Patients working full-time had some positive effect of atomoxetine on pain facilitation (p < 0.05). Unemployed patients had some negative effect of citalopram on pain tolerance and experienced exercise-induced hypoalgesia (p < 0.05). (4) Conclusions: A single dose of citalopram or atomoxetine did not result in changes in hypoalgesia at rest and in response to exercise. These results do not support the use of SSRI or selective NRI to overcome impaired hypoalgesia at rest or in response to exercise in people with chronic WAD. Effect of exercise and medication on pain in patients with chronic WAD is influenced by the occupational status.(1) Background: Noradrenaline and serotonin have modulatory roles in pain signaling and in exercise-induced hypoalgesia. Patients with chronic whiplash-associated disorders often show impaired exercise-induced hypoalgesia. Therefore, this study aimed to examine the isolated effect of activating serotonergic or noradrenergic descending pathways on hypoalgesia at rest and in response to exercise in patients with chronic WAD by using respectively a single dose of a selective serotonin reuptake inhibitor (SSRI) and a selective norepinephrine reuptake inhibitor (NRI). (2) Methods: Twenty-five people with chronic WAD participated in this double-blind randomized controlled crossover experiment. Serotonin and noradrenaline concentrations were modulated by the oral ingestion of a single dose of citalopram  or atomoxetine . Quantitative sensory testing (including pressure pain thresholds and conditioned pain modulation) was measured before and after exercise in combination with no medication (1), atomoxetine (2), or citalopram (3) at three different test days. (3) Results: Random-intercept linear mixed models analysis was used to analyze pain outcomes  before and after exercise over the three conditions in patients with chronic WAD. No differences in pain at rest were found between the three conditions before exercise. The effect of exercise on pain outcome measures was not influenced by medication intake. The occupational status of the participants had a significant influence on the effect of exercise and medication on pain outcomes ( Descendtivation ,3. This tivation . These etivation . HoweverWAD are the result of an acceleration–deceleration trauma of the neck. Patients with chronic WAD primarily have persistent neck pain, but the clinical representations can also include fatigue, concentration difficulties, headaches, and reduced quality of life ,7. The cIn normal circumstances, aerobic exercise will lead to an increase in pain thresholds and a decrease in pain ratings ,15. ThisFor the reasons outlined above, this study aims at unravelling the biological nature of impaired hypoalgesia at rest and in response to exercise in patients with chronic WAD. More specifically, it is aimed to examine the isolated effect of activating serotonergic or noradrenergic descending pathways on hypoalgesia at rest and in response to exercise in patients with chronic WAD by using respectively a single dose of a selective serotonin reuptake inhibitor (SSRI) and a selective norepinephrine reuptake inhibitor (NRI). We hypothesized that activation of serotonergic and/or noradrenergic descending pathways would improve hypoalgesia at rest and in response to exercise in patients with chronic WAD. In addition, it is aimed at examining whether activation of serotonergic and/or noradrenergic descending pathways prevents post-exertional malaise following submaximal exercise in chronic WAD patients. In order to examine the study aims, the study comprised a double-blind randomized controlled crossover experiment comparing three conditions: (1) no medication intake (baseline condition), (2) after intake of 20 mg citalopram (SSRI), and (3) after intake of 40 mg atomoxetine (selective NRI). The a priori sample size calculation was conducted with G*Power 3.1.5  . The samIn order to prevent recruitment bias and optimize the external validity of the study findings , people People with chronic WAD were eligible if they had persistent neck pain lasting at least 3 months resulting from a motor vehicle collision or traumatic event classifiable as WAD I, II, or III according to the Quebec Task Force criteria . FurtherBaseline assessments were performed on the first test day without medication intake. These assessments consisted of the completion of a demographic questionnaire, the Neck Disability Index (NDI), and a visual analogue scale (VAS) to investigate self-reported levels of pain. Next, pressure pain thresholds (PPTs), conditioned pain modulation (CPM), and temporal summation (TS) were examined. Pain measurements  were assessed immediately before and immediately after a single submaximal aerobic exercise bout. In addition, participants were also asked to indicate their level of pain (VAS pain) 24 h after the exercise. Finally, cognitive performance was also assessed at baseline and after exercise, but the methods and results of the cognitive performance tests are reported elsewhere . After baseline assessment, an independent researcher who was not involved in recruitment, assessments, interventions, or statistical analyses randomly allocated the participants to one of the 2 groups (group 1 = day 8: selective NRI + day 15: SSRI and group 2 = day 8: SSRI + day 15: selective NRI) according to a computer-generated randomization list. On day 1, participants received their first single dose of medication (blinded) for day 8 as well as further verbal and written instructions regarding its administration see . One weeAll assessments in each patient were performed by the same researcher. After the final assessment, the success of patient and assessor blinding was examined by asking the patient and the assessor to indicate group allocation, including the percentage of certainty . If applicable, the reasons for withdrawal from the study were monitored. The measurements of a participant sample presenting considerable overlap with the current study sample was used in our previous studies with regard to the effect of exercise on pain and additional influence of SSRI and selective NRI medication on cognitive performance in people with chronic WAD and healthy controls ,24.® ) 4 h and atomoxetine ) 1.5 h before the scheduled start of their next appointment. Participants were instructed not to ingest food thirty minutes before and thirty minutes after medication intake to ensure that the attainment of the peak concentration was not slowed down. Both pills had exactly the same visual appearance. They were transparent hard-shelled capsules filled with dry white powder.In order to ensure peak concentrations at the time of testing, all participants were instructed to take citalopram , with the seat adjusted to be appropriate for each participant. Once the participant was adjusted to the resting position for 2 min and the heart rate monitor  was switched on, resting heart rate was recorded. The workload started at 25 W and was increased by 25 W every minute until the participant reached the submaximal level . The target heart rate is defined as 75% of the age-predicted maximal heart rate: (220–age) × 0.75. Participants were instructed to cycle at a constant pedaling rate of approximately 60 rounds per minute. Heart rate was recorded at the end of every minute. The submaximal exercise was terminated when participants reached their individual target heart rate. Cooling down comprised 1 min of cycling at a workload of 25 W and a rate of 60 rounds per minute. The test duration was maintained below 15 min to avoid early fatigue in the lower extremities due to insufficient physical fitness. This exercise protocol is defined as the aerobic power index test , which hDemographic characteristics such as age, sex, height, weight, disease duration, occupational status, educational level, possible legal conflict, and medication use were questioned.The NDI was used to investigate neck-pain-related disability levels (0–100) ,33. HighParticipants had to indicate their present levels of pain on a VAS by drawing a vertical line on a 100 mm horizontal line with the left marked “no pain” and at the right “worst possible pain”. A score ranging from 0 to 100 was obtained. The VAS was filled out 3 times for each test day: immediately before, immediately after, and 24 h after the submaximal exercise to investigate post-exertional symptom changes. This patient-reported measure shows good validity and reliability ,37.To investigate pain sensitivity, endogenous hypoalgesia, and pain facilitation, participants were subjected to experimental pain assessments: PPTs, CPM, and TS. Experimental pain measurements were executed before and after every submaximal aerobic exercise. The experimental pain assessments consisted of the following four-phase procedure. The first phase comprised the determination of the PPTs at the right shoulder  and at the right calf muscle belly  with an analogue Fisher algometer . In order to determine PPTs at each location, pressure was gradually increased at a rate of 1 kg/s until the participant reported first onset of pain (participants were instructed to say “stop” at that point). The PPT was determined as the mean of two consecutive measurements (30 s in between). The second phase comprised the examination of TS: at each location , TS was provoked by means of ten consecutive pressure pulses (test stimulus). The magnitude of these pressure pulses corresponded to the previously determined PPT (explained in the previous paragraph). To preclude bias originating from possible sensitization of PPT assessment, TS was initiated 2 min after the determination of the PPT. For each pressure pulse, pressure was gradually increased at a rate of 2 kg/s to the predetermined PPT and maintained to that point for 1 s before being released. An interstimulus interval of 1 s was used. The participants were asked to rate the intensity and unpleasantness of the pain of the 1st, 5th, and 10th pressure pulse on a verbal numerical rating scale . After TS was measured on the shoulder as well as on the calf, a rest period of 5 min was allowed before investigating CPM . TS was calculated as the VNRS score of the 10th pressure pulse minus the VNRS score of the 1st pressure pulse. During the third phase, the measurement of CPM was performed. The conditioning stimulus was the inflation of an occlusion cuff at the participant’s left arm to a painful intensity. The occlusion cuff was inflated at a rate of 20 mmHg/s until “the first sensation of pain” was reported. This cuff inflation was maintained for 30 s. The participant was then asked to rate the pain intensity on a VNRS (0 = no pain to 10 = worst possible pain). Depending on the VNRS score, the cuff inflation was then increased or decreased until pain intensity was rated by the participant as 3/10 . Next, the above-mentioned TS procedure  was repeated during maintenance of the cuff inflation ,39. To fIn sum, outcomes for the experimental pain measurements were as follows: PPT shoulder, PPT calf, TS shoulder, TS calf, CPM shoulder, CPM calf, and cuff pressure VNRS 3. p < 0.05 (2-sided) was considered significant.All data were analyzed using SPSS, version 25 . Normality of demographic variables was checked using the Shapiro–Wilk test, and appropriate statistics were calculated for the participant characteristics. To assess the difference in pain outcomes between the three experimental conditions in response