To assess the safety and efficacy of external trigeminal nerve stimulation for acute pain relief during migraine attacks with or without aura via a sham-controlled trial.This was a double-blind, randomized, sham-controlled study conducted across three headache centers in the United States. Adult patients who were experiencing an acute migraine attack with or without aura were recruited on site and randomly assigned 1:1 to receive either verum or sham external trigeminal nerve stimulation treatment (CEFALY Technology) for 1 hour. Pain intensity was scored using a visual analogue scale (0 = no pain to 10 = maximum pain). The primary outcome measure was the mean change in pain intensity at 1 hour compared to baseline.n = 52; sham: n = 54). The primary outcome measure was significantly more reduced in the verum group than in the sham group: −3.46 ± 2.32 versus −1.78 ± 1.89 (p < 0.0001), or −59% versus −30% (p < 0.0001). With regards to migraine subgroups, there was a significant difference in pain reduction between verum and sham for ‘migraine without aura’ attacks: mean visual analogue scale reduction at 1 hour was −3.3 ± 2.4 for the verum group versus −1.7 ± 1.9 for the sham group (p = 0.0006). For ‘migraine with aura’ attacks, pain reduction was numerically greater for verum versus sham, but did not reach significance: mean visual analogue scale reduction at 1 hour was −4.3 ± 1.8 for the verum group versus −2.6 ± 1.9 for the sham group (p = 0.060). No serious adverse events were reported and five minor adverse events occurred in the verum group.A total of 109 participants were screened between February 1, 2016 and March 31, 2017. Of these, 106 patients were randomized and included in the intention-to-treat analysis (verum: One-hour treatment with external trigeminal nerve stimulation resulted in significant headache pain relief compared to sham stimulation and was well tolerated, suggesting it may be a safe and effective acute treatment for migraine attacks.ClinicalTrials.gov Identifier: NCT02590939. Current available acute migraine treatments are mainly pharmacologic therapies , and ‘migraine-specific’ drugs such as ergots and triptans) –3 that hExternal trigeminal nerve stimulation (e-TNS) was initially found to produce a sedative effect  and subs9The study protocol was reviewed and approved by the Institutional Review Boards (IRBs) at Columbia University Medical Center  and Yale University School of Medicine. Written informed consent was obtained from all participants.The ACME study was a prospective, double-blind, randomized, sham-controlled clinical trial conducted across three headache centers in the United States .Male or female adults (aged 18–65 years) were eligible for enrollment if they had a diagnosis of migraine with or without aura  section 1) and were experiencing a migraine attack with or without aura, with headache lasting for at least 3 hours and pain severity stable for at least 1 hour prior to enrollment; subjects may have used any acute medications to treat the attack, but not within the 3 hours before enrollment. The requirement for a minimum headache duration of 3 hours prior to enrollment was implemented to enable, as much as possible, a stable pain intensity at baseline and to minimize the potential for spontaneous headache remission. Exclusion criteria were the following: pregnancy; treatment with botulinum toxin to the head in the prior 4 months; supraorbital nerve blocks in the prior 4 months; diagnosis of other primary or secondary headache disorders, except of medication overuse headache; headache location not involving the frontal, retro- or peri-orbital regions; forehead skin allodynia; use of opioid medications; intake of acute migraine medication within the 3 hours prior to enrollment; implanted metal or electrical devices in the head; cardiac pacemaker or implanted or wearable defibrillator; or previous experience with e-TNS.Patients were recruited at the three centers through the following means: (i) during a routine outpatient office visit; (ii) at the clinic’s or hospital’s urgent care headache unit; or (iii) during an on-demand appointment arranged at the time of a qualifying migraine attack (for patients having been informed about the study beforehand at a standard care visit or via advertisement). Recruited patients were randomly assigned to receive a 1-hour e-TNS session with verum or sham stimulation at the study site. Headache pain intensity was measured using a visual analogue scale (VAS) following the International Headache Society guidelines for controlled trials of drugs in migraine . PatientNeurostimulation was applied via the e-TNS Cefaly® device  for a 1-hour session. The device is a constant current generator for a maximum skin impedance of 2.2 kΩ that delivers rectangular biphasic symmetrical pulses with a zero electrical mean. The pulse frequency used in the current study for the verum device is 100 Hz and pulse width is 250 µs; the total maximum dose of current delivered by a 1-hour session is 1.284 C. The intensity increases linearly to reach a maximum of 16 mA after 14 minutes and then remains constant for 46 minutes. The electrical pulses are transmitted transcutaneously via a supraorbital bipolar self-adhesive electrode (30 × 94 mm) placed on the forehead, designed to cover and excite  the supratrochlearis and supraorbitalis nerves bilaterally .Figure Patients were randomly assigned to a verum or sham e-TNS device. The devices were sequentially numbered following a random allocation sequence generated by the R&D department of the device manufacturer and stratified by center with a 1:1 allocation to one of the two treatment groups (verum or sham) using a block size of 4. Details of the allocated group were sent in a sealed envelope to the coordinating investigator. All site investigators and research staff, as well as patients, remained blinded to the device identities throughout the course of the study. The sham device was strictly identical in shape and color to the verum device, along with identical beeping and flashing. It was not possible for the patient nor for the investigator  to distinguish which device was verum or sham. Both devices used identical rectangular biphasic symmetrical pulses of 250 µs width that induced paresthesia: the sham device via low-frequency pulses of 3 Hz and the verum device via high-frequency pulses of 100 Hz .The primary outcome measure was the mean change in pain score at the 1-hour time point compared to baseline. Secondary outcome measures were the following: mean change in pain score at the 2-hour and 24-hour time points compared to baseline, as well as the proportion of subjects not having used migraine rescue medication at 2 hours and within 24 hours after initiation of the e-TNS session. The primary and secondary outcome measures were selected to determine if e-TNS would be effective in providing headache pain relief, though not necessarily to completely abort a migraine attack.Exploratory outcome measures were the following: proportion of subjects pain-free at 1-hour, 2-hour, and 24-hour time points; proportion of subjects with ≥30% pain relief at 1-hour, 2-hour, and 24-hour time points; proportion of subjects with ≥50% pain relief at 1-hour, 2-hour, and 24-hour time points. A safety assessment was based on the number of reported AEs and their severity. No outcome measures were assessed for sedation.t-test for two independent samples.Results of our recent, open-labeled pilot trial on the acute treatment of migraine using e-TNS showed a reduction in mean pain score of 59% after 1 hour and 55% after 2 hours ; the staAnother placebo-controlled acute migraine study had previously reported use of rescue medication in 71% of subjects from the placebo group, compared to 41.33% for the active treatment group on average . Considen), the arithmetic mean and the standard deviation. Categorical data were summarized by absolute (n) and relative (%) frequency tables. Within the same group (verum or sham), comparison between baseline and treatment results was performed using the Wilcoxon signed-rank test for paired samples. Comparison between the verum and sham groups was performed using the Mann–Whitney test for the outcomes related to change in pain score and the Fisher’s exact test for the outcomes related to proportion of patients. Statistical analysis was carried out on an intention-to-treat (ITT) basis  using R statistical software . Two-tailed p-values were computed with a cut-off for statistical significance set to 0.05. If a subject used rescue medication, pain scores following the medication intake were not included in the analysis; in such cases, the last value carried forward method was used for data imputation. In order to account for possible imbalance in baseline characteristics between the verum and sham groups, a post hoc statistical analysis was performed for the difference in mean VAS scores at 1 hour (primary outcome) in both groups using an analysis of covariance (ANCOVA) model with covariates of baseline VAS score, treatment, site, sex, migraine type (with or without aura), migraine duration, and prior acute medication use.All relevant general, safety and efficacy data were descriptively summarized at each time point of the study. Continuous data were summarized by the number of patients , and therefore eligible for the ITT analysis. Of these 106 randomized patients, seven subjects did not receive the full 1-hour e-TNS treatment: three patients (two verum and one sham) could not bear the paresthesia feeling and requested the stimulation be discontinued before the first 5 minutes elapsed, and four patients (three verum and one sham) withdrew from the study and stopped the stimulation before the end of the 1-hour e-TNS session. Therefore, a total of 99 randomized patients (47 verum and 52 sham) completed the 1-hour treatment phase and provided their pain scores at baseline and at the 1-hour time point. The trial profile of all patients is presented in p < 0.0001) in the verum and sham groups, but much more in the verum (−59%) than in the sham group (−30%); the effect size was large, with a Cohen’s d value of 0.88 (p < 0.0001).Outcome measures are detailed in  of 0.88 . Applyinp = 0.026). Mean pain score reduction at the 24-hour time point compared to baseline was likewise greater in the verum group compared to the sham group (−57% vs −40%), reaching statistical significance (p = 0.037). The evolution of the relative pain reduction after 1 hour, 2 hours and 24 hours compared to baseline is depicted in The mean pain score reduction at the 2-hour time point compared to baseline was also greater in the verum group compared to the sham group (−50% vs −32%) and reached the level of statistical significance (p = 0.0016), but not at the 2- and 24-hour time points. The proportion of subjects achieving ≥50% pain relief was significantly higher in the verum group than in the sham group at the 1-hour time point  but not at the 2-hour and 24-hour time points. The proportion of subjects achieving ≥30% pain relief was significantly higher in the verum group compared to the sham group at the 1-hour time point , but not at the 2- and 24-hour time points.Regarding our exploratory endpoints, the proportion of pain-free subjects was significantly higher in the verum group (29%) than in the sham group (6%) at the 1-hour time point . However, none of the secondary outcomes reached statistical significance when correction for multiple comparisons was applied.When correcting the n = 47; sham: n = 52). In the mITT analysis, the primary outcome measure was significantly more reduced in the verum group (−65%) than in the sham group . The secondary and exploratory outcomes in the mITT analysis were similar to those in the ITT analysis. Notably, the difference in the proportion of subjects who were pain-free at the 24-hour time point , and who had ≥30% sustained pain relief (43% vs 21%), were statistically significant .A modified intention-to-treat (mITT) post hoc analysis was additionally performed including only compliant patients (i.e. those who completed the 1-hour treatment phase and provided pain scores at baseline and at the 1-hour time point). A total of 99 patients were included in this mITT analysis (verum: p < 0.0001).A subgroup analysis was also performed for those patients who did not use any acute medications for their qualifying migraine attack at any point prior to enrollment and administration of e-TNS. Among these 70 patients, the mean VAS score reduction at 1 hour was significantly greater in the verum group than in the sham group . For the ‘migraine with aura’ attacks, pain reduction was numerically greater for verum versus sham, but did not reach significance: mean VAS reduction at 1 hour was −4.3 ± 1.8 for the verum group versus −2.6 ± 1.9 for the sham group (p = 0.060).With respect to migraine subgroups, there was a statistically significant difference in pain reduction between verum and sham for the ‘migraine without