Pain is a highly prevalent symptom experienced by patients across numerous rare musculoskeletal conditions. Much remains unknown regarding the central, neurobiological processes associated with clinical pain in musculoskeletal disease states. Fibrodysplasia ossificans progressiva (FOP) is an inherited condition characterized by substantial physical disability and pain. FOP arises from mutations of the bone morphogenetic protein (BMP) receptor Activin A receptor type 1 (ACVR1) causing patients to undergo painful flare-ups as well as heterotopic ossification (HO) of skeletal muscles, tendons, ligaments, and fascia. To date, the neurobiological processes that underlie pain in FOP have rarely been investigated. We examined pain and central pain mechanism in FOP as a model primary musculoskeletal condition. Central nervous system (CNS) functional properties were investigated in FOP patients (N = 17) stratified into low  and high (≥ 4) pain cohorts using functional near-infrared spectroscopy (fNIRS). Associations among clinical pain, mental health, and physical health were also quantified using responses derived from a battery of clinical questionnaires.Resting-state fNIRS revealed suppressed power of hemodynamic activity within the slow-5 frequency sub-band (0.01–0.027 Hz) in the prefrontal cortex in high pain FOP patients, where reduced power of slow-5, prefrontal cortex oscillations exhibited robust negative correlations with pain levels. Higher clinical pain intensities were also associated with higher magnitudes of depressive symptoms.Our findings not only demonstrate a robust coupling among prefrontal cortex functionality and clinical pain in FOP but lays the groundwork for utilizing fNIRS to objectively monitor and central pain mechanisms in FOP and other musculoskeletal disorders. Pain is a highly common driver of reduced quality of life across rare, musculoskeletal diseases , 21, 32.ACVR1) [Here, we aimed to determine whether and how clinical pain is centrally represented in fibrodysplasia ossificans progressiva  patients. FOP is an ultra-rare disease with an estimated 1:800,000–1:3,000,000 prevalence worldwide (285 cases in the United States) , 38. FOPACVR1) . The mutACVR1) , 13, 14,ACVR1) , 49.The induction as well as the expansion of HO lesions are often preceded by soft tissue swellings termed “flare-ups” , 37, 46,This investigation was approved by the Boston Children’s Hospital Institutional Review Board and met the Helsinki criteria for the study of human subjects. Each participant was given a detailed overview of study procedures as well as read and provided informed written consent prior to study participation. For individuals below 18 years of age, informed consent was also obtained from their parent or legal guardian.ACVR1 [A total of 17 consecutive patients diagnosed with FOP between 7 and 61 years of age  gave consent and were enrolled in the current study  database were utilized to capture patient reported levels of (1) pain intensity , where 0 is no pain and 10 is the worst pain imaginable, (2) manifestations of pain, (3) quality of pain , (4) physical stress, (5) physical ability, (6) psychological stress, (7) anxiety, and (8) depressive mood. Parents or guardians of pediatric FOP patients also completed the Adult Response to Children’s Symptoms (ARCS) questionnaire. The ACRS (29 items) was utilized to determine the parents’ or guardians’ behaviors in response to the child’s pain. Study participants also provided demographic data (age and gender). Each ACRS question was scored on a five-point Likert scale (Never: 0 to Always: 4). All questionnaires were administered and completed online using REDCap (https://www.project-redcap.org). It is noted that two study participants did not fully complete questionnaires and thus the cross-correlation analysis was restricted to an N = 15 FOP patient population.We designated a 0–3 pain rating as low pain, while ratings ≥ 4 were classified as high pain. The rationale for choosing this criterion stems from prior work noting pain interference in patients’ daily life occurring at pain levels of 4 or more , 44 or tWhile methods such as functional magnetic resonance imaging (fMRI) remain critical for characterizing CNS pain pathways in healthy subjects and clinical populations, undergoing an MRI-based assessment can be extremely difficult and, in some cases, impossible, due to the physical limitations experienced by FOP patients. Therefore, CNS hemodynamic properties , deoxygenated hemoglobin (HbR) and total hemoglobin) in FOP patients were measured using a multichannel continuous wave fNIRS system  operating at 690 nm and 830 nm wavelengths. Each patient was first comfortably positioned either in a chair or in many cases, remained in their own wheelchair. Once study participants were positioned and at rest, pain intensity ratings  were obtained. Subsequently, an fNIRS cap—one for adults and one for children—consisting of 6 light sources, 8 standard-separation detectors, and 6 short-separation detectors was placed on the participant’s head  of 50 ± 10. Thus, a t-score of 40 is one SD below the mean. Higher scores for symptom measures  suggest worse symptom presentation, while higher scores for functional measures  correspond with higher functioning. Spearman's rank correlation coefficients were calculated to explore the association between each PROMIS-based measure. A false discovery rate (FDR) adjusted p-value (α = 0.05) was subsequently calculated. Statistical comparisons between low and high pain FOP study cohorts was performed using a two-tailed t-test (α = 0.05).https://homer-fnirs.org), was utilized to preprocess all fNIRS datasets. Briefly, the raw optical intensity data were first transferred to changes in optical density by taking the logarithm of the signal. Optical density time courses were then visually inspected for quality assurance/control (QA/QC) across the 6-min acquisition period for any signal drifts or spikes, indicative of head motion  toolbox, HomER2 . Pain ratings between participants less than 18 years of age vs. adult patients was moderately significant (p = 0.046). A comparison of pain levels between the first (fNIRS data acquisition) and second  evaluation time points demonstrated that while pain intensity remained relatively stable for many FOP patients, others showed increases or decreases in pain . Similarly, a significant difference between FOP patients less that 18 years compared to individuals over the age of 18 was not observed at the subsequent time point (p = 0.18). Analgesics, including prescription opioids, were used by both study populations with some patients utilizing treatments on an intermittent or as needed basis, while others had more consistent usage. A Fisher’s Exact test was utilized to assess the association between pain (≥ 4 vs < 4) and analgesic usage (Any usage = 1 vs. Otherwise = 0). No association between pain and analgesics usage was observed with the p-value being highly non-significant (p = 1.0). Clinical questionnaire data acquired from FOP patients showed that individuals in the high pain cohort (N = 7) relative to the low pain group (N = 9) had altered emotional functioning in domains such as anxiety in conjunction with physical symptoms, mainly physical stress (Table p = 0.0016) in addition to the magnitude physical stress experienced . Interestingly, significant relationships were further observed between level of anxiety experienced by patients, sensory aspect of pain and physical stress, suggesting an interaction among these three domains in FOP. Finally, across pediatric FOP patients, the mean ± SE ARCS questionnaire response was 2.31 ± 0.26. Low ARCS scores were likely reflective of low pain levels experienced by pediatric FOP patients.Of the 17 enrolled FOP patients  and C7 (FDR-pcorr = 0.013)) as well as more lateral (channel C5 (FDR-pcorr = 0.015)) components of the prefrontal cortex . Across all study participants, self-reported pain levels were negatively correlated with prefrontal cortex, slow-5 power . A significant correlation was not detected between slow-5 power and severity of depressive symptoms . The age of the patient did not correlate with the magnitude of prefrontal cortex, slow-5 power . As low-frequency oscillations at the slow-5 range are involved with long-range interaction of brain regions, these finding suggests that FOP patients experiencing higher levels of pain likely possess a greater magnitude of dysfunctional long-range communication involving the prefrontal cortex [d (Range): 0.03–0.79) indicated a low to moderate pain-dependent effect on slow-5 power in somatosensory cortices. A correlation between clinical pain intensity ratings and slow-5 power for any somatosensory channel, channels C9-C16, was not observed . Significant differences between low and high pain FOP patients were not detected in other frequency sub-bands  and in either prefrontal or somatosensory cortices.As shown in Fig. l cortex .  or events (flare-ups) can cause patients to experience pain. However, across rare and also more common musculoskeletal diseases, there is a frequent discrepancy between objective measures of disease burden or peripheral trauma and patient-reported pain levels . FindingIn FOP, HO of musculoskeletal tissue causes long-term, severe disability. However, alongside the physical limitations that many FOP patients undergo and which can begin during childhood stages of life , 33, 36,We found that pain in FOP can be variable, both across subjects and time. Monitoring patients across a 2–3-week period demonstrated intra-subject fluctuations in pain intensity with some individuals reporting increased levels of pain during this interval, while others showed little to no change in pain intensity. The site of pain often corresponded to the location of known HO lesions; however, there were cases where pain was altogether absent, or was experienced only across a subset of HO lesion sites. A pain level ≥ 4 was moderately associated with gender. A trend of higher pain levels or higher chronic pain prevalence in female FOP patients is in accord with the large body of data demonstrating higher perception of pain and more frequent occurrence of chronic pain conditions in women , 47. AddImplementation of fNIRS enabled an objective assessment of CNS function in FOP patients and equally important, an understanding of whether and how cortical activity relates to subjective accounts of pain in this disease. Patients with moderate to severe pain were characterized by a reduced amplitude of slow-5 (0.01–0.027 Hz), low-frequency oscillations occurring within the prefrontal cortex, where higher clinical pain severity negatively correlated with more suppressed prefrontal cortex fluctuations. Using resting-state functional magnetic resonance imaging (fMRI), highly similar frequency-dependent changes have been reported in multiple chronic pain conditions. In trigeminal neuralgia , postherThe alterations in low-frequency dynamics have been previously linked with changes in functional connectivity . Slow-5 We project that the frequency-dependent and pain-dependent effects observed in our FOP cohort of patients are a collective and cyclical outcome of living with a chronic illness such as FOP, withstanding recurrent and severely painful flare-up episodes as well as enduring persistent pain over several months or even years. Nonetheless, the impact of aberrant activin-A- or ACVR1/ALK2-dependent activity with the CNS must be considered. In FOP patients , 41 lesiThis investigation represents the first functional CNS imaging study in FOP and a novel application of fNIRS. fNIRS was implemented as an alternate approach to probe CNS function, as MRI-based assessments are not easily feasible for many FOP patients. This study, in conjunction with other recent efforts, demonstrates fNIRS's utility towards elucidating central pain mechanisms , 35. HowIn conclusion, fNIRS was applied to characterize cortical function in FOP patients in low and high pain states. Suppressed power within the slow-5 frequency band of prefrontal cortex in FOP patients was associated with greater clinical pain. We also have demonstrated the interaction amongst pain, mental health and physical health in FOP. This investigation provides further rationale for utilizing fNIRS to further elucidate mechanisms of pain modulation in FOP and other musculoskeletal disorders.Additional file 1. QA/QC and functional connectivity analyses of fNIRS data.


