Pain management is a central focus for the plastic surgeon’s perioperative planning, and it no longer represents a postoperative afterthought. Protocols that rely on opioid-only pain therapy are outdated and discouraged, as they do not achieve optimal pain relief, increase postoperative morbidity, and contribute to the growing opioid epidemic. A multimodal approach to pain management using non-opioid analgesic techniques is an integral component of enhanced recovery after surgery protocols. Careful perioperative planning for optimal pain management must be achieved in multidisciplinary collaboration with the perioperative care team including anesthesiology. This allows pain management interventions to occur at 3 critical opportunities—preoperative, intraoperative, and postoperative settings. Opioids remain the mainstay of perioperative pain management, despite well-recognized adverse events including nausea, vomiting, pruritus, sedation, constipation, respiratory depression, and opioid-induced hyperalgesia.3 In addition, opioid misuse and abuse has reached epidemic status. The surgeon’s contribution to the opioid epidemic is an undeniable reality. While surgeons are responsible for 10% of all opioid prescriptions,4 the most common reason for new opioid prescriptions is for acute postoperative pain.5 In 2017, the Commission on Combating Drug Addiction and the Opioid Crisis reported that “with approximately 142 Americans dying every day [from the opioid crisis], America is enduring a death toll equal to September 11th every three weeks.6” According to the US Center for Disease Control, 130 deaths per day are attributable to the opioid epidemic.7 In 2017, among 70,237 drug overdose deaths reported in 50 states, 47,600 (67.8%) involved an opioid.8 Two focused areas of concern describe potential surgeon contribution to the problem. The first is the creation of chronic opioid addiction in postsurgical patients who were previously opioid naive, termed “new persistent use.” For patients undergoing plastic surgery, specifically, the rates of new persistent use have been reproducibly demonstrated to be between 5% and 13% across a variety of plastic surgery procedures.10 For surgeons operating on pediatric patients, it is also important to note that the pediatric population is not immune to the development of new persistent use, with rates between 2% and 15% depending on the operation.12 Second, overprescribing by surgeons results in the inadvertent distribution of unused opioids into the community. Overprescribing increases the risk of “diversion” or the redirection of legally obtained prescription opioids for illicit abuse.14 Plastic surgeons are uniquely positioned to play an important role in the reduction of the opioid epidemic because of the efficacy of multimodal analgesia and ERAS protocols for plastic surgery procedures and because of the ability to influence multispecialty surgical collaboration.15 Multimodal analgesia is particularly applicable and effective for plastic surgery procedures, and the most prevalent strategies are reviewed herein.Optimal pain management is an essential component of enhanced recovery after surgery protocols (ERAS) that are becoming standard of care because they have been shown to reduce postoperative complications and expedite recovery.17 Multimodal analgesia is directed toward 4 goals: (1) improvement in the patient experience through better pain control, (2) reduction in postoperative morbidity and mortality, (3) reduction in healthcare costs, and (4) decreased physician-contribution to the global opioid epidemic.Multimodal analgesia is a strategy that reduces reliance on opioids through the use of non-opioid analgesics that have different mechanisms of action.18 In addition, patients should receive some form of local/regional anesthetic technique . Furthermore, it is necessary to balance the invasiveness of the analgesic technique with the expected severity of postoperative pain and balance the efficacy of the analgesic technique and the potential adverse effects including the influence on ambulation.18 An example of how to incorporate these principles is presented in a sample multimodal analgesia protocol for abdominal wall reconstruction  and analgesic adjuncts . It is recommended that all surgical patients should receive “basic analgesics”, which include acetaminophen and either an NSAID or a COX-2-specific inhibitor unless there is a contraindication in a “scheduled” manner, perioperatively, preferentially over “as needed” or pro re nata administration.19With rare exception, local and/or regional anesthesia can and should be used as a matter of routine for most plastic surgery procedures. Local anesthetic medications inhibit neuronal action potentials via voltage-gated sodium channel blockade. The mode of administration can occur via single injection techniques or by catheter-based infusion techniques that administer local anesthetic either intermittently or continuously. Special consideration must be paid toward refining delivery techniques for local anesthetic administration to optimize patient comfort, especially for awake procedures.21 Therefore, it is imperative that the surgeon be familiar with anatomy and injection techniques and engage in a multidisciplinary approach to maximize the number of patients receiving regional anesthesia when clinically indicated.22 Joshi et al22 highlight that the persistent underuse of peripheral nerve blocks can be at least partially overcome by surgeon familiarity and administration of intraoperative interfascial plane blocks and appropriately performed surgical site infiltration. Technical considerations for surgical site infiltration as well as interfascial plane blocks have been recently reviewed.24Evidence exists supporting the role of local anesthetics for opioid reduction, decreased postoperative nausea and vomiting (PONV), decreased pain scores, decreased lengths of stay, decreased rates of certain postoperative complications, and decreased healthcare costs across a variety of plastic surgery procedures.25The challenge of short duration of action for most local anesthetics (approximately 8–12 hours) has been met by catheter infusion techniques or through the development of extended release formulations such as liposomal bupivacaine. In a systematic review of 28 publications encompassing plastic surgery procedures, catheter-based infusion of local anesthetic resulted in an opioid-sparing effect in 92% of studies reviewed.16 Liposomal bupivacaine for regional blockade in the transversus abdominis plane is commonly used in abdominal procedures such as abdominally based microsurgical breast reconstruction and abdominal wall reconstruction,26 demonstrating opioid reduction, decreased lengths of stay, and improved pain scores31 over traditional catheter-based infusion techniques29 without increases in wound complications.32 Studies have demonstrated either equivalent28 or long-term cost-effectiveness of liposomal bupivacaine including decreased length of stay and lower 30-day readmission rates.33Recent evidence has emerged highlighting the benefit of extended release formulations due to prolonged duration of analgesia, ease of single-injection technique that does not necessitate catheter placement, and long-term cost-effectiveness. A 2016 meta-analysis demonstrated safety, tolerability, and either comparable or increased efficacy for pain control for the use of liposomal bupivacaine in plastic surgery.34 Moreover, frontline providers in both the inpatient and office setting must be educated on signs of local anesthetic toxicity, with protocols in place for management.22It is not only critical for the plastic surgeon to become familiar with techniques of local and regional anesthesia but also frequently refresh knowledge of the management of complications associated with these medications.22Use of local and/or regional anesthesia is highly recommended. For many plastic surgery procedures, single regional injection of extended release formulations has the advantage of long duration of action without the need for catheter placement and management. Surgeons must become familiar with regional anatomy and techniques and implement protocols including refresher education for frontline providers on symptoms and management of local anesthetic toxicity.35 In outpatient breast plastic surgery, the use of NSAIDs within a preoperative multimodal analgesia protocol reduced opioid requirements in the postanesthesia care unit by 40% and improved pain scores by 40%.36 NSAIDs are more effective than other adjunct oral medications with lower numbers needed to treat.37NSAIDs form the basis of an optimal multimodal analgesic technique. For core plastic surgery procedures, the use of celecoxib has been shown to reduce pain scores, reduce opioid consumption, expedite return of bowel function and return to activities of daily living, and improve patient satisfaction.38 Controversy surrounds the risk of impaired platelet function and potential surgical bleeding risk associated with NSAIDs, specifically as it relates to reduction mammoplasty.39 However, there remains no high-level evidence to support their contraindication in most plastic surgical patients, and several large reviews have concluded that there is no difference in hematoma rates associated with NSAID use.42 A recent meta-analysis reviewing 15 studies with 3064 cumulative patients demonstrated no increase in hematoma with the use of several types of NSAIDs across a variety of plastic surgical procedures including breast surgery.43 In breast and body contouring procedures, Kelley et al reviewed 106,279 patients; among these, 4,924 (4.6%) patients received postoperative ketorolac.44 Multivariable regression analysis demonstrated that ketorolac was not associated with hematoma , concluding that the benefits of NSAID use outweigh the risks. In sum, the anecdotal frequency of hematoma formation secondary to NSAIDs is overestimated, with evidence supporting the use of NSAIDs in the appropriately selected patient.COX-2 selective inhibitors have a more favorable side effect profile with regard to bleeding than nonselective modalities but are contraindicated in those with preexisting coronary artery disease because of their association with higher rates of cardiac events. NSAIDs and COX-2 selective inhibitors should also be avoided in those with acute or chronic renal disease, and iatrogenic acute renal injury is also a consideration for older perioperative patients, though its absolute risk is not well-defined for plastic surgery procedures.The benefits of NSAID or COX-2 selective inhibitor use in the appropriately selected patient outweigh the risks. Preoperative, intraoperative, and postoperative incorporation of these analgesics into multimodal analgesia regimens is recommended.45 The mechanism of action is unknown, although is thought to be from activation of descending serotonergic pathways and inhibition of COX-mediated prostaglandin synthesis in the central nervous system.46 The safety profile of acetaminophen is favorable, with the exception of hepatotoxicity above the maximum dosage of 4 g per 24 hours. Avoiding acetaminophen usage in patients with known liver disease should be considered. Controversy has centered around the effectiveness of oral versus parenteral formulations and its relation to cost. A recent meta-analysis demonstrates no clear advantage of parenteral administration over oral administration for appropriately selected patients for the indication of perioperative pain control.47 Oral administration has been reproducibly demonstrated to be effective for preoperative and postoperative analgesia, specifically.49 Oral dosage protocols range from 650 to 1000 mg and favor “around-the-clock” administration, typically every 6 hours. There have been no high-level studies comparing the effectiveness of dosage differences for the indication of perioperative pain management. With “around-the-clock” acetaminophen regimens, it is recommended to avoid the use of acetaminophen–opioid combination formulations for breakthrough pain because of the risk of inadvertent acetaminophen overdose. This warrants special mention because combination formulations are the most commonly prescribed by plastic surgeons for breakthrough pain.50Acetaminophen is an effective perioperative analgesic with efficacy for both pain control and opioid reduction across all surgical specialties.Acetaminophen