Pain is one of the most important domains affecting health-related quality of life (HRQoL) in patients with psoriatic arthritis (PsA). Secukinumab has demonstrated rapid and sustained improvements in signs and symptoms, including HRQoL, among patients with active PsA. This analysis evaluates the effect of secukinumab on patient-reported pain in PsA through 104 weeks of treatment.Pain was assessed through week 104 using clinically relevant measures, including change from baseline in a pain visual analog scale (VAS) and Short Form-36 (SF-36) bodily domain scores; proportion of patients reporting improvements equal to or better than minimum clinically meaningful differences in the pain VAS and SF-36 bodily pain domain scores; and proportion of patients with no, moderate, or extreme pain/discomfort measured by the EuroQoL 5-Dimension 3-Level Questionnaire (EQ-5D-3 L) pain item scores. Correlations of pain measures were analyzed using Pearson’s correlation coefficient. Pre-specified analyses of TNF-naïve patients and patients who stopped TNF-inhibitors (TNFis) due to inadequate responses or safety/tolerability (TNF-IR patients) were performed using “as-observed data.”P < 0.0001 with secukinumab 300 mg and − 12.6; P < 0.05 with secukinumab 150 mg) and sustained through week 104. SF-36 bodily pain domain scores were significantly greater with 300 mg secukinumab and secukinumab 150 mg versus placebo by week 4 , and these changes were maintained through week 104. With both secukinumab 300 mg and secukinumab 150 mg, improvements equal to or better than the minimum clinically meaningful differences in pain VAS and SF-36 bodily pain were significant versus placebo at week 3 and week 4, respectively. At week 4, 15%, 9%, and 5% of patients receiving secukinumab 300 mg, secukinumab 150 mg, and placebo, respectively, reported “no pain/discomfort” measured by EQ-5D-3 L; these proportions increased to week 104 with both secukinumab doses. Similarly, improvements in pain measures were significant in both TNF-naïve and TNF-IR patients.Mean improvements from baseline in pain VAS scores were greater with secukinumab versus placebo by week 3  contains supplementary material, which is available to authorized users. Psoriatic arthritis (PsA) is a chronic progressive, clinically heterogeneous inflammatory arthritis that can manifest as peripheral arthritis, axial disease, enthesitis, dactylitis, and psoriasis of the skin/nails , 2. The The combination of ongoing pain, fatigue, physical impairment, and anxiety likely influence the impact of PsA and reduce health-related quality of life (HRQoL) . SpecifiSecukinumab, a fully human monoclonal antibody (mAb) that selectively neutralizes interleukin (IL)-17A, has been shown to have significant efficacy in the treatment of moderate-to-severe psoriasis and active PsA, demonstrating rapid onset of action and sustained responses with a consistent safety profile , 14. SinDetails of FUTURE 2 (NCT01752634), an ongoing, multicenter RCT, have been reported previously  and willFUTURE 2 was conducted at 76 centers throughout Asia, Australia, Europe, and North America, in accordance with the principles of the Declaration of Helsinki, and all centers received approval from independent ethics committees or institutional review boards. Patients included in this trial were aged ≥ 18 years, met the Classification criteria for Psoriatic Arthritis (CASPAR), had ≥ 3 tender and ≥ 3 swollen joints despite treatment with non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), or TNFis. Patients who had not responded adequately to up to three treatments with TNFis were eligible for inclusion.A TNFi wash-out period ≥ 4 weeks prior to randomization was mandatory. Patients on concomitant oral corticosteroids who received a stable dose for ≥ 2 weeks prior to randomization (≤ 10 mg/day) and patients who were on methotrexate and received a stable dose for ≥ 4 weeks prior to randomization (≤ 25 mg/week) were allowed throughout the trial. Patients were excluded from the study for previous use of biologic agents other than TNFis; active inflammatory diseases other than PsA; active infection within 2 weeks prior to randomization or a history of chronic, ongoing, or recurrent infections; pregnancy; or malignancy within the past 5 years, with the exception of basal cell carcinoma or actinic keratosis, in-situ cervical cancer, or non-invasive malignant colon polyps.Patients were randomized 1:1:1:1 to receive subcutaneous secukinumab 300 mg, secukinumab 150 mg, secukinumab 75 mg, or placebo at baseline, weeks 1, 2, and 3, and then every 4 weeks from week 4. At week 16, patients were classified as responders (≥ 20% improvement from baseline in tender and swollen joint counts) or non-responders. Placebo-treated patients were randomly assigned again in a 1:1 ratio to receive subcutaneous secukinumab 300 mg or 150 mg every 4 weeks from week 16 (non-responders) or week 24 (responders). This study was blinded from baseline to week 52 and then open label until week 104.Pain was assessed through week 104 by the mean change from baseline in the pain VAS and Short Form-36 (SF-36) bodily pain domain scores; proportion of patients reporting improvements equal to or better than the minimum clinically meaningful difference (MCID) in the pain VAS score (mean change from baseline ≥ 20%) ; proportP values were calculated using the chi-square likelihood ratio test. The proportion of patients with VAS improvement ≥ 20% were reported using as-observed data and P values were calculated using Fisher’s exact test. The proportion of patients with improvement ≥ 5 in the SF-36 bodily pain domain score were reported using as-observed data and P values were calculated using Fisher’s exact test. Pre-specified subgroup analyses (TNF-naïve and TNF-IR) were performed using MMRM through week 24 and data were reported as observed starting from week 28. Only the results for patients receiving the approved doses – secukinumab 300 mg and secukinumab 150 mg – are reported in this article. Due to the re-randomization of patients in the placebo group at week 16, statistical comparisons of secukinumab versus placebo are presented up to week 16. Analyses were exploratory in nature and conducted without adjustment for multiple comparisons.Mean changes from baseline in the pain VAS and SF-36 bodily pain domain scores were analyzed using a mixed-effect model for repeated measures (MMRM) through week 24 with treatment regimen, analysis visit, and randomization stratum (TNF-naive or TNF-IR) as factors, weight and baseline score as continuous covariates, and treatment by analysis visit and baseline score by analysis visit as interaction terms, and an unstructured covariance structure. Mean changes from baseline were reported as observed starting from week 28. Frequencies of patient EQ-5D-3 L pain/discomfort domain response were reported using observed data up to week 104. Correlation with pain measures was analyzed using Pearson’s correlation coefficient and Overall, 397 patients with active PsA were randomized for this trial. Demographics and baseline disease characteristics have been previously reported for patients in this study and are presented in Additional file P < 0.0001) and secukinumab 150 mg . Improvements in mean changes from baseline in pain VAS scores continued to week 16 and were sustained to week 104 with both doses of secukinumab . For both doses of secukinumab, the proportion of patients with improvements equal to or better than the MCID in pain VAS scores continued to increase to week 16 and similar levels of attainment were reported at week 104  with secukinumab 300 mg . Continued improvement in SF-36 bodily pain domain scores were reported up to week 12 with both secukinumab doses, and initial improvements were sustained to week 104 for both secukinumab doses . For both doses of secukinumab, the proportion of patients with improvements equal to or better than the MCID in SF-36 bodily pain domain scores were maintained to week 104  and secukinumab 150 mg (16.3) compared with placebo  and EQ-5D pain/discomfort domain scores . Similarly, improvements from baseline in mean SF-36 bodily pain scores were significantly correlated with improvements in EQ-5D pain/discomfort domain scores at weeks 16, 24, 52, and 104 .At weeks 16, 24, 52, and 104, improvements from baseline in mean pain VAS scores were significantly correlated with improvements from baseline in mean SF-36 bodily pain scores . With both doses of secukinumab, improvements continued to week 104 (Table P < 0.05 vs placebo) and secukinumab 150 mg . Due to the smaller number of TNF-IR patients there was more volatility in responses over time. Nonetheless, improvements were maintained over time.TNF-naive and TNF-IR patients both demonstrated significant improvements in mean changes from baseline in pain VAS scores and SF-36 bodily pain scores. TNF-naïve patients receiving secukinumab 300 mg reported significant improvements in mean change from baseline in pain VAS score compared with placebo beginning at week 3 . Over time, the degrees of improvement in SF-36 bodily pain scores were similar with both doses of secukinumab in TNF-naïve patients. In TNF-IR patients, there were significant mean improvements from baseline in SF-36 bodily pain scores at week 8 with both secukinumab 300 mg  and 150 mg  compared to 5.7 with placebo. Mean changes from baseline in SF-36 bodily pain scores were similar over time between TNF-naive and TNF-IR patients with secukinumab 300 mg.Significant mean improvements from baseline in SF-36 bodily pain scores were also reported by both TNF-naive and TNF-IR patients receiving secukinumab Table . At weekBoth TNF-naive and TNF-IR patients also reported improvements in the EQ-5D-3 L pain item scores. At week 16, 22% of TNF-naive patients receiving either dose of secukinumab reported no pain or discomfort compared with 6.9% of patients receiving placebo  and − 0.48 with secukinumab 150 mg (P = 0.0555 vs placebo) [In this post-hoc analysis of the phase-3, FUTURE 2 study, secukinumab 300 mg and secukinumab 150 mg both provided rapid and sustained pain relief to patients with PsA over 2 years’ treatment. Improvements in pain with secukinumab were consistent across three different patient-reported measures  and were observed regardless of prior exposure to TNFis. Improvements in pain reported in this trial are consistent with findings of improved pain and HRQoL in other secukinumab trials. In FUTURE 1, improvement was observed in both mean pain VAS and SF-36 bodily pain domain scores . FurtherIn this trial, improvements in pain with secukinumab treatment were sufficient to meet or exceed established definitions for MCID in pain for PsA and were observed irrespective of previous exposure to TNFis. Due to the level of improvement in pain with secukinumab treatment, it is interesting to consider whether pain alleviation is due to overall improvement in inflammation or through a direct role of IL-17 inhibition. Plasma levels of IL-17A are elevated in patients with fibromyalgia and in mice, IL-17 contributes to neuroinflammatory responses and pain hypersensitivity following neuropathic injury , 24. TheThere was significant correlation between the improvement from baseline in mean pain VAS scores and mean SF-36 bodily pain scores and EQ-5D pain/discomfort domain scores and significant correlation between improvement from baseline in mean SF-36 bodily pain scores and EQ-5D pain/discomfort scores. Together these correlations indicate that secukinumab consistently improves pain regardless of the specific measurement used for assessment.Secukinumab 300 mg and secukinumab 150 mg also improved pain in both TNF-naive and TNF-IR patients measured by the pain VAS, SF-36 bodily pain scores, and EQ-5D-3 L pain/discomfort domain. Not surprisingly, TNF-naïve patients reported numerically greater changes from baseline in all three pain outcomes than those reported by TNF-IR patients.Limitations of this study include that it was a post-hoc analysis, the lack of an active comparator, and lack of placebo control after week 24.Secukinumab has previously demonstrated efficacy in treatment of the signs and symptoms of PsA, inhibition of radiographic progression in patients with PsA, and a favorable safety profile –17. In tAdditional file 1:Table S1. Baseline demographics and disease severity characteristics. (DOCX 13 kb)