To determine whether cervical cord levels of metabolites are associated with pain sensation after spinal cord injury (SCI) by performing magnetic resonance spectroscopy in patients with SCI with and without neuropathic pain (NP).Cervical cord single-voxel spectroscopic data of 24 patients with SCI  and 21 healthy controls were acquired at C2/3 to investigate metabolite ratios associated with neuroinflammation (choline-containing compounds to myoinositol [tCho/mI]) and neurodegeneration . NP levels were measured, and Spearman correlation tests assessed associations between metabolite levels, cord atrophy, and pinprick score.p = 0.024) compared to pain-free patients and negatively related to cord atrophy . Better pinprick score was associated with higher tCho/mI levels . In pain-free patients, tCho/mI levels were not related to cord atrophy  or pinprick score . tNAA/mI levels were similar in both patient groups (p = 0.396) and were not associated with pinprick score in patients with NP  and pain-free patients .In patients with NP, tCho/mI levels were increased  were elevated in patients with NP, its magnitude being associated with less cord atrophy and greater pain sensation . This suggests that patients with NP have more residual spinal tissue and greater metabolite turnover than pain-free patients. Neurodegenerative metabolite levels  were associated with greater cord atrophy but unrelated to NP. Identifying the metabolic NP signature provides new NP treatment targets and could improve patient stratification in interventional trials.This study provides Class II evidence that levels of magnetic resonance spectroscopy–identified metabolites of neuroinflammation were elevated in patients with SCI with NP compared to those without NP. In patients with SCI with NP, higher tCho16 and mI15–18 were identified in key brain areas of pain processing compared to pain-free patients. In contrast, tNAA was decreased to a similar extent and unrelated to NP.15 In the injured cervical cord, Wyss et al.9 observed trauma-induced reductions in tNAA and tCho and elevated mI. Crucially, these neurodegeneration- and neuroinflammation-related changes showed clinicopathologic relationships.Magnetic resonance (MR) spectroscopy (MRS) can noninvasively quantify metabolite levels,However, how metabolic changes associated with neuroinflammation and neurodegeneration in the cervical cord relate to the presence of NP in patients with SCI is understudied. This study therefore aimed to investigate by means of spinal MRS metabolic changes at the cervical level C2/3 and their clinicopathologic associations in patients with SCI with chronic NP and pain-free patients with SCI.9The local ethics committee of Zurich approved the study protocol , which was conducted in accordance with the Declaration of Helsinki. All participants of this study were informed before study enrolment about the aim and procedure and provided written informed consent. A subset  of the data of this study was previously reported to assess metabolite ratios in the cervical spinal cord after SCI.The primary research question of this study was whether levels of metabolites of neuroinflammation assessed by cervical cord MRS are elevated in patients with SCI with NP compared to those without NP.This article describes a diagnostic accuracy study that provides Class II evidence that levels of MRS-identified metabolites of neuroinflammation were elevated in patients with SCI with NP compared to those without NP.Twenty-four patients with SCI and 21 healthy controls were recruited between March 2016 and September 2018. Patients with SCI fulfilled the following inclusion criteria: (1) chronic traumatic injury (>1 year after injury), (2) no other neurologic or mental disorders, and (3) MRI compatible. Exclusion criteria of the study participants, including healthy controls, were preexisting neurologic, mental, or medical disorders affecting the outcome. One patient had to be excluded due to scan artifacts and another one because he did not fit in the neurovascular coil.All study participants underwent MR measurements on a 3T Philips scanner  using a 16-channel SENSE neurovascular coil . Spectra were acquired from the cervical spinal cord at level C2/3 . The participants lay in the scanner in a head-first supine position, and the total scan duration was ≈45 minutes. MR measurement sequences included a survey scan, anatomic T1-weighted and T2-weighted (T2w) scans, and spectroscopic measurements.19 was then applied in combination with inner volume saturated PRESS20 using broadband outer volume suppression pulses with optimal flip angles21–23 as reported previously.9 In addition, we used a second-order projection-based shimming routine.25 To reduce patient motion to a minimum, the spectroscopic acquisition was split into measurement acquisition blocks of 128 or 256 signal averages, and voxels were readjusted on the basis of an updated T2w image .At spinal level C2/3, T2w images  were used to place the spectroscopic voxel . The metabolite cycling (MC) techniqueThe spectroscopic measurement blocks were checked for motion artifacts. No measurement block had to be excluded. Metabolic concentration values could be determined for all metabolites  in all measurements. Representative planning images and spectra are shown for a healthy control, a pain-free patient with SCI, and a patient with SCI with NP . An over19 Before quantification, truncation and zero filling were used in the time domain after 200 milliseconds. Relative values of metabolite concentrations were obtained by scaling them to mI (as previously reported9) because absolute quantification by internal spinal water referencing is not reliably feasible due to the pulsating surrounding CSF as previously shown in supplementary figure 1 in reference 9. Spectroscopic data of the cervical spinal cord were fitted and quantified with LCModel.26 A basis set for echo time of 30 milliseconds was used, including simulated basis set model data of N-acetylaspartate, N-acetyl-aspartyl-glutamate, glutamate, glutamine, glycerophosphocholine, phosphocholine, creatine, scyllo-inositol, and mI. Strongly overlapping resonance lines required a combination of the spectra of the following metabolites: N-acetylaspartate + N-acetyl-aspartyl-glutamate = tNAA, glycerophosphocholine + phosphocholine = tCho, and glutamate + glutamine is the combined expansion of Glx. A spectral range of 0.4 to 4.0 ppm was used in the fitting settings. To prevent artificial cutoff effects introduced by a cutoff value of 20%,27 we included metabolic ratios with Cramer-Rao lower bounds <100%.We used MATLAB 2014b  and the commercially available MRecon framework  for reconstruction of the spinal cord spectroscopic data from the raw data of the scanner. Eddy current, phase, and frequency alignment parameters were extracted from the unsuppressed water spectrum reconstructed from the MC series. Subsequently but before merging of all acquisition blocks, eddy current correction and frequency alignment were applied to the metabolite spectra reconstructed from the MC subseries by an add-subtract scheme as previously reported.28 for the automatic calculation of SCA. Last, we manually adjusted the SCA outline in those slices of study participants in which automatic cord determination did not work properly (5 cases). Cross-sectional SCA could not be calculated for 1 patient due to motion artifacts during the MR acquisition.We used Jim 7.0  to assess the cross-sectional spinal cord area (SCA) at cervical level C2/3 on T2w images in all healthy control participants and patients with SCI. SCA was measured in 3 consecutive slices at the bottom of vertebra C2/3. In a first step, we determined a region of interest in the middle of the spinal cord on axial slices. In a next step, we used an active-surface model29 and the European Multicenter Study About Spinal Cord Injury (EMSCI) pain questionnaire .All patients with SCI were clinically assessed with a comprehensive clinical protocol including the International Standards for Neurologic Classification of Spinal Cord Injury (ISNCSCI) protocol for pinprick and light-touch scoresWith the ISNCSCI protocol, patients were classified as American Spinal Injury Association Impairment Scale (AIS) A , B, C, or D , or AIS E  according to the neurologic classification of SCI. The neurologic level of injury (NLI) is defined as the uppermost segment with neurologically intact motor and sensory scores.30 All patients completed the full protocol.In all patients with SCI, the EMSCI pain questionnaire was used as a screening tool for pain after SCI. This pain questionnaire examines various aspects of pain . The pain intensity was rated with an 11-point numeric rating scale with 0 indicating no pain and 10 indicating the worst imaginable pain. In addition, the type of pain was explored and grouped into nociceptive  or NP . To be classified as at-level NP, ongoing pain had to be experienced within the 3 dermatomes below the NLI, 1 dermatome above the NLI, or both. Below-level NP, on the other hand, was defined as NP >3 dermatomes below the NLI.31 (version 3.4.3) and Stata software , which was also used for visualization. We applied a 1-way analysis of variance followed by a Bonferroni post hoc test for pairwise comparison of healthy controls, patients with SCI with NP, and pain-free patients with SCI regarding their age at the time point of measurement. Unpaired 2-tailed t tests were used to compare the pinprick score and time since injury between patients with NP and pain-free patients. Between-group comparison graphics of metabolic ratios show box plots including the median and