Evaluation of safety and efficacy of topical ocular SAF312 (Libvatrep) in post–photorefractive keratectomy (PRK) pain.In this placebo (vehicle)–controlled, participant- and investigator-masked study, 40 participants were randomized (1:1) to two treatment sequences in a bilateral PRK crossover design . Primary endpoints were visual analog scale (VAS) pain scores at 6 hours after first drop of study drug and average VAS scores over 0 to 12 hours postoperatively. Secondary endpoints included postoperative oral rescue medication (ORM) use and adverse events (AEs).P = 0.005, −25%) at 6 hours postoperatively and −8.56  over 0 to 12 hours. Mean VAS pain scores with SAF312 were consistently lower than with vehicle from 1 hour postoperatively up to 30 hours (P ≤ 0.10 observed in 8/11 time points). Less ORM was taken with SAF312 up to 0 to 72 hours postoperatively, with a trend of fewer participants taking ORM at 0 to 24 hours postoperatively with SAF312 versus vehicle. No serious AEs were reported. All ocular AEs were mild and transient, and none were drug related. SAF312-treated eyes showed no delay in wound healing and had a lower grade 4 conjunctival hyperemia 24 hours postoperatively versus vehicle-treated eyes.All 40 participants completed the study. Both primary endpoints were met; mean difference in VAS pain scores between SAF312- and vehicle-treated eyes was −11.13 (SAF312 was well tolerated and effective in reducing ocular pain post-PRK.Topical SAF312 presents a new therapeutic option for patients undergoing PRK. The study was approved by the institutional review boards of all clinical sites and adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants.The study used a bilateral crossover designMale and female participants aged 18 to 75 years who were eligible for bilateral PRK (1) had a normal eye exam except for refractive error at baseline, and (2) the planned myopia correction did not exceed −4.00 diopters (sphere) and 3.00 diopters of astigmatism, with spherical equivalent not higher than −4.50, confirmed by manifest refraction at baseline.The complete exclusion criteria are provided in The primary objective was to evaluate pain control in the immediate post-PRK period. The coprimary endpoints were (1) visual analog scale (VAS) pain assessment at 6 hours postoperatively and (2) average ocular pain VAS assessments from the first postoperative assessment up to the 12-hour predose assessment. Secondary endpoints included (1) incidence and amount of ORM needed from 6 hours to 3 days postoperatively after each PRK surgery; (2) adverse events (AEs) and serious AEs (SAEs); (3) size of epithelial defect by slit-lamp exam, visual acuity (VA), blink rate, and tear production; (4) all VAS measurements during the first 3 days after surgery; and (5) plasma concentration and pharmacokinetic (PK) parameters of SAF312.To account for the potential influence of the rescue medication on the primary endpoints, three different approaches of analyzing the VAS pain scores and calculating the average (0–12 hours) were planned in advance and evaluated after data collection. The three different approaches included any recorded VAS pain score at time points within 4 hours after the use of rescue medication, which was imputed by the record taken at the time of rescue medication use. This method was applied as the primary sensitivity analysis, as per the FDA guidance in 2014.The exploratory endpoint included is the Ocular Pain Assessment Survey (OPAS) outcome. OPAS was designed and validated to measure ocular pain and quality of life in patients with corneal and ocular surface pain at initial and follow-up visits in the clinic over a 6-month period.VAS pain assessments were captured digitally in real time with a handheld (electronic patient-reported outcome [ePRO]) device at the protocol-specified time points. VAS uses a numeric assessment of pain between 0 and 100, with 0 representing no pain and 100 representing the worst imaginable pain. Safety assessments consisted of AEs and SAEs, with their severity and relationship to the study drug. Ocular hyperemia was assessed using the McMonnies redness scale  in four regions of the bulbar conjunctiva . Each eye and each region were graded by severity (0–5).The details of other assessments performed in the study are provided in P value ≤0.10 was considered statistically significant. The statistical power of the study was expected to be higher than a traditional two-group design due to the bilateral crossover design,This study was powered based on the difference in mean 6-hour VAS score because there were insufficient data to calculate an exact sample size for the second coprimary endpoint of average VAS from 0 to 12 hours. Further, with a prespecified false-positive rate (α) for all tests of 0.10, a P value testing treatment difference at a given time point were obtained from the model at each time point.VAS pain assessments were analyzed 6 hours postoperatively using a linear mixed model for repeated measures, which accounted for the crossover nature of the trial. VAS pain assessment up to 12 hours postoperatively was assessed with a mixed-effect model accounting for the crossover effect for average (0–12 hours) VAS. The difference in least squares mean VAS scores between SAF312-treated eyes and vehicle-treated eyes, the 90% confidence interval, and P values were reported. The amount  of oral analgesics taken in each period by each participant was analyzed by the Wilcoxon signed-rank test; the associated P values were reported. Patient demographic and baseline characteristics, safety, and PK analyses were summarized descriptively.To assess the secondary endpoint of oral rescue medication use, McNemar's test was used to analyze the difference between the number of participants who did not take oral analgesics between SAF312 and vehicle treatment during the intervals of interest ; the associated All 40 randomized participants completed the study and were included in the safety analysis set. The first 10 randomized participants were excluded from the primary endpoint analysis (5 participants each from both treatment sequences) due to an ePRO device failure; the primary and secondary endpoints were successfully collected in the next 30 participants using a completely different ePRO device. All 40 randomized participants were included in the secondary endpoint and safety analysis sets .The demographic characteristics were well balanced between the participants of both treatment sequences. The mean age of the participants was 34 years , 53% were male, and the majority were Caucasian (88%) .P = 0.005, −25%) at 6 hours postoperatively and −8.56  averaged over 0 to 12 hours postoperatively, respectively (P ≤ 0.10) observed in 8 of 11 time points from 1 to 30 hours postoperatively. From 36 to 72 hours after PRK, the differences in VAS scores between SAF312 and vehicle were nominal (insignificant) with mild pain or less in both treatment groups  differences observed during the intervals of 0 to 6, 0 to 24, 0 to 48, and 0 to 72 hours postoperatively (The mean number of ORM (number of acetaminophen/codeine tablets) taken during SAF312 treatment was fewer at every time interval compared to vehicle, with statistically significant  of vehicle-treated patients reported a reduction in pain scores when treated with SAF312 after crossover  experienced at least one treatment-emergent AE. Due to the crossover design, some patients accounted for the AEs in both SAF312 and vehicle treatment groups. Eight patients experienced AEs during treatment with SAF312, and five patients experienced AEs during treatment with vehicle. With SAF312 and vehicle treatments, 8 of 40 and 5 of 40 participants had at least one AE, respectively . There wThere were no notable differences in best-corrected visual acuity (BCVA) and uncorrected visual acuity (UCVA) between SAF312- or vehicle-treated eyes. The mean (SD) BCVA and UCVA in both the treatment groups at baseline, day 2, day 3, and end of study (EOS) are summarized in P value for this difference in the superior quadrant  was 0.04 in favor of SAF312 over vehicle (Twenty-four hours after PRK surgery (day 2 postoperatively), the frequency of grade 4 hyperemia in all quadrants was lower in SAF312-treated than vehicle-treated eyes . The P v vehicle A. Forty- vehicle .2 . By 48 hours postoperatively (day 3), there was no difference between the SAF312- and vehicle-treated eyes, and the area of the wound was pinpoint. Almost all eyes had completely healed by 72 hours (day 4), and the duration of healing was consistent with the expected time anticipated for complete healing after PRKThere was no clinically significant difference between SAF312 and vehicle treatment toward the epithelial wound area at any time point . At 24 hNo relevant differences were observed in blink rate, tear production, or corneal staining between the treatment groups. There were no clinically significant changes in blink rate or tear production at EOS when compared with baseline. Most participants had normal corneal staining (grade 0) at baseline, day 8, and EOS, with no clinical difference observed between eyes treated with SAF312 and vehicle.max was at 0.459 hours and 0.467 hours after the 1st (day 1) and 13th (day 4) doses of SAF312 2.5%, respectively. Arithmetic mean Cmax (percent coefficient of variation [CV%]) following the first dose on day 1 was 0.454 ng/mL (49.9%) and 2.40 ng/mL  after the 13th dose on day 4. Corresponding mean AUClast (CV%) values were 0.638 ng⋅h/mL (46.0%) and 4.38 ng⋅h/mL (67.0%), representing a 6.9-fold increase over the 4 days  6 hours after one drop of SAF312 at the end of surgery and (b) average VAS scores over 0 to 12 hours postoperatively after two eye drops (one immediately after surgery and one 6 hours later). These findings are clinically significant considering that acute pain after PRK begins shortly after the procedure and lasts until reepithelization is complete; intense pain is typically experienced within the first 12 hours of surgery, with the peak occurring around 4 to 6 hours after surgery.The efficacy of SAF312 versus vehicle as measured with VAS pain scores throughout 72 hours after the PRK was also assessed as the primary endpoints were set only for the first 12 hours. No significant differences in pain intensity between SAF312 and vehicle group were observed from 36 to 72 hours post-PRK. It is important to reduce both the maximum and overall pain that participants experience during the immediate postoperative period. The difference in VAS pain scores at 6 hours and averaging over 0 to 12 hours for SAF312-treated eyes was 11.1 (34.63 vs. 45.76) points and 8.56 (30.90 vs. 39.46) points lower than for vehicle-treated eyes, respectively. It has been reported that analgesic interventions following surgery that provide a change of 10 out of the 100-mm pain VAS score signifies a minimal clinically important difference, and a VAS ≤33 indicates acceptable pain control.The reduction in pain provided by topical ocular SAF312 is comparable to previous reports for NSAID eye drops and oral opioids. In a study that evaluated diclofenac 0.1% and ketorolac 0.5% applied 2 hours before PRK and continued every 6 hours for 2 days, the VAS pain score  at 24 hours post-PRK was 4.94 and 6.59 points, respectively.,Consistent with the primary outcomes, participants with SAF312 treatment reported lower ORM use at all time points, and a higher proportion of participants on SAF312 had adequate pain control and did not require ORM during the first 24 hours postoperatively. SAF312, like topical NSAIDs, reduced the need for ORM and may be opioid sparing for optimal management of post-PRK pain.