should be used routinely for preoperative, intraoperative, and postoperative analgesia in an “around-the-clock” manner to reduce pain and opioid consumption. It is not recommended to prescribe acetaminophen–opioid combination tablets for breakthrough pain with this regimen because of the risk of acetaminophen overdose. Both oral and parenteral formulations are effective. Consideration should be given to avoid acetaminophen in patients with known liver disease.52 A meta-analysis encompassing 18 studies and 1,181 patients demonstrated that perioperative gabapentin resulted in 35% reduction in total opioid consumption and pain within the first 24 hours after surgery while simultaneously increasing early ambulation.53 A large randomized controlled trial encompassing a variety of surgical procedures demonstrated effectiveness of perioperative gabapentin toward supporting postoperative opioid cessation, with a regimen consisting of 1,200 mg preoperatively and 600 mg 3 times daily postoperatively for 10 doses.54 In the burn population, gabapentin is uniquely beneficial because of its ability to reduce burn-associated pruritus, in addition to decreasing opioid consumption.56Gabapentin is the most widely used anticonvulsant as an adjunct perioperative pain medication. In the perioperative setting, gabapentin decreases postoperative pain and opioid consumption, as well as PONV.2 Furthermore, gabapentinoids are associated with several adverse effects including dizziness, somnolence, and respiratory depression. For this reason, gabapentinoids should be used selectively when basic analgesic techniques are not possible or contraindicated and patients are at a high risk of persistent postoperative pain.2 Also, it is recommended to avoid or dose-reduce the medication for the elderly, patients with significant comorbidities, and those with reduced lung function including chronic obstructive pulmonary disease or known or suspected obstructive sleep apnea.57Of note, most studies assessing the analgesic benefits of gabapentinoids did not use the basic analgesics  or local anesthetic techniques. The benefits of gabapentinoids over basic analgesic techniques appear to be limited.Gabapentin is a useful analgesic adjunct in the preoperative and postoperative setting that can reduce opioid consumption and improve the patient’s postoperative experience. However, gabapentin should be used in selective patient populations and surgical procedures that are at a high risk of persistent postoperative pain. In these situations, gabapentin should not be avoided because of physician lack of familiarity with the drug. Concerns with gabapentinoids include dizziness and sedation, as well as potential for respiratory depression, particularly in the patients with significant comorbidities, the elderly, and patients with known or suspected reduced lung function such as chronic obstructive pulmonary disease or obstructive sleep apnea.58 A 2013 meta-analysis demonstrated that postoperative patients have decreased pain scores and opioid consumption when dexamethasone is included as a multimodal adjunct.59 Few studies address the role of dexamethasone in plastic surgery, specifically. A recent prospective, double-blind randomized trial in head and neck microvascular reconstruction similarly demonstrated decreased pain and opioid consumption after dexamethasone inclusion. However, hyperglycemia and insulin requirements were problematic for patients in the treatment group, leading the authors to conclude that the risks for reconstructive patients outweighed the benefits.60 In contrast, systematic reviews have concluded that the benefits from dexamethasone outweigh the concerns of hyperglycemia, except for patients with brittle diabetes mellitus. No evidence currently exists correlating dexamethasone use with an increased occurrence of postoperative wound infection or wound healing delay.61Glucocorticoids reduce postoperative pain through anti-inflammatory mechanisms and possess antiemetic properties, serving as a key adjunct for PONV prophylaxis.Dexamethasone reduces pain and opioid consumption and reduces PONV. A single intraoperative dose of dexamethasone 8 mg, IV should be considered as an integral component of multimodal analgesia and antiemetic prophylaxis for all procedures unless there is a contraindication . Those at risk for complications associated with postoperative hyperglycemia represent less ideal candidates.61 For plastic surgery patients, specific points that should routinely be communicated to patients in the preoperative clinic setting include (1) discussion of the medical risks of opioids, in terms of known postoperative side effects and potential for abuse, (2) purpose and importance of alternative medications and regional procedures, and (3) proper medication storage and proper disposal  and not as a primary pain management strategy. While direct comparisons between protocols do not exist for a majority of plastic surgery operations, principles of multimodal analgesia carry through Table . It is iJ.B. was supported by the National Institutes of Health (NIH) T32AI106704-01A1, NIH F32HL144120-01A1, and the Ohio State University President’s Postdoctoral Scholar Program.


Background/Aims: Functional anorectal pain (FARP) is a functional gastrointestinal disease, which belongs to chronic pelvic floor pain. The mechanisms of its development are not fully understood. We designed this experiment to evaluate the characteristics of rectal sensory evoked potential (RSEP) and anorectal manometry (ARM) in this population, so as to explore the pathophysiology of FARP.Methods: The rectal sensory evoked potentials (RSEP) and anorectal manometry (ARM) were performed in 23 patients with FARP and 23 healthy controls. The correlation between the two measurements was investigated.Results: The results of RSEP showed that (1) the median latency to the first positive peak was 69.2 ± 15.9 ms in patients, compared with 46.5 ± 5.8 ms in controls (P = 0.000). (2) The amplitude of evoked potential peaks in the FARP patients was significantly lower than the healthy controls . (3) Compared with the controls, the patients showed a lower maximum voluntary squeeze pressure (P = 0.009), lower rectum (P = 0.007), and anal sphincter pressures (P = 0.000) during strain; and increased maximum tolerance threshold to rectal distention (P = 0.000). (4) The resting pressure of the anal sphincter was correlated with the peak amplitude of the RSEP . Considering the different pathophysiological mechanisms of levator ani syndrome and proctalgia fugax, we analyzed data on unspecified functional anorectal pain and obtained similar results.Conclusions: The RSEP can be used to evaluate the state of afferent pathways in FARP patients; The longer latency and lower peak amplitude of RSEP indicate the functional defects of the anorectal afferent pathway. It can provide an objective evidence for the neuropathy of FARP. In addition, the pathophysiology of FARP is also associated with pelvic floor muscle motor and coordination dysfunction. The correlation between the peak amplitude of the RSEP and the resting pressure of the anal sphincter suggests that there seems to be a correlation between anal pressure and the afferent signaling pathway in patients with FARP. Functional anorectal pain (FARP) is a disabling disease and can be caused by a variety of factors. Rome IV divides FARP into three subtypes: proctalgia fugax, levator ani syndrome, and unspecified functional anorectal pain –3. LevatThe pathophysiology of FARP is still unclear. At present, it is generally believed that the over contraction and high tension of pelvic floor muscle are one of the important mechanisms. Levator ani syndrome is considered to be closely related to pelvic floor spasm and can usually be relieved by the biofeedback therapy , 7. Rao Abnormal regulation of the nervous system may also lead to FARP. The function of gastrointestinal tract is controlled by the central nervous system, autonomic nervous system, and enteric nervous system. There is a biphasic regulatory pathway between the digestive tract and the central nervous system ; the braNeurophysiological tests can provide useful information regarding the integrity of neuronal innervation and neuromuscular function of the gut. During the last few years, some techniques have provide information regarding gut-brain communication such as Positron Emission Tomography (PET) or functional magnetic resonance imaging (fMRI). Recently, RSEP has been introduced as a new technique that can provide an quantifiable method to evaluate the connections between the afferent tracts, spinal cord, and the cerebral cortex . In thisThis study was reviewed and approved by the Ethics Committee of Nanjing Hospital of Chinese Medicine (KY2018004). The participants provided their written informed consent to participate in this study. Twenty three patients with FARP were recruited from patients seen in the Anorectal Clinic of Nanjing Hospital of Chinese Medicine. All patients met the Rome IV criteria for functional anal pain. Patients with a history of anorectal surgery, secondary anorectal pain with clear etiology, serious gastrointestinal diseases or oral drugs affecting gastrointestinal functions, serious neurological diseases, spinal injury, or surgery were excluded, as were pregnant women.In order to exclude the influence of age and gender, the control group consisted of 23 healthy people whose sex and age matched with the patients. These healthy people did not have FARP and diseases listed below: gastrointestinal diseases, severe perianal diseases, or severe cardiovascular. Individuals with any cerebrovascular, urological, gynecological, orthopedic, or malignant tumors were also excluded.For rectal stimulation, a St. Mark's stimulation electrode was fixed at the tip on the index finger while the other electrode was located at the root of the index finger, and the electrodes were connected to an electrical stimulator . For recording of evoked potential, an active electrode was placed on the subject's central scalp (Cz); a reference electrode was placed on the forehead (Fz); and a grounding electrode was placed on the ankle. This was in accordance with the International Electroencephalogram Society standard . The tesAfter electrical stimulation, three typical main waveforms could be recorded , which aAnorectal manometry (ARM) was performed via an 8-channel radially distributed water perfusion catheter with a latex balloon attached at the tip of the catheter . Before anorectal manometry, all participants were required to empty their stools to ensure that the rectum was empty. The patient lay on the left side and remained relaxed; the examination was performed by a well-trained doctor. Following measurements were made: rectal motility functions  and rectal sensory functions . Other measurements included the length of functional anal canal, rectum anal inhibitory reflex (RAIR), contractile reflex of the anorectum during coughing (cough reflex) and defecation reflex. The procedures and measurements followed the standards of previous studies , 20.U-test was used to compare the latency and amplitude of RSEP waves, and parameters of anorectal manometry between the FARP patients and healthy controls. The correlations between the parameters of RSEP and the parameters of anorectal manometry were analyzed by Pearson or Spearman correlation analysis.SPSS 20.0 version was used for statistical analyses. The data are expressed as mean ± standard deviation with 95% confidence interval. Counting data is expressed by frequencies and percentages, Fisher's exact tests is used for comparison between groups. The Mann Whitney All 23 patients with FARP were enrolled in the study. There was 21/23 patients with unspecified functional anorectal pain (Unspecified-FARP), and 1/23 patient with proctalgia fugax (PF),1/23 patient with levator ani syndrome(LAS) The average age of the patients was 52.48 (±12.98) years old and gender distribution of the two groups was 18/5 (F/M). There was no significant difference in height, weight or BMI between the patients and healthy controls . The femA reproducible RSEP pattern was recorded in all subjects after rectal stimulation. Typical examples of the morphology of RSEP response are shown in P < 0.01). There was no significant difference in N1 and P2 latency between the two groups. The amplitude of each wave in the FARP patients was