to the exercise intervention, a random-intercept linear mixed models analysis was applied. For each outcome measure, the best fitted model was achieved by use of the Akaike information criterion (AIC) . Every model included the “experimental condition” , “time” , and “experimental condition × time interaction” as fixed effects together with a random intercept for each patient. Further covariates were added in a stepwise manner and included when this led to a significant decrease in AIC. Covariates that could be included were age, sex, body mass index, duration of illness, involved in legal conflict, occupational status, use of pain medication prior to study participation, and randomization. Medication use was used to account for possible influences of medication use prior to study participation. The randomization was used as a covariate to control for possible carry-over effects and the influence of order in which medications had been administered. Neither medication nor randomization had a significant influence on the outcome measures. The covariate occupational status had a significant influence on almost all outcome parameters. Therefore, sub-analyses using random-intercept linear mixed models were carried out to investigate the main outcome parameters in the subgroups “working full-time” and “unemployed”. These two groups were formed out of the main analysis, which demonstrated a significant difference between these groups. Post hoc analyses with Bonferroni correction were executed if the factors “experimental condition”, “time”, or “experimental condition x time” appeared significant. This mixed model analysis allowed us to take dropouts into account. All available data were included in the models, even if only data of one or two of the three test days was available. p > 0.05). Further characteristics of the participants are presented in In total, 25 people with chronic WAD were included in the study (10 men and 15 women). The mean age of the participants was 40 years, ranging from 18 to 59 years. One person was using antidepressants but discontinued its use two weeks prior to baseline. Eight participants reported the use of analgesics but refrained from intake on assessment days. At baseline, the mean pain-related disability level as measured with the NDI was 40.2/100, which corresponds to a moderate level of impairment . The levp-values ranging from 0.096 to 0.913, The results regarding cognitive performance are reported elsewhere . The resp = 0.022). Other outcome measures did not show any significant time effect. The self-reported and experimental pain measurements were analyzed over the three experimental conditions. Detailed results are reported in n = 8) and participants who were unemployed (n = 9). “Unemployed” participants are considered to be part of the active working population but who are currently not at work; this group does not entail students or retired persons. Unemployed participants had their whiplash accident more recently with a median duration since the accident of 6 months (IQR 4 months) and a higher disability  compared to the participants working full-time . Regarding the pain outcome measures in the unemployed group, the cuff pressure VNRS 3 showed a significant effect of the experimental condition. Bonferroni post hoc analysis showed that the citalopram condition had a lower cuff pressure VNRS 3 compared to the baseline condition (mean difference 21.3 (8.3 SE) p = 0.042), although it was not significant for the atomoxetine condition (mean difference 20.2 (8.7 SE) p = 0.077). Further, in the unemployed group, significant effects of time were found for TS and CPM at the shoulder. Bonferroni post hoc analysis showed a significantly higher TS  and higher CPM values  after aerobic exercise compared to less pain facilitation and better hypoalgesia pre-aerobic exercise (TS: mean difference −0.394 (0.189 SE) p = 0.044; CPM: mean difference −0.458 (SE 0.214) p = 0.039). No significant condition effects were found in the subgroup of participants who had a full-time occupation. Besides a marginally significant interaction effect for TS at the calf , Bonferroni post hoc analysis of this interaction effect revealed an effect of time: reduced TS  after aerobic exercise compared to pre-exercise but only in the no medication condition (mean difference 0.938 (SE 0.397) p = 0.024). This interaction effect also contained significant results during the pre-exercise phase: a reduced TS  in the atomoxetine condition compared to the no medication (mean difference 1.063 (SE 0.397) p = 0.024) and citalopram conditions (mean difference 1.167 (SE 0.414) p = 0.034). Details regarding the sub-analyses and post hoc analyses can be found in Within all the best fitted mixed models, for six out of seven outcome parameters, the covariate occupational status appeared to have a significant influence . Post hoThis study aimed at examining the isolated effect of activating serotonergic or noradrenergic descending pathways on hypoalgesia at rest and in response to exercise in patients with chronic WAD. Contrary to our hypothesis, neither a single dose of SSRI nor selective NRI improved hypoalgesia at rest or in response to exercise in patients with chronic WAD. It was also found that a single dose of SSRI or selective NRI is unable to prevent post-exertional malaise following submaximal exercise in patients with chronic WAD. Taken together, a single dose of SSRI or selective NRI was unable to change hypoalgesia at rest, exercise-induced hypoalgesia, or post-exertional malaise in patients with chronic WAD. However, the occupational status of the patients with chronic WAD was identified as a confounder, as it had a consistent influence on the results. The intake of one dose of atomoxetine or citalopram neither influenced the self-reported pain levels nor the experimental pain measurements in patients with chronic WAD. Serotonin and noradrenaline reuptake inhibitors have been proposed as one of the preferred pharmacological options for pain in patient with predominant nociplastic pain . TheoretThe intake of one dose citalopram or atomoxetine in combination with an acute bout of submaximal aerobic exercise did not influence pain experience or experimental pain outcomes in patients with chronic WAD. These results do not support the hypothesis that an SSRI or selective NRI can improve exercise-induced hypoalgesia. Serotonin is involved in exercise-induced hypoalgesia in both humans and animals . ExercisBesides the serotonin system, the adrenergic system is also activated during exercise and may participate in exercise-induced hypoalgesia. With the release of hormones and neurotransmitters such as catecholamines, these catecholamines may modulate the nociceptive pathways, leading to reduced firing rates of excitable cells . The stuThe bout of submaximal aerobic exercise did influence the pain experience in response to exercise in patients with chronic WAD. Patients demonstrated reduced local endogenous hypoalgesia (measured with the CPM paradigm) at the shoulder after exercise. However, SSRI or selective NRI intake did not influence this response. At the calf, CPM demonstrated hypoalgesia before as well as after exercise, with no differences between experimental conditions. Results of the no medication condition in comparison with healthy participants have been reported elsewhere . In summThe two most extreme groups—patients who were working full-time versus unemployed patients—did experience an effect of atomoxetine and citalopram intake. Within the unemployed group, the intake of citalopram resulted in lower cuff pressure, indicating a lower pain tolerance level. This negative effect of the single dose of SSRI was not seen for the other outcome parameters. Patients with chronic WAD are likely to have nociplastic pain, making them more vulnerable to side effects  . FurtherTaken together, the results of the sub-analysis indicate that patients with chronic WAD who are unemployed demonstrate a worse reaction on exercise and intake of citalopram had a negative influence on their pain. Patients with a full-time occupation demonstrated some positive effects of exercise on pain measurements and the intake of a selective NRI had a positive effect when not combined with exercise. The disease duration on itself did not influence outcome measures, indicating that the occupational status is not a reflection of the stage of chronicity. These results should be interpreted with caution since this is a sub-analysis based on small groups. Still, the results are surprising since the medication intake was expected to be more effective in patients with a worse clinical picture compared to patients with milder symptoms. These findings underline the importance of subgroup identifications and strategies to develop individualized pharmacological treatment plans in patients with chronic pain  or patieThe results should be seen with the recognition of some limitations. Firstly, the study aimed to investigate the short-term effect of a single dose of atomoxetine and citalopram. Nonetheless, this type of medication is usually taken for a longer period and different responses might be seen investigating the interaction with exercise in patients with a stable intake of these medications. SSRIs have at least two weeks of steady state administration to produce noticeable anti-depressant effects for depressive disorders or analgesic effects for neuropathic pain, while the effect onset of atomoxetine in adults is approximately 2 weeks. Secondly, the participants were blinded for whether they had taken citalopram or atomoxetine, but unfortunately it was not possible to blind them for the test day without medication. The intake of a placebo would have solved this, but this was omitted from the study protocol for ethical reasons. Third, temporal summation is typically elicited with application of stimuli <0.33 Hz, which was not achieved in this study. Fourth, a healthy control group would have been useful for comparison and to establish whether or not hypoalgesia at rest and exercise-induced hypoalgesia in patients with chronic WAD was (dys)functional.This study also has several strengths. First, this is one of the only human experimental studies in patients with chronic pain that explores the potential role of various brain neurotransmitters in explaining dysfunctional pain modulation at rest and during exercise. The crossover experimental design is another major strength. The study design allows us to single out the effect of the various experimental conditions without between-subject variability. The used statistical methodology is also a strength of this study. The mixed models analysis that accounted for the many possible confounding factors allowed us to interpret the data with knowledge of its influencing factors and without data loss due to dropout. This study showed that a single dose of citalopram or atomoxetine was unable to improve hypoalgesia at rest, exercise-induced hypoalgesia, or post-exertional malaise in patients with chronic WAD. However, the occupational status of the patients with chronic WAD was identified as a confounder, with patients who were unemployed seeming to have more negative effects of exercise and experience the additional negative effect of citalopram, whereas patients with a full-time occupation experienced some benefit of exercise and might have additional positive effects of the intake of atomoxetine.


