Pain, the main symptom of osteoarthritis (OA), can lead to functional disability in patients with knee OA. Understanding the association factors related to knee pain is important since preventing OA-induced disabilities can be achieved by modifying these pain-associated issues. Therefore, this study was aimed to investigate the association factors for OA-induced knee pain in Taiwanese patients who received total knee replacements (TKR).In this retrospective study, 357 subjects who had undergone TKR at the Taipei Municipal Wan-Fang Hospital were recruited. The distribution of pain severity among patients with knee OA was evaluated. Demographic data and clinical parameters were analyzed to determine relationships between these variables and the severity of knee OA pain.2) were significantly associated with severe knee pain in OA patients. A significant correlation between severe knee pain and serum creatinine or eGFR was demonstrated by Pearson correlations.Of the 357 patients studied, 54% and 33% had moderate and severe knee pain, respectively. Furthermore, a multivariate logistic regression analysis revealed that serum creatinine (>1.5 mg/dL) and an estimated glomerular filtration rate (eGFR) (<60 mL/min/1.73 mTaken together, the renal insufficiency defined by an elevated serum creatinine or a low eGFR in OA patients who required TKR was associated with severe knee pain. These variables must be considered while treating knee OA pain, especially in those patients with severe pain. In Asian populations, such as southern China, the prevalence of knee OA is about 13% and even higher in rural areas.–6 In patients aged over 65 years in Taiwan, the prevalence of knee OA was 9.6% in 2005, and may rise to 14% in 2020. In the global health, the prevalence of OA is increasing due to population aging and an increase in related factors such as obesity. An estimated 10% to 15% of all adults aged over 60 have some degree of OA. Thus, OA becomes a challenged health issue around the world.Knee osteoarthritis (OA) is considered a degenerative joint disease involving progressive cartilage degeneration, subchondral bone changes, osteophyte formation, and synovitis.,9 Furthermore, severe knee pain makes patient disabled, limiting their daily functions, and impairing their quality of life.,11 Pain management of OA includes analgesic medication of nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular steroids, acupuncture, and physical therapy. A total knee replacement (TKR) is a final procedure to treat patient with symptomatic knee OA or severe knee pain after failing pain relief treatments.,13 Nonetheless, the severity of knee pain and functional disability are the strongest factors for patients to receive a TKR.Symptoms of knee OA are joint pain, stiffness, muscle weakness, and a limited range of motion. A major symptom is pain that is triggered by peripheral and central changes within the pain pathways.,15 Reported risk factors for knee pain in previous studies included a female gender, age, obesity, radiographic OA, previous knee injuries, and knee-straining work.,17 Understanding the risk factors related to the OA knee pain and its severity is necessary because prevention of the pain-induced disabilities can be achieved by modifying those associated factors. As a result, this retrospective study was aimed to investigate the association factors for knee OA pain in those patients who have received TKR surgery.Knee pain is the main compliant of knee OA patients, and it is a leading cause to make functional disability.22.1 We excluded those who had a knee trauma history, rheumatoid arthritis, septic arthritis or revision TKR on the ipsilateral side of the OA knee. From patients’ medical records, we gathered data of demographic information, knee pain severity, and clinical variables .In this retrospective study, we collected information on clinical characteristics of patients at the Wan Fang Medical Center, Taipei Medical University, Taipei, Taiwan, from 2006 to 2012. This study was approved by the joint-institutional review board of the Taipei Medical University. We included 357 TKR patients aged over 45 years old with knee pain, and with radiographic evidence of an OA knee, or an orthopedist-diagnosed OA knee according to American College of Rheumatology criteria.2.2 To define renal insufficiency, we used cut-off values of the estimated glomerular filtration rate (eGFR) <60 mL/min per 1.73 m2 , and serum creatinine exceeding 1.5 mg/dL.We included patients’ age, gender, body height, body weight, body mass index (BMI) and also information on the presence or absence of cardiovascular disease, diabetes mellitus, and hypertension according to physicians’ diagnoses. The smoking status was also identified as a former/current smoker, or nonsmoker. Data of preoperative laboratory blood chemistry of serum creatinine and serum hemoglobin were obtained. Anemia was defined that serum hemoglobin level of <13 g/dL in men, and <12 g/dL in women, according to the criteria of the World Health Organization (WHO).2.3Knee pain was assessed by reviewing a patient's medical records. When a patient was admitted, the worst knee pain on the OA knee within 1 month before admission was rated by the patient, using a 10-point numeric rating scale (NRS), from no pain (0) to the worst pain (10). Based on NRS scores, patients’ pain severity was classified into 3 groups: (mild pain: (0–3), moderate pain: (4–6), and severe pain: NRS (7–10), the cut-off value between each severity level was based on a previously published report.2.4 Greater than grade 1 was defined as radiographic knee OA. One well-trained rater who was blinded to this study's subjects, read all of the knee radiographic images, and reported the K/L grading scales.A knee radiographic imaging examination, using an anterior-posterior view in a weight-bearing position, was obtained before the operation in each patient. The severity of the radiographic knee OA was defined by the Kellgren–Lawerence (K/L) grading scale: grade 0 ; grade 1 (doubtful osteophytes); grade 2 (definite osteophytes and possible narrowing of the joint space); grade 3 ; grade 4 .2.52, no bilateral OA knee history, nonsmoker, OA severity grade II and without heart disease, diabetes mellitus, hypertension, perioperative anemia, or renal insufficiency. A significant correlation was determined by Pearson correlation test. Differences were considered significant if P-values were <.05.We performed data analysis with the Statistical Package for Social Science vers.17.0 . Demographic information , bilateral OA knee history, past history of heart disease, diabetes mellitus, hypertension, imaging evidence of OA knee severity, hemoglobin and creatinine data were evaluated by a 1-way analysis of variance to determine differences between individual OA knee pain group. We used a multivariate binary logistic regression to evaluate the adjusted odds ratio (OR) of factors associated with severe knee pain, compared to mild and moderate knee pain. A stepwise regression was performed when a logistic regression was used. Reference categories included male, aged <65 years, BMI <25 kg/m33.12. On radiographic assessment, according the K/L grading, 34 (9.5%) patients were defined as grade 2, 171(47.9%) patients as grade 3, and 152 (42.6%) patients as grade 4. Patients planning to receive TKR were mostly categorized into moderate to severe radiographic OA grades.This study included 357 knee OA participants with knee pain who had undergone TKR surgery at the Wan Fang Medical Center, Taipei Medical University, from 2006 to 2012. Table 3.2Figure 3.3P < .01), higher serum creatinine level  and lower eGFR .Table 2 had higher ORs for severe knee pain . While morbid obesity (BMI >35 kg/m2) was likely to have a lower risk for developing severe knee pain .The multivariate binary logistic regression for evaluating association factors associated with knee pain also revealed similar results. As shown in Figure r = 0.13, P = .02 and r = −0.11, P = .04, respectively). However, other continuous variables showed no significant correlation with the knee pain score.These results were further approved by Pearson correlation test. Table 3.4P < .05. None of the remaining variables show a significant difference among the 3 groups.Patient's demographics data and clinical characteristics by 3 K/L grading groups are described in Table 4Our present study examined factors associated with knee OA pain. We analyzed data from patients with end-stage knee OA who received TKR. Data of the National Health Insurance Research Database (NHIRD) in Taiwan from 2000 to 2005 showed that 35,805 patients received TKR surgery, at an average age of 72 years, and that 25,963 (72.51%) were female patients. Comparing our study findings with data from the NHIRD, we selected 357 OA knee patients from 1 medical center, at an average age of 71.47 years, and 282 (79%) patients were female. Therefore, we contend that our study patients can represent general Taiwanese knee OA patients. Patients with total knee arthroplasty are to alleviate OA-induced pain, to restore knee function, or to improve life quality. The NRS is an index scoring the patients’ knee pain severity. Pain is one of critical causes driving patients to undergo total knee arthroplasty. In this study, there are 44 patients with mild severity of knee pain but operating total knee arthroplasty because of other causes because they would like to repair knee function or expand quality of life.P < .05). Significant correlations of pain score with serum creatinine and eGFR were also approved by Pearson correlation test. According to the clinical guidelines of the American Academy of Orthopedic Surgeons, NSAIDs are recommended as the initial drug to treat persistent knee OA pain. Currently, selective cyclooxygenase (COX)-2 inhibitors are commonly used as an anti-analgesic drug for pain management because it avoids upper gastrointestinal bleeding complications, but a nephrotoxic effect is still a concern.,24 In a previous study, Koseki et al reported that 14 of 235 early rheumatic arthritis patients on NSAIDs suffered from mild reversible elevated serum creatinine. It is well established