AimWe aimed to analyze the influence of preoperative piroxicam, diclofenac, paracetamol, tramadol, and placebo tablets as measured in the time required for rescue analgesia for postoperative pain relief after the extraction of impacted mandibular third molar.Materials & methodsth hours. The time required for escape analgesia was measured. Forty-four patients who needed extraction of impacted mandibular third molar were arbitrarily categorized into four groups namely, piroxicam, diclofenac, paracetamol with tramadol, and placebo. The test medicine was given one hour preoperatively before the surgical removal. The pain was assessed using visual analog scale (VAS) and verbal rating scale (VRS) scores preoperatively and at the third and 24ResultsThe mean VAS and VRS scores showed significant differences across the groups after 24 hours. The mean score was lowest for the patients taking piroxicam (1.30+1.95) and highest for patients taking tramadol + paracetamol (4.50+2.59). As far as escape analgesia is concerned piroxicam group was by far superior.ConclusionThe pain scores and the rescue analgesic requirement suggested that piroxicam analgesic significantly reduced pain; moreover, it is a safe as well as an efficacious substitute to the conventional non-steroidal anti-inflammatory drugs (NSAIDs) for mandibular third molar impactions. Wisdom tooth impaction is a commonly diagnosed problem that often demands tooth removal. Pain, difficulty in opening the mouth, and edema are frequent consequences following surgical extraction of impacted third molars. This is a result of localized inflammatory mediators, in particular cyclooxygenase (COX) and prostaglandins . Good suThe degree of pain , quality , duration , and radiation  can all change. Despite pain being a largely sensory experience, it has significant cognitive and psychological effects; it is related to or defined by suffering. According to The International Association for the Study of Pain (IASP), pain is "an unpleasant sensory and emotional experience associated with present or potential tissue damage or characterized in terms of such harm" . People often link dental treatments with discomfort, which makes them avoid or postpone treatment, which makes it more difficult to manage . The effPostoperative analgesia can be delivered through the application of local anesthesia or the administration of non-steroidal anti-inflammatory drugs (NSAIDs), opioids, or a combination of the two. Preoperative use of NSAIDs possibly is more beneficial than postoperative use ; similarNSAIDs are beneficial for treating postoperative pain. The most probable method of action is inhibition of prostaglandin production . ParacetDiclofenac is an NSAID that comes as potassium salt tablets for oral administration as well as sodium salt extended-release and delayed-release tablets. Diclofenac has shown an advantage in rodent acute inflammatory models caused by kaolin, carrageen, or adjuvant arthritis in pharmacologic investigations, in part due to suppression of the enzymatic transition of arachidonic acid into prostaglandin at extremely low concentrations . DiclofeThe objective of this randomized, placebo-controlled, double-blind study is to see if piroxicam, diclofenac, PCM with tramadol, and placebo tablets could help relieve postoperative pain after removal of the affected mandibular third molar.This randomized controlled trial was carried out at Saveetha Dental College and Hospitals in Chennai, in the Department of oral and maxillofacial surgery (OMFS). In 44 patients, the researchers compared the preoperative pain relief effectiveness of oral piroxicam, diclofenac, PCM, tramadol, and placebo on pain management following surgical removal of affected third molars. The protocol was authorized by Institutional Ethical Committee, and the study followed the ethical criteria for human experimentation outlined in the Declaration of Helsinki (2000). Before taking part in the study, all patients supplied written informed consent. The study included patients in age between 18 to 45 years with impacted mandibular third molar.Patients who had used analgesics or sedatives before surgery, pregnant or lactating women, and those with systemic disorders were all excluded from the study. Previously reported observations were utilized to calculate the sample size. A sample size of 44 participants was determined by a power calculation of 90%. The investigator recorded the duration of operation as well as the impaction score for each tooth (based on Pell & Gregory's classification as explained by Pederson) at the time of surgery. Treatment regimen allocation was randomized using block randomization with a block size of eight. The patient was blinded with regard to the drug being given. Patients were placed in four different groups: patients in group I got 20mg of piroxicam orally an hour prior to the extraction of impacted mandibular third molars, while patients in group II received 50mg of diclofenac sodium orally an hour prior to the extraction of impacted mandibular third molars. Patients in group III got 37.5mg tramadol + 325mg PCM orally an hour prior to the extraction of impacted mandibular third molars, while patients in group IV received placebo (capsule becosule) orally an hour prior to the extraction of impacted mandibular third molars.Surgical procedureExtraction of the affected third molar surgically was performed on all the patients under local anesthesia . The inferior alveolar nerve (IAN), lingual nerve, and long buccal nerve were blocked. Ward's incision was made from the distobuccal aspect of the second molar. Extended anteriorly and inferiorly, continued along the buccal aspect of impacted third molar and extended distally and laterally. A mucoperiosteal flap was reflected to expose the tooth. Bone was removed with bur under continuous irrigation of sterile isotonic saline solution to reduce the heat generated, followed by splitting and elevation of the impacted tooth. The bony margins were filed and smoothened, and the gingival margins were trimmed. The wound was irrigated with a sterile isotonic solution. The flap was repositioned, and the wound was sutured with non-resorbable black silk suture material. A pressure pack was given to attain hemostasis. Postoperatively, for all patients, amoxicillin 500mg thrice daily was given. The sutures were removed for all patients on the seventh postoperative day.Rescue medicationAs a rescue medication, aceclofenac (100mg) + PCM (325mg) combination was given to patients who did not attain sufficient pain relief. Patients who had consumed rescue medication before three hours were excluded from the final analysis.Efficacy assessmentVisual Analogue Scale (VAS)Patients had to use the VAS scale with readings from 0 to 10 with a gradation of 1. The pain intensity was recorded one hour before surgery, immediately before taking a pre-emptive analgesic, then in the third and 24th hour after the surgery. Anchor points were 0, which indicated no pain, and 10, which indicated severe pain. Verbal Rating Scale (VRS)Patients were asked to use a VRS scale with readings as a) no pain, b) mild, c) moderate, and d) severe pain.Time to remedicationThe time to remedication is the time between the termination of surgery and the patient's need for rescue medication. The time that a participant received rescue treatment (aceclofenac + PCM) was recorded.Descriptive and inferential statistics were employed to execute the statistical analysis, along with the Kruskal-Wallis test, Mann-Whitney test, and Chi-square test. The software used in the study was SPSS version 27.0 , and the significance level was analyzed as p<0.05.All of the patients followed the research protocol, endured the surgical procedures well, and returned for follow-up appointments. Forty-four patients who met our eligibility criteria agreed to take part in this study and underwent surgical removal of affected third molars. Out of these 44 patients, one patient was withdrawn because of an adverse drug reaction, and two patients had to be excluded from the analysis because of intake of rescue medication before the third-hour evaluation of pain.DemographicsOut of 44 patients in this study, 10 patients in the diclofenac group had eight males and two females. Out of 10 patients who were in the piroxicam group, seven were males and three were females. There was an equal distribution of males and females in PCM with the tramadol group. There were five males and six females in the placebo group of 11 patients. There was no substantial distinction in terms of patient distribution based on impaction difficulty (Table Pain scoresTable The mean VAS score showed a significant difference across the groups after 24 hours. The mean score was lowest for the patients taking piroxicam (1.30+1.95) and highest for patients taking tramadol + PCM (4.50+2.59). The difference across the groups at 24 hours was statistically significant (p<0.05).Table Table Table Extraction of the affected mandibular third molars surgically is one of the most common dentoalveolar interventions in oral and maxillofacial surgery, which is linked with variable degrees of postoperative discomfort. The most common postoperative complaints are pain, trismus, and edema; hence it may affect the quality of life of a patient in the days post-surgery .Acute tissue injury caused by surgical operations results in activation of peripheral nociceptors, which has an impact on the central nervous system. The resulting primary and secondary hyperalgesia best exemplifies the extensive influence of local site injuries on the nervous system . PrimaryRecent literature suggests that prostaglandins and cyclooxygenases, in addition to their roles in the peripheral nervous system, also have crucial roles in the central nervous system . As a reProstaglandins are crucial molecules involved in peripheral nociceptors sensitization, which leads to primary and secondary hyperalgesia. Prostaglandins are produced by activating phospholipase A2 in damaged tissue, which results in the creation of arachidonic acid from membrane phospholipids. After that, cyclooxygenase (COX)-dependent mechanisms convert arachidonic acid to different prostaglandins. Prostaglandin D2 (PGD2), PGE2, thromboxane A2 (TxA2), PGI2 (prostacyclin), and prostaglandin F2 (PGF2) alpha are the five major prostanoids in the prostaglandin family. These prostaglandins then have an effect on the body by attaching to certain G-linked receptor proteins. The prostanoid PGE2 is especially important in acute inflammation, and its levels are linked to the degree of pain following wisdom teeth extraction . As prostaglandins are not present in large quantities in normal tissues to be active and must first be generated, they aren't involved in the first reaction to pain that leads to tissue damage . After tThe idea of using NSAIDs to alleviate postoperative pain, either as a single therapy or combined with other medications, is getting popular as more is revealed about their mechanisms of action . NSAIDs The aim of this study is to compare the effect of preoperative analgesia in the four groups as measured in the time required for rescue analgesia for the relief of postoperative pain. Medication with the aceclofenac-PCM combination was allowed to the patient on the occurrence of pain postoperatively before the scheduled dosage of the test drug. The piroxicam group consumed less rescue analgesia than the other groups. In a study by Ong et al., prophylactic intravenous ketorolac 30 mg was shown to be more beneficial than tramadol 50 mg in preventing postoperative tooth discomfort . AnotherTramadol is an excellent postoperative painkiller; however, the considerable adverse effects of vomiting and nausea limit its widespread use . Since 3This is the first of its kind of study to compare piroxicam, diclofenac, and PCM to tramadol before surgery. Piroxicam, a non-selective cyclooxygenase inhibitor, is one of the NSAIDs which is beneficial for the treatment of various types of pain and inflammatory processes when taken at a suggested dose of 20 mg once a day or 10 mg twice a day . Kohli ePain control is the most critical aspect to be considered following impacted teeth surgical removal for effective perioperative pain management. In this study, piroxicam 20mg given one hour preoperatively significantly reduced rescue analgesia requirement. This study adds to the growing knowledge of the use of piroxicam as preoperative analgesia in perioperative pain management during third molar surgery. Piroxicam, a non-selective cyclooxygenase inhibitor, is one of the NSAIDs which is beneficial for the treatment of various types of pain and inflammatory processes when taken at a suggested dose of 20 mg once a day or in a divided dose.