quartiles. These group differences between the healthy control group, patients with SCI with NP, and pain-free patients were assessed for metabolite concentration ratios of tCho/mI and tNAA/mI at spinal level C2/3 with a Kruskal-Wallis test followed by pairwise Mann-Whitney U tests. We used Spearman rank correlation tests to investigate associations between the amount of cervical cord atrophy in patients with SCI, assessed by the cross-sectional SCA at cervical level C2/3, and metabolite concentration changes at the same level. Last, we analyzed relationships between clinical measures of pain perception (pinprick score) and the metabolite ratio of tCho/mI at C2/3 using Spearman rank correlation tests.Statistical analyses were performed with the R software packagep ≤ 0.05 were regarded as significant. We did not adjust for multiple testing to reduce type II errors, which potentially increased type I errors. Age was included as a covariate of no interest in the statistical model to adjust for age dependency.The confidence interval (CI) was set to 95%. Results with an uncorrected value of Anonymized grouped data will be shared by request from a qualified investigator.p = 0.145, 95% CI −41.3 to 6.5). Patients with NP reported a mean pain intensity of 4.3  on a scale from 0 to 10. Mean age at injury was 40.9 years (SD 14.0 years) for the patients with SCI with NP and 31.6 years (SD 13.5 years) for the pain-free patients with SCI. The participants' mean age did not differ between any of the groups (p = 0.245). There was no significant difference in mean time since injury in years between the patient groups .Fourteen patients with SCI with NP , 10 pain-free patients with SCI , and 21 healthy control participants  were recruited. From all patients with SCI, 12 were classified as functionally complete (AIS A) and 12 as functionally incomplete (AIS grades B–D) . The NP p = 0.010) as previously reported for patients with SCI and healthy controls in a subset of this population.9 Patients with SCI with NP had a tCho/mI ratio  compared to pain-free patients. In turn, the tCho/mI ratio was lower in pain-free patients with SCI compared to healthy controls .We first confirmed that there was a difference in tCho/mI levels between groups . In pain-free patients with SCI, the tCho/mI ratio was not related to cross-sectional SCA  or pinprick score .In patients with SCI with NP, a higher tCho/mI ratio was positively associated with a larger cross-sectional SCA . Within paraplegic patients, the tCho/mI ratio was elevated in patients with NP compared to pain-free paraplegics , but this effect was not seen within the tetraplegic patient group .To assess the effect of lesion level, we found that the tCho/mI ratio was not different between paraplegic and tetraplegic patients with NP (p = 0.023) as previously reported for patients with SCI and healthy controls in a subset of this population.9 Patients with SCI with NP had a tNAA/mI ratio . In pain-free patients, tNAA/mI levels  were lower compared to healthy controls.We first confirmed that there was a difference in tNAA/mI levels between groups . Pinprick score and tNAA/mI ratio were not associated in patients with NP . There was no association between tNAA/mI levels and NP intensity in patients with NP .Lower levels of tNAA/mI were associated with a greater decrease of cross-sectional SCA in pain-free patients with SCI . The tNAA/mI ratio was not different between paraplegic patients with NP and pain-free patients , nor was it different between tetraplegic patients with NP and pain-free patients .There was no difference in the tNAA/mI ratio between paraplegics with NP and tetraplegics with NP  over mI  was increased in patients with SCI with chronic NP, but not in pain-free patients. This was distinct from markers of neurodegeneration  that related to cord atrophy but not to NP. This study identified tCho/mI levels as a potential sensitive metabolite biomarker of NP in the injured cervical cord.32 of patients with SCI compared to healthy controls.9 This likely reflects ongoing neurodegeneration and activation of glial cells in the injured spinal cord,33 especially because the reduction of the metabolic ratios was greater in tetraplegic compared to paraplegic patients.Regardless of NP, lower ratios of tNAA/mI and tCho/mI were evident in the atrophied cervical spinal cord34 is believed to be a key player in the origin of NP,36 which manifests as an abnormal sensation of tingling and pricking , painful sensations induced by nonnoxious stimuli , or increased or decreased responses to painful stimuli .4 In the spinal cord of patients with SCI with NP, this study shows higher tCho/mI ratios than in pain-free patients. In patients with SCI with NP, the concentration of tCho/mI was in the range of healthy controls. Higher tCho/mI ratios might relate to enhanced pain transmission in the spinal cord possibly due to an interplay of hyperactive spinothalamic neurons37 and inflammatory-induced glial activation.37 At the cellular level, this would relate to an increased membrane and myelin turnover 11 of spinothalamic neurons or activated glial cells .39 Moreover, mI might be decreased and tCho/mI levels therefore increased due to less myelin breakdown in patients with SCI with NP.40 However, we are unable to disentangle the exact processes at the molecular level because both tCho and mI could drive the ratio differences. Nevertheless, we are confident that elevated tCho is significantly contributing to the ratio differences because it was shown that tCho was specifically elevated in distinct brain regions of the pain network  of patients with SCI with NP.17 These regions, together with the prefrontal cortex, sensorimotor cortex, and spinal cord, showed NP-associated bidirectional volume changes.42Aberrant activity of spinothalamic neurons in the spinal dorsal horn9 indicating that the magnitude of neurodegenerative processes is lesion level dependent. This finding is in line with a preclinical study reporting higher tNAA levels in a rabbit model of SCI with a light compared to a severe injury.43To address the question of whether the metabolite level changes relate to NP or lesion level, we performed a subgroup analysis between paraplegic and tetraplegic patients. No lesion level–dependent difference in tCho/mI levels was evident. However, tNAA/mI levels were lower in tetraplegic compared to paraplegic pain-free patients, which is in agreement with our previous report,9 patients with SCI showed clinicopathologic relationships. However, previous analysis was performed regardless of NP. In this study, patients with SCI with NP showed a 3-way relationship between elevated tCho/mI ratios, less cord atrophy, and more preserved pain sensation . This suggests that patients with SCI with NP have less degenerated spinal pathways  and a greater metabolite turnover due to enhanced glial activation and proliferation.39 It is thus well imaginable that patients with SCI have a secondary complication  compared to pain-free patients with SCI and show a higher potential for greater functional recovery due to the spared but somewhat disturbed tract and circuit function that is reflected by higher cervical cord tCho/mI levels. Similar to our results, an association between better recovery of pinprick score at 12 months and less cord atrophy immediately after the injury was previously reported in patients with SCI.44 In contrast, in pain-free patients with SCI, tCho/mI levels were not associated with cord atrophy or pinprick sensation. However, a lower tNAA/mI ratio was associated with greater cord atrophy, indicating processes of neurodegeneration. The 3-way relationship between metabolite levels, cord atrophy, and function speaks to the potential of levels of tCho/mI as a metabolite marker of inflammatory-induced glial activation and aberrant activity of spinothalamic neurons in NP states.As recently reported in a subset of this population,9 to other metabolites and not as absolute values, unlike MRS values in the brain.8 This is due to the current lack of a reliable water reference signal in the spinal cord owing to the pulsating surrounding CSF (see supplementary figure 1 in 45 with the extent, intensity, and quality of the perceived pain, would enable a better characterization between metabolite turnover and the presence of NP. Third, our sample size was rather small. Given the fact that we were using MRS markers, we were not able to assess the extent of measurement error for the outcome measures. However, this does not invalidate our presented group comparisons and significant findings: it is possible that, in the future, variability due to measurement error may be reduced, in which case the required sample sizes would be smaller, reflecting the reduced measurement noise. Finally, sex was not equally represented in our patient cohort. However, the male-to-female patient ratio in this study closely reflects the general SCI population with a ratio of 4:1.46 Furthermore, healthy controls were age and sex matched.This study has limitations. First, the metabolites measured are presented as ratiosThis study identifies levels of tCho/mI, a marker of neuroinflammatory processes, as a discriminator of patients with SCI with NP from pain-free patients with SCI. Using spinal MRS, spinal cord atrophy assessments, and a clinical measure of pain sensation, we identified clinicopathologic associations. Thus, tCho/mI levels are a promising metabolite biomarker of neuroinflammation in the context of NP after SCI. Cervical cord MRS holds potential to be used in clinical trials for patient stratification, therapy monitoring, and outcome prediction.