–,,,Topical ocular SAF312 2.5% treatment after PRK demonstrated a safety profile comparable with vehicle, with no serious or drug-related AEs and no delay in cornea reepithelization. There were no clinically relevant changes observed for visual acuity, blink rate, tear production, or corneal staining after SAF312 administration compared with vehicle. OPAS results also support the well-tolerated safety profile of SAF312, with participants reporting symptoms of redness, burning, sensitivity to light, and tearing to be slightly lower or comparable with vehicle treatment. Fewer SAF312-treated eyes showed severe conjunctival hyperemia on day 2. In contrast, ocular hyperemia and stinging are common AEs associated with topical ophthalmic NSAID treatment.TRPV1 channel antagonists, such as SAF312, offer advantages over other pain management strategies as they prevent ocular pain by blocking a receptor where pain is generated, as opposed to traditional analgesic drugs that either inhibit pain transmission  or suppress inflammation . The study also confirmed that topical ocular administration of SAF312 2.5% led to a quick but very low level of systematic exposure, consistent with the findings of the FIH study.Owing to the low systemic exposure and the chemical properties of the SAF312 molecule, there seems to be a low risk on the CNS or other systemic side effects.A different TRPV1 antagonist, AMG-517, promoted peripheral neuronal regeneration in rats after unilateral sciatic nerve injury by attenuation of TRPV1 activation. However, the role of SAF312 on the neuronal regeneration is yet to be explored.The strength of the study is its unique bilateral crossover PRK study design, where participants received either SAF312 2.5% or vehicle in the first treated eye and later switched study drug after PRK in the second eye, thereby acting as their own controls. Further, in this study, VAS and ORM use details were captured using a real-time electronic app, adding to its strength as written diaries are prone to error and fabrication. Thus, the results obtained using the ePRO device are more robust.–,Study limitations include a relatively small sample size. In this study, pain after PRK was primarily assessed using electronic VAS on a 100-mm scale. Literature on a similar topic assessed pain after PRK using various methods besides VAS, including the NRS,In addition, participants in this study had the option of using ORM at any time during the study, which had the potential to confound the VAS pain severity efficacy results. To decouple the effect of ORM on VAS primary efficacy endpoints, any prespecified VAS reading taken within 4 hours of any ORM use was replaced with the VAS value recorded at the time the ORM was taken. Additional sensitivity analyses, including VAS scores after ORM use as missing and ignoring ORM use, were performed to examine the use of ORM on the study conclusions; all sensitivity analyses produced similar results and confirmed the robustness of the findings on drug effect (data not shown). Although bandage contact lens and corticosteroids are routinely used as postoperative standard of care (SOC), it serves as an additional confounding factor in the assessment of the effects of SAF312. This may have created some variability to the number of patients experiencing pain and the severity of their pain.Thus, in this phase 2 clinical trial, topical ocular SAF312 2.5% (dosed four times daily for 3 days) showed efficacy in decreasing the severity of ocular pain associated with corneal epithelial defect after PRK surgery, no delay in wound healing, and a well-tolerated safety profile. The results of the study highlight that SAF312 can be a promising therapeutic option for patients with ocular pain after PRK. Further studies with additional patient-reported outcomes, such as quality of life, will provide better insights into the potential uses of topical SAF312 for ocular pain management.


Painful diabetic peripheral neuropathy (PDPN) is a key concern in clinical practice. In this systematic review and meta-analysis, we compared duloxetine and placebo treatments in terms of their efficacy and safety in patients with PDPN.Following the PRISMA guidelines, we searched the Cochrane Library, PubMed, and Embase databases for relevant English articles published before January 11, 2021. Treatment efficacy and safety were assessed in terms of pain improvement, patient-reported health-related performance, and patients’ quality of life.P < .00001). Furthermore, duloxetine significantly improved the patients’ quality of life, which was assessed using the Clinical Global Impression severity subscale , Patient Global Impression of Improvement scale , and European Quality of Life Instrument 5D version . Severe adverse events were rare, whereas nausea, somnolence, dizziness, fatigue, constipation, and decreased appetite were common; approximately, 12.6% of all patients dropped out because of the common symptoms.We reviewed a total of 7 randomized controlled trials. Regarding pain improvement, duloxetine was more efficacious than placebo (mean difference [MD] − 0.89; 95% confidence interval [CI] − 1.09 to − 0.69; Duloxetine is more efficacious than placebo treatments in patients with PDPN. The rarity of severe adverse events indicates that duloxetine is safe. When a 60-mg dose is insufficient, 120 mg of duloxetine may improve PDPN symptoms. Our findings may help devise optimal treatment strategies for PDPN.PROSPERO CRD42021225451The online version contains supplementary material available at 10.1186/s13643-023-02185-6. Painful diabetic peripheral neuropathy (PDPN) is caused by chronic hyperglycemia and characterized by nerve damage and intolerable pain . ApproxiThe precise pathophysiology of PDPN remains debatable. A commonly accepted hypothesis is that distal nerve fiber damage would result in altered peripheral signaling and compensatory changes in the central nervous system, thereby disrupting the mechanisms underlying the inhibition of endogenous pain; this would promote the hyperexcitability and sensitization of pain-transmitting pathways and cause severe and persistent pain , 7.The neurotransmitters serotonin (5-hydroxytryptamine) and norepinephrine help modulate nociceptive transmission by descending pain inhibitory pathways in the brain and spinal cord –10. DuloCurrently, duloxetine and pregabalin are the only drugs approved by the US Food and Drug Administration (FDA) for treating PDPN. Pregabalin and duloxetine have been recommended as the first-line therapy in a total of 5 and 4 relevant guidelines, respectively. The 4 guidelines recommending duloxetine are the Neuropathic Pain Special Interest Group guideline , European Federation of Neurological Societies guideline, National Institute for Health and Care Excellence guideline (UK), and Canadian Pain Society guideline –17. The This systematic review and meta-analysis were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines . The stuWe searched the Cochrane Library, PubMed, and EMBASE databases for relevant RCTs published in English before January 11, 2021. Keywords used for the search in each database were as follows: (((DM or “diabetes mellitus” or diabet*) and ) or  or  or )) and . In addition, the reference lists of the included studies were manually searched for additional eligible studies.After removing duplicate studies, 2 reviewers (CS Wu and YR Huang) independently reviewed the titles and abstracts of the eligible studies. Non-RCTs and non-eligible studies were excluded (upon reviewer consensus) from further analyses. Subsequently, the full texts of the included articles were analyzed. Both reviewers independently assessed the risk of bias by using the Cochrane risk-of-bias tool for RCTs (RoB 2.0) . Any disI2 statistic, and 25%, 50%, and 75% values indicated low, moderate, and high degrees of heterogeneity, respectively [P < 0.05. The meta-analysis was performed using RevMan (version 5.4) [Odds ratio (OR) and 95% confidence interval (CI) values were calculated using the Mantel–Haenszel method for dichotomous outcome data, whereas the mean difference (MD) and 95% CI values were calculated through inverse variance weighting for continuous data. Outcome data, such as sample size, mean, and standard deviation (SD), were extracted for each treatment. If the included articles reported only standard error values, the corresponding SD values were calculated using relevant software. Heterogeneity was investigated using the ectively . The pooion 5.4) .Our search returned a total of 1862 relevant articles; of them, 1475 were excluded after the removal of duplicates. Next, 794 studies were excluded after the titles and abstracts were screened. The full texts of the remaining 681 articles were reviewed, and 674 of them were eliminated on the basis of the exclusion criteria. Finally, a total of 7 eligible RCTs –40 were The 7 included studies comprised a total 2205 patients . Patients received 20, 40, 60, and 120 mg of duloxetine per day. Six studies had a follow-up duration of 12 weeks, and one study had a follow-up duration of 8 weeks . ReductiZ = 7.79, P < 0.00001, and I2 = 36%; Fig. P = 0.14). Head-to-head comparisons between the effective doses revealed no significant differences.A total of six studies reported improvements in weekly mean pain scores. Duloxetine was more efficacious than placebo, with low to moderate heterogeneity noted across studies , CGI , EQ-5D, and SF-MPQ (sensory component) tools were reported by 7, 7, 5, 4, and 4 studies, respectively. Overall, the efficacy of duloxetine in improving the aforementioned scores was significantly higher than that of the placebo, with low to moderate heterogeneity observed among studies . The study by Yasuda 2011 had some concerns in domains 1 and 2 because allocation concealment was not explained clearly. The study conducted by Gao et al. incompletely described the processes of randomization sequence generation and allocation concealment, leading to some concerns in domains 1 and 2.The quality of the included studies was assessed