that older adults are at higher risk of NSAID-induced renal insufficiency. Due to the renal toxicity of NSAIDs, patients who have been prescribed with a higher dose of NSAIDs for severe knee pain might develop renal insufficiency after a long-term exposure to high dose NSAIDs. In this study, most knee OA patients received COX-2 inhibitors for pain relief before receiving TKR. The positive correlation between serum creatinine and pain scores and the negative correlation between the eGFR and pain scores might be possibly associated with the use of NSAIDs. Although currently, most patients have subclinical renal insufficiency, chronic renal failure might be developed under long-term analgesic medication for pain relief. Another possible explanation is a lower dosage or even avoidance of analgesics might be prescribed in knee OA patients with renal insufficiency. Thus, inadequate pain relief might be encountered in those patients and led to more severe pain. Furthermore, glucosamine, a common symptomatic treatment for OA can also cause apoptosis in renal tubular and mesangial cells in experimental animal studies.,29 The introduction of glucosamine resulted in loss of renal function has also been reported previously.,30 This renal toxicity of glucosamine might also involve in the development of renal insufficiency in patients with severe OA pain. It need further studies to confirm why renal insufficiency was associated with severe knee pain. We should care more about their medication application for those patients with greater pain due to OA of the knee.In this study, we found that elevated serum creatinine and a lower eGFR were significantly associated with severe knee OA pain  was found to have a significantly reduced risk of developing severe pain . However, no significant correlation was found between the BMI and knee pain severity by Pearson correlation. Previous studies showed that obesity is a strong predictor of knee pain. Jhun et al pointed out that obesity is a factor for knee pain and pain severity. Creamer et al also disclosed that the BMI is an important factor in determining the severity of knee OA pain. Disagreement in our results between knee pain severity and the BMI may have been due to limited daily functions in knee OA patients with a higher BMI and greater knee joint damage. In our retrospective study, we could not further distinguish the pain scores reported were at rest or during movement. Since Knee pain is commonly induced by specific activities such as climbing stairs and walking, and these activities would be difficult for extremely obesity patients. Thus, less knee pain reported by those patients with higher BMI might be related to less daily activities.Our present results also demonstrate a significant difference between knee pain severity in terms of BMI. Inversely, severe knee pain was associated with a lower BMI, compared to other 2 groups. In addition, our results show that morbid obesity (BMI ≧35 kg/m,36 Advanced imaging studies such as magnetic resonance imaging and bone scintigraphy, were shown to be correlated to knee OA pain severity.,38 An extra-articular structure as the knee pain source was also reported in a recent study. In clinical practice, knee OA patients with the same K/L grading may complain of different knee pain severities. A female gender was reported to be a well-known risk factor of knee OA.,41 It was compatible with our results. In this study, the majority of patients who received TKR were females. However, female was not a risk factor of severe pain. Although a higher proportion of females was demonstrated in each knee pain group, we demonstrated that females were not significantly associated with severe knee OA pain, compared to mild to moderate knee OA pain. The study findings might be explained by females having more knee pain, but not specific to any knee severity.As shown in Figure 4.1Readers are warned against over-interpreting our study findings because this study had 3 major limitations. In this retrospective study, knee OA patients defined the worst knee pain themselves by the NRS. But knee pain is not defined as to how it was induced such as at rest, walking, or climbing stairs. And almost all subjects were prescribed anti-analgesic drugs until the day before the operation, so we could not rule out the effect of drugs on pain severity. Using only a single pain scale to define knee pain severity by patients might not be totally precise, and another pain scale such as Western Ontario and McMaster Universities Osteoarthritis Index could simultaneously be used to define the pain scale in future studies.The authors express their gratitude to Dr. Yen-Kuang Lin, a statistical expert of Research Center of Biostatistics, College of Management, Taipei Medical University, Taipei, Taiwan, for assistance of data analyses.Conceptualization: Chung-Ching Chio, Man-Kit Siu, Yu-Ting Tai, Tyng-Guey Chen, Wei-Pin Ho, Ruei-Ming Chen.Data curation: Chung-Ching Chio, Man-Kit Siu, Yu-Ting Tai, Tyng-Guey Chen, Wei-Pin Ho, Jui-Tai Chen, Hsiao-Chien Tsai, Ruei-Ming Chen.Formal analysis: Man-Kit Siu, Yu-Ting Tai, Jui-Tai Chen, Hsiao-Chien Tsai, Ruei-Ming Chen.Funding acquisition: Chung-Ching Chio, Ruei-Ming Chen.Investigation: Chung-Ching Chio, Man-Kit Siu, Yu-Ting Tai, Tyng-Guey Chen, Wei-Pin Ho, Ruei-Ming Chen.Methodology: Man-Kit Siu, Yu-Ting Tai, Wei-Pin Ho, Jui-Tai Chen, Hsiao-Chien Tsai, Ruei-Ming Chen.Project administration: Ruei-Ming Chen.Resources: Chung-Ching Chio, Yu-Ting Tai, Tyng-Guey Chen, Ruei-Ming Chen.Supervision: Chung-Ching Chio, Tyng-Guey Chen, Wei-Pin Ho, Ruei-Ming Chen.Validation: Chung-Ching Chio, Man-Kit Siu, Jui-Tai Chen, Ruei-Ming Chen.Visualization: Yu-Ting Tai, Hsiao-Chien Tsai, Ruei-Ming Chen.Writing – original draft: Chung-Ching Chio, Man-Kit Siu, Yu-Ting Tai, Ruei-Ming Chen.Writing – review & editing: Chung-Ching Chio, Man-Kit Siu, Yu-Ting Tai, Tyng-Guey Chen, Wei-Pin Ho, Jui-Tai Chen, Hsiao-Chien Tsai, Ruei-Ming Chen.


However, opioid consumptions were lower in the predicted group compared to the control group . This study showed that offering a predicted dose of opioids according to pain sensitivity did not affect the incidence of nausea and pain scores.Individualized administration of opioids based on preoperative pain sensitivity may improve postoperative pain profiles. This study aimed to examine whether a predicted administration of opioids could reduce opioid-related adverse effects after gynecological surgery. Patients were randomized to the predicted group or control group. Participants received a preoperative sensory test to measure pressure pain thresholds. Patients were treated with a higher or lower (15 or 10 μg/mL) dose of fentanyl via intravenous patient-controlled analgesia. The opioid dose was determined according to pain sensitivity in the predicted group, while it was determined regardless of pain sensitivity in the control group. The primary outcome was the incidence of nausea over the first 48 h postoperative period. Secondary outcomes included postoperative pain scores and opioid requirements. There was no difference in the incidence of nausea (40.0% vs. 52.5% in predicted and control groups, respectively;  The treatment of postoperative pain is an ongoing challenge for anesthesiologists, despite the introduction of modern multimodal analgesia ,2,3. PosThus, optimal dosing of opioids after gynecological surgery requires offsetting the desired effects against the potential undesirable effects ,15. HoweTherefore, this study aimed to determine whether a predicted administration of opioids, based on preoperative pain sensitivity, could reduce opioid consumption, drug-related side effects, and improve pain scores after gynecological surgery. We hypothesized that a predictive approach would reduce unnecessary opioid medications and opioid-related side effects. To test these hypotheses, we examined the postoperative analgesic properties and potential adverse effects between predicted and non-predicted administrations of postoperative opioids in patients receiving gynecological surgery.This prospective, randomized, double-blind, single-center trial was approved by the institutional review board of Seoul National University Hospital (No. 1707-078-869) and was registered with ClinicalTrials.gov . This study adheres to the Consolidated Standards of Reporting Trials (CONSORT) guidelines . All patThis study included adult patients with American Society of Anesthesiologists physical status I/II/III, who were scheduled to undergo elective gynecological surgery under general anesthesia. Eligible surgeries included laparoscopic ovarian cystectomy, laparoscopic salpingo-oophorectomy, laparoscopic hysterectomy, abdominal hysterectomy, abdominal myomectomy, and vaginal hysterectomy. Patients with contraindications to receiving fentanyl, chronic pain, preoperative use of any chronic pain medications, such as opioids, nonopioid or nonsteroidal anti-inflammatory drugs, renal insufficiency, morbid cardiovascular impairments, body weight <40 kg or >90 kg, or pregnancy, were excluded from the study.All patients underwent quantitative sensory tests using an electronic handheld pressure algometer  to determine the pressure pain thresholds the day before surgery. Briefly, a flat probe  was applied to the left forearm and the pressure was increased at a speed of 2 N/s A. PatienThe study involves two potential regimens (higher- or lower-dose) of intravenous (IV) fentanyl via patient-controlled analgesia (PCA) for postoperative pain management. The higher- and lower-dose regimens were fentanyl 15 and 10 μg/mL, respectively. Both regimens included nefopam 0.8 mg/mL. These are the standard regimens of IV PCA after gynecological surgery in our institution. Patients were randomly assigned to the predicted or non-predicted regimen using a computer-generated table of random numbers. In predicted group, sensitive and non-sensitive patients used the higher- and lower-dose regimens, respectively. In the non-predicted (control) group, patients used one of the two regimens, regardless of their own pain threshold, by pairing to the predicted group. Group allocation was concealed using a sequentially