Considering the existing contradictions regarding effectiveness of intravenous (IV) lidocaine, especially in emergency department (ED), the present study was designed to compare the analgesic effect of IV lidocaine and morphine sulfate in pain management for extremity bone fractures.In this triple blind clinical trial, 15 to 65 year-old patients with extremity fractures and in need of pain management were randomly allocated to either IV lidocaine or morphine sulfate group and were compared regarding severity of pain 5, 10, 15, 20, 25, and 30 minutes after infusion via intention to treat analysis. The absolute risk reduction, number needed to treat and relative risk of IV lidocaine after 30 minutes were 0.40 (95%CI: 0.25 – 0.64), 7 (95%CI: 3.7 – 23.1), and 20.71 (95%CI: 10.91 – 30.51), respectively.280 patients with the mean age of 32.50 ± 12.77 years were randomly divided into 2 equal groups of 140 . The 2 groups had similar baseline characteristics. 15 minutes after injection success rate was 49.28% in lidocaine and 33.57% in morphine sulfate group (p = 0.011), and after 30 minutes it reached 85.71% and 65.00%, respectively (p < 0.001). Based on the results of the present study, IV lidocaine could be considered as a reasonable alternative choice for pain management in ED.  Pain is an unpleasant mental and sensory experience that often occurs after a tissue injury and secretion of inflammatory cytokines . VariousAlthough many studies have indicated the role of IV lidocaine in pain relief after trauma or surgery and decrease in the need for other opioids, there are also studies that do not agree . For exaTherefore, considering the limited number of studies on the effect of IV lidocaine in pain management, especially in emergency department (ED) and the existing contradictions regarding its effectiveness, the present study was designed with the aim of assessing the analgesic effect of IV lidocaine compared to IV morphine sulfate in relieving the pain caused by traumatic extremity bone fractures.Study designThe present clinical trial was carried out during a 6 month period from June 2016 to Nov 2016 on patients presenting to ED of Imam Khomeini and Golestan Hospitals in Ahvaz, Iran, who needed pain management due to traumatic bone fractures. Before including the patients in the study, informed consent was obtained from them and they were given explanations regarding the study process. Throughout all steps of the study, the researchers adhered to the principles of Helsinki Declaration and confidentiality of patient data. All costs of the project were covered by the researchers and no additional costs were inflicted on the patients. This study was approved by the ethics committee of Ahvaz University of medical sciences and has been registered on Iranian registry of clinical trials under the number IRCT2015052622423N1.ParticipantsThe study population consisted of patients aged 15 to 65 years who had fractures in the long bones of their upper or lower extremities and the fracture was evident in physical examination and the patient needed pain management (moderate to severe pain). Pregnant and lactating women; patients with altered level of consciousness; hemodynamic instability; evidence of intra-abdominal or pelvic hemorrhage; mental retardation; history of allergy to lidocaine or morphine; history of addiction; underlying illness ; and consuming cardiac drugs were excluded from the study. No limitations were considered regarding sex and fracture type and being open or closed fracture. Physical examination and patient selection was done by a senior emergency medicine resident and a senior orthopedics resident.InterventionAfter selecting the patients that met the inclusion criteria of the study, they were divided into 2 groups receiving either IV lidocaine (1.5 mg/kg during 2 minutes) or IV morphine sulfate (0.1 mg/kg during 2 minutes). The study was designed as a triple blind manner as the patient, the person injecting the drug, and data analyzer were all blind to the type of drug consumed. Both drugs were colorless and odorless and to make them look alike, both drugs were injected in a 10cc volume with syringes with the same shape and color. Injection was performed by either an emergency medicine specialist or a senior resident of emergency medicine under complete cardiac, respiratory, blood pressure, level of consciousness and pulse oximetry monitoring. Before the injection of drug, vital signs of the patient and their pain score using visual analog scale (VAS) were measured and recorded.Data gatheringA checklist consisting of demographic data , vital signs  and pain severity on presentation and 5, 10, 15, 20, 25, and 30 minutes after injection was filled for all the patients. The senior emergency medicine resident in charge of the patient was responsible for gathering the data, but evaluation of vital signs of the patient was performed by someone other than the one injecting the drugs, who was blind to the type of drug used.To measure pain severity, VAS scale was used. Pain score of 3 to 6 was considered as moderate pain and score ≥6 was considered as severe pain. At least 3 points drop in pain score was considered as success in pain management.If pain was still present after 30 minutes, IV fentanyl with 1.5 mg/kg dose was prescribed for the patients as bolus.Outcometh and 30th minutes. In addition, patients were assessed regarding manifestation of any side effects such as confusion; tremor; stupor; seizure; restlessness; anxiety; lethargy; sleepiness; hallucination; strabismus; syncope; hypotension; bradycardia; cardiac failure; new arrhythmia; cardiac failure; anaphylaxis; status asthmaticus; edema; nausea; vomiting; rash and tinnitus. It was determined that in case of any drug side effects, the patient should be excluded from the study and be rapidly treated for relieving the side effect.At least 3 scores drop in pain severity was considered as success and less than 3 scores as failure in treatment on 15Statistical analysisNon-probability convenience sampling was used and analysis of data was done with intention to treat method via SPSS 21 statistical software. Quantitative variables were reported as mean ± standard deviation (SD), and qualitative data as frequency and percentage. To report the effectiveness of the drug, absolute risk reduction (ARR), number needed to treat (NNT) and relative risk (RR) were used with 95% CI. To do comparisons between the 2 groups, chi square and t-test were used. P < 0.05 was considered as level of significance.280 patients with the mean age of 32.50 ± 12.77 years (15 - 65) were randomly divided into 2 equal groups receiving either IV lidocaine (140 patients) or morphine sulfate (140 patients) . No cases of hypotension, respiratory depression, dysrhythmia and drop in arterial oxygen saturation were detected in either group during the initial 30 minutes after drug injection.Based on the results of the present study, success rate of IV lidocaine in relieving the pain caused by extremity fractures was significantly higher than that of morphine sulfate, 15 and 30 minutes after injection. Other indices of effectiveness such as RR, ARR and NNT also confirmed the proper effect of IV lidocaine for management of acute pain. In addition, no drug side effect was detected in either group.While about half of the patients who received IV lidocaine experienced at least 3 points drop in their pain score during the first 15 minutes after injection, this rate was 33% for the group receiving IV morphine. In other words, using lidocaine led to 15% to 20% drop in unsuccessful pain management cases 15 and 30 minutes after injection.Relative risk or risk ratio of using lidocaine 15 and 30 minutes after injection were 0.40 and 0.76, respectively. In other words, the probability of not controlling the pain in lidocaine group relative to morphine sulfate group was less than 1, which confirms its higher effectiveness.Numerous studies have confirmed the effectiveness of IV lidocaine for successful pain management and its role in decreasing the need for opioid use , 14, 15.A clinical trial by El-Tahan et al. in 2009 showed that IV lidocaine prescription before cesarean section surgery leads to less increase in heart rate, average arterial pressure and concentration of plasma cortisol. Their findings indicated that IV lidocaine can be considered as a safe and effective choice for reducing stress response of the mother to surgery during cesarean delivery .Findings of Yardeni et al. in 2009 showed that injection of IV lidocaine before and during surgery can be effective in improvement of pain management after surgery as well as reduction of immune interference and release of pain and inflammation inducing mediators due to surgery (Need for morphine sulfate in the first 72 hours post operation was lower in the group that had received IV lidocaine before surgery .Based on the findings of the present study, it seems that IV lidocaine has proper effectiveness in controlling acute pain caused by extremity fractures. Probably, the main reason for the low rate of using this option for pain management in ED is fear of side effects such as dysrhythmia. It seems that since most of the patients participating in the present study were either young or in their midlife, the probability of showing cardiac side effects was naturally lower. It seems more logical to decide on the side effects of injecting the drug after studies on various age groups and considering their various underlying illnesses.If the results of the present study are confirmed in other studies, we can count on IV lidocaine as an option and proper replacement for pain management of patients in ED.LimitationsLonger follow up of the patients and calculating the patients’ need for using analgesics after probable relapses are among the points that can decrease the limitations of the present study. Measuring serum level of lidocaine to avoid reaching toxic levels of the drug can also be considered in future studies. Repeating the study in populations with various age ranges and considering various types of underlying illnesses can be beneficial. In addition, for a more accurate comparison, fracture types and their location should better be homogenized between the 2 groups. However, random allocation of the patients prevented this confounding factor affecting the results to a great extent in the current study.Based on the results of the present study, success rate of IV lidocaine in relieving pain caused by extremity fracture was significantly higher than IV morphine. Using lidocaine led to 20% decrease in unsuccessful pain management cases until 30 minutes after injection with risk ratio of 0.76.


