High Frequency electrical Stimulation (HFS) of the skin induces enhanced brain responsiveness expressed as enhanced Event-Related Potential (ERP) N1 amplitude to stimuli applied to the surrounding unconditioned skin in healthy volunteers. The aim of the present study was to investigate whether this enhanced ERP N1 amplitude could be a potential marker for altered cortical sensory processing in patients with persistent pain after surgery.Nineteen male patients; 9 with and 10 without persistent pain after inguinal hernia repair received HFS. Before, directly after and thirty minutes after HFS evoked potentials and the subjective pain intensity were measured in response to electric pain stimuli applied to the surrounding unconditioned skin.The results show that, thirty minutes after HFS, the ERP N1 amplitude observed at the conditioned arm was statistically significantly larger than the amplitude at the control arm across all patients. No statistically significant differences were observed regarding ERP N1 amplitude between patients with and without persistent pain. However, thirty minutes after HFS we did observe statistically significant differences of P2 amplitude at the conditioned arm between the two groups. The P2 amplitude decreased in comparison to baseline in the group of patients with pain.The ERP N1 effect, induced after HFS, was not different between patients with vs. without persistent pain. The decreasing P2 amplitude was not observed in the patients without pain and also not in the previous healthy volunteer study and thus might be a marker for altered cortical sensory processing in patients with persistent pain after surgery. High Frequency electrical Stimulation (HFS) of peptidergic primary C-fiber afferents induces Long-Term Potentiation (LTP) of excitatory synaptic transmission between these C-fibers and secondary lamina I dorsal horn neurons projecting to the parabrachial area in the brainstem In healthy human volunteers, similar HFS of peptidergic C-fibers in human skin results in increased pain sensitivity to single electrical pain stimuli activating the conditioned pathway (i.e. homotopic effect)In order to investigate central nervous system responsiveness after HFS we measured Event-Related Potentials (ERPs) in response to painful electrical stimuli applied to the unconditioned surrounding skin r = .35, p = .15)  which might indicate that although both effects are induced by the same conditioning stimulation they probably reflect different underlying processes.The fact that both phenomena; 1) a behaviorally increased sensitivity to mechanical stimulation and 2) an enhanced ERP N1 amplitude to electrical stimulation are observed at the same time and in the same skin area might suggest a relationship between the two. However, there was no significant correlation between the HFS-induced changes of mechanical punctate sensitivity and HFS-induced changes of evoked N1 amplitude . All patients signed an informed consent form.Nineteen male patients (9 with and 10 without persistent pain) who underwent inguinal hernia repair (i.e. open anterior mesh-based repair procedure) 6–7 years ago were randomly recruited from a clinical trial database of the Canisius-Wilhelmina Hospital Nijmegen ‘What is the averaged intensity of the inguinal hernia repair-related pain during the last three months on a numeric 0–10 rating scale?’). Other demographic and clinical characteristics that were obtained are: age, body weight, length, operation type, medication use and co-morbidity  was based on a question (obtained via interview by telephone) asking whether the patient experienced ongoing pain (yes or no) as a result of the inguinal hernia repair treatment. For confirmation, the same question was asked again on the day of measurement, together with an additional question (only if the patient experienced pain) regarding pain intensity as a measure of past experienced pain load (dity see .Data about the type of pain and pain-related sensory signs in the patients with pain were collected using the DN4 (Douleur Neuropathique 4) questionnaire All patients received trains of 100 Hz  for 1 sec. repeated 5 times at 10 sec intervals with an intensity of 20 × detection threshold on the forearm 5 cm distal to the cubital fossa. The stimulation trains were delivered via a constant current stimulator  and a specifically designed electrode able to activate peptidergic nociceptive afferents in the skin Changes in pain perception during experimental conditioning stimulation (HFS) were tested by asking the patients after each train to rate the amount of pain on a Visual Analogue Scale (VAS) ranging from 0 cm = “no pain” to 10 cm = “unbearable pain”.In order to quantify changes in central nervous system responsiveness as a result of experimental conditioning stimulation, blocks of twenty single painful electrical pulses  were applied to both arms (conditioned and control) before (t0), directly after (t1) and thirty minutes (t3) after experimental conditioning stimulation. We chose thirty minutes as a late measurement after conditioning stimulation because Klein et al. For the conditioned arm, the stimuli were applied at 2.5 cm outside the area of conditioning stimulation; on the control arm the same area was stimulated. The pulses were delivered with a random inter-pair interval ranging from 7 to 10 seconds via a concentric electrode (CE). Stimulation with this electrode produces a well localized pinprick-like painful sensation In order to quantify the amount of pain as a result of this test stimulation, subjects were asked to rate four times within the block of twenty stimuli, i.e., at random times within a set of 5 single pulses, the pain intensity of the last received stimulus on a VAS. The VAS ranged from 0 cm = “no pain” to 10 cm = “unbearable pain” and was used by the subject by moving the mouse pointer  on a horizontal bar.The electrical test stimuli were delivered via a constant current stimulator  and with an intensity of 150% of the individual pain threshold. This individual pain threshold was determined at the beginning of the experiment by delivering an ascending sequence of increased current intensities  starting from 0 mA and with steps of 0.1 mA. This procedure stopped when the pain threshold (pricking painful sensation) was achieved, as verbally reported by the subjects. This threshold determination protocol was performed twice and the mean was used in the experiment.During stimulation, subjects were comfortably seated in a chair and were instructed to passively perceive the stimuli with eyes closed, without making any movements. A computer display was placed in front of the subject (0.5 m) together with a computer mouse. The display was used to display the VAS, preceded by a tone (65 dB). Participants were instructed to open their eyes after the tone and use the mouse to mark the VAS, after which they closed their eyes again.In order to measure the evoked brain responses (ERPs) as a result of the heterotopic test stimulation, a multi-channel (28 channels) EEG (Brainvision system) was recorded . The electrodes were mounted in an elastic electrode-cap and arranged according to the international 10–20 system. Eye movements were detected by horizontal and vertical Electro-OculoGram (EOG) recordings . Horizontal EOG was measured from the outer canthus of the left eye, and vertical EOG supra orbitally to the left eye. Impedance was kept under the 20 kΩ for all leads. The (separate) reference electrode was placed in FCz.At the beginning of the experiment individual pain thresholds for the electrical pinprick-like test stimulation were determined. The arm on which this pain threshold was determined (conditioned or control arm) was balanced across patients. After this pain threshold determination patients received two blocks (one at each arm) of electrical pain stimuli (t0). The sequence regarding which arm was tested first was balanced across patients. After the baseline measurement (t0) the experimental conditioning (HFS) followed. After receiving conditioning stimulation two post measurements t1 (directly after conditioning stimulation) and t2 (thirty minutes after conditioning stimulation) followed. The procedures for these two post measurements were the same as for the pre measurement. Patients were instructed not to consume caffeine-containing beverages for twelve hours before the start of the experiment to avoid the caffeine-induced theta decrease in EEG The EEG was analyzed offline using the software Brain Vision Analyzer v. 2.0 and Matlab 2011a. As a first step the continuous EEG was referenced to a common average . Next, the EEG signal (500 Hz) was high-pass filtered at 1 Hz and low-pass filtered at 30 Hz. Based on the onset of the stimulus, the EEG was segmented into epochs from −100 ms pre-stimulus to 1000 ms post-stimulus with a total period of 1100 ms. Bad segments containing ocular artifacts were corrected using the Gratton-Coles method Individual ERP latencies were determined in the individual GFP plot corresponding to the windows of the grand average GFP latencies TIME of measurement (pre (t0) vs. post ) and ARM (control vs. conditioned). The between-subject factor was GROUP (patients with vs. without pain). The dependent variables were the pain VAS-score observed after each HFS train and during test stimulation and ERP (N1 and P2) amplitude and latency. In those cases where the data violated the assumption of sphericity the F-value was corrected by Greenhouse-Geisser. In all tests the level of significance was set at p<.05 (two-sided). For post hoc testing the p-value was Bonferroni corrected for the number of tests.For statistical analysis the software SPSS v. 18.0 was used . To statistically test whether there are differences in behavioral and electrophysiological measures after HFS between the two groups a General Linear Model (GLM) mixed design ANOVA analysis was performed. The within-subject factors were In four patients (three in the without pain group and one in the pain group) the conditioning stimulation had to be stopped before receiving all five trains because they could not tolerate the stimulation anymore. The patient in the pain group received only one train, one patient of the group without pain received two trains and two patients received three trains. They were excluded in the further statistical analyses.The demographical and clinical characteristics of both patient groups are shown in p>.7).The mean (and standard deviation) electrical detection thresholds used for conditioning stimulation (HFS) were 5.14 (1.68) mA for the patients without pain and 4.88 (1.96) mA for the patients with pain. No statistically significant differences in detection thresholds between the two groups were observed (independent t-test: p>.7).The mean (and standard deviation) intensities used for the electrical test stimuli were 3.30 (1.35) mA for the patients without pain and 3.51 (1.43) mA for the patients with pain. No statistically significant differences in electrical stimulation intensities between the two groups were observed  = 10.607, p = .002, η2 = .449). This means that the pain VAS-score differed between the different trains across all patients (with and without pain). Univariate within-subject contrasts showed that the perceived pain intensity statistically increased:Mean (and standard deviations) pain ratings for each subsequent train are: 5.8 (2.1), 6.3 (1.8), 6.8 (1.7), 7.0 (1.8), 6.7 (2.4) for the patients without pain and 5.3 (2.5), 6.1 (2.5), 6.7 (2.1), 7.1 (2.0), 7.2 (2.2) for the patients with pain. The GLM mixed design ANOVA analysis revealed a significant main effect of p = .001, η2 = .566, andbetween train 1 (M = 5.5) and train 2 (M = 6.2) : F  = 16.933, p = .005, η2 = .460, but not between:between train 2 and train 3 (M = 6.8) : F  = 11.060, p = .079, η2 = .218, andtrain 3 and train 4 (M = 7.1) : F  = 3.625, p = .580, η2 = .024.train 4 and train 5 (M = 7.0) : F  = .322, There were no statistically significant differences in perceived pain intensity (VAS scores) obtained after each train between the two groups see .Time  = 4.363, p = .053, η2 = .251). This means that when we ignore the different arms (control vs. conditioned) the pain VAS-score differed between the different measurements across all patients (with and without pain). Univariate within-subject contrasts showed that the perceived pain intensity (VAS-scores) was marginally signifcantly different between t0 (M = 3.0) and t1 (M = 2.4)  and also between t0 (M = 3.0) and t2 (M = 2.5) . There were no statistically significant differences in perceived pain intensity between the two groups.The GLM mixed design ANOVA analysis revealed a marginally significant main effect of The grand average evoked potential waveforms for both groups (with and without pain) and each measurement  and arm (conditioned vs. control) are shown in Time × Arm interaction effect for the N1 amplitude  = 5.435, p = .011, η2 = .295). This means that the N1 amplitude was statistically significantly different between the two arms at the different measurements across all patients (with and without pain). The univariate within-subject contrasts revealed that the N1 amplitude was different between the two arms thirty minutes after experimental conditioning stimulation  = 8.329, p = .013, η2 = .391). The