significantly lower than the healthy controls . In order to further explore the mechanism of unspecified functional anorectal pain, we compared the RSEP examination of unspecified-FARP patients with that of healthy controls . Meanwhile, the FARP patients showed a significantly lower anal sphincter pressure and rectal pressure during straining (P < 0.01). There was no significant difference between the two groups in resting anal pressure, sphincter length. In addition, analrectal manometry results in 13 patients with unspecified-FARP were analyzed, and similar results were obtained .There was no significant difference between the two groups in first sensation threshold or the urge to defecate threshold .RAIR was present in all patients and all controls. The mean volume of rectal distention needed to initiate RAIR in the healthy controls was 12.63 ± 5.03 mL, while patients needed larger volumes to elicit RAIR . Cough reflex was normal in all subjects.7/15 patients who received ARM showed abnormal defecation reflex, including the patient with levator ani syndrome. However, only one of the healthy controls showed abnormal defecation reflex. There is a significant difference between the two groups     and the a= 0.047) . There w= 0.020) . There wChronic anorectal pain is a refractory functional gastrointestinal disease. The Rome Classification provides well-defined diagnostic criteria for functional anorectal pain. However, it is still unclear of the pathophysiology of FARP and a huge challenge to treat FARP, though some advances in the treatment of functional anorectal pain have made recently –24. The ARM is widely used for the detection of abnormalities of sphincter function and rectoanal coordination . We founSomatosensory EPs (SEPs) has advantages over other brain imaging techniques given its relative portability, inexpensiveness, availability. It can be used to evaluate the somatosensory pathway at the peripheral, spinal, cortical, and subcortical level . By stimConscious perception implies sensory connectivity between the rectum and the brain . SensoryThe RAIR is a phenomenon in which the anal internal sphincter is temporarily relaxed due to the transient distension of the rectum. It plays an important role in bowel control and defecation . StudiesThe limitations of our study include the small sample size and a comparative study among different subtypes could not be performed. Also, in this study, we didn't evaluat efferent pathways in FARP patients, and also deserves further study.In conclusion, rectal sensory evoked potential is safe and well-tolerated and appears to be a useful technique for the detection of neuropathy, the test can provide an objective evidence for neuropathy and a new dimension toward our understanding of the mechanisms of FARP.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics Committee of Nanjing Hospital of Chinese Medicine. The patients/participants provided their written informed consent to participate in this study.MN and BJ conceived and designed research. QiZ and YL conducted research and wrote the initial paper. QioZ, YZ, and SW collected date. MN revised the paper and had primary responsibility for final content. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Pain management after the total joint arthroplasty is still challenging, but worthy of attention, because good pain management can improve the outcomes of patient. It is still controversial whether fascia iliaca compartment block (FICB) can effectively decrease the opioid consumption and pain after total hip replacement (THR) owing to the number of published investigations is small. The purpose of this present study is to assess the efficacy and safety of FICB for postoperative analgesia after THR.–1 of epinephrine and 40 mL of ropivacaine 0.2%. Primary outcomes are pain score at different time point. Visual analog scale is used to assess the pain (10: the maximum possible pain and 0: absent pain). The secondary outcomes are the postoperative complications, length of hospital stay and total consumption of opioid. All the needed analyses are implemented through utilizing SPSS for Windows Version 15.0.This is a single center, placebo-controlled randomized trial which is performed in accordance with the SPIRIT Checklist for randomized studies. It was authorized via the Chifeng Municipal Hospital institutional review committee (H2020-19-8). 100 patients undergoing THR will be included in this study. Patients are randomly divided into 2 groups: FICB group or Non-FICB group, FICB with 5mgmLFigure 1 will show the primary and secondary outcomes.This trial can provide an evidence for the use of FICB for analgesia after THR. Numerous strategies have been implemented to reduce postoperative pain following THR including local infiltration analgesia, epidural analgesia, intravenous non-steroidal anti-inflammatory agents and peripheral nerve block.–9 Each method has its limitations and opioids are used as an alternative method to reduce pain. However, opioid can cause many side effects, such as gastrointestinal reactions, respiratory depression, retention of urine and constipation.,11 Therefore, multimodal analgesia has been extensively used in perioperative period of THR.Total hip replacements (THRs) are quite successful surgery for many end-stage hip diseases in terms of pain relief and functional recovery. They are all the part of lumbar plexus, which means that blocking lumbar plexus provides an elegant method for the postoperative analgesia after THR. FICB has no effect on muscle strength of quadriceps femoris and theoretically, it will not increase the risk of fall during rehabilitation. Several articles have suggested that FICB was related to the reduced consumption of opioid analgesics and the improvement of pain relief in patients with THR.,14 However, others reported that there was no positive effects for postoperative pain management.Fascia iliaca compartment block (FICB) is a kind of anterior method to lumbar plexus. The hip joint is supplied via the branches of sciatic, obturator, and femoral nerves.It is not clear that whether FICB is a kind of effective approach for the postoperative analgesia after THR. Therefore, we conduct this randomized controlled study protocol in order to evaluate the efficacy and safety of FICB for analgesia after THR. Our assumption is that FICB could reduce the consumption of opioid and pain score after operation in the early postoperative period.2This is a single center, placebo-controlled randomized trial which is performed in accordance with the SPIRIT Checklist for randomized studies. It was authorized via institutional review committee in the Chifeng Municipal Hospital (H2020–19-8) and then was registered in research registry (researchregistry5894). The orthopedic surgeon will explain the details of trial, afterward, patiently answer all the questions from patients. These patients are then presented with the written information of our trial. Each of patient received a written informed consent. Since all patients participated voluntarily, they could withdraw at any time during the trial.2.1−1 of epinephrine and 40 mL of ropivacaine 0.2%. Physicians, statisticians, data collectors and evaluators are all blinded to the allocation.100 patients undergoing THR will be included in this study. In the random envelope, all participants will be assigned a random number via utilizing the random number table, and the result of allocation is hidden. Patients are randomly divided into 2 groups: FICB group (n = 50) or Non-FICB group (n = 50), FICB with 5mgmL2.22, with the history of renal and hepatic dysfunction, with the clinical evidence of peripheral neuropathies, coagulation disorders, and opioid dependence.The inclusion criteria included patients aged between 55 and 70 years old, with ASA physical condition I-III, and receiving the total hip arthroplasty in our hospital. The exclusion criteria included refusal or inability to sign the informed consent, intolerance to any drug utilized in our study, BMI above 35 kg/m2.3−1 of midazolam and 0.5mgkg-1 of fentanyl. All patients will undergo the spinal anesthesia in lateral position. The level and midline of the intervertebral spaces of L3–4 and L4–5 are determined, afterward, spinal anesthesia is performed by injecting 10 mg 0.5% bupivacaine hyperbaric solution with the 25-gauge Quincke needle. Patients are placed promptly in supine position. After the addition of 18 intravenous cannula to the ankle, all the patients receive THR in an independent lateral position via a hip surgeon with fifteen years of experience. The patient is then transferred into a separate ward. After the standard monitoring, the patients in group FICB are performed with ultrasound; Afterward, both 2 groups of patients start the patient-controlled intravenous analgesia.Patients are given intravenously 0.02mgkg2.4−1 0.2% epinephrine and 40 mL of ropivacaine.In supine position, the chlorhexidine and betadine are utilized to disinfect inguinal crease area. A 5 MHz-12 MHz linear probe is placed parallel to inguinal ligament at inguinal crease, and the fascia iliaca, fascia lata, femoral artery, femoral nerve as well as iliacus muscle are found. After the probe is rotated 90 to 135 degrees counterclockwise, we makes this probe parallel to vertebral axis. From this view, a 22G Tuohy needle, connected to a venous extension tube between syringe and the needle, is inserted in the plane and then pushed toward the iliacusmuscle and fascia iliaca. After we confirm that the needle passed through the fascia iliaca, we inject the local anesthetic prepared in advance. After the injection of normal saline, we utilize the hydrodissection technique under the guidance of real-time ultrasound. In hydrodissection technique, a small amount of the local anesthetic (1–2 mL) is injected, and then the needle is extended to proximal side for proximal local anesthetic diffusion. Through this hydrodissection process, the needle passes through the proximal end, goes deep into the fascia iliaca, and enters iliac fossa, and only enters space created via the fluid collection. Prior to the entire needle is inserted into skin, this hydrodissection technique need to repeat. And the total volume is 5mgmL2.5 The secondary outcomes are the postoperative complications, length of hospital stay and total consumption of opioid.Primary outcomes are pain score at different time point. Visual analog scale is used to assess the pain (10: the maximum possible pain and 0: absent pain).2.6t-test or the Mann-Whitney U test is utilized for the comparison between groups. Chi-square detection is utilized to compare the categorical variables among the groups. A P < .05 is regarded the significant in statistics.All the needed analyses are implemented through utilizing SPSS for Windows Version 15.0. All the data are represented with proper characteristics as median, mean, percentage as well as standard deviation. Independent samples 3Figure 4 About 6 to 10 percent of the patients may experience moderate to severe pain lasting at least 3 months after the operation, which is considered as the chronic postoperative pain. Different institutions have different postoperative treatment protocols, which may lead to different techniques used and patterns, and affecting long-term results and success. The lack of a definitive “gold standard” and various postoperative pain treat programs indicate that there is considerable room for improving the standard of care. The techniques of regional anesthesia can decrease postoperative pain scores and the consumption of opioid, so as to improve patient satisfaction and better treatment outcomes.,19 It is still controversial whether FICB can effectively decrease the opioid consumption and pain after THR owing to the number of published investigations is small. We conduct this protocol to evaluate the safety and efficacy of FICB in postoperative analgesia after THR.Pain management after the total joint arthroplasty is still challenging, but worthy of attention, because good pain management can improve the outcomes of patient.5This trial can provide an evidence for the use of FICB for analgesia after THR.Xizhe Zhang design the protocol. Qi Zhou review and edit the study protocol. Yan Qiao perform conduction of experiments. Jiannan Song finish the manuscript.Investigation: Yan Qiao.Methodology: Yan Qiao.Writing – original draft: Jiannan Song.Writing – review & editing: Qi Zhou.


