Different research techniques indicate alterations in muscle tissue and in neuromuscular control of aching muscles in patients with chronic localized pain. Ultrasound can be used for analysis of muscle tissue dynamics in clinical practice.This study introduces a new muscle tissue sensitive ultrasound technique in order to provide a new methodology for providing a description of local muscle changes. This method is applied to investigate trapezius muscle tissue response – especially with respect to specific regional deformation and deformation rates – during concentric shoulder elevation in patients with chronic trapezius myalgia and healthy controls before and after pain provocation.deformation and deformation rate. Hereafter, max, mean, and quadratic mean values (RMS) of each variable were calculated and compared before and after pain provocation/exercise.Patients with trapezius myalgia and healthy controls were analyzed using an ultrasound system equipped with tissue velocity imaging (TVI). The patients performed a standardized 3-cm concentric shoulder elevation before and after pain provocation/exercise at a standardized elevation tempo (30 bpm). A standardized region of interest (ROI), an ellipsis with a size that captures the upper and lower fascia of the trapezius muscle (4 cm width) at rest, was placed in the first frame of the loop registration of the elevation. The ROI was re-anchored frame by frame following the same anatomical landmark in the basal fascia during all frames of the concentric phase. In cardiac measurement, tissue velocities are measured in the axial projection towards and against the probe where red colour represents shortening and red lengthening. In the case of measuring the trapezius muscle, tissue deformation measurements are made orthogonally, thus, indirectly. Based on the assumption of muscle volume incompressibility, blue represents tissue contraction and red relaxation. Within the ROI, two variables were calculated as a function of time: This new methodology seems valuable when looking at local muscle changes and studying the mechanism behind chronic muscle pain. The univariate analyses indicate that patients with chronic trapezius myalgia after pain provocation due to exercise at group level showed decreased strain and unchanged strain rate while healthy controls had unchanged strain and increased strain rate. However, the multivariate analysis indicates that most patients showed lower levels according to both strain and strain rate after exercise compared to most controls.Tissue velocity imaging can help describe musculoskeletal tissue activity and dynamics in patients with chronic pain conditions. An altered muscle tissue dynamic after pain provocation/exercise among the majority of trapezius myalgia patients compared with the healthy controls was found. Musculoskeletal disorders comprise one of the most common and costly public health issues in western countries . In the dynamic activity in parts of the contraction cycle [Local muscular processes may explain chronic pain, but the role of these processes are questioned by some authors . For exaon cycle -17. Usinon cycle  and acuton cycle .Studies with different research techniques indicate alterations in muscle tissue and in neuromuscular control of the aching muscle in patients with chronic localized pain. Analysing muscle tissue movements during dynamic muscle performances might be of great value in clinical practise. Ultrasound can provide such an opportunity. Several methods have been developed to describe tissue deformation (strain) ,21. ElasA new type of software package for analyzing tissue functionality based on ultrasound has been developed within echocardiography ,28. ThisThe overall aim of this pilot study was to introduce a new muscle tissue velocity sensitive ultrasound technique and to apply this technique to investigate trapezius muscle tissue response during concentric shoulder elevation in patients with chronic trapezius myalgia and healthy controls. In order to exemplify the technique regional deformation and deformation rates are considered.deformation and deformation rate. Hereafter, max, mean, and quadratic mean values (RMS) of each variable were calculated and compared before and after pain provocation/exercise.This study introduces variables to describe tissue motion and tissue deformation based on ultrasound-generated images ). The methodology was used on 14 female patients with trapezius myalgia and 13 healthy controls when performing a 3-cm concentric shoulder elevation before and after pain provocation/exercise. A standardized region of interest (ROI) had a shape of an ellipsis and with a size that captures the upper and lower fascia of the trapezius muscle (4-cm width) at rest. The ROI was placed in the first frame of the loop registering the elevation and was subsequently re-anchored frame by frame in all frames of the concentric phase according to a certain acoustic pattern in the basal fascia that was used as a reference tag. In this way, the same tissue area was followed during all frames of the concentric phase and the quantitative measurements were calculated within the same tissue area. Within the ROI, two variables were calculated as a function of time: A GE-Vivid 7 was equipped with separate non-commercial research software. A 12 MHz linear multi-hertz probe was used for all registrations. All analyses were made post-processed on custom-made non-commercial software.To optimize the reproducibility of location of the probe, the SENIAM standard point of the trapezius  was usedIn this study, a single bi-polar EMG electrode  was used to synchronize the ultrasound registration. The EMG electrode was placed at the medial edge of the probe 2 cm from the SENIAM point. The EMG was used as a reference indicating the electrical activation of muscle tissue. It was also used to ensure that the trapezius muscle was relaxed before and after the shoulder activation.To describe tissue activity, two fundamental concepts are used: 'movement' and 'deformation'. The most important difference between them is whether there is a presence of acceleration. To use a metaphor, imagine a train with some cabins. If no accelerating/decelerating force is present, the train will travel with constant speed and at a certain time point a certain distance is reached. The parameters used to describe this situation by way of ultrasound loops is velocity and displacement. However, when the train alters its speed, starts or brakes, an acceleration or deceleration occurs and the distance between the cabins will either be elongated or compressed. Thus, a deformation between the cabins of the train set occurs. Deformation is measured according to rest values and labelled strain when analyzing the ultrasound images, and the rate of deformation is labelled strain rate. In summary, to describe movement the terms velocity and displacement are used; to describe deformation, the terms strain and strain rate are used. The relationships between the four variables are given in Figure Because the skeletal muscle is an elastic entity, functional movements are part of variations in the neuro-motor activation pattern. This will result in a fine-tuned muscle tissue response. This response can be described in terms of compression or elongation. When a tissue is compressed, shortened, a contraction is present. Consequently tissue elongation is related to relaxation.L0 is the original length and L is the measured new length of the object. As a consequence, negative strain implicates compression and positive elongation.The concept of strain was originally used by Mirsky and Parmley (1973)  to descrStrain rate ,39 is thThe graphical ultrasound interface presents both a qualitative visualization and quantitative results of the described variables. The qualitative information in gained from a colour-coded superimposed image calculated from the velocity calculations described above. Hence, by stacking all images as a function of time, the alteration due to muscle response can be visualized Figure . The quard image in Figure nd image in Figure The calculation principle is illustrated in Figure In the first image from the left, the grey scale image of the trapezius muscle is seen. The second image is the velocity mapping where the blue color represents velocities moving away from the probe and red towards the probe. To illustrate how the third image in Figure The fourth image in Figure Thus, the images in Figure To quantify the tissue activity, a region of interest (ROI) is manually placed in the first frame of the loop (in this case an ellipsis is chosen that captures the centre part of the trapezius). Average strain rate and strain values within the ROI are calculated frame-by-frame and presented as a function of time Figure . As a reFive variables were calculated from the velocity, strain rate, and strain parameters. According to velocity and strain rate, the mean value and quadratic mean value (root mean square (RMS)) were calculated while mean, RMS, and maximum values consistent with strain were considered.n values x1, x2, ..., xn is calculated usingRMS is a statistical calculation that measures the magnitude of a varying curve. It is especially useful when the measurements vary between positive and negative. The RMS calculation for a collection of Furthermore, with respect to each variable the differences between the values before and after pain provocation were calculated. These variables form the basis of describing the results of the study.To study the above described method, trapezius myalgia patients were recruited along with healthy controls. The patients were recruited among female out-patients who had been referred to the Pain and Rehabilitation Centre, University Hospital, Linköping, Sweden due to chronic neck and shoulder pain. Exclusion criteria were widespread pain, prior neck trauma, rheumatoid arthritis, drug or alcohol abuse, overweight, and grave depression. Medical records were assessed and former patients were identified as possible participants. These potential subjects were invited by mail to participate in the study. The participants were examined using a standardized clinical examination . To ensu1. Pain present in the neck and shoulder region at the clinical examination two weeks before and on the experimental day;2. A tight trapezius muscle: a feeling of stiffness in the descending region of the trapezius muscle reported by the patients during lateral flexion of the head;3. Palpatory tenderness of the trapezius muscle of the painful side; and4. Normal or slightly decreased range of movement of the cervical columna.In all, 14 women – mean age: 38 years, median 40 years (range: 24–48); mean height: 168 cm, median height 168 cm (range: 158–175); mean weight: 65 kg, median weight 63 kg (range: 51–81) – comprised the pain group. No detailed information was available concerning the duration of chronic pain, but the medical records clearly reported ongoing pain of more than 6 months duration.Thirteen healthy women without neck and shoulder pain in the same age groups – mean age: 43 years, median 41 years (range: 36–55); mean height 168 cm, median height 168 cm (range: 158–175 cm); mean weight: 65 kg, median weight 56 kg (range: 47–75) – were recruited among staff and students at the Linköping University Hospital. The healthy controls were investigated using the same exclusion criteria and clinical examination as the patients. One patient and one healthy control were excluded due to a shadowing scapula during the shoulder elevation according to the ultrasound registrations. One healthy control was excluded for not being present at the time of the tests.The person handling the ultrasound equipment knew whether the subjects were patients or controls.All participants of both groups gave their informed written consent and the study conformed to The Declaration of Helsinki, and the study was approved by the Ethical Committee of Linköping University (Dnr M103-06).Two weeks after the clinical examination, the