numbered, sealed opaque envelope, which was opened only by a separate investigator and delivered to the nurse who prepared the IV PCA. The investigator and nurse had no further involvement with the patients and every IV PCA had an identical appearance; thus, participants, anesthesiologists, and outcome assessors were blinded to group allocation. The gynecological surgeons and nurses were blinded to the study protocol.All patients received the following standardized anesthetic managements. No premedication was administered before surgery. Upon arrival in the operating room, standard monitoring was applied. General anesthesia was induced and maintained by target-controlled infusion of propofol and remifentanil. The bispectral index was used to monitor the depth of anesthesia. After administration of 0.8 mg/kg rocuronium, tracheal intubation was performed. During the operation, the bispectral index was maintained between 40 and 60. Remifentanil was titrated to maintain systolic arterial pressures between 100 and 140 mmHg throughout the surgery. Local anesthetic was not administered for skin closure. The amount of intraoperative remifentanil used was recorded. No opioids medications other than remifentanil were administered during surgery.An IV PCA pump  was connected at the end of surgery. The IV PCA was set to deliver 1 mL bolus with a 15 min lockout time, and 1 mL/h background infusion. All patients received IV ramosetron 0.3 mg before the start of the IV PCA for prophylaxis against postoperative nausea and vomiting (PONV).After the surgery, patients were transferred to the post-anesthesia care unit (PACU). Patients were discharged from the PACU after a score of 10 was obtained on the 14-point modified Aldrete’s scoring system by a blinded PACU nurse.Standardized postoperative analgesia was provided to every patient until hospital discharge. IV PCA was maintained for the first 48 h postoperative period in principle, and in the case of discontinuation before the 48 h, the timing and reasons were recorded. IV ketorolac (30 mg) was used as a rescue analgesic for breakthrough pain as required for a numerical rating scale (NRS) ≥4 during the postoperative 3-day periods. Regular oral analgesics, including 80 mg of zaltoprofen every 8 hours, were administered on postoperative days 1 and 2. IV ramosetron (0.3 mg) was administrated for PONV prophylaxis on postoperative day 1. If PONV occurred, 10 mg of IV metoclopramide was administered as a rescue antiemetic.The primary outcome was the incidence of postoperative nausea during the 48 h study period. Secondary outcome variables included postoperative pain scores at 3, 24, and 48 h after the completion of surgery, cumulative fentanyl consumption via IV PCA within the first 3 h, 3–24 h, and 24–48 h postoperatively, rescue analgesic consumption within the 48 h study period, opioid-induced adverse events, including vomiting, pruritus, shivering, respiratory depression, and urinary retention, and patient’s overall satisfaction scores with postoperative pain management  for the first 48 h postoperatively. Cumulative nefopam consumptions within the first 3 h, 3–24 h, and 24–48 h were also analyzed.Regular postoperative follow-up assessments were conducted at 3, 24, and 48 h after the completion of surgery by a blinded investigator. Pain intensity was recorded on the verbal NRS from 0 to 10. The requirements of rescue analgesics and cumulative dose of rescue analgesics were recorded at 3, 24, and 48 h after the end of surgery. The occurrence of postoperative nausea, vomiting, and urinary retention was recorded. In patients who experienced nausea, the severity of nausea was rated on the NRS (0 = none and 10 = worst imaginable).2 test. Categorical variables were analyzed using Fisher’s exact test when the expected counts were < 5 for at least 25% of the cells. Intergroup differences in the incidence of postoperative nausea during the 48 hours study period, the primary outcome, were assessed for significance using the Pearson χ2 test. Continuous data were tested for normality using the Shapiro–Wilk test. Data showing a normal distribution were presented as mean (SD), and data showing a non-normal distribution were presented as median (interquartile range). Continuous variables were analyzed using Student’s t test or Mann–Whitney U test for intergroup differences, as appropriate. Pain scores and the amount of fentanyl consumptions were considered continuous variables. Two-tailed P values < 0.05 were considered statistically significant. Repeated measurements (pain scores and amount of fentanyl consumptions) were analyzed using the Mann–Whitney U test with Bonferroni correction. The criterion for rejection of the null hypothesis for the repeated measurement at each time point was p < 0.017. Pre-specified subgroup analyses included the sensitivity to pressure pain.Data were analyzed using SPSS Statistics for Windows  and R software . All data were analyzed on an intention-to-treat basis. Categorical data were expressed as a number  and analyzed using the Pearson χSample size was calculated based on preliminary data obtained in the patients undergoing gynecological surgery at our institution. The observed incidence of nausea after gynecological surgery was 45%. We hypothesized that the use of a predicted regimen of opioids could reduce the incidence of postoperative nausea to 20%. To achieve a power of 0.8 and an alpha error of <0.05, 54 patients were required in each group. To allow for dropout, 59 patients were randomized to each group.Of 123 patients who underwent randomization, 14 patients were excluded because of withdrawal of patient consent; therefore, 109 subjects completed the study . The basp = 0.042; p = 0.191; p = 0.691; Providing patients with a predicted dose of fentanyl according to their preoperative pain sensitivity significantly reduced the opioid consumption via IV PCA during the first 48 h postoperative period ; We conducted pre-specified subgroup analyses according to patient’s pain sensitivity. Fifty-nine patients were considered as sensitive patients . Among these patients, 51 patients were administered with the higher dose regimen, which corresponded to their sensitivity, while eight patients were administered with the lower dose regimen. The pain scores, fentanyl consumption, nefopam consumption, and incidences of postoperative nausea at each recorded time point were not significantly different between the patients receiving a higher or lower dose .p = 0.015; p = 0.498; Fifty patients exhibited a threshold ≥26 N and were considered as non-sensitive patients (mean threshold 36.8 N). We treated 17 patients with a higher dose regimen, which did not correspond to their sensitivity, and 33 patients with a lower dose regimen, which corresponded to their sensitivity. The incidence of nausea was significantly lower in patients treated with a lower dose regimen compared with a higher dose regimen  received laparoscopic surgery, and median fentanyl consumption for the 48 h study period showed no statistically significant difference between the groups among these patients  or co-primary outcomes might have altered the results.The non-predicted administration strategy in this trial also requires discussion. We measured pain sensitivity in both groups to blind all participants to group allocations. In the control group, we used the regimen paired with the administered regimen in predicted groups to balance the administered opioid regimens between the intervention and control groups. We did not use a deliberately un-matched regimen to patient’s sensitivity because we considered that this would not occur in a clinical setting; therefore, it would not reflect real practice. Moreover, we considered this to be potentially unethical. As a result, 58% of patients in the control group were treated with a regimen that corresponded to their sensitivity in this study. Thus, even if there are some beneficial effects of the predicted approach, these might not be detected in the current trial.The following limitations should be considered when interpreting the results of our study and these limitations may suggest some implications for future investigations. First, we used only the threshold to pressure pain in this study. Other measurements of preoperative pain sensitivity, including threshold or tolerance to thermal or electrical stimuli, may lead to different results. Second, although the cut-off value to divide patients into the sensitive or non-sensitive patients was determined by a preliminary study and the previous literature, the nature of this sensitivity was not discrete but continuous. Third, we could not record the number of bolus administrations of PCA since the PCA pump used in this study had no record of the number of bolus given. Fourth, we had set the study follow-up period as 3 days postoperatively, but we changed it to 48 h postoperatively, for consistency between patients, before commencing the trial. However, the changes were not adequately reflected in our registry protocol, and it should be considered when interpreting our data. Fifth, we did not determine the regimen based on the patients’ body weight. Lastly, a relatively large proportion (58%) of patients in the control group received the regimen correctly matched to their sensitivity; therefore, the results of this study should be interpreted cautiously. Further research with better design and sufficient sample size is required on this subject.This study failed to observe clinically relevant benefits of a predicted administration of opioids based on preoperative pain sensitivity for postoperative analgesic profiles in women undergoing gynecological surgery. However, offering a predicted dose of opioids according to a preoperative pressure pain threshold of each patient did lead to reduction in opioid consumption in the 48 h postoperative period, without a difference in pain scores and drug-related side effects between two groups. Further studies are required to determine whether individualized pain treatment protocols based on the patient’s own pain sensitivity improve analgesic profiles compared to “one-size fits all” protocols in postoperative settings.


