To measure the effects of real-time visualisation during urethrocystoscopy on pain in patients who underwent ambulatory urethrocystoscopy.An observational study was designed. From June 2012 to June 2013 patients who had ambulatory urethrocystoscopy participated in the study. In order to measure pain perception we used a numeric rating scale (NRS) 0 to 10. Additional data was collected including gender, reason for intervention, use of a rigid or a flexible instrument and whether the patient had had urethrocystoscopy before.185 patients were evaluated. 125 patients preferred to watch their urethrocystoscopy on a real-time video screen, 60 patients did not. There was no statistically relevant difference in pain perception between those patients who watched their urethrocystoscopy on a real-time video screen and those who did not (p = 0.063). However, men who were allowed to watch their flexible urethrocystoscopy experienced significantly less pain, than those who did not (p = 0.007). No such effects could be measured for rigid urethrocystoscopy (p = 0.317). Furthermore, women experienced significantly higher levels of pain during the urethrocystoscopy than men (p = 0.032).Visualisation during urethrocystoscopy procedures in general does not significantly decrease pain in patients. Nevertheless, men who undergo flexible urethrocystoscopy should be offered to watch their procedure in real-time on a video screen. To make urethrocystoscopy less painful for both genders, especially for women, should be subject to further research. Pain relief is one of the most important tasks of every doctor. It is one of the most common reasons for consultation and a basic skill of the medical profession. Therefore, pain relief is something patients expect from their doctors. Unfortunately, it is also one of the most complicated tasks and often the best medical practice requires procedures that are not only uncomfortable, but inflict pain.One such a procedure is the urethrocystoscopy. It is not invasive enough to justify the risk of complete anaesthesia but also too uncomfortable to be not taken seriously. As a frequently used tool in diagnosis and a treatment of various urological conditions such as bladder carcinoma, tumour infiltration and haematuria, the significance of urethrocystoscopies in everyday urological practice has increased .Various attempts have been made in the past to make urethrocystoscopy less painful. The biggest achievement in patient comfort probably presents the invention of the flexible urethrocystoscope. Before, men and women alike were examined with a rigid instrument. Due to gender related anatomical differences rigid urethrocystoscopy on men was quite painful . This chOver the past few years evidence occurred that patients might benefit from watching their urethrocystoscopy real-time on a video screen –11.Up to now only specific parts of the patient population were investigated. Men who were to undergo flexible urethrocystoscopy and women who had rigid urethrocystoscopy. Results of previous studies show –11, thatWe generated a prospective observational study in everyday clinical practice to measure the pain patients experienced during urethrocystoscopy while visualising the procedure on a real-time video screen compared with the pain patients who did not visualise their procedure experienced. The aim was to test whether visualisation aided in increasing patient comfort during urethrocystoscopy.We expected that distraction would decrease the level of pain patients experienced during the procedure .To access the differences in pain perception between patients who were able to watch their urethrocystoscopy real-time on a video screen and patients who were not, we conducted a prospective observational study. Our aim was to stay as close as possible to everyday clinical practice to provide a clear image of patients’ pain perception in an everyday clinical setting. Everyday clinical practice is influenced by many different factors which have to be eliminated in a randomised controlled trial. Therefore what has been evaluated in a randomised controlled study cannot necessarily be applied to everyday clinical practice. Hence, we decided not to randomise our study. As the study was done to investigate clinical data of patients treated solely at our institution, and data obtained was anonymized concurrently, approval of the local ethics committee  was therefore not required according to the German Ethics Committees regulations.The patient population consisted of all patients who underwent an ambulatory urethrocystoscopy from June 2012 to June 2013 in the urological outpatient clinic of the Department of Urology and Paediatric Urology at the university hospital of Marburg. Exclusion criteria were the necessity of systemic or local anaesthesia and the use of sedatives or analgesics other than Instillagel®. In total 185 patients were included.The procedure patients received was not randomized. They could choose whether they wanted to visualise the procedure on a real-time video monitor along with the urologist or whether they preferred not to.Pain perception and pain control depend on various factors and differ greatly between individuals . To takeThe urethrocystoscopy was performed according to the standardised scope technique of the Department of Urology and Paediatric Urology of the University hospital, Marburg. The procedure was performed in lithothomy position. Pelvis and legs were covered and anus and genitals were disinfected. For rigid urethrocystoscopy Storz, Wolf or Olympus 70/120° instruments were used and the flexible urethrocystoscopy was also performed with Storz, Wolf and Olympus instruments.Instillagel® was applied 10 min before the procedure as recommended in recent studies . In maleIn order to avoid limitations in our results based on the skill of a single urologist, the urethrocystoscopy was performed by different urologists. Therefore interindividual differences in technique and skill were taken into account, as they are a part of everyday clinical practice.After the procedure patients were asked by the attending nurse to quantify their pain on a numeric rating scale (NRS) from 0 to 10. 0 was defined as no pain, 1–4 mild pain, 5–7 moderate pain and 8–10 as severe pain .p value of < 0.05 was considered statistically significant.Additional data was collected including the patients gender, reasons for intervention, the use of a rigid or flexible instrument, whether the patient had had urethrocystoscopies before and what kind of instrument was used. Furthermore we assessed whether patients thought themselves to be sensitive to pain or no. All data was computerised on Microsoft Excel® 2013  and analysed with IBM SPSS® Statistics for Windows Version 22  using the Mann – Whitney – U – test. A 185 patients were evaluated (age 17 to 91 years). The mean age of the 44 female patients was 59 years (17 – 91 years). The mean age of the 141 male patients was 65 years (26 – 89 years). 125 patients (66 %) wanted to follow their urethrocystoscopy in real – time on video with the urologist, 60 (34 %) patients preferred not to. 131 had flexible urethrocystoscopies. 91  of these patients watched their procedure real-time and 40  did not. Of the 54 patients who underwent rigid urethrocystoscopy 34 (63 %) wanted to watch the procedure on the video screen and 20 (37 %) did not. 105 (55 %) patients had undergone an urethrocystoscopy before and for 80 (45 %) patients it was the first time they had had the procedure. Patient data is summarised in Table The median value on the numeric rating scale was 2  for patients who watched their procedure in real-time on a video screen and 3  for those who did not without statistical difference  vs 3.5 , p = 0.007; see Fig. When using the rigid urethrocystoscope no significant differences could be shown.Experience with the procedure proved to be significant in pain perception. Patients who had had the procedure before had significantly less pain (p < 0.005). Women who had had experience with urethrocystoscopy still had significantly more pain than their male counterparts (p = 0.031). Pain perception was not significantly lower in patients with experience who watched the procedure than in those who did not (p = 0.165).Of the 127 patient who had flexible urethrocystoscopies only 2 (1.6 %) were women. Therefore, no valid results could be obtained about the benefit of real-time visualisation in women who had flexible urethrocystoscopies. In contrast, 41 patients who had rigid urethrocystoscopies were women  and 14 were men.Analysed separately women who could watch their rigid urethrocystoscopy on a real-time video screen did not feel significantly less pain than women who did not . No valid results could be obtained regarding men who had rigid urethrocystoscopies, as only two men decided not to watch their urethrocystoscopy.Female patients  had significantly more pain than male patients  during urethrocystoscopies (p = 0.032, see Fig. In our observational study we investigated the differences in pain during urethrocystoscopy between patients who could watch their procedure on a real-time video screen and patients who could not in an everyday clinical setting. We found that only men who underwent flexible urethrocystoscopy and wanted to watch their procedure on a real-time video screen perceived their urethrocystoscopy as significantly less painful. For other patients this effect was not observed. Furthermore, women who underwent urethrocystoscopy have significantly more pain than men.To our knowledge only a few studies so far have examined the impact of real – time visualisation on pain perception during urethrocystoscopy. Clement et al.  conducteSo far only Clements et al.  showed tA number of differences between the randomised controlled studies and this observational study make direct comparison difficult.First, in our study we used a numeric rating scale 0 to 10 to measure perceived pain. Patel et al. used a 100 mm visual analogue scale in both of his studies , 15. CleSecond, inclusion and exclusion criteria were different in the studies mentioned. In order to best approximate everyday clinical practice our exclusion criteria were broadly defined as the use of general or local anaesthesia and analgesics. In the other studies exclusion criteria were more narrowly defined , 14, 15.Third, different numbers of urologists performed urethrocystoscopies on the included patients. In Soomro study and our study more than one urologist performed the urethrocystoscopy, so that the results would not be limited to the skill of one person . In ClemThe greatest limitation of our study is that it was not randomised. Patients could choose whether they wanted to observe their own urethrocsytoscopy or not. Pain is a very subjective parameter. Therefore, it is difficult to assess and to generalise . We trieOur data showed that visualisation on a real-time screen does not make urethrocsytoscopy less painful for patients in general. Kesari et al. investigated the role of visualisation on a real-time video screen with thorough explanation during the procedure . In thisFocusing on flexible urethrocystoscopies our results confirm the results found by Clements et al., Patel et al., Soomro et al. and Zhang et al. –11. Men In our patient cohort only 2 women had flexible urethrocystoscopy. Therefore based on this data no assumptions can be made about the effect real time visualisation has on pain during flexible urethrocystoscopy on women. This might be due to the recommendations regarding flexible urethrocystoscopy on women based on the recent findings of Gee et al. and Quiroz et al. , 20. TheCornel et al. found that patients who had experience with urethrocystoscopy did not find it more comfortable than those who had not . We founIn regard to pain prevention in urethrocystoscopy three valuable conclusions can be drawn from this study. First, men who undergo flexible urethrocystoscopies should be offered to watch their procedure in real – time on video along with the urologist. If they agree to watch they will benefit from their decision. Second, more effort should be put into making urethrocystoscopy more comfortable for women, especially because female patient’s pain threshold might be lower than the pain threshold of male patients . It is tNew efforts should be made to improve patients’ comfort level during urethrocystoscopy procedure. An example of such efforts can be found in the new observations made by Yeo et al. and Zhang et al. who found that using music to help patients relax during urethrocystoscopy may lead to benefical results , 24.


