Cognitive behavioral therapy is known to improve the management of chronic pain. However, the components of this therapy are still being investigated and debated.This study aimed to examine the effectiveness of an integrated cognitive behavioral therapy program with new components  delivered via videoconferencing.This study was unblinded and participants were recruited and assessed face-to-face in the outpatient department. We conducted a randomized controlled trial for chronic pain to compare 16 weekly videoconference-based cognitive behavioral therapy (vCBT) sessions provided by a therapist with treatment as usual (TAU). Thirty patients  with chronic pain were randomly assigned to either vCBT (n=15) or TAU (n=15). Patients were evaluated at week 1 (baseline), week 8 (midintervention), and week 16 (postintervention). The primary outcome was the change in pain intensity, which was recorded using the numerical rating scale at 16 weeks from the baseline. Secondary outcomes were pain severity and pain interference, which were assessed using the Brief Pain Inventory. Additionally, we evaluated disability, pain catastrophizing cognition, depression, anxiety, quality of life, and cost utility.P=.36), there was a significant improvement in the comprehensive evaluation of pain by total score of Brief Pain Inventory . Further, significant improvement was seen in pain interference by using the Brief Pain Inventory  and in disability by using the Pain Disability Assessment Scale  compared with TAU. As for the Medical Economic Evaluation, the incremental cost-effectiveness ratio for 1 year was estimated at 2.9 million yen  per quality-adjusted life year gained.In the eligibility assessment, 30 patients were eventually randomized and enrolled; finally, 15 patients in the vCBT and 14 patients in the TAU group were analyzed. Although no significant difference was found between the 2 groups in terms of changes in pain intensity by the numerical rating scale scores at week 16 from baseline (The findings of our study suggest that integrated cognitive behavioral therapy delivered by videoconferencing in regular medical care may reduce pain interference but not pain intensity. Further, this treatment method may be cost-effective, although this needs to be further verified using a larger sample size.University Hospital Medical Information Network UMIN000031124; https://tinyurl.com/2pr3xszb Global reports indicate that chronic pain affects an estimated 20%-50% of people -4. The CCognitive behavioral therapy (CBT) is a structural intervention that encourages the transformation of a patient’s cognition and behavior and directly addresses major psychological problems associated with chronic pain, such as repetitive ideation, concerns, emotions, and behaviors. CBT is recognized and recommended as an effective treatment for managing chronic pain . The latThe use of remote treatment across the internet has been increasing and its effectiveness has been demonstrated for various intractable diseases -14. InteOnly a few studies have examined the effectiveness of videoconference-based CBT (vCBT), which is face-to-face CBT using a videoconference system and not a general internet-delivered CBT for chronic pain management -26. The This study was designed as a prospective randomized unblinded pilot trial comparing vCBT as the intervention group to TAU as the control group at the academic outpatient clinic of the Cognitive Behavioral Therapy Center at Chiba University Hospital. Patients with intractable chronic pain, aged 18-75 years, were randomized and enrolled in one of the two groups. The intervention period was 16 weeks for both groups. The vCBT group received 1 weekly session of an integrated CBT program in addition to regular medical care. The TAU group continued outpatient consultation more than once for 8 weeks. For primary and secondary outcomes, patients were evaluated at week 1 (baseline), week 8 (midintervention), and week 16 (postintervention).Although it is difficult to define intractable chronic pain, it is considered “drug-resistant” because almost all patients with acute pain receive pharmacotherapy. A review of evidence-based clinical trial designs for chronic pain pharmacotherapy states that “regulatory agencies such as the United States Food and Drug Administration and European Medicines Agency require studies of 12-weeks duration for chronic pain such as neuropathic pain to demonstrate the durability of response” . AnotherThis study was conducted with the approval of the Institutional Review Board of the Chiba University Hospital . In addition, the Clinical Research Ethics Review Committee oversaw the proper implementation of the test at least once a year. The trial registration number was University Hospital Medical Information Network UMIN000031124. The patients willing to participate in this study were informed of the study objectives and were asked for their consent to participate. Each patient was informed that participation was voluntary and full anonymity would be provided. Each patient was required to provide written consent for participation.We recruited participants through web-based and newspaper advertisements from April 2018 to November 2019. Patient recruitment was announced by the doctors at outpatient clinics in the Department of Orthopedics and Pain Anesthesiology at Chiba University Hospital and in all medical institutions in the Chiba prefecture as well. All recruitment materials referred patients to our study website, which explained the study in detail. All participants who gave their permission to be enrolled in the study were required to continue treatment with their general practitioners as TAU. Patients who were interested in the study could inquire about the details via email. This mail was also used as an application form to ask patients to record their age, sex, condition of chronic pain, contact information, and so forth.Written informed consent was obtained face-to-face from all patients after they were fully briefed on the procedure. Following this, a screening eligibility assessment for inclusion and exclusion criteria was performed. Participants were asked to record their pain intensity rated by the Numerical Rating Scale (NRS) daily for a week. Inclusion criteria were as follows: (1) fulfillment of the criteria of somatic symptom disorder, with predominant pain according to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), (2) age ranging from 18 to 75 years to avoid the risks from cognitive decline, (3) not showing moderate to remarkable improvement despite receiving sufficient pharmacotherapy for more than 8 weeks or due to poor tolerability, and (4) appropriate mental and physical conditions to maintain therapy. In the case of patients with depression or other anxiety conditions, they met the criteria to take part in the study if their pain was the primary impairment. The exclusion criteria were (1) comorbidity of serious mental disorders such as neurocognitive disorder, psychotic disorder, bipolar disorder, or substance-related disorder based on the criteria in DSM-5; (2) major pain caused by cancer; (3) if their pain did not interfere with their daily life ; (4) mental retardation, neurocognitive disorders (dementia), and autism spectrum disorder; and (5) litigation or compensation concerning pain symptoms. In this study, patients were required to be able to use a videoconferencing system at home. In case of patients who did not have an internet connection in their houses, we rented tablet computers and mobile Wi-Fi devices for them.The eligible patients were randomly assigned to either the vCBT group or the TAU group using the minimization method used in clinical trials to ensure a balance in pain intensity score and gender. Per the allocation adjustment factor, the pain intensity score on NRS was allocated at 6.3 for each group . The ranThe intervention period was from May 2018 to April 2020. In both groups, patients underwent 16 weeks of intervention and answered questions regarding primary and secondary outcomes at 1 week (baseline), 8 weeks (middle), and 16 weeks (post). All patients continued the regular medical care that they would normally receive as treatment. While participating in this study, no patient was permitted to seek any new treatment other than those that their primary care doctor ordered. In addition to regular medical care, those allocated to the vCBT group received weekly 50-minute sessions over 16 weeks of integrated CBT program using real-time internet videoconferencing. If the therapists or patients found it impossible to continue owing to adverse events, a gap of maximum 30 days during the intervention was permitted.The CBT program that we adopted is an integrated CBT program that is longer than conventional interventions and consists of several new sessions not used in traditional CBT protocols. Our developed protocol with face-to-face CBT sessions provided by the videoconference system (web-based CBT) has been shown to improve catastrophic cognition, disability, and mood . ConventTactile attention-shift training (session 4): Patients with chronic pain tend to demonstrate “attention bias.” Excessive attention causes patients’ pain to increase. Patients were trained to flexibly shift their attention. Furthermore, it has been found that pain may be relieved by gentle strokes that promote the secretion of oxytocin. This is referred to as the Science Touch method and suggests relief from chronic pain . AttentiMemory work based on the peak-end rule (session 10): With significant chronic pain, patients tend to consider their memory of pain to be worse than the actual intensity of the pain. This is because the memory of an intense pain experience is saved as a traumatic memory . The peaSharpening behavioral image training (session 11): We were inspired by sports training and poststroke rehabilitation ,35 to coVideo feedback (session 12): We developed this session in line with the principles of mirror therapy, a treatment used for phantom limb pain . In thisIn this study, we adopted the ISO 27001-certified Cisco WebEx as the internet conference system. Countermeasures against unauthorized access, information leakage, and others were taken, and safety problems were cleared.After enrollment, we assessed the baseline characteristics of the patient’s sex, age, education, marital status, comorbidity, employment status, age at onset of pain, duration of pain, and treatment history before they entered the intervention period shown in . The folAll adverse events were reported irrespective of their relevance to the intervention of this study, and serious adverse events were immediately reported to the institutional review board of the Chiba University Hospital and registered with the hospital risk management system as well. Moreover, an independent data monitoring committee accurately verified the detailed records of the clinical study’s progress, critical efficacy variables, and safety data.The primary outcome was the change in the pain intensity from baseline to week 16, as indicated by the NRS score. The NRS is a self-rated questionnaire that measures pain intensity on a scale of 0-10, where 0=nothing and 10=severe. Patients were made to keep a daily pain diary. They recorded (1) maximum pain throughout the day, (2) minimum pain, (3) usual pain, and calculated the weekly average for pain on the day of the session . Numerical values obtained by averaging the values in (1), (2), and (3) were taken as the main evaluation items comprising the composite value of NRS. The measurement has been shown to be reliable and valid .All secondary outcomes were measured at 8 weeks and 16 weeks from the baseline.Pain intensity: The secondary outcome was change in pain intensity  from baseline to week 8 on the NRS.Comprehensive pain score: Comprehensive pain was assessed with the Japanese translation of the Brief Pain Inventory (BPI) . BPI is Cognition related to pain: Catastrophizing one’s perception of pain was measured using the Pain Catastrophizing Scale (PCS). This scale has been shown to have high internal consistency (Cronbach α range .67-.87) . The PCSDisability: The degree of life disability due to pain was measured using PDAS. It is composed of 3 factors and supported by a high level of internal consistency (Cronbach α range .87-.95). It consists of 20 items on a 4-point Likert scale and is evaluated from 0 to 60 points, with a higher score indicating a higher degree of daily disability . The cliDepression and anxiety: Depressive symptoms were assessed with Beck’s Depression Inventory II and Patient Health Questionnaire-9 items (PHQ-9). BDI-II has an internal consistency of approximately .90, and the test-retest reliability ranges from .73 to .96. It consists of 21 items with 4 response statements designed to assess the severity of current symptoms of depressive disorders. The total scores on the measure range from 0 to 63. Scores below 10 are regarded as reflecting “minimal or no” depression, whereas score ranges of 10-18, 19-29, and 30-63 reflect “mild to moderate,” “moderate to severe,” and “severe” depression, respectively ,46. PHQ-Health-related quality of life: European quality of life 5-dimensions 5-level (EQ-5D-5L) is a widely applied, valid, and reliable measure of quality of life. Its reliability was shown by Cronbach alpha (.70) . EQ-5D-5All enrolled patients were asked to collect and submit receipts of their medical and