BackgroundDental extraction is one of the common procedures in the field of dentistry. However, fear and anxiety about local anesthetic injections are unavoidable for most patients. Topical anesthetics, distraction techniques, acupuncture, and the application of heat or cold have been used in practice to alleviate injection-related pain. The specific aim of this study was to compare the pain-relieving efficacy of eutectic mixture of local anesthetics (EMLA) vs. ice during the administration of a long buccal nerve block (LBNB) before dental extraction.Materials and MethodsIn total, 20 healthy adult patients who required bilateral mandibular posterior teeth extraction under local anesthesia were enrolled. The study was conducted in the Department of Oral and Maxillofacial Surgery, Saveetha Dental College and Hospitals, Chennai, from January 2023 to May 2023. It was a prospective split-mouth study in which each participant was divided into two groups according to the operative site: Group 1, which received a 5% EMLA cream, and Group 2, which received an application of ice before administration of LBNB. There was a one-week interval between the two interventions. The levels of pain and satisfaction were assessed using the visual analogue scale (VAS) and pain perception was evaluated by the sound, eye, motor (SEM) scale. Mann-Whitney U test was applied for the statistical analysis.ResultsThe study included a total of 20 participants, with 14 being male and six being female. The mean age of the study population was 42 ± 15 years. When analyzing the pain scores using the VAS, it was found that Group 1 had a mean score of 2.4 ± 0.44, while Group 2 had a mean score of 3.0 ± 0.44. This difference between the two groups was statistically significant (P = 0.001). It was also found that the mean patient satisfaction score for Group 1 was 9.8 ± 0.22 and for Group 2 was 9.2 ± 0.40 which was statistically significant (p = 0.003). Similarly, Group 1 had a mean SEM score of 1.1 ± 0.1, while Group 2 had a mean SEM score of 1.30 ± 0.46 which was also statistically significant (P =0.016).ConclusionThe study results revealed that EMLA has a significant advantage over ice in terms of lower levels of pain, more patient satisfaction, and higher comfort levels. EMLA can be considered the first choice of topical anesthetics, however, ice is recommended in resource-constrained dental set-ups as it is cost-effective. The administration of local anesthetics through injections is a distressing and anxiety-inducing aspect of dental procedures, impeding the delivery of appropriate dental care. Long buccal nerve block (LBNB), in particular, causes significant pain due to the contact of the needle with the underlying periosteum. Various criteria such as the patient's anxiety, fear perception, and individual pain tolerance during injections, lead to the exploration of topical anesthetic agents as potential solutions . VariousThe most widely recommended approach for minimizing pain during local anesthesia is to apply a topical anesthetic before the injection. Research demonstrated that patients felt more comfortable when a topical anesthetic was applied beforehand, resulting in reduced anxiety and diminished pain from the needle prick . The sitEven though ELMA has excellent topical anesthetic properties in the skin, it has conflicting results in the oral mucosa . To our Study designIn total, 20 healthy adult patients who required bilateral mandibular posterior teeth extraction under local anesthesia were enrolled. The study was conducted in the Department of Oral and Maxillofacial Surgery, Saveetha Dental College and Hospitals, Chennai, from January 2023 to May 2023. The study commenced after obtaining ethical clearance from the Institutional Human Ethical Committee (IHEC/SDC/OMFS-2201/23/167). Inclusion criteria for this study were that participants had to be at least 18 years old, classified as American Society of Anesthesiologists (ASA) class I, have not taken analgesics or painkillers within the past 24 hours, have no contraindications for undergoing the extraction of posterior mandibular teeth under local anesthesia; they also had to be available after one week for a second intervention. Patients with systemic disorders, lactation, pregnancy, a history of allergies, or any concomitant pathologies were excluded from this study. Participants who met the inclusion criteria were enrolled after giving their informed consent.Randomization and allocation process http://www.randomization.com was used for the random assignment of the site for the group allocation. The treatment allocations for the clinician were provided in sealed, opaque envelopes, generated randomly. Once a patient agreed to participate in the trial, an envelope was opened, revealing the assigned treatment regimen. The treatment was then performed on the patient after obtaining informed written consent. One side of the treatment area of 20 sites receiving EMLA 5% cream (containing 2.5% lidocaine w/w (25 mg/g) and 2.5% prilocaine w/w (25 mg/g)) was designated as Group 1 while the contralateral side was designated as Group 2, with 20 sites subjected to the precooled ice application. The data collectors and analysts involved in the study were blinded to ensure impartiality when recording and evaluating the treatment outcomes.Participants who volunteered for this study were randomly divided into two groups, each consisting of 20 individuals, resulting in a total of 40 sites. The random number generator from the website Surgical techniqueThe patient was kept in an upright position in the dental chair to prevent the topical agent from flowing toward the soft palate and pharynx. To ensure a dry surface, the clinician used a sterilized 2x2 cm gauze to remove the saliva from the buccal mucosa distal to the second molar. Out of the total 40 sites, half were subjected to treatment with EMLA 5% cream Figure , while tPrimary outcomesThe VAS is considered the most appropriate tool because of its simplicity; less than a minute is sufficient for recording and no special training is required hence many authors already used it in their studies ,5. It waStatistical analysisStatistical analysis was done by Statistical Package for Social Sciences (SPSS) for Windows version 20.0.  and Microsoft Excel v. 2007. Quantitative variables were summarized using the mean and standard deviation, while categorical variables were summarized using frequency and percentage. The primary outcomes, which include the mean scores of VAS pain, VAS satisfaction, and SEM, were compared between the two groups using the Mann-Whitney U test. A p-value < 0.05 was considered statistically significant. Twenty patients were enrolled in the study; hence 40 sites were equally allocated between Group 1 and Group 2 according to randomization. Among the participants, 14 (70%) were male, with ages ranging from 35 ± 5 years and six (30%) were female with ages ranging from 42 ± 5 years. The commonest extracted tooth in patients was the mandibular right third molar tooth (20%) and the mandibular left second molar tooth (7%) as shown in Table Visual analogue scale The study results revealed that Group 1 mean VAS pain score was 2.4 ± 0.44 and Group 2 mean VAS pain score was 3.0 ± 0.44 (mean ± standard deviation), respectively. This difference was found to be statistically significant (p = 0.001). The pain score demonstrates that Group 1 experienced minimal pain compared to Group 2. In addition, it was also found that the mean patient satisfaction score for Group 1 was 9.8 ± 0.22 and Group 2 was 9.2 ± 0.40. This difference in pain satisfaction between the two groups was statistically significant (p = 0.003). This suggests that Group 1 was more satisfied than Group 2. SEM scaleAccording to the statistical study, Groups 1 and 2 had mean SEM scale values of 1.1 ± 0.1 and 1.30 ± 0.46 (mean ± standard deviation), respectively. This difference was found to be statistically significant (p = 0.016). The analysis indicated that Group 1 had a higher level of comfort compared to Group 2, as reflected by a lower score for pain perception on the SEM scale for Group 1. This difference was statistically significant, highlighting the superior comfort experienced by Group 1 patients. Both the group's mean values of the primary outcome variables are shown in Table When undergoing dental extractions, patients frequently struggle with issues such as dental anxiety and a fear of needles. A medical condition known as needle phobia, which affects approximately 10% of the population, has been linked to a variety of changes in a person's physiology, including variations in blood pressure, heart rate, electrocardiogram, and stress hormones . A numbeCryoanesthesia is an additional method for the elimination of pain. This technique involves blocking local neural transmission by cooling the area that is experiencing pain. The application of refrigerant sprays and the utilization of ice are both viable options for accomplishing this goal. Ice application for the purpose of pre-cooling has been used for achieving anesthesia in the local site and analgesic effects for thousands of years . A studyOur study results found that patients who had undergone EMLA had significantly less pain and reported a higher level of overall satisfaction than those who had undergone ice treatment. Between the two groups, the pain difference (p = 0.001) and the patient satisfaction score difference (p = 0.003) were statistically significant. These findings are in accordance with the studies carried out by Vickers and Punnia-Moorthy as well as Pere et al.; in both studies, it was found that EMLA cream containing 5% was the most effective topical anesthetic for reducing the amount of pain that was experienced during the insertion of a needle ,15. StudThe patient's response to stimulation was evaluated in our study using the SEM scale, which measures the patient's reactions in terms of sound, eye, and motor reactions. This allowed us to get a more accurate picture of the patient's overall level of comfort. The comparison of the EMLA and ice groups' levels of comfort in terms of pain perception revealed a distinction that was statistically significant between the two categories (p = 0.016). The study reveals that EMLA demonstrates a significant advantage over ice in diminishing pain and enhancing patient contentment. Surprisingly, the clinical evaluation scores for both EMLA and ice groups exhibited minimal disparity concerning pain and satisfaction. Nonetheless, it is worth noting that ice remains a viable and cost-effective substitute for EMLA cream, readily accessible for use . The unpThe patients and the operator both felt the cold during pre-cooling, so it was impossible to blind either of them to the results of the study. This was one of the limitations of our investigation. The use of cream also made it difficult to achieve the desired effect of blinding. Because the effects of the topical anesthesia produced by ice wore off more quickly than expected, the injection of the local anesthetic had to be done more quickly . In our The study results revealed that EMLA has a significant advantage over ice in terms of lower levels of pain, more patient satisfaction, and higher comfort level. EMLA can be considered the first choice of topical anesthetics, however, ice is recommended in resource-constrained dental set-ups as it is cost-effective.