aura’ attacks: mean VAS reduction at 1 hour was −3.3 ± 2.4 for the verum group versus −1.7 ± 1.9 for the sham group  and no adverse device effects (ADEs) reported throughout the course of the study. In terms of minor AEs, three patients (two in the verum group and one in the sham group) were unable to tolerate the paresthesia sensation during the nociceptive threshold test phase (before the first 5 minutes of stimulation elapsed), and the treatment was stopped before proceeding to the full stimulation phase. Four patients (three in the verum group and one in the sham group) discontinued treatment before the end of the full stimulation hour: among the patients who received verum stimulation, one withdrew due to nausea that was not present before the beginning of the session (which subsequently resolved without intervention after 20 minutes) and the other two patients discontinued treatment shortly after the initial stimulation test phase as they sensed the paresthesias to be painful. There were no other adverse effects or subjective complaints reported for either group within the 24 hours after the beginning of the treatment.Previous open-labeled pilot studies have suggested a role for e-TNS in the acute treatment of migraine –18; howeThis study met the primary outcome measure, indicating that e-TNS (using the previously specified stimulation parameters) is more effective than sham stimulation for the acute treatment of migraine. Although there was no difference in rescue medication intake following e-TNS compared to sham , the verum device demonstrated significantly superior pain relief compared to sham at the 1-hour, 2-hour, and 24-hour time points (discounting pain scores following any rescue medication intake). The proportion of pain-free patients was also significantly higher for the verum device at the 24-hour time point in the mITT analysis. In a recent observational survey , patientThe efficacy results in the current study were more robust than reported in prior pilot studies ,17 that With regards to limitations of our study, there was a small sample size  and unbalanced baseline characteristics between the verum and sham groups for migraine type, migraine duration, and prior acute medication use. These differences in baseline characteristics were subsequently accounted for in a post hoc ANCOVA analysis, without modifying the significance of the treatment effect defined by the primary outcome.Another limitation of the current study was the execution in a clinic setting. This was designed to ensure correct application of the electrode and device (supervised by study staff) and to maximize data compliance, as the primary outcome measure was collected on site. However, the results could differ from the ‘real-world’ context and may not be generalizable to use of e-TNS at home. In addition, application of e-TNS at the clinic may enhance the placebo effect – pain reduction for the sham group (−30% at 1 hour) is higher than published in a previous pharmacologic acute migraine study   and when pain intensity is moderate–severe compared to mild ,27. In tDirect comparison of efficacy to standard acute migraine treatments (e.g. triptans and NSAIDs) is limited by differences in trial design. Our objective here was to determine whether e-TNS is effective in providing acute headache relief, while the primary endpoint in the triptan trials is typically defined as the proportion of pain-free subjects at the 2-hour time point, as recommended by the International Headache Society guidelines for controlled trials of migraine drugs . FurtherThe mode of action of e-TNS in migraine is not fully understood; it may have segmental ‘gate control’ mechanisms, as well as supra-segmental actions. Scarce evidence for a segmental mechanism comes from a pilot study in which amplitude of the nociceptive blink reflex (nBR) was transiently reduced after one 20-minute e-TNS session . A singlp < 0.0001). e-TNS is safe and well tolerated, offering migraine patients a non-invasive, acute treatment option that lacks the systemic side effects associated with conventional migraine medications.The results from this multi-center, randomized, double-blind, sham-controlled trial demonstrate that e-TNS is effective for acute pain relief during migraine attacks in adult subjects, providing a reduction of mean pain intensity at 1 hour of 59% (vs 30% in the sham group, This is the first randomized, double-blind, sham-controlled clinical trial evaluating the safety and efficacy of e-TNS for the acute treatment of migraine attacks with or without aura.Use of e-TNS during a migraine attack provided a significant reduction in mean headache pain intensity at 1-hour, 2-hour, and 24-hour time points compared to sham stimulation.The acute treatment of migraine with e-TNS was safe and well tolerated.


The outcome of ST-elevation myocardial infarction (STEMI) is significantly influenced by the total tissue ischemic time. In spite of efforts for reducing the in-hospital delay by full-time provision of primary percutaneous coronary intervention (P-PCI) in the 24/7 program, pre-hospital delay still persists. As a first report in Iran, we aimed to assess the duration of pre-hospital delay and its contributing factors in STEMI patients in the P-PCI era.The present cross-sectional study evaluated 2103 STEMI patients who underwent primary PCI from 2016 to 2018. Demographic, personal and socioeconomic factors, index event characteristics, past medical history, pain onset and door times of patients were recorded and independent factors of pre-hospital delay were calculated.Median (IQR) of pain to door (P2D) time was 279 (120-630) minutes. In multivariate analysis, female gender , being uneducated , the onset of chest pain between 00:00 to 6:00  or 7:00 to 12:00 , self-transportation  or referral from another hospital , atypical chest pain , history of hypertension , and opium abuse  were associated with a significantly higher log(P2D), while history of CABG was associated with shorter P2D.Our study showed that P2D is still very high in Iran and revealed the high-risk groups associated with longer P2D. Effective actions should be implemented to increase the public awareness about the symptoms of STEMI, and the importance of immediate appropriate help-seeking. Ischemic heart disease is still the most common cause of death worldwide -3. SeverWhile in-hospital delay has been reduced in many countries, even developing ones , 9, onlyDue to the implementation of full-time (24/7) provision of P-PCI services in our country by the ministry of health and medical education, the in-hospital delay has been reduced in recent years . HoweverThere is no large-scale study evaluating the accurate duration of pre-hospital delay in STEMI patients in our country. Given this lack of information, we aimed to assess the duration of prehospital delay and it’s contributing factors in STEMI patients undergoing P-PCI.Study design and settingThe present cross-sectional study, we enrolled 2407 consecutive STEMI patients who underwent P-PCI between January 2016 and December 2018, in a tertiary cardiac center (Tehran Heart center) , Tehran,ParticipantsThe study population consisted of all STEMI patients who were referred to the mentioned Hospital during the study period and underwent P-PCI. Patients were excluded if the STEMI had occurred in the hospital (n=23). In addition, patients with missed data on pain or door times were excluded from the analysis (n=281). Finally, 2103 STEMI patients were included.Data GatheringData on the patients’ demographic information, personal and socioeconomic factors, marital status, educational level, ethnicity, place of longest stay, insurance type, physical activity level, mode of transfer to hospital, pain characteristics, pain onset time, door times, cardiovascular risk factors, and patients’ past medical history, as well as the infarct related artery were extracted from ischemic heart disease, angiography and angioplasty registries of the hospital, which have been described in detail before . Physical activity level was defined as high in professional athletes, intermediate in those who do usual daily activities and low in patients with the least or lack of physical activity. Statistical analysisth – 75th interquartile ranges: IQR) if they failed to assume normal distributions. Discrete variables were presented as numbers (percentages). P2D was compared between groups using Mann–Whitney test and Kruskal–Wallis test as appropriate. The predictors exhibiting a borderline statistical relationship with pain to door time in the univariate analysis (P ≤ 0.15) were taken for a multivariate logistic regression analysis to investigate their independence. Backward elimination regression analysis was used to remove insignificant variables and log(P2D) was considered as a dependent variable. A P ≤ 0.05 was considered statistically significant. All the statistical analyses were conducted using IBM SPSS Statistics for Windows, version 24.0 .Continuous variables were presented as mean ± standard deviations (SDs) if they assumed normal distributions and as medians . Contributing factors of P2D delay The results of univariate analysis are presented in The P2D time was significantly shorter in those who were transferred to the hospital by EMS (p<0.001). Despite the presence of some meaningful patterns, statistical significance was not observed regarding marital status (p=0.137) and physical activity status (p=0.507).Description of symptoms as atypical or typical chest pain (p=0.005) and also epigastric pain (p=0.007) was significantly associated with longer P2D. In addition, the history of diabetes (p=0.029) and hypertension (p=0.004) were associated with longer P2D. Although P2D was not different among those with and without the history of coronary stenting (p=0.924), the history of coronary artery bypass graft (CABG) was associated with shorter P2D with borderline significance . Contributing factors of P2D delay After nine steps of the backward elimination method, eight variables remained in the final model . Female Based on the findings of the present study, female gender, being uneducated, the onset of chest pain in 00:00 to 6:00 or 7:00 to 12:00, self-transportation or referral from another hospital, description of symptoms as atypical chest pain, history of hypertension and opium abuse were associated with longer P2D while history of CABG was associated with shorter P2D time.Several studies have been performed in different countries to estimate the interval between pain onset and hospital arrival time. Limited studies with small sample sizes have been conducted regarding prehospital delay in Iran . As is eIn the current study, using multivariate analysis, pain to door time was found to be significantly higher in female gender, uneducated patients, those with onset of chest pain between 00:00 to 6:00 or 7:00 to 12:00, self-transported patients or individuals who were referred from other hospitals, patients with atypical chest pain and history of hypertension and opium abuse; while history of CABG was associated with shorter pain to door time.In a study by Noorani et al. , prehospIn a study by Moser el al.  several In the current study we found that patients with chest pain between 00:00 to 6:00 or 7:00 to 12:00 had higher prehospital delays. On the contrary, patients transferred by EMS and educated individuals had lower pain to door time. Infarct related artery had no significant effect in pain to door time in our study population. Our findings are in line with those of Peng et al.  who asseIn our study, the level of education was negatively correlated with pain to door time. Similar to our work, the study of Heo et al. , reporteOur study showed that P2D is still very long in Iran and revealed the high-risk groups associated with longer P2D. We assume that effective actions should be implemented to increase the general population’s knowledge about the presentations of acute MI in order to decrease the time to seek treatment.Limitations and StrengthsBeing single-centered and retrospective design of the current work can be considered as our study limitations. We had missing values in pain or door times in 281 patients and thus we excluded them from the final analysis. We had no information regarding the patients’ place of living and could not retrieve the data on their distance from the hospital. Meanwhile, the present study is the largest study that has been done to evaluate P2D in Iranian patients and the first study that has published after starting the 24/7 program. Unlike IPACE2 study, only STEMI patients, for whom P2D is applicable and can be defined, were included in our study.In the present study female gender, transfer via vehicles other than ambulance, atypical chest pain, low level of education, late night and morning onset of pain, history of hypertension and opium abuse were associated with higher prehospital delay while history of CABG was associated with shortened P2D.


