The primary outcome was the numerical rating scale (NRS) score at rest at 6 h postoperatively, and the non-inferiority limit was set to 1. Secondary outcomes were pain severity and incidence of nausea and vomiting for 48 h postoperatively. Mean differences (MD) in primary outcome between the N and F groups were 0.4  −0.5 to 1.3). The upper limit of 95% CI exceeded the non-inferiority limit. The N group showed higher pain scores than the NF group  in pairwise comparisons. No significant intergroup differences were observed in the cumulative dose of PCA usage and incidence of postoperative nausea and vomiting (PONV). In laparoscopic gynecological surgery, nefopam alone showed limited efficacy for postoperative pain control.Opioid-sparing effects of nefopam during patient-controlled analgesia (PCA) are well demonstrated. We hypothesized that postoperative pain control with an opioid-equivalent dose of nefopam as a single analgesic agent for PCA would not be inferior to fentanyl in laparoscopic gynecologic surgery. In total, 135 patients were randomly assigned to the N (nefopam 200 mg), NF (fentanyl 500 mcg + nefopam 100 mg), and F (fentanyl 1000 mcg) groups ( Nefopam is a non-opioid, non-steroidal centrally acting analgesic and is widely to control mild to moderate pain . It inhiPrevious studies have shown that nefopam, when used in combination with opioids, reduces opioid consumption and adverse effects while providing sufficient analgesia ,3,4. It Pain control after laparoscopic gynecological surgery is primarily based on patient-controlled analgesia (PCA) using opioids. Patients undergoing laparoscopic gynecological surgery show an increased incidence of postoperative nausea and vomiting (PONV) . In thesTo the best of our knowledge, no previous study has compared the analgesic effect of PCA using nefopam alone and fentanyl alone after laparoscopic gynecological surgery. We hypothesized that analgesia with nefopam alone was non-inferior to that with fentanyl alone. Additionally, we compared to combination group made with equivalent dose of each drugs. Thus, we investigated the most effective approach to control pain without adverse effects in gynecological patients undergoing laparoscopic surgery.This randomized, double-blind, non-inferiority study was conducted at the Chungnam National University Hospital, Republic of Korea, from October 2019 to June 2020. The study protocol was approved by the Chungnam National University Hospital Institutional Review Board (IRB CNUH 2019-05-032-004) and registered in the Clinical Research Information Service (KCT0004212). Written consent was obtained from participants prior to anesthesia according to the statement of the purpose and method of the study. This study was conducted in accordance with the Consolidated Standards of Reporting Trial (CONSORT) statement.Study participants were patients aged 20–70 years with American Society of Anesthesiologists (ASA) physical status I or II who were scheduled to undergo laparoscopic gynecological surgery. Exclusion criteria included ASA class higher than III, refusal to participate in this study, pregnancy or plans to become pregnant, hypersensitivity or allergies to fentanyl or nefopam, or preoperative analgesic treatment.®); F, fentanyl; NF, nefopam and fentanyl) at a ratio of 1:1:1 by using a computer-generated table of random numbers with 3, 6 block sizes. To conceal the allocation, the table was uploaded through REDCap (Research Electronic Data Capture) software in our hospital and was accessible only to the researcher who prepared the study drug. The assessor who performed group assignment was blinded to the patients and the physicians who assessed outcomes. Thus, a total of 135 patients were assigned to group N (nefopam), group NF (fentanyl and nefopam), or group F (fentanyl).Participants were randomly assigned to one of the three groups  was adjusted to 35–40 mmHg. Anesthesia was maintained with sevoflurane 1.5–2.5 vol% at 40% FiO2 using intravenous remifentanil (0.05–0.1 μg/kg/min) to achieve a mean arterial blood pressure and heart rate within 20% of the preinduction value.The patients received premedication with intramuscular (IM) injections of glycopyrrolate 0.2 mg/kg and midazolam 2 mg at 30 min before surgery. They also received general anesthesia with standardized monitoring. After pre-oxygenation for 3 min, general anesthesia was induced using propofol 2 mg/kg and remifentanil 1 µg/kg. After the administration of rocuronium 0.6 mg/kg, endotracheal intubation is performed when the train-of-four (TOF) count was 0. The cuff pressure of the tube was set to 20–30 mmHg, the tidal volume was adjusted to 6–8 mL/kg of the ideal body weight, and the target end tidal COThe direct equivalent dose of fentanyl and nefopam is unknown; hence, the conversion was calculated based on the equi-analgesic intravenous dose of morphine. According to a previous study, 20 mg of nefopam provides an analgesic effect equivalent to that of 6–12 mg of morphine [All PCA devices were set to administer a loading dose of 3 mL, basal dose of 1 mL/h, and bolus dose of 1 mL, with a lockout time of 15 min and a total allowable volume of 100 mL [Sufficient preoperative presentations of PCA devices were performed. PCA devices were applied after obtaining informed consent from patients after sufficiently explaining to them regarding how to use and what are the side effects before surgery. In addition, after surgeries, PA nurses went up to the ward for PCA management to interview patients personally and provided education related to the use of PCA and identified the effects and the side effects of PCA once again.The patients were observed in the post-anesthesia care unit (PACU) for an hour and then transferred to the ward, where they were continuously monitored for adverse effects, such as pain and PONV. Additional analgesics and antiemetics were administered at the discretion of the attending physician, and analgesics were generally added at the request of the patient or when the patient experienced pain with a numerical rating scale (NRS) score of 6 or higher.The quality of postoperative functional recovery was assessed using the validated Korean version of the Quality of Recovery-40 (QoR-40) questionnaire . This quThe brief pain inventory (BPI) was used to assess multiple dimensions of postoperative pain .The primary outcome was the postoperative pain score at 6 h after surgery, and the non-inferiority limit was set to 1. Secondary outcomes included pain (at rest and during coughing) and nausea severity at 1, 6, 24, and 48 h after surgery; cumulative dose of PCA usage; QoR-40 questionnaire score; brief pain inventory score; and patient satisfaction. Primary outcome was assessed by the intention-to-treat analysis, and per-protocol analysis was applied when serious deviations of the protocol were noted in questionnaire assessments at 1 h and 6 h after surgery. The pain score was assessed by the patient using the numeric rating scale , and nausea and vomiting were assessed by yes or no question to participants. In addition, the use of additional analgesics or the incidence of other adverse effects, such as chills, sweating, itchiness, dizziness, drowsiness, and tachycardia, was checked in the nursing record. The PCA device was collected, and the log records were stored in the research computer for evaluation of usage time, bolus frequency, and PCA discontinuation. Patient satisfaction is evaluated using a 5-point Likert scale .The sample size was calculated on the basis of the primary endpoint in accordance with the non-inferiority hypothesis. In this study, an NRS pain score difference of 1 was considered as the non-inferiority margin. Based on a previous study , a stand2 test or Fisher’s exact test, as appropriate, with the results expressed as number (%). For all calculations, two-tailed p < 0.05 was considered statistically significant. For pairwise comparisons of categorical variables, p-values were adjusted using Bonferroni correction. All statistical analyses were performed using R software version 4.0.0 .The normality of continuous data was assessed using the Shapiro–Wilk test. If normality was satisfied, then independent t-tests were used for two-group comparisons (primary outcome), and one-way analyses of variance were used for three-group comparisons, with the results expressed as mean ± standard deviation. If normality was not satisfied, then Kruskal–Wallis test was performed, and the results were expressed as median (interquartile range). Post-hoc pairwise comparisons for continuous variables were performed using Tukey’s honestly significant difference test or Dunn’s Kruskal–Wallis multiple comparisons, as appropriate. Categorical data were compared using the χA total of 137 patients were eligible for the study, two of whom refused to participate in the study. Thus, a total of 135 patients were enrolled in this study, with 45 patients randomized into each of the three groups. One patient in the N group underwent an open conversion due to a plan change during surgery, and one patient in the F group and two patients in the N group withdrew from the study before 6 h postoperatively. Thus, a total of 135 patients were included in the intention-to-treat (ITT) analysis, and 131 patients were included in the per-protocol (PP) analysis .The groups showed no significant differences in demographic and clinical characteristics .In the ITT analysis with a non-inferiority margin of 1, the mean difference (MD) and 95% confidence interval (CI) for NRS score at 6 h postoperatively between the F and N groups was 0.4 . The MD and 95% CI for the PP analysis was 0.3 . Both analysis demonstrated that the upper limit of 95% CI exceeded the non-inferiority margin of 1 .p = 0.02) and 24 h (p = 0.015) after surgery showed significant differences among the three groups. In pairwise comparison, the N group showed increased pain score compared with that of the NF group at 6 h  and 24 h  postoperatively. There was no significant difference in the dose of PCA usage over time among the three groups (The changes in NRS scores for the three groups over time are shown in e groups , and thee groups .Except for PONV, the frequency of adverse effects, such as dizziness and drowsiness, showed significant differences among the three groups . HoweverAlthough laparoscopic surgery is less invasive than open surgery, the procedure can cause severe pain . TherefoIn previous studies, nefopam, a non-opioid centrally acting analgesic, at a dose of 20 mg demonstrated the same effect as that of morphine at a dose of 6–12 mg . Yoon etThe NRS score was high in all groups in this study. To investigate the reason for this finding, the correlation between the NRS score and drug use through PCA was examined by exploratory analysis, but no clear correlation was observed. This finding suggests that patients did not actively use PCA, despite complaining of severe pain. In addition, adverse effects and PCA usage were also compared to rule out restrictions on PCA use due to adverse effects, but no distinct difference was observed. If there were no other restrictions on the use of PCA other than adverse effects, it seems possible that the patients who reported high NRS scores did not actively press the bolus because of lower PCA compliance. In order to compensate for this point, encouragement and education promoting the use of PCA for active pain control will be more needed.Opioids are known to induce PONV in 20–40% of patients ,18, whilThe incidence of drowsiness and dizziness is another point to be noted in this study. The rates of drowsiness and dizziness were reported to be the lowest in the N group, with significant differences from the rates in the F group for dizziness and the NF group for drowsiness. However, rather than focusing on the significance of the detailed results, it should be noted that even patients with an NRS score of 4 or higher complained of dizziness and drowsiness. In general, additional pain control is recommended for patients with an NRS pain score of 4 or higher , and whiThis study had several limitations. First, the loading and bolus dose of PCA were fixed in all patients, and better pain control would have been achieved if these doses were based on the patients’ body weight. Second, even though sufficient explanation and training were provided before and after surgery on how to use PCA, there were situations in which the patients did not use sufficient bolus doses; thus, pain control was not properly achieved. Third, because of the ethical issue, the study did not include a placebo group; thus, the true effect size of the analgesic agents were not acquirable within current study. Moreover, the exact equivalent dose of nefopam to fentanyl was not known; hence, the conversion analgesic dose of nefopam was applied. Thus, additional studies on the equivalent and safe dose with larger samples are required.In laparoscopic gynecological surgery, nefopam alone was not non-inferior to fentanyl alone as an analgesic agent for PCA for postoperative pain control. Additionally, PCA alone showed limited efficacy for postoperative analgesia in our study. Future studies combining additional analgesics as a multimodal approach for PCA are required.