using RoB 2.0; the details are presented in Fig. The efficacy of duloxetine in treating PDPN has been demonstrated in a total of 4 RCTs conducted between 2005 and 2011 –37. In tAs mentioned, duloxetine and pregabalin are the only 2 FDA-approved drugs for PDPN. Some studies have reported that the efficacy of duloxetine in PDPN pain relief is non-inferior , 47 to oP < 0.00001). The TWM values of the reductions in the weekly mean values of average pain scores on BPI, night pain scores, and 24-h worst pain scores were –2.64 (MD − 0.84 and P < 0.00001), − 2.80 (MD − 0.82 and P < 0.00001), and − 3.02 (MD − 1.00 and P < 0.00001), respectively. Furthermore, 45.6% and 64.5% of all patients experienced 50% and 30% pain reduction, respectively, which highlights the clinical efficacy of duloxetine in the treatment of PDPN. Duloxetine considerably improved the physical and mental health and the quality of life of patients with PDPN, as evident from their scores on the following tools: CGI (TWM =  − 1.39), PGI-I (TWM = 2.47), EQ-5D (TWM = 0.13), SF-36 , and SF-MPQ (TWM =  − 7.80). .Compared with placebo, duloxetine significantly improved patients’ pain scores on every item; the total weighted mean (TWM) of the reduction in the weekly mean of 24-h pain scores was − 2.62 , and no significant differences were observed between them. However, the 120-mg dose was associated with numerically better outcomes than the 60-mg dose in terms of pain reduction , and health performance, and quality of life. Thus, the 120-mg dose of duloxetine may be useful when the 60-mg dose fails to ensure adequate relief in patients with PDPN.Duloxetine was found to be safe in the treatment of PDPN: the incidence of severe adverse events was low, not higher than that associated with placebo treatments. However, complications such as nausea, somnolence, dizziness, fatigue, constipation, and decreased appetite were common; because of these common adverse events, approximately 12.6% of patients dropped out of the studies. Approximately, 71.3% of all patients experienced at least 1 adverse event. Therefore, when administering duloxetine, patients must be informed about these adverse effects, and they must be closely monitored for the incidence and severity of common adverse events. Symptomatic interventions should be administered as required.n = 405) and comprehensive data on pain relief were reported by the RCT, we could provide considerable additional and updated data regarding the efficacy and safety of duloxetine in the treatment of PDPN. Of the studies included in the present study, the study by Gao et al. (2010) [The present study has some limitations. We found only 1 additional eligible study  compared. (2010)  reportedThe findings of our systematic review and meta-analysis suggest that duloxetine is more efficacious than placebo treatments in terms of pain relief and improvements in the quality of life of patients with PDPN. Duloxetine is safe, as indicated by the rarity of severe adverse events; however, patients receiving this drug should be monitored for some common complications, such as nausea, somnolence, dizziness, fatigue, constipation, and decreased appetite. This study may serve as a reference for future studies aimed at developing suitable interventions and optimal treatment strategies for patients with PDPN.Additional file 1.


Pain is the most common side effect in cesarean section with spinal anesthesia. It seems that oxygen therapy and chamomile aromatherapy may diminish pain. The present study was conducted to examine and compare the effect of chamomile aromatherapy with and without oxygen on the severity of pain of women following cesarean section surgery with spinal anesthesia.The present randomized clinical trial study was carried out on 136 women undergoing cesarean section surgery with spinal anesthesia at Imam Sajad Hospital, Yasuj, Iran in 2020. The eligible women were assigned into four 34-member groups including oxygen therapy plus aromatherapy, oxygen therapy, aromatherapy, and control via block randomization. Each of these interventions were performed 6, 6.30 and 7 h post operation. In the first intervention group, one drop of chamomile essential oil with distilled water was poured into a small nebulizer using a simple mask connected to 6 L of oxygen. The second intervention group received oxygen without chamomile aromatherapy at similar times, and the third intervention group received chamomile aromatherapy without oxygen. The control group received only routine interventions. The instrument used in the research was visual analog scale which was completed by the researcher 6, 12, 18 h after cesarean section. The data were analyzed by the SPSS software version 20.There was a significant difference in the intensity of pain of patients between the various groups of study following the interventions (P < 0.001). Pain intensity reduced significantly in the group receiving combined intervention of chamomile aromatherapy plus oxygen compared to the other three groups. Moreover, the pain intensity diminished more in the groups undergoing each of these interventions alone as compared to the control group (P < 0.05).The combined intervention of chamomile aromatherapy with oxygen was more effective than each of the chamomile aromatherapy and oxygen interventions alone in reducing the pain of cesarean section patients though each intervention alone was still effective in lowering pain post-operation. VASVisual analog scaleWHOWorld Health OrganizationFDAFood and drug administrationNSAIDsNon-steroidal anti-inflammatory drugsCOX-2Cyclooxygenase-2C-sectionCesarean-section1The World Health Organization (WHO) has recommended 10–15% Cesarean section (C-section) rate for live births . C-sectiWHO recognizes the significant role of alternative and complementary medicine in the treatment and prevention from chronic diseases and improving the quality of life. One of these supplementary treatments is aromatherapy. Aromatherapy refers to the application of aroma extracted from plants in the enhancement of physical, psychological, spiritual health as well as maintaining health . It is uIn a study by Najafi et al. chamomile Flower Essence inhalation caused a reduction in postoperative pain in women undergoing elective caesarean section under spinal anesthesia . MoreoveIn several animal models, oxygen therapy reduced pain . Oxygen The results of the mentioned studies indicated a contradiction in the effect of oxygen and chamomile aromatherapy on pain. Furthermore, there is the lack of study on the combined effect of the two on pain. Therefore, the present study was conducted to determine and compare the effect of chamomile aromatherapy with and without oxygen on the pain of women post C-section with spinal anesthesia.22.1The present randomized clinical trial study was a parallel-controlled trial study registered on Iranian Registry of Clinical Trials under the code IRCT20141222020401N7. The study was conducted on 136 women referring to Imam Sajjad hospital of Yasuj, Iran, for elective C-section with spinal anesthesia from January 05, 2020 to march 18, 2020. The research population consisted of women hospitalized in the obstetrics ward of the hospital due to non-emergency cesarean section with spinal anesthesia.In the present study, interventions included chamomile aromatherapy, oxygen, and the combination of chamomile essential oil with oxygen, and the pain was the result. Control and tree intervention groups participated in this study, and the pain at 6 (baseline), 12, and 18 h’ post-operation were compared between and within the study groups. The intervention was single-blind. Only statistical analyzers did not know in which group they were.2.2The Participants consisted of women referring to Imam Sajjad hospital of Yasuj, Iran for elective C-section with spinal anesthesia who were eligible and had inclusion criteria.The sample size was determined as 34 in each group and 136 individuals overall based on the parameters of α = 0.5, 1-α = 0.95, A total of 136 participants were chosen by the researcher through available sampling and then assigned into four groups intervention 1 (chamomile aromatherapy with oxygen), intervention 2 (oxygen), intervention 3 (chamomile aromatherapy), and control group (n = 34 in each group) through block randomization method by the researcher, as follow: Labels A, B, C, D were written on four sheets, and the names of each of the research interventions were also written on four separate sheets, and a colleague who did not know about the study was asked to put a label for each intervention randomly. Hence, due to the existence of four groups in the study, twenty-four blocks were obtained based on the four-factorial law, the size of each block was different, and the order of their placement was different. At that point, the blocks were randomly selected by placement, and after determining the order of placement of the patients in each block, the patients were assigned to each group. The selection of blocks continued until 34 samples were placed in each group.The inclusion criteria were as follows: volunteers of elective C-section with spinal anesthesia who had no problem regarding spinal anesthesia according to the physician, and volunteered to participate in the study. Exclusion criteria included sensitivity to chamomile, any middle-ear disease, pregnancy toxicity, asthma, acute or chronic diseases, allergy and olfactory problems, smoking cigarette and consuming alcohol.3The data were collected using a form which included data such as age, body mass index, number of pregnancies, duration of surgery, pre-operation hemoglobin, and Spo2 in the ward . The datIn different Iranian and international studies, the reliability and validity of the VAS has been confirmed. VAS is a valid and standard instrument applied in different countries on various groups with different types of patients .3.1Necessary instructions were given to three nurses who cooperated with the researcher in conducting research interventions. The day prior to the operation, the list of C-section operations of the next day was prepared and the inclusion criteria for patients present in the list were examined through asking questions from patients. The measurement outcome was pain intensity of the site of C-section. Each group of the patients were studied in separate groups depending on the group they were in (control or intervention); four rooms were considered for this purpose. After entering the operation room, the patient was located on the operating room bed and the monitoring device was connected to the patient. The patients were prescribed 400 cc of intravenous normal saline. At that point the patient was put in a sitting position and after preparation and drep of the anesthesia site, spinal anesthesia was performed at the L4-L5 intervertebral level with the Quincke spinal needle model, No. 25 of Dr-J company. 