Although venous cannulation is imperative during perioperative period, it inevitably causes venipuncture pain. Eutectic mixture local anesthetics (EMLA) has been used to reduce this pain, and various studies have been conducted to evaluate the efficacy of EMLA. But these studies did not elucidate the effect of EMLA exactly, because there were large individual differences in pain sensitivity. The aim of this study is to accurately evaluate the efficacy of EMLA cream for venipuncture pain relief compared with lidocaine tape in the same patients.Participants were randomly allocated into EL or LE group. Participants received EMLA cream at one side dorsum of hand and lidocaine tape at another dorsum of hand before entering operation room. Local anesthetics were strictly applied according to their manufacturers’ instruments, respectively. In the EL group, participants received venipuncture at EMLA cream site firstly. In LE group, participants, conversely, received venipuncture at lidocaine tape site firstly. Before anesthetic induction, local anesthetics were removed followed by venous cannulations. After cannulation, participants evaluated the pain by visual analog scale (VAS) and verbal rating scale (VRS).The primary outcome was VAS, and the secondary outcome was VRS.p = 0.001, 95% CI − 25 to − 6). The VRS of EMLA cream was also significantly lower than that of lidocaine tape . The local skin adverse events were observed in five patients at EMLA cream applied hands.Data from 24 patients were analyzed. The VAS of EMLA cream was significantly lower than that of lidocaine tape (4 [0–18] vs 17 [8–45], We conducted a comparative study to elucidate the efficacy of EMLA cream for venipuncture-pain comparing with lidocaine tape in the same patients. Our results strongly suggest that EMLA cream is more effective for venipuncture pain relief than lidocaine tape.UMIN000023030. Registered 5 July 2016.UMIN Clinical Trials Registry,  Venous cannulation is a mandatory procedure for hydration and drug intravenous administration during the perioperative period. However, this procedure must be accompanied by pain. Various methods have been devised to attenuate this pain, one of which is the application of a eutectic mixture of local anesthetics (EMLA) cream. Although few decades have passed since the start of clinical usage of EMLA cream and several clinical studies evaluating its efficacy have been published , in all This single-center, prospective, randomized, interventional study was conducted at Tomakomai City Hospital, Hokkaido, Japan, from July 2016 to March 2017. The study was approved by the institutional review board of Tomakomai City Hospital, Japan  and was registered in the UMIN-Clinical Trials Registry . Written informed consents were received from all patients before participation in this study. Eligible participants were patients aged 16 years and above, American Society of Anesthesiologists physical status I–III, who required two venous access lines during elective surgery under general anesthesia. Exclusion criteria were patients who had local anesthetic allergy and skin abnormalities at the site of venipuncture. Patients with severe hepatic, renal, and cardiac diseases which might influence drug metabolism were also excluded. According to manufacturers’ instructions strictly, 1 g of 5% EMLA cream®, containing 25 mg of lidocaine and 25 mg of prilocaine per gram , was applied on the dorsum of one hand and covered by Tegaderm™ transparent film dressing  60 min before entering the operation room, while a lidocaine tape  was applied on the dorsum of the other hand 30 min before operating room entrance for all participants. All participants were randomly allocated, according to computer randomization, to EL group: received venipuncture at EMLA cream site firstly and lidocaine tape site secondarily, or LE group: received venipuncture at lidocaine tape site firstly and EMLA cream site secondarily . Data were presented as median [interquartile range]. A p value less than 0.05 was determined statistically significant. The sample size was calculated by G*power 3.1 . A VAS difference of 18.1 was considered as a clinically meaningful difference, based on the results of the study by Çelik et al. [Both VAS and VRS scores, subgroup analysis, and the comparison of first and second puncture pain intensities in all participants were analyzed by the Wilcoxon signed-rank test, while the comparisons of first and second puncture pain intensities at EMLA and lidocaine sites were analyzed by the Mann-Whitney p = 0.001, 95% CI − 25 to − 6)  . In detail, four of 24 hands that received the EMLA cream became paler following EMLA cream application, and one of 24 hands developed a skin flare with Tegaderm™ application, although these skin changes disappeared by the next day. No local adverse event was observed in lidocaine received hands. None of the patients experienced systemic adverse events in response to local anesthetic application, including symptoms of toxicity.A total of 24 patients were screened for inclusion in this trial, and all of the participants were included in this study. The 12 patients were allocated into EL group and other 12 patients were allocated into LE group. The characteristics of all participants are presented in Table  6) Fig. . VRS sco.2) Fig. . Subgrou.2) Fig. . The freWe evaluated the efficacy of local anesthesia with EMLA cream and lidocaine tape for venipuncture before induction of general anesthesia in the same patients. The study results indicate that EMLA cream is more effective for pain relief during venipuncture than lidocaine tape. The novelty of this study lies in the fact that it compares two local anesthetic methods in the same person. Although some previous randomized-control studies on EMLA cream do exist, their participants were divided into two groups, and each group received only one local anesthetic method . As is wAs confirmed by our study, EMLA cream provides more effective pain relief than lidocaine tape. A possible reason for this difference in efficacy is that EMLA cream is a eutectic mixture of local anesthetics that exhibits high skin permeability. However, considering a previous report that EMLA cream is superior to 1% lidocaine infiltration for arterial cannulation , the mecIn this study, subgroup analysis and the comparison of first and second puncture-pain intensities were performed to clarify the influence of puncture order on pain severity evaluation. The second puncture pain intensity was higher than the first puncture’s pain, although this difference was not statistically significant. Moreover, the VRS in LE group was not statistically significant. These results suggest that the second puncture pain might become more severe than the first puncture pain. According to past reports, there is a positive relationship between anxiety and pain in clinical settings , and anxIn terms of the safety of local anesthetics, local anesthetic toxicity is the most important problem. In our study, serum concentrations of lidocaine and prilocaine were not measured. Oni et al. measured the serum concentration of lidocaine after application of 30 g of 2.5% EMLA cream on facial and neck skin . The aveAnother side effect of topical anesthetics is alteration of skin color, such as pallor and flare. EMLA frequently produces blanching of the skin by causing vasoconstriction . AlthougThis study has two major limitations. The first is that we evaluated pain caused by venous cannulation using only subjective measurements. To evaluate pain objectively, heart rate and blood pressure should be measured before and after venipuncture. But, these parameters were also influenced by emotional factor easily, and the accuracy for evaluating venipuncture pain was very limited. The second limitation is that the serum concentrations of lidocaine and prilocaine were not measured to elucidate the safety of EMLA cream and lidocaine tape. Although none of the patients expressed symptoms of local anesthetic toxicity in this study, the time course of serum concentrations of lidocaine and prilocaine should be measured until 90 min after the application of EMLA to confirm the safety of this drug .We performed this prospective comparative study to accurately elucidate the efficacy of EMLA cream and lidocaine tape on pain relief during venipuncture in the same patients. These results definitely indicate that EMLA cream provides more effective relief of the pain resulting from venous cannulation. A more detailed study is necessary to confirm the safety of EMLA cream in various patient groups and under different clinical conditions.