The use of available treatments for Fabry disease (FD) (including enzyme replacement therapy [ERT]) may be restricted by their limited symptom improvement and mode of administration. Lucerastat is currently being investigated in the MODIFY study as oral substrate reduction therapy for the treatment of FD. By reducing the net globotriaosylceramide (Gb3) load in tissues, lucerastat has disease-modifying potential to improve symptoms and delay disease progression.ClinicalTrial.gov: NCT03425539); here we present the rationale and design of this study. Eligible adults with a genetically confirmed diagnosis of FD and FD-specific neuropathic pain entered screening. Patients were randomized (2:1) to receive either oral lucerastat twice daily or placebo for 6 months; treatment allocation was stratified according to sex and ERT treatment status. The main objectives of MODIFY are to assess the effects of lucerastat on neuropathic pain, gastrointestinal (GI) symptoms, FD biomarkers, and determine its safety and tolerability.MODIFY is a multicenter, double-blind, randomized, placebo-controlled, parallel-group Phase 3 study  validation study, using a novel eDiary-based PRO tool to assess the validity of evaluating neuropathic pain as a primary efficacy endpoint in MODIFY. Results from the PRO validation study are included.To date, MODIFY is the largest Phase 3 clinical study conducted in patients with FD. Enrollment to MODIFY is now complete, with 118 patients randomized. Results will be presented in a separate publication. Long-term effects of lucerastat are being assessed in the ongoing open-label extension study (NCT03737214). •There remains a need for treating patients with Fabry disease.•MODIFY investigated lucerastat as substrate reduction therapy for Fabry disease.•Limited tools are available to assess neuropathic and GI symptoms in Fabry disease.•MODIFY assessed neuropathic pain and GI symptoms as primary and secondary efficacy endpoints.•MODIFY used FDA-recommended validated tools for primary and secondary efficacy endpoints. DespiLucerastat is a novel inhibitor of glucosylceramide synthase (GCS) in development as oral substrate reduction therapy (SRT) for the treatment of FD . In FabrLucerastat oral monotherapy is currently being investigated in the pivotal Phase 3 MODIFY study. Here, we describe the intent and design of the MODIFY study. We also present results of a validation study that evaluated the content validity of an eDiary-based PRO tool to assess neuropathic pain and GI symptoms as primary and secondary efficacy endpoints, respectively, in MODIFY.22.1Multicenter, dOuble-blind, ranDomized, placebo-controlled, parallel-group Phase 3 study to determine the clinical effIcacy and safety of lucerastat oral monotherapy in adult patients with FabrY disease. The study is comprised of a screening period lasting 6–7 weeks and a double-blind treatment period lasting 6 months. Patients who complete the 6-month treatment period have the option to enter into an open-label extension study ; patients who do not enter the extension study continue to the safety follow-up period .MODIFY is a p period , which l2.1.1The primary objective is to determine the effect of lucerastat on neuropathic pain in patients with FD. Secondary objectives are to: 1) determine the effects of lucerastat on GI symptoms in patients with GI symptoms at baseline; 2) confirm the effect of lucerastat on biomarkers of FD; and 3) determine the safety and tolerability. Other objectives include the evaluation of lucerastat on renal function, cardiac parameters, depression, and quality of life and the documentation of the pharmacokinetics (PK) of lucerastat.2.1.2GLA mutation) and Fabry-associated neuropathic pain in the 3 months prior to screening. Full inclusion and exclusion criteria are listed in MODIFY specifically enrolled adult patients with a diagnosis of FD , twice daily. The starting dose of lucerastat is based on a patient's estimated glomerular filtration rate (eGFR) value at screening. During the study, the dose of lucerastat is adjusted if a patient's eGFR crosses boundary thresholds, defined in 2 or in the event of acute kidney Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or above; in the event of heart failure leading to in-patient hospitalization or prolongation of hospitalization; in the event of stroke CTCAE grade 3 or above; or if a patient becomes pregnant while on study treatment.Patients will permanently discontinue study treatment at any time during the study: if eGFR <15 mL/min/1.73 m2.1.4The results from a novel PRO validation study (see 2.2) were used to inform the suitability of the primary efficacy endpoint, which is the response to lucerastat on neuropathic pain, defined as a change from baseline to Month 6 in the “modified” Brief Pain Inventory-Short Form item 3 (BPI-SF3) score of “neuropathic pain at its worst in the last 24 h”. Secondary efficacy endpoints are the change from baseline to Month 6 in: 1) plasma Gb3; 2) average daily 11-point numerical rating scale (NRS-11) score of “abdominal pain at its worst in the last 24 h” in patients with GI symptoms at baseline; and 3) the number of days with at least one stool of Bristol stool scale (BSS) consistency Type 6 or 7 in patients with GI symptoms at baseline. Other efficacy endpoints, including renal function and echocardiography endpoints, are summarized in 2.1.4.1Based on early interaction in 2016 and 2017 with FDA, and prior to commencement of MODIFY, a dichotomous responder-based analysis for the primary efficacy endpoint was described in the protocol . In early 2020, further interaction with FDA led to a methodological change of the analysis of the primary efficacy endpoint to a continuous analysis (change from baseline to Month 6 in the “modified” BPI-SF3 score of “neuropathic pain at its worst in the last 24 h”).Analyzing the primary efficacy endpoint as a continuous variable avoids a loss in information caused by the dichotomization of the endpoint variable and, therefore, requires fewer patients to maintain the statistical power to detect a difference between lucerastat and placebo.2.2In clinical studies, the NRS-11 “pain at its worst in the last 24 h” has been used to assess pain severity; the use of an NRS is supported by IMMPACT recommendations for assessing pain . DespiteWe conducted a PRO validation study in patients with FD. The primary objectives were to spontaneously elicit definitions and descriptions of neuropathic pain experienced in FD and to cognitively debrief and test the patient acceptability of the PRO instruments on an electronic device.2.2.1The PRO validation study comprised two parts: 1) concept elicitation (CE) telephone interviews to elicit definitions and descriptions of neuropathic pain associated with FD (Appendix A 1); and 2) face-to-face cognitive debriefing (CD) and usability testing (UT) interviews (Appendix A 2) to assess the content validity of the primary and secondary efficacy endpoint measures, test the usability of the eDiary, and to gain input about meaningful change from the patient perspective. Interviews were conducted by a specialized vendor, and the study was approved by the University of California, Irvine (UCI) independent review board (IRB) (UCI IRB HS#2017-3815).2.2.2Adult  patients were required to have a diagnosis of FD , Fabry-associated neuropathic pain for at least 3 months prior to study entry, and be fluent in US English . Patients were not eligible if they had a disease with a pain component or disease of the gastrointestinal tract that could interfere with the assessment of neuropathic pain or GI symptoms, respectively.2.2.3Concept elicitation (CE) telephone interviews (lasting approximately 1 h) were audio-recorded and conducted using a semi-structured CE interview guide comprised of open-ended questions that encouraged spontaneous reporting of concepts from patients. Interview guides included topics, questions, and probes to understand how patients with FD experience neuropathic pain. Audio recordings were transcribed verbatim and anonymized, and each transcript was considered a unit of analysis. A coding scheme was applied and operationalized using ATLAS.ti version 7 and was initially developed based on the interview guide and study objectives. For CE interviews, the coding scheme catalogued concepts spontaneously reported by patients (without prompting from the interviewer), and the coding process was guided by grounded theory and constant comparative method. The coding scheme was updated as necessary to reflect actual terms patients used to describe concepts. Codes were applied to specific text within each transcript and then queries for frequency across transcripts.Saturation was considered to be achieved at the point when additional interviews were unlikely to yield new information  .During CD interviews (audio-recorded and lasting approximately 90 min) patients were asked to complete an eDiary using a think-aloud method . Under this methodology, the interviewer simply reminds respondents to verbalize their thought process  . The UT 3The results of the PRO validation study are presented here. Fifteen patients with FD were screened from one site (UC Irvine), of which 13 were successfully recruited into the PRO validation study and participated in the CE interviews (two patients did not report experiencing neuropathic pain). Ten of the thirteen patients participated in the CD/UT interviews. Demographics were generally balanced between the two parts of the study .Table 4PPatients with FD shared their experience of FD when asked non‑leading questions, and the concepts elicited are summarized in The eDiary device demonstrated good usability among patients with FD. Ninety percent of patients rated the overall ease of use and ability to select an answer as a five  . Overall3.1•▪constant pain of variable intensity. You may also get attacks of intense, excruciating pain that starts in the hands and feet and spreads to other parts of the body. Your pain may occur randomly. It may also be triggered by heat or cold, weather change, being sick or having a fever, diet, stress, tiredness, and/or physical activity”.