N1 amplitude observed at the conditioned arm (M = −4.0) was larger than the N1 amplitude observed at the control arm (M = −1.4)  .p = .016]. There were no statistically significant differences in N1 amplitudes between the two groups.Post-hoc testing revealed that thirty minutes after HFS the N1 amplitude of the control arm (M = −1.4) was significantly lower than the amplitude observed at baseline  .The univariate within-subject contrasts revealed that the amplitude was statistically significant different between the two groups between t0  = 5.108, p = .013, η2 = .282). The P2 amplitude was statistically significantly different between the two arms at the different measurements and between the two groups. Only the univariate contrast that compared the P2 amplitude between t0 and t2 regarding two arms (conditioned vs. control arm) and between the two groups (patients with vs. without pain) was significant  = 6.488, p = .024, η2 = .333). At baseline the difference in P2 amplitude between the two arms was similar for both groups: patients without pain ; patients with pain . Thirty minutes after HFS (i.e. t2) this difference became larger in the patients with pain compared to the patients without pain. The P2 amplitude of the control arm in both groups was similar at t2: patients without pain (Mcontrol arm = 5.1); patients with pain (Mcontrol arm = 5.0), while the P2 amplitude of the conditioned arm in the patients with pain was smaller (Mconditioned arm = 2.1) than in the patients without pain (Mconditioned arm = 6.2).The GLM mixed design ANOVA also revealed a statistically significant p<.012].Post hoc testing revealed that in the patients with pain the P2 amplitude observed at the conditioned arm at t2 (M = 2.1) significantly decreased in comparison to t0 (M = 4.3) [t (7) = 3.636, No statistically significant differences on P2 latency were observed after conditioning stimulation between arms and/or groups.The aim of this study was to test the hypothesis that the effect of HFS on the ERP N1 amplitude thirty minutes after HFS is different in patients with pain compared to patients without pain. In agreement with the previous healthy volunteer study Surprisingly, we did observe statistically significant ERP P2 amplitude differences thirty minutes after HFS between the two groups of patients. Post hoc testing revealed a significant decrease of the P2 amplitude at the conditioned arm in the patients with pain. This P2 amplitude effect might be a marker for altered cortical sensory processing in patients with persistent pain.High frequency electrical stimulation of human skin typically induces a behaviorally increased sensitivity to mechanical stimulation in the surrounding unconditioned skin In contrast to the lack of increase of perceived pain intensity after HFS, we did observe a statistically significant decrease directly, and thirty minutes after HFS. One explanation could be that this decrease reflects habituation; a decrease in response to a stimulus when that stimulus is presented repeatedly Despite the lack of sensitivity of an electrical stimulus in detecting the behavioral correlate of the induced heterotopically increased sensitivity after HFS we continued to use it in the present experiment. Firstly, because we wanted to compare the outcomes of this experiment with the ones of the healthy volunteer study In agreement with the healthy volunteer study The present study shows that there are no differences in ERP N1 effect -induced after HFS- between the two groups of patients. Nevertheless, it would be interesting to investigate in detail what process this ERP N1 effect reflects.Interestingly, thirty minutes after HFS a decrease of P2 amplitude at the conditioned arm is observed in the patients with pain. This effect is unexpected because it is not observed in the previous healthy volunteer study The amplitude decrease might reflect a similar phenomenon as the one observed by Valeriani et al Electrical stimulation applied via a concentric intra-epidermal electrode seems capable in activating Aδ fibers selectively provided that low stimulation intensities are used  One of the important methodological limitations of this study is the small sample size. Nevertheless, substantial effect sizes are observed which supports the relevance of our findings. Hence, future studies with larger sample sizes are necessary to confirm the results of the present paper.This is the first study that investigated the effects of HFS in patients with persistent pain after surgery. It shows that the ERP N1 effect induced after HFS was not different between patients with and without persistent pain. Surprisingly, we did observe a difference in P2 amplitude between the patients with and without pain. The decreased P2 amplitude might be a marker for altered cortical sensory processing in patients with persistent pain after surgery.


Purpose. Percutaneous ganglion balloon compression (PBC) is a minimally invasive procedure for treatment of trigeminal neuralgia. Materials and Methods. Twenty-seven  patients, who presented with classical symptoms of trigeminal neuralgia, were included. Age ranged from 34 to 91 years (median 62 years), 33 procedures were performed. Duration of the symptoms ranged from 1 year to 30 years (median 5 years). Results. After the procedure, pain relief was reported in 25 (93%) patients. In two patients, the pain remained the same. The pain free period ranged from 2 to 74 months (median 15 months). A mean duration of analgesia was longer in patients with ideal pear shape of balloon at the time of the procedure compared to nonideal shape (P = 0.01). No major complications occurred in our group of patients. Conclusions. Percutaneous trigeminal ganglion balloon compression is a safe, simple, and effective method for temporary pain relief in a selective group of trigeminal neuralgia patients. The diagnosis and medical management of trigeminal neuralgia (TN) can be one of the most frustrating and rewarding challenges in neurosurgical practice. Exact cause of it is not known, and various types of treatment modalities are possible, and yet no surgical treatment for TN meets ideal requirements . TN is dAccording to the classification of the International Headache Society, TN can be classified as classical or idiopathic and on symptomatic or secondary , 6. BurcPathophysiology is not completely understood. Ephaptic conduction caused by segmental demyelination and artificial synapse formation is speculated to be the cause –11. In eDiagnosis of TN is based on history. Classical symptoms of TN include paroxysmal, “electric” pain in the trigeminal distribution on one side of the face; trigger areas that, when stimulated by cold air, washing, speaking, eating, or touch, bring this classic type of pain; periods of remission and exacerbation; pain that is typically more severe in the morning and absent during sleep; periodic pain relief when treated with an adequate trial of carbamazepine. The physical exam is generally normal in TN. Trigeminal sensory deficits, bilateral involvement, abnormal trigeminal reflexes, and herpetic vesicles are signs of symptomatic TN. Magnetic resonance imaging (MRI) is used not only to identify patients with structural causes—tumors, MS, but also to demonstrate neurovascular conflict , 9. In dWithin a ten-year period (from 2000 until 2010), 33 PBC were performed in 27 patients at the Department of Neurosurgery of UCC Maribor. There were 19 female and 8 male patients. Age ranged from 34 years to 91 years (median 62 years). Patients included in the study were suffering from classical symptoms of trigeminal neuralgia, 22 cases had nature of type 1 TN and 11 cases of type 2 TN. One patient had bilateral trigeminal neuralgia, 16 patients were affected on the right side and 10 on the left side. All patients were treated with medications prior PBC without sufficient pain relief. The median duration of the symptoms before PBC was 5 years, ranged from one year to 30 years, 5 patients had already undergone surgery, among them three previously had MVD, one alcohol rhizotomy, and one section of the trigeminal sensory root. On 27 patients 33 procedures were performed—three patients had two procedures on the same side and one patient had four procedures, three on the same side and one on the other side.For PBC Mullan percutaneous trigeminal ganglion microcompression set  was used. Patient was positioned supine on the operating table. Procedures were done in general anesthesia with a short-acting anesthetic agent. X-ray control of pyramid and foramen ovale was performed. A specially designed 14-gauge needle with thin stylet was passed 6 cm into the depth towards foramen ovale through entry point located 2.5 cm lateral to the corner of the mouth . Forament-test for numeric variables and Kaplan-Meier analysis for duration of analgesia. Statistically significant were values with P < 0.05. The software used was SPSS 17.0.The medical and surgical records of all patients were retrospectively reviewed and analyzed. The following data were collected: gender, age, side of trigeminal neuralgia, duration of symptoms prior PBC in years, previous surgical procedures, time of balloon inflation in minutes, the shape of the balloon, number of consecutive PBC, type of pain, complications during and after procedure, hypoesthesia after PBC, duration of analgesia after PBC in months, need for analgesics after 12 months, and procedures done after PBC. Descriptive statistical analysis was performed and patients' parameters were statistically analyzed with Fischer exact test for descriptive variables, independent Student's After one or more procedures pain relief was reported in 25 (93%) of patients. In two patients the pain remained the same. Pain-free period in remaining 25 patients ranged from 2 to 74 months with mean value 15 ± 13.2 months .P = 0.38). Analgesic consumption after 12 months was none or lower in type 1 TN in 17 cases (77%) and in type 2 TN in six cases .Twelve months after the PBC patients needed less analgesics than before PBC in 22 (67%) cases and no analgesics in one (3%) case. In 8 (24%) cases the needed dose of analgesic was the same and in two (6%) cases patients needed more analgesic than before PBC. In the case of pain recurrence a brief period of increased medical therapy was sufficient to control the pain. In refractory patients another procedure was performed. After repeated procedure patients remained pain-free with minimal medication for additional 6–12 months. There were 22 cases of type 1 TN and 11 cases of type 2 TN. We found no statistically significant difference between types of TN in respect to gender or age. Number of previous procedures was higher in type 2 TN (6 out of 11 in type 2 TN and 6 out of 22 in type 1 TN), but it was not significant. The mean duration of symptoms prior PBC was in type 1 TN seven years and in type 2 TN eight years. Hypoesthesia after PBC was found in 13 (59%) cases of type 1 TN and six (55%) in type 2 TN. Duration of analgesia after PBC was in type 1 TN 15 ± 15.4 months and in type 2 TN 12 ± 7.6 months (P = 0.76).We analyzed correlation between clinical parameters before PBC and outcome of the procedure . Outcomes were compared in dependence of gender, age of patients (60 years and younger versus 61 years and older), duration of symptoms (5 years and less versus 6 and more years), and previous surgical treatment. None of the parameters showed statistically significant correlation with outcomes. However, mean duration of analgesia was longer in females, younger patients and shorter duration of symptoms before PBC. According to previous surgical treatment mean duration of analgesia was almost the same with or without previous surgical treatment. Use of analgesic at 12 months was generally with all parameters lower than before PBC. Results are summarized in P = 0.01). In seven out of 33 procedures premature balloon rupture occurred, without any immediate consequences for the patients. Three patients developed cheek hematoma; this subsided with cold compression. In nineteen cases mild to moderate degree of transient ipsilateral facial sensory loss—numbness was noted.No major complications occurred in our group of patients. Non-ideal shape of the balloon was reported in 8 (24%) procedures. A mean duration of analgesia was longer in patients with ideal pear-shape of balloon at the time of the procedure (17.4 ± 13.7 months) compared to non-ideal shape (4.4 ± 4.0 months)  the patient's medical condition, (2) previous procedures, and (3) the patient's willingness to accept the associated risks and benefits of each procedure.Percutaneous techniques are recommended for elderly patients with higher operative risk factors. In general, PBC should be reserved for patients rejecting or not suitable for MVD. Contraindications for PBC are rare. Caution is needed in the case of the contrast agent allergy because rupture of the balloon catheter can occur. In case of recurrence after PBC, the patient may be treated with carbamazepine. It provides satisfactory relief at a tolerably low dose. If carbamazepine fails, PBC may be repeated. Advantages of PBC with comparison of other surgical options for treatment of TN are minimal invasiveness, high portion of pain-free patients after procedure, and low incidence of complications.