To evaluate the safety and efficacy of dexmedetomidine in patients undergoing total knee and hip arthroplasty for postoperative pain control.An updated systematic review and meta-analysis of randomized controlled trials (RCTs) identified in systematic searches of MEDLINE, EMBASE, Google Scholar, the Cochrane Database and the Chinese SinoMed Database.2 = 90.0%, P < .001) compared with scores in the control group after total hip arthroplasty (THA) and total knee arthroplasty (TKA). Furthermore, the rate of postoperative delirium was also markedly decreased with dexmedetomidine therapy . Moreover, compared with the control group, dexmedetomidine treatment was associated with a decreased risk of postoperative nausea and vomiting in patients undergoing TKA , and there was a similar risk of hypotension  regardless of whether patients underwent TKA or THA. However, the rate of bradycardia was significantly increased with dexmedetomidine treatment in those undergoing TKA .Fourteen RCTs with a total of 1220 patients were included. Overall, dexmedetomidine therapy was associated with significantly decreased pain scores 24 hours after surgery (WMD, −0.36; 95% CI, −0.49 to −0.22; IDexmedetomidine therapy seems to be an effective treatment for pain control and postoperative delirium in patients undergoing TKA/THA. However, the incidence of bradycardia is markedly increased in patients undergoing TKA. Hence, much larger prospective clinical studies are warranted to confirm these findings. Previous studies have found that postoperative pain can affect early mobilization and psychological state and can delay patient discharge and early rehabilitation in patients with knee arthroplasty.,4 Therefore, adequate pain management is very important to reduce morbidity and promote recovery.Patients who undergo total knee or hip arthroplasty are associated with significant postoperative pain, However, none of these anesthetics are free from limitations such as the need for special equipment and monitoring or the risk of complications that may delay discharge or cause readmission.Many agents have been used to provide effective postoperative pain control, including local anesthetics such as lidocaine and bupivacaine, opioids such as morphine, and α2-adrenergic receptor agonists such as clonidine. Many studies have demonstrated that dexmedetomidine can significantly decrease pain scores and postoperative diclofenac sodium consumption and can improve the duration of the analgesic effect.,8 Furthermore, the incidence of postoperative delirium and postoperative nausea and vomiting (PONV) decreases with the use of dexmedetomidine therapy. However, several studies have shown that dexmedetomidine administration is associated with an increased risk of hypotension and bradycardia requiring atropine. Therefore, the safety and efficacy of dexmedetomidine therapy in patients undergoing total knee arthroplasty (TKA) and total hip arthroplasty (THA) is still debatable. Moreover, previous studies are limited by a small size and low quality. Therefore, as the amount of evidence has been recently increasing, we performed a meta-analysis to evaluate the safety and efficacy of dexmedetomidine therapy in patients with TKA/THA.Dexmedetomidine is a highly selective, specific, and potent α2-adrenergic receptor agonist.22.1We searched MEDLINE , EMBASE (2005 to April 2018), the Cochrane Controlled Clinical Trials Register Database (to April 2018), and the ClinicalTrials.gov website (to April 2018) using the terms “total knee arthroplasty”, “total hip arthroplasty”, “dexmedetomidine”, “pain intensity”, “pain score”, “delirium”, and “randomized trial” in each database. Manual reference checking of the bibliographies of all relevant articles was performed. The reference list of relevant studies was additionally screened. No language restrictions were applied. There is no need for an approval from ethics committee because our study belongs to a retrospective type focusing on literature review.2.2We first conducted an initial screening of titles and abstracts; the second evaluation was based on a full-text review. Trials were considered eligible if they met the following criteria:1)the study was a prospective randomized controlled trial (RCT);2)the intervention consisted of dexmedetomidine treatment; and3)the primary outcome of interest was the change in pain intensity.The exclusion criteria were1)non-RCTs and2)duplicate data.2.3Two reviewers (QY and YR) extracted data concerning patient characteristics, dexmedetomidine use, study quality, and clinical outcomes using a standard data-collection form. Disagreements were resolved via discussion by 2 reviewers (QY and YR) and the corresponding author (XSW).The primary outcome was the change in pain intensity at rest and upon movement 24 hours postoperatively. The secondary outcomes were the rate of postoperative delirium, dose of opioid consumption, duration of the analgesic effect, and time to first analgesic request. Adverse events included PONV, hypotension, bradycardia, and somnolence.2.4 was followed. Two reviewers (QY and YR) assessed the quality of the selected trials based on the Jadad Scale and the Cochrane Collaboration method. The components used for quality assessment were randomization (0–2 points), blinding (0–2 points), dropouts and withdrawals (0–1 points).The Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) statement2.5 in consultation with one statistician. We calculated the pooled relative risk (RR) for dichotomous outcomes and the weighted mean difference (WMD) for continuous data with 95% confidence intervals (CIs).The results were analyzed quantitatively with STATA 14.0 software  using the random-effects model2 statistic and the chi-squared test. A value of I2 > 50% was considered a substantial level of heterogeneity. Once heterogeneity was noted, publication bias was assessed quantitatively using Egger regression test (P ≤ .10) and qualitatively with the visual inspection of funnel plots of the logarithm of RRs versus their standard errors. Sensitivity analyses were conducted to determine the influence of individual trials on the overall pooled results. All analyses were performed according to the intention-to-treat principle. Statistical significance was set at P < .05.Heterogeneity was examined with the I33.1We initially identified 223 potentially relevant articles. Sixty-five studies were considered to be of interest and were retrieved for full-text review. Fifty-one articles were excluded due to duplication (n = 9), reviews (n = 24), incorrect comparisons n = 13) and a lack of primary clinical outcomes (n = 5). Therefore, 14 randomized trials including 1 study identified in the references were finally included in the analysis. Figure 3 and a l3.2–33 published RCTs with a total of 1220 patients were included. The total number of patients in each study ranged from 40 to 296. The participants’ ages ranged from 72.3 ± 12.5 years. Most patients were male, with a percentage of 64.3%. The mean duration of surgery was 78.6 minutes. All patients in the treatment group were treated with dexmedetomidine alone (0.5–2 ug/kg) or in combination with ropivacaine, bupivacaine, or propofol. Patients in the control group were treated with saline, ropivacaine, bupivacaine or propofol. Two studies had thee comparisons because of different dexmedetomidine concentrations. The Jadad scores of all included studies varied from 3 to 5; all 14 studies were considered to be of high quality according to the quality assessment , regardless of whether the patients underwent THA  or TKA  . The funnel plot showed marked asymmetry according to Begg's test (P = .03) and Egger test (P = .02). However, sensitivity analysis was performed by removing each of the trials one at a time, which did not detect any influence on the change in pain intensity , regardless of whether the patients underwent THA  or TKA  , and this result was comparable in patients undergoing THA  , regardless of whether the patients underwent THA  or TKA  , and this result was comparable in patients undergoing THA  (Fig. The incidence of hypotension4Our meta-analysis of 14 highly qualified randomized controlled clinical trials showed that dexmedetomidine therapy could significantly decrease pain scores compared with placebo in patients undergoing TKA/THA. Furthermore, the risk of postoperative delirium was markedly decreased in the dexmedetomidine group. Moreover, the incidence of PONV was significantly lower in patients undergoing TKA with dexmedetomidine treatment, and the rate of hypotension was similar between the groups. However, the incidence of bradycardia was markedly increased in those undergoing TKA and administered dexmedetomidine. Although many pain-relieving remedies have been employed as regular measures, it is still a challenge to optimize postoperative pain control. Opioids typically play a large role in the treatment of postoperative pain after TKA, which may result in a high risk of respiratory depression in patients.,36 Compared with the opioid-only pain management strategy, a combination of dexmedetomidine with opioids is conducive to decreasing postoperative pain and simultaneously reducing opioid requirements and opioid-related adverse events. Furthermore, dexmedetomidine therapy alone has also yielded promising results.,39 In addition, our study confirmed that dexmedetomidine could decrease pain scores in the first 24 hours, which suggests that the analgesic benefits of dexmedetomidine extend beyond its biological half-life of 2 hours. However, the mechanism underlying this long-term analgesic effect remains unclear. A previous study suggested the existence of different action pathways between the sedation and analgesic effects of dexmedetomidine as a possible mechanism. While the effect of dexmedetomidine is mediated by the ascending noradrenergic pathway in the locus coeruleus, the analgesic effect occurs via an α2- adrenergic receptor-dependent descending pathway in the spinal cord. However, the comparison of dexmedetomidine vs opioids for postoperative pain management remains unclear due to limited data.Postoperative pain is one of the most commonly reported discomforts after TKA/THA surgery and is described as severe by more than half of patients. Many risk factors are related to postoperative delirium, such as exposure to general anesthetics, pain and the postoperative inflammatory response. Preclinical and clinical studies have found that dexmedetomidine attenuates neurotoxicity induced by general anesthetics, improves postoperative analgesia and inhibits the inflammatory response after surgery.,43 Several studies have found that the intraoperative use of dexmedetomidine can prevent postoperative delirium, but the data are inconsistent. In pediatric patients undergoing tonsillectomy and cardiac surgery, intraoperative infusion of dexmedetomidine lowers the incidence of emergent delirium.,45 For adult patients undergoing cardiac surgery and microvascular free flap surgery, intraoperative dexmedetomidine slightly decreased the incidence of delirium compared with normal saline, although the differences were not statistically significant between the 2 groups, possibly due to the underpowered sample size. Su et al found that prophylactic low-dose dexmedetomidine significantly decreased the occurrence of delirium during the first 7 days after noncardiac surgery. For elderly patients undergoing joint replacement, several studies confirmed that dexmedetomidine treatment during surgery significantly reduced the incidence of postoperative delirium.,48,49 Inconsistent with previous studies, our pooled data indicated that dexmedetomidine could markedly lower the risk of postoperative delirium in patients undergoing TKA/THA. However, in a recent study, the use of dexmedetomidine during general anesthesia did not reduce delirium after major noncardiac surgery, including arthroplasty, in elderly patients. Therefore, more studies are warranted to confirm the effect on postoperative delirium.Of the postoperative complications, delirium is common among elderly patients and is associated with poor clinical outcomes.The present study has a few limitations. First, our study is based on study-level data and as such shares the flaws of original studies. Notwithstanding the value of patient-level meta-analyses, we believe that a meta-analysis of aggregate data can answer this question. Second, our study enrolled patients with different dexmedetomidine concentrations, which are associated with different safeties and efficacies that can impact the therapeutic potential. Moreover, although the inclusion criteria were broad across all 14 studies, slight differences remained in terms of the characteristics of patients and the doses of dexmedetomidine used. We cannot exclude geographical variations. Third, the sample size was inadequate for excluding small differences in outcome between the 2 groups. Therefore, the power of the studies selected was not high. In this sense, our meta-analysis is just a possible indication, and future studies will require larger numbers of patients and careful matching of key clinical and technical variables to definitively quantify the potential effects of dexmedetomidine therapy in patients undergoing TKA/THA.Given the clinical data, dexmedetomidine therapy appears to provide clinical benefits with respect to postoperative pain control and delirium prevention for patients with TKA/THA. More studies are needed to evaluate the safety of dexmedetomidine treatment for TKA/THA.5In summary, dexmedetomidine is effective for postoperative pain control, and there is a decreased risk of postoperative delirium in patients undergoing TKA/THA. However, an increased risk of bradycardia is among the side effects of dexmedetomidine.Data curation: Yi Ren, Xisheng Weng.Formal analysis: Qi Yang, Yi Ren.Investigation: Qi Yang.Methodology: Qi Yang, Bin Feng.Resources: Xisheng Weng, Bin Feng.Software: Qi Yang.Supervision: Xisheng Weng, Bin Feng.Validation: Xisheng Weng, Bin Feng.Visualization: Xisheng Weng.Writing – original draft: Qi Yang, Yi Ren.Writing – review & editing: Yi Ren, Bin Feng.


