We explored whether increased C-nociceptor excitability predicts analgesic effects of topical lidocaine in 33 patients with mono- (n = 15) or poly-neuropathy (n = 18). Excitability of C-nociceptors was tested by transcutaneous electrical sinusoidal (4 Hz) and half sine wave (single 500 ms pulse) stimulation delivered to affected and non-affected sites. Analgesic effects of 24 hrs topical lidocaine were recorded. About 50% of patients reported increased pain from symptomatic skin upon continuous 4 Hz sinusoidal and about 25% upon 500 ms half sine wave stimulation. Electrically-evoked half sine wave pain correlated to their clinical pain level . Lidocaine-patches reduced spontaneous pain by >1-point NRS in 8 of 28 patients . Patients with increased pain to 2.5 sec sinusoidal stimulation at 0.2 and 0.4 mA intensity had significantly stronger analgesic effects of lidocaine and in reverse, patients with a pain reduction of >1 NRS had significantly higher pain ratings to continuous 1 min supra-threshold sinusoidal stimulation. In the assessed control skin areas of the patients, enhanced pain upon 1 min 4 Hz stimulation correlated to increased depression scores (HADS). Electrically assessed C-nociceptor excitability identified by slowly depolarizing electrical stimuli might reflect the source of neuropathic pain in some patients and can be useful for patient stratification to predict potential success of topical analgesics. Central neuronal circuitry assessment reflected by increased pain in control skin associated with higher HADS scores suggest central sensitization phenomena in a sub-population of neuropathic pain patients. Neuropathic pain is a common complaint of patients with peripheral neuropathy and considered one of the most disabling neuropathic symptoms . NeuropaCutaneous electrical stimulation is generally used to activate peripheral axons. The geometry of the electrodes and the temporal stimulation profile is critical for a selective activation of peripheral nerve fibers –14. SlowAssuming that our excitability tests primarily assess the most superficially located skin nociceptors we hypothesized that topical lidocaine as a potent sodium-channel blocker widely used in the treatment of neuropathic pain  should bThe Institutional Review Board of the North-West Ethics Committee (Switzerland) and the Ethics Committee II at the Medical Faculty Mannheim of the University of Heidelberg (Germany) approved the study protocol (project #2016–02048 and #2016-568N-MA). All institutional and governmental ethical regulations for human research were considered and the research conducted in accordance with the Declaration of the World Medical Association. Patients were informed about the study procedure and signed written informed consent.Subjects suffering from chronic pain were recruited at the Center for Pain Medicine in Nottwil (Switzerland) and the Pain Center of the Department of Anesthesiology at the Medical Faculty Mannheim of the University of Heidelberg (Germany). Inclusion criteria of the patients were (i) age 18 to 65 years, (ii) sufficient understanding of German language, and (iii) definite or at least probable peripheral neuropathic pain according the current criteria . Exclusi® tester . Diagnosis of peripheral neuropathic pain was made according the medical history, clinical examination and concomitant current criteria of neuropathic pain [All patients underwent a comprehensive neurological interview including pain history and neurological disease. Experienced physicians and neurologists (G.L. and B.G.) performed a clinical neurological examination, which included the assessment of muscle power, reflexes and sensory profiles . Briefly, mechanical and cold dysesthesia/allodynia, and pinprick hyperalgesia were identified using a standardized brush , a metal roll  kept at room temperature (20–23°C), and the tip of a Neuropenhic pain . PatientA standardized pain history was obtained using the validated pain questionnaire and pain drawings of the German Society for the Study of Pain . AnxietyAll patients underwent a training session to familiarize with the transcutaneous electrical stimulation paradigm and the use of the numeric rating scale . In this session we delivered sinusoidal 4 Hz pulses for 2.5 sec at intensities of 0.05, 0.1 and 0.2 mA intensity, as well as single half sine wave pulses (500 ms duration) of 0.2, 0.4 and 0.8 mA intensity, respectively, to the patients non-affected forearm skin. Electrical stimuli were administered by means of a pair of bipolar platinum electrodes  mounted in a 3D-printed applicator and held by the investigator attached to the patients’ skin surface. Sinusoidal 4 Hz and 500 ms half sine wave pulses were generated by a constant current stimulator  connected to a Digital-Analogue Converter  controlled by Dapsys 8 software . For each stimulus paradigm patients rated the corresponding pain intensity on a numeric rating scale (NRS) with the endpoints 0 (no pain) and 10 (maximum pain that can be imagined). Data of the training session were not included in the analysis.Sinusoidal stimuli of 4 Hz were delivered to non-affected (control) and neuropathic skin for 2.5 sec (10 pulses) and with random intensities of 0.05–0.4 mA. Patients estimated the maximum perceived pain for each stimulus on the NRS (0–10). Continuous 4 Hz sinusoidal stimuli of supra-threshold intensity (definition see below) were delivered for 60 sec to non-affected (control) and painful (neuropathic) skin sites, respectively, and the corresponding pain intensity (NRS 0–10) recorded from the patient at 5 and 10 sec after stimulus onset, and thereafter in 10 sec intervals until stimulation termination. The current intensity for supra-threshold stimulation was defined by a pain of NRS 2–3 reported during the 10 sinusoidal pulses  assessed before from the patients’ painful (neuropathic) skin site. Thereafter, single half sine wave stimuli of 500 ms duration were administered with randomized current intensities of 0.2–0.4–0.6–0.8–1 mA to the non-affected and painful skin site, respectively.All tests  were performed twice for each current intensity and body site . In unilateral pain syndromes, such as mononeuropathy or radiculopathy, the contra-lateral body site was chosen as non-affected (control) skin site. In bilateral pain syndromes, such as polyneuropathy, a non-affected proximal limb area was chosen as control test area.In addition to the recorded NRS data, delta values of perceived pain were calculated by subtraction between neuropathic and non-affected control skin sites for 2.5 sec sinusoidal 4 Hz pulses delivered with 0.2 and 0.4 mA, for the final 30 sec of continuous 1 min 4 Hz sinusoidal stimulation, and for half sine wave pulses of 0.8 and 1 mA intensity, respectively. Patients who perceived the stimuli more painful at the neuropathic site as compared to control skin by NRS differences ≥ 1 were classified “hyper-responsive”. Patients who perceived the stimuli less painful at the neuropathic sites (NRS differences ≤ -1) were grouped “hypo-responsive”, and patients who felt the stimuli similarly painful between the sites (NRS difference -1 to 1) were defined “normal-responsive”.®, Grünenthal, Stolberg (Germany) and Neurodol Tissugel®, IBSA Institut Biochimique SA, Pambio-Noranco (Switzerland)) on the patients’ neuropathic (painful) skin. Dependent on the area and field size of neuropathic pain, the patch covered 7x5 cm , 7x10 cm  or 14x10 cm , and the electrically tested site. Spontaneous (acute) pain (NRS 0–10) was recorded prior to patch application (t 0) and patients instructed to monitor the sensation at this site 30 min, 1h, 2h, 3h, 4h, 6h, 8h, 12h and 24h thereafter. Efficacy of the lidocaine 5% patch on spontaneous pain was assessed by calculating the difference between t 0 and the average pain estimates recorded during 3h and 12h lidocaine application, respectively. Thereupon, NRS differences ≤ -1 were defined as pain amelioration upon patch administration and NRS difference ≥ 1 as pain increase. NRS values in between indicated no effect on spontaneous pain.After assessment of transcutaneous electrical nerve fiber stimulation we applied a lidocaine 5% patch . Analysis of variance (ANOVA) was calculated between the factorial groups “neuropathic skin”–“stimulus intensity”–“stimulation time” and post hoc Fisher’s Least Significant Test (LSD) test. In addition, NRS of patients grouped into “hyper-responsive”–“hypo-responsive”–“normal-responsive” were analyzed by ANOVA and Fisher’s post-hoc comparison to identify significant differences between the groups (p < 0.05). The 95% confidence interval (CI) are mentioned in the text. Spearman’s rank correlation coefficient was assessed for NRS differences of electrically evoked pain between neuropathic and control skin site, maximum perceived pain within the last 7 days, acute (spontaneous) pain perceived at investigation time, and the pain relief upon lidocaine 5% patch. Also, sensory symptoms upon thermal and mechanical stimulation, as well as HADS and SF-12 questionnaire scores, respectively, were correlated to electrically and spontaneous (acute) pain. All values are depicted as mean ± SD.In total, 33 patients  were recruited from both Pain Centers and subclassified into “mono-neuropathy” (n = 15) and “poly-neuropathy” (n = 18), respectively . PatientClinical characterization revealed at neuropathic skin sites dysesthesia to touch in n = 8 patients, allodynia to touch in n = 8 patients, and hypoesthesia to touch in 10 patients . HyperalHADS scores of the patients indicated elevated levels of anxiety (9.4 ± 4.2) and depression (8.7 ± 4.4). SF-12 values indicated low physical (29.6 ± 8.6) and mental (43.7 ± 10.9) health related quality of life . The vasversus control skin site . Pain estimates were significantly lower in neuropathic skin compared to the non-affected sites at current intensities of 0.1 to 0.4 mA  induced current intensity dependent pain  and a significant difference between the patients’ neuropathic Dependent on the NRS during 2.5 sec of 4 Hz stimuli and as defined above, we administered supra-threshold 4 Hz sinusoidal pulses continuously for 1 min to the patients’ skin sites. A current intensity of 0.1 mA was applied in n = 6 patients, 0.2 mA in n = 22, and 0.4 mA in n = 6 patients. Notably, in the latter group (0.4 mA stimulation), n = 3 patients reported an NRS < 1 upon the 10 sinusoidal pulses delivered at their painful skin site.During continuous supra-threshold 4 Hz sinusoidal stimulation, pain recorded from neuropathic and control skin was significantly different over time . In particular, pain recorded from control skin declined after 20 sec of stimulation, but remained elevated in neuropathic skin , revealiversus NRS 2–3 in control skin . In contrast, patients classified “hypo-responsive”  reported NRS 2–4 in neuropathic compared to NRS 5–6 in control skin , the delivered “current intensity” and the investigated “skin site”  for pain upon 2.5 sec 4 Hz sinusoidal pulses. Average pain in “hyper-responsive” patients (n = 7) was NRS 5–6 in neuropathic Continuous 1 min 4 Hz supra-threshold sinusoidal stimulation evoked in 17 patients enhanced pain, particularly during 30 to 60 sec of stimulation, in neuropathic  compared to control skin sites . 