To assess the impact of Doxazosin Oral Intake Therapy on urinary symptoms and pain in patients with indwelling ureteral stentsA total of 239 patients with ureteral stone-related hydronephrosis who underwent a double-J stent insertion after ureteroscopic lithotripsy were enrolled. Patients were randomized to receive doxazosin cotrolled release 4 mg once daily for 4 weeks or matching placebo. Patients completed the brief-form Chinese version Ureteric Stent Symptom Questionnaire (USSQ) and quality of life (QoL) score 2 weeks and 4 weeks after stent placement and 4 weeks after stent withdrawal. The analgesic use was also recorded during the stenting period.Patients in Doxazosin Oral Intake Therapy group, in the first 2 weeks and second 2 weeks with the stent in situ, expressed significant lower daytime frequency (p=0.028 and p=0.038), nocturia (p=0.021 and p=0.008) and urgency (p=0.012 and p=0.014), respectively. Similarly, flank pain score, QoL score and analgesic use were also significant less in the stenting period. There was no significant difference in scores of urinary symptoms, pain and QoL during the post-stent period between two cohorts.Doxazosin Oral Intake Therapy reduced stent-related urinary symptoms, pain and the negative impact on QoL. More than four decades have passed since the first description of an indwelling ureteral stent by Zimskind et al. . PlacemeSeveral studies have demonstrated α-blockers, such as alfuzosin and tamsulosin, improving stent-related symptoms -7. HowevThis study was conducted with the institutional review approval. From June 2013 to February 2015, patients with unilateral hydronephrosis associated with ureteral stone to be treated with ureteroscopic lithotripsy and an indwelling ureteral stent insertion for 4 weeks were assumed for enrollment in the study. After documentation of informed consent, patients were randomized (using a Table with random number) to 1 of 2 treatment groups: doxazosin controlled release 4mg daily for 4 weeks  or matching placebo once daily for 4 weeks. Both investigators and patients were blinded to the randomization scheme and medication. Patients were asked to take 1 tablet on postoperative day 1.Patients with bilateral stones, pregnancy or probable pregnancy, nursing, symptoms of BPH, urinary tract infection, chronic pain history, α-blocker or anticholinergic use in previous 3 months, hypotension or orthostatic hypotension history (resting blood pressure less than 100/70mmHg), age less than 18 years and other contraindications indicated in package insert were excluded.Ureteroscopic lithotripsy was initially conducted with a Wolf 8F/9.8F semirigid ureteroscope in all patients. Stones were fragmented to less than 2mm using 0.8J 10Hz Holmium: YAG laser and a 200μm fiber. When flexible ureteroscope was required, a 12/14F dual lumen ureteral access sheath  was introduced over a working guidewire. A 6Fr indwelling double-J stent  was placed under fluoroscopic and cystoscopic control. Appropriate length was evaluated according to patient height. Stent position was examined radiographically.The primary endpoints were the assessment of urinary symptoms and pain. The secondary endpoints included QoL, analgesics use and treatment emergent adverse event (TEAE). To assess urinary symptoms and pain associated with ureteral stent, patients were asked to complete the brief-form Chinese version USSQ 2 weeks and 4 weeks after stent placement and 4 weeks after stent withdrawal . The outThe brief-form Chinese version USSQ, a simplified condition-specific questionnaire for evaluation of stent-related urinary symptoms and pain in the past 2 weeks, was adopted from the validated International Prostate Symptom Scale (IPSS) . The proA sample size of 218 patients was calculated based on a power of 80% and a significant level of 0.05 to detect 30% difference in flank pain scores and 26% difference in frequency scores in the first 2 weeks with the stent in situ . DescripA total of 239 patients were enrolled, 231 of whom were randomly assigned to either Doxazosin Oral Intake Therapy or placebo group. The total number of patients that completed the study at 2 weeks and 4 weeks after stent placement and 4 weeks after stent withdrawal were 219, 212 and 201, respectively. The main reasons for discontinuation were loss during follow-up, protocol deviation, withdrawal of consent and TEAE.Patient demographics are listed in The overall study results are presented in There was no significant difference in scores of urinary symptoms, pain and QoL in the post-stent period between two groups, which were considered as the baseline characteristics.Four patients in Doxazosin Oral Intake Therapy experienced mild TEAE (dizziness in 3 and orthostatic hypotension in 1), and two of them discontinued medication, and symptoms disappeared after discontinuation.To our knowledge, this is the first double-blind, placebo controlled study to demonstrate the effectiveness of Doxazosin Oral Intake Therapy in reducing ureteral stent-related discomforts. A range of patient urinary symptoms and pain were improved, including frequency, nocturia, urgency, flank pain, abdominal pain. Patients QoL seemed to be better preserved also. The sample size per group in the study was the biggest in relevant literature. The same type of stent and indication were controlled to minimize related biases.Although there have been lots of advances in ureteral stent composition and constructions design directed at improving biocompatibility and patient relevant symptoms, the ideal biomaterial for stent has yet to be discovered , 15. In Deliveliotis et al. firstly reported that alfuzosin improved a subset of urinary symptoms and pain in patients with an indwelling double-J stent using USSQ 4 weeks after stent insertion , 6. MetaRecently, Dellis et al. reported that tamsulosin and alfuzosin reduced stent-related symptoms in patients with hydronephrosis associated ureteral stone who underwent stent placement, routinely for 4 weeks, after extracorporeal shock wave lithotripsy  or ureteroscopic lithotripsy (n=44) using the USSQ as originally intended by Joshi et al. 1 week and 4 weeks after stent placement and 4 weeks after stent removal . In our The pathophysiology of stent-related symptoms may be associated with irritation of the trigone, smooth muscle spasm in ureter and bladder, reflux of urine to kidney, or a combination of them . α1-adreDoxazosin is a long-acting selective α1-adrenergic receptors antagonist with a half life of 16-20 hours. Doxazosin Oral Intake Therapy has been shown to offer enhanced pharmacokinetic profile, delivery rate and tolerability , 9. It mThe beneficial effect of Doxazosin Oral Intake Therapy on stent symptoms was primarily shown in the first two weeks with the stent in situ. The results in the second two weeks with the stent in situ further indicated the efficacy of Doxazosin Oral Intake Therapy on stent symptoms, which were less dependent on patient surgical complications, preoperative condition and postoperative recovery. The outcomes obtained at 4 weeks after stent withdrawal were proposed to be the baseline data without the impact of ureteral calculi and related hydronephrosis . HoweverOur study has several limitations. Firstly, we didn't evaluate all aspects of stent-related morbidity using USSQ initiated by Joshi et al., because the whole USSQ was not translated, adapted and validated in Chinese population. Secondly, Doxazosin Oral Intake Therapy was not compared with other α-blockers such as alfuzosin and tamsulosin. Thirdly, though the sample size per group was big enough for daytime frequency and flank pain, it might be relatively small to detect small differences of other parameters between two cohorts. Finally, since the brief-form Chinese version USSQ is used to assess symptoms associated with ureteral stent in previous 2 weeks, the discomforts were not evaluated on postoperative day 3 or 1 week after surgery when the outcomes were thought to be more relevant .Future randomized study with larger patient population using validated USSQ is warranted to further ascertain the efficacy of Doxazosin Oral Intake Therapy on stent-related morbidity and find the best way to address those discomforts by comparison between Doxazosin Oral Intake Therapy and other drugs already studied, such as tamsulosin or anticholinergics.The administration of Doxazosin Oral Intake Therapy 4mg once daily reduced stent-related urinary symptoms, pain and the negative impact on QoL.


