Recurrent myelitis is one of the predominant characteristics in patients with neuromyelitis optica (NMO). While paresis, visual loss, sensory deficits, and bladder dysfunction are well known symptoms in NMO patients, pain has been recognized only recently as another key symptom of the disease. Although spinal cord inflammation is a defining aspect of neuromyelitis, there is an almost complete lack of data on altered somatosensory function, including pain. Therefore, eleven consecutive patients with NMO were investigated regarding the presence and clinical characteristics of pain. All patients were examined clinically as well as by Quantitative Sensory Testing (QST) following the protocol of the German Research Network on Neuropathic Pain (DFNS). Additionally, plasma endocannabinoid levels and signs of chronic stress and depression were determined. Almost all patients (10/11) suffered from NMO-associated neuropathic pain for the last three months, and 8 out of 11 patients indicated relevant pain at the time of examination. Symptoms of neuropathic pain were reported in the vast majority of patients with NMO. Psychological testing revealed signs of marked depression. Compared to age and gender-matched healthy controls, QST revealed pronounced mechanical and thermal sensory loss, strongly correlated to ongoing pain suggesting the presence of deafferentation-induced neuropathic pain. Thermal hyperalgesia correlated to MRI-verified signs of spinal cord lesion. Heat hyperalgesia was highly correlated to the time since last relapse of NMO. Patients with NMO exhibited significant mechanical and thermal dysesthesia, namely dynamic mechanical allodynia and paradoxical heat sensation. Moreover, they presented frequently with either abnormal mechanical hypoalgesia or hyperalgesia, which depended significantly on plasma levels of the endogenous cannabinoid 2-arachidonoylglycerole (2-AG). These data emphasize the high prevalence of neuropathic pain and hyperalgesia in patients with NMO. The degree of mechanical hyperalgesia reflecting central sensitization of nociceptive pathways seems to be controlled by the major brain endocannabinoid 2-AG. Neuromyelitis optica  is a demyelinating inflammatory autoimmune disease of the central nervous system leading to recurrent optic neuritis (ON) and episodic myelitis Apart from the deterioration of visual and motor function, the presence of severe pain in a substantial proportion of NMO patients with a high impact on their health-related quality of life was only recently reported Although spinal cord inflammation is a defining aspect of NMO, there is still no knowledge of the pattern of somatosensory changes accompanying the disease, nor the degree of on going stress and depression frequently observed in NMO patients suffering from chronic pain. Thus, it is essential to characterise the complete somatosensory phenotype of patients with NMO, since this may contribute to a better understanding of the underlying pathophysiological mechanisms of pain generation in NMO, which may enable potential treatment options Eleven consecutive Caucasian patients with NMO seen at the Institute for Clinical Neuroimmunology were included into the study. All of them fulfilled diagnostic criteria of definite AQP4-antibody positive NMO After given written informed consent nine female and two male patients with a median age of 51 years ranging from 24 to 69 were included . Median time since onset of disease was 8 years ranging from 3 months to 24 years . MedicalThe patients were interviewed for the presence, intensity, location, and characteristics of pain. Neuropathic pain was considered to be present if pain was (a) located in the area corresponding to CNS lesion, (b) could not be attributed to any other condition and (c) had specific characteristics of neuropathic pain according to the DN4 neuropathic pain scale Venous blood samples for endocannabinoid measurements were taken peripherally and drawn into Lithium-Heparin containing tubes , immediately centrifuged and then stored at –80°C to minimize ex-vivo synthesis of endocannabinoids from nucleated blood cells as has been described earlier QST was conducted under minimal distraction in a silent, air-conditioned room, with an ambient temperature of 24–25°Celsius. QST followed the standardised protocol as described by the German Network on Neuropathic Pain (DFNS) Thermal testing included Warm Detection Threshold (WDT), Cold Detection Threshold (CDT), Thermal Sensory Limen (TSL), Cold Pain Threshold (CPT), Thermal Sensory Limen (TSL), Cold Pain Threshold (CPT) and Heat Pain Threshold (HPT). Furthermore, Paradoxical Heat Sensations (PHS), that means identification of a cold stimulus as either hot or burning pain, were recorded. For mechanical testing we determined Mechanical Detection Threshold (MDT), Vibration Detection Threshold (VDT), Mechanical Pain Threshold (MPT), Mechanical Pain Sensitivity for pinprick stimuli (MPS), Wind-up Ratio (WUR), Pressure Pain Threshold (PPT), and Dynamic Mechanical Allodynia (DMA). For an elaborate discussion see The presence and severity of depression was assessed by the German version of the Center for Epidemiological Studies Depression Test (CES-D). Presence of stress symptoms such as sleep disturbances, nightmares and generalized irritability were measured using the German Version of the Post-Traumatic Stress Symptom 10-Questionnaire (PTSS-10) Overall health-related quality of life (HRQL) was assessed by the German version of the Short Form 36 (SF-36). reference data base)/SD reference data base). The sign of the respective z-score was adjusted in a way that a gain of function was indicated by a positive sign, whereas a negative sign indicated a loss of function http://home.clara.net/sisa/binomial.htm) All QST data  were transformed into decadic logarithms to achieve secondary normal distributions Data of SF36 were normalized as described above to a representative sample of the US-General population (n = 2393). In addition, correlations between QST results, endocannabinoid levels and the time since last relapse of NMO were calculated.Clinical and MRI characteristics of NMO patients are shown in Eight out of the eleven consecutive NMO patients (72%) reported on going pain , in the arms or shoulder (n = 5), in thoracic or abdominal dermatomes (n = 8) or combined (n = 7). Five patients had spontaneous on going pain as well as painful paroxysms; two patients complained of either solely attacks or constant pain, respectively .Pain was treated continuously with analgesic or co-analgesic drugs in 7/11 patients (63%), all of whom needed more than one analgesic substance. One patient only took medication on demand during pain attacks and two more patients received antiepileptic drugs during previous relapses that where associated with pain but had recovered completely. Three patients administered a combination of sodium channel blocker to treat electric shooting pain attacks and a calcium channel blocker to reduce constant burning pain .Mean number of traumatic memories was 0.91; PTSS-10 score was 26.1±7.9. Three patients indicated no traumatic memories (PTSS-10∶18.3±4.2), 6 patients had one traumatic memory (27.8±7.9), while 2 patients displayed two traumatic memories (32.5±0.7). However, no patient displayed a PTSSD score>35, which would be firmly indicating comorbid posttraumatic stress disorder. Mean CES-D score was 34±8 indicating the presence of clinical relevant depression. Patients with NMO showed a significant decrease in three of the eight dimensions of SF 36, namely physical functioning, general health and noteworthy bodily pain .10mean ± SEM: −0.017±0.032) and −1.79°C in the feet (log10mean ± SEM: 0.253±0.065), NMO patients detected cooling not until at a much more larger temperature change of −3.04°C (log10mean ± SEM: 0.483±0.107) and −7.85°C (log10mean ± SEM: 0.895±0.106), respectively (both p<0.001).Thermal detection  was significantly impaired in NMO patients in upper and lower extremities as compared to healthy controls (10mean ± SEM: −0.231±0.036) in the hands and +4.31°C (log10mean ± SEM: 0.635±0.050) in the feet, while NMO patients detected warming only at a temperature change of +4.16°C  and +7.51°C , respectively. Likewise, combined alternating warm and cold stimuli (TSL) was significantly increased in the hands and feet of patients with NMO . Warming was detected at a stimulus temperature difference of +1.70°C (logDetection of vibration (VDT) assessed by an 8/8 calibrated Rydel-Seiffer tuning fork in NMO patients was strongly reduced in the hands , where only one NMO patients exhibited vibration sensitivity in the normal range of bedside testing (>6/8) and none compared to a reference data base Cold pain thresholds (CPT) did not differ significantly between NMO patients and healthy controls in hands and feet (both p>0.30). In contrast, heat pain threshold (HPT) was significantly decreased in the hand , indicating significant heat hyperalgesia. Heat pain thresholds in the feet, however, were unaltered  excluding those without cervical lesions . While patients without cervical spinal lesion did not differ from healthy controls at all regarding their heat pain threshold , patients with structural cervical lesions displayed a highly significantly reduction of heat pain threshold , as compared to control group at the upper extremities . Consequently, there was a highly significant correlation of heat pain thresholds with time since last relapse of NMO for both hand and feet , which reached normal thresholds not until one year after the last NMO relapse .PHS was a very frequent finding in TSL trials with NMO patients at either the examined hands or feet. Overall, PHS was detected in 8/11 patients with NMO, and 33 of 66 trials (50%) at the feet, but only in 8 of 66 trials at the feet of healthy controls . Moreover, whereas none of the healthy controls showed PHS in any trial at the dorsum of their hand, PHS regularly occurred in 8/9 patients with NMO at the hands, and was experienced in 26 of 66 trials, .Concerning the mechanical pain thresholds, QST testing revealed no signs of mechanical hyperalgesia. Neither mechanical pain thresholds (MPT), pressure pain threshold (PPT) nor wind-up ratio (WUR) following pin-prick stimulation differed significantly in any extremity of NMO patients compared to healthy controls . In addition, pain sensitivity for pinprick stimuli (MPS) was significantly reduced in the hand of NMO patients (p<0.05), accompanied by a strong trend towards MPS reduction in the feet . Mechanical detection thresholds were abnormal in 50% of patient test sites, but remained relatively unchanged overall, since abnormal sensitivity encompassed a similar proportion of abnormal gains or losses . AdditioSecondly, patients with NMO exhibited thermal hyperalgesia (to painful heat and cold stimuli), when they exhibited signs of cervical spinal lesion as a marker of inflammatory spinal cord damage. The amount of hyperalgesia was strongly correlated to the time since the last relapse of NMO. In contrast, mechanical pain parameters did not reveal clear signs of hyperalgesia.Thirdly, NMO patients displayed distinct signs of dysesthesia in both hands and feet, namely the frequent occurrence of paradoxical heat sensations following alternating warm/cold stimulation, and significant pain to light touch.Finally, the magnitude of on going pain at the time of QST assessment was strongly negatively correlated to any of the QST pain parameters with no difference between thermal and mechanical pain modalities  suggesting a deafferentation-type of central neuropathic pain.The two major chemically related cannabinoid lipids anandamide and 2-arachidonoylglycerol (2-AG) were elevated in patients’ plasma compared to age and gender-matched healthy controls. 