Regarding the TFM-induced responses of skin microcirculation, the blood flow ratio was significantly higher in the patients than in the asymptomatic participants (p < 0.05). In conclusion, postintervention hyperemia determined through noninvasive LDF may be an indicator for the understanding of the mechanism underlying massage therapies and the design of interventions for postural pain.Vascular impairment is a crucial factor associated with chronic muscle pain, but relevant research from the microcirculatory aspect is lacking. Here, we investigated the differences in neck muscle microcirculation detected through laser-doppler flowmetry (LDF) and cervical biomechanics by a videofluoroscopic image in asymptomatic participants and patients with postural neck and shoulder pain. To understand the mechanism behind the effect of myofascial treatment, transverse friction massage (TFM) was applied and the immediate effects of muscular intervention on microcirculation were monitored. In total, 16 asymptomatic participants and 22 patients  were recruited. Their neck muscle microcirculation and spinal image sequence were assessed. The differences in the baseline blood flow between the asymptomatic and patient groups were nonsignificant. However, the standard deviations in the measurements of the upper trapezius muscle in the patients were significantly larger ( In a work environment, people frequently complain about neck, shoulder, and back problems, especially when using a computer or smartphone while in an inappropriate posture for a long period. In such a position, the head moves forward, which increases the weight of the head supported by the neck muscles, and this may lead to pathological changes in the head and neck regions . This muIn physical medicine, good posture refers to the proper alignment of the body segments between the postural extremes. Excessive or reduced spinal curvature is considered deviation from the neutral alignment. In an ideal posture, the proper alignment of the bony segments requires the least amount of energy to maintain a balanced position ,5,6,7,8.The cervical muscles are important for maintaining the stability and posture of the head and neck, and the sustained neck and shoulder posture that is frequently assumed by office workers, is a possible risk factor in work-related neck and upper limb disorders ,2. The iAlthough circulatory impairment is usually acknowledged as an important contributing factor for acute or chronic muscle pain, little attention has been paid to the mechanism underlying postural neck and shoulder pain and clinical muscular intervention by the microcirculatory aspect. Laser-doppler flowmetry (LDF) is one of the most popular techniques applied to the assessment of tissue blood perfusion. In Strøm’s  study, iSince both the symptoms of microcirculatory insufficiency  and the The sample size was calculated through software GPower   In orderIn total, 16 healthy adults (8 men and women) without any neck symptoms within recent 4 weeks participated in this study. A participant was excluded if they (1) had a history of cervical trauma or surgery, (2) had bone pathology, (3) had an arthritic or other inflammatory disorder, (4) were pregnant, and (5) had restrictive muscle spasms. The participant age ranged from 20 to 50 years. Next, 22 age-matched patients (11 men and women) with neck and shoulder pain or symptoms such as pain, muscle spasm, and motor dysfunction within the recent 3 months were recruited. A patient was excluded if they (1) had a history of cervical surgery, such as disc replacement, bone fusion, and discectomy; (2) had significant potential for spinal cord injury, such as cord impingement from a large disk herniation; (3) had advanced cervical spondylosis; (4) had severe spinal stenosis; (5) had inflammatory arthritic disorders, including ankylosing spondylitis and rheumatoid arthritis; (6) had severe spinal instability; and (7) were pregnant. The clinical characteristics and Neck Disability Index (NDI) questionnaire responses of all the participants were documented. The NDI is a 10-item questionnaire about symptoms relevant to cervical spine pathology. The NDI consists of ten domains—pain intensity, personal care, lifting, reading, headache, concentration, work, driving, sleep, and recreation- designed to assess the level of disability in patients with neck pain .The confirmation of the myofascial trigger points was performed using the five diagnostic criteria described by Simons et al. : (1) preBefore data collection, the participants were asked to stay in the experimental environment with the temperature maintained at 26 ± 1 °C for at least 10 min. The participants adopted a sitting position with back support for watching a computer monitor. The microcirculation of upper trapezius, sternocleidomastoid (SCM), and masseter muscles was individually measured through LDF. For each muscle, a 210 s baseline was obtained in the relaxed state, and the muscles received the TFM for 2 min afterwards. Then, the other 210 s measurement was taken to monitor the effect of the muscular intervention. To correctly locate the position of the two measurements, the holder used to fix the probe was not removed during the massage. The skin probe of high-power LDF was placed on the midpoint between the cervical 7 (C7) vertebra and the acromion. The skin probe of the low-power LDF was placed lateral to that of the high-power one at a 1 cm distance. The measurements were conducted on both sides of the participants.The microcirculatory flux of a muscle was simultaneously detected using high-power LDF  and low-power LDF . A noninvasive skin probe including two flexible glass optic fibers was used; of these fibers, one transmitted a 785 nm laser to the tissue surface, whereas the other collected the light scattered from the tissue and moving blood cells and transmitted back to LDF. If the light scattered from the moving blood cells, the light frequency shifted to a higher frequency, and the frequency difference between the incident and scattered light—which is called Doppler shift—is proportional to the velocity of the moving cells. High-power LDF along with a wide separation of transmitting and receiving fibers in the probe (VP1-V2-HP) enables a greater sampling depth and a larger volume to be monitored; this reduces site-to-site variations. With a wide separation of fibers (4.0 mm) for the high-power LDF versions, the sampling depth can be >1.4 mm , and theTo compare the effects of massage on microcirculation between the groups, the mean value of the post-intervention blood flow was divided by the individual baseline value to obtain the normalized blood flow—which was named blood flow ratio. Here, a ratio of >1 indicated that post-intervention blood flow was higher than the baseline value. Normalization could also eliminate the individual differences.For the neck movement imaging, a videofluoroscopy system for Toshiba —comprising an X-ray generator that can operate at low milliamperage settings—was applied to evaluate cervical spine movement at a rate of 30 frames/s. An image intensifier as an image receptor was used for videofluoroscopy, and this permitted imaging with very low radiation exposure. The videofluoroscopy screen procedure lasted 10–20 s, which is equivalent to one or two typical chest X-ray radiation doses (0.06–0.12 mSv) but much lower than the natural background radiation dose of 2.0 mSv per year or a conventional chest CT of 2.0 mSv.Before actual screening, the participants stood in front of an X-ray beam of videofluoroscopy and practiced active cervical flexion and extension movement three times with correction to reduce the trunk and out-of-plane motions. The flexion and extension movements were performed within 10 s. The recorded video images of spinal motion were then transformed into the sequences of bitmap images with the aid of the software program Canopus Edius . In total, 10 images in evenly divided intervals of each cervical motion range were selected for digitizing. During image processing, the positions of the 22 bony landmarks were digitized using SigmaScan  on a high-resolution monitor. The anatomical identification of the bony landmarks was based on the well-accepted radiographic method of Frobin et al. . These wThe MATLAB computer programs were written to construct the midplanes of the vertebrae defined as a line running through the midpoints between the anterior and posterior two corners, and the bisectrix between the two midplanes were derived . The perp < 0.05 was considered statistically significant. Analyses were performed using the Scientific Package for Social Sciences .For the microcirculation status, the paired Student’s t-test was used to analyze the variation of the microcirculatory perfusion between the baseline and postintervention within each group. Independent Student’s t-test was used to compare the difference in the effects of intervention and videofluoroscopic imaging data between asymptomatic participants and patients with postural neck and shoulder pain. According to the central limit theorem, the distribution of sample means approximates a normal distribution regardless of whether the source population is normal or skewed, provided the sample size is sufficiently large . As the microcirculatory perfusion was monitored on the participants bilaterally, there were collectively 32 and 44 measurements for asymptomatic and patient groups respectively in this study. Consequently, the F-test was performed to compare the standard deviations of the two groups under the promise of normal distribution. p > 0.05). The demographic information of asymptomatic participants and patients with postural neck and shoulder pain are presented in p < 0.001).We included 16 asymptomatic participants and 22 patients with postural neck and shoulder pain —regardless of whether low-power or high-power LDF was used.The microcirculatory blood flow is proportional to both the intensity and the Doppler shift of the light scattered back by the moving cells. The algorithm used to calculate the blood flow has been reported in our previous study . Here, tp < 0.01). By contrast, both superficial and deep skin microcirculation increased significantly  at three sites after the intervention in patients with postural neck and shoulder pain.Compared with the individual baseline, the postintervention blood flow in the superficial skin (detected by low-power LDF) significantly increased at the SCM muscles and that in the deep skin (detected by high-power LDF) significantly increased at the upper trapezius, SCM, and masseter muscles in the asymptomatic participants  for calculating the intervertebral movement varied between 0.823 and 0.955 (average = 0.903), and the corresponding mean absolute difference (MAD) between examiners was 0.51°. The interexaminer ICC of the calculated disc spaces ranged from 0.824 to 0.926 (average = 0.875), and the corresponding MAD between examiners was 0.61°. Our results indicated that the high-reliability tests within and between examiners for identifying the vertebral landmarks and intervertebral movement in sequential videofluoroscopic images are high.p = 0.005, 0.012, and 0.037, respectively).The intervertebral flexion and extension movements in the C2/3, C3/4, C4/5, C5/6, and C6/7 segments for the asymptomatic participants and the patients with postural neck and shoulder pain were shown in To provide additional insights into cervical biomechanics related to postural neck and shoulder pain and muscular intervention from the microcirculatory aspect, the resting and postintervention microcirculation in the major neck muscles were monitored. The results demonstrated that even though the difference in the averages of the resting (baseline) between the asymptomatic participants and the patients was nonsignificant, the significantly larger standard deviation revealed a larger variation of resting value among patients. Regarding the effects of the muscular intervention on skin microcirculation, the blood flow ratio of >1 in both the patient and asymptomatic groups, but the effects were more significant in the patients than the asymptomatic participants.no pain) to 10 (unbearable pain). However, this phenomenon was not found in individuals with regular physical activities, whose pain levels were only 1.5 ± 2.2. In addition, Strøm et al., suggested the importance of the interaction between microcirculatory vasodilation and nociceptors in the activation of muscle nociceptors [Compared with the asymptomatic group, the patient group has a larger standard deviation of the resting skin blood flow, which potentially revealed that microcirculatory regulation was impaired in some patients with neck and shoulder pain, especially around the upper trapezius muscle. The large standard deviation indicated that the data were more spread out—revealing that some patients were in a high-blood-flow state but the others were in a low-blood-flow state. In the study of the correlations of neck and shoulder skin microcirculation and pain symptoms in office workers with sedentary lifestyles , the skiiceptors  because iceptors  investigp < 0.01). The blood flow ratio was significantly larger in the patients than in the asymptomatic participants—regardless of whether low-power or high-power LDF was used for monitoring. Considering that the blood circulation system is similar to a water supply system, the end of the system