This study sheds important light on the association between sino-nasal symptoms and global quality of life in patients with chronic rhinosinusitis waiting for endoscopic sinus surgery. Using patient-reported information collected pre-operatively, the primary objective was to report on patients’ pre-surgical sino-nasal symptoms and their association with self-reported pain and depression. The secondary objective was to report on levels of depression and pain among patients in the sample reporting severe sleep problems.This is a cross-sectional study of patient-reported outcomes collected prospectively from a cohort of 261 patients assigned to the wait list for elective endoscopic sinus surgery in a large urban region of Canada.p < 0.01). Subsequently, chronic rhinosinusitis patients with severe sleep problems were 82% likely to report moderate or severe depression and pain.Younger patients and patients with other medical comorbidities were most likely to report significant symptoms of chronic rhinosinusitis and substantial associated pain and depression. In the primary analyses, patients reporting significant symptoms of chronic rhinosinusitis were more likely to report moderate depression or high pain  contains supplementary material, which is available to authorized users. The syndrome of chronic rhinosinusitis (CRS) is a heterogeneous cluster of sino-nasal symptoms associated with mucosal inflammation. First line treatment for CRS includes medical/pharmacological interventions, such as steroids  and antibiotics. It is estimated that more than 5% of the Canadian population suffer from CRS-related symptoms, resulting in almost one million prescriptions per year , 2 and cMany patients with CRS eventually fail pharmacological intervention and progress to endoscopic sinus surgery (ESS) for treatment. This is problematic for many provincial health care systems, where demand for elective (scheduled) surgery outstrips supply which, in turn, results in substantial wait times for CRS patients. For example, in 2016, Nova Scotia reported the median wait time for ESS of approximately 4 months  – similaTo manage those patients awaiting elective surgery, regional health authorities in Canada use wait lists. These wait lists are registries for elective surgeries, recording demographics, diagnosis, surgery and date information – including the date that patients were assigned to the wait list and the date of their scheduled surgery. The Achilles heel of the wait list is that very little is known regarding symptom severity or the health status of those patients in the registry. As previous study into the wait list registry has observed, there is no relationship between the self-reported severity of patients’ symptoms and their level of triage on the wait list .The discordance between the severity of patients’ symptoms and the length of time they wait for surgery is concerning, particularly in the case of CRS. Sino-nasal symptoms have been documented to be associated with significant anxiety and depression , 11; espTo address this knowledge gap, the purpose of this descriptive study is to measure the symptom burden and the prevalence of pain or depression among CRS patients waiting for ESS after failed medical management. Previous work has established a need for this information in order to identify opportunities to improve the health status of waiting patients .To do so, this study uses validated patient-reported outcomes (PROs) designed to systematically measure the severity of symptom and functional impairments. The primary analyses is to measure the association between depression or pain with patients’ self-reported symptoms of chronic rhinosinusitis. The secondary objective is explore emerging findings regarding relationship between self-reported sleep problems with depression or pain . The resPROs were prospectively collected from a cohort of CRS patients assigned to the surgical wait list for ESS in the Vancouver Coastal Health (VCH) Authority, a region encompassing Vancouver, Canada – home to over one million residents. Vancouver Coastal Health is responsible for managing the wait list for elective surgeries performed in its acute hospitals.The population of potential study participants included all patients newly enrolled on VCH’s wait list for bilateral endoscopic sino-nasal surgery with a surgeon identified diagnosis of ‘chronic sinusitis/nasal polyposis’. Specific surgical codes are provided in Additional file Comorbidity information was collected from participants using a checklist of common chronic and acute conditions. Age and sex was collected via the wait list from participants and non-participants; these groups were compared based on available demographic information. This study reports on participants’ cross-sectional PROs data collected between September 2012 and April 2016. The University of British Columbia’s Behavioral Research Ethics Board (BREB) approved the study.A number of different PRO instruments were completed by participants, including the Sino-Nasal Outcomes Test (SNOT)-22, the Patient Health Questionnaire (PHQ)-9, and the PEG, representing pain intensity (P) and interference with enjoyment of life (E) and general activity (G). The SNOT-22 was used to measure the severity of CRS-related symptoms. The SNOT-22 is a widely used instrument that has previously demonstrated strong validity, reliability, responsiveness, and ease of interpretation . As its Depression in patients was measured using the PHQ-9 . This PRThe PEG was used to measure comorbid pain . The PEGAnonymized data was analyzed using SAS 9.4 . Age and gender sub-groups were compared between participants and non-participants to ascertain possible participant bias. Univariate analyses of the SNOT-22 score were presented overall, by age group, gender and count of reported comorbidities. Few participants reported more than three chronic health conditions, so comorbidity data was categorized into counts of 0, 1, 2, 3 and greater than 3.Depression scores (PHQ-9) and pain scores (PEG) were summarized, presented using cut-points validated in the literature , 20. ParP-values for the regression models were reported. Since the analyses were exploratory, no attempt was made to adjust p-values for multiple comparisons.Independent multivariate models were used to measure associations between patients’ SNOT-22 score with their PHQ-9 and PEG scores and other variables in the three models, including age, sex and category of count of comorbidity. Residuals were assessed visually to detect departures from the models’ assumptions. P-values were reported after assessing goodness of fit.A linear model was used to analyze SNOT-22 scores to measure whether there was an association between SNOT-22 scores with PHQ-9 depression or PEG pain scores, after adjusting for age, sex and comorbidities. The PHQ-9 and PEG scores were included in the analysis of covariance model as continuous variables. Patients’ sleep quality was evaluated. The SNOT-22 sleep score was calculated as the sum of the items associated with sleep quality, items 11–18. The sleep score ranged from 0 to 40, where a score of 40 represented the worst state of sleep health-related quality of life. Patients’ sleep scores were stratified by cut-points of the PHQ-9 and PEG representing moderate depression and high pain, respectively. For each quintile of SNOT-22 sleep score, mean (and standard deviation) PHQ-9 and PEG scores were calculated.The study sample included 261 participants, evenly split between males and females, with the modal age group between 51 and 70 years of age . Participants with more comorbidities reported higher SNOT-22 scores than those without – participants with three or more comorbidities reported SNOT-22 scores 28 points higher than those participants without comorbidities (p < 0.01). There were no differences in SNOT-22 scores between genders (p = 0.16).Analysis of participants’ SNOT-22 scores are provided in Table p < 0.01). Participants with more than one comorbidity reported higher levels of depression. Further, participants with three or more comorbidities reported PHQ-9 scores 2.7 points higher than those without any significant comorbidities (p < 0.01).Overall, 19.2% of participants reported symptoms associated with clinical depression. As shown in Table p = 0.20). Participants with comorbidities reported higher pain scores. Participants with three or more comorbidities reported pain scores 0.78 higher compared to those with no comorbidities (p < 0.01).Among participants, 44.6% reported PEG scores of three or greater, indicating high pain. Pain was highest among participants 50 years of age or less; relative to the oldest age group, this age group reported PEG scores 1.6 points higher. There were no differences in pain scores between genders (p < 0.01). Adjusting for patient demographics and comorbidities, each point increase in PHQ-9 score was associated with a 1.41 point increase in SNOT-22 score (p < 0.01). For a CRS patient with treatable depression, and PHQ-9 score of 10, there was an expected increase of 14 points in the participants’ SNOT-22 score.As shown in Table p < 0.01). Each point increase in the PEG was associated with a 2.42 point increase in SNOT-22 score. This relationship meant that for a patient with high pain – a PEG score of 3 – there was an expected 7 point increase in the participants’ SNOT-22 score.Pain was also highly significantly associated with SNOT-22 score after adjusting for patient demographics and comorbidities . Younger participants were more likely to have worse SNOT-22 scores, higher rates of depression and pain after adjusting for other comorbidities. This finding is important, as the relationship between the SNOT-22 score (a condition-specific instrument) and other specific instruments designed to be sensitive to depression and pain, was previously unclear. These are important domains which have been previously reported to be inadequately measured by the SNOT-22 , though The results also found that the worst pain and depression was reported by a subset of patients with severe sleep problems. Indeed, relationships between depression, pain and sleep have been raised by others . The assThe implications of these findings are substantial. Since this study’s participants’ SNOT-22 scores were comparable to those reported in literature , 22, 23,There are some limitations of these findings. Study participants were a subset of patients recruited from the VCH wait list, though there was no evidence to believe that patients participating in this study were substantially different from those that declined to participate. Nor do these findings mean that the results are true in all regions of Canada. Finally, as this was a cross-sectional analysis, one cannot draw conclusions regarding possible causal pathways between waiting for ESS for CRS and physical and mental health.The knowledge generated from this study is timely from a policy perspective, as BC has been directing additional funding into elective surgeries to reduce wait times . The proCRS is a highly prevalent condition and its treatment by ESS is very common. This study underscores that approximately one-fifth of patients waiting for ESS report clinically significant depression and/or pain. While an Otolaryngologist should be attentive to pain and depressive symptoms in all patients, when faced with lengthy waits for ESS, multi-disciplinary treatment, such as involving psychologists or pain management, is indicated for patients who pre-operatively screen with high SNOT-22 scores.