2-AG plasma levels were doubled , while anandamide exhibited only a trend  . While pBoth, 2-AG and anandamide were not significantly related to the time since last relapse . In contrast, there were significant relationships of both lipid signalling molecules to the patients’ somatosensory status. Anandamide levels were positively, but weakly correlated to pain sensitivity as calculated by normalized pain thresholds  is a frequent, but often neglected phenomenon in various forms of CNS diseases such as NMO. Notwithstanding, mechanisms underlying this type of pain are poorly understood. Accordingly, pain has recently been described as another key symptom of NMO, but the predominant quality of pain has not yet been characterized As almost all patients reported pain at the time or in the three months preceding the examination, our data emphasize the high incidence of pain also in Caucasian NMO patients compared to patients with multiple sclerosis (28%−47%) or spinal cord injury (30−40%)The pain characteristics in NMO patients were burning or tingling, sensory descriptions discriminating neuropathic from non-neuropathic pain states Similar to previous findings, we consistently found significantly reduced scores in three of the eight dimensions of the SF 36 reflecting impaired Health Related Quality of Life, Consequently, we strongly recommend the routine use of supplementary questionnaires amending the EDSS, in order to achieve timely recognition and treatment of pain as well as depression in NMO.As the pattern of pain suggested a neuropathic origin of the ongoing pain in patients with NMO, in the next step we used QST in order to delineate the accompanying somatosensory changes and to get insights into the pathophysiological background of neuropathic pain in NMO as recently published for a n>1200 cohort of neuropathic pain patients In NMO patients, the ability to detect either warm or cold was considerably impaired, indicated by the threefold increase in CDT, WDT and TSL. The occurrence of negative thermal sensory signs is characteristic for patients with all kinds of neuropathic pain disorders, regardless of a peripheral or central site of lesion Similarly, a pronounced impairment of vibration detection was observed, which is a characteristic of somatosensory changes in patients with neuropathic pain as well There was apparently no overall mechanical hyperalgesia to pinprick or blunt pressure. However, approximately 20% of the patients nevertheless displayed abnormal mechanical hyperalgesia, yet balanced by patients with mechanical hypoalgesia . ImportaThe most conspicuous positive mechanical sign was dynamic mechanical allodynia (DMA), i.e. pain to stroking light touch stimuli, which marks a crosstalk of tactile inputs into pain pathways, and is considered as a hallmark sign of central sensitization However, the low incidence of abnormal pain sensation (wind up pain sensation), despite clear signs of central sensitization is not contradicting the finding of central nociceptive sensitization, as central sensitization and wind-up represent independent phenomena Hyperalgesia to noxious heat or cold is usually attributed to peripheral sensitization of primary afferent C fibers, a hallmark sign of inflammatory processes In animal models of neuropathic pain, gliopathy, involving microglia in the early stages and astrocytes in the later stages, parallels persistent pain in spinal cord injury Currently, there is no comprehensive characterization of the interaction between analgesic medication and somatosensory testing and we cannot rule out interference with analgesic treatment. However, no influence of antidepressant medication on thermal thresholds could be found in patients suffering from major depression , for which we propose a double inhibitory role on both mechanical hyperalgesia and potentially also on neuroinflammation.In aggregate, patients with NMO are displaying both the clinical as well as the typical somatosensory signs of neuropathic pain. The “unhappy” trias of central lesions, accompanied by central sensitization of pain pathways and contemporaneous CNS inflammation in NMO accounts for the high incidence of neuropathic pain. Additionally, the pain phenotype appears to be modulated by 2-AG, the major endogenous cannabinoid of the brain


The Neck Disability Index (NDI) is the most commonly used outcome measure for neck pain. This study aimed to determine the psychometric properties of a German version of the NDI. Cross-cultural translation and psychometric testing of the NDI were performed.2,1). To determine convergent validity, pain intensity , pain on movement (VAS), and quality of life  were correlated with the NDI. Correlation with range of motion and sensitivity to change were also assessed in a subsample of 49 patients.The 10-item NDI was translated into German and administered to 558 patients with chronic unspecific neck pain . The factor structure and reliability of the NDI were assessed using factor analysis, Cronbach’s alpha, split-half reliability (Spearman-Brown coefficient), and intra-class correlation . Significant correlations were found for pain intensity , pain on movement , quality of life , and range of motion . Patients who reported global improvement of health after an exercise or yoga intervention showed a higher decrease on the NDI than patients who reported no global improvement (p < 0.01).The German version of the NDI has a comparable factor structure as the original version, acceptable psychometric properties, and is sensitive to change after physical activity. Neck disability is associated with other measures of neck pain. With a mean lifetime prevalence of about 50%, neck pain is a major public health problem in all industrialized countries. DespiteTherefore, this analysis of 558 patients suffering from chronic non-specific neck pain aimed to determine reliability and validity of a German version of the Neck Disability Index.Patients from 10 randomized controlled trials on chronic non-specific neck pain were included in psychometric testing. The trials had been conducted at the Department of Complementary and Integrative Medicine, Kliniken Essen-Mitte, Germany-22 and aTo be included, adult patients of both genders had to suffer from chronic non-specific neck pain for at least 5 days a week for at least 12 consecutive weeks with a mean pain intensity of at least 40 mm on a 100 mm visual analog scale (VAS) from 0 mm (no pain) to 100 mm (worst pain imaginable). Patients with neck pain that was likely to result from specific causes such as neck trauma, disc protrusion, rheumatic diseases, spinal canal stenosis, or neoplasms as well as patients with serious physical or mental comorbidities such as active oncologic diseases, diabetes mellitus, coronary artery disease, affective disorders, addiction, or psychosis were excluded.The psychometric sample consisted of 558 patients of which 134 (24.0%) were male and 424 (76.0%) were female. Age ranged from 19 to 81 years with a mean age 49.9 ± 11.4 years. The mean pain intensity was 45.7 mm ± 20.8 mm on a VAS; mean pain duration was 7.54 ± 7.52 years  was used. The NDIMean neck pain intensity during the past 7 days was measured on a 100-mm VAS.Pain on movement was assessed for 6 consecutive head movements . The pain elicited by each of these movements was scored on a 100-mm VAS.Health-related quality of life was assessed using the Short Form 36 Health Survey Questionnaire (SF-36). This coIn a subsample of 49 patients, cervical range of motion was measured for 6 cervical movement directions  using an electromagnetic, motion-tracking device ,27. A smGiven that prior cross-cultural adaptations of the NDI had revealed either single factor or two factor solutions, no a priori assumptions about the underlying factor structure of the German NDI were made and an exploratory factor analysis using the principle components extraction and the varimax rotation was performed on the 10 items of the NDI to explore the instrument’s structure. Factors were extracted if their eigenvalue was >1. Domain scores of any resulting factors, or of a total score, were calculated as a sum of the component item scores. A major requirement for factor analysis is a considerably large subject:item ratio. A minimum ratio of 20:1 has been proposed to ensure strong factor structures are replicated reliably. This re2,1) and its 95% confidence interval (CI) was used to assess agreement between measures.To assess internal consistency of the NDI, Cronbach’s α, alpha if item deleted, item-scale correlations, and item difficulty were calculated. Split-half reliability was assessed as the Spearman-Brown coefficient for the first 5 items  and the last 5 items . Two-way random intra-class correlation  weekly 90-minute classes with a certified instructor. After tAll statistics were performed using the statistical package IBM SPSS Statistics . A p-value of <0.05 (two-tailed) was considered significant in all analyses.Mean item values ranged from 0.45 to 2.24 .The German translation of the Neck Disability Index demonstrated a single factor structure with good internal consistency, intra-class correlation, and split-half reliability. The original English version was developed as a one-factor instrument. The sinConsistent with findings on other versions, the instrument was positively correlated with pain intensity and negatively with quality of life and neck range of motion-36. ThisThe instrument was sensitive to change after exercise or yoga interventions. Global impression of improved health was associated with improved neck disability. Several randomized trials have shown that exercise can improve global health and neck disability in chronic neck pain patients,42. ThisThis study has several limitations. First, the sample was not recruited specifically for the purpose of validating the Neck Disability Index but was drawn from a number of randomized trials. All available patients from the respective trials were included in the analysis. Thus, no a priori sample size calculation was performed. However, the achieved sample was considerably larger than that of most other cross-cultural adaptations of the NDI,32,36,40Comparable to the original English version, the German version of the Neck Disability Index demonstrated a single factor structure. The instrument has acceptable to good psychometric properties and is associated with other measures of health. The instrument further is sensitive to change after physical activity. As the original instrument, the German version of the Neck Disability Index seems to present a useful measure of neck disability in patients with chronic non-specific neck pain.The authors declare that there are no financial or non-financial conflicts of interest.HC was responsible for conception and design of the study, analysis and interpretation of data, participated in acquisition of data, and drafted the manuscript. RL participated in conception and design of the study, acquisition of data, analysis and interpretation of data, and critically revised the manuscript. JL and GD participated in conception and design of the study, and critically revised the manuscript. AM participated in conception and design of the study, acquisition of data, and critically revised the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/15/91/prepubGerman version of the Neck Disability Index (NDI).Click here for file


To assess the feasibility of utilizing a web-based data collection system as the research infrastructure for conducting multi-site outcomes research to evaluate complementary, alternative, and integrative medicine.The study was a longitudinal observational, cohort study with data collected at baseline and three months. Nine integrative medicine clinics housed at academic health centers that were members of the Consortium for Academic Health Centers for Integrative Medicine (CAHCIM) were invited to participate. Each academic health center was asked to obtain IRB approval for the study. Clinic patients enrolled in the study were given instructions for logging on to the project website to complete the following questionnaires: demographic, quality of life (SF-12), brief pain inventory, and an evaluation of the web-based system. Three months after completing baseline questionnaires patients were notified by email with instructions to complete final quality of life and pain questionnaires. Change in quality of life and pain were analyzed by paired t-test.All nine centers obtained IRB approval and subjects gave informed consent. Eighty patients from eight centers were enrolled and 48% (38/80) completed the baseline questionnaires. Of those that completed baseline questionnaires, 58% (22/38) completed the 3-month questionnaires. Eighty-four percent (32/38) at baseline completed the evaluation rating their experience with the system and 74% (28/38) responded that the web-based system was easy to navigate. Only 16 participants completed both baseline and 3-month quality of life and pain questionnaires, limiting interpretation of this data. Significant improvements in the mental health component of SF-12 , pain severity (p=0.02) and pain interference (p=0.01) were observed.The study shows the feasibility of web-based data collection from multiple sites. Limited study resources likely contributed to a significant number of enrolled participants not completing surveys. Although limited, the data showing improvements in MCS and pain warrant further investigation.