drug expenses for chronic pain during this study (for 4 months). The incremental cost-effectiveness ratio (ICER) for the comparators vCBT versus TAU was estimated based on prepost evaluation (from baseline to 16 weeks), differences in medical costs, and effects of the condition. To estimate the cost utility of the intervention, quality-adjusted life years (QALYs) were calculated using the utility score of EQ-5D. To calculate the ICER, QALY values were calculated by multiplying one life year by the quality of life score. Quality of life scores were measured using the EQ-5D. We could not use quality of life scores 1 year (52 weeks) after the start of the intervention since the follow-up study had not been done. Therefore, we assumed that quality of life scores at week 16 could return to baseline at 1 year (week 52) as the minimum effect case. Conversely, we assumed that quality of life scores at week 16 could be the same as baseline at 1 year (week 52) as the maximum effect case.t test. As a result, the required number of subjects per group was estimated to be almost 20. In the main analysis, analysis of covariance (ANCOVA) with the allocation factor as the covariate was used, and the detection power was calculated to be 82%. As this study is a pilot study, the number of cases was determined based on its feasibility.In this study, we assumed that the difference in the amount of change in the NRS was 1.67 and the standard deviation was 1.8 and set the detection power to 80% and bilateral significance level to 5% in the two-sided All data were properly managed by the submitting the case report form to the Clinical Research Data Center. In this center, researchers entered all the data using an access-log-restricted data system, which could be verified, and they created data sets. Independent data monitoring committees were regularly held and they performed risk-based monitoring. After the intervention was finished, the responsible doctors confirmed their data sets and locked the data. Then the locked data were transferred to the Pharmaceutical Statistics Office of the Department of Clinical Trials, Chiba University Hospital.t test for continuous variables. The significance level was set at .05. For the primary analysis of comparing treatment effects, the means of the least squares and their 95% CIs were estimated by ANCOVA with the change in the NRS composite score at week 16. This ANCOVA model took into account the variation caused by treatment effects, and gender and baseline NRS scores (≥6.3 and <6.3) were entered as covariates. As a sensitivity analysis, we showed the transition over time of the NRS scores of each group, confirmed the time course measurement data using the linear mixed effect model, and confirmed that it was not significantly different from the covariance analysis result. All comparisons were planned, and all P values were two-sided. P values <.05 were considered statistically significant. No special complementary processing by statistical methods was performed for the missing values. However, if necessary, complementary analysis using Mixed Model Repeated Measure was carried out for exploratory analysis. This analysis plan was created before the trial was started, and the protocol was approved. All statistical analyses were performed using SAS V.9.4. .Statistical analysis and reporting of this trial were conducted in accordance with the Consolidated Standards of Reporting Trials guidelines. Baseline variables were compared using Fisher exact test for categorical outcomes and an unpaired two-tailed A total of 93% of the patients (14/15) completed all 16 sessions of the vCBT program and participated in the intervention throughout its duration; 2 patients missed 1 session each due to adverse events (see below). No patients in the vCBT group were excluded from the analysis. One patient in the TAU group did not report receiving regular medical treatment at week 8 and was excluded from the analysis. Finally, 15 patients in the vCBT and 14 patients in the TAU group were analyzed.In this study, 4 adverse events were reported by 4 different patients in the vCBT group. The first patient was hospitalized owing to worsening Behcet disease and declined to participate in the study for the fourth session. The second patient had sudden difficulty in opening his eyes due to medically unexplained eyelid pain and declined to participate in the study for the fifth session. The third patient had common cold. The fourth patient had temporomandibular joint disorders.P=.24, P>.99, P=.73, P=.70, P=.73; respectively). Duration of illness in vCBT (mean 11.03 [SD 12.64] years) was significantly longer than that in TAU (mean 7.56 [SD 5.84] years). In both groups, more than 65% (19/29) of the patients were women. All patients in the vCBT group had an education period of 12 years or more (high school graduation or above), and TAU group had also 12 years or more except for one patient (9 years). There was no significant difference between the two groups. At baseline, nearly 70% (20/29) of patients were not working . Patients were living with at least one family, and only 1 patient receiving vCBT lived alone. The most reported site of chronic pain was lower back pain. Many patients had orthopedic pain, while others had oral pain such as tongue pain, toothache, and general pain such as rheumatism and fibromyalgia.P=.36). P values lesser than .05 were considered statistically significant. No significant difference was found between the 2 groups regarding changes in maximum, minimum, and usual NRS scores at week 16 from the baseline. In addition, there was no significant difference in the changes in all NRS scores at week 8 from baseline.df=24; P=.01). There was no significant difference between the 2 groups in the adjusted mean reduction of BPI pain severity at 16 weeks. The adjusted mean reduction of BPI pain interference in vCBT was significantly larger than that of TAU at 16 weeks . There was no significant difference between the 2 groups in the adjusted mean reduction of BPI total score, pain severity, and pain interference at 8 weeks.Comprehensive pain score: The adjusted mean reduction of the total BPI score in vCBT was significantly larger than that of TAU at 16 weeks . There was no significant difference between the 2 groups in the adjusted mean reduction of PDAS at 8 weeks.Disability: The adjusted mean reduction of the PDAS score in vCBT was significantly larger than that of TAU at 16 weeks . There was no significant difference between the 2 groups in the adjusted mean reduction of PCS at 8 weeks.Catastrophizing cognition: The adjusted mean reduction of the PCS score in vCBT was larger than that of TAU at 16 weeks, although the difference was not statistically significant . There was also no significant difference between the 2 groups in the adjusted mean change of the EQ-5D-5L index score at 8 weeks.Health-related quality of life: The adjusted mean change of the EQ-5D-5L index score in vCBT was larger than that of TAU at 16 weeks, although the difference was not statistically significant   patients in the vCBT group and 12 (80%) patients in the TAU group with their informed consent. The data consisted of medical expenses covered by public health care insurance, prescription drug prices, and uncovered health care expenses for chronic pain during the intervention period (16 weeks or 4 months). The mean total cost per person for 4 months was 145,846 yen (1 USD=114.05 yen) in vCBT and 169,312 yen in the TAU group, thereby showing no significant difference between the 2 groups (P=.73) . To calcP=.73) .To our knowledge, this study is the first RCT to evaluate the effectiveness of vCBT for chronic pain. In addition, we performed a cost-effectiveness analysis of the CBT program by using ICER. Although composite pain intensity by the NRS did not change, vCBT significantly improved the total BPI score, especially pain interference and disability in daily life. Furthermore, in the medical economic evaluation, although our results showed no statistically significant difference, it has been suggested that vCBT may be more cost-effective than TAU for various reasons that we discuss in the following sections.The latest systematic review of 75 RCTs about the effectiveness of face-to-face CBT has shown that CBT versus TAU at the treatment end for pain, disability, and distress showed a small effect size, and versus active treatment showed few effects n=9401) [401 [9]. As reported by multiple internet-based CBT studies, use of self-care programs or apps, treatments in which specialists check progress every other week, or telephone sessions have been demonstrated to be effective. Such internet-based CBT does not require multiple therapists, and interventions can be conducted for many patients concurrently. However, there is insufficient evidence for the effectiveness of the treatment. Chronic pain is unique to each individual and therefore, there is a need to consider stepped care for chronic pain, which is a system of delivering an evidence-based staged approach and provides treatment that matches individual needs and status. Ideally, it is desirable for patients to receive internet-based CBT in the early stage as first aid, such as through a self-care smartphone app. Moreover, patients who do not respond well to first aid should receive vCBT as the second aid.vCBT is intended for the treatment of higher levels of chronic pain. We need to examine treatments for several levels of pain for treating complex and intractable chronic pain. This was the first RCT on vCBT showing significant improvement in interference (distress) and disability. Our primary outcome, pain intensity as measured using NRS, was not significantly different; however, we adopted the BPI total score as a comprehensive pain score, which showed significant results. The reason for the NRS result could be that TAU also improved pain intensity. According to the BPI total score, pain interference appeared to greatly improve, while pain severity only showed a slight change, which comprehensively improved the total score. We hypothesized that patients who received CBT increased their previously avoided daily movement by doing the CBT-related homework and confronting their pain, thus maintaining their pain intensity. Conversely, it was possible for patients with TAU to avoid several behaviors owing to pain; as a result, their pain interference score worsened gradually. Considering this development, a composite score such as a BPI total score should be adopted for assessing the effectiveness of treatment for chronic pain. A recent consensus recommended the use of comprehensive indicators such as a BPI . In partWe expected improvement of cognition-related pain-related catastrophic thoughts, anxiety, and depressive symptoms, because a previous review had shown small-to-moderate effect size of catastrophic thinking and mood . MoreoveWe thus added a new session to address emotions such as anxiety and depression. However, in this session, many patients could not recognize the emotions related to pain. They thought of their pain and emotions as separate and did not acknowledge emotions that accompanied the pain memory or emotions that accompanied the moment pain was felt. An RCT found that emotion-focused exposure intervention (10-15 sessions) compared to normal CBT for chronic pain is effective for catastrophic cognition and depression, in addition to other outcomes . The resIn medical economic evaluation, a cost-benefit analysis showed that ICER was almost 2.9 million (yen/QALY), which was lesser than Japan's WTP of 5 million yen. Furthermore, it was also shown to be lesser than the British WTP of £23,000 (approximately 3 million yen) and the United States WTP of $62,000 (approximately 6.7 million yen) . At postThis study has several limitations. First, the sample size was relatively small. In addition, this study was performed as a single-center study at our hospital. In the near future, large-scale multicenter trials are necessary. Second, further studies targeting patients with specific types of chronic pain will be required to examine the effectiveness of this vCBT program. Third, because we did not use a psychological placebo group as a control condition, we were unable to control nonspecific factors and unravel the concrete effects of the vCBT program. Finally, the lack of follow-up data limited the generalizability of the conclusions. Long-term follow-up studies should be conducted in the future.Despite the problems in this study, vCBT has the possibility of usability and effectiveness for patients with chronic pain. During COVID-19, in particular, vCBT may provide safety and alleviate the patient’s stress through face-to-face counseling. In the future, we may study other pandemics and help patients to decrease their anxiety and symptoms by using internet-based CBT.In summary, videoconference-based integrated CBT for chronic pain could improve pain interference and disability in daily life, and as a result, could even relieve comprehensive pain. Therefore, this program can be a valuable addition to regular medical care. Further research is needed to examine augmentation strategies, including an examination of the components of CBT that are best suited for different types of pain. Furthermore, while this study indicated the cost-effectiveness of this treatment within a small sample, this needs to be verified with a larger sample size.