Patients with vertebral fragility fractures often experience chronic pain, postural and balance disorders, and poor quality of life (QoL). Although several studies have investigated the role of rehabilitation in severe osteoporosis, the effectiveness of this intervention in patients with multiple vertebral fractures is poorly known. The aim of our longitudinal cohort study is to evaluate the effectiveness of rehabilitation, including postural training, resistance exercises, and visual stabilization exercises, for a 7-week period, on the pain, postural balance, and QoL of subjects with at least two vertebral fragility fractures receiving denosumab and vitamin D. We investigated, before (T0) and after  rehabilitation, the following outcome measures on 28 patients: pain ), self-perceived QoL (36-Item Short Form Survey (SF-36) and Mini-Osteoporosis Quality of Life Questionnaire (Mini-OQOL)), dizziness (Dizziness Handicap Inventory (DHI-I)), mobility (Timed-Up and Go (TUG) test), and instrumental posturographic assessment (FreeMed posturography system). At the end of the treatment, improvements of pain and QoL were recorded. Pain relief was highly obtained in patients with more than two vertebral fractures. Moreover, a significant functional improvement (TUG test) was found in those with two vertebral fractures, without any statistically significant change reported for other outcomes. Our findings suggest that combined intervention, including anti-osteoporotic drugs and postural rehabilitation, should be proposed to osteoporotic patients with multiple vertebral fractures. Osteoporosis is a systemic disease characterized by poor bone quality, reduced bone mass, and consequently, an increased risk of fragility fractures ,2,3,4. TIn the multidisciplinary approach to osteoporotic patients with fragility fractures, pharmacological therapy is a key intervention considering its efficacy in preventing incident fractures . AntiresThe aim of our study is to evaluate the effectiveness of rehabilitative intervention on pain, postural balance, and quality of life in postmenopausal women with at least two vertebral fragility fractures being treated with denosumab.We carried out a prospective cohort study involving 52 women recruited at our Metabolic Bone Diseases Clinic of Physical Medicine and Rehabilitation. The study was led according to the principles of the Helsinki Declaration after the approval of the local ethics committee: Palermo Ethics Committee I (protocol number 05/2019 of the meeting of the 22 May 2019). The study protocol was fully explained, and written informed consent was obtained from each participant.Inclusion criteria were diagnosis of postmenopausal osteoporosis with at least two vertebral fragility fractures; ongoing pharmacological treatment with denosumab for at least 6 months combined with cholecalciferol supplementation; serum 25(OH)D3 ≥ 20 ng/mL. Non-ambulatory patients and those with ear diseases , cerebellopontine tumours, other neurological, and/or severe psychiatric diseases were excluded.All patients underwent a first evaluation before the treatment protocol and a second one after the end of the treatment period (7 weeks). All patients received the rehabilitation treatment led by a physiotherapist with expertise in postural rehabilitation, also integrating exercises to improve balance and walking pattern, resistance training, and visual stabilization exercises. This treatment protocol was administered 3 times per week, with 45 min sessions, for a total of 20 sessions, in a 7-week period.After medical history collection and a standard musculoskeletal examination, pain, quality of life, posture, and balance at baseline were comprehensively assessed. Pain intensity was measured by the Numerical Rating Scale (NRS), a unidimensional measure of pain intensity in adults with chronic pain ; it is aSelf-perceived QoL was investigated through the 36-Item Short Form Survey (SF-36) and Mini-Osteoporosis Quality of Life Questionnaire (Mini-OQOL), respectively. SF-36 consists of 36 items divided into eight health domains: general health (GH), physical functioning (PF), physical role (rP), body pain (BP), vitality (v), social functioning (SF), emotional role (re), and mental health (mH) . Each doThe Mini-OQOL evaluates the QoL in patients affected by osteoporosis investigating five health areas  . For eacPostural and balance were clinically assessed by the Timed-Up and Go (TUG)-Test , while tDizziness burden was investigated by the Dizziness Handicap Inventory in Italian version (DHI-I) ,29. DHI-2) between feet and for each foot, the plantar surface of both feet and the superficial extension of the backfoot and forefoot of each foot (cm2), the podalic angle, and axe were measured. In stabilometric examination, we considered the bundle length (mm) that is the size of the trait designed by the oscillation of the centre of pressure (CoP) during the test; the ellipse surface (mm2) is the area including 90% of the trait of the CoP; X-medium (mm) indicates the medium position maintained in frontal plane during the lateral oscillations, and Y-medium (mm) is the medium point of the centre of gravity on the sagittal plane during anterior-posterior oscillations; ΔX (mm) is the range of right-left oscillations, and ΔY (mm) is the range of anterior–posterior oscillations. All patients also underwent a dynamic biomechanical evaluation of gait and were asked to walk along the full length of the platform10 times, with their sight in neutral position. We analysed the maximum load and medium load (Kg and %), plantar maximum and medium surface (Kg and %), the maximum pressure point of feet and medium pressure point of feet (gr/cm2), the step length and the half-step length (mm), the medium walking velocity (mm/s), the number of steps per minute, the time permanence of each foot on the ground (ms), the total duration time of the test (s), and the number of footprints scanned. Moreover, for each footprint in every phase of the step, data related to load (%), surface (mm2) of the feet toes, metatarsal bones, and medial and lateral plantar arch were analysed.Posturographic assessment was registered in a sound-isolated booth using the FreeMed posturography system, including the FreeMed baropodometric platform and the FreeStep v.1.0.3 software. The system was set to sample postural sway at 100 Hz. The sensors, coated with 24 K gold, guarantee repeatability and reliability of the instrument . The posturographic analysis was led by a stabilometric platform. Baropodometric examination was performed asking patients to maintain their static position without shoes, with their arms by their sides, head, and consequently, sight in neutral position with open eyes for 5 s; they also underwent a static analysis (stabilometric examination) maintaining standing position with feet placed together with an angle of 30 grades between right and left heels at 2 cm apart, firstly, with open eyes for 51.2 s, and after that, with closed eyes for 51.2 s too, in order to analyse the time and frequency of oscillations and self-adjustments of the patient excluding the visual input. In baropodometry, the following parameters were considered: pressure of right and left foot on the ground (kg and %), pressure load of both left and right forefoot and backfoot (%), and the relation between backfoot and forefoot (%). Additionally, the maximum pressure point and the medium pressure point . All data were presented as the mean ± standard deviation (SD) for continuous variables and as the median (interquartile range) for ordinal variables. All analyses are performed using R software . Differences in the demographic characteristics; parameters of stabilometric, static, and dynamic baropodometry; and the questionnaires that were administered between the first and the second examination (T0 and T1) were compared using a Student’s Out of 52 women included, five of them were excluded because of severe systemic disorders diagnosed during the study . Then, 19 of them were excluded because of missing data at follow-up (T1). Finally, 28 women completed the rehabilitation protocol  .The baseline characteristics of study population are reported in In static baropodometry, there were no statistically significant differences between T0 and T1 in all patients and both Group 1 and Group 2 for any of the parameters assessed, except for the Right Pod Degree in Group 1 .Additionally, in both the stabilometric analysis and dynamic evaluation, no statistically significant differences between time points for all patients and in both Group 1 and Group 2 for any of the parameters assessed were found. All patients completed the treatment protocol, and no adverse event was reported .To the best of our knowledge, this is the first study to investigate the effectiveness of a combined approach, including denosumab and vitamin D administration, and rehabilitation interventions in patients with multiple vertebral fractures in terms of key outcomes, including pain, mobility, postural control, and quality of life. Our findings suggest that this treatment strategy might be effective for pain relief, particularly in osteoporotic women with more than two vertebral fractures. Moreover, the same intervention might also improve mobility in women with two vertebral fragility fractures. It should be underlined that the rehabilitation treatment was well tolerated, despite the severity of bone fragility in our population.Osteoporotic fractures have significant detrimental effects in terms of pain, mobility limitations and postural balance, and QoL ,31. RecePain control could promote adherence to rehabilitation treatment with putative improvement of muscle impairments that are commonly observed in patients with severe osteoporosis, including those with multiple vertebral fractures ,34. In aMore recently, a putative role of the OPG/RANK/RANKL pathway has been suggested in the pathogenesis of skeletal muscle wasting. An experimental study demonstrated that the systemic injection of OPG restores muscle strength and improves muscle quality in mice models of muscular dystrophy . FurtherConcerning mobility impairment, our results are in line with those reported by a recent Cochrane Systematic Review, which found moderate-quality evidence supporting the efficacy of exercise in improving physical performance, specifically TUG, in patients with vertebral fractures . MoreoveHowever, our study has some limitations, including the small sample size, the lack of core muscle strength evaluation, and the lack of a control group.It can be speculated that the synergy between pharmacotherapy and rehabilitation treatment might be effective in reducing pain, thus improving the QoL of women affected by severe osteoporosis. In this context, therapeutic exercise, including postural techniques and resistance training, might be effective in improving postural balance by increasing the strength of the trunk muscles, thus reducing the risk of hyperkyphosis, falls, and incident fractures .These findings can inform clinicians and stakeholders about the importance of combined approaches in women with multiple vertebral fragility fractures, also considering the association among better QoL, pain relief, and functional improvement in this population .In this study, performed on a cohort of women suffering from osteoporosis with multiple vertebral fragility fractures, it seems that a combined approach, including antiresorptive drugs and rehabilitation intervention, might reduce pain relief and improve QoL, although further studies comparing this approach to pharmacological treatment alone, or therapeutic exercise alone, might improve the quality of evidence on this topic. Our findings suggest that this intervention is useful and should also be proposed to osteoporotic patients with severe conditions, including those with multiple vertebral fractures.