Refractory chronic migraine (rCM) is a debWe analyzed 76 patients (64 F), mean age 52 years (23-82 yr) with rCM referred to the RRCCD of the Careggi Hospital, between 2011-2014. The patients were treated (after informed consent) with OnabotA injection in 31/39 sites at the total dosage of 155/195U every 3 months, according to the PREEMPT protocol. The frequency of headache days (F), intensity of pain (I) and the consumption of drugs (D) were measured using a Headache Diary. Two groups of patient were identified by the type of pain reported: type 1  and type 2 [All 76 patients received the toxin treatment at least four times (a one-year follow-up). Of these 44/76 responded to treatment (38 F). The parameters F, I, D showed a progressive and gradual decline with time (p 0.001 for each variable), reaching the maximum effect from the fourth treatment. The F and D were statistically significantly reduced in both groups, more in patients with type 1 pain (p < 0.001), while the I group was found to ameliorate without a difference between the different pain type groups. There were no changes for age, sex and menstrual cycle. Only one patient (1.3%) dropped out of the study because of neck pain.In our four years of follow-up study a high percentage of rCM patients (58%) showed an improvement in the quality of life with a reduction of F, I and D. The kind of pain in migraine patients affects the efficacy of the treatment itself, and is more successful in patients with type 1 pain in respect to patients with type 2 pain. OnabotA is a safe treatment, well tolerated and effective as a prophylactic treatment in rCM.Written informed consent to publication was obtained from the patient(s).


Lumbosacral radicular syndrome (LRS) is a self-limiting, benign, painful and impairing condition caused by lumbar disc herniation and inflammatory processes around the nerve root. Segmental epidural steroid injections (SESIs) are helpful to reduce radicular pain on a short-term basis. It is unknown whether SESIs are an effective addition to usual pain treatment of LRS in general practice. In our study, we assessed the effectiveness of SESIs on pain and disability as an addition to usual care for acute LRS in general practice.A pragmatic, single-blinded, randomized controlled trial in Dutch general practice was conducted. Circumstances of daily practice were closely followed. Care as usual (CAU) was compared to care as usual combined with an additional SESI in 63 patients in the acute phase of LRS. To detect a minimal clinically important difference of 1.2 points on a numerical rating scale for back pain and a common within-group standard deviation of 1.7 with a two-tailed alpha of 0.05 and a power of 0.80, we needed 33 subjects in each group. Statistical analysis was carried out using mixed models.A small significant effect in favour of the intervention, corrected for age, sex and baseline values, was found for back pain, impairment and Roland-Morris disability score. The differences, though statistically significant, were too small to be considered clinically relevant. Patients from the intervention group were significantly more satisfied with the received treatment than patients from the control group.We found a small, statistically significant, but not clinically relevant positive effect of SESIs on back pain, impairment and disability in acute LRS. We do not recommend implementing SESIs as an additional regular treatment option in general practice.The online version of this article (doi:10.1186/1471-2474-15-341) contains supplementary material, which is available to authorized users. Lumbosacral radicular syndrome (LRS) is defined as pain, radiating from the back into the leg, (“sciatica”) in combination with Lasègue’s sign and/or neurological symptoms originating from a single nerve root. In the Netherlands, LRS is treated by general practitioners (GPs) who adhere to the Dutch College of General Practitioner’s Guideline on LRS. According to this guideline, treatment of LRS consists of pain treatment by taking analgesics as needed, and maintaining normal daily activities as much as possible. The prognosis of LRS is favourable: within eight weeks, 80% of patients have reached bearable pain levels and resumed their work . Some paLRS is most commonly caused by protrusion of a lumbar intervertebral disc, which results in an inflammatory response around the nerve root , 4. ThisEfficacy of SESIs in LRS is controversial. Some studies are underpowered, others lack methodological quality to justify definite conclusions , 9–12. ISince patients in the acute phase of LRS are cared for by GPs, SESIs are a possibly useful treatment option in general practice. Most RCTs, however, have been conducted to assess efficacy rather than effectiveness , in specialist practice, in heterogeneous patient groups, with a short-term follow-up and using a single measuring moment. To our knowledge, no study has assessed effectiveness in general practice, with multiple measuring points and a long term follow-up, in a homogeneous patient group. We assessed the effectiveness of adding SESIs to usual pain treatment for patients with acute LRS in general practice, by means of a pragmatic randomized controlled trial measuring pain, disability and recovery in acute LRS patients with profound sciatica.st 2005 and December 31st 2007 and followed for one year. This study was approved by the Medical-Ethical Committee of the University Medical Center Groningen in 2005, code 2005/154, and was registered in the Dutch trial register as SLURP, code NTR342. This study was funded by the UMCG, there was no additional funding from external sources.Our trial took place in and around the city of Groningen, the Netherlands, in 41 general practices with 76 participating GPs. Patients were recruited between January 1Our research question calls for a pragmatic study design, which demands that real life conditions are followed as closely as possible. Usual care was therefore not standardized but defined as the treatment decided on by the patients and their GPs. Since Dutch GPs generally adhere to the Dutch College of General Practitioner’s guidelines, usual care consisted of advice and analgesic medication and/or referral as needed , 23. TheInclusion criteria were a diagnosis of LRS established by the GP, complaints of LRS for at least two weeks and no more than four weeks duration and patient age between 18 and 60 years. The upper age limit of 60 was chosen because complications of epidural injections are more common in the over 60 age group, due to osteoporosis. Exclusion criteria were a history of spinal surgery or spinal trauma, maintenance therapy with corticosteroids or anticoagulants, bleeding disorder, cauda equina syndrome, a body mass index of more than 35, inadequate mastery of the Dutch language, allergy to corticosteroids, pregnancy or an active wish to become pregnant, breastfeeding and mental disability. Patients with insulin-dependent diabetes mellitus were not excluded but instructed to measure their serum glucose levels regularly in the 48 hours after the intervention.Patients in whom the GP established the diagnosis of LRS were given written information on the study, a baseline symptom questionnaire and an informed consent form. Patients were asked to complete the questionnaire and the informed consent form and send them to the research centre. Upon receiving this information, subjects were contacted by the primary researcher to check inclusion and exclusion criteria with a protocolled inclusion form. In the absence of exclusion criteria, the inclusion form was completed.Randomization was performed by an independent colleague with no further involvement in the study. Pre-prepared, sequentially numbered, opaque, sealed envelopes containing stickers labelled either “SESI” or “CAU”, balanced after 40 assignments, were used. Upon randomisation, the consecutive envelope was opened and the sticker with the allocated treatment was fixed on the completed inclusion form. Inclusion forms, containing personal patient information, were coded and kept separately from follow-up questionnaires. To keep the primary researcher blinded until after the final analysis of the results, follow-up questionnaires were provided with the same codes but contained no personal patient information.Patients allocated to the intervention group were presented to the department of anaesthesiology of the University Medical Centre Groningen (UMCG). SESIs were administered by a non-involved anaesthesiologist within 48 hours after randomisation. SESIs consisted of 80 milligrams of triamcinolone in 10 millilitres of normal saline and were administered using a lumbar translaminar approach without additional imaging, one level above the presumed LRS in either sitting or lateral position. The skin was anaesthetised with lidocaine, but no local anaesthetics were injected epidurally to avoid problems with mobility and bladder emptying. After the injection, patients were referred back to their GPs for further usual care. When a patient was randomized to the CAU-group the GP provided usual care from the start. The translaminar injection technique without additional imaging, rather than a transforaminal approach with fluoroscopic guidance and administering of local anaesthetics, was chosen because of the pragmatic study design - given the shorter waiting time and better accessibility, the intervention would be applied this way in normal practice as well.Follow-up in both groups was performed using postal questionnaires regarding pain, disability, and satisfaction with treatment, measured at 2, 4, 6, 13, 26 and 52 weeks after the start of the treatment. The 24-point Roland-Morris Disability Questionnaire (RMDQ) was used for measuring disability . For meaPower calculations were based on the NRS back pain score at four weeks from the start of the treatment. A difference in NRS back pain score of 1,2 - 2,0 is considered clinically relevant in primary care attendants with low back pain –32. To mThis study was performed to achieve two goals. The first goal of the study was to test the difference over time between the means of the two treatments. The second goal of the study was to estimate the differences between the means of the two treatments at every time point of measurement. On average, a study of this design would enable us to report the mean difference with a precision (95.0% confidence level) of plus/minus 0.84 points.All analyses were performed using an intention-to-treat basis. Mixed model regression analysis was performed using SAS 9.2 PROC MIXED. No data imputation is necessary using this model . PatientEighty-four patients were presented to us by their GPs, of whom 73 patients were eligible and included in the study. A flow schedule is presented in Figure For the 63 study participants, we sent out 441 questionnaires, of which 408 92,5%) were returned. Means and standard deviations of all variables in both groups for every time point of measurement are presented in Table ,5% were Finally, we found a significant difference in mean patient satisfaction between the two groups. The intervention group rated their treatment 9,0 on a 0 to 10 scale, and the control group rated their treatment 7,2 on a 0 to 10 scale . No complications or adverse effects of the intervention were reported.In this study, SESIs yielded a significant overall effect on RMDQ score, back pain, and self-perceived impairment as an additional