This study aimed to validate Italian versions of Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scale and Pain DETECT questionnaire (PD-Q) and evaluate the ability of these questionnaires to discriminate between nociceptive and neuropathic pain. Subjects and Setting. One hundred patients were included with a diagnosis formulated by a specialist in outpatient settings .  Multicenter prospective validation cohort study.  The Italian versions of both questionnaires according to Italian cultural characteristics were performed according to the following steps: (1) translation of the questionnaires from English into Italian; (2) review by a bilingual individual for consistency; (3) proposed version after a mail round between experts; (4) backward translation; (5) comparison with the original English version by the experts; (6) approved version of the questionnaires. One hundred patients were enrolled and completed the two questionnaires administered by a specialist or blinded nursing staff, at the baseline and after 24/48 hours. Internal consistency, stability, validity, and discriminative power were analyzed. α; LANSS showed a good test-retest reliability with an ICC of 0.76, and PD-Q showed a high test-retest reliability with an ICC of 0.96. For interrater reliability, there was a concordance rate of 83.3% between reference diagnosis and LANSS .  Statistically significant differences were reported about the ability of both questionnaires to discriminate between patients affected by neuropathic or nociceptive pain. Internal consistency for the Italian version of the LANSS was 0.76, and for PD-Q, it was 0.80, assessed by Cronbach's  This study validated the Italian versions of LANSS and PD-Q as reliable instruments with good psychometric characteristics, for pain evaluation, discriminating between nociceptive and neuropathic pain. Our findings were similar to those observed in the original study. Furthermore, we have reported the test-retest reliability for both questionnaires, not addressed in original validation studies. Pain treatment is a key element in the management of many chronic diseases. In this regard, traditional therapeutic strategies addressed pain intensity, while, recently, a more appropriate approach taking into account the pathogenic mechanisms of pain has been widely used . HoweverThis is especially true when it comes to treating neuropathic or mixed pain. To correctly identify patients who can respond to a specific intervention, validated assessment tools have been produced. In particular, several questionnaires have been created and validated in different languages to discriminate between different types of pain, such as the Pain DETECT questionnaire (PD-Q) and the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scale , 4, whicThe objectives of this study were to translate and validate Italian versions of the LANSS and PD-Q scales, as well as to investigate the ability of these tools to discriminate between inflammatory/mechanical (nociceptive) and NeP.A multicenter prospective cohort study was conducted with an overall duration of 8 months , involving 5 outpatient services belonging to the Italian Society for Unified and Interdisciplinary Management of Musculoskeletal Pain and Algodystrophy  for the inclusion of 100 patients.Italian versions of both questionnaires were first developed through translation and back-translation and then analyzed for internal consistency, stability, validity, and discriminative power.The guidelines of Beaton et al.  were useIn this study, we considered three paradigmatic diseases causing nociceptive or neuropathic pain, namely, osteoarthritis, and trigeminal or postherpetic neuralgia, respectively.A series of 100 subjects, of which 50 with nociceptive pain and 50 with NeP were included. Sociodemographic information on the patient and data about the general characteristics of the index disease was collected . The patients enrolled in the validation study were selected by the specialist of the different centers in the routine clinical practice. Inclusion criteria were age ≥18 years; diagnosis of trigeminal neuralgia or postherpetic neuralgia (NeP group) or a diagnosis of knee osteoarthritis (OA) according to American College of Rheumatology (ACR) criteria   consists of 5 questions scored from 1 to 5 depending on the items whenever the answer is affirmative, and 0 if this is absent. The following descriptors are most frequently used by patients with NeP: bursting, electric shocks, changes in skin temperature/color, and others. It is the only neuropathic screening that investigates autonomic changes [The PD-Q was originally developed for people with low-back pain and showed good sensitivity 85%) and specificity (80%) when compared to clinical diagnosis of a predominantly nociceptive  or neuropathic  origin . The PD-5% and spt-test (two independent sample t-tests were used), while categorical variables were analyzed with chi-squared test.Statistical analyses were performed using SPSS version 15.0 for Windows . All continuous data were described by mean ± standard deviation and qualitative data by percentage. The significance of the differences between continuous variables was analyzed using the one-way analysis of variance (ANOVA) and Student's α was used to assess the internal consistency [For reliability analysis, Cronbach's sistency , and intsistency . The corp values <0.05 were considered statistically significant.In all analyses, The study involved 100 patients, 50 patients affected by NeP   and 50 patients affected by nociceptive pain (knee OA)  . Cronbach's alpha value was 0.76 for the total LANSS score. Regarding LANSS stability, 100 patients have been retested within 48 hours, and the scores have shown high stability (ICC = 0.76). For the validity of the LANSS scale, using a cutoff ≥12, we obtained a sensitivity of 87% and specificity of 72%; the overall classification was 82%, positive predictive value (PPV) was 83%, and negative predictive value (NPV) was 79%. The diagnostic concordance rate between the clinical diagnosis and the LANSS scale was 83.3% .For the validity of PD-Q, we obtained a sensitivity of 85% and specificity of 75%; the overall classification was 81%, positive predictive value (PPV) was 82%, and negative predictive value (NPV) was 76%. The diagnostic concordance rate between the clinical diagnosis and the PD-Q was 83.5% .α. The mean overall score of the PD-Q was 16.33 ± 8.35 at baseline and 15.9 ± 8.17 when performing the retest measurement. The PD-Q test-retest reliability had a result of 0.96 for the total score, ranging from 0.84–0.96 for individual items. No floor or ceiling effect was observed.The internal consistency of the Italian version of PD-Q was 0.80 assessed by Cronbach's Statistically significant differences were reported about the capability of the questionnaires to differentiate patients affected by neuropathic or nociceptive pain, without differences in the same type of pain between the results reported at baseline and at retest . SpecifiThis study was designed to validate the Italian versions of LANSS and PD-Q by analyzing the psychometric properties of these questionnaires and to define the ability of these diagnostic tools in discriminating between nociceptive and NeP.Our results demonstrated a correspondence of Italian translations of LANSS and PD-Q to the original versions; these questionnaires were well accepted by the patient even when readministered after 24/48 hours, with a good patients' reading comprehension and ability to answer.In particular, the good psychometric properties of the original version have been confirmed for both questionnaires, with a consistent capacity to distinguish between nociceptive and NeP. Moreover, both LANSS and PD-Q were shown to be extremely stable at test-retest analysis, a psychometric property not assessed in the original reference studies , 4.This study confirmed the validity and reliability of these questionnaires for comprehensive NeP assessment.α of 0.76 in line to the result demonstrated in the original study (Cronbach's-α of 0.74) [α value (0.65) was shown by Batistaki et al. in the Greek LANSS validation study [For reliability, LANSS internal consistency was determined as acceptable with a Cronbach's-on study .α value of 0.80, and the observed value was similar to that observed in the original study  [α value of 0.86; 7 Likert items, Cronbach's-α value of 0.89, respectively) [For PD-Q, there was a good internal consistency with Cronbach's-ctively) . Two quer = 0.94, p < 0.001) in Greek translation of LANSS [Our results demonstrated a good test-retest reliability for LANSS (ICC 0.76). The original LANSS version did not assess test-retest reliability , and ourof LANSS .p < 0.05); this data was not included in the original study, conducted on patient with low-back pain, considered of limited utility on estimation of pain measure reliability [Similarly, for PD-Q, we found a high test-retest reliability  between reference diagnosis and LANSS , consistent with the original study (Cohen's kappa = 0.65)  and with3.3% betwFor the accuracy assessment, using as cutoff a value ≥12 , LANSS cFurthermore, PD-Q investigates peculiar details of gradation of descriptors, pain course pattern, and radiating pain. For example, for the sensory descriptors, NeP group had an intensity distribution mainly between moderate and strong, particularly for “temperature evoked pain” and “numbness sensation,” defined as absent or mostly “hardly noticed” in the nociceptive group. Instead, regarding pain course pattern, we obtained similar results in both groups. No patient referred radiating distribution in other body regions. Moreover, we reported that, in NeP group, our translated version of PD-Q was able to identify the pain course pattern specific of the neuropathic syndromes included in our study  according to descriptors found in literature , 11.Finally, the good concordance rate between the reference diagnosis and the mean value of LANSS confirmed that our translated version of the questionnaire may be considered a useful screening tool in daily clinical routine and in the therapeutic management of this insidious kind of pain.p > 0.05). This result suggests that a specialized approach to pain is strongly advised to discriminate between different pain phenotypes and also to consider several aspects of painful experience, particularly when chronic pain occurs.As expected, using a unidimensional scale such as VAS, at the T0, we observed similar results in the two groups in terms of pain intensity  and peripheral (nociceptors) activity, also known as central sensitization , 12. ThiIn a study that evaluated Self-Complete LANSS (S-LANSS) and PD-Q in patients with knee OA, Moreton et al. demonstrated that PD-Q is a good surrogate measure of augmented central pain processing, while it is still debated which questionnaire between S-LANSS and PD-Q is most accurate to discriminate neuropathic pain mechanisms in knee OA .In addition, LANSS successfully detects neuropathic features also in rare painful conditions such as Complex Regional Pain Syndrome type I (CRPS I) . This coA limitation of our study could be that it was performed in a clinical setting, reducing generalizability of the results.This study is the first validation of Italian versions of LANSS and PD-Q. Our results demonstrated good psychometric and discriminant pain features of the translated questionnaires, with appropriate patient comprehension. Moreover, our study provides more information about the test-retest reliability, not available in original validation studies.Reliable pain assessment, including the identification of neuropathic features, is critical to plan an appropriate therapeutic strategy. This study confirms the validity of LANSS and PD-Q as screening tools for NeP symptoms, thus improving clinical judgment in the pain management.