ultrasound (US) investigation was performed. The participants were asked not to use any medications due to pain 48 hours before the experimental day and were instructed not to perform any shoulder or neck-training exercise for 48 hours before the study, except for ordinary daily working and/or leisure duties. Furthermore, the participants were asked not to use nicotine or caffeine in any forms after midnight the day before the US examination.The dynamic movement registered by the ultrasound image sequence (approximately 3-sec duration) covered the whole shoulder movement; i.e., both the concentric and the eccentric phase. The results of the present study are based on the concentric phase. The frame rate of the registrations is 141 frames per second giving a time resolution of approximately 7 ms. Thus, the rate at which the shoulder movement is registered is reasonably high enough to capture small intramuscular changes.The subjects were asked to stand in an upright position with their arms hanging beside their body and their hands in a neutral position. The test subjects held a 1-kg dumbbell in the hand on the same side as the shoulder with pain; for the non-pain controls, the right arm was used. To standardize the shoulder elevation, a stand with an orthogonally placed level arm was used. The level arm was individually placed at each subject's shoulder at rest and a stop level was placed 3 cm above the shoulder in the elevation direction. The tempo of the movement was measured by a metronome and was set to 30 beats per minute. The subjects were instructed about the movements by the test leader and verbally led through the exercises concerning the tempo when performing the movements. Each subject performed two separate shoulder elevations at the start of the test. During the first elevation, the probe was held in a coronal position; during the second elevation, the probe was in a sagital position. Just a very short rest was present between the two elevations coinciding with the same procedure of the US loop. In this study, the coronal projection was used as this projection made it possible to follow a region of interest in the image sequence during the elevation. Thus, the before pain provocation procedure consisted of two subsequent elevations, which was registered by ultrasound. Hereafter, in mean three additional subsequent elevations were performed to achieve a pain intensity of 6 out of 10 according to a visual analogue scale  without ultrasound registrations. When the patient had reached VAS 6, two subsequent ultrasound registrations were performed where ultrasound registrations were captured . As for the healthy controls, the procedure was 2 + 6 + 2 elevations where ultrasound registrations were performed during the first and last two elevations.The next step was pain/exercise provocation. The patients were asked to perform repetitive arm abductions holding the 1-kg dumbbell until the pain intensity according to VAS reached the level of 6. When the level was reached, the applicator provided two additional shoulder elevations in the same manner as at the start. First the applicator held the probe in a coronal position and then in the sagital projection. The number of additional repetitions varied slightly (between 2 and 3). As the healthy controls didn't report any pain at all, a standard choice of six repetitions was carried out by the controls. This choice was to make sure that the healthy subjects did not perform fewer repetitions than the patients  without becoming fatigued.Immediately after this provocation, the same procedure concerning shoulder elevation and probe position was repeated as before pain provocation. All US registrations were stored for post-process analysis.All statistical evaluations were made using the statistical packages SPSS (version 12.0) for traditional statistics and SIMCA-P+ (version 11.5) for multivariate statistics. Generally, results in the text and tables are given as mean values ± one standard deviation (± 1SD). As the number of subjects incorporated in this pilot study was small, non-parametric statistics were used. Mann Whitney, Wilcoxon, and Fisher's Exact tests were used to test group differences and differences within groups.loading plot. These projection techniques generate two corresponding plots, one for the observations and one for the variables. These plots are correlated according to the positions in one plot and correspond to the same position in the other plot. The score plot is used in the interpretation in such a way that correlation patterns among the observations are revealed, and the loading plot reveals the impact of each variable on the model. Variables that have high loadings (with either positive or negative sign) on the same component are inter-correlated. A component consists of a vector of numerical values between -1 and 1, referred to as loadings. When obtaining more than one component, the vectors are orthogonally projected to each other and thus uncorrelated. Variables that have high loadings (positive or negative sign) on the same component are inter-correlated. Items with high loadings (ignoring the sign) are considered to be of large or moderate importance for the component under consideration.Principal component analysis (PCA) was used for the multivariate analyses. PCA can be viewed as a multivariate correlation analysis. The PCA also gives the opportunity to multivariately investigate how subjects cluster into subgroups and how certain subgroups differ. PCA detects whether a number of variables reflect a smaller number of underlying components by linear combinations. A cross-validation method, which keeps part of the data out of the model development, is used to assess the predictive power of the model. The result of this procedure is a test of the significance of the components. A graphical plot is provided by the components. This plot could be seen of as a window (a plane) that is built on two t-vectors. All original variables are then projected onto this plane and receive a t-score represented by the coordinate values in plane. Next the orientation of the plane is calculated in relation to the original variable space where the angles between the plane and original space reveal the closeness between the model and the original space. Hence each variable receives a weight that expresses the impact each variable has on the model. Therefore, this projection window is called a 2 and Q2. R2 describes the goodness of fit – the fraction of sum of squares of all the variables explained by a principal component. Q2 describes the goodness of prediction – the fraction of the total variation of the variables that can be predicted by a principal component using cross validation methods. Outliers were identified using the two powerful methods available in SIMCA-P: score plots in combination with Hotelling's T2 (identifies strong outliers) and distance to model in X-space (DModX) (identifies moderate outliers). In all statistical analysis, p ≤ 0.05 was regarded as significant.Two concepts are further used to describe the results: RThe pain intensity according to a 10-unit VAS scale was on average 2.5 (SD 0.94) for the TM group and 0 (SD 0) for the healthy control group before pain provocation. After pain provocation, the patient group scored 6.5 (SD 0.65), while the control group remained at VAS 0 (SD 0).Initially, a univariate analysis was performed Table . No signWe also made within group analyses with respect to before  versus after  the pain/exercise provocation tests Table . No signIt is reasonable to assume that several of the variables shown in Table 2cumulative: 0.90; R2first component: 0.48, R2 second component: 0.33; and R2 third component: 0.09). As the third component only explained 9% of the variation, the graphic overview of the relationships between the subjects and variables are presented according to the first and second components in Figures The model calculation generated three significant components explaining 90% of the variance in X  an indirect measurement is still possible. It is also possible to confirm the contraction by visual inspection of the ultrasound loops where the diameter of the muscle belly becomes thicker/thinner as the shoulder elevation enters either of the concentric or eccentric phases of the movement. During elevation, the muscle expands in a vertical direction. Therefore, we used relative rather than absolute measurements.Another methodological aspect concerns the fact that the probe is handheld. Of course reproducibility can be questioned. However, reproducibility according to cardiac applications that are similar to the situation of registering motions from a skeletal muscle has been shown to be reliable ,42. To oAs this is a pilot study, further studies are needed in order to confirm the results indicated in this study. To improve the study design, full EMG should be provided. Interpretations can then be with respect to the relationship between neuromotor activation and muscle tissue response. This matter will be presented in a forthcoming study. Pain intensity ratings should also be made after the first two elevations to evaluate the intermediate pain ratings. Also a larger study including more patients would be of great value.The number of performed repetitions could have been chosen differently. There is a variation in pain intensity between 6–8 (VAS) in the patient group. It is in accordance with a reasonable variation as the response to a certain activity is not easy to foresee and the estimation according to the VAS scale is not a direct correlation to biological activity. The VAS scale is used as a reference instrument to standardize a cut off for the purpose of providing a moderate pain rather than a mild pain.It could be argued that some subjects used less force after pain provocation and thus lower degree of activation and this can of course be a relevant objection. In this study, the task to be performed was not a heavy one. On the contrary, a 3-cm shoulder elevation carrying a weight of just 1 kg was performed. The shoulder elevation was short and standardized in terms of height of elevation and tempo of the movement. The interesting finding from a qualitative point of view is that less of the muscle seems to be contracted and this part is in the middle/deeper part surrounded by more passive trapezius muscle tissue segments after pain provocation compared to before pain provocationIn future studies it will be an advantage if the applicator of the US registration is blinded with respect to group belonging.variable profile rather than just a single variable: the distribution of variables provides patterns of variables that in turn describe the internal variable structure in relation to the identified cluster of subjects.Multivariate statistics have been used in this pilot study. The strength of this procedure is that during the analysis subjects are not clustered a priori, e.g., in categories as patients and controls. Instead, subjects are seen as uncategorized and are graphically projected based on the results from the variable analysis. Furthermore, the variables have been scaled and mean-centred so each variable has the same impact, i.e., the same possibility to affect the model. Yet another benefit is that clusters of subjects can be related to a This study focuses on the intra-muscular activity in the upper part of the trapezius muscle. Strain rate is a variable that represents the rate at which small (8 mm) muscle tissue segments deform and hence contribute as an important variable to describe muscle activity and intra-segmental coordination pattern. Because the rate of deformation is calculated by the tissue velocity algorithm, the presence of force is at least to some extent part of the measurement. Hence, strain rate can also be thought of in terms of contractility. Strain, on the other hand, is a regional tissue deformation parameter that presents muscle tissue activity as an additive presentation of a regional tissue progress as a function of the progress