will be the last to be irrigated; here, when the water supply decreases, water will retreat. As blood supplementation is not needed to repair injuries in healthy people, the circulation system regulates and makes the stimulating effect of massage smaller or fade away quickly. As low-power LDF measures the blood flow in the superficial layer (the end of the microcirculation), the hyperemia measured through low-power LDF was found to be less obvious, whereas the responses faded but remained significant in deep skin in the asymptomatic participants. By contrast, for the patients with pain, hyperemia due to massage can treat local injuries; therefore, hyperemia can be maintained for a long period not only in the deep skin but also in the epidermis.Although the variation in baseline blood flow is so large that distinguishing whether the tissue is chronically injured by the value of blood flow is impossible, the larger massage-induced blood flow ratio was found in the patients with pain . NotablyTransverse friction massage (TFM) is commonly used for identifying muscle injuries, relieving pain, reducing adhesion, and improving circulation. Bell  applied The phenomenon of hyperemia maintenance after massage  also appThe differences in the total ROM in the C2/3, C3/4, and C4/5 segments between the asymptomatic participants and patients with postural neck and shoulder pain were significant. The SCM muscle was most active in the extended neck posture, whereas the upper trapezius muscle was most active in the flexed neck posture. This anatomical orientation may require the aforementioned muscles to support the shoulder during forceful arm exertion and lifting. A study found that patients with chronic neck pain demonstrate reduced motion and altered patterns of muscle control in the SCM and upper trapezius muscles during specific coordination tasks . The autAs the massage therapies were effective in increasing active ROM and decreasing overall pain, the higher hyperemia reaction caused by TFM provides indirect evidence of improved microcirculation for the healing effect. This finding revealed that postintervention hyperemia determined through noninvasive LDF could be developed as an indicator for mild and unnoticeable muscle and fascia injuries due to an inappropriate or prolonged static posture. In addition, the patients’ high-blood-flow state should be considered for early treatment if it is related to chronic inflammation and occurs constantly. This is because chronic inflammation has been a well-established risk factor for cardiovascular diseases ,37. WithOur findings can serve as the basis for understanding neck and shoulder pain and the effects of muscular intervention from the microcirculatory aspect. Compared with the asymptomatic participants, the patients with neck and shoulder pain had higher NDI and limited cervical ROM. Simultaneously, the massage-induced responses at the skin microcirculation around the muscles controlling the head and neck posture and motion were considerably vigorous. In addition, from the microcirculatory measurement of resting state, the ischemic and hyperemic skin perfusions were only noted in the patients with pain. With the advantages of safety and non-invasive measurement, LDF could be applied for further research on musculoskeletal disorders with different muscular interventions for developing assessment methods and therapeutic strategies.


IntroductionSo far, investigations in patients with rotator cuff diseases have used pain measurement tools such as visual analog scale (VAS) for nociceptive pain as well as neuropathic pain (NeuP) specialized ones like Douleur Neuropathique 4 Question (DN4) and Pain Detect. The study’s goal was to look at the existence of NeuP in patients with chronic shoulder pain, as well as variables that may be predictive of its progression.MethodsThere were 112 outpatients in all. Current and previous pain intensity levels were documented with the numerical rating scale (NRS), the Shoulder Pain and Disability Index (SPADI) was used to assess pain and disability levels, and the S-LANSS  was used to diagnose NeuP. The Pearson Chi-Square test was employed to check for any relationships between variables. The Mann-Whitney U test was also employed to check for between-group differences (with or without NeuP). To investigate factors that may be utilized as a prognostic for NeuP, logistic regression was performed, with those components  that were statistically significant being included.ResultsAccording to the S-LANSS questionnaire for NeuP diagnosis, 21 patients had NeuP. According to S-LANSS, chi-square test findings revealed that NeuP is independent of sex, smoking, size, and location or rotator cuff tear. Univariate analysis with Mann-Whitney U test revealed statistically significant differences in SPADI and NRS scores between the two patient groups (p < 0.001). Α multivariate analysis using S-LANSS as the binary dependent variable and NRS currently, NRS average last month and SPADI total score as independent variables  revealed that total SPADI score may be considered as an independent prognostic factor for NeuP .LimitationsDue to the limited number of patients who participated in the study, the findings were deemed insufficient in terms of statistical power. In particular, the power analysis of the study (type I error probability being [a] = .05) was less than 80% , hence relatively small. As a result, there is a limited probability of a type I error.ConclusionsUsing S-LANSS, we discovered that 18.8% of patients with rotator cuff tears had NeuP. The SPADI scores (pain and disability) in the NeuP group were substantially greater than in the nociceptive pain group. As previous studies have suggested utilizing certain levels of the VAS for pain assessment and specialized questionnaires for NeuP evaluation, we recommend that SPADI be included as a tool for emphasizing the neuropathic features of shoulder pain. Globally, there has been a trend in study toward identifying variables that might emphasize the various aspects of neuropathic pain (NeuP) in musculoskeletal disorders because this will affect prognosis and treatment . A systeThis study aimed to investigate the existence of NeuP in patients with a rotator cuff tear, as well as factors that may be prognostic of NeuP development. So far, investigations in patients with rotator cuff diseases have employed pain measurement tools like visual analog scale (VAS), as well as more NeuP specific ones like Douleur Neuropathique 4 Question (DN4) and Pain Detect ,7. To thThe present study involved patients who had consulted with an orthopedic surgeon for their shoulder pain and were scheduled for surgery between March 2016 and March 2019, with a referral for pre-operative physiotherapy . The patients provided their written informed consent for the collection of their data and the research complied with all principles of the Helsinki Declaration. Outpatients with >3 months of chronic shoulder pain of a non-traumatic origin were included in the study (inclusion criteria). Conversely, patients with previous shoulder surgery, rheumatic diseases, cancer, mental disorders, neurological pathologies, cardiovascular diseases, and the use of painkillers were excluded from the study (exclusion criteria).Data from 153 patients were gathered, 37 of whom did not meet the admission criteria, while four refused to participate  is a reliable and valid tool, composed of five general questions related to the characteristics of pain and two related to self-evaluation of pain by the patients . The scoThe SPADISPADI (Shoulder Pain and Disability Index) is a self-administered questionnaire suitable to investigate shoulder pain and related dysfunction . It compNRSThe NRS  is one of the most commonly used pain scales in medicine ,13. NRS MRIMagnetic resonance imaging (MRI) examination was performed and the scans were collected for all patients showing symptoms of shoulder pain. The scans were then inspected to assess the size and the position of the rotator cuff tear, suggesting high sensitivity and specificity (91.1%) .Statistical analysisTo discover the possible dependencies in patients with a rotator cuff tear, between NeuP and qualitative variables , we used the Pearson Chi-Square test. In addition, the Mann-Whitney U test was performed to test the differences between the two groups (with or without NeuP). In order to assess whether the SPADI score could be used as a prognostic factor for NeuP, logistic regression was performed using the statistically significant factors that emerged from the univariate analysis. Statistical analyses were performed by using the IBM SPSS Statistics v.22 for Windows , with the statistical significance for all tests set to 0.05. In addition, a power analysis was performed with the GPower 3.1.9.4, to calculate the post-hoc power required for any statistical relation to be established as significant.Table The findings of the MRI assessment revealed that 31.3% (n = 35) had a first-grade tear (<3mm deep), 66.1% (n = 74) a second grade (3-6mm deep), and only 2.7% (n = 3) were categorized as having a third-grade tear. As far as the side of tear was concerned, 32.1% (n = 36) were articular, a 51.8% (n = 58) were bursal, and 16.1% (n = 18) were intratendinous. In terms of tear location, the majority of patients, 87.5% (n = 98), had the tear in the supraspinatus, followed by 8.9% (n = 10) in the infraspinatus, and lastly 3.6% (n = 4) in the subscapularis.Twenty-one patients (18.8%) were assigned to the NeuP group according to the S-LANSS score ≥12), while 91 patients (81.3%) were assigned to the nociceptive pain group. According to SLANSS questionnaire data, NeuP is independent of sex, smoking, size, and location or rotator cuff tear  were significantly higher . Similarly, the NeuP group’s mean SPADI scores  were significantly greater than the nociceptive pain group Table .The results of multivariate analysis, multiple logistic regression, with S-LANSS as the binary dependent variable and NRS ''now'', NRS average last month, and SPADI total score as independent variables with statistical significance, revealed that the total SPADI score can be regarded as an independent prognostic factor for NeuP  in contrast to the other variables Table .The model correctly classified 88.4% of cases that confirm the effectiveness of the predicted classification against the actual classification. Furthermore, the model fits the data well , and, with an odds ratio for total SPADI score (Exp(B) = 1.189) greater than 1, it implies that the possibility under research is more likely to occur in the first group of NeuP.The S-LANSS was selected as a tool since it can detect NeuP and has high sensitivity and specificity , withoutIt is frequently difficult to pinpoint the specific location of common shoulder discomfort since it tends to spread. According to Bayam et al , discomfChronic shoulder diseases, as described by Bayam et al , produceAdditionally, 25.9 % (n = 29) described their pain as tingling, while only 2.7 % (n = 3) noticed a change in shoulder color, 26.8% (n = 30) were excessively sensitive to pain, 25.9% (n = 29) felt “electric shocks,” 25.0% (n = 28) a shooting pain, 3.6% (n = 4) a different friction sensation, and 17.0% (n = 19) a different contact sensation.Patients with rotator cuff tears, in particular, exhibit neuropathic features -7,22. ReFurthermore, the presence of NeuP corresponds with higher SPADI scores, despite the fact that in many studies, high VAS pain rates appear to be related to the presence of NeuP . The maiThe developer of the SPADI scale recommends it as a tool for measuring both pain and functional discomfort. Although it proposes five issues for pain and eight for disability, several studies have reached differing findings of whether questions favor the first or the second factor -27. TherAccording to this study, one unit increase in SPADI total score increases the odds of having NeuP by 19% when compared to patients who scored low in SPADI. While Haampaa et al.  propose Given that the existence of NeuP may influence the outcome of the operation ,6, it woLimitationsThe statistical power of the findings was deemed inadequate due to the limited number of patients who participated in the research. The power analysis for the study (type I error probability being [a] = .05) was less than 80% , suggesting that the sample size was small. As a result, the likelihood of committing a type I error is low. We propose performing more studies on a larger sample size to confirm the current findings. Aside from that, this study relied on self-reported assessments of pain and impairment levels; however, future studies should incorporate a clinical objective evaluation (such as a measure of motion range).We discovered that 18.8 % of patients may have NeuP by utilizing the S-LANSS as a specialized questionnaire for NeuP screening. Furthermore, multiple logistic regression revealed that the SPADI total score may be used safely as a prognostic factor for NeuP in patients with chronic pain due to rotator cuff tears. The SPADI scores (pain and disability) in the NeuP group were substantially greater than in the nociceptive pain group. As previous studies have suggested utilizing certain levels of the VAS for pain assessment and specialized questionnaires for NeuP evaluation, we recommend that SPADI be included as a tool for emphasizing the neuropathic features of shoulder pain.


