Trends of an increase and a decrease in the AF in pain- and sensory-related regions, respectively, were also observed from low to high frequencies (Bonferroni-corrected α level of P < 0.05/84). In addition, in the bilateral rectal gyrus, a significant association was identified between the AF in the five specific frequency bands and disease status (P < 0.05). These findings suggest that in LBLP patients, intrinsic functional plasticity related to low back pain, leg pain and numbness affects the AF of the pain matrix and sensory-processing regions in both low- and high-frequency bands.Understanding the central mechanisms responsible for lumbar nerve root compression may facilitate the development of new therapeutic strategies. In this study, our aim was to investigate the amplitude of fluctuations (AF) in five specific frequency bands and the full-frequency band realm to provide novel insight into the rhythm of the neuronal activity of low back/leg pain (LBLP) patients (n = 25). Compared with healthy controls, LBLP patients exhibited a significantly altered AF in multiple brain regions, including the right or left middle and inferior temporal gyri, bilateral precuneus, right anterior insula/frontal operculum, right or left inferior parietal lobule/postcentral gyrus, and other locations at five specific frequencies  Although the pain is often caused by a peripheral event, there is increasing concern regarding associated brain changes such as structural impairment in specific cortical and subcortical areas . Increased activation in several brain regions of the pain matrix, such as primary sensory cortex (S1) and secondary sensory cortex (S2)8, the insula and the prefrontal cortices10, and disrupted connectivity in the default mode network (DMN) have also been shown14. In addition, central sensitization has been observed in a subgroup of patients with low back pain and associated brain changes.Low back pain is an extremely common disorder characterized by acute episodes of pain or chronic pain that is associated with disability in middle-aged and elderly persons. Low back pain affects millions of individuals each year15. In fact, approximately one-quarter to one-third of these LBLP patients continue to exhibit pain after surgery or failed back surgery syndrome16. Leg pain intensity and paresthesia coverage are the primary and secondary outcomes/prognostic factors, respectively17. Therefore, understanding the role of neural plasticity or the rewiring of the brain in patients with LBLP will improve our knowledge of pain symptoms and the mechanisms underlying LBLP-associated central modulation. In the resting brain, LBLP patients process spontaneous background pain and paresthesia (numbness) stimuli continuously; these stimuli interact with and modulate other intrinsic brain networks through numerous oscillatory waves that, together, constitute a complex dynamic system18, which can be studied using blood-oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI). According Buzsáki’s framework7, oscillatory BOLD waves can be divided into the following five specific frequency bands: slow-6 (0–0.01 Hz), slow-5 (0.01–0.027 Hz), slow-4 (0.027–0.073 Hz), slow-3 (0.073–0.198 Hz) and slow-2 (0.198–0.25 Hz). Oscillations within specific low-frequency ranges  have been shown to be linked with a variety of neural processes, including input selection, plasticity, binding and consolidation and the cyclic modulation of gross cortical excitability and long-distance neuronal synchronization20. Although controversial, alterations in relatively high-frequency bands have been shown in the resting state and, thus, may be of physiological importance in pain22, including chronic somatic pain23, visceral pain24 and fibromyalgia25.Lumbar disc herniation (LDH) is a common cause of low back pain. Approximately 60% of patients with low back pain due to LDH also experience radiating pain to the leg(s). Low back/leg pain (LBLP) due to LDH (LBLP hereafter) in patients is associated with poorer recovery than is observed in patients with low back pain alone14, we have reason to believe that the relatively high-frequency bands of BOLD waves can be modulated by dual-stimulation (pain and numbness) and, thus, may be of physiological importance in LBLP. We investigated the brain regions with altered AF in the five specific frequency bands and studied their correlations with disease severity and duration, pain level based on a visual analogue scale (VAS) and tactile discrimination ability  in LBLP patients.In accordance with the above findings, we hypothesize that the dual-stimulation (pain and numbness) in LBLP may contribute to the alterations of neuronal activity in the low- and high-frequency bands of BOLD waves. In the present study, we examined the amplitude of fluctuations (AF) of intrinsic oscillations in five specific frequency bands and full-frequency bands  in LBLP patients compared with healthy controls. In view of the currently available data on idiopathic chronic low back painduration: 37.08 ± 10.23 months); 23 (92%) of these patients also presented with left or right leg pain and numbness; and 2 (8%) of these patients also presented with bilateral leg pain. There were no significant differences in age , sex  or mean head motion by framewise displacement (Jenkinson)  between the LBLP patients and the HCs. Compared with HCs, the LBLP patients showed significantly lower scores in the Japanese Orthopaedic Association (JOA) Back Pain Evaluation  and higher VAS scores . In the LBLP patients, decreased performance on the two-point tactile discrimination (TPTD) test was observed in the right (30.8 ± 1.65 mm) and left (31.1 ± 1.21 mm) feet and right (25.3 ± 1.23 mm) and left (26.1 ± 1.25 mm) hands.Two LBLP patients were excluded due to a vascular malformation and an infarction, and 4 LBLP patients and 3 healthy subjects were excluded due to head motion. Ultimately, a total of 25 LBLP patients and 27 healthy control (HC) subjects were selected for group comparisons. All the 25 LBLP patients presented with low back pain  theory correction, cluster-level P < 0.05). Compared with HCs, the LBLP patients consistently exhibited a trend showing an increase in the AF in the right CPL ).Figure. CPL Fig.  and a deCPL Fig.  from the, where there were significant decreases in the AF in the slow-6, slow-5 and slow-4 bands, but slight increases in the AF in the slow-3 and slow-2 bands in the LBLP patients .A significant interaction was identified between the frequency bands and disease status in the bilateral rectal gyrus Fig. , Table 2nts Fig.  (two-taiP = 0.045) and right MTG/ITG  were moderately positively correlated with the TPTD performance of the right hand. The AF in the slow-5 band in the right MTG/ITG was moderately positively correlated with TPTD performance in the left foot  and the right hand . An increase in the AF in the slow-5 band in the right CPL/BS  and a decrease in the AF in the bilateral PCUN  were moderately positively correlated with VAS scores. However, there were no significant associations after Bonferroni correction.For correlational analyses, the AF values were extracted from brain areas showing significant differences between the two groups in the five specific frequency bands  and from the voxel-based AF comparisons. Partial correlations between the abnormal AF values and the neuropsychological assessment scores were calculated for the LBLP patients. Age, sex and mean FD were considered covariates of effects in this study. The results are shown in Fig. The current study investigated the altered amplitudes of spontaneous BOLD fluctuations in different frequency bands in patients with LBLP. The LBLP patients showed significant differences in the AF in five specific frequency bands compared with HCs, which involved the pain matrix and sensory-processing brain regions. Importantly, we demonstrated that LBLP patients exhibited significantly increased oscillatory patterns in the full-frequency band (0–0.25 Hz) in the right CPL and the left and right MTG/ITG and significantly decreased oscillatory patterns in the right IPL/PoCG, bilateral CAU and bilateral PCUN. Moreover, there were pain-related alterations in the AF in the slow-5 band in the right CPL/BS and bilateral PCUN, which were related to the VAS pain scores. There were also sensory-related alterations in the AF in the slow-4 band in the left and right MTG/ITG and in the slow-5 band in the right MTG/ITG, which were related to performance on the TPTD test. These findings provide the full picture of the AF observed in BOLD waves, which is potentially useful for selecting specific frequencies to improve the detection of LBLP-related brain activity.21, and in various disease states 27. In the above studies, the strategy of frequency division was advantageous, enabling the detection of significant differences in the AF in specific frequency bands, including high-frequency bands. Although the dynamic oscillations of high-frequency bands are not fully understood, these oscillations may originate from the neuronal discharge of pyramidal cells as the receptive field “enslaves” the basket cells through resonance tuning7. There is also growing evidence that high-frequency fluctuations of BOLD waves can be modulated by different stimuli and are not simply noise but may be of physiological importance. Therefore, there is reasonable evidence that the altered regions of AF in both relatively low- and high-frequency bands may be of physiological importance and may reflect