of a movement. In other words, there are no rapid fluctuations between positive and negative strains as a consequence of muscle activation as is the case in the strain rate parameter, but instead the gradual distribution of tissue contraction beyond a certain degree of deformation is compared to rest. The benefit of the strain parameter is that a certain degree of deformation can be chosen and hence variations in the coordination pattern can be visualised and compared as a function of a certain degree of deformation. As a consequence, activation patterns according to fine-tuned tissue activations can also be studied.It is interesting that strain rate and strain did not differ significantly before pain provocation, neither according to the univariate Table  or multiThe univariate analysis revealed significant differences according to mean strain rate and RMS strain rate in the healthy controls indicating a higher strain rate after exercise than before. A combination of a warming-up effect together with a dynamic muscle tissue could be one explanation of the increase of the deformation rate after several repetitions. The multivariate analyses Figures , 5 and 6In healthy subjects, from a muscle physiological point of view, these results taken together could be interpreted as a more dynamic tissue. Possible explanations for these findings might be warming-up effects due to increased blood flow (exercise hyperemia) and increased neuromuscular control. The pain in itself may also be factor to be considered. Studies have shown that the interplay and coordination according activities in prime and secondary movers may be affected by pain in the sense that a decrease in an agonist muscle activity may result in an increase in an antagonist muscle activity -17,19. IIn agreement with the physiological interpretation above, the TM group has a less flexible or dynamic muscle tissue as a consequence of exercise and pain provocation. As briefly referred in the introduction, several studies indicate morphological, biochemical, and neuromuscular alterations in chronic trapezius myalgia when compared to healthy controls. The morphological alterations, such as increased prevalence of RR-fibres, are less likely as direct explanations to decrease strain. If such changes were important for strain and strain rate, then a lower strain would reasonably have been observed before pain provocation. This was not the case, however.Based on studies using microdialysis of the trapezius, our group has reported that patients with chronic work-related trapezius myalgia have increased interstitial concentrations of potassium, serotonin, lactate, pyruvate, and glutamate at rest ,10. The A third explanation is related to altered neuromuscular control due to increased pain as a consequence of exercise. Le Pera et al.  describeThis pilot study indicates that tissue velocity imaging, as a method, seems promising as a way to describe musculoskeletal tissue activity and dynamics in patients with chronic pain conditions. The study also indicates an altered muscle tissue dynamic after pain provocation/exercise among the majority of trapezius myalgia patients compared with the healthy controls. In future studies that attempt to validate the tissue velocity method, it is desirable to validate the technique in other movements and against biomechanical output , multichannel surface-EMG, interstitial situation , or muscle morphological characteristics0: The original length before muscle activation; Q2: The degree of prediction of a model; R2: The degree of explained variation of a model; RMS: Root mean square; SD: standard deviation; SI: Strain imaging; SRI: Strain rate imaging; TM: Trapezius myalgia; TVI: Tissue velocity imaging.App: After pain provocation; Bpp: Before pain provocation; Diff: Difference; dL: The derivative according to length; DModX: Distance to model among the X-variables; dt: The derivative according to time; L: The measured new length of the muscle after activation; LThe authors declare that they have no competing interests.MP: Study design, performer of the study, analyzing and interpreting data, author of manuscript. BL: Selecting and including patients based on journals, critically revising manuscript. LÅB: Co-developer of the analyzing software package, critically revising manuscript. BG: Study design, interpreting data, author of manuscript.The pre-publication history for this paper can be accessed here:


The objective of this study was to demonstrate the clinical equivalence of immediate-release and sustained-release formulations of hydromorphone and morphine for chronic cancer pain.Long-acting opioid formulations are advocated for maintaining pain control in chronic cancer pain. OROS200 patients with cancer pain  participated in this double-blind, parallel-group trial. Patients were randomized to receive hydromorphone or morphine . Efficacy was assessed with the Brief Pain Inventory (BPI), investigator and patient global evaluations, Eastern Cooperative Oncology Group performance status, and the Mini-Mental State Examination. The primary endpoint was the 'worst pain in the past 24 hours' item of the BPI, in both the immediate-release and sustained-release study phases, with treatments deemed equivalent if the 95% confidence intervals (CI) of the between-group differences at endpoint were between -1.5 and 1.5. No equivalence limits were defined for secondary endpoints.® hydromorphone compared with controlled-release morphine . Scores for other secondary efficacy variables were similar between the two sustained-release treatments. At endpoint, > 70% of investigators and patients rated both treatments as good to excellent. The safety profiles of hydromorphone and morphine were similar and typical of opioid analgesics.Least-squares mean differences (95% CI) between groups were 0.2  in the immediate-release phase and -0.8  in the sustained-release phase (intent-to-treat population), indicating that the immediate-release formulations met the pre-specified equivalence criteria, but that the lower limit of the 95% CI (-1.6) was outside the boundary (-1.5) for the sustained-release formulations. BPI 'pain now PM' was significantly lower with OROS® hydromorphone and controlled-release morphine. The direction of the mean difference between the treatments (-0.8) and the out-of-range lower limit of the 95% CI (-1.6) were in favor of OROS® hydromorphone.Equivalence was demonstrated for immediate-release formulations of hydromorphone and morphine, but not for the sustained-release formulations of OROSClinicalTrials.gov: NCT0041054 Opioid analgesics are highly effective for the treatment of pain, enabling 85% to 95% of patients to gain functional control of their lives ,2. Opioi® hydromorphone is a unique long-acting opioid formulation that utilizes Push-Pull™ active osmotic technology developed by ALZA Corporation . The Push-Pull™ system maintains consistent hydromorphone plasma concentrations throughout the 24-hour dosing interval, providing long-lasting analgesia  and sustained-release [SR] formulations) using the 'worst pain in the past 24 hours' item of the Brief Pain Inventory (BPI). Morphine was selected as the active comparator since it is the gold standard for pain control. Controlled-release (CR) morphine is available in twice-daily and once-daily formulations and is widely used to alleviate cancer pain; in this study the twice-daily formulation (dosing every 12 hours) was used.This study was a multicenter, phase III, randomized, double-blind (double-dummy), active-controlled, parallel-group, equivalence trial. It was conducted at 37 centers in Belgium, Canada, France, Germany, The Netherlands, Spain, Sweden, and the United Kingdom. The study enrolled inpatients, outpatients, and day-patients ≥ 18 years of age who had moderate to severe chronic cancer pain requiring 60 to 540 mg of oral morphine  every 24 hours. The criteria used for patient selection are listed in Table ®, Abbott Laboratories] or morphine  every 4 hours (6 times daily) for 2 to 9 days. Patients underwent conversion from previous therapy to 1 of 6 possible initial dose levels, based on individual patient characteristics and generally accepted morphine equivalent conversion factors. Doses were selected according to the available tablet strengths and a working conversion ratio of 1:5 , in the ranges hydromorphone IR 12–108 mg/day and morphine IR 60–540 mg/day. The dose was titrated to the next higher dose level if the patient had more than 3 breakthrough pain episodes requiring breakthrough pain medication within the previous 24 hours. Daily doses were titrated up to the next higher dose level, with no dose levels skipped, at most once a day. Dose titration was continued until dose-stable pain control was achieved. Patients who experienced 2 consecutive days with no more than 3 breakthrough pain episodes requiring rescue medication per day were considered to have achieved dose-stable pain control and could begin the SR phase of the study. Patients who did not achieve dose stable pain control by day 9 were withdrawn from the study, and end-of-study evaluations were carried out.Patients were randomized 1:1, with a central computer-generated randomization list, to receive hydromorphone or morphine for up to 24 days  twice-daily. They were started on the same dose level number on which they had achieved dose-stable pain control in the preceding IR phase, which was then adjusted as required, at most every 2 days, in single steps so that no dose level was skipped. Doses were selected according to the available tablet strengths and a working conversion ratio of approximately 1:5 (hydromorphone:morphine), in the ranges OROS® hydromorphone 16–96 mg/day and CR morphine 60–520 mg/day. The SR phase was completed after a minimum of 10 days (maximum of 15 days) on OROS® hydromorphone or CR morphine if pain was controlled and the dose was stable for at least the previous 2 days.The duration of the SR phase was 10 to 15 days. In this phase, patients continued to receive the same study drug but in an SR formulation: OROS® hydromorphone group took OROS® hydromorphone and placebo CR morphine in the morning and placebo CR morphine in the evening; patients in the CR morphine group took CR morphine and placebo OROS® hydromorphone in the morning and CR morphine in the evening.In the IR phase, the dosing regimen was the same for both drugs: patients received a dose of study medication 6 times a day, every 4 hours, at 0600, 1000, 1400, 1800, 2200, and 0200. In this phase, all treatments were over-encapsulated resulting in identical capsules. In the SR phase, dosing was done twice each day at 1000 and 2200. To maintain the blind in this phase, matching placebo tablets and capsules were used: patients in the OROSIn both study phases, patients could also receive breakthrough pain medication as needed, either hydromorphone or morphine, supplied as the IR formulation. A single dose of breakthrough pain medication contained approximately one-sixth of the patient's daily dose.Baseline efficacy assessments were done before dosing on day 1 of the IR phase and included: the BPI  , the MinPrimary equivalence of efficacy was assessed using the BPI assessment of 'worst pain in the past 24 hours' on an 11-point scale ranging from 0 (no pain) to 10 (worst pain imaginable). This was selected as the primary efficacy measure because evidence suggests that severely intense pain is what interferes most significantly with activities of daily life . SecondaPatients rated BPI 'worst pain in the past 24 hours' once daily (just before taking the mid-morning dose of study medication) and 'pain now' twice daily  throughout the study and recorded responses in daily diaries. The other BPI assessments, plus investigator and patient global evaluations of treatment effectiveness, MMSE, and ECOG, were evaluated at the end of both phases.Adverse events (AEs) and concomitant medications were recorded throughout the study. Physical examinations were carried out at baseline and at the end of each study