and flare -9. NeverNeuropathic patients are already suffered from altered pathways and central sensitization. Our hypothesis is that the sympathology may be localized in some area or another. Global central sensitization is likely to produce abnormalities anyway within central nervous system which had never been explored beforeThe aims of this study were 1) to evaluate reproducibility, safety and tolerability of pain and sensitization produced by TDES in (a) patients with chronic lumbo-sacral pain with radicular neuropathic features and (b) Normal Healthy Volunteers (NHV) and 2) compare the differences in the pain endpoints of hyperalgesia and allodynia between those two groups.Two experiments one on patients and the other on NHV with similar experimental paradigm was performed. Each of them consisted of two identical sessions, at least one week apart, and was conducted to assess reproducibility and tolerability of TDES. 16 healthy volunteers were recruited for the first experiment and 16 patients suffering from lumbosacral pain with radicular neuropathic features were recruited for the second experiment. Subjects were seated comfortably in a reclining chair, with the forearms resting with the volar side up. Room temperature was controlled at 20 - 24 degree Celsius. The same investigator performed both sessions for each subject. The assessments for the NHVs study were performed by a single investigator (investigator 1); whereas the assessments for the patients study were performed by two different investigators: investigator 1 (same as for the NHVs study) assessed patients ID01 to ID06, ID13 and ID14, and investigator 2 assessed patients ID7 to ID12.After approval from the Institutional Ethic Committee 16 male NHVs  were recruited and 16 male patients  diagnosed with chronic lumbosacral pain with radicular neuropathic features were recruited. If English was not the subjects' first language, the investigator would assess their understanding of the process, and make a decision on whether they could give informed consent before entering them into the study. Informed consent was obtained from each volunteer.Chronic pain was defined as pain with intensity of at least 5 on the 0-10 Numeric rate Scale (NRS) scale with duration of at least 3 months. Diagnosis was based on expert opinion and neuropathic features were additionally confirmed by DN4 questionnaire  ,19. BecaA recently described High Voltage Pain Stimulator (HV-1) was used . HV-1 prElectric stimulation was applied to the non-dominant forearm via the High Voltage Pain Stimulator HV-1). At the beginning of each session the intensity of stimulation (number of pulses in the train) was gradually increased every 5 minutes over 15 minutes, targeting a pain rating of five on the 11-point numeric rating scale . This was done in order to take into account individual sensitivity to electrically evoked pain as this varies substantially across subjects. For the rest of the session  the electric intensity was kept constant. Throughout the stimulation the endpoints were measured every 5 minutes in the first 15 minutes and then every 10 minutes once the electricity intensity was constant. The paradigm of electric stimulation and measurements is graphically presented at Table . At the Four endpoints were measured:1. Ongoing pain. Throughout the duration of experiment subjects were asked to rate the pain sensation induced by electric stimulation using Numeric Rate Scale  and Visual Analogue Scale . Due to subjective character of pain intensity measurements two different, independent pain scales was used for better validation.2. Flare field. The size of the visual flare field was measured as a diameter of skin redness. The skin was observed, and diameter was measured in line parallel to the axis of the forearm. The diameter was expressed in centimeters.3. Allodynic field. The size of the allodynic field was measured as a diameter of brush evoked dynamic allodynia to a response to foam brush stimulation. The skin was gently brushed in two linear paths parallel to the axis of the forearm from distant starting points towards the stimulation site until the volunteer reported an increase in sensation related to brushing. Volunteers and patients reports this sensation as unpleasant . The applied force was higher than the published mean mechanical pain threshold (129 mN) on the hand in NHVs [4. Hyperalgesic field. The size of the pin-prick punctuate hyperalgesic field was measured as a diameter of pin-prick punctuate hyperalgesia  showed for some subjects sensitization on dorsal area of forearm making measurements on axis perpendicular to forearm very difficult.http://www.vsn-intl.com.For each endpoint, pain scores, visual flare, allodynia and hyperalgesia diameters, the average value over the 15 to 75 minutes-electrical stimulation period  was calculated and used as a summary measure; a mixed effect model with subject as random effect, and visit as fixed effect was fitted to each endpoint summary measure. Model assumptions were checked by plotting residual