treatment for LRS in a pragmatic general practice setting. Small differences between pain severity scores and other outcomes, however, may be statistically significant but clinically trivial. As differences of 1.2 – 2.0 on the NRS and a 30% reduction from baseline (which amounts to 4.5 points in our study) in RMDQ score can be considered clinically important to patients, the effects of our intervention are too small to be relevant –32.The intervention group was significantly more satisfied with their treatment than the control group, rating a mean of 9.0 versus 7.2 on a 0 to 10 scale . As no clinically relevant effect was yielded in our study, the more positive evaluation of the intervention by patients should most probably be attributed to the effect of receiving extra attention and care.Our study is the first pragmatic trial undertaken in general practice, where most patients with LRS are seen and treated in an early stage. It is one of the few studies aimed to assess effectiveness rather than efficacy of SESIs. To our knowledge this has been done only once before, 15 years ago and in a hospital setting . OutcomeThis study has some possible limitations. One is the fact that the intervention group unfortunately differed significantly from the control group in baseline values. Since randomization was adequately performed, we have no explanation for these differences. In the mixed model regression analysis the baseline differences were corrected for by including the baseline values as a covariate. Baseline differences between groups do, however, raise questions about whether those groups are truly comparable. The MCIDs of measuring instruments may vary between categories of baseline severity in symptoms. According to the literature, comparing our groups was allowed , 33. We It can be argued that for our study goals, the RMDQ-score would have been a more appropriate primary outcome measure than the NRS back pain score. We chose back pain for calculating our sample sizes because the MCID of the NRS back pain score is extensively used and well described in primary care back pain patients , 32, 33.No adverse effects of our intervention were reported by our subjects. One of the subjects, however, died during our study period due to Burkitt lymphoma, which initially caused radicular pain. Epidural steroids are known to relief symptoms of spinal cord compression caused by tumors or metastases . It is cPlacebo-controlled double blinded randomized trials have yielded positive results for the efficacy as a pain treatment of SESIs on LRS. Our study shows that the intervention has a significant beneficial effect as an additional treatment in general practice as well. This effect however, is too small to be considered clinically relevant to patients. Although our patient sample was small, we do not recommend that administering SESIs for the pain treatment of LRS be implemented as a regular intervention in general practice. Further research should be aimed at adequately treating pain in patients with acute LRS with other interventions.


Objective: To determine the efficacy of Sustained Natural Apophyseal Glides (SNAGs) with and without Isometric Exercise Training Program (IETP) in Non-specific Neck Pain (NSNP)Methods: This randomized control trial of one year duration was conducted at out-patient department of Physiotherapy and Rehabilitation, Khyber Teaching Hospital (KTH) Peshawar, Pakistan from July 2012 to June 2013. The sample of 102 patients of NSNP were randomly selected through simple random sampling technique, and placed into two groups. The SNAGs manual physical therapy technique with IETP was applied on 51 patients in group A and SNAGs manual physical therapy techniques was applied alone on 51 patients in group B. The duration of intervention was 6 weeks, at 4 times per week. The Neck Disability Index (NDI) and Visual Analog Scale (VAS) for neck pain were assessment tools used for all patients before and after 6 weeks of physical therapy intervention. All the patients were assessed through NDI and VAS before intervention and at the completion of 6 weeks program. The data of all 102 was analyzed by SPSS-20 and statistical test was applied at 95% level of significance determine the efficacy of both the treatments interventions and compare with each other. Results: The patients in group A, treated with SNAGs and followed by IETP for 6 weeks, demonstrated more improvement in pain and physical activity as assessed by VAS (p=0.013) and NDI (p=0.003), as compared to the patients treated with SNAGS alone, as pain and function assessed by VAS (p=0.047) and NDI (p=0.164). In group A the NDI score improved from 40 to 15 and VAS from 7 to 4, while in group B the NDI score improved from 42 to 30 and VAS from 7 to 4. Conclusion: Patients with non-specific neck pain treated with SNAGs manual physical therapy techniques and followed by IETP was more effective in reduction of pain and enhancement of function, as compared to those patients treated with SNAGs manual physical therapy techniques alone. Neck pain is usually felt in the neck, but can be caused by numerous other spinal problems.1 Neck pain affects about 330 million people globally as of 2010 (4.9% of the population). It is more common in women (5.7%) than men (3.9%). It is less common than low back pain.2Neck pain or cervicalgia is a common neuro-musculo-skeletal problem, according to the available statistics with two-thirds of the population having neck cervical vertebrae.3 Joints or muscles problems in the neck causes neck pain, upper back or upper extremity. It is usually diagnosed by physical examination, special orthopedic tests, X-rays, and MRI.4Neck pain may arise due to bad postural, muscular tightness in both the neck and upper back, and pinching of the nerves emanating from the 5 The conservative physical therapy management includes; muscle strengthening, flexibility, and stabilization exercises, mobilization, manipulation, and mechanical traction procedures.6Neck pain can be managed by conservative means including, medication interventional pain management techniques, and surgery. Physical therapy is an important component of conservative management of neck pain and post surgical rehabilitation after neck surgeries.7 The aim of this study was to determine the efficacy of Sustained Natural Apophyseal Glides (SNAGs) with and without Isometric Exercise Training Program (IETP) in Non-specific Neck Pain (NSNP).There are different Mobilization techniques for neck pain, and mulligan’s technique is one of them. It has two techniques Sustain Natural Apophyseal Glides (SNAGS) and Natural Apophyseal Glides (NAGS).This randomized control study of one year duration was conducted at out-patient department of Physiotherapy and Rehabilitation, Khyber Teaching Hospital (KTH) Peshawar, Pakistan from July 2012 to June 2013. The sample of 102 patients of NSNP were randomly selected through simple random sampling technique, and placed into two groups. The study was approved by the institution review committee and a written informed consent was taken from all the study participants at the start of the treatment program.The SNAGs manual physical therapy technique with IETP was applied on 51 patients in group A and SNAGs manual physical therapy techniques was applied alone on 51 patients in group B by a manual physical therapist skilled in both the techniques.The duration of intervention was 6 weeks, at 4 times per week. The follow up of the patients were ensured through telephonic contact and no drop outs were observed during the study. All the patients were assessed through NDI and VAS before intervention and at the completion of 6 weeks program. The data of all 102 was analyzed by SPSS-20 and statistical test was applied at 95% level of significance determine the efficacy of both the treatments interventions and compare with each other.All 102 patients of non-specific neck pain, in both the groups had four weeks of physical therapy intervention. The patients in group A, treated with SNAGs and followed by IETP for 6 weeks, demonstrated better improvement in pain and physical activity as assessed by VAS (p=0.013) and NDI (p=0.003), in comparison to the patients in group B treated with SNAGS alone, VAS (p=0.047) and NDI (p=0.164). In group A the NDI score improved from 40 to 15 and VAS from 7 to 4, while in group B the NDI score improves from 42 to 30 and VAS from 7 to 4. 9The results of this study demonstrated that the SNAGs and followed by IETP can better manage pain and disability as compared with the SNAGs alone in the management of Non-specific Neck Pain (NSNP). Brosseau and colleagues developed evidence-based clinical practice guidelines on therapeutic massage for neck pain on Ottawa panel and suggested that a multi-modal management strategy using mobilization or manipulation plus exercise is beneficial for relief of mechanical neck pain. Weaker evidence suggests less benefit to either manipulation/mobilization or exercise therapy done alone. This study strongly supports the result of our study.10Bronfort and team conducted a randomized control trial to determine the relative efficacy of spinal manipulation therapy (SMT), medication, and home exercise with advice (HEA) for acute and sub-acute neck pain in both the short and long term. They concluded that for participants with acute and sub acute neck pain, SMT was more effective than medication in both the short and long term. However, a few instructional sessions of HEA resulted in similar outcomes at most time points.11Tsakitzidis and colleagues carried out a systematic review to review  the literature published on interventions for NS-NP and provide advice for health care providers to make evidence-based treatment decisions and to optimize their delivery of care for diagnosing, treating and managing adults with NS-NP. The history taking, excluding red flags and radicular pain/radiculopathy and assessing self-rated disability was deemed crucially important prior to selecting management and treatment modalities for NS-NP. They concluded that the evidence based practice is a multimodal approach including Manipulation/mobilization and supervised exercises.12 Miller and colleagues carried out a systematic review on Manual therapy and exercise for neck pain and concluded that Moderate quality evidence supports this treatment combination for pain reduction and improved quality of life over manual therapy alone for chronic neck pain.13Gross and colleagues conducted a systematic review on Manipulation or mobilization for neck pain to determine the, and concluded that both the techniques had the same effects in neck pain.14Leaver and colleagues conducted a randomized control trial on comparing manipulation with mobilization for recent onset neck pain and based on their results they concluded that the neck manipulation is not appreciably more effective than mobilization. The use of neck manipulation therefore cannot be justified on the basis of superior effectiveness.Patients with non-specific neck pan treated with SNAGs manual physical therapy techniques and followed by IET is more effective in reduction of pain and enhancement of function, as compared to those patients treated with SNAGs manual physical therapy techniques alone.AA and SSR: Conceived, designed and did statistical analysis & editing of manuscript.AA, SSR, and FS: Did data collection and manuscript writing.SSR: Did review and final approval of manuscript.