12.5 mg of 5% bupivacaine (2.5 cc) of Cobel Darou company was injected intrathecally. Then the patient was positioned in a supine position and the level of anesthesia was brought to the T8 vertebral level with the help of the tilt of the operating room bed. Afterwards, the surgeon was permitted to perform the operation. No analgesics were used during surgery. Nonetheless, in the recovery room, after the operation, 500 mg of Apotel of Cobel Darou was injected to all patients.Each intervention was completed three times: 6, 6.30, and 7 h post operation, and each time for 5 min by the first author (nursing student in MSc).3.1.1Chamomile aromatherapy with oxygen: Chamomile essential oil was purchased from Zardband Company in Iran. At the time of entrance to the obstetric ward post-operation, one drop of chamomile essential oil was rubbed on the wrist of each patient participating in this group in order to diagnose any possible sensitivity (patch test) so that in case of sensitivity the patients would be excluded. In this group, one drop of chamomile essential oil plus 3 cc distilled water was poured into a small nebulizer connected to a simple mask , with th3.1.2The participants of this group received 6 L of oxygen per minute with simple mask without chamomile aromatherapy.3.1.3Following the patch test, they received chamomile aromatherapy with nebulizer and without oxygen.3.1.4Received only routine interventions. Note that all the four groups received therapeutic interventions and the common recommended interventions in the ward.All C-section patients received diclofenac sodium 100 mg suppository according to the ward's routine immediately after entering the ward. Moreover, Narcotics or Diclofenac suppository and preferably Diclofenac suppository was prescribed as PRN (Pro Re Nata) by the physician for each patient in all the study groups, which was given if only requested by the patient.During anesthesia, recovery, and in the ward, the blood oxygen saturation level was measured using finger pulse oximeter, and then recorded in the data collection form. The intensity of pain was measured and recorded in the data collection form using VAS at times of 6 (baseline), 12 and 18 h post-operation.3.2The normality of data in the groups was initially evaluated using the Kolmogorov-Smirnov test. Regarding the normal distribution of the data, the parametric Analysis of Variance (ANOVA) and non-parametric Median and Friedman tests were used as well. Moreover, post hoc multiple comparison test with Bonferroni correction to follow the differences between the groups was used. The p-value in this study was considered less than 0.05.3.3The ethics code with the number of IR.YUMS.REC.1398.036 on 2019-06-25 was granted by the ethics committee of research at Yasuj University of Medical Sciences. Written informed consent was obtained from the patients and their spouse. The research interventions, process of spinal anesthesia, side effects of anesthetics and analgesics on mother and fetus were explained to all patients in the studied groups. Based on previous clinical trials, usage of oxygen and chamomile aroma with the prescribed values is safe for C-section women. The patients in the present research were not deprived of routine treatments, and none of the groups had restrictions to receive analgesics after the surgery. All methods were performed in accordance with the relevant guidelines and regulations in accordance with the Declaration of Helsinki.44.1The data was collected from 136 women who underwent cesarean section with spinal anesthesia. All participants remained in the study until the end of the intervention . The ove5It was indicated that the severity of pain  of womenBetween-group comparisons indicated that the four groups significantly differed from each other in median of the severity of pain at 12th and 18th hours .Table 2BPairwise comparisons for pain variable indicated that the group of aromatherapy with oxygen significantly (p = 0.001) differed from the other three groups. Moreover, the results of pairwise comparisons correspondingly indicated that women who received aromatherapy (the aromatherapy group) or oxygen (the oxygen therapy group) significantly (p = 0.001) scored lower in the severity of pain than women in the control group; however, the two groups did not differ significantly .Table 3PThe results of the present study indicated that there were significant differences among the three study times in the severity pain scores for the all groups. Within-subject comparison using Friedman's test indicated that women on all groups significantly (p = 0.001) reported lower severity of pain at 18 h than 12 h as well as at 12 and 18 h than 6 h post-operation .Table 4W6The effect of chamomile aromatherapy and oxygen was determined on the severity of pain among women post C-section operation with spinal anesthesia. No study was found to have explored the combined effect of chamomile and oxygen on the intensity of pain of C-section with, which highlights the novelty of the present research. At 12 h post-operation, this combined intervention reduced the pain intensity more considerably than all intervention groups and the control, though the aromatherapy intervention was also more effective on reducing pain intensity. At 18 h post-operation, all intervention groups were more effective than the control for mitigating pain intensity.The present study displayed that aromatherapy with chamomile essential oil alone reduced the pain after the cesarean section of women. Yet, the combination of chamomile aromatherapy with oxygen alleviated the pain after cesarean section more than chamomile aromatherapy alone. On the other hand, chamomile aromatherapy did not significantly affect the pain of these patients compared to oxygen. Similar to the present results, Stea et al. reported the effect of inhaling essential oils on postoperative pain . Also, tLikewise, in the study by Saghafi et al. on patients suffering from mastalgia, the effectiveness of essential oil of chamomile was demonstrated in controlling mastalgia . The abo. In addition, a study by Zargaran et al. indicated that the flavonoids of volatile chamomile oils could relieve migraine pain [Similar to the results of the present study, in Aradmehr et al.'s study, chamomile cream effectively reduced episiotomy pain in women . In the ine pain , which i1 macrophages which have anti-inflammatory effects [The analgesic pains of chamomile may be attributed to the following reasons: (1) the effect of Chamazulene and apigenin on activated macrophages leads to the inhibition of propagation and synthesis of nitric oxide; (2) chamomile flavonoids with potent inhibitory effects against prostaglandin E2 in macrophages can play a selective COX-2 inhibitor; (3) chamomile polyphenols can reduce pain because of inhibiting anti-inflammatory biomarkers in THP effects . It has  effects . Thus, i effects . In the  effects . The ant effects .Unlike the results of the present study, Pazandeh et al. found that the chamomile essential oil with steam distillation method did not reduce episiotomy pain . In the Although 12 h of oxygen therapy did not significantly reduce the pain, but on the other hand 18 h of oxygen therapy reduced the pain of the patients after the operation. The study by Shuh-Hofer et al. indicated that oxygen by preventing plasma protein leakage in the dura mater reduced inflammation of neural tissues; thus, oxygen was effective in treating headache . FurtherIn the present study, oxygen and chamomile aromatherapy indicated the greatest pain mitigation followed by aromatherapy and oxygen. These results suggested that oxygen with chamomile can have synergistic effects on reducing the severity of pain at the site of C-section, though they can also alleviate pain. A study in Egypt indicated that lavender aromatherapy through oxygen mask could reduce C-section pain . In the One of the strengths of the present study was that patients showed a greater desire to use traditional therapy such as chamomile aromatherapy or oxygen therapy for pain relief compared to analgesics, and this led to more patient cooperation in the research.However, the present study had some limitations. Since VAS is subjective in measuring pain, the scores given by patients may have had random errors. In addition, it was necessary for the patients with pain intensity above 3 to receive analgesics (PRN). However, despite the explanation about the lack of side effects of analgesics on the newborn, the patients were not eager to receive analgesics, particularly narcotics, since they were worried about transferring them to the newborn through their milk. It would have been better to use a placebo for the patients in the control group, but it was not possible because of the smell of chamomile. Moreover, it would have been more desirable to continue the pain measurement in 24 h after the cesarian section, but it was not considered in the design of the study.If these results are replicated in subsequent studies, the combined intervention of oxygen and aromatherapy is suggested as a cheap and side-effect free complimentary treatment for reducing pain of C-section patients undergoing spinal anesthesia post-operation.7The results of the present study suggest that the combined intervention of chamomile aromatherapy and oxygen had a more marked effect compared to oxygen and chamomile aromatherapy alone on reducing the pain post cesarean operation with spinal anesthesia, though each of them alone were also effective.Further studies are needed for the effect of these interventions on pain in a larger sample size by starting interventions faster after surgery, increasing the duration and frequency of interventions, and measuring pain 24 h after cesarean section in addition to the times of the present study. Moreover, the authors suggest that in future studies, measuring other variables such as anxiety associated with pain, analgesics required by patients, nausea and vomiting, sleep quality, and patients' overall satisfaction with the treatment received following chamomile aromatherapy with and without oxygen should be assessed.The authors stated no conflict of interest.Vice Chancellery of Research of Yasuj University of Medical Sciences, Iran.A part of this project was financially supported (Grant No. 960588) by the Nazafarin Hossein: Conceived and designed the experiments; Analyzed and interpreted the data; Wrote the paper. Afshin Mansourian: Analyzed and interpreted the data. Mahboubeh Mansourian: Contributed reagents, materials, analysis tools or data. Hajar Zamani: Performed the experiments; Analyzed and interpreted the data; Wrote the paper. Ardashir Afrasiabifar: Conceived and designed the experiments.Data will be made available on request.The authors stated no conflict of interest.