Cooled radiofrequency ablation (CRFA) and cryoneurolysis (CRYO) are two novel methods of genicular neurolysis to relief pain in symptomatic knee osteoarthritis (KOA). In this study, the two methods will be compared, giving us the opportunity to investigate their efficacy, safety and complications.In this prospective randomized trial 70 patients with KOA will be recruited using a diagnostic block of four genicular nerves. Two groups will be created through software randomization: a CRFA group (35 patients) and a CRYO group (35 patients). The target of the interventions will be four genicular nerves; the superior medial, superior lateral, inferior medial, as well as the medial (retinacular) genicular branch from vastus intermedius. The primary outcome of this clinical trial will be the efficacy of CRFA or CRYO at 2-, 4-, 12-and 24-weeks post-intervention using the Numerical Rating Pain Scale (NRPS). The secondary outcomes are the safety of the two techniques, as well as the clinical evaluation using the Knee Injury and Osteoarthritis Outcome Score (KOOS), the Oxford Knee Score (OKS), and the 7-point scale of Patient Global Impression of Change (PGIC).These two novel techniques can block pain transmission through genicular nerves in different ways. In contrast to cryoneurolysis, the CRFA method has been well documented in the past. This is the first clinical trial to compare CRFA vs CRYO and draw conclusions about their safety and efficacy.https://doi.org/10.1186/ISRCTN87455770]. Registered 29/3/2022, first patient recruited 31/8/2022.ISRCTN87455770 [ Knee osteoarthritis (KOA) is a degenerative joint disease that is mainly characterized by damage and loss of articular cartilage, remodeling of the subchondral bone, osteophyte formation, ligamentous laxity, weakening of periarticular muscles, and, in some cases, synovial inflammation . AccordiRadiofrequency ablation (RFA) is a process of thermal nerve degradation using a probe that provides radiofrequency energy. CRFA uses a water-supply system to cool the RFA probe internally. While internally cooled probes operate at a temperature of 60 °C, the temperature of the surrounding tissues reaches 80 °C, thus providing a larger lesion around the probe . This prCryoneurolysis involves the application of cold temperatures (− 20 to − 100 °C) to a peripheral nerve, leading to Wallerian degeneration and subsequent analgesia, while the nerve retains its ability to regenerate –16. In cClinical evidence in general, suggests that both CRFA and CRYO are safe and effective procedures for the symptomatic management of KOA pain –18.The primary objective of our proposed trial is to evaluate the efficacy of CRFA or CRYO at 2-, 4-, 12- and 24-weeks post-intervention in patients with painful KOA using the Numerical Rating Pain Scale (NRPS).The secondary objectives are the comparison of safety and tolerability of the two interventions, as well as the patient’s clinical outcome at 12- and 24-weeks post-intervention, using the Knee Injury and Osteoarthritis Outcome Score (KOOS) and the Oxford Knee Score (OKS). Also, the 7-point scale of Patient Global Impression of Change (PGIC) will be used at 2-, 4-, 12-, and 24-weeks post-intervention to capture the patients’ feelings of improvement.This study protocol describes the design of a prospective, single-blinded RCT with an allocation ratio of 1:1, between CRFA and CRYO. Our main hypothesis is that substantial relief of pain would be achieved with both techniques (CRFA and CRYO) compared to baseline values and that both methods would be effective and tolerable in the intermediate management of KOA.  of our University Hospital has approved the study (11846/05/10/2021), and written informed consent from participating patients will be obtained. The study will be conducted in accordance with all applicable laws and regulations as specified in the International Conference on Harmonization Guideline for Good Clinical Practice and the Declaration of Helsinki.. Patients will be asked to rate the percentage of their knee pain according to NPRS while performing ambulation, squatting, and other maneuvers that typically provoke their pain during the next 30 min in the office. After the diagnostic block of the six main anatomical sites described below the patients will then be asked to rate any reduction in their knee pain while performing the same maneuvers in the office. The primary investigators will rate these results and decide on their eligibility. Patients will be only enrolled in the study if they report, at least 50% reduction in pain (as measured in the NRPS). Eligible patients will be then randomizing as 1:1 to either CRFA or CRYO. Participants with bilateral KOA will not be excluded; only one knee will be screened and enrolled as the “index knee” for treatment.After establishing the diagnosis of knee osteoarthritis according to the eligibility criteria outlined below, the patients will visit the Department for initial clinical assessment and diagnostic block of the genicular nervesthe NICE clinical criteria  of primaRadiological confirmation of knee arthritis (grade ≥ 2) according to the Kellgren and Lawrence classification .Chronic knee pain for a minimum duration of 6 months.Pain intensity ≥ 4 on the (NRPS).A decrease of ≥ 50% in NRPS scores with diagnostic genicular nerve block.The ability to communicate in Greek.Patients of either sex can participate in the clinical trial if they have:Inflammatory or posttraumatic knee arthritisPatients who received CRYON or CRFA treatment in the pastInjection of hyaluronic acid, PRPs, or corticosteroids within the previous 3 monthsSignificant structural deformities affecting locomotion and knee function asidefrom osteoarthritis and which might cause chronic knee pain2Body mass index ≥ 40 kg/mUncontrolled serious diseases Unstable psychiatric illnessesCoagulopathy or bleeding disordersActive systemic or local infectionsDisease associated with reactions to the cold, such as cryoglobulinemiaPatients who belong to any of the following groups will be excluded:Patients who fulfill the inclusion criteria will be then informed about the proposed treatment options (CRFA or CRYO). The current literature on CRFA has shown promising results for pain relief up to 12 months , whereas data are scarce for CRYO 13,14,16) which has been less investigated thus far. Treatment with cryoneurolysis is still in its early stage and further studies are needed to determine methodological strategies optimizing its potential therapeutic effects. Nyggard et al. [,16 whichThe baseline assessment will include: (a) the medical history of the patient ; (b) radiological classification using standing AP and lateral x-rays of the knee joint and (c) baseline clinical evaluation using the NRPS, OKS, and KOOS. The OKS is a 12-item patient-reported outcome score, specifically designed and developed to assess function and pain after total knee replacement (TKR) surgery . It is vPatients who fulfill the inclusion criteria and have no exclusion criteria will be informed about the clinical trial in detail, and a consent form will be required to proceed.Precise targeting of genicular nerves using fluoroscopic guidance is mandatory for a successful procedure. Most of the current CRFA studies are using the classic radiological targets proposed by Choi et al. , McCormiIn the current study the target of the diagnostic block or final intervention will be the SMGN, the SLGN, and the IMGN, as well as the medial (retinacular) genicular branch from vastus intermedius (MRGN) Fig. . For theFor the nerve blocking procedure 1–2 ml of 2% lidocaine would be injected in the six different areas that mentioned previously, and the patients will then be asked to rate the percentage reduction in their knee pain while performing ambulation, squatting, and any other maneuvers that typically provoke their pain during the next 30 min in the office. Patients with a reduction in pain (> 50%) will proceed to the next phase, whereas those who experience no change in perceived pain will be excluded from the clinical trial., according to previously described methods.Patients will be placed in the radiolucent table at the Department of Interventional Radiology in a supine position with a bolster under the knee to produce 30° of flexion; this position flattens the suprapatellar joint space, thus minimizing needle trespass, and also allows for an unobstructed lateral view of the knee. The treated knee will be draped and sterilized in a standard manner. Patients will be continuously monitored and administered conscious sedation (1–2 mg IV midazolam and/or fentanyl 25–100 mcg IV) and supplemental oxygen. Fluoroscopic images will be obtained to align the femur in an anteroposterior (AP) view in order to target the genicular nerves at locations above the femoral condyles and for the IMGN a greater caudal tilt of the fluoroscope will be obtained to square off the tibial plateau for an appropriate AP view. A sealed and opaque envelope will be brought to the operating theatre, dictating the group of each patient. The location of the nerves  will be identified using fluoroscopyTwo to 3 ml of 1% lidocaine is used to anesthetize the skin and subcutaneous tissues before cannula insertion at each target site under fluoroscopic guidance. Thereafter, a 50–150 mm 17-gauge introducer needle will be placed to ablate the SLGN, SMGN, IMGN, and MRGN. One milliliter of 2% lidocaine will be injected through the introducer needles to anesthetize the area before ablation. After placement of the introducer needle, a 18 gauge, internally cooled 4-mm active tip RFA electrode  will be placed into the introducer needle, and the positioning is checked again using fluoroscopy. The introducer is connected to COOLIEF* Cooled RF Advanced Generator that allows staggered start, stop and adjusting of 4 independent channels. Motor nerve activity will be excluded by testing at 2 Hz and 1 mA. The CRFA probes will be advanced, and ablation will be performed with lesion settings at 60 °C (80–90 °C adjacent tissue temperature) for 2.5 min. As mentioned before, this type of ablation creates a spherical lesion at the tip of the probe. Cooled RF electrodes include a thermocouple at the active electrode tip to provide a temperature-controlled lesion formation. This involves water-cooling of the active electrode tip during the duration of the process without tissue charring at the electrode tip; this mechanism doubles the lesion radius and increase the lesion volume by 5 times.Two to 3 ml of 1% lidocaine is used to anesthetize the skin and subcutaneous tissues before probe insertion at each target site under fluoroscopic guidance. A cryoneurolysis probe  will be inserted in the proximity of the six target points, guided by fluoroscopic visualization, as previously described. VisualICE generator  will be used for cryoneurolysis which utilizes Argon as a coolant and Helium to thaw. The procedure will be performed with a single freeze cycle: 30 s at an effect of 20% and 2 min 30 s at 60% effect. After freezing cycle, 1 min of active thaw and 1 min of passive thaw will be used. As mentioned before the CRYO probe creates a spherical lesion  that surrounds the active tip. The temperature gradient away from the probe increases importantly; the typical isotherm with the needle has a temperature of − 40 °C in an area