Background: Subjective cognitive dysfunction (SCD) is common in fibromyalgia (FM), where it has been called 'fibrofog.' But its predictors and correlates are not well understood, including the extent to which SCD is present in fibromyalgia and non-fibromyalgia clinical populations. In addition, there are no studies available concerning SCD and fibromyalgia in the general population. We investigated these issues in a longitudinal rheumatic disease research databank and two cross-sectional general population studies.Methods: 11,150 unselected patients with rheumatoid arthritis completed an assessment of FM and cognitive severity (CS) status using the full 0-3 fibromyalgia 2016 criteria assessment. In addition, CS was dummy coded as present/absent (CS+). Assessments of SCD and fibromyalgia prevalence were available in two German general population studies.Results: Fibromyalgia was present (FM+) in 2,493 (21.7%) of clinical subjects and absent (FM-) in 9,017 (78.3%) by FM 2016 criteria. Cognitive severity was present in 1,304 (52.3%) of those with fibromyalgia and 1,009 (11.2%) of non-fibromyalgia subjects (FM-). In two general population studies, 42.0% to 52.3% of those with fibromyalgia were CS+ as were 1.4% to 5.5% of FM- subjects. Patients with CS+ had more abnormal scores for every measure of rheumatoid arthritis (RA) severity, fibromyalgia severity, and general health. The presence of CS+ was strongly related to somatic and non-somatic symptoms scores and less strongly to pain variables. The best predictor of CS+ in the clinic and the general population was the symptom severity scale (SSS), a criterion of fibromyalgia.Conclusions: Persons with SCD have high counts of somatic and psychological symptoms. Subjective cognitive dysfunction is best predicted by a simple symptoms score, and not by pain extent scores. Although SCD is called fibrofog in patients with FM, 43.6% of CS+ cases occurred in FM- subjects. Fibromyalgia and CS are correlated but appear to be different parts of a symptom severity continuum. 'Fibrofog' as a phenomenon linked only to fibromyalgia is a misnomer because it can be identified in many non-fibromyalgia patients as well. Cognitive dysfunction as it relates to patients with musculoskeletal pain is almost universally diagnosed based on self-report. We use the term subjective cognitive dysfunction (SCD), as it has been used by others -4, to inThe complex but tenuous relation of SCD to objective mental impairment has been the subject of many studies but is not the subject of this report. Instead, we seek to understand the prevalence, predictors, and consequences of SCD in patients with and without fibromyalgia. No previous studies have evaluated SCD and fibromyalgia from this perspective.In the report that follows, and in the context of clinical and fibromyalgia variables, we examined SCD and multiple covariates and outcomes in 11,510 patients with rheumatoid arthritis (RA) who chose one of four responses to the question, 'Do you have trouble thinking or remembering?' The options were 0: No problem; 1: Slight or mild problems, generally mild or intermittent; 2: Moderate, considerable problems, often present and/or at a moderate level; or 3: Severe, continuous, life-disturbing problems. This question is part of the series of American College of Rheumatology (ACR) related criteria for fibromyalgia , therebyWe studied SCD in RA patients participating in a longitudinal research databank because they were evaluated with a full range of physical, social, and psychological variables. At the same time, their participation was unbiased as the presence, absence, or status of fibromyalgia-as participation was determined only by RA diagnosis. Due to the presence of pain in patients RA, they effectively are “pain” controls. We have previously shown that patients with RA are accurately diagnosed with fibromyalgia . We alsoDatasetsThe primary dataset for this study used data from 11,510 persons with rheumatoid arthritis (RA) participating in the semi-annual questionnaire assessment of the National Data Bank for Rheumatic Diseases (NDB) study of longitudinal outcomes. The characteristics of the NDB have been reported previously . In the We also analyzed data from two studies of the prevalence of fibromyalgia in the German general population. The first study utilized the 2011 criteria , includiDefinition and abbreviations of cognitive dysfunctionCognitive status refers to the subjective cognitive dysfunction severity assessment question outlined in the fibromyalgia criteria -7, as shIn addition to the full cognitive severity scale (CS-F), cognitive severity positive indicator (CS+), and compressed cognitive severity scale (CS-C), we use the term SCD to refer to the subjective cognitive dysfunction concept. SCD+ is effectively equivalent to CS+.Fibromyalgia-related variablesWidespread Pain Index (WPI)A 0-19 score of painful sites is a measure of the extensiveness of pain . WidesprSymptom Severity Score (SSS)The SSS is a 0-12 measure of symptom severity first defined in the American College of Rheumatology (ACR) 2010 criteria and its 2011 self-report modification . It inclAdjusted SSS (ASSS)This is the SSS score with the cognitive difficulties questions omitted. Its use allows the assessment of symptom severity and its correlates without using the cognitive difficulties score. The range of ASSS is 0-9.Polysymptomatic Distress Scale (PSD)The PSD, also called the fibromyalgia severity scale (0-31), is the sum of the WPI and SSS . The PSDAdjusted PSD (APSD)This is the sum of WPI and ASSS.FM 2011A modification of the ACR 2010 fibromyalgia criteria that allows for self-report .FM 2016A modification of FM 2011. Fibromyalgia diagnosis requires 1) WPI ≥ 7 and SSS ≥5 OR a WPI of 4-6 and an SSS score ≥9, 2) the presence of widespread pain, and 3) symptoms of at least three months duration [Non-widespread pain and fibromyalgia variablesWe measured the severity of pain and fatigue using 0-10 visual analog scales (VAS) in the NDB samples. The VAS measures pain intensity while WPI measures the extent of pain sites involved. Functional status was measured using the Health Assessment Questionnaire Disability Index (HAQ) , and ovePsychiatric illness now or ever was determined by respondent’s affirmative endorsement of current or ever depression, mental illness, alcohol, or drug abuse.The full symptom count (0-37) was a count of 37 symptoms that may have been experienced by patients in the last six months. It comprised the following variables: abdominal pain, alopecia, anorexia, anxiety, asthma, bruising, constipation, depression, diarrhea, dizziness, dry eyes, dry mouth, dyspnea, epigastric pain, fatigue, fever, headache, hearing problem, heartburn, memory problem, muscle pain, muscle weakness, nausea, oral ulcers, paresthesias, photosensitivity, pleurisy, pruritus, rash, Raynaud’s phenomena, seizures, sleep problem, taste, tinnitus, urticaria, vision problem and vomiting.The non-pain non-fibromyalgia variable symptom count (NONPNONS) of 0-26 was a shortened version of the full symptom count developed for this study. It included only variables that were not related to musculoskeletal or widespread pain, pain severity, or fibromyalgia characteristics such as alopecia, anorexia, anxiety, asthma, bruising, constipation, diarrhea, dizziness, dry eyes, dry mouth, dyspnea, fever, hearing problem, nausea, oral ulcers, paresthesias, photosensitivity, pruritus, rash, Raynaud’s phenomena, seizures, taste, tinnitus, urticaria, vision problem, and vomiting.The Patient Health Questionnaire 15 (PHQ-15) is a measure of somatic syndrome severity. It contains 13 somatic and two psychological items. The PHQ-15 scores of 5, 10, and 15 represent cutoff points for low, medium, and high somatic symptom severity . The PHQAs additional criteria, we also studied the prevalence of fibromyalgia and CS using the London fibromyalgia criteria  and the StatisticsData were analyzed using Stata . Comparisons of CS-F groups for the study variables in the tables were performed by least square and logistic regression analyses, unadjusted for age and sex to test if there were differences between CS-F levels. Due to the very large sample size , essentially all statistical comparisons were statistically significant. We chose not to report p-values, given the circumstances, except to flag the single nonsignificant case. The strength of association with CS+ was assessed by correlation and receiver operating curve i.e., area under the curve (ROC AUC) analyses. Pearson correlations were used throughout. Figures were derived from logistics and ordered logistic regression analyses followed by marginal prediction using Stata’s margins and marginsplot procedures.EthicsEthical approval for each database used in this study was obtained from an institutional review board (IRB) and was conducted as per the Declaration of the World Medical Association. Informed consent from human subjects was obtained as required.German Population StudiesThis first study was approved by the Institutional Ethics Review 18260 Board of the University of Leipzig (Az2-12-05032012). The second study was approved by the Institutional Ethics Review Board of the University of Leipzig (Az 145/19-ek).National Data Bank for Rheumatic Diseases DatabaseThis study was approved by the Via Christi IRB, Wichita, Kansas, USA (FWA00001005).The relation of SCD to clinical and demographic variablesOf the 11,510 RA patients in this study, 20.1% reported moderate or severe SCD (CS+) as seen in Table For almost all demographic and clinical variables studied, increasing CS-F scores were associated stepwise with more abnormal clinical states or changes in demographic characteristics as seen above in Table Fibromyalgia was present (FM+) in 2,493 (21.7%) of clinical study patients and absent (FM-) in 9,017 (78.3%) as per the 2016 criteria; and was common regardless of the definition of fibromyalgia used. Of the NDB patients, 43.0% to 52.3% of fibromyalgia cases satisfied the CS+ definition  there was a stepwise increase in severity with the different FM/CS groups, with PSD demonstrating the clearest stepwise increase. However, differences did not increase stepwise in the transition from FM- CS- to FM- CS+ for WPI, while SSS, anxiety, and self-reported disability increased disproportionately. This effect can also be seen in the changes in the ratio of SSS to WPI. These data indicate that CS status change is more correlated with symptom variable levels  and less correlated with WPI.a superscript include the actual CS score. Variables with a b superscript omit CS scores and are an appropriate study variable, as we do not want to evaluate the effect of CS when both sides of the equation contain CS. Among the variables that best predict CS-F and CS+ status is the short symptom severity score (ASSS) (CS question omitted), with a correlation of 0.608 and a receiver operating characteristic curve and area under the curve (ROC AUC) of 0.855. This variable classifies 83.7% of cases