“The following question is about the neuropathic pain you may have because of your Fabry disease. This type of pain usually feels like burning, shocks, or shooting pain, tingling, pins and needles, stabbing, and/or numbness in the hands and feet. You may have “Please rate your neuropathic pain  in your hands and feet by selecting the number that best describes your neuropathic pain at its WORST in the last 24 h”Based on these findings, the wording of the neuropathic pain severity question for MODIFY was revised by adding additional descriptors and triggers (bolded) to the definition of neuropathic pain (“modified” BPI-SF3):For the abdominal pain severity question, although four patients suggested rewording the concept to “pain/discomfort”, no changes were made since more recent IBS studies focus on pain and treat pain as conceptually distinct from abdominal discomfort. Furthermore, this is aligned with the FDA guidance on IBS studies .3.2The findings from the PRO validation study helped inform the suitability of assessing neuropathic pain as a primary endpoint within MODIFY; furthermore, the experience gained through employment of the eDiary helped shape how the eDiary could be used within MODIFY. During MODIFY, each patient was provided with a portable eDiary, trained to use the device by study personal during screening, and completed the eDiary according to the protocol schedule. All PRO assessments collected either on a daily basis (evening diary) or during a site visit were recorded in the eDiary. Patients rated their neuropathic pain (daily) from screening until Month 6. Neuropathic pain intensity was rated on an NRS-11 to respond to the modified BPI-SF3 in the eDiary. Patients rated (daily) their abdominal pain and the number and consistency of bowel movements from screening to Month 6. The patients' impression of disease severity was assessed by two Patient Global Impression of Severity (PGIS) questionnaires  at each site visit. Two Patient Global Impression of Change (PGIC) questionnaires assessed the patient's impression of change since study treatment start in disease severity (PGIC-DS) and neuropathic pain (PGIC-PS) at each site visit. In addition, the full BPI-SF was completed by the patient at each site visit, while a quality-of-life questionnaire  and a depression scale  were completed by the patient both at randomization and Month 6. The eDiary was used to collect pain medication use.Plasma and urinary levels of Gb3 and lysoGb3 were quantified at each site visit by a central laboratory. To minimize the possibility for systematic unblinding, results of FD biomarker assessments were not communicated to the study site or sponsor until the study database was locked. Renal function and echocardiography-based parameters were assessed from baseline to Month 6. Safety assessments included adverse events (AEs), serious AEs, physical examination, vital signs , weight, and electrocardiography (ECG) assessment (12‑lead ECG) and laboratory evaluation of blood and urine.3.3t-test for independent samples.The planned sample size for MODIFY was originally 108 patients. However, with the change to the methodology used to analyze the primary efficacy endpoint , a sample size of approximately 99 patients provides 87.2% power to detect a treatment difference of 2 points, with an assumed standard deviation of 3 points  primarily based on a test for the mean difference between lucerastat and placebo in the change from baseline to Month 6 in the “modified” BPI-SF3 score. Calculations were conducted using East 6.5 based on a two-sided The primary statistical approach will be performed according to the intent-to-treat approach. The Type I error rate will be controlled at a two-sided alpha of 5% for the testing of the four null hypotheses associated with the primary and secondary efficacy endpoint comparisons employing a fixed-sequence statistical testing strategy.4To date, MODIFY is the largest pivotal Phase 3 study conducted in FD. The primary objective of MODIFY is to determine the effect of lucerastat on neuropathic pain in patients with FD. Safety, as well as the effect of lucerastat on other key symptoms of FD, will also be assessed.Current management of FD consists of conventional symptomatic and supportive managements, ERT, and chaperone therapy. Despite the use of ERT, a large proportion of patients still exhibit clinical symptoms, and improvements in neuropathic pain are limited . FurtherMODIFY is the first clinical study in patients with FD to measure neuropathic pain as a primary endpoint, which uses an FDA-agreed PRO instrument to collect symptom information on a daily basis. Previously, neuropathic pain (or simply pain) has been assessed as a secondary or tertiary endpoint in most FD clinical studies, and only once as a primary endpoint in a single study . There aGI symptoms in patients with FD can be episodic, alternating between diarrhea and periods of normal (and sometime reduced) bowel activity, and often mimic symptoms of FGID, such as IBS. Although the Gastrointestinal Symptom Rating Scale (GSRS), a PRO developed in other indications, has been previously used in FD studies, the recall period (7 days) is too long to capture symptoms that fluctuate on a daily basis . The FABThe MODIFY study includes suitable and validated tools to assess primary and secondary endpoints for use in patients with FD, in line with health authority guidelines on endpoints in FD clinical studies. Study enrollment was completed in December 2020 with 118 patients randomized. Patients who complete MODIFY will have the option to enroll into an open-label extension study (NCT03737214), which will assess the long-term safety and tolerability of lucerastat, as well as the long-term effects on renal and cardiac function.Idorsia Pharmaceuticals Ltd.The MODIFY study was supported by


Clinical trials have demonstrated galcanezumab as safe and effective in migraine prevention. However, real-life data are still lacking and overlook the impact of galcanezumab on those different migraine facets strongly contributing to migraine burden. Herein we report the clinical experience from an Italian real-world setting using galcanezumab in patients with migraine experiencing previous unsuccessful preventive treatments.Forty-three patients with migraine and failure of at least 3 migraine preventive medication classes received monthly galcanezumab 120 mg s.c. At the first administration and after 3 and 6 months, patients underwent extensive interviews to assess clinical parameters of disease severity. Furthermore, validated questionnaires were administered to explore migraine-related disability, impact, and quality of life as well as symptoms of depression or anxiety, pain catastrophizing, sleep quality and the ictal cutaneous allodynia.After the third and the sixth administration of monthly galcanezumab 120 mg s.c., headache attacks frequency reduced from 20.56 to 7.44 and 6.37 headache days per month, respectively. Moreover, a significant improvement in headache pain intensity (from 8.95 to 6.84 and 6.21) and duration (from 9.03 to 3.75 and 2.38) as well as in scores assessing migraine related disability and impact, depressive and anxious symptoms, and pain catastrophizing was observed. Furthermore, we demonstrated a significant reduction in the values of “whole pain burden”, a composite score derived from the product of the average of headache frequency, intensity, and duration in the last three months.Real-world data support monthly galcanezumab 120 mg s.c. as a safe and effective preventive treatment in reducing headache frequency, intensity, and duration as well as comorbid depressive or anxious symptoms, pain catastrophizing and quality of life in both episodic and chronic migraine patients with previous unsuccessful preventive treatments. Furthermore, we demonstrated that monthly galcanezumab 120 mg s.c. is able to induce a significant improvement in the scores of “whole pain burden”. The latter is a reliable and easy-to-handle tool to be employed in clinical setting to evaluate the effectiveness of preventive drugs  or when the decision of continuing the treatment with anti-CGRP mAbs is mandatory.The online version contains supplementary material available at 10.1186/s10194-022-01436-6. The last years represented a breakthrough in migraine preventive treatments due to the approval of specific monoclonal antibodies targeting the trigeminal sensory calcitonin gene-related peptide (CGRP) or its receptor . TherefoReal-life data from a recent observational Italian study confirmed that galcanezumab is highly effective and well-tolerated for the treatment of high-frequency episodic and chronic migraine patients . NeverthWe report the clinical experience from an Italian real-world setting using galcanezumab in a cohort of high frequency and chronic migraine patients with previous unsuccessful treatments. Herein, we focused on galcanezumab effectiveness beyond the mere reduction of headache days per month considering changes in the whole pain burden  as well as in the response to painkillers, comorbid psychiatric symptoms, pain coping, cutaneous allodynia, and sleep quality in these patients.Specifically, all patients fill in a paper headache diary consisting of a table with the days of the month (up to 31 days) on the abscissa and the hours of the day (up to 24 hours) on the frames. The patient should mark the onset and the end of every attacks and the time of pain-killer intake to allow us the calculation of both the attacks duration and the response to the symptomatic drugs, and also in order to evaluate the reduction of painkiller intake/month. In the case of headaches present at both the time of falling asleep and waking up, the night hours were considered as attack hours. Moreover, the patient inserted the intensity of the attacks  . These data were used also to assess a composite score that we defined as “whole pain burden”, derived from the product of headache frequency (i.e. mean of attacks per month in the last three month) per headache intensity  per headache duration (mean headache hours when treated). As an example, consider a patient who has - in the last three months - an average frequency of 9 headache days per month whit an average intensity of 8/10 on the NRS scale lasting an average of 6 hours. In this case, the “whole pain burden” score for the last three months would be calculated as product of 9 × 8 × 6 that is 432. All patients received galcanezumab subcutaneous (s.c.) injection, with the first loading dose of 240 mg and then every month with 120 mg. At the first administration (T0), at the end of the third (T1) and the sixth month (T2) of galcanezumab treatment, the headache diaries were analyzed to assess headache days per month, migraine attacks per month, pain intensity , headache duration (mean headache hours when treated), response to painkiller (pain-free after two hours), acute pain medication intake. Moreover, all patients underwent an extensive interview aimed to explore a) migraine-related disability (MIDAS) and impact by Headache Impact Test (HIT-6), b) the presence of comorbid depression and anxiety by the Beck Depression Inventory-II (BDI-II), Hamilton Depression Rating Scale (HDRS), and Hamilton Anxiety Rating Scale (HARS); c) quality of sleep by the Medical Outcomes Study (MOS) Sleep Scale d) quality of life by the migraine-specific quality-of-life questionnaire (MSQ), e) Allodynia Symptom Checklist-12 (ASC-12) and f) Pain Catastrophizing Scale (PCS) [This was an observational, prospective, non-randomized, open-label study evaluating the efficacy and safety of galcanezumab as preventive treatment in migraine patients with failure of at least 3 previous preventive strategies. Forty-three patients with episodic high frequency (8 pts) and chronic migraine (35 pts)   were recle (PCS) –21. DuriThe protocol was reviewed and approved by the Ethical Committee of the University of Campania “Luigi Vanvitelli”. Each patient gave a free, informed consent for participation in the study and the analysis and publication of the protocol data (code 30564/20). The study was done according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines .1) and of the sixth month (T2) of galcanezumab treatment compared with the baseline.The primary endpoints of the study were the reduction in monthly headache days, pain intensity, attacks duration as well as in the “whole pain burden” score, at the end of the third  proportion of patients who achieved at least 50% and 75% reduction from their individual baseline in monthly headache days, ii) proportion of patients who achieved at least 50% reduction from their individual “whole pain burden” score, iii) change in monthly painkillers intake as both days with painkillers intake and number of painkillers intake (i.e. as pills/tablets/injection) iv) change in MIDAS, HIT-6, MSQ, BDI-II, HDRS, HARS, PCS, MOS sleep scale, and ASC-12 scores, and, finally, iv) the percentage of patients converting from chronic migraine to episodic migraine as well as v) the percentage of patients converting from not-responders to responders to pain killers.t-test was used to compare the mean headache days per month, mean pain intensity, mean headache attack duration and “whole pain burden” score at baseline (T0) and at the end of the third (T1) and the