plots. The back-transformed ANOVA-adjusted means values for each group of subjects were derived together with the 95% confidence intervals based on the standard error of the mean. From each model, the estimates of intra-subject and inter-subject variances were obtained to assess endpoint reproducibility. Analysis was completed using GenStat 8th edition All data from the 16 male NHVs and the 16 patients were included in the analyses. Data for the second visit was missing for one NHV due to this subject moving to another city and for two patients, one due to repetitive non-compliancy with appointment times and the other due to technical error for the other.The stimulation was well tolerated by all subjects. Despite no physical contact between the electrodes and skin, some injury was created by the electric discharge but for most volunteers the injury was almost undetectable. One volunteer and two patients has obvious injury bigger than 1 mm and less than 2 mm. All injuries healed spontaneously in few days. Future studies could include skin microphotography for formal injury assessment.During the ramping-up period, the current intensity was increased until reaching a pain score of 5 on the NRS scale or until reaching the maximum current allowed, a current intensity of 4 Figure . OverallDuring the constant stimulation period, the intensity of pain gradually decreased, despite the fact that the current intensity remained constant, and after 75 minutes of electrical stimulation the pain scores were on average VAS ≥ 30 for NHVs and VAS ≥ 25 units for patients, and NRS>3 units for NHVs and NRS~2.5 units for patients.  in all volunteers upon electrical stimulation. The diameter of flare gradually increased, reaching a maximum at 50 minutes, and then gradually decreased independently of the electrical stimulation to disappear by 100 minutes post-stimulation Figure .In the present study, one NHV did not experience hyperalgesia and two patients experienced hyperalgesia only to a limited extend. Interestingly, one of these patients did experience a strong allodynic response, whereas the other one did not experience any. Overall the diameter of allodynia was within that of secondary hyperalgesia.Diameter static pin-prick hyperalgesia and dynamic brush allodynia followed a similar time course, gradually increasing and reaching their maxima in 35 minutes, achieving an almost plateau effect Figures , then grFrom the raw mean plots, the ANOVA-adjusted mean plots and the ANOVA model means and variance components estimates, there did not seem to be any evidence that the mean allodynic response over the 15-75 min period, and the inter- and intra-subject variabilities differed noticeably between NHVs  and patients  Figure .In contrast, applying the same analysis to the hyperalgesia data Figure  suggesteOver the last decade, it has been recognized that the traditional way of drug development (three phases) can not be sustained and a new two phase has been suggested. An exploratory phase where a proof of concept is required followed by a full development program. A validated model that can act as a surrogate marker, would be a useful step in making the exploratory program both efficient and meaningful . The usePreclinical animal models have provided many crucial insights in our understanding of pain mechanisms. Nonetheless, their predictive value has increasingly come to be questioned. In addition, relying totally on NHVs models rather than patients' models may lead to similar questionable predictability as prompted by animal models.These current studies have demonstrated that Transdermal Electric Stimulation (TDES) can produce, robust and highly reproducible data for ongoing pain, hyperalgesia and allodynia in NHVs and patients suffering chronic lumbo-sacral pain with radicular neuropathic features. Transdermal Electric Stimulation (TDES) was safe and well tolerated in both groups.TDES has produced the features of central sensitization that are associated with chronic neuropathic pain syndrome. The spread of the pain and hypersensitivity from the site of injury, the amplification if the pain beyond the peripheral nerve distribution and the brush evoked allodynia are all common manifestation of chronic pain and now recognized as a result of central sensitization .Hyperalgesia was the most reproducible endpoint in both NHV and patients in this study. Comparing the data of hyperalgesia induced in patients and NHV, our results seem to imply there is a significant difference between patients and NHVs in the size of hyperalgesia field, being smaller in patients. This interesting observation may be explained either by the fact that the nociceptive pathways in chronic pain patients have been modified, so the response to a further stimulation is reduced or by the chronic use of medications by patients can alter the extent of further sensitization. Group of patient was heterogeneous, not age-matched to volunteers which could have confounding the results.Allodynia was marginally less reproducible than hyperalgesia. It