The aim of this study was to analyze pain after surgery with the use of self-fixated meshes, which are commonly used as an alternative for sutured mesh in open inguinal hernia repair.This prospective randomized clinical trial was conducted from November 2018 to March 2021, with a follow-up duration of 12 months. Male patients, aged 18–85, and suitable for day case surgery, were included. The patients received the self-adhesive Adhesix™ mesh or the self-gripping Progrip™ mesh in open inguinal hernia surgery. The primary outcome was the number of additional follow-up visits due to post-operative pain. Secondary outcomes included intensity of pain, quality of life measures, and complications.P = 0.333). Two hernia recurrences (1.0%) were established, one in each group.Two hundred seventy patients were included in this trial, 132 with Adhesix™ (A group), and 138 with Progrip™ (P-group). All patients’ medical records were reviewed 12 months after surgery, and 207 patients (76.2%) completed 12-month follow-up. The number of patients needing additional follow-up visits 3–12 months after surgery were comparable . The numeric rating scale was low at 12 months after surgery . The incidence of chronic pain, that is moderate or severe pain during exercise, was 5 patients (5.2%) with Adhesix™ and 8 patients (7.4%) with Progrip™ (At 1 year after hernia surgery, the use of self-gripping and self-adhesive meshes lead to successful pain reduction and quality of life improvement.Trial registration.ClinicalTrials.com NCT03734224. Groin hernia is a common disease, with more than 20 million patients worldwide undergoing hernia surgery each year . The tenThe main symptom caused by inguinal hernia is pain or discomfort in the inguinal area, occasionally affecting daily activities , 2. The Originally, the mesh was fixed using non-absorbable sutures in the Lichtenstein procedure . Today, The aim of the present study was to evaluate post-operative pain after open inguinal hernia surgery using two different self-fixated meshes. The short-term results of our randomized trial  demonstrThis was a prospective, randomized clinical trial. Patients were randomized in parallel groups, using two different self-fixating meshes in open inguinal hernia repair. Two surgical units in Finland, Helsinki University Hospital and Päijät-Häme Central Hospital, participated in this study from November 2018 through to March 2021.The study was approved by the ethics committee of Helsinki University Hospital (HUS/459/2018) and registered at ClinicalTrails.gov (NCT03734224). According to the study plan, an interim analysis was performed halfway through the study for safety reasons as well as to determine whether one of the groups had significantly better results than the other necessitating preterm stopping of the patient recruitment.Male patients aged from 18 to 85 years, suitable for day case surgery and presenting a symptomatic primary unilateral inguinal hernia, were included in this study.Exclusion criteria were bilateral, recurrent, or incarcerated hernia, an American Society of Anaesthesiologists physical status (ASA) of IV or more, and a body mass index higher than 35 or lower than 18. Also, teaching surgery  or cases, where the surgeon was inexperienced with both meshes (a minimum of five times use of both meshes was required) led to patient exclusion. Patients with inadequate language skills or patients not willing to participate were not included. The excluded patients were recorded  or self-gripping mesh  in an otherwise equal operation.n = 8) were experienced in open hernia surgery. The surgery was done preferably under local anesthesia, alternatively under general anesthesia, if local anesthesia was insufficient or at patients request. The operating surgeon administered the local anesthetics (Ropivacaine). Routine operative technique was used, with an anterior approach to the inguinal area. Indirect hernia sacs were dissected, and resected, and direct hernias were inverted. The regional nerves were preserved when possible. No additional mesh fixation was used, and the self-fixated mesh was placed on the pubic bone, the inguinal ligament, and the internal oblique aponeurosis.The operating surgeons  due to pain after the operation during the first three months was the primary outcome for this trial. Different measures of pre- and post-operative pain, i.e., the intensity of pain  and the use of pain medication, were secondary endpoints. Also, quality of life measures  and posDemographic data and pre-operative pain intensity were registered before the operation. The form of anesthesia, the duration of the operation, the hernia type, and the type of mesh used and possible nerve resection were recorded. Clinical examination was carried out before the operation. The follow-up at 1, 3, and 12 months after the operation was performed by inquiries collected by the surgeons. Additional evaluation at the outpatient clinic was performed only in patients with pain or complications needing treatment. All patients’ medical records were reviewed post-operatively.NRS pain scale (from 0 to 10) was assessed at rest, when coughing and during physical activity before surgery and at follow-up. The NRS scale is a simple and commonly used pain measurement tool, from 0 to 10, where 0 being “no pain” and 10 “the worst pain imaginable.” The RAND 36-Item Health Survey  is scoreα 0.05, β 0.80). With an estimated dropout rate of 10%, we aimed for 480 patients in total. Halfway, an interim analysis was conducted. A significant difference between the groups in primary outcome was found, and the recruitment of the patients was terminated.Sample size estimation for this study was based on our earlier published retrospective study , indicatt test or Mann–Whitney was used. Comparison of categorical data between the groups was performed by the chi-square test or Fisher’s exact test. Data is presented as mean (standard deviation) for numeric data and as frequency for categorical variables. A value of P < 0.05 was considered statistically significant.Variables were tested for normality of distributions with the Kolmogorov–Smirnov test. For numeric data, the independent samples All statistical analyses were performed using IBM SPSS statistics version 27 .The recruitment of patients was discontinued in June 2021 since a formal interim analysis for the primary endpoints was performed with significant differences in pain. Data of 270 patients were reviewed, and the results of the 3-month follow-up were reported previously . In May Two hundred seventy patients were randomly assigned into two groups between November 2018 and March 2021, 132 of whom received Adhesix™ mesh (A group), and 138 Progrip™ mesh (P group).Baseline characteristics and operating details were similar between the two groups, as shown in Table n = 19 vs. n = 4, P = 0.001), as presented in detail in our previous report [P = 0.502). To assess the total number of patients needing additional follow-up during the first year after surgery, all patients’ (n = 270) medical records were reviewed. Twenty-two (15.9%) patients in the P group and 6 (4.5%) in the A group (P = 0.002) suffered from pain leading to an evaluation at the operating hospital or health care center, with the vast majority of visits taking place during the first postoperative month. Table The primary outcome of this study was the number of patients needing follow-up visits in the health care center after the operation, due to post-operative pain in the inguinal area. During the first 3 months, the number of follow-up visits in the P group was significantly higher than in the A group (s report . At 1-yeP = 0.057) was diminished at 1-year follow-up .The degree of pain was estimated with the numeric rating scale (NRS) assessed at rest, when coughing and during physical activity. The mean NRS score at rest was low pre-operatively and at post-operative follow-up . At exercise, the mean NRS score was significantly improved at 1- and 3-month follow-up compared to the pre-operative state, after which it remained quite stable . Further, during exercise, 5 patients (5.2%) with Adhesix™ and 8 patients (7.4%) with Progrip™ suffered from moderate or severe pain (P = 0.333).Patients with NRS 0 have no pain, whereas NRS 1–3 describe mild pain, NRS 4–6 intermediate pain, and NRS 7–10 severe pain. At 1-year follow-up, most patients (87.3%) had no pain at rest, additionally 10.7% of all patients suffered from mild pain (NRS 1–3), with no significant difference between the groups. In the A group, none of the patients had moderate (NRS 4–6) or severe pain (NRS 7–10) at rest, and in the P group, 4 patients (3.7%) reported moderate pain  reported frequent pain at 1-year follow-up, while 80 patients (40%) rarely suffered from pain in the inguinal region. There was no significant difference between groups.Similarly, the questions regarding pain in the RAND-36-Item Health Survey showed significantly less pain up until 3 months post-operatively  compared to the preoperative  and early post-operative state . After that time point, the severity of pain was stable without differences between the groups .The dimensions in RAND-36 affected by pain are physical functioning and role limitations due to physical problems. At 1-year follow-up, both groups have high ratings in physical functioning  and only minor limitations due to physical problems . The RAND-36 survey results during follow-up are presented in Fig. n = 2, 1.0%), one in each group, were established at 1-year follow-up, one of whom had already been re-operated at 1-year follow-up. No other post-operative complications were detected. All early complications until 3 months after surgery were presented in our previous report [Two hernia recurrences  or visual analogue scale (VAS) to assess pain intensity. Hjermstad et al.  showed tMoreover, the advantage of self-adhesive mesh over self-gripping mesh, with respect to acute postoperative pain and faster recovery after surgery, which was detected in this trial , was no The indication for operative treatment of inguinal hernias is mainly pain or discomfort in the inguinal area  and the Except from pain-related issues, this study observed low recurrence rates; however, with an insufficient follow-up time, as only few recurrences are detected during the first year. Other research , 4, 10 aThis study has some limitations. First, reliable pain measurement is difficult. Many factors influence the sensation of pain. Therefore, we tried to present clinically relevant measurement which directly affect the patient or the health care system. Second, not all patients responded to the follow-up, nor where they routinely checked-up after surgery, although, as we have a national electronic health care database, considerable post-operative problems would have been detected during the reviewing of patients’ medical records at one year after surgery. Third, due to ethical reason, the recruitment of patients was terminated half-ways affecting the total number of recruited patients. The smaller sample size might have led to the lack of statistical differences between the groups. Also, the use of block randomization may cause imbalance in terms of secondary diseases such as diabetes mellitus. The strength of this study is the randomized clinical design and the comparable follow-up between the groups. This data provide knowledge on postoperative pain and its influence on actual daily life during the first year after surgery.To conclude, the data from this study demonstrate that surgical treatment of inguinal hernia significantly reduce pain in the inguinal area and improves quality of life. Although the self-adhesive mesh was slightly preferable than the self-gripping mesh in the initial recovery, the meshes were equivalent at 1-year follow-up, and the use of either mesh is appropriate in open inguinal hernia repair.