Arteriovenous fistula puncture pain is a serious problem for patients undergoing dialysis and a good indication for topical anesthetics. No previous study has compared lidocaine/prilocaine cream (EMLA) with lidocaine tape for pain relief during arteriovenous fistula puncture in patients undergoing maintenance hemodialysis. To this end, we conducted a multicenter randomized crossover study including 66 patients  undergoing maintenance hemodialysis thrice/week. Subjects were assigned to Sequence EL  or Sequence LE . All subjects completed the study. At each puncture site, 1 g EMLA (25 mg lidocaine + 25 mg prilocaine) or one sheet of lidocaine tape (18 mg lidocaine) was applied 1 h or 30 min prior to arteriovenous fistula puncture, respectively. The primary endpoint was puncture pain relief, which was measured using a 100-mm visual analog scale. The secondary endpoints included quality of life, which was measured by SF-36, and safety. EMLA produced a 10.1-mm greater visual analog scale improvement than lidocaine tape (P = 0.00001). However, there was no statistically significant difference in the quality of life between the two groups, and no significant carryover/period effect was observed in any analysis. Further, no drug-related adverse events were observed. Taken together, these results suggest that EMLA cream is superior to lidocaine tape for the relief of arteriovenous fistula puncture pain in patients undergoing maintenance hemodialysis.Trial registration: University Hospital Medical Information Network Clinical Trials Registry (UMIN000027885). Japan is the second country with the largest number of patients receiving chronic maintenance dialysis worldwide, after the United States . The numIn Japan, lidocaine tape is typically applied at the puncture site to alleviate pain during AVF puncture. However, in many cases, it is difficult to reach a sufficient anesthesia due to low skin permeability . LidocaiThe present study was conducted across six Japanese hemodialysis facilities  from June 2017 to September 2018. We recruited patients aged ≥20 years who were undergoing chronic maintenance hemodialysis three times per week via forearm AVF (autologous blood vessel) for vascular access and who were able to provide written informed consent for participation. After signing the informed consent, the patient was included in the study. We excluded 1) patients with allergies to local anesthetics, 2) patients with a history of contact dermatitis in response to topical medication, 3) patients with severe liver disease [aspartate aminotransferase  or alanine aminotransferase (glutamic pyruvic transaminase) levels ≥100 IU/L in the last periodic blood sample], 4) patients with methemoglobinemia, 5) patients with porphyria, 6) pregnant or lactating female patients, 7) patients with skin abnormalities in or around the puncture site, 8) patients with severe sensory disorders, 9) patients who participated in another clinical trial within 3 months prior to study drug administration, and 10) patients scheduled to move to another dialysis facility during the study period.The present study was approved by the institutional review board of Kanazawa Medical University (No. M427), conducted in accordance with the ethical principles based on the Declaration of Helsinki, and registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000027885).In the present study, we conducted case registration using the central registration method and randomized assignment using a software cloud service . The randomization method used age, sex, baseline visual analog scale (VAS) of Period 0 (P0), and the presence or absence of diabetes as adjustment factors for stochastic minimization. Stochastic minimization was consistent with the method described by Pocock and Simon . The resThe coinvestigators at each facility confirmed that the intervention was performed in accordance with the protocol for all patients.The investigational drug, EMLA , contained 25 mg of lidocaine and 25 mg of prilocaine in 1 g. The control drug, lidocaine tape , contained 18 mg of lidocaine in one sheet (180 mg of plaster).AVF puncture requires the puncture of two sites in each hemodialysis session, one on the blood removal side and one on the blood return side. In the present study, the treatment intervention was performed using a topical anesthetic at two sites: one for blood removal prior to hemodialysis and one for the return of blood. According to the usage dose described in the package insert of each drug, EMLA (1 g) was applied using a dedicated fixation tape at each puncture site 1 h before the AVF puncture; lidocaine tape was applied at each site to be punctured 30 minutes before the AVF puncture. The diameter of the puncture needle was 16 gauge for all patients.The primary endpoint of the present study was AVF puncture pain and was measured using a 100-mm straight line VAS, with the left end indicating minimal pain, “no pain at all,” and the right end indicating maximum pain, “worst pain I have experienced.” All patients indicated the intensity of their pain by drawing a slash on the line based on their perceived pain by intuition. The distance from the left end of the written slash was taken as the evaluation score. Two VAS scores, one for the blood removal side puncture and one for the return side puncture, were measured for each session of dialysis and the mean was used as the VAS score of one dialysis session. To prevent recall bias, patients marked the VAS scale immediately after the AVF punctures, and both patients and investigators were completely isolated at the time of VAS measurement.The secondary endpoints included assessment of the quality of life (QOL) and safety evaluation. The QOL was evaluated using the following six subscales in the SF-36 Japanese version 2 scale, acute form –23 -controlled, 2-group 2-phase crossover study. Patients were randomly assigned to Sequence EL (SEL) and treated with EMLA followed by lidocaine tape or to Sequence LE (SLE) and treated with lidocaine tape first followed by EMLA .We measured the baseline VAS and SF-36 scores without a topical anesthetic at the end of the final hemodialysis of P0 and Wash-out period (PW); the measured value of P0 was defined as the baseline before the intervention of Period I (PI), and the measured value of PW was defined as the baseline before the intervention of Period II (PII).PI and PII are intervention periods. We calculated the mean VAS score in three sessions of hemodialysis of PI and PII; the calculated value of PI was defined as VAS, and the calculated value of PII was defined as VAS.Additionally, SF-36 score was measured at the end of the final hemodialysis of PI and PII; the measured value of PI was defined as SF-36 , and the measured value of PII was defined as SF-36.Using the above measurement items, the amount of improvement in VAS and SF-36 before and after each treatment intervention (⊿VAS and ⊿SF-36) necessary for the analysis of the crossover study were calculated by each sequence .Carryover effects were minimized by maintaining a wash-out period of approximately 1 week between the treatments in each Sequence . The US FDA Bioequivalence Test Guidelines  recommenIn the Japanese Phase I trials , 26, theAll statistical analyses were performed using Stat Flex Ver6 .2 in each case. The covariance between subjects for both treatments, the within-subject variance of VAS score improvement by EMLA, and the within-subject variance of VAS score improvement by lidocaine tape were estimated to be 100 mm2 each. An approximate 10-mm difference has been proposed as the minimum clinically significant difference (MCSD) in VAS score for acute pain in previous studies  + ⊿SF-36} with {⊿SF-36 + ⊿SF-36}, {⊿SF-36–⊿SF-36} / 2 with {⊿SF-36–⊿SF-36 } / 2, and {⊿SF-36–⊿SF-36} / 2 with {⊿SF-36–⊿SF-36 } / 2 between Sequence groups using unpaired t-tests.The recruitment of participants ended when we were able to secure the number of patients needed for analysis (at least 32 patients per Sequence group). In total, 182 patients were screened for eligibility, 66 of whom met the eligibility criteria and were randomized between June 2017 and September 2018 . All ranThe baseline characteristics of the patients in the present study are shown in The results for the reduction in pain are shown in The results for the QOL assessment are shown in No adverse events due to either drug were observed.The results of the present study demonstrate that EMLA significantly reduces AVF puncture pain compared to lidocaine tape. However, there is no definite consensus concerning MCSD of VAS pain score; thus, it is difficult to definitively conclude that the observed 10.1-mm (95% CI: 5.9–14.2 mm) difference in VAS score improvement between the two treatments in the present study is clinically significant.The MCSDs proposed by four major studies on MCSD using VAS pain scores are 9 mm (95% CI: 6–13 mm) , 13 mm . Fifth, as the included patients were patients with renal disease, we cannot rule out the possibility that the SF-36 scale, a comprehensive QOL scale, did not sufficiently allow for the extraction of QOL changes after the therapeutic intervention. Generally, comprehensive QOL scales measure disease symptom characteristics; however, they are less informative and often less sensitive to changes in health conditions over time than disease-specific QOL scales. Therefore, additional investigations are necessary using renal disease-specific QOL scales, such as the KDQOL-SF scale .The results of the present RCT point to the superiority of EMLA cream to lidocaine tape in terms of AVF puncture pain alleviation in patients undergoing chronic maintenance dialysis.S1 FigThere were no significant differences in the amount of improvement in VAS by the administration of both drugs among the 6 dialysis facilities .(TIF)Click here for additional data file.S1 Table(DOC)Click here for additional data file.S2 Table(DOC)Click here for additional data file.S1 File(DOC)Click here for additional data file.S2 File(DOC)Click here for additional data file.S3 File(DOCX)Click here for additional data file.