sixth month (T2) of galcanezumab treatment. Wilcoxon rank test was used to compare HIT-6, MIDAS, MSQ, BDI-II, HDRS, HARS, PCS, MOS sleep scale, and ASC-12 scores. Statistical significance was set at p < 0.003 after Bonferroni correction for multiple comparison (0.05/14 comparisons). Due to the observational approach of the study, the power analysis has not been performed. A squared partial correlations analysis has been conducted to explore whether included parameters  explain the variance of “whole pain burden” score. To explore the validity of the construct of the “whole pain burden” composite score, the Spearman’s rank correlation was used to determine the correlation of the MSQ to “whole pain burden” composite score at baseline. Multivariate regression analysis was conducted, including clinical parameters of disease severity  to determine the independent predictors of response to galcanezumab treatment . All analyses were performed using Stata version-16 .All demographic and clinical data were checked for normality using Shapiro–Wilk test. Continuous variables are reported as mean ± standard deviation (SD), categorical variables are expressed as median ± interquartile range, rates values are reported as subjects-counts and percentage. In all subjects, the paired The whole population consisted of 43 migraine patients with a history of treatment failures to at least three preventive medication classes .Headache attack frequency reduced from 20.56 to 7.44 and 6.37 headache days per month after the third and the sixth administration of monthly galcanezumab 120 mg s.c., respectively (p < 0.001).Headache attack pain intensity reduced from a NRS score of 8.95 to 6.84 and 6.21 after the third and the sixth administration of monthly galcanezumab 120 mg s.c., respectively (p < 0.001).Headache attack duration (treated) reduced from a 9.03 to 3.75 and 2.38 headache hours after the third and the sixth administration of monthly galcanezumab 120 mg s.c., respectively (p < 0.001) , moreover, we observed a reduction in the number of patients with MOH (from 32 to 8 and 8 after the third and the sixth administration).A significant reduction was observed in the number of monthly days with painkillers intake from baseline 18.40 to 6.74 and 6.12 as well as in total painkillers intake (i.e. as number of pills/tablets/injection per month) from baseline 22.58 to 8.65 and 7.05 after the third and the sixth administration of monthly galcanezumab 120 mg s.c. respectively (p < 0.001) and impact on daily living assessed by MSQ (p < 0.001) after the third and sixth administration when compared with baseline   significantly improved from baseline since the third administration .Cutaneous allodynia symptoms experienced during the attacks (assessed by ASC-12) improved after the third and sixth administration but did not reach statistical significance after correction for multiple comparison (n = 26 and 28) of chronic migraine patients converted to episodic migraine (11.54% and 10.71% high frequency and 88.46% and 89.29 low frequency), while the 87.5% and 100% (n = 7 and 8) of high frequency migraine patients converted to low frequency migraine after the third and sixth administration  increased from the 55.81% to 69.77% and 72.09% after the third and the sixth administration of monthly galcanezumab 120 mg s.c., respectively.b coefficients of the multivariate regression analysis found baseline high headache intensity and PCS scores as statistically significant prognostic factors of response to galcanezumab treatment   , pain intensity (p = 0.04) and attack duration (p < 0.001) explain the variance of “whole pain burden” score. The “whole pain burden” composite score exhibited a significant correlation with MSQ score at baseline .The squared partial correlation analysis showed that each “whole pain burden” parameter among headache attacks frequency  reported in the course of treatment systemic AE. Among these, 7 pts. (16.27%) reported constipation, 3 pts. (6.98%) reported fatigue, and 1 pts. (2.32%) reported acrocyanosis. None of the above-mentioned AE led to discontinue the treatment. No serious AE were observed  or reported by patients.In the present study, we report the effectiveness of monthly galcanezumab 120 mg s.c. administration in a cohort of high frequency and chronic migraine patients, with at least 3 previous preventive treatments failure, during a six-month period. Beyond the improvement of headache frequency, intensity and duration, we observed a significant improvement in scores assessing migraine related disability and impact, depressive and anxious symptoms, pain coping, cutaneous allodynia and quality of life. Furthermore, we considered a composite score derived from the product of headache frequency, headache intensity, and headache duration (the last as a proxy of response to painkillers) that, for sake of shortness, we named “whole pain burden”.Migraine is recognized as the second-highest cause of years lived with disability, the first in patients aged between 15 and 49 years  and undeThe availability of CGRP-mAbs as novel specific, effective and well-tolerated therapeutic option has represented a breakthrough in migraine preventive treatment , 30. AmoNevertheless, previous galcanezumab studies did not deeply investigate the impact of this drug on overlooked aspects that strongly contribute to migraine burden, such as coexistent depressive and anxiety symptoms, the cognitive strategies to face with pain, experience of cutaneous allodynia as well as sleep quality.Herein, we demonstrated the effectiveness of galcanezumab over a six-month period in a group of 43 migraine patients with documented failure to at least three migraine preventive medication classes. Specifically, we observed a decreased number of headache days per month from 20.56 to 7.44 and 6.37 with a reduction of at least 50% of headache days per month in 72.09% and 74.42% of patients after the third and the sixth administrations of monthly galcanezumab, respectively. These data are in line with those emerging from a recent prospective study showing that anti-CGRP mAbs induce a significant reduction in monthly migraine days from the first month of treatment, followed by a further slight decrease until month 6. This may suggest that at least 6 months of galcanezumab treatment are needed to reach the therapeutic plateau necessary to counteract the neurobiological mechanisms underpinning CGRP desensitization .Beyond mere pain related parameters, several patient-reported outcomes (PROs) have been considered. In this context, the high headache impact (by means of HIT-6) and the severe disability (by means of MIDAS) as well as the critical impairment in migraine-specific quality of life (by means of MSQ) registered at the baseline showed a significant improvement after the third and, even more, the sixth monthly galcanezumab administration in these patients.Furthermore, at baseline 46.51% and 27.91% of patients showed mild depression (by mean of HDRS and the self-administrated BDI-II) and moderate anxiety comorbidities (by mean of HARS) respectively. Statistically significant improvements have been observed since the third administration of monthly galcanenumab leading to mean scores values consistent with the absence of both depressive and anxiety contents. It is noteworthy that depressive and anxious symptoms are able to worsen migraine attacks increasing the rates of progression to chronic migraine and making migraine treatment more challenging, reducing quality of life and increasing the overall disease burden –34. SincBeyond depressive and anxiety symptoms, the 58.14% of our patients showed PCS scores at baseline above the cut-off value, witnessing negative orientation toward actual or anticipated pain experience. A significant reduction in PCS scores, in all sub-domains, was found since the third monthly galcanezumab administration.Maladaptive pain coping strategies, consisting on negative cognitive and affective behavior in response to pain, such as the so-called “pain catastrophizing”, are well-reported in migraine patients . In partFurthermore, in our patients group, we assessed sleep quality using the MOS-sleep scale, a self-administered scale able to evaluate 6 different disturbances . The incidence and prevalence of sleep disorders are significantly higher in migraine patients when compared to general population and sleep-wake rhythm and the quality of sleep abnormalities surely represent trigger factors for migraine attacks , 41. In p = 0.01) although it became not statistically significant after correction for multiple comparison. Nevertheless, we can argue that galcanezumab-induced peripheral CGRP inhibition may be able to indirectly inhibit the central trigemino-thalamic pathway sensitization known to be involved in ictal CA and, in turns, putatively inhibiting chronification mechanisms. It is well-known that CA is reported in about two-thirds of migraine patients as the perception of pain induced by trivial stimuli to normal skin, during or between headache episodes [In our patient sample, 31% reported ictal cutaneous allodynia (CA) at baseline. After the third and sixth monthly galcanezumab administrations we noted a remarkable reduction of ASC-12 scores , and duration. This approach let us to observe, after the third and sixth galcanezumab administration, a significant reduction of the “whole pain burden” score in migraine patients.One of the main findings of the present study is the identification of a composite score derived from the product of headache frequency per headache intensity per headache duration (the last as a proxy of response to painkillers) in the last three months, that for sake of shortness, we named “whole pain burden” score. Previously, a composite measure has been already employed to fully assess the potential benefit of migraine treatment strategies  obtained by multiplying duration (hours) of migraine headache and maximum pain severity  for each migraine headache day and summing these over the days in a month . The “to> 50% has been found in a significant percentage of patients  with < 50% reduction in headache days per month and, therefore, to be considered, strictly speaking, poor responders to galcanezumab treatment. The partial correlation analysis demonstrated that each element employed to calculate the “whole pain burden” score significantly contributes to its determination. The value of the “whole pain burden” composite score, as a comprehensive tool to evaluate the complexity of headache experience as well as the potential benefit of migraine preventive treatments on the quality of life, is further supported by a convergent validity witnessing the correlation between the “whole pain burden” scores and a parameter of quality of life related to migraine as the MSQ.Interestingly, “whole pain burden” score reduction It could be argued that a limitation of the “whole pain burden” composite score is the low weight attributed to the number of symptomatic drugs administered. On the other hand, we would underline that the “whole pain burden” is a composite score aimed to an effective and rapid evaluation of the treatment-related changes of the experience of headache. It is noteworthy that some important aspects beyond the pain experience itself are overlooked by the “whole pain burden” composite score, such as the number of pain-killers intake and the impact of the migraine accompanying symptoms. Although aware of the limits related to the patients reported outcomes  , we cannIn the present real-life experience, there were no patients reporting serious AE or willing to discontinue treatment due to poor tolerability, although a low percentage of migraine patients experienced, beside the pain in the