Cryotherapy is the most common non-pharmacological pain-relieving method. The aim of this pilot study was to ascertain whether intranasal evaporative cooling may be an effective intervention in an acute migraine attack. Studies have previously demonstrated effectiveness of a variety of cryotherapy approaches. Intranasal evaporative cooling due to vascular anatomy, allows the transfer of venous blood from nasal and paranasal mucous membranes to the dura mater, thereby providing an excellent anatomical basis for the cooling processes.We conducted a prospective, open-label, observational, pilot study. Twenty-eight patients who satisfied the International Classification of Headache Disorders (ICHD 2) diagnostic criteria for migraine were recruited. A total of 20 treatments were administered in 15 patients. All patients provided pain severity scores and migraine-associated symptoms severity scores .Out of the 20 treatments, intranasal evaporative cooling rendered patients’ pain and symptoms free immediately after treatment, in 8 of the treatments (40%), a further 10 treatments (50%) resulted in partial pain relief (headache reduced from severe or moderate to mild) and partial symptoms relief. At 2 hours, 9 treatments (45%) provided full pain and symptoms relief, with a further 9 treatments (45%) resulting in partial pain and symptoms relief. At 24 hours, 10 treatments (50%) resulted in patients reporting pain and symptom freedom and 3 (15%) provided partial pain relief. In summary 13 patients (87%) had benefit from the treatment within 2 hours that was sustained at 24 hours.Intranasal evaporative cooling gave considerable benefit to patients with migraine, improving headache severity and migraine-associated symptoms. A further randomised, placebo controlled, double blinded, parallel clinical trial is required to further investigate the potential of this application.NCT01898455.Clinicaltrials.gov registered trial, ClinicalTrials.gov Identifier:  Mechanical techniques to alleviate migraine symptoms have been used for many years, cooling and compression being the most frequently applied. Cryotherapy is the most common non-pharmacological self-administered pain-relieving method currently used by migraine sufferers . The firNeurovascular mechanism: Application of cold induces vasoconstriction with subsequent decreased downstream blood flow [ood flow , 10. Thiood flow , 12.Pain gating by differential effect on nerve conduction: Cryotherapy induces analgesia by slowing nerve conduction velocity, with small myelinated fibers being affected first, followed by large myelinated fibers and the unmyelinated fibers being affected last [ted last , 14. Viated last , 16.Metabolic mechanism: Cryotherapy decreases metabolic and enzymatic activity, due to reduced demand for adenosine triphosphate (ATP) and oxygen [d oxygen .Transient Receptor Potential (TRP) channels: Recent studies suggest that TRP channels may have a role in headache and pain genesis due to their response to environmental stimuli such as temperature changes [ changes .Several pathophysiological mechanisms of action have been proposed. These mechanisms include:The nasopharynx provides a large diffuse surface area that is highly vascular. Cooling via the nasopharynx therefore offers the ability to cool across the thin cribriform plate via both direct conductive mechanisms that do not rely on spontaneous circulation as well as indirect haematogenous mechanisms. Numerous subarachnoid and pial arterial branches exposed to the cerebrospinal fluid (CSF) have diameters in the range of the vessels of the retia mirabilia of animals in which selective brain cooling has been clearly established experimentally . VasculaThe aim of this study was to ascertain whether intranasal evaporative cooling might be an effective and safe intervention in acute migraine treatment.© intranasal cooling system for the acute relief of migraine in an adult population, through short periods of intranasal cooling.This study is an investigator-initiated clinical trial, investigating the effectiveness of the RhinoChillWe conducted a single-centre, prospective, open-label, observational, pilot study. Participants were enrolled from October 2013 to July 2014, from the outpatient clinics of the Neurology Department, Cumbria Partnership NHS Trust, and through a community engagement advertising campaign.Study design consisted of a screening visit or phone call, baseline visit, minimum of one treatment and a follow-up phone call at 2 and 24 hours after each treatment. The principle of the intranasal cooling, procedure and safety aspects of the intervention were explained to each of the participants.The study participants were otherwise healthy adults who met ICHD 2 diagnostic criteria for episodic migraine with or without aura, or chronic migraine and were capable of giving informed consent. Exclusion criteria included history of any current co-morbid illness or difficulty with insertion of the nasal cannula due to congenital anatomical narrowing of the nasal passages.© Intranasal cooling device is a portable unit consisting of a control unit, a disposable nasal catheter and a 1-liter bottle of coolant. The device requires a supply of oxygen or medical air to drive the evaporation process of the coolant. The 10 cm long intranasal catheters have spray ports on the dorsal surface to distribute coolant into the nasal cavity, upwards towards the base of the skull , a six-chain perfluorocarbon. PFH is a colorless, odourless, radiolucent liquid. PFH belongs to a class of perfluorocarbon fluids that are fully fluorinated with no functional reactive groups. They do not oxidize or hydrolyze and are thus chemically and biologically inert. They cannot undergo biological oxidation-reduction reactions to form reactive aldehydes, acid fluorides, radicals, or other acids. Since PFH does not react directly with biological tissue, they can form no reactive metabolites. PFH surface tension is lower than water so it will spread uniformly and quickly throughout the space in which it is sprayed. These properties facilitate RhinoChill coolant dispersion to the large diffuse surface area of the nasal cavity to maximize cooling.Evaporation of the coolant provides rapid cooling to the nasal cavity of approximately 2°C, absorbing heat through evaporation and cooling local structures through direct conductive mechanisms and indirect haematogenous mechanisms. Safety of the device has been established in the cardiac arrest population where it has been used to induce rapid brain cooling for therapeutic hypothermia as neuroprotection , 22. In This trial was a feasibility study. To ensure patient safety, participants attended the hospital Day Case Unit during a migraine attack, to obtain their treatment under medical supervision. At onset of a migraine attack, the patient would contact the trial researcher and come into the hospital for treatment. On arrival, baseline observations were taken including infrared tympanic thermometry, non-invasive blood pressure (NIBP), pulse and oxygen saturation. Migraine pain severity was assessed using a visual analogue scale , which was extrapolated to provide a categorical scale of pain intensity using the Glaxo-scale of Severe, Moderate, Mild and None. The use of both scales allow for comparison with other published literature regarding non-pharmaceutical and pharmaceutical approaches to acute migraine treatment. The associated migraine symptoms  were also scored using VAS, whereby the patient provided a subjective composite score regarding the overall severity of their combined associated symptoms.Following confirmation of an acute migraine attack, treatment was commenced. Lubricated nasal cannulae were inserted into both nostrils. If full insertion proved intolerable then a shallow insertion only  was completed. A maximum of 20 minutes of cooling was provided with predetermined early stoppage if there was full relief of pain or at the participant’s request due to discomfort.Migraine pain severity score, tympanic thermometry and NIBP, as well as pain and discomfort associated with the cooling device, was measured every 5 minutes throughout the treatment. Immediately after treatment was terminated, 2 hours post treatment and at 24 hours after treatment, pain severity and migraine-associated symptom composite scores were recorded. The participants were required to stay within the unit for a minimum of 1 hour following their treatment as a safety precaution. The patient was then phoned at 2 hours to enable recording of a migraine pain and symptom severity score.The primary endpoint for this study was the reduction of pain and associated symptoms from baseline assessment, just after the treatment, at 2 and 24 hours post-treatment. Secondary endpoints were tolerance to RhinoChill cooling during treatment, pain and discomfort levels due to the cooling procedure itself, and adverse events noted throughout the treatment phase and during follow up.T-test and the χ2 test, where p < 0.05 would be considered