Moreover, patients with FM showed greater pain impact (p < 0.001) and bigger somatosensory (p < 0.001) and motor deficiencies (p < 0.001) than patients with CLBP. Further research should explore the possible reasons for the greater deterioration in patients with FM in comparison with other chronic pain conditions. Our results, showing the multiple areas susceptible of deterioration, make it necessary to adopt interdisciplinary interventions focused both on physical and emotional dysfunction.Fibromyalgia (FM) and chronic low back pain (CLBP) have shared pathophysiology and have a considerable impact on patients’ daily activities and quality of life. The main objective of this study was to compare pain impact, somatosensory sensitivity, motor functionality, and balance among 60 patients with FM, 60 patients with CLBP, and 60 pain-free controls aged between 30 and 65 years. It is essential to know the possible differences existing in symptomatology of two of the major chronic pain processes that most affect the population, such as FM and CLBP. The fact of establishing possible differences in sensory thresholds, motor function, and proprioceptive measures among patients with FM and CLBP could bring us closer to a greater knowledge of the chronic pain process. Through an observational study, a comparison was made between the three groups  evaluating functional performance, postural balance, kinematic gait parameters, strength, depression, fatigue, and sensitivity to pain and vibration. Patients with chronic pain showed worse somatosensory sensitivity ( Chronic pain represents one of the most important public health problems, accounting for significant personal, social, and economic burdens. Fibromyalgia (FM) and chronic low back pain (CLBP) are chronic pain conditions with high frequent medical consultation in primary care and a high negative impact on function and quality of life .FM is a chronic disease of idiopathic etiology, which is estimated to affect 2–4% of the population . FM and CLBP present common characteristics in comparison with pain-free controls. Thus, both conditions show hyperalgesia, signs of central pain sensitization, increased excitability in the central nervous system, and abnormal endogenous pain modulation . MoreoveDespite the clinical similarities between FM and CLBP, little is known about the differences between these two chronic pain conditions in terms of somatosensory and motor symptoms. Thus, for example, it is unknown whether gait or balance are more impaired in FM than in CLBP or vice versa. To our knowledge, there are no studies that directly compare FM and CLBP patients on motor function, balance, and somatosensory parameters. Thus, the major aim of the present study was to compare patients with FM and CLBP regarding some clinical symptoms , as well as regarding parameters of pain and vibration sensitivity, functional gait, and balance. Based on previous evidence indicating that CLBP in many patients preceded the typical generalized pain of FM , we hypoThis observational study was approved by the Research Ethics Committee of the Balearic Islands (Spain) (Reference: IB-2586/15 PI) and was conducted in accordance with the Declaration of Helsinki of 1975. All subjects included in the study signed the informed consent form.Patients with FM and patients with CLBP, as well as pain-free controls matched in age, gender, and sociodemographic characteristics, were recruited from different health centers and patients’ associations in Majorca (Spain), through publicity talks, during the months of January and February 2016. Sixty patients with FM, 60 patients with CLBP, and 60 pain-free controls agreed to participate in the study. Inclusion criteria were: (1) age between 30 and 65 years and (2) clinical diagnosis of FM or CLBP, or pain-free healthy volunteers. Patients with FM were included in the study if they fulfilled the criteria of the American College of Rheumatology for fibromyalgia . Only loThe assessment session was performed in a spacious and silent room (14 m × 12 m) in the Fibromyalgia Association of Palma (Spain) by two investigators, members of the research team. After informed consent was signed, participants firstly completed the self-report questionnaires and secondly performed the motor function and sensitivity tasks. Finally, the static and dynamic balance task was video recorded. Four types of measures were obtained: self-report questionnaires, motor function, somatosensory sensitivity, and static and dynamic balance. Evaluations were carried out in the same order for all participants. The complete assessment lasted about one hour and was performed during the months of March, April, May, and June 2016.Fibromyalgia Impact Questionnaire (FIQ) [re (FIQ) . This isMcGill pain Questionnaire (SF-MPQ) [(SF-MPQ) . This abPressure pain thresholds (expressed in newtons) were assessed by means of a standard digital force gauge  using a flat rubber tip [bber tip . PressurVibration thresholds were evaluated by using a Vibratron  [NJ, USA) . The VibNJ, USA) . The meaThe Berg scale [rg scale  is a funrg scale  and CLBPrg scale .The six-minute walking test [ing test  is a funing test  and CLBPing test .Timed up and go test [ go test . Patient go test  and CLBP go test .Isometric back muscle strength was determined by using a back muscle dynamometer . Participants were asked to place their feet on the top of one platform, bend forward with 30° of lumbar flexion, and pull by extending their back to put the body as vertical as possible. The average force from two trials was computed [computed . Strengtcomputed .The Borg scale [rg scale  is a selStatic balance was assessed by using a modified version of Romberg’s balance test . This teDynamic balance was tested by means of a gait task [ait task ,16,41. Pp = 0.05 was used for statistical significance.Statistical analyses were performed by using the SPSS software. Kolmogorov–Smirnov tests were previously carried out to test the normality of the dependent variables. The null hypothesis that data were sampled from a normally distributed population was examined by using Shapiro–Wilk tests, and differences between patients and pain-free controls were analyzed by using ANOVAs with Group as an intersubject factor and post-hoc comparison analysis by pairs with Bonferroni adjustment. A value of http://www.imim.es/ (accessed on 8/1/2016)). The prevalence of FM in Spain is 2.4% (95% CI: 1.5–3.2), with a 21:1 female/male ratio [Sample size calculation was performed by using the GRANMO sample size calculator (GRANMO: le ratio . The estle ratio . A samplp > 0.05). In addition, groups were similar in their sociodemographic characteristics  confirmed that individuals with chronic pain had longer pain duration than pain-free controls. Post-hoc comparisons showed significant differences between each of the two groups of chronic pain (FM and CLBP) and pain-free controls (both p < 0.001), although not between patients with FM and patients with CLBP (p > 0.05).The Kolmogorov–Smirnov and Shapiro–Wilk tests indicated that all dependent variables fulfilled the normality assumption for parametric analyses  = 580.96 p < 0.001). Post-hoc comparisons showed significant differences between each of the two groups of chronic pain (FM and CLBP) and pain-free controls (both p < 0.001) and objectified higher values in patients with FM than patients with CLBP (p < 0.001), indicating a high impact of chronic pain on daily life. We also found significant group differences in the following subscales: pain  = 382.45, p < 0.001), fatigue  = 366.65, p < 0.001), anxiety  = 486.57, p < 0.001), and depression  = 453.24, p < 0.001), with post-hoc comparisons showing the same trend (higher scores in both groups of chronic pain compared to pain-free controls and higher scores in patients with FM compared to patients with CLBP). Group differences were also found in the subscales ability to perform tasks  = 486.57, p < 0.001), missed job  = 142.83, p < 0.001), do job  = 74.7, p < 0.001), and stiffness  = 382.29, p < 0.001). Post-hoc comparisons showed significant differences between the two chronic pain entities and pain-free controls (both p < 0.001) but no significant differences between patients with FM and patients with CLBP .Significant group differences were found in the total scores of the McGill Pain Questionnaire, significant group differences were observed in the three subscales: in the sensory/affective components of Subscale A  = 165.62, p < 0.001), in pain intensity measured by a visual analog pain scale   = 1162, p < 0.001), and in the verbal descriptor inventory   = 1152.7, p < 0.001). Post-hoc comparisons also showed significant differences between each of the two groups of chronic pain and pain-free controls  and that patients with FM reported higher scores than patients with CLBP in all subscales . Again, higher scores in these subscales indicated greater pain impact in