Chronic neck pain is a common musculoskeletal disorder that is associated with functional disability and decreased of quality of life. Electrophysical agents are commonly used to relieve pain, however the effects of combined use of these agents are little studied. The objective is to investigate the efficacy of photobiomodulation and electrical stimulation to relieve pain, both in isolation and combined.This a 4-arm randomized placebo-controlled trial with patient and evaluator blinded. This study will be performed in Department of Physical Therapy at Federal University of São Carlos, São Carlos/SP, Brazil. One hundred and forty-four patients with chronic neck pain will be randomized into 4 groups: active photobiomodulation therapy with active electrical stimulation, active photobiomodulation therapy, active electrical stimulation, or placebo treatment. They will receive 10 sessions of treatment. Primary outcome: pain intensity  posttreatment. Secondary outcomes: pain during movement, neck disability, range of motion, pressure pain threshold, temporal summation, conditioned pain modulation, depressive symptoms, pain catastrophizing, quality of life, analgesic intake, and global perceived effect at posttreatment (10 sessions). Pain intensity and global perceived effect will also be measured after 6 weeks randomization.The findings of this study might clarify the importance of using the photobiomodulation therapy and transcutaneous electrical nerve stimulation for patients with chronic neck pain.https://clinicaltrials.gov/ct2/show/NCT04020861?term=NCT04020861&draw=2&rank=1.NCT04020861.  Low-level laser therapy is nonthermal and it may have a stimulating effect on target tissues. Therefore, it is used in several musculoskeletal conditions to decrease pain and inflammation as well as stimulate collagen metabolism and wound healing. Côté et al, in their clinical practice guidelines, recommend the use of PBMT in combination with patient education for the treatment of chronic neck pain and associated disorders. This recommendation was based on 6 randomized clinical trials (RCTs),12–16 in which PBMT was better than placebo treatment and, in the majority of studies, the neck pain was associated with myofascial pain syndrome. Having been established as an effective treatment, it is then important to verify whether PBMT is superior to other analgesic agents including electrical currents.Photobiomodulation therapy (PBMT) and analgesic electrical currents are non-pharmacologic resources used in the treatment of patients with neck pain.,18 Typically, TENS units deliver pulsed electrical currents with either balanced asymmetrical or symmetrical biphasic rectangular waveforms in which frequency, pulse duration, and amplitude can be adjusted.,18 It is widely used in both acute and chronic painful conditions.–19 Some studies have hinted that TENS might be more effective than placebo or as effective as other interventions for patients with neck pain.,7,20–24 Unfortunately, the evidence is of low quality, the studies are heterogeneous, and more trials should be performed with larger patients samples, higher quality, and attention to adequate principles of application and evaluation of TENS.Normally, electrical currents are applied through adhesive electrodes over the skin surface. This method is known as transcutaneous electrical nerve stimulation (TENS).Both therapies, PBMT and TENS, are commonly used in clinical practice for patients with neck pain. The use of these electrophysical agents is important to decrease pain and may have the added benefits of decreasing the use of painkillers and facilitating exercise during therapy. However, the literature is still controversial, the studies are heterogeneous and of low quality and most of them only investigated pain and functional impairment. Therefore, more high-quality trials are required to verify the efficacy of these agents and the best methods of applying them. In addition, until this moment, no studies were found that investigated the combined effect of PMBT and TENS. These electrophysical agents have different ways of producing analgesia so we hypothesize that combined treatment with PMBT and TENS may have a synergistic action and result in a decrease in pain faster and/or for a longer time. Therefore, the objective of this study is to verify the efficacy of PBMT and TENS, isolated or combined, in relation to pain, functional disability, range of motion, pressure pain threshold, temporal summation, conditioned pain modulation, depressive symptoms, pain catastrophizing, quality of life, analgesic intake, and global perceived effect in patients with non-specific chronic neck pain.22.1This protocol study was written following the recommendations of Standard Protocol Items: Recommendations for Interventions Trials (SPIRIT) and this 4-arm randomized placebo-controlled superiority trial with patient and evaluator blinded to the allocation group will follow the guidelines recommended by Consolidated Standards of Reporting Trials (CONSORT). Figure The study has been approved by the Human Research Ethics Committee of the Federal University of São Carlos , São Paulo, on March 2018. The protocol of this study has been registered on Clinicaltrials.gov (NCT04020861). All the patients included in the study will validate their participation by signing an informed consent form that will be explained by evaluator.2.2Patients will be recruited through the internet, posters, and radio dissemination. The study will be performed in Department of Physical Therapy of Federal University of São Carlos, Brazil, from January, 2020 until July 2019.2.3The study evaluator will verify whether the patients will be eligible to participate in the study based on patient history and clinical examination.2.4Patients with non-specific chronic neck pain, defined as pain or discomfort in the posterior cervical region between the superior nuchal line and the first thoracic spinous process and/or shoulder girdle;Neck pain for at least 3 months;Neck disability index (NDI) score of 5 points or higher;Numeric rating scale (NRS) score of ≥3 for pain intensity;Aged between 18 and 65 years;Men and women.2.5Neck pain associated with nerve root compromise ;Previous spinal surgery;Patients treated with physical therapy for neck pain within 3 months prior to the study;Severe spinal disorders such as fractures, tumors, inflammatory, and infectious diseases;Any contraindication to low-level laser therapy or transcutaneous electrical nerve stimulation;Rheumatic, metabolic, neurological, or cardiopulmonary diseases;Patients who require artificial cardiac pacemakers;Patients with sensory deficits;Skin diseases, mainly at the current application site;History of tumors or cancer in the last 5 years;Pregnancy;Having started any physical activity in the last 2 weeks.2.6Patients will work with 2 separate researchers, 1 serving as the evaluator and the other serving as a therapist. Both are physiotherapists. The patients will be evaluated before the treatment, after the treatment (10 sessions) and 6 weeks after randomization. On the first session, the evaluator will collect sociodemographic data, medical history, and data related to the study outcomes. Then, the therapist will give each patient 10 consecutive days of treatment, with the exception of weekends, after which they will be re-evaluated by the evaluator. After 6 weeks randomization the evaluator will be in contact by telephone to the patients for a follow-up evaluation. All data entry will be coded and double-entered into an Excel spreadsheet for analysis.2.7The patients will receive 10 consecutive days of treatment, with the exception of weekends. Each session will last around 1 hour, and it will be conducted by the same therapist during the same period of the day. After the initial evaluation, the patients will be randomly allocated to one of 4 groups: PBM + TENS group, PBM group, TENS group, and Placebo group. In the PBM + TENS group (n = 36) the patients will undergo the active PBMT and active TENS, in the PBM group (n = 36) the patients will be undergo the active PBMT and placebo TENS, in the TENS group (n = 36) the patients will undergo the placebo PBMT and active TENS, and in the Placebo group (n = 36) the patients will undergo the placebo PBMT and placebo TENS. The patient will be prone. If laying prone is not possible, they will be seated. The treatment area will be defined as the painful area. A simulation of laser application will be performed for the placebo PBMT. The cluster probe will be positioned on the painful area for the same duration as active PBMT, the equipment will be turned on and set, but the trigger will be not activated, and no beam will be applied.The equipment Antares  will be used for active and placebo photobiomodulation therapy (PBMT). Table 2)  will be positioned around the painful area as reported by patient. The following parameters will be used: frequency of 100 Hz, phase duration of 125 μs, 30 minutes of current stimulation, and the pulse amplitude will be increased until the patient reports a strong but comfortable paresthesia (including motor level stimulation but no pain). The amplitude will be adjusted (if necessary) every 5 minutes to keep a strong but comfortable paresthesia. For placebo TENS, the device will be customized to deliver a current for 30 seconds (both channels) and then ramp off over the next 15 seconds so that it will be active only for a total of 45 seconds. This will permit the patient to feel the TENS sensation while applying the settings. The unit will also display an active indicator light suggesting to the patient that the unit is actively emitting current even after the 45 seconds. In a study comparing this placebo-TENS approach to standard placebo-TENS methods and active TENS, this transient placebo-TENS was found to improve blinding of evaluators without providing analgesia. Patients will be instructed to report when they feel the stimulation and every 5 minutes the patients will be asked if they are feeling comfortable.The Neurodyn Portable TENS unit , which has a balanced asymmetric biphasic pulsed current, will be used for active transcutaneous electrical nerve stimulation (TENS). The patient will be prone. If laying prone is not possible, they will be seated. Two or four standard square self-adhesive electrodes (5 × 5 cm2.82.8.1Pain intensity after treatment (10 sessions).2.8.2Pain intensity during movement; neck disability; cervical range of motion; pressure pain threshold (PPT); temporal summation (TS); conditioned pain modulation (CPM); depression symptoms; pain catastrophizing; quality of life; analgesic intake; and global perceived effect. Secondary outcomes will be measured at baseline and posttreatment (10 sessions). Pain intensity and global perceived effect will also be measured in contact by telephone after 6 weeks randomization.2.9 The pain evaluation will be carried out verbally with the patient reporting the pain intensity.Pain intensity will be evaluated using a NRS, which is a simple and easy-to-use measuring scale that consists of a sequence of numbers from 0 to 10, in which 0 represents “no pain” and 10 represents “the worst pain imaginable.” Then, patients rate their pain based on these parameters.2.10 It will be used to include patients with neck pain in the study.Neck disability will be evaluated using the neck disability index (NDI) that consists of a 10-item questionnaire that assess the impact of pain on daily activities using a score from 0 to 5 for each section, with higher values indicating more severe impact. This instrument has been translated and cross-culturally adapted for the Brazilian population.2.112,3) and it was reported as excellent for flexion , extension , inclination to the right , inclination to the left , rotation to the right , and rotation to the left .Cervical range of motion will be measured with a fleximeter . The intra-rater reliability of cervical range of motion was tested in 10 asymptomatic subjects by a single evaluator at 48-hour intervals. Reliability has already been estimated by calculating the intraclass correlation coefficients . The intra-rater reliability of measurement of PPT was tested in 10 asymptomatic subjects by a single evaluator at 48-hour intervals. Reliability has already been estimated by calculating the intraclass correlation coefficients  and it was reported as excellent for the posterior cervical region and shoulder girdle  as well as for the tibialis anterior muscle .Pressure pain threshold (PPT) will be measured using a Somedic Type II pressure algometer  consisting of a circular rubber probe  and the levator scapulae (2 cm superior to the superior angle of the scapulae) and on the middle third of the right tibialis anterior muscle. All patients will have 3 demonstrations of the PPT measurement on their right superior limb to ensure that they understand the PPT concept prior to starting the measurements.For PPT measurement, the circular algometer probe will be positioned perpendicular to the skin and applied at a uniform and constant rate of 40 kPa/s. The patients will be instructed to close their eyes and to press the algometer sensor when the pressure sensation becomes painful. Three measurements will be collected with 30 seconds intervals between them and the mean will be used for data analysis. Patients will be not allowed to see the algometer readings during measuring. Six PPT recording points on cervical and shoulder girdle areas will be evaluated bilaterally: 2 cm lateral to the C2,2.132. The intra-rater reliability of pain TS was tested in 10 asymptomatic subjects by a single evaluator at 48-hour intervals. Reliability has already been estimated by calculating the intraclass correlation coefficients  and it was reported as good for upper trapezius muscle . For TS, 10 stimuli will be performed with a pressure of 40 kPa/s up to the mean value obtained from algometry performed prior on the most painful upper trapezius or, if the pain is the same between the sides or there is not pain in the upper trapezius, the dominant upper trapezius. Each TS stimuli will be maintained for 1 second before being released and the stimuli will be spaced at 1 second intervals. A timer will be used to ensure that the intervals are respected and that the stimuli are maintained. Patients will be asked about their pain using NRS at the first, fifth, and tenth stimuli. To prevent sensitization interference from the previously performed pain pressure threshold evaluation, the test will begin 5 minutes after PPT evaluation.Temporal summation (TS) will be induced by a Somedic Type II pressure algometer  with a circular rubber probe of 1 cm2.14 A noxious stimulus will be used as a conditioning stimulus to induce a reduction in the perception of pain from another test stimulus. The conditioned stimulus for eliciting CPM will be the cold pressor test and the test stimulus will be the assessment of PPT on the upper trapezius muscle.Conditioned pain modulation (CPM) represents a pain modulatory phenomenon in humans such that pain perception may be decreased by a nociceptive stimulus applied distantly from excitatory site. In the case of bilateral pain, the patient will be instructed to report the more painful side. If there is no consensus on which side is the most painful, the dominant side will be used. Thereafter, patients will be instructed to immerse the same hand (up to the wrist) in an ice water bath maintained at 4 °C. Patients will be asked to keep their hand moving (opening and closing the hand to prevent warming around the hand) in the water bath for 1 minute. During the conditioned stimulus, after 30 seconds, patients will rate the perceived pain intensity of the ice water on an 11-point verbal numeric pain rating scale with responses ranging from 0 (“no pain”) to 10 (“worst imaginable pain”). After 1 minute of immersion, the patient will be asked to remove their hand of ice water bath.First, the patients will receive clear instruction about the test procedure. Next, for the conditioned stimulus, a hand on the side ipsilateral to the most painful neck pain region will be immersed in a water bath maintained at room temperature (22 °C) for 1 minute to standardize the hand temperature. For analysis of CPM efficacy, the mean PPT measured before the cold pressor test will be subtracted from the mean PPT measured after the cold pressor test. Hence, a lower CPM value reflects less efficient endogenous pain inhibition.The PPT measure (test stimulus) will occur at the middle point of the upper trapezius muscle (between C7 and the acromion) contralateral to the immersed hand before the conditioned stimulus and, in order to avoid distraction bias, immediately after removing the hand from the ice water.2.15The depressive symptoms will be evaluated using the Portuguese version of the beck depression inventory (BDI). The scale consists of items including symptoms and attitudes whose intensity range from neutral to a maximum level of severity, rated from 0 to 3. It has 21 items related to sadness, pessimism, feeling of failure, lack of satisfaction, feeling guilty, self-deprecation, self-accusations, suicidal thoughts, crying crises, irritability, social retraction, indecision, distortion of body image, inhibition of work, sleep disturbance, fatigue, loss of appetite, weight loss, somatic concern, and decreased libido. Scores higher than 15 detect dysphoria and scores over 20 indicate depression.2.16 The PCS is a self-administered questionnaire that consists of 13 items to assess catastrophizers. The items are rated on a 5-point Likert-type scale in which both intensity and frequency information are represented, with the following 5 levels of response for each Likert item: (0) not at all, (1) to a slight degree, (2) to a moderate degree, (3) to a great degree, (4) and all the time. The total score is computed by summation of all items and the total score ranges from 0 to 52 points. Higher scores indicate greater catastrophizing of pain.,43Pain catastrophizing will be performed with the Portuguese version of the pain catastrophizing scale (PCS) validated and adapted by Sehn et al.2.17The quality of life assessment will be performed using the 12-Item Short-Form Health Survey (SF-12) version 2 questionnaire. This is a self-report measure that assesses physical  and mental  health on a scale of 0 to 100. Higher scores represent better levels of quality of life.2.18,46 Non-opioid analgesic medications will be converted to acetaminophen equivalents using the conversion table. During the treatment, the patient will be asked to record any medication used for their neck pain. These records will be important to determine if there will be a change in a medication dose per week used during treatment in relation to medication dose used week prior to the treatment. In addition, it will allow the researchers to determine whether the results will be biased as a result of medication use.All patients will be asked to report all analgesic medications (both opioids and non-opioids) taken 1 week prior to evaluation. The name, means of delivery, dose, pills per day, and number of days used in the past week will be recorded. All opioid medications will be converted into an equianalgesic dosage of oral morphine.2.19The global perceived effect (GPE) scale, translated and validated for Portuguese, evaluates the patient's global perception of recovery. It consists of an 11-point scale that ranges from –5 (vastly worse) through 0 (no change) to 5 (completely recovered). At baseline, after the treatment, and at follow-up, the patients will be asked “Compared to when this episode first started, how would you describe your back these days?” A higher score represents a better condition.2.20www.randomization.com by a researcher not involved in the patient recruitment or data collection. It will be performed as block randomization with a 1:1:1:1 allocation. Patients will be stratified by sex to ensure equal numbers of women and men in each group and randomly allocated to 1 of 4 groups (n = 36 per group): Photobiomodulation + TENS, Photobiomodulation, TENS, or Placebo. The concealed allocation will be performed in consecutively numbered opaque envelopes. The envelopes will be sealed, and they will be stored in a secure cabinet. Prior to initiation of treatment, the therapist responsible for the treatment will open the sealed envelope to know in which group the patient will be included. Patient and evaluator will be blinded throughout the treatment. The same researcher will not apply therapies and perform evaluations.The randomization will be generated on the site 2.21Assessment of the effectiveness of blinding will be performed after the conclusion of the posttreatment evaluation. The evaluator will answer whether he thinks that the application of photobiomodulation and electrical current was real, placebo, or he does not know. After that, the evaluator will ask the patient: “Do you think that the application of photobiomodulation was real, placebo, or did not know?” and “Do you think that the application of electrical current was real, placebo, or do you not know?” Their responses will be recorded and used to gauge the adequacy of subject and investigator blinding.2.22 Statistical power of 80% was considered with an alpha of 5% and possible sample loss of up to 15%. Accordingly, a total of 144 patients will be required for the study. The sample calculation was performed using the Minitab software, version 17, .The sample size of the study was performed based on the pain intensity outcome  with mean difference of 2.3 points and an estimated standard deviation of 2.76 points.2.23 The Shapiro-Wilk test will be used to verify the normality of the data. If the data present a normal distribution, a parametric test will be used. Otherwise, a nonparametric test will be used. The level of significance adopted will be P < .05. Data analysis will be performed using the SPSS software version 17  by a researcher blinded to the division of the groups.All study-related information will be stored securely at the study site. All participant information will be stored in locked file cabinets in areas with limited access. The principles of intention-to-treat analysis will be used for the statistical analysis.3This randomized controlled trial will investigate the effect of isolated and combined of photobiomodulation and electrical stimulation for chronic neck pain patients.It will be possible to determine whether the application of one agent is superior to the other and/or whether the application of both is superior to isolated application of one of them, as well as whether they are superior to placebo treatment.It will be possible to verify the efficacy of these agents not only in relation to intensity of pain but also in relation to range of motion, pressure pain threshold, central sensitization, functional disability, pain catastrophizing, depressive symptoms, and quality of life.It has a high-quality design that leads to strong clinical evidence. The findings of this study might clarify the importance of using the PBMT and TENS for patients with chronic neck pain.“Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001.”EPRS and REL were responsible for conceiving and designing the study. REL is the study coordinator. EPRS, ALMA, VRS, CGNB are responsible for data collection. All authors have contributed for writing and approved this manuscript.Érika Patrícia Rampazo orcid: 0000-0002-2984-6902.