Twenty-two patients with enduring pain after a rear impact car accident (Whiplash Associated Disorder grade II) and 14 healthy controls were investigated. Patients displayed significantly elevated tracer uptake in the neck, particularly in regions around the spineous process of the second cervical vertebra. This suggests that whiplash patients have signs of local persistent peripheral tissue inflammation, which may potentially serve as a diagnostic biomarker. The present investigation demonstrates that painful processes in the periphery can be objectively visualized and quantified with PET and that 11C-D-deprenyl is a promising tracer for these purposes.There are few diagnostic tools for chronic musculoskeletal pain as structural imaging methods seldom reveal pathological alterations. This is especially true for Whiplash Associated Disorder, for which physical signs of persistent injuries to the neck have yet to be established. Here, we sought to visualize inflammatory processes in the neck region by means Positron Emission Tomography using the tracer  Chronic musculoskeletal pain syndromes are common, cause extensive individual suffering and place a large burden on health care in society. Yet, pain remains notoriously difficult to visualize and diagnose objectively. Furthermore the pathophysiology of persistent pain is elusive and there is a great need for ways to visualize and quantify pain mechanisms. One common chronic pain syndrome is Whiplash Associated Disorder (WAD), where the onset is a soft tissue sprain of the neck caused by a rear end motor vehicle collision or a similar trauma. The injury is usually benign 11 (S-(+)-(d)-D-deprenyl, or DDE). High DDE retention has been demonstrated in the synovium in arthritic knee joints One candidate PET tracer for musculoskeletal injuries and inflammation is CTwenty-two patients  with chronic neck pain after car accident involving whiplash trauma were recruited through hospital patient registries. 12 of the patients experienced a rear end collision, 5 patients experienced combined lateral and frontal collisions. Detailed collision descriptions were not available from 5 patients. All patients were diagnosed with whiplash associated disorder (WAD) grade II Fourteen healthy control subjects were also investigated. Control group A consisted of eight healthy and pain free volunteers  recruited through advertisements. Control group B consisted of six patients with acute musculoskeletal pain (sprained ankle), but otherwise healthy and without current or prior neck pain . General exclusion criteria for patients and controls were psychiatric disorder, somatic disease, substance abuse and pregnancy. The study was approved by the local ethical review board  and the local radiation protection committee . All participants provided written informed consent before entering the study.Prior to the PET investigation, participants rated their pain intensity on a 0-100 visual analogue pain scale (VAS), and completed the state portion of the Spielberger State Trait Anxiety Inventory (STAI-s) Carbon-11 marked DDE was produced for each PET investigation at GE healthcare, Uppsala Imanet following published procedures During the course of the study, a new PET-CT  was installed and control subjects were investigated on this scanner, allowing for fusion of PET and CT images giving higher confidence in anatomical definitions. As different scanners were used for patients and controls, three of the 22 WAD patients were first investigated in the PET scanner and then also reinvestigated in the PET-CT scanner in order to ensure reproducibility across the two scanners. The time between these two investigations was about one month.Control group A  was investigated on the PET-CT scanner, which has 24 rings of bismuth germinate crystal detectors. This scanner enabled the acquisition of 47 contiguous planes of data with a distance of 3.27 mm, resulting in a total axial field of view of 15.7 cm Images were first analyzed visually and locations of elevated tracer retention were specified with guidance from anatomical atlases and CT images when available. To quantify DDE retention, a series of regions of interest (ROIs) were defined in each subject. ROIs of identical size and shape were delineated in (I) a sphere in the non glandular regions with the most elevated retention, , (II) a sphere left or right of the spineous process of axis , (III) a sphere in the spongeus bone of the cervical vertebra 2 through 6 (vertebra ROIs), and (IV) a larger prolate spheroid in muscle tissue region without visually evident elevated retention (muscle ROI), see Three patients were imaged with both the Siemens HR+ PET and the GE discovery PET-CT system. Reproducibility across scanner type and session was evaluated by extracting the SUV TAC data at the 12 time points for the above specified ROIs from each subject in both PET scans. In addition, two more peak ROIs were generated for the regions with the second and third highest tracer uptake in each patient. As a metric of test reproducibility, the Pearson product moment coefficient of determination was calculated for SUV values at all time point from the HR+ and the PET-CT system in each patient for each ROI. See Several soft tissue regions displayed visually evident elevated tracer retention in WAD patients, see WAD patients had significantly higher DDE retention than controls in tissue regions adjacent to spineous process of the second vertebra , in the normal muscle tissue (p = 0.027) and in the peak soft tissue ROI (p = 0.035), but similar levels in the in the spongeus bone of the cervical vertebra (p = 0.48) see Peak retentions were located around the spineous process of C2 in most patients, and also at the insertion of rectus capitis posterior major in the occipital bone, see Patients reported significantly elevated VAS neck pain ratings (patients (n = 22) mean ±SD = 47±21, control group A (n = 8)  = 4±8, p<0.001). Control group B (n = 6) reported pain due to their acutely sprained ankle pain at rest , but no neck pain. Patient's ratings of neck disabilities (NDI) were also significantly elevated (patients (n = 22) mean ±SD = 18±5, controls (n = 8)  = 2±1). No differences were found with respect to ratings of anxiety (STAI-s) at the time of investigation (patients (n = 22) mean ±SD  = 31±7, controls (n = 8)  = 30±5). Within the patient group, VAS pain ratings displayed a trend towards a positive correlation with DDE uptake in the C2 ROI .2) between the first and the second scan in SUV measures of the vertebra and muscle tissue was r2 ≥0.74 (p<0.001). In the presumably abnormal soft tissue peak ROIs, r2 was ≥0.63 (p<0.001). In the right and left C2 ROI's the lowest observed r2 was ≥0.93 (p<0.001) and r2 ≥0.86 (p<0.001) respectively. See also The test reproducibility between the two PET scanners used was high in all ROIs for the three subjects investigated on both scanners. The lowest observed coefficient of determination  from the dynamic PET-data show a rapid increase in the first frames followed by a plateau in the last frames as with specific binding or trapping of the tracer. In regions with high blood flow, such as the carotid artery , there w18F] fluorodeoxyglucose (FDG) PET is used to detect tumors, an uptake somewhat resembling the current finding has been observed in patients who are cold The main limitation of this study is that we do not yet know the exact mechanism of the increased DDE uptake. (S-(+)-(d)-D-deprenyl is the mirror isomer of L-deprenyl, a well established MAO B inhibitor also known as selegeline This study represents a phase 1 diagnostic study The present investigation demonstrates that painful processes in the periphery can be objectively visualized and quantified with PET and that DDE can be regarded as a promising tracer for these purposes. A large subset of patients with chronic pain after a whiplash injury displayed elevated DDE retention, suggestive of persistent peripheral tissue inflammation. The possibility to visualize and quantify sites of inflammation in chronic pain may be very useful in diagnosis and treatment monitoring. Inflammation imaging may also guide in examining and specifying mechanisms in debilitating chronic pain.Figure S1Patient A, B and C scanned in both the Siemens HR+ PET (top row) and the GE Discovery PET-CT (bottom row). Data is expressed as SUV values normalized for bodyweight and injected dose.(TIF)Click here for additional data file.