The number of people living with soft-tissue and bone sarcomas is increasing due to improved individual therapy and changes in demographics. At present, there are no recommendations for psychological co-treatment, occupational and social reintegration following the treatment of soft tissue and bone sarcomas.Seventy-four patients, 42 males and 32 females, aged between 18 and 80 years (54.58 ± 16.99 yr.) with soft-tissue (62) and bone sarcomas (12) were included to answer five standardized and one personal questionnaire regarding quality of life, function, reintegration and participation after surgical treatment.A number of tumour-specific and patient-specific factors were identified that affected the therapeutic outcome. Patients with sarcoma of the lower extremity described poorer mobility. Patients who underwent amputation reported a higher anxious preoccupation. Patients with a higher range of education were less fatalistic and avoiding. The size of tumours or additive radiation therapy did not affect the post-therapeutic quality of life, coping and function. There was a good correlation between anxiety and depression with occupational reintegration, function, quality of life and coping.Patients with sarcomas of the lower limb have a higher demand for postoperative rehabilitation and need more help in the postoperative occupational reintegration. Furthermore patients that underwent limb-preserving operations reported better postoperative function and quality of life. Risk assessment using patient-specific factors and an intensive psychological co-treatment may have a large role in the co-treatment of patients from the beginning of their cancer therapy. Malignant diseases are the second most common cause of death in modern industrialized countries. The number of people living with cancer is increasing due to the demographic change and the extended survival of malignant tumours through continuous improvement of their therapy –3. For iIn 2013 cancer was the cause of an incapacity to work in around 200,000 cases in Germany and 1 in 8 nursing cases had a cancer disease as primary diagnosis [The treatment of sarcomas usually includes resection of the tumour-bearing tissue with a safety margin. This may have an effect on the function of a limb, the patient’s body image and thus the psychosocial outcome of the patient.In addition to resection, factors such as the size of the tumour, the affected region or tissue type may also influence the postoperative outcome. Radiotherapy, isolated limb perfusion or chemotherapy may also be used as part of the therapy , 7; theiIn all malignant musculoskeletal tumours, a follow-up for the early detection of recurrence is suggested. However, we lack evidence that this has an influence on overall outcome and there is no recommendation regarding aid in occupational and social reintegration following the treatment of those malignancies. This is especially important in cases where treatment may be prolonged such as in cases of Ewing’s or osteosarcoma which may last almost 1 year , 7.While the main focus is on the functional aspects of tumour surgery and oncological follow-up, the psychological diagnosis and adjuvant treatment is usually very under-represented in treatment guidelines. Occasionally, patients are hardly screened for existing disorders or symptoms are not properly recognized. Pirl et al. reported that 10 to 25% of cancer patients have concurrent depression or depressive disorders . SimilarDoes the affected tissue type and the localization have an impact on subsequent occupational reintegration and quality of life?Do the size of the tumour, use of radiation therapy and/or the surgical treatment have an influence on function, occupational reintegration and quality of life?Does post-therapeutic function have an impact on quality of life and occupational reintegration?Does the patient’s level of education have an impact on occupational reintegration, quality of life and mental adjustment to cancer?Do patients with depressive or anxious traits experience poorer occupational reintegration, quality of life and adjustment to cancer?Therefore, based on the above considerations, this study aimed to examine the following study questions:This study is a retrospective analysis of 782 patients who underwent surgery for a musculoskeletal tumour including benign lesions and metastasis in the period from July 2004 to January 2018 at our institution.Patients were included in this study if they were at least 18 years of age, were treated for a soft tissue or bone sarcoma, had the primary operative treatment in our institution and were at least 6 months after the completed cancer treatment including radiation therapy. Patients were excluded if they were treated in palliative intention, had a recurrence of the disease or a relevant secondary tumour.Ninety-one of these patients were included in accordance with the inclusion and exclusion criteria. Seventy-four of these patients consented to participate in the study, completed the necessary questionnaires and could thus be included in the study.The SMFA  is a practicable and reliable questionnaire for patient-centred assessment of musculoskeletal dysfunction consisting of 5 scales for function  and 1 scale for bother , 12.The HADS  is a questionnaire for the assessment of anxiety and depression in patients with physical illnesses, developed by Zigmond and Snaith in 1983 , 14. TheThe QLQ-C30  is an instrument to measure quality of life developed by the European Organization for Research and Treatment of Cancer, applicable to all tumour entities and validated in numerous studies , 17. A tThe SF-36 (Short Form 36) is a tool for general health assessment based on the short form 20 scores of the Medical Outcomes Study in 1988 [The last part of the questionnaire is the MAC , a self-assessment tool depicting various reactions to cancer like “Fighting Spirit”, “Anxious Preoccupation”, “Fatalism”, “Helpless−/Hopelessness” and “Positive Avoidance”. It is used specifically for the detection of disease processing in cancer patients (“coping”) . ReliabiAll patients were given a questionnaire, either by post or at the time of follow-up in the outpatient clinic, consisting of five standardized and one personal questionnaire; analysing school and vocational training, employment before and after the disease diagnosis, family support and residential situation. The standardized part of the survey included the following questionnaires in their validated German versions:p < 0.05 was considered statistically significant.Microsoft Excel 2013  and IBM SPSS Version 25  were used for data analysis. For classified variables, the frequency and percentage of each pattern were calculated, and detected by a χ2 test according to Pearson. The measurement data showed no normal distribution so non-parametric tests had to be used to determine differences; the Mann-Whitney-U-test in case of two categories; the Kruskal-Wallis-test in case of more than two categories. The respective results were controlled by uni- and multivariate analysis (ANOVA and MANOVA). Metric variables were calculated using the Pearson Bivariate Correlation Test. In the text the respective median with inter quartile range is shown. A The patient cohort consisted of 42 males and 32 females; aged between 18 and 80 years at the time of diagnosis, with average of 54.58 ± SD 16.99 yr. Sixty-two patients had a soft tissue sarcoma and twelve patients had a bone sarcoma. The distribution of tumour localization showed four tumours of the trunk, fifteen of the upper extremity and 55 of the lower extremity. Sixty-nine cases were limb preserving whilst five patients had to undergo an amputation of the diseased limb due to extent and localization of the tumour. Adjuvant Radiotherapy was used in 48 cases. 55.4% of the patients were in employment or training before diagnosis; 40.5% had already retired and the remaining 4.1% received an EU pension or were unemployed.p = 0.43). Analysis of tumour localization and musculoskeletal dysfunction measured by SMFA revealed a significant difference in the scale “mobility” (p = 0.015), having a median of 22.22 (5.56–44.44) in the “lower extremity” group, 4.17 (0.70–40.98) in “trunk” and 2.78 (0–13.89) in “upper extremity”. Similar results for the item “mobility” could be demonstrated in the multivariate analysis   in the Kruskal-Wallis-test, being 21.00 (19.00–24.00) in median compared to 17.50 (16.25–22.50) for trunk and 19.00 (16.00–21.00) for upper extremity. These findings were however not significant in the multivariate analysis .There was no correlation between tumour localization and occupational reintegration  had no significant influence on occupational reintegration, musculoskeletal dysfunction, quality of life or coping of tumour.p = 0.82), function by SMFA, quality of life using SF-36 and QLQ-C30 and coping with the disease by MAC. Furthermore, the influence of adjuvant radiotherapy on the occupational reintegration and the other measured parameters was not significant (p = 0.11).In the patient cohort no significant correlation between tumour size classified in groups according to the TNM-classification of soft-tissue sarcomas and outcome was found, in terms of occupational reintegration (p = 0.002). There were also significantly worse values in the amputation group for most of the functional and some related quality of life scores , as well as the “fatalism” item of the MAC that could be demonstrated using univariate and multivariate analysis (MANOVA Wilks-Lambda p = 0.003).When considering the mode of surgical reconstruction; whether limb preservation could be achieved or amputation was necessary, there was a significant impact on the occupational reintegration (p < 0.001).There was a direct linear relationship between the Functional Index of the SMFA and the perceived impairment, as measured by the Bother Index of the SMFA , “Emotional Status” (p = 0.001), “Mobility” (p = 0.002), Function Index (p = 0.001), Physical Functioning of the SF-36 (p = 0.003) and Physical Functioning of the QLQ-C30 (p = 0.003) showed a significant correlation with reintegration into professional life (MANOVA Wilks-Lambda p = 0.007).Finally, the relation between the different scores measuring function and occupational reintegration were analysed. The items “Daily Activity” (p = 0.91) or vocational training (p = 0.12) and occupational reintegration.There was no significant relation between school education (p = 0.026) and “Positive Avoidance” (p = 0.005) in patients with higher school education (MANOVA Wilks-Lambda p = 0.004). Similar results were found for vocational training for the item “Positive Avoidance”   as well as between depression and coping with the disease . The relationships are presented in Fig. In the patient cohort there was a clear correlation between anxiety and coping with cancer  and depression (p = 0.002).Occupational reintegration showed a significant correlation with the results of the HADS with respect to anxiety  as well as depression  measured by HADS (Fig. There was a significant correlation between function assessed by SMFA and anxiety (Daily Activity Considering the correlation between quality of life and anxiety as well as depression, there was a significant correlation for most items of the SF-36, Table The various factors influencing post-therapeutic outcome of patients with sarcomas can be differentiated in tumour-specific and patient-specific.As expected, patients with sarcomas affecting the lower extremity described a poorer mobility than patients with tumours in other localizations and a higher anxious preoccupation. It appears that the size of the tumour and an additive radiation therapy do not affect the post-therapeutic quality of life, coping and function. The crucial factor is, whether a limb-preserving resection is possible or if an amputation is necessary. Patients following ablative surgery had a significantly worse function, quality of life and coping with cancer. There is a direct correlation between post-therapeutic function and post-operative quality of life as well as coping with the disease. These results underline the need for specific reconstructive surgery and intensive post-treatment.Of the patient-specific factors, the patient’s educational background had an influence on coping with cancer. Patients with a higher level of education were less fatalistic and avoiding. Regarding anxiety and depression there was a clear correlation with all factors of the post-therapeutic outcome including occupational reintegration, function, quality of life and coping with the disease. Since the questionnaires examining these two traits were completed after the treatment, some of the results could be biased. However these findings highlight the importance of an intensive psychological co-treatment from the beginning of the cancer therapy.Limitations of the study are the relatively small number of patients and the resulting heterogeneity of individual groups. For example, only a distinction was made as to whether limb preservation or amputation took place - but not more precisely the surgical and reconstruction technique or the amputation level. This is due to the extreme rarity of sarcomas.Another limitation is the studies retrospective design, which makes it difficult to evaluate the results of the survey on anxiety and depression. Finally, these could also be influenced by the existing poor function and restrictions in quality of life. Furthermore the questionnaires were completed at variable time points after treatment which might have an influence on the reported results.Patients with sarcomas of the lower limb have a higher demand for postoperative rehabilitation and need more help in postoperative occupational reintegration. Furthermore this study demonstrated that limb-preserving operations and a better postoperative function improve the quality of life of sarcoma patients. The results regarding patient-specific factors demonstrate that a survey of patient-specific risk factors including the social history and the expected coping options has to be carried out before the actual tumour therapy is initiated. An adapted intensive psychological co-treatment should be offered and implemented during the entire treatment process.