patients with chronic pain than in pain-free controls and higher pain impact in patients with FM than in patients with CLBP.Regarding the pressure pain thresholds, significant effects due to group  = 202.17, p < 0.001) and group x body location  = 26.99, p < 0.001), but not due to body location  = 2.31, p = 0.104), were observed. Post-hoc comparisons revealed that pressure pain thresholds were significantly different at the three body locations within each of the groups , except between epicondyle and trochanter in fibromyalgia patients (p = 0.802). Post-hoc comparisons also showed significant differences between the two groups of chronic pain and healthy people in epicondyles, greater trochanters, and index fingers ; these analyses also showed that patients with FM were more sensitive at epicondyles and greater trochanters than patients with CLBP . However, no significant differences between patients with FM and patients with CLBP were found in index fingers (p > 0.05) (For  > 0.05) .vibration thresholds, significant main effects of body location (index finger vs. toes) were observed  = 703.64, p < 0.001), with higher thresholds for toes. Moreover, a significant interaction effect of group x body location was observed  = 17.21, p < 0.001). Post-hoc comparisons revealed that pain-free controls were more sensitive (lower thresholds) to vibration stimuli in the two locations than both groups with chronic pain . Moreover, it was found that patients with FM were less sensitive than patients with CLBP both at the toes (p = 0.032) and the index finger (p = 0.042) (For = 0.042) .Berg scale, timed up and go test, six-minute walking test, Borg scale, and isometric back muscle strength). Thus, significant group differences were found in performance scores of the Berg scale  = 458.68, p < 0.001), showing an impaired motor function of the two groups of chronic pain compared to pain-free controls (both p < 0.001) and worse performance in patients with FM than in patients with CLBP (p < 0.005). Statistical analyses of the six-minute walking test also revealed significant differences among groups  = 183.82, p < 0.001), with both chronic pain groups walking less distance than pain-free controls  and patients with FM walking less distance than patients with CLBP (p < 0.005). In a similar way, significant group differences in the performance of the timed up and go test  = 122.34, p < 0.001) indicated the faster performance of the pain-free controls compared to the chronic pain groups (both p < 0.005), and faster performance in the CLBP than in the FM group (p < 0.001). Ratings on self-perceived effort obtained from the Borg scale after the six-minute walking test revealed significant group differences in fatigue  = 225.9, p < 0.001); post-hoc analysis showed that fatigue was higher in the groups of chronic pain than in healthy controls (both p < 0.001) and higher in patients with FM than in patients with CLBP . Finally, significant group differences in isometric back muscle strength  = 296.80, p < 0.001), showed lower strength in patients with FM and patients with CLBP compared with pain-free controls  and in patients with FM compared with patients with CLBP (p < 0.05).In general, patients with chronic pain performed worse than pain-free controls and patients with FM performed worse than patients with CLBP in all measures of motor function  = 50.52, p < 0.001) and standard deviations in anteroposterior  = 23.4, p < 0.001) and mediolateral sway  = 31.18, p < 0.001). Post-hoc analysis showed that both groups of chronic pain displayed higher scores of mean velocity in comparison with pain-free controls (both p < 0.001), and patients with FM displayed greater scores of mean velocity than patients with CLBP (p < 0.001). Moreover, both groups of chronic pain displayed greater body sway than controls in the anteroposterior (both p < 0.05) and mediolateral directions (both p < 0.01), and patients with FM displayed greater scores than patients with CLBP in both directions (both p < 0.001). Dynamic balance. Analyses of gait task kinematic parameters indicated that patients with FM and patients with CLBP had significant deficits in dynamic balance and gait performance compared to pain-free controls. Significant group differences were observed in gait velocity  = 13.25, p < 0.001), stride length  = 11.54, p < 0.001), single support percentage  = 8.18, p < 0.001), and percentage of swing phase  =5.81, p < 0.001). Post-hoc comparisons revealed that patients with FM and patients with CLBP displayed reductions in these parameters in comparison with pain-free controls , but no differences were observed between patients with FM and patients with CLBP .The aim of the present study was to compare pain impact, somatosensory sensitivity, motor functionality, and static and dynamic balance in two groups of patients with chronic pain  and pain-free controls. Based on previous evidence that objectified chronic pain impairments in motor functionality, balance, and somatosensory sensitivity ,8, it waAs expected, both groups of chronic pain scored worse results than healthy pain-free controls in all the sensory and motor variables. Similar to previous studies, our patients with chronic pain reported greater sensitivity to pain , togetheIn the present study, CLBP was encompassed between pain-free controls and FM. Thus, although patients with CLBP showed some indicators of altered pain processing, they did not reach the extent of patients with FM. Particularly, patients with CLBP reported less pain impact and lower pain sensitivity than patients with FM, in accordance with other studies reporting higher deep-tissue hypersensitivity, lower pain tolerance, and higher temporal summation of pain stimuli in FM compared to CLBP . InteresIn addition, this study showed significant differences in motor performance and static and dynamic balance between both groups of patients with chronic pain, highlighting the greater severity of motor and balance alterations in patients with FM. Poor balance has been considered a predictor of widespread musculoskeletal pain . The lacDepression and anxiety are common predictors of widespread pain , opioid Our findings point to the need to establish a more precise diagnosis in chronic pain processes that include the analysis of specific motor, somatosensory, and balance parameters. Nevertheless, some limitations must be considered for the adequate interpretation of the present results. Although medication was controlled, it was not suppressed in participants with chronic pain, and opioids, tricyclics, hypnotics, or benzodiazepines have been demonstrated to have side effects on postural stability. A further limitation of the study is the heterogeneity of pain conditions, especially low back pain, that may have affected the test scores. Moreover, anxiety and depression were scored as subscales of a specific questionnaire for FM, which could have affected the results, especially when low back pain was assessed. Although most patients were postmenopausal, our study did not consider the possible effects of the phase of the menstrual cycle on pain sensitivity. Finally, the fact that most of the participants were women and that especially in the FM group the rate of women was higher than the CLBP could have biased some of the results. Therefore, future research must address these biases and elucidate whether the greater impact of FM on somatosensory sensitivity, motor function, and balance compared to CLBP could be mediated by some of these factors.Patients with chronic pain  showed worse pain impact, somatosensory sensitivity, motor function, and balance than pain-free controls. Furthermore, although FM and CLBP may have similar symptoms and share a common pathophysiology, our findings revealed that FM patients showed a greater pain impact and more somatosensory, motor, and balance disturbances than did CLBP patients. Some authors consider CLBP as a stage prior to FM, pointing to pain severity as the most important clinical risk factor for the transition to FM. Indeed, a high percentage of patients with CLBP develop FM where back pain is no longer dominant. This fact highlights the need for early intervention to mitigate the severity of pain symptoms and to alter the course towards FM. Because FM is a prevalent chronic pain syndrome with few effective therapeutic options available, once the possible reasons for the greater deterioration in patients with FM are known, compared to other chronic pain entities such as CLBP, it is necessary to adopt effective treatments in order to prevent it. Our results show that there are multiple areas susceptible to deterioration, so it is necessary to adopt interdisciplinary interventions focused on both physical and emotional dysfunction. Interventions that integrate somatic, physical, and emotional factors into the same rehabilitation program should be considered when developing clinical programs.