The pain management of postherpetic neuralgia (PHN) remains a major challenge, with no immediate relief. Nitrous oxide/oxygen mixture has the advantages of quick analgesic effect and well-tolerated. The purpose of this study is to investigate the analgesic effect and safety of nitrous oxide/oxygen mixture in patients with PHN.This study is a single-center, two-group (1:1), randomized, placebo-controlled, double-blind clinical trial. A total of 42 patients with postherpetic neuralgia will be recruited and randomly divided into the intervention group and the control group. The control group will receive routine treatment plus oxygen, and the intervention group will receive routine treatment plus nitrous oxide/oxygen mixture. Data collectors, patients, and clinicians are all blind to the therapy. The outcomes of each group will be monitored at baseline (T0), 5 min (T1), and 15 min (T2) after the start of the therapy and at 5 min after the end of the therapy (T3). The primary outcome measure will be the pain intensity. Secondary outcomes included physiological parameters, adverse effects, patients’ acceptance of analgesia, and satisfaction from patients.Previous studies have shown that nitrous oxide/oxygen mixture can effectively relieve cancer patients with breakthrough pain. This study will explore the analgesic effect of oxide/oxygen mixture on PHN. If beneficial to patients with PHN, it will contribute to the pain management of PHN.ChiCTR1900023730. Registered on 9 June 2019Chinese Clinical Trial Register The online version contains supplementary material available at 10.1186/s13063-020-04960-5. Postherpetic neuralgia (PHN) is a major complication of herpes zoster (HZ), and the definition of PHN is arbitrary but involves pain that lasts for 90 days or more from the onset of the HZ . PHN is Spontaneous pain is common in PHN and can be intermittent or persistent. Pain has a variety of qualities, such as burning, throbbing, aching, stabbing pain, or electric-shock-like pain. Besides, allodynia and hyperalgesia have also been reported , 7. PHN As mentioned above, PHN not only is physical pain but also causes irreparable detriment to all aspects of the patients. Effective treatment for PHN is urgently needed. However, there is no cure for PHN, and the main goal of current treatment is pain relief , 11. TheN-methyl-d-aspartic acid receptor [Nitrous oxide/oxygen mixture has been shown to have a fast and safe analgesic effect. In 1799, Humphrey discovered that nitrous oxide had anesthetic and analgesic effects . The nitreceptor . Studiesreceptor , 27. In receptor . The nitreceptor . Now, itreceptor , dental receptor , burn drreceptor , cancer receptor , lumbar receptor , and othreceptor . Also, nreceptor . Side efreceptor . Taking This study hypothesizes that the inhalation of nitrous oxide/oxygen mixture will be able to relieve pain in patients with PHN. It will be possible to replace opioids if nitrous oxide/oxygen mixture can effectively and rapidly relieve pain in patients with PHN, thereby reducing the risk of opioid abuse and lightening the financial burden on patients.To evaluate the safety of the fixed nitrous oxide/oxygen mixture by monitoring patients’ physiological parameters and adverse effectsTo determine the satisfaction of patients with the analgesic effect of the fixed nitrous oxide/oxygen mixtureTo investigate the acceptance of patients to the fixed nitrous oxide/oxygen mixture analgesiaThe main aim of the study is to evaluate the analgesic effect of the fixed nitrous oxide/oxygen mixture on patients with PHN. There are three secondary aims of the study:This study is a single-center, two-group 1:1), randomized, placebo-controlled, double-blind clinical efficacy trial. We intend to investigate the analgesic effect and safety of nitrous oxide/oxygen mixture for PHN patients. Eligible participants will be randomly assigned to either the intervention group (nitrous oxide/oxygen mixture) or the control group (oxygen) based on computer-generated random numbers. The whole study design is shown in Fig. :1, randoThe protocol was approved by the Ethics Committee of the General Hospital of Ningxia Medical University (Reference No: 2018-373). The trial was registered with the Chinese Clinical Trial Registry (ChiCTR1900023730) on 9 June 2019. We adhered to Standard Protocol Items Recommendations for Interventional Trials (SPIRIT) for the design of the test ;Over the age of 18;Pain score ≥ 4 according to the Numerical Rating Scale (NRS); andVolunteered to participate and signed the informed consent.Patients who meet the following inclusion criteria will be enrolled in the trial:Women who are pregnant;The patient diagnosed with intestinal obstruction, air embolism, pneumothorax, and obstructive respiratory disease;The patient’s clinical history includes epilepsy;The patient suffers from otorhinolaryngologic diseases, such as sinusitis, middle ear disease, and eardrum transplantation;Patient who is unable to report pain; andCritically ill patients: (1) patients in intensive care, (2) patients after surgery, (3) patients with severe trauma or extensive burns, (4) patients with ventilator-assisted breathing, and (5) patients with life-threatening conditions requiring monitoring of vital signs.Patients who have one of the following conditions are not allowed to participate in the trial:This study will be conducted in the pain department of the General Hospital of Ningxia Medical University. The number of PHN patients admitted to the pain department each year is enough to meet the sample size of this study. We will recruit participants through the pain department’s WeChat public platform, posters, and medical staff introductions. For patients who wish to participate in the study, researchers will elaborate on the purpose, methods, possible risks, and rights of participants. If the patient is fully aware of the study and agrees to participate and meets the inclusion criteria, the investigator will have the patient sign the informed consent.Patients who meet the inclusion criteria will be randomly assigned to the intervention group and control group at a 1:1 allocation ratio after recruitment. The randomly assigned list will be computer-generated and performed by a statistician who is not involved in the trial and will be stored in a sealed, opaque envelope kept by the project manager. To ensure that the trial is double-blind, no investigator or patient will know about the randomization, only the project manager responsible for the gas distribution. The nitrous oxide/oxygen mixture and the oxygen will be supplied by the Ningfeng Oxygen Company, and the cylinder packaging of the two gases is identical. The letters A and B will be used to identify the two gases, and only the project manager will know what type of gas each letter represents. The project manager will distribute the gas according to the randomly assigned list.A clinician is responsible for assessing the patient’s condition on the ward, determining whether the patient meets the inclusion criteria, and informing the patient of the purpose of the trial, methods, possible risks, and rights of participants. Patients who meet the inclusion criteria will sign an informed consent form after agreeing to participate in the trial. The project manager will group patients who agree to participate in the trial based on the randomly assigned list and escort the patient to the treatment room, where the trial will be conducted. All patients in the trial will receive routine treatment . Patients in the intervention group will inhale nitrous oxide/oxygen mixture with a facemask, which is a visible intervention measure. To eliminate the influence of psychological factors on the experimental results of patients in the control group, patients in the control group will inhale oxygen by a facemask. Patients in the intervention group will receive routine treatment plus a fixed nitrous oxide/oxygen mixture (contains 65% nitrous oxide and 35% oxygen), while patients in the control group will receive routine treatment plus oxygen. Before inhaling the gas, the data collector will teach the patient to use the NRS to report pain intensity. Besides, the data collector will inform patients that they have the right to stop or quit the trial at any time if they experience discomfort during the study. Before the trial begins (T0), the data collector will record the patient’s demographic and baseline characteristics; assess the patient’s pain intensity; measure heart rate, blood pressure, and percutaneous oxygen saturation; and teach the patient to inhale gas using a facemask. Patients in both groups will inhale gas using an oral-nasal mask, which is disposable and has a one-way valve. According to our previous research, the gas intake will last for 15 min , 34. WheNitrous oxide/oxygen mixture has been widely used for pain relief with mild adverse effects and quick recovery . AdverseTo improve patients’ ability to adhere to the intervention, researchers will do the following strategies. First, the investigator will explain to the patient in detail the purpose of the study, the methodology, the possible risks, and the rights of the participants. Second, the researchers will closely monitor patients’ physiological parameters during the trial to ensure the safety of their lives. If patients have any discomfort during the trial, they will be available for medical treatment at any time. Third, patients who complete the trial will receive a free visit from a pain specialist. The investigator will create a chart to record the patient’s adherence to the trial. Patients can ask to withdraw from the trial at any time without affecting subsequent treatment. The data collector will record and analyze the reasons for the withdrawal.Members of the research team will be trained before the study. The training includes protocols for trial design , use of gas devices , data collection , and experimental contingency planning . Besides, data collectors and investigators will be fixed during the trial, and data will be double-entered to ensure accuracy. The Data Monitoring Committee (DMC) members will periodically review the database to improve data quality see the “” sectionPatients will participate anonymously and their personal information will not be disclosed. The patient’s anonymous code will be randomly generated by the computer and kept by the project manager. The trial data will be stored in a folder on the computer that can only be accessed through password authentication. Researchers can check this data only with the authorization of the project manager. When the experiment is complete, the researchers will have access to the data for statistical analysis.We will use a form to collect the baseline characteristics of patients, including age, gender, weight, height, education level, employment status, medical burden , location of pain, and course of the disease. Besides, the patients’ pain intensity, physiological parameters , patients’ acceptance of the analgesia, patients’ satisfaction with pain relief, and adverse effects will be recorded.NRS will be used to assess the intensity of pain, ranging from 0 to 10, where 0 means “painless” and 10 means “worst pain imaginable” . In mostStarting with gas inhalation, the data collectors will carefully observe and record any adverse effects on the patient. The expected adverse effects of nitrous oxide/oxygen mixture therapy include nausea, vomiting, dizziness, drowsiness, headache, hypotension, and oxygen desaturation . If any The primary outcome measure is pain intensity, which will be measured by NRS. The data collector will assess pain intensity at baseline, T1, T2, and T3. Before trial, patients will be taught to use the NRS to assess the pain intensity by pointing out the appropriate number (range = 0 to 10), without having to take off the facemask, thus ensuring