correctly. The regular symptom severity scale has a correlation of 0.773, a ROC AUC of 0.932, and a correct classification of 88.5%.To further understand stronger and weaker correlates of SCD and how PSD components affect the probability of CS+, we ranked relevant predictors according to correlation with CS-F and with ROC scores for CS+ cases Table . VariablBy contrast, the pure musculoskeletal pain variable WPI, is a much less effective predictor, with a correlation of 0.391, a ROC AUC of 0.724, and a correct classification of 79.9%. As shown in Figure To examine more fully the relationship of somatic and psychological variables and CS+ cases, we studied SCD in the context of the NONPNONS symptom scale, as that scale contained individual symptoms generally not related to the key symptoms of the SSS scale or the WPI. The NONPNONS had a correlation of 0.476 and a ROC AUC of 0.768. It correctly classified 81.5% of cases. We regressed CS+ on each variable contained in the NONPNONS scale in Table In this study, we found that somatic and psychological symptoms rather than pain or pain and symptom variables were the best predictors of CS+. In fact, the addition of pain extent and location variables such as WPI and widespread pain, as in the PSD scale, did not improve CS+ prediction or identification by SSS score. The SSS score had a ROC AUC of 0.932. When the CS variable was omitted in the short SSS, the ROC AUC was 0.855-the second-best predictor. When WPI, a central component of the ACR fibromyalgia diagnostic criteria was examined , its ROCIn the NDB data set of this study, other effective predictors of CS+ (seen in Table Persons reporting increased CS scores have worse outcomes for all RA variables and for all fibromyalgia-related variables Tables  and 5. FMost previous studies have approached the idea of SCD in patients with fibromyalgia, and not in chronic pain patients of differing causes. Where controls were present, they tended to be “healthy” controls. No studies used formal fibromyalgia criteria applied at the time of the study. Comprehensive clinical and fibromyalgia status variables were usually not available. Williams et al. studied 72 persons with fibromyalgia and 44 matched controls -27, and Recent studies with which our data agree conclude that cognitive impairment is associated with a variety of pain conditions including the “regional condition of low back pain, the widespread condition of fibromyalgia, the neuropathic condition of diabetic neuropathy” , and oveOne possible limitation to our report is that we determined cognitive dysfunction with a single question that was part of the ACR 2010 criteria -7, but hA characteristic feature of SCD appears to be high counts of somatic and psychological symptoms. In a population of pain patients, 56.4% of those who are CS+ will satisfy FM 2016 criteria and 43.6% will not satisfy FM 2016 criteria. Among CS-C negative subjects, 12.9% will satisfy FM 2016 criteria. Persons with CS+ have abnormal scores on virtually every clinical and fibromyalgia-related assessment. The SCD is best predicted by a simple symptoms score, and not by pain extent scores. Although SCD is called fibrofog in patients with FM, 43.6% of CS+ cases occurred in FM- subjects. Fibromyalgia and CS are correlated but appear to be different parts of a symptom severity continuum. 'Fibrofog' is a misnomer. We suggest that it may be more appropriate to consider both conditions as part of continuums in many diseases rather than thinking of fibromyalgia symptoms, including cognitive problems, as a discrete disorder.


Low back pain (LBP) is caused by disc herniation, spinal stenosis, facet syndrome or etc. This LBP could be either nociceptive or neuropathic pain (NP). In addition, these neuropathic pain is a major contributor to chronic low back pain. It is already known that lumbar epidural steroid injection (ESI) is effective for low back pain, but no study has assessed both nociceptive and neuropathic pain separately. This study investigated whether neuropathic or nociceptive pain was better improved after an epidural steroid injection.This was a prospective study. Patients were classified according to the pre-procedure painDETECT questionnaire (PD-Q) score. If the PD-Q score was ≤12, it was considered as nociceptive pain, and it the PD-Q was ≥19, it was considered NP. The patients were given a transforaminal (TF) or interlaminar (IL) epidural steroid injection (ESI). The PD-Q was filled out by each patient prior to the ESI (baseline), and again at 4 weeks after the ESI. Outcomes was assessed using a numerical rating scale (NRS) score, short form McGill Pain Questionnaire (MPQ), and revised Oswestry Back Disability Index (ODI) at 1 month later.A total of 114 patients were enrolled and of these, 54 patients with a PD-Q score of ≤12 were classified into the nociceptive pain, and 60 patients with a PD-Q score ≥19 were classified into the neuropathic pain group. At 1 month after treatment, both groups had significantly lower than improved their mean NRS score. Not withstanding these improvements and difference between NRS, the differences in MPQ and ODI after treatment between the groups (nociceptive vs. neuropathic) not significant. After the procedure (TF-ESI or IL-ESI), the patients in group 1  had no change in their PD-Q score. Among the patients in group 2 , 13 patients moved to a PD-Q score <12 and 15 patients had a PD-Q score of 13–18.For the short-term relief of neuropathic pain, ESI was effective for both nociceptive and neuropathic pain, therefore ESI could be treat the try neuropathic pain component in patients with low back pain. When the compression of the nerve root occurs, patients experience pain due to a strong inflammatory reaction, therefore epidural injection of corticosteroids appears to be a reasonable treatment option An epidural steroid injection (ESI) is often used to treat neuropathic pain (NP) Neuropathic pain can be caused by actual neural compression or neural damage, but nociceptive pain is reaction to painful stimuli However, no study has examined the proportion of pain relief that could be attributed to treating the neuropathic pain component. The current study examined which component of pain (neuropathic or nociceptive) was most improved after an epidural steroid injection.2.The protocol for this prospective observational study was approved by the Ethics Review Committee.The study inclusion criteria were as follows: aged 18–80 years; lumbar radicular pain/or low back pain that had not responded to traditional treatments  within the previous 4 weeks; confirmed the pathology of the lumbar radicular pain confirmed by magnetic resonance imaging; and absence of a remarkable motor deficit and bowel/urinary incontinence. The study exclusion criteria were as follows: under 18 or over 80 years of age; low back pain only; diabetes; a progressive neurological disorder; history of allergic reactions to local anesthesia, opiates, contrast agents or steroids; history of opioid abuse or currently on long-term opioid treatment.The interlaminar epidural steroid injection (IL-ESI) was performed with a 20-gauge Touhy needle and 5 mg of dexamethasone mixed with 5 mL of 0.5% lidocaine. The transforaminal epidural steroid injection (TF-ESI) was performed with a 22-gauge needle and a solution of 5 mg dexamethasone in 3 mL of 0.5% lidocaine. The patients did not receive any anticonvulsants or antidepressants during the observation period, but during a 2 week period after the procedures, all subjects were received NSAID, and muscle relaxant. Patients who experienced breakthrough pain received 50 mg tramadol as a rescue medication.The painDETECT questionnaire (PD-Q) was filled out by each patient prior to the ESI (baseline), and again at 4 weeks after the ESI. If the PD-Q score was ≤12, it was considered nociceptive pain, and PD-Q was ≥19, it was considered as NP.Outcomes were assessed using the numerical rating scale (NRS) score, short form McGill Pain Questionnaire (MPQ), and revised Oswesry Back Disability Index (ODI) measured at pre-treatment and 1 month later.All data were analyzed using IBM SPSS Statistics for Windows, Version 23.0  The statistical analyses were performed using basic methods of descriptive statistics. The Student's t-test or Mann Whitney U test was used for comparing mean values. P-values ≤ 0.05 were considered statistically significant. The sample size of 114 was specified in advance to provide 90% power to detect a difference.3.The study enrolled a total of 114 patients. Based on the pre-procedure PD-Q score, 54 patients had a PD-Q score of ≤12 (nociceptive pain) and 60 patients had a PD-Q score ≥19 .The mean values of NRS, MPQ, and ODI before treatment were not significantly different between the two groups . At 1 mo4.In the present study, there was no difference in pain reduction between the nociceptive pain and neuropathic pains after ESI was not significant, and we found that the difference in providing relief for neuropathic pain between triamcinolone and dexamethasone was not significant.Our findings are consistent with those from a previous studies Neuropathic pain is caused by damage to the afferent peripheral or central nervous system. Additionally, neuropathic pain may be caused by mechanical compression of nerve roots , lesions of nociceptive sprouts within a degenerated disc , or by the actions of inflammatory mediators such as chemokines and cytokines, which can originate from a degenerative disc even in the absence of mechanical stress ithat causes nflammatory neuropathic root pain An epidural steroid reduces inflammation Generally, triamcinolone (particulate steroid) or dexamethasone (non-particulate steroid) are used for ESI. There has been some debate as to which steroid is superior. Patients who received transforaminal ESI with triamcinolone reported more frequent pain relief of greater than 50% at short-term follow-up compared with those who received betamethasone Triamcinolone and dexamethasone have different durations of activity action and anti-inflammatory potency. Dexamethasone acts rapidly and long duration of action with greater anti-inflammatory potency than triamcinolone We postulated that patients in the nociceptive pain group would obtain more pain relief than those in the neuropathic pain group. However, our results showed that the difference in pain reduction was not significant. Although, the etiology of neuropathic pain is highly variable when compared with the etiology of nociceptive pain, some drugs are only effective for treating a single specific type of pain (either nociceptive or neuropathic pain).There has been controversy on the safety of ESI The study was limited by the fact that patient outcomes were assessed only by the patients' self-reported pain scores and that short follow-up period was short.In conclusion, ESI was effective in both nociceptive and neuropathic pain, therefore ESI could be try to treat neuropathic pain component in patients with chronic low back pain.