equivalent to 15 × 23 mm. Already at 23 × 29 mm the temperature has risen to − 20 °C and at 33 × 37 mm the temperature is up to 0 °C. The thawing phase (2 min) is not considered active treatment but is necessary for the ice-ball to melt gradually for later safe removal of the probe. The active ablation time of CRYO (3 min) is similar to that of CRFA (2.5 min) but with a different mechanism. The area of ablation is spherical in both techniques thus increasing the probability that a targeted sensory nerve will be captured in the “sphere” of tissues neuroablated. Finally, the “slow” effect of freezing (20% for 30 s and 2 min 30 s at 60%) has been already proposed for genicular nerve ablation  in patiePatients will discontinue all pain medications , supplements, chondroprotective drugs, and other alternative therapies for KOA for 10 days prior to the screening/baseline visit. During follow-up, patients will be prohibited from undergoing any other adjunctive treatment for KOA, including steroid injections, viscosupplementation, and pain medications. Serious local complications from either CRFA or CRYO and the need for medications for pain relief will be a criterion for study discontinuity.Patients will be assessed at baseline and 2-, 4-, 12-, and 24-weeks post-intervention . The secondary outcomes will be the potential improvement of the KOOS, and OKS at 12- and 24-weeks post-intervention. Patients will be also asked about their impression of improvement using the 7-point scale of Patient Global Impression of Change (PGIC) ; PGIC reAccording to the protocol, the patients will be randomly assigned into two groups, and they will all be evaluated (with NPRS) four more times after the baseline assessment . The main objective is to examine the possible diversity in NPRS (primary outcome) improvement among patients in different groups. The regular statistical approach to do this is to perform repeated measures ANOVA (rmANOVA), taking as given that all ANOVA assumptions are met . Thus, the statistical power analysis for an rmANOVA procedure is as follows: we, as a priori, assume a number of groups equal to two and a number of measurements (except baseline) equal to four. More specifically, the NPRS is expected to be reduced in the two groups (CRYO and CRFA) at least 30%, relative to baseline assessment. According to Cohen , this faApproximately 400 patients with symptomatic KOA visit our clinic annually. A small percentage of patients have end-stage disease and are only amenable to total knee replacement. Most remaining patients initially require conservative measures to control their symptoms, and among those, a respectable percentage has not been able to respond to oral medications, physiotherapy, loss of weight, and injectable therapies. This will be the pool of patients that will participate in our randomized trial. We estimate that we will be able to include 70 patients in the study in 10–12 months.A total of 70 patients will be included in the study  Randomization sequence will be created using Stata 9.0  statistical software and will be stratified with a 1:1 allocation ratio using random block sizes of 2, 4, and 6. An investigator not involved in the main study (J.L.) will perform the randomization process. These data will be stored on computer and will be available at the day of the intervention.For each surgical session including four patients, J.L. will seal patient details and the randomized treatment in an opaque envelope that will be given to the coordinated nurse just before the start of the intervention. The patients, relatives, investigators, nurses, and all relevant personnel would be blinded to the indented treatment. The envelope will be opened by the coordinated nurse after the patient is sedated and placed to the radiological table, the knee is properly prepared and the surgeons are sterile and ready to apply the intervention. Both generators for CRFA or CRYO would be available at the interventional radiological department. After opening the envelope, the procedure will be unblinded for all participants.Enrolment of participants will be performed by the main investigators  at the outpatient office of our department according to the eligibility criteria listed above. The allocation sequence will be created by an investigator not involved in patient care ((J.L.), and the assignment of participants to interventions by a coordinator nurse at the radiological department who will be responsible for arranging the sessions. The primary investigators  will be blinded to the intended treatment until the time of intervention; CRFA or CRYO will be applied to each patient after the opening of the sealed opaqued envelope inside the interventional radiological department. Clinical evaluation at 15 days , 4 weeks , 12 weeks , and 24 weeks  will be performed by an orthopedic resident (P.A.) not involved in the initial patient evaluation who will also be blinded to the applied intervention. Data analysists (J.L.) and outcome adjudicators will be also blinded during the implementation of the data. Unblinding will be performed in case of severe adverse effects .Data will be collected in paper forms at baseline and 2-, 4-, 12-, and 24-weeks post-intervention. Quality assessments and proper training sessions will be conducted to ensure that all information is collected properly. Outcome data include the NPRS, KOOS, OKS, and PGIC, all of which are patient-reported questionnaires. Demographic data, radiographs (downloaded from PACS and saved in JPEG format), and intraoperative pictures of skin marks or videos from the interventions will also be collected. A hard copy folder will be created for each patient, including all paper forms, demographic data, and intervention details. These folders will be kept safe in the hospital office of the primary investigator (A.P.) inside a special locker. The other main investigator (P.T.) will transfer all the data into an Excel database using the desktop computer at the office of the primary investigator (A.P.). Patient identification will be performed using only the national insurance number (11-digit number). Excel forms without patient names will be used for data analysis. Paper forms and computerized data could be assessed only by the two primary investigators. These files will be kept for at least three years after the last enrolled patient for future expansion of the research. We are not expecting participants to discontinue or deviate from the primary intervention. The coordinator nurse will be responsible for contacting them for missing appointments of clinical evaluation, either by phone or email. In case of refusal to attend, we plan to send the questionnaires by mail or make home visits. No other efforts will be made to minimize the loss of follow-up. Missing data from more than one time point will be a reason for dropout from the study.Data entry, coding, security, storage, assessment of quality and creation of Excel tables will be under the responsibility of the two main investigators. Excel database would be password-protected. Personal information about potential and enrolled participants before, during, and after the trial will be collected to ensure confidentiality .The sample size and power in the study have been previously described. Another statistical approach for the study is to evaluate all follow-up (post-intervention) measurements separately from the baseline. This may occur in two possible ways: one with the use of an ANCOVA procedure and the other with the use of ANOVA on the difference in the scores (follow-up minus the baseline). As Borm et al.  suggesteInterim analyses will be performed when at least half of the CRFA and CRYO patients have been recruited; reasons for discontinuance would be serious complications or significant differences in clinical outcomes . Although the sample size is small, we plan to perform additional subgroup analyses for age, sex, arthritis stage, and deformity type .Knee osteoarthritis is a common disease, yet the currently proposed conservative treatments have unsatisfactory overall efficacy and have been linked to an elevated risk of complications , 37–39. Radnovich et al. , in theiIn contrast to cryoneurolysis treatment, where the literature is scarce, the method of radiofrequency ablation for the treatment of symptomatic knee pain in osteoarthritic knees has been well documented in the past. In a cross-sectional survey, McCormick et al.  demonstrTwo recent systematic reviews have demonstrated promising results for the treatment of severe chronic knee pain using radiofrequency ablation, with minimal complications. Gupta et al.  reportedIt is apparent that there is an increasing body of evidence showing the effectiveness of CRFA and cryoneurolysis as treatment modalities for the osteoarthritic knee. Both techniques will be tested in the same manner in our study to investigate their capacity to control pain and disability in a mid-termed period of 6 months, while we will have the opportunity to record complication rates and failures. These treatment options may prove to be a significant aid for patients with KOA who are not at the end stage and for patients on waiting lists for surgery. Safety could also prove to be favorable as pharmacological treatments are associated with complications.This will be a single-blinded randomized control trial with a follow-up period of six months. The strengths are the recruitment of enough patients to demonstrate a statistical significance of 90%, the precise targeting of the nerves in six different areas in accordance with old proven clinical reports and the new landmarks provided by recent anatomical studies and also that both techniques (CRFA and CRYO) would be applied at the same manner. Technical limitations also exist, as the effectiveness of these treatments relies heavily on accurate spotting of the genicular nerves and also from the fact that we are not able to spot all the nerves of the knee joint capsule. The extent of nerve damage and its capacity to regenerate also depends on parameters that cannot be fully controlled in this clinical trial. CRFA has a different mechanism of action (thermoablation with permanent? nerve damage) compared to CRYO that provokes cryoablation with Wallerian degeneration. This might reduce potential risks associated with the CRYO procedure but might also attenuate treatment effects. If CRYO turns out to be more effective or safer than CRFA would be probably considered as a novel non-pharmacological option for KOA that would be covered by medical insurances in the future.Cooled radiofrequency ablation and cryoneurolysis are two techniques that aim to block pain transmission in different ways; CRFA induces thermal nerve degradation, and cryoneurolysis causes Wallerian degeneration and subsequent analgesia, while the nerve retains its ability to regenerate. Spherical areas of ablation, time of procedure, targeting of genicular nerves and outcome evaluation are similar in both techniques. This will be the first instance where cryoneurolysis will be performed on the genicular nerves, in the same manner as the more investigated CRFA. The main goal is to demonstrate whether these techniques offer a stronger analgesic effect, while checking for and reporting potential side effects to better understand their role in the treatment of knee osteoarthritis.