modulations as a result of the disease state in LBLP patients.In this study, we investigated frequency band-specific changes in spontaneous BOLD fluctuations in the resting state. We further demonstrated robust changes in the AF in the full-frequency bands (0–0.25 Hz) in the right CPL, bilateral PCUN, bilateral caudate CAU and right IPL/PoCG of LBLP patients. In previous studies, specific AF changes in intrinsic fluctuations or hemodynamic brain activity at different frequency bands have been observed in different physiological states, such as when the eyes are open or closed28. In the pain matrix, there are decreases in the cortical density7 and thickness7 and a change in the white matter integrity4 in the aINS/fO. Changes in insular volume may contribute to the transition from acute to chronic pain5. S1 (PoCG) is a component of the lateral pain system that encodes sensory-discriminative aspects of pain perception. Patients with low-intensity LBLP show decreased functional connectivity of S1 compared with matched HCs, and when chronic LBLP patients experience high-, rather than low-intensity pain, the functional connectivity at S1 increases. These functional changes in S1 may exist in the context of structural plasticity  in chronic LBLP patients8. Paresthesia or numbness, a “tingling, pricking” sensation, with other sensory modalities activating SI/SII regions, may result in cognition by engaging mutual cortical-level processing30. In the current study, the increased AF in the right CPL and right aINS/fO and the decreased AF in the bilateral CAU and PoCG imply that there are differences in pain perception depending on the context and meaning of pain. The decreased AF observed in the LBLP patients may be due to diminished sensory input as a result of paresthesia (numbness) of the lower extremities.The aINS/fO, CAU, PoCG and CPL are involved in pain processing. Human brain imaging studies have revealed multiple pathways and several discrete brain regions that are involved in pain processing. Afferent nociceptive information enters the brain from the spinal cord and travels through the spinocerebellar, spinothalamic-insula, spinothalamic-S1 and spinoparabrachio-amygdaloid-basal ganglia pathways32. In the current study, the increased AF in the left or right MTG/ITG was correlated with the TPTD performance of the right and left feet, indicating functional compensation or plasticity in parts of the spatial sensory-processing regions.In this study, we also observed an increase in the AF in the bilateral MTG/ITG in the LBLP patients. The MTG and ITG are involved in the visual processing of distance-related information and spatial awareness, respectively. In patients with low back pain, the MTG and ITG may be activated by somatosensory stimuli14. Altered neuronal activity of the DMN has been demonstrated in chronic low back pain patients during external stimulation and in the resting state and can be functionally reversed by acupuncture treatment33. More recent rs-fMRI studies have shown that connectivity within the DMN is altered in other chronic pain conditions, including migraines34, fibromyalgia25, chronic somatic pain23 and diabetic neuropathic pain35. Therefore, the DMN has been proposed as a biomarker for several chronic pain conditions36.We also found that the altered regions of the bilateral PCUN and left IPL consistently showed low- and high-frequency bands. The PCUN and IPL belong to the DMN, and disrupted connectivity of the DMN has been reported in previous studies of low back pain, implying dynamic impairment beyond the feeling of painet al.12 observed a graded shift phenomenon of power from low- to high-frequency bands in the visual ventral stream, suggesting that a closed relationship exists between the anatomical structures and the full spectrum of intrinsic oscillations. Lower-frequency fluctuations reflect long-distance neural activity due to a higher magnitude of power, while higher-frequency fluctuations reflect local neural activity due to a lower magnitude of power38. Evidence from neuroimaging and neuropsychology studies shows that the rectal gyrus is important in processing rewards and punishments and in linking pleasant and painful touch sensations39. Therefore, the findings of the current study may suggest that LBLP patients exhibit a reduced ability to process long-distance neural activity and an increased ability to process local neural activity in the rectal gyrus, hinting that painful inhibition by reward appears to distinguish neural representations. However, this assumption needs to be confirmed in future studies.In this study, significant interactions were identified between the five specific frequency bands and disease status in the bilateral rectal gyrus, suggesting that different frequency bands may have specific pathological relevance in this region. In the bilateral rectal gyrus, there were significant decreases in the AF in the slow-6, slow-5 and slow-4 bands and slight increases in the AF in the slow-3 and slow-2 bands. In a previous study, Baliki 41. Recent studies have demonstrated increased activity and functional connectivity between the cerebellum, brainstem and periaqueductal grey matter during stimulation of nociception, involving the descending antinociceptive network41.The correlational analyses showed that the changes in AF in the slow-5 band were related to the VAS pain scores, while the sensory-related changes in AF in the slow-4 and slow-5 bands were related to TPTD performance. The cerebellum plays a cross-modal modulatory role in the nociceptive processing of pain through electrical and/or chemical means and the processing of pain corresponding to emotion, cognition and motor control42. However, as a key area of the DMN, the PCUN did not contribute to the actual representation of pain and mainly predicted individual differences in sensitivity to pain. In the resting state, the patients spend nearly half of their time on mind wandering to cope with pain, while they are subjected to increased dynamic functional communication with the region mediating pain suppression43. One possible explanation is that the PCUN dysfunction observed in this study might underlie or be related to a reduced ability to pay attention. In short, an increased AF of the right CPL/BS and decreased AF of the PCUN in these pain-related regions may reflect maladaptive pain processing that influences affective responses to pain experiences34. A previous study of nociceptive and stolidity stimuli in LBLP patients revealed similar responses in the ipsilateral and contralateral S2 regions, which integrate inputs across multiple sensory modalities45. In this study, the TPTD test was used to assess the tactile spatial resolution, and the performance of the LBLP patients indicated that these patients exhibited hyperesthesia. The MTG/ITG is associated with visual stimuli processing for distance-related information and spatial awareness. In this study, although the MTG/ITG, and not S2, was associated with TPTD performance, we believe that these results may provide evidence of clinical measurements related to functional plasticity in areas that exhibit dynamic oscillatory waves of BOLD signals in LBLP patients.In this study, a positive correlation was found between a decreased AF of the bilateral PCUN and pain intensity (VAS scores) in LBLP patients. This finding indicates that when LBLP patients feel higher pain, they have relatively little ability to reduce the AF value in the PCUN. Does this finding seem to be contradicted by previous studies? Many studies suggest that pain-induced DMN deactivations or hypo-activity is negatively correlated with pain intensityThis study has several technical and biological limitations that must be acknowledged. First, this study involved mostly middle-aged to elderly LBLP patients. Due to factors such as brain atrophy in the elderly population, only patients younger than 65 years of age were included in the AF analyses. Second, for statistical consistency, P < 0.01 was set for the voxel- and ROI-level analyses; however, the AF values extracted for ROIs were mean values from overlapping regions of the five specific frequencies. Therefore, caution should be exercised in interpreting the comparison of AF between groups in the five specific frequency bands and the 84 narrow band bins. Third, all of the LBLP patients presented pain and numbness, or “dual-stimulation”, as characteristics of this cohort. However, other features of this “dual-stimulation”  have not been characterized. Therefore, in this study, the observed moderate relationships may be generically related to the chronic pain and/or paresthesia state without multiple comparisons, and it is likely that one or more false discoveries or type I errors are made; however, the findings are interesting nevertheless. When interpreting the results, the fact that the brain regions where AF is reduced are not the same regions that are associated with TPTD in the correlational analyses should be addressed at some level. Finally, this study is limited by its small sample size and the fact that 23 (92%) of the patients also presented with both pain and numbness, which should be considered when interpreting the results in the analyses of TPTD and specific AF correlations. In the near future, we will divide our patient sample by a median split for VAS scores (high/low) to determine whether the broad patterns of increases and decreases in the AF compared with the HCs hold for both groups.In