Targeting the correct spinal level is essential in dorsal root ganglion (DRG) stimulation. Anatomical selection of the DRG alone is not ideal since the pain area is not necessarily confined to the borders of the dermatomes. This study aims to establish the role of periradicular infiltration therapy (PRT) in the preoperative assessment of the correct level for DRG stimulation performed under general anesthesia.We report a prospective study of 20 patients selected for DRG stimulation and submitted to a PRT for identification of the spinal level. Lead implantation for the stimulation trial occurred under general anesthesia: 19 patients experienced positive results and underwent implantation of the pulse generator. All patients suffered from chronic neuropathic pain unresponsive to best medical treatment. PRT levels were compared with the levels targeted with DRG leads. Patients were followed for up to 12 months; pain intensity and coverage of the painful area were assessed.In 12 patients, the trial leads were placed on the same level as previously tested positive by PRT. In 6 patients, leads were placed in the PRT target and additionally in adjacent spinal levels. In one case, the selected target for the trial diverged from the PRT target because of intense fibrosis in the chosen level. Coverage of the target area of at least 50% was achieved by two-thirds of the patients. For the six subjects with additional implanted leads as a consequence of the PRT results, 80% achieved a coverage of at least 50%. A total of 47.4% of the patients achieved sustained significant pain relief in the last follow-up. None of the patients needed a repeated surgery for implantation of additional leads.PRT is a helpful tool to confirm the stimulation targets. A PRT preceding the stimulation trial is an additional opportunity to optimize the coverage of the target area with stimulation-induced paresthesia for patients operated under general anesthesia. The therapy of chronic neuropathic pain remains a challenge today. To date, only 30 to 40% of patients with neuropathic pain can be treated satisfactorily with medication alone . The ACCThe initial selection of the correct DRG for stimulation is mostly based on the pain distribution among dermatomes. After a spinal level is targeted, a DRG stimulation lead is normally implanted with an extension lead externalized for a stimulation trial. If the patient benefits from this trial, the implantable pulse generator (IPG) can be inserted in a second procedure. Alternatively, both leads and IPG can be implanted in the same procedure, all-in-one. The issue is that an anatomical selection of the DRG alone is not ideal since the pain area is not necessarily confined to the borders of the dermatomes. Additionally, dermatomes often show unique distributions with overlap.In the literature, selective radiofrequency (RF) stimulation of the DRG has been discussed as a method for predicting the correct spinal level for stimulation, possibly giving important information for lead implantation in a stimulation trial or even in an all-in-one procedure . Only twThis is a prospective single-arm study that evaluates the outcomes of patients undergoing implantation of a DRG stimulation system. Twenty patients scheduled for DRG stimulation were prospectively observed between 2016 and 2018. All patients were at least 18 years old with an indication for DRG stimulation due to a chronic pain disorder refractory to best pharmacological treatment. No patients were excluded due to previously known intolerances to local anesthetics administered as part of PRT or to other contraindications to the procedure.The baseline pain assessment was performed using a visual analog scale (VAS). On the same day or in the following days a PRT of the presumptive affected DRG was performed , the tarFor the trial period, one to three leads were placed using a minimally invasive epidural approach under general anesthesia. No intraoperative paresthesia testing was done. Leads were anchored to the muscular fascia and were attached to an external trial stimulator using externalized extensions; stimulation was provided for 3 to 7 days. At the end of the trial, a new evaluation of the pain condition was performed using VAS. With a pain reduction of 50% and/or objective functional improvement of the patient, the trial was considered successful and the implantation of the IPG was performed . Patients with an increased surgical risk as well as patients with a clearly positive PRT result according to the experience of the responsible surgeon underwent all-in-one surgery. After the implantation of the complete neurostimulation system, the patient was interviewed in the regular out-patient visits within 1 week, as well as 1, 3, 6, and 12 months postoperatively using VAS, questionnaires, and pain/paresthesia maps. The existence of paraesthesia in the previously painful area as well as the percentage of painful area covered with paraesthesia was documented. Patients with a pain relief of at least 50% under DRG stimulation were considered responsive.All study elements were approved by the local ethics committee, and each patient gave written informed consent prior to the beginning of any study activities.Twenty patients with the indication for DRG stimulation were evaluated regarding pain development Fig. . PreoperFrom overall 20 included patients, PRT was congruent with the pain region in 18 cases (90%). The two patients with incongruent results were however trialed for DRG because the pain region was clearly related to a very specific dermatome—one case did not achieve relevant pain relief during the trial and was later treated with an SCS; the other one was responsive during the trial and progressed to IPG implantation (patient 14). Because this single patient underwent an SCS, DRG stimulation was performed on 19 patients during this study.In the 18 patients with congruent PRT, five patients were selected for an all-in-one implantation at the discretion of the treating surgeon because the PRT yielded an adequate coverage of the painful area with a significant pain reduction. Out of this group, only two patients (40%) reported relevant sustained pain relief under DRG stimulation.The remaining 13 patients with congruent PRT that were not considered for an all-in-one implantation were submitted to a trial; 12 patients had a positive trial. These subjects had a sustained significant pain relief under DRG stimulation in 53.8% of the cases in the last follow-up (7/13). The only congruent PRT result but insufficient trial result was selected for the implantation of the IPG at discretion of the treating neurosurgeon for reasons that include significant functional improvement. No significant pain relief was achieved in this particular case. Considering now all patient groups, mean reduction in pain intensity under DRG stimulation was 31.7%; a total of 47.4% of the patients achieved sustained significant pain relief in the last follow-up (9/19).In 11 patients, the trial leads were placed on the same level as previously tested positive by PRT Table . In the Data to coverage of the painful area with paraesthesia was available for 12 patients, all of them with a previous congruent PRT result. Two-thirds of them reported a coverage of the target area of at least 50%. For the six patients with additional implanted leads as a consequence of the PRT results , 80% achieved a coverage of at least 50%, with data being unavailable for patient 8.A total of 7 patients underwent revision surgery, which included broken leads and lead defects, among other causes. One patient died before the end of the study unrelated to the DRG system or surgery, the remaining 18 implanted patients were observed over a period of 12 months.The aim of the study was to investigate whether the preoperative periradicular therapy is eligible in a preoperative protocol for identifying the correct spinal level for DRG stimulation regarding the coverage of the painful area with stimulation-induced paresthesia. Compared to the past case studies on methods for predicting targets for DRG stimulation by Zuidema et al.  on retroIn our department, PRT has become the standard of care in almost all patients being screened for DRG for confirmation of the target level. Bupivacaine is usually preferred and has a longer elimination half-life than lidocaine. Lead implantation occurs on the following day so that no analgesic effect of the PRT should be present. In this study, however, all lead implantations were done under general anesthesia without paresthesia control. Even when the initial PRT does not cover the entire painful area, it orientates the surgeon when choosing the target DRG. If the first PRT result is not congruent with the painful area, a second PRT may be helpful, which was the case of three patients in this study. In case of insufficient coverage after PRT, the direct implantation of another leads in the trial without prior testing becomes more justifiable when a first PRT confirmed at least partial improvement. As a single-arm study, no comparisons can be made with the coverage rates of a control group that did not undergo a preoperative PRT. Our study was, however, able to show that the PRT results modified the original targets established by the responsible surgeons based on anatomical landmarks in a considerable number of patients. It is true that insufficient coverage can also be detected in the trial phase, but the preoperative PRT turns the trial into a second opportunity to evaluate the adequate coverage of the painful area before implantation of the definitive system. Unfortunately, we did not find any references regarding the incidence of second or even third procedures for the implantation of new DRG leads after the implantation of the IPG because of insufficient pain coverage. It is intuitive, however, that a preoperative PRT could reduce the length of hospital stay and the risks of new surgical procedures because more affected levels are earlier identified additionally to the clinically inferred ones. It might offer an additional option to reconsider the neuromodulation strategy for every individual patient. In this study with 19 subjects submitted to DRG stimulation, a second operation for implantation of new leads did not occur.Not as intuitive is the possible predictive value of preoperative PRT over the outcomes of DRG stimulation. These therapies have different mechanisms of action, but such a relationship would be of considerable interest, as it might indicate which patients would not benefit from DRG stimulation—whose technique for lead placement is particularly more difficult when compared with traditional spinal cord stimulation. For a matter of comparison, the positive predictive value of a successful trial for sustained significant pain relief achieved 53.8% in this study. As only one patient had a negative trial and was submitted to DRG stimulation later, nothing can be said about its negative predictive value based on these data.Particularly interesting is the case of the five patients submitted to an all-in-one implantation of DRG leads following a very successful PRT testing. In these cases, when PRT results were most promising considering adequate coverage and reduction of pain intensity, the positive predictive value for final significant pain relief was only 40% and 50% for coverage of at least 50% of the painful area. This result regarding pain reduction is lower than the predictive value of a trial (53.8%), which remains as the gold standard for the selection of patients for implantation of the definitive system. The predictive value regarding coverage of the painful area was also lower than the value obtained considering all 12 patients with available coverage data (67%). The indication for an all-in-one implantation of DRG leads is given at discretion of the responsible surgeon and should be specially considered in patients with higher surgical risk, but data of this study with a limited sample size supports a stepwise approach with a stimulation trial—independent of how promising PRT results are.This study evaluated only the congruence of PRT effect with the painful area and not the effect of PRT over the pain intensity. No conclusions can be drawn regarding its predictive value to stimulation outcomes. It is however relevant to mention that the variability of PRT results is influenced by physician experience and technical aspects, such as anesthetics used and addition of steroids. Therefore, insufficient pain relief after PRT would not change our indication for a DRG trial, as it was the case with patient 14. The inclusion of PRT in our clinical routine is independent of its positive predictive value over final clinical outcomes.The success of the DRG stimulation depends on the correct lead placement, and PRT is a helpful tool to confirm the stimulation targets. A PRT preceding the stimulation trial represents an additional opportunity to optimize the coverage of the target area with stimulation-induced paresthesia for patients operated under general anesthesia.