The primary objective of this study was to compare the WALANT  technique with local anesthesia associated with sedation in relation to pain intensity for minor hand surgical procedures. The secondary objective was to evaluate the need for analgesic complementation.A prospective, randomized, comparative, and clinical study was carried out. The sample size in each group was determined after statistical evaluation of the results of a pilot project. The participants were allocated to one of two groups; those in group 1 were submitted to the WALANT technique, and those in group 2, to local anesthesia associated with sedation, for elective surgery. The surgical procedures were carpal tunnel syndrome, De Quervain’s tenosynovitis, synovial cyst, finger cyst, and trigger finger. Pain intensity, need for complementation and evolution to complex regional pain syndrome were evaluated.There was no difference between groups in pain intensity after WALANT and need for intraoperative complementation. There was no significant difference in the amount of opioid applied postoperatively between the groups. There was no difference between groups regarding comfort during surgery. There was no difference in adverse effects and complications between the groups. Hematoma was the most frequent adverse event. No severe adverse events were observed.The WALANT technique promoted an analgesic effect similar to that of local anesthesia associated with sedation, without increasing adverse effects. In the past, local anesthetics associated with a vasoconstrictor should not be administered to extremities because it causes ischemia, with the worst event being digit necrosis. In a review of the literature from 1880 to 2000, one author noted that most reported cases of finger necrosis were not associated with the use of adrenalineMinor surgical hand procedures are usually performed under local anesthesia and sedationIn the WALANT technique, the surgery is performed with the patient awake and injection of solution with 9 mL of 1% lidocaine with adrenaline and 1 mL of 8.4% sodium bicarbonateThe primary objective of this study was to compare the WALANT technique with the local anesthesia technique associated with sedation regarding pain intensity for minor hand surgical procedures. The secondary objective was to compare the need for complementary analgesics.A prospective, randomized, and comparative study was conducted.The study was conducted after approval by the Ethics Committee (CAAE 34666920.3.0000.5505), and the patients’ signing of the informed consent form. All research was based on Resolution no. 466/12 of the National Health Council, which defines the guidelines and standards for research involving human subjects. The study was carried out according to the Consolidated Standards of Reporting Trials (CONSORT)The allocation of the participant to one of the two groups was as such. We used www.random.org to allocate numbers to patients and the group they would join. We had patients from 1 to 56 and groups 1 and 2. When a patient was scheduled to surgery, the hospital’s secretary, which was responsible for booking the surgery, would assign a ballot to the patient, that number would be from 1 to 56. Then, in a sheet she would see what group that number referred to. For example, the first patient to enroll the study could have been drawn the ballot number 42, which by random.org randomization would be group 2, for instance, and so on.To determine the sample calculation, a pilot project was conducted with 10 participants in each group, and the necessary information was obtained from it. Then, type error up to 0.05, and type-II error of 0.2 were applied, which results in study power of 80%, for a comparison test between independent groups, based on normal distributions. The pain score of 0 to 10 was employed for primary outcome, with the aim of identifying a minimum clinically significant difference of 2. Data from the pilot study of 10 participants were used to identify variability in the sample data, which identified a standard deviation of 2.7. Thus, it was identified that a sample size of 28 individuals in each group would be necessary to achieve a study power of 80%.The study included patients: 18 years of age or older; of either gender; ASA I or II, by the American Association of Anesthesiologists; undergoing minor hand surgery  confirmed by physical examination or complementary tests ; ambulatory; operated on by a physician specialized in hand surgery. The following patients were excluded: cognitively impaired (unable to understand the study); psychiatric illness; vasospastic disorder; thromboangiitis obliterans; infection at the puncture site; drug allergy; previous surgery; use of anticoagulants; and pregnant.WALANT group received lidocaine with epinephrine and sodium bicarbonate. In the procedure room out of the operating room, after antisepsis, the patient underwent local infiltration with 9 mL of 1% lidocaine with adrenaline 1:100,000 associated with 1 mL of 8.4% sodium bicarbonate according to the literatureIn the operating room, after monitoring the patient and obtaining venous access, propofol bolus and infusion were administered by the anesthesiologist. After local anesthesia made by the surgeon with 10 mL of lidocaine 1%, without adrenaline, the upper limb was exsanguinated with an Esmarch strip, and another strip placed near the axilla to keep the limb exsanguinated. Afterwards, a pneumatic tourniquet was inflated to 250 mmHg, and the surgery was performed without the use of electrocautery, followed by dressing and removal of the tourniquet. The patient was moved to the anesthesia recovery room, pending hospital discharge criteria: lucid, oriented patient, no pain, no nausea, stable vital signs, no signs of bleeding at the surgical siteAt discharge, patient was instructed to use dipyrone 1 g if pain ≥ 4 to 6 times a day. If pain persisted ≥ 4 times after dipyrone, the patient could take tramadol (50 mg) up to 400 mg a day. The patient was required to record the intensity of pain before medication administration.Patients were assessed for: need for complementary intraoperative analgesia, pain intensity by verbal numeric scale after seven days, 14 days and one month, patient comfort during surgeryThe primary outcome was a reduction in postoperative pain intensity. Secondary outcomes were a reduction in the need for analgesics and in the progression to complex regional pain syndrome.For statistical analysis, categorical data were described by their absolute occurrence and their relative frequency between groups, and the comparison between groups was performed by Pearson’s or Spearman’s chi-square test. Continuous data were tested for their distribution, Shapiro-Wilk’s test, and described by the mean and standard deviation. Student’s t-tests were used for pain intensity in the first week and age, the Mann-Whitney’s test for weight, height, duration of surgery, and pain intensity in the second week and one month, and the chi-square test for gender and complications/adverse effects. A p ≤ 0.05 was considered significant.The CONSORT flowchart is shown in The infiltration with local anesthetic with vasoconstrictor for hand surgery promoted analgesic effect similar to local anesthesia associated with sedation, without the increase in adverse effects and complications. In this study, all patients were evaluated preoperatively and operated on by the same surgeon, a board certified hand surgeon.The local anesthetic is acidic, causing pain during its administration, and the bicarbonate has the action of neutralizing the acidity, decreasing considerably the pain of the injection. The pain is mild to none as long as the infiltration is applied slowly and with pauses.Patients could feel discomfort when undergoing surgery without sedation, however, on the questionnaire, they reported no discomfort from being awake, and comfort during surgery was similar regardless of the anesthetic technique,There was no further need for anesthetic or analgesic complementation after the procedure in both groups. The volume of local anesthetic (10 mL) is in agreement with the literature as sufficient to perform all proposed surgeriesIn surgery with local anesthetic associated with sedation, bleeding is not observed through the use of pneumatic tourniquet. The WALANT technique must respect some principles, one of them is to wait for the vasoconstrictor to take effect before starting the surgery. According to one study, this time is between 25 to 30 minutesIn this study, the surgery was of short length, decreasing the time of tourniquet and ischemia of the sedation group. Also, the time to discomfort of the patient undergoing surgery without sedation was mild. In this study, the duration of surgery was not statistically significant, but it was longer in the WALANT group by a small margin. In a systematic review, the duration of surgical time was longerIn this study, 25 minutes were waited before the surgical incision in the WALANT group, as in the literatureThe duration of WALANT surgery in this research was slightly longer as in a systematic reviewThe intensity of postoperative pain in this study, with no difference between the groups, and the anesthesia used did not interfere with postoperative pain control, and opioid use was similar for conventional anesthesia and WALANT technique as in a study in the literatureIn this study, the most frequent adverse event was hematoma, but with no difference between the groups. Hematoma can be related to the lack of tourniquet in the WALANT technique, but we haven’t found any reports in which the end of the epinephrin effect could cause an increase in bleeding. We haven’t found any reports suggesting the end of the use of tourniquet caused an increase in bleeding and hematoma neither, even though the sedation group had similar cases of hematoma as the WALANT group. In one review, the authors reported no difference in patient complicationsThe adverse effects in this study were similar in the groups, and no serious adverse events such as ischemia associated with vasoconstrictor use were observed. After hand surgery, it is a frequent occurrence to develop complex regional pain syndrome, impairing rehabilitation. The Budapest criteria is used for the clinical diagnosis of complex regional pain syndromeThe comparison between adrenaline and non-adrenaline anesthesia without sedation cannot be done. Even though the expected surgery time for all diseases in the study is short, the non-adrenaline group need to exsanguinate the upper limb for surgery to be done. The exsanguination is painful for the non-sedated patient, and if surgery takes longer, the patient will feel a lot of discomfort. If exsanguination is not done, the surgery time of the non-adrenaline group would rise and with that the possibility of more complications, such as infection, hematoma and possibly others.One advantage of the WALANT technique is that it can be done as in office procedure, without the need of a complete surgical setting. Another one is that the patient is discharged right after surgery, which can potentially decrease cost, and since sedation is not performed the patient does not need to be fasting. One disadvantage is the possibility of vasovagal reflex, that is easily reversed by stopping the local anesthesia and elevating the patient legs until they feel better.As limitations of the study, it is not possible to blind the study completely. The sample was small compared to other similar studies, and, even though all illnesses had similarities with the surgery done, it is hard to compare different diseases that can have different outcomes postoperatively. A larger study with only one disease comparing the two techniques would be necessary.The WALANT technique promoted an analgesic effect, patient comfort and the necessity for complementation similar to that of local anesthesia associated with sedation, without increasing the adverse effects for hand surgeries.WALANT is the authors’ preferred technique for minor hand surgeries.