this study, we showed that LBLP patients exhibit alterations of the AF in both low and high ranges of frequency bands involving the pain matrix and sensory-processing regions. Moreover, in all specific frequency bands, the pain-related alterations in the AF were frequency-dependent in several brain regions, which was related to clinical indices. These findings suggest that specific frequency ranges, even high-frequency bands, should be selected for the detection of pain-related intrinsic activity in future studies of LBLP patients.This case-control study was approved by the Medical Research Ethics Committee and the Institutional Review Board of the First Affiliated Hospital of Nanchang University. All subjects provided written informed consent and were identified only by number before undergoing an MR scan. All of the research procedures were performed according to the ethical principles of the Declaration of Helsinki and approved guidelines.15. The inclusion criteria were as follows: (1) clear evidence of discogenic compression in a lumbar CT and/or MRI; (2) radiating pain (VAS score > 4) from the lumbar region to the buttock(s) and lower limb(s) that increases with abdominal pressure ; (3) a positive straight-leg raise test and pick-up test and weak or non-existent patellar and Achilles tendon reflexes; (4) self-reported failure of improvement of pain with non-steroidal anti-inflammatory drugs  and acetaminophen  without opioids; and (5) an age of 35–65 years and volunteering to enroll in the study. The exclusion criteria were as follows: (1) spinal canal compression due to trauma or infection; (2) previous spinal surgery or pre-existing spinal abnormality; (3) other neurological disorders, such as a history of stroke, epilepsy, Parkinson’s disease, dementia or multiple sclerosis; (4) cardiovascular, cerebrovascular, liver, kidney or hematopoietic diseases; (5) the presence of calcifications on a spinal protrusion, lateral recess stenosis, spinal stenosis, pyriformis syndrome or sciatica; and (6) diagnosis of LDH without clinical symptoms. In addition, participants who refused or had contraindications for MRI, such as claustrophobia or metallic implants or devices, were excluded. Participants whose resting-state fMRI (rs-fMRI) revealed head motion with maximum displacement in the orthogonal direction  > 3 mm or maximum rotation  > 3.0° were excluded.From Oct. 2016 to Jul. 2017, a cohort of 61 participants, including LBLP patients and age-, sex- and education-matched HCs, were recruited from our hospital and from the local community. All patients were clinically diagnosed using available computed tomography (CT) and/or MRI images. Patients were included if they had more than 1 ruptured annulus fibrosus with compressed soft tissue, resulting in low back and leg pain for at least the last month that had failed to respond to conservative treatment with medications, exercise and physical therapy46, the Barthel index (0–100) for performance in activities of daily living and the TPTD test to assess the tactile spatial resolution ability47.All subjects underwent the following clinical evaluations before the MRI: the VAS (0–10) for pain, the JOA Back Pain Evaluation questionnaire (−6 to 29) to examine the impact of neuropathic or nociceptive pain on quality of life1-weighted magnetization-prepared rapid gradient-echo (MP-RAGE) sequence was employed to obtain anatomical images using the following settings: TR/TE = 1900 ms/2.26 ms, FOV = 215 mm × 230 mm, matrix = 240 × 256 and 176 sagittal slices at a 1.0 mm slice thickness with no gaps.All subjects underwent MRI in a Trio 3.0-tesla Siemens whole-body scanner with an 8-channel head coil . For rs-fMRI, the following settings were used: repetition time (TR)/echo time (TE) = 2000/30 ms, matrix = 64 × 64, field of view (FOV) = 220 × 220 mm, 30 interleaved axial slices, 4 mm thickness, inter-slice gap of 1.2 mm and 240 volumes in 8 min. During rs-fMRI, the subjects were asked to keep their eyes closed, clear their mind and not fall asleep. A 3-dimensional, high-resolution T2-weighted and T2-fluid-attenuated inversion recovery (FLAIR) sequences were acquired for the diagnosis of LBLP. Sagittal and axial conventional T1-weighted, T2-weighted and T2-fat suppression sequences were acquired for the lumbar spine and discs from L1 to S3. At the end of the scanning sessions, all participants reported that they had not fallen asleep during the scan according to the Epworth Sleepiness Scale (ESS) questionnaire.Additional conventional T48 (http://rfmri.org/dpabi) based on statistical parametric mapping , which was run on MATLAB 8.4.0 . The main preprocessing steps included the following: (1) after format transformation (dicom to nifti), the first 10 images were discarded for stabilization; (2) the remaining 230 images underwent slice timing, spatial realignment and voxel-specific head motion calculations ; (3) the group differences in head motion were evaluated according to the criteria described by Jenkinson et al. (including criterion: framewise displacement < 0.2 mm)49; (4) the high-resolution individual T1-weighted images were co-registered to the mean functional image using a linear transformation; (5) the Montreal Neurological Institute (MNI) space was transformed with the Diffeomorphic Anatomical Registration Through Exponentiated Lie algebra (DARTEL) tool and was re-sampled as 3 × 3 × 3 mm3 cube voxels; (6) spatial smoothing was performed with a 6-mm full-width-half-maximum Gaussian kernel; and (7) to reduce the effects of head motion and non-neuronal BOLD fluctuation, after linear detrending, nuisance linear regression was performed for the white matter, the cerebrospinal fluid, the global signal, six head motion parameters at a single time point and at one time point earlier and the 12 corresponding squared items (Friston 24-parameter model).The preprocessing of rs-fMRI images was performed using a toolbox for Data Processing & Analysis of Brain Imaging7, the preprocessing fMRI data were divided into five specific frequency bands: slow-6 (0–0.01 Hz), slow-5 (0.01–0.027 Hz), slow-4 (0.027–0.073 Hz), slow-3 (0.073–0.198 Hz) and slow-2 (0.198–0.25 Hz).(1) Predefined settings were used to calculate the AF in the five frequency bands. According to the Buzsáki framework50.(2) Predefined settings were used to characterize the changes in the AF with the evolution of frequencies in the full-frequency bands. The preprocessing fMRI data were divided into 84 narrow band bins with each narrow frequency band covering 0.003 Hz51. The AF was transformed into Fisher-z values for voxel-wise group analyses. The calculation of the AF was performed using the Data Processing & Analysis of Brain Imaging toolbox.(3) The AF was defined as the sum of the amplitudes within a predefined frequency domain using the fast Fourier transform procedure  for each voxel’s time series, extended from the calculation of the amplitude of low-frequency fluctuationst-test was performed on individual z-AF maps in a voxel-by-voxel manner. To calculate the correlation between the specific frequency band and group in the AF, we performed an ANOVA  using SPM12 with the groups (LBLP and HC) as a between-subject factor and the frequency band (slow-2 to slow-6) as an independent measure. All significant clusters were reported on the MNI coordinates, and T-values of the peak voxel were determined. Significance was determined at a voxel-level threshold (P < 0.01) with the GRF theory correction at a cluster-level threshold .To explore the differences in the AF between the LBLP and HC groups in the five specific frequency bands, a second-level random-effect two-sample t-tests were performed in each narrow band bin .The main brain regions showing an altered AF in the LBLP versus HC groups were identified as the ROIs for subsequent full-frequency band analyses. The AF values of each ROI were extracted from 84 amplitude maps with narrow frequency bands. Two-sample t-tests and χ2-tests in SPSS . In addition, partial correlational analyses were performed between the clinical indices  and the AF values for brain areas that exhibited significant differences between the LBLP and HC groups using the SPSS 13.0 software program (P < 0.05); the effects of age, sex and mean FD were considered. Bonferroni corrections were employed to correct for type I error across analyses .Comparisons of clinical characteristics and indices between the two groups were conducted using two-sample Supplementary table