significant. Shapiro-Wilks and Friedman’s non-parametric test were used to test the validity of the pain and symptom severity VAS scores.Data were analyzed using SPSS version 20.0 using paired sample The study protocol was approved by the NRES Committee North West - Lancaster Ethics Committee. This study is registered at clinicaltrials.gov (NCT01898455). All participants provided written consent before taking part.Trial registration: Clinicaltrials.gov registered trial, ClinicalTrials.gov Identifier: NCT01898455.Data are presented as an extended case series with qualitative data to support the acceptability aspects of the nasal cooling in migraine treatment. Data analysis was performed ‘per treatment’ due to the variation of treatment numbers received by the patients in the trial. However, overall treatment response per patient is also described.Twenty-eight adult patients were recruited into the trial of whom 15 patients received one or more treatments, providing 20 treatments in total. Eleven patients had a single treatment, while 3 patients had 2 treatments and 1 patient had 3. All patients were reviewed on entry to the clinic when they attended for treatment and asked about their current frequency of migraines. The most common reasons for lack of repeated treatments was due to migraines occurring outside of the operating hours of the trial, as well as inability to travel due to severity of migraine, not being able to leave work and having difficulty with childcare arrangements. The 13 patients who did not receive a treatment stated that they had migraines at times that were out-of-hours offered by the trial centre. The cohort comprised 12 (80%) female and 3 (20%) male patients, with mean age of 43 years (range 29–66 years). When asked about the normal duration of headache with standard medication and treatments, 14 (93%) patients stated that their headaches usually lasted longer than 24 hours after onset (Table All patients provided pain severity scores as well as a migraine-associated symptoms severity scores (single composite score) based on the visual analogue scale. This occurred on arrival to the department, throughout the treatment, immediately at the end of the treatment, at 2 and 24 hour post treatment. Results for pain scores and migraine-associated symptom severity scores are shown in Figures Out of the 20 treatments provided to patients in this trial, intranasal evaporative cooling rendered patients’ pain and symptoms free immediately after treatment in 8 of the treatments (40%). A further 10 treatments (50%) resulted in partial pain relief (headache reduced from severe or moderate to mild) and partial symptoms relief. At 2 hours, 9 treatments (45%) provided full pain and symptoms relief with a further 9 treatments (45%) resulting in partial pain and symptoms relief. At 24 hours, 10 treatments (50%) resulted in patients reporting pain and symptom freedom. Of those treatments remaining, 3 (15%) provided partial pain relief. Relapse of migraine after a period of relief occurred in 5 (25% of treatments). Two treatments (10%) did not respond to intranasal cooling.When examining data on a ‘per patient’ basis rather than ‘per episode’, using mean scores for those patients who had one or more treatments and with the classification of treatment response as being a reduction in pain severity from severe/moderate to mild/none 13 patients (87%) had a positive treatment response to Intra-nasal cooling at two hours post-treatment that was sustained at 24 hours.Comparing the group of patients suffering from chronic migraine (n = 7) with episodic migraine (n = 8), no difference was seen in treatment response rate albeit that the small numbers involved do not allow any firm conclusions to be drawn on any differences that there may be between treatment response in episodic and chronic migraine patients.Reduction in both pain severity score and migraine-associated symptom severity score from baseline to each time point was statistically significant (p ≤ 0.001) representing a consistent downward trend in both pain and symptoms score.Shapiro-Wilks test were carried out to test the validity of the pain and symptom severity VAS scores. For the pain and symptom severity score the distribution became less normal over time as the scores tended towards zero .When looking at mean arterial pressure across all treated migraine episodes (n = 20), the difference between baseline mean arterial pressure (MAP) and 10 minutes into treatment as well as baseline MAP and immediately after treatment are both significantly different . As catheter insertion depth is decreased, the difference between MAP readings also starts to decrease Figure . MAP forAdverse events recorded are listed in Table Early termination due to side effects was required in 5 treatments. This included discomfort due to excess non-evaporated coolant dripping out of the nose (two), discomfort/pain related to nasal catheter placement (two), in one case together with transient hypertension, and one episode of mild epistaxis . In four of these episodes, despite early termination, the patients still recieved a treatment benefit. Out of those patients who terminated early, 3 out of the 5 stated that they would use the device again if it was available within the NHS.All side effects were mild and subsided spontaneously, without need for further treatment. No treatment related side effects were reported at the 24 hour follow up call.This pilot trial demonstrated a significant therapeutic effect with intranasal evaporative cooling as an acute treatment for migraine. The study findings suggest that intranasal cooling rapidly relieves pain as well as migraine-associated symptoms.Migraine is considered to be a neurovascular disorder. Even though the event initiating the actual migraine attack remain unknown, activation of the trigeminovascular system is considered to play an essential role in pathophysiology of the migraine attack . We beliThe effect of cooling might have impact on metabolic and enzymatic activity, albeit it is not clear what the mode of action is which impacts on the release of local neuropeptides.Recent studies indicate that Transient Receptor Potential (TRP) channels may have a role in the headache and pain genesis due to their response to stimuli such as temperature, changes in osmolality, pH and environmental products , 24, 25.Intranasal cooling might have had a stimulating effect on TRP channels, likely in antagonistic inhibitory way for TRPV1, TRPA1, and possibly as an agonist on TRPM8 channel.Other inhibitory factors such as differential alteration of nerve conduction velocities mediated its effect via gate control mechanism, might have played a part in the process leading to the pain and symptoms termination.A vasoconstrictor response of brain vessels to 100% oxygen inhalation has been known for decades. In patients with acute hemispheric infarction, regional vasoconstrictor responsiveness to 100% oxygen inhalation was decreased . Whilst The coolant, a non-ozone depleting six chain perflurocarbon, perfluorohexane (PFH), does not oxidize or hydrolyze and cannot undergo biological oxidation-reduction reactions to form reactive aldehydes, acid fluorides, radicals, or other acids. Since it does not react directly with biological tissue, and cannot form reactive metabolites or react with receptors, or channels, so we anticipate PFH doesn’t have any direct benefit in the migraine treatment, other than acting as a coolant.The therapeutic effect of intranasal evaporative cooling was not diminished by the shallow insertion of catheter, nor impacted by premature termination of the treatment. With respect to the duration of the treatment and depth of the nasal catheter insertion, further evaluation is required involving a study with a larger number of participants.Our trial highlighted the importance of a non-pharmacological approach. Further trials to examine a non-pharmacological approach are warranted.We acknowledge that a major limitation of this study is the small sample size and lack of a control group. A further randomized, placebo controlled trial is therefore essential to confirm the effectiveness of intranasal cooling as an acute treatment in migraine.In conclusion we found that there is a therapeutic effect from intranasal evaporative cooling in patients with migraine, giving benefit on headache as well as accompanying migraine symptoms to 13 patients (87%) at 2 hours post-treatment; even though this was an in-hospital treatment with a device and thus the placebo effect may be pronounced.This study did not reveal any significant or severe side effects. Nasal cooling was well tolerated by majority of the participants and we found that nasal cooling was safe to use for this indication.While these results are promising, a randomized placebo controlled, double blinded trial is needed to confirm the efficacy of intranasal cooling as an acute treatment in migraine. Further studies will also be required to clarify the mode of action of this therapeutic intervention.