After PSM, 38 patients  were analyzed. The median overall survival (OS) in the LEN + TIT group was significantly higher than that in the LEN monotherapy group : 28.1 months vs. 11.6 months, p = 0.014). The OS in the LEN combined with transcatheter arterial chemoembolization and LEN combined with hepatic arterial infusion chemotherapy groups was significantly higher than that in the LEN monotherapy group . Independent factors associated with OS were alpha-fetoprotein and LEN combined with TIT. The indications for LEN combined with TIT were age <75 years and modified albumin bilirubin (m-ALBI) grade 1. We concluded that LEN combined with TIT may improve prognosis compared with LEN monotherapy in patients with advanced-stage HCC.This study aimed to evaluate the effect of lenvatinib (LEN) combined with transcatheter intra-arterial therapy (TIT) for advanced-stage hepatocellular carcinoma (HCC) after propensity score matching (PSM). This retrospective study enrolled 115 patients with advanced-stage HCC who received LEN treatment. The patients were categorized into the LEN combined with TIT group ( Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths, and its incidence is increasing worldwide, including in Asia . CurrentThe characteristics of the 115 patients with advanced-stage HCC are summarized in The objective response rate (ORR) and disease control rate (DCR) according to mRECIST, the ORR and DCR were 26.1% (30/115) and 78.7% (79/115), respectively .The median survival time (MST) was 12.8 months .p < 0.001) (p = 0.578), the OS in the LEN + TACE and LEN + HAIC groups was significantly higher than that in the LEN monotherapy group   A. Althouctively) B.To minimize the influence of confounding factors, PSM was conducted considering the following variables: age, sex, etiology, ALBI score, tumor size, tumor number, EHS, MVI, and AFP. After matching, there were no significant differences in age, ALBI score, or MVI between the LEN combined with TIT and LEN monotherapy groups .p = 0.032; 94.7% vs. 63.1%, p = 0.017, respectively).The therapeutic responses of the two groups are shown in p = 0.014) (p = 0.705), the OS in both the LEN + TACE and LEN + HAIC groups was significantly higher than that in the LEN monotherapy group   A. Althouctively) B.In the univariate analysis, tumor size, LEN combined with TIT, and AFP levels were included as variables. The multivariate analysis identified low AFP levels (<200 ng/mL) and LEN combined with TIT as independent predictors of better survival .The swimmer plot for patients treated with a combination of LEN and TIT after PSM is shown in p < 0.001)  .p = 0.559)  .In this study, the rate of LEN combined with TIT in all subjects was 26.1% at the time of study cessation. A decision-tree analysis was performed to determine the profiles associated with LEN combined with TIT. Age was identified as the first split variable for the rate of LEN combined with TIT. Among patients aged ≥75, the rate of LEN combined with TIT was only 0.3%, while among patients aged <75, the rate of LEN combined with TIT was 37.5%. Within the group of patients aged <75 years, the m-ALBI grade was selected as the second split, and the rate of LEN combined with TIT was 50% among patients with m-ALBI grade 1 .Severe AEs, defined as ≥3 as determined by the attending physician, are shown in In this study, we have shown that AFP levels and the combination of LEN with TIT were significant predictors of OS in patients with advanced-stage HCC after PSM. Our findings suggest that patients aged <75 years and with m-ALBI grade 1 should be considered for aggressive treatment with LEN combined with TIT.The present study revealed that the ORR and DCR were 26.1% and 78.7% according to mRECIST, and 12.2% and 78.7% according to RECIST, respectively, in patients with advanced-stage HCC treated with LEN. These therapeutic effects of LEN are consistent with those reported in a Phase III randomized clinical trial , indicatIn this study, we have demonstrated that low AFP levels and the combination of LEN with TIT were independent prognostic factors in patients with advanced-stage HCC after PSM. Alpha-fetoprotein (AFP) is a commonly used serum biomarker for assessing HCC management, tumor progression, and treatment response ,19,20. PRecent studies have also highlighted the potential benefits of combining TIT and LEN in improving clinical outcomes for patients with u-HCC ,11,22. ANotably, in the LEN combined with HAIC therapy group, the MST was 30.2 months, despite 75.0% of the patients having MVI. MVI is a critical condition that directly impacts liver function and is associated with a poor prognosis and shorter survival time ,33. Prevp = 0.001, respectively)  . The shoThis study has some limitations. First, it was a retrospective study. Second, there was selection bias in the classification of the LEN combined with TIT and LEN monotherapy groups. Third, the decision to add on-demand TIT was made by the attending physicians, introducing potential bias. Fourth, we could not provide enough experimental evidence. Thus, a randomized, controlled, prospective validation study is required to determine the efficacy of LEN combined with TACE and HAIC in a larger number of patients with advanced-stage HCC.n = 30) or the LEN monotherapy group (n = 85)  age > 18 years, (ii) Eastern Cooperative Oncology Group performance status (PS) < 2, (iii) Child–Pugh class A, and (iv) complete availability of clinical data and follow-up data until the end of the study period (31 May 2023) or death. Exclusion criteria were as follows: (i) Child–Pugh class B or C; (ii) BCLC stage 0, A, or B; and (iii) a history of allergy to iodine contrast media. A total of 193 patients were excluded, leaving 115 patients who were classified into two groups: the LEN combined with TIT group ((n = 85) . After P(n = 85) . The stuLEN  was administered orally to patients with u-HCC. The recommended oral dosage of LEN was 12 mg/day for patients with a body weight of ≥60 kg or 8 mg/day for patients with a body weight of <60 kg, as per the manufacturers’ instructions. However, a modified treatment protocol for LEN was employed, utilizing a 5 days on/2 days off administration schedule  , and theTherapeutic response was evaluated by performing dynamic computed tomography or magnetic resonance imaging every 4–6 weeks after the start of treatment, according to the modified response evaluation criteria in solid tumors (mRECIST) . The ComIn cases in which a therapeutic response to LEN treatment was observed, the treatment was continued. However, for patients who experienced disease progression following LEN treatment, especially when intrahepatic lesions were negatively correlated with patient survival ,43, we rTACE was conducted using the following procedure: angiography was performed through the celiac and common hepatic arteries using a 3 or 4 Fr catheter, and digital subtraction angiography was carried out employing a nonionic iodine contrast agent. After assessing the tumor-contained segment using imaging techniques such as cone-beam computed tomography, a 1.7 or 1.9 Fr microcatheter  was inserted towards the tumor-feeding artery. TACE was performed using 20–50 mg of epirubicin  or cisplatin  with lipiodol , based on the size and number of tumors, in addition to absorbable gelatin sponge particles  . SubsequTo implant the HAIC catheter, a 5-Fr-W-spiral catheter (Piolax) was inserted through the right femoral artery. The catheter was positioned with its distal end extending into the hepatic or gastroduodenal artery, and a subcutaneous port  was implanted in the front femoral region . For theA decision-tree algorithm was constructed to elucidate the relationship between the profiles and the administration of LEN combined with TIT, following the guidelines provided in the R software package (R-4.3.1), as previously described . Data miPSM is a method that addresses the variability in covariate distributions among individuals assigned to specific interventions. It is generated by considering potential covariates that may influence group allocation . In thisp < 0.05. Overall survival (OS) was calculated using the Kaplan–Meier method and assessed using the log-rank test or the Bonferroni method. Between-group comparisons were conducted using the Mann–Whitney U test and nonparametric analysis of variance. If the one-way analysis of variance yielded a significant result, differences between individual groups were examined using Fisher’s least significant difference test. The treatment duration of LEN and TIT, as evaluated by the investigators, was depicted using a Swimmer plot, as previously described [All data were presented as numbers or medians with ranges. Statistical analyses were carried out using JMP software . Statistical significance was defined as escribed . UnivariIn conclusion, we have demonstrated that LEN combined with TIT improves the prognosis compared to LEN monotherapy in patients with advanced-stage HCC after PSM. Moreover, our findings suggest that patients below 75 years of age and those with m-ALBI grade 1 may be suitable candidates for intervention with LEN combined with TIT.