After-surgery pain is an extremely variable clinical condition, in a continuously changing evolution, where environmental and personal factors have combinations and results not easily predictable. It puts the subject into a state of physical and mental subjection so as of powerlessness. It could be feared more than the surgery itself and anesthesia. Such fears can bring the patient to delay surgery, increasing its risks, scope and post-surgery pain itself: this may lead to a progression of the pathological condition, and make recovery and convalescence more complicate .After-surgery pain treatment allows to: limit neurovegetative storms and the states of neuroendocrine activation; avoid, as much as possible, the development of "persistent pain" situations; facilitate the re-establishment of the previous psyco-physical function and functional state, so improving the general "patient satisfaction".The results of recent case studies have shown that after surgery pain management is insufficient; this implies negative economic consequences to the National Health Service, including the increase of unsatisfied patients number, longer hospitalization and frequent re-hospitalizations .The aim of our study is to compare the analgesic effect Ketorolac + Tramadole vs the analgesic effect of Meperidine only, in pain management after Major Surgery. We also focused our attention on the possible occurrence of adverse reactions, identified as every effect occurring within 48 hours after surgery .The study population consists of 70 patients Table  referredAt the end of surgery each patient had the elastomer according to the protocol and was followed in the next three days, monitoring the possible occurrence of adverse reactions. In both groups, the elastomeric pump was reloaded the day after surgery.We assessed after surgery pain using the Visual Analogue Scale (VAS); this scale consists of a straight line (100 mm long) representing an intensity sequence between the two ends: "no pain" and "the strongest pain imaginable".The record of pain intensity was written on the "Pain chart" every three hours and suspended when VAS was equal or lower than three, without any treatment, after three registrations in a row.As shown in the graph figure , VAS hasAfter two days of observation we suspended the treatment with the elastomeric pump and monitored the patient every 3 h, reporting VAS on the "pain chart" and preparing for the eventual administration, in case of need, of 1000 mg of paracetamol, which occurred in 12 patients, 5 of which were in M group.Three cases of nausea were recorded in T group vs 12 cases in M group, 2 of which with connected vomit.After surgery, intestinal gas emission was slower in M group, with an average delay of 12h with respect to T group.Our study demonstrates that the two treatments can overlap as for the long time analgesic effect, while it puts into evidence that whenever is recommended a fast recovery of an effective intestinal propulsion, it is of particular disturbance the constipating action of opioids; in fact the extended use of intravenous Meperidine caused, in some patients, intestinal function problems. On the contrary, Tramadole shows a less constipating effect.Moreover, multimodal analgesia is strongly recommended in after-surgery pain management since it can potentially improve the analgesic effect by affecting various mechanisms and/or by reducing each single agent dose, so minimizing any dose - depending adverse effec as well . It is oThe experience of acute pain, as isolated event in someone's life, is a kind of experience that does not imply psychological and behavioral adaptations but, on the contrary, it is connected to an individual reactivity and related to the surgical situation which often implies high levels of psychological distress, since it causes a detrimental action to the individual's body. After surgery analgesic therapy and pain management during the entire patient hospitalization are fundamental as part of the recovery process .


Objective: The aim of this study was to compare conventional surgery with carbon dioxide (CO2) laser in patients with oral leukoplakia, and to evaluate the postoperative pain and swelling. Study design: A total of 48 patients  with a mean age of 53.7 ± 11.7 years and diagnosed with oral leukoplakia were randomly assigned to receive treatment either with conventional surgery using a cold knife or with a CO2 laser technique. A visual analog scale (VAS) was used to score pain and swelling at different postoperative time points. Results: Pain and swelling reported by the patients was greater with the conventional cold knife than with the CO2 laser, statistically significant differences for pain and swelling were observed between the two techniques during the first three days after surgery. Followed by a gradual decrease over one week. In neither group was granuloma formation observed, and none of the patients showed malignant transformation during the period of follow-up. Conclusions: The CO2 laser causes only minimal pain and swelling, thus suggesting that it may be an alternative method to conventional surgery in treating patients with oral leukoplakia. Key words:Oral leukoplakia, treatment, laser surgery, cold knife, pain, swelling. Oral leukoplakia is a predominantly white lesion of the oral mucosa that cannot be characterized as any other definable lesion; some oral leukoplakias will transform into cancer -6. The eAs regards the treatment of oral leukoplakia, intervention first should focus on the associated risk factors: with the suppression of smoking, alcohol abuse, and local irritating factors and overinfections. The second intervention, when the associated risk factors have been eliminated, it must be the oral biopsy. A number of treatment regimens have been proposed for oral leukoplakia without dysplasia, including surgical techniques such as scalpel excision, electrocoagulation, cryotherapy and laser CO2 therapy and also medical treatments such as vitamin A and retinoids, antioxidants and topical bleomycin ,7-17. LeThe CO2 laser is currently accepted as the technique of choice in the management of oral leukoplakia and some malignant oral lesions , compareSome authors have examined postoperative pain in the surgical treatment of soft tissue lesions ,20, thouThe aim of the present study was to compare conventional cold knife surgery with the CO2 laser in patients with oral leukoplakia, and to evaluate pain and swelling during the first postoperative week.-Study subjectsA total of 48 patients with oral leukoplakia who went to the Department of Oral Medicine of the University Clinic of Dentistry of the University of Murcia (Spain) between January of 2005 and December of 2010 were enrolled into the study, and the study was approved by the Ethics Committee of the University of Murcia. All patients had an incisional biopsy performed under local anesthesia prior to surgical treatment. The clinical diagnosis of the lesions was based on the criteria proposed by Axell et al. .Informed consent was obtained from all patients before inclusion in the study. The patients received a complete physical head and neck examination. The possible etiological factors smoking and alcohol were identified, and advice on risk factor elimination was given before surgical treatment. The lesions were classified according to location and clinical appearance. All surgeries were performed by the same surgeon and carried out under local anesthesia with 4% articaine and 1:100,000 adrenalin .The patients were randomized (with an informatics system) by receiving stamped envelopes containing the numbers 1 or 2, indicating which group they would be placed in. Group 1  was treated by standard cold knife surgery. Group 2  was treated by CO2 laser . Appropriate safety regulations for the use of lasers were followed by the operating personnel and patients .In group 1, the lesions were excised with a cold knife including 3 mm of clinically normal mucosa at the periphery. In group 2, the lesions were excised with CO2 laser in continuous mode, defocalized, with 15 mm of distance focus-lesion and a power setting of 5-15 W (5-15 seconds)  ; but in group 2 the wounds regeneration were by second intention healing.A VAS of 100 mm in length was used to evaluate the intensity of pain and swelling. This scale converted the visual analogical evaluation made by the patient into a numerical value: from 0 (corresponding to 0 mm on the VAS and showed no pain and no swelling) to 10 . Each patient was told how to use the VAS and was asked to mark the intensity of pain and swelling 12 and 24 hours after surgery and then on each day for the follow-ing 6 days. After the surgical intervention, 600 mg of Ibuprofen was prescribed every 8 hours for the first four postoperative days. Finally, the patients were revised at 7 days after treatment.-Statistical analysisData were analyzed using the SPSS version 12.0 statistical package . A descriptive study was made of each variable. The Kolmogorov-Smirnov normality test and Levene variance homogeneity test were applied, and the data showing a skewed distribution were analyzed using a nonparametric ranking test. The associations between the different qualitative variables were studied using Pearson’s chi-squared test. We used the Kruskal-Wallis test (for more than two samples), the Mann-Whitney U-test (for two independent samples) and the Wilcoxon test (for two related samples), for quantitative variables. A probability p£0.05 was accepted as significant.The mean sample age was 53.7 ± 11.7 years (range 28-74). As regards the oral leukoplakia risk factors, 39 of the 48 patients included in the study (81.3%) were cigarette smokers while 9 (18.8%) were non-smokers. Alcohol consumption was generally mild: social alcohol consumption (1 or 2 units per day) was recorded for 17 patients (35.4%), while 31 reported no alcohol intake (64.6%).With respect to the clinical presentation of the lesions, 46 were homogeneous leukoplakias and 2 were no-homogeneous leukoplakias.The lesions were distributed as follows: 10 in cheek mucosa (20.8%), 24 in gums (50%), 8 in palate (16.8%), 3 in tongue (6.2%) and 3 in floor of the mouth (6.2%).The two study groups (cold knife and CO2 laser) were homogeneous in terms of patient age (p=0.592), gender (p=0.461), location (p=0.257), extent of the lesions (p=0.072) and the presence of dysplasia (p=0.471) .The mean duration of follow-up was 27.90 ± 12.05 months (range 1-40) Fig. . In neitPain and swelling reported by the patients was greater with the cold knife than with the CO2 laser, with statistically significant differences between the two techniques during the first three days after surgery . Followed by a gradual decrease over one week in both groups .In the CO2 laser group, on comparing the median (range) pain scores (recorded at peak pain intensity: between 12-24 hours after surgery) and swelling scores (recorded at peak swelling intensity: between 12-48 hours after surgery), statistically significant differences were observed for pain (p=0.021) and swelling (p=0.019) with respect to lesion size .In turn, in the cold knife group, on comparing the median pain scores (recorded at peak pain intensity: 12 hours after surgery) and swelling scores (recorded at peak swelling intensity: 24 hours after surgery) no