8 patients reported that the 4 Hz stimuli were similarly painful in neuropathic and control skin , whereas 8 patients, however, indicated stronger pain at the control sites  pain was rated by the patients on average NRS 3.4 ± 0.5 at the neuropathic skin site t 0, . During We evaluated whether the pain reduction upon lidocaine was associated with the magnitude of patients’ acute (spontaneous) or maximum pain perceived during the last 7 days prior assessment, respectively. NRS changes evoked by 12 hours lidocaine patches correlated significantly to spontaneous pain intensity in 7 patients who reported a pain amelioration  and maximum 7-day pain, to pain amelioration upon 3 respectively 12 hours lidocaine 5% patches, and to pain evoked by transcutaneous electrical stimuli delivered at high current intensities . ElectriC-nociceptor excitability in neuropathic pain patients as assessed by slowly depolarizing electrical pulses was increased in symptomatic skin in about 1/3 of the patients. Patients that were hyper-responsive to short bursts of 4 Hz stimulation showed a significantly higher analgesic effect to topical lidocaine. Patients who reported a pain reduction of > 1 NRS to topical lidocaine had significantly higher pain ratings during ongoing 1 min 4 Hz sinusoidal stimulation, suggesting C-nociceptor excitability tested by slow electrical depolarization might be related to mechanisms generating neuropathic pain and could potentially improve patient selection for topical analgesic therapy.Slowly depolarizing transcutaneous electrical stimulation  induced burning pain in healthy subjects, activated primary afferent C-nociceptors, and revealed substantial accommodation upon continuous 4 Hz sinusoidal stimulation , 17, 18.No significant correlation was identified between electrically evoked pain to sinusoidal stimulation and the patients’ intensity of acute (spontaneous) or maximum 7-days pain, respectively. In contrast, a sub-population of patients reported significantly stronger pain upon a single 500 ms half sine wave pulse in neuropathic skin that positively correlated to their maximum 7-days pain. It could be hypothesized that significantly elevated pain at this body site upon a single electrical half sine wave stimulus indicated increased supra-threshold responses of mechanical- and heat-sensitive  nociceptors being activated by this stimulation paradigm . EnhanceWe were not able to provide a clear correlation between our electrically induced read-outs and the patients’ pain reported from neuropathic skin. This observation highlights the yet unsolved problem to mechanistically differentiate neuropathic patients with and without chronic pain . HoweverWe further explored the efficacy of a topical lidocaine 5% patch on spontaneous (acute) and maximum 7-days pain and its correlation to electrically induced pain. There is a controversial discussion about the efficacy of topical lidocaine for the treatment of neuropathic pain (for review see ). Here, On the other hand, patients reporting a beneficial effect of lidocaine experienced stronger pain in neuropathic skin upon 1 min sinusoidal but not half sine wave stimulation. Activation of C-nociceptors by 4 Hz sinusoidal pulses also provoked an axon-reflex mediated vasodilation , thus thSlowly depolarizing ramp currents evoke a strong sodium channel NaV1.7 ramp current , 40 and Our results suggest that hyperexcitability of C-nociceptors might contribute to clinical neuropathic pain in a subgroup of our patients. Analgesic effects of topical lidocaine were higher in patients positive for touch evoked allodynia, hyperexcitable to sine wave stimulation, and with higher baseline pain levels. These aspects might therefore be considered useful for a patient stratification. On the other hand, the link between higher anxiety and depression levels correlating to increasing pain ratings to 4 Hz sinusoidal stimulation in control skin highlights the important role of central nervous system circuitry in chronic neuropathic pain.S1 FigAnalysis between pain reduction upon 3 hours lidocaine 5% patch  and pain recorded from neuropathic (delta NRS from control skin sites) during (A) 2.5 sec 4 Hz sinusoidal pulses of 0.2 and 0.4 mA, (B) within the last 30 sec of 1 min 4 Hz supra-threshold sinusoidal pulses, and (C) upon 500 ms single half sine wave pulses of 0.8 and 1 mA. Patients are grouped “hyper-responsive” (solid squares”), “hypo-responsive” (open squares) or “normal responsive” (open circles) to transcutaneous electrical stimuli.(TIF)Click here for additional data file.S2 FigAnalysis between pain from neuropathic skin sites (delta NRS neuropathy vs. control) and acute (spontaneous) pain (left panel) or maximum pain perceived during 7 days (right panel) upon (A) 2.5 sec 4 Hz sinusoidal pulses of 0.2 and 0.4 mA, (B) within the last 30 sec of 1 min 4 Hz supra-threshold sinusoidal pulses, and (C) upon 500 ms single half sine wave pulses of 0.8 and 1 mA. A significant correlation was identified between neuropathic skin site pain upon half sine wave stimulation and the 7-day maximum pain (p < 0.05). Scatterplot depicts patients’ groups by their lidocaine-patch response of acute (spontaneous) “pain-amelioration” (solid squares), “pain elevation” (open squares) or “no change” (open circles), respectively.(TIF)Click here for additional data file.S1 Table(A) Spearmans rank correlation between sensory profiles and NRS scores. (B) Spearmans rank correlation between questionnaire scores (HADS and SF-12) and acute (spontaneous) pain, 7-day pain, and electrically evoked pain in neuropathic (NP) and control (ctr) skin.(DOCX)Click here for additional data file.


Preoperative LBP rated three on a numeric rating scale (NRS) had the highest combined sensitivity (75.3%) and specificity (58.3%). Patients with LBP above NRS 3 had more severe postoperative pain than those who did not , leading to more opioid requirement in the recovery room . Preoperative LBP intensity is a useful factor for identifying patients at risk for pain after gynecologic laparoscopy.We hypothesized that preoperative lower back pain (LBP) may be associated with the severity of postoperative pain after gynecologic laparoscopy. This prospective observational study aimed to investigate the association between preoperative LBP and postoperative pain. We assessed the intensity of LBP before surgery and the postoperative pain after surgery. The abilities of preoperative LBP intensity, age, body mass index, and anesthetic duration time to predict moderate-to-severe postoperative pain were measured using receiver operating characteristic analysis. The data of 148 patients were analyzed. Only preoperative LBP intensity showed a significant association with moderate-to-severe postoperative pain (area under the curve, 0.71; 95% confidence interval, 0.63–0.79;  Although laparoscopic surgery has advantages such as enhanced postoperative recovery and decreased hospital stay in comparison with open surgery ,2, the iThe lithotomy position required during gynecologic laparoscopy is ergonomically difficult on the lower back. Therefore, if the patient has preoperative lower back pain (LBP), the severity of LBP will increase due to the lithotomy position, which naturally leads to a negative impact on postoperative pain. However, to our knowledge, no reports have validated such claims. We hypothesized that preoperative LBP is associated with more severe postoperative pain in the recovery room.This study aimed to investigate the association between preoperative LBP and postoperative pain after gynecologic laparoscopy and the ability of preoperative LBP intensity to predict moderate-to-severe postoperative pain in the recovery room.This prospective clinical observational study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of Seoul St. Mary’s Hospital, Catholic University of Korea  on 7 March 2021, and registered at ClinicalTrials.gov (NCT04793191). Written informed consent was obtained from 150 female patients scheduled for gynecologic laparoscopy including hysterectomy, adnexectomy, cystectomy or cyst enucleation, and myomectomy.The exclusion criteria were incapacity to provide consent, emergency surgery, cancer surgery, chronic pain except LBP, chronic substance use, history of psychiatric disease, pregnancy, or lactation. Before starting the study, patients were instructed on how to assess their pain intensity using a numeric rating scale . Moreover, the patients were asked the following question: “Have you had any pain in your lower back? If any, how much is the worst pain you have experienced?” LBP intensity was recorded using the NRS.All patients underwent standard induction of anesthesia  and orotracheal intubation. Anesthesia was maintained with 4–6% desflurane (expired concentration) in 40% air/oxygen  to maintain a bispectral index between 30 and 60. Ventilation was controlled mechanically and adjusted to maintain an end-tidal carbon dioxide value between 25 and 40 mmHg throughout the surgery. Additional rocuronium was administered, as required. Laparoscopy was performed under video guidance, with three punctures in the abdomen. The intraperitoneal pressure was maintained at approximately 12 mmHg. To prevent postoperative nausea and vomiting (PONV), all patients received 5 mg intravenous dexamethasone at the beginning of surgery and 75 μg intravenous palonosetron at the end of surgery. For postoperative pain control, multimodal analgesia, consisting of intravenous acetaminophen (500 mg) and ketorolac (30 mg), was administered 30 min before the end of surgery. These non-opioid analgesics were continued throughout the hospital stay in the ward.After confirming self-respiration, patients were extubated and transferred to the recovery room. Postoperative pain intensity was assessed using the NRS upon arrival in the recovery room and every 15 min thereafter. If the patient complained of pain (NRS > 4), 0.5–1 μg/kg intravenous fentanyl was administered immediately after assessing and recording the pain intensity. If the patient complained of nausea and/or vomiting, 10 mg intravenous metoclopramide was administered. After leaving the recovery room, intravenous patient-controlled analgesia  was applied to all patients. In the recovery room, pain