continued inhalation of the gas.Patients’ satisfaction with pain reliefPatients’ acceptance of analgesiaAdverse effectsPhysiological parameters The following are the secondary outcomes:Data collectors will collect data on patients’ satisfaction with pain relief, patients’ acceptance of analgesia, and adverse effects at T3. Patients’ physiological parameters will be collected at baseline, T1, T2, and T3 .p < 0.001). Therefore, we used the pain intensity recorded at T1 as a reference in calculating the sample size. Our pilot trial involved 14 patients, with a 1:1 ratio between the intervention group and the control group. The sample size of this study was calculated by the following formula:We performed a pilot trial to calculate the sample size. According to our previous study on breakthrough pain , the samn1 and n2 represent the sample sizes of each group. δ is the difference value between the two population means. σ represents the population standard deviation. According to the pilot trial, the pain severity during the test reported by all control group patients (n = 7) revealed a mean (SD) of 6.71 (1.28) out of 10. Patients (n = 7) in the intervention group reported a mean (SD) of 4.50 (1.80). So we got δ = |μ1 − μ2| =2.21. The standard deviation of the entire sample (n = 14) was 1.93, which was σ =1.93. α represents a significance level of 5% for a two-sided test, uα = 1.96. β was the type II error, which was set to 0.1; thus, uβ = 1.282. We substituted these data into the formula and calculated that n1 and n2 were 16.9. Therefore, the sample size of each group was about 17. Taking into account the 20% drop-out rate before the end of the study, we decided to enroll a total of 42 participants (21 per group).t test. A rank sum test will be used to compare the satisfaction with pain relief between the two groups. A chi-square test will be used to analyze the patients’ acceptance of analgesia. Adverse effects will be tested by the chi-square test. Physiological parameters will be compared using the repeated measures analysis of variance. Besides the complete case analyses, multiple computations are used to replace the missing values in the resulting parameters. Data will be performed with an intention-to-treat analysis. All results are statistically significant with p < 0.05.The test data will be analyzed by a statistical expert using SPSS version 22.0 . The statistical expert is not involved in the experiment and is only responsible for the analysis of the data. We will use descriptive statistical methods to measure demographics and baseline clinical features. The difference in the primary outcome between the two groups will be examined using the PHN is a potentially debilitating neuropathic pain that is often undertreated. Viral damage to central and peripheral nerves may be the cause of PHN pain, which may be spontaneous, intermittent, or chronic, with no pattern . PHN oftp < 0.01). Furthermore, there were no serious adverse events associated with the nitrous oxide/oxygen mixture. The results of Liu et al.’s study indicated that the nitrous oxide/oxygen mixture can provide rapid and safe analgesia. Therefore, in this study, we will attempt to explore the analgesic efficacy and safety of a fixed nitrous oxide/oxygen mixture on PHN.In a previous research, Liu et al.  investigTo date, this study is the first randomized controlled trial to investigate the effects of a nitrous oxide/oxygen mixture for pain relief in PHN patients. If this study proves that nitrous oxide/oxygen mixture is beneficial for PHN patients, it could be used as an emergency therapy for rapid relief of severe acute pain. PHN can be treated with nitrous oxide/oxygen mixture to compensate for the slow onset of systemic treatment and to reduce opioid use.There are some limitations in this study. First, the definition of PHN used in this study is different from other studies because this study is conducted in a hospital in China, so the diagnostic criteria of Chinese postherpetic neuralgia are adopted . The results of this study should be analyzed and discussed with the related research on postherpetic neuralgia. Second, this study is a single-center study with relatively limited research objects, which cannot fully represent the overall level. In the future, we will conduct multi-center research.Recruitment of patients began on 8 October 2019. At the time of manuscript submission, the recruitment for this study is ongoing. Due to the prevalence of COVID-19, completion of this trial has been delayed and is expected to be completed until April 2021, originally scheduled for August 2020. At present, the trial has already recruited 20 participants. This is protocol version 3.0, dated 22 July 2019.Additional file 1. SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents.


Since the emergence of the chikungunya virus in Brazil in 2014, more than 700,000cases have been reported throughout the country, corresponding to one-third ofall cases reported in the Americas. In addition to its high attack rates,resulting in hundreds of thousands of cases, the disease has high chronicityrates with persistent joint manifestations for more than 3 months, which canspread to more than half of the patients affected in the acute phase. Painassociated with musculoskeletal manifestations, often disabling, has an effecton patients’ quality of life at different stages of the disease. Currently, thechallenge faced by specialists is identifying the best therapy to be institutedfor symptom relief despite the limited number of published intervention studies.In 2016, a multidisciplinary group published pharmacological treatment protocolsfor pain in patients with chikungunya, which was incorporated into theguidelines for clinical management of the Brazilian Ministry of Health in 2017;in that same year, a consensus was published by the Brazilian Society ofRheumatology about diagnosis and treatment. After 5 years of experience withchikungunya epidemics, in 2019, specialists involved in the protocols of theBrazilian Society of Rheumatology and Brazilian Ministry of Health prepared anupdate with the main objective of developing flowcharts for the therapeuticapproach of musculoskeletal manifestations in adult patients to enablespecialists at different levels of healthcare to spread and apply this guidelinein a systematic and simplified manner.  Togaviridae, genus Alphavirus. The firstreports of chikungunya outbreaks were described in Tanzania in 1952, and it did notreach the Americas until December 2013. However, within a 5-year period of thevirus’s arrival, 2,673,671 cases were reported, with 773,000 (29%) of them occurringin Brazil-The chikungunya virus (CHIKV) is an arbovirus of the family-In 2016, the year with the highest number of reported cases since the CHIKV was notedin Brazil, 277,882 cases were reported, with 86% of notifications concentrated inthe northeast region of the country. Currently, all states of the federation havereported CHIKV cases,,The disease has a high attack rate, and a large percentage of those infected aresymptomatic compared with those infected with other arboviruses. Attack rates reach35-75% of a population in a single epidemic,In Brazil, there are few seroprevalence studies; this does not allow theidentification of the attack rate in different regions of viral circulation, andconsequently, an estimation of the percentage of susceptible individuals in newepidemic outbreaks,. estimated that 43% of patients had chikungunya symptoms formore than 3 months, and the persistence of symptoms after 12 months was reported in21% of these cases. The study suggested that the prevalence of chronification may berelated to the strain of the virus and that this may be higher among the genotypesof the Indian Ocean and the Asian lineage (39%)The percentage of patients who become chronic varies among studies, with about 40-80%of cases evolving with persistence of musculoskeletal complaints. conducted in Bahia, thepersistence of joint symptoms was reported in 68.1% of study participants in theneighborhood of George Américo and 75% in Alto Cemitério, higher than the prevalencereported in the literatureIn the seroprevalence study by Dias et alAedes vector,Brazil is a country of continental dimensions, with 8 million square kilometers andabout 209 million inhabitants. When we were analyzing case reports from severalstates in the Southeast, Midwest, and Northern Brazil, we observed small incidencerates compared to some states in the Northeast, the epicenter of the epidemic; thisfinding increases the probability that millions of inhabitants in the country willbe susceptible in the event of new epidemics because several regions of the countryhave high rates of home infestation by the From a clinical presentation perspective, there is an initial pattern of acutefebrile illness, but musculoskeletal manifestations are responsible for the greaterfrequency of the symptoms of the disease, occurring in the acute phase andpersisting after the regression of fever for months to even years. ,The pain and discomfort associated with joint manifestations in their differentphases causes significant physical incapacity, thereby affecting the quality of lifeof the patients affected with the disease. Suffering related to the infection iscaused by pain and mental, mood, and sleep disorders in a significant proportion ofpatients. involving 106 chikungunya cases, pain intensityassessed by visual analogue scale (0-10) averaged 5.8. The authors reported thatmany of the patients’ pain symptoms did not respond to prescribed analgesics, withonly 26% experiencing pain relief greater than 70%; it was also reported that 18.9%of the cases were characterized by neuropathic painPain related to CHIKV, beyond intense, is unresponsive to analgesics. In a study byAndrade et alDespite the importance of the topic, only three guidelines worldwide systematize thetreatment of musculoskeletal disease: the first was published in 2015 by a FrenchgroupAfter 5 years of experience with chikungunya epidemics, in 2019, specialists involvedin the protocols of the BSR and BMH prepared an update with the main objective ofdeveloping flowcharts for the therapeutic approach of the musculoskeletalmanifestations in adult patients to enable specialists at different levels ofhealthcare spread and apply this guideline in a systematic and simplified manner. ,Because of the limited number of studies on the theme and seeking the update ofBrazilian guidelines, the authors prepared a narrative review,-Data on the literature of specific therapies for chikungunya at different stagesof the disease are limited. There are no high-quality randomized clinical trialsevaluating the efficacy of different therapies. Moreover, few prospectivestudies have evaluated drug efficacy, and these studies have severallimitations, including the use of different methodologies, the lack of adequaterandomization in some studies, different therapeutic doses, short follow-uptimes, and sometimes, a small number of cases or heterogeneous comparisongroups, that make comparisons difficult. There are also other case-seriesstudies and reported experiences of pain management experienced inepidemicsThe data currently available do not allow definitive conclusions, whetherfavorable or not, about the efficacy of specific therapies or between differentdrug therapies. Currently, recommendations are mainly based on previousexperience acquired with epidemics or by extrapolating specialists’ experienceswith these drugs in chronic rheumatological diseases. However, with theemergence of new, high-quality scientific evidence, these recommendations can beadjusted. Chronologically, the clinical spectrum of the disease involves three phases:acute (up to 14 days), post-acute (15-90 days), and chronic (after 3 months).Musculoskeletal disease represents the most frequent clinical