The aims of this study were to examine whether patients’ psychosocial profiles influence the location of pain, and to identify the clinical and psychosocial predictors of high levels of pain-related disability in temporomandibular disorders (TMD) patients with chronic pain at least 6 months in duration.The Research Diagnostic Criteria of TMD (RDC/TMD) data for Axis I and II were obtained for 104 consecutive patients seeking treatment.t-test, Mann–Whitney U-test, chi-square test, One-way ANOVA, Kruskal-Wallis test, and binary multiple logistic regression tests. Patients were classified into two groups according to Graded Chronic Pain Scale scores: Grade III and IV were scored for patients with high levels of pain-related disability, whereas Grade I and II were scored for patients with low disability.Data were analyzed using descriptive statistics, Muscle and joint pain were found in 64.9% and 31.8% of the patients, respectively, and 27.3% of the patients suffered from both muscle and joint pain.Psychosocial disability was found in 26% of patients. There were no statistically significant differences among the diagnostic subgroups with regards to the demographic, behavioral, psychological, and psychosocial characteristics. Patients with high levels of pain-related disability had significantly higher depression, somatization, pain intensity and jaw disability scores than those with low levels of pain-related disability.Patients with high levels of pain-related disability were more likely to have higher pain intensity, to report higher somatization symptoms and functional impairment, and were less likely to have joint pain than those with low levels of pain related disability.In conclusion, the Turkish version RDC/TMD, based on a dual axis system, may be used to screen chronic TMD patients at high-risk for pain-related disability who need comprehensive care treatment program. Temporomandibular disorders (TMD) are now recognized as a group of biopsychosocial illnesses characterized by chronic painful conditions and dysfunction in the muscles of mastication and the temporomandibular joint -4. The cResearchers have reported that pain-related disability is associated with widespread pain ,28, the Previous studies suggested that TMD patients with muscle disorders may present a higher rate of psychosocial impairment than those with articular disorders ,26,35,36Recent studies from Turkey showed that jaw pain is the most frequently reported symptom of TMD in adult population , while mResearchers suggested that further studies are required to improve the integrated knowledge on the relationship between the different axis I and II diagnoses and it may provide valuable information regarding the clinical predictors of high levels of pain-related disability that influence clinical decision-making process ,42. To oThe aims of this study were, (a) to examine whether patients’ psychosocial profiles influence the location of pain , and (b) to identify the clinical and psychosocial predictors of high levels of pain-related disability in TMD patients with chronic pain at least 6 months in duration.This cross-sectional study was carried out on a series of consecutive patients seeking treatment for the complaints regarding the masticatory muscles and TMJ in the Department of Prosthodontics, Faculty of Dentistry, Istanbul University, between July and September 2012. A total of 104 patients  were selected from 152 consecutive patients who referred to the Department of Prosthodontics. Of the 104 patients who were enrolled, 43 were self-referred and 61 were referred from general and specialist dental or medical practitioners in the community. The inclusion criteria were the presence of a painful TMD as classified according to RDC/TMD, and complaint of pain at the temporomandibular region and/or masticator muscles for at least 6 months in duration. Patients were excluded if they: (1) had no TMD diagnosis based on the RDC/TMD; (2) had acute TMD pain for less than 6 months; (3) had systemic rheumatic disease; (4) were under the age of 18 years; (5) had a history of psychiatric illness; (6) were pregnant; or (7)were unable or unwilling to consent. Accordingly, 48 patients were excluded, and 41 patients did not meet the inclusion criteria . In addition, 7 patients who had arthralgia, arthritis, or arthrosis were excluded due to small numbers.The study was approved by the ethics committee of Istanbul Faculty of Medicine and conducted in accordance with the principles of the Helsinki declaration. All subjects were informed about the nature of the study by a clinic assistant (A. B.). Informed consent was obtained from each subject who agreed to participate in the study prior to filling out the questionnaires.After finishing the questionnaire, all patients were clinically examined by a trained clinic assistant (M. O.K.) in accordance with the RDC/TMD version 1.0 guidelines . A transAll participants were subsequently divided into 3 groups based on their RDC/TMD axis I diagnostic groups. These were as follows: group A, myofascial pain only (n = 43); group B, joint pain only due to disk displacement (n = 20); and group C, myofascial and joint pain due to disk displacement (n = 41).Subjects completed the RDC/TMD Axis II self-report measures, which include the Graded Chronic Pain Scale (GCPS), the Jaw Disability Checklist, and the Revised Symptom Checklist (SCL-90-R).Functional status was evaluated using the jaw disability checklist that contains 12 items concerning limitations in activities related to mandibular functioning. The answer to each item might be ‘No’ (0)or ‘Yes’(1). Total scores might range from 0 to 12 [Psychosocial functioning was assessed using the GCPS, which is an indicator of the extent to which pain is perceived by the patient and the degree to which the pain is disabling ,24. The The GCPS was used to classify individuals according to the chronic pain grades: I = low pain intensity and low levels of pain-related disability, II = high pain intensity and low levels of pain-related disability, III = moderate pain-related disability and IV = severe pain-related disability. The study sample was then split into two groups, based on GCPS scores, which were assumed as the indicators of treatment need. The first group included subjects with high levels of pain-related disability (GCPS grades III and IV), whereas the second group included subjects with low levels of pain-related disability (GCPS grade I and II).The psychological status was assessed through depression and non-specific physical symptom (somatization) scores measured with subscales of SCL-90-R . The quePatient’s treatment-seeking status before attending Prosthodontics Clinics of Istanbul University was evaluated by a single specific question of the RDC/TMD axis II questionnaire: "Have you ever gone to physician, dentist, chiropractor or other health professional for facial ache or pain?” Then, the patients were classified into two groups according to their response: treatment-seeking group and non-treatment-seeking group.Additional data related to nonspecific pain condition, general health status perception, pain medication use, education level, employment, and marital status of patients were gathered using the axis II questionnaire and a single-item measure of the frequency of pain medication. These data were not included in the analysis, because it will be used in a future study evaluating the premorbid psychosocial and behavioral risk factors of chronic TMD pain.Descriptive data on frequencies, proportions, and on means and standard deviations were obtained with respect to the demographic, behavioral, psychological, and psychosocial characteristics of the groups. Subsequently, the normality of the SCL–90-R subscale scores, age, CPI, jaw disability scores and pain duration was checked using Kolmogorov-Smirnov test. Continuous data were analyzed by means of One-way ANOVA and Kruskal-Wallis test, for detection of possible differences between the variables under investigation among the TMD diagnostic subgroups, and categorical variables were analyzed using Pearson's chi-square test.U-test for continuous non-parametric data. The internal consistency of the Axis II measures was evaluated using the Cronbach's alpha reliability coefficient. A priori power analysis was performed by using an online calculator (http://statpages.org/index.html#Power) to determine sample size needed for the binary logistic regression analysis. Sample size calculations based on an alpha of 0.05, 10 predictor variables, expected effect size of 0.20 (moderate effect size), and power of 0.80 indicated a required sample size of 91 subjects.Patients with high and low levels of pain – related disability were compared with regards to socio-demographic, behavioral, psychological, and psychosocial characteristics using chi-square tests for categorical data, t-tests for continuous parametric data and Mann–Whitney A binary logistic regression analysis with stepwise backward elimination (likelihood ratio) was performed to identify the significant associations between the predictors  and the outcome (dependent variable: high levels of pain- related disability). The predictive power of the model was tested using Omnibus Test of Model, and Hosmer and Lemeshow tests were used to examine goodness of the fit of the model. Nagelkerke R square was generated to express the proportion of variance explained by the model. The odds ratio (OR) and 95% confidence intervals (95% CI) were calculated using binary logistic regression models. Statistical significance was achieved when p < 0.05. Statistical analysis was performed using IBM SPSS Statistics 19 for Windows .The study sample consisted of 104 patients  with a mean age of 33.46 ± 10.51 years. The mean chronic pain duration at the time of the assessment was 25.90 ± 28.76 months (range 7–168 months). Fifty-nine percent of these patients reported treatment-seeking for TMD pain before referring to the Prosthodontics Clinics of Istanbul University. From 104 patients, 51% (n = 53) were single, 48.1% (n = 50) had a formal school education of less than or equal to 8 years, 54.8% (n = 57) were employed, 32.7% (n = 34) rated their health status as moderate, and 87.5% (n = 91) reported a recent history of headache or pain in the lower back, chest/heart, or nausea/abdominal pain (data not shown).The frequencies of the TMD diagnostic subgroups were as follows: group A, 41.3%; group B, 19.2%; and group C, 39.4%. There were no statistically significant differences among the TMD diagnostic subgroups with regards to the demographic, behavioral, psychological, and psychosocial characteristics as seen in Table Based on GCPS scores, psychosocial disability (grade III or IV) was revealed in 26% of TMD patients.Bivariate analysis showed that patients with high levels of pain-related disability had significantly higher depression, somatization, CPI and jaw disability scores than patients with low levels of pain-related disability. No significant differences were found between patients with high and low levels of pain-related disability in terms of age, gender, RDC/TMD diagnostic sub- groups, and pain duration. Patients who had never been treated before referring to our clinic reported lower levels of pain–related disability Table .χ2 = 61.745, p < 0.0001; Hosmer and Lemeshow goodness of fit χ2 = 6.910, p = 0.546) and overall correctly classified 83.7% of the patients.Stepwise binary logistic regression analyses were performed to examine the association of the variables under investigation with higher levels of pain- related disability. In the final model, only four variables were found to be associated with higher levels of pain-related disability after removing non-significant variables. The final model had a statistically significant predictive power , pain characteristics , demographic factors , treatment-seeking behavior, pain-related impairment, jaw functional limitation were not associated with a specific pain location. Our results are inconsistent with a previous study reporting differences in pain intensity among RDC/TMD Axis I diagnoses . This stManfredini et al.  reportedBivariate analysis revealed significant differences between patients with low and high levels of pain-related disability in depression, somatization, CPI and jaw disability scores as well as in treatment-seeking behavior. We found no significant differences between patients with high and low levels of pain-related disability in terms of age, gender, RDC/TMD diagnostic sub-groups, and pain duration. In contrast with the results of our study, Maixner et al.  reportedThe relatively small number of studies examining the relationship between depression and somatization levels in pain-related impairment. In previous studies, pain-related disability was found to be strongly related with depression and somatization levels ,22 and pMultivariate analysis showed that patients with high levels of pain- related disability were more likely to have higher pain intensity, to report higher somatization symptoms and mandibular functional impairment, and were less likely to have joint pain due to disk displacement than those with low levels of pain related disability. Consistent with our study, Manfredini et al.  found thWe found a strong relationship between pain–related disability and jaw disability. In accordance with this finding, Kafas and Leeson  reportedIt should be noted that we did not find pain duration to be a predictor of high disability in patients with chronic TMD pain, while the duration of pain greater than 6 months was found to be the most important predictor for high disability in TMD patients ,25. We fManfredini et al.  found thTo the best of our knowledge, this is the first study using “high-risk versus low-risk” model to identify clinical and psychosocial predictors of pain-related disability in patients with chronic TMD pain. Each measures of the translated Turkish version of the RDC/TMD Axis II Questionnaire showed satisfactory internal consistency. There are several limitations to this cross-sectional study that should be considered when interpreting these findings. The study was conducted in one of the three dental faculties in Istanbul, limiting the generalizability of the results and the conclusions. Regarding the health – care seeking behavior, patients who attend a tertiary hospital clinic are probably not representatives of their source population that has the same condition and do not seek any treatment. Therefore, future community – based studies are needed to increase representativeness of groups investigated and generalizability of the findings . PatientAdditional studies are needed to assess the premorbid psychosocial risk factors  for chronic TMD pain that may affect the treatment plan in Turkish TMD patients -33,36,49In conclusion, the results of this study emphasize the importance of obtaining both Axis I and Axis II assessments for identifying TMD patients at a high risk for pain- related disability who are characterized by the absence of joint pain, and by increased pain intensity, jaw disability, and somatic symptoms. In our clinic, TMD patients were treated with intra-oral appliances and/or occlusal therapy without considering the patient's psychosocial status. If treatment is unsuccessful, patients are primarily referred to the Multidisciplinary Temporomandibular Joint Diagnosis and Management Unit at Faculty of Medicine, Istanbul University. The Turkish version of a dual-axis system for the diagnosis of TMD may be used by clinicians to screen high-risk patients for pain- related disability who need comprehensive treatment care program.The authors declare having no competing financial interest/funding for this paper.MOK, KP, AB and EBT were principal investigators of this study. They contributed to the interpretation of the data and review of the manuscript. MOK and KP conceptualized the study, contributed to the interpretation of the data and wrote the manuscript. EBT participated in study design. AB contributed to the data collection. OU contributed to the study design and data analysis and calculated the required sample size. All authors read and approved the final manuscript.