Around 20% of patients undergoing spinal fusion surgery have persistent back or leg pain despite surgery. Pain catastrophizing is the strongest psychological predictor for chronic postsurgical pain. Psychological variables are modifiable and could be target for intervention. However, randomized controlled trials evaluating the effectiveness of psychological interventions to reduce chronic pain and disability after spinal fusion in a population of patients with high preoperative pain catastrophizing scores are missing. The aim of our study is to examine whether an intervention targeting pain catastrophizing mitigates the risk of chronic postsurgical pain and disability. Our primary hypothesis is that targeted perioperative cognitive behavioral therapy decreases the risk of chronic postsurgical pain and disability after spinal fusion surgery in high catastrophizing patients.We will perform a two-center prospective, single-blind, randomized, controlled study comparing lumbar spinal fusion surgery outcome between 2 cohorts. Adult patients selected for lumbar spinal fusion with decompression surgery and a minimum score of 24 on the pain catastrophizing scale will be randomized with 1:1 allocation for either perioperative cognitive behavioral therapy (intervention group) or a perioperative education plus progressive exercise program (control group). Patients randomized to the intervention group will receive six individual sessions of cognitive behavioral therapy, two sessions before the operation and four after. Primary outcome is the Core Outcome Measures Index at 12 months. Secondary outcomes include pain, disability, depression and quality of life.This is the first trial that evaluates the effectiveness of cognitive behavioral therapy as a perioperative tool to improve pain and disability after spinal fusion surgery in comparison with an educational/exercise control intervention, in patients with high levels of pain catastrophizing. If perioperative cognitive behavioral therapy proves to be effective, this might have important clinical implications, reducing the incidence of chronic postsurgical pain and improving outcome after spinal fusion surgery.NCT03969602). Registered 31 May 2019,Clinicaltrials ( The incidence of moderate to severe chronic postsurgical pain (CPSP) 12 months after surgery is around 12% in Europe, depending in part upon the surgical procedure . PeriopeCPSP and disability after spinal surgery poses a large problem. Around 20% of patients have persistent or recurrent pain in the back or limbs despite spinal surgery , 10. PaiPsychological variables are modifiable and could be a target for intervention. Patients who have participated in psychological interventions for chronic pain, including cognitive behavioral therapy (CBT) and acceptance and commitment therapy (ACT), report less pain, pain-related disability, and mood disturbance , 18.Although psychological treatments delivered in the perioperative period have the potential to influence the trajectory of CPSP in patients undergoing spinal fusion , surgicaThe aim of our study is to examine whether a perioperative intervention that targets pain catastrophizing can mitigate the risk of CPSP, i.e. improve the outcome of the surgical intervention, in patients that report high levels of pain catastrophizing and for whom lumbar spinal fusion surgery is indicated. We will start CBT already before surgery, to give patients the appropriate tools to manage symptoms during the immediate postoperative phase. The control group is offered an educational plus progressive exercise program . We hypothesize that perioperative CBT, specifically designed to reduce pain catastrophizing, will improve outcome and decrease the risk of CPSP and disability after spinal fusion surgery, assessed by the Core Outcome Measures Index (COMI) questionnaire in high catastrophizing patients. Additionally, we will include a cohort of low catastrophizing patients receiving usual care to compare the outcome of spinal fusion surgery in low catastrophizing patients with high catastrophizing patients after perioperative CBT.This study has received funding from the Advisory Board of Ente Ospedaliero Cantonale (ABREOC) (NSI-TD/NCH-01), and from the Neurosurgical/Orthopedic research fund Zuyd of the Zuyderland Medical Centre Heerlen/Sittard-Geleen, the Netherlands.This is a two-center prospective, single-blinded, randomized, controlled trial, in high pain catastrophizing patients with an indication for lumbar spinal fusion and decompression surgery, comparing two groups: one that receives perioperative CBT and one that receives the educational program. Figure Ethical approval has been granted by the Research Ethics Committee of the Canton Ticino, Switzerland (2018–00880 - CE 3361) and the Medical Ethical Committee Zuyderland, Heerlen, the Netherlands. Informed consent will be obtained in writing from all participants prior to study enrollment.Adult patients who are undergoing surgery for a degenerative condition of the lumbar spine  using any kind of surgical decompression  associated with fusion, and able to read and speak Italian (site in southern Switzerland) or Dutch (site in the Netherlands) will be eligible for inclusion. One hundred and fifty patients will be enrolled at the outpatient clinic of the Department of Neurosurgery, Neurocenter of Southern Switzerland, Regional Hospital of Lugano, Lugano, Switzerland (Site 1) and the Department of Neurosurgery of Zuyderland Medical Center, Heerlen, The Netherlands (Site 2). All patients entering the screening phase will be registered on a Patient Registration Log and a unique registration number will be assigned. Clinical data will be assessed to evaluate a subject’s eligibility.Plans to undergo major surgery within six months after current lumbar spinal fusion surgeryComorbid severe psychiatric conditions such as schizophrenia or personality disorderKnown or suspected non-compliance, drug or alcohol abuseInability to follow the procedures of the study, e.g. due to dementiaThe presence of any serious medical comorbidity such as sepsis or cancer that might cause disability or worsen the patient’s general health conditionPregnancyAn opioid intrathecal pumpPrisonersPatients will be excluded from the study if they meet any of the following criteria:Patients eligible for participation will be evaluated at least 6 weeks before surgery and asked for informed consent, and then to complete the PCS . PatientA non-randomized group, consisting of low catastrophizing patients (score < 24 PCS), will be included as an observational cohort. These patients will not undergo any additional intervention besides usual care but will undergo the same data-collection as the high catastrophizing randomized groups.A computer-generated randomization will be used to allocate the participant to either CBT or educational program with a 1:1 allocation. We will use block randomization stratified by center, with block sizes of 6. The randomization is performed by the Principal Investigator per site, who is not blinded for group assignment. The patients will be randomized immediately after they are included and have completed the PCS (one of the baseline assessments) to be able to make two pre-operative appointments with the patients in the intervention and control group.The CBT protocol was specifically developed for the present study by a team of psychologists with longstanding experience in the treatment of chronic pain patients. The intervention consists of six sessions, individually delivered by clinical video teleconferencing, and specifically aiming to reduce pain catastrophizing . Two sesEach patient will be treated by a single therapist. At the Swiss site, CBT will be delivered by one of the clinical psychologists who was involved in developing the protocol. At the Dutch site, CBT will be delivered by one of two clinical psychologists. Both have prior experience in pain management and are additionally trained in working with the current protocol by one of the psychologists involved in its development. All CBT providers have to follow the guideline that was created for this study, to assure that all sessions will be held in the same way. All patients in the CBT group will receive a workbook with pages to fill out for every session and with some additional exercises.The control intervention consists of biomedical and surgery-specific education before surgery and an exercise manual after surgery. To control for differences in attention between the two interventions, patients in the educational program will also have two meetings before and four meetings after surgery with members of the research team (in person or through telephone).The pre-surgical, biomedical and surgery-specific education is based on a previously developed educational intervention for spinal patients . In the After surgery and before discharge from the hospital, a physiotherapist will meet the patient (meeting of circa 20 min) and provide him with instructions about the exercise program. Patients will receive a manual describing exercises to be performed in the weeks following surgery. The exercise program is based on the program of Abbott et al.  and consAll patients, independently from randomization into one of the groups, will be routinely prescribed medications for pain control and will be referred for physical therapy on an out-patient basis in different sites or an in-patient basis in specialized rehabilitation centers following lumbar spinal fusion surgery, depending on the needs.Primary and secondary outcomes will be measured at baseline preoperatively and 2, 6 and 12 months after surgery  for back and leg pain. Pain intensity is assessed on an 11-point scale ranging from 0  to 10 (the worst imaginable pain) .Oswestry Disability Index (ODI): a self-administered questionnaire, assessing a patient’s limitations in activities of daily living. The ODI has ten questions scored on a 6-point scale. The total score ranges from 0 to 100, with higher scores denoting higher functional disability .European Quality of Life Five Dimension Five Level Scale (EQ-5D-5L): This questionnaire assesses health related quality of life in terms of five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression . Each ofDepression is measured by the PROMIS (Patient-Reported Outcomes