This study investigates the validity of the psychometric properties of the Brief Pain Inventory (BPI) in patients with bone metastases and determines if patients with lower body pain exhibit higher levels of activity interference than those with upper body pain.Three hundred and eighty-six patients treated, between May 2003 and June 2007, for painful bone metastases were included in this analysis, 336 patients with complete data were included in further analyses. Cronbach’s Alpha, confirmatory factor analysis (CFA), and discriminant validity tests were performed to analyze the psychometric properties of the BPI. One-way analysis of variance was used to compare mean scores of BPI subscales  in patients with upper or lower bone metastases.Internal consistency of two- and three-factor BPI analysis was high. In both cases, consistency was further improved when the sleep item was removed. CFA confirmed these results and showed that three-factor analysis was recommended. Patients with lower body metastases reporting moderate to severe pain exhibited greater levels of functional interference. A single fraction radiotherapy dose of 8 Gy was as effective as multi-fraction therapy where the predominant fractionation was 20 Gy in 5 fractions.Our data confirms the psychometric validation of the BPI and the recommendations to use three-factor analysis in patients with bone metastases. Patients exhibiting lower extremity pain should receive prompt pain interventions and functional aid. Approximately 50 - 75% of patients with advanced cancer will develop bone metastases and the pain that results is often the first sign of disseminated disease . Common Treatment for bone metastases includes orthopedic interventions , radionuclides, systemic therapies, conventional radiotherapy , stereotThe purpose of this study is to validate the psychometric properties of the Brief Pain Inventory (BPI) for patients with bone metastases and determine if patients with lower skeletal pain exhibit higher levels of functional interference than those with upper skeletal pain.The Rapid Response Radiotherapy Program (RRRP) at the Odette Cancer Center, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada is a dedicated palliative radiotherapy clinic designed to provide quick access to palliative radiotherapy. Patients seen at the RRRP between May 2003 and June 2007 were screened for eligibility into a prospective research ethics board-approved study designed to evaluate both pain and functional interference in patients with painful bone metastases treated with conventional palliative radiotherapy using the BPI assessment tool.The BPI is a multidimensional self-assessment tool commonly used to evaluate cancer pain , 13. It Demographic results were expressed as mean, standard deviation (SD), median and inter-quartiles for continuous variables, and proportion for categorical variables. Ideally, BPI assessments would be completed for all patients; however, there were some patients with missing values in one or more interference items. Patient characteristics between those who completed the BPI instrument in its entirety (study patients) versus those with one or more missing items (excluded patients) were compared using Wilcoxon rank-sum test (for continuous variables) or Fisher exact test .The three pain items  and seven BPI functional interference items were categorized as pain and interference respectively . Interference was further separated into subscales of activity and affect . The activity subscale includes the BPI items regarding interference with general activity, walking ability, work and sleep, while the affect subscale includes interference with mood, enjoyment of life and relations with others. Within each subscale, item-item correlations were examined to identify redundant questions. Internal consistency was examined in two (pain and interference) and three subscales . Standardized Cronbach’s alpha was applied to estimate internal consistency within each subscale . The staConfirmatory factor analysis was used to examine the scale structure of the BPI as a single construct (one factor), two-factor and three-factor models . One-fac2/[Sum(A)2 + Sum(B)], where sum(A) indicates sum of standardized factor loading and sum(B) indicates sum of measurement error . The minimum acceptance level of composite reliability is 0.70, and the minimum critical t value is 3.29 for P = 0.001.Standardized factor loadings, associated statistics , and composite reliability were provided for the best two-factor and three-factor models. Composite reliability is a measure of the overall reliability of a collection of heterogeneous but similar items. It is defined as Sum(A)Discriminant validity tests  were carried out to further evaluate highly correlated factors within the three-factor model. The confidence interval, including the value of 1.0, indicates significance. The variance extracted estimates the amount of variance that is explained by an underlying factor in relation to the amount of variance due to measurement error. Fornell and Larcker suggested that constructs should exhibit estimates of 0.50 or larger . It shouPatients who received radiotherapy to the lumbar spine, sacrum, or any of pelvic girdle , femur , and tibia were defined as having “lower skeletal pain”. Patients who were irradiated to the cervical or thoracic spine, shoulder girdle/upper extremity, ribs, and skull were grouped as those having “upper skeletal” bone pain. Those receiving radiotherapy to the thoracolumbar spine were excluded from this analysis as a potential confounder given that disease involving both thoracic and lumbar vertebrae may not be reliably categorized as upper vs. lower pain. One-way analysis of variance (ANOVA) was used to compare mean scores of BPI subscales  in patients with upper vs. lower bone metastases. Pain subgroups were further stratified according to the following severity index: mild (≤ 4), moderate (5 - 6), and severe (≥ 7). Test of heterogeneity of effect on mean activity scores between pain subgroups and upper/lower skeletal groups (interaction term) were conducted by general linear model.All analyses were performed using Statistical Analysis System (SAS version 9.2 for Windows) software. Confirmatory factor modeling was carried out using SAS covariance analysis of linear structural equations (PROC CALIS) procedure. A two-sided P-value of less than 0.05 was considered as statistically significant.A total of 386 patients had some form of baseline and demographic information in our database and 336 (87.3%) had complete information. The most commonly missed item on the BPI was normal work (29 patients) and least commonly missed was worst pain (1 patient). Only one patient was excluded for reporting all pain scores as zero. A comparison between study and excluded patient characteristics is shown in The median age of the 336 study patients was 67 years (range 30 - 91) and most prevalent primary cancers were breast (27%), prostate (24%) and lung (25%) . The medAmong 336 study patients, worst, average and current pain had median values of 8.0, 5.0 and 3.0, respectively. With respect to interference, pain interfered most with general activity , walking ability , normal work  and enjoyment of life .The internal consistency of both two and three subscales was high . The staBoth the null, 10-item single factor and the established two-factor default model demonstrated poor fit, the latter being slightly better than the first. By removing the sleep item and allowing specific error terms to co-vary from the analysis, the two-factor and three-factor models were markedly improved . AdjusteDiscriminant validity was used to analyze activity and affect and overall showed varying results. Chi-square difference test revealed a value of 18.5 , indicative of significance between mixed and separated support. The confidence intervals demonstrated significance . The square of the correlation between activity and affect was 0.88, which was greater than both variance extracted estimates for affect (0.54) and activity (0.78). If the variance extracted estimates were higher than the square of the correlation, it would have shown successful discriminant validity. However, the variance extracted test failed to confirm the validity. Ultimately, the combination of different validity analyses confirmed the validity of the construct.From above results and the reasonably high levels of internal consistency, composite reliability and discriminant validity can be demonstrated in both two-factor and three-factor models. Overall, the three-factor model with removal of sleeping item was preferred because of fewer covariance terms for fitting the model, and its clinical importance in differentiating patients with different sources of pain.Among the 336 patients with completed data, 199 had lower body and 130 had upper body skeletal metastases treated with palliative radiotherapy; seven patients were excluded as their radiation field covered the thoracolumbar spine. Mean pain scores were not significantly different between both patient groups  P = 0.3. PatientResearch regarding functional interference resulting from pain in advanced cancer patients is lacking. The BPI is a common tool used to assess functional interference; however, the psychometric properties have not been validated in patients with bone metastases until recently. Wu et al. conducted an analysis of 258 patients receiving radiotherapy for painful bone metastases and suggested that the three-factor analysis of the BPI with the sleep item removed is preferred and patients with lower body pain will experience higher levels of functional interference than those with upper body pain . In thisOur analysis of the psychometric properties of the BPI is compared to that by Wu et al. in The improvement in the model with removal of the sleep item makes sense as the relationship between sleep and pain is very complex in nature. Literature has identified predisposing and perpetuating factors that may lead to insomnia , and emoIn our analysis of upper versus lower skeletal pain, the latter group suffered more from activity interference, however, only when their pain was categorized as being moderate or severe. In the analysis by Wu et al., only those with mild and moderate pain had significant differences in interference. This discrepancy requires more investigation but suggests that clinicians need to be more aware of the functional impact of symptomatic bone metastases located in the lower skeleton.A further point of research would be to test correlation with other musculoskeletal functional scales, such as the Western Ontario and McMaster University Osteoarthritis Index (WOMAC)  and the In summary, we have obtained similar results to Wu et al. and agree with their findings. The BPI is a valid measurement tool for patients with bone metastases and should be analyzed using three factors as it satisfies three of four IMMPACT recommendations. Sleep interference does not correlate well with activity or affect subgroups and its removal from analysis improves correlation between other BPI items. The sleep item should be further investigated to examine its relationship to bone metastases specific pain. Patients with moderate to severe lower skeletal pain exhibit higher levels of activity interference than those with upper body skeletal pain and therefore should be given prompt treatment and additional assistance due to their increased functional impairment. Although single dosage radiotherapy being as effective as multi-fraction treatment is not new, it is a point currently being emphasized by the American Society for Therapeutic Radiology and Oncology (ASTRO).