phase. Blood and urine samples were collected for laboratory analysis  at baseline and at the end of the SR phase.Patients were contacted daily during the IR phase and every 3 to 4 days during the SR phase . Contact was also made 3 days after the last dose of study drug to determine the patient's AE status.Assuming variability  in the primary efficacy variable of 2.0  and a 30All statistical analyses were pre-specified. All efficacy variables were analyzed using the intent-to-treat (ITT) population, which included all patients who took at least 1 dose of study medication and had at least 1 assessment from each study phase. A per-protocol (PP) analysis, excluding data from patients with major protocol deviations, was also done. All patients taking at least 1 dose of study medication were included in the analysis of safety. All efficacy analyses included a pre-specified adjustment for baseline value and country to control for potentially confounding variables.The primary efficacy analysis used the mean of the last 2 post-baseline recorded values  for BPI 'worst pain in the past 24 hours'. The primary measure was calculated separately for the IR and SR phases (there were therefore two primary outcomes). An analysis of covariance (ANCOVA) was used to calculate the 95% two-sided confidence interval (CI) for the difference between the adjusted means for the 2 treatments at endpoint of each phase. An equivalence test was used to compare the mean scores of the primary efficacy measure at the end of each phase -19. The P values (not adjusted for multiple comparisons) are reported for secondary endpoints. Statistical significance was declared at the α = 0.05 level.For secondary endpoints , 'pain relief in past 24 hours', 'pain interference in past 24 hours', MMSE, and ECOG) an ANCOVA model was used to calculate 95% two-sided CIs for the difference between the adjusted treatment means at the end of the IR and SR phases. The adjusted means were estimated by the same approach used for the primary endpoint, with the baseline score designated as a covariate; however, no equivalence limits were specified for the secondary endpoints. Time to dose stabilization during both study phases was analyzed by the log-rank test. Summary statistics with 95% CIs were produced for investigator and patient global evaluations of treatment effectiveness and to assess the number of medication doses taken for breakthrough pain in the last 2 days of each phase. 202 patients were enrolled into the study . 200 patients were randomized and took study medication. 163 patients (81.5%) completed the IR phase and 133 (66.5%) completed the SR phase. Figure ® hydromorphone .At the end of the IR phase, mean scores for the secondary efficacy variables  . BPI 'pain interference' scores were also similar between treatment groups at endpoint, , and LS mean MMSE scores .LS mean BPI 'pain relief' at endpoint was 69.7% for the OROS® hydromorphone group and 3.3 ± 0.98 for the CR morphine group (p = 0.6696); mean ± SD investigator global assessment scores were 3.2 ± 1.07 and 3.3 ± 0.91, respectively (p = 0.4760).The majority of both investigators and patients > 70%) rated the treatments as good, very good, or excellent at the end of each study phase . The number of patients requiring dose-level changes during the SR phase was similar for both groups (19 of 77 [24.7%] OROS® hydromorphone recipients and 23 of 86 [26.7%] CR morphine recipients). Comparison of dosage levels at the end of the SR phase generally showed that similar proportions of patients received OROS® hydromorphone or CR morphine at each of the 5 (approximate 1:5 hydromorphone to morphine) lower dosage levels, although more patients in the OROS® hydromorphone group (10% versus 2% in the CR morphine group) received the highest dosage level evaluated in this study  numbers of breakthrough pain medication doses taken on the last 2 days were as follows: IR phase, 1.8 (2.2) and 1.3 (1.8) for the IR hydromorphone and IR morphine groups, respectively; SR phase, 1.6 (2.2) and 1.4 (1.9) for the OROS® hydromorphone and CR morphine groups, respectively. The mean total doses of breakthrough pain medication as a percentage of the mean daily consumption were 39.4% and 27.1% for hydromorphone and morphine in the IR phase, and 13.8% and 10.3% for OROS® hydromorphone and CR morphine in the SR phase. There were no statistically significant treatment differences in the numbers of patients who took breakthrough pain medication or in the amount of medication taken in either phase.In the IR phase, 61.6% of patients taking IR hydromorphone and 52.5% of those receiving IR morphine required medication for breakthrough pain on the last 2 days of the phase. In the SR phase, the corresponding percentages in the OROSThe overall safety profiles of hydromorphone and morphine were comparable, with a similar number of patients in each group reporting AEs. Overall, irrespective of study phase, 81 of 99 (81.8%) hydromorphone-treated patients and 90 of 101 (89.1%) morphine-treated patients reported at least 1 AE.® hydromorphone . Most AEs were mild or moderate in severity and no clear treatment difference was seen in the relative severity of the most commonly reported AEs. Approximately 30% of patients with AEs reported events that were considered unlikely to be related or not related to study therapy.The most commonly reported AEs during the IR and SR phases of the study are listed in Table ® hydromorphone group and 9 in the CR morphine group in the SR phase [2 patients had serious AEs in both phases]). Many of the serious AEs were associated with the underlying disease, although approximately one third were considered definitely or probably related to study therapy. Three patients in the morphine group died during the study . None of the deaths was considered related to the study medication.Serious AEs were reported for 24 patients during the double-blind period . There was no statistically significant difference between treatment groups in the time to withdrawal, irrespective of phase . The use of concomitant medications, including the use of non-opioid analgesics, was similar for both treatment groups in both the IR and SR phases.Twenty-six patients withdrew prematurely from the study because of AEs, 16 during the IR phase  and 10 during the SR phase (6 OROS® hydromorphone. The upper limit of the 95% CI (-0.01) was within the 1.5 boundary, but the lower limit (-1.6) was less than the -1.5 limit. Therefore, according to the pre-specified criteria, equivalence was not demonstrated; the direction of the difference was in favor of OROS® hydromorphone. The BPI item 'worst pain in the past 24 hours' was selected as the primary endpoint of the trial based on previous studies showing it to be the most sensitive BPI measure in the clinical trial setting [This was a short-term, randomized, double-blind comparative study testing the clinical equivalence of IR and SR formulations of hydromorphone and morphine in patients with chronic cancer pain. In each study phase (IR and SR), mean values for BPI 'worst pain in the past 24 hours' (the primary efficacy endpoint) decreased with both hydromorphone and morphine. In the IR phase, the LS mean difference between the treatment groups was 0.2 points, and the 95% CI  was within the pre-specified equivalency range of -1.5 to 1.5. In the SR phase, the LS mean difference was -0.8 points in favor of OROS setting ,20-22.® hydromorphone provides consistent pain relief over 24 hours, and that pain levels in the evening were significantly lower after OROS® hydromorphone compared with CR morphine treatment. This finding reflects the 'pain now PM' measure being scored at the end of morphine dosing (i.e. trough levels) but at the midpoint of hydromorphone dosing. The comparable results between groups for the other secondary efficacy variables  support similarity in the treatment efficacy. Withdrawal from the study owing to lack of efficacy was more common in patients randomized to hydromorphone (n = 11) compared with morphine (n = 4). This is a potentially negative finding for hydromorphone; however, the numbers are too low to draw any definite conclusions.The results of the present study further suggest that OROS® hydromorphone group and 88% of the CR morphine group received the equivalent of morphine 240 mg/day or less.Results of the dose analysis were generally consistent with those of previous reports, which indicate that most cancer pain can be controlled with ≤ 240 mg of oral morphine daily . In the ® hydromorphone group (from 61.6% to 48.1%). At the end of the SR phase, there was no significant difference between the groups in use of breakthrough medication.The frequency of breakthrough medication use remained stable throughout both phases in the morphine group , but decreased from the IR phase to the SR phase in the OROSThe occurrence of 3 deaths and 23 serious AEs during the study was not unexpected, given the severity of the patients' conditions and the progressive nature of the disease. In fact, many of the serious AEs were associated with the underlying disease.The participants in this study are representative of the overall population afflicted with chronic cancer pain. The mean baseline BPI score for 'worst pain in the past 24 hours' was 6.3 on an 11-point scale, a score indicative of moderate to severe pain . This isThe major positive aspect of this study was the robust design: it was multicenter, randomized, double-blind, and active controlled. It also used a widely utilized and well validated primary outcome measure, the BPI. On the negative side, there was a relatively poor completion rate, with only 60 out of 99 patients (60.6%) randomized to hydromorphone and 73 out of 101 patients (72.3%) randomized to morphine completing both treatment phases. However, this completion rate was reasonably good when taking into consideration that this study was carried out in patients with cancer which was advanced enough to require strong opioid analgesics. In addition, a dropout rate of at least 30% was anticipated. Furthermore, the duration of the study was relatively short (up to 24 days), so it was not possible to make evaluations of the sustained efficacy of the formulations.® formulation relative to the dosing used in those studies. The consistent release of hydromorphone over 24 hours has been demonstrated in previous studies, in which steady-state plasma concentrations were achieved by 48 hours and sustained throughout the dosing interval [Two previous randomized, double-blind, crossover studies have compared CR formulations of hydromorphone and morphine in patients with cancer pain ,27. Moriinterval .Practicing clinicians are acutely aware of the need for multiple pain management alternatives, because it is clear that the response to a particular opioid agent varies among individuals. Although our understanding of the causes of individual differences remains incomplete, receptor and receptor-binding studies suggest that they may result not only from differences in the class of opioid receptors to which each agent binds , and BPI 'interference with normal work' scores were significantly lower for IR hydromorphone. None of the other secondary efficacy analyses showed significant treatment differences in either phase. The overall safety profiles of the 2 treatments were generally similar and most AEs were typical of opioid analgesic therapy.This study demonstrates that while IR hydromorphone is equivalent to IR morphine for relieving chronic cancer pain, equivalence was not demonstrated for OROSMH was a paid advisor for Janssen-Cilag.MH was an investigator in this study and was 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:


Proximal major limb amputations due to malignant tumors have become rare but are still a valuable treatment option in palliation and in some cases can even cure. The aim of this retrospective study was to analyse outcome in those patients, including the postoperative course, survival, pain, quality of life, and prosthesis usage.Data of 45 consecutive patients was acquired from patient's charts and contact to patients, and general practitioners. Patients with interscapulothoracic amputation (n = 14), shoulder disarticulation (n = 13), hemipelvectomy (n = 3) or hip disarticulation (n = 15) were included.The rate of proximal major limb amputations in patients treated for sarcoma was 2.3% (37 out of 1597). Survival for all patients was 42.9% after one year and 12.7% after five years. Survival was significantly better in patients with complete tumor resections. Postoperative chemotherapy and radiation did not prolong survival. Eighteen percent of the patients with malignant disease developed local recurrence. In 44%, postoperative complications were observed. Different modalities of postoperative pain management and the site of the amputation had no significant influence on long-term pain assessment and quality of life. Eighty-seven percent suffered from phantom pain, 15.6% considered their quality of life worse than before the operation. Thirty-two percent of the patients who received a prosthesis used it regularly.Proximal major limb amputations severely interfere with patients' body function and are the last, albeit valuable, option within the treatment concept of extremity malignancies or severe infections. Besides short survival, high complication rates, and postoperative pain, patients' quality of life can be improved for the time they have remaining. Due to sophisticated operative techniques and multimodal approaches, limb salvage in extremity malignancies has become possible in most of the cases ,2. Only Against the background of rare detailed reports about long term outcome after proximal major amputations -10, thatFrom 1991 to 2006, 45 consecutive patients were treated by proximal major amputations at our institution. Patients who had received interscapulothoracic amputation , shoulder disarticulation (n = 13), hemipelvectomy (n = 3) or hip disarticulation (n = 15) were included in this retrospective study. Patients' data concerning their medical history and hospitalisation was obtained from the patients' charts. Follow-up data regarding the clinical course and outcome was collected from the patients' charts, interviews of the patients, their relatives and their general practitioners. Data concerning life quality and satisfaction with the aesthetic result was gathered at the regular follow-up visits at the time of complete wound closure and consisted of a simple score according to the German school mark system . Postoperative ratings were compared to preoperative ratings that were asked for retrospectively.At the time of treatment, the patients' ages averaged 56 years (range: 28–89 years); twenty (44%) were female. Eighty-two percent (n = 37) were operated on for sarcomas including two Ewing sarcomas, two chondrosarcomas, and one osteosarcoma, 18% (n = 8) for carcinoma . The rate of proximal major amputations in patients treated for sarcoma was 2.3% (37 out of 1597). Nineteen of the 45 patients with malignant disease (42%) were operated on for recurrent tumors. Twenty-eight out of those 45 had metastatic disease at the time of the proximal major amputation (62%) and were treated with palliative intention, 31 had already received chemotherapy and radiation, respectively (69%), of whom 19 had undergone both treatment modalities. Thirty-eight of the patients had an average of 4.2 previous diagnosis-related operations (range: 1–15), with up to nine operations for local recurrences.Several preoperative aspects are illustrated in figures Three patients were lost to follow-up and no follow-up information could be gained; 38 patients (84%) had already died. The mean follow-up time was 20 months (range 0–118 months). Four patients who were alive could be interviewed personally. In the other cases, data was obtained from the close relatives and the attending general practitioners. Data was acquired retrospectivelly and may therefore be biased.For statistic analysis, SPSS Version 15.0 for Windows  was used. The correlation of different events was calculated by crosstabs : prosthesis usage, quality of life, pain, complications; the means of parametric data by ANOVA (prosthesis usage) and the rank of nonparametric data by Mann-Whitney, Wilcoxon and Kruskal-Wallis tests .P-values ≤ 0.05 were considered significant. Survival and influencing factors were calculated using the Kaplan-Meier Method (Log-Rank (Mantel-Cox)).This study was approved by the Ethics Committee of the BG-University Hospital Bergmannsheil (number: 3041-07).In 17 patients who had no metastases at the time of the amputation, complete resection (R0-status) could be achieved in 11 (65% of 17). In 4 patients (24% of 17) positive surgical margins (R1-status) were histologically documented and in 2 (12% off 17) additional patients macroscopic tumor residuals were left in situ (R2). Seven . Sixteen patients had to be re-operated on those complications . Among the complications, partial flap necrosis was the most common , followed by wound infection , hematoma, seroma and wound dehiscence in two cases each (4%) and one hernia after hip disarticulation. The occurrence of wound healing difficulties such as wound infection, seroma, and necrosis was higher in patients with preoperative radiation of the amputation area but the finding was not significant (p = 0.153). Preoperative chemotherapy (p = 0.890) and the amount of intra-operative blood transfusion (p = 0.874) also had no significant influence on the occurrence of wound healing difficulties.In spite of the radical operation, local recurrence was observed in 8 tumor patients (18%) of whom two had received a complete resection (R0), four had been resected with positive surgical margins (R1) and two had only received a tumor mass reduction (R2). After the amputation operation these patients had a progression free interval of 7 months on average (range 1–20 months) and died after 17 months (range 4–39 months).Survival for all patients was 42.9% after one year and 12.7% after five years. The four patients who were alive could be interviewed personally at follow-up times of 3, 40, 42, and 118 months. Survival was significantly reduced in patients with positive surgical margins  Fig . NeitherFor postoperative pain relief, including pain at the operation site as well as phantom pain, 24 patients received opioids, 12 pain catheters, and ten received other pain medication. Pain intensity as well as the occurrence of phantom pain was documented in 40 and 39 patients, respectively. All except one suffered from pain in the operated region. Pain intensity or the occurrence of phantom pain was not significantly influenced by the fact if postoperative pain therapy was performed by i.v. or oral opioids, catheters or other modalities of pain management (p = 0.512) and by the kind of amputation that was performed (p = 0.315). Pain reduction could be achieved in 46% of the patients in comparison to the preoperative situation (when receiving the same medication as preoperative), whereas 31% had more pain afterwards and 22% reported no change. Neither the different preoperative diagnoses (p = 0.702), nor the kind of amputation operation (p = 0.512), had significant influence on the changes from pre to postoperative pain.Twenty-four patients received a custom made prosthesis but only seven out of 22 of those that could be followed up used it regularly (32%). Eleven used it only rarely (50%) and four had never used it (18%). The reasons given for rare or no use of the prosthesis were complicated handling and inoperability in all cases. One patient could not wear it because it caused intolerable pain  with a range from 2 to 5, whereas the average rating in the hemipelvetomy cases was 3.0, in the hip disarticulation group was 3.2, in the ISTA patients was 3.2 and 3.3 was the rating in the shoulder disarticulation group. In 32 patients an assessment of their quality of life changes after the operation was documented: Six-teen considered it improved postoperatively, 11 felt no change, and five found it worse than before. The improvement in the hip disarticulation group was significant (p = 0.029), the shoulder disarticulation group tended to do better (p = 0.052), but the changes in the ISTA-patients were not significant (p = 0.584). Statistical analysis in the hemipelvectomy group could not be performed because quality of life data was documented in two patients only. Quality of life after wound healing was independent from the localization of the amputation (p = 0.624), postoperative pain management (p = 0.563), and the occurrence of postoperative complications (p = 0.410). The higher the preoperative pain intensity (p = 0.009) and the poorer the quality of life (p = 0.001), the better was the postoperative quality of life. No other factor, be it the preoperative diagnosis or the kind of amputation, contributed significantly to changes in quality of life.In 37 patients, we documented whether patients would undergo the procedure again.Twenty-two had answered yes (59%), 15 (41%)would not agree to the procedure again with their present knowledge.New surgical techniques and a better understanding of the tumor biology, supported by multimodal therapy, presently make functional limb sparing tumor resections the therapy of choice and have reduced proximal major limb amputations to rare indications ,12,13. TIntra-operative blood replacement largely concurs with the volumes reported in the literature ,20. The The results of this study show that complete resection correlated with longer survival. The probably aggressive tumor biology and incomplete resection may explain the high local recurrence rate . So far The negative patients selection with a predominance of patients with recurrent and metastatic disease is responsible for the low long term survival rates that corresponds to time frames given by other authors after proximal major amputations for sarcoma, who reported five-year survival rates of 10–39.3% ,21-24. IThe patients' benefit of proximal major amputation can be questioned against the background of those numbers, but pain relief and the improvement of quality of life quantified in this study may suggest otherwise.In contrast to other series, we could not detect any significant influence of the postoperative pain management on long term pain sensation or the occurrence of phantom limb syndrome in our patients, of whom the vast majority suffered from this complication . PhantomA study dealing with long term pain results showed, that pain decreases slightly with time, with 72% having phantom pain after 8 days, 65% after 6 months, and 60% two years postoperative , but, inOur findings of only moderate acceptance of the prosthetic supply comply with the reports of others who stated that amputations at trunk level lead to a three times higher prosthesis rejection rate than distal amputations  and docuWe could not identify predictive factors of long term use of the prosthesis to justify an exclusion of patients from prosthetic fitting. Therefore prosthesis initially should be provided for every patient who asks for it, but the possible benefit and disadvantages should be discussed in detail.A limb is an essential part of the patients' body schema and the often disfiguring postoperative results put strain on the patients Fig . AdditioMost of the data was acquired retrospectively limiting the interpretation of the results, but in agreement with other studies that reported pain relief and improvement of quality of life  we affirThe authors declare that they have no competing interests.ML participated in the study design and helped drafting the manuscript. AK acquired the data and did the statistical analysis. JH prepared the figures and did the literature research. LS helped aquiring the data and corrected the manuscript. SL was helpful conceptualizing the study and weighed the data. OG interpreted the data and was helpful with the review of the literature. HS initiated the study and corrected the manuscript. All authors read and approved the manuscript.