Pain perception in individuals with prolonged disorders of consciousness (PDOC) is still a matter of debate. Advanced neuroimaging studies suggest some cortical activations even in patients with unresponsive wakefulness syndrome (UWS) compared to those with a minimally conscious state (MCS). Therefore, pain perception has to be considered even in individuals with UWS. However, advanced neuroimaging assessment can be challenging to conduct, and its findings are sometimes difficult to be interpreted. Conversely, multichannel electroencephalography (EEG) and laser-evoked potentials (LEPs) can be carried out quickly and are more adaptable to the clinical needs. In this scoping review, we dealt with the neurophysiological basis underpinning pain in PDOC, pointing out how pain perception assessment in these individuals might help in reducing the misdiagnosis rate. The available literature data suggest that patients with UWS show a more severe functional connectivity breakdown among the pain-related brain areas compared to individuals in MCS, pointing out that pain perception increases with the level of consciousness. However, there are noteworthy exceptions, because some UWS patients show pain-related cortical activations that partially overlap those observed in MCS individuals. This suggests that some patients with UWS may have residual brain functional connectivity supporting the somatosensory, affective, and cognitive aspects of pain processing , rather than only being able to show autonomic responses to potentially harmful stimuli. Therefore, the significance of the neurophysiological approach to pain perception in PDOC seems to be clear, and despite some methodological caveats , remain to be solved. To summarize, an accurate clinical and neurophysiological assessment should always be performed for a better understanding of pain perception neurophysiological underpinnings, a more precise differential diagnosis at the level of individual cases as well as group comparisons, and patient-tailored management. Prolonged disorders of consciousness  (PDOC) represent a possible evolution of coma, a condition following severe brain injury, characterized by a loss of wakefulness and awareness (mainly owing to a lesion in the ascending reticular system or diffuse (bi)hemispheric damage) ,2. PDOC Consistently with this premise, UWS patients should not perceive anything, including pain, even if they can show reflexive response to stimuli, including the nociceptive, but without any stimulus-related differentiation . The discovery of residual traces of awareness, covert awareness, and brain activity modulation in response to command and stimuli in some patients clinically labeled as UWS using advanced neuroimaging or electrophysiological techniques put in crisis the former assumption that patients with UWS are unable to perceive anything, including pain. Some individuals may have a dissociation of motor and cognitive function , i.e., tIt remains, therefore, unclear whether and how UWS patients can show signs of possible covert capacity for subjective pain perception, potentially indicating that some patients behaviorally diagnosed as with UWS may have a residual capacity of pain perception (and are thus in MCS). Nonetheless, we may argue that there are good reasons to think that these patients could experience pain. This argument stems from three main issues.Firstly, the efficacy of clinical assessments on detecting aware pain responses is limited. Pain assessment in PDOC individuals is limited to the clinical appreciation of responses to nociceptive stimuli using, e.g., the Coma Recovery Scale-Revised (CRS-R)  or the NSecondly, the evidence of brain activations within some brain areas concerning nociceptive stimulation in a way resemble those detectable in aware individuals ,36,37. MThirdly, if a patient is aware, they are presumably able to feel pain, because if awareness does not imply sentience, the absence of awareness excludes any sentience. Some works showed isolated cortical activations that document retained modular function without the integrative processes necessary for consciousness ,41,42,43These data could suggest that brain activations, when complex, are a marker of ongoing conscious perception or pain awareness . FurtherConsistently with these issues, studies showing neurophysiological pain signatures in patients with PDOC at an individual level are not conclusive. Therefore, to implement clinical use of neurophysiological techniques in combination with behavioral assessment of pain, one needs to know the sensitivity and specificity of these methods, and which stimuli are the most potent in detecting pain responses.Another essential issue to consider is that pain may represent a chronic, lasting condition in patients with PDOC, as a sort of inner nature of PDOC itself owing to central sensitization mechanisms leading to pain hypersensitivity . In thisThe functional neuroimaging devices used to estimate pain perception in PDOC patients are limitedly available in rehabilitation and neurologic centers, and not all of the patients with PDOC can be subjected to such devices. Conversely, neurophysiological paradigms are more accessible and adaptable to clinical needs. In this scoping review, we sought to investigate the neurophysiological basis underpinning pain perception in PDOC, suggesting that its assessment might help in reducing the PDOC misdiagnosis rate. We adopted a scoping review to describe the landscape of available evidence, identify gaps in the existing literature, and illuminate areas for further research. A scoping review methodology was also selected because of the relatively circumscribed nature of the field.To be included in the present scoping review, papers needed to deal with or focus on neurophysiologic evaluations of pain perception in PDOC individuals. Peer-reviewed journal papers were included without time restrictions if they described a measure for pain in relation to awareness, involved adult human participants, and were written in English. Studies such as randomized clinical trials, case-studies, and reviews  were included in order to consider different aspects of assessing pain in relation to awareness. Papers were excluded if they did not fit into the conceptual framework of the study, focused on a non-PDOC condition , or belonged to gray literature, including letters, commentaries, textbook chapters, technical or theoretical descriptions, abstracts, and conference proceedings. Furthermore, it was ascertained that the study patients were provided with a behavioral assessment tool for assessing the level of consciousness, i.e., the CRS-R, which has acceptable standardized administration and scoring procedures, excellent content validity, substantial evidence of good interrater reliability, and it is the only scale to address all Aspen Workgroup criteria . In addiWe searched the following bibliographic databases to identify the potentially relevant documents: PubMed, MEDLINE, Google Scholar, and Cochrane Database. The search strategies were drafted by L.P. and A.N. and further refined by C.M.E., who also settled all disagreements regarding article inclusion at each review phase. The final search strategy included the keywords vegetative state/UWS OR minimally conscious state AND pain.The research returned 261 papers . The authors L.P., A.N., and R.S.C. discussed the titles and the abstracts, and amended the screening and data extraction manual before beginning screening for this review, to increase data consistency. Thus, 59 full-text articles were identified to be retrieved and assessed for eligibility by using the abovementioned keywords, main judgment criteria, and publication types. Both L.P. and A.N. independently reviewed all articles, sequentially evaluating the titles, abstracts and then the full text of all publications identified by our searches for potentially relevant publications. The author C.M.E. settled all disagreements regarding article inclusion at each review phase discussion with other reviewers if needed.n = 31), or were not original quantitative research (n = 12). The remaining 16 studies were considered eligible for this review  , are eliThese measures include heart rate variability (HRV) and blood pressure, which qualify as independent indicators of the interactions between the central nervous system (CNS) and the autonomic nervous system (ANS) ,59,60. TAnother work focused on PDOC patients’ electrodermal activity. The authors found that cutaneous responses were preserved only in the UWS patients who regained consciousness ,72. SimiLEPs were identified in all the patients with a significant N2 and P2 latency increase, despite the absence of late somatosensory potentials showing a significant N2 and P2 latency increase, and the presence of auditory mismatch negativity in all the patients . Later, Further confirmation and deepening of the matter came from some studies illustrating that LEPs were with lower amplitudes and more delayed latencies in UWS individuals than in MCS persons . This diAdditional data on residual awareness preservation came from studies that deeply analyzed LEP features. In one study, the effects of repetitive laser stimulation on gamma-band oscillation (GBO) power were evaluated . An incrSubsequent studies analyzed the spectral features of C-LEP and confirmed that a fine cortico–subcortical regulation of such measures exists in some UWS patients. This presupposes partial integrity of distinct thalamo–cortical loops, which are a well-known prerequisite for awareness to emerge, even covertly. Furthermore, when investigating the inter-peak interval (IPI) between the N2 and P2 components of LEP, a correlation between IPI and the NCS-R was found, suggesting that IPI could represent an objective marker of behavioral responsiveness to nociceptive stimulation independent from the sensory part of pain processing, which is critically influenced by the stimulation intensity . In thisDistinguishing between studies that showed neurophysiological pain signatures in patients with PDOC on an individual-level beyond a group level is crucial if one aims to reason for clinical utility of these methods. Actually, in a clinical setting, one needs to know the sensitivity and specificity of these techniques in detecting subjective pain perception . We did not systematically investigate these aspects, but the studies we reviewed did not identify significant within-group differences concerning the neurophysiological pain signature, with very few exceptions concerning a few patients that were tested using different, advanced methodological approaches  ,73,74.Furthermore, neurophysiological pain evaluation may play a role in the prognosis of awareness recovery. In this regard, a 68-year-old woman with a five-year UWS secondary to a severe brain hemorrhage was prognosticated as likely suffering from a cognitive–motor dissociation syndrome three years before using a neurophysiological protocol based on a PMI assessment. This protocol shows extensive nociceptive processing within large frontoparietal networks. In fact, after three years, the subject emerged from UWS and then from MCS (as being able to communicate appropriately) .Pain diagnosis and management in PDOC is still a thorny issue. The potential to experience pain and suffering is frequently raised concerning treatment, ethical, and legal questions in individuals with PDOC. To date, the international practice guidelines for DPC  recommenThe studies we reviewed suggest that some electrophysiological tools   98,99,1,102,103 However, the potential of these electrophysiological techniques in detecting pain perception is limited because no established veridical benchmark of level of consciousness or pain perception exists concerning patients with PDOC ,111,112.Furthermore, the evidence regarding the spectral and oscillatory components of the EEG measures and CNS–ANS interactions to detect residual pain awareness is still not consistent, owing to non-homogeneous samples, methodological differences, and data processing . AdditioOne could concern that the detection of purposefully cognitive responses using active paradigms ,136,137 Finally, the instrumental assessment can only offer a quantitative assessment of whether a patient may experience pain. Indeed, qualitative assessment is not achievable. Further research should investigate autonomic and cortical activations expressing covert measures of somatosensory and nociceptive information processing in PDOC patients, preferably using a standardized multi-methods approach.The need for a more objective assessment of PDOC patients goes far beyond the differential diagnosis and prognosis because it has relevant consequences on personalizing the rehabilitation approach. In this regard, distinguishing between studies that show neurophysiological pain signatures in patients with PDOC at the individual level beyond a group level is crucial if one aims for the clinical utility of these methods. The studies we reviewed did not identify significant within-group differences concerning neurophysiological pain signatures, with very few exceptions concerning the same patients tested using different, advanced methodological approaches  ,74,75. TConsequently, even a methodologically accurate electrophysiological paradigm may still be clinically inaccurate, because there are no independent methods for confirmation. However, the clinical utility of electrophysiological assessment benefits from comparing findings in PDOC with the performance of healthy controls under identical experimental conditions (with the abovementioned precautions) ,132,133 Furthermore, as research develops, it will be possible to benefit from neurophysiological data concerning the effectiveness of a treatment strategy ,151,152.Solving the bias results toward false positives or false negatives between analysis methods remains a highly challenging obstacle in the research setting. Overcoming the obstacle of false positives or false negatives may consist of reanalyzing previous neuroimaging findings with alternative statistical methods ,153, anaOf note, research should be oriented at a single-level rather than only at a group-level, if the neurophysiological data have to be adopted as a tool for patient-tailored care plans. The development of technology and methods should aim to increase the availability of objective electrophysiological assessments of functional connectivity and analysis at the level of individual cases and group comparisons . In thisAdditionally, larger sample studies are also necessary to enable comparisons among different groups of patients. Lastly, a serial and multimodal neurophysiological assessment may provide us with more profound knowledge of the effects of patients’ clinical features and comorbidity profiles on pain processing to understand better pain perception.Consistently with the limitations of the clinical assessment, clinicians should be cautious in making definitive conclusions about pain and suffering in individuals with PDOC. The available data suggest that neurophysiology may contribute significantly and actively to clarify the neural correlates of pain perception in patients with PDOCs. Indeed, large-scale brain activations in response to nociceptive stimuli may suggest a conscious perception of pain despite behavioral unresponsiveness. On the other hand, it should be at least assumed that negative results during active paradigms do not necessarily imply the absence of cognitive processes, in keeping with the diagnostic limitations of the electrophysiological paradigms we reviewed. In such cases, further clinical and multiple instrumental evaluations are necessary to prove pain (non)perception ,157,158.