statistically significant differences were observed for the variables studied .The present study involves two groups of patients with oral leukoplakia: one subjected to conventional surgical treatment with a cold knife and the other to CO2 laser surgery. In both groups the postoperative pain and swelling were evaluated.The CO2 laser is currently accepted as the technique of choice in the management of many soft tissue lesions in the oral and maxillofacial regions. Compared to the scalpel, the CO2 laser affords a hemostatic effect particularly in highly vascularized areas. This in turn results in a clearer surgical field and therefore a reduction in operating time. Treatment with the laser has certain advantages, such as the selective removal of affected epithelium and minimal damage to surrounding healthy tissue, resulting in excellent wound healing with minimal or no scar tissue, and a good functional outcome -19. OtheIn our study, the patients with oral leukoplakias treated with CO2 laser showed a lower postoperative pain and swelling than the patients treated with a cold knife, with statistically significant differences during the first three days after surgery. None of the patients showed malignant transformation during the period of follow-up (27.90 ± 12.05). Nevertheless, Schoelch et al. , after sThe most important disadvantage of CO2 laser evaporation of oral leukoplakia is the fact that the lesion is not available for histological study, in this sense an incisional presurgical biopsy must be obtained in all cases. The location of the lesion therefore must be carefully chosen. If the lesion is large or shows different clinical aspects, more than one biopsy is recommended -20.One characteristic difference between the CO2 laser and cold knife is the generation of a coagulated tissue layer along the walls of the laser incision. This zone of thermal damage may impede the graft consolidation and reduce tensile strength during the period of wound healing, especially in extensive zones .Measurement of postoperative pain is inherently difficult, as it comprises both physical and psychological aspects. Subjectively, the true character of pain experience is not directly accessible to the examiner. Therefore, the examiner must rely on the patient’s ability to communicate his or her perception and interpretation of the pain. In the laser group, on comparing the pain scores (recorded at peak pain intensity: between 12-24 hours after surgery) and swelling scores (recorded at peak swelling intensity: between 12-48 hours after surgery), no statistically significant differences were observed in relation to age, gender, smoking habit, location of lesion or dysplasia presence. Nevertheless, statistically significant differences were observed with respect to lesion size, with more pain and swelling in the most extensive lesions. In this sense, Van de Hem et al. , after sThe main problem of oral leukoplakia is its possible malignant transformation, reported to occur in 1.2-9% of cases ,19,24. HIn an observational retrospective study published by Schepman et al.  comparedTo date, our experience with the surgical removal of oral leukoplakia has been satisfactory with both of the described techniques in this study. Nevertheless, the studied sample is small and the follow-up period brief. These limitations must be taken into account and studies involving larger patient series and regular follow-up over longer periods of time are needed in order to derive more reliable information on the role of invasive surgical resection in the prevention of oral cancer in patients with oral leukoplakia.In the present study, we found the CO2 laser to cause only minimal pain and swelling, thus suggesting that it may be an alternative method to conventional surgery in treating patients with oral leukoplakia.


Chronic pain is a medical condition that severely decreases the quality of life for those who struggle to cope with it. Interactive voice response (IVR) technology has the ability to track symptoms and disease progression, to investigate the relationships between symptom patterns and clinical outcomes, to assess the efficacy of ongoing treatments, and to directly serve as an adjunct to therapeutic treatment for chronic pain. While many approaches exist toward the management of chronic pain, all have their pitfalls and none work universally. Cognitive behavioral therapy (CBT) is one approach that has been shown to be fairly effective, and therapeutic interactive voice response technology provides a convenient and easy-to-use means of extending the therapeutic gains of CBT long after patients have discontinued clinical visitations. This review summarizes the advantages and disadvantages of IVR technology, provides evidence for the efficacy of the method in monitoring and managing chronic pain, and addresses potential future directions that the technology may take as a therapeutic intervention in its own right. During the past two decades, there has been considerable growth in the use of computer-mediated technologies for assessment and treatment. One such technology is interactive voice response (IVR), an automated telephone-based interface that provides patients and research subjects with direct access to pre-recorded questionnaires, educational materials, custom messages, and even therapeutic assistance . TypicalSome of the simplest and most common applications of IVR to clinical research are participant screening, study enrollment, and group randomization , 4. CompIn addition to passively using IVR to monitor ongoing medical conditions, IVR is also applied as an adjunct to medical treatment. For example, IVR has been employed to assist with weight loss and cholesterol management , to faciIVR has proved to be an extremely effective tool in the study of chronic pain, as well. Most patients with chronic pain experience periods of fluctuating symptom severity. Due to this variability, IVR can be a powerful monitoring tool in that patients are able to report symptom severity on an hourly, daily, weekly, or real-time event-contingent basis, allowing clinicians and researchers to control or, if utilized in a properly designed study, eliminate the influence of recall bias on perception of symptom severity. IVR is also useful for keeping track of medication need and adherence, efficacy and adverse side effects of medications, and effectiveness of ongoing therapeutic regimens. Overall, it has been clearly demonstrated that inclusion of IVR in chronic disease management has the potential to improve clinical outcomes while decreasing treatment-associated costs , 43. ThiThe major appeals of using IVR in clinical research are its convenience of remote access, high level of accessibility, and cost-effectiveness . TelephoUnlike traditional telephone interviews and written questionnaires, IVR systems are capable of collecting information and immediately storing it in a computer database without the need for labor-intensive clinician or researcher involvement , even foOne of the few difference observed between symptom reporting via IVR and in-person interviews is that some groups of subjects report an increased sense of anonymity that allows them to honestly disclose sensitive information to an automated system that they might be too embarrassed or otherwise unwilling to discuss face-to-face or via a written questionnaire , 50–53. Compared to in-person and live telephone surveys, IVR ensures consistent phrasing, pacing, and intonation of questions being asked, and negates any interviewer bias that might otherwise exist . IVR canResearch has shown that levels of IVR compliance tend to be relatively high. In two longitudinal studies utilizing daily reporting, participants placed calls more than two out of every 3 days when reporting on the severity of pain symptoms and medication usage , as wellOne of the most useful advantages of IVR systems is that they allow subjects to easily place reports in an event-contingent, real-time basis  or according to a specific schedule, both of which have advantages over reports placed retrospectively. These momentary and daily assessments result in more accurate reports than retrospective assessments, possibly by reducing or eliminating recall biases –66. PossSome disadvantages of IVR in research include the initial time and financial commitments required to write scripts, develop recordings, and acquire the necessary hardware and software to run an IVR system, as well to maintain equipment and back-up data over time . HoweverAnother major disadvantage of IVR is that some participants of low socioeconomic status or who live in remote regions may not have regular access to telephone service. There is evidence that cellular phone use is prevalent enough even in developing countries  to suppoWhile IVR compliance rates are high, they are not perfect. Sophisticated statistical techniques such as multi-level analyses , 70 are Another concern in IVR use for symptom monitoring is reactivity: high-frequency reporting might actually influence the severity of symptoms being reported. For example, some concern exists that frequent reporting of symptoms might result in rumination/catastrophizing regarding those symptoms, thereby increasing their severity , though One proposed weakness of IVR is the lack of personal interaction that comes with in-person interviews. Though this can actually be considered a strength when collecting sensitive information about socially unacceptable behaviors, depressed research subjects reported a stronger ability to describe their feelings during in-person interviews and rated interview experiences with clinicians higher than IVR . While cMost patients experience fluctuations in pain severity that last hours, days, weeks, or months. IVR technology allows patients to monitor and report the severity of their symptoms as frequently as desired or in real time on an event-contingent basis . Daily data concerning pain severity, negative affective components of pain, and the deleterious effects of chronic pain on day-to-day life can be monitored to create a bigger picture of the progression of the disorder on a short-term and longitudinal basis.IVR has been utilized to track changes in the severity of pain symptoms and treatment outcomes in patients with both short-term  and chroIVR is also a useful tool for tracking changes in symptom presentation over extended periods of time , 74, 75.These findings are important because they provide insight into the relationships between negative emotions and pain, and suggest that therapeutic interventions for chronic pain might be effective in reducing both pain severity and negative emotions. The novel use of IVR to perform accurate symptom monitoring may extend the gains of chronic pain treatment by providing regular and/or real-time assessments of the chronic pain progression and its relationship to mood, stress, and coping. Taken one step farther, IVR is also a useful tool for gauging the efficacy of ongoing treatments.As useful a tool as IVR is for monitoring symptom status and pain progression under normal daily circumstances, it is also a helpful tool for quantifying the effectiveness of ongoing treatments for chronic pain. IVR is utilized during pharmaceutical trials in order to track pain symptoms, negative emotions associated with