Propofol is one of the most frequently used medications for inducing and maintaining anesthesia. However, propofol injection causes pain and discomfort in more than 70% of patients. This study was performed to determine the comparative effects of ketamine, sodium-thiopental, and magnesium sulfate on reducing pain at the onset of anesthesia induced by propofol injection.This single-blind randomized clinical trial was conducted on a population of patients, requiring nonemergency surgeries. The sample size was determined as 25 patients per group. The eligible samples were randomly divided into three groups. An 18-gauge intravenous catheter was inserted in the dorsum of the hand for all patients. Three groups received 0.5 ml/kg of ketamine, 30 mg/kg of magnesium sulfate, and 0.5 ml/kg of sodium-thiopental, respectively. Next, 2.5 mg/kg of propofol 2% was administered at a rate of 1 ml/s. The verbal rating scale (VRS) was applied to assess the severity of pain during injection.According to the results, the prevalence of pain was 36% in the magnesium sulfate group, 16% in the sodium-thiopental group, and 4% in the ketamine group. The ordinal logistic regression test showed that patients from the ketamine group experienced less pain, compared to the magnesium sulfate group . However, no significant difference was observed between the ketamine and sodium-thiopental groups .Ketamine and sodium-thiopental can be effective medications in reducing pain caused by propofol injection. According to the results, magnesium sulfate is not recommended for reducing pain due to propofol injection. Propofol is one of the most common medications for inducing and maintaining anesthesia, with advantages such as rapid action and recovery. However, propofol injection causes pain and discomfort in more than 70% of patients . There aVarious drugs are currently used to relieve pain caused by propofol injection, such as lidocaine , tramadoKetamine is another drug with analgesic effects, used in anesthesia induction. It is an N-methyl-D-aspartate (NMDA) receptor antagonist with strong analgesic effects, even at low concentrations. Some studies have revealed that ketamine can significantly reduce the pain caused by propofol injection , 9. MagnSodium-thiopental is another frequently used anesthetic agent. In this regard, the results of a study on children showed that a mixture of sodium-thiopental and propofol can lead to a greater reduction of pain, caused by propofol injection . AnotherThe pain caused by propofol injection is still a common problem in anesthesia. Considering its extensive use and necessity of mitigating the associated complications, examination of various strategies seems essential.The present study was conducted to determine the comparative effects of ketamine, sodium-thiopental, and magnesium sulfate on reducing propofol injection pain at the onset of anesthesia.This single-blind, parallel-design, randomized clinical trial was conducted on a population of patients, requiring nonemergency surgeries at Booali Hospital of Sari, Iran. The inclusion criteria were age range of 18–65 years and class I and II ASA, while the exclusion criteria were highly increased intracranial pressure, unstable hemodynamics, severe mental disorders, history of allergy to drugs, kidney, liver, or heart dysfunction, addiction, and use of calcium or magnesium blockers.Considering 90% confidence interval, 80% power, and 30% difference based on a previous study , the samBefore the intervention, an 18-gauge intravenous catheter was inserted in the dorsum of the hand for all patients. One minute prior to propofol injection, all patients received the study drug through a 5 mL syringe. In the ketamine group, the patients received 0.5 ml/kg of ketamine  , 12–14, Next, 2.5 mg/kg of propofol 2%  was administered at a rate of 1 ml/sec. The verbal rating scale (VRS) was immediately used after injection of drugs to assess the severity of pain during injection . It invoIn the VRS, “none” describes patients who experience no pain; “mild pain” describes patients who respond to feelings of pain when questioned, but have no facial grimacing and do not cry; “moderate pain” describes patients who have facial grimacing, show withdrawal of the hands, respond positively to feelings of pain, or complain of pain spontaneously; and “severe pain” describes patients who voluntarily complain of pain, have facial grimacing, and show withdrawal of the hands .P< 0.05.The proper concentration of propofol was injected to complete anesthesia induction. For muscle relaxation, 0.5 mg/kg of atracurium was administered. Oral intubation was performed, and anesthesia was maintained with isoflurane and 50% nitrous oxide and oxygen. The collected data were analyzed in SPSS version 20, using descriptive statistics  and analytical tests  at a significance level of After obtaining approval from the Ethics Committee of Mazandaran University of Medical Sciences and collecting written informed consents from the patients, they were assured of the confidentiality of data. The eligible participants were then given a brief description about the study. The participants were randomly divided into three groups via block randomization method. Recruitment of participants was sequential in the study. The samples were also blind to the type of intervention.P< 0.05.The severity of pain was evaluated with VRS and compared between the groups, using the ordinal logistic regression model. Numerical data are presented as mean and standard deviation. Data were analyzed in SPSS version 20, and the significance level was set at A total of 71 patients were recruited in this study (27 patients per group). Two patients were excluded from the ketamine group due to severe anxiety. Also, two patients were eliminated from the magnesium sulfate group due to lack of an appropriate intravenous line and face flashing. Moreover, phlebitis and lack of pain assessment resulted in the exclusion of patients from the sodium-thiopental group . The meaP= 0.008). However, no significant difference was observed between the ketamine and sodium-thiopental groups   .Despite the lack of a significant difference in pain between the ketamine and sodium-thiopental groups, the ketamine group reported less pain. The highest level of pain was reported by patients from the magnesium sulfate group. In agreement with the results of the present study, Saadawy et al. compared the effects of ketamine (0.4 mg/kg), sodium-thiopental (0.5 mg/kg), pethidine (0.4 mg/kg), lidocaine (1 mg/kg), and normal saline (3 mL) and found the prevalence of pain to be 8% and 32% in the ketamine and sodium-thiopental groups, respectively. The findings showed that administration of ketamine prior to propofol injection is the best strategy to reduce pain caused by propofol injection .Özkoçak et al. compared the effects of 2 mL of normal saline, 70 μg/kg of epinephrine, and 0.5 mg/kg of ketamine on pain caused by propofol injection and found no significant difference in the incidence of pain between the groups; however, the severity of pain was significantly different between the ketamine and other groups . In theiIn addition, Zahedi et al. compared the effects of three different doses of ketamine on pain caused by propofol injection. They divided the patients into five groups, receiving 1 mg/kg of lidocaine, normal saline, and ketamine at concentrations of 50, 75, and 100 μg/kg, respectively. The findings showed a significant difference in the incidence and severity of pain between the normal saline (placebo) and other groups. The incidence and severity of pain were lower in the 100 μg/kg ketamine group, compared to the 50 μg/kg ketamine and lidocaine groups .Previous studies have shown that the analgesic effects of low ketamine doses can complement the sedative effects of propofol injection . CombinaThe results of the present study showed no significant difference in pain between the sodium-thiopental and ketamine groups. Overall, many studies have examined the effects of sodium-thiopental prior to propofol injection. In this regard, Agarwal et al. compared the effects of normal saline, lidocaine 2% (4 mg), and sodium-thiopental at doses of 0.5 and 0.25 mg/kg on pain caused by propofol injection. Pain-related complaints were reported in 77% of patients from the saline group, 39% of patients from the lidocaine 2% group, 32% of patients from the 0.5 mg/kg sodium-thiopental group, and 3% of patients from the 0.25 mg/kg sodium-thiopental group. Accordingly, administration of 0.5 mg/kg of sodium-thiopental was recommended one minute before propofol injection .Additionally, Pollard et al. examined the effects of sodium-thiopental on propofol injection pain among children. The patients were divided into propofol plus lidocaine and propofol plus sodium-thiopental groups. According to the results, the incidence of pain was 14% in the propofol plus sodium-thiopental group and 35% in the propofol plus lidocaine group; a significant difference was observed between the groups . AlthougIn the present study, the magnesium sulfate group reported greater pain, compared to other groups. In contrast, Memis et al. in their report showed that magnesium sulfate can reduce the pain due to propofol injection. In their study, the patients were divided into normal saline and magnesium groups. The results showed a significant difference in pain scores between the groups . In contIn another study, Agarwal et al. showed that intravenous magnesium and lidocaine were equally effective in reducing pain caused by propofol injection. However, administration of magnesium in isolation appears to induce pain, and its use cannot be justified .There are some potential limitations in the present study. If pain assessment was combined with other techniques, it would have become more accurate. Also, further use of lidocaine, as the gold standard for propofol pain reduction, needs to be considered. Another limitation of this study was our inability to assign uniformed nursing staff to intravenous catheter insertion procedures; this might have in fact limited our control over confounding variables.Ketamine and sodium-thiopental can be ideal medications for reducing pain caused by propofol injection. However, considering its analgesic and sympathomimetic properties, ketamine appears to be a more suitable agent. According to the results, magnesium sulfate is not recommended for reducing the pain caused by propofol injection. Further studies are required to confirm the external validity of the results.