The identification of a neuropathic component to subacromial pain may lead to different pain management strategies. The purpose of this study was to adapt the Dutch modified painDETECT (mPDQ-NL) Knee, which discriminates between nociceptive and neuropathic pain, to fit patients with subacromial pain syndrome and subsequently assess its validity and reliability.The mPDQ-NL Knee was adapted into the mPDQ-NL Shoulder to fit and use for patients with subacromial pain syndrome. The study population consisted of patients suffering from subacromial pain syndrome who were asked to fill in the Dutch mPDQ-NL Shoulder, the self-completed Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) and the Disabilities of the Arm, Shoulder and Hand (DASH) to determine construct validity  of the mPDQ-NL Shoulder. Regarding reliability, internal consistency was determined and the mPDQ-NL Shoulder was assessed a second time with a two-week interval to determine measurement error and reliability.A total of 107 patients were included in the validity analysis and 58 in the reliability analysis. Validity (86% of predefined hypotheses met), internal consistency  and reliability (ICC 0.7) of the mPDQ-NL Shoulder were good, however, a systematic bias might be present.The mPDQ-NL Shoulder was successfully modified from the mPDQ-NL Knee. This study shows that the mPDQ-NL Shoulder seems to reflect neuropathic-like pain symptoms experienced by patients with SAPS. Whether it may also be used as a tool to record change over time or after treatment has to be further assessed. Subacromial pain syndrome (SAPS) is a common cause of shoulder pain, with a high societal burden ,2. ThereThere is growing evidence that pain in SAPS might not be purely nociceptive, but that central sensitization can be present –12. ThisCentral hypersensitivity might be associated with large numbers of patients with SAPS who have persistent pain or a limited range of motion for several years despite treatment ,8. It isAmong existing measures, the painDETECT questionnaire appears the most appropriate for use in SAPS to identify patients with a neuropathic pain profile; it was developed to discriminate between nociceptive and neuropathic pain in adults with chronic low back pain and has proven to be a valid and reliable screening tool . It was The study was approved by the Medical Ethical Committee of University Medical Center Groningen (no. METc 2015–025). The methods, particularly the statistical analyses, have been previously described by Rienstra et al. [Patients suffering from SAPS who were receiving any form of conservative treatment or were on the waiting list to undergo surgery were eligible to participate. A random sample of 309 patients with SAPS at the outpatient clinic between April 2015 and October 2016 was obtained from the records of the Department of Orthopedic Surgery of Martini Hospital Groningen, The Netherlands. All patients were diagnosed with SAPS with rotator cuff tendinopathy or chronic subacromial bursitis as contributing pathologies through anamnesis and physical and radiological examination by their orthopedic surgeon. All patients had powerful rotator cuff tests during physical examination. Exclusion criteria were age under 18, other shoulder pathologies , previous shoulder surgery, other chronic pain disorders, severe comorbidity, cognitive or psychiatric disorders, and inability to understand written Dutch.Eligible patients were mailed a letter regarding informed consent, the voluntary nature of the study and the anonymous data-processing methods, together with the mPDQ-NL Shoulder, a questionnaire on demographic characteristics and comorbidities, and a prepaid reply envelope. To assess validity patients also received the self-completed Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) ,17, the We developed the mPDQ-NL Shoulder from the Dutch mPDQ-NL Knee by replacing the target joint “knee” with “shoulder” in every question, with a few other minor changes related to the anatomical site (i.e. the location on the body map). The pre-final version of the mPDQ-NL Shoulder was tested in a pilot study consisting of 20 patients with SAPS visiting the orthopedic outpatient clinic of Martini Hospital to test for comprehensibility of the questionnaire. No problems or comments were reported while filling out the questionnaire, measured via a response form regarding instructions, unclear questions and any additional comments. See The mPDQ-NL Shoulder is a self-report questionnaire consisting of 12 items in four components about neuropathic pain symptoms of the left or right shoulder experienced during the last week. The first component evaluates pain radiation using a body map. The second component assesses pain pattern and course. In the third component pain quality is evaluated for seven items on a six-point Likert scale . A fourth VAS component evaluates pain intensity on three items . The total score is the sum of the first three components and ranges from -1 to 38 points, with higher scores indicating a more neuropathic pain profile. Cut-off points were chosen in accordance with the original PDQ . A scoreThe Self-Completed Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) is an English-validated and reliable self-report questionnaire to identify pain of predominantly neuropathic origin in patients with chronic pain from any cause ,17. It cThe Disabilities of the Arm, Shoulder and Hand (DASH) is a 30-item valid and reliable self-report questionnaire that measures physical function and symptoms of the past week on a 5-point Likert scale in people with any of several musculoskeletal disorders of the upper limb ,19. The VAS pain. Visual Analogue Scales (VAS) are widely used to measure pain. Patients place a marking on a horizontal line that represents their pain, where the left end of the line represents “no pain at all” and the right end “worst pain imaginable”. The found value was rounded up and represents the pain score. Patients were asked to record average shoulder pain at rest and during physical activity for the last week. VAS scales have been reported as valid and reliable measures for pain intensity [ntensity .Based on Cosmin guidelines a sample size of at least 100 is considered excellent for studies on measurement properties of questionnaires; a sample size of 50 is considered adequate for determining test-retest reliability . Hence wStatistical analyses were conducted using IBM SPSS, version 22.0 . A p-value <0.05 was considered to indicate statistical significance. When missing items were present on the mPDQ-NL Shoulder, total score could not be determined. Missing items of the DASH and S-LANSS were treated according to the guidelines proposed by the developers of the used questionnaires. If patients reported no pain on all three VAS items of the fourth component of the mPDQ-NL Shoulder, they were excluded from the analyses. Patient characteristics were reported using descriptive statistics.Kruskall Wallis tests were used to assess differences between subgroups based on the mPDQ-NL Shoulder scores . Posthoc analyses were performed with Mann-Whitney U tests to determine between groups differences. Correction for multiple comparisons was done by a Bonferroni correction and resulted in a significance level of 0.05/18 tests = 0.003.Validity of the Dutch m-PDQs was expressed in terms of construct validity due to absence of a gold standard. Construct validity is used to determine how well a test measures what it is supposed to measure .Structural validity. Structural validity refers to the degree to which items of a questionnaire measure the dimensionality of the construct. While the original PDQ measured pain in patients with chronic low back pain, it had to be investigated whether the items of the mPDQ-NL Shoulder reflect the neuropathic-like symptoms of patients with SAPS. The original PDQ measured two determinative components [mponents . Exploramponents . Factorsmponents .Hypotheses testing. The mPDQ-NL Shoulder was compared with the S-LANSS, DASH, VAS at rest and VAS during physical activity , which can be derived by dividing the standard deviation of the mean differences (SDdiff) between test and retest by est by 2 . The sma6xSEMx2n . Absolut6xSEMx2n  by calcuReliability. Reliability was assessed using intraclass correlation coefficients (ICC) with the corresponding 95% confidence interval (CI) for the total score of the mPDQ-NL Shoulder. The ICC two-way random effects model, type agreement [greement , was usegreement .Floor and ceiling effects were inspected. They are present when 15% of the participants achieve the minimum or maximum scores, respectively. This reduces the validity and reliability of an instrument, as participants with extreme scores cannot be distinguished from each other .In total, 309 patients were approached to participate in the study; 121 patients (39%) returned the questionnaires, 107 (35%) of whom were included in the validity and reliability analysis. For the reliability study 102 patients were approached. The response rate for the reliability analysis was 71 participants (70%), 58 (57%) of whom were included in the analysis. Two patients were excluded from the analysis, since an intervention was carried out between test-retest periods. At the first measurement, the number of cases lost because of missing items was 12 out of 121 respondents (10%). For the second assessment of the questionnaire this was 9 out of 71 respondents (13%). Flow chart for inclusion is shown in Patient characteristics are presented in burning sensation, tingling or prickling sensation, pain at light touch, sudden pain attacks, pain at cold or warm stimulus, numbness and pain at light pressure. The second factor consisted of one item, pain pattern, and the third factor consisted of pain radiation using a body map. See Table 1 in Three factors with an eigenvalue ≥1 were revealed with exploratory factor analysis. The first factor contained the items The correlations between the mPDQ-NL Shoulder and the S-LANSS, DASH, VAS pain at rest and VAS pain during physical activity are presented in Cronbach’s alphas were 0.8 for the overall mPDQ-NL Shoulder questionnaire, and 0.9 for the VAS pain score.Reliability measures for the mPDQ-NL Shoulder are presented in No floor  or ceiling effects  were seen for the total mPDQ-NL Shoulder score. No ceiling