Atherosclerotic blockages in the leg arteries, cause leg pain with ambulation , impair gait and substantially reduce the walking ability of patients with peripheral artery disease (PAD). Ankle-foot orthoses are being developed and applied so patients can walk more and with less pain. Roll-over shape (ROS) is a potential design objective for such assistive devices. In the proposed work, we study roll-over characteristics in patients with PAD and healthy older subjects. Gait data of ten healthy older individuals (Age: 72.8 ± 5.5 years) and twenty patients with PAD (Age: 64.1 ± 6.6 years) were collected at self-selected walking speed. In patients with PAD, gait data were collected before the onset of pain and after claudication pain was induced. To generate ROS, the center of pressure data was transformed to the shank-based coordinate system and circular arcs were fit using an optimization program in MATLAB. Independent t-tests with Bonferroni corrections were used to separately compare roll-over radius differences (p<0.05) between healthy older to both walking conditions in patients with PAD. The mean roll-over radius was not significantly different between healthy older vs PAD pain-free (p=0.468) or PAD pain-induced (p=0.289) walking conditions. Our results indicate invariance of ROS radius in patients with PAD, which is consistent with previous literature showing general invariance of ROS in healthy young individuals. Previous biomechanical studies show gait kinematics and kinetics are more affected by PAD than by age. Future studies should focus on the potential adaptive mechanisms in patients with PAD achieving invariant ROS.


The short-term and long-term consequences of the most frequent painful procedures performed in the ICU are unclear. This study aimed to identify the risk factors associated with pain-related discomfort perceived by critically ill patients during the whole ICU stay as self-reported by patients at the end of their ICU stay.The study involved 34 ICUs. Adult patients who survived an ICU stay of 3 calendar days or more were eligible for inclusion. Discomforts, including the pain-related discomfort, were assessed using the French 18-item questionnaire on discomfort in ICU patients, the “Inconforts des Patients de REAnimation” (IPREA). Patients scored each item from 0  to 10 . Associations between patient characteristics at ICU admission, life support therapies and main potentially painful procedures performed during the ICU stay and pain-related discomfort scores assessed at the end of the ICU stay were analyzed.n = 2130) were included. The median pain-related discomfort score was 3 (IQR 0–5). From the univariate analysis, pain-related discomfort scores were negatively correlated with age and positively correlated with ICU stay duration; surgical patients reported significant higher pain-related discomfort scores than medical patients; chest drain insertion, chest drain removal, use of bladder catheter, central venous catheter (CVC) insertion, complex dressing change, and intra-hospital transport were associated with pain-related discomfort scores. From the multivariate analyses using generalized estimating equations models, only age, chest drain removal, use of a bladder catheter, CVC insertion, and intra-hospital transport were the main risk factors associated with pain-related discomfort scores.Patients with complete IPREA questionnaires  than patients who did not experience these events. This study may pave the way for further targeted studies aiming at investigating a causal link between these common procedures in the ICU and adult critically ill patients’ perceptions of their ICU stay regarding recalled pain.Trial Registration: Clinicaltrials.gov Identifier NCT02442934, retrospectively registered on May 13, 2015 Critically ill patients in intensive care units (ICUs) are exposed to stressful conditions and experience discomfort from multiple sources, such as the environment or the treatment being provided, which depends on the organization  and the patient’s health status –6. AmongSeveral hypotheses may explain why the program was ineffective for reducing pain scores. First, previously implemented health policies for pain management may have previously been be prioritized over managing other discomforts. Second, measures to reduce pain reported by critically ill patients may require more time to implement, because of complexity of pain management in adult critically ill patients due to highly individual pain patterns, and unique features in the ICU such as impaired communication and altered mental status, potentially painful procedures and use of invasive devices . MoreoveBetter identification of procedures that cause the pain reported at the end of ICU stays would enable developing more effective strategies against pain in the ICU. Frequent ICU-associated procedures that can cause pain include arterial blood gas sampling and tracheal suctioning in mechanically ventilated patients, which lead to more frequent arterial catheter insertions and greater care for tracheal suctioning , 11. PatThis study was an ancillary study of the IPREA3 study , a multiThe effectiveness of the program was assessed from the French questionnaire on ICU-related self-perceived discomforts Table  15, 16], 1615, 1The study included 34 centers, all in France: medical, surgical, and mixed medical–surgical ICUs at academic tertiary care hospitals or community hospitals.All patients aged 18 years or older who survived an ICU stay of 3 calendar days or more were eligible for inclusion. We excluded patients who died during the ICU stay, patients under trusteeship, patients whose diminished mental capacity (as assessed by the bedside ICU nurse at her discretion) prevented the administration of the IPREA questionnaire, patients who did not understand French sufficiently to answer the questions, and patients transferred to another ICU while mechanically ventilated. During the IPREA3 study, all 34 ICUs enrolled patients during three 1-month periods (at baseline and 6- and 12-month post-baseline), respectively, in October 2014, April 2015, and October 2015. The patient sample for this study comprised all patients included in the IPREA3 study during these three periods, regardless of the group, control or interventional, resulting from the randomization of the ICUs.“Have you had more pain than usual for you? For example from needles, catheters, tubes, being turned or washed”. As each of the discomfort items, the pain-related discomfort was scored from 0  to 10  [The pain-related discomfort score, used as the dependent variable, is derived from the IPREA questionnaire and corresponded to item 9 and the following question: comfort) . Each pacomfort) . The ranRegulatory monitoring was performed in accordance with the French law requiring the approval of the French Ethics Committee . All records and patient identities remained confidential in accordance with the regulations of the French National Committee of Informatics and Liberties  and the French Consultative Committee for data processing in health research . Consent was obtained from all participants.Demographic and clinical characteristics were collected from patients at admission or during their first day in the ICU, including age, sex, first 24-h Simplified Acute Physiology Score (SAPS II), scores exploring prior health status , reasonP value of ≤ 0.10, and with potential interest for adjustment (group and inclusion month). The center was used as within-subject effect. The final models produced beta coefficients and standard errors. Independent variables with higher beta coefficients are those with greater relative effect on pain-related discomfort score. Statistical analyses were performed in accordance with the statistical analysis plan using SPSS software . All tests were two-sided. P < 0.05 was considered statistically significant.Sample characteristics were described using numbers and percentages, mean and standard deviation (SD), and median and interquartile range (IQR). Pain-related discomfort scores were compared between subgroups , seven were medical ICUs, and 15 were mixed  ICUs. Twenty-two of the 34 ICUs were located at tertiary care hospitals; 12 were at community hospitals. During the three 1-month enrollment periods of the IPREA3 study, 2130 patients were included; 634, 758, and 738 were included in November 2014, April 2015, and November 2015, respectively. Table The median pain-related discomfort score was 3 IQR 0–5). From the univariate analysis, age was negatively correlated with pain-related discomfort score and positively correlated with the ICU stay duration. Medical patients reported less pain-related discomfort than did surgical patients, and patients treated with MV during their stay reported greater pain-related discomfort than did other patients Table . Patient. From thWe used a large sample of 2130 French ICU patients treated at academic tertiary care and community hospitals to determine factors modulating pain-related discomfort during ICU stays. All the patients were previously included in the IPREA3 study, whose primary endpoint was the overall discomfort score derived from the French 16-item IPREA questionnaire. This first version of the IPREA questionnaire was validated  through a process based on international guidelines using a large sample of critically ill patients hospitalized in different ICU types  at different institutions  . HoweverTo our knowledge, this was the first study exploring the weight of a large panel of potentially pain- or discomfort-inducing procedures or treatments used to treat critically ill patients.The four procedures undergone by patients during the ICU stay that were associated with greater pain-related discomfort were chest drain removal, bladder catheter use, CVC insertion, and intra-hospital transport.Chest drain-related procedures  seemed to more strongly affect pain perception during ICU stays than did most other procedures considered invasive or discomfort-inducing . It is also important to note that no specific mandatory measure to reduce pain associated with either chest drain insertion or chest drain removal has been implemented during the study period in the participating ICUs. Previous studies that found chest drain-related procedures to be painful , 22 ofteIntra-hospital transport during ICU stays was also associated with self-reported pain-related discomfort. Intra-hospital transport of critically ill patients is a well-known risk factor for unexpected adverse events and complications, such as pulmonary complications, hemodynamic complications, infection, interruption of critical drugs, etc. –31, but As previously reported, younger people were also independently associated with higher self-reported pain-related discomfort scores compared with those of older people .Sex, patient type , prior health status, and ICU stay duration were not independently associated with pain scores.We used a comprehensive approach because the patients interviewed at the end of the ICU stay were not specifically informed of precisely what happened to them during their ICU stay before the discomfort assessment. Moreover, the interviewed patients were not asked if they remembered having undergone a particular procedure but only to score each of the 18 discomfort items. For example, patients may be unaware of having a chest drain inserted or withdrawn, a bladder catheter, a CVC insertion or being transported outside the ICU at any time during their stay. The healthcare team did not control or influence patients’ memories, thus reducing any suggestive bias. Moreover, the patients were not interviewed immediately after the potentially painful event as is the case in most studies aiming to assess or prevent procedural pain .Our study had several limitations. First, even if the bedside nurse asked patients to rate the severity of each discomfort for the entire stay in the ICU, patients may have reported discomforts, including pain, experienced only during the final part of the ICU stay if they could not remember what they experienced at the beginning of their ICU stay. Thus, events occurring during the last days of their ICU stay, such as chest drain removal after the clinical situation improved, may have had more influence on the pain-related discomfort score than did events that occurred at the beginning of their ICU stay, such as arterial catheter insertion or bronchoscopies. Future studies should record and analyze the time course of all procedures and life support therapies undertaken during the ICU stay. Second, all discomfort item scores, particularly the pain-related discomfort scores, were obtained with the help of a nonblinded bedside nurse (or assistant nurse), which could introduce bias. We accepted that conducting a pragmatic trial to explore potential benefits in the ICU with such an easily reproducible program would require participation from bedside nurses. Third, we could not assess the link between potential painful or discomfort-inducing procedures or life support therapies and the overall ICU-induced pain burden experienced in nonsurvivors during their ICU stay because ICU nurses administered the IPREA only to survivors on the day of discharge. This limitation also applied to patients who could not be questioned such as those with diminished mental capacity, those with language barriers, those who were transferred to another ICU while mechanically ventilated, or those who were urgently discharged. The issue of representativeness of this sample of ICU survivors among the general population of critically ill patients remains uncertain. Fourth, we could not analyze the impact of analgesic or sedative drug dosages or nonpharmacological therapies used during the procedures or the implementation of life support therapies. Fifth, we did not record details concerning chest drain-related procedures , 36. DraHowever, despite these limitations and without being able to affirm the causal link between these events and the painful memorization of the ICU stay at discharge, these first results showing an association between the occurrence of such potentially painful procedures and the pain-related discomfort scoreshould encourage us to properly assess the balance of the benefits and risks of these common procedures such as maintenance of a bladder catheter, intra-hospital transport for an iterative CT scan, CVC insertion or thoracic drainage.Our study showed that adult ICU patients who underwent chest drain removal, bladder catheter, CVC insertion, and intra-hospital transport during their ICU stay reported higher pain-related discomfort scores (regarding the entire ICU stay and assessed at the end of the ICU stay) than patients who did not experience these events. This study may pave the way for further targeted studies aiming at investigating a causal link between these common procedures undergone by adult critically ill patients during their ICU stay and recalled pain at ICU discharge.