Chart abstracted data was obtained from 166 patients seeking care in a family medicine clinic. Depression was measured by the PHQ-9 and opioid misuse was measured using the Current Opioid Misuse Measure. Pain severity and interference questions came from the Brief Pain Inventory. Cross-tabulations were computed to measure the association between depression and opioid misuse stratified on pain location. Exploratory logistic regression modeled the association between depression and opioid misuse after adjusting for pain location and pain severity and interference. Depression was significantly associated with opioid misuse in CPOL but not in CLBP. Regression results indicate pain interference partly accounts for the depression–opioid misuse association. These preliminary results from a small patient sample suggest depression may co-occur with opioid misuse more often in CPOL than in CLBP. Further research is needed to compare this comorbidity in specific pain diagnoses such as arthritis, fibromyalgia and CLBP.Patients with chronic pain and depression are more likely to develop opioid abuse compared to patients without depression. It is not known if this association differs by pain location. We compared the strength of association between depression and opioid misuse in patients with chronic low back pain (CLBP)  Patients with comorbid chronic pain and depression are more likely to receive a longer duration of opioid treatment at higher doses and are more likely to develop opioid abuse compared to non-depressed patients ,2. To ouThus, this limited literature provides some evidence that CLBP is associated with more depression and psychological distress than other pain types with the exception of fibromyalgia when data are obtained from patient populations. Given the strong association between opioid misuse and depression, we hypothesized that patients with CLBP would have a higher prevalence of depression and opioid misuse and this association would be stronger in CLBP than in patients with Chronic Pain of Other Location (CPOL).vs. those with CPOL; and (2) the association between depression and risk of opioid misuse differed in patients with CLBP vs. those with CPOL.We computed exploratory analysis to determine if: (1) the prevalence of depression and risk of opioid misuse differed among patients with CLBP Data for this cross-sectional study were obtained from a retrospective chart review of 166 chronic pain patients receiving pain management services at an academic family medicine clinic between January 2013 and December 2014. As part of routine care, patients presenting to the service completed the Brief Pain Inventory (BPI), Patient Health Questionnaire-9 (PHQ-9) and the Current Opioid Misuse Measure (COMM) at each visit. Data from initial clinical encounters were abstracted into an anonymized data set for the present study. After removing patients with missing data on any variable, the analytic data file contained 122 patients.Pain conditions: From 22 primary pain diagnoses, we created a binary variable indicating the patient had CLBP, (n = 61) or CPOL (n = 61). Conditions among the CPOL group were osteoarthritis (n = 18), cervicalgia (n = 10), fibromyalgia (n = 7), migraine (n = 6), rheumatoid arthritis (n = 4), neuropathic pain (n = 4), HIV neuropathy (n = 2), avascular necrosis of the hip (n = 2), temporomandibular joint pain (n = 1), osteogenesis imperfecta (n = 1), lymphedema (n = 1), lower extremity trauma (n = 1), diffuse idiopathic skeletal hyperostosis (n = 1), complex regional pain syndrome (n = 1), chronic post stroke pain (n = 1) and abdominal pain (n = 1).The three main measures assessed in this study were depression, risk of opioid misuse and pain interference.The PHQ-9 questionnaire was utilized to assess depression. PHQ-9 is a self-report tool used in screening, diagnosing, monitoring and measuring severity of depression. The tool measures Diagnostic and Statistical Manual of Mental Disorders—4th Edition (DSM-IV) depression symptoms with nine items. Scores range from 0–27 and suggested thresholds are 5 (mild), 10 (moderate), 15 (moderately severe) and 20 (severe depression) [The Current Opioid Misuse Measure (COMM) questionnaire was used to measure risk of opioid misuse . This quWe used the Brief Pain Inventory (BPI) short form  as a tooDemographic data available from chart abstraction included age, gender and race. Due to small numbers of minority groups other than African-Americans (AA) we created a binary white/non-white race variable.This study was approved by the IRBs of participating institutions.p < 0.05.Frequencies, means and associations were computed using SPSS 23 . Differep < 0.001). Among CLBP patients, depression was not related to positive opioid misuse (p = 0.19). A Breslow-Day test showed that depression and opioid misuse were more strongly associated among CPOL than among CLBP patients (p = 0.019). Average COMM score was significantly greater among depressed compared to non-depressed CPOL (p < 0.0001) and CLBP (p < 0.01) patients; however the difference between depressed and non-depressed was larger  among CPOL (difference = 13.0) patients than CLBP patients (difference = 5.8). Among CPOL, but not among CLBP patients, average pain severity was significantly higher among depressed vs. non-depressed patients. Pain interference was significantly greater among depressed vs. non-depressed patients in both CPOL and CLBP patients. The relationship of BPI measures and depression were similar across pain location strata.p-value = 0.050). Both pain severity and pain interference were positively related to COMM positive status among CPOL patients. Conversely, only pain interference was higher among COMM positive CLBP patients compared to COMM negative CLBP patients. There were no between strata differences in the relationship of opioid misuse and pain characteristics.p = 0.019) of the variance in opioid misuse risk and increased the odds of opioid misuse risk by over 3-fold . Pain location did not significantly explain any additional variance in opioid misuse risk; however, adding an interaction term of pain location and depression in a final model explained an additional 4.5% of the variance (p = 0.025). The significant interaction term showed that the odds ratio for the relationship of depression and opioid misuse risk increased by over a factor of 10 comparing CPOL to CLBP .In patients seeking treatment at a family medicine pain clinic, we observed evidence that the association between depression and opioid misuse differed in patients with CLBP compared to CPOL. Results of bivariate analysis stratified on pain location revealed that depression was more strongly associated with opioid misuse among CPOL patients than in patients with CLBP. This observation is not explained by pain interference which showed similar significant associations with depression in both CPOL and CLBP. Exploratory hierarchical logistic regression found that depression increases the odds of opioid misuse after adjusting for pain location and pain characteristics (severity and interference) and that this relationship is over 10 times stronger in CPOL than in CLBP. While pain severity was not significantly associated with opioid misuse risk in adjusted analysis, results suggest that pain interference independently contributes to opioid misuse risk after accounting for depression.etc.Our data expand on the existing literature on the prevalence of depression among different pain types ,6,7,8,9 et al. [vs. 83.3%).Because neuroticism is thought to be more common in CLBP  we expecet al.  that necvs. CLBP. In addition BPI scores were significantly greater in the depressed CPOL compared to non-depressed CPOL patients but did not differ by depression status in the CLBP patients. BPI scores were also higher in COMM positive vs. COMM negative patients in the CPOL patients but not CLBP patients. Greater pain severity in CPOL may lead to both depression and opioid misuse in patients with CLBP. Although pain severity was not significant when modeled with pain interference in regression analysis, this does not preclude the possibility that pain severity leads to greater pain interference which then increases depression and opioid misuse. Longitudinal data collection is needed to confirm this possibility.One potential explanation for the stronger association between depression and opioid misuse in CPOL patients could be the significantly higher BPI score, higher average least pain and higher average pain level among CPOL There are several biological mechanisms proposed for the association between pain and depression. Common vulnerability due to past psychopathology or trauma leads to chronic pain via changes in catecholamines, substance P and cytokine activity and less responsive opioid receptors that may perpetuate or worsen depression . AnotherLimitations include small sample size which limits the precision of our conclusions. We did not have enough subjects to compare CLBP to specific types of CPOL such as arthritis or fibromyalgia; however, sensitivity analysis removing fibromyalgia which is often comorbid with depression, did not change our conclusions. We also lacked sample size to conduct stratified multivariable logistic regression models. The data did not contain type of opioid or co-medication which may bias results if CLBP or CPOL systematically differed in morphine equivalent dose because higher daily opioid morphine equivalent dose is associated with depression ,18 and oWe found depression was more strongly associated with opioid misuse in patients with CPOL compared to patients with CLBP. The well-established association between depression and opioid misuse may be less prominent in CLBP than in other pain types. Further research with larger samples should compare this association in CLBP, arthritis, fibromyalgia and neuralgia. Refining which pain patients are most likely to develop comorbid depression and opioid misuse can inform clinical care and target limited resources to patients at greatest risk for this comorbidity.