The surgical removal of the lower third molars is a procedure generally followed by side effects such as postoperative pain. The aim of this study was to evaluate the efficacy of socket irrigation with an anesthetic solution in relieving pain following impacted third molar surgery.Thirty-four patients , aged 18-24 years, with bilateral impacted lower third molars were selected. Both third molars were extracted in one surgical session. Tooth sockets in each patient were rinsed randomly either with 4 mL of 0.5% bupivacaine hydrochloride plain (without vasoconstrictor) anesthetic solu-tion or 4 mL of normal saline, used as control. The patients were instructed not to use analgesics as long as possible, and if not, they were instructed to use an analgesic, and record the time. Pain severity was assessed using a visual analogue pain scale (VAPS) at 1-, 6-, 12-, and 24-hour intervals post-operatively. Data were analyzed using Pearson’s chi-square test and P <0.05 was considered statistically significant.Post-operative pain difference between the two groups was statistically significant at 1-, 6-, 12- and 24-hour post-operative intervals (P <0.05). Post-operative pain increased in both groups to a maximum 12 hours after surgery with signif-icant improvements after that.Based on the results, the irrigation of surgery site with bupivacaine after third molar surgery significantly reduces post-operative pain. The technique consists of socket irrigation with the anesthetic agent after tooth extraction.15 Potential complications are minimal since neither a needle nor an injection is involved. Consequently, the risk of intravascular or intra-neural injection of the anesthetic agent is extremely remote;17 in addition, there is no need for administration of drugs such as NSAIDs, which results in complications like gastrointestinal lesions.18There are several methods for post-operative pain relief.We postulated that a similar technique might be effective in relieving post-operative pain after surgical tooth extraction. To test this hypothesis, we designed a prospective, randomized, double-blind clinical trial to study the effect of socket irrigation with 0.5% bupivacaine hydrochloride plain solution on reducing the severity of post-operative pain after surgical tooth extraction.Consecutive patients undergoing surgery for third molar extraction in the Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran, were enrolled in this study. Inclusion criteria were:Age between 18 and 24 years19)Bilateral impacted lower third molars , which does not contain vasoconstrictors, was prepared. In the control group, 4 mL of normal saline was placed in the syringe. Neither the operating surgeon nor the assistant was aware of the contents of the syringe. The nursing personnel were made aware that a study was in progress; however, they were not told which irrigation solution each surgery site received. The contents of the syringes and the amount of solution used were recorded in the patients’ file. Before closure of the wound at the end of the surgery, the socket was rinsed with either one of the solutions. After irrigation, the wound was sutured. Patients were asked to stay in the waiting room for 30 min after surgery, when their blood pressures were measured again. The patients were recommended not to use analgesics as long as possible. If needed, the patients could use acetaminophen and record the time of its use, in order to be excluded from the study after this time.Pain severity was assessed using a visual analogue pain scale (VAPS) at 1-, 6-, 12-, and 24-hour intervals post-operatively by the assistant surgeon, who was still unaware of irrigation solutions each side had received. The assistant questioned the patients with respect to nausea and their pain severity on each side. Patients were instructed to say a number (0-10) for their pain intensity on each side. The patients were aware that the scale served to analyze the presence and intensity of pain alone and was not a representation of generalized post-operative discomfort. Post-operative pain was assessed in a double-blinded manner; neither the patient nor the assistant was aware of the solution administered to each side.Data were assessed using Pearson’s chi-square test. In this study, p<0.05 was considered statistically significant.A total of 34 patients, 17 females and 17 males , participated in this study. Surgical operations were carried out on a total of 68 third molars (34 right and 34 left lower third molars).Bupivacaine irrigation was administered on 17 right and 17 left tooth sockets after surgical extraction. Two patients were excluded from the study because they used an analgesic. Post-operative pain, as recorded on VAPS, was significantly less in the group receiving bupivacaine irrigation compared with the controls . The dif22 In many cases, this requires oral narcotic analgesics for pain relief. An alternative method to the oral administration of medications for achieving analgesia has been well known since late 19th century: local injection of an anesthetic agent. However, local injection of anesthetic agents is associated with complications such as nerve injury, vascular injury, spread of infection, and intravascular or intra-neural injection of the anesthetic agent.17The present study evaluated the efficacy of socket irrigation with bupivacaine in comparison with normal saline irrigation in reducing post-operative pain severity associated with third molar surgery. Moderate-to-severe pain often accompanies third molar surgery during the first 12 hours after surgery.15A method for delivery of local anesthetics during surgery has recently been described, which involves irrigation of the socket with an anesthetic solution using a blunt-tipped catheter after tooth extraction. This method successfully delivers the anesthetic agent. Because no injection or needle is involved, the potential risks of the procedure are limited to hypersensitivity reaction to the anesthetic agent.21 Some complications of bupivacaine are cardiac toxicity, nausea, paroxysm, and vertigo, but these complications are related to plasma concentrations of bupivacaine.24Bupivacaine hydrochloride is an anilide anesthetic agent similar to lidocaine but has a much longer duration of action. Since its introduction in the United States in the 1970s, it has been tested extensively. Bupivacaine’s duration of action of up to 12 hours makes it an ideal medication for use in surgical procedures, such as impacted tooth extraction, in which the bulk of the post-operative discomfort occurs within the first 24 hours.Our study indicates that socket irrigation with 0.5% bupivacaine hydrochloride plain provides effective pain relief in the majority of patients undergoing third molar surgery. In addition, the use of such socket irrigation appears to be safe in individuals without a history of hypersensitivity to local anesthetic agents or cardiac complications. This method is also simple, convenient, and cost-effective.26 One study investigated the efficacy of local anesthetic infusion for pain control after cesarean section and found that there were no significant differences in patient demographics or visual analog pain scales at any time interval between the bupivacaine and placebo groups. However, narcotic requirements to produce this amount of pain relief were significantly less in patients who received bupivacaine infusion rather than normal saline solution at all time intervals.26 In another study comparing the effect of mandibular nerve block with bupivacaine versus lidocaine for pain relief after third molar surgery, it was reported that bupivacaine significantly reduced post-operative pain experience only at an 8-hour period. No difference in analgesic requirements or cardiovascular responses was observed with the respective toxic threshold concentrations. Since an injection method was employed, factors like infection and distance from the site of injection could affect the results. Moreover, the intensity of pain in the bupivacaine and lidocaine groups was assessed in different subjects, which introduces the effect of individual differences in pain perception on interpretation of the results. Therefore, the findings could not be as reliable as it was performed in the present study, i.e. assessments on two sides of the mouth in the same patient.27 In another study investigating the effect of intra-operative bupivacaine irrigation for management of shoulder-tip pain following laparoscopy, it was shown that mean shoulder-tip pain scores as recorded on visual analogue pain scale were significantly lower in the bupivacaine group than in the control group 4 to 24 hours after surgery. Post-operative analgesia requirement also significantly decreased in patients receiving bupivacaine irrigation.28 In addition, the efficacy of retrobulbar bupivacaine irrigation for relieving post-operative pain after scleral buckling surgery was evaluated in a study which revealed this method is a safe and effective way to achieve post-operative pain relief after surgery for scleral buckling.16 In the two previously mentioned studies, patients were under general analgesia, which may bias the results. The design of the study also involved evaluation of different individuals which involves the afore-mentioned limitation.Several studies have investigated the effects of local anesthetic agents used to irrigate or to be injected into the surgery zone for post-operative pain relief.31 In addition, patients who took analgesics were excluded from the study, which eliminated the interventional effect of medications such as NSAIDs from the results.In our study, third molar surgery on two sides was performed in one patient simultaneously by one surgeon. One surgery site was rinsed with bupivacaine solution and the other with normal saline. Such design in the study allowed unbiased comparison of post-operative pain intensity with regard to differences in pain perception between individuals.According to the findings of the present study, it can be concluded that socket irrigation with bupivacaine significantly reduces post-operative pain following third molar surgery. In conclusion, the results of this study demonstrate the effectiveness of bupivacaine irrigation in reducing post-operative pain 1, 6, 12, and 24 hours after surgery without any significant complications.