This study evaluates the effect of oral pancreatic enzyme supplements on pain, analgesic requirementand the incidence of complications in patients with acute pancreatitis. This double blind, prospectivelyrandomised placebo controlled study included 23 patients. Pain was monitored using a visual analoguescale; the analgesic requirement was assessed with a numerical score.        p = 0.069). Analgesicrequirements were: placebo 20 (6–60) and enzymes: 16 (0–63) (p = 0.56). This study has shown nobeneficial effect of oral pancreatic enzyme supplements in the initial management of patients withacute pancreatitis.No significant differences were noted between the median (range) pain scores of patients whoreceived placebo: 22 (17.1–58) and those who received enzymes: 23 (11.3–63). Hospital stay was 7(5–10) days in patients on placebo and 8 (6–24) days in the enzyme group (


We report a case of a 81-year-old Caucasian man with colorectal carcinoma, treated by surgery in 1998, referred for palliative treatment of a refractory painful caused by osteolytic metastases of 2.5 cm in back-upper ilium spine. Plasma-mediated radiofrequency ablation was performed under conscious sedation, using Fluoroscopic Computer Tomography guidance. After completing the ablation phase of the procedure, a mixture of bone cement and Biotrace sterile barium sulfate was injected into the ablated cavity.Patient was evaluated by using the Brief Pain Inventory and considering pain interference with daily living at day 1 and 3 and week 1, 2, 3, 4 by means of a telephone interview. A post-procedure Computer Tomography scan was performed to examine the distribution of cement deposition few minutes after the procedure. The plasma mediated RFA and cementoplasty were well tolerated by the patient who did not develop any complication. Pain management in terminally ill patients with metastases involving bone can be challenging. Conventional therapeutic options for pain control include: radiation therapy (RT), chemotherapy, surgery and the use of analgesic drugs .Despite these measures, the quality of life for these patients is often poor because of intolerable pain. There are many reasons for failure of traditional therapies to control pain: (a) radiation insensitivity of the neoplasm or limitations of radiation dose to normal structures, (b) poor therapeutic response or toxicity of the chemotherapeutic agent, (c) contraindication of major surgery in patients with advanced disease and poor functional status and (d) intolerable analgesic-related side effects that may develop increasing of analgesic doses .Investigators have so explored several alternative strategies for the treatment of painful metastatic disease; these involve the use of percutaneous image-guided methods to locate tissue ablative devices into focal metastatic lesions: ethanol , laser-iThis study investigates clinical viability of a novel technique for the treatment of painful bone metastases: the plasma-mediated RFA assisted with cement injection.The plasma-mediated RFA was choice instead of simple RFA because: the exterior margin of the cortical bone was interrupted and this may result in a leakage of cement in the nearby tissues and because the non plasma-mediated RFA sometimes can give a coagulative necrosis which doesn't permit a correct allocation of the cement inside the cavity.We present a case of 81-year-old Caucasian man with a history of colorectal carcinoma treated by surgery in 1998 was referred for palliative treatment of a refractory painful, osteolytic metastasis of 2.5 cm in back-upper ileum spine, as showed in the Computer Tomography (CT) scans performed before the treatment .Prior to treatment, patient was assessed by Brief Pain Inventory (BPI), visual-analogue scale (VAS) and recording the use of analgesic drugs.Before the RFA, the daily therapy of our patient consisted in the following analgesics: 60 mg of morphine, 20 mg of ketorolac-tromethamine and 5 mg of haloperidol; furthermore, he used morphine, at most 30 mg/day, and paracetamol 500 mg, at most 2 g/day.In the BPI, patient is asked to rate his worst pain in 24 hours, least pain in 24 hours, and average pain, with allowed responses ranging from 0 to 10. Relief of pain through the use of analgesic medications is scored on a scale of 0% (no relief) to 100% (complete relief). Pain interference with daily living is evaluate with questions concerning general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life, also on a 0-10 scale . The patient was asked to answer these questions with respect to the lesion that was to be treated.Before RFA an imaging-guided biopsy was performed and the frozen specimen sent to Anatomy Patology Laboratory to obtain confirm of malignancy.An informed written consent was obtained for the patient.3) and prothrombin time  were obtained within 24 hours of the procedures.A complete blood count , alfentanyl (0.5 mg) and midazolam (3 mg). The patient received oxygen during the procedures and continuous monitoring of heart rate, electrocardiographic tracing, oxygen saturation, and respiratory rate were obtained, and blood pressure was determined every 4 minutes. Patient skin entry site of the planned needle puncture was anaesthetized with 2% carbocaine. The procedure was performed under fluoro-CT guidance (Aquilion 64/Toshiba/Tokyo/Japan) with the patient in the prone position. Access to the ilium spine was gained by using a 11 G bone marrow harvesting needle that was placed in the back-upper iliac spine to made a biopsy. The bipolar radio-frequency-based device  was advanced into the delivery port (harvesting needle or introducer kit) until its tip protruded beyond the cannula tip. The needle tip was placed with different orientations to obtain a cavity; ablation was ceased when a noticeable reduction in tactical resistance was detected. When inserting the device towards the anterior aspect of the ileum spine, the tissue dissolution setting was used. A total of 4 passes were made to complete the cavity; it was left in place while preparing the bone cement for insertion. After completing the ablation, a mixture of bone cement  and Biotrace sterile barium sulfate  was injected into the ablated cavity under CT-fluoroscopic guidance. On average, 3 ml of bone cement was found to be sufficient to fill the ablated lesion in the back-upper ilium spine. A post-procedure CT scan was performed to examine the distribution of cement deposition few minutes after the procedure. Patient was evaluated for severity of pain by using the BPI and considering pain interference with daily living at day 1 and 3 and week 1, 2, 3, 4 by means of a telephone interview.The needle was correctly deployed inside the lesion, and the total ablation time was of about 10 minutes. The procedure was considered efficacious and no operative or post-operative complications were observed. The patient experienced a decrease in worst pain over the course of the follow-up period; on the bases of BPI, at day 1 is worst pain had score of 4 in the least 24 hours and the interference of pain with daily living had score of 5. Further, before plasma-mediated RFA, morphine was reduced to 15 mg/day; worst pain remained stable up to week 1. Length of stay in the hospital was 3 days, included the day of the treatment.Approximately 40% of patients with cancer develop metastatic disease; of these patients, 50% have poorly controlled pain. Achieving adequate pain control is often difficult, and quality of life for the patients is poor . RT is cAlthough RT is generally considered effective for metastatic bone cancer, this therapy may be administered a single dose; however, most RT schedules involve daily treatments over 2-3 weeks.The time required to derive maximal benefit following RT for solitary and multiple metastases is usually 12-20 weeks, it confirms that the time to achieve a benefit from RT may be more prolonged than the time achieve symptom relief in patients treated with RFA .Conventional palliative external beam RT for painful metastases includes several different local and wide-field methods . UnfortuChemotherapy, by reducing the cancer volume, usually reduces pain in 20%-80% of patients.A positive response often occurs within 2 weeks and can last for several months. Unfortunately, patients develop multidrug resistance, and recurrence of bone pain is common. Toxic effects, especially because of myelosuppression, are also common with chemotherapy for bone pain .Up to 70% of patients with cancer report relief from bone pain after hormonal therapy or after single or multiagent chemotherapy . HoweverRadiopharmaceuticals, which have known benefit in patients with diffuse painful metastases involving bone, are not considered standard of care for patients with isolated, painful lesions.Surgery is usually reserved for patients with impending fracture or with spinal cord compression . AnalgesRFA represent a valid and potential alternative method for palliation of painful osteolytic metastases and many publications confirmed that RFA is a safe and effectiveness procedure in the treatment of localized, painful osteolytic metastases involving bone ,5. The mIn addition with RFA, other Authors -13 propoSchaefer et al  reportedGeorgy et al  have demA tissue cavity can be achieved using other means, such as the kyphoplasty system. We believe that the advantage of using plasma-mediated RF based technology is the ability to create such a cavity using a tissue dissolution process, as opposed to simply displacing it. Moreover this technique provides the additional theoretic benefit of improving interdigitation of the cement, which normally be blocked by displaced tissue.According with Georgy experience , we beliAlthough larger series are needed to confirm our data, our experience suggest that plasma-mediated RFA assisted with cement injection is a new and potentially efficacy treatment for painful extra-vertebral bone metastases.This technique may be safer than conventional cementoplasty of RFA associated to cementoplasty by providing a space for bone cement placement and plasma-mediated RFA could be more efficacious than non plasma-mediated because it limits the cement leakage damage to the nearby tissues.Further clinical experience and prospective studies are needed to determine the long-term efficacy of combined RFA and percutaneous cementoplasty.