Botulinum toxin type-A (BTX-A) has been successfully utilized to treat trigeminal neuralgia. In this study, through the use of a new technique, the efficacy of the injection of BTX-A to the maxillary and mandibular nerves was evaluated.A total of 27 patients were injected with 100 Units of BTX-A to the maxillary and mandibular nerves. Visual analogue scale score and pain frequency were assessed before treatment and at the first week, second month, and sixth month after treatment. Patients with ≥50% reduction in mean pain score at the second and sixth month were defined as responders.A total of 27 patients were included in the study. BTX-A significantly reduced pain intensity and pain attack frequency at the first week, second month, and sixth month after treatment. At the second month, 74.1% of patients, at the sixth month, 88.9% of patients responded to treatment. Forty-four percent of patients did not experience any pain at the sixth month. The mean recurrence period was 87.7 ± 20.4. BTX-A was well tolerated and showed few treatment-related adverse events.Injection to the maxillary and mandibular roots seems to be a highly effective method. In the event of recurrence, after each injection, the pain severity and attack frequency decreased. Yet, 25% to 50% of cases become refractory to the drug therapy. Surgical intervention is occasionally used to treat severe and often untreatable TN as it can cause complications that may be worse than at the primary point. Although the therapeutic effect of botulinum toxin type-A (BTX-A) has been reported, it has not been widely used in the treatment of TN.Trigeminal neuralgia (TN) is defined as sudden, usually unilateral severe brief stabbing recurrent episodes of pain within the distribution of one or more roots of the trigeminal nerve. The prevalence of the disease is 4 to 29 per 100,000 in the worldwide population.1, C2, D, E, F, and G) of botulinum neurotoxin. It was reported to be effective for cases of TN.–12 In these studies, BTX-A was mostly administered intradermally and subcutaneously.Onabotulinum toxin A is of the serotype , they were diagnosed with classical TN.Entry criteria for the study were failure of the current treatment; baseline pain intensity should be ≥4; and attack frequency should be ≥4 per day. Exclusion criteria for the study included any systemic disease or usage of any agents that might interfere with BTX-A. Women who were pregnant or planning pregnancy during treatment were excluded.Clostridium botulinum type A neurotoxin complex, 0.5 mg of human albumin, and 0.9 mg of sodium chloride. The content was diluted in 2 mL saline solution (0.9%). For each root 50 U (1 mL) was injected.Each vial of Allergan BOTOX (onabotulinum toxin A) contains 100 Units (U) of 2.1We used a dental needle of 0.40 × 50 mm for injection. For the injection to the maxillary root, through the upper edge of the zygomatic arch, patients were in a sitting position and their heads were supported by a headrest. At the upper edge of the zygomatic arch, midway between the external ear and the orbital rim, the needle was pointed toward the zygomatic bone on the other side of the skull (forming obtuse angles to the front and below) at a depth of 50 mm around the pterygopalatine ganglion. For the injection to the mandibular root, through the lower edge of the zygomatic arch, the position was the same. Their mouths were slightly open. The needle was pointed transversely along the base of the skull toward the middle and inserted below the middle of the zygomatic arch. After striking the pterygoid process, the needle was withdrawn slightly and rotated craniodorsally about 5 to 10 mm and the solution was administered around the trigeminal ganglion.A radioscopic or echographic guide was not used during the procedure. Anatomical picture is shown in Figure 2.2The severity of pain was evaluated through the visual analogue scale (VAS) . VAS and pain frequency were recorded just 24 hours before the treatment, at the first week, the second month, and the sixth month. If pain recurred, the same treatment was repeated and then VAS and pain frequencies were recorded.The overall response to treatment was assessed through the Patients Global Impression of Change (PGIC) scale. The PGIC is a self-evaluation of the patients overall change since the beginning of the study according to a 7-point scale . Response to treatment was defined as patients with ≥50% reduction in mean pain score from baseline to end point. The adverse events were recorded at each visit.P < .05.Statistical analyses were performed using PASW Statistics 18.0 software. Frequency distributions and percentages were calculated. Repeated measures were compared by means of the Wilcoxon signed-rank test. Response rates at different time periods were compared with the McNemar test. Results were considered to be statistically significant at the level of 3A total of 27 patients were included in the study. Their ages ranged from 27 to 77 years (the mean age being 54.8 ± 4.5). There were 6 males (22%) and 21 females (78%). The mean duration of the disease was 4.2 ± 2.6 years. One root was affected in 10 patients whereas 2 roots were affected in 17 patients.P = .000, P = .000, and P = .000, respectively). Attack frequency was calculated as the number of attacks per day. The mean baseline attack frequency was 217.7 ± 331.5, it was found to be 71.5 ± 196.3 at the first week, 54.8 ± 196.3 at the second month, and 55.15 ± 196.20 at the sixth month. There was a statistically significant difference between baseline frequency and the frequency at the first week, the second month, and the sixth month  (Table The mean baseline pain score (VAS) was 9.7 ± 0.6. It was found to be 3.5 ± 3.2 at the first week, 2.4 ± 3.1 at the second month, and 1.6 ± 2.4 at the sixth month. There were significant differences between the baseline VAS score and the first week score, the second month score, and the sixth month score  of patients reported very much improved or much improved pain score at the first week, 21/27 (77.7%) of patients reported a very much improved or much improved pain score at the second month, and 23/27 (85.1%) of patients reported a very much improved or much improved pain score at the sixth month , at the second month 20/27 (74.1%), and at the sixth month 24/27 (88.9%) of patients responded to the treatment. Out of 27, 12 (44.4%) patients were pain-free at the end of 6 months. Out of 27, 15 (55.5%) patients experienced recurrence after a mean period of 54.7 ± 30.5 (9–97) days, and they were treated for a second time. Out of 15, 7 (47%) patients experienced a second recurrence after a mean of 87.7 ± 20.4 (59–120) days. Despite being given a third injection over the 6-month period, 1 patient did not experience any change whatsoever in pain frequency and severity.Adverse events: 1 patient experienced short-term facial weakness on the injection side, this side effect disappeared within 2 months. Masseter weakness on the injection side was observed in 2 patients, and after the third injection, remained mild and permanent.4These results indicated that patients receiving BTX-A experienced statistical and clinical improvement in pain intensity and attack frequency at each follow-up.In this study, it was found that the VAS score significantly decreased at the first week and continued to decrease more and more at the second month, and at the sixth month. A recurrence was not observed in around half of the patients at the sixth month. In the remaining half, recurrence developed. The recurrence period varied between 9 and 120 days. The follow-up of patients is still ongoing. We also aim to publish the long-term results of the study. As it stands, 2 patients have been recurrence-free for 2 years. The pain severity and attack frequency decreased more and more after each injection. These patients are continually being followed-up. In this study, we did not use the same technique as other authors. This technique showed that pain severity decreased by almost 90% at the sixth month.,12,14–16 In our previous study, we injected 50 U of BTX-A above the zygomatic arch and 50 U of BTX-A below the zygomatic arch. It showed a 70% decrease of mean VAS score at the sixth month.BTX-A in TN has been used over the last decade, almost in all studies BTX-A was injected subcutaneously, intracutaneously, and into the trigger zone in the painful facial area.Wu et al reported that BTX-A for the treatment of TN was effective and safe, they injected intradermally and submucosally where pain was experienced. Their response rate was also high at 70% at week 8.,16Jian-Huo Xia et al treated 86 patients with TN; they also injected intracutaneously in the painful facial area. Their efficacy rate was 80% at the eighth week. Other studies reported that BTX-A injection in the facial pain area significantly relieves pain in TN.Batifol et al have recently found that the injection into the trigger zone required considerably lower doses. The effectiveness of the BTX-A showed high response rate in their study.Sheta et al reported in their single-blinded randomized placebo-controlled study that there was significant pain reduction in the BTX-A group when compared to placebo group. There was also a significant decrease in the number of acute medication and an increase in quality of life.Zhang et al reported in their double-blinded randomized placebo-controlled trial, administered 25 U to one group and 75 U to another and compared with a placebo group. Results showed that the response rates were significantly higher in BTX-A groups than placebo group, but there was no statistically significant difference between 25 U and 75 U groups.Evidence from systematical review showed that only 4 randomized controlled studies were undertaken up to the 2016. In total, 176 TN patients were treated. According to their results, BTX-A is a significantly effective and beneficial substance in the treatment of TN when compared with use of a placebo. Their injection technique was subcutaneous and/or intradermal.With our injection technique, the injection was administered in close proximity to the maxillary and mandibular nerve roots around the ganglions. We observed 88.9% success rate with this method. These results were slightly more effective than the other methods.No significant safety concerns were recorded in this study. Masseter weakness was noticed by the patient after detailed questioning. Despite this adverse event, the patients wanted to continue with injections due to satisfaction.4.1Most important limitation of this study is that it is not a placebo-controlled study. Second limitation, the fact that our study is an open label study may create bias. One of the main antinociceptive effects of BTX-A is probably related to its ability to block the transport of nociceptive input to centers modulating nociception. BTX-A negatively modulates nociceptive neurotransmitters. Its action can be preganglionic, on CGRP,–25 substance P and glutamate, or postganglionic, on synaptic terminations, blocking the release of norepinephrine (NE) and adenosine triphosphate (ATP).,29The mechanism of onabotulinum toxin A in controlling pain in TN remains uncertain. Several studies have been conducted to explore the mechanism underlying the potential analgesic action of BTX-A. After being injected in the subcutaneous tissue, BTX-A is taken up by endocytosis at nerve terminals of C fibers and rises by retrograde axonal transport through the trigeminal ganglion to the spinal trigeminal nucleus.In conclusion, this study showed that this injection technique seems to be a highly effective method. In the event of recurrence, a repeat of injections should not be avoided. Evidence of longer and well-designed and randomized controlled trials is required.