Different profiles of pain progression have been reported in patients with knee osteoarthritis (OA), but the determinants of this heterogeneity are still to be sought. The aim of this systematic review was to analyze all studies providing information about knee OA pain trajectories to delineate, according to patients’ characteristics, an evidence-based evolution pattern of this disabling disease, which is key for a more personalized and effective management of knee OA. A literature search was performed on PubMed, Web of Science, Cochrane Library, and grey literature databases. The Cochrane Collaboration’s tool for assessing risk of bias was used, and a best-evidence synthesis was performed to define the predictors of pain evolution. Seven articles on 7747 patients affected by knee OA (mainly early/moderate) were included. Daily knee OA pain trajectories were unstable in almost half of the patients. In the mid-term, knee OA had a steady pain trajectory in 85% of the patients, 8% experienced pain reduction, while 7% experienced pain worsening. Low education, comorbidities, and depression were patient-related predictors of severe/worsening knee OA pain. Conversely, age, alcohol, smoking, pain coping strategies, and medications were unrelated to pain evolution. Conflicting/no evidence was found for all joint-related factors, such as baseline radiographic severity. Knee osteoarthritis (OA) is, according to the World Health Organization (WHO), the eleventh leading cause of long-term disability worldwide . Knee OAThus, recent research efforts have been made to better characterize the different types of pain in patients with knee OA. In particular, different profiles of pain progression have been reported, but the determinants of this heterogeneity are still to be sought . A betteThe aim of this systematic review was to analyze all studies providing information about pain trajectories in knee OA patients, in order to delineate the evolution patterns of this disabling disease. Furthermore, a best evidence synthesis was performed to provide a characterization of patients with different pain progression, in order to identify the predictors of specific pain trajectories in patients with knee OA.Methods of the analysis and inclusion criteria were specified in advance and documented in a protocol which was preregistered on PROSPERO (CRD42019119065). As compared to the previously published protocol of this systematic review, which initially also considered the trajectory of pain after total knee arthroplasty (TKA), this systematic review was then focused only on pain in patients with knee OA.The eligibility criteria are reported in A systematic literature search was performed on 25 June 2020 on PubMed, Web of Science, Cochrane library, and grey literature databases .The search was performed using the string: (“pain trajectories” OR “pain trajectory” OR “pain curve” OR “pain curves”). No limits were used.At first, extracted records were screened for duplicates’ removal and subsequently selected applying the eligibility criteria previously reported . A firstRelevant information from eligible articles was independently collected by two authors (D.P. and L.A.), using a previously structured table according to Cochrane .Information on study methodology concerned: level of evidence, study design, pain score, method of pain trajectories assessment, inclusion/exclusion criteria, and origin of data. Data on the characteristics of the study population were also extracted: number of patients, follow-up, sex, age, race, body mass index (BMI), level of instruction, psychological profile , comorbidities, activity level, symptoms’ duration, functional scores, characteristics of pain and patient’s pain experience (pain coping strategies), perceived health status, use of medications, surgery rate, and radiological severity of knee OA.The Cochrane Collaboration’s tool for assessing the risk of bias of prognostic studies was used. This tool consisted of 8 questions: 2 questions about selection bias, 4 questions about information bias, and 2 questions about confounders. To be considered as having a low risk of bias, a study should satisfy at least 6 out of 8 criteria and at least 1 criterion for each risk of bias category . Studies with a moderate risk of bias satisfy at least 5 out of 8 criteria and at least 1 criterion in 2 of the risk of bias categories. All other cases were considered as high risk of bias. The final decision was the result of the consensus between two of the authors (D.P. and G.D.L.F.).The distribution of patients in the different pain trajectories was computed and expressed as the proportion of the number of patients with a specific pain trajectory over the total number of patients. The range of proportions of patients belonging to that specific pain trajectory reported in the studies that identified such pain trajectory was also shown.2 metric were used to quantify heterogeneity. The statistical analysis was performed with the packages meta (v4.9-7) and metafor (v2.1-0) in R Studio (v1.2.5019). However, the high heterogeneity of the retrieved data limited the statistical strength of the analysis and could not be resolved with the commonly accepted methods due to the low number of included studies. Thus, in order to avoid a misleading interpretation of the data, results were reported only as proportions, as explained in A meta-analysis of proportions was attempted to quantify the prevalence of the different pain trajectories in patients with knee OA, as planned. Both fixed and random effects analyses were used, but the results of the random effect were preferred because of the heterogeneity of the included studies. Cochran’s Q statistic and IFinally, a best evidence synthesis was performed , followiThe initial search resulted in 454 titles from the included databases; among these, 191 were removed because they were duplicate references. Of the remaining 263, 249 were excluded according to the eligibility criteria, being studies without information on pain evolution or without discrete data for patients with knee OA, studies on patients treated with TKA or other surgical and non-surgical treatments, expert opinions (level of evidence V), reviews, systematic reviews and meta-analyses, or preclinical or ex vivo studies. Thus, 14 studies were assessed for eligibility, and out of these, seven full-text articles were excluded: two studies without discrete data on knee OA, two studies on patients with prevalent patello-femoral OA, one study on pain trajectories after TKA, one study on patients undergoing therapeutic exercise, and one study with unclear OA diagnosis. Thus, a total of seven articles, published from 2014 to 2018, were included in the systematic review . Data onThese studies included 7747 patients, 7155 of which were examined until the last follow-up. Four studies included only one knee per patient (the most painful one), whereas three studies included both knees. Six studies had a follow-up of more than 5 years (range 5–8 years) ,28,29,302 97.6%). In particular, a constant minimal pain  was detected in 43.5% of the patients , constant mild pain  was detected in 27.6% of the patients , constant moderate pain  was detected in 11.7% of the patients , and a constant severe pain  was detected in 2.6% of the patients .In 5 out of 6 studies with a mid/long-term follow-up, the majority of patients reported a constant level of pain over the years. Among the 6 included studies, the proportion of patients included in a trajectory with constant pain was 85.4% . In particular, no increasing trajectory in patients with initial minimal pain was reported in any of the included studies, an increasing mild pain was reported by 2.3%  of the patients, an increasing moderate pain was reported by 2.2%  of the patients, and an increasing severe pain was reported by 2.2%  of the patients.The mean percentage of patients included in a trajectory with an increasing pain was 6.7% . In particular, patients with decreasing mild pain were 3.4% , patients with decreasing moderate pain were 3.9% , patients with decreasing severe pain were 0.6% , whereas none of the studies detected a group of patients with decreasing minimal pain.The mean percentage of patients included in a trajectory with a decreasing pain was 7.9%  characterized 59.5% of the patients, whereas an unstable pain trajectory (pain peaks during more than 50% of the month) characterized 40.5% of the patients. None of the patients reported a “stable with few peaks” pain trajectory (pain peaks during 25–50% of the month).A meta-analysis of proportions was attempted to quantify the prevalence of the different pain trajectories in patients with knee OA. However, since the paucity and the high heterogeneity of the retrieved data limited the statistical strength and the relevance of the results of the meta-analysis, results were reported only as proportions, as explained in The risk of bias was judged to be low in 2 of the included studies, moderate in 4, and high in 1. Selection bias was almost surely absent in 3 of the included studies, which clearly defined their inclusion criteria that were representative of the general knee OA population, and reported baseline detailed characteristics of the included patients. Some degree of selection bias, the risk of selective loss to follow-up, and the possible presence of confounders in their analysis entailed a moderate to high risk of bias in the other included studies. There was a 96% agreement between the two authors involved in the evaluation of the risk of bias.Patient-related factors identified as predictors of a severe or progressing pain trajectory, with a strong level of evidence, were low education level and presence of comorbidities . In partRegarding joint-related factors, the current literature did not present predictors or related factors that could be identified with a strong or moderate level of evidence . ConflicOnly one study was focused on short-term pain trajectories, thus providing only limited evidence. A long-lasting disease (>5 years), a higher incidence of flare-ups, and a long-lasting morning stiffness (>15 min) were related to an unstable pain trajectory. No correlations were found for age, gender, BMI, professional activities, anxiety, depression, pain intensity, joint stiffness, knee function, and neuropathic characteristics of pain.The main finding of this systematic review is that approximately 85% of the patients with early/moderate knee OA had a constant level of pain over time during a mid-term follow-up, whereas 7% of the patients experienced a worsening pain trajectory and 8% of them reported a reduction of pain.The identification of different pain trajectories supports the hypothesis that several knee OA phenotypes exist , with a A best evidence synthesis was performed in order to characterize patients who have a higher risk of presenting a severe or worsening pain trajectory. Interestingly, only patient-related factors such as low education level, high number of comorbidities, and depression were identified, with a strong to moderate level of evidence, as predictors of a worse pain trajectory. Joint-related factors, such as baseline function and radiographic severity, were reported with conflicting evidence, underlying the unclear relation between bone deformities and symptoms ,41. TherIn this light, this systematic review underlined the usefulness of methods that allow to analyze information about inter-individual differences in the evolution of symptoms over time. The heterogeneous pain progression patterns identified by this study suggest that describing the entire population of knee OA using a single trajectory estimate oversimplifies the complex progression patterns of this disease. Latent growth modeling approaches, such as latent class growth analysis and growth mixture modeling, have been extensively used in other fields for identifying homogeneous subpopulations within the larger heterogeneous population and for the identification of meaningful groups or classes of individuals ,50,51. TThe literature analysis showed an overall focus on the mid-term OA progression, with only one study specifically focusing on the short-term assessment. This study allowed to underline another important aspect. When data were collected on a daily basis, approximately 40% of the patients had an unstable pain trajectory. These results state that, even though in the vast majority of the cases knee OA-related pain is constant in the mid-term follow-up, patients frequently experience unstable pain on a daily basis with frequent severe knee symptoms. In this light, a more frequent assessment method could be extremely important to collect the whole pain experience . In factOverall, the limitations of this study include the low number of published articles on pain trajectories in knee OA. This hindered the possibility to analyze some potential predictors of pain evolution  and led to conflicting findings for other factors. In addition, the multifactorial and subjective nature of pain in OA has to be acknowledged, together with the impossibility of the included studies to take into account these aspects . New trials should analyze these factors in order to provide a better characterization of the different pain trajectories. Moreover, the data of the included trials were from four large databases that enrolled a relatively small number of patients in developed countries  and thus could only be representative of a part of the knee OA population. Unfortunately, a strong meta-analytic quantitative synthesis was not possible due to the high heterogeneity and the paucity of the included data. Thus, data on the prevalence of the different pain trajectories could be reported only as proportions. Finally, the current review on pain trajectories did not allow to investigate specific threshold levels, which would necessitate dedicated analyses to take into consideration the faceted nature and inter-cultural variability of pain and the impact of this symptom on patient life- and health-related decisions.Despite the aforementioned limitations, this study allowed to highlight some important features of pain evolution in patients with early/moderate knee OA. Approximately 85% of the subjects had a constant level of pain during a mid-term follow-up, whereas 7% of the patients experienced worsening pain and 8% of them reported a reduction of pain. Among the studied predictors of pain evolution, only patient-related factors such as low education level, high number of comorbidities, and depression were found, with a high to moderate level of evidence, to be predictors of pain evolution in knee OA. No correlation was documented with joint-related factors. This is likely to be related to the limited sensitivity of current methods to characterize OA joints, with broad classifications affected by low accuracy. Future studies should focus on a better characterization of OA patients, both in terms of anatomic features, as well as biological and psycho-social characteristics, in order to identify other key predictors for the evolution of pain trajectories and better manage patients with early/moderate knee OA.


Chronic back pain affects 20% of the adult population in the United States and is a significant source of disability and healthcare expenditure. One of the most common causes of chronic back pain is spondylosis. These changes result from age-related degeneration of the lumbar spine. As a result of this degeneration, spondylolisthesis can develop. Spondylolysis is a fracture of the pars interarticularis. It affects younger patients and is more prevalent in adolescents and elite athletes. It can be a debilitating condition that may force athletes into retirement as well as impair them with chronic pain and disability. Traditional treatment options include conservative management such as medications, rest, physical therapy, and rehabilitation. Surgery is reserved for patients who do not respond to conservative measures. Here we present the case of a 39-year-old mixed martial arts fighter with bilateral L4 pars interarticularis fractures and chronic low back pain. After failing conservative treatment options, this patient finally obtained significant relief with steroid injections at the level of the defect. The patient continues to do well with occasional injections and is able to maintain his mixed martial arts career. This case report provides evidence that injection therapy is a feasible alternative to surgery in patients who fail conservative therapy. Spondylolysis refers to a posterior fracture at the pars interarticularis. It affects 3%-10% of the population and can be a cause of low back pain (LBP). Etiology may include repetitive microtrauma of the spine as well as acute traumatic injuries. Spondylolisthesis occurs when there is translation of the vertebral bodies and can also occur with these injuries. Continued degeneration at the vertebral levels can lead to facet instability, neuroforaminal stenosis, and pressure on exiting nerve roots . These iConservative therapy is effective in 84%-95% of patients and includes rest, discontinuation of high-impact sports, nonsteroidal anti-inflammatory drugs (NSAIDs), bracing, and physical therapy (PT) . SurgeryThe patient was a 39-year-old male who was an active MMA fighter. He had been practicing MMA since childhood and reported severe LBP for several years. He presented to the pain clinic endorsing constant LBP that occasionally radiated to the left lateral thigh. He also endorsed moderate buttock pain. The pain was stabbing in nature and worse during MMA training activities and rotational movements. The pain was rated as 9/10 intensity on a numerical rating scale (NRS). The pain drastically interfered with his ability to continue MMA activities. He underwent X-ray imaging which revealed no obvious defects. However, a CT scan of the lumbar spine demonstrated bilateral L4 pars interarticularis fractures (Figure The patient had tried medication management with ibuprofen and acetaminophen with minimal relief. He also completed an extensive course of PT without any improvement. The patient was not interested in surgical options and was offered interventional pain injections targeting the defects. The patient was counseled regarding the risks and benefits of these injections and consented to proceed with the procedure.He underwent bilateral injections at the L4 level targeting the pars interarticularis fractures. The solution used for the injections included 0.5 mL of 1% lidocaine mixed with 20 mg methylprednisolone per side. The blocks were performed under fluoroscopy without complications Figures .The patient reported significant improvement of his pain shortly after the injections and noted 0/10 pain on NRS that lasted for six months. The patient underwent repeat injections at the same level after six months and again obtained significant relief. He was also able to participate fully in MMA training activities. The patient continues to get occasional steroid injections with excellent results. He has also been able to continue his MMA career. The patient has been followed for three years with successful injection treatments, no complications, and complete pain relief.LBP causes significant morbidity and carries an estimated healthcare spending cost of $67.5 billion to $94.1 billion annually in the United States . UnfortuSpondylolysis is unique in that it more commonly occurs in younger patients and elite athletes. Patients who fail to respond to conservative treatment may be forced into a dilemma of considering surgery or discontinuing high-impact activities. Injection therapy has been used extensively for chronic pain conditions and has an established safety profile. These interventional pain procedures offer an additional option to patients suffering from spondylolysis who fail to respond to conservative therapy but are not interested in surgical management. Physicians should consider the risks and benefits of interventional pain injections for patients with spondylolysis before referral for surgical management. Additionally, future clinical trials should be considered to further investigate the effectiveness of this treatment for bilateral pars interarticularis fractures.