Adequate pain control is essential in the treatment of patients with traumatic rib fractures. Although epidural analgesia is recommended in international guidelines, the use remains debatable and is not undisputed. The aim of this study was to describe the efficacy and safety of epidural analgesia in patients with multiple traumatic rib fractures.  A retrospective cohort study was performed. Patients with ≥3 rib fractures following blunt chest trauma who received epidural analgesia between January 2015 and January 2018 were included. The main outcome parameters were the success rate of epidural analgesia and the incidence of medication-related side effects and catheter-related complications. n=4), medication-related side effects (n=4), and catheter-related complications (n=6). In 17 patients (22%), the epidural catheter was removed after one or multiple additional interventions due to insufficient pain control. Minor epidural-related complications or side effects were encountered in 36 patients (47%). One patient had a major complication (opioid intoxication).  A total of 76 patients were included. Epidural analgesia was successful in a total of 45 patients (59%), including 22 patients without and in 23 patients with an additional analgesic intervention. In 14 patients (18%), epidural analgesia was terminated early without intervention due to insufficient sensory blockade ( Epidural analgesia was successful in 59% of patients; however, 30% needed additional analgesic interventions. As about half of the patients had epidural-related complications, it remains debatable whether epidural analgesia is a sufficient treatment modality in patients with multiple rib fractures. Thoracic trauma is frequently encountered in the emergency department and is responsible for 10% to 15% of all trauma admissions . Rib fraAdequate pain control is key in the management of rib fractures. Pain associated with rib fractures and other thoracic injury can lead to inefficient ventilation resulting in respiratory complications, need for mechanical ventilation, and prolonged recovery , 8. ConsThe use of epidural analgesia remains an important topic of discussion. Over the past decades, several studies reported on beneficial outcomes of epidural analgesia and encouraged the use of epidural analgesia over other analgesic modalities , 10–16. Epidural analgesia may be insufficient due to the high risk of failure and catheter-related problems. In previous studies on the use of epidural analgesia after surgery, failure rates have been reported up to 47% . FurtherFurther research on the use of epidural analgesia is needed. There is limited literature regarding the efficacy and complications of epidural analgesia in thoracic trauma. Therefore, the aim of this retrospective cohort study was to describe the efficacy and risk of complications of epidural analgesia for patients with multiple traumatic rib fractures.A single-center retrospective cohort study was conducted in the University Medical Center Utrecht, a level 1 trauma center in the Netherlands. To analyze current practice, all adult patients with three or more rib fractures following blunt chest trauma who were admitted between January 2015 and January 2018 were eligible for inclusion. Patients who received epidural analgesia according to clinical documentation in the electronic patient file were included. Data collection was performed with the use of the Dutch National Trauma Registry, a national prospective database containing all trauma patients admitted to the emergency department in the Netherlands. In multitrauma patients, all concomitant injuries were graded using the abbreviated injury scale (AIS) . PatientAccording to our hospital's pain protocol, epidural analgesia was indicated for patients with three or more fractured ribs with insufficient pain control despite the use of paracetamol, nonsteroidal anti-inflammatory drugs, and morphine. Epidural analgesia was also indicated in case of an increased risk of respiratory insufficiency due to preexistent comorbidities. Indication for epidural analgesia was made primarily in the emergency department, or secondarily, after admission in the surgical ward. The degree of pain was assessed according to the Numerical Rating Scale (NRS) pain score. The NRS is an 11-point scale to measure pain intensity, ranging from 0 (no pain) to 10 (worst imaginable pain) .Contraindications for epidural analgesia included patient refusal, vertebral fractures, spinal cord injury, traumatic brain injury, Glasgow Coma Scale < 15, unstable pelvic fracture, hemodynamic instability, local infection at the insertion site, or coagulopathy. Epidural catheter placement was performed by anesthesiologists at the level of the thoracic injury. The loss of resistance technique was used to guide a 17-gauge Tuohy needle. After reaching the epidural space, a test dose of 3 ml lidocaine 2% was administered to exclude intravascular or intrathecal positioning. Following appropriate catheter insertion, an initial bolus dose with local anesthetics was administered and a continuous epidural infusion was started with a mixture of bupivacaine 2.5 mg/ml and morphine 0.04 mg/ml. The initial infusion rate was 4 ml/hr. According to the patient's response and degree of pain relief, the infusion rate was gradually increased up to a maximum of 6 ml/kg/h. If the epidural block is still not provided with satisfactory pain relief with sufficient dermatomal coverage despite a maximum administration of epidural analgesia, the epidural mixture was diluted 50% with a mixture of bupivacaine 1.25 mg/ml and morphine 0.02 mg/ml. The maximum infusion rate after dilution was 12 ml/hr. All patients received paracetamol in combination with a nonsteroidal anti-inflammatory drug , unless contraindications were present. A urinary catheter was inserted in all cases and remained in place during administration of epidural analgesia.The NRS scores were measured every 8 hours by the ward nurses. A specialized pain team visited the patients daily to evaluate the adequacy of sensory block, side effects, and complications. Additionally, data regarding catheter placement difficulties, duration of infusion, number of top-ups, need for additional pain medication, reason for epidural catheter termination, and conversion to another analgesic modality were recorded. A top-up was defined as an additional bolus administration of 3 ml lidocaine 2% or bupivacaine 0.25% to provide or restore a sufficient sensory block.Data were retrieved from a prospective database and completed by checking the electronic patient files. Baseline characteristics included patient demographics , trauma mechanism, injury severity score (ISS) and AIS scores, concomitant injuries, and rib fracture-related characteristics including number and place of fractured ribs, presence of flail segment, bilateral involvement, dislocation, presence of dorsal fracture, first rib involvement, fractures in upper/middle/lower part of the thorax, and indication for rib fixation. Fracture characteristics were evaluated with the use of computed tomography scans.The primary outcome measure was the success rate of epidural analgesia during the first 5 days of administration. Successful application of epidural analgesia was defined as follows: (1) sufficient pain control or sensory block and (2) no early termination due to medication-related side effects, or catheter-related complications. Epidural analgesia was also classified as successful in case the catheter was removed within the first 5 days due to satisfactory pain, or if necessary for early mobilization. A distinction has been made between success with or without an additional analgesic intervention. Analgesic interventions included epidural top-up/bolus, adjustment of epidural analgesia, and/or administration of intravenous analgesia. Insufficient pain control was defined, according to the hospital pain protocol, as ongoing severe pain (NRS ≥ 7) with the maximum administration of paracetamol, nonsteroidal anti-inflammatory drugs, and morphine . Insuffi2/FIO ratio smaller than 100 mmHg.Secondary outcome measures included the rate of other complications, length of stay in the intensive care unit (ICU) and hospital, duration of mechanical ventilation, and mortality . Respiratory complications included pneumonia, need for intubation, atelectasis, acute respiratory distress syndrome, and the need of tracheotomy. Pneumonia was defined by presence of clinical symptoms  requiring antibiotic treatment, regardless of a negative or positive culture. Diagnosis was confirmed by examination of a chest radiograph. Atelectasis was defined as collapse or incomplete expansion of pulmonary parenchyma confirmed on a chest radiograph or computed tomography scan. Acute respiratory distress syndrome was defined by severe hypoxemia with a PaOData were described using frequencies and percentages for dichotomous and categorical variables, mean and standard deviation (SD) for normally distributed continuous data, and median and interquartile range (IQR) for non normally distributed continuous data.p < 0.05. All statistical analyses were performed using Stata® 13.0 .To assess possible rib fracture characteristics independently associated with epidural analgesia failure, a multivariable logistic regression was performed. Subgroup analysis was performed for success of epidural analgesia on in-hospital outcome measures. Statistical significance was defined as A total of 527 patients were identified with the Dutch National Trauma Registry. Ultimately, 76 patients who received epidural analgesia were included in this study .n=61, 80%). The median ISS was 14 (IQR 10-17) (The included patients had a mean age of 58 (SD 14) years and were predominantly male (R 10-17) . The meaR 10-17) .Sixty-five patients (86%) received an epidural catheter primarily upon time of admission. In 11 patients (14%), catheter placement occurred secondarily during admission since sufficient pain control could not be achieved.n=4), medication-related side effects (n=4), and catheter-related complications (n=6). In 17 patients (22%), the epidural catheter was removed after one or multiple additional interventions due to insufficient pain control.As demonstrated in the flowchart in n=10, 13%), pruritus , and hypotension with need of vasopressin support . One patient (1%) experienced a major side effect due to morphine intoxication with severe systemic effects, most likely because of coadministration of transdermal fentanyl. Minor catheter-related complications occurred in 9 patients (12%) and included primary placement failure , accidental dislocation , disconnection , occlusion , loosened filter , and leakage , and in one patient (1%), epidural medication was administered intravenously. No major complications occurred.Medication-related side effects and catheter-related complication were encountered in 37 patients (49%) . Minor mThe epidural catheter was removed in only 5% of all patients due to one of the medication-related side effects, and in only 8% of all patients due to a catheter-related complication. All other medication-related side effects could be remedied by adjusting the medication.A multivariable analysis was performed to identify rib fracture characteristics that were independently associated with epidural analgesia failure. The following rib fracture-related characteristics were included in our analysis: number of rib fractures, bilateral involvement, dislocation, first rib involvement, presence of dorsal fracture(s), and location of fractures . No rib fracture characteristics appeared to be independently associated with epidural analgesia failure.International guidelines recommend epidural analgesia in patients with traumatic rib fractures. However, the evidence regarding the effects and safety of epidural analgesia remains inconclusive . The aimPrevious studies on epidural analgesia after different types of surgery, reported incidence rates of epidural analgesia failure ranging from 13% to 47% . A studyAbout half of the patients in our study had complications or side effects after epidural analgesia. The majority were minor medication-related side effects such as pruritus, nausea, and hypotension. Other complications reported in the literature include bradycardia, respiratory depression, or decreased consciousness, and catheter-related complications such as epidural hematoma or abscess . In our The question whether epidural analgesia is beneficial over other analgesic modalities in patients with traumatic rib fractures is debatable , 17, 28.In a recent systematic review and meta-analysis of both observational studies and randomized controlled trials, effects of epidural analgesia were compared with other analgesic modalities in patients with one or more traumatic rib fractures. Nineteen studies were included, representing a total of 2801 patients. This study showed that epidural analgesia provided better pain relief than other analgesic modalities, although few studies reported on pain scores. No beneficial effects from epidural analgesia could be demonstrated for the outcome measures hospital and intensive care unit length of stay, duration of mechanical ventilation, respiratory complications, and mortality [Several difficulties are associated with the use of epidural analgesia in patients with traumatic rib fractures that are insufficiently highlighted in current practice while important information for decision-making. According to a recent systematic review, incidences of epidural-related complications are poorly reported . Also, tThis study had several limitations. First, due to the retrospective nature of this study, results are subject to missing data and underreporting. Pain perspective is an important outcome measure; however, this could not be accurately assessed due to missing data. Therefore, we could not provide an overall presentation of the pain scores of this cohort. Additionally, there were insufficient data to calculate the daily used intravenous morphine. However, the number of patients who received additional intravenous opioids has been described. Second, patients were selected using the AIS thorax which might have resulted in a specific subgroup of patients limiting generalizability of the study results. Third, the number of included patients was relatively small. So, although we did not identify a significant difference in mortality between patients with or without successful epidural analgesia, it must be considered that this might be due to a limited power.Finally, the available literature reporting on the efficacy of epidural analgesia in patients with multiple traumatic rib fractures remains scarce; therefore, this study contributes to the current literature and discussion of optimal management of these patients.Epidural analgesia was successful in 59% of patients; however, 30% needed additional analgesic interventions. As about half of the patients had epidural-related complications, it remains debatable whether epidural analgesia is a sufficient treatment modality in patients with multiple rib fractures. Future research could focus on other regional analgesic modalities that are more effective and less susceptible to complications.