BackgroundThe incidence and consequences of the perirenal extravasation of the irrigation fluid during retrograde intrarenal surgery (RIRS) are not fully elucidated. The objective of this study was to assess the incidence, risk factors, and complications of perirenal extravasation of irrigation fluid during RIRS.MethodsThis prospective observational study was conducted in the Department of Urology, Bir Hospital, Kathmandu, Nepal, from January 2020 to March 2021. Patients undergoing RIRS for renal stones less than 2 cm in diameter were included in the study. Irrigation during the procedure was performed using isotonic normal saline under gravity at 50 cm from the symphysis pubis of patients with intermittent manual compression if required. Lithotripsy was performed with 120-Watt Ho:YAG laser using 200-micron laser fiber. Retrograde pyelogram was performed after the completion of lithotripsy to document the presence or absence of extravasation on fluoroscopic images. A double-J stent was placed at the end in all patients. Patients were observed for systemic inflammatory response syndrome (SIRS) features. Postoperative abdominal ultrasonography was performed on the first postoperative day to assess the perirenal collection together with complete blood count. The visual analogue scale (VAS) was used to assess pain in postoperative period. The preoperative patient’s and stone characteristics, hydronephrosis, intraoperative characteristics, and postoperative findings were analyzed.ResultsA total of 71 patients who underwent RIRS during the study period were analyzed. The mean (SD) stone size was 13.19 (3.12) mm. Intraoperative perirenal extravasation of contrast was noted in eight (11.26%) patients; however, no patient had ipsilateral perirenal collection on ultrasonography obtained on the first postoperative day. No significant differences were observed among patients with or without perirenal extravasation in terms of mean stone size, laser settings, operative duration, and lasing duration. Use of ureteral access sheath (UAS) was associated with lower incidence of extravasation; however, it was not significant. SIRS was documented in eight patients overall, with none of the patients with extravasation having features of SIRS. Patients with extravasation experienced more postoperative flank pain (p<0.05).ConclusionPerirenal extravasation was common during RIRS and was associated with higher postoperative pain scores. Stone size, use of UAS, laser settings, operative duration, and lasing duration were not associated with an increased risk of extravasation. Extravasation was not associated with increased postoperative complications. Retrograde intrarenal surgery (RIRS) is increasingly being a preferred procedure for renal stones by patients and surgeon alike owing to its low complication rate and minimal invasive nature . With suAlthough perirenal extravasation of the irrigation fluid is a recognized complication, its exact incidence and consequences are sparsely reported in the existing literature. The objective of this study was to assess the incidence, risk factors, and complications or sequelae of perirenal extravasation of irrigation fluid during RIRS.This prospective observational study was conducted in the Department of Urology, Bir Hospital, National Academy of Medical Sciences, Kathmandu, Nepal, from January 2020 to March 2021. Ethical approval was obtained from the Institutional Review Board of National Academy of Medical Sciences, and written informed consent was obtained from all patients.Patients older than 14 years with renal stones less than 2 cm in diameter undergoing RIRS were included in the study. Patients with no preoperative CT scan, bilateral procedures, obstructed system, ureteral stricture, ureteric stones, renal anomaly, simultaneous endopyelotomy, simultaneous infundibulotomy, and calyceal diverticular stone were excluded. Patient demographics including age, sex, BMI, relevant medical history, and CT KUB/IVU  were obtained to assess hydronephrosis, the stone location, density, and Hounsfield unit. Sterile urine culture was obtained before surgery.Surgical procedureAll the surgeries were performed by a single consultant urologist (A.S.). Prophylactic antibiotic (ceftriaxone 1 gm) was administered prior the induction of general anesthesia, and the patient was placed in the lithotomy position. Irrigation during surgery was performed under gravity using 1 L of normal saline, with the lower margin of the irrigation bag maintained at a height of 50 cm from the level of the symphysis pubis of the patient with an intermittent manual pump with Pathfinder or TraxerFlow™ . Cystoscope was used to place hydrophlic guidewire  upto the ipsilateral pelvicalyceal system under fluoroscopic guidance. The ureteric access sheath (UAS)  was routinely used if negotiable, and sheathless procedure was performed in cases where the UAS was not negotiable. Inspection of all calyces was performed, and stone considered in unfavorable location for laser lithotripsy in situ by the operating surgeon was relocated before lithotripsy using various zero tip nitinol baskets . Laser lithotripsy was performed using Ho:YAG laser (120H Lumenis) using 200-micron laser fiber. Laser lithotripsy was performed employing the following settings:(1) high power setting: Dusting - 0.2-0.5J and 40-70 Hz; fragmentation - 1J and 10 Hz; pop dusting - 0.5J and 50 Hz(2) low power setting: Dusting - 0.5 -0.8J and 10-15 Hz; fragmentation - 1J and 10 Hz, popcorning - 1-1.2J and 15-20 HzLithotripsy was performed till the fragments were easily floated or dislodged with gentle irrigation. At the completion of lithotripsy, retrograde pyelogram (RPG) was performed using 1:1diluted contrast diatrizoate meglumine and diatrizoate sodium (76%), and 5 mL of solution was injected slowly each time with fluoroscopy to the maximum volume of 10 mL over 10-15 seconds. Presence or absence of extravasation of contrast was documented. A double-J stent was inserted in all cases at the end.Intravenous analgesics (Paracetamol six hourly) and oral alpha blocker  were administered in the postoperative period. Patients were given injection ketorolac and/or tramadol in case of inadequate pain relief. Postoperatively, patients’ vital parameters were monitored  hourly, and severity of the flank pain was assessed using visual analogue scale (VAS) on the first postoperative day three hours after the last dose of the parenteral analgesia. On the first postoperative day, complete blood count and ultrasound of the abdomen  were performed. Patients were usually discharged on the first postoperative day. The double-J stent was removed after 14 days, and patients were followed up till four weeks.The operative duration was considered from the time of placement of cystoscope for guidewire placement till the placement of the double-J stent at the end of procedure. The total lasing energy utilized and lasing duration were recorded. Pain severity was assessed using VAS and categorized as 0 for no pain, 1-2 for mild pain, 3-5 for moderate pain, 6-7 for severe pain, 8-9 for very severe pain, and 10 for the worst pain possible. Systemic inflammatory response syndrome (SIRS) was recorded in the immediate postoperative period. Presence of equal to or more than two components of SIRS was considered significant ) followed by the middle pole calyx (n=2 [2.8%]) (Table % during Mild postoperative pain was present in 59 (83.1%) patients and moderate postoperative pain was present in 12 (16.9%) patients, and the pain intensity assessed by VAS was significantly higher in patients with extravasation (p=0.024). Although eight patients had RPG detected extravasation, none of the patients had perirenal collection or parenchymal or subcapsular hematoma in ultrasonography obtained on the first postoperative day. Overall, SIRS was documented in two patients and RPG leak was not associated with the incidence of SIRS (p=0.786). There were no major complications as three patients developed postoperative complications, with one patient having grade 1 and two patients having grade 2 complications according to the Clavien classification  while the threshold for pyelovenous and pyelosinous absorption has been shown to be in the order of 30-45 mmHg (40-60 cmH2O), and sustained pressure above that limit may lead to forniceal rupture resulting in perirenal extravasation [The normal intrarenal pressure is identified to be less than 10 mmHg 13 cmHO while tvasation ,9. In ouStudies had documented an increased risk of infectious complications with increased intrarenal pressure. Since perirenal extravasation is also a consequence of increased intrarenal pressure, it may be associated with increased complications. In our study, overall febrile illness occurred in three (4.2%) patients, and none of the patients developed sepsis. Similar observations were noted by Berardinelli et al. in their study on infective complications in RIRS . In our There was no significant difference observed in the patients with or without perirenal leak in relation to the mean stone size, average lasing time, and laser power setting (high versus low). High power laser settings can lead to increased temperature on the system and increased chances of injury to mucosa with resultant increased risk of extravasation. However, no relation with laser settings was observed in our study. The larger stone size would require longer duration for lithotripsy, and the increased number of fragments would more likely to impair vision, thus necessitating manual irrigation as well as longer operative duration and hence increasing the risk of extravasation; however, no such relation was observed in our study. Regular use of UAS and relocation of stone in unfavorable location before lithotripsy would have led to the results in our study.The use of UAS has been shown to reduce intrarenal pressure . In our In our study, most patients (83%) had mild pain while the remaining 17% had moderate pain in the postoperative period assessed using VAS, and a significantly higher number of patients with extravasation experienced moderate pain. It could be explained by the increased distension of the renal capsule. The available literature remains unclear regarding the associated factors with pain after flexible ureteroscopy. However, the larger stone burden, prolonged operative duration, and duration of the UAS in situ were associated with significantly higher pain scores after laser lithotripsy with semirigid ureteroscopy .The effect of a ureteral J-stent on postoperative pain inserted at the end of the operation is still debatable . While TSimultaneous intrarenal pressure measurement was not performed in our study to correlate the relation with perirenal extravasation. Small sample size limits the generalizability of the results.Minor perirenal extravasation of irrigation fluid was not uncommon during RIRS for renal stones. The presence of extravasation is usually associated with significantly higher flank pain in the postoperative period. The extravasation detected intraoperatively resolved within the first postoperative day without major sequelae.Measures to reduce intrarenal pressure such as use of UAS and judicious use of manual irrigation intraoperatively and postoperative use of a double-J stent may help reduce the risk of perirenal extravasation.