pain, and adverse side effects of specific medications , 79–81. The effectiveness of therapeutic interventions such cognitive behavioral therapy and coping skills training for treating chronic pain disorders has been known for some time , 84–92. Patient use of CBT skills over time tends to decline once CBT has ceased, and treatment gains accomplished by CBT are not maintained if patients stop using coping skills , 95–97. This specific TIVR regimen consists of four components: 1) automated access to self-monitoring of symptoms, (2) didactic review sessions of coping skills, (3) guided behavioral rehearsals of pain management skills, and (4) personalized encouragement and reinforcement. The relationship between these four components of TIVR and their roles in relapse prevention are outlined in Fig.  automateSymptom self-monitoring is comprised of a daily questionnaire to assess levels of pain, mood, and stress, use of pain medications, and a variety of other parameters. Didactic review sessions and guided behavioral rehearsals are offered for eight different coping skills learned previously during group therapy such as relaxation techniques, cognitive skills, activity–rest pacing, and reappraisal of pain. This variety of coping techniques ensures that patients are aware of multiple options for coping with pain, an important part of the relapse prevention model , 99. TheThe relapse prevention model suggests that this regular monthly feedback, which simulates the weekly feedback provided during the initial CBT training, likely helps patients to gauge their progress and recognize successes and problems in coping with difficult situations . The perAfter 4 months of TIVR, patients reported that the method reinforced the skills that they learned during face-to-face CBT, enhanced their motivation to continue using coping skills, and provided structure that helped the new skills become habits , 71. TheSince TIVR was first demonstrated to be an effective adjunct to therapy for chronic pain, a similar system was employed to treat pain and other symptoms in cancer patients . In thisCurrent research is being conducted to test the hypothesis that TIVR without personalized monthly messages from a therapist can be as effective as with monthly messages. If confirmed, the TIVR method would become even more affordable to the general public. Because some patients might benefit from using a more visual interface than that provided by IVR, further investigation is required to determine whether the effectiveness of TIVR could be further improved by adaptation to an internet-based approach. Such an approach could include pre-recorded visual interactions with an actual or simulated therapist, or even just written text presented simultaneously with pre-recorded messages/questions. It would even be possible to incorporate video communication into this type of approach, allowing for both automated and live interactions with a therapist. Adaptation of TIVR to a smartphone application is another possible next step for this emerging technology. This would allow both the visual interactions that are currently achievable via the internet as well as the convenience of accessing the IVR system using a portable, hand-held device.Another possibility that merits further investigation is whether IVR as a therapeutic intervention is effective enough to actually replace CBT for people who cannot afford therapy or for whom CBT is unavailable. Overall, IVR has so far proven to be an effective, convenient, inexpensive, and reliable method for monitoring symptom severity, tracking treatment progress, and for extending the therapeutic gains of clinical interventions for chronic pain. As technology improves, and as more questionnaires, surveys, and therapeutic interventions are adapted for automated administration, IVR will likely play an increasingly important role in both clinical research and treatment regimens for patients with many different psychological and physiological disorders. We therefore recommend that IVR-based treatment approaches be employed by multidisciplinary clinics and practitioners who treat patients with chronic pain. Further, as IVR-based interventions are clinically beneficial, versatile, and cost-effective; we advise that policymakers endorse insurance coverage of IVR for pain management as part of comprehensive treatment plans.


P < 0.001). Similarly, significantly more patients reported total migraine freedom at 2 h after rizatriptan (51 %) than after placebo (8 %) . Rizatriptan was also more effective than placebo on most secondary endpoints. We confirm in a placebo-controlled study our previous data suggesting that the presence of unilateral cranial autonomic symptoms in migraineurs predicts a positive response to triptans, probably owing to intense trigeminal peripheral afferent activation which strongly recruits peripheral neurovascular 5-HT1B/1D receptors. Acute and preventive pharmacological trials in migraine should focus also on this subset of migraine patients.The objective and background is to confirm in a double-blind, placebo-controlled study the high triptan response rates we had previously reported in an open study in migraine patients with unilateral cranial autonomic symptoms. In this randomized, double-blind, placebo-controlled study 80 migraineurs with unilateral cranial autonomic symptoms were assigned to receive rizatriptan 10 mg wafer or placebo (ratio 1:1) and treated for a single moderate or severe migraine attack. The primary endpoints were pain freedom at 2 h and total migraine freedom at 2 h. Secondary endpoints included pain relief, no associated symptoms and sustained pain freedom or relief. Significantly more patients reported pain freedom at 2 h after taking rizatriptan (54 %) than after placebo (8 %) (therapeutic gain 46 % ;  Migraine pain depends on trigeminovascular system activation that induces vasoactive neuropeptide release from trigeminal perivascular axons leading to neurogenic inflammation that stimulates meningeal sensory fibers and transmits nociceptive information centrally, along the trigeminal axons, to the trigeminal nucleus caudalis, and from there rostrally to the thalamus and cortex . In someIn an open study with sumatriptan 50 mg, we previously suggested that UAs in migraineurs may predict a positive response to triptans . The comIn this study, to find out more about triptan response rates in patients with UAs, in a randomized, double-blind, placebo-controlled, parallel-group study we used oral rizatriptan 10 mg, one of the most commonly used and effective triptans , for acuFor this randomized, double-blind, placebo-controlled, parallel-group, outpatient study to assess the efficacy of rizatriptan 10 mg wafer in treating a single acute migraine attack in migraineurs with UAs, patients were consecutively recruited from our Headache and Pain Unit. Patients were eligible for the study if they were ≥18 years of age, had a history of migraine with or without aura for at least 1 year, and in the 2 months before screening had experienced 1–8 moderate or severe migraine attacks per month . Patientat least one of the following symptoms: unilateral conjunctival injection, lacrimation, nasal congestion/rhinorrhea, ptosis, eyelid swelling or forehead/facial sweating?” [Patients attended the hospital for a screening visit to assess eligibility and undertake physical examinations. The interview determined whether patients experienced UAs by asking the following question: “During the migraine attack do you also have eating?” . PatientThis protocol was approved by the institutional review board at San Raffaele Pisana Scientific Institute and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. All patients gave their informed consent prior to their inclusion in the study.>7 days after treatment to allow physicians to review the diary, assess medication compliance and monitor tolerability. Headache severity was recorded using a four-grade scale  at six time points, baseline (time of taking study drug) and at 0.5, 1, 1.5, 2, and 24 h thereafter. The presence or absence of associated symptoms  was recorded at the same time points as the headache severity ratings. For those patients who had pain relief (pain reduction to mild or none) or pain freedom (no pain) at 2 h, another variable recorded was the presence or absence of headache worsening (recurrence) within 2–24 h. In all patients we also recorded use of rescue medication within 24 h. Tolerability and safety were assessed by asking patients to report spontaneous adverse events (AEs).During the 24 h after taking the initial dose of study medication, patients recorded subjective assessments of pain severity, presence or absence of associated symptoms, use of rescue medication, and the onset of, if applicable, headache recurrence at specified time points in a paper migraine diary. Subjective adverse experiences were recorded in the diary and rated as mild, moderate or severe. Patients were asked to return to the study site as soon as possible and The primary endpoints were pain freedom at 2 h and total migraine freedom (pain freedom and absence of associated symptoms) at 2 h. Secondary endpoints were pain freedom at 0.5, 1 and 1.5 h, pain relief at 0.5, 1, 1.5 and 2 h; absence of nausea, photophobia and phonophobia at 0.5, 1, 1.5 and 2 h; 2–24 h sustained pain relief (pain relief from 2 to 24 h without rescue medication); and 2–24 h sustained pain freedom (pain freedom from 2 to 24 h without rescue medication).The random allocation sequence, including details of any restrictions was produced by Computer Generated Masked Allocation Schedule, Blocking Factor: 4. The allocation sequence was generated by the Pharmaceutical Research and Development Labeling System, Merck & Co., USA. Numbered containers were used to implement the random allocation sequence. The sequence was concealed until unblinding was necessary. The principal investigator assigned participants to the groups, following the masked allocation schedule numbers. All the participants, those administering the treatments and those assessing the outcomes were blinded to group assignment. The success of blinding was guaranteed using similar shaped containers and tablets and by the sealed masked allocation schedule.Sample size was calculated assuming that the therapeutic gain over placebo for migraineurs with UAs treated with rizatriptan 10 mg is similar to that reported in the general migraine population, i.e., 31 % pain freedom at 2 h and 33 % pain relief at 2 h [t test for continuous variables, and the Pearson’s Chi-square test (or Fisher’s exact test with expected cell frequencies <5 %) for categorical variables. A binomial regression analysis was run to test the effect of rizatriptan 10 mg versus placebo, and the therapeutic gain (defined as the change in outcome induced by rizatriptan 10 mg minus the placebo effect) with its relative 95 % confidence interval (CI), was estimated for all outcome measures. The absence of nausea, phonophobia and photophobia after treatment was analyzed in a subset of individuals who experienced these symptoms at baseline (when the attack began).The presence of heterogeneity between the two treatment groups according to demographic and baseline characteristics was assessed using the unpaired P value <0.05 was the threshold