NCT01127100.A number of studies have been published proposing various approaches to the treatment of neuropathic pain; however, to our knowledge, no attempts have been made to compare gabapentin and fentanyl in patients with lumbar radiculopathy. We evaluated the relative efficacy and safety of fentanyl matrix and gabapentin for the treatment of chronic neuropathic pain of radicular origin. The study was designed as a randomized blind multicentered parallel-group noninferiority trial. A total of 108 patients with moderate-to-severe pain  were randomly prescribed either fentanyl matrix or gabapentin over a period of 56 days. In the primary analysis, the noninferiority of fentanyl matrix treatment was evaluated in relation to the efficacy of gabapentin based on the pain intensity difference (PID) at 56 days after the first dose of the drugs. Secondary endpoints included pain relief, improvement in functional status (the Korean-Oswestry Disability Index (K-ODI)), improvement in depressive symptoms (Korean-Beck Depression Index (K-BDI)) between the 28th and 56th day, and adverse events (AEs). Analysis of the primary efficacy endpoint established the noninferiority of fentanyl matrix compared with gabapentin, with no statistically significant difference observed in the PID after 56 days for the two treatment groups. Similarly, analysis of pain relief revealed no significant differences between the groups on days 28 and 56. There was no difference in the K-ODI and K-BDI between the groups during the study period. The overall incidence of at least one AE was similar for fentanyl matrix (67.3%) and gabapentin (69.6%). The most commonly reported AEs for patients treated with fentanyl matrix and gabapentin included dizziness , somnolence (26.9% vs. 35.7%), and constipation (15.4% vs. 17.9%). This study demonstrated that the analgesic effect of fentanyl matrix is noninferior in comparison with gabapentin and supports the use of fentanyl matrix as an effective and safe treatment for moderate-to-severe chronic neuropathic pain. This trial is registered with  Neuropathic pain is defined as “pain caused by a lesion or disease of the somatosensory system” . It has Because of its ubiquity, various medications are used to treat neuropathic pain. Gabapentin is an anticonvulsant that is recommended most commonly for neuropathic pain due to its efficacy for diabetic neuropathy, postherpetic neuralgia, and other neuropathic conditions as demonstrated in several randomized controlled trials (RCTs) –4.Opioids, which are the most effective broad-spectrum analgesic for acute pain, have increasingly been used to treat neuropathic pain, even though controversy remains over their efficacy and safety –23. An eSeveral studies have reported on the efficacy of medications for the treatment of neuropathic pain, but to our knowledge, no attempts have been made to compare gabapentin and fentanyl in the treatment of pain arising from lumbar radiculopathy. With a focus on the safety and convenience of transdermal fentanyl, we planned an RCT comparing gabapentin and transdermal fentanyl for chronic neuropathic pain in a noncancer setting.This clinical trial was conducted using a single protocol at seven hospitals, each with its own clinical investigator from May 26, 2010, to November 28, 2011. Based on the inclusion/exclusion criteria described below, 108 patients were selected and stratified by site and randomized into the study drug or comparator group at a 1 : 1 ratio using stratified block randomization. Subject questionnaires were assessed by a rater who was blind to the randomization process.Patients were enrolled if they complained of chronic neuropathic pain for more than three months before the study began and if they were at least 20 years old. Patients were considered for inclusion only if their mean pain intensity for the three days before entering the study entry was higher than 4 on a numeric rating scale (NRS) and if they were judged by the investigator to be able to follow the overall study process and to complete the questionnaires.The criteria for the diagnosis of neuropathic pain in the subjects were pain radiating into the corresponding dermatome, motor or sensory change, a symptomatic area that was consistent with an anatomical lesion as observed in magnetic resonance imaging, radiculopathy that was confirmed with electromyography (EMG) test, and a score of more than 12 on the self-reported version of the Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS).Patients were excluded if they had received treatment with gabapentin, pregabalin, fentanyl matrix, or long-acting oral opioid analgesics within the 30 days before the trial began; had a history or a laboratory discovery of neuropathy of other origins ; had a concurrent disease causing other pain that was more intense than the neuropathic pain; and if other opioid analgesics were contraindicated. Patients who were not expected to provide written consent, who could not understand the warnings, cautions, or contraindications in the instructions, and whose welfare might be threatened were also excluded from the study.All of the subjects were given an explanation of the study and then signed a written informed consent form, which was approved by the Institutional Review Board, before the treatments began. Drugs that had been used within the past month and those that were being used at the time were documented. During the study, the concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase-2 (COX-2) inhibitors, acetaminophen, aspirin, and tricyclic antidepressants that were being taken before the study commenced was allowed, and their dosages were maintained during the study period. On the other hand, the initiation of any new analgesics other than the drugs under investigation was not allowed. However, the prophylactic use of antiemetics was allowed at the beginning of the treatment to prevent the nausea and vomiting that might be caused by opioid analgesics. Medications were allowed for the treatment of adverse events (AEs) even during treatment with the target drugs.The subjects received the study drug (fentanyl matrix) or the comparison drug (gabapentin) after the first baseline assessment. The minimal dose (12 mcg/h) of the study drug was administered for six days, after which the pain was assessed every six days until day 28, during which time the dose was increased gradually by 12 mcg/h when the mean NRS was higher than 2. Finally, the last dose in the previous stage was maintained from days 29 to 56 .Gabapentin was administered at a dose of 300 mg once in the evening on day 1, 300 mg twice on day 2, 300 mg three times on days 3 and 4, and 300 mg both in the morning and afternoon and 600 mg in the evening on days 5 and 6. Subsequently, the dose was increased gradually by 300 mg per day up to 2400 mg/day when the mean NRS was higher than 2 during the pain assessments conducted every six days until day 28. Finally, the last dose in the previous stage was maintained from days 29 to 56. In the presence of possible AEs, the investigator was allowed to control the rate at which the dosage was increased .The primary efficacy parameter of this study was the pain intensity difference (PID) from baseline at eight weeks after the first dose of the study drug , with an objective to demonstrate that the study drug group was noninferior to the comparator group. Pain intensity was measured on an 11-point numeric rating scale (0 = no pain and 10 = the highest degree of pain). Secondary efficacy parameters that were also assessed were pain relief , Korean-Oswestry Disability Index (K-ODI), and Korean-Beck Depression Inventory (K-BDI). The ODI is widely used to estimate functional disability due to low back pain. It contains ten categories: intensity of pain, lifting, ability to care for oneself, ability to walk, ability to sit, sexual function, ability to stand, social life, sleep quality, and ability to travel. The BDI is a 21-question multiple-choice self-report inventory, one of the most widely used psychometric tests for measuring the severity of depression. The subjects visited the investigational site on days 29 and 57 for an assessment of any AEs caused by the drugs under investigation and the assessment of the efficacy parameters.post hoc power analysis to calculate the actual power of the study using the collected data and found that it was greater than 90% .To decide the target sample size, variations due to changes in pain intensity in the study drug and comparator groups were calculated based on previous research, and the noninferiority margin  between the study drug and comparator groups in relation to the PID was estimated. The target was set at 58 subjects per group  based on the following assumptions: (1) a one-sided 2.5% (two-sided 5%) significance level, (2) a test power of 90%, (3) a minimal clinically significant difference (non-inferiority margin) in the PID of 1.39 between the study drug and comparator groups, (4) a change in the PID after eight weeks of 1.87 in both groups, (5) no difference in the PID between the groups in the population, (6) a follow-up loss of 30% in both groups during the study, and (7) 40 subjects per group for per-protocol (PP) analysis . We condSubjects were considered to have completed the clinical trial when they had completed the third assessment on day 57. Subjects were removed from the study for the following reasons: (1) treatment was no longer possible due to AEs, (2) the subject decided to discontinue the treatment for safety reasons, (3) a major protocol violation occurred, (4) the subject did not cooperate with the procedures of the study, (5) the subject or his/her caregiver withdrew the consent to participate in the study, (6) the patient did not attend a follow-up, or (7) a female subject became pregnant.The study subjects for whom the efficacy parameters were assessed were divided into intention-to-treat (ITT) and PP populations. The ITT population consisted of any subjects