Measurement Information System) Short Form v1.0 - Depression 8b . The eigPatient’s Global Impression of Change (PGIC): This scale assesses patient’s own assessment improvement or deterioration over time on a 7-point scale (1. very much improved - 7. very much worse).Pain Catastrophizing Scale (PCS): The PCS is a 13-item scale that measures catastrophic thinking in relation to pain. Each item is scored on a 5-point scale ranging from 0 (never) to 4  . Higher Medication Quantification Scale (MQS): The MQS is an instrument or quantifying medication regimen use in chronic pain populations. The score is calculated for each medication by taking a consensus-based detriment weight for a given pharmacologic class and multiplying it by a score for dosage. The calculated values for each medication are then summed for a total MQS score. The score can provide a useful point measure of medication usage for any pain medication regimen , 39.Work productivity and activity impairment will be assessed using the Work Productivity and Activity Impairment questionnaire: Low Back Pain (WPAI:LBP) . This quSecondary outcomes are leg/back pain, disability, quality of life, depression, patient’s global impression of change, pain catastrophizing, pain medication regimen, and work productivity and activity impairment. These will be measured using the following questionnaires:The following patient characteristics will be gathered: gender, age, weight, height, civil state, employment status , type of working activity , educational level, smoking status, allergies, low back pain duration, other chronic pain complaints, sickness benefits and length of current sick leave, self-reported psychiatric problems, and concomitant physiotherapy.The following medical data will be gathered: type of operation, surgical indication, American Society of Anesthesiologists (ASA) classification.Patient-Reported Outcomes Measurement Information System) Short Form v1.0 – Anxiety 4a. The PROMIS Anxiety instruments measure self-reported fear , anxious misery , hyperarousal , and somatic symptoms related to arousal . Additionally, surgical fear will be measured by the ten-item Surgical Fear Questionnaire as a predictor of physical and emotional recovery [Preoperative state anxiety will be assessed by the PROMIS  . This isd is 0.80. Inclusion of 42 patients per intervention group will yield a power of 0.95 at a type-I error rate of 0.05. In addition, 42 patients with low pain catastrophizing scores will undergo the same assessments, but not receive any intervention besides care as usual. Taking into account a drop-out rate of 15%, 150 patients will be included in total.The primary outcome is the difference in the COMI between the study groups, 12 months after surgery. A difference of two points is considered clinically meaningful . With anBaseline patient characteristics will be stratified by group and presented as mean and standard deviation (SD), median and first and third quartile, and count and percentage, as appropriate. Differences in baseline characteristics between randomized groups will not be statistically tested, whereas differences with the separate control cohort will be tested using the independent-samples t-test for continuous variables, and Pearson’s chi-square test for categorical variables. In case of expected cell counts of less than 5, Fisher’s Exact test will be used instead.> 24) will be analyzed in an intention-to-treat analysis. To test for a difference between the CBT and control group in the COMI at 12 months, linear regression will be used, with correction for baseline COMI and center. In addition, the difference in the trajectory of COMI over time will be assessed by means of linear mixed-effects regression, taking all follow-up measurements into account. Adjustment for center, type of surgery, age and gender will be made and, if necessary, for other prognostic variables significantly associated with the outcome . Stepwise backward elimination using the Wald test will be used to select prognostic variables significantly associated with the outcome. Any control variables that are incomplete will be imputed if the proportion of incomplete patients exceeds 0.05. We will use multiple imputation with fully conditional specification with the number of imputations set to the percentage of incomplete patients. Predictive mean matching will be used to draw values to be imputed. Secondary outcome variables will be analyzed similar to the primary outcome. For these, logistic regression analysis adjusted for center will be used to test for differences in proportions at 12 months postoperatively.All patients randomized  undergoing care as usual. Linear mixed-effects regression for the three groups will be performed with primary and secondary outcomes at the three postoperative assessment periods and controlling for preoperative values. This analysis will indicate whether high catastrophizing patients follow a similar trajectory of pain and functioning after spinal fusion surgery compared non-catastrophizing patients.Over the past 15 years, an increase in the number of spinal fusion procedures for degenerative diseases has been observed. A recent analysis on a large national database  reportedControversies about indications for spinal fusion pose specific problems since these patients are at risk for CPSP, which has a significant impact on patient’s quality of life and can even lead to new-onset psychiatric diseases . The bion = 65) or a control group, consisting of exercises only (n = 65). Exercise plus CBT was found to be superior to the ‘exercise only’ program in reducing disability, dysfunctional thoughts, and pain, and enhancing the quality of life, with effects lasting for at least 1 year after the end of intervention. Abbott et al. [So far, only a few studies have investigated the impact of a psychological intervention in the perioperative period in patients undergoing spinal fusion –57. Montt et al.  offered t et al. , 54 was n = 59) or physiotherapy only (n = 31). The intervention consisted of 4 preoperative and 2 postoperative CBT sessions. At 1-year follow-up, no significant difference in disability was found between the two groups, but the CBT group achieved a significant reduction in disability earlier than the control group.Two more recent studies offered both pre- and postoperative CBT sessions to spinal fusion patients. Lotzke et al.  examinedIt should be noted that none of the above studies preselected patients based on a psychological high-risk profile (i.e. high pain catastrophizing or anxiety/fear) despite the fact that at least some of these interventions were specifically designed to reduce these risk factors. Lotzke et al. speculated that their null finding may have been due to the high degree of variability in fear-avoidance beliefs in their patients . TherefoIn line with this recommendation, a crucial aspect of the current study is that we will offer CBT specifically to patients reporting high levels of pain catastrophizing. Another feature, which sets out study protocol apart from most previous studies in this area, is the inclusion of an active control intervention consisting of an educational and progressive exercising program. This allows us to assess the effect of CBT per se and control for non-specific effects such as expectancy, contact time and attention. In addition, starting treatment before surgery may be expected to lead to more profound intervention effects than post-surgical intervention only, because it might decrease early postoperative pain, which is among the most prominent predictive factors for developing CPSP . FinallyThere are some limitations of our study protocol that should be mentioned. The main limitation is patient’s compliance to the intervention. In fact, very few data exist that analyze the impact and feasibility of CBT in the perioperative period after spinal fusion surgery. Another possible limitation is related to potential differences in levels of catastrophizing between the populations of the two centers. Moreover, the exact proportion of high catastrophizing patients (defined in this study as having a PCS ≥ 24) is not known in advance and could vary between the two centers. Additionally, a potential weakness of our study protocol is related to the control condition, conceived to reduce patient’s expectation bias, augmenting contact time and attention, and therefore reducing non-specific effects on outcome. It is well known in psychological research that expectation is one of the most important non-specific factors that may modulate patients outcomes . HoweverFurthermore, this study can demonstrate efficacy of the CBT intervention for high catastrophizing patients, but it does not assess cost-effectiveness. Although some cost elements are included , no full cost analyses will be conducted. Moreover, if this study shows a positive effect on pain and disability from perioperative CBT, this will not clarify the optimal dosage of the intervention or the ideal timing. Finally, it cannot clarify whether a PCS score of 24 or higher is the most optimal cut-off for offering patients CBT. Future studies should conduct sensitivity analyses to establish at which level of pain catastrophizing intervention should be offered, to come to an optimal cost-benefit ratio.In conclusion, the results of this study are expected to provide valuable information that will potentially change clinical practice of lumbar spinal fusion surgery. If our study can demonstrate that perioperative CBT is effective in improving clinical outcome after lumbar spine fusion surgery in high catastrophizing patients, it is highly recommended to perform prescreening to identify this subgroup for which a perioperative psychological treatment will be indicated. If CBT will not prove to be superior and if this study will confirm that high levels of pain catastrophizing have a negative impact on clinical outcome, that might be a reason to be very reluctant in offering these patients a spinal fusion procedure, trying to opt for less invasive treatment options.Participant recruitment started in February 2020 and is planned to continue until November 2022. An interim analysis is planned after 6 months follow up of 21 patients. It is expected that data regarding the intervention effects will be available at the end of 2023.