effects were seen in any of the items.2 = 86.6; df = 2; p <0.001). Baseline characteristics and differences of the posthoc analyses of the subgroups are shown in Analyses of the subgroups showed a significant difference based on scores of the mPDQ-NL Shoulder . Cronbach’s alpha of the original PDQ was not available for comparison.With a range for the total mPDQ-NL Shoulder score from -1 to 38 points, a 3.4 SEM seems acceptable. An SDC value at the individual level of 9.5 and a low SDC value at the group level of 1.2 indicate that the mPDQ-NL Shoulder might be useful for group comparisons rather than detecting changes at the individual level. To distinguish clinically important changes from measurement errors, the SDC values should be smaller than the minimal important change (MIC) . As the No significant floor and ceiling effects were observed for total mPDQ-NL Shoulder scores. The floor and ceiling effects of our study are comparable with those found for the mPDQ-NL Hip and Knee .With the development of the mPDQ-NL Shoulder we can now identify patients with a neuropathic pain profile in SAPS. Patients with other chronic pain conditions might be more at risk to also develop a neuropathic pain syndrome of the shoulder. As we excluded them in the current study, this needs to be addressed in further research. A limitation of our study is the use of the S-LANSS in the validation study, which is validated for English but translated into Dutch according to the guidelines of Beaton for this purpose. Furthermore, the study has a high rate of non-responders, but demographics (age and gender) of these patients are comparable to those of the included patients. A reason for not responding might be having mailed the questionnaires without informing the patient in person at the outpatient clinic. Moreover, as we did not investigate responsiveness, whether the tool can record change over time with a sensitivity-to-change analysis has to further assessed. In addition, we did not use neurological, electrophysiological or psychophysical tests to demonstrate the presence of neuropathic pain in our population. Such tests have been used before in other validation studies. Though, these show that, for example, pain pressure thresholds seem to measure different aspects of the pain experience compared to patient-reported assessment of pain experience .Identification of patients with a neuropathic pain profile has important implications, especially considering this population is perhaps larger than expected, with 41% of patients showing a possible or likely neuropathic pain profile in the current study. In addition, these patients with a neuropathic pain profile tended to experience more symptoms. The subgroup analyses showed a significant difference in reported pain between patients without or a possible neuropathic pain profile compared to patients with a likely neuropathic pain profile. Higher reported pain in patients could predict to patients with a neuropathic pain pattern in SAPS. As a result it may facilitate customized treatment, with different kinds of neuromodulating medication, and it may prevent unwanted surgery. In future research, it may assist in assessing the true effectiveness of treatment when stratification of patients with and without neuropathic pain-like symptoms is possible.The mPDQ-NL Knee was adapted to fit Dutch patients with SAPS. It shows good construct validity, internal consistency and reliability. However, a systemic bias might be present. To conclude, this study showed that the mPDQ-NL Shoulder seems to reflect neuropathic-like pain symptoms experienced by patients with SAPS. Whether it also may be used as a measure to record change over time or after treatment has to be further assessed.S1 Appendix(PDF)Click here for additional data file.S2 Appendix(PDF)Click here for additional data file.S3 Appendix(PDF)Click here for additional data file.S4 Appendix(PDF)Click here for additional data file.S1 Database(SAV)Click here for additional data file.


Carpal tunnel syndrome (CTS) is a common entrapment neuropathy causing significant, and often disabling, pain. We aimed to establish the prevalence of anxiety and depressive symptoms in patients who were referred with suspected CTS and identify potential determinants.All patients underwent nerve conduction studies (NCS) and were classified into mild, moderate, severe, and no CTS groups. Volunteers, without symptoms or signs of CTS, formed the control group. Anxiety and depressive symptoms were assessed via the Hospital Anxiety and Depression Scale.n = 20), moderate CTS (n = 21), severe CTS (n = 11), and no CTS (n = 31). CTS patients had significantly higher depression scores compared to controls but not anxiety scores. Patients experiencing pain and itchiness had significantly higher anxiety scores compared to those who did not. Patients who reported symptoms suggestive of CTS but did not meet the electrodiagnostic criteria for a diagnosis had significantly higher anxiety and depression scores compared to CTS patients and controls.Ninety‐one patients and 41 controls were recruited. Following NCS the patients were classified as follows: mild CTS (Patients suffering with CTS may be at an increased risk of depression. Experiencing pain in CTS may further increase the likelihood of experiencing mental health difficulties. Poor mental health can give rise to functional symptoms, similar to those seen in CTS, demonstrating the need for electrophysiological testing before considering surgical intervention. It is well regarded as the most common nerve entrapment syndrome .Symptom details were also obtained and included type of symptom , duration of pain when present, and intensity of pain on a Visual Analogue Scale (ranging from 0 to 10).Edinburgh Handedness Inventory (EHI) . The active recording ring electrode was placed around the base of the proximal phalanx of the third digit. The reference ring electrode was placed between the proximal phalanx and the middle phalanx of the third digit. Stimulation was 2 cm proximal to the wrist crease.Orthodromic Ulnar SNAP. The active recording ring electrode was placed around the base of the proximal phalanx of the fifth digit. The reference ring electrode was placed between the proximal phalanx and the middle phalanx of the fifth digit. Stimulation was 2 cm proximal to the wrist crease.Median compound muscle action potential (CMAP). The active recording electrode was placed over the belly of the abductor pollicis brevis (APB). The reference recording electrode was placed over the tendon of the APB at the base of the proximal phalanx of the thumb. Stimulation was 2 cm proximal to the wrist crease.The following parameters measured using Natus equipment were used for this study:2.4Mild CTS: median motor distal latency (MDL) < 4.5 ms, median sensory conduction velocity (SCV) < 45 m/s.Moderate CTS: median MDL ≥ 4.5 ms, median SNAP > 0 μV.Severe CTS: median MDL ≥ 4.5, absent median SNAP.No CTS: median MDL < 4.5 ms, median SCV ≥ 45 m/s.The classification of mild, moderate, and severe CTS was adapted from the Canterbury grading scale for CTS as follows Bland, :Mild CFor patients who had bilateral CTS with a different CTS classification in each hand, the worst severity they were given was taken as their overall CTS classification.2.5Statistical analyses were performed using the Statistical Package for the Social Sciences  for windows. A Chi‐squared test was used to identify whether frequencies of clinical characteristics and demographics differed significantly between groups.U test or the Kruskal‐Wallis one‐way analysis of variance test, respectively. The Bonferroni correction was applied for multiple comparisons.The data failed to meet the assumption of normally distributed data assessed by the Shapiro‐Wilk test. Therefore, the means of continuous variables between two or more groups were compared using the Mann‐Whitney Correlation analyses, using Spearman's test, were performed to assess the relationship between continuous variables.p < 0.05 was considered to be statistically significant.A 33.1n = 20), moderate CTS (n = 21), severe CTS (n = 11), and “no CTS” (n = 39).Ninety‐one patients with symptoms suggestive of CTS and 41 controls were recruited. Based on the results from their NCS, the 91 patients were classified into mild CTS , compared to moderate (28.6%) or severe 18.2%). No other significant differences regarding neuropathic symptoms were observed between the groups. Demographic and clinical characteristics for all groups are summarized in Table 8.2%. No 3.2P < 0.001). No significant differences occurred between any other groups.The “No CTS” group had the highest mean HADS‐A score (9.4 ± 4.1), followed by the severe CTS (7.0 ± 5.5), mild CTS (6.8 ± 4.5), moderate CTS (6.5 ± 3.5), and control group (5.4 ± 3.3). Post hoc comparisons showed that HADS‐A scores were only significantly higher in the “No CTS” group compared to the healthy controls (3.3The “No CTS” group had the highest mean HADS‐D score (6.9 ± 4.0), followed by the severe CTS (5.6 ± 3.8), moderate CTS (5.2 ± 2.8), mild CTS (4.5 ± 3.1), and control group (2.4 ± 2.1). Post hoc comparisons showed that HADS‐D scores were significantly higher in the moderate CTS, severe CTS, and “No CTS” groups compared to the control participants. No significant differences occurred between any other groups.3.4N = 28) and unilateral CTS patients (N = 24) on HADS‐A and HADS‐D scores. Moreover, within the unilateral CTS participants there were no statistically significant differences on HADS‐A and HADS‐D scores between those with CTS in their dominant hand (N = 17) and those with CTS in their nondominant hand (N = 6).No statistically significant differences were found between bilateral CTS participants (3.5p = 0.042). There was no significant correlation found between the pain intensity and the HADS‐A score . HADS‐D scores did not vary significantly between participants who reported pain and those who reported no pain.Pain was reported by 75 patients (82.4%). HADS‐A test scores were significantly higher in those who reported pain compared to those who reported no pain .Itchiness was reported by 36 patients (39.6%). The HADS‐A and HADS‐D scores were significantly higher in those who reported itchiness compared to those who did not . All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.