site of injection, constipation (16.27%), acrocyanosis (6.98%), nausea (2.32%), supporting galcanezumab as highly effective preventive treatment with a very low percentage of side-effects.Linear regression analysis showed that both low pain intensity at baseline and high PCS scores at baseline represent negative predictors of response to galcanezumab treatment. It can be speculated that, as previously demonstrated with Onabotulinumtoxin-A , the proThe present study is not free from some limitations. First of all, being a non-randomized open-label study, there was no placebo or active comparator arm . HoweverOur real-world data support monthly galcanezumab 120 mg s.c. as an effective preventive treatment able to reduce headache frequency, intensity and duration in a significant percentage of migraine patients experiencing previous unsuccessful preventive treatments. In addition, galcanezumab showed a significant effect on disability and impact on daily living related to migraine, as well as on both depressive and anxiety symptoms, health-related quality of life, pain catastrophizing and CA.Furthermore, we considered a composite measure, the so-called “whole pain burden”, that may be more aligned to the personal experience of pain in patients with migraine. Indeed, the “whole pain burden” may better reflect what clinicians and patients discuss regarding the individual’s pain experience in the course of the attacks. Moreover, our experience suggests that “whole pain burden” is an easy-to-handle tool able to evaluate the effectiveness of preventive drugs for migraine  and suitable when the decision of continuing the treatment with anti-CGRP mAbs is mandatory.Additional file 1: Supplementary material 1. Flowchart of patients selectionAdditional file 2: Supplementary material 2. Headache diaryAdditional file 3: Supplementary material 3. Table about drug class failure


Perioperative pain management is one of the most challenging issues for patients with spinal neoplasms. Inadequate postoperative analgesia usually leads to severe postsurgical pain, which could cause patients to suffer from many other related complications. Meanwhile, there is no appropriate analgesic strategy for patients with spinal neoplasms.This is a protocol for a randomized double-blind controlled trial to evaluate the effect of esketamine combined with pregabalin on postsurgical pain in spinal surgery. Patients aged 18 to 65 years scheduled for spinal neoplasm resection will be randomly allocated into the combined and control groups in a 1:1 ratio. In the combined group, esketamine will be given during the during the surgery procedure until 48-h postoperative period, and pregabalin will be taken from 2 h before the surgery to 2 weeks postoperatively. The control group will receive normal saline and placebo capsules at the same time points. Both groups received a background analgesic regimen by using patient-controlled intravenous analgesia (containing 100 μg sufentanil and 16 mg ondansetron) until 2 days after surgery. To ensure the accuracy and reliability of this trial, all the researchers and patients will be blinded until the completion of this study. The primary outcome will be the proportion of patients with acute moderate-to-severe postsurgical pain  during the 48-h postoperative period. The secondary outcomes will include the maximal VAS scores (when the patients felt the most intense pain over the last 24 h before being interviewed) at 0–2 h, 2–24 h, 24–48 h, and 48–72 h after leaving the operating room and 24 h before discharge; the incidence of acute moderate-to-severe postsurgical pain at each other time point; chronic postsurgical pain assessment; neuropathic pain assessment; and the incidence of drug-related adverse events and other postoperative complications, such as postoperative delirium and postoperative nausea and vomiting (PONV).The aim of this study was to evaluate the effect of esketamine combined with pregabalin on acute postsurgical pain in patients undergoing resection of spinal neoplasms. The safety of this perioperative pain management strategy will also be examined.ClinicalTrials.gov NCT05096468. Registered on October 27, 2021The online version contains supplementary material available at 10.1186/s13063-023-07178-3. Pain is one of the most common complications for patients undergoing surgery. According to previous studies, almost 80% of patients undergoing spinal surgery suffer from acute postoperative pain , and oveOne of the most challenging issues during the perioperative period is providing appropriate pain control measures to enhance the recovery of patients. Over the last decade, opioids have been the most commonly used drug in perioperative pain management strategies. However, the administration of opioids could be compounded by aspects of misuse, overdose, and addiction. Furthermore, clinical adverse events such as nausea and vomiting and respiratory depression have limited the use of opioids. In 2016, the American Society of Anesthesiologists (ASA) and American Society of Regional Anesthesia and Pain Medicine (ASRAPM) jointly published consensus guidelines for acute pain management. These guidelines indicate that ketamine  and pregd-aspartate (NMDA) receptor activation [The mechanisms underlying postsurgical pain might be peripheral and central sensitization because of nerve injury and inflammatory responses at the operative site. Previously, researchers have suggested that central pain sensitization might be related to N-methyl-tivation . Ketamintivation . S-Ketamtivation . UnfortuAt the same time, gabapentinoids  have gained more attention from researchers for their significant effect on neuralgia. These compounds can inhibit the modulation of neuronal excitability by blocking α2–δ subunits of presynaptic, voltage-dependent calcium channels, which are upregulated in central sensitization processes . A meta-Thus, we designed a randomized controlled study to explore the analgesic effects of a combination of esketamine and pregabalin after resection of spinal neoplasms to investigate whether the combined therapy could improve postoperative analgesia. The fundamental aim of this study was to find an effective and safe analgesic treatment to help patients undergoing spinal surgery and provide a new perspective regarding perioperative pain management strategies.ClinicalTrials.gov on October 27, 2021 (NCT05096468). All participants or their legal representatives will provide written informed consent after screening and before randomization.This study will be a single-center, randomized, double-blind, controlled trial with two parallel study arms. This equivalence trial aims to evaluate the analgesic effects of esketamine in combination with pregabalin after resection of spinal neoplasms. The enrolled subjects will be randomly allocated into the combined group  and the control group  in a 1:1 ratio. This study was approved by the Institutional Review Board of Beijing Tiantan Hospital, Capital Medical University, Beijing, China (KY-2021-081-02). This study (protocol version 1.4/date 2021.10.08) was registered on The recruitment of this trial will be conducted in Beijing Tiantan Hospital from 1 December 2021 to 31 August 2022, and the follow-up will be until 31 December 2022. Based on the electronic medical records of the hospital, potential participants will be individually screened after admission. Almost 100 patients underwent surgery in the spinal neurosurgery department at Beijing Tiantan Hospital in 1 month, and the proportion of patients with spinal neoplasms was nearly 60% in this population. The sample size is only 90 for our study. Therefore, the predicted 8-month duration of this study is enough to complete the recruitment. No extra measures will be taken to recruit a sufficient number. Participants meeting the eligibility criteria will be visited by the research staff to sign informed consent forms and provide baseline information. The flow chart of the study is shown in Fig. Patients meeting the following inclusion criteria and not meeting the exclusion criteria at the time of randomization will be considered for enrollment.Scheduled to undergo elective resection of spinal neoplasmsAge between 18 and 65 years oldASA I–IIISigned informed consentPrevious adverse reaction to ketamine, S-ketamine, or pregabalinA diagnosed history of severe chronic pain Long-term medical history of analgesic treatment (gabapentin/opioids/ketamine)Aphasia or inability to cooperate with the pain assessmentsA diagnosed history of hepatic and renal dysfunctionA diagnosed history of psychiatric disorderThe patient was treated with gabapentin/pregabalin in the last 3 monthsDrug use disorder2Body mass index > 35 kg/mPregnancy or lactationPatients will be randomized 1 day before surgery using blocked, stratified randomization by independent research staff to 1 of 2 treatment groups (the combined group or the control group) after study enrollment. We will randomize the patients in a 1:1 ratio in blocks of four. The randomized allocation list will be generated by using a real-time, online system on the day before surgery. The randomization results will be maintained by independent researchers who will not participate in any other work of this study to guarantee allocation blinding. The presence of moderate or severe preoperative pain will be used as a basis for the stratification of patients .Allocation concealment will be achieved using study capsules and intravenous infusions with identical appearance for placebo and drugs. All the trial drugs will be provided by a medicine company  with no other contribution to this trial. The appearance of all trial capsules  will be the same. Esketamine will be diluted to a concentration of 0.5 mg/ml with normal saline. Colorless 50-ml syringes containing clear esketamine or placebo  solution will be prepared in a blinded manner by an independent research assistant. The randomization code will be marked on the syringes and the drug bottles of the study capsules. Only the study investigator who assigns participants to interventions will be unblinded to the treatment assignment. All other study researchers will be blinded to the treatment assignment, including responsible anesthesiologists and the neurosurgeons in charge of the patients, the outcome assessors, data analysts, and other relevant investigators.In the combined group, the patients will be given both esketamine and pregabalin during the perioperative period. The patients will receive 2 capsules of pregabalin  1~2 h before the surgery and 1 capsule twice daily during the 7-day postoperative period , followed by dose reduction to 1 capsule once daily for 7 days . At the same time, patients will be administered a bolus dose of 0.5 mg/kg esketamine after the induction of anesthesia and then receive continuous intravenous infusion at 0.12 mg/kg ·h (2 μg/kg ·min) during the 48-h postoperative period.In the control group, the patients will be given the same number of placebo capsules as the combined group at the same time points , alongside a normal saline bolus after induction of anesthesia and intravenous saline infusion for the 48-h postoperative period.Perioperative anesthesia management will be standardized. After entering the operating room, the patients will be given standard electrocardiography monitoring. Anesthesia will be induced with propofol, sufentanil, and rocuronium/cisatracurium. Total intravenous anesthesia depends on target-controlled infusions and will be chosen to maintain anesthesia with propofol and sufentanil and keep the bispectral index between 40 and 60. Remifentanil will be prohibited in this study. For the potential impact on the evaluation of the operation, nerve block will not be