The Analgesia Nociception Index (ANI) is a new method of identifying nociception-analgesia balance. In this study, we investigate the correlation between the ANI and numeric rating scale (NRS) values immediately before and after extubation. The NRS values were recorded in the postanesthesia care unit, in a group of patients who underwent laparoscopic cholecystectomy, with the aim of evaluating the potential use of ANI values in the prediction of postoperative pain levels.The ANI and NRS values, heartbeat rate (HR), systolic and diastolic arterial pressure (SAP/DAP), and oxygen saturation (SpO2) values of the patients were recorded into three groups based on the initial NRS values recorded in the postanesthesia care unit . Patients whose ANI values were lower than 47, considered as the pain threshold, and the groups to which these patients belonged were also recorded. Statistically significant increases were noted in HR, SAP, and DAP after extubation, while there was no significant change in ANI values. A weak correlation was identified between the ANI and NRS values of all patient groups. We failed to identify a correlation between ANI and NRS values before and after extubation. Previous studies suggested that the ANI provides more valuable information in anesthetized patients, whereas our findings show that it is ineffective in the prediction of potential postoperative pain. A pain-free life is one of the fundamental human rights, and controlling pain, particularly in the postoperative period, is of vital importance for patient comfort and the following recovery period. Approximately 20%–40% of patients suffer from severe postoperative pain that begins immediately after surgery [1]. Such severe pain occurs not only after long-lasting and complicated surgical operations, but may also be seen after various minor or moderate surgeries, such as tonsillectomy, hemorrhoidectomy, laparoscopic cholecystectomy, and appendectomy [1]. The optimum method for assessing pain severity in postanesthesia care units (PACUs), where patients are monitored immediately after an operation, is still a matter of debate. In conscious and cooperative patients who have come out of anesthesia, commonly used assessment tools include visual analog scale (VAS/0–100), verbal rating scales (VRS/1–5), and numerical rating scales (NRS/0–10) . While VAS ≤ 30 and NRS ≤ 3 are considered as evidence of analgesia or tolerable pain, scores of VAS ≥ 70 and NRS ≥ 7 are considered to indicate severe pain [4]. There are, however, large groups of patients who are unable to communicate , who face a risk of receiving insufficient pain treatment despite all measures. Methods such as skin conductivity and pupillary reflex measurements have been tested in these patients to detect levels of pain [5–7]. In recent years, the Analgesia Nociception Index , which assesses the nociception-analgesia balance by measuring the parasympathetic system tonus, has emerged as a new method for the numerical and objective assessment of the sufficiency of perioperative analgesia . The ANI measures the duration between two R waves within heart rate variations by filtering based on the variations in respiratory cycles, and it provides a numeric measure of parasympathetic tonus that varies between (p∑) 0 and 100. Based on this index, values of 50 and above indicate sufficient anesthesia, 30–50 indicate moderate pain, and values lower than 30 indicate severe pain [9–12]. Over the last few years, researchers have reported preliminary findings suggesting that the severity of potential postoperative pain can be predicted objectively, irrespective of the physician’s subjective assessment, based on ANI values recorded immediately after surgery [13], and these data may even allow the prediction of the severity of early postoperative pain . In the present study, we investigate whether or not a correlation exists between the ANI values recorded at the completion of an operation and immediately before and after extubation and the NRS values recorded in the PACU in a group of patients who underwent laparoscopic cholecystectomy, with the goal of evaluating the potential use of ANI values for the prediction of postoperative pain levels. We gained approval for the study from the ethics committee (İstanbul Arel University/69396709-050.01.01) to study with patients who provided informed consent for the use of all their medical data in medical research, as long as their identity was kept confidential. Thirty-six patients who underwent laparoscopic cholecystectomies under sevoflurane/remifentanil anesthesia at our hospital between 1 May and 15 August 2018, who were monitored using the ANI and who were assessed for postoperative pain based on the NRS in the PACU, were included in the study. The study exclusion criteria included patients with ASA score other than ASA I–II, age below 18 years or above 75 years, apparent cardiac disorders  and marked preoperative pain.Additionally, we excluded patients with an autonomous nervous system abnormality , chronic hypertensive patients taking beta-blockers, patients with a diagnosis of diabetes mellitus, and patients who had been given ketamine, atropine, beta-blockers, or other vasoactive substances at any time during surgery. In order to minimize potential differences in pain levels based on the surgical technique used, all surgical operations were performed by the same surgical team when feasible. The routine general anesthesia protocol of our clinics for intraabdominal laparoscopic surgeries was followed for all patients who agreed to take part in the study. The monitoring procedures included a 5-electrode 2-channel ECG, oxygen saturation (SpO2), noninvasive arterial blood pressure, end-tidal carbon dioxide (ETCO2), body temperature monitoring, and the recording of the ANI using an ANI monitor . As the only difference from the routine anesthesia protocol, spontaneous resolution of neuromuscular blocker activity was awaited or a specific antidote (sugammadex) was administered to the patients in the study group during the postoperative period. In order to conclude that neuromuscular activity was resolved spontaneously, we expected to observe that the patient had sufficient respiration, coughing, and swallowing of secretions. Additionally, the patient had to have eyes open, keeping the head lifted for more than 5 s, keeping the mouth firmly shut, and positively reacting to the tongue test. Sugammadex was used based on the decision of an anesthesiologist with at least 10 years of experience to eliminate risks of residual muscle weakness, which is a major risk for postoperative respiratory complications. Patients who were given an acetylcholinesterase inhibitor and/or anticholinergic due to clinical need were excluded from the study. As is the case for all patients scheduled for surgery in our clinics, the patients in study group were informed of the postoperative use of the NRS and were told how the postoperative pain evaluation would be performed during preoperative visits, as per the routine clinical protocol. Premedication was performed with midazolam (0.03 mg/kg) and fentanyl (1 mgr/kg) in the operating room. Propofol (1.5 mg/kg) was used for anesthesia induction, while orotracheal intubation and muscle relaxation were facilitated by rocuronium bromide (0.6 mg/kg). Sevoflurane (0.8–1.2 MAC) and an air/O2 mixture to maintain fiO2 of 50% and remifentanil infusion (0.04 μg/kg/min) for analgesia were performed for anesthesia maintenance. Volume-control mode with 6–8 mL/kg tidal volume to maintain SpO2 between 96% and 100% and EtCO2 between 35% and 40% was preferred for ventilation. If necessary, additional muscle relaxation by rocuronium bromide (0.15 mg/kg) was done. Our choice for perioperative fluid infusion was crystalloids . Pneumoperitoneum was maintained by maximum carbon-dioxide gas insufflation pressure of ≤15 mmHg. The body temperature was kept stable between 36.5 °C and 37.0 °C by intravenous fluids at body temperature and external heating during the perioperative period. Sugammadex (2–4 mg/kg) was used if clinically indicated for those patients who did not meet the above-mentioned criteria.The ANI values of the patients were recorded immediately prior to extubation in the operating room and after extubation in the PACU, and pain scores were recorded based on the NRS within 10 min of the admission of the patients to the PACU, as well as hemodynamic data  of the patients at the same time points. As per the clinical indication, patients with an NRS of >3 were given 1 mg/kg tramadol (30 min of slow IV infusion in 100 mL of 5% dextrose) for postoperative analgesia. Patients who experienced no problems during routine monitoring were transferred to the surgery inpatient wards.For data evaluation, the patients were classified into 3 groups  according to the initial NRS values recorded in the PACU. The demographic parameters, durations of operations, and ANI values were compared between the three groups. The Patients whose ANI values were lower than 47, considered as the pain threshold, and the groups to which these patients belonged were recorded . Correlations between the ANI values recorded before extubation and at the time of coming out of anesthesia, immediately after the completion of surgery, and after extubation in the PACU, and the NRS values recorded in the PACU, were analyzed. Qualitative data were compared using the chi-square test, while quantitative data were compared between the groups using Student’s t-test for normally distributed parameters and the Mann–Whitney U-test for nonnormally distributed parameters. For within-group comparisons, a paired t-test was used for normally distributed parameters, and the Wilcoxon signed ranks test was used for nonnormally distributed parameters. For all tests, P < 0.05 was considered statistically significant, while P < 0.001 was considered highly significant. Correlations between the ANI values and NRS were investigated by Pearson’s correlation test, and r values were used to evaluate statistical significance. Based on these analyses, r values of 0.00–0.29 indicated weak, 0.30–0.49 indicated low, 0.50–0.69 indicated moderate, 0.70–0.89 indicated strong, and 0.90–1.00 indicated very strong correlations. A total of 36 ASA I–II patients, including 21 women and 15 men, were included in the study. The mean age of the study population was 45.33 ± 12.43 years, and the mean body weight, height, and BMI of patients was 74.22 ± 12.64 kg, 167.55 ± 7.72 cm, and 26.21 ± 4.49 kg/m2, respectively. The average duration of operation was 68.41 ± 15.81 min, and following the operation, the NRS values of the patients recorded in the PACU were ≤3 in 17 (47.22%) (group I) and between 4 and 6 in 11 patients (30.56%) (group II). The NRS was ≥7 in eight patients (22.22%) (group III). Table 1 summarizes the demographic data, the duration of operation, and NRS values in all groups. During the stable phases of perioperative anesthesia, i.e. during the intraoperative period in which only routine surgical and anesthetic procedures were applied without any unexpected events, the mean HR, SAP, DAP, and ANI values of the patients were 65.31 ± 16.76 beats/min, 95.67 ± 15.06 mmHg, 59.72 ± 12.34 mmHg, and 70.78 ± 16.66, respectively. Before extubation, the mean HR, SAP, and DAP increased to 70.44 ± 15.42 beats/min, 111.97 ± 18.89 mmHg, and 71.44 ± 14.39 mmHg, respectively, whereas the mean ANI decreased to 59.81 ± 14.46. While there was a partial increase in hemodynamic parameters and a partial decrease in ANI, these differences were not statistically significant (P ≥ 0.05). Following extubation, the mean HR, SAP, and DAP increased but ANI decreased with values of 79.03 ± 14.37 beats/min, 127.14 ± 18.48 mmHg, 75.47 ± 12.16 mmHg, and 60.16 ± 12.61, respectively. The increases in all three hemodynamic parameters were statistically significant (P < 0.05). While there was a decrease in the ANI, the difference was not statistically significant (P > 0.05). Table 2 summarizes these findings.Group I comprised a total of 17 patients (47.22%), including five ASA I and 12 ASA II patients whose postoperative NRS was ≤3. The group was made up of 7 women and 10 men, with a mean age of 45.41 ± 11.53 years, a mean body weight of 74.41 ± 12.12 kg, a mean height of 168.24 ± 7.44 cm, and a mean BMI of 26.04 ± 4.09 kg/m2. The mean duration of operation in this patient group was 67.26 ± 11.56 min, and the mean ANI values recorded before and after extubation were 58.47 ± 15.32 and 62.71 ± 15.61, respectively. Group II consisted of 11 patients (30.56%), including 7 women and 4 men, whose NRS was between 4 and 6. The mean age of these patients was 42.36 ± 8.74 years, and 9 patients were ASA I while the remaining 2 patients were ASA II. The mean body weight, height, and BMI of patients in this group were 73.57 ± 11.09 kg, 168.27 ± 7.01 cm, and 25.71 ± 2.91 kg/m2, respectively. The mean duration of operation was 69.48 ± 14.37 min, and the mean ANI values recorded before and after extubation were 62.73 ± 15.49 and 61.73 ± 14.32, respectively. A total of 8 patients (22.23%), including three ASA I and five ASA II, with 7 women and 1 man, made up group III with NRS of ≥7. The mean age of the patients in this group was 47.87 ± 14.94 years and mean body weight, height, and BMI were 78.21 ± 11.82 kg, 165.13 ± 9.41 cm, and 27.34 ± 3.39 kg/m2, respectively. The mean duration of operation was 68.45 ± 13.76 min, and the mean ANI values recorded before and after extubation were 58.50 ± 15.16 and 55.13 ± 13.54, respectively. While these values were numerically lower than in the other groups, the differences were not statistically significant (P ≥ 0.05). The other demographic findings, duration of operation, and ANI values were also not significantly different between the three groups. In addition, the ANI measurements were lower than the pain threshold level (47 for ANI) in 6 patients before extubation , and also they were lower in 7 patients after extubation . Only one patient who had an ANI value lower than 47 before