manifestation, andits management is related to these different phases. In addition, in thepost-acute and chronic phases, the therapeutic approach depends on theidentification of the pattern of joint manifestation, which may be predominantlynon-inflammatory/musculoskeletal  or inflammatory with arthritis andperiarticular manifestations (tenosynovitis), which may also present tendonitis,enthesitis, fasciitis, capsulitis, and periostitis. The acute phase of CHIKV is characterized by fever and intense polyarthralgiaand/or arthritis. The fever is high and continuous, with several episodes a day;it is typically more intense in the first 3 days but can persist for up to 7days. Arthralgia has been described in more than 90% of adult patients in the acutephase, with a polyarticular and symmetrical pattern, mainly affecting the jointsof the hands, wrists, shoulders, knees, ankles, and feet. The pain can beincapacitating and makes it difficult for patients to perform daily activitiessuch as walking, brushing their teeth, and picking up objects. Edema(periarticular and/or articular), as well as tenosynovitis and joint stiffness,is frequently observed at this stage. It is important for physicians to identify different clinical patterns andidentify whether there is joint pain  associated with edema(arthritis) or not. At this stage, the treatment goal is the relief of acutepain with the use of analgesics and opioids. However, non-steroidalanti-inflammatory drugs (NSAIDs) should not be prescribed because of increasedrisk of bleeding or kidney damage in these patients; in addition, other acutefebrile diseases may have chikungunya-like clinical manifestations in theinitial phase, and NSAIDs are also contraindicated . In the initial evaluation of cases with pain, it is necessary to apply theanalogue visual scale of pain, thereby transforming subjective data intoobjective data that allow the evaluation of the therapeutic response andadequate case management. To avoid chronic pain, pain should be effectively treated, and the drugs used inthis phase should be prescribed in fixed doses and never on an “as needed’basis. The opioids prescribed for intense pain are potent analgesics that aresafe since they are monitored, and patients are warned about any adverse events.Their main side effects are drowsiness in older people, nausea, andconstipation. Following the acute phase, 45-75% of adult patients have symptoms that persistafter 14 days and can last up to 3 months. At this stage, fever usuallydisappears but musculoskeletal complaints are persistent, with polyarthralgiaand/or polyarthritis of variable intensity that can range from strong tomild.The exacerbation of pain may reach previously affected joints and may beaccompanied by multiple post-acute tenosynovitis, with predominant involvementin the wrists and ankles associated with morning stiffness. Neuropathic pain andcarpal tunnel syndrome are often reported. In addition, generalized symptomssuch as asthenia, depression, and even alopecia may accompany this phase. A clinical evaluation and eventually imaging methods are performed to define thepredominant clinical pattern: a) localized or diffuse non-inflammatorymusculoskeletal pain; b) arthritis/tenosynovitis (articular or periarticulardisease associated with edema); and c) neuropathic pain. It is important toreinforce the possibility of a patient presenting associated pattern such asarthritis or non-inflammatory musculoskeletal pain associated with neuropathicpain . Some authors suggest including other indices to evaluate the therapeutic responseof the patient, such as a global evaluation by the patient and by the physicianand a count of the joints with pain and edema, to calculate the index ofactivity and other scales commonly applied by rheumatologists. The BMH suggestsa broader approach when a high number of cases are identified following anepidemic and where patients are not likely to have access to a specialist. Inaddition, there is no evidence that these approaches are more effective inmanaging cases; hence, the general practitioner must be able to manage thesecases to control symptoms in the initial treatment stages. In the case of localized or diffuse non-inflammatory musculoskeletal pain,patients should be administered NSAIDs  and reassessed after 10 days. If the response is good, this treatmentcan be maintained for up to 4 weeks, with subsequent gradual reduction towithdrawal. For patients with contraindications or risks for NSAID use,analgesics isolated or associated with opioids should be prescribed for 4 weeks,with the consideration of cyclobenzaprine (a muscle relaxant). In disease cases with an inflammatory component (arthritis/tenosynovitis),corticosteroid use after 14 days is effective. Prednisone 0.5 milligram perkilogram per day (maximum dose being 40 milligrams) alone or in combination witha common analgesic or weak opioid should be prescribed. After 4 weeks, inpatients who present a good response, the dose should be withdrawn slowly(weaning), reducing a quarter of the dose every 7 days . Abrupt suspension or rapid withdrawal may lead to a rebound of themanifestations. Contraindications to corticoid use should be considered. In the presence of a neuropathic component, specific therapy needs to beinstituted. The Douleur Neuropathique 4, a questionnaire for neuropathic painshould be applied ; thiscoLaboratory tests should be performed before initiating drug therapy and duringthe use of NSAID and corticosteroid, including blood counts, fasting bloodglucose, urea, creatinine, and transaminases. Rehabilitation with physiotherapy and alternative therapies such as acupuncture,physical activity, and patient education is important in parallel withpharmacological treatment.. in French Polynesia,60% of patients experienced chronification, of whom 72 were followed up for 3years, with 45% having persistent arthralgia, 24% having initial recoveryfollowed by recurrence, and 31% experiencing complete recovery from the acutephasePatients whose musculoskeletal complaints persist for periods longer than 3months are considered chronic. At this stage, complaints are characterized bypain in a persistent or recurrent pattern that can maintain its intensity fromprevious phases, may be intense and disabling, or mild and even decreasing inintensity. In a study by Schilte et alThe joints most commonly affected are those of the hands, wrists, knees, andankles, with associated morning stiffness and edema. Patients may also reportthe involvement of the cervical region and shoulders with determinate pain andmovement limitations. Neuropathic pain affects approximately 20% of patients and is often neglected,which in many cases constitutes therapeutic failure because they are notresponsive to analgesics and opioids, instead requiring specific therapy. analyzed the effect of the diseaseon the quality of life of these patients after 36 weeks and associatedlimitations in regard to performing their usual activities. Concerning suchlimitations, 62.9% of patients reported difficulty in lifting themselves up froma sitting position; 54.8% had trouble walking; 54.8% experienced difficultypicking up objects; 53.2% had trouble opening bottles and other containers; and37.1% reported having difficulty bathing. Suffering related to CHIKV infectionis not limited to pain; a significant segment of patients presented with mental,mood, and sleep disorders. The disease also had an effect on emotional status,often leading to sleep disorders (56.4%), depression (50%), memory disorders(43.5%), and concentration disorders (38.7%)The study by Schilte et al. classified 112 (70%) of them as having chronicinflammatory rheumatic disease, with 40 cases fulfilling the clinical andradiological criteria for rheumatoid arthritis, 33 for spondyloarthritis, and 21for undifferentiated polyarthritis; none of these patients had a previoushistory of rheumatic diseaseSome patients’ conditions may advance to progressive erosive arthritis with apattern of rheumatoid or psoriatic arthritis. The authors’ experience shows thatonly a minor percentage of patients develop an inflammatory pattern of thechronic disease. The patients in this phase of chikungunya usually show aclinical condition of non-inflammatory pain and stiffness. However, in theevaluation of 159 patients referred to a rheumatologist, Javelle etalIn different studies, several factors have been associated with the risk ofchronification of musculoskeletal complaints. Factors to highlight include thefollowing: being a female; being older than 45 years; severe pain, presence ofedema, rigidity, or polyarthritis during the acute phase; previous jointdisease; diabetes; high viral load; elevated levels of protein C in the acutephase; and persistently elevated immunoglobulin (Ig) M. At this phase, analgesics, opioids, NSAIDs, and corticosteroids may be institutedfor refractory or recurrent cases or as a bridge, pending the initiation ofchronic-phase drugs . FurtherThe BSR suggests that patients at this chronic stage should be tested forchikungunya IgG serology and should also have specific tests for differentialdiagnoses with other rheumatological diseases, including rheumatoid factor,citrullinated anti-peptide antibody, and in suspected cases of spondyloarthritisshould be serchead the human leucocyte antigen B27. In primary care approach, or when evaluation is made by a non-rheumatologyspecialist, the initial evaluation may not include the performance of specifictests, leaving these to specialists following the therapeutic failure of thedrugs proposed for chronic phase .The drugs of choice at this stage are antimalarials, preferablyhydroxychloroquine (HCQ). In this guideline, methotrexate (MTX) is an option forinflammatory joint disease  and HCQ for less-severe forms. Patients should be evaluated after 8 weeks, and in cases of favorable clinicalresponse, they should maintain the drug for another 6 months. In the event offailure to respond to HCQ, MTX should be prescribed. For cases of MTX failure,the physician should refer the patient to a rheumatologist. Most patients’ symptoms tend to decrease with the suggested therapies, leaving asmall percentage of patients who require rheumatological evaluations, which willbroaden the clinical investigation, consider a differential diagnosis, performlaboratory and specific imaging tests, and decide on therapeutic options to beadjusted or instituted. Some patients with chronic inflammatory joint diseasewho experience therapeutic failure may even require immunobiological evaluation(following recommendations used for treating rheumatoid arthritis orspondyloarthritis). Physicians should be aware of the adverse effects, typical of each treatmentclass prescribed at this stage of treatment and the need for specific clinicaland laboratory monitoring before and during use. For immunosuppressive drugs,specific tests are required, such as screening for hepatitis B , hepatitis C (antibody to hepatitis C virus) and humanimmunodeficiency virus, the Mantoux test, and chest x-ray. Physiotherapeutic treatment is recommended in all three phases of the disease, aswell as other alternative therapies .One factor that is important to acknowledge is that, in groups that have hadepidemics of chikungunya, only a small percentage of patients will need drugssuch as MTX. Most patients can achieve pain control with the use of NSAIDs,analgesics, and physiotherapy once the most common pattern of chronic diseaseseen on the authors’ clinical practice is the non-inflammatory. It is important to remember that this chronological division of therapy in phasesis ideal, but some patients may not visit a doctor until they have reached thechronic phase (after 3 months of onset of symptoms) and thus, may never havebeen offered post-acute phase therapy. In this case, despite when symptoms wereexperienced, the previous phase therapy can be offered.