for statistical significance. To take into account the type I error inflation generated by multiple comparisons, the Bonferroni correction was applied (new threshold for type I error <5 %: P < 0.0019).To remove the effect of rescue medication, data were analyzed after excluding patients who took a rescue medication before the scheduled time point of outcome measurement. A STATA/SE V10 was used for all statistical analyses.Of the 100 outpatients screened, 10 failed to meet all the inclusion criteria, 1 declined to participate and 89 were randomly assigned to rizatriptan 10 mg wafer (45 patients) or placebo (44 patients). Four patients in the rizatriptan group and 5 patients in the placebo group were excluded from the efficacy assessment because they lacked a qualifying event      Table . All theThis randomized, double-blind, placebo-controlled parallel-group trial using rizatriptan confirms the results obtained in our previous open study using sumatriptan showing that the presence of UAs in migraineurs predicts highly positive response rates to triptans . DesigneThe distinctive finding in our study is the high therapeutic gain for both primary and secondary endpoints. Although our study was not designed to investigate whether migraine patients with UAs respond better to triptans than those without, it offers meaningful evidence-based data on outcomes for comparison. When compared with the therapeutic gain reported in two meta-analyses , 11 inveThe unexpectedly low placebo effect we found in this study is difficult to explain. Although age is a major variable predicting a placebo effect, patients over 50 years of age being less likely to respond to placebo and more likely to respond to rizatriptan , in our When we screened for UAs in the migraineurs recruited for the study, some reported UAs spontaneously whereas others reported them only after specific questioning. UAs are more frequent in patients with migraine than might be believed. A population-based study using combined postal mail and telephone interviews showed that 26.9 % of migraine patients report at least one of the UAs during their migraine attack regularly, whereas a survey with face-to-face interviews in a headache center discloses UAs in 45.8 % of migraineurs , 4. The A plausible explanation for our patients’ remarkable response to rizatriptan is that intense trigeminal peripheral afferent activation or sensitization in migraine patients with UAs strongly recruits peripheral neurovascular 5-HT1B/1D receptors, those targeted by triptans. The greater headache severity in these patients presumably reaches the pain threshold above which the autonomic reflex discharges and triggers UAs. This hypothesis receives support also from the clinical finding that patients usually report experiencing UAs when their migraine headache peaks . The preOur study helps identify a more tailored strategy for treating acute migraine. The search for strategies to improve responsiveness to triptans, given that these anti-migraine drugs fail to achieve good results in many individuals when studies consider strong endpoints , identifies as a crucial issue treatment timing. Treating an attack early widens responsiveness to triptans in allodynic patients by preventing central sensitization from developing . Our finDespite its strong point as a randomized, double-blind, placebo-controlled pharmacological trial in migraine patients with UAs, our study has limitations, for example the lack of direct comparison between migraine patients with and without UAs and the fact that we did not enrol only triptan-naïve patients.In conclusion, migraine patients with UAs, a frequent yet often underdiagnosed category, are a clinically homogeneous migraine population who share a very good response to rizatriptan (and probably to other triptans) even when they use this drug to treat migraine headache that is already moderate or severe. We suggest that pharmacological trials for acute or preventive migraine medications should focus also on this subset of migraine patients.


Poorly controlled postoperative pain is a longstanding and costly problem in medicine. The purposes of this study were to characterize the acute pain trajectories over the first four postoperative days in 83 cardiac surgery patients with a mixed effects model of linear growth to determine whether statistically significant individual differences exist in these pain trajectories, and to compare the quality of measurement by trajectory with conventional pain measurement practices. The data conformed to a linear model that provided slope (rate of change) as a basis for comparing patients. Slopes varied significantly across patients, indicating that the direction and rate of change in pain during the first four days of recovery from surgery differed systematically across individuals. Of the 83 patients, 24 had decreasing pain after surgery, 24 had increasing pain, and the remaining 35 had approximately constant levels of pain over the four postoperative days. Intense pain typically follows surgical procedures, and the control of postoperative pain is still a major challenge –9. In 19Uncontrolled pain following surgery appears to be a risk factor for the development of chronic pain , 21, 22.Good pain control during recovery from surgery requires good pain measurement in the individual patient. Unfortunately, current pain measurement methods suffer from low precision due to unreliability in scores within individuals . MoreoveSeveral statistical approaches under the general rubrics of growth curve modeling , 28 multChapman et al.  use mixeThe purposes of this paper are to examine the acute pain trajectories over the first four postoperative days in cardiac surgery patients with a mixed effects model of linear growth to determine whether statistically significant individual differences exist in these pain trajectories, and to compare the quality of measurement by trajectory with conventional pain measurement practices.Y, for a given person is a function of two parameters: Y = bo + b1t, where bo is the intercept, and b1 is the slope. The variable t represents the point in time at which the measurement occurred.The linear trajectory has two principal features: intercept and slope. The intercept is the level of the pain at the possibly hypothetical time zero assessment point. The second feature, slope, represents rate of change per unit assessment interval. This is the rate at which the pain problem resolves or, in the case of some patients, worsens. Expressed algebraically, the pain score, From a quantitative modeling perspective, a pain trajectory is a type of growth curve, in which growth can be either positive or negative , 32–34. The classical approach to measurement assumes that the individual patient is the only relevant source of information about pain magnitude. It is possible, however, to estimate individual pain levels more precisely by incorporating knowledge about other individuals from the population. Donaldson and Moinpour have presented a general approach to measurement of individual treatment responses in clinical studies that yield repeated assessments on the same individuals . In thisBroadly speaking, the individual predictions of change or growth are “measurements” that usually prove superior to classical measures of each patient at each time. Individual trajectories predicted by linear mixed models resemble those for trajectories based exclusively on individual data but are somewhat more precise because they compensate for unreliability inherent in collecting small samples of data from each patient. In the analyses below, we treat the estimated individual trends as constituting the measurements of the underlying postoperative pain processes. The linear mixed model approach is a statistically efficient method for integrating individual and population responses in a single analysis. Similar, though less precise, conclusions would result from obtaining individual trend coefficients for each patient, one at a time, and treating these as measurements of the patients.At the Chaim Sheba Medical Center in Tel Aviv, Israel, R. Zaslansky and A. Shinfeld obtained and de-identified pain measures from patients after midsternotomy cardiac surgery. Inclusion criteria included midsternal surgery, extubation, and ability to communicate on the first postoperative day. The Chaim Sheba Medical Center Institutional Review Board approved the project. Patients ranged in age from 23–92 years, with a median of 67. Of the 83 patients, 18 were female. Most patients underwent either coronary artery bypass graft surgery or atrial or mitral valve replacement. The primary objective in collecting the data was to assess pain levels and pain medications prior to development of a pain treatment protocol. Patients spent 1 to 2 days in the Cardiac Intensive Care Unit and thereafter transferred to the Cardiac Surgery Ward, where they stayed until discharge. All patients remained in hospital for five or more days after surgery.A single research nurse, trained for the task, collected data from all patients at approximately noon each day, repeating assessment for the first 4 postoperative days. She used a five-category Category Pain Scale (CPS): no pain, mild, moderate, severe, unbearable pain. To evaluate pain during movement, the nurse asked patients to take a deep breath during the first two postoperative days  and to cough during the third and fourth postoperative days .Examination of the data on a patient-by-patient basis suggested that patients used the CPS as though the rating categories were equally spaced. An ordinal logistic regression of pain scores on postoperative day provided threshold estimates for the categories, which supported this impression. The distances between the threshold estimates were approximately equal across the range of the CPS. Because the patients used the CPS as though the categories were equally spaced, we treated the CPS ratings as numbers on an interval-level scale. Translated for convenience to numbers on a more familiar 10-point scale, the scores were 0, 2.5, 5, 7.5, and 10. This linear transformation did not distort the data in any way, nor did it alter precision of measurement.We analyzed the data using a linear mixed effects models approach to change trajectories , 36. Bas The mixed effects approach allows each combination of fixed effects to have its own average trajectory, and each patient to have a unique trajectory about the fixed-effects averages. An advantage of mixed-effect models is that, by including both random and fixed effects, they address multiple sources of variation. After allowing for fixed effects, the approach takes into account residual systematic between-subject variation and distinguishes these systematic individual differences from measurement and other error. Another advantage is that such models, unlike conventional longitudinal methods, can accommodate many patterns of systematically missing repeated measures data without bias.Patients received modest amounts of medication for pain control that included intravenous morphine, oxycodone/acetaminophen tablets, and metamizole. To estimate the potential influence of analgesic medication on pain scores for each postoperative day, we examined intravenous morphine usage on a 24-hour basis, converted 24-hour oral