Background and Objectives: Chondroitin sulfate ABC endolyase (condoliase) was launched as a new drug for chemonucleolysis in 2018. Few studies assessed its clinical outcomes, and many important factors remain unclear. This study aimed to clarify the preoperative conditions in which condoliase could be highly effective. Materials and Methods: Of 47 patients who received condoliase, 34 were enrolled in this study. The mean age of the patients was 33 years. The average duration since the onset of disease was 8.6 months. We evaluated patients’ low back and leg pain using a numerical rating scale (NRS) score at two time points (before therapy and 3 months after therapy). We divided the patients into two groups (good group (G): NRS score improvement ≥ 50%, poor group (P): NRS score improvement < 50%). The parameters evaluated were age, disease duration, body mass index (BMI), and positive or negative straight leg raising test results. In addition, the loss of disc height and preoperative radiological findings were evaluated. Results: In terms of low back and leg pain, the G group included 9/34 (26.5%) and 21/34 (61.8%) patients, respectively. Patients’ age  was significantly lower in the G group for low back pain (p = 0.001). High-intensity change in the protruded nucleus pulposus (NP) and spinal canal occupancy by the NP ≥ 40% were significantly high in those with leg pain in the G groups . Conclusions: The efficacy of improvement in leg pain was significantly correlated with high-intensity change and size of the protruded NP. Condoliase was not significantly effective for low back pain but could have an effect on younger patients. The first clinical study on collagenase (nucleolysin) was reported in 1981 [Chemonucleolysis has been considered a minimally invasive treatment for cervical and lumbar disc herniation (LDH) for more than 50 years . Althoug in 1981 . Subsequ in 1981 . Severe  in 1981 ,19.Proteus vulgaris was developed. To date, several basic experimental studies have shown promising results [A safer and more effective chemonucleolysis enzyme was necessary, and chondroitin sulfate ABC endolyase (condoliase) from  results ,23,24,25Phase 1–3 clinical trials of condoliase were conducted in Japan. Matsuyama et al. reported the results of phases 2 and 3 trials of chemonucleolysis for the treatment of LDH  . In thisHere, we report our therapeutic experience of 34 cases that were available for follow-up for more than 3 months out of 47 cases treated with condoliase in our hospital from August 2018 to August 2019.LDH patients complaining of low back and/or leg pain were conservatively treated with medications and block therapy for at least 1 month. Chemonucleolysis with condoliase was considered in patients in whom the unilateral leg pain did not improve even after 1 month and in patients who did not wish to undergo surgery.The inclusion criteria were as follows: (1) LDH of the extrusion and subligamentous extrusion types, in which spontaneous regression is difficult; and (2) the transligamentous extrusion type of LDH in which only a part of the posterior longitudinal ligament (PLL) is ruptured. Chemonucleolysis with condoliase was performed in 47 patients  in our hospital from August 2018 to October 2019. We could include only 34 patients  who could be followed-up for 3 months or more without any additional intervention .In the early stage of this study, chemonucleolysis with condoliase was performed on an intraforaminal LDH with spondylolisthesis in a 68-year-old woman; however, the leg pain worsened, and full-endoscopic spine surgery (FESS) was required 3 months after chemonucleolysis. Subsequently, we excluded patients with spondylolisthesis  and/or with instability . Among the 13 patients who dropped out, two underwent surgical treatment within 3 months after chemonucleolysis owing to poor pain relief. The remaining 11 patients could not be evaluated using postoperative plain radiographs or magnetic resonance imaging (MRI) because they did not visit our outpatient clinic.®, Seikagaku Corporation, Tokyo, Japan) dissolved in 1.2 mL of saline was injected. To ensure a prompt response in case of unexpected adverse events such as anaphylaxis, an intravenous line was established prior to the injection, and an antibiotic was administered 30 min before the procedure. The patients were hospitalized on the day of the injection [Patients were carefully log rolled into the prone position. During the procedure, a fluoroscope was placed across the center of the operating table to ensure appropriate positioning of the needle. In case of restricted fluoroscope movement, pelvic tilting was often performed to confirm the disc space and the needle trajectory . After marking the site of entry on the skin, the skin was disinfected and covered with a surgical drape. Under local anesthesia, a 22-gauge spinal needle with a stylet was inserted into the center of the disc space using a posterolateral approach, from the side opposite to the side of radiculopathy. The position of the needle tip was confirmed with a posterolateral fluoroscopic view during insertion. The final position of the tip (the center of the NP) was confirmed by both anteroposterior and lateral fluoroscopic views. The use of contrast medium was disallowed during the entire process. The stylet was removed, and 1.25 U of condoliase  score  was performed using a questionnaire that was filled by the patients themselves. The scores were evaluated before and 3 months after the procedure. The straight leg raising (SLR) test was performed in the outpatient department before the procedure. Plain radiographs and MRI were taken before and 1 month after the procedure and before and 3 months after the procedure, respectively.The change in the height of the intervertebral disc was evaluated from pre- and postoperative plain radiographs. We calculated the Brandner’s disc index  using thThe anterior intervertebral disc height reduction rate is (B/A-B’/A’)/B/A × 100 (X is before the procedure X’ is after the procedure). The posterior intervertebral disc height reduction rate is (C/A-C’/A’)/C/A × 100 (X is before the procedure X’ is after the procedure). When we found at least one intervertebral disc height reduction rate ≥ 25%, we judged “disc height decreases ≥ 25%” . The occupancy ratio of the spinal canal by the protruded NP was measured using T2-weighted MRI on axial view. The areas of protruded NP and the corresponding spinal canal were calculated using an image measurement software. The area of the spinal canal was defined as the region enclosed by the original dorsal surface of the annulus fibrosus and the ventral edge of the ligamentum flavum. The area of the protruded NP was defined as the region enclosed by the original dorsal surface of the annulus fibrosus and the dorsal surface of the protruded NP. The occupancy ratio was calculated using the following formula: occupancy ratio of the spinal canal is the area of the protruded NP (blue line area)/the area of the spinal canal (red line) × 100 (%) .The HIC of the protruded NP was determined on the sagittal view of the T2-weighted MRI. We defined HIC of the protruded NP when the intensity of the protruded NP was higher than the intensity of the surface of the protruded NP .p-value < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS version 20.0 . We first evaluated whether each variable  followed the normal distribution, using the Shapiro–Wilk normality tests. Age was found to be normally distributed, while disease duration, NRS score, and BMI were not normally distributed. For age, paired t-tests were performed as a parametric test. For the NRS score, Wilcoxon signed-rank test was performed as a nonparametric test. For disease duration and BMI, the Mann–Whitney U test was used as a nonparametric test. We divided the patients into two groups based on the improvement in NRS score (low back pain and leg pain). Good group (G): NRS score improvement ≥ 50%, poor group (P): NRS score improvement < 50%. Both groups were compared using the chi-square test or Fisher’s direct method. A The average age was 32.4 years . The average duration since the onset of disease was 8.6 months . There were 32 cases with intracanal LDHs, and 1 case each with foraminal LDH and extraforaminal LDH. Cases with LDH type  were as follows: protrusion in 5 patients, subligamentous extrusion in 24 patients, and trans-ligamentous extrusion in 3 patients. The LDH level was L4/5 in 25 patients and L5/S in 9 patients. Except for one patient with recurrence, the remaining 33 patients had de novo LDH .p = 0.001) (We divided the patients into two groups (good group (G): NRS score improvement ≥ 50%, poor group (P): NRS score improvement < 50%). In terms of low back and leg pain, the G group included 9/34 (26.5%) and 21/34 (61.8%) patients, respectively. The NRS score for leg pain improved significantly 3 months after chemonucleolysis with condoliase . Regardi= 0.001) . Regardi= 0.001) . Furtherp = 0.04) (p = 0.03) (The preoperative imaging findings were not significantly different between the two groups in patients with low back pain . However = 0.04) . A signi = 0.03) .In some patients, low back pain increased within 1 month after chemonucleolysis; however, it usually improved within 1 month by taking analgesics. In one patient, low back pain worsened significantly after chemonucleolysis. The patient was a case of LDH with spondylolysis. We speculate that the decrease in the height of the intervertebral disc caused mechanical stress to the pars interarticularis defect, leading to the aggravation of low back pain .Chiba et al. reported a domestic phase 3 trial of condoliase for the treatment of protrusion type and sub-ligamentous extrusion type of LDH, in which an improvement in visual analog scale (VAS) score (improvement of VAS of leg pain ≥50% 12 weeks after administration of condoliase) was seen in 59/81 patients (72%) . We usedFrom this study, it can be suggested that the size of the protruded NP might be a predictive factor for the improvement of leg pain. Chemonucleolysis with condoliase might be less effective in cases with protrusion type and the small subligamentous extrusion type; however, it is difficult to precisely distinguish between the two on MRI. Nevertheless, a spinal canal occupancy ratio ≥ 40% is highly predictive of improvement in leg pain. Various surgical approaches from decompression alone to fixation, have been reported for the treatment of large central LDHs, which are difficult to treat ,34,35,36Banno et al. investigated the signal intensity of the protruded NP and reported that patients with high intensity on T2-weighted MRI showed a better response to chemonucleolysis with condoliase . From thWe also obtained insightful information from patients who did not see an improvement or had aggravation of low back and/or leg pain after chemonucleolysis and underwent discectomy. Two patients underwent surgical intervention within 3 months and were excluded from the above analysis . Six of the 34 patients underwent surgical intervention after 3 months of follow-up. Among the patients, eight required surgical intervention and two each had recurrent LDH, protrusion type LDH, and small sub-ligamentous extrusion type of LDH. The size of the protruded NPs did not change after chemonucleolysis. For recurrent LDH, scar formation following a previous surgery might affect the penetration of condoliase and shrinkage of the NP. The pre- and postoperative spinal canal occupancy ratio did not change in these eight patients. Therefore, recurrent LDH, protrusion type of LDH, and small sub-ligamentous extrusion type of LDH should be excluded from the indication for chemonucleolysis with condoliase. We also pathologically examined the removed disc material and confirmed the preservation of the cartilaginous endoplate. Furthermore, we compared pathologic tissues obtained from patients (32-year-old man) who underwent surgery 3 months after condoliase injection and the similar-aged patients (32-year-old man) in whom condoliase was not injected. Decrease of toluidine blue staining in the intercellular space of condoliase injection indicates the degradation of glycosaminoglycans , which is a main component of the nucleus pulposus. However, chondrocyte necrosis was scarcely observed in both specimens . This fiWith respect to low back pain, Chiba et al. reported that there was no significant difference in the treatment group compared with the placebo group in terms of improvement at 3 months after administration . In our The limitations of this study are its retrospective nature, a low number of patients, an unequal distribution between males and females, and short follow-up period.This was a study of 34 patients with LDH, who underwent chemonucleolysis with condoliase. It was found that chemonucleolysis with condoliase was more effective for leg pain than for low back pain. Preoperative high signal intensity of the protruded NP on T2-weighted MRI and large protruded NP  were potential predictive factors for condoliase response. Although chemonucleolysis with condoliase was not significantly effective for low back pain, it might be more effective for low back pain in the younger population (<20 years). It is concluded that chemonucleolysis with condoliase is a safe and effective treatment for LDH that is resistant to conservative therapy. It is expected that the indications will be expanded to juvenile LDH and other vertebral areas in the future.