The aim of this study was to examine the relationship between chronic neuropathic pain after incomplete peripheral nerve lesion, chronic nociceptive pain due to osteoarthritis, and the excitability of the motor cortex assessed by transcranial magnetic stimulation (TMS). Hence in 26 patients with neuropathic pain resulting from an isolated incomplete lesion of the median or ulnar nerve , 20 patients with painful osteoarthritis of the hand, and 14 healthy control subjects, the excitability of the motor cortex was tested using paired-pulse TMS to assess intracortical inhibition and facilitation. These excitability parameters were compared between groups, and the relationship between excitability parameters and clinical parameters was examined.We found a significant reduction of intracortical inhibition in the hemisphere contralateral to the lesioned nerve in the neuralgia patients. Intracortical inhibition in the ipsilateral hemisphere of neuralgia patients and in both hemispheres of osteoarthritis patients did not significantly differ from the control group. Disinhibition was significantly more pronounced in neuralgia patients with moderate/severe pain intensity than in patients with mild pain intensity, whereas the relative compound motor action potential as a parameter of nerve injury severity did not correlate with the amount of disinhibition.Our results suggest a close relationship between motor cortex inhibition and chronic neuropathic pain in the neuralgia patients, which is independent from nerve injury severity. The lack of cortical disinhibition in patients with painful osteoarthritis points at differences in the pathophysiological processes of different chronic pain conditions with respect to the involvement of different brain circuitry. Lesions of a motor or mixed peripheral nerve lead to short- and long-term reorganization of the motor cortex, as demonstrated in a large number of animal studies -3. SimilIn the present study, we assessed ICI and ICF by paired-pulse TMS in patients with chronic neuropathic pain due to an incomplete peripheral nerve lesion, and with chronic nociceptive pain due to osteoarthritis. Our aim was to examine the relationship between chronic neuropathic pain of peripheral origin and cortical excitability changes in the motor cortex, and to assess possible differences between chronic neuropathic and nociceptive pain conditions.2,57 = 2.612, p = 0.082). Neuralgia patients did not significantly differ from osteoarthritis patients with respect to current (p = 0.173) and mean (p = 0.700) pain intensity, whereas maximum pain intensity was significantly higher in the osteoarthritis patients . Duration of pain did not significantly differ between both groups (p = 0.788).There was no significant difference between the neuralgia group, the osteoarthritis group and the healthy controls with respect to the patients' age , and a significant interaction between "side" and "group" , whereas the factor "side" did not reach significance . Post hoc analysis revealed a significantly reduced ICI at the neuralgia patients' affected side (relative amplitude 69.1 ± 53.4%) as compared to their unaffected side , whereas no significant side-to-side differences were observed in the osteoarthritis patients and the control group. ICI did not significantly differ between the osteoarthritis group and the control group. However, ICI was significantly reduced at the neuralgia patients' affected side as compared to the controls' left hand , whereas no significant difference was seen between the neuralgia patients' unaffected side and the controls' right hand  , there was a significant "group" effect , and a significant interaction between "side" and "group" , whereas the factor "side" did not reach significance . Again, post hoc testing revealed a significantly reduced ICI at the neuralgia patients' affected side (71.0% ± 61.8%) in comparison to their unaffected side , but also in comparison to the controls' left hand , whereas no significant difference was seen between the neuralgia patients' unaffected side and the controls' right hand (p = 0.253) , similar results were obtained: ANOVA also revealed a significant "group" effect  or the factor "group" , and also no significant interaction between both factors . Similar results were obtained when the values obtained from the muscle supplied by the unlesioned nerve  were included in the analysis  , there was no significant effect of the factor "side"  as well as from the muscle supplied by the unlesioned nerve  in the neuralgia group .In the paired pulse TMS-paradigm used in this study, the intensity of the test stimulus (TS) was adjusted to evoke a MEP of approximately 1 mV. Therefore, a side-to-side-difference or a between-group-difference for the MEP amplitudes after single test stimuli should be excluded. This was confirmed by statistical testing including the results from the muscle supplied by the lesioned nerve   or the factor "group" , and also no significant interaction between both factors . Relative TS intensity was 124.0 ± 5.5% of MT at the affected and 123.6 ± 6.1% at the unaffected side in the neuralgia patients, 121.1 ± 6.7% at the affected and 122.3 ± 5.3% at the unaffected side in the osteoarthritis patients, and 121.2 ± 5.2% at the left hand and 122.9 ± 5.8% at the right hand in the control group.Looking at the TS intensity relative to the motor threshold (MT), and including the neuralgia group results obtained from the muscle supplied by the lesioned nerve  in the statistical analysis, there was no significant effect of the factor "side" , "group"  or the interaction between "side" and "group"  was detected either. Relative TS intensity was 123.7 ± 7.1% of MT at the affected and 123.3 ± 5.8% at the unaffected side in the neuralgia patients.Including the results obtained from the muscle supplied by the unlesioned nerve  in the analysis for the neuralgia group, no significant effect of the factor "side" , nor when the results from the muscle supplied by the unlesioned nerve  were included . MT in the neuralgia group was 55.5 ± 10.2% at the affected and 55.0 ± 10.6% at the unaffected side when recordings were drawn from a muscle supplied by the lesioned nerve, and 56.0 ± 8.8% at the affected and 54.5 ± 9.4% at the unaffected side when recordings were drawn from a muscle supplied by the unlesioned nerve. In the osteoarthritis group, MT was 52.5 ± 9.7% at the affected and 51.8 ± 10.0% at the unaffected side, and in the control subjects 58.2 ± 9.7% at the left and 55.9 ± 9.4% at the right hand.There was no significant effect of one of the factors, neither when the results from the muscle supplied by the lesioned nerve  were included in the analysis .In order to further differentiate between the repercussion of neuropathic pain and the repercussion of peripheral nerve lesion on ICI, patients with peripheral nerve lesion were divided into two separate groups according to their current pain intensity as assessed by numeric rating scale (NRS). Neuralgia patients with NRS≥4 were considered to have moderate/severe pain, patients with NRS<4 to have mild pain ,17. Two There was no significant correlation between ICI and the relative amplitude of the compound muscle action potential (CMAP) after supramaximal electrical stimulation of the lesioned nerve at the wrist , neither when the recordings were drawn from a muscle supplied by the lesioned nerve , nor when the recordings were drawn from a muscle supplied by the unlesioned nerve . There was no significant correlation between ICI and the pain duration either.Our main finding was a significant reduction of ICI in the motor cortex contralateral to the affected hand in neuralgia patients, whereas painful osteoarthritis patients showed no abnormalities of ICI with respect to an age-matched control group.In patients with entrapment of the median nerve at the carpal tunnel, which constituted a subgroup of patients in our study, it was previously shown that the chronic pathological modification of peripheral sensorimotor inputs leads to an enhanced excitability and a reorganization of the somatotopic map in the contralateral primary somatosensory cortex (S1) -21. SimiOur results in neuralgia patients resemble the changes of ICI observed in the contralateral motor cortex of patients with upper or lower limb amputation ,13. GiveIn our study, the reduced ICI was not restricted to recordings drawn from a muscle supplied by the affected nerve, but was also present when recordings were drawn from a muscle supplied by an unaffected nerve, indicating a more widespread lack of inhibition in the hand area of the hemisphere contralateral to the lesioned nerve. This finding points at reorganizational processes in areas adjacent to the cortical representation of the lesioned nerve. It is in line with findings in patients with upper limb amputation, who also exhibited reorganization in the cortical representation of proximal stump muscles ,27. BesiAs a possible methodological problem, the MEP responses recorded from the APB muscle might have been contaminated by responses from ulnar muscles of the thenar eminence, and therefore contain information from muscles supplied by the lesioned as well as from muscles supplied by the unlesioned nerve. However, since ICI did not significantly differ between patients with median and ulnar nerve lesions, this might not have influenced our results.In previous studies, it has been shown that the intensity of the TS is critical for the assessment of ICI, and that differences in TS intensities might confound ICI comparisons ,30. EspeMotor cortex disinhibition was only seen in the neuralgia group, whereas the osteoarthritis patients did not differ from the control group. In osteoarthritis, pain is thought to arise as a consequence of physiological activation of primary nociceptive afferents by tissue-damaging stimuli and processing of this activity within the nociceptive system, whereas in chronic neuropathic pain such as neuralgia, pain arises by activity generated within the nociceptive system without physiological stimulation of nociceptors . This diThe finding of a pain-related motor cortex disinhibition in patients with chronic neuropathic, but not in chronic nociceptive pain may have an impact on our understanding of the therapeutical use of invasive or non-invasive motor cortex stimulation in chronic pain conditions. The restoration of defective ICI might be a crucial mechanism to achieve pain relief in chronic neuropathic pain, as previously demonstrated by means of rTMS applied to the motor cortex . InteresOur results suggest a close relationship between motor cortex inhibition and chronic neuropathic pain in the neuralgia patients, which is independent from nerve injury severity. The lack of cortical disinhibition in patients with painful osteoarthritis points at differences in the pathophysiological processes of different chronic pain conditions with respect to the involvement of different brain circuitry.We studied 26 patients  with isolated incomplete lesion of the median (n = 16) or ulnar (n = 10) nerve as revealed by previous clinical and electroneurographical/electromyographical examination. In all patients, the relative amplitude of the distal compound muscle action potential (CMAP) after supramaximal electrical stimulation of the lesioned nerve at the wrist  was determined, and served as a measure of nerve injury severity. All patients had a history of ongoing or intermittent neuropathic pain  due to the peripheral nerve lesion. Peripheral nerve lesion was due to trauma in 14 patients, due to entrapment of the median nerve at the carpal tunnel in ten patients, and due to entrapment of the ulnar nerve at the elbow in two patients. Patients with concomitant neurological disorders were excluded. The patients' age was between 24 and 77 years (mean 50.9 ± 11.7 years), and duration of the neuralgia between 3 and 190 months (mean 39.3 ± 44.8 months). The patients did not take any central acting drugs when participating in the study. Immediately before starting the TMS session, the current pain intensity was assessed, and the patients were also asked to retrospectively judge the mean and maximum ongoing pain intensity during the week prior to the TMS session using a numeric rating scale . Clinical details of the neuralgia patients are reported in Table In addition, 20 patients with unilateral painful primary degenerative osteoarthritis of the hand as a model of nociceptive, non-neuropathic pain  were examined. A concomitant neurological disorder was excluded by clinical examination performed by an experienced neurologist (PS). Clinical details of the osteoarthritis patients are also reported in Table Results obtained in the patients were compared with results recorded from a control group of 14 right-handed healthy volunteers . All subjects participating in the study gave their informed consent. The study was approved by the ethical committee of the Ruhr-University Bochum.TMS was performed using a bistim module, which was connected to two Magstim 200 stimulators . The stimuli were applied through a circular coil (outer diameter 14 cm) positioned over the vertex with the current flowing anticlockwise in the coil in order to activate predominantly the left hemisphere, and clockwise in order to activate predominantly the right hemisphere. Earlier studies had shown that focal and circular coils elicited comparable results in paired-pulse studies . While sTo control for a possible influence of TS intensity on results of ICI and ICF, TS intensity (which had been adjusted to achieve an unconditioned MEP of approximately 1 mV) relative to MT was calculated and compared between groups.To analyze excitability parameters, results obtained at the neuralgia patients' affected side from the muscle supplied by the lesioned nerve were considered separately from results obtained from the muscle supplied by the unlesioned nerve. An ANOVA for repeated measurements was calculated, with "side" (affected vs. unaffected) as within-subjects factor, and "group"  as between-subjects factor, to analyze the different parameters. In the control group, the left hand was defined as the affected side, and the right hand as the unaffected side for statistical purposes. Greenhouse-Geisser procedure was used with epsilon-corrected degrees of freedom, if data showed significant deviations from sphericity. Paired and unpaired t-tests were used for post-hoc analysis if the ANOVA revealed a significant effect for one of the factors, or a significant interaction between factors. Single-factorial ANOVA was used to compare patients' age between groups, and unpaired t-tests to compare current, mean and maximum pain intensity as well as pain duration between neuralgia and osteoarthritis patients. Unpaired t-tests were also used to compare excitability parameters between subgroups of neuralgia patients with or without hypesthesia, dysesthesia, mechanical allodynia or muscle paresis, between neuralgia patients with lesions of the median or ulnar nerve, and between neuralgia patients with moderate/severe (NRS≥4) or mild (NRS<4) current pain intensity. A paired t-test was used to compare MT determined in both a muscle supplied by the lesioned nerve and a muscle supplied by the unlesioned nerve in neuralgia patients. Additionally, Cohen's d as an indicator of effect size was calculated if t-tests yielded a significant p value. Cohen's d is generally interpreted as follows: ≥1.0 very large; ≥0.8 large; ≥0.5 moderate; 0.2-0.4 small .Pearson's correlation coefficient was calculated in order to detect a possible relationship between excitability parameters and pain duration, as well as between excitability parameters and the relative CMAP amplitude as a parameter of peripheral nerve injury severity.For all statistical tests, the SPSS 14.0 software package  was used, and significance was assumed at the 0.05 level.PS, AKR and OH conducted the TMS experiments, performed the statistical analysis and drafted the manuscript. AS, MT and CM participated in the design and coordination of the study, and in the discussion of the results. All authors read and approved the final manuscript.