Degenerative disc disease (DDD) is one of the main causes of lower back pain. In this study, we evaluate the efficacy of percutaneous intradiscal GelStix administration in patients with discogenic pain due to lumbar DDD who were unresponsive to conservative methods. A total of 29 patients were included in the study, which took place between 2013 and 2017. Sedation was performed in the prone position in the operating room, and a C-arm was located so as to provide a lateral view of the surgical field. A 22-G, 3.5-inch needle was inserted into the center of the disc under fluoroscopy guidance, and a percutaneous intradiscal GelStix implantation was performed. All patients were evaluated using the Oswestry Disability Index (ODI) and a visual analogue scale (VAS) before and after treatment, and using the Patient Satisfaction Scale at 12 months following treatment. The mean VAS scores were 7.14 ± 0.64 at baseline and 2.48 ± 0.63 at 12 months (P < 0.001). The mean ODI scores were 28.14 ± 1.81 at baseline and 17.35 ± 0.67 at 12 months (P < 0.001). There was a statistically significant decrease in the VAS and ODI scores before and after treatment. A total of 86.2% of the patients rated the procedure as very good or good at 12 months. Our study results suggest that GelStix treatment is useful in pain relief in patients with DDD from the first month of treatment. Degenerative disc disease (DDD) is closely related with aging and lumbar back pain (LBP), which affects 70%–85% of the population during their lifetimes [1]. The prevalence of back pain increases with aging. Approximately 20% of young individuals have mild disc degeneration. The incidence of degeneration increases with aging, particularly in males; therefore, nearly 10% and 60% of discs in people aged 50 and 70 years, respectively, are severely degenerated [2]. The most important change caused by degeneration is the loss of proteoglycans (PGs). This may lead to a decrease in the osmotic pressure of the discal matrix and loss of hydration [3]. Furthermore, impaired nutrient transport in degenerated discs may lead to the formation of lactic acid and decreased pH levels [4]. There are many additional patient-specific factors that can contribute to the pathogenesis of the disease, and that have the potential to alter the natural course of disc degeneration. These include age, sex, genetics, smoking, cardiovascular disease, morbid obesity, physical inactivity, occupational factors (recurrent heavy lifting and vibration), constitutional weakness, low-grade discitis, spinal instability, and malignancy .Hydrogels are water-soluble, and their hydrophilic features are suitable for minimally invasive spinal surgery, particularly surgery in which the hydrogel is transformed into a different form after implantation. In such cases, the minimized aqueous nature allows the implant to act as an interspinal expander [6].There is a need for percutaneous interventional treatments between conservative and surgical methods that address the etiology of DDD but cause minimal damage to the annulus fibrosus (AF). It is difficult for the native nucleus pulposus (NP) to achieve self-renewal; however, hydrogels may serve as a substitute for the NP thanks to their hydrophilic and rheological properties and their similarities to native NP tissue. A hydrogel agent that ideally is injectable into the disc may improve the regeneration of NP and increase the mechanical function of the degenerative motional segment, particularly in patients with early or moderate degeneration who are unresponsive to conservative treatments . In the present study, we evaluate the efficacy of percutaneous intradiscal GelStix administration in patients with discogenic pain due to lumbar DDD who were unresponsive to conservative methods.GelStix  is a modified filamentous version of polyacrylonitrile that enlarges in volume after implantation. As with previously used in situ hydration polymers, a number of complications have been reported, including disintegration of the gel after swelling [8]. Accordingly, NP-class polymers for NP implant hydration have been used with caution . GelStix implants take the elongated hydrogel form of the registered polymer of RMI and are produced as matched bone that can be inserted under local anesthesia via 22-G needles. GelStix Nucleus Augmentation hydrates by absorbing the body’s own liquids, and its volume is expanded around tenfold and is reduced in less than 15 min.The inclusion criteria were as follows: being older than 18 years of age; being within American Society of Anesthesiologists Class I–II; having a visual analogue scale (VAS) score of ≥5/10 points; having discogenic pain due to 1 or 2 degenerative disc diseases; having a black disc, as confirmed by magnetic resonance imaging (MRI) compatible with clinical examinations; negative facet joint blocks and medial branch blocks; and having refractory symptoms despite physical therapy, muscle relaxant, and antiinflammatory treatment for at least 3 months. 2.The exclusion criteria were as follows: patients with root compression or zygapophyseal arthrosis as documented by plain X-ray and lumbar MRI, and those with vertebral fractures, previous lumbar spine surgery, signs or symptoms of lumbar canal stenosis, psychological disorders, localized or systemic infections, tumors, coagulopathy, pregnancy, osteoarthritis-disc herniation-annular tear , disc height of 5 mm or less than 50% of the original height, and a body mass index of ≥35 kg/mOf the total patients involved in the study, 8 had middle lumbar axial pain (n = 8) and mild radiculopathy (n = 3). The study was approved by the Ethics Committee and was conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from each patient. The data of patients who were treated in our pain clinic with percutaneous intradiscal GelStix implantation for LBP between 2013 and 2017 were analyzed retrospectively, and data related to lumbar disc degeneration, medical history, physical examination, plain radiography, and MRI findings were recorded. The procedures were carried out under sterile conditions using fluoroscopy with a standard oblique intradiscal approach. Prior to the procedure, 1 g of intravenous cefazolin for prophylaxis and 2–5 mg of midazolam to reduce anxiety and discomfort were administered. The patients were thus calm but alert and conscious, and able to talk to the practitioner to report any unusual pain. During the procedure, blood pressure, heart rate, electrocardiography, oxygen saturation, and respiration rate were monitored for all patients.The participants were placed in the prone position on the operating table, the operational area was cleaned and covered with sterile cloth, and an interventional point was identified under fluoroscopy and marked 8–10 cm laterally from the lumbar vertebrae on the side of intervention. A local anesthetic of 60 mg of prilocaine was injected into the subcutaneous tissues, and a 22-G, 3.5-inch needle was inserted into the center of the disc under fluoroscopy guidance. After entry was made, the position of the needle within the disc was checked via both anteroposterior and lateral views. Before installing the GelStix cartridge, liquids were removed using a stylus. The protective cap of the implant holder was removed and the holder was then pushed into the proximal end of the introducer needle and locked. It was confirmed that the tip of the needle was located at the center of the disc cavity by fluoroscopy, and the piston of the holder was pushed to allow the implant to completely pass the needle, with 3 implants placed at each disc level. Care was taken to avoid twisting the needle. While the needle tip was still at the center of the nucleus, the intradiscal area was washed out with 40 mg of gentamicin, an appropriate prophylactic local antibiotic. At the end of the procedure, the needle was pulled out and a sterile bandage was applied as a dressing. No sutures were used.All patients were allowed unlimited walking, standing, and sitting, and all were instructed to avoid heavy lifting, forward skin bending, or crushing. After 10 to 14 days, light work and home-based exercises with gentle flexions and extensions were allowed.All patients were evaluated using the Oswestry Disability Index (ODI) and a VAS before treatment and at 1, 3, 6, and 12 months after treatment, and using the Patient Satisfaction Scale at 12 months following treatment.The data analysis was carried out using SPSS V 21.0 statistical software . Descriptive data were expressed as mean ± standard deviation (SD) for continuous variables and as number (n) and percentage (%) for nominal variables. The compatibility of the variables to normal distribution was checked with a Kolmogorov–Smirnov test. For abnormally distributed variables, intragroup distribution was compared using Friedman’s analysis of variance (ANOVA) test. If present, multiple intertime comparisons of the differences were evaluated using the Bonferroni adjusted Wilcoxon signed-ranks test. The power for nonparametric tests was unable to be calculated [11]. Clinical significance was assessed using Kendall’s W correlation coefficient for Friedman’s ANOVA and a correlation coefficient for the Wilcoxon signed-ranks test. Kendall’s W correlation coefficient was interpreted using Cohen’s guidelines of 0.1 , 0.3 (medium effect), and above 0.5 (strong effect). The effect size of the Wilcoxon signed-ranks test was interpreted according to Cohen’s criteria, and the values of 0.2, 0.5, and 0.8 were considered small, medium, and strong effect sizes, respectively. P < 0.05 was considered statistically significant. A total of 29 patients were included in the study, and of these, 14 were female and 15 were male, with a mean age of 49.21 ± 6.82 years for women and 46.26 ± 7.18 years for men. All patients were followed for 12 months in the pain clinic.  