intensity, requirement for pain killers, and incidence of PONV were assessed. These were again evaluated in the ward 24 h after surgery.The calculation of the sample size was based on the aim of detecting any clinically meaningful value of preoperative LBP intensity to predict moderate-to-severe acute pain (NRS 4–10) in the recovery room, defined as an area under the curve (AUC) of the receiver operating characteristic (ROC) curve of at least 0.7. To detect such differences, 50 patients in each group  were deemed necessary. Based on our clinical experience and previous research [t-test or Mann–Whitney U test was used to analyze quantitative variables, and the chi-squared or Fisher’s exact test were used to analyze qualitative variables. The abilities of preoperative LBP intensity, age, body mass index (BMI), and anesthetic duration to predict moderate-to-severe acute pain (NRS 4–10) were measured using ROC analysis. Cut-off values used for the calculation of sensitivity and specificity were calculated based on goodness of fit (highest combined sensitivity and specificity). Kaplan–Meier curves were used to evaluate the time to rescue fentanyl in the recovery room, using the log-rank test. All analyses were performed using SPSS version 20 . Statistical significance was set at p < 0.05.Data were tested for normal distribution using the Kolmogorov–Smirnov test and are presented as means with standard deviations or medians with 25th and 75th percentiles. The independent Between March 2021 and January 2022, a total of 150 patients meeting the inclusion criteria were included in this study, and two patients were excluded because of conversion to open surgery. Data from 148 patients were analyzed.n = 2), mild , moderate , or severe pain . To investigate the ability to predict moderate-to-severe (NRS 4–10) postoperative pain, ROC analysis was performed for preoperative LBP intensity, age, BMI, and anesthetic duration. Among these parameters, only preoperative LBP intensity showed a significant association with moderate-to-severe pain  and specificity (58.3%). Additionally, we performed binary logistic regression to analyze the factors influencing moderate-to-severe postoperative pain. The presence of the moderate-to-severe postoperative pain (yes or no) was the independent variable. The dependent variables were age, BMI, anesthetic duration, adhesion (yes/no), type of laparoscopic surgery (hysterectomy/adnexectomy/cystectomy or cyst enucleation/myomectomy), and preoperative LBP intensity (NRS ≥ 3/NRS < 3). For the goodness-of-fit test of the multivariate model, we performed the Hosmer–Lemeshow test. We found that patients with preoperative LBP ≥ 3 had a higher risk of moderate-to-severe postoperative pain than the other patients [odds ratio (OR) 3.79, 95% CI 1.77–8.10, ive pain .Consequently, we compared patients who had preoperative LBP intensity levels ≥ 3 with those who did not. There were no significant differences in the demographic or surgical data between patients who had preoperative LBP intensity ≥ 3 and those who did not, except preoperative LBP intensity .p < 0.001, p = 0.014) and more severe postoperative pain scores among patients in the ward .However, the postoperative pain score in the recovery room was significantly higher in those with LBP intensity ≥ 3 than in those with LBP intensity < 3 .Moreover, the proportion of patients who did not receive postoperative fentanyl within 60 min after awakening was significantly lower in those reporting preoperative LBP intensity levels ≥ 3 than in those reporting levels < 3. Postoperative fentanyl was administered significantly earlier in patients with preoperative LBP intensity ≥ 3 than in those with preoperative LBP intensity <3  can be used to predict moderate-to-severe postoperative pain after gynecologic laparoscopy. Preoperative LBP intensity ≥NRS 3 was associated with earlier and more frequent administration of opioids in the recovery room.Laparoscopy is generally expected to result in less postoperative pain than laparotomy is. However, patients frequently experience more severe pain than expected after awakening from general anesthesia, which was confirmed by our results showing that 66% (41 + 56/148) of patients had moderate-to-severe postoperative pain in the recovery room. This is in accordance with a previous report where laparoscopy caused unexpectedly high levels of postoperative pain, and 70% of the patients did not receive adequate analgesia . These fThe well-known risk factors are sex , age (young vs. old), and type of surgery (open surgery vs. laparoscopy) ,8,9,10. In general, females have more postoperative pain than males . ConsideAlthough opioids are potent analgesics without ceiling effects , they arThis study has some limitations. First, this finding might not extend to other surgeries, such as laparotomy. However, considering the overwhelmingly large proportion of laparoscopies performed for gynecologic benign disease , our resIn conclusion, this study shows that preoperative LBP intensity above NRS 3 is associated with more severe postoperative pain and with earlier and more frequent administration of opioids after gynecologic laparoscopy. Preoperative LBP intensity is a useful factor for identifying patients at risk for pain after surgery, which can lead to more appropriate management of these patients. In addition, a preoperative assessment of LBP can be easily performed without specific equipment or training.


Root canal treatment (RCT) eliminates damaged pulpal tissue and protects the tooth from recurrent microbial invasion. Post-endodontic pain (PEP) is a frequently encountered complication of root canal therapy. It can have an impact on patients’ quality of life (QoL) and their subjective perception of treatment options. Thus, a self-assessment questionnaire was used to evaluate and compare the influence of manual, rotary, and reciprocating file shaping procedures on immediate post-operative quality of life (POQoL) involving single-visit root canal therapy. It was a double-blinded, randomized, controlled clinical trial. A total of 120 participants were randomly assigned sequentially to three groups comprising 40 patients in each group: Group A: Hand K file (positive control); Group B: ProTaper Next file system; and Group C: WaveOne Gold. Post-operative pain was evaluated using a 4-point visual analog scale (VAS) after 12 h, 24 h, 48 h, 72 h, and 1 week. The highest post-operative pain was with manual instrumentation using hand K files, and the lowest was with reciprocating and rotating instrumentations. No significant difference was noted between the parameters of quality of life assessed, suggesting the filing system or technique had a similar effect.  Root canal therapy (RCT) is a conservative therapeutic option that entails the removal of diseased pulpal tissue and prevents or treats pulpal/periradicular pathosis and safeguards the treated tooth from recurrent microbial invasion ,2.Post-endodontic pain (PEP) is a hallmark symptom of root canal therapy and a determinant of long-term failure. PEP typically develops because of acute inflammation in the tissues surrounding the root. Numerous factors can contribute to it, such as preparation that extends past the apical endpoint, insufficient pulp tissue removal, excessive root canal filling material, and the extrusion of dentinal and pulpal debris into the periapical region. Even when the preparation is kept at the apical endpoint, apical extrusion can still happen while using any instrumentation approach, whether manual or mechanical . During Debris extrusion has been reported to vary between various rotary systems, which can be attributed to variations in cross-sectional geometry, cutting blade design, taper, flute depth, tip and file sequence, kinematics, and cutting efficacy. Additionally, it has been proposed that the reciprocating motion itself may contribute to the packing of the debris into the irregularities of the root canal space and pushing them past the apical foramen, raising the possibility of post-operative discomfort. Employing nickel–titanium (NiTi) shaping instruments in rotary or reciprocating motion reduces cycle fatigue and improves root canal centering ability. Because varying amounts of irritants are extruded from the root canal area, different nickel–titanium (Ni-Ti) rotational systems may produce varied patterns of neurogenic inflammatory response in the periodontal ligament . The recSodium hypochlorite (NaOCl) is the most preferred irrigant administered during root canal therapy because of its many advantages, including its antibacterial activity, antibiofilm activity, and organic tissue dissolving effectiveness. However, it can irritate periapical tissues, particularly at high concentrations, and can elicit an inflammatory response even at concentrations as low as 0.5%, which may indicate a higher chance of post-operative discomfort .Patient quality of life (QoL) and subjective assessments of treatment options can both be impacted by post-operative pain. In the context of a person’s expectations, comfort is a complicated issue relating to socioeconomic, cultural, and health demands. It is an annoying experience for the patient, undermining the patient–clinician relationship. QoL following dental treatment can be evaluated through self-assessing questionnaires such as oral health-related quality of life (OHIP) and post-operative quality of life (POQoL) surveys. The subjective evaluation of the therapy’s effect on the quality of life for seven days after treatment is used in POQoL assessments, which gauge how everyday activities, including eating, speaking, sleeping, and engaging in social interactions, are affected . In earlier studies that examined the relationship between root canal therapy and patient quality of life, it was discovered that many patients perceive it negatively because it is frequently associated with pain. More consideration is being given to the viewpoints of the patients in their care, and post-operative QoL may be used to assess the overall efficacy of endodontic therapy ,5. Few studies have suggested that rotary shaping is related to a higher post-operative quality of life because it reduces debris extrusion past the apex during canal instrumentation . Spohr eThis randomized controlled clinical trial  was prepared and presented in accordance with CONSORT criteria . This stn = 40) in each group. The sample size was calculated using G-Power 3.1.9.2. A power analysis was performed based on where α = 0.05, Power = 0.80, and Effect size 0.91. A total of 120 sample size was calculated considering loss to follow-up, which was divided into  in a single visit to minimize interpersonal variability in the treatment procedures. A thermal test and an