oxycodone intake to its intravenous morphine equivalent, and summed the two to obtain an index of daily opioid intake in intravenous morphine units.On the first postoperative day, 98% of patients received opioid medication, and the 24-hour mean morphine intake was 7.18 mg. On the second postoperative day, 78% of patients received opioids, and the mean 24-hour intake was 3.54 mg. Seventy-three percent of the patients received opioids on the third postoperative day and 66% on the fourth postoperative day, with a mean intake of 3.21 mg for each day. There was no statistically significant relationship between opioid intake and pain scores on any of the four postoperative days. Analgesic medication use did not distort the pattern of pain reports.P = .018). This analysis, after adjusting for random error, revealed significant (P < .0001) variation in the true slopes across individuals (estimated standard deviation = .48). This effect indicates that the patients in our sample do not reflect a homogeneous population sharing a similar trajectory but instead vary systematically about the population average of −.28 with a typical person differing by .48 pain points per day. Thus, a typical patient might have an average pain decline as steep as −.76  (−.28 − .48) points per day, or an increase of  .20  (−.28 + .48) points per day. Approximately, 95% of the patients fall within the range defined by an improvement of 1.24 points per day and worsening by  .68 points per day. Variation in observed pain trajectory across the postoperative course includes a pure error component (error variance = 4.34) and also reflects systematic variation due to true differences across individuals. The systematic differences are large; the typical person-to-person difference in slopes  is more than twice as large as the average slope difference from zero. The individual differences dominate the average difference.To evaluate the systematic individual differences in the sample pain trends, we allowed slopes to vary across individuals as a random factor in a mixed effects analysis, , 30, 35 We examined the estimated slopes for important individual differences in pain trajectory. To classify patients more rigorously, we formed 50% confidence intervals for the mixed model predicted  individual slopes and evaluated whether the intervals contained zero . Patientσ is the standard deviation of the measurement and ρyy′ is its reliability. The SEM thus increases with variability among the scores and decreases with the reliability of the assessment.The standard error of measurement (SEM) of an assessment gives the typical deviation of an obtained score about the true underlying quantity for that person. Smaller SEMs indicate more precise measurement because typical observations are closer to their true values. The SEM of an assessment is In our data, independent psychometric criteria suggest that the reliability for the daily pain assessment falls within the range of  .25–.53, values that are quite low by conventional measurement standards. However, an estimated reliability of  .50 for our data is generous. Independent analyses, including an item response theory model that does not assume linearity or interval-level data, confirm that the reliability at the first assessment is about.06, while the reliabilities at the remaining assessments are approximately.4. Under the best scenario, the typical error of measurement is about 1.70 on a 0–10 pain scale for such patients. To have 95% confidence that a single score obtained on a single day contains the true value, one can construct intervals that extend approximately two SEMs on either side of the measured value. For example, the 95% confidence interval for a pain score of 4 is, therefore, 4 ± 3.4: the patient's true score might be as low as 0.6, which does not require intervention, or as high as 7.4, which would merit aggressive medication. A large SEM in pain measurement thus compromises the ability of even the most skilled clinician to control pain.tj is given by the standard error of estimate for regression: T is the total number of time points for the patient. The average of this prediction error was 1.31, substantially less than the equivalent value of 1.70 for treating the observations as single measures. This gain in precision derived from incorporating a model for all the data for the individual, not just the single observation. The mixed model estimates, which are optimized, obtain somewhat greater gain in precision.We evaluated the gain in measurement precision from estimating individual slopes directly versus treating each time point as a separate measurement. Using ordinary least squares regression for a single patient, the estimated error in predicting the expected value of the patient's pain score at time Examination of changes in pain over days revealed more striking gains in precision. The SEM for the difference in pain report between two time points is 41% higher than the SEM for the static assessment. The SEM for the change in measured pain between any two days is 2.40. For the linear model-based approach, the expected error in estimating the change in an individual's expected pain level varies with the temporal distance:.58 for adjacent days, 1.16 for two-day separations, and 1.74 for three-day separations. Thus, for any change, the error is much less than the measurement error of the difference between two assessments considered statically. As in the comparison of individual time points, important gains in precision derive from assuming a model of the postoperative pain process and estimating features of the process rather than individual daily scores. To avoid obscuring this main point, we presented the above comparison based on standard within-person measurement. The mixed model estimate, which is also optimized, actually yields somewhat greater gains in precision than our example indicates.Although it is sometimes convenient for researchers to treat unexplained variation across patients in pain scores as random variations about a population mean, this does not help clinicians, who must treat patients one at a time and for whom hardly any patient closely resembles the estimated mean of the population. For most experienced clinicians, there is no question that people differ in pain following a common tissue trauma; the only question is whether they differ randomly or in some meaningful way. The commitment to measure pain as an individual clinical outcome signifies acceptance that these outcomes can differ reliably across patients; but how well can we measure these differences that we know are real? Pain measurement is the scaling of phenomenal awareness through introspection and report, and this is at most an approximate marker of nociception. Because introspection originated with Fechner and the field of psychophysics , most clThe practical limitations of current pain measurement methods contribute to the high variability in pain ratings, both across and within individuals. One fundamental problem is that not all patients can engage in meaningful introspection and scaling. Another is that the anchors at the upper end of pain scales always have unique meanings for individual patients. For example, “pain as bad as it can be” depends on personal experience and can change with new experience. It may mean a broken leg to one patient, childbirth to another, and a migraine headache to yet another. Consequently, the standard measurement tools scale everyone differently. Experienced clinicians invariably say that a score of “7” from patient X does not mean the same thing as the score of “7” from patient Y, and yet clinicians and researchers treat such scores as though they are in fact the same.If we treat individual variation in pain scoring as random error, then this variation will cancel out when we average scores over individuals in a large patient sample. Consequently, simple pain ratings often prove informative in clinical trials that examine means. Addressing chronic pain, Rodgers et al. made a cogent point: conventional pain reports work adequately for making group comparisons, but they are not precise enough to indicate, with confidence, how much pain an individual is experiencing . This prConventional approaches to postoperative pain management focus on controlling immediate pain without regard to controlling the process behind it. In the United States, the Joint Commission for the Accreditation of Health Care Organizations (JCAHO) has introduced standards for the assessment and management of pain in accredited hospitals and other health care settings . JCAHO pThe concept of pain trajectory suggests that the slope of the trajectory, and not the daily score, should be the target of pain control intervention. Our findings indicate that, in at least some postoperative patient populations, significant patterns of individual difference exist in pain trajectories, and clinicians managing postoperative pain should identify such differences as they emerge and treat patients accordingly.First, although this study succeeded in demonstrating significant individual differences within a sample of postoperative patients, we did not obtain additional measures that might allow us to characterize the patients within each of the different patterns of postoperative pain resolution, and this reduces the clinical utility of our findings. Numerous studies have attempted to account for postoperative pain intensity and the abnormal persistence of postoperative pain on the basis of patient pathogenic and demographic factors , 42, 43,Second, in this study, we could follow patients for only four days, and this modest number of repeated measurement occasions constrains measurement precision. In a previous study with over 500 patients, we examined postoperative pain trajectories for six days , and in Finally, a linear growth curve model works well for some types of acute pain resolution, especially postoperative pain. However, many forms of acute pain are unsuitable for linear modeling. Some pain states come on slowly, peak, and then resolve gradually. Examples include oral mucositis resulting from anticancer interventions and most headaches. Other acute pains such as menstrual cramping, toothache and the vaso-occlusive pain of sickle cell crisis are irregular and inconsistent across individuals. Pain associated with nephrolithiasis results from a moving and changing noxious stimulus, and pain resolution is unlikely to follow a linear pattern. Therefore, although a linear approach seems to work for postoperative pain, we do not advocate modeling all acute pain with a linear fit. Latent growth curve modeling can use nonlinear trajectories to quantify both systematic change over time and interindividual variability in this change.Acute postoperative pain is a dynamic process, and its assessment requires longitudinal measurement. Growth curve modeling of acute pain trajectories reveals that the rate of acute pain resolution is an informative outcome measure that can reveal statistically significant and clinically meaningful individual differences. The common practice of evaluating postoperative pain by using a single measure obtained on the first postoperative day can prove misleading, as a substantial number of patients report low pain initially that steadily worsens as time passes.