Recent evidence has shown that many patients suffer from persistent pain and impaired function after primary or revision total knee arthroplasty (TKA). Post-surgical complications may in addition decrease physical performances and lead to more pain and impacted quality of life.The purpose of the study was to assess the changes in pain intensity and functional capacity among patients with post-surgical complications after TKA three weeks of intensive, personalized multimodal rehabilitation.A retrospective cohort study consisting of 217 patient of which 166 had primary TKA and 51 had revision TKA was conducted. On average, primary TKA patients and revision TKA patients were 3.7 and 2.7 months post-surgical, respectively. All patients have had post-surgical complications and were referred to an inpatient rehabilitation department, where they received a personalized three-week intensive, multimodal rehabilitation protocol. The rehabilitation consisted of sessions targeting neuromuscular function, postural control, and flexibility, sessions focusing on improving muscle strength and cardiovascular function and sessions with focus on gait retraining. The frequency of training was 2–4 sessions/day. The primary outcome was the Knee injury and Osteoarthritis Outcome Score (KOOS) and secondary outcomes were pain intensities measured using numerical rating scale, 6 min. walking test, stair-climbing test and range of motion for knee flexion and extension. Outcome measures were assessed at baseline upon referral and at follow-up before discharge.p < 0.001) and 6.9 to 10.8 in the revision group (p < 0.001). For the TKA group, effect sizes were medium-to-large for all KOOS subscales, 6 min. walking test, stair-climbing test, and pain intensity during activity. For the revision group, effect sizes were medium-to-large for KOOS subscales symptoms and activity of daily living, 6 min. walking test, stair-climbing test, and knee flexion.All outcomes, except pain at rest in the revision group, improved significantly. KOOS subscales, improved 8.5 to 14.2 in the primary TKA group (Patients with post-surgical complications after primary or revision TKA experienced clinical relevant improvement in self-reported outcomes, pain relief, and improved physical performances after three weeks of personalized multimodal rehabilitation. The results suggest that an intensive, multimodal approach might be useful to obtain clinically relevant improvements. Osteoarthritis (OA) is considered the most frequent cause of disability and pain in the elderly population, and the knee joint is one of the joints most commonly affected , 2. End-Pain and surgery lead to a temporary loss of motor function and muscle strength, which often seems to improve in the post-operative phase, especially following a rehabilitation regimen –14. WhenBased on the lack of knowledge about management of patients with post-surgical complications after TKA, it is necessary to study the outcomes of intensive multimodal rehabilitation. Hence, there is a need for clinical studies using “best practice” as treatment and including validated outcomes measures to allow for interpretation of the benefits from the treatment. This may elucidate whether intensive rehabilitation can be an effective approach in patients with complications after primary or revision TKA. Therefore, the purpose of this retrospective pragmatic cohort study in real-life settings was to investigate the short-term effect of 3-weeks of intensive, multimodal rehabilitation in patients with complications after primary or revision TKA . The hypothesis was that self-reported outcomes and objective physical performance would improve and pain levels would decrease. Although this observational cohort study did not include a control group, it could provide important information of effect sizes and thereby, be used for designing future randomized controlled trials.2 and 4) post-surgical complications based on surgeon or family physician examination. Exclusion criteria were lack of complete follow-up and lack of ability to adhere to the treatment. Overall, 166 patients with primary TKA and 51 patients with revision TKA were included in the analysis  patients with primary TKA or revision TKA, 2) 40–80 years old, 3) body mass index (BMI) within 19–40 kg/mAll patients referred to Montebello – Department of Rehabilitation undergo a standardized, personalized multimodal treatment protocol. The protocol is a 3-week stay in a rehabilitation hospital during which patients receive intensive, multimodal rehabilitation supervised by physiotherapists. The rehabilitation consisted of sessions targeting neuromuscular function, postural control, and flexibility, sessions focusing on improving muscle strength and cardiovascular function and sessions with focus on gait retraining. Rehabilitation was based on evidence-based exercise programs , 23 and All patients referred to the hospital undergoes a test battery at baseline after admission and at re-test before discharge, measuring self-reported outcomes, pain intensity, physical performance during activities of daily living (ADL) and active knee ROM, which are areas that has previously been highlighted as important quality indicators for rehabilitation in clinical practice after TKA , 25. In Secondary outcomes consists of pain intensity ratings and physical performance measurements. For the index knee, the pain intensity during rest and during activity  was assessed. A numerical rating scale (NRS) was used, where “0” represents “no pain” and “10” represents “maximal pain”.The included physical performance measures are part the recommended core set of outcome measures from the OsteoArthritis Research Society International (OARSI) . The 6 mData was checked for normality by assessing data frequency in histograms, QQ-plots, and Shapiro-Wilk tests.For normal distributed outcomes, paired samples t-tests for all continuous outcomes were applied. Data is presented as mean (SD) unless otherwise stated. For the non-normal distributed outcomes, Wilcoxon signed rank test were used and data is presented with median and min-max.d = (MeanAfter - MeanBefore)/SDpooled. Effect sizes were interpreted as 0.2 = “small” effect size, 0.5 = “medium” effect size and 0.8 = “large” effect size, as suggested by Cohen [Effect sizes were calculated as Cohen’s by Cohen .The significance level was set to 0.05 and results are displayed with 95% confidence intervals. All analysis were performed with the use of the statistical software SPSS, Version 25.0 .A total of 217 patients  were included in the analysis. The mean age in each group was 62 and 64 years, respectively. The mean time-since-surgery was 3.7 and 2.7 months in each group  . This asRegarding the primary outcome on the KOOS subscales, both the primary and the revision TKA groups experienced improvement ranging from 9–14 and 7–11 points, respectively. Thus, the improvement in KOOS can be considered clinically relevant . HoweverThe results of the current study indicates that some patients needs a more intensive and comprehensive approach regarding rehabilitation, than the often used 2–3 exercise sessions pr. week , 36, 37 There are obvious limitations in a retrospective cohort study. Due to exclusion of patients because of no data available from the KOOS questionnaire, a secondary analysis between those patients with and without KOOS scores were performed. This analysis revealed no clinical or significant differences regarding pain intensities and functional performance (Additional file The present retrospective study showed that, patients with post-surgical complications, undergoing three weeks of intensive, personalized multimodal rehabilitation after primary or revision TKA resulted in clinical relevant improvement in self-reported outcomes, significant pain relief, and improved physical performances. The results indicated that a tailored multimodal approach might be useful to obtain improvements in a cohort of patients with post-surgical complications after primary and revision TKA. Further randomized control trials assessing the effects of multimodal rehabilitation after primary or revision TKA are warranted.Additional file 1. TIDieR-checklist.Additional file 2. Rehabilitation protocol.Additional file 3.Table S4 illustrating a secondary analysis.Additional file 4.Table S5 illustrating a secondary analysis.