To compare postoperative pain scores and opioid consumption in patients after transoral robotic surgery (TORS).Single institution retrospective cohort study.TORS was performed at a single academic tertiary care center.This study compared traditional opioid‐based and opioid‐sparing multimodal analgesia (MMA) regimens in patients with oropharyngeal and supraglottic malignancy after TORS. Data were obtained from the electronic health records from August 2016 to December 2021. The average postoperative pain scores and total opioid consumption in morphine milligram equivalents were calculated for postoperative days (PODs) 0 to 3. The secondary objectives were to quantify and characterize opioid prescriptions upon hospital discharge.p = 0.001), POD 1 (p = 0.001), and POD 3 (p = 0.004). Postoperative opioid consumption decreased significantly in the MMA cohort from 37.7 to 10.8 mg on POD 0 (p = 0.002), 65.9 to 19.9 mg on POD 1 (p < 0.001), 36.0 to 19.3 mg on POD 2 (p = 0.02), and 45.4 to 13.8 mg on POD 3 (p = 0.02). The number of patients discharged from the hospital with a prescription for narcotics was significantly lower in the MMA cohort (71.4%) compared with the non‐MMA cohort (98.3%) (p < 0.001).A total of 114 patients were identified for this study, 58 patients in the non‐MMA cohort and 56 in the MMA cohort. Postoperative pain levels in the MMA cohort were statistically lower on POD 0 (Implementation of our MMA pain protocol reduced pain levels and narcotic consumption in the immediate postoperative period. While multimodal analgesia (MMA) protocols have existed for over 2 decades for pain management, they have become more widely adopted due to the opioid crisis.MMA is a central component of enhanced recovery after surgery (ERAS) pathways, which aim to optimize patient outcomes postoperatively.However, there are few studies on MMA protocols for trans‐oral robotic surgery (TORS). TORS has become a primary treatment modality for early‐stage oropharyngeal cancers.The University of Southern California (USC) Institutional Review Board approved our retrospective cohort study (IRB Number: HS‐20‐00921). HNC patients undergoing planned TORS for primary SCC of the oropharynx and supraglottic larynx were consecutively enrolled from June 2019 to December 2021 in the MMA cohort. A retrospective control cohort of patients from August 2016 to May 2018 who received identical procedures but were not treated with an MMA protocol were enrolled consecutively for comparison. These procedures were performed at a single academic tertiary care center where patients were operated on by 1 of 3 microvascular trained otolaryngologists at the Keck Medical Center of USC.All subjects were over the age of 18 and underwent first‐time TORS for oropharyngeal and supraglottic laryngeal malignancy. Pregnancy was an exclusionary criterion. Patients undergoing repeat TORS, and those receiving TORS for nonmalignant etiologies were excluded from the study. Patients with a history of minor H&N surgery, H&N radiation, chemotherapy, and prior exposure to opiates were included.The H&N ERAS protocol was created by collaborative efforts between the departments of otolaryngology and anesthesia at the Keck Medical Center of USC. The H&N protocol integrates the core principles outlined by Dort et al at the ERAS society in 2017Preoperative data collected from our institution's electronic medical records (EMR) for secondary analysis included age, sex, alcohol and tobacco use, Charlson Comorbidity Index, prior history of H&N radiation, chemotherapy, and opiate use. Operative data collected included the primary site of malignancy. Postoperative data collected included surgical complications, final pathologic T‐ and N‐stage, patient‐reported numeric pain scores, strength and dose of opiate medication prescribed at discharge, admissions within 30 days, and emergency department admissions. Pain scores were reported by patients using an 11‐point pain scale ranging from 0 to 11  and recorded in the EMR by nursing staff. Patient controlled analgesia was not included in our analysis as these values are not uniformly recorded in our institution's EMR.Opioid consumption was converted to morphine milligram equivalents (MME), a standardized reporting scheme utilized in previously published work.The primary outcomes of this analysis were pain scores and opioid consumption documented within the first 72 hours postoperatively. Secondary outcomes were opioid prescribing patterns upon hospital discharge, hospital length of stay (LOS), and ICU LOS.χ2 and Fisher's exact test were used to analyze categorical variables and associations between treatment groups. Student's t‐tests were utilized to analyze continuous variables. Statistical significance was established as p < 0.05.Statistical analysis was performed using SPSS Statistics software . Descriptive statistics, including means, standard deviations, medians, and ranges, were used when appropriate. Pearson's p = 0.6), preoperative opioid use (p = 0.9), history of H&N irradiation (p = 1.0), T‐stages 1 through 4 , primary site of malignancy , human papilloma virus status (p = 1.0) and surgical complications. Demographic and hospital data are shown in Table A total of 114 patients were identified for this study, 58 patients in the non‐MMA cohort and 56 in the MMA cohort. The combined study population was 97 males (85.1%), 78 Caucasian (69%), and 101 (91.8%) non‐Hispanic or Latino patients. There were no significant differences in race (p = 0.001), POD 1 (p < 0.001), and POD 3 (p < 0.001). The overall average postoperative pain levels  were significantly lower (p < 0.001) in the MMA group  compared with the non‐MMA group  with a large effect size (d = 1.02). Postoperative opioid consumption (MME) decreased significantly in the MMA cohort from an average of 37.7 to 10.8 mg on POD 0 (p = 0.002), 65.9 to 19.9 mg on POD 1 (p = 0.001), 36.0 to 19.3 mg on POD 2 (p = 0.02), and 45.4 to 13.8 mg on POD 3 (p = 0.02). Average MMEs consumed postoperatively  were significantly lower (p < 0.001) in the MMA group  compared with the non‐MMA group  with a large effect size (d = 0.81). There was no significant reduction in ICU (p = 0.3) and hospital (p = 0.1) length of stay between each cohort. The primary and secondary objectives of this study are outlined in Table Average postoperative pain levels in the MMA cohort were statistically lower on POD 0  in the MMA cohort (71.4%) compared with the non‐MMA cohort (98.3%) (Table p < 0.001) patients  in the MMA cohort  were discharged with strong opiates compared with the non‐MMA cohort . Patients in the MMA  cohort were discharged with significantly more prescriptions for Tramadol (p = 0.004) than the non‐MMA cohort . The MMA cohort  received significantly fewer hydrocodone prescriptions (p < 0.001) at discharge than the non‐MMA cohort . The total average MMEs prescribed at hospital discharge for the MMA (203.6) was less than the non‐MMA (252.1), but not significantly reduced (p = 0.4) . Similarly, postoperative opioid consumption (MME) decreased significantly in the MMA cohort on POD 0, 1, 2, and 3. Average MMEs consumed postoperatively were significantly lower in the MMA group compared with the non‐MMA group with a large effect size (d = 0.81).Our study revealed a statistically significant reduction in the immediate postoperative pain levels and opioid requirements for patients with oropharyngeal and supraglottic SCC surgically treated with TORS. Average pain levels on POD 0, 1, and 3 were significantly lower in the MMA cohort compared with the non‐MMA cohort. Total pain levels averaged throughout the hospital admission for the MMA cohort were significantly reduced compared with the non‐MMA cohort with a large effect size . This trend continued when the prescribed opioids were dichotomized as strong or weak, in accordance with WHO and DEA regulations, showing MMA patients receiving significantly fewer strong opioids (p < 0.001). Specifically accounting for this result was a department‐wide shift in practice to discharge MMA patients with tramadol  in the place of previously opted for hydrocodone . This prescription pattern in the non‐MMA is not unique to our institution,p = 0.4) reduction in the MMA cohort (203.6 mg) compared with the non‐MMA cohort (252.1 mg). Reflecting on this data is essential to the manner our department addresses postoperative pain for TORS patients. If lower postoperative pain levels can be achieved with restrained use of narcotics, then perhaps patients do not require routine opioid prescriptions at discharge and should be evaluated more carefully.Upon hospital discharge, there was a significant decline in patients discharged with any opioid medication in the MMA cohort (A robust pain protocol is intimately linked with postoperative surgical outcomes. Ineffectually addressing postoperative pain may contribute to prolonged immobility, poor functional outcomes, and secondarily to wound infection, modest wound healing, extended hospital stays, and diminished quality of life.Our study adds to previously published work supporting the benefit of MMA protocols for robotic‐assisted surgery.This study has limitations warranting further discussion. The retrospective cohort design of this study may introduce a level of bias in so far as at the time of treatment, the attending physicians and residents were aware of the pain regimen each patient was assigned to. This knowledge could have raised the threshold at which providers were likely to order narcotics to address postoperative pain in the hospital and at discharge. We report on patient cohorts with primary SCC in various anatomic subsites of the oropharynx and larynx. The heterogeneity in disease sites may contribute to differences in the subjective experience of postoperative pain. However, the sites of primary malignancy did not vary between each cohort. When evaluating the impact of MMA on pain and opioid requirements among HNC patients, the variety in surgical procedures and heterogeneity in MMA protocols referenced in the literature contribute to the difficulty in comparing data in the relevant literature.The outlined MMA regimen is effective for pain management and opioid use reduction in the immediate postoperative period for patients treated with TORS for primary SCC of the oropharynx and supraglottic larynx at our institution. Additionally, the patient cohort treated with an MMA protocol was prescribed fewer strong‐classification opioids and overall opioids with no differences in postoperative complications, ICU, and hospital length of stay. The addition of MMA pain pathways in H&N surgery is a relatively new, yet a promising approach that will benefit from long‐term surveillance and constant reflection on prescribing practices and patient outcomes.Carlos X. Castellanos, drafting the work, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved, acquisition of data, conception of the work, data analysis, revision of the work critically for important intellectual content; Marcus Paoletti, drafting the work, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved, acquisition of data, data analysis; Ruben Ulloa, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved, data analysis; Celeste Kim, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved, acquisition of data, conception of the work, data analysis; Michelle Fong, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved, acquisition of data; Meredith Xepoleas, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved, acquisition of data; Uttam Sinha, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved, revision of the work critically for important intellectual content, final approval of the version to be published; Niels Kokot, conception of the work, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved, revision of the work critically for important intellectual content, final approval of the version to be published; Mark S. Swanson, conception of the work, acquisition of data, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved, revision of the work critically for important intellectual content, final approval of the version to be published.None.None.None.