Initial management of the acute pain crisis (APC) of sickle cell disease (SCD) is often unsatisfactory, and might be improved by developing a standardised analgesia protocol. Here, we report the first stages in developing a standard oral protocol for adolescents and adults. Initially, we performed a dose finding study to determine the maximal tolerated dose of sublingual fentanyl (MTD SLF) given on arrival in the acute care facility, when combined with repeated doses of oral oxycodone. We used a dose escalation algorithm with two dosing ranges based on patient’s weight (<50 kg or >50 kg). We also made a preliminary evaluation of the safety and efficacy of the protocol. The study took place in a large tertiary centre in London, UK. Ninety patients in the age range 14–60 years were pre-consented and 31 treatment episodes were evaluated. The first 21 episodes constituted the dose escalation study, establishing the MTD SLF at 600 mcg (>50 kg) or 400 mcg (<50 kg). Further evaluation of the protocol indicated no evidence of severe opioid toxicity, nor increased incidence of acute chest syndrome (ACS). Between 0 and 6 hours, the overall gradient of reduction of visual analogue pain score ) was 0.32 centimetres (cm) per hour  = 0.20 to 0.44, p < 0.001). For episodes on MTD SLF, there was median (interquartile range (IQR)) reduction in VAS score of 2.8 cm (0–4.2) and 59% had at least a 2.6-cm reduction. These results are supportive of further evaluation of this protocol for acute analgesia of APC in a hospital setting and potentially for supervised home management. Severe episodes are distressing, disruptive to normal activity, associated with life-threatening complications such as acute chest syndrome (ACS), and may predispose to chronic pain. Initial management in the emergency department (ED) or other acute care setting requires rapid assessment and administration of first dose of analgesia, usually opioid, within 30–60 minutes.35 Afterwards, repeated doses of analgesia are generally required, together with mandatory monitoring in order to ensure adequacy of analgesia, to anticipate additional complications of APC and to avoid opioid toxicity.6 There is no standard analgesia protocol for paediatric, adolescent or adult patients and controversy remains around a number of aspects of the treatment pathway including choice of opioid, timing and route of administration, and differences in practice between children, adolescents and adults. This prompted the National Heart Lung and Blood Institute (NHLBI) panel in the United States7 and the National Institute of Clinical and Health Care Excellence (NICE) in the United Kingdom to recommend studies to determine optimal management of APC.The acute pain crisis (APC) is the commonest acute complication of sickle cell disease (SCD). is a mu receptor agonist, metabolised mainly through glucuronidation by the enzyme UGT2B7. The resulting metabolites include morphine-6-glucuronide (M6G), which is pharmacologically active and has been associated with an increased risk of ACS. Oxycodone and fentanyl are strong opioids which differ from morphine in pharmacokinetics, undergoing extensive first-phase metabolism via CYP2D6 and CYP3A4 pathways, enzymes which are potentially activated or inhibited by a range of drugs that could affect the therapeutic response. Oral oxycodone is commonly used for home management of pain in the United States, but might be a suitable alternative to morphine for management of acute sickle cell pain in patients who have not been heavily exposed to strong opioids.Morphine, the most commonly used opioid, Although evidence for this effect in patients with SCD is lacking, we believe that there is cause for concern about adverse effects associated with repeated doses of intravenous opioids given over a prolonged period in this patient group. Studies in children which show that a standardised oral-based opioid protocol can be effective and safe14 suggest that this kind of protocol could also be evaluated in adolescents and adults.With regard to the route of administration, the intravenous route is generally accepted as the gold standard, but there are a number of considerations which justify efforts to develop non-intravenous opioid protocols in both paediatric and adult SCD populations. First, delays in administration of analgesia often occur because of poor venous access. Second, there is evidence from the addiction literature both from animal studies and human observation studies, that rapid and frequent elevations in plasma and brain drug levels during intravenous administration are more likely to induce tolerance and dependency. For instance, the onset of action for sublingual fentanyl is 8–10 minutes and peak effect at 40–60 minutes. The transmucosal route of administration could potentially enable rapid action of the first dose of opioid analgesia, avoiding delays entailed with intravenous administration. By restricting transmucosal opioid to the first dose only, the potential risks associated with sharp elevations in plasma and brain opioid levels may be mitigated. Intranasal and buccal fentanyl have been used to manage acute sickle pain in children and adults, but it is not clear how best to incorporate additional rapid-acting opioid analgesia into a standard protocol for acute pain.18 We have previously shown that intranasal diamorphine (IND) given as a single acute dose in combination with a pre-scheduled protocol of oral morphine can provide effective analgesia in children and potentially reduce the time to first analgesia compared to intravenous opioid.19 Some problems with use of IND were identified. First, 35% of children found IND uncomfortable, particularly adolescents, who are administered a higher concentration of diamorphine solution because of their greater weight. Second, diamorphine is not available in some health care systems and uptake might be limited by perceived association with drug dependency.Opioid drugs can be rapidly absorbed through the oral and nasal mucosa, leading to a rapid rise in plasma drug levels.®) given on arrival in the acute health care facility, when combined with a programmed dosing schedule of oral oxycodone. Oxycodone was chosen in this protocol building on our previous experience of using oxycodone as a replacement opioid in adolescent and adult patients treated in our institution who had adverse effects, or poor pain control with morphine. The study also aimed to obtain preliminary data on efficacy and safety which could be used to design a follow-up randomised controlled trial comparing this protocol with standard analgesia.The overarching aim of our programme of work is to develop a standard oral-based analgesia protocol, suitable for rapid administration in the ED. In this study, we assessed the maximal safe dose of sublingual fentanyl  on first arrival in ED, to obtain rapid increase in plasma drug concentration and rapid analgesic effect. The pharmacokinetics of oral short-acting opioid are slower than for transmucosal, but we predicted that if the oral short-acting opioid is administered simultaneously with transmucosal, drug levels should reach analgesic levels simultaneously with the decrease in drug levels of transmucosal opioid. In this way, we aimed to ensure sustained opioid drug levels and analgesia effect during the first few hours of pain management. In this study, we modified this analgesia protocol for use in adolescents and adults by replacing IND with sublingual fentanyl . For breakthrough analgesia, short-acting oral morphine was replaced with oral short-acting oxycodone , and for background analgesia, controlled-release morphine was replaced with controlled-release oxycodone . The protocol is shown in Our standard institutional analgesia protocols are based on short-acting oral morphine for breakthrough and controlled-release morphine for background analgesia. Some adults, particularly those with more severe or frequent hospitalisations, are treated with subcutaneous injections combined with controlled-release oral long-acting opioid for background analgesia. The study was part of a long-term programme of work in our service to improve pain management and patient experience, involving consultation with patients, families and the wider SCD multi-disciplinary team. as a regular daily analgesic prescription at home. There was no limit to the annual rate of admissions with APC prior to participation in the study.Patients were consented in the out-patient setting and consent confirmed on presentation with APC. Inclusion and exclusion criteria are shown in In the event of APC requiring treatment in hospital, the patient or parent/guardian was asked to phone the trial centre to inform of their intention of attending. Children were directed to the paediatric ED, adults (age >16 years) either to the adult ED or, if there was a bed available, to the haematology day unit (HDU). The trial was implemented with the assistance of a dedicated nurse and a trial manager. Paediatric and emergency medicine clinical research teams contributed to delivery of the trial in their respective areas. Monitoring and treatment over the first 6 hours were done by the trial nurse, while management after 6 hours was undertaken by standard care clinical and nursing staff. The intention was to continue oral analgesia according to the trial protocol, after the first 6 hours of treatment on the protocol, but there was an option to switch to alternative oral opioid or injected opioid using institutional protocols. Ibuprofen and paracetamol at standard recommended dosage were routinely prescribed and administered as additional analgesic medication. with two dose options depending on the patient’s weight (<50 kg or >50 kg). The dose of short-acting oxycodone was fixed at 10 mg (<50 kg) and 15 mg (>50 kg). The range of doses of fentanyl is shown in https://www.rcplondon.ac.uk/projects/outputs/national-early-warning-score-news-2). These consisted of respiratory rate (RR) and sedation according to the AVPU scale . The lowest anticipated effective dose was initially used and after three episodes had been completed, the trial safety monitoring committee (TSMC) assessed safety at time points t = 0, 30 minutes, 1 hour and hourly up to 6 hours. A patient was classified as intolerant if the AVPU score was P or U, or if RR was below 8 per minute at any of these time points. If all patients were tolerant, the dose was increased by one iteration. If one or more patients were intolerant, the dose was reduced by one increment. The MTD was to be the most commonly used dose after 21 adjudicated episodes.Sequential dosing of groups of three episodes was undertaken using a ‘group up-and-down’ algorithm,After completion of the dose finding study, we aimed to obtain further data on safety and efficacy using MTD SLF to determine suitable end points for a controlled trial. Although not formally powered, the protocol envisaged a total of 30 episodes at MTD (including episodes treated during both Parts 1 and 2), but the study was actually terminated after a total of 22 episodes at MTD SLF, due to funding constraints.Patient satisfaction was elicited by verbal and written feedback as part of the protocol-specified follow-up 28 days after discharge.https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf).The main safety parameters were RR and sedation score. These were evaluated systematically for the first 6 hours after administration of study medication. After 6 hours, safety parameters were evaluated 3-hourly by the care team according to standard institutional protocols and these were recorded on standard institutional observations charts, reviewed by the trial team over time period 6–24 hours, and daily thereafter until discharge from hospital. Other opioid adverse effects  were monitored at baseline, 3 and 6 hours and then averaged daily until discharge from hospital, and graded on a 0–4 scale based on a published terminology of categories  and potentially life-threatening complication of SCD including acute stroke, acute complication requiring exchange transfusion or admission to intensive care unit.Supplementary Appendix 1. The study was adopted by the National Institute for Health Research (NIHR) Clinical Research Network trials portfolio and conducted with the assistance of Pediatric and Emergency Medicines research teams at our institution.The trial was funded by a grant from the Barts Charity (reference no. 1704), the National Institute for Health Research North Thames Clinical Research Network Divisional Contingency Funding, and unrestricted grants from Kyowa Kirin and Napp Pharmaceuticals. It was registered under the European Directory of Clinical Trials with reference number 2013-004161-14, and sponsored by Barts Health NHS Trust and Queen Mary University of London. Approvals for the initial protocol and subsequent amendments were obtained from the London City and