Background. Many critically ill patients with a traumatic brain injury (TBI) are unable to communicate. While observation of behaviors is recommended for pain assessment in nonverbal populations, they are undetectable in TBI patients who are under the effects of neuroblocking agents. Aim. This study aimed to validate the use of vital signs for pain detection in critically ill TBI patients. Methods. Using a repeated measure within subject design, participants (N = 45) were observed for 1 minute before (baseline), during, and 15 minutes after two procedures: noninvasive blood pressure: NIBP (nonnociceptive) and turning (nociceptive). At each assessment, vital signs , heart rate (HR), respiratory rate (RR), capillary saturation (SpO2), end-tidal CO2, and intracranial pressure (ICP)) were recorded. Results. Significant fluctuations (P < 0.05) in diastolic (F = 6.087), HR (F = 3.566), SpO2 (F = 5.740), and ICP (F = 3.776) were found across assessments, but they were similar during both procedures. In contrast, RR was found to increase exclusively during turning  and was correlated to participants' self-report. Conclusions. Findings from this study support previous ones that vital signs are not specific for pain detection. While RR could be a potential pain indicator in critical care, further research is warranted to support its validity in TBI patients with different LOC. Many patients with a traumatic brain injury (TBI) are unable to self-report their pain in the intensive care unit (ICU) because of altered levels of consciousness (LOC), mechanical ventilation, and/or aphasia . In nonvP < 0.05) during nociceptive procedures  suctioning) compared to nonnociceptive procedures (compression stocking applications and catheter dressing change). However, this study was conducted with unconscious patients only, and the relationship between vital signs' fluctuations and patients' self-report of pain  could not be examined. Other studies have shown inconsistent findings in relation to vital signs for the detection of pain. In one study with 48 cardiac surgery ICU patients [2), and end-tidal CO2) were not associated with patients' self-report of pain during a nociceptive procedure (turning). Yet, in a similar study [r = 0.69; P ≤ 0.001) was found between HR fluctuations and self-reported pain intensity and a mild negative correlation  was found between SpO2 fluctuations and pain intensity during the nociceptive procedure (turning with or without ET suctioning).Because the autonomic nervous system may be activated during exposure to a painful event, fluctuations in vital signs could be indicative of the presence of pain . In one patients , systolipatients  with 55 ar study  with 105Some methodological limitations in the studies mentioned previously are worth noting. First, in all studies, vital signs were documented only once during each assessment period which lasted from one to several minutes. Given that vital signs are recorded every second by ICU monitoring devices to mimic true hemodynamical changes , the useSo far, the validity of relying on vital signs for pain assessment has been examined mainly using two validation strategies called discriminant validation  and criterion validation  . Althoug2, CO2, and ICP) recorded across different assessment periods , procedures , and LOC ,for discriminant validation, to describe and compare TBI participants' fluctuations in vital signs .This study aimed to validate the use of vital signs for the purpose of pain assessment in critically ill TBI adults. The main study objectives were:(3)explore the potential influence of TBI severity, TBI localization, and therapeutic regimen  on TBI participants' fluctuations in vital signs during the nociceptive procedure.A secondary objective of the study was toFor this study, a repeated measure within subject design was used to replicate the ICU experience of trauma patients who are commonly submitted to several consecutive procedures. A convenience sample of TBI patients admitted to the ICU of a Level I trauma center in Montreal, Quebec, Canada, was recruited. Patients  meeting the following inclusion criteria were considered eligible: (1) 18 years and older and (2) admitted to the ICU following a TBI (with or without other injuries) for more than 24 hours. Patients were excluded if they had (1) a score of 3 (unarousable) on the Glasgow Coma Scale (GCS) ; (2) anySociodemographic characteristics  and medical information such as severity of injury (injury severity score: ISS) , predictTBI participants were observed during two procedures routinely performed in the ICU: (1) noninvasive blood pressure with cuff inflation: NIBP (known as a nonnociceptive procedure)  and (2) It is important to mention that both procedures (NIBP and turning) were performed by the ICU nursing staff as this procedure is commonly used in the validation studies of physiologic parameters for the detection of pain in critical care –10. As t2, end-tidal CO2, and when available ICP) available through bedside ICU monitoring were recorded continuously using a data collection computer connected to it with a port-serial cable . All participants wore a five-cable monitoring system  and a finger pulse oximeter (for SpO2). In addition, participants wore either a CO2 sensor when mechanically ventilated or a CO2 nasal cannula when nonmechanically ventilated for recording of end-tidal CO2.Vital signs  with the five-point descriptive pain scale and good discriminant validation  with higher pain intensity score during a nociceptive procedure  compared to rest in ICU adults [Self-reports of pain were obtained by asking conscious participants to report (a) the presence of pain (yes or no) and (b) pain intensity . Pain intensity was measured using the faces pain thermometer (FPT)—a vertical thermometer ranging from 0 (no pain) to 10 (worst pain imaginable). It includes six faces adapted from the work of Prkachin . The FPTU adults .2, end-tidal CO2, and ICP) recorded during initial data collection at different assessment periods  and for both procedures . Two-way repeated measures analysis of variance (RM ANOVA) were performed to examine the main effects and the interaction effect of assessment periods and procedures on mean fluctuations in vital signs. According to RM ANOVA assumptions [t-tests with Bonferroni correction was applied when appropriate [t-tests were performed to compare vital signs' fluctuations observed from baseline to turning at initial data collection in unconscious, altered LOC and conscious participants. Paired t-tests were also performed in the subsample of participants involved in a second data collection, but exclusively in conscious participants as only 4 altered LOC participants were included in this subsample—not providing enough power for paired comparison.Descriptive statistics  were performed for all study variables. To examine the first research objective, means and standard deviations were computed for each vital sign  and Pearson correlation (rp: for continuous versus continuous variables) were performed to examine the relationship between mean vital signs' fluctuations and participants' self-reports of the presence of pain (yes or no) and pain intensity (0–10) during turning.For the second objective, mean fluctuations in vital signs of TBI participants who reported pain during turning were compared to mean fluctuations in vital signs of those who reported no pain. Point-biserial correlation  and Pearson correlations (rp) were computed to explore the influence of variables related to participants' therapeutic regimen  on mean vital signs' fluctuations recorded during turning. To facilitate data analysis, analgesics were converted into equianalgesic doses of morphine  [For the secondary objective of the study, mixed measures ANOVAs were conducted to explore the influence of TBI severity and TBI localization on mean vital signs' fluctuations recorded during both procedures (NIBP and turning). Then, Spearman correlations (orphine) . SedativN = 45 participants were included in the study. According to our research objectives, an initial data collection was completed in all participants and a second data collection was completed in a subsample of n = 13 participants who changed LOC category within the first month of ICU stay, for a total of 58 data collections. Participants (N = 45) involved in the initial data collection were mostly men , with a mean age of 55.18 years old (SD = 22.08), and were mainly hospitalized for moderate to severe TBI. Participants involved in a second data collection (n = 13) were also mostly men , but had a mean age of 43.00 years old (SD = 19.82), and were all hospitalized for severe TBI. During both initial and second data collections, participants had severe injuries but low risk of intrahospital complications according to a median ISS score of 9 and a median APACHE score below 20 in both samples. Regarding therapeutic regimen, 75% of unconscious participants (n = 8) were receiving a combination of fentanyl and diprivan infusions prior to the initial data collection, whereas less than 50% of altered LOC participants (n = 21) were receiving fentanyl and/or diprivan infusions and 18.8% of conscious participants (n = 16) received subcutaneous (s/c) boluses of hydromorphone. Prior to the second data collection, only 25% of altered LOC participants (n = 4) were receiving fentanyl and/or diprivan infusions, while 22.2% of conscious participants (n = 9) were receiving s/c boluses of hydromorphone and/or diprivan infusions. Although this was not an exclusion criterion, it is worth noting that participants were not under any type of vasopressors or inotropic drugs and were pacemaker-free at the time of data collection(s). Information about TBI participants' sociodemographic characteristics, medical variables, and therapeutic regimen are available in Tables A total of old SD = 2.08, andF = 6.087; P ≤ 0.01), HR , RR , SpO2 , and ICP  were observed across assessment periods   was found between both procedures . Accordingly, a significant interaction effect between assessment periods and procedures on mean RR fluctuations  was found. Interestingly, a significant interaction effect of assessments and procedures on mean ICP fluctuations  was also observed. Post hoc analysis using paired t-tests with Bonferroni correction showed that a significant increase in mean RR values occurred between baseline  and turning procedure  and that a significant decrease in mean RR values occurred between turning and 15 minutes postprocedure (t = 3.365) , but for NIBP only.During initial data collection, significant fluctuations in diastolic pressure (ocedure) . Among a= 3.365) . In addin = 8) at initial data collection, except for ICP which was found to increase significantly during turning   and HR  were also observed during turning of altered LOC participants (n = 21) at initial data collection. Interestingly, while a significant increase in RR  was observed during turning of conscious participants (n = 16) at initial data collection, no significant changes in vital signs were observed during turning of conscious participants (n = 9) at second data collection.According to LOC, no significant fluctuations in vital signs were found between baseline and turning in unconscious TBI participants ( ≤ 0.05) . Signifi2, and CO2 values remained quite stable in those participants  and RR  were strongly correlated  with TBI participants self-report of the presence of pain, but no correlation  was found with pain intensity.Thirteen conscious participants were able to report presence of pain (yes or no) and 12 of them were also able to report pain intensity (on the 0–10 FPT) during initial or second data collection. During turning, mean increases in diastolic pressure, MAP, HR, and RR were found in participants who reported pain, while systolic pressure, SpOicipants . HoweverPotential influence of TBI severity and TBI localisation on mean fluctuations in vital signs across assessment periods  and procedures (NIBP and turning) in participants at initial data collection were explored using mixed measure ANOVAs. No significant differences in vital signs' fluctuations were found according to these variables.rp = −0.634; P ≤ 0.05).Correlations  were performed to explore the relationship between level of sedation and administration of analgesics/sedatives on mean fluctuations in vital signs during turning of participants at initial data collection. No significant correlations between vital signs' fluctuations during turning and TBI participants' level of sedation and administration of sedatives were found. However, a negative significant correlation between equianalgesic doses of morphine received within 4 hours prior to data collection and RR fluctuations was found  reporting the presence of pain. However, fluctuations in RR during a nociceptive procedure could be dependent on patients' LOC. In our study, RR was mostly elevated in conscious and altered LOC TBI patients and remained quite stable in unconscious ones. This result contrasts with previous findings [RR was the only parameter that fluctuated significantly and exclusively during turning at initial data collection. RR was also found to be associated with TBI patients' self-report of pain. This result is consistent with previous findings  in whichfindings , 10 wherWith respect to therapeutic regimen, a negative correlation between equianalgesic doses of morphine received prior to the nociceptive procedure and mean increases in RR during turning was noted in TBI participants at initial data collection. Considering that TBI patients receiving higher doses of analgesics could be in less pain during a nociceptive procedure, this result further supports the potential usefulness of changes in RR for the detection of pain in TBI patients. Yet, another explanation would be that analgesics (mainly opioids) have a depressive effect on respiratory rate —suggestiThis study was not without limitations. First, the administration of analgesics and sedatives could not be standardized. Secondly and as mentioned previously, patients' vital signs may have been altered by the procedures themselves independently of their type—nociceptive or not. Third, in a complex context of care like the ICU, it is difficult to associate vital signs' fluctuations solely to pain. Indeed, vital signs may also be affected by several emotional states including anxiety and distress. Unfortunately, emotions may be difficult to evaluate in critically ill TBI patients as they often have short attention span and limited cognitive capacities .Our study findings support discriminant and criterion validation of the use of RR for pain assessment in conscious TBI patients. However, further research is needed to further explore the criterion validation of RR with TBI patients' self-reports of pain (which was possible with only 13 TBI participants in our study). Until then, ICU nurses should use RR exclusively as a cue to begin further assessment of pain until more empirical data are available , 3. Fina