electric pulp-testing device  were used to assess the sensibility of the pulp. The code for different instrumentation techniques was assigned by the principal investigator. The patients were randomly allocated to 3 groups  of 40 ean = 40): The canals were instrumented using a modified step-back technique with stainless steel hand files . Minimal preliminary instrumentation was performed using a 15/0.02 hand file. During the modified step-back preparation, coronal 2/3rd was flared using Gates–Glidden burs 2 and 3. Apical 3rd was prepared to the master apical size of 25 K/0.02, and then the step-back technique was performed to 40 K/0.02. The depth of insertion of each larger file was reduced by 1mm. Apical patency was controlled using a 25 K/0.02 file. The flutes of the instrument were cleaned after every instrumentation. A new set of files was used in every study patient. Group 1: Modified step-back (n = 40): The canal was instrumented using a ProTaper Next  rotary file. Minimal preliminary instrumentation was performed using a pathfinder file, i.e., Path File, and prepared until X2 (025/0.06) in the sequence of X1 (017/0.04), X2 (025/0.06) at a rotational speed of 300 rpm and 200 g/cm torque according to the manufacturer’s instruction. The instruments were handed down up to the working length. The flutes of the instrument were cleaned after every instrumentation. A new set of files was used in every study patient. Group 2: Rotational technique (n = 40): The canals were instrumented using WaveOne Gold  files as per the manufacturer’s instruction. Minimal preliminary instrumentation was performed using a Glider file No.015/0.02. The canal was prepared up to a size of 25/0.08 in a slow in-and-out pecking motion combined with a brushing motion. The instrumentation was performed until working length. The flutes of the instrument were cleaned after every instrumentation. A new set of files was used in every study patient. Group 3: Reciprocating technique  included response scores on a 5-point Likert scale coded as 0 = Never; 1 = Hardly ever; 2 = Occasionally; 3 = Fairly often; 4 = Very often. A trained dental assistant who was blinded to the study procedures instructed the patients to complete a modified Heft–Parker visual analog scale (VAS) to rate their pain at 12 h, 24 h, 48 h, 72 h, and 1-week post-operative intervals. The patients were instructed to take mild analgesics (400 mg of ibuprofen every 6 h) if they felt pain and required pain relief. However, they were also asked to record the number of analgesic tablets on their modified Heft–Parker VAS forms. Post-operative pain was evaluated using a 4-point VAS scale after 12 h, 24 h, 48 h, 72 h, and 1 week, where 1: No pain; 2: Mild pain—mild discomfort, no need for treatment; 3: Moderate pain—discomforting, relieved by analgesics; 4: Severe pain—difficult to bear . Computer-generated tables were used to establish the randomized sequence. An operator who was not administering the clinical therapy generated blinded envelopes with each patient’s randomized allocation. The allocation was given to the clinician by the same operator after the initial patient evaluation and before root canal instrumentation.p-value less than 0.05 was considered to be statistically significant. The collected data were statistically analyzed using the Statistical Package for the Social Sciences . Data were compared using particular statistical tests to determine the statistical significance of the comparisons. To establish the normality of the data for quality of life and pain metrics for the three separate file-treated groups, the Kolmogorov–Smirnov and Shapiro–Wilk tests were used. Both tests revealed no significant differences, confirming that the data were normally distributed. Variables were compared using mean values and standard deviation. One-way Analysis of Variance (ANOVA) was run to find significant differences between the three groups for quality of life before and after treatment. Paired t-test compared the quality of life in the same group. Repeated measures ANOVA was applied to find significant differences in each group at various time intervals of 12 h, 24 h, 48 h, 72 h, and 1 week for pain. A p = 0.035, with Group 3 having a greater mean followed by Group 1 and Group 2  in endodontic patients treated before and after treatment when treated with three different types of filing systems. QoL remained similar in all groups for all the domains except Physical Disability which was statistically significant at  Group 2 .No significant difference was noted between the parameters of quality of life assessed after treatment among the groups, as seen in F = 32.603, p = 0.000), Group 2 , Group 3 . Therefore, we can conclude that the results for the ANOVA indicate a significant time effect for VAS as measured in all groups, as seen in Repeated-measures ANOVA test determined that mean VAS scores differed significantly across 5 timepoints for Group 1  questionnaires and post-operative quality of life (POQoL) surveys. POQoL evaluation is based on the subjective judgment of the therapy’s influence on QoL for 7 days after treatment and assesses the impairment of everyday activities such as eating, speaking, sleeping, and social connections. The OHIP-14 is sensitive to change in the setting of endodontic therapy and is likely to be effective in assessing patients’ perceptions of endodontic care results. As a result, in this randomized clinical trial, POQoL was assessed using an OHIP-14 questionnaire [Pre-operative pain is a predictive factor of post-operative pain. As a result, only teeth with vital pulp that were suggested for endodontic treatment due to various causes were chosen for the current investigation . This stThe 120 participants were randomly assigned following simple randomization procedures using the lottery method, without any differentiation or discrimination on the basis of age or gender. Patients were sequentially assigned to three groups comprising 40 patients in each group: Group A: Hand K file (positive control); Group B: ProTaper Next file system; Group C: WaveOne Gold. The hand K file (Group A) was used as the control group in the study using the step-back method. Manual technique with stainless steel files for biomechanical preparation has been more popularly used and, thus, was included in our study. In the current clinical trial, ProTaper was chosen to evaluate the impact of a varied taper along the length of the file in contributing to PEP. Based on M-wire technologies, ProTaper Next claims up to 400% reduced cyclic fatigue than the original NiTi instrument. The design features include multiple progressive tapers, which decreases the possibility of taper lock . ReciproCold lateral compaction is considered the gold standard against other obturation techniques and, thus, was used in the present study because it has been reported that this technique resulted in minimum post-operative pain comparatively. This was also similar to a study by Shaik et al. in 2022 . Each roThere were discernible variations in post-operative discomfort between the three file systems in the current investigation. The duration of pain was the longest in more patients treated with manual instrumentation and least in patients treated with reciprocating instrumentation. Our finding was contrary to that of Atul et al. in 2017, as we found the highest post-operative pain was with manual instrumentation using hand K files, and the lowest was with reciprocating and rotating instrumentations. However, their study findings revealed that K files and ProTaper Next found mild continuous pain in both groups, but the duration of pain was longer for hand instrumentation . ResearcWhen ProTaper rotary and reciprocating WaveOne Gold’s instrumentation were utilized, the pain was minimal. This might be because the flutes on these instruments have a tendency to draw debris back into the orifice, which lowers the amount of extrusion of debris by rotating systems. In contrast, the manual step-back technique tends to plunge the material through the apical foramen, leaving insufficient room for it to be expelled coronally, increasing the likelihood of irritation and pain . RotatinThe WOG group had a quicker improvement in the post-operative conditions, which was accompanied by a greater quality of life score in the early posttreatment days. This was likely caused by reduced debris extrusion . AdditioA study conducted by Shaik et al. in 2022 stated that the incidence of pain followed a similar trajectory, increasing at 8 h in both groups before significantly decreasing at 24 and 48 h . Our finIn a study conducted by Lakshmi et al. in 2021, “physical pain” and “psychological discomfort” were the post-operative period’s worst effects. Higher scores were also identified in the domains of physical pain and psychological discomfort in studies examining the association between endodontic factors and OHRQoL, demonstrating that symptoms and harm are the first lines of communication for endodontic disorders . In our The dentist must provide care that can prevent or treat the side effects of such therapy in addition to conducting root canal preparation with adequate disinfection and pain control. A more holistic approach results in a greater dedication to post-operative care, which unquestionably affects the quality of life. A reduced sample size in each group and the exclusion of variances between single- and multiple-rooted teeth are two limitations of the current study. This observational study’s shortcomings may also be attributed to the patients’ psychological well-being, subjective assessments of their level of discomfort, level of understanding of the questionnaire by the participants, and opinions about root canal therapy. Further prospective studies are needed to ascertain the causative factors of post-operative pain, taking into consideration the central and peripheral pathways of pain. More systematic reviews and meta-analyses need to be documented to help us discover the association of post-operative pain with instrument design and kinematics. Within the parameters and limitations of this randomized clinical trial, the following conclusions can be drawn. Hand, rotary, and reciprocating systems tested elicit post-operative pain following single-visit root canal treatment.The intensity of post-operative pain varied between the three groups tested. The PTN group exhibited statistically less pain. The order of intensity in the three groups was PTN < hand file < WOG.At 12 h, higher pain levels were seen, and at 24, 48, and 72 h, the intensity of the pain steadily decreased.No significant difference was noted between the parameters of quality of life assessed, suggesting the filing systems or techniques had a similar effect.