East Research Ethics Committee (reference no. 14/LO/0165), the UK Medicines and Health Products Regulatory Agency (protocol no. 008414) and the National Health Research Authority. Details of protocol amendments during the study are given in MTD of SLF administered was considered the primary end point. A number of protocol-defined efficacy and safety end points were evaluated for potential use in a subsequent controlled trial. These were principally focussed on the first 6 hours of treatment, but data were also collected beyond 6 hours for analysis of overall efficacy and safety during admission and after discharge. Visual analogue scale (VAS) pain score between baseline and 6 hours was analysed using time series regression analysis. Predictor factors were MTD versus not MTD, sex, paediatric versus adult and weight >50 kg or <50 kg.Ninety patients were consented. Overall, 31 treatment episodes in 23 patients were evaluated, including 21 episodes in 19 patients in Part 1 for determination of MDT SLF and a further 10 episodes in seven patients at MTD SLF in Part 2. Sixty-three episodes in 34 consented patients were not evaluated. Forty (63.5%) of these episodes were treated outside of normal working hours of the trial team and 23 (36.5%) did not meet inclusion criteria. Reasons for not meeting inclusion criteria included presentation for causes unrelated to pain, administration of alternative opioid analgesia in ED, taking excluded additional medication and previously treated more than permitted number of times in study. Excluded episodes were treated with standard institutional analgesia protocols. Altogether, including episodes in Parts 1 and 2, 22 treatment episodes in 14 patients were evaluated at MTD SLF. The consort diagram for the study is shown in SLF dose was increased sequentially up to the maximum specified on the algorithm (600 mcg for >50 kg or 400 mcg for <50 kg). This being the most frequently used dose, it met the criteria for MTD SLF. During the first 6 hours of treatment, there was no evidence of respiratory depression (RR <8/min) and no significant difference in RR at different dose increments. There was one episode associated with sedation (AVPU score of P in episode 11), but this episode was a presentation with severe ACS; sedation occurred after switching to intravenous opioid analgesia and was associated with hypoxaemia due to acute pulmonary sickling. This was reversed with urgent exchange transfusion instituted within 6 hours of triage.The analgesia protocol included pre-specified doses of short-acting oxycodone during the first 6 hours. All patients received the initial oxycodone dose simultaneously with SLF, but at subsequent time points, scheduled doses were not given in some cases. The main reasons for withholding doses were physician decision that the patient was becoming too drowsy , and particularly towards the end of the 6-hour study period because pain had settled and the patient was considered ready for discharge.Median verbal pain score on presentation was 7 (range 5–10) . After cSupplemental Table 1).Thereafter, the gradient of reduction of VAS pain score was 0.32 cm per hour  = 0.20 to 0.44, p < 0.001). There was no significant difference in gradient between patients on MDT SLF and sub-MDT SLF, between males and females, and between those in the highest and lowest quartiles for age and weight. Further efficacy end points are detailed in Readmission included ED attendances and hospital admissions. There were a total of 13 readmissions (42% of episodes) of which 6 were within 7 days (19%) and 7 within 14 days (23%). Duration of hospital stay and readmission rate were lower in patients on MTD SLF compared with sub-MTD SLF, but these differences were non-significant .Opioid adverse effects observed during the first 6 hours of treatment are illustrated in Serious adverse events (SAEs) were observed in seven episodes in six patients. Four SAEs were due to prolonged hospitalisation, and in these cases, there were no additional complications of SCD. There were three cases of ACS in two patients. The first presented with symptoms of ACS prior to receiving study medication. This patient underwent emergency exchange transfusion and was switched from study analgesia protocol to intravenous fentanyl PCA at 3 hours, making a rapid recovery. A second patient presented with uncomplicated pain episode and was treated with the study protocol and made a rapid recovery. This patient represented on two further occasions over the next 2 weeks, on the second occasion had a rapid deterioration in respiratory function and died. During the second and third admissions, the patient was treated with a standard institution analgesia protocol. The enquiry into this tragic fatal event identified delay in recognising ACS and instituting emergency exchange transfusion. Since the event occurred 10 days after administration of a single dose of SLF, it was not considered related to study medication or procedures.Supplemental Table 1). One patient experienced ACS, related to two of the three treatment episodes.The protocol allowed up to two treatment episodes per patient in Part 1 and a total of three treatment episodes per patient in total. During the study, five patients were treated more than once (three patients treated three times and two patients treated twice). All 13 of these treatment episodes were at MTD SLF. There was marked variability in efficacy when episodes within an individual patient were compared. None of the patients treated for repeated episodes were observed to have significant opioid adverse events (Supplementary Appendix 2).Feedback on the standard protocol questionnaire was obtained 28 days after discharge for 25 episodes in 19 patients. Feedback was not available for six episodes, because patient was uncontactable (5) or patient deceased (1). In 23 of 25 (92%) episodes surveyed, the patient stated they would like to receive the protocol again. Additional written feedback was received which was highly supportive of the protocol (We have shown that a single dose of SLF at 400 mcg (<50 kg) or 600 mcg (>60 kg) when combined with a pre-scheduled dosing of oral oxycodone is safe for adolescents and adults and can be used for initial management of APC in the acute care setting. and by the NICE in the United Kingdom. Our protocol addresses some of the areas of uncertainty about optimal care, including alternative routes of opioid administration, and treatment in the adolescent and young adult age group.There is an evidence gap in management of APC which has been acknowledged by the NHLBI in the United States2326 and our results do not suggest a higher rate of ACS with oral opiates. We suggest that the risk of ACS associated with oral opioids, as reported in a study of oral versus intravenous morphine, is probably overstated.With regard to safety, patients were carefully evaluated over the first 6 hours of observation. There was no evidence of significant over-sedation or respiratory depression, the primary concerns with use of strong opioids. Reporting of other adverse effects was as expected, with mild pruritis, nausea and dizziness frequently reported, mostly at mild severity. ACS was reported in three episodes (9.6%), but none were considered causally related to the analgesia protocol. Rates of ACS in previous studies have been variable, ranging from 3% to 57%,2729 leading to the suggestion that a change in pain intensity between 1.3 and 2.6 cm on a 10-cm VAS scale would be considered clinically significant. For episodes treated with MTD SLF in this study, the data suggest a clinically significant reduction in pain, with median reduction of 2.8 cm and 59% of episodes demonstrating at least a 2.6-cm reduction in VAS at the 6-hour time point. In comparable trials of analgesia, the mean reduction was in the range of 2–4 cm.2729 We observed that most of the efficacy measures evaluated showed greater efficacy of MTD SFL over sub-MTD SLF, and this supports a policy of administering the highest safe dose of rapid-acting opioid analgesia.Although not formally designed to evaluate efficacy, the data suggest similar efficacy to other analgesia protocols used in SCD. Changes in the VAS pain score over the first 6 hours of treatment or until decision on disposition in ED have previously been evaluated,31 It is not yet clear how the readmission rate relates to efficacy and acceptability of the study analgesia and we plan to investigate this end point in a randomised controlled study. The evaluation at 28 days was intended to enable full recovery from the episode and withdrawal of analgesic medications which could interfere with judgement of satisfaction. In general, patients had a good recollection of their experience during treatment after the 28-day interval. Participant feedback was generally very positive, and a high proportion of those surveyed wished to be treated again with the same protocol. In an ancillary study where a group of our service users participated in developing a questionnaire to evaluate patient satisfaction with pain management in hospital, we found that satisfaction was not primarily determined by the analgesia protocol, but by the quality of communication, and attitudes of staff in ED and medical wards. The benefit of one-to-one nursing care given by the trial nurse during the first 6 hours of the protocol was particularly notable in this study. This suggests that continued communication, reassurance and support sustained over the first 6 hours of management in ED and, if admitted, on transfer to the hospital ward were highly valued and contributed to the overall patient-reported outcome. Resources should be directed to this aspect of care.In our experience, some patients continue to experience pain in the first 1–2 weeks after discharge, and in some cases require readmission to hospital. ED re-attendance and hospital readmission rates were high, but similar to recent studies of patients treated with intravenous opioids in the United States of 35–50%.19 In this study, we did not attempt to address timeliness of this first dose, recognising that in the trial setting, delays occur in assessing eligibility, obtaining consent and administering an investigational medicinal product. In order to confirm a satisfactory performance with regard to time to first analgesia, the protocol would need to be formally implemented with training of acute care staff, and further evaluation undertaken by auditing outcomes during routine care.The protocol was developed following our experience with use of combined IND and short-acting oral morphine in children. We demonstrated that the first dose of IND could usually be delivered by ED staff well within the recommended time limit. In this study, some patients became drowsy (AVPU score of ‘V’) with repeated doses of oral oxycodone, and some scheduled doses were omitted on the decision of the trial physician. We would therefore suggest a revision to the protocol with scheduled dose of oxycodone omitted if VAS pain score is <3.In a previous study with oral opioid protocols, we found that dosing needed to be proactive in the first 6 hours and scheduled doses given even if pain is at the mild end of the scale (VAS score 1–3), to avoid relapse.32 The protocol is unlikely to be successful for patients who are already heavily exposed to opioids, and may not be acceptable to some patients who are already established on intravenous protocols for pain management in hospital. We suggest that a comparative trial would be of most value in adolescent and young adult populations who are not frequent attenders to hospital and are not yet heavily exposed to opioids.Patients who used strong opioids on a daily basis were excluded from the study, and only 38% of patients treated in this study used strong opioids episodically for home management of acute pain, compared to 75% in some adult studies in the United States.In conclusion, these results provide evidence that the study protocol is safe, acceptable and potentially effective for initial pain management of APC in adolescents and adults. Use of SLF on arrival in ED, combined with pre-scheduled oral opioid, could reduce time to first analgesia as well as preventing short- and long-term complications associated with repeated use of intravenous opioids. We suggest that the protocol should be further evaluated in different health care settings, including supervised treatment at home, as well as being formally compared to protocols based on injected opioids.Click here for additional data file.Supplemental material, sj-pdf-1-bjp-10.1177_20494637211033814 for A non-injected opioid analgesia protocol for acute pain crisis in adolescents and adults with sickle cell disease by Paul Telfer, Jonathan Bestwick, James Elander, Arlene Osias, Nosheen Khalid, Imogen Skene, Ruben Nzouakou, Joanne Challands, Filipa Barroso and Banu Kaya in British Journal of Pain