NCT01947205.The aim of the study was to investigate the analgesic efficacy of preoperative oral dexketoprofen trometamol, intravenous paracetamol, lidocaine spray, and paracervical block with ultracaine on curettage procedure. A total of 111 subjects with the request of pregnancy termination between 5 and 7 weeks of gestation were included in the study. The first group (control group) consisted of 20 participants without medication. The second group consisted of 25 participants receiving 2 puffs of lidocaine sprays on cervical mucosa. The third group consisted of 20 participants receiving oral 25 mg dexketoprofen trometamol. The fourth group consisted of 23 participants receiving 1000 mg intravenous paracetamol and the fifth group consisted of 23 participants receiving paracervical block with ultracaine. Paracervical block reduced pain score significantly in both intraoperative and postoperative periods. All analgesic procedures were significantly effective for reducing pain in postoperative period. Paracervical block may be the best method for reducing pain scores in intraoperative and postoperative periods during curettage procedure. All analgesic procedures such as lidocaine, paracetamol, ultracaine, and paracervical block with ultracaine can be used for reducing pain score in postoperative period. This trial is registered with  Curettage, a surgical procedure, is commonly used for the first-trimester pregnancy termination. Patients frequently experience pain from moderate to severe during gynecologic procedures that involve the uterine cavity . CliniciAlso known as “paracetamol,” acetaminophen (N-acetyl-4-aminophenol), which has not only analgesic but also antipyretic properties and has been widely used as an active ingredient in many approved drugs, is one of the most widely used medicines in the world . It has It is revealed that cervical dilation, contraction, or cramping pain is transmitted by sympathetic fibers, which travel in the uterosacral ligament and insert into the cervix. Therefore, paracervical injections may be best for preventing this cramping pain. Moreover prior studies showed that paracervical block can be used as an anesthetic procedure for suction curettage . LidocaiWe conducted a prospective, randomized, placebo-controlled trial to investigate the analgesic efficacy of preoperative oral dexketoprofen trometamol (Dexofen 25 mg tb Atabay Ilaç Turkey), intravenous paracetamol (Parol 1 mg Atabay Ilaç Turkey), lidocaine spray (Xylocaine Pump 100 mg 50 mL Sprey Astra Zeneca), and paracervical block with ultracaine on curettage procedure.A randomized, double-blind, placebo controlled trial was designed at our family planning clinics between November 2012 and August 2013. The study protocol was approved by the ethics committee of Erciyes University. Study and control groups consisted of pregnant multiparous participants between 35 and 48 days of gestation (5 to 7 weeks of gestation) with a single viable intrauterine pregnancy requesting termination of pregnancy. These participants were scheduled for performing suction curettage and none of the participants received medication such as analgesics and misoprostol, up to 7 days.Exclusion criteria were incomplete abortions, diabetes mellitus, tendency to bleed such as thrombocytopenia, factor deficiency and functional disorders of platelets, pelvic infection, known cervical stenosis, significantly impaired respiratory or cardiac conduction functions, active liver disease, renal disease, previous adverse reaction to any of the drugs used in the study, and patients who are unable to understand how to score a 10 cm visual analog scale (VAS) pain score. Moreover, patients who described chronic pelvic pain prior to the study or patients who rated their pain level on a continuous 100 mm VAS different from 0 (no pain) just before the study were not included in the study.Previously published studies for assessing pain scores during minor gynecologic surgical procedures illustrated that at least a 2.73 cm difference between the pain scores could be regarded as a clinically significant difference . It was After providing their informed consent, a total of 111 subjects with request of pregnancy termination between 5 and 7 weeks of gestation were randomly assigned into 1 of 5 study groups. Subjects received 25 mg of oral dexketoprofen trometamol, 1000 mg IV paracetamol, two-puff xylocaine administration on cervical surface, paracervical block with ultracaine, or similar-appearing placebo drugs by using a computer-generated random number chart  before the study. The first group (control group) consisted of 20 participants and they did not receive any treatment. In this group, 5 of the patients received placebo tablet, 5 received saline solution, 5 received paracervical isotonic solution, and 5 received puff saline solution. The second group consisted of 25 participants receiving lidocaine spray on cervical mucosa. The third group consisted of 20 participants receiving oral dexketoprofen trometamol. The fourth group consisted of 23 participants receiving 1000 mg intravenous paracetamol and the fifth group consisted of 23 participants receiving paracervical block with ultracaine. In all, 111 consecutive patients' numbers were written on envelopes, while the assignment codes were written on separate papers that were put into the consecutively numbered yellow opaque envelopes, which were then pasted. During curettage, the envelope with the patient number on its cover was opened to reveal the randomization by the responsible nurse and she prepared the trial medications accordingly.The patients, the anesthetist performing VAS, and the gynecologist performing the procedure were blinded to the contents of the oral, intravenous, paracervical, and puff medications. The oral, intravenous medications were administered 30 minutes before the suction curettage due to the pharmacokinetic properties of dexketoprofen, paracetamol, since they are known to possess a very rapid onset of action (within 30 minutes of administration) with a long-lasting effect (at least for 6–8 hours). The suction curettage was performed by the same gynecologist to maintain consistency and limit confounding variables. We administered 2 puffs of lidocaine spray on cervical surface and waited for three minutes to allow the anesthetic to take effect.The procedure and paracervical block were performed according to our clinics description as the following: a sterile bivalve speculum was introduced into the vagina, then cervix and vagina were washed with antiseptic solution. The cervix was grasped with tenaculum and straightened according to the uterine axis. Paracervical block was achieved using a 27-gauge spinal needle. Ultracaine was injected at the tenaculum site, and the remainder was distributed equally around the cervicovaginal junction at 5 and 7 o'clock.The suction curettage was accomplished through the following steps: the cervix was dilated to Hegar number 5 to 6  if necessary; the uterine depth was measured using a hysterometry; and then a 60 mL syringe with a self-locking mechanism of the plunge was used for performing suction curettage.t1), during the procedure  (t2), and 30 minutes after the procedure (t3). We documented the patients' demographics: age, parity, weight, and height.The patients were observed for 30 minutes after the curettage procedure. No further followup was scheduled. Patients were asked to rate their pain level on a continuous 100 mm VAS from 0 (no pain) to 10 (the worst pain ever). Pain scoring was performed at 3 different time points: prior to the procedure . All analyses were performed using IBM SPSS Statistics 20.0  and P < 0.05 was considered statistically significant.To test the normality assumption of the data, Shapiro-Wilk and Kolmogorov-Smirnov were used, respectively. Variance homogeneity assumption was tested with Levene test for the variables age, BMI, and gravida. Values are expressed as mean ± standard deviation or median (25th percentile–75th percentile). One-way analysis of variance (ANOVA) test or Kruskal-Wallis Patients who described chronic pelvic pain prior to the study or patients who rated their pain level on a continuous 100 mm VAS different from 0 (no pain) just before the study were not included in the study. All participants reported their pain level 0 on a continuous 100 mm VAS prior to the study. General characteristics and pain scores of both control and study groups are illustrated in t2: intraoperative). All analgesic procedures were significantly effective in reducing pain in postoperative period. Significant pain reduction was achieved for both intraoperative and postoperative periods by using paracervical bloc.Paracervical block was the best choice for reducing pain during curettage procedure , 1 (4%), 3 (15%), 2 (8.69%), and 2 (8.69%) in control, lidocaine spray, dexketoprofen, paracetamol, and paracervical block group, respectively. The cheapest method was lidocaine spray for postoperative analgesia, however lidocaine did not reduce pain scores effectively during intraoperative period.Blumenthal and Remsburg showed that suction curettage might be performed on an outpatient basis under local anesthesia and cost of patients might be reduced by using suction curettage practice on an outpatient basis . FollowiParacetamol, a nonopioid agent, is believed to primarily act upon the central nervous system by way of central cyclooxygenase inhibition and probably has an indirect influence on the serotoninergic system. Paracetamol has a good safety profile and easily passes through the brain barrier, which assures it as an effective analgesic . Api et Lidocaine spray (Xylocaine Pump 100 mg 50 mL Sprey Astra Zeneca) is a simple and convenient local anesthetic agent with minimal adverse effect. However, there is limited evidence regarding the effectiveness of its use in pain control during suction termination of pregnancy . ParacerXu et al. claimed that dicaine-containing lubricant jelly for suction termination of first-trimester pregnancy had no effect on pain scores. However, the same study reported significantly more satisfactory cervical dilatation in the group using dicaine-containing lubricant jelly compared with the group using lignocaine injection . ConversPrior studies showed that paracervical block can be used as an anesthetic procedure for suction curettage . OvolabiOur results showed that paracervical block provides better pain relief than dexketoprofen. Although paracervical block provided significant pain relief during surgical procedure and postoperative period, there are some concerns among authors regarding the use of paracervical block. It can be an insufficient anesthetic method for curettage because pain signals of uterine fundus are carried by different neurons compared to cervix and paracervical block which has well-known adverse effects, which range from mild toxicity such as numbness around the mouth and dizziness to convulsion and respiratory arrest. Five deaths were reported due to lidocaine use to induce paracervical anesthesia .Lidocaine, paracetamol, and dexketoprofen can be accepted as relatively less invasive analgesic methods than paracervical block. However, in order to provide an effective analgesia during intraoperative period, at least paracervical block should be used. This situation requires choosing a reliable, innocent, and effective anesthetic method in patients undergoing curettage in outpatient settings; therefore, there is a clear need for well-designed, large-scale, prospective observational studies in the field of curettage and pain.