Background and Objectives: Acute postoperative pain is one of the most undesirable experiences for a patient in the postoperative period. Many options are available for the treatment of postoperative pain. One of the methods of multimodal analgesia is a combination of opioids and adjuvant agents, such as ketamine. The aim of this study was to evaluate the effect of a pre-incisional single injection of low-dose ketamine on postoperative pain after remifentanil infusion in patients undergoing laparoscopic gastric bypass or gastric plication surgery. Materials and Methods: The prospective, randomized, double-blinded and placebo-controlled trial took place at the Hospital of the Lithuanian University of Health sciences KaunoKlinikos in 2015–2017. A total of 32 bariatric patients (9 men and 23 women) were randomly assigned to receive a single pre-incisional injection of ketamine (0.15 mg/kg (LBM))  or saline . Standardized protocol of anesthesia and postoperative pain management was followed for all patients. Postoperative pain intensity, postoperative morphine requirements, incidence of side effects and patients’ satisfaction with postoperative analgesia were recorded. Results: Thirty-two patients undergoing bariatric surgery: 18  and 14  were examined. Both groups did not differ in demographic values, duration of surgery and anesthesia and intraoperative drug consumption. Postoperative pain scores were similar in both groups (p = 0.105–0.941). Morphine consumption was 10.0 (7.0–12.5 mg) in group S and 9.0 (3.0–15.0 mg) in group K (p = 0.022). The incidence of side effects was similar in both groups (p = 0.412). Both groups demonstrated very high satisfaction with postoperative analgesia. Conclusions: Pre-incisional single dose ketamine reduces postoperative opioids consumption, but does not have an effect of postoperative pain intensity and side effects after remifentanil infusions. Very high patient satisfaction is achieved if standard multimodal analgesia protocol with an individual assessment of pain and dosage of medications is followed. Acute postoperative pain is one of the most undesirable experiences for patients in the postoperative period . EffectiThe prospective, randomized, double-blinded and placebo-controlled trial took place at the Hospital of the Lithuanian University of Health Science KaunoKlinikos in 2015–2017. After approval of the local Ethics Committee  and with the patients’ written consent, 32 morbidly obese patients were enrolled in the study. The inclusion criteria were: II or III ASA physical status, age >18 years, bariatric surgery with general remifentanil anesthesia. Patients with anamnesis of using opioids for the treatment of chronic pain and opioid dependence, younger than 18 years, were excluded from the study.The patients were randomly assigned to receive a single pre-incisional injection of ketamine (0.15 mg/kg)   or saline . Dosage of medications was based on the patient lean body mass.2.In the operating room standard monitors were used: ECG, non-invasive blood pressure, pulse oximetry and EtCOAnesthesia was induced after pre-oxygenation by face mask with 100% oxygen with intravenous (i.v.) fentanyl 1.2–1.5 mcg/kg, i.v. propofol 2 mg/kg and i.v. cisatracurium 0.1 mg/kg.Anesthesia was maintained with sevoflurane 0.7–0.8 MAC, remifentanil 0.2–0.5 mcg/kg/min and noradrenaline 0.01–0.04 mcg/kg/min, based on heart rate and blood pressure stability according to judgement of an experienced anesthesiologist . 2 35–45 mmHg).The lungs were ventilated with a mixture of 60% of oxygen and air in the pressure control mode, to maintain normocapnia .Standard post-operative monitoring was applied: ECG, non-invasive blood pressure, pulse oximetry. All patients were administered 2–4 l/min oxygen by nasal cannula. Patients were monitored in PACU for 2.5 h and pain intensity was recorded every 15 min. Postoperative pain was treated with boluses of i.v. morphine (3 mg) at 3 min intervals on request, if pain intensity exceeded the score of 5 according to the numeric pain rating scale (NPRS). After the transfer of patients’ to regular unit, pain intensity was recorded every 6 h. General pain characteristics, duration of surgery and anesthesia, pain intensity, postoperative morphine requirements, incidence of side effects and patient satisfaction with postoperative analgesia were recorded. 2 test. A p-value less than 0.05 was considered significant. Statistical analyses were performed using Statistical Package for Social Sciences (SPSS) software version 23.0. Continuous variables were presented as median ± min/max values. Categorical variables are summarized as frequencies. Differences in continuous variables between the two groups were evaluated using the Mann–Whitney U test. Categorical variables were compared using the Pearson χThirty-two patients were enrolled in the study .Patient demographic data are shown in The total amount of morphine during the first 2.5 h after surgery is shown in r (Spearman) = 0.818, p < 0.001 and no relation in the saline group, r (Spearman) = 0.19, p = 0.465   . p = 0.412)  .We did not notice ketamine side effects  in any of the patients. p = 0.21)  . p = 0.47 and p = 0.47, respectively).We also analyzed whether patients would choose the same type of pain treatment if they need to repeat the surgery or would they recommend it to their loved ones. No statistically significant difference was found between the two groups (r (Spearman) = 0.36 (p = 0.045).Total morphine consumption and patient satisfaction. The higher the morphine dose was administered for patients in PACU, the higher their satisfaction with postoperative pain management was, r (Spearman) = 0.51 (p = 0.003).Postoperative pain intensity and patient satisfaction. The more severe the pain was experienced by the patients, the more satisfied they were with analgesia, During the research, we found a positive relationship between:p < 0.05). Saumier and other authors in the study published in 2013 [p = 0.08) [Sufficient pain management is critical for full early rehabilitation and associated better outcomes after surgery. During the study, we found that in the treatment of pain after laparoscopic gastric bypass and gastric plication surgeries, the required morphine dose in both groups was low (from 3 to 15 mg). Nevertheless, in our study, pain was managed effectively (the NPRS median during the observation time ranged from zero to four). We assume that this was affected by active patient monitoring (every 15 min), individual attention and communication with the subjects in the PACU. A similar total morphine amount used in the treatment of postoperative pain for the first two hours, in the PACU, after bariatric surgeries was demonstrated by Hasanein et al. in the study in 2011 [ in 2013  also pre = 0.08) . p = 0.022). The same results are presented by other authors in various operations [r (Spearman) = 0.396 (p = 0.025). This has been found by other authors following traumatology surgery [r (Spearman) = 0.396 (p = 0.025). Such results, potentially, indicate that ketamine, acting through the NMDA and opioid receptors, provides favorable conditions for adequate postoperative pain management. We found that the need for morphine in postoperative patients who received ketamine was lower than in patients who have not received it  [The undesirable post-anesthetic morphine-related effects and adverse reactions were not common. In the study, we found that 34% of patients were nauseous and only 3% of them vomited. We believe that such favorable results were due to careful observance of postoperative nausea and vomiting (PONV) prophylaxis recommendations. We found only one clinical study where, in order to evaluate the efficiency of PONV prevention medicines and their combinations, the patients in the control groups did not receive any PONV prevention medications at all. It was found that the combination of ondansetron (4 mg) and dexamethasone (8 mg) reduced the incidence of POVN from 85% (placebo group) up to 10% (research group) ( 0.0001) . We did Patient satisfaction with analgesia was also researched. Most of the patients (84.4%) of our study were highly satisfied with postoperative pain treatment. Only one patient (3.1%) was very dissatisfied with our services on the next day after operation. After analyzing this case, we noticed that even before the operation he had a panic attack. We believe that this affected the inadequate sensation of pain and excessive dissatisfaction with postoperative analgesia. This is confirmed by the systematic analysis published by Vivian et al.  in 2009,r (Spearman) = 0.51 (p = 0.003). This phenomenon has been described by anesthesiologists at John Hopkins University in Baltimore in 2012. They found that patient satisfaction was higher when medical staff make all their efforts to reduce postoperative pain rather than the methods in which the pain is actively managed [It is a paradox, but we found a direct relationship between patient satisfaction and postoperative pain intensity. The stronger the pain, the more satisfied patents were with analgesia,  managed . Our study involved only 32 patients, and, therefore, the research was limited to a small sample, which was determined by the number of patients treated in our hospital. Starting our study, we opted to enroll all consecutive bariatric patients in our facility. Eight patients were excluded from the study. The reason for exclusion was non-standard surgical technique: these patients have undergone previous abdominal surgical procedures, resulting in difficulties of surgical access and significantly longer duration of bariatric surgery . We felt that these patients were not eligible for the analysis due to higher intraoperative consumption of anesthetic medications. To highlight the role of ketamine, a larger study should be performed using other, higher doses and different administration routes . We believe this could be the subject of further research in our clinic. Pre-incisional administration of a single 0.15 mg/kg dose of ketamine reduces postoperative opioids consumption, but does not have an effect of postoperative pain intensity and side effects after remifentanil infusions. Very high patient satisfaction is achieved if standard multimodal analgesia protocol with an individual assessment of pain and dosage of medications is followed.