To evaluate the effect of intraperitoneal normal saline instillation (INSI) of 15 mL/kg body weight on postoperative pain after a gynaecological laparoscopic procedure.Randomised controlled trial.University Hospital in Kuala Lumpur, Malaysia.Patients aged 18–55 years, with American Society of Anaesthesiologists (ASA) classification I–II, scheduled for an elective gynaecological laparoscopic procedure for a benign cause.The patients were randomly allocated to two groups. In the intervention group, 15 mL/kg body weight of normal saline was instilled intraperitoneally, while the control group received the conventional combination of open laparoscopic trocar valves with gentle abdominal pressure to remove the retained carbon dioxide.The outcomes measured were the mean pain scores for shoulder and upper abdominal pain at 24 h, 48 h, and 72 h postoperatively.A total of 68 women completed the study, including 34 women in each group. There was no difference in the shoulder pain score at 24 h, 48 h, and 72 h postoperatively. However, a significant improvement in the upper abdominal pain score after 48 h  and 72 h  postoperatively were observed.INSI of 15 mL/kg body weight does not lower postoperative shoulder pain compared to no fluid instillation. A modest pain score improvement was observed in the upper abdominal area at 48 h and 72 h after surgery. An INSI of up to 30 mL/kg body weight may be required to eliminate shoulder pain. Care must be taken before administering a higher amount of INSI, considering the potential risk of peritoneal adhesions.Clinical registration ISRCTN Identifier: 87898051 (Date: 26 June 2019) https://doi.org/10.1186/ISRCTN87898051 Postoperative pain should be addressed effectively as it can complicate a patient’s recovery process. Inadequate postoperative pain control is associated with impaired quality of life, delayed recovery, and prolonged use of opioids, with a concurrent increase in healthcare costs . DespiteIntraperitoneal normal saline instillation (INSI) is a pain reduction method that functions by washing out residual carbon dioxide –9. MoreoIn gynaecological surgery, this pain reduction technique has been implemented in several different studies. It was found that INSI significantly reduced shoulder and upper abdominal pain compared to no fluid instillation –11, 13. A laparoscopic surgeon should take extra precautions when considering INSI. The peritoneum is composed of a single layer of mesothelial cells and is responsible for facilitating the gliding of the bowel via its microvilli, glycosaminoglycans, and surfactants . Periton2, well-controlled diabetes mellitus/mild hypertension, mild lung disease). Patients with known drug allergies to substances in parecoxib, celecoxib, paracetamol, or having received analgesia 12 h before the scheduled procedure were excluded. This study was registered and approved by the Ministry of Health Research and Ethics Committee (MREC) of the National Medical Research Register (NMRR) and the Clinical Research Centre, Malaysia (NMRR-19-1532-48232) on 06/03/2019 and the Medical Research Ethics Committee of the University Malaya Medical Centre (MREC ID No: 201926-7106) on 20/03/2019. Furthermore, the International Standardised Randomised Controlled Trial Number (ISRCTN) for this study was registered with an ID of ISRCTN87898051 (https://doi.org/10.1186/ISRCTN87898051), dated 26/06/2019. This trial was conducted in accordance with the Declaration of Helsinki (2000) for human studies.This study was carried out in the general operating theatre of the University Malaya Medical Centre, Kuala Lumpur, Malaysia. Written informed consent was obtained during patient visits to the gynaecology clinic a few weeks before the date of surgery or during ward admission a day before the surgery. Patients assigned to the American Society of Anaesthesiologists (ASA) physical classification  of I or www.randomization.com) by a research assistant (RA-A) who was not involved in the recruitment process. The same research assistance kept the master list for the randomised treatment allocation sequences. Concealment was performed using serially numbered opaque, sealed envelopes containing a paper with the legend ‘INSI’ or ‘Control’. The following available randomisation number was assigned to the patient once she consented to participate. Upon arrival at the theatre, the allotted envelope was subsequently given to the operating theatre nurse, who was not involved in managing the patient. The envelope was opened at the end of the surgery before the removal of laparoscopic trocars. Patients who withdrew from the study before surgery were replaced by the next consenting patient. However, patients who withdrew from the study at the end of surgery were counted as dropouts, and no replacement was made.Women were assigned to two groups in a 1:1 ratio using a random-permuted block randomisation algorithm via a web-based system , fentanyl (1–2 mcg/kg), metoclopramide (10 mg), and atracurium (0.3–0.6 mg/kg). Anaesthesia was maintained with 50% nitric oxide, 50% oxygen, and 1–2% sevoflurane. No other analgesic was administered intraoperatively.For each laparoscopy, while the patient was in the supine position, a sub-umbilical incision was made, and a 10-mm trocar was inserted sub-umbilically under direct vision. Pneumoperitoneum was created by insulating 2.5 L of carbon dioxide into the peritoneal cavity. Another 5-mm trocar was inserted into the right iliac fossa, left iliac fossa, or suprapubic region. At the end of the surgery, patients allocated to both groups were placed in the Trendelenburg position (30°). Subsequently, trial protocols were carried out as follows:The intervention group (INSI): Intraperitoneal normal saline (15 mL/kg body weight) , 11 was The control group: Trocar sleeve valves were left open to allow carbon dioxide to escape from the abdominal cavity with gentle abdominal pressure.In both groups, the trocar incision site was closed in two layers using Vicryl 3/0 or Monosyn 3/0. Patients were then placed in a neutral position, and standard protocols of anaesthesia reversal were carried out.The patients received standard postoperative care in the ward and were discharged according to the discretion of each managing team. A standard regime of analgesia was administered to all women, in which 1 g of paracetamol and 40 mg of parecoxib were administered intravenously, or 75 mg of suppository diclofenac acid was administered at the end of the surgery. This was followed by standard regular doses of 1 g paracetamol every 6 h for 5 days. Additional doses of analgesia , when administered, were recorded.The outcomes of this study were the severity of pain in the shoulder and upper abdominal areas at 24 h, 48 h, and 72 h after the laparoscopic surgery. It was measured using a 0–10 visual analogue score (VAS), where 0 = no pain and 10 = worst possible pain. The VAS has been adapted by the Ministry of Health Malaysia as a pain assessment tool .Women rated their postoperative pain using the VAS at rest and during movement, at a specific location (shoulder and upper abdomen) and time  postoperatively. The occurrence of nausea, vomiting, and abdominal distension was documented as secondary outcomes. The data were recorded by another research assistant (RA-B), who was blinded to the patients' assigned group. If the patients were discharged before day 3 (72 h), the patients were contacted over the phone by the research assistant RA-B, who was blinded to the assigned group of patients to obtain their pain scores.The sample size was calculated using the G*Power software version 3.1.94. Based on a previous study , the meaStatistical analysis was performed using standard parametric and non-parametric statistics with JMP Pro 14.1 . Data were expressed as mean ± SD or number (%). Fisher’s exact test was used to analyse categorical variables, while the independent sample t-test or one-way ANOVA test was used to analyse continuous variables. A two-sided p-value < 0.05, was considered as the threshold for significance.A total of 72 patients with benign gynaecological conditions scheduled for laparoscopic surgeries from April 2019 to October 2019 were recruited. One patient declined participation, and one patient was excluded based on the exclusion criteria . Subsequently, 70 patients were included; however, two patients had their laparoscopy procedure converted to laparotomy . Therefore, 68 patients completed the study  and 72 h (p = 0.007) postoperatively during movement than those in the control group. The mean (± SD) pain score recorded at postoperative 48 h was 3.29 ± 1.77  and 2.21 ± 1.97 (95% CI: 0.34–1.52) in the control and INSI groups, respectively. After postoperative 72 h, the mean (± SD) pain score was 1.56 ± 1.5 (95% CI: 0.27–1.01) and 0.65 ± 1.1 (95% CI: 0.19–0.26) in the control and INSI groups, respectively  complained of nausea, and 3  complained of vomiting. In terms of initiation of oral feed, 31 patients from the control group and 33 patients from the INSI group began to ingest meals per orally 24 h after surgery. At postoperative 24 h, 13 patients from the control group and 8 patients from the INSI group complained of abdominal distension, of which only 3 patients experienced distension up to 48 h after surgery . Majority of the patients from both the groups were able to pass flatus at postoperative 24 h . No other complications, such as fluid leakage through the incision site or infection, were observed in the interventional or control groups. Most patients were discharged between day 1 and day 2 post-surgery . Only one patient was discharged 4 days after surgery because of personal logistic issues.In contrast to other studies, the results obtained from this trial demonstrated that 15 mL/kg of INSI did not significantly reduce shoulder pain compared to no fluid instillation at 24 h, 48 h, or 72 h post gynaecological laparoscopy procedure. However, similar to previous trials, our data revealed that upper abdominal pain was significantly improved at 48 h and 72 h after INSI of 15 mL/kg.In our opinion, this trial was designed with adequate precaution to eliminate preventable bias and modestly fill the research gap on the efficacy of INSI 15 mL/kg body weight in reducing postoperative pain, the lowest dose tested by previous researchers.Our study has certain limitations. First, the sample size of this study was relatively small, limiting the generalisation of the results. Second, the differences in patient characteristics were a source of bias that could affect the stability of the results. Moreover, although all surgeons were advised to actively evacuate the retained carbon dioxide with gentle pressure on the abdomen, some surgeons may have performed it better than others, contributing to another source of bias.Another major limitation is lack of blinding of the laparoscopic surgeons. Complete blinding is not practical as the act of not instilling and instilling fluid is not concealable from the surgeons performing the surgery.Our findings were inconsistent with the findings of previous researchers, which could be due to the amount of INSI we chose to instil and/or characteristic differences in our patients.We opted for a lower amount of INSI in order to minimise excessive indwelling normal saline in the peritoneal cavity. In the trials carried out by Tsai et al. , 11, theExcessive indwelling intraperitoneal normal saline promotes formation of peritoneal adhesions , 21, 28.Second, compared to Tsai et al. , the patOther advantages of INSI include its potential to provide long-lasting and persistent pain relief . SimilarIn conclusion, instillation of normal saline of 15 mL/kg body weight at the end of any benign gynaecological laparoscopic surgery does not improve shoulder pain. However, a modest improvement in pain score was observed in the upper abdominal area 48 h and 72 h post-procedure. The option to increase the amount of saline instillation to up to 30 mL/kg body weight in order to improve pain score should be carefully evaluated, considering that INSI may result in development of peritoneal adhesions even at lower amounts. Thus, a longitudinal controlled randomised trial should be conducted to address the occurrence of postoperative peritoneal adhesions after INSI.