During acute coronary syndromes patients perceive intense distress. We hypothesized that retrospective ratings of patients' MI-related fear of dying, helplessness, or pain, all assessed within the first year post-MI, are associated with poor cardiovascular outcome.We studied 304 patients  who after a median of 52 days (range 12-365 days) after index MI retrospectively rated the level of distress in the form of fear of dying, helplessness, or pain they had perceived at the time of MI on a numeric scale ranging from 0 ("no distress") to 10 ("extreme distress"). Non-fatal hospital readmissions due to cardiovascular disease (CVD) related events  were assessed at follow-up. The relative CVD event risk was computed for a  2-point increase of distress using Cox proportional hazard models.During a median follow-up of 32 months (range 16-45), 45 patients (14.8%) experienced a CVD-related event requiring hospital readmission. Greater fear of dying , helplessness , or pain  were significantly associated with an increased CVD risk without adjustment for covariates. A similarly increased relative risk emerged in patients with an unscheduled CVD-related hospital readmission, i.e., when excluding patients with elective stenting . In the fully-adjusted models controlling for age, the number of diseased coronary vessels, hypertension, and smoking, HRs were 1.24 (95% CI 1.04-1.46) for fear of dying, 1.26 (95% CI 1.06-1.50) for helplessness, and 1.26 (95% CI 1.01-1.57) for pain.Retrospectively perceived MI-related distress in the form of fear of dying, helplessness, or pain was associated with non-fatal cardiovascular outcome independent of other important prognostic factors. Myocardial infarction (MI) is an unexpected life-threatening event which is perceived as stressful by many patients who may expect death or serious disability ,2. For iDistress during ACS profoundly impacts psychological adjustment in the wake of the cardiac event, particularly bringing on symptoms of anxiety, depression, and posttraumatic stress disorder. For instance, patients who were more distressed and frightened during ACS showed higher levels of anxiety and depressive symptoms, one week and three months, respectively, after the cardiac event . Fright The aforementioned studies suggest that distress conceptualized as MI-related fear of dying, helplessness or pain might be an important clinical entity, since it is associated with negative affective risk factors for cardiovascular morbidity and mortality, including depression, anxiety, and posttraumatic stress disorder -11. VirtAs a first step of testing the value of MI-related distress for post-MI prognosis, we investigated the hypothesis that greater fear of dying, helplessness, or pain intensity  would be associated with increased risk of future hospital readmissions due to non-fatal cardiovascular events and related interventions. We further hypothesized that MI-related distress would be associated with poor cardiovascular outcome independent of other important prognostic factors.All participants provided written informed consent to the study protocol that was approved by the ethics committee of the Canton of Bern, Switzerland, as part of the ongoing longitudinal Swiss Heart and Mind Study. The flowchart shows the recruitment of the 304 patients available for the present investigation. As previously detailed , betweenPatient characteristics including sex, age, type of index MI (first-time vs. recurrent MI), left ventricular ejection fraction (LVEF) measured by ventriculography during coronary angiography, and the number of diseased coronary vessels, were abstracted from hospital charts recorded at the time of the index MI. Hypertension (yes/no) was defined by either a positive history for treatment or systolic and/or diastolic blood pressure ≥140/90 mmHg at rest. Diabetes (yes/no) was defined by a positive history that, if unclear, was verified by one-time glucose level >200 mg/dl. The status of current smoking (yes/no) was also obtained from the charts. Data on LVEF, hypertension, diabetes, and smoking status were missing in 9 (3.0%), 6 (2.0%), 14 (4.6%), and 15 (4.9%) patients, respectively. The use (yes/no) of aspirin, statins, beta blockers, and angiotensin-converting enzyme (ACE) inhibitors was noted with respective data missing in 4 (1.3%), 5 (1.6%), 9 (3.0%), and 4 (1.3%) patients, respectively.fear of dying: "During my referral to the hospital, the emergency unit, or the intensive care unit, I was afraid I was dying." ; b) helplessness: "When the doctor told me I had a heart attack, I was frightened, felt helpless, and was afraid of losing control of the situation." ; c) pain intensity: "Please indicate how strong your pain was during the heart attack." . Cronbach's alpha for the three scales was 0.76 suggesting acceptable reliability for the measured construct of "MI-related distress".The patients retrospectively rated three aspects of subjective perception of distress related to MI on a numeric rating ranging from 0 to 10 points : a) fearThe follow-up period referred to the time interval between assessment of distress and a semi-structured telephone interview during which patients were asked whether they had been hospitalized because of a new cardiovascular event or related intervention specified as follows a priori: recurrent MI, elective and non-elective percutaneous coronary intervention with stent implantation, coronary artery bypass grafting, pacemaker implantation, cardiac arrhythmia, cardiac arrest, cerebrovascular insult, transient ischemic attack, hypertensive crisis, heart failure. A positive answer was verified by contacting the treating physician by phone. We also asked whether the patient had received mental health treatment  and whether he or she had had non-specific chest pain after the index MI. Eleven patients confirmed the latter and were excluded from the analysis because thoracic pain might potentially affect retrospective ratings of distress.t test, Pearson chi-square test, and Fisher's exact test where appropriate. Pearson correlation coefficients were computed to estimate the correlation between two variables. We ran three separate Cox proportional hazard models to estimate the relative risk  of a hospital readmission during follow-up because of a CVD event or CVD-related intervention (combined endpoint) as the outcome in relation to a 2-point increase of MI-related distress ratings. That is, we first assessed distress measures with the 10-point scale, then divided the score by two, and used the obtained value in analysis. Using a 0 to 10 numeric rating scale, changes of approximately 2 points or 30% to 36% represent clinically meaningful changes in pain severity [Data were analyzed using SPSS 15.0 statistical software package . Two-tailed level of significance was set at p < 0.05. Differences between groups were calculated using Student's severity . For theTo avoid overfitted and thus unstable models, the 45 outcome events Figure  allowed The median duration of follow-up after assessment of MI-related distress measures was 32 months range 16-45) during which a CVD-related hospital readmission occurred in 45 patients (14.8%). The type of CVD events and interventions is shown in Figure 6-45 duriThere were positive associations among all distress measures; i.e., between fear of dying and helplessness , fear of dying and pain , and helplessness and pain . More time elapsed since the MI correlated with greater fear of dying  but not significantly so with helplessness or pain. Younger age was associated with higher scores of fear of dying , helplessness , and pain . Smokers showed greater helplessness than non-smokers . Patients who had received antidepressant medication indicated greater fear of dying , greater helplessness , and more intense pain  during MI than those who were not prescribed antidepressants. There were no significant correlations between any distress measure and gender, hypertension, diabetes, measures of CHD severity, cardiac medications, and psychotherapy since index MI.As shown in Table It is possible that at the time of distress assessment, the 10 patients who underwent elective stenting during follow-up already knew about a planned readmission such that they might differ in their distress ratings from the 35 patients who experienced an unscheduled CVD-related event. Therefore, we conducted a sensitivity analysis excluding patients having undergone elective stent implantation; this analysis showed an increase in the relative risk for an unscheduled CVD-related hospital readmission of 26%, 26%, and 30%, respectively, for a 2-point increase in fear of dying, helplessness, or pain  are widely used in clinical settings. Particularly, the numeric rating scales applied in this study to measure distress are easy administrable even in a busy clinical setting and thus of potential clinical applicability in screening post-MI patients at risk of poor cardiovascular outcome. The association between MI-related distress and poor cardiac outcome was independent of other important prognostic factors. The downstream psychopathology and behavior as well as the underlying physiology of this association remain to be elucidated.The authors declare that they have no competing interests.All authors participated in the design of the study, helped to draft the manuscript and read and approved the final manuscript. RvK performed statistical analysis and wrote the first draft of the manuscript. RH performed all the telephone interviews. RH and JPS collected all the additional data reported in this manuscript. RvK, SB and HS critically supervised data acquirement and made important intellectual contribution to the interpretation of the data.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/11/98/prepub