who met the inclusion/exclusion criteria at screening and who were randomized at baseline. The PP population consisted of subjects in the ITT population whose pain intensity was assessed at the third assessment after completing the study without removal for any of the reasons stated above.U test or t-test for continuous variables and Pearson's chi-square test or Fisher's exact test for dichotomous variables. The descriptive statistics for continuous variables were presented as means with standard deviation (SD), and dichotomous variables were presented as frequencies with percentages in parentheses.The PID, primary efficacy parameter, was analyzed mainly for the PP population using one-sided 95% lower confidence limits for the difference in the mean PID, as measured between the baseline scores and the assessment scores on day 57, between the study drug and comparator groups. If the lower confidence limit was equal to or greater than the noninferiority margin of −1.39, pain reduction in the study drug group was judged to be noninferior to that of the comparator group. Similarly, if the one-sided 95% lower confidence limit exceeded 0, pain reduction in the study drug group was judged to be superior to that of the comparator group. The secondary parameters were analyzed mainly for the ITT population using the Mann–Whitney P values lower than 0.05 were considered statistically significant. All analyses were conducted using the statistical software package SAS 9.X .For missing data, no imputations were performed, and the data were treated as missing for all variables. All statistical tests except for the noninferiority test were two-sided. Of the 108 subjects who provided informed consent and participated in this study, 67 (62.0%) completed the third assessment after receiving the study drug or comparator for 56 days and 41 (38.0%) were removed from the study . The mosBaseline age, weight, height, and mean pain intensity were not statistically significantly different between the two groups . Spinal P=0.8727). In the ITT population, the study drug and comparator groups demonstrated statistically significant decreases from baseline in the intensity of their pain at both the second and third assessments  and 2.6 (±2.0), respectively. Because the lower confidence limit was −0.7935, which was higher than the noninferiority margin of −1.39, the decrease in mean pain intensity in the study drug group was judged to be noninferior to that in the comparator group at a one-sided 95% significance level . Followiessments .P=0.3359, P=0.8698, P=0.4095, Student's t-test).In the ITT population, there was no between-group difference in pain relief at the second and third assessments after treatment with the study drug and comparator  complained of AEs at least once, with 35 (67.3%) and 39 (69.6%) in the study drug and comparator groups, respectively. The most common AE was dizziness , while AEs that occurred in more than 10% of subjects included somnolence , nausea , constipation , vomiting , and asthenia , followed by dizziness , somnolence , vomiting , and constipation . In the gabapentin group, dizziness  was the most common AE, while somnolence , constipation , and asthenia  occurred in more than 10% of subjects.P=0.7049  and  0.7341, respectively).Twenty patients (18.5%) were removed from the study due to AEs . In bothAntidepressants and anticonvulsants are conventional treatments for neuropathic pain. The currently recommended first-line treatments are anticonvulsants such as gabapentin and pregabalin, serotonin-norepinephrine reuptake inhibitors such as duloxetine and venlafaxine, and tricyclic antidepressants . AlthougThe transdermal fentanyl delivery system is a formulation that is absorbed through the skin over an extended period. Transdermal fentanyl has been reported to be effective in relieving neuropathic and cancer pain, to have fewer constipation and sedative effects, and to lead to significantly higher patient satisfaction because of the convenience of application. Fentanyl matrix patches have also been found to relieve neuropathic pain that is not sensitive to other opioids and has been reported to be effective and safe for opioid-naive patients –21.We believe that fentanyl matrix may be a good alternative to oral drugs for neuropathic pain in primary clinical settings. Although several reports have compared gabapentin to oral opioids, few comparisons have been made between anticonvulsants and transdermal fentanyl in terms of efficacy and safety. Therefore, we decided to compare fentanyl matrix with gabapentin even though these agents are administered via different routes and have different pharmacokinetic profiles. To our knowledge, this is the first RCT comparing transdermal fentanyl with gabapentin in patients with chronic noncancer neuropathic pain.The efficacy of gabapentin in relieving neuropathic pain has been proven in many studies and is recommended as a first-line treatment , 23, 25.The number of dropouts due to AEs was lower in the fentanyl group (9 subjects compared to 11 in the gabapentin group). The most serious issue that arises during treatment with strong opioids is that patients often voluntarily discontinue treatment due to AEs such as nausea, vomiting, and constipation. The significance of transdermal fentanyl in our study is that the incidence of early AEs is not different from that existing in first-line treatments. With the recent focus on the misuse and abuse of prescription drugs, there is a trend for strong opioids  to be classified as third-line treatments, which warrants long-term follow-up studies .Although pain intensity frequently is measured on an 11-point pain intensity NRS, it is difficult to interpret the clinical importance of minor changes from baseline using this scale . Farrar et al.  reportedThe dropout rate was relatively high in this study (38.0%). The dropout rate due to AEs was 18.5%, which was similar to that of previously reported studies , 29. A sOur results should be interpreted carefully based on the study design. For example, the raters of the questionnaires used in this study were blinded to the treatments, but the subjects were not. A double-dummy or double-blind design might have overcome this bias, but a comparison of the two medications with completely different routes of administration without using a placebo has its inherent limitations. In addition, patients who had received an extended-release opioid within the past 30 days were excluded from the study, but the remaining patients were not necessarily all opioid-naive. Strong opioids generally are recommended for patients who do not respond to treatments with conventional NSAIDs or weak opioids. If the target patients were narrowed down to opioid-native patients or those who did not respond to conventional opioids, the incidence of AEs would be higher or the effect of study drugs would decrease, respectively. In addition, differences between routes of administration, mechanism of action, alterations in absorption/drug levels, and variability between formulations (brand vs. generic) also are limitations of the current study.We did not exclude subjects who were on antidepressants, which may have had a role in the treatment of neuropathic pain, because they are widely used for purposes other than pain relief. Other analgesic drugs that the patients were allowed to take may have interacted differently with the drugs under investigation and significantly influenced the outcomes. In addition, the frequency of intake, the clearance time, and other pharmacokinetic parameters related to these drugs might have affected the findings. However, patients were prohibited from starting new drug treatments during the study period.The presence of radiculopathy was confirmed using EMG for all of the patients, and they were all judged to be experiencing neuropathic pain based on S-LANSS assessment. However, it is difficult to apply these criteria when prescribing medications in real-world clinical settings. A number of patients with a spinal degenerative disease experience both nociceptive and neuropathic pain , which sThe outcomes observed from the administration of the two different drugs mostly overlapped in this study. Opioid and anticonvulsant have different mechanisms in relieving neuropathic pain. We believe that there was no significant difference in the clinical results between the two groups because we focused on the neuropathic features of lumbosacral radiculopathy. If the target pain had included a nociceptive component such as low back pain, the outcomes might have been different. In addition, although the overall incidence of AEs did not differ between the two groups, dizziness and somnolence were more frequent in the gabapentin group, whereas nausea and vomiting were more frequent in the fentanyl patch group.Despite the increasing prescription of fentanyl for chronic, cancer, and postoperative pain, little research has been conducted on its effect on neuropathic pain. A Cochrane review in 2016 , in whicAlthough lumbar radiculopathy is a common disease with neuropathic features, few clinical trials have been conducted for various medications targeting neuropathic pain of radicular origin. Given that transdermal fentanyl was noninferior to gabapentin, which is a first-line treatment for neuropathic pain, our research indicates that transdermal fentanyl could be beneficial in terms of efficacy and safety for patients who are not comfortable with oral gabapentin. However, further studies are warranted to determine the appropriate treatment guidelines.This clinical trial comparing fentanyl matrix and gabapentin in patients with chronic neuropathic pain demonstrated that both drugs were equally effective in reducing neuropathic pain. The pain reduction in the fentanyl matrix group was noninferior to that of the gabapentin group, with no difference between the two groups in terms of patient functional status, depressive symptoms, and the occurrence of adverse events.