Most patients who undergo laparoscopic cholecystectomy (LC) experience moderate to severe pain in the first 24 hours after surgery. The transversus abdominal plane (TAP) is currently used for post-LC analgesia. Posterior, subcostal, or rectus sheath TAP blocks are the conventional approaches used. The aim of the current study was to compare the efficacy of combinations of various peripheral blocks on pain intensity and the use of pain killers, shortly after LC.  This was a prospective, double-blind study, in which 200 patients who were about to undergo a LC procedure were recruited and randomized into 4 groups: patients receiving one of the following: TAP block alone, subcostal Tap block alone, subcostal TAP block with a TAP block, or subcostal TAP with a rectus sheath block. The intensity of pain (VAS score) and the use of painkillers were monitored in the recovery unit and in the department for up to 24 hours after surgery.  Pain levels decreased with time from 3.6 ± 3.2 at 30 minutes to 0.9 ± 2.0 at 24 hours after the surgery. Nevertheless, no difference between the various block types groups was noted. The percentage of patients who consumed analgesic medications decreased over time, from 83% at 30 to 21% at 24 hours after surgery. The mean/median number of medications consumed by each of the patients was lower among the patients who received a combination of 2 blocks compared to those who received a single one .  A combination of peripheral nerve blocks reduced the use of analgesic consumption during the 24 hours after LC surgery, compared to standalone blocks. The laparoscopy technique is considered to be superior to open surgery due to lower postoperative pain and early recovery . This prritoneum , 6. The ritoneum .n = 100) or without TAP (n = 100) in a retrospective cohort study. The mean postoperative opioid consumption was significantly lower among the patients who had LC with TAP compared to those who did not receive TAP . Patients who had LC with TAP reported at the follow-up visit that they used less of their prescribed opioids in comparison to patients who underwent LC without TAP (P < 0.001) [Postoperative pain is among the primary causes of reduction in respiratory function after upper abdominal surgery . Efficie< 0.001) .Although the conventional method of the TAP block is the posterior approach, the subcostal TAP block has been recently reported to induce an effective analgesia for the upper abdominal incisions . By thisAn additional technique to provide analgesia to the anteromedial abdominal wall is the rectus sheath block, first described in 1899 by Schleich. This technique targets the area between the rectus abdominis muscle and the posterior rectus muscle sheath. It blocks the anterior cutaneous branches of the intercostal nerves (at T7-T11) and therefore is well suited for postoperative analgesia for midline abdominal incisions , 26. HamThe aim of the current study was to compare the efficacy of combinations of various peripheral blocks on pain intensity and the use of pain killers, shortly after LC. Tap and subcostal TAP as standalone blocks were compared to the combination of subcostal TAP + TAP blocks and subcostal TAP + rectus sheath blocks.This was a prospective, double-blind study, in which 200 patients who were about to undergo a LC procedure were recruited. The study was approved by the Institutional Review Board  and registered at the My Trial database of the Israeli Ministry of Health (registration number MOH_2019-12-12_008555). All patients signed an informed consent form. The patients were randomized into 4 groups: patients receiving one of the following a TAP block alone, a subcostal Tap block alone, a subcostal TAP block with a TAP block or a subcostal TAP with a rectus sheath block. All those peripheral blocks were injected after the administration of the general anesthesia, before any surgical incision was performed. No sedatives were administered to the patients before the surgery procedure.The anesthesia was performed by a specialist anesthesiologist with over 10 years' experience who had over two years practice in the administration of the tested peripheral blocks.2 were excluded from the study.Male and female patients aged 18–70 years who were about to undergo a LC procedure participated in the study. Patients with any sensitivity to the anesthetic or with BMI ≥40 kg/mIn the operating room, the patient was attached to a standard monitor, recording electroencephalogram, noninvasive blood pressure, and saturation.Preoxygenation was performed for 4 minutes with 2 mg/kg fentanyl administered intravenously (IV), 2 minutes of 2 mg/kg propofol and 0.5 mg/kg rocuronium. The patient was then intubated and connected to an anesthesia machine. The anesthesia was maintained by isoflurane 1 MAC, muscle relaxants according to monitoring (3-4 mg/kg fentanyl). Additional monitoring of end-tidal carbon dioxide, body temperature, anesthetic gases, and breathing parameters was conducted after intubation. The administration of the various peripheral blocks was done after the patient was connected to the anesthesia machine. The blocks included 0.25% Marcaine (30 ml) and 2 mg dexamethasone. After surgery and extubation, the patient was transferred to the recovery unit.The intensity of pain and the use of painkillers were monitored in the recovery unit and in the department for up to 24 hours after surgery. Time points of monitoring were 30 and 60 minutes, 6, 12, and 24 hours after surgery.Pain intensity was monitored by the Visual Analogue Scale (VAS).Painkillers included NSAIDs and opioids. The consumption of the following painkillers was monitored: paracetamol (1 gr.), tramal (100–200 mg.), morphine (10 mg.), IV dipyrone (1 gr.), ketorolac (20–60 mg.), pethidine (50–100 mg.), and diclofenac (75 mg.).χ2 tests were used to identify the relationship between gender and categories of pain levels as well as drug types in each block and time point. One-way ANOVA was used to compare the mean number of drugs of the various blocks.The Pearson correlation coefficient was calculated for the correlation between age and pain levels; A mixed model analysis of variance calculated differences in the decrease in pain levels over time within each block and between the different blocks. P < 0.05 was considered significant.One hundred and eighty-nine patients were recruited for this study and were randomized equally into the 4 study groups. Most of the patients were females (66%). The mean age of the patients was 53.02 ± 17.1 years (range 18–80 years).As reported by the patients, pain levels decreased with time from 3.6 ± 3.2 at 30 minutes to 0.9 ± 2.0 at 24 hours after the surgery. A decrease in the levels of pain within time was also noted in all the block types groups, but no statistical significance between the groups was noted  = 57.843 and P < 0.001). Nevertheless, no difference between the various block types groups was noted (F(12.590) = 7.118 and P = 0.420).A mixed model analysis of variances also revealed that there was a clear difference in the decrease in pain levels over time . χ2 tests showed that there was no correlation between the gender and the pain level at any time point.A 2-tailed Pearson correlation coefficient test found a statistically significant relationship between age and level of pain at the time points of 30 minutes and 24 hours; as age increases, the level of pain decreases . Six hours after the surgery, tramal, dipyrone IV, and paracetamol were the medications most administered . Twelve hours after surgery, tramal and dipyrone IV were the main administered medications . Twenty-four hours after surgery, dipyrone IV was the most dispensed medication (administered to 8% of the patients) .Interestingly, the mean/median number of medications consumed by each of the patients was lower among the patients who received a combination of 2 blocks compared to those who received a single one . An independent-samples median test revealed that the difference in the mean/median between subcostal TAP single block treatment and the combined treatment of subcostal TAP + TAP was statistically significant with a P value of 0.025 .In addition, an independent-samples Kolmogorov–Smirnov test demonstrated that when pooling data of the number of medications consumed by each patient from the single block treatments and comparing it to the pooled data of the combined blocks treatments, a statistically significant difference was noted. Moreover, fewer medications per patient were administered to the patients receiving a combination of blocks compared to those who were treated with a single block  .It is important to note that during the 24 hours in which the patients were monitored, no side effects were reported, neither in the single block nor in the combined blocks treated patients.Post-LC pain is multifactorial, and therefore, multimodal analgesia has been suggested for its treatment. There are several methods for postoperative pain management, including peripheral nerve block techniques, which have received much attention recently due to their positive effect in reducing postoperative pain and good tolerance . TAP, suP = 0.31) However, fentanyl consumption in the recovery room was significantly lower in the TAP group (P = 0.0079) [P ≤ 0.001) [There are studies that have demonstrated the efficacy of each of the above blocks in reducing LC postoperative pain scores and lowering the consumption of painkiller. For example, Kadam et al. conducted a study aimed to evaluated postoperative pain and analgesic use during the first day after LC surgery, compared to local anesthetics and the TAP block. There were no significant differences in the postoperative pain scores between the local anesthetic and TAP block groups ( 0.0079) . In an a≤ 0.001) . Pain se≤ 0.001) . In a re≤ 0.001) . In a sy≤ 0.001) .In addition, comparative studies which examined the effect of TAP block versus subcostal TAP block have been published. Bhatia et al. conducted a prospective, randomized, double-blind study in which 60 patients who underwent LC received the standard general anesthesia or an ultrasound-guided posterior TAP or a subcostal TAP block. At the initial postoperative measurement times, the subcostal and posterior TAP groups had comparable pain scores. However, 4 hours after the operation, the scores were significantly lower in patients who had received the subcostal TAP block compared to those who were treated with posterior TAP . In a prHowever, as of yet, there have not been extensive studies of the effect of combined peripheral nerve block techniques in reducing LC postoperative pain scores and the reduction of the consumption of additional analgetic medications. The rationale underlying the combination of the blocks is that administration of both peripheral blocks, each affecting different nerve areas , could affect and block the entire area of surgery. Thus, the aim of the current study was to evaluate the postoperative pain control of a combination of TAP + subcostal TAP blocks and subcostal TAP + rectus sheath blocks compared to TAP or subcostal TAP blocks as a standalone treatment. The maximal level of pain upon LC is recorded during the first 24 hours after surgery [n = 20), oblique subcostal TAP block alone, and a conventional port-site infiltration group as a control group (n = 20). The combined group as well as the oblique subcostal TAP block alone presented lower pain scores during the time points up to 24 hours postoperation, as well as the reduced use of analgesia compared to the control group [Jung et al. examined the effect of the combination of subcostal and lateral TAP blocks on the quality of recovery among 38 patients who underwent LC compared to control patients who underwent a sham block. The primary outcome of the study was the score of the quality of recovery-40 (QoR-40) questionnaire. The combination of the two blocks did not improve the QoR-40 or analgesic consumption during the first 24 hours after the surgery . A prospol group . Those sThe lack of difference in the pain level and consequent analgesic consumption between the various block combinations and the standalone blocks might be explained by the fact that the analgesia regimen administered to patients obscured the blocks effect. In addition, the various antinociceptive agents which are included in multimodal general anesthesia affect multiple neurotransmitters and neural relays and thus offset the supposed additive effects of the combined or the standalone blocks .The results of the present study indicated that a combination of peripheral nerve blocks reduced the use of analgesic consumption during the 24 hours after LC surgery, compared to standalone blocks. Considering these findings, we recommend their use for reducing the administration of additional analgesics shortly after LC.The present study has some limitations. It was a single-center study with a small sample size. Pain assessments were not performed by a single caregiver, which could have led to a bias in the reporting scores. Also, the pain scores did not evaluate the patient's pain during movement. In addition, nausea and vomiting were not assessed.