Given the role of vitamin B6 on pronociceptive/antinociceptive neurotransmitters balance, metabolic reactions, and inflammation, it is important to clarify the effect of vitamin B6 on pain and psychological disturbance in fibromyalgia (FM). This study aimed to evaluate whether an 80-mg daily dose of vitamin B6 improves pain, disease severity and psychological symptoms of FM compared to a placebo.This randomized, double-blinded, placebo-controlled trial was performed on the FM patients whose diagnosis was confirmed by a rheumatologist based on the 2016 American College of Rheumatology (ACR). 90 Patients were randomized to receive either vitamin B6 (80 mg daily) or placebo in a 1:1 ratio, with a permuted block size of 30 stratified by disease severity. Primary outcomes included the Revised Fibromyalgia Impact Questionnaire (FIQR), Hospital Anxiety and Depression Scale (HADS), 12-item short-form health survey (SF-12), and pain visual analog scale (pain-VAS)). The mean differences in outcomes (before and after treatment) were compared between the vitamin B6 and placebo groups using an independent T-test. An ANCOVA model adjusted for baseline outcome value was also provided to compare the outcomes between the two groups.Of 90 eligible patients, 60 patients (31 patients in vitamin B6 and 29 in the placebo group) completed the trial. Overall, the FIQR, pain-VAS, and HADS-anxiety scores improved after treatment in both vitamin B6 and placebo groups; However, there was no statistically significant intergroup difference regarding primary outcomes. ANCOVA model also showed no difference in the treatment effects.Our results showed no priority for vitamin B6 over placebo in FM patients. Considering the potential ameliorating role of vitamin B6 on pain and psychological symptoms, acknowledgment of vitamin B6 as a relatively safe adjuvant treatment needs larger future studies.IRCT20200920048782N2 on 2021/10/04.Iranian Registry of Clinical Trials:  Fibromyalgia (FM) has been characterized by widespread chronic pain, fatigue, sleep disturbances, cognitive dysfunction, and polysymptomatic complaints . It is aNeurobiological studies of central sensitization show evidence of neurochemical imbalances between pronociceptive and antinociceptive brain areas in FM patients. High levels of excitatory neurotransmitters of glutamate and substance P and reduced levels of serotonin, norepinephrine, and γ-aminobutyric acid (GABA) have been found in FM patients , 4. In aVitamin B6, as an essential cofactor in the metabolic reactions of homocysteine, regulates the transformation of various neurotransmitters such as GABA, epinephrine, serotonin, and melatonin which are involved in the diverse behavioral processes, including sleep, learning, memory, and sensation of pain , 9. TherDespite the apparent potential benefit of vitamin B6 on pain and depression, no research has investigated the clinical implication of vitamin B6 on the pain or psychological profile of FM patients. FM, as the prototypical nociplastic pain condition, shows the aforementioned neurotransmitter imbalance and mild inflammatory status that can be targeted by vitamin B6 treatment. Given FM as a difficult therapeutic condition and the relative safety of vitamin B6 treatment, it would be reasonable to evaluate the effect of vitamin B6 on pain, FM impact, and health status of these patients. In this study, we aimed to assess the effect of the administration of vitamin B6 on the physical pain, disease severity, and psychological symptoms of FM patients compared to placebo groups. Our secondary objective was to evaluate whether vitamin B6, as an anti-inflammatory agent, could change the status of inflammatory markers in FM patients.This study was a randomized, double-blinded, placebo-controlled, parallel-group trial on 90 FM patients admitted to the FM clinic of Razi academic hospital affiliated with Guilan University of Medical Sciences (GUMS) from October 2021 to January 2022. The diagnosis of FM was made by one rheumatologist (B.GH) according to the 2016 American College of Rheumatology (2016 ACR) criteria [www.irct.ir) on 2021/10/04 (registration number: IRCT20200920048782N2). All participants were informed about the study design and then written informed consent was obtained from all volunteers. They were informed that their level of care wouldn't be affected if they discontinued the study.The study protocol was approved by the ethics committee of Guilan University of Medical Sciences (IR.GUMS.REC.1400.258) in accordance with the World Medical Association's code of ethics  and registered at an ICMJE and WHO recognized registry of clinical trials  , were formed. Thereafter, for each stratum, randomization in the block size of 30 was performed. The allocation ratio for each block was 1:1, and patients were randomized to the vitamin B6 or placebo groups. A random sequence for each block was generated using the Randomization.com website. A research staff, who wasn't involved in data collection and data entry, was in charge of generating randomized sequence and allocation concealment. For allocation concealment, the sequentially numbered, sealed, opaque envelopes were used. Active drug and placebo were kept in completely identical  plum bottles, codded as either A or B. Group allocation was unknown to the investigators, data collectors, and patients. Three medical students were responsible for enrolling eligible patients, calculating disease severity, and assigning them to either receive vitamin B6 or a placebo according to the randomized sequence.At the initial visit, patients were evaluated for demographic data  and outcome measures. A secondary visit at day 60 ± 3 was made to re-evaluate the outcome measures.Primary outcome measures included the Revised Fibromyalgia Impact Questionnaire (FIQR), Hospital Anxiety and Depression Scale (HADS), 12-item short-form health survey (SF-12), and pain visual analog scale (pain-VAS). Three medical students helped patients to fulfill the questionnaires.Secondary outcomes were defined as platelet distribution width (PDW), mean platelet volume (MPV), red blood cell distribution width (RDW), and neutrophil leukocyte ratio (NLR).Patients were instructed to take either vitamin B6 or a placebo twice daily for 60 days. The intervention group received the pills of vitamin B6 , and the placebo group received pills with the same shape as vitamin B6 (containing lactose monohydrate (78%), corn starch (20%), aerosil (0.5%), talc (1%) and magnesium stearate (0.5%), produced under standard condition by Pharmacology faculty of Guilan University of Medical Sciences).Patients taking prior medication to relieve FM symptoms were encouraged to continue their regimen. Patients who were already taking any supplement containing vitamin B6 were asked to stop taking them for a minimum of 2 weeks before the study. An intake calendar was given to patients to track their compliance. The patients were also informed to report any unpredicted symptoms at any time during the study.Patients were referred to a private laboratory accredited by the health ministry  for blood sampling and laboratory analysis. Blood samples were collected from non-fasting patients at baseline and after 60 ± 3 days. Blood samples were analyzed for complete blood count and differentials and erythrocyte sedimentation rate (ESR). Platelet distribution width (PDW), Mean platelet volume (MPV), red blood cell distribution width (RDW), and Neutrophil leukocyte ratio (NLR) were recorded as secondary outcomes.The FIQR is a 21-items questionnaire with an 11-point numeric rating scale for each question which assesses clinical symptom severity and disease impact in patients with FM . The totHADS is a 14 items questionnaire with two subclasses: 7 questions for anxiety and 7 questions for depression. Each question scores between 0 to 3, with a maximum score of 21 for each subclass. Higher scores mean a higher level of anxiety and depression .The sample size was calculated using G*Power 3.1 . Since tDescriptive statistics were used to calculate the mean, median, and standard deviation for continuous variables and frequency for categorical variables. Shapiro–Wilk test was used to test the normality of data, and Levene's test was used for the equality of variances. To compare before and after treatment effects within each group, we used Paired t-test and Wilcoxon test for normally distributed and non-normally distributed scores' changes, respectively. To compare the outcomes between vitamin B6 and placebo groups, an independent T-test and Mann–Whitney U test were used for parametric and non-parametric data, respectively.For each outcome, an ANCOVA model, adjusted for the baseline value of the outcome, was developed. Partial eta squared, and Cohen's d were used as effect sizes in ANCOVA and Independent t-test, respectively.Cohen's d was calculated using the following formula :\documenWith t = t statistic of the independent t-test (assuming homogeneity of variances) and n1 and n2 = the two sample sizes.To calculate Cohen’s d in Mann–Whitney U test, we used an online calculator developed by Lenhard et al. . The effp values < 0.05 were considered significant. Statistical calculations were performed using the IBM SPSS Statistics for Windows, version 26 .All statistical tests were two-tailed, and p value > 0.05).Of 90 eligible patients, 45 were randomized to the vitamin B6 group and 45 to the placebo group. 