Bone marrow harvesting is a means to obtain stem cells to treat certain hematologic conditions in related or unrelated individuals. The most cited complication after bone marrow harvesting is surgical site pain. We developed a protocol incorporating regional anesthesia to improve pain control and reduce opioid use. A retrospective chart review was performed on three pediatric patients who underwent bone marrow harvesting for a sibling recipient and were managed via a standardized regional pain protocol. Each patient was treated with bilateral quadratus lumborum blocks in the operating room, prior to incision. Anesthesia records were reviewed for opioid administration intraoperatively and postoperatively. Two of three patients underwent successful QL blocks as evidenced by pain scores of 0/10 and lack of opioid administration in the post-anesthesia care unit. One patient was found to have a failed block and exhibited pain in the immediate and post-discharge time frame. Following this outpatient procedure, all patients were discharged home to the care of their parents, and no patients required admission due to pain. By utilizing the framework of a successful regional anesthesia model adapted from our adult bone marrow donor patients, we were able to employ a minimal opioid anesthetic and reunite patients with their families efficiently. We continue to use quadratus lumborum blocks in our pediatric patients to facilitate perioperative analgesia. Bone marrow harvesting (BMH) is a means to obtain bone marrow and utilize hematopoietic stem cells to treat certain malignant or nonmalignant hematologic conditions in another individual. Pediatric patients, specifically sibling donors, represent a unique patient population undergoing an anesthetic for the sole benefit of their sibling . Goals oBMH requires that a patient undergo general anesthesia in the prone position to allow access to the posterior iliac crests bilaterally. Harvesting physicians obtain a volume of bone marrow that is safe for donor extraction and at a sufficient cell dose for the recipient . No consBone marrow is the preferred graft source in pediatric patients, and it is used in more than two-thirds of cases ,6. Many Complications following BMH include fatigue, anemia, and nausea, but the most common complication is pain ,7-9. ThiAfter the Medical University of South Carolina Institutional Review Board approval, a waiver of patient consent was obtained, and a retrospective review of patient charts was performed. This manuscript adheres to the CARE case report guidelines.Anesthetic records, patient characteristics, and PACU documentation were reviewed for each patient and are presented in Table All patients described underwent lateral QL blocks bilaterally via ultrasound guidance. Lateral QL blocks were utilized because of provider familiarity and to mirror the protocol by the adult regional team for non-pediatric patients undergoing the same procedure at our institution. Patients remained supine for the block procedure on the stretcher after induction of general endotracheal anesthesia. Using ultrasound guidance with an aseptic technique, a linear transducer was placed in a transverse orientation at the midaxillary line between the costal margin and iliac crest. The transducer was moved posteriorly until the aponeurosis of the transversus abdominis muscle was identified. A 22-gauge peripheral nerve block needle was inserted with an anterior-to-posterior needle trajectory until it penetrated the aponeurosis. A local anesthetic was then injected after a negative aspiration for blood. Following the block, patients were positioned prone on the operating room table for the remainder of the procedure.Case 1The first patient was a 16-year-old male who was identified as a suitable sibling bone marrow donor and was scheduled for bone marrow harvesting under general anesthesia. After the induction of anesthesia and placement of an endotracheal tube, he underwent bilateral QL blocks with ropivacaine 0.5%, 20 mL per side. He was positioned prone and maintained with sevoflurane. Figure No opioids were administered intraoperatively. Additional perioperative adjuvant medications included intravenous acetaminophen, ketorolac, and dexmedetomidine. He was extubated in the operating room and then transferred to the PACU. He required no opioids in the PACU and reported a pain score of 0/10. After meeting the discharge criteria, he was released to the care of his parents and taken to the oncology floor to be with his family for his sibling’s bone marrow transplant. He did not require a refill of pain medication or an emergency room visit because of uncontrolled pain.Case 2The second patient was a nine-year-old male who was identified as a suitable sibling bone marrow donor and was scheduled for bone marrow harvesting under general anesthesia. After the induction of anesthesia and placement of an endotracheal tube, he underwent bilateral QL blocks with ropivacaine 0.2%, 20 mL per side. He was positioned prone and maintained with sevoflurane. One opioid dose was administered intraoperatively at the time of procedure start. Figure He was extubated in the operating room and then transferred to the PACU. Additional perioperative adjuvant medications included oral acetaminophen and intravenous ketorolac. He required no opioids in the PACU and reported a pain score of 0/10. He did require a postoperative blood transfusion, which led to a prolonged recovery room stay. After meeting discharge criteria, he was released to the care of his parents and taken to the oncology floor to be with his family for his sibling’s bone marrow transplant. He did not require a refill of pain medication or an emergency room visit because of uncontrolled pain.Case 3The third patient was a nine-year-old female who was identified as a suitable sibling bone marrow donor and was scheduled for bone marrow harvesting under general anesthesia. After induction of anesthesia and placement of an endotracheal tube, she underwent bilateral QL blocks with ropivacaine 0.2%, 20 mL per side. She was positioned prone and maintained with sevoflurane. One dose of opioid was administered intraoperatively at the time of the procedure start. Figure She was extubated in the operating room and then transferred to the PACU. She did require rescue opioid administration in the PACU and reported a pain score of 7/10. Additional perioperative adjuvant medications included intravenous acetaminophen. After meeting the discharge criteria, she was released to the care of her parents and taken to the oncology floor to be with her family for her sibling’s bone marrow transplant. Despite a period of acute surgical pain, she did not require a refill of pain medication or an emergency room visit because of uncontrolled pain. Her parent did report increased opioid-related side effects secondary to the oral oxycodone administered once the patient was home.This case series illustrates a change in practice for pediatric patients undergoing BMH for sibling donation. We observed three distinct trends to suggest the success or failure of the block in our pediatric patients.The first outcome, shown in Case 1 Figure , was delAs outlined in the various observed outcomes above, block failure is a possible outcome and, in that case, it is appropriate to administer intravenous opioids for adequate pain control. Additionally, when block placement is expeditiously followed by the start of the procedure, intravenous opioids may need to be administered to the anesthetized patient to facilitate appropriate intraoperative pain control until the analgesic effect of the local anesthetic is evident.These findings of pain control evidenced by low opioid utilization in patients where a block was successfully performed are consistent with previously published literature outlining the use of this technique in adult bone marrow donors . Opioid When evaluating the patient with the block failure Case 3), this patient was able to verbalize pain in the PACU, therefore confirming suspicions that the block was unsuccessful. Figure , this paOverall, families were very satisfied with their child's pain control, but this is not the only factor that impacts family satisfaction scores in the perioperative setting. Organizational aspects, communication, teamwork, and quality of clinical care have all been shown to affect a family’s satisfaction in the time surrounding their child’s surgery . A compoChildren are different from adults in that they have varying degrees of procedural understanding and fears depending on their age ,14. MoreA randomized controlled trial would provide the most impactful data to show the efficacy of this protocol incorporating QL blocks for pediatric sibling donors; however, our case series combined with prior adult data makes us hesitant to withhold a beneficial pain control modality in the meantime. This case series is small, but it adequately represents the challenges and successes faced by pediatric patients in the logistics of initiating a new protocol for pain management.Future directions include a multicenter study evaluating current practice for pain control in pediatric bone marrow donors and the introduction of a novel method, QL blocks. Identification of standardized outpatient pain scores and opioid administration will be paramount in determining the efficacy of the block in pediatric BMH donors. As patients are unlikely to be admitted, ensuring sound study design and outpatient follow-up will provide the most impactful results. Education and buy-in from anesthesia and bone marrow transplant divisions will be crucial to the ongoing success of this initiative.In this case series, we describe the adaptation of an adult regional anesthetic protocol to improve postoperative analgesia for three pediatric patients undergoing bone marrow harvesting. This report serves as a starting point to guide discussions with patients and families regarding the utility of QL blocks for postoperative analgesia. Additionally, the description of these three patient scenarios may serve as the foundation for further investigations with the goal of improving the perioperative experience for bone marrow donors.