Inherited epidermolysis bullosa (EB) comprises a group of rare disorders that have multi-system effects and patients present with a number of both acute and chronic pain care needs. Effects on quality of life are substantial. Pain and itching are burdensome daily problems. Experience with, and knowledge of, the best pain and itch care for these patients is minimal. Evidence-based best care practice guidelines are needed to establish a base of knowledge and practice for practitioners of many disciplines to improve the quality of life for both adult and pediatric patients with EB.The process was begun at the request of Dystrophic Epidermolysis Bullosa Research Association International , an organization dedicated to improvement of care, research and dissemination of knowledge for EB patients worldwide. An international panel of experts in pain and palliative care who have extensive experience caring for patients with EB was assembled. Literature was reviewed and systematically evaluated. For areas of care without direct evidence, clinically relevant literature was assessed, and rounds of consensus building were conducted. The process involved a face-to-face consensus meeting that involved a family representative and methodologist, as well as the panel of clinical experts. During development, EB family input was obtained and the document was reviewed by a wide variety of experts representing several disciplines related to the care of patients with EB.The first evidence-based care guidelines for the care of pain in EB were produced. The guidelines are clinically relevant for care of patients of all subtypes and ages, and apply to practitioners of all disciplines involved in the care of patients with EB. When the evidence suggests that the diagnosis or treatment of painful conditions differs between adults and children, it will be so noted.Evidence-based care guidelines are a means of standardizing optimal care for EB patients, whose disease is often times horrific in its effects on quality of life, and whose care is resource-intensive and difficult. The guideline development process also highlighted areas for research in order to improve further the evidence base for future care.The online version of this article (doi:10.1186/s12916-014-0178-2) contains supplementary material, which is available to authorized users. Inherited epidermolysis bullosa (EB) comprises a group of rare disorders, generally thought of as skin diseases. However, EB has multi-system effects and patients present with a number of both acute and chronic pain care needs . Effectsper se, itching is a major source of discomfort . The. The8]. Given the paucity of data for statistical analysis, it was deemed appropriate to conduct a face-to-face consensus meeting on 4, 5 May 2012 in Cincinnati, OH. The LEGEND tool for Judging the Strength of a Recommendation  or medical routines , and chronic pain conditions such as headache, abdominal pain or other disease-related conditions. Psychological therapies include cognitive behavioral therapy (CBT), hypnosis, biofeedback and relaxation training, among others. CBT focuses on changing the catastrophic thinking and negative emotions surrounding pain as well as modifying lifestyle to promote wellness behavior despite chronic pain . HypnosiAs an adjunct to relaxation training, biofeedback monitors physiological functions  in order to improve control of bodily processes that might ease chronic pain. Frequently, sensors are attached to the skin by adhesive, which is relatively contraindicated in EB. Clip on pulse oximeter probes can be safely used in patients with EB to track heart rate, and provide an alternative method of biofeedback.Psychological therapies have been shown to be effective in decreasing pain intensity and frequency in other pediatric chronic pain conditions ,17] wit wit17] wPsychological interventions are useful for the management of acute pediatric pain (see Box 1) although evidence for their efficacy varies depending on the type of pain. For procedure related pain, particularly needle procedures, distraction, hypnosis and CBT are effective, evidence based interventions -24]..24].In a review of non-pharmacological treatments to reduce the distress due to acute wound care in burn patients, some evidence has been shown that healthcare provider interventions (massage and maximizing patient control and predictability), child interventions  practices constitute therapies that are often requested by patients and families for a variety of chronic pain conditions. This class of treatments includes, but is not limited to: acupuncture, meditation, massage, herbal preparations, yoga and chiropractic work. The evidence for therapies such as acupuncture , music tot clear . Thus, tAssessment of the suitability of psychological therapies for EB patients experiencing chronic and acute pain should always take into account developmental issues including age, cognitive level and psychopathology . IncludeAs a multisystem disorder, EB causes a variety of disruptions to body systems that are amenable to surgical intervention. While there are no controlled trials of postoperative pain therapies in EB, general principles of pain care apply.As for all patients, pain should be regularly assessed, and then reassessed after intervention to evaluate analgesic efficacy and detect side effects. Numeric rating scales have been shown to be effective for children of a developmental level above eight years who can verbalize their pain scores as well as for adults. Pain assessment in younger or nonverbal patients can be completed using the Face Legs Arms Cry Consolability (FLACC) and Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS) ,40] aug aug40] aAnalgesic treatment starts before and during surgery and includes the use of opioids, non-steroidal anti-inflammatory drugs, acetaminophen and, when appropriate for the type of surgery, regional anesthesia ,42]. Pa. Pa42]. In the postoperative period, EB patients may be slow to resume oral intake, especially after oropharyngeal procedures, such as esophageal dilatation or dental rehabilitation. For patients lacking gastrostomy tubes, intravenous analgesia may be required. Intravenous analgesia should be multimodal and may include opioids , nonsteroidal anti-inflammatory drugs ) and acetaminophen . Given the high rate of superficial bleeding from skin wounds, cyclooxygenase-2 inhibitors may have a role to play, given they have prothrombotic features in some studies . Due to Patients with prolonged postoperative pain because of extensive surgery may benefit from the use of opioid-based PCA with dose adjustments that take into consideration prior opioid use. While no EB-specific literature exists, this modality is standard treatment in many centers for patients old enough to understand the concept . Activation of the dosing button may be limited by pseudosyndactyly, so use should be determined on a case-by-case basis. PCA-by-proxy (dose administered by a nurse or designated family member) is practiced in some pediatric centers and may be an alternative approach to PCA dosing for children.The preoperative pain status of the patient should be taken into consideration when choosing opioid dose, both intra- and post-operatively. Many EB patients have recurring acute and/or chronic pain and may be taking opioids daily, either prior to bathing/dressing changes or for ongoing pain. These patients require increased doses of opioids for adequate analgesic effect, due to the development of tolerance. Their usual daily opioid intake should be considered the baseline opioid dose to which the postoperative analgesia should be added (see Box 2). Drug pharmacokinetics may be altered in patients chronically exposed to sedatives and opioids. Flexibility in dosing, review of prior anesthetic records and discussion with the patient or family can aid appropriate dosing.Some common procedures  in EB patients include: fundoplication  -50], ha, ha50], Regional anesthesia techniques should be modified in patients with EB to minimize damage to the skin. Skin preparation may be performed by pouring prep solution (povidone-iodine or chlorhexidine) on the site without rubbing, then blotting and allowing the solution to dry. Ultrasound guidance can be used for peripheral nerve blocks with generous use of gel to minimize skin abrasion when moving the probe. When a catheter is placed , it may be tunnelled subcutaneously if desired  then secNon-pharmacologic techniques should also be employed in combination with the pharmacologic techniques listed above. These include, but are not limited to, distraction , visualization, imagery/virtual reality and breathing techniques . Effective approaches used in the past should be discussed with the patient or parents and their use supported whenever possible.Postoperative pain can be managed as for other patients in the same setting, with modifications to account for the ability to self-administer medications, prior drug exposure, and the condition of the skin at potential regional anesthesia injection/catheter sites.EB has a large number of painful complications, some chronic and others acute but repetitive. Care of EB involves painful interventions on a daily basis. Almost every organ system can be affected, but the following are the major sources of pain: skin, gastrointestinal tract, musculoskeletal system, eyes.The classic presentation of EB is the development of skin wounds that are painful in their own right, but which often become infected, heal poorly and frequently lead to scarring. This combination makes skin and wound pain a prominent complaint of patients with EB.Dressings that are non-adhesive upon removal, such as silicone-based products, are helpful in reducing skin-trauma pain. Different subtypes of EB and different individuals seem to have varying dressing requirements . NutritiThe pharmacological treatment of skin and wound pain is non-specific, with no evidence in the EB population to promote one treatment over another. NSAIDs, acetaminophen, tramadol and opioids are used with success. Cannabinoids have some anecdotal support. Itch is a major problem (see below) that can lead to increased scratching and subsequent development of painful wounds. Hence, managing pruritus is important to prevent wound-related pain.Many patients with severe types of EB use long-acting opioid preparations to provide a basal comfort level. Of note, there are no clear guidelines that long-acting opioids are preferable to use of intermittent opioids for non-cancer pain , althougRegular and frequent dosing of opioids is common and merits special attention. Regardless of the opioid chosen, chronic use of opioids may have endocrinologic effects, such as hypogonadism . MonitorMethadone merits particular consideration. Dose titration can be unpredictable due to long and variable half-life as well as to saturable plasma protein binding . The lonAmong the common side effects of opioids, constipation  and prurThe pain of extensive wounds has a quality suggestive of neuropathic pain; both are often described as `burning’ in quality. There is evidence supporting the use of gabapentin for neuropathic pain in other conditions . MedicatFor localized wounds, topical lidocaine jelly (2% concentration) has been used anecdotally. Morphine mixed in hydrogel formulations has been used in different types of localized painful wounds ,73] but but73] bBlood draws and intravenous access as well as the need for skin biopsies are minor technical procedures that can be very distressing, especially for children. Topical anesthetics