GelStix implants were applied to 25 patients, to a single level in L4–L5 in 16 patients, to L5–S1 in 9 patients, and to 2 levels  in 4 patients. According to the Patient Satisfaction Scale, which was evaluated at 12 months following the procedure, 4 patients rated the procedure as very good, 21 as good, and 4 as moderate. Overall, 86.2% of the patients rated the procedure as very good or good (Table 1).The mean VAS scores were 7.14 ± 0.64 at baseline, 3.69 ± 0.60 at 1 month, 2.93 ± 0.59 at 3 months, 2.62 ± 0.49 at 6 months, and 2.48 ± 0.63 at 12 months . Based on the results of a Friedman test, the differences between the VAS scores at baseline and at 1, 3, 6, and 12 months were found to be statistically significant (P = 0.001) (Table 2).Kendall’s W value for the VAS was calculated as 0.802, which is higher than 0.5, indicating a strong effect size by Cohen’s criteria. This result was also clinically significant . When comparing binary months, all of the differences between the VAS scores were statistically significant (P < 0.05), while only the difference between months 6 and 12 was not significant (P = 0.317). When the effect size of binary comparisons for the VAS scores was assessed according to Cohen’s criteria, the VAS scores for months 6–12 were below mild clinical significance, 3–6 about mild, and 3–12 between mild and moderate clinical significance, while the other time comparison results had more than moderate clinical significance [13] . The differences in the ODI scores of the patients were found to be statistically significant (P = 0.001) using a Friedman test. The mean ODI scores were 28.14 ± 1.81 at baseline, 18.59 ± 1.84 at 1 month, 18.00 ± 1.10 at 3 months, 17.79 ± 1.01 at 6 months, and 17.35 ± 0.67 at 12 months. A decrease in the ODI scores in patients with GelStix treatment was noted . Kendall’s W value for the ODI scores was calculated at 0.635, which is higher than 0.5, indicating a strong effect size by Cohen’s criteria. This result was also clinically significant. When comparing binary months, the differences between the ODI scores were statistically significant (P < 0.05), except for the differences between the 1st and 3rd months (P = 0.110) and the 3rd and 6th months (P = 0.295). When the effect size of the binary comparisons of the ODI scores was assessed according to Cohen’s criteria, the ODI scores for months 3–6 had below mild clinical significance, 1–3 and 1–6 had about mild, and 3–12, 6–12, and 1–12 had between mild and moderate clinical significance, while the other time comparison results had more than moderate clinical significance (Table 3). Disturbances of nutrient transport in degenerated discs cause lactic acid formation and decreased pH levels [4]. Accumulations of lactic acid modify cellular activity by downregulating PG synthesis, and it is the enzymes that degrade the extracellular matrix that cause Gelstix to stop the disk degeneration cycle. GelStix increases pH in the disc: low pH is associated with degeneration and inflammation, while increased pH causes the natural PGs to swell and increase hydration. Adding liquid and volume increases osmotic pressure, and low pH weakens the ability of PGs to bind to water; these factors lead to reduced hydration within the disc and further deterioration of the nutrient transport. , iii) it must be strong and have adequate durability, iv) it must have sufficient distension pressure with various loads, v) it must support cell proliferation and matrix, and vi) it must prevent adverse effects [14]. A hydrogel should support cell growth and matrix, and should also have sufficient mechanical strength for NP renewal. The ideal hydrogel must meet the following requirements for NP renewal: i) it must be injectable, ii) it must prevent the cells or gel from escaping after implantationIn our study of patients with DDD, we observed a time-dependent decrease in the patients’ VAS and ODI scores with GelStix treatment, and the changes before and after the procedure indicated that the process contributed significantly to the reduction in VAS and ODI scores. At 12 months, the mean VAS scores had decreased from 7.14 at the beginning to 2.48 at the 12th month (P = 0.001), and the mean ODI scores had decreased from 28.14 to 17.35 (P = 0.001).Singh et al. [15] administered GelStix implantations for 22 patients with DDD in 2012 and found the VAS scores to decrease from 8.5 to 3.0 (P < 0.0001) and the ODI scores to decrease from to 25.1 to 10.2 (P < 0.0001) after the first 4 weeks of treatment. In our study, the VAS and ODI scores of all patients with DDD at 12 months were similar to those in the aforementioned studies, and none of the patients in the study developed permanent neurological damage or complications requiring additional surgery. Response to treatment following GelStix implantation was noted early on in the treatment according to the selection of suitable patients and application by experienced operators. In patients with no history of severe radiculopathy, the rapid development of symptoms immediately after implantation suggests a possible misplacement at the annular ring [16]. In all patients, the cannula was carefully drained after it was clarified as being located most centrally in the nucleus pulposus via lateral and anteroposterior views from the C-arm.GelStix can grow rapidly by absorbing water and can lead to an increase in radicular symptoms via root compression or can cause a protruding disc to exert pressure, resulting in direct radiculopathy. In 2 previous case reports, the medical history of the 2 patients involved revealed signs of disc compression and radiculopathy prior to the procedure, and their symptoms intensified after 4 and 6 months. This finding suggests that both patients had a broad-base protruding disc and a degenerated annulus fibrosis defect before the procedure . The first-line treatment of DDD is conservative [18], and if conservative treatment fails, the current surgical treatment options are to surgically immobilize the degenerated disc segment, either with a fusion procedure or with a mechanical arthroplasty device . It was not possible to compare the outcomes of our patients to results found in a systematic review of the conservative treatments for DDD [21], as the DDD patients were undergoing drug and physical therapy for general back pain. In the treatment of chronic LBP, multiple physical and rehabilitation interventions are effective in the short-term but ineffective in the long-term [22], and intensive and long-term physical therapy programs have been found to increase the severity of pain in certain cases [23]. Nonsteroidal antiinflammatory drugs (NSAIDs) and antidepressants with pain-relieving effects of opioids have been reported as having less pain-relieving effects in cases of chronic pain, and NSAIDs and opioids in particular have been reported as having serious side effects related to their long-term use [24].The application of GelStix contributes to discal restoration in discogenic back pain and mild radicular pain, but it requires skilled practitioners as much as the selection of suitable patients due to the potentially serious complications. If the pain migrates towards the epidural space in the case of a newly developed injury or a preexisting weakness in the wall of the annular ring, the risk of complications and the need for surgery may increase due to severe radiculopathy. Based on the results of the present study, it can be suggested that GelStix intradiscal implant applications may be considered as a long-term pain-relieving, effective, and functionally beneficial treatment method for patients with DDD in experienced centers when based on appropriate patient selection.In terms of evaluating the long-term results of Gelstix application after returning to routine daily life, the patients’ smoking habits and alcohol intake, weight loss or gain, occupational changes, and long-term quality of sleeping could have been detected individually and stated in the discussion. Thus, we could have had the chance to analyze the reasons for VAS and ODI changes during the control periods of 3 months. However, the data of the patients in our study were only collected at the beginning and specified follow-up times.