31 patients in the vitamin B6 group and 29 patients in the placebo group completed the study protocol and were recruited for the final analysis. The most common reason for exclusion in both study arms was non-adherence to the medications or taking over the counters (OTCs) containing vitamin B6 . Although both groups showed a mild improvement in their pain-VAS scores after treatment , the intergroup difference in pain-VAS was not statistically significant .Comparing the treatment effect on the disease severity in each group (intragroup comparison) showed a significant improvement in FIQR scores . The mean change of total FIQR was -11.18 ± 19.78 and -12.02 ± 21.93 in the vitamin B6 and placebo groups, respectively. However, there was no statistically significant difference in the score changes between the two groups (intergroup comparison) . Neither group showed any significant improvement in the HADS-depression score .Regarding psychological profile, patients in the vitamin B6 group and placebo showed an improvement in the mean scores of HADS-anxiety . However, the psychological improvement between the vitamin B6 and placebo groups was not statistically different  had no superior effect to placebo in improving the pain, disease severity, psychological symptoms, health status, and inflammatory markers of the FM patients.Given the role of vitamin B6 or pyridoxine on metabolic reactions, neurotransmitters balance, removing oxidative agents, and inflammation , it is cAlthough our results showed an improvement in pain, FM impact, HADS-anxiety score, and health status after vitamin B6 treatment, the same effect was also seen in the placebo arm of our participants. It must be noted that FM patients show a higher placebo response compared to other diseases. This effect has been reported even with FDA-approved medications for FM, which emphasizes the benefits of using placebo as dose extenders. It means that by pairing a placebo with physiologically active drugs, the medication dosage can be lowered without affecting the treatment response . ConsideAlthough the theoretical benefit of vitamin B6 on psychological illness is compelling, our results didn't confirm this hypothesis. Existing systematic reviews have shown inconclusive results about the positive effects of vitamin B6 on emotional, cognitive, and mood disorders , 29. TheIt must be noted that FM is a heterogeneous nociplastic pain condition with a wide etiopathogenesis spectrum. It incorporates diverse comorbidities such as cognitive and psychological disturbance, and other comorbid nociplastic pain conditions such as headache, irritable bowel syndrome, and so on . It woulFurthermore, the previous studies on the effect of vitamin B6 supplementation in other types of pain have implied the controversial results . They doFurthermore, our study did not show any positive effect on the inflammatory markers after vitamin B6 treatment. Although several studies support the anti-inflammatory effect of vitamin B6 in different inflammatory conditions , this efOur study had some limitations. First, we recruited only female participants from one tertiary center; thus, the study findings cannot be extrapolated to the general FM population. Second, we used a single dose of vitamin B6 as adjuvant therapy; Trial studies with different dosages of vitamin B6 in naïve patients may lead to different results. Third, given the nature of the large placebo effect in FM patients, it would be desirable to evaluate the effect of vitamin B6 in a larger population size of control studies compared with placebo and FM FDA-approved drugs. Although designing such studies may be difficult from point of practical perspective, it can clarify the effects of vitamin B6 on pain and psychological impacts of FM patients.Vitamin B6 mechanistically shows a potential role in modifying pain and psychological disturbance in nociplastic pain, including FM. While the clinical and preclinical data on this issue is contradictory, the positive effects of vitamin B6 on the mentioned outcomes have been promising in a different situation. This study aimed to shed more light on the vague effects of vitamin B6 treatment in FM as a disputing condition in the management. Acknowledgment of vitamin B6 as a relatively safe adjuvant treatment needs future and larger controlled studies.


Primary and secondary outcome measures: The primary outcome was the number of days to achieve a 50% pain reduction. Secondary outcomes included areas under the 50% numeric rating scale reduction curve: pain, disability, quality of life, and safety. Results: The Chuna manual therapy + usual care group  required significantly fewer days to achieve 50% pain reduction compared to the usual care group . Regarding pain severity, functional index, and quality of life index, Chuna manual therapy and usual care were more effective than usual care alone. Safety was acceptable in both groups. Conclusions: In patients with subacute whiplash injury, Chuna manual therapy showed a rapid rate of recovery, high effectiveness, and safety. Objectives: We aimed to compare the effectiveness and safety of Chuna manual therapy combined with usual care to those of usual care alone for treating whiplash injuries. Design: A two-arm, parallel, assessor-blinded, multicenter pragmatic randomized clinical trial. Setting: Three hospitals in Korea. Participants: Overall, 132 participants between 19 and 70 years of age, involved in traffic accidents and treated at three hospitals in Korea, >2 but <13 weeks prior to enrollment, with neck pain consistent with whiplash-associated disorder grades I and II and a numeric rating scale score ≥5 were included. Interventions: Participants were equally and randomly allocated to the Chuna manual therapy and usual care ( The term “whiplash-associated disorder” (WAD) refers to an acceleration-deceleration movement and the resulting energy transfer to the cervical region after an accident . This suTreatments of WAD were divided into three groups: acute (less than two weeks), subacute (two to 12 weeks), and chronic (longer than 12 weeks) stages, according to time from injury to a clinician’s assistance in deciding on an appropriate treatment course. Most treatment takes place in the subacute phase for whiplash patients  and it iFor WAD patients, South Korea has a dualistic health care system covered by traffic accident insurance that combines Western and Korean medicine. As a Western treatment, medicine and physical therapy are usually provided, and as a Korean medicine treatment, acupuncture, herbal medicine, pharmacopuncture, Chuna manual therapy are usually provided . Korean Moreover, one Korean retrospective chart review study found the average number of days for WAD who received Korean medicine treatment was 28.98 days, which was shorter than in others. The mean score for satisfaction in Korean medicine treatment for WAD was 7.16 points, while the most satisfactory treatment among various Korean medicine treatments was Chuna manual therapy (CMT) ) than in the UC group (3.0 [1.0]). The SF-12  significantly increased in both the CMT + UC  and UC groups , with no significant between-group difference . An overall analysis of the results revealed that compared to the UC group, the CMT + UC group showed significant pain reduction, except for the NRS score at f/u4. NDI showed improved scores within the f/u period. In SF-12, there were no significant treatment effects.This study observed 29 adverse events; none of the reactions were serious. Online Online The participants were further classified into the WAD1 and WAD2 subgroups for subgroup analysis. Online The management of patients with WAD still presents challenges . Over thA recent study suggests that acute WAD management, prompt return to normal function, pain management, encouragement of self-management, and reductions in fear and anxiety should be considered . Thus, cCMT has favorable effects on pain and functional improvements caused by musculoskeletal diseases, such as temporomandibular joint disorder, neck pain, lower back pain  and safeThere have been five WAD Korean randomized controlled trials on CMT . Among tThere are few randomized clinical trials demonstrating the effectiveness of WAD. Although the effectiveness of manual therapy (MT) as a treatment for WAD has been reported and guidelines have been developed accordingly , the lowTo reflect real clinical conditions, the Korean medicine treatment, which is covered by automobile insurance in South Korea and accounts for approximately half of the medical expenses for automobile accidents, was set as the UC group ,42. For In patients with subacute WAD neck pain, concomitant CMT with UC alleviated pain and decreased the days to 50% pain reduction. The NDI was indicative of the positive effects of concomitant CMT. Continuous six-month f/u showed significant positive effects except for some outcomes. NRS-AUC showed a significant difference of 1.4 times, and the hazard ratio was 2.151, suggesting that concomitant CMT therapy was twice as likely to reduce neck pain by at least a half. Moreover, a scientific review reported that although MT reduced neck pain, approximately 50% of patients undergoing MT experienced minor-to-moderate adverse events . In contThe strengths of this study lie in its well-designed multicenter clinical study design regarding the treatment of WAD using the Chuna method. Additionally, unlike previous studies that only evaluated the NRS score, this study introduced the 50% pain reduction days from baseline as a temporal index. We conducted a Kaplan-Meier survival analysis and measured quality of life and functional outcomes to comprehensively assess the effects of concomitant CMT. This study has several limitations. First, blinding could not be performed during the intervention period considering the nature of the intervention. Random group allocation and allocation concealment were performed, and the assessors were blinded to prevent selection and detection biases. Second, neither the type nor the intensity of UC was standardized because they were not set in this study, which may have caused bias in the study results. Third, the medical systems for addressing traffic accidents differ across countries. To address this, further collaborative research with other countries is warranted, using conventional drugs and physical therapy for whiplash injuries as a control group.This study introduced 50% pain reduction days from baseline as a temporal index, in addition to using the pain numerical rating score as an outcome measure.This was a well-designed multicenter trial with random group allocation and blinding of assessors.Blinding of participants could not be performed due to the nature of the intervention.Neither the type nor intensity of usual care was standardized.Based on the present study, we found good evidence for CMT showing a rapid recovery rate, high effectiveness, and safety. These results support the need to consider recommending Chuna manual therapies as primary care treatments for WAD neck pain. However, more manual therapy study should be conducted to provide additional evidence.