Dextromethorphan, the D-isomer of the codeine analog levorphanol, is a weak, noncompetitive N-Methyl-D-Aspartate (NMDA) receptor antagonist. It has been suggested that NMDA receptor antagonists induce preemptive analgesia when administered before tissue injury occurs, thus decreasing the subsequent sensation of pain.The study was conducted in the Dr. Ali Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran, between February 2005 and December 2006. In this study, 72 patients scheduled for elective cholesyctectomy were randomized into three groups to receive either oral dextromethorphan 45 mg (Group D45 = 24), dextromethorphan 90 mg (Group D90 = 24), or placebo , as premedication, 120 minutes before surgery. A visual analog scale (VAS) for pain of each patient was measured at arrival in the ward and six and 24 hours after surgery.The demographic characteristics of patients, ASA physical status class, duration of surgery, and the basal VAS pain score were similar in the two groups. There was no significant difference in the mean of the VAS pain scores measured over time or morphine consumption among the three groups.Dextromethorphan 45 mg and 90 mg, administrated orally, two hours before surgery, had no effect on postoperative morphine requirement and pain intensity. Opioids are frequently administered to patients undergoing major surgery to alleviate postoperative pain, however, they may cause adverse effects such as nausea and vomiting, pruritus, urinary retention, and respiratory depression.As the analgesia and the side effects of opioids are dose-dependent a multimodal offset may enhance analgesia, while minimizing the side effects.Dextromethorphan (DM), the D-isomer of the codeine analog levorphanol, is a weak, noncompetitive N-Methyl-D-Aspartate (NMDA) receptor antagonist that has been used as an antitussive drug for more than 40 years.3It has been suggested that NMDA receptor antagonists induce preemptive analgesia when administrated before tissue injury occurs, thus decreasing the subsequent sensation of pain.3 There iThe purpose of the current study is to determine whether preoperative administration of 45 mg and 90 mg of oral DM would reduce postoperative pain and opioid consumption in comparison with a control group.The study was conducted in the Dr. Ali Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran, between February 2005 and December 2006. The proposal was approved by the Institutional Ethics Committee and informed written consent was obtained from the patients. Seventy-two patients, 25-50 years, classified as ASA physical status I and II, who were undergoing open cholesyctectomy (midline approach) under general anesthesia, were enrolled in this randomized, double-blinded, and placebo-controlled study.Patients who received opioids within 48 hours of surgery and sedatives or centrally acting drugs  21 days prior to surgery; those with a history of chronic pain, psychotic disorders or addiction including opioids, those with any contraindications to DM, and pregnant or lactating women were excluded from the study. All participants were given full explanations of DM and the visual analog scale for pain (VAS) on the day before surgery.All drugs were given by an anesthesiologist who was not involved in patient observation, thus both the observer and patients were blinded to the group assignment. Patients were randomly assigned into three groups of either control , DM 45 mg , or DM 90 mg,  using a computer-generated randomization list.The patients in group C received placebo, group D45 received 45 mg DM, and those in group D90 received 90 mg DM orally, 120 minutes before surgery. Placebos were similar capsules containing sucrose.2O (50%); 0.05 mg/kg cisatracurium and 0.2 μg/kg sufentanyl were administered half hourly. Ventilation was adjusted to maintain normocapnia . Patients were actively warmed to keep core temperature  normothermic. At the start of the skin suturing, drug administration was stopped and the neuromuscular block was antagonized by IV administration of 2.5 mg of neostigmine, along with 1.25 mg of atropine. The patients were considered to be awake when they opened their eyes on demand or after gentle tactile stimulation; they were later extubated.On arrival in the operating room, all patients were monitored with an electrocardiogram (ECG), noninvasive blood pressure, and pulse oximetry. An 18-gauge cannula was inserted and lactated ringer solution 7 ml/kg was administered. Anesthesia was induced with 2 mg/kg propofol and 0.3 μg/kg sufentanyl; and endotracheal intubation was facilitated with 0.15 mg/kg cisatracurium. After tracheal intubation, anesthesia was maintained by isofluran and NThe severity of postoperative pain was measured and recorded using a 10 cm VAS, where 0 = no pain and 10 = the worst possible pain. The patients were asked to score the pain during coughing or movement at arrival in the ward, and 6 and 24 hours after surgery. The patients could request rescue analgesia at any time. Morphine, 0.1 mg/kg, was given as rescue analgesia at eight-hour intervals.P < 0.05 was taken as significant.According to the previous studies, a sample size of 24 in each group would be sufficient to detect a difference of three scores in the mean of the pain score, and to estimate a power of 80% and a significance level of 5%. Statistical analysis was performed using SPSS package , version 11.5. Normality of distribution was checked as needed. For statistical analysis of demographic data and for comparison of groups, one way ANOVA, repeated measure analysis of variance, Fishers exact or Chi-square tests were appropriate. Two tailed We randomized 72 patients. Three patients were excluded from the study because of surgical complications (two from C group and one from D45 group).Demographic characteristics of patients, ASA physical status class, and the duration of surgery were similar in the two groups .There were no significant differences in the mean of the morphine consumption (12.39 ± 5.24 mg in the D45 group and 13.71 ± 4.28 mg in the D90 group versus 11.88 ± 5.29 in the C group) and the time for first morphine request (3.1 ± 1.7 hours in the D45 group and 3.2 ± 1.9 in the D90 group versus 2.9 ± 1.1 in the control group) .There was no significant difference in the mean of VAS pain scores measured over time among the three groups  .The current study demonstrates that in patients undergoing open cholecystectomy, oral premedication with 45 or 90 mg DM or morphine consumption did not decrease postoperative pain intensity when compared with patients who received placebo.Our findings are not consistent with the earlier reports that dextromethorphan reduces pain and analgesic requirement after various surgeries.–10N-methyl-D-aspartate receptor antagonism inhibits wind up or central hypersensitivity of the dorsal horn neurons in response to noxious stimulation.11 Dextro21214The ability of DM to attenuate pain is controversial. Not all investigators agree that DM reduces opioid consumption or acute pain. Although DM has been used successfully as premedication for postoperative pain and morphine consumption reduction in some investigations,–10 otheret al. studied 50 patients undergoing non-malignant elective abdominal hysterectomy. The study was a double-blinded, randomized design that compared postoperative analgesia requirements and pain scores in patients who received preoperative DM or placebo. DM reduced morphine requirements in this sample and a modest (but non-significant) reduction in pain scores was found. They found that oral dextromethorphan 150 mg reduced PCA morphine consumption immediately (0-4 hours) after hysterectomy, without prolonged effects of pain or wound hyperalgesia.[Ilkjaer ralgesia.et al. failed to demonstrate the specific opioid sparing effect expected from DM administration. In this 66 patient experimental sample, the investigators concluded that DM did not improve acute pain scores even at high doses.[Thematic of the controversy surrounding the role of DM in acute pain management, Wadhaw gh doses.Many surgical procedures were included in both positive and negative studies, and there did not appear to be one specific procedure that yielded more benefit than the other. In the dextromethorphan studies, four negative studies used the oral route, and in two of these trials, at smaller doses of the drug, there was no direct analgesic effect of the intervention.–19The NMDA blocking properties of DM are probably less potent compared to ketamine. It is poFurther investigations are required to determine whether larger doses or repeated doses of oral dextromethorphan will attenuate postoperative pain. However, undesirable side effects of dextromethorphan, including sedation and ataxia, are common in adults when the dose is increased above that recommended for antitussive therapy and may limit the usefulness of this strategy.The power analysis for this study indicated that there were sufficient numbers of patients in each group to detect 25% reduction in morphine use and 30 mm reduction in VAS for pain on moving.Dextromethorphan, 45 mg and 90 mg, administrated orally two hours before surgery had no effect on postoperative morphine requirement or pain intensity.