extubation had a similar ANI value after extubation. All the relevant values are presented in Table 3. When postextubation NRS-ANI correlations were investigated between the three groups, classified based on NRS values, the correlations with preextubation values were found to be “weak” for group I (r = 0.016), “weak” for group II (r = –0.286), and also “weak” for group III (r = –0.293), representing the NRS ≥ 7 group. When the postextubation ANI values were considered, the correlation coefficients indicated weak correlations for group I (r = 0.135), group II (r = –0.069), and group III (r = –0.290). The ANI and NRS values of the patients and the correlations between these values are presented in Table 4 for preextubation and in Table 5 for postextubation time points, and the Figure summarizes the NRS-ANI distribution and correlation curves. The ANI is commonly thought of as a numerical and objective indicator of perioperative analgesia levels [15], although some authors have suggested that potential hemodynamic changes can be predicted based on perioperatively monitored ANI values [16], while there have been further studies reporting the contrary . Overall, almost all of those studies indicated that the ANI values may be in line with clinical status, even during spontaneous respiration in sedated patients under the influence of anesthesia [17–19]. In addition, some studies tested the use of the ANI to detect the level of analgesia in pediatric patients, and the results of such preliminary studies were found to be positive .Extending these general considerations, some authors argued that the severity of potential postoperative pain can be measured objectively based on the ANI values recorded at the end of the perioperative period [13], and even that the level of pain can be predicted based on these values, therefore allowing the early identification of severe pain risk and the making of effective interventions accordingly . In the present study, while 35.48% of the patients had mild pain that required no analgesia, 64.52% required additional postoperative analgesics. Of all the patients, 22.23% had NRS ≥ 7, or in other words, severe pain. This considerably high rate detected during a relatively minimally invasive operation such as laparoscopic surgery is proof of how important the concerns and actions to find a solution are. The rate identified in this study is consistent with previously reported rates in the literature [1]. In the present study, we failed to identify a correlation between the ANI and postoperative NRS, as suggested previously by some authors, and no significant correlation was noted between the ANI values recorded before and after extubation and the NRS values in any of our patient groups. In all patient groups, only a weak correlation was identified between the ANI and NRS values. In addition, despite some limitations, our findings suggested that the ANI was ineffective in the prediction of potential postoperative pain, and these findings are consistent with those of some other researchers .The patient exclusion criteria used in this study are similar to those used previously in almost all studies on this issue, although there are some differences between these studies in terms of the types of operation, the anesthesia protocols, and the study design . While the ANI values recorded immediately before extubation were considered as the measurement parameter in one of the first studies reporting a positive outcome [14], another study took into account the ANI values recorded after extubation [13]. In the present study, we investigated the ANI values recorded at both time points, and in this respect, we believe that our study is more inclusive. In the present study, the ANI values recorded in the postoperative period immediately after extubation were found to be slightly lower than those recorded during the perioperative period. However, the difference between these values was not statistically significant. This can be easily attributed to the status of patients, who are still partially under the influence of anesthetic medications, and who are gradually coming out of anesthesia and the effects of analgesic medications. There have also been several studies reporting that the ANI values were markedly higher during deep sedation when compared to the awake periods, although this relationship is not proportional to the degree of sedation [22]. This is most probably also true for our patient group. The ANI values also did not change significantly after extubation. In addition, the variations in ANI values were not parallel to the NRC values at either measurement time point. Low or high ANI values could be recorded in patients with apparent pain or in patients without any pain at all. In addition, aside from one patient, none of those who had an ANI value below 47 before extubation and were theoretically assumed to have pain had an ANI value below the threshold of 47 after extubation. Other than pain, it is also possible that other factors that might affect the sympathetic nervous system, such as nausea, vomiting, agitation, anxiety, voice, and others, may be involved and negatively affect the parameters measured in PACUs. All of these factors may affect HR and may consequently influence the ANI scores. Even authors who suggested that the ANI can be used for the prediction of postoperative pain underlined these potential effects [14]. In addition, there are authors who may be considered pioneers in supporting the use of the ANI during the perioperative period also, who reported that the effectiveness of the ANI is markedly decreased in conscious patients [17]. More recently, the results reported in two studies including healthy conscious subjects identified no direct relationship between NRS and ANI, highlighting the potential differences in individual responses . In another study performed in 2016, Jess et al. reported that the ANI could not differentiate between painful, painless, and fake stimuli in conscious subjects and failed to detect nociception in conscious patients, while the values were affected by stress and emotional status. Based on all these findings, Jess et al. argued that the ANI lacked the ability to assess pain severity in conscious and stressed individuals [25]. In 2017, Issa et al. revealed a very weak negative correlation between the ANI and NRS in healthy conscious individuals, and they did not recommend the use of the ANI in an emergency unit or intensive care setting [26]. Indeed, there have been some researchers who contributed to the development of the ANI, such as De Jonckheere, who recently highlighted the relationship between the ANI and emotional status and even recommended use of the ANI for the detection of parasympathetic changes in different emotional moods . Based on our findings, we also believe that the ANI is better able to reflect pain under anesthetic conditions, whereas the values recorded after the patients come out of anesthesia are rather complicated due to the interactions between other confounding factors and do not correctly reflect the balance between the sympathetic and parasympathetic nervous systems. On the other hand, we are currently engaged in further studies on the ANI in the different patient groups in our clinics.Apart from all the above-described factors, ANI scores may also be affected by the applied anesthetic medication and the duration of exposure to such medications. While the mean duration of operation was approximately 65 min in all patient groups, the durations of operations in previous positive or negative studies varied between 30 and 180 min. Although there were studies that did not provide any clear data on this parameter, none of these studies considered the duration of operation to be a parameter with a direct effect on the outcomes [29]. We believe that as duration of operation affects the total time of exposure to anesthetic agents and, therefore, the total dose of analgesic medications, it should be considered as making a considerable difference. One of the reasons for the conflicting results reported by previous studies may be the differences in study designs. In the majority of studies reporting positive outcomes, total intravenous anesthesia (TIVA - propofol) was the preferred method of anesthesia, and these studies demonstrated that the performance of the ANI was better when using TIVA (propofol) than when using halogen-based agents . Propofol and halogen-based agents have different effects on HR [30] and heart rate control via the baroreflex pathway [31]. While propofol decreases parasympathetic tonus in parallel to the degree of hypnosis, halogen-based volatile anesthetics have no such effects [32]. On the other hand, desflurane and isoflurane have been shown to decrease neural system activity in total, and to have a direct effect on sympathetic/parasympathetic balance [33]. Moreover, there have been other studies demonstrating that, compared to TIVA, high sympathetic activity that may affect HR and elevated plasma noradrenaline levels can be seen after sevoflurane-based anesthesia [34]. Still, it is apparent that halogen-based agents  are used much more often in daily anesthesia practice when compared to TIVA. In the present study, sevoflurane was used for the maintenance of anesthesia in all patients, and for this reason, we believe that our anesthesia protocol more realistically reflects PACU conditions. Accordingly, we conclude that the potential differences in the effects of the agents used for anesthesia maintenance should be considered in future studies and, more importantly, addressed in validation studies. The types of narcotic agents used represent another difference in the study designs. Contextually, the differences of the opioids used to provide general anesthesia relate to their elimination half-lives. Nevertheless, almost all eventually have the same effects on the HR. Narcotic agents inhibit sympathetic activity while preserving or increasing parasympathetic activity [35–38]. While Boselli et al. used remifentanil in both studies, demonstrating favorable findings , Ledowski et al. reported unfavorable results in their study using fentanyl as a narcotic agent [22]. It would appear, therefore, that it is more realistic to consider the preferred narcotic agent as having minimal effect on the outcome [29]. Our protocol also included the use of remifentanil, and the patients had completely overcome the effects of the applied narcotics at the time of admission to the PACU, considering that they were given time to regain spontaneous respiration after the operation.Indeed, other than anesthetic agents, there are several factors affecting the HR at varying rates, although the effects of sex, age, awareness, varying hemodynamic and autonomic conditions, and percentage of inhaled oxygen and the interactions between these parameters are unclear . Different classes of medications may also affect the HR [42], among which acetylcholinesterase inhibitors used for the reversal of neuromuscular blockages and the anticholinergic agents used to prevent their cholinergic activity are of particular importance . Although we excluded patients using medications affecting HR from the present study, and we waited for the spontaneous resolution of neuromuscular blockage, or used a specific antagonist, sugammadex, in the presence of a clinical indication, we believe that our findings are not confounded by these factors. Accordingly, it can still be argued that the ANI may not correctly reflect autonomous system balance in routine use, given the common use of different medications with different effects on HR in daily practice. Generally speaking, these problems are not exclusive to the ANI. When studies investigating other methods of perioperative analgesia assessment, such as skin conductivity or surgical stress index, are reviewed, it is apparent that the relationship between these alternative methods with postoperative pain could not be proven for similar reasons [45]. It is necessary for us to underline some limitations of this study. Although the number of patients included in the study was comparable to previous studies, it should still be kept in mind that there were only a limited number of patients and no control group. Moreover, all of the patients fell within a certain age interval, and the study included ASA I/II and relatively healthy patients who were not receiving any concomitant medications. Indeed, the target patient population that stands to benefit from these findings is somewhat different from the patient groups in our study and previous studies. Furthermore, the study exclusion criteria, which are common in all studies, are actually a part of the daily anesthesiology routine.In conclusion, based on the data collected in this study, we identified a weak correlation between the NRS and ANI values in patients who were not under the influence of anesthetic agents. Although, based on the information we gathered before starting this study as well as our satisfactory personal experience, we believed that ANI monitoring for anesthetized patients could at least provide alternative data on the present status of postoperative pain, the data collected in this study did not lead us to any positive conclusions. In addition, we believe that while ANI values are valuable for anesthetized patients, they cannot be used for the prediction of postoperative pain severity, contrary to the findings of other researchers. More reliable results on this matter could be obtained through controlled, randomized, and prospective studies investigating different anesthesia protocols for operations with longer durations and involving larger patient groups. We also recommend that new studies be carried out to develop an ideal analgesia-monitoring system adjusted for different scenarios in distinct patient groups, such as those at risk of insufficient pain treatment, nonverbal patients, and pediatric, geriatric, or noncooperative patients who cannot use VAS, NRS, or other conventional pain scales.