The use of local infiltration anesthesia (LIA) has become one of the cornerstones of rapid recovery protocols in total knee arthroplasty patients during the past decade. In total hip arthroplasty (THR), however, the study results are more variable and LIA has therefore not yet been generally accepted. There is no consensus on which structure should be infiltrated and the cutaneous nerves are generally neglected. Hence, we hypothesized a pain-reducing effect of specifically blocking these nerves.We performed a single-center randomized placebo-controlled trial in 162 subjects to evaluate the infiltration of the lateral cutaneous femoral and subcostal nerve with ropivacaine in patients undergoing total hip arthroplasty via a straight lateral approach. The primary endpoint was pain at rest after 24 hours. Patients were followed up to 6 weeks postoperatively.After correction for multiple testing, no statistically significant differences in pain scores were found between the ropivacaine compared with the placebo group after surgery. In addition, no differences were observed in the use of escape pain medication, complications, and the length of hospital stay.We found no clinically meaningful differences in pain scores between placebo and ropivacaine patients in the postoperative period after THA performed via a straight lateral approach under spinal anesthesia and a multimodal pain regimen. Moreover, our primary endpoint, pain reduction after 24 hours, was not met. Further research should focus on the composition and volume of the LIA suspension, the optimal localization of the infiltration, and should be evaluated for every surgical approach separately. While the use of local infiltration anesthesia (LIA) in total knee arthroplasty (TKA) has been embraced by orthopedic surgeons worldwide, the use in total hip arthroplasty (THA) patients has remained a matter of debate . All patient received the ropivacaine or placebo in addition to multi-modal pain management in a fast-track recovery protocol. The primary endpoint was pain at rest 24 hours after surgery.After written informed consent had been obtained, 162 patients with primary osteoarthritis undergoing elective THA at the Department of Orthopedic Surgery, Spaarne Gasthuis Hospital location Hoofddorp, from August 2014 to September 2016 were enrolled in this randomized trial. Exclusion criteria included known allergy to ropivacaine, general anesthesia, opioid dependency, malignancies, co-morbidities compromising pain perception , ASA grades 3–4. In addition, patients suffering from peroperative complications interfering with postoperative pain and perception or mobilization were excluded. Preoperatively, patient demographics, visual analogue pain scores (VAS) in rest and during mobilization, as well as the Hip disability and Osteoarthritis Outcome Score (HOOS), Short form Survey (SF-12) and Oxford Hip Score (OHS) questionnaires were documented.All patients were admitted on the day of surgery. A standardized pain protocol was used. 2 hours preoperatively patients received 1000 mg acetaminophen, 15 mg meloxicam, and 600 mg gabapentin. All surgeries were performed under spinal anesthesia, using low-dose bupivacaine. Postoperative patients received 1000 mg acetaminophen every 6 hours, 15 mg meloxicam once daily both at least until discharge, and 600 mg gabapentin 3 times a day for a period of 5 days. When the protocol medication was insufficient to control pain, escape medication consisting of Oramorph oral solution (morphine sulfate) or Dipidolor (piritramide) intramuscular (both 5–10 mg) was available and its usage documented.On the day of surgery, blinded numbered 50 cc syringes containing either ropivacaine  or placebo (0.9% NaCl) were provided by the department of pharmacy, which used a block randomization scheme to control group volume. Surgeons, patients, nurses, and investigators were all blinded for treatment. Standard hip arthroplasty surgeries ) were performed by 6 different orthopedic surgeons or coupled residents via a straight lateral approach according to Hardinge. Prior to the surgeries an instruction video was shown to all surgeons on multiple occasions. The video shows exactly how to infiltrate with the highest chance of blocking the targeted nerves. In addition, a single physician assistant was instructed to control the infiltration and was present at the theatre at all surgeries. At the end of the surgeries before wound closure, 0.5 mL/kg body weight of the syringes was infiltrated at 2 different locations: (1) half of the volume was infiltrated anterior to the superior iliac spine, where the LCFN passes below the inguinal ligament; (2) the other half of the volume was infiltrated in the tissues of the upper part of the wound extending from the anterior iliac spine to the iliac crest just cranial of the wound to anaesthetize all sensible end nerves of the subcostal nerves.Postoperatively, VAS at rest, escape medication, and complications every 6 hours on the first day and every 8 hours on the second day were registered. Nausea, vomiting, and urinary retention were also documented. The primary endpoint of the study was the VAS at rest 24 hours postoperatively. Discharge criteria included stable vital signs, the ability to walk with crutches, to walk the stairs, and VAS <4. After discharge, patients were seen at the outpatient clinic 6 weeks postoperatively and the HOOS, SF-12, and OHS questionnaires as well as complications were documented. After the last patient was seen in the outpatient clinic the randomization key was provided to the investigators by the pharmacy department.Intention to treat analyses were performed by use of IBM SPSS Statistics for Windows version 24 . All variables are summarized according to their distribution by use of means with standard deviations (SD) or frequencies with accompanying percentages. Patient characteristics and baseline variables were compared between treatment groups using Student’s t-tests and chi-squared tests (or Fisher’s exact tests) for continuous and categorical variables respectively. The effect of the intervention on patient-reported outcome measures  was analyzed by use of univariate and multivariate regression analysis to correct for potential confounders  at primary (24 hours) and secondary endpoints, and mean between group difference with 95% confidence intervals were calculated at each follow-up moment. Additionally, escape medication usage and complications were compared by use of chi-squared tests (or Fisher’s exact tests). For the main analysis (NRS pain at 24 hours) a p-value of ≤0.05 was considered statistically significant. Holm’s procedure was used to correct for multiple testing for secondary outcomes. Sensitivity analysis, using multiple imputation, was performed for all cases to assess presence of bias. 10 fully observed datasets were imputed with complete data and were analyzed to conform with the previously stated protocol, and results were aggregated.The randomized double-blind placebo-controlled study was approved by the local ethics committee (protocol no. M013-034). Written informed consent was obtained from all participants. The study was registered at EudraCT registry (2013-004031-71) and Dutch CCMO registry (NL45740.094.13). No competing interest declared. No funding was received for this study.166 patients were randomized into 2 groups . 4 of thWe found that a double nerve block of the lateral cutaneous nerve and subcostal nerves does not result in significant pain relief in the postoperative period. No differences in complications or other adverse events were observed. Moreover, the pre-determined primary endpoint of the current trial, a lower pain score after 24 hours, was not met. Although initially a significant reduction of pain scores after 6 hours was found, the difference was lost after using a multiple comparisons procedure to control for the inflation of the type 1 error rate. And even when significance had remained, it was not clinically relevant, since the VAS was only 0.9 point in favor of the LIA group; it has been suggested that differences in VAS become clinically meaningful when exceeding 1.3 points (Gallagher et al. Postoperative pain is a complex clinical condition that is still not fully understood. One of the main causes is the local tissue damage due to the surgical approach. This may be the main reason why LIA has reliable outcomes in TKA patients in whom the surgical approach hardly differs between trials. In THA on the other hand, there is a highly variable surgical preference to approaching the hip, which is reflected by the different approaches used in LIA studies see . It is iWe used a straight lateral approach, which was only used in 2 prior studies (Bianconi et al. One of the possible limitations of our study is that the suspension contained only ropivacaine. Earlier studies in TKA showed superior results with the addition of an anti-inflammatory agent such as ketorolac (Andersen et al. Our primary endpoint was pain reduction after 24 hours. It might be questioned whether ropivacaine is still working at that time point, in view of its half-life of 2–6 hours. However, we surmised if pain was reduced early postoperatively this would have resulted in earlier effective mobilization and thereby a longer reduction of pain and earlier discharge. Obviously, choosing an earlier endpoint in the current study would not have resulted in another conclusion since no differences were observed at all. The maximum follow-up was 6 weeks, since we did not expect any differences in the long term. Few studies have looked at the long-term effects of LIA in arthroplasty patients. Interestingly, a recent study showed that LIA in hip arthroplasty patients reduced postsurgical pain after 1 year (Wylde et al. In summary, we show that a double nerve block of the lateral cutaneous nerve and subcostal nerves does not result in a clinically relevant reduction of postoperative pain in THA patients with surgery performed by a straight lateral approach under spinal anesthesia. Further research should focus on the composition and volume of the LIA suspension, the optimal localization of the infiltration, and should be evaluated for every surgical approach separately.The authors would like to thank all the patients for their participation in the study. In addition, the authors are grateful to Paul Spruijt, José de Droog and the orthopedic surgeons performing the surgeries as well as the people involved in the outpatient clinic, operating theater, and clinical department.JLB and MV designed and coordinated the study, JV was involved in data collection, INS performed the statistical analysis, DdV wrote the pain protocol, HJK performed the randomization, JLB drafted the manuscript and MV revised the manuscript.Acta thanks Henrik Husted and Johan Rader for help with peer review of this study.