Total knee arthroplasty is currently a reliable treatment for end-stage knee osteoarthritis. However, chronic postsurgical pain (CPSP) is substantially thought to reduce patient satisfaction. NSAID-based oral analgesics were used to manage CPSP, but research on the duration of postoperative analgesic use (DAU) and prolonged analgesic use (PAU) are presently scarce.Preoperative, perioperative, and one-year or above postoperative follow-up data were collected from 162 patients who underwent total knee arthroplasty between 1 June 2018 and 1 March 2019, and the DAU and the discontinuation time of each patient after discharge were recorded. Observational statistical analysis, diagnostic test, and predictive nomogram construction were performed on the collected data.The 3-month DAU has good diagnostic utility for poor outcome of postoperative months twelve (POM12). The constructed nomogram shows that gender, preoperative Numeric Rating Scale (NRS) movement pain scores, duration of surgery, postoperative days three (POD3) moderate to severe movement pain, and POD3 pain rescue medication were significant prognostic predictors of PAU after discharge. The area under the curve (AUC) of the 3-month, 6-month, and 12-month nomogram receiver operating characteristic (ROC) curves were calculated to be 0.741, 0.736, and 0.781.PAU was defined as more than three months of NSAID-based oral analgesic use after TKA. Prognostic predictors of PAU after TKA were identified, and visualized nomogram was plotted and evaluated. The evaluation indicated that the prediction model had the good predictive ability and was a valuable tool for predicting PAU after discharge. Knee osteoarthritis (OA), the most common degenerative musculoskeletal disorder, is a significant factor responsible for increasing years of living with disability (YLDs) . AlthougOral analgesics, playing a pivotal role in the management method of CPSP, can lead to adverse consequences if being overused for a long time (whether opioid or nonopioid) –8. In thBased on the results of this study, PAU was defined as more than three months of NSAID-based oral analgesic use after TKA. The aim of this study is to explore the situation of analgesic use in patients after TKA and evaluate factors that may be associated with PAU. It is hypothesized that the DAU is closely associated with prognosis and can be predicted by multiple variables.This study was approved by the Ethics Committee of the hospital (SHSY-IEC-4.1/20-21/01), and adhered to the tenets of the Declaration of Helsinki. Informed consents were obtained from all participants enrolled in the study. The study collected retrospective data from patients who underwent TKA between 1 June 2018 and 1 March 2019. Baseline demographics, patient preoperative characteristics, perioperative treatment details, one-year or above postoperative follow-up outcomes, and several other factors were collected and analyzed subsequently.Inclusion criteria: (1) aged over 50 years old; (2) elective total knee arthroplasty (include primary surgery and revision); (3) no history of joint infection. Exclusion criteria: (1) periarticular tumor; (2) TKA combined with other operations simultaneously; (3) incomplete data and lack of one or more laboratory indicators.via medial parapatellar approach under a tourniquet. All surgical patients were given general anesthesia, and additional ultrasound-guided femoral nerve block was provided to a subset of patients at the anesthesiologist's discretion based on patient condition. At the end of the surgery, 150 mg ropivacaine, 7 mg compound betamethasone, and 1 g tranexamic acid were mixed as a 50 ml injection solution and used for periarticular local Infiltration. Patients received a 48-hour patient-controlled intravenous anesthesia (PCIA) consisting of a continuous intravenous infusion (butorphanol 0.12 mg/ml with dexmedetomidine 1 µg/ml at a rate of 2 ml/h) and patient-activated bolus doses of 0.5 ml of the solution with a 15-min lockout period after each activation.All surgeries were performed separately by five senior surgeons in the hospital tid, and cryotherapy was performed around the surgical incision. Breakthrough pain does not react to the above protocol was managed by rescue medication consisting of pethidine 100 mg plus promethazine 25 mg. All patients received and implemented perioperative and postoperative rehabilitation training according to clinical guidelines  consisting of morphine sulfate 10 mg and ketorolac 60 mg every 12 h and gabapentin 0.3 g After discharge, the analgesic prescription was filled and refilled by the attending doctor according to the World Health Organization Three-Step Analgesic Ladder. All patients were instructed to use analgesic medications only as needed after discharge and to stop the medication when the pain was relieved to easily tolerable mild pain. Levels of pain were recorded utilizing the 11-point Numeric Rating Scale . Furthermore, postoperative pain greater than four was defined as moderate to severe pain.All patients were recommended to receive regular follow-up visits after discharge. Patients were generally followed up at 1, 3, 6, and 12 months for the first year and every six months thereafter. Patients' satisfaction, Lysholm score, and rest/movement pain were evaluated and recorded at postoperative months twelve (POM12) follow-up. Cases that have the following four conditions at POM12 were defined as POM12 poor outcome: (1) POM12 satisfaction score <50; (2) POM12 Lysholm score <70; (3) POM12 moderate to severe rest pain; (4) POM12 moderate to severe movement pain. Cases with the same one of the above conditions were considered subgroups of POM12 poor outcomes.Data such as patient characteristics, comorbid conditions, laboratory indicators, information about surgery, and immediate outcomes during hospitalization were collected from medical records. The follow-up data were obtained from the outpatient records, and further information was obtained from the telephone follow-up if needed. The data extraction was implemented by two researchers  manually.The obtained data are summarized and classified into measurement data (including continuous and discrete variables) and categorical data . Descriptive statistics were performed on the collected data. To assess the clinical implications of DAU, a diagnostic test evaluation using DAU to diagnose adverse prognosis was performed.p < 0.10) in the univariate analysis were screened with stepwise regression and included in the multivariate Cox regression analysis. Kaplan–Meier survival analysis was performed to further analyze categorical variables in prognostic factors, and nonparametric group comparisons were performed using the log-rank test. Moreover, a predictive nomogram model was constructed using the results of the Cox multivariate analysis to visualize the predicting of the 3-month, 6-month, and 12-month PAU. The predictive power of the nomogram was verified by plotting receiver operating characteristic (ROC) curves and calibration curves. The model performance for predicting results was further evaluated by calculating Harrell's concordance index (C-index), and the internal verification was carried out using 1,000 sets of bootstrap sampling.In the next step of prediction model construction, the preoperative and perioperative predictor variables were all included in the univariate analysis of the Cox proportional hazards regression model at first. Endpoint events were defined as cessation of analgesic use after discharge and no or only slight tolerable pain at this time. Based on Akaike information criteria (AIC) and Bayesian information criterion (BIC), potential prognostic factors , including the “survival” and “rms” packages. A total of 182 patients met the inclusion criteria and were eligible for the study, and 20 were excluded for withdrawing from follow-up. Therefore, the final cohort consisted of 162 patients with at least one year of postoperative follow-up, and their discontinuation time and clinical data were recorded. The flow chart of the study process, including patient selection details, is illustrated in t-test indicates that the DAU of cases with adverse outcomes were significantly longer than their counterpart   .p-values < 0.10 in the univariate analysis, were dropped from the multivariate fitting model via the stepwise regression method. With the lower AIC (1284.489) and BIC (1299.706) value, the model including five predictors  is the better predictive model. The K-M survival curves for categorical data were plotted and shown in As A nomogram was built using the results of the multivariable analysis to predict prognostic outcomes visually . The ROCIn reviewing the literature, no data was found about the situation of the duration of NSAID-based analgesic use after TKA. One of the aims of this study was to investigate the DAU after TKA and to define PAU. The current study found that the DAU of patients who underwent TKA is non-normally distributed . The DAUAnother aim of the current research was to find the predictors of PAU. Preoperative NRS movement pain scores and POD3 moderate to severe movement pain partially represent preoperative pain and APSP. A strong relationship between acute postsurgical pain (APSP) or preoperative pain and CPSP had been extensively validated –21. HowePrevious studies have demonstrated that patients' preoperative pain sensitivity correlated with MP but not with RP , 29, 30.One unexpected finding was that the longer operative time was predictive of PAU, while the different operators did not influence the PAU. This finding is inconsistent with previous studies, which demonstrated that the duration of arthroplasty did not affect postoperative pain and patient satisfaction . The durAnother finding of the current study is that although intraoperative nerve block, PCIA, and rescue medication (RM) are all optional components in the MMPM, nerve block and PCIA have no significant effects on PAU development. Unlike nerve block and PCA (which are primarily at the physician's discretion), whether RM is administered or not depends on the patient's subjective reported pain intensity. On the one hand, a possible explanation for the significant association of RM with PAU is the psychological factors. Psychological factors represented by catastrophizing amplified the patient-reported pain intensity, promoting RA use and further prolonged analgesia use, which means that fear of pain leads to anticipation and dependence on analgesics. Therefore, it can be assumed that appropriate patient education and psychological interventions for postoperative arthroplasty patients can influence patient analgesic use and pain. Future studies on the current topic are recommended. On the other hand, RA did represent patients' acute postoperative pain intensity, so the occurrence of breakthrough pain postoperatively was significantly associated with PAU. Future research should investigate the mechanisms underlying acute postsurgical pain, including breakthrough pain, to develop novel targets and therapies to prevent PAU.A limitation of this study is that the restricted sample size causes some categorical data-based classifications to be too small and may bias the statistical results. Future studies with larger sample sizes need to be carried out. Secondly, because of the limitation of retrospective study, the patients were not tested for some inflammatory markers at the time. The relationship between inflammatory markers and PAU is worthy exploring in the future.The present study was designed to explore the situation of analgesic use in patients after TKA and evaluate factors that may be associated with PAU. Based on the diagnostic test results, PAU was defined as more than three months of NSAID-based oral analgesic use after TKA. Moreover, the Cox proportional hazards regression model results reveal that gender, preoperative NRS movement pain scores, duration of surgery, POD3 moderate to severe movement pain, and POD3 pain rescue medication were prognostic predictors of PAU after TKA. A visualized nomogram was plotted according to the results of multivariable analysis, and the model evaluation demonstrated that it had a good predictive ability. The current study is the first to investigate the long-term use of NSAID-based oral analgesics for CPSP after discharge, and the specific mechanisms of PAU and pain remain to be determined.