Coronary angiography can cause pain and fatigue in patients. Hand reflexology as complementary and integrative care approach has been suggested to help with the reduction of patient's pain and fatigue.  This study aimed to investigate the effect of hand reflexology on pain and fatigue in patients after coronary angiography.  A randomized controlled clinical trial. n = 45) and control (n = 45) groups. Hand reflexology was performed for 20 minutes in the intervention group. Pain and fatigue in the groups were measured immediately, 4 and 6 hours after the intervention.  This study was conducted on 90 patients in an angiography department of a referral hospital in an urban area of Iran. The patients were randomly divided into two interventions (P = 0.001). The intervention had medium to large effects on the patients' pain and fatigue. Hand reflexology as a nonpharmacological and safe technique can be used by nurses along with other pharmacologic interventions in order to reduce patients' suffering related to invasive procedures. The trial is registered with IRCT20110912007529N17. Statistically significant differences were observed in pain and fatigue scores between the groups after the intervention ( Cardiovascular disease (CVD) is the major cause of morbidity and mortality across the world . It has Coronary angiography has been recognized as the best method for the diagnosis of CVD . Since tPain is considered the most important complaint experienced by patients after coronary angiography. While analgesic medicines are prescribed to patients after this invasive procedure, they often report mild to moderate pain . After cA great challenge of nursing care is to ensure the patient's comfort and relaxation after invasive and painful procedures . PharmacReflexology is one of the most common complementary methods, but the mechanism underlying its effect has not been clearly understood. It has been suggested that during reflexology energy circulates in the body through vertical zones from the leg toward the head. Therefore, the application of pressure on a reflective point of an organ can impact all organs, glands, bones, and muscles . ReflexoVarious theories have been presented to describe the effect of reflexology and one of them is the stimulation of neural receptors through emphasizing the relationship between the central and peripheral nervous systems , 24, 27.Current studies have shown that reflexology is a noninvasive and safe nursing intervention , 36, 37.This was a randomized controlled clinical trial with a pre-post intervention design. The outcome measure was the impact of hand reflexology on patients' reported pain and fatigue after coronary angiography. This study was conducted on patients scheduled for an elective coronary angiography in a high turnover coronary angiography department of a hospital affiliated with a University of Medical Sciences in an urban area of Iran, from 2 March 2018 to 31 July 2018. This coronary angiography department treats over 280 patients every month.The following inclusion criteria were used to select participants: age >18 years, scheduled to undergo coronary angiography for the first time, no invasive procedures such as transesophageal echocardiography prior to coronary angiography, non-emergency coronary angiography, no previous history of coronary angiography, no vascular injuries in the upper limbs and sensory-motor disorders in hands, absence of abnormalities such as corns, burns, amputations, and skin lesions in hands, lack of intervertebral disc herniation, no previous history of mental disorder, and no disturbance in the consciousness level.Exclusion criteria were hemodynamic instability including dysrhythmia, respiratory disorders, and severe changes in blood pressure that require emergency interventions, bleeding after coronary angiography, and unwillingness to participate in this study.Given the sample size of a previous study , alpha 0α = 5%, β = 20%, d = 3.80, s1 = 3.05, s2 = 2.97, group = 2. Total sample = 2∗45 = 90.Lost = 20% = 7 per group. The head nurse of the coronary angiography unit was informed of the study's purpose and inclusion criteria to help with the identification of eligible patients. The patients were selected using a convenient sampling method and were assigned to intervention and control groups using a random sampling method. The group assignments were performed using the block basis sequence by the second author who was unaware of the patients' assignments using a table of random numbers. The random allocation sequence with 23 quadruple blocks with letters A or B indicating the sequence was generated by the statistical adviser. Sealed opaque envelopes containing cards were used, and the size of blocks was not announced to prevent selection bias. The sampling process continued until the required number of the participants was recruited to intervention (hand reflexology) and control (routine nursing care) groups.Data was collected using a questionnaire consisting of three parts as follows.It was filled out using the patient's medical file or through interviewing the patients. It included items about the patients' age, gender, education level, marital status, employment status, history of smoking or drug use, and medical diagnosis.The effect of hand reflexology on self-reported pain was measured using the NSR as a valid instrument for pain assessment in critically ill patients. It is an 11-point scale with equal divisions for self-reporting of pain by adults and children aged 10 years old or older. The range of scores was between 0 and 10 with the following ratings: 0 (lack of pain), 1–3 (mild pain), 4–6 (moderate pain), and 7–10 (severe pain) .It consists of a 10 cm line with extremely positive statements on one end and extremely negative statements on the other end. The most positive and negative fatigue statements were scored between 0 and 10, respectively. The ratings of this line were from 0 (lack of fatigue), 1–3 (mild fatigue), 4–6 (moderate fatigue), 7–9 (severe fatigue) to 10 (very severe fatigue). The test-retest method has shown the reliability of this instrument to be 0.93 .After obtaining permission to conduct the study, one male nurse and one female nurse received education and training on reflexology for 3 months under the suprevision of a reflexology expert. After 2 hours of coronary angiography, baseline data was collected. The nurses greased the patients' hands using sweet odorless almond oil and performed hand reflexology according to the Ingham's method for 20 minutes as 10-minute pressure on the right hand and then the left hand. First, the whole palm was given the pressure for 2 minutes. Three areas reflecting the solar plexus, heart, and pituitary were pressured. The downward pressure was applied with the thumb in the heart, pituitary, and solar plexus , 45. NexIt was impossible to blind the patients with regard to the groups' assignment due to the nature of the intervention. Also, the blindness of the theatre nurses due to the presence of the reflexologist in the unit was impossible. Nevertheless, the statistical analyzer was unaware of the patients' allocation to the groups. In addition, the randomization code was available only to a research fellow who was not connected to this study and was disclosed to the researchers after completing the statistical data analysis.t-tests, and Cramer's V to investigate the intervention's effectivness and its effect size.Descriptive and inferential statistics were used for data analysis via the SPSS software version 20 . The Kolmogorov-Smirnov test was used to assess data in terms of normal distribution. Data was coded and tabulated to present them in terms of frequency, percentage, mean, and standard deviation. Inferential statistics consisted of the Chi-square test, IRCT20110912007529N17.The permission to enter the research zone was granted by the ethics committees affiliated with Shahed University (decree code: IR.Shahed.REC. 1396.52). All participants gave their informed consent prior to entering the study. For illiterate patients, the informed consent documentation was read aloud by their companions or relatives and they were asked to add their fingerprints if they were willing to take part in the study. Verbal informed consent was also obtained. Numbers rather than names were used to deidentify the participants and ensure confidentiality and anonymity. The purpose and method of the study were described to the patients. Also, their confidentiality throughout the study was ensured. A cardiologist was available during the procedure to intervene if any adverse effect occurred, but no adverse events or complications related to angiography or hand reflexology were reported by the patients indicating the safety of reflexology. The study research protocol was registered on the Iranian Registry of Clinical Trial under the code of Of 123 patients assessed for eligibility, 90 patients met the inclusion criteria and were recruited. All approached agreed to participate and were assigned to either the intervention or the control group (n = 45 in each group). P > 0.05) The patients in the intervention and control groups had a mean age of 60.60 ± 12.77 years and 57.75 ± 10.34 years, respectively. No statistically significant differences were reported between the groups in terms of sociodemographic and clinical characteristics at the baseline (P > 0.05). However, it showed statistically significant differences between the groups during the measurement times (P=0.001), and the severity of the effect of reflexology was reported to be large . After the intervention, statistically significant differences between the groups during the measurement times were reported (P < 0.05). The severity of the effect of reflexology was reported to be moderate immediately after the intervention and was reported large 4 and 6 hours after it (At the baseline, the fatigue level had no statistically significant difference in the control and intervention (after it .This study aimed to investigate the effect of hand reflexology on the patients' reported pain and fatigue after coronary angiography. After the intervention, it was found that hand reflexology reduced the patients' pain and fatigue. The hand reflexology group reported lower pain and fatigue levels than the control group. While the effect of hand reflexology after coronary angiography has not been studied in the past, our findings concur with those of previous studies indicating the effectiveness of hand reflexology for managing pain or fatigue in patients with various health conditions. Aliasgharpoor et al. and Shaer Moghadam et al. , 41 founThe application of hand reflexology only for one session can be considered a limitation of this study. Therefore, to remove the effect of the “healing crisis” or “cleansing process,”  the reflHand reflexology reduced fatigue and pain in patients after coronary angiography. It is a nonexpensive and safe intervention that does not need any special equipment unless specific instructions that are given to nurses on how to implement it and how to incorporate it into routine nursing practice. The use of complementary and integrative medicines as safe and nonpharmacologic interventions for the reduction of pain and fatigue in patients undergoing invasive procedures can improve nurses' independence in decision-making and increase their self-confidence during patient care. Therefore, its education is suggested to be incorporated into academic nursing education and on-the-job training in critical and intensive care units. Further studies are required to investigate the impact of hand reflexology in comparison with other complementary medicines approaches on pain, fatigue, and wellbeing in patients undergoing painful and invasive procedures. Also, the use of a placebo group can enable making firmer conclusions regarding the impact of reflexology on patients' reported pain and fatigue in relation to the attentive presence of the reflexologist. Replicating this research in other healthcare settings and on patients with chronic diseases is suggested.