Disease remission has become a feasible goal for most rheumatoid arthritis (RA) patients; however, patient-reported symptoms, such as pain, may persist despite remission. We assessed the prevalence of pain in RA patients in remission according to the Disease Activity Score (DAS28-CRP4) and the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission criteria.Data were analyzed from RA patients in the Brigham Rheumatoid Arthritis Sequential Study with data at baseline and 1 year. DAS28 remission was defined as DAS28-CRP4 <2.6. The ACR/EULAR remission criteria included (a) one or more swollen joints, (b) one or more tender joints, (c) C-reactive protein ≤1 mg/dl, and (d) patient global assessment score ≤1. Pain severity was measured by using the pain score from the Multi-Dimensional Health Assessment Questionnaire (MDHAQ). The associations between baseline clinical predictors and MDHAQ pain at baseline and 1 year were assessed by using multivariable linear regression.P ≤ 0.0005) and longitudinal analyses (P ≤ 0.03). Low swollen-joint counts were associated with high MDHAQ pain in longitudinal analyses (P = 0.02) but not cross-sectional analyses. Other measures of inflammatory disease activity and joint damage were not significantly associated with MDHAQ pain at baseline or at 1 year.Among the 865 patients with data at baseline and 1 year, 157 (18.2%) met DAS28-CRP4 remission criteria at both time points. Thirty-seven (4.3%) met the ACR/EULAR remission criteria at baseline and 1 year. The prevalence of clinically significant pain (MDHAQ pain ≥4) at baseline ranged from 11.9% among patients meeting DAS28-CRP4 remission criteria to none among patients meeting ACR/EULAR remission criteria. Patient global assessment, MDHAQ function, MDHAQ fatigue, MDHAQ sleep, and arthritis self-efficacy were significantly associated with MDHAQ pain in cross-sectional (Clinically significant pain continues among a substantial proportion of patients in DAS28 remission but not among those in ACR/EULAR remission. Among patients in DAS28 remission, patient global assessment, disability, fatigue, sleep problems, and self-efficacy are strongly associated with pain severity at baseline and 1 year, whereas inflammatory disease activity and joint damage are not significantly associated with elevated pain severity at either baseline or 1 year. Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes significant pain and disability. Sixty-eight percent of RA patients rate pain as their highest priority for improvement, and 90% of RA patients rate pain as one of their top three priorities . With thIn a study of Disease Activity Score DAS28) remission in the Arthritis and Rheumatology Clinic of Kansas and the Rheumatoid Arthritis Evaluation Study databases, mean and median pain scores were 2.43 and 1.50 on a 0-to-10 visual analogue pain scale [ remissioPresented with a patient with tender joints and/or pain but no other evidence for inflammatory disease, physicians must decide whether to escalate or add other disease-modifying therapy. If they decide not to increase immunomodulation, they are left with the dilemma of how to address the pain. Currently, very little data exist to guide this treatment decision. The American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) consensus conference for the definition of remission recognized the potential impact of non-inflammatory causes of pain and called for studies to investigate the role of non-RA pain among patients in remission .In this article, we examine the prevalence of clinically significant pain among RA patients in remission according to the DAS28-CRP4 and the ACR/EULAR criteria. Among patients who met the DAS28-CRP4 criterion for remission, we also assess whether pain severity is associated with inflammation or other factors, such as fatigue and sleep problems, which may be indicative of a non-inflammatory chronic widespread pain syndrome.The primary cohort includes the 157 RA patients in the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) who met DAS28-CRP4 remission criteria ,11 at boThe DAS28-CRP4 was calculated from the tender-joint count, swollen-joint count, C-reactive protein (CRP), and patient global assessment . DAS28-CParticipants provided demographic and clinical information, including detailed lists of comorbidities and medication histories. A modified Charlson comorbidity index was constructed by using available data . HemipleSamples of blood were collected for a standard laboratory panel, including the CRP. Baseline hand radiographs were obtained, and Sharp scores were calculated based on joint-space narrowing and erosions. A physician performed a 28-joint count and assessment of disease activity. Participants also completed the MDHAQ, Mental Health Index-5 (MHI5) and the Arthritis Self Efficacy Scale (ASES). The MDHAQ is a validated instrument that includes assessments of pain, fatigue, and function, scored on 0-to-10 scales  . SpecifiMeans and standard deviations (SDs) were calculated for normally distributed variables. Median values and interquartile ranges (IQRs) were determined for variables that were not normally distributed. Continuous independent variables were categorized based on tertiles.To examine the prevalence of pain, clinically significant pain was defined as an MDHAQ pain score ≥4. This threshold was determined based on literature reports requiring pain-severity levels ≥4 of 10 or 40 of 100 for inclusion in clinical trials of pain medications to treat painful conditions, including arthritis .Multivariable associations between baseline clinical variables and baseline MDHAQ pain score were examined by using multivariable linear regression. All multivariable models were adjusted for age and gender. The same methods were used to examine the longitudinal relation between baseline clinical variables and 1-year pain severity, except, in the primary multivariable analyses, baseline MDHAQ pain score was also included as a covariate. Secondary analyses were also conducted, adjusting for age and gender but excluding baseline MDHAQ pain score as a covariate. All statistical analyses were performed by using the SAS 9.2 software package .At baseline, the prevalence of DAS28-CRP4 remission was 24.9%, and the prevalence of ACR/EULAR remission was 8.8% among the 1,118 individuals in the BRASS cohort. The prevalence of remission did not differ significantly between those with 1-year follow-up data  and those who were lost to follow-up .Among the 865 patients with both baseline and 1-year data, 157 (18.2%) patients remained in sustained DAS28-CRP4 remission at both baseline and 1 year  were female patients  and MDHAQ function scores (P < 0.0001) were the only disease-related variables significantly associated with high baseline MDHAQ pain scores (Table P < 0.0001) and the MDHAQ sleep-problems score (P = 0.0005) were strongly associated with high baseline MDHAQ pain scores. Lower ASES scores (P = 0.0005) and MHI scores (P = 0.004) were also significantly associated with high baseline MDHAQ pain scores.In multivariable analyses adjusted for age and gender, baseline patient global assessment ratings (es Table . SwollenP = 0.008), disease duration (P = 0.02), and patient global assessment (P = 0.03) were the only disease-related variables positively associated with MDHAQ pain scores at 1 year. Baseline swollen-joint count was negatively associated with MDHAQ pain scores at 1 year (P = 0.02). Baseline MDHAQ fatigue score (P = 0.0001), MDHAQ sleep-problems score (P = 0.001), and ASES score (P = 0.01) were all significantly associated with 1-year MDHAQ pain score (Table P < 0.0001).In multivariable analyses adjusted for age, gender, and baseline MDHAQ pain score, baseline MDHAQ function score  , and MDHThe association between disease duration and 1-year MDHAQ pain may reflect joint damage that accrues with increasing disease duration, or it may reflect time-dependent changes in pain processing that lead to a hyperalgesic state. However, disease duration was not significantly associated with baseline MDHAQ pain. This finding weakens the argument that disease duration acts as a proxy for joint damage and raises the possibility that the association between disease duration and 1-year MDHAQ pain may be attributable to chance. Alternatively, these observations are compatible with the hypothesis that increased pain is due to a hyperalgesic state, such as fibromyalgia, that is established and/or enhanced between the baseline and 1-year visits.The strong association between baseline fatigue, sleep problems, poor self-efficacy, and baseline and 1-year pain severity also supports the existence of an enhanced, non-inflammatory pain state among these patients with pain despite DAS28-CRP4 remission. Fatigue, sleep problems, and poor self-efficacy are part of a noninflammatory symptom cluster associated with "symptom intensification" syndromes -28. ThesLimitations of this study include the use of the DAS28-CRP4 threshold of 2.6 as the primary criterion for remission. Although the DAS28-CRP4 remission criterion is the most commonly used definition for remission, it is not a perfect measure of inflammatory disease activity. Critics have noted that the DAS28-CRP4 remission threshold of 2.6 permits patients to have multiple tender and swollen joints . In thisIn recognition that the DAS28-CRP4 remission criterion may be too permissive of residual inflammation, we also examined the prevalence of clinically significant pain among patients meeting 2010 ACR/EULAR remission criteria. The prevalence of clinically significant pain in this group was much lower, none at baseline and 5.7% at 1 year. This low prevalence is likely due to the ACR/EULAR criterion limiting the patient global assessment score to ≤1. Because the patient global assessment is heavily influenced by pain , this crAn additional limitation of this study is the homogeneity of the study population. The study was conducted at a single academic center, and 93.6% of this population was Caucasian. Other studies have reported higher rates of pain among racial minorities , and assPain continues to persist in a substantial subgroup of patients who meet the DAS28-CRP4 threshold for remission, whereas nearly all patients with clinically significant pain are excluded by the ACR/EULAR remission criteria. Among RA patients who meet the DAS28-CRP4 threshold for remission, pain was not associated with inflammatory markers and did not diminish despite continued control of inflammation over a 1-year period. Pain was associated with fatigue, sleep problems, and self-efficacy. These findings stress the importance of assessing alternative causes of pain and modifying therapy to address specific modulators of pain, rather than assuming that pain is an indicator of inflammation that should be treated by increasing immunosuppressive therapies.ACR: American College of Rheumatology; ASES: Arthritis Self Efficacy Scale; BRASS: Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study; CRP: C-reactive protein; DAS28: disease activity score in 28 joints; DAS28-CRP4: disease activity score in 28 joints calculated by using CRP and patient global assessment; DMARD: disease-modifying antirheumatic drug; EULAR: European League Against Rheumatism; IQR: interquartile range; MDHAQ: Multi-Dimensional Health Assessment Questionnaire; MHI5: Mental Health Index-5; RA: rheumatoid arthritis; SD: standard deviation.YCL has stock in Merck, Novartis, and Elan Corporation and has a research grant from Forest. NAS receives research grant support from Biogen Idec, Crescendo Biosciences, and Amgen. MEW receives support from Biogen Idec and Crescendo Biosciences. DHS receives research support from Abbott and Amgen. No other authors have competing interests.YCL conceived the hypothesis for the manuscript, participated in data collection, conducted the initial statistical analyses, wrote the first draft of the manuscript, and had primary responsibility for the manuscript process. JC, BL, and MLF contributed to data management and statistical analyses. CKI, NAS, and MEW participated in the design of the study and the interpretation of data. DHS participated in study design and analysis and interpretation of data. All authors critically reviewed, contributed to, and approved the final manuscript. All authors read and approved the final manuscript.