Chronic pelvic pain (CPP) is one of the main problems of endometriosis, leading to a significant impairment of quality of life. Understanding the pain mechanisms and the pelvic floor muscles (PFM) changes in these patients is essential to integrate additional therapeutic strategies. We hypothesize that endometriosis patients have changes in PFM and that targeted vaginal electrostimulation can be a treatment option for CPP in this disease.Fifteen patients with endometriosis and chronic acyclical pelvic pain were included. PFM electromyography with the Multiple Array Probe Leiden (MAPLe) was performed. Mapping of PFM was utilized and targeted electrostimulation of the hypertensive muscles was conducted. Control electromyography was performed afterward to evaluate the electrostimulation therapeutic effect.puborectalis (10/15—66.7%). Most of the patients showed serious changes in the average resting tone (aRT) of PFM. aRT was significantly increased in all patients and decreased after stimulation, whereby the difference prior to and after stimulation was not significant (p = 0.064). The detailed separated analysis of the hypertensive muscles showed a significant (p = 0.026) reduction in their resting tone (hRT), after targeted stimulation.In 12/15 (80%) patients, the myofascial trigger point could be localized by digital examination. The most frequently affected muscle was the Vaginal electrostimulation is a promising and feasible complementary treatment option for CPP in endometriosis patients. Targeted treatment of pelvic floor dysfunction should be included in clinical trials. Endometriosis is an unrecognized chronic inflammatory gynaecological disease affecting approximately 270 million women worldwide . ChronicThe pathogenesis of pain generation is very complex –3. A comCurrently, the standard treatment options are not able to resolve the chronic pain situation in these women sufficiently , 11. WhiTo analyze the pelvic floor function in patients with endometriosis, we performed pelvic floor muscle electromyography (EMG) with the Multiple Array Probe Leiden (MAPLe) . In addiThis prospective pilot study was conducted at the Endometriosis Centre of Charité—Universitätsmedizin Berlin, Germany, from December 2019 to May 2020.Iliococcygeus muscle, Pubococcygeus muscle, Puborectalis muscle) which were palpated for tenderness on each side. Tenderness on each side was rated by the patient as absent or present. Patients in whom a pelvic examination could not be performed  were excluded.Fifteen patients with histologically confirmed endometriosis and CPP were included (age 18–49). They suffered from CPP not responding to hormonal, analgesic, and anti-inflammatory treatment. Numerous studies have utilized this procedure on both patients and healthy individuals, and it has been shown to have low risks and side effects. Some people may experience mild tingling or twitching under the electrode area, but this sensation goes away immediately once the stimulation stops. However, individuals with severe or untreated internal, neurological, or psychiatric conditions, those who are pregnant or breastfeeding, people with cardiac pacemakers, myocardial damage, arrhythmias, and epilepsy patients were excluded from the study. We assessed the PFM of all participants before the intervention using a single-digit pelvic examination of the levator ani muscles  before the intervention. The pain intensity was determined with the help of a visual numerical analogue scale .For the EMG measurement, we utilized the MAPLe device. The probe from this device contains a matrix of 24 electrodes  that measure EMG signals from the different layers and sides of the PFM as shown in Fig. After the affected painful and hypertensive muscles had been identified through the process described, a targeted focal electrostimulation (intervention) based on the control gate theory  was applp ≤ 0.05.Statistical analyses were performed using IBM SPSS Statistics, Version 26 . Data were described by median and percentiles. A non-parametric Spearman correlation analysis was performed to examine the association between the Resting tone (RT) before and after intervention. Two one-sample Wilcoxon sign rank tests were conducted to test if the RT before and the RT after intervention differed from the critical value for an increased RT of 2 µV . FinallyFifteen patients were recruited from daily practice and analyzed. Demographic characteristics are summarized in Table puborectalis (10/15—66.7%). In one endometriosis woman, the Pubococcygeus muscle was affected.In 12 (80%) patients, the myofascial trigger point could be localized by digital examination. In 3 (20%), it was not possible to identify the myofascial trigger point, but the tout bands of PFM. The most frequently affected muscle was the p = 0.002). After the intervention, the median aRT decreased to 3.00 , but was still higher than the critical value (p = 0.017) . The difference between the median aRT before and after the stimulation was not significant (p = 0.064).Before the intervention, the median aRT was 3.30 , which was significantly higher than the critical value for an increased RT (p = 0.002). After the targeted stimulation, the median hRT decreased to 3.00  and did not differ from the critical value for an increased RT (p = 0.937). A statistical significance was obtained with the difference between hRT before and after the stimulation (p = 0.026)  was evaluated separately before and after the intervention. The median RT of the affected hypertensive muscle before the electrostimulation was 4.00 , significantly higher than the critical value for an increased RT  recognized the targeted area as one of the painful points. All patients (15–100%) relate the experience as pleasant; 12 (80%) felt pain relief a couple of hours later; 14 (93.3%) patients felt pain relief a day after the intervention that lasted for a couple of hours.p (0.064) is promising as it suggests that an effect of the intervention would be obtained in a larger sample or after the electrostimulation repetition, thus underlining the importance of the continuation of this study. The detailed analysis of the hypertensive muscle groups showed a higher RT (hRT) in endometriosis patients compared to healthy controls [In this pilot study, a new intravaginal device was used for targeted electrical stimulation of myofascial trigger points to relieve CPP in women with endometriosis. Using MAPLe allowed us to analyze the different parts of the PFM separately. As expected, the analysis has shown a significant increase in the aRT of the PFM in this group of patients compared to the aRT in healthy volunteers in the validation study . Althougcontrols . MoreoveFor the better development of treatment strategies for CPP in endometriosis, the underlying mechanisms of the pathogenesis of the disease need to be studied in more detail. One of the underestimated sources of pelvic pain is not the pelvis itself, in terms of the comprised visceral organs and the peritoneum, but the pelvic floor and its layering of different levator ani muscles. As a result of endometriosis-related pain, patients search for pain-resolving positions, however, malposition leads to asymmetric reflector contraction of the PFM, resulting in CPP and PFM dysfunction. In 2015, Stratton was one of the first who raised the possible influence of the pelvic floor on pain generation [Most of the few trials published are based on invasive therapies. Myofascial trigger points injection, with or without a topical anesthetic , is another common form of myofascial treatment being studied. Direct injection of a local anesthetic such as lidocaine is thought to diminish the ability to transmit pain signals through these hyperactive neural networks, providing additional pain relief that may be more durable than myofascial trigger points needling alone , 17. ProSeeking alternatives for a more efficient treatment of endometriosis and CPP, physical activity and exercises come to light. In a recent review , the autPrevious studies using electrotherapy demonstrated the benefits relieving CPP related to endometriosis. Self-applied transcutaneous electrical nerve stimulation (TENS) involves the application of adhesive electrodes to the skin with subsequent electrical stimulation of painful areas . InterfeTo the best of our knowledge, only our group has evaluated a target vaginal electrical stimulation (using MAPLe). Even though our pilot study has some limitations, such as the short therapy duration (one session of electrostimulation) and the small number of participants, promising results could be seen. Vaginal electrostimulation is an encouraging and feasible complementary treatment option for CPP in endometriosis patients, and future clinical trials should include this approach. Endometriosis is an under diagnosis and undertreated complex disease. Multimodal treatment strategies should be established to improve the quality of life of these patients.