The aim of this study is to assess whether administration of gabapentin and methylprednisolone as “pre-emptive analgesia” in a group of patients above 65 years of age would be effective in complex pain management therapy following total knee arthroplasty (TKA). One hundred seventy patients above 65 years were qualified for the study, with exclusion of 10 patients due to clinical circumstances. One hundred sixty patients were randomly double-blinded into two groups: the study group (80 patients) and the control group (80 patients). The study group received as “pre-emptive” analgesia a single dose of 300 mg oral (PO) gabapentin and 125 mg intravenous (IV) methylprednisolone, while the control received a placebo. All patients received opioid and non-opioid analgesic agents perioperatively calculated for 1 kg of total body weight. We measured (1) pain intensity level at rest , (2) life parameters, (3) levels of inflammatory markers , and (4) all complications. Following administration of gabapentin and methylprednisolone as “pre-emptive” analgesia, the NRS score at rest was calculated at 6, 12 (p < 0.000001), 18 (p < 0.00004) and 24 (p = 0.005569) h postoperatively. Methylprednisolone with gabapentin significantly decreased the dose of parenteral opioid preparations (p = 0.000006). The duration time of analgesia was significantly longer in study group (p < 0.000001), with CRP values lower on all postoperative days , and leukocytosis on day 2 (p < 0.0086) and 3 (p < 0.00042). No infectious complications were observed in the first postoperative days; in the control group, one patient manifested transient ischemic attack (TIA). The use of gabapentin and methylprednisolone as a single dose decreased the level of postoperative pain on the day of surgery, the dose of opioid analgesic preparations, and the level of inflammatory parameters without infectious processes. Surgery, as a mechanical factor, initiates the pain process, incites nociceptors, evokes hyperalgesia, releases inflammatory mediators at the site of surgical incision and through damaging the vessels along with the anticoagulative and antiadhesive lining covering the vascular endothelial cells, initiates local as well as generalized inflammatory process4.Total knee arthroplasty (TKA) is performed in older patients due to degenerative lesions and to improve the quality of life. The postoperative period is associated with inconveniences, including pain of maximal intensity on day 110 has been also initiated since 2013. The Lundbeck Foundation of Denmark has been recommending using the medication as an element of the Enhanced Recovery After Surgery (ERAS) protocol in TKA11.Prolonged administration of glucocorticoids in patients with osteoarthritis limits the inflammatory process and reduces chronic pain through inhibitory factors evoking hyperalgesia, synthesis of proinflammatory factors and blocking elements of the inborn immune system. The use of methylprednisolone at the dose of 125 mg as “pre-emptive” analgesia13.Gabapentin is employed in managing chronic pain due to its’ effects exerted on cerebral modulation and perception of pain, as well as postoperative somnolence as an adverse effect, which is beneficial to the patient and fits well with multimodal pharmacotherapy of painThe objective of this study was to assess the employment of methylprednisolone and gabapentin in complex pain management during the perioperative period in patients above 65 years of age subjected to TKA. The authors attempted to answer whether administration of a single dose of methylprednisolone and gabapentin as “pre-emptive” analgesia would reduce: (1) the level of postoperative pain using the numerical rating scale (NRS) at rest and every 6 h starting on day 0, (2) the dose of parenteral analgesics agents, mainly opioids, used by the patients, (3) the occurrence of adverse effects that would delay early rehabilitation, (4) the inflammatory process parameters, and (5) maintain stable glycemic levels.This study was a single-center, prospective, double-blind randomized controlled trial conducted in a tertiary care hospital. The study started after obtaining approval at the Bioethics Committee Jagiellonian University meeting on the research plan presented. The Bioethics Committee of the Jagiellonian University, Kraków, Poland, confirmed its consent by letter no. 1072.6120.11.2020, 23/01/2020. The research was registered with ClinicalTrials.gov . All research was performed in accordance with relevant guidelines and the Declaration of Helsinki. After obtaining oral and written informed consent to participate in the study, consecutive patients above 65 years of age, were operated on with unilateral TKA in the period of June 1st to December 31st, 2019, and the ERAS protocols were recruited following the procedures. We excluded patients due to clinical circumstances that (1) restricted glucocorticoid administration, such as: diabetes type 1 and 2, CRP levels above normal values (≥ 5 mg/l), current chronic steroid treatment, peptic ulcers treated within the past 30 days, and (2) chronic pain such as: in the course of gonarthrosis, patients being treated in Pain Clinics, high intensity pain above 6 points on the NRS scale, inability to perform activities of daily living, and night pain at rest despite multimodal pharmacotherapy already requiring the use of additional transdermal and less often oral opioids.Before surgery, all of the patients were randomized into two groups: the study  and the control . The allocation was performed in the preanesthetic clinic by an individual not involved in the study, who prepared block randomization (block sizes 4 and 6), and used sealed envelope technique for all allocation concealments, including “pre-emptive analgesia” among the two sets. Each kit included a “pain reliever tablet” (gabapentin or placebo) and pre-filled syringe with “steroid”  prepared by the Hospital Pharmacy. Clinical trial was coded by the topic manager without affecting the experimenters.First and foremost, prior to anesthesia induction, each patient received prophylactically intravenous (IV) cephazolin 2.0 g as an antibiotic, tranexamic acid 1.0 g for hemostasis control, and an anti-emetic agent—ondansetron 8 mg. Patients were then subjected to the standardized procedure of subarachnoid anesthesia with subsequent unilateral femoral nerve block on the operated side, followed by the surgical procedure—unilateral TKA (P.F.C. SIGMA DePuy Synthes) using parapatellar approach. Fluid crystalloids administration was standardized to 12 ml/kg in the first hour of surgery, followed by 6 ml/kg for the remainder of surgery. Packed red blood cells were prepared in case of blood loss exceeding 600 ml and hemoglobin concentration reaching < 10 g/l during the time of operation. Pain management was carried out based on the results of the NRS scale at rest, as well as assessment of the duration of the analgesic femoral nerve block. The time of the femoral nerve blockade separated two points on the NRS scale and were determined by return of the superficial sensation of skin temperature changes (cold vs warm). The measurements were carried out every hour, and statistical calculations were performed every 6 h. On postoperative day zero, analgesia was started if the pain level on the NRS scores was 2–4 points, with intravenous (IV) paracetamol one to four times per day up to a maximum dose of 4 g, or metamizole one to two times a day up to a maximum dose of 5 g. When the pain level was at an NRS score of ≥ 4, the patients received intravenous (IV) oxycodone hydrochloride as PCA . All pain medications were calculated for 1 kg of total body weight. In keeping with the ERAS protocol, on the day of surgery, patients received oral fluids and meals, and were mobilized and rehabilitated. On postoperative day zero, rehabilitation included standing up, walking up to 20 m with crutches and continuous passive movement with a rehabilitation splint. On the next day, walking distance with crutches was increased, with addition of stair exercises and continuation of passive movements with the rehabilitation splint in order to obtain a knee flexion of 90 degrees. Each patient had wound drainage applied by the surgeon during the operation. Fluid samples from the drains were collected to assess the level of CRP. The wound drainage was removed 24 h postoperatively.In the preoperative room, patients received “pre-emptive analgesia” as one of the prepared coded kits. The study Group M received a kit containing oral (PO) gabapentin 300 mg and a pre-filled syringe of intravenous (IV) methylprednisolone 125 mg. The control Group K received an oral (PO) placebo and a pre-filled syringe of intravenous (IV) 0.9% saline solution. The statistical analysis of the groups addressed the demographic dates, life parameters, general condition in keeping with the ASA (American Society of Anesthesiology), POSSUM  score, total dose of analgesic medications administered parenterally calculated for 1 kg of total body mass in response to values of NRS at rest on day 0, time of administration of the first dose, and duration of peripheral nerve block. On the day of surgery and on subsequent days, indicators were made based on glycemic levels and inflammatory markers: C-reactive protein (CRP) and leukocytosis (WBC) levels. The primary outcome was pain intensity level measured by the NRS scale. The secondary outcomes were demographic dates, life parameters, general condition in keeping with the ASA, POSSUM Mortality and Morbidity score, total dose of analgesic medications, time of administration of the first dose, duration of peripheral nerve block, glycemic levels and inflammatory markers levels: C-reactive protein (CRP) and leukocytosis (WBC).The statistical analysis was performed using the T-Student test for independent groups employing the Cochran-Cox modification. A two-way ANOVA test or linear correlation (r Pearson) was used to determine the influence of two different categorical independent variables on one continuous dependent variable (NRS pain score); the resultant statistical