Differences in somatosensory profiles in different localisations in 1 distinct disease  were shown. This might have implications for future research and treatment regimes. Animal experimental evidence suggests that mechanisms of pain generation and response to treatment differ between neuropathic pain in the cephalic and the extracephalic innervation territories.The objective of the study was to examine whether in humans an identical peripheral painful neuropathy is associated with different pain qualities and sensory abnormalities in the face as compared with the thoracic region.We retrospectively analysed epidemiological and clinical data of 639 patients with postherpetic neuralgia (PHN) in the face and at the trunk who were collected within a cross-sectional cohort survey and compared the respective sensory symptom profiles captured with the painDETECT questionnaire.Two hundred twenty-four patients suffered from trigeminal PHN and 415 from thoracolumbar PHN. There were no significant differences in sex-ratio, age, body mass index, and pain duration. Patients with trigeminal PHN were more often severely depressed. Anxiety and sleep scores were not different. The average pain intensity was slightly higher in thoracolumbar PHN than trigeminal PHN . Postherpetic neuralgia in the thoracolumbar region showed significantly more intense burning sensations, allodynia, painful attacks, and significantly less prickling and numbness than PHN in the face.The differences in sensory symptom profiles between facial PHN and truncal PHN might be associated with different pathophysiological mechanisms and different treatment response. Drugs that primarily act on sensitization processes in the peripheral nociceptive system may work better in thoracolumbar PHN than in trigeminal PHN. If new medications are tested in patients with PHN, it would therefore be of interest to include an analysis of the treatment results in regard to subgroups based on the localisation of pain in patients with PHN. In the periphery, every afferent nerve of the body can be affected. There is, however, animal experimental evidence that mechanisms of pain generation and response to treatment differ between the cephalic and the extracephalic innervation territories.18Neuropathic pain, ie, pain which occurs as a direct consequence of a lesion or disease of the somatosensory system3To translate this body area–related discrepancy into pain mechanisms to human pain states, we investigated whether an identical peripheral painful neuropathy, ie, postherpetic neuralgia (PHN), is associated with different pain qualities and sensory abnormalities in the face as compared to the thoracic region. The sensory phenotype of patients with neuropathic pain can be used to speculate about different underlying mechanisms of pain generation in both groups.DETECT) performed in collaboration with the German Research Network on Neuropathic Pain (DFNS).We analysed epidemiological and clinical data of more than 600 patients with PHN in the face and at the trunk who were collected within a cross-sectional cohort survey in Germany  participated in this study, not each 1 of the 919 centers could recruit patients for the study. Therefore, a total number of 639 patients were included. Patients presenting with PHN, at least 18 years old, used a hand-held computer to complete electronic patient-reported questionnaires for the cross-sectional epidemiological and clinical survey. The study protocol was approved by the ethical committee of the University of Düsseldorf.The patient selection was retrospectively performed based on electronic pain drawings performed by the patients. The hand-held computer is equipped with a body drawing with 34 predefined body areas. Patients with PHN (pain >3 months after acute shingles) who marked their major pain in the trigeminal area or in the thoracolumbar dermatomes were included in the study.DETECT questionnaire (PD-Q8) was used  To eliminate interindividual differences of the general perception of sensory stimuli , a score was calculated in which the given 0 to 5 score of each question was subtracted by the mean of all values marked in the 7 questions. In this individual score, values above 0 indicate a sensation which is more intense than the individual mean perception and values below 0 indicate a sensation which is less intense than the individual mean perception To elimi9) and for depressive disorders and panic and anxiety disorders, the German-language Patient Health Questionnaire .In addition to standard demographic questions, the following validated questionnaires were used to assess comorbidities: for sleep disturbances, the Medical Outcomes Study sleep scale .Descriptive statistical analyses were performed. For each patient, a score was calculated in which the given 0 to 5 score of each question was subtracted by the mean of all values marked in the 7 questions to eliminate individual perception differences for sensory stimuli. Continuous variables were presented within tables by mean plus/minus SD, with 95% confidence intervals or ranges. Differences were evaluated for statistical difference by the 2-sample Complete data sets from 639 patients with PHN were available for further analysis . The total painDetect score did not differ significantly between the 2 groups . The intensity of the sensory symptoms was remarkably different between both groups. Postherpetic neuralgia in the thoracolumbar region showed significantly less prickling and numbness than PHN in the face  to the sciatic nerve in rats induced an overexpression of the proinflammatory cytokine IL-6 and subsequent microglia activation in the dorsal horn. This mechanism is believed to be involved in the development of central pain hypersensitivity. By contrast, no such upregulation could be found in the spinal nucleus of the trigeminal nerve after trigeminal CCI.13 In addition, differential treatment effects on neuropathic pain behavior were shown in the cephalic vs the extracephalic territories.16 Triptans and calcitonin gene-related peptide receptor antagonists alleviated pain behavior caused by CCI to the infraorbital nerve but not the sciatic nerve in rats.17According to these results, animal experiments suggest that there are fundamental pathophysiological differences between pain syndromes caused by an injury to the trigeminal nerve as compared to a lesion of other peripheral nerves. In rats, Tal and Devor3 Furthermore, it has to be kept in mind that these are overall results and that individual cases can naturally present with different sensory profiles.There are some limitations of the study. The results of this study refer to patients suffering from PHN, a peripheral neuropathic pain condition. At this point, it is not known if these results can be transferred to other neuropathic conditions, especially to central neuropathic pain. Another limitation of the study is that there was no control for the analgesic medication the participating patients were taking. Accordingly, an influence of analgesics on the somatosensory symptoms described by the patients cannot be ruled out completely. Other studies using data of large cohorts of patients suffering from neuropathic pain were facing the same problems and we know that the influence of the medication on different subgroups of patients cannot be crucial because it has not been shown that a majority of patients (>50%) was treated with the same drug or the same drug combination.10 Facing future studies, it would therefore be interesting to include an analysis of the treatment results in regard to subgroups based on the localisation of pain in patients with PHN.5The differences in sensory symptom profiles and potentially also in pathophysiological mechanisms between facial PHN and truncal PHN might have implications for the interpretation and design of clinical trials in this indication. It is very well conceivable that drugs that primarily act on sensitization processes in the nociceptive system may work better in thoracolumbar PHN than in trigeminal PHN.S. Rehm has received speaking fees from Grünenthal GmbH, Bayer Vital GmbH and Pfizer and travel support from Astellas. M. Großkopf has received travel support from Sanofi-Genzyme GmbH. R. Freynhagen reports research support, personal consulting, or lecture fees in the past 2 years from Astellas, Develco Pharma, Galapagos, Grünenthal, Lilly, Merck, Mitsubishi Tanabe Pharma, and Pfizer. T. Tölle has given lectures and/or participated in advisory boards on behalf of Astellas, Grünenthal, Ely-Lilly, Pfizer, Mundipharma, Teva, Nevro, Angelini, and Dompe. R. Baron has received grants/research support from Pfizer, Genzyme GmbH, Grünenthal GmbH, and Mundipharma. He is a member of the EU Project No 633491: DOLORisk. A member of the IMI “Europain” collaboration (grant agreement 115007) and industry members of this are: AstraZeneca, Pfizer, Esteve, UCB-Pharma, Sanofi Aventis, Grünenthal GmbH, Eli Lilly, and Boehringer Ingelheim Pharma GmbH&Co.KG.German Federal Ministry of Education and Research (BMBF): Member of the ERA-NET NEURON/IM-PAIN Project (01EW1503). German Research Network on Neuropathic Pain (01EM0903), NoPain system biology (0316177C). German Research Foundation (DFG). He has received speaking fees from Pfizer, Genzyme GmbH, Grünenthal GmbH, Mundipharma, Sanofi Pasteur, Medtronic Inc. Neuromodulation, Eisai Co Ltd, Lilly GmbH, Boehringer Ingelheim Pharma GmbH&Co.KG, Astellas, Desitin, Teva Pharma, Bayer-Schering, MSD GmbH, and Seqirus. He has been a consultant for Pfizer, Genzyme GmbH, Grünenthal GmbH, Mundipharma, Allergan, Sanofi Pasteur, Medtronic Inc. Neuromodulation, Eisai Co Ltd, Lilly GmbH, Boehringer Ingelheim Pharma GmbH&Co.KG, Astellas, Novartis, Bristol-Myers-Squibb, Biogenidec, AstraZeneca, Merck, Abbvie, Daiichi Sankyo, Glenmark Pharmaceuticals, Seqirus, Teva Pharma, Genentech, Galapagos NV, and Kyowa Kirin GmbH. The remaining authors have no conflicts of interest to declare.This research was supported by a grant from Pfizer Germany without restriction on publication.