Low back pain (LBP) is high prevalent and it is the leading cause of years lived with disability in both developed and developing countries. The sacroiliac joint (SIJ) is a common reason that caused LBP. At present, the treatment of chronic LBP attributed to SIJ is mainly conservative treatment and surgical treatment. However, there are still controversies between the 2 treating methods, and there is no recognized standard of treatment or surgical indications. Recent publications indicated that minimally invasive sacroiliac joint arthrodesis was safe and more effective improving pain, disability, and quality of life compared with conservative management in 2 years follow-up, which re-raise the focus of sacroiliac joints fusion. This paper will systematically review the available evidence, comparing the effectiveness of sacroiliac joint fusion and conservative therapy for the treatment of gait retraining for patients suffered from LBP attributed to the sacroiliac joint.A systematic review and meta-analysis of relevant studies in Pubmed, Embase, SCOPUS, and Cochrane Library will be synthesized. Inclusion criteria will be studies evaluating clinical outcomes  comparing sacroiliac joint fusion and conservative therapy in populations sacroiliac join related LBP; studies with less than 10 participants in total will be excluded. The primary outcomes measured will be pain score, Oswestry Disability Index (ODI), and adverse events during treatment. Review Manager  software will be used for data synthesis, sensitivity analysis, meta-regression, subgroup analysis, and risk of bias assessment. A funnel plot will be developed to evaluate reporting bias and Begg and Egger tests will be used to assess funnel plot symmetries. We will use the Grading of Recommendations Assessment, Development and Evaluation system to assess the quality of evidence.Our aim is to publish this systematic review and meta-analysis in a peer-reviewed journal. Our findings will provide information comparing the efficacy and safety comparing sacroiliac joint fusion and non-surgical treatment for patients with LBP attributed to the sacroiliac joint. This review will not require ethical approval as there are no issues about participant privacy. It is a review that included most recent studies that compared sacroiliac joint fusion and non-surgical treatment for patients with LBP attributed to the sacroiliac joint.The Cochrane Collaboration tool and The Grading of Recommendations Assessment, Development and Evaluation will be used to further evaluate study findings.Methodological and clinical heterogeneities will be exit based on the varied treatment including different surgical methods  and conservative treatments  in both groups of studies. Moreover, varied functional assessing methods  in included studies can contribute to heterogeneities.Different surgical approaches and duration of conservative treatment may not be comparable.1 Thought to be a frequent source of LBP, the sacroiliac joint increasingly raised doctors’ attention and it is thought to be involved in 15% to 30% of all patients with chronic low back pain.–5 The burden of disease associated with sacroiliac joint (SIJ) pain is at least as high as that associated with other musculoskeletal conditions such as hip osteoarthritis, degenerative spondylolisthesis, or spinal stenosis, conditions that are often treated surgically.,7 The treatment of this disease includes conservative and surgical treatment. Conservative treatments are often symptomatic treatment, such as wearing waist circumference, articular steroid injection, acupuncture, massage, etc, but the literature reports that the effective rate of these treatments is low, only about 50% of patients’ symptoms were relieved. The surgical treatment of this disease has been proposed since 1900, which was open sacroiliac joint fusion. Through continuous development of surgical technique and surgical instruments, triangular tantalum screw internal fixation of the sacroiliac joint has become the most common surgical method. Related studies have reported that it can achieve good clinical efficacy.–12 However, the best treatment for such diseases is still controversial. Previous systematic reviews have described sacroiliac joint fusion, which has significant clinical effects in relieving pain and improving symptoms, with fewer complications in mid to long-term follow-up. According to the relevant systematic reviews, there is no statistical difference in the effect of conservative treatment compared with surgical treatment, and the former showed a lower incidence of complications. Recent published literature points out the opposite view that surgical treatment can relieve pain and improve function better than conservative treatment.–17 Therefore, a systematic review of recently published clinical evidence is necessary. In our study, we planned to conduct a systematic review and a meta-analysis to evaluate the evidence from all available randomized controlled trials (RCTs) that evaluate effect of sacroiliac joint fusion for relieving pain and improving function of low back.Low back pain (LBP) is a common disease that can affect the patient's social life and work and even lead to disability.2We will conduct a systematic review and if available, meta-analysis will be performed to identify relevant studies involving sacroiliac joint fusion and LBP in electronic databases Fig. . Two rev2.1The inclusion criteria will be defined before searching, and the study inclusion eligibility was determined by the following population, intervention, comparator, outcomes, and study design criteria: studies evaluating efficacy and safety between sacroiliac joint fusion and conservative treatment were considered. The age of the patients and follow-up periods were not restricted, and the publication language was limited in English. Studies with less than 10 participants in total were excluded.2.2Two investigators will independently extract the relevant data from each study, which included the first author's name, year of publication, country, study design, details of the intervention and control including gender, age, number of participants, etc, and the follow-up duration and outcome measurements for each study. Any uncertainty will be discussed by 2 reviewers and resolved by consensus with discussion with another reviewer. We will contact the corresponding authors of the included RCTs to obtain any missing data when necessary. The Cochrane Collaboration tool will be used to assess the methodological quality and risk of bias of the included studies, including randomization, allocation concealment, blinding method, selective reporting, group similarity at baseline, incomplete outcome data, compliance, timing of outcome assessments, and intention-to-treat analysis. The Grading of Recommendations Assessment, Development and Evaluation approach will be used to evaluate the quality of evidence of the included studies. Reviewers will take into account limitations of the study, inconsistencies, indirect evidence, inaccuracies, and publication bias.2.3The primary outcome measures that will be evaluated in our review included visual analogue scales (VAS) to assess pain intensity of low back. Oswestry Disability Index (ODI) to evaluate the function and complications during treatment to evaluate the safety. The secondary outcomes will be Shot Form-36, recurrence rate of LBP, and satisfaction of participants.2.4I2 statistic. I2 ≥ 50% represented high heterogeneity. To detect the impact of each data set on the overall effects of the analyses, sensitivity analysis will be performed by sequentially deleting a single study involved in the meta-analysis. Subgroup analysis will be performed based on the different follow-up periods. Risk ratios (RRs) with a 95% CI were used to assess dichotomous outcomes. The inverse variance and Mantel–Haenszel methods will be used to combine separate statistics. We will evaluate whether asymmetry was due to publication bias or to a relationship between the trial size and effect size using funnel plots. A P value < .05 will be considered statistically significant.The meta-analyses will be performed using Review Manager . Given the characteristics of the data extracted for the review, continuous outcomes will be expressed as the mean difference (MD) with 95% confidence intervals (CIs). An assumption that the standard deviations (SDs) of outcome measurements are the same in both groups will be required in all cases, and the standard deviation would then be used for both intervention groups. Heterogeneity will be assessed using the 2.5No patients will be involved in this study.3 There is lacking of gold standard in diagnosis of LBP attributed to the sacroiliac joint. Moreover, some patients in the diagnosis of the disease and performed fusion surgery suffering consistent pain postoperatively and surgical complications cannot to be neglected. Although minimally invasive surgery has become a trend, there are still many problems, the high patient dissatisfaction rate and high incidence of complications indicated that the treatment of LBP attributed to the sacroiliac joint still needs more large sample with high-quality and well design studies to evaluate the effectiveness and safety. Patients with history of lumbar surgery, misdiagnosed, and personal factors may contribute to the effect of different treatment.The primary objective of this study was to determine whether sacroiliac joint fusion was superior than conservative treatment for patients with LBP in pain and function. The result of this study will illustrate whether there is significant difference between 2 treatments. Whereas acceptance of the SI joint as a potential source of low back pain has grown, confirming that it is the cause of a patient's pain remains a diagnostic challenge.,21 and radiofrequency ablation of sacral nerve roots also suggested a positive effect. However, return of pain 6 to 12 months following ablation is common.Although pain is generally regarded as originating in the lumbar spine, it has been estimated that in 15% to 30% of patients LBP originates from the sacroiliac joint. Conservative therapies for SIJ pain include medication, physiotherapy, and external orthotics such as pelvic belts. Intra-articular steroid injection has been shown to give short-term pain relief and additionally, pain relief confirms the SIJ as the pain generator. Common non-surgical treatments for LBP attributed to the sacroiliac joint include medication management, sacroiliac joint belts, physical therapy, manipulation, intra-articular steroid injections, etc. Periarticular steroids injection was suggested by some clinical trials as obvious short-term effectiveness was found and triangular titanium implants have been developed that are designed to confer the benefits of permanent SIJ stabilization recently.,23Failure of pain relief using conservative therapies may require surgical treatment. A variety of techniques and approaches have been described both open and minimal incision surgery. Sacroiliac joint fusion was first introduced in 1908. However, it was not routinely used because of collateral damage to the surrounding anatomic structures. Therefore, minimally invasive techniques with novel implants including hollow modular anchor screws,15,24 As for safety, it was reported that complications occurring in both the surgical and non-surgical groups were not remarkably different across treatment groups at month 6. In general, the overall complication rate from surgery was modest and typical of what would be expected from such a minimally invasive procedure. Complications that required surgical revision occurred in 3 subjects (3%) assigned to SIJF and 1 additional subject who underwent fusion surgery as a crossover procedure.A recently published trial has reported the improvements in pain, disability, and quality of life observed following surgery were significant given the long duration of pain and the high rate of failure to respond to prior non-surgical management. And the study showed marked improvement in all measures in the surgical group with only minor changes in the non-surgical group. And from a safety perspective, the incidence of postoperative outcomes in the surgery group was low, with a low rate of revision surgery.,26 The indirect costs arising from patients who cannot work because of chronic SIJ pain are even higher; to this end, analysis of data from this study suggests that SIJF may improve worker productivity in this population, indicating that minimally invasive SIJF may also be cost-effective from a societal perspective.Previous studies have demonstrated that direct medical expenses associated with non-surgical treatment were not inconsequential. However, varied conservative treatments and surgical methods were measured in previous studies. Moreover, there are lack of well design and long-term follow-up studies. A recently published prospective multicenter randomized controlled trial indicated surgical treatment was associated with large improvements in pain and disability, along with marked decreases in opioid use. It is necessary to further evaluate the effect of non-surgical treatments and sacroiliac joint fusion for patients with LBP attributed to sacroiliac joint pain. We aim to use enough studies to ensure adequate power for the meta-analysis. We expect to systematically assess whether surgical treatment can better release pain and improve functional outcome than non-surgical treatments. This study will include the largest amount of studies that systematically assess the efficacy and safety comparing non-surgical and non-surgical treatment for patients suffered from LBP attributed to sacroiliac joint pain. The results of this review may help to give available suggestions for clinical options.The effectiveness of non-surgical treatments and sacroiliac joint fusion for LBP attributed to sacroiliac joint remains debatable. Although previous systematic review has assessed the value of SIJF for running injuries, and concluded surgical intervention for LBP attributed to sacroiliac joint is beneficial in a subset of patients.We thank American Journal Experts for its linguistic assistance during the preparation of this manuscript.Conceptualization: Yingfeng Cai.Data curation: Haodong Liang.Investigation: Qining Qin, Tianzhao Tian, Baoxin Liu.Methodology: Qining Qin, Baoxin Liu.Resources: Min Shi.Software: Haodong Liang, Min Shi.Writing – original draft: Liye Chen.Writing – review & editing: Yingfeng Cai.