PurposeThe purpose of this study is to compare the effect of pregabalin in reducing the neuropathic pain in postoperative patients who have undergone single-level microdiscectomy for prolapsed intervertebral lumbar disc.MethodsA randomized control clinical trial was conducted from June 2018 to April 2020 in three campuses Dr. Ziauddin University Hospital, Karachi, by two spinal surgeons. This study included 84 patients who underwent either emergency or elective microdiscectomy surgery. The patients randomized into two equal groups of 42,  and (group-B: placebo). Both groups also received routine analgesia along with the pregabalin and placebo capsules. In the intervention group, pregabalin was administered preoperative and postoperative defined times. The pain scores were recorded by visual analog scale (VAS) and Roland-Morris score system on the preoperative day and compared to the scores on follow-up on postoperative day seven.ResultsThe pain scores were significantly better in group-A compared to group-B with similar baseline variables. The mean VAS scores of pains in group-A on postoperative day seven on follow-up were compared to VAS pain scores in group-B showing better pain control. The Roland-Morris scores were also significantly better for group-A.ConclusionsThe use of pregabalin in addition to the routine analgesia has better control of postoperative neuropathic pain in patients with single-level microdiscectomy compared to the patients who are receiving only routine analgesia. Other factors like cost, dose, side effects, and frequency should also be considered. Lower back pain with severe radiculopathy is caused by the herniation of the lumbar disc into the spinal column with nerve root compression. This herniation can lead to devastating outcomes if not treated. In case of complications of untreated prolapsed discs like cauda equina syndrome, urgent surgical intervention is required. A minimally invasive approach to this surgery like "microdiscectomy" is necessary to relieve pain and to prevent further progression of damage.Discectomy is a routine procedure performed by orthopedic surgeons and neurosurgeons, and it is associated with mild to moderate levels of postoperative pain. Multimodal treatments have been used to reduce side effects and doses to achieve adequate analgesic effects . TreatmeAs the number of day-care procedures has increased by a significant number globally, newer, and more complex methods are being devised almost daily. While this may have its own benefits , these pAlmost 80% of patients still suffer from postoperative pain despite all the recent advances  which poIt is often noted that the risk of inappropriate pain control in patients undergoing surgery, has been relatively higher in patients who are suffering from chronic back pain, as they have already developed a tolerance to strong analgesic . One of It has been noted that administration of epidural analgesia has shown promising results in significantly reducing postoperative pain after spinal surgeries . It has When discussing the management of acute and/or chronic states of pain, such as diabetic peripheral neuropathy, gabapentin has not shown to have much significance over other agents, such as tricyclic antidepressants (amitriptyline), and thereby are often used alone or in combination depending on the condition of the patient and their comorbidities , howeverPregabalin is structurally a gamma-aminobutyric acid (GABA) and has the same characteristics and mechanism of action as its precursor gabapentin . For manPregabalin has been administered as part of analgesic regimens for various procedures, including lumbar spine surgery, in a few studies. One such study conducted by Mohsin et al., revealed, the effectiveness of both agents , for postoperative management for single-level microdiscectomy was almost equivalent. In other studies, pregabalin was either compared to a placebo or there were limitations in the study design, with respect to the pharmacodynamics of the drug, such as it being utilized just before the surgery, instead of administering it at least a week prior in order to produced successful results, as seen in reality ,19. ThusTherefore, we intended to compare the postoperative pain control in patients with the usage of low dose pregabalin along with routine analgesia to those with patients who received only routine analgesia pre and postoperatively.We hypothesized that the pain in the pregabalin group would be less than that in the without pregabalin group.This study is a single-blinded, parallel-group, randomized clinical trial that was conducted in the orthopedics department of Dr. Ziauddin University Hospital Karachi. Conducted on patients who were suffering from chronic sacral radiculopathy and diagnoses to have PID , undergoing elective lumbar microdiscectomy. The study started with IRB  approval and written/verbal informed consent from the patients. Then they were randomly allotted in two groups: group-A  and group-B (control group). Each group consisting of 42 patients each with a total of 84 patients, aged between 27 years to 61 years. The exclusion criteria included patients with previous lumbar surgery, patients allergic to gabapentinoids, patients with renal impairments, patients already on opioids, benzodiazepines, barbiturates, ethanol , diabetes, and other drugs that depress the central nervous system and on angiotensin-converting enzyme (ACE) inhibitors as they may enhance the adverse/toxic effect of pregabalin. In this study, the patients received pregabalin 75 mg or placebo (sucrose) twice daily from preoperative day till one week of surgery. All medications were identical and provided by the hospital pharmacy in sealed opaque envelopes. Along with this, all patients were getting regular postoperative pain management with paracetamol 1 gram six hourly and nonsteroidal anti-inflammatory medication (Ketorolac) 30 mg I/V ter die sumendum (TDS) as a primary protocol for pain management. Opioids were given on pro re nata (PRN) bases if the pain was not controlled via the primary protocol. All patients were given three pain scale questionnaires Roland-Morris disability scale and visual analog scale (VAS) pain to fill, preoperatively, and then after one week of surgery, and the results were compared.Data was analyzed using Excel 2013 and IBM SPSS Statistics ver.20 . Contingency tables were analyzed using Fisher exact test, P values <0.05 were considered statistically significant.Our study comprised of 84 patients, equally divided into two groups based on random selection; group A consisted of 42 patients, who received pregabalin pre and postoperatively, and group B consisted of the remainder of patients who did not receive pregabalin. Amongst our participants, 58% (n=49) of participants were females, while the remaining 42% (n=35) were males. The age of the participants ranged between 27 years to 61 years, categorizing them as adults, and thus all the participants received the standardized adult dosage of the analgesics . For the assessment of pain, two international scoring systems; the 10-point VAS and the 24-item patient-reported Roland-Morris scoring system for lower back pain (RMS), were used. The pain was assessed both preoperatively and one week postoperatively, in both groups. Keeping the significance of P at <0.05, the results of our research are as follows:When comparing the pre and post-operative VAS scores of group A, Figure , 95.2% , which rPain relief was almost comparable in both genders, with almost 83% (n=29) of males enduring mild pain and only 8% (n=3) enduring moderate pain postoperatively, while 77% (n=38) of females experienced mild pain and almost 10% (n=5) of them feeling moderate pain. Neither gender reported severe pain postoperatively Figure . For malThe average RMS for group A, who were administered pregabalin pre and postoperatively, was 16.43 preoperatively, which considerably reduced to 6.90 postoperatively. However, for group B the scores did not show a great improvement, with the score being 16.19 preoperatively going down to only 9.74 postoperatively  while that of group B was 90% (n=38) as illustrated in  compared to regular analgesia  (significance of p= <0.05).It has been noted that pregabalin has been more effective in providing analgesic effects for neuropathic pain, ,20 such Pregabalin exhibits its anticonvulsant, analgesic, and anxiolytic activity by binding to the ligand for the alpha-2-delta subunit of voltage-gated calcium channels in the central nervous system which thereby reduces depolarization-induced calcium influx along with a modification in the release of excitatory neurotransmitters. Pregabalin inhibits the release of neurotransmitters including glutamate, noradrenaline, calcitonin gene-related peptide, and substance P . The redThe extensive and rapid absorption of pregabalin is proportional to the dose. Maximal plasma concentration is attained in approximately one hour while steady-state is accomplished within 24-48 hours which shows that the observed onset of efficacy for pregabalin, is as early as day two in most clinical trials. The mean elimination half-life is calculated to be around 6.3 hours. These aforementioned factors predict a dose-response relationship in clinical practice, thereby allowing an effective starting dose of 150mg/day to be administered without any need for titration .In our study, we administered pregabalin to our patients preoperatively, approximately (24) hours before the surgery. As a result, it is expected that the peak plasma concentration for pregabalin was achieved.We also found in our study that preoperative pregabalin decreased usage of postoperative opioid use for pain management significantly. . Our results also correspond with a randomized controlled study which concluded that in the first 48 hours post-procedure, the number of doses needed for rescue analgesia, and total required dose of morphine, were significantly less (p=<0.0001) .A study conducted in Denmark on women undergoing hysterectomy concluded that by administering spinal or epidural anesthesia, there is blockade of the central impulse traffic, that produces a protective effect towards the development of chronic pain, eventually preventing extreme postoperative discomfort ,27. TherIn another study conducted in March 2017 by Liu B, et al. it was concluded that when patients undergoing spinal surgery, were administered gabapentinoids preoperatively, they had a significant reduction in postoperative pain, total consumption of morphine, and morphine-related complications postoperatively . GabapenThe use of pregabalin in addition to the routine analgesia has better control of postoperative neuropathic pain in patients with single-level microdiscectomy compared to the patients who are receiving only routine analgesia. Other factors like cost, dose, side effects, and frequency should also be considered.