considered. In addition, local wound infiltration (0.5% ropivacaine 20 ml) will be permitted before skin suturing if required by the surgeon. All the participants will be given the usual postoperative analgesia therapy by postoperative patient-controlled intravenous analgesia  with a lockout period of 15 min, 100 ml total), which will include 100 μg sufentanil and 16 mg ondansetron during the 2-day postoperative period. In the ward, all patients will receive parecoxib sodium (40 mg IV BID) or flurbiprofen axetil (50 mg IV BID) to receive the standard postoperative analgesic for at least 3 days. If the patients are experiencing moderate or severe pain (VAS score ≥ 40 mm), rescue analgesia will be given, including 0.5 μg sufentanil IV in the postanesthesia care unit (PACU) or 1 tablet Tylox (contained 325 mg acetaminophen and 5 mg oxycodone per tablet) in the ward. If the pain persists, the patients will receive 1 dose of 50 to 100 mg of intramuscular tramadol. All analgesic doses and names will be clearly recorded.All of the participants will receive conventional postoperative care in the ward. The postoperative treatment will not be changed whether the patients enter the trial. The interventions of this trial are a combination of analgesic management added to the basic analgesic treatment, which will help the patients to get more comfortable feelings. The interventions are common drugs in the clinic, and the dosages are lower. Thus, the patients will be at low risk during the interventional period. Therefore, there is no anticipated harm or special posttrial care for the participants.The assessment of outcomes will be performed by two independent researchers. The results during hospitalization will be collected by the investigators through bedside interviews. The collection of postdischarge outcomes will be performed by telephone interview.The primary outcome was the proportion of patients with acute moderate-to-severe postsurgical pain during the 48-h postoperative period (defined as a VAS score ≥ 40 mm). The schedule of enrollment, intervention, and assessments is presented in Fig. Acute pain assessment: the maximal VAS score (when the patients felt the most intense pain over the last 24 h before being interviewed) 0–2 h, 2–24 h, 24–48 h, 48–72 h after leaving the operating room and 24 h before discharge; the incidence of acute moderate-to-severe postsurgical pain at each other time point (defined as the VAS score ≥ 40 mm)Subacute or chronic pain assessment: The incidence of postsurgical pain was assessed by a number rating scale (NRS: 0~10) at 1 month and 3 months (defined as an NRS score > 3)Neuropathic pain assessment: the short-form McGill pain questionnaire-2 (SF-MPQ-2) scores at 1 month and 3 months postoperativelyTotal opioid consumption within the 48 h period after surgeryEffective or noneffective button presses for PCIAQuality of anesthesia emergence evaluated by a 15-item quality of recovery scale (QoR-15) on POD3 and at dischargeThe incidence of psychotic side effects  was determined using the Brief Psychiatric Rating Scale (BPRS) and Clinician-Administered Dissociative States Scale (CADSS) at 2 h after surgery, POD1, POD2, and POD3Adverse events included drug-related  and operation- or anesthesia-related complications, the incidence of PONV, and the incidence of postsurgical delirium at 2 h after surgery, POD1, POD2, and POD3Other outcomes: perioperative depressive/anxious symptoms assessed by the Patient Health Questionnaire 9 (PHQ-9) and Generalized Anxiety Disorder scale (GAD-7) on POD3, at discharge, and 1 month and 3 months after surgerySecondary outcomes include the following:All the clinical information will be recorded in the unified case report forms designed specifically for this project and other paper documents, including informed consent forms and the protocol. After the follow-up is completed, the research paper documents will be locked in a single secure office in Beijing Tiantan Hospital, and the key will be kept by only the primary investigator and trial manager. Research data will be coded with a unique trial ID number, and no personal identifiers will be contained in the research data. The trial ID number that links identifying information to study subjects will be accessible only to the study investigators. The data will be entered into an enciphered electronic database after completion of this study. Only the principal investigator will know the password of this electronic database. All of the paper materials and the electronic database will be managed by the principal investigator until the study is complete.t tests, Mann–Whitney U tests, and chi-square or Fisher’s exact tests as appropriate. We will use the modified intension-to-treat (mITT) analysis to report our results, and we will use per-protocol (PP) analysis to perform the sensitivity analysis. The methods for estimating effects and 95% CIs will be reported in our outcomes. Sensitivity analyses will be applied to determine the statistical nature of the missing data. A two-sided P value of 0.05 was considered statistically significant for the primary outcome. Because of the repeated measurement, the Holm–Bonferroni method will be used to adjust the P value for secondary outcomes. Statistical analysis will be implemented using SPSS version 23.0 software and Stata version 14.0.Continuous data will be described as the mean with standard deviation (SD) or median with interquartile range (IQR) based on its distribution. The histogram and Kolmogorov–Smirnov tests will be used to evaluate the normality of the data distribution. Categorical variables will be summarized as counts and percentages. The primary outcome is categorical and will be analyzed by using the chi-square test or Fisher’s exact test. Regarding the secondary outcomes, based on the type of each variable, the difference between groups will be analyzed using P values of 0.05).According to a previous randomized controlled trial that investigated the effect of combined ketamine and pregabalin on persistent postoperative pain, the prevalence of moderate-to-severe acute postoperative pain at 24 h after surgery was 42% in the combined group and 78% in the control group . Among pBecause of the low-risk interventions, the short-term duration, and the small sample size, there are no interim analyses planned.This is a single-site study designed, performed, and coordinated at Beijing Tiantan Hospital. There is no steering committee or adjudication committee. Day-to-day running and management of the trial are based on the regular meeting and led by the chief investigator . The study team meets via a teleconference or face-to-face at least twice a month. The content of regular meetings includes the following: (1) study investigators report the process of the trial, including recruitment, informed consent, assessment, and intervention procedures according to protocol; (2) trial managers raise the problems during the performance of the study; and (3) principal investigators provide oversight for all aspects of the trial and give support to study investigators in each link.In agreement with the Institutional Review Board (IRB) of Beijing Tiantan Hospital, a DSMB was not appointed for this study. Because this study is a short-term study, the interventional drugs of this trial are conventional clinical analgesics with safe dosages. The risks of the interventions are minimal. Moreover, enrolled subjects in this study are adjunctive to routine treatment through the spinal neurosurgery department in Beijing Tiantan Hospital. The population in this trial will be monitored carefully during hospitalization, and regular perioperative treatment will not be altered by study participation. Two knowledgeable anesthesiologists and a spinal neurosurgeon were responsible for the safety of this study. Once adverse events are suspected, they will be asked to diagnose whether the suspected adverse event is related to interventions and will guide the next treatments for safety measures when indicated. The study team will submit the annual tracking reports to IRB institutions to upload the process information of the study once a year. If there is any modification in this trial, the trial manager will need to submit the application in a timely manner, and the IRB will approve if it is feasible.The follow-up investigators will pay close attention to the subjects during the intervention. If any adverse events (AEs) occur, the responsible investigator will report to the principal researcher immediately. If AEs are common and the patients’ symptoms are mild, we will supply thorough symptomatic support and treatments with close monitoring. If AEs become severe, the intervention will be stopped at once, professional doctors from various fields to immediately help the patients. Based on the relationships between AEs or serious adverse events (SAEs) and the drugs being assessed in this study, the project management team will consider whether unblinded allocated interventions are needed. If the AEs are so serious that they might impact regular clinical treatment and threaten patient safety, the research team will perform the emergency unblinding process and report the interventions to the surgeon in charge of the subjects at once. All AEs will be followed up until resolution. All adverse events will be documented in the final written report of this study and will be reported to the Institutional Review Board by the principal investigator.Patients and the public were not involved in the trial design. Participants will have access to the findings of the study on request.This proposed study will measure the efficacy and safety of esketamine combined with pregabalin on postsurgical pain in patients undergoing elective resection of spinal neoplasms. The participants will receive esketamine from the beginning of surgery until 48 h postoperation, along with a total dose of 150 mg pregabalin for 1 week postoperatively  followed by a reduced dose of 75 mg pregabalin for the next week (POD 8~14). Both acute and chronic postoperative pain will be assessed during the 3 months after surgery. Other complications and safety outcomes will also be observed.The primary concern is the potential inadequate analgesia in the control group after the surgery. The PCIA device is not a regular part of the therapeutic regimen during the postoperative period in this study hospital. As a result, we designed a usual PCIA procedure for all the participants to ensure basic postoperative analgesic treatment. If the participants experienced a moderate or severe level of pain, rescue analgesia was administered. The secondary concern is in regard to active placebo for the preoperative pregabalin capsule. In 2017, Hah’s team designed a randomized clinical trial to evaluate the effects of perioperative gabapentin on pain resolution in a mixed surgical population [The choice of the dosages of these two trial drugs was deliberate. Based on a related meta-analysis , intraveIn conclusion, this study is a randomized controlled trial to explore a better method to treat postsurgical pain. The expected outcome is that perioperative esketamine combined with pregabalin can safely and effectively relieve postsurgical pain, and the results of this study can expand the understanding of perioperative pain management.ClinicalTrials.gov on October 27, 2021 (NCT05096468). The first participant will be recruited on December 1, 2021. The conclusions of this study will be published in peer-reviewed journals.This study was approved by the Institutional Review Board of Beijing Tiantan Hospital, Capital Medical University, Beijing, China, on November 20, 2021 (KY-2021-081-02). It was registered on Additional file 1. CONSORT 2010 Flow Diagram.


