Chronic opioid use is a serious global health problem and surgery is often the point of initial exposure for many chronic opioid users. Multimodal analgesia (MMA) is an approach designed to reduce or eliminate opioid use in surgical patients, but it has not been studied in patients having major head and neck surgery. This study explores the impact of an MMA protocol on opioid prescribing practices in patients having major head and neck surgery with flap reconstruction. The results of this study will provide evidence to inform and guide pain management practice in this important patient population. The results of this study could also be applied to other areas of otorhinolaryngology. MMA is an important tool in the effort to reduce chronic opioid use.n = 41), prior to the implementation of MMA, and were compared to an MMA-treated cohort treated between December 2017–June 2019 (n = 97). The primary outcome was the proportion of opioids prescribed and oral morphine equivalents (OMEs) consumed during the hospitalization. The secondary outcome was pain control. We found that the post-MMA group consumed fewer opioids in the postoperative period compared to the pre-MMA group. Prior to post-operative day (POD) 6, pain control was better in the post-MMA group; however, the pain control lines intersect on POD 6 and the pre-MMA group appeared to have better pain control from PODs 7–10. In conclusion, our data suggest MMA is an effective method of pain control and opioid reduction in patients undergoing surgery for head and neck cancer with free flap reconstruction. MMA use was associated with a significant decrease in the quantity of opioids consumed postoperatively. The MMA protocol was associated with improved pain management early in the postoperative course. Finally, the MMA protocol is a feasible method of pain control and may reduce the adverse side effects associated with opioid use.Postoperative opioid use has been linked to the subsequent development of opioid dependency. Multimodal analgesia (MMA) can reduce the use of opioids in the postoperative period, but MMA has not been well-studied after major head and neck surgery. Our goal is to explore the association between MMA and postoperative opioid use and pain control in patients undergoing major head and neck surgery. We performed a retrospective study in adult (age ≥ 18 years) patients undergoing primary head and neck cancer resection with free-flap reconstruction. All patients were treated using an established care pathway. The baseline group was treated between January 2015–December 2015 ( Adequate postoperative pain control is imperative for successful recovery and rehabilitation following surgery . Pain isOpioids have a significant side effect profile, including postoperative nausea and vomiting, constipation, sedation, and impaired mobilization. These side effects create further barriers to patients’ postoperative recovery. There is also growing evidence showing an association between opioid use in the acute postoperative period and the subsequent development of chronic opioid use ,6,7,8,9.An enhanced recovery after surgery (ERAS) guideline for head and neck cancer patients addresses 17 topic areas within the preoperative, intraoperative, and postoperative care time periods . EffectiOur centre recently implemented a head and neck ERAS protocol which includes an MMA order set for managing postoperative pain . The CalTM). Two patient groups were compared. A pre-MMA cohort that included patients who underwent surgery between January 2015–December 2015 and were managed using the Calgary Head and Neck Enhanced Recovery Program (CHERP) protocol [Data were prospectively collected, and retrospectively analyzed, on adult patients age ≥ 18 years) undergoing primary head and neck cancer resection with free-flap reconstruction at a tertiary, academic head and neck surgical oncology program . Eligible patients were identified from a prospectively annotated database  provided data for pain control ), as well as the type, timing, and frequency of all analgesics administered. Opioid consumption (primary outcome) was measured in two ways: proportion of pain medications that were opioids and quantity of opioids administered. To simplify comparison of opioid amounts, opioid doses were converted to oral morphine equivalents (OMEs). Pain intensity (secondary outcome) was measured using the NRS. Additional outcomes measured were time to mobilization, length of hospital stay, and complications. Complications were graded using the Clavien-Dindo classification system.p-value of less than 0.05.Data management and analyses were carried out using Stata version 16 . The analysis was directed by a biostatistician who was a collaborator on the project (GHF). Categorical variables are displayed as proportions and continuous variables are reported as means or medians along with measures of variation as appropriate. Categorical variables are compared using a chi square or Fisher’s exact test and continuous variables are compared using appropriate parametric or non-parametric analyses. Count data  were analyzed using a truncated negative binomial regression approach. Statistical significance is indicated by a Opioid and pain score data were complex and required model-based analytical approaches. Therefore, much of the analysis in this paper is model-based and are forms of logistic regression. The logit (log odds) is considered to be conditional on subjects and one then considers the regression coefficients as being assumed common to subjects. The estimates of the regression coefficients are then said to be adjusted for subjects. These conditional models are also traditionally called mixed models. We used the command melogit (Stata version 16) which provides estimates of the regression coefficients and predictions of the subject components. For example, we presented models for the log of the odds of receiving opioids as functions of the intervention (MMA: yes/no) and indicators for the day of the trial (postoperative day). We further studied a number of models that allowed us to consider a number of potential modifiers/confounders such as age, sex, tumor stage, and others. On the balance of many issues, we decided not to include any additional confounders or modifiers in our reported results. Therefore, only adjustments for within-subject variation were performed. A similar approach was used to analyze the pain score data.The authors used A Project Ethics Community Consensus Initiative (ARECCI) framework to assess for and mitigate ethical risks, including the ARECCI Ethics Screening Tool and the ARECCI Ethics Guidelines. The project was deemed a quality improvement initiative with a minimal risk (ARECCI score = 1) .Daily opioid consumption as a proportion of total analgesics given is shown in p = 0.04 Wilcoxon). Patients in the post-MMA group consumed fewer opioids over the duration of their hospital stay. Mean daily opioid consumption was 29.7 mg (SD 5.0) in the post-MMA group versus 43.3 mg (SD 18.8) in the pre-MMA group (p < 0.001 Wilcoxon). Neither complications nor length of stay were different between the two groups.We also evaluated time to first mobilization, length of stay, and overall complications (measured by Clavien-Dindo classification). These data are reported in This study shows that MMA is associated with a lower proportion of opioid use and lower opioid consumption as measured by OMEs in patients undergoing surgery for head and neck cancer with free flap reconstruction. Furthermore, MMA use was also associated with lower pain scores early in the postoperative period (POD 0–6). The pre- and post-MMA cohorts had comparable rates of postoperative complications suggesting MMA use is not associated with increased complications. MMA, therefore, appears to be a feasible method of pain control for postoperative head and neck cancer patients and may reduce the adverse side effects associated with opioid use.Postoperative opioid use has been linked to the subsequent development of opioid dependency. Surgical patients are four-times more likely to be discharged with an opioid prescription compared to their nonsurgical counterparts ,23. HeadMultiple surgical specialties have implemented postoperative MMA protocols in an effort to decrease the use of opioids in the postoperative period and the subsequent development of chronic postoperative use. A recent study in breast reconstruction patients by Astanehe et al. showed significantly reduced OMEs in an MMA managed cohort . In OtolMMA protocols used in other surgical populations minimize the use of opioids while providing stable