was postulated that the mechanisms of allodynia are distinct from the mechanisms of hyperalgesia[eralgesia. In thisOngoing pain was observed in both patients and volunteers with some fading. Several theories have been put forward for this phenomenon: depletion of neurotransmitters, habituation of nerve fibres, long-term depression [pression  and actipression . It is iAfter the stimulator was switched off, pain disappeared immediately. In contrast, the field of sensitization  was observed to decay gradually over a 30 minute period of post-stimulation. Interestingly, the decay of sensitization after switching off the stimulator was much slower in the patient group, which further indicates the involvement of the central sensitization processes (data was not shown).Visual flare was very similar for both groups of subjects. The production of a visible flare is believed to be strictly due to peripheral mechanisms; therefore it was not anticipated that a difference would be observed between NHVs and patients with neuropathic pain who are believed to suffer from an alteration occurring at the CNS level.Hyperalgesia and allodynia represent different features of central sensitisation. It appears that in this model particularly for patients rather than volunteers that the mechanism involved may be totally separate. As the result of that hyperalgesia differences appears between patients and between volunteers where allodynia as the separate pathway and a possible separate pathophysiological mechanism appeared to be different. This is an interesting finding from particularly this study, which shows the importance of analysing hyperalgesia and allodynia as separate and highlight potential differences between patient and volunteers.The multi modal nature of the response in this model may make it ideal for use in the early phases of drug development. Differences in time trends for pain, hyperalgesia, allodynia and flare suggests that this pain model would allow us to separately observe the mechanism involved in the above processes. The study design was to assess validity and reproducibility of TDES methodology. Sample size data need to be taken with caution for future drug evaluation studies for both: healthy volunteers and patients. Some pharmacological testing could require assessment of reproducibility on repeated administration of the same stimulus intensity. Table Pain is not a reflex; it is a perceptual experience with powerful emotional and motivational components. Like all sensory systems, attributes of pain such as intensity, quality, duration, location, and extension depend upon cerebral processing. This applies to both laboratory animals and humans. Chronic pain necessarily results from abnormal activity in pain transmission systems, perturbing a hyperactive/hypersensitive pain pathway. Experimental stimulation should have the potential to reveal some differences that could improve our understanding and facilitate new modalities for treatment .Pain is one of the therapeutic areas of greatest clinical need where there are few existing therapies and have the least well-validated models or surrogate markers. This is a first study which have tested the reproducibility and validity of transdermal electric stimulation pain model in both normal healthy volunteers and patients with neuropathic manifestation. This study has showed a very good reproducible data both in volunteers and patients with some subtle differences. The next option for utilizing this model will be use it for pharmacological drug development both for neuropathic and non-neuropathic pain medications.AUC: Area Under Curve; NHV: Normal Healthy Volunteers; NRS: Numeric Rate Scale; TDES: Transdermal electric Stimulation; PWM: Pulse Width Modulation; VAS: Visual Analogue ScaleThe authors declare that they have no competing interests.RL: contributed equally to: study design, carry out experiments, data analysis and drafting manuscript. He read and approved the final manuscript. JA: contributed equally to: study design, carry out experiments, data analysis and drafting manuscript. He read and approved the final manuscript. JG: contributed equally to: study design, carry out experiments, data analysis and drafting manuscript. He read and approved the final manuscript. KS: contributed equally to: study design, carry out experiments, data analysis and drafting manuscript. He read and approved the final manuscript. MH: contributed equally to: study design, carry out experiments, data analysis and drafting manuscript. He read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/10/5/prepub


The role of operation, particularly pancreaticojejunostomy, in the treatment of abdominal pain fromchronic pancreatitis is controversial, but relief of pancreatic duct obstruction may decrease the rate ofpancreatic organ failure. Our results over 6 years in 13 carefully selected patients suggest that pancreaticdrainage does relieve pain but is less effective in preventing pancreatic exocrine failure. Pain was theindication for operation in all patients.