significance was p < 0.05 (PQStat v 1.6.8 software). A priori statistical power analysis was also conducted to validate the adequacy of the sample size. An NRS pain score was used to calculate the sample size. A sample size of 73 in each group was calculated; the level of significance was fixed at 5% and the power of the study at 80%. Expecting a 10% drop out rate, sample size was calculated at 80 for each group .The analysis included a group of electively picked 170 patients above 65 years of age who had a unilateral TKA operation performed in the period of June 1st to December 31st, 2019, with the procedures following the ERAS protocols in our surgical department. From the study, 10 patients were excluded due to clinical circumstances that (1) restricted glucocorticoid administration, such as: diabetes type 1 and 2, CRP levels above normal values (≥ 5 mg/l), current chronic steroid treatment, peptic ulcers treated within the past 30 days, and (2) chronic pain such as: in the course of gonarthrosis, patients being treated in Pain Clinics, high intensity pain above 6 points on the NRS scale, inability to perform activities of daily living, and night pain at rest despite multimodal pharmacotherapy already requiring the use of additional transdermal and less often oral opioids. The schematic flowchart as per the CONSORT is given in Fig. The two groups of patients were numerically comparable, consisting of 80 patients in each group. No differences were seen between the groups in mean age, duration of surgery, initial and postoperative life parameters (excluding the pulse rate on day 0 in the control group), perioperative risk according to the ASA scale, postoperative efficiency, possible complication development, perioperative mortality on the POSSUM scale, as well as comorbidities. Significantly longer time of postoperative hospitalization values were seen in the control group Tables , 2. ThisIn the postoperative period the analysis focused on pain sensation on day 0 based on the NRS scale at rest calculated every 6 h, and the dosage of analgesic agents administered on the day of surgery. The duration of femoral nerve block and the elapsed time without pain before NRS pain score reached a level of 2 points correlates with the time of administration of the first postoperative analgesic dose Fig. , 5. ThesOnly 21 of 80 subjects (26%) received oxycodone hydrochloride in view of an NRS score at rest ≥ 4 in the study group, whilst 71 of 80 patients (89%) in the control group. A statistically significant difference (p = 0.000139) is confirmed with a positive linear correlation (r Pearson) Fig. The analysis in the postoperative period also included triggers of pain such as inflammatory parameters in the two groups: leukocytosis (WBC) levels and CRP values on postoperative day 0, 1, 2, 3 in blood and fluid collected from surgical wound drains. Glycemic levels in consecutive postoperative days were determined Table .Table 3L15. This preceding mobilization limits the time of hospitalization, as well as the risk of infectious and other complications15.The large joint arthroplasty in agreement with the ERAS protocol requires analgesic management for initiation of rehabilitation as early as on the day of surgery18 equaling 3.01 days in the study group. In the control group this time was significantly longer by 2 days (p = 0.0113) due to (1) prolonged and more severe pain on day 0, as illustrated by the level of pain on the NRS scale, which necessitated employing higher doses of analgesics including opioids   18 equal16. Similarly, in Gotland’s hospitals in the period of 2011–2015 the postoperative hospitalization time of 6374 patients following TKA was shortened from 5 to 3 days 17. Vehmeijer et al. presented the evaluation of the so-called “outpatient” hospitalization after TKA based on data from Danish centers in the years 2014–2017, only 15 to 20% of patients were discharged earlier than 23 h of postoperative hospitalization, the remaining individuals required hospitalization longer than 1 day19.The ERAS protocol reduced the postoperative time of hospitalization following TKA an average of 3 days, similar to our study. The observation is illustrated by the meta-analysis addressing the years 1990–2015 presented by Osinski et al.20. In our procedures, all patients received regional anesthesia with analgesic peripheral nerve block. In the study and control groups, we observed two patients with difficulties in achieving satisfactory flexion of the operated joint. Two patients in the study group achieved satisfactory flexion of the joint in half the time by post-op day 5, compared to the control group’s average of post-op day 8 and 9. This difference in time resulted from the studied variable: administration of IV methylprednisolone and PO gabapentin as “pre-emptive analgesia” as part of a complete pharmacological sequence of “multimodal pain therapy”.The analysis of 1246 patients by Osinski et al. evaluated the effect of the type of anesthesia with analgesic peripheral nerve block employed in the course of unilateral TKA. The mean postoperative hospitalization time was shorter by 0.9 day in patients who received regional anesthesia as compared to general anesthesia and were able to achieve better knee flexion by a mean value of 10 degrees by postoperative day 413. Gabapentin used as an analgesic medication due to its inhibitory effects exerted on the nociceptors, is employed alone or in combination with celecoxib as “pre-emptive” analgesia15. A significant decrease of the dose of analgesic preparations, including opioid agents, as employed in pain management on the day of TKA followed by their use in consecutive three days 1 h before mobilization allowed for effective rehabilitation and achieving proper degree of knee joint flexion as presented by Lindberg-Larsen et al.8. Gabapentin has no effect on the level of blood morphotic elements, including leukocytosis, glycemia and CRP.Gabapentin, an anti-epileptic drug, shows structural similarity to an inhibitory neurotransmitter γ-aminobutyric acid (GABA) in the central nervous system, binding to the subunit α-2-δ G proteins which regulate voltage gated calcium channels (VGCC), and inhibit excitability and hypersensitivity of neurons of the spinal cord and central nervous system. Gabapentin also reduces activity of the NMDA spinal cord receptors. It causes reduction of pain and hyperalgesia14 as an element of multimodal analgesia in orthopedic surgery24.Glucocorticoids, including synthetics such as dexamethasone and methylprednisolone, maintain the integrity of the blood vessel lining that directly covers the endothelial cells, which in turn preserve anticoagulative and antiadhesive properties. This has an antiedematous effect and restricts the systemic initiation of inflammation. Every surgical procedure, including arthroplasties, breaks the continuity of the vascular endothelium, increasing vascular permeability, leading to edema formation and initiation of the inflammatory cascade in the operative site. Through effects on the activity of cyclooxygenase and lipoxygenase, methylprednisolone imposes restrictions on factors that stimulate nociceptors and directly affects the neuronal pathway of acute pain. Meta-analyses based on studies employing methylprednisolone and placebo present a significant difference in pain assessment using the VAS/NRS scale after 6, 12, 24 and 48 h, and in narcotic agents (morphine preparations) administered parenterally per 1 kg of total body mass on the day of surgery25. Our materials showed no intergroup differences in the initial state, however, severity of comorbidities with respect to their state was measured by the ASA and POSSUM scales , the leukocytosis levels were significantly lower 25.As it was demonstrated in the present material, a single dose of methylprednisolone and gabapentin did not significantly affect fluctuations of glycemic levels in the analyzed patients; however, it should be emphasized that patients with glucose intolerance were excluded from the study Table . SimilarOur study has some limitations that should be taken into account. First, we assessed selected laboratory parameters that were considered important. Second, we used subjective NRS scores for assessment of pain intensity level, as it is commonly accepted and used.30.PROSPECT (procedure specific postoperative pain management) Working Group and the European Society of Regional Anaesthesia and Pain Therapy formulates guidelines for pain therapy with numerous publications outlining the treatment of acute pain in selected major operations. Multimodal analgesics with numerous agents and adjuvants are introduced while employing nerve blocks in order to eliminate narcotic substances and their adverse effects. Multimodal analgesia after knee joint replacement is pending current guidelines. Application of gabapentin is controversial as shown by Kang et al. in a meta-analysis based on 7 studies that compared administration of gabapentin versus placebo. Gabapentin did not demonstrate a decrease in postoperative pain and morphine consumptionIn our study, gabapentin as a “pre-emptive analgesic” in combination with methylprednisolone showed signs of positive effect in reduction of pain and opioid doses after TKA on postoperative day zero.In summary, the use of a single dose of gabapentin and methylprednisolone as “pre-emptive analgesia” in the study group of patients above 65 years old (1) measurably decreased postoperative pain levels as assessed by the NRS scale at rest during all time intervals on the day of the unilateral TKA surgery, and decreased the dose of analgesic agents, including opioid preparations (oxycodone hydrochloride), (2) significantly lowered the levels of inflammatory parameters: CRP values on all postoperative days and leukocytosis (WBC) levels on postoperative day 2 and 3, (3) showed support of circulatory system stability, (4) demonstrated no statistical difference in glycemic levels, and (5) prevented any adverse effects that would delay early rehabilitation in accordance with the ERAS protocol.