BackgroundPreviously many studies have found the use of anti-epileptic drugs such as pregabalin, carbamazepine, and gabapentin in pain management. In addition, levetiracetam (LEV), an effective anti-epileptic drug, has shown analgesic effects in animal models. We aimed to evaluate the effect of oral LEV as pre-emptive analgesia in patients who underwent laparoscopic cholecystectomy under general anaesthesia and postoperative fentanyl requirements.Material and methodsForty-two patients of the American Society of Anaesthesiologists (ASA) grade I and II of either gender posted for elective laparoscopic cholecystectomy surgery were included in this double-blind, randomised, placebo-controlled study. Patients were divided into two equal groups of 21 each to receive either tablet LEV 500 mg or a matching placebo tablet, given 1 hour before surgery. Postoperative pain was assessed by a visual analogue scale (0-100 mm), where 0 meant no pain and 100, worst pain. In addition, patients received IV fentanyl as rescue analgesia during the first 24 hours of the postoperative period.ResultsNineteen patients in the LEV group and 20 in the placebo group completed the study. Patients in the LEV group had significantly lower pain scores at all time intervals except 0 hours and reduced fentanyl consumption postoperatively in the first 24 hours (p<0.05). Side effects were comparable in both groups.ConclusionA single, preoperative dose of oral LEV 500 mg significantly decreases post-surgical pain and fentanyl demand as rescue analgesia in elective laparoscopic cholecystectomy. Elimination and treatment of postoperative pain continue to be a major challenge in the postoperative area and plays a crucial role in the early mobilization and well-being of the post-surgical patient. Multimodal analgesia techniques that include pre-emptive analgesia can be used successfully in preventing postoperative pain. The reasoning behind pre-emptive analgesia is that antinociceptive treatment started before surgery is more beneficial in reducing postoperative pain rather than treatment started in the early postoperative period . After eLevetiracetam (LEV) is a second-generation anti-epileptic drug (AED) that belongs to the pyrrolidone family, a class of drugs with a wide range of action. Experimental evidence indicates that LEV provides antihyperalgesic effects in inflammatory, chronic, and neuropathic pain models . AlthougAfter institutional ethical committee approval and CTRI registration (CTRI/2018/06/014404), written informed consent was taken from all patients. Forty-two adults (between 18 and 60 years of age), ASA I and II of either sex scheduled to undergo elective laparoscopic cholecystectomy, were included in this prospective, randomised, double-blinded, placebo-controlled study. Patients with alcohol abuse, known hypersensitivity to the study drug, significant respiratory, cardiac, renal or hepatic dysfunction or on chronic pain medication, anticonvulsant or antidepressant drugs, and uncooperative patients were excluded. In addition, patients who received analgesics 48 hours prior to the operation were not included in the study.Patients were enrolled per inclusion criteria and randomly allocated into two equal groups of 21 patients using a computer-generated random number. The allocation was concealed in an opaque envelope and was only opened by a junior resident who was not participating in this study. Randomly assigned patients received oral LEV or matching placebo was given one hour prior to surgery. Patients were induced with propofol 2 µgkg-1, fentanyl 2 µgkg-1, and rocuronium 1 µgkg-1 for anaesthesia and endotracheal intubation. Patients were maintained with a mixture of oxygen and nitrous oxide in the ratio of 1:1 and isoflurane and a non-depolarising muscle relaxant. After surgery, patient reversal was achieved with glycopyrrolate 0.01 µgkg-1 and neostigmine 0.05 µgkg-1, and the patient was extubated. All patients who were enrolled in this study were counselled one day before about the visual analogue pain scale. Postoperative surgery pain was recorded at an interval of 0, 0-4, 4-8, 8-12, and 12-24 hours on the visual analogue scale  at rest. Pain assessment was done in the post anaesthesia care unit (PACU) (0 hours) and then every hour for up to 24 hours till the study ended. From collected pain score data, the highest pain scores during the time intervals of 0, 0-4, 4-8, 8-12, and 12-24 hours were evaluated for statistical analysis. Postoperative analgesia regimen included opioid analgesic with fentanyl injection 1 mcg/kg whenever the pain score was more than 40 mm on the VAS scale. As the onset of action of fentanyl is within 3-5 minutes, patients quickly get relieved. However, when the VAS score was more than 40 mm, the opioid was repeated after 1 hour. The total fentanyl requirement in the first 24 hours as rescue analgesia was recorded. The acuteness of postoperative pain and the requirement of fentanyl in the postoperative area were considered primary outcomes. Secondary effects were the incidence of side effects such as postoperative nausea and vomiting (PONV) and sedation. The intensity of PONV was graded on a four-point ordinal scale . All patients with PONV of a grade of more than 2 received ramosetron 0.3 mg IV. The Ramsay sedation scale  was used to assess the sedation . PatientStatistical analysisThis study was designed to assess the pre-emptive effect of LEV on fentanyl consumption in patients undergoing laparoscopic cholecystectomy. To evaluate, we did a pilot study on ten patients. Based on these data, SD in the control group was 69.15 and in the study group was 48.44, with a mean difference of 90 based on fentanyl consumption. For the result to be statistically significant with an alpha error of 5% and power of 90%, the required sample size in each group was nine patients. Assuming the dropouts increase the number of participants, the sample size in each group was taken as 21 patients. Patient characteristics and other continuous data were analysed with an independent sample t-test. Mann-Whitney U-test was used to analyse the postoperative fentanyl consumption and VAS pain scores. The incidence of side effects was evaluated using Fisher’s exact test. A p-value of less than 0.05 was considered statistically significant. The package SPSS 21  was used for statistical analysis.A total of 42 patients were assessed and received study drugs from June 2018 to January 2019. One patient from the control group and two from the study group were considered dropouts after initial randomisation due to conversion to open cholecystectomy, and therefore, they were not analysed for further statistical analysis.There was no statistical difference among the groups with regard to age, weight, sex, duration of anaesthesia, and duration of surgery (P>0.05) Tables -4.In this study, we detected that a single preoperative dose of LEV 500 mg was efficient in decreasing postoperative fentanyl consumption and postoperative pain in patients of elective laparoscopic cholecystectomy.After oral intake of LEV, rapid absorption takes place, achieving its peak concentration after 1.3 hours. Its bioavailability is >95%. It has a volume of distribution of 0.5-0.7 Lkg-1. The plasma concentrations increase in proportion to the dose over the clinically acceptable dose range from 500 to 5000 mg, and there is no sign of accumulation during multiple administrations. Within 24-48 hours, the blood concentration of the drug achieved a steady state. LEV elimination half-life is 6-8 hours. Approximately 34% dose of LEV is metabolized, and the rest 66% is excreted unmetabolized via urine. However, it is not metabolized in hepatic but primarily in blood by hydrolysis [Cortes-Altamirano JL et al.  reviewedA study by Rossi S et al. found that LEV is well-tolerated, working usefully against central pain, thereby enhancing the quality of life in multiple sclerosis patients. However, in this initial study, the power to recognize a significant effect in the placebo group was reduced because of its size and baseline pain level. The author concluded that larger samples of patients required with a double-blind design are necessary to approve these results . LEV sigThe limitations of our study are that we did not use patient-controlled analgesia (PCA). However, when the study was proposed, the literature was inadequate about the effect of LEV on postoperative pain. Therefore, we principally wanted to express whether there was a reduction in postoperative fentanyl consumption. As the number of patients enrolled was less in this study, further studies are suggested to focus on the LEV effect in postoperative pain and its role as ‘pre-emptive’.In conclusion, we found that preoperative administration of LEV 500 mg was effective in lowering postoperative fentanyl consumption in 24 hours in patients who underwent elective laparoscopic cholecystectomy. In addition, the side effects were not significant in either group. We, therefore, recommend that a single dose of LEV 500 mg before elective laparoscopic cholecystectomy reduces pain and consumption of fentanyl in postoperative period.