This study evaluated pre-defined aspects of content validity of the 18-item NCCN FACT-Ovarian Symptom Index (NFOSI-18) and its Disease-Related Symptoms-Physical (DRS-P) subscale, as clinical trial outcome tools for patients with advanced ovarian cancer.Twenty-one women (mean age 59.5 years) diagnosed with advanced ovarian cancer completed the NFOSI-18 and participated in a cognitive interview to explore: (1) whether ‘pain’ and ‘cramps’ are considered redundant; (2) whether ‘fatigue’ and ‘lack of energy’ are overlapping concepts; (3) whether patients consider severity when responding to the item “I am bothered by constipation;” and (4) factors considered when responding to the item “I am sleeping well.” Interviews were audio-recorded, transcribed, and analyzed qualitatively.Pain was associated with discomfort, hurt, and life interference; ‘cramps’ was associated with pain, muscle tightening, and menstrual or digestive issues. Most (81%) considered the items “I have pain” and “I have cramps in my stomach area” to be more different than similar. Participants associated ‘fatigue’ with intense tiredness and ‘lack of energy’ with motivation and capability to complete daily activities. Item comparisons revealed a majority (65%) considered the items to be more different than similar. When responding to “I am bothered by constipation,” patients indicated constipation severity was related to bother. Finally, patients considered disease, treatment, and other factors when responding to “I am sleeping well.”Findings support content validity of the NFOSI-18 and its DRS-P as originally constructed. We propose an alternative scoring option that excludes the item “I am sleeping well” from the DRS-P when used as a symptom-focused index for clinical research in a regulatory context. Ovarian cancer represents the second most common and deadliest gynecologic cancer . Due to The NCCN-FACT Ovarian Symptom Index-18 (NFOSI-18) was developed to provide a clinically meaningful patient-reported symptom index reflecting the symptoms and concerns identified as most important by women with advanced ovarian cancer , 4. FourFACIT.org  like a very specific passing pain. That’s like deep in your abdomen…like you can tell [it is] a muscle pain.” Terms used to describe the pain associated with ‘cramps’ were shooting, sharp, debilitating, radiating, aching, severe, slight, passing, dull, and tenderness. In addition to pain/discomfort, nearly half  defined cramps as muscle tightening, a gripping feeling or tightening of the muscles. For example, Pt 010 shared, “cramps are a pain that feels like my stomach in a certain area or whatever area is cramping is balling up…preventing me from breathing comfortably.”When defining the meaning of cramps as used in the item “I have cramps in my stomach area” women referenced concepts such as pain/discomfort, muscle tightening, menstrual cramps, or digestive issues. Over half  likened the sensation to that of menstrual cramps. For example, Pt 001 shared, “at times I have felt the same kind of cramping as when I had menstrual cramps…I thought I shouldn’t be having these anymore…does that mean something because I am feeling cramping when I don’t have a uterus?” Similarly, Pt 013 elaborated, “When you have cramps, they can be very painful, you know it’s like having periods. The cramps of your period. They are painful, but we call them cramps. It’s like a sub-category.” Additionally, when asked to define the meaning of cramps, a few noted that as women, they instinctively think of menstrual cramps, like Pt 011, “…as woman I automatically think of menstrual cramps, and what I feel now is very different…so that’s why I was like, ‘Do you mean pain or like that crampy, like that sort of clinching consistent feeling?’”. On the other hand, 6 (29%) considered digestive issues such as diarrhea, constipation, or gas when responding to the item or defining ‘cramps.’ While several reported experiencing cramps as a symptom prior to diagnosis and treatment, for most, the symptom subsided following treatment.In addition to patient interpretations of cramps as related to pain, discomfort, and muscle tightening, a subset  women considered the items to be “different” or “similar but different”, and many elaborated that the item “I have cramps in my stomach area” refers to a targeted area, whereas “I have pain” is broad and could encompass various forms of pain. For example, Pt 003 explained “because you can have pain in your joints or in your muscles where the other one is a specific area…I think they’re completely different.”While there was some overlap in patient interpretation of ‘pain’ and ‘cramps’, distinctions also emerged. As illustrated in Table Our exploration of patient interpretation of ‘fatigue,’ as used in the item “I feel fatigued”, revealed five prominent conceptualizations of ‘fatigue’ including tiredness, intensity, energy, rest, and comparison.tiredness, which reflects feeling or being tired, as described by Pt 014, a “general overall tiredness.” Moreover, 9 (43%) defined the quality of ‘fatigue’ in terms of intensity, describing fatigue as another level of tiredness or an extreme version of exhaustion, using qualifiers such as “overwhelming tiredness” (Pt 019), “total exhaustion” (Pt 018), being “very, very tired” (Pt 021), and “[fatigue is] that one more step, [an] extreme” (Pt 005). Others described the intensity of ‘fatigue’ as “fatigue takes over” (Pt 015) or “I don’t even feel like I can move” (Pt 013). Furthermore, 8 (38%) conceptualized ‘fatigue’ in terms of one’s energy level, specifically having a lack of or no energy at all. As Pt 002 explained, “lack of energy, you know just feeling tired and lack of energy and wanting to nap.” Moreover, a subset  qualified ‘fatigue’ as something that requires rest, the need to sit or lie down, or a need for sleep. As Pt 001 explained, “being too tired to accomplish a task without resting.” Some  framed their current level of fatigue in comparison to a previous state using qualifiers such as “more than I would normally [have]” (Pt 006), “compared to how I was on chemo” (Pt 016), and “before I got sick” (Pt 008).Most women  defined ‘fatigue’ in terms of one’s level of Our investigation into patient interpretations of ‘lack of energy’ when responding to the item “I have a lack of energy” revealed five prominent ways that patients conceptualize the concept, including energy, tiredness, capability, motivation, and comparison.n = 15, 71%) defined ‘lack of energy’ in terms of one’s energy level, specifically having little energy or no energy at all. For example, Pt 010 shared, “I don’t feel energetic enough or upbeat enough to perform my daily usual daily routines.” On the other hand, 9 (43%) interpreted the phrase in terms of the presence of tiredness, specifically feeling or being “tired” or “wiped out.” Moreover, nearly half  defined ‘lack of energy’ in terms of their capability, or the impact that low energy has on one’s ability to perform routine tasks or exercise. For example, Pt 018 defined it as “not being able to take a walk or get up and do routine household stuff.” Alternatively, women used terms indicative of motivation, as described by Pt 017 that “having a lack of energy means not feeling like doing things.” Specifically, 9 (43%) defined the phrase as having “no motivation”, “inspiration”, or “desire” to begin or complete a task or action, such as getting up from the couch or going to the grocery store. Finally, 8 (38%) defined the phrase by making a comparison between their current energy level and how they felt at another point in time, such as before having cancer.Patients most commonly  considered the items to be “different” or “similar but different.”As shown in Table A majority  indicated constipation severity influenced how much constipation bothered them Table . Of the n = 15, 71%) reported the item “I am sleeping well” as relevant to their experience with ovarian cancer, several notable themes related to sleep quality emerged. Patients described consideration of their ovarian cancer experience when responding to this item in three ways, including disease-related factors affecting sleep, treatment-related factors affecting sleep, and emotional concerns affecting sleep  considered disease-related factors when responding to the item. Although they did not identify specific disease processes affecting sleep, women attributed sleep disturbances to the experience of having ovarian cancer, in general. For example, Pt 003 stated, “…it’s everything combined. In the back of my mind you still hear that Stage IV ovarian cancer diagnosis.”A subset  stated that their sleep was affected by factors related to treatment. A subset of patients cited treatment, in general, as negatively impacting sleep. Patients also specifically described chemotherapy as a factor affecting sleep quality. For example, Pt 003 shared, “usually two days after chemo I don’t sleep and that’s what bothers me.” In addition to the effect of chemotherapy on sleep, patients also described thinking about other cancer-related therapies when responding, as Pt 007 explained, “I take steroids on Sunday…and I think it’s very directly related to the treatment and not stress or anything like that…because it’s very clearly Mondays, Sundays…[are] nights I might have disrupted sleep.”Nearly half  considered the emotional impact when responding to the item, “I am sleeping well,” citing anxiety, worry, racing mind, and depression when describing emotional interference with sleep quality. Although some described anxiety affecting sleep generally, others specifically stated that ovarian cancer-related anxiety and having an uncertain future affected sleep. For example, Pt 008 explained, “I think that in my case it’s a concern that is coming next, it’s interesting how this comes because I think one of my difficulties in sleeping is I think too much about what’s gonna’ happen to me.”On the other hand, a subset  reported considering factors unrelated to having ovarian cancer when responding to this item. Several described a longstanding history of sleep difficulty predating their cancer experience, as demonstrated by Pt 002, “I had problems with sleeping before [cancer]…I don’t know some age thing or what, but I can’t say it’s really connected…[my] sleeping issue didn’t happen as a result of my cancer or my chemo.” Patients also described sleep interference related to non-cancer medical conditions, such as hot flashes and need to use the restroom at night.n = 11; 52%) and treatment-related factors .Finally, when asked whether the item was related to disease-related symptoms, treatment-related side effects, or other factors,This study provides further evidence for the validity of the NFOSI-18 and its 9-item DRS-P for use in clinical research within a regulatory context. Specifically, we sought to further evaluate the content validity of these instruments to explore: (1) whether patients consider ‘pain’ and ‘cramps’ as to be redundant concepts; (2) whether ‘fatigue’ and ‘lack of energy’ are overlapping concepts; (3) whether the item “I am bothered by constipation” assesses severity; and (4) factors patients consider when responding to the item “I am sleeping well.” The results of this study provide further support for the content validity of the NFOSI-18 DRS-P as appropriate for use among women diagnosed with advanced ovarian cancer.Our findings provide qualitative insight into patient interpretations of key item content that assess related yet distinct concepts. First, our investigation into whether women with advanced ovarian cancer consider pain and cramps to be redundant, revealed that women consider cramps to be a subset of pain. Moreover, while there was some overlap in the way patients described pain and cramps as a form of discomfort, key differences emerged. For example, patients distinguished cramps from pain through depictions of muscle tightening. Moreover, similar to prior content validity findings , patientExperts and patients alike report fatigue as the most important symptom for advanced cancer patients who have undergone chemotherapy and therefore it is vital to accurately capture the symptom on PROs and symptom indices . In lighNext, our qualitative exploration of patient considerations when responding to the item “I am bothered by constipation,” revealed that patients respond according to the perceived severity of their constipation. In addition to reporting they would be more or less bothered if the constipation worsened or improved, patients further elaborated on factors that would increase bother, such as more pain or spasms or an increased frequency or duration, all of which are indicators of constipation severity. Thus, the item “I am bothered by constipation” can be regarded as a measure of constipation severity, a finding that is reinforced by prior reports of a significant association between severity of incontinence and bother –18. RelaFinally, our exploration of the factors considered when patients respond to the item “I am sleeping well,” revealed women considered a number of disease, treatment, and other factors. Nevertheless, because sleep quality is an issue of great importance for cancer patients throughout the disease course, we recommend retaining the item on the NFOSI-18 DRS-P; however, we suggest an alternative scoring option to exclude the item from the DRS-P if it is to unambiguously be referred to as a measure of disease-related symptoms , 21–23.There are three limitations that deserve mention. First, while there was some diversity, the vast majority of cognitive interview participants were White and of non-Hispanic/Latino origin. Second, participants were recruited through a single institution. Both of which limit the generalizability of our findings. Third, although the sample size was determined according to well-established qualitative research practices for cognitive interview sample size –26, it iThe findings of this cognitive interview study provide further evidence in support of the NFOSI-18 for assessment of PROs in clinical research and practice. Furthermore, the current study adds to prior validation efforts by focusing specifically on the content of the DRS-P, which may be of greatest relevance to clinical trials and ongoing examinations of validity due to changing treatment regimens and symptom profiles over time. While we do not recommend edits to the NFOSI-18, we do propose an alternative scoring option that excludes the item “I am sleeping well” from the DRS-P when used as a symptom index for clinical research. The present findings extend our understanding of patient interpretations of related, yet distinct constructs and patient considerations when responding to ‘bother’ items on PRO measures.