For patients who have anterior hip pain evaluated by Patrick’s test and tenderness at Scarpa’s triangle, we perform periarticular debridement based on the hypothesis that extra-articular pathologies are responsible for the hip pain. The purpose of this study was to categorize the endoscopic extra-articular findings and to evaluate the clinical significance of periarticular pathologies in anterior hip pain.Arthroscopic findings of 77 patients who underwent periarthritic debridement were evaluated. As extra-articular pathologies, injuries of the direct head and reflective head of the rectus femoris muscle were evaluated. A thin layer of fat tissue normally exists on the anterior inferior iliac spine (AIIS), the attachment site of the direct head of the rectus femoris muscle. The macroscopic appearance of the fat pad on the AIIS was categorized as normal, blood vessel-rich adipose tissue or adipose tissue with fibrosis or scar formation and histologically confirmed. Adhesion of gluteal muscles to the joint capsule was also evaluated.Of the 77 patients, 75 had rupture of the direct head of the rectus femoris. In contrast, rupture of the reflective head was extremely rare. Seven patients had a normal fat pad on the AIIS, 11 had blood vessel-rich adipose tissue and 55 had adipose tissue with fibrosis. Fat tissue was completely replaced by fibrous scar tissue in another 4 patients. In 64 patients, adhesion between the anterior joint capsule and gluteus muscles was marked. Groin pain disappeared soon after the operation even when labral tears were not repaired and all patients returned to daily life and sports activities within 2 weeks after operation.Rectus femoris tendinosis, fibrosis of the AIIS fat pad, and adhesion of gluteal and rectus femoris muscles are common extra-articular pathologies in patients with anterior hip pain. Management of only these lesions induces rapid relief of anterior hip pain even in the absence of labral tear repair. My observations suggest that it is desirable to be aware of the presence of periarticular pathologies as a cause of groin pain. Groin pain is a common problem and is known to be a complex issue . The widPatrick’s test is a manual examination to evaluate the pathology of the hip joint . This tePermission to conduct research involving human participants was obtained through the appropriate institutional review board. All participants were informed of the purpose of the study, and they provided written informed consent before participating. It is well known that Patrick’s test can reveal several pain sites: anterior, lateral and posterior. The pain site is defined based on the structures damaged. I have developed a hypothetical diagnostic algorithm for hip pain and decide the treatment option according to this algorithm. If patients feel hip pain anteriorly in Patrick’s test and have tenderness at Scarpa’s triangle, tendinosis of the direct head of the rectus femoris muscle is suspected. Ultrasound-assisted lidocaine injection into the region of the anterior inferior iliac spine (AIIS) is helpful to make a diagnosis of anterior periarthritis. If patients feel surface lateral hip pain in Patrick’s test and have tenderness over the greater trochanter, greater trochanter bursitis is suspected. Pain relief is confirmed by lidocaine injection into the greater trochanter bursa. If patients feel deep lateral discomfort, we suspect a labral tear and confirm it by lidocaine injection into the hip joint.Since April 2016, 416 patients with hip pain have visited to our clinic. Of these, 297 had anterior hip pain in Patrick’s test and tenderness at Scarpa’s triangle. The diagnosis of anterior periarthritis of the hip joint was confirmed by ultrasound guided lidocaine injection into the region of the AIIS. After the diagnosis of anterior periarthritis, all patients underwent physical therapy for at least 6 weeks and symptoms were relieved in 220 patients (74.0%). Surgical treatment was carried out for the remaining 77 patients who were resistant to the conservative therapy and they were included to this study .Those with radiographic parameters consistent with FAI  were diagnosed as having FAI ,7. The pAll the surgical procedures were performed with the patient in the supine position using a traction table. Routine diagnostic arthroscopy was performed to assess the ligamentum teres, cartilage surfaces, and labrum. As I hypothesized that intra-articular pathologies were not responsible for the hip pain in this cohort, we never repaired the injured labrum. We next assessed the extra-articular lesions, direct head and reflective head of the rectus femoris muscle, the thin fat pat on the AIIS and anterior joint capsule. Any torn fibers of the direct head of recuts femoris muscle were debrided with a shaver and electrocautery, leaving healthy intact fibers. The AIIS fat pad was also debrided with a shaver and electrocautery and bony protrusions of the AIIS were decorticated with a bone cutting bar. Formal physical therapy was begun on postoperative day 1 without any restriction of weight bearing or the range of motion. Patients were returned to the normal activities of daily life and sports activities 2 weeks after the operation.Ligamentum teres tears were classified according to the system of Gray and Villar . The patOutcomes were evaluated for all hips using the modified Harris Hip Score (mHHS)  and the t-test.Statistical analyses were performed using IMB SPSS Statistics 22.0 (IBM SPSS Inc. USA). The mean and standard deviation were used for descriptive statistics with 95% confidence intervals (CI). Pre- and postoperative scores were compared using the paired The patient population consisted of 27 male and 50 female patients with a mean age of 38.1±19.7 years . Their demographic data are shown in Based on the hypothesis that not intra-articular pathologies but rather periarticular lesions around the AIIS are responsible for the groin pain in patients who have anterior hip pain in Patrick’s test, only periarticular debridement was performed. We never repaired the labrum. Neither cam decompression for FAI nor acetabuloplasty for acetabular dysplasia was performed. The procedure included arthroscopic debridement of the torn direct head of the rectus femoris and fibrotic fat pad using a shaver or electrothermal probe. Adhesions of muscles to the joint capsule were also released. Cauterization of any visible vascularization in the diseased tissue completed the procedure. Groin pain disappeared soon after the operation even when the torn labrum was not repaired. All patients returned to their daily life and sports activities within 2 weeks after operation. They were all followed-up with a mean follow-up period of 8.3 months . There were significant improvements in the postoperative mHHS and VAS .I have presented the endoscopic findings in patients with anterior hip pain confirmed by Patrick’s test. In addition to intra-articular pathologies, all patients had periarticular pathologies. Tendinosis of the direct head of the rectus femoris muscle was common and fibrosis of the fat pads on the AIIS and anterior joint capsule was more severe than we originally thought.MR images showed the fibrosis of the thin AIIS fat pad. I also confirmed this lesion histologically. However, the mechanism of the injury of the direct head of the rectus femoris muscle remains unclear. Based on the macroscopic and histologic findings, I speculate that this is not a simple trauma but a repetitive degenerative process. Repetitive eccentric and concentric stresses may cause microtears of the tendons and a reactive ischemic gelatinous response that spreads to the adjacent fat pad, resulting in inflammatory cell infiltration and myxomatous degeneration of adipocytes. The prolonged and persistent reaction would lead to the production of fibrous tissue and result in the formation of fibrous scar tissue and adhesion of the muscles. In our case series, the majority of the lesions were composed of fibrosis and scar tissue formation. I think that tendinosis of the rectus femoris tendon and chronic fibrous degeneration of adipose tissue are major pathologies of patients with recalcitrant anterior hip pain. As with tendinosis of the ECRB in tennis elbow, I assume the same pathology as AIISpinitis, even in the hip joint ,14.The technical and instrumental development of hip arthroscopic surgery enabled us to treat intra-articular pathologies. Most clinicians focus on the acetabular labrum as the target lesion of hip pain. Hip impingement surgery is now common and satisfactory mid-term clinical results have been reported by many institutions . HoweverThis study has several limitations. First, it was a simple observational study with a small sample size. At present, normal anatomy of this periarticular area is not well understood. To confirm my hypothesis, a comparative study with asymptomatic patients is necessary. It is critical to make a preoperative diagnosis of the injury of the direct heads of rectus femoris muscle. However, MRI cannot detect it clearly. This is also a limitation of this manuscript. The establishment of the MRI imaging method to detect the tendinosis of the direct head of rectus femoris muscle is mandatory. Due to the very short follow-up periods, it is premature to decide the clinical effectiveness of periarticular debridement for the management of groin pain. Therefore, I have no intention to argue this point. Even if these are very early results, however, the fact that hip pain was relieved soon after the operation can provide strong evidence for the determination of extra-articular pathologies being responsible for groin pain. I think this is a strong point of this manuscript.Rectus femoris tendinosis, subacute /chronic fibrosis of the fat pad and muscle adhesion are common extra-articular pathologies in patients with anterior hip pain. In addition, management of these lesions results in rapid relief of the hip pain. Current observations suggest that it is desirable to be aware of the presence of periarticular pathologies as a cause of groin pain.S1 MovieThin layer of fat tissue was normally exists on the AIIS and anterior joint capsule.(MP4)Click here for additional data file.S2 MovieNormal fat fad), blood vessel-rich adipose tissue, fat pad with septal fibrosis, fat pad replaced by fibrous scar were shown.(MP4)Click here for additional data file.S3 MovieAdhesion between anterior joint capsule and gluteus muscles, rupture of direct head of rectus femoris muscle at the insertion to AIIS, neovascularized mature fat tissue between rectus femoris muscle and iliocapsularis muscle and Iliopectoralis bursitis were shown.(MP4)Click here for additional data file.