are commonly used in non-EB populations with good effect. Amethocaine appears to be more effective than a eutectic mixture of local anesthetics (EMLA®) . These mPrevention and rapid healing of wounds through non-adherent dressings, optimal nutrition and infection control are priorities.Bathing and bandage changes are a source of significant recurrent pain and anxiety for patients with EB.Oatmeal and salt have been added to bath water to reduce the pain of immersion . The forAnalgesics used by patients with EB have included enteral opioids, NSAIDs and acetaminophen. The nasal route may permit administration of medications when intravenous access is absent . FentanyKetamine can be administered enterally for wound care pain, for which there are data from adult and pediatric burn populations ,83] but but83] bInhaled nitrous oxide has been suggested for pediatric wound care in EB in some texts and review articles ,87], bu, bu87], The pain caused by baths and dressing changes is commonly cited by families as generating anxiety in the patient, which in turn is stressful for the caregiver. Medications used for acute anxiolysis in this population include midazolam, diazepam and lorazepam and are considered good treatment for acute anxiety in other populations .Bathing and dressing changes are recurrent sources of both pain and anxiety. Therapy should focus on both symptoms, using environmental, psychological and pharmacologic approaches.Gastrointestinal complications are common in children and adults with EB with specific complications linked to different subtypes -97]..97].Oral ulceration, blistering and mucositis are the most frequent gastrointestinal complications in patients with EB . While oPolyvinylpyrrolidone-sodium hyaluronate gel (Gelclair®) either used as a mouth rinse or applied directly to a mouth lesion in children, has been used anecdotally in EB. Secondary evidence comes from two recent reviews which showed that Gelclair® may be useful as an adjunctive therapy in decreasing the painful lesions of oral mucositis in cancer patients ,101]. C. C101]. 2-blockers and proton pump inhibitors and, rarely, surgery  . A valid neonatal pain scale should be used, considering both physiologic and behavioral measures. Some examples include: the Premature Infant Pain Profile (PIPP) ,140], t, t140], As for older patients, procedures are one of the major sources of pain for infants with EB. Wound care specifically requires a multidisciplinary team approach to ensure consistent and optimized pain control. There is evidence that a variety of pharmacologic and non-pharmacologic interventions are helpful in both term and pre-term infants . TherefoTo maintain appropriate moisture levels and facilitate the healing of wounds, dressings should be non-adherent as for older patients and appropriate in size. Infected wounds will require more frequent dressing changes ,152]. C. C152]. In addition to environmental adjustments, many infants will require analgesics with bath and dressing changes. NSAIDs, acetaminophen and opioids are all used, as for older patients (see Section-Bathing and Dressing Changes) (see Box 8). Codeine is not recommended, when alternatives are available, as neonates lack the capacity to metabolize the drug into active metabolites, and clinical responses are highly variable at all ages, due to polymorphisms in codeine’s metabolic pathway ,154]..154].Severely affected newborns with deep tissue damage may require extensive pharmacologic support to achieve a level of comfort (see Box 8). These infants may require around the clock or continuous infusion of opioids and an adjuvant. A transition to methadone for better steady state levels should be considered (refer to sub-section on systemic approaches under Skin and Wound Pain) for caveats about methadone use). A case study has shown effective pain control in an infant with severe chronic pain (and possibly pruritus) when treated with gabapentin . PatientOral ketamine has been used to supplement opioids when pain associated with dressing changes is severe . Use of Infants benefit from the same range of analgesics as older patients. They can uniquely benefit from oral sucrose for brief painful episodes. Careful monitoring is crucial in infants receiving sedating medications. Babies with EB and their parents benefit from close physical contact like any other families. Holding and cuddling can be done safely, with scrupulous attention to lifting and handling in order to prevent new lesions and pain.The epidemiology of death in EB varies by type , but is The palliative approach to pain experienced by individuals who are facing life-threatening illness addresses the physical, emotional and spiritual suffering of the patient and includes support for the whole family -167] . Patients in the palliative phase of their illness may be given an oral opioid sustained release medication . OpioidsMany EB patients will have been treated with adjunctive agents such as amitriptyline or gabapentin earlier in their illness, often with good effect ,155]. T. T155]. Parenteral administration of analgesia may be needed in the palliative phase, when ability to take enteral medications is no longer an option or if rapid escalation of therapy is needed. There has been an historic reluctance to use continuous subcutaneous infusions, due to the fear of precipitating further blistering. However, subcutaneous infusions have been reported to be tolerated in the final days of life in an adult EB patient  . Some patients prefer sedating formulations at bedtime  and others non-sedating preparations during the day . Efficacy is variable and recommendations are based on anecdotal experience for lack of good evidence in EB and other dermatologic conditions. Centrally acting medications, such as gabapentin and pregabalin, have evidence for efficacy from the burn literature ,188],, and may Other medications that have shown sporadic clinical success in treating itch in EB include: cyproheptadine; selective serotonin re-uptake inhibitors  ; tricyclIt is common practice for medications from different drug classes to be used concurrently and for agents in the same class to be rotated due to the observation that a particular medication may have improved efficacy after intermittent drug holiday.A combination of environmental, cognitive-behavioral and pharmacologic therapies is available for use for EB-related pruritus, which can be a severe symptom of the disease.These guidelines represent the initial effort to organize pain management for patients with EB based on existing evidence. While the guidelines were developed using current evidence and a rigorous evaluation process, there are limitations in the clinical use of the recommendations. The two broad areas of concern involve practical limitations of implementation and the level of available evidence. Tables (Grade: B)For chronic pain management use cognitive behavioral therapy (CBT). (Grade: B)For acute pain management, offer the patient distraction, hypnosis, visualization, relaxation or other forms of CBT. (Grade: C)Consider habit reversal training, and other psychological techniques for management of pruritus. (Grade: A)Basic perioperative pain assessment and treatments should be used as for non-EB patients, with modification. (Grade: B)Transmucosal  should be considered for short procedures and pain of brief duration when intravenous and enteral routes are unavailable. (Grade: B)Perioperative opioid use must take preoperative exposure into consideration, with appropriate dose increases to account for tolerance. (Grade: C)Regional anesthesia is appropriate for pain resulting from a number of major surgeries. Dressing of catheters must be non-adhesive and monitored carefully. (Grade: D)Maintain optimal nutrition and mobility and treat infections as indicated (Grade: C)Consider topical therapies for pain (Grade: B)Systemic pharmacologic therapy should be adapted to treat both acute and chronic forms of skin pain. (Grade: C)Monitor potential long-term complications of chronically administered medications. (Grade: B).Anxiolytics and analgesics should be used for procedural pain and fear. Care must be taken when combining such medications due to cumulative sedative effects (Grade: B).Cognitive behavioral techniques should be implemented as the child becomes old enough to use them effectively. Specifically, distraction should be used for younger children (Grade: B).Environmental comfort measures are recommended; these include adding salt to the water to make it isotonic and keeping the room warm (Grade: C)Topical treatments are recommended for oral and perianal pain. (Grade: C)Therapy should be directed to manage gastroesophageal reflux and esophageal strictures using standard treatments. (Grade: C)Constipation should be addressed nutritionally, with hydration and addition of fiber in the diet to keep stool soft, with stool softeners and by minimizing medication-induced dysmotility. (Grade: C).Joint pain should be treated with mechanical interventions, physical therapy, cognitive behavioral therapy and surgical correction (Grade: D).Osteoporosis should be treated to reduce pain in EB (Grade: C).Back pain should be addressed with standard multi-disciplinary care (Grade: C).Care should include general supportive and analgesic care, protecting the eye from further damage and topical therapies (Grade: A)Assess patients as needed and prior to and after interventions; health care workers should use validated measures. (Grade: B)Sucrose solutions should be administered for mild to moderate pain alone or as an adjunct. (Grade: B)Standard analgesics should be used in infants as in older patients with careful attention to dosing and monitoring. (Grade: A)Assess and manage physical, emotional and spiritual suffering of the patient, while providing support for the whole family. (Grade: B)Opioids are the cornerstone of good analgesia in this setting. Opioid rotation may need to be considered to improve analgesia and reduce side effects, and adjuncts may need to be added. (Grade: D)Consider targeted medication for neuropathic pain or when pain proves refractory to convention therapies. (Grade: C)Continuous subcutaneous infusion of medication is an option when parenteral therapy is needed in the terminal phase. (Grade: B)Where needed, breakthrough medication can be given transmucosally  for rapid onset and avoidance of the enteral route. (Grade: C)Use environmental and behavioral interventions for itch control. (Grade: D)Antihistamines are recommended and can be chosen depending upon desirability of sedating effects. (Grade: C)Gabapentin, pregabalin, TCA, serotonin norepinephrine reuptake inhibitors (SNRIs) and other non-traditional antipruritic agents should be strongly considered for itch treatment. This work was initiated and led by KRG with active input from all authors. JG, EH, CL, ALJ, AEM, LGM and DSL participated in the review process and recommendation/guideline draft, see text for details. DSL led the systematic evidence analysis and provided methodological support and guidance. Multi-disciplinary clinician input was obtained as was input from patients and families early in the process . The consensus meeting (see text) was attended in person or via Skype by KRG, ALJ, EH, JG, CL, LGM and BK (see Acknowledgements). All authors read and approved the final manuscript.Additional file 1: EB-specific articles that were excluded from use in making recommendations, with rationales.(DOC )Authors’ original file for figure 1Below are the links to the authors’ original submitted files for images.