The biopsychosocial mechanism by which exercise leads to improvement in chronic low back pain (CLBP) remains unstudied. This prospective cohort study was performed to examine the effectiveness of exercise on pain, disability, and psychological status for CLBP. We also tested path analytic models in which changes in these variables were included.  CLBP patients who visited the Interdisciplinary Pain Center of Keio University Hospital from July 2018 to April 2020 were included. The propensity score matching was performed between patients who underwent exercise (the exercise group) and those who did not (the control group). At the first visit and at the 3-month follow-up, pain ), disability ), and psychological status (Pain Self-Efficacy Questionnaire (PSEQ), and Pain Catastrophizing Scale (PCS)) were assessed. Changes in pain and disability at the follow-up were compared between the groups. The relationships between changes in pain, disability, and psychological variables were examined using Pearson's correlation and mediation analysis. N = 49) than in the control (N = 49) (p < 0.05). Increased PSEQ scores were significantly correlated with decreased NRS scores in both groups. In the exercise group, decreased PDAS fully mediated the relationship between increased PSEQ and decreased NRS (P < 0.05).  A significantly larger decrease in the PDAS was observed in the exercise group ( Exercise improved disability, and the improved disability by exercise mediated the effect of increased self-efficacy on pain relief in CLBP patients. Chronic low back pain (CLBP) is associated with psychological distress and functional disability. The fear-avoidance model explains the chronicity of pain as a result of excessive avoidance of physical and social activities based on negative pain beliefs such as fear, catastrophizing, and low self-efficacy , 2. It iThe objective of this prospective cohort study was to compare changes in pain and disability at a 3-month follow-up between patients with CLBP who underwent an exercise program and those who did not. We also examined the relationships between changes in pain, disability, self-efficacy, and catastrophizing beliefs in each group and analyzed path models in which changes in these variables were included.This study was performed in accordance with the Declaration of Helsinki and was approved by the Institutional Ethics Committee of Keio University School of Medicine (authorization number: 2017039). All methods in this study were carried out in accordance with the relevant guidelines and regulations. The ethics committee waived off the requirement to obtain written informed consent since this observational cohort study was noninterventional and therapeutic options were decided according to current clinical practice, independent of participation in the study. However, we provided patients with a written statement regarding the research and obtained verbal consent. In addition, participants were given an opt-out option for the use of data on a tablet device before and after answering questionnaires.Patients with CLBP persisting for three months or longer who visited the Interdisciplinary Pain Center of Keio University Hospital from July 2018 to April 2020 were included in this cohort study. Patients with cognitive disorders, cardiopulmonary diseases, bone fractures, cancer, and infections were excluded. A specialized pain management program for CLBP in our interdisciplinary pain center included pharmacotherapy, nerve blocks, and exercise. Treatment options were combined based on the discretion of the pain specialists and the patient's response to treatments. Patients with CLBP were informed about physiotherapy by their pain specialists and referred to rehabilitation physicians if they opted to consult them. Participation in our exercise program was determined by rehabilitation physicians from the pain center; indications, contraindications, and patient background information, such as their accessibility to our center, were all taken into consideration when making these determinations. Patients who underwent exercise therapy were defined in the exercise group and those who did not were defined in the control group.Patient characteristics, duration of pain, and the site of pain were obtained by medical interview. According to the International Classification of Disease ICD-11), CLBP was categorized into “primary” and “secondary” CLBP based on neurological examination and imaging findings. CLBP was categorized as “primary” if it was not accounted for by another diagnosis , 9. Pain, CLBP waThe exercise program was conducted by a physical therapist with 3 years of experience in chronic pain management, and the patient's physical function was rigorously assessed. The program consisted of exercises designed for individual patients, including strength training, stretching, and aerobic exercises (ergometer). To strengthen their core muscles, they performed draw-in, back bridge, and hand and knee exercises. Stretching of the erector spinae muscle, gluteus maximus muscle, hamstrings, and iliopsoas muscles was performed to improve the flexibility of the trunk and lower limbs  15]. Th. Th15]. Changes in the NRS and PDAS at the 3-month follow-up were measured as the two primary outcomes. The secondary outcomes were the changes in the PCS and PSEQ scores at the 3-month follow-up.t test or the Wilcoxon rank sum test for variables that were not normally distributed. Categorical data such as gender, duration of pain (<6 months or ≥6 months), ICD-11 classification (primary pain or secondary pain), and cotreatments such as nerve blocks and pharmacotherapy were compared between groups using the chi-square test for dichotomous variables. After the propensity score matching, changes in the NRS, PDAS, PSEQ, and PCS scores between baseline (at the first visit) and the 3-month follow-up (post-treatment) were examined using the paired t-test. Differences over time in pain and disability between the exercise group and control group were examined using repeated measures analysis of variance (ANOVA). A Bonferroni correction for multiple testing was applied . The Pearson correlation coefficient was used to examine the relationships between changes in the NRS, PDAS, PSEQ, and PCS scores in each group. For these correlation analyses, Bonferroni correction was applied . Next, we investigated the group difference of the correlation coefficient, where Fisher's z-transformation was applied to the correlation coefficients and statistical significance was examined under a standard normal distribution. To identify relationships between the correlated variables, we performed a mediation analysis with 5000 permutations using MATLAB 2018a. All statistical analyses other than mediation analyses were performed with JMP ver.14.2.0. Statistical significance was identified by p values < 0.05.Propensity score-matched analyses were conducted to evaluate the effectiveness of the exercise program in improving pain, disability, and pain-related psychological status between the exercise group and the control group. The propensity score was estimated using age, gender, duration of pain, ICD-classification, history of spinal surgery, cotreatment with nerve blocks, and the baseline scores of the NRS, PDAS, HADS, PSEQ, and PCS at the first visit. Patients in the exercise group were matched 1 : 1 with those in the control group by using the nearest-neighbor matching method. Age, body mass index (BMI), and the baseline scores of the NRS, HADS, PSEQ, and PCS were compared between the exercise group and the control group using the unpaired student's A total of 189 patients with CLBP (54 patients in the exercise group and 135 patients in the control group) were included and followed up for over 3 months. After propensity score matching, 98 CLBP patients (49 patients in the exercise group and 49 in the control group) were analyzed. There were no significant differences in baseline demographics, pain intensity, disability, psychological measures, or the rate of cotreatments during the follow-up period between the exercise group and the control group .Significant improvement was observed in both groups in the NRS, PSEQ, and PCS scores during the follow-up period; the significant improvement in the PDAS scores was observed in the exercise group but not in the control group .F value = 1.91, p=0.17, NRS, F value = 0.21, p=0.65).The repeated measures of ANOVA showed significant differences in the longitudinal data between the exercise group and control group for the PDAS scores, while there were no statistical differences for the NRS between the groups . Twenty-Based on these correlation analyses, we tested two hypothetical path models in which changes in the NRS, PDAS, and PSEQ in the exercise group were included . The firThis cohort study revealed significant improvement in pain from the baseline, with or without exercise, in patients with CLBP under specialized pain management. However, a significant improvement in disability was observed only in those who underwent exercise therapy. Improvement in self-efficacy was significantly correlated with improvement in pain in both groups, and the improvement in disability by exercise fully mediated this relationship.The exercise program led to a significant reduction in pain intensity from the baseline but with no superior effect on this goal compared to that of the propensity score-matched controls. This result suggests that a specialized pain management setting with rigorous assessment of multidimensional factors could provide successful pain relief with or without exercise. On the other hand, a significant improvement in disability was observed in the exercise group compared with the control group. Several systematic reviews showed mixed results with regard to the effectiveness of exercise on pain and disability in CLBP, possibly because of heterogeneous interventions , 16. A mIn the current study, regardless of participation in the exercise program, self-efficacy significantly increased, and this improvement was an important associating factor in pain improvement. In our pain center, healthcare providers repeatedly gave patients advice regarding the importance of self-management during their regular visits. This awareness-building could have led to the observed increase in self-efficacy, which consequently resulted in pain relief. With regard to the relationships between self-efficacy, catastrophizing beliefs, disability, and pain, these variables changed significantly, correlating with each other in the exercise group but were inconsistent in the control group. In addition, our correlation analysis showed that exercise strengthened the relationship between changes in self-efficacy and disability and between the changes in disability and pain intensity. To date, few studies have examined the biopsychosocial mechanism of how exercise could lead to improvement in CLBP . Our resThere were several limitations to the interpretation of our data. First, its nonrandomized design with a small sample size limited its ability to control residual confounding. However, we believe that the observer bias and confounding factors could be reduced by using a digital self-rating system on a tablet device and propensity score matching analyses. Second, the study population consisted of patients with relatively severe chronic pain who visited a multidisciplinary pain center and were managed under specialized pain therapy. Therefore, our results may not reflect treatment response in chronic pain patients with less severity. Third, all participants in the exercise group could attend the scheduled sessions. However, since no unified diary was prepared to record their daily exercise, their compliance with home exercise may not have been accurately assessed. Finally, the study subjects did not include all CLBP patients who visited our pain center during the same study period. Although there were no significant differences in demographic, etiological, and psychosocial factors at the first visit between the study subjects and the rest of our patients, our data might have selection bias.Exercise therapy improved disability in chronic back pain patients. We suggested a biopsychosocial mechanism in which change in disability by exercise mediates the relationship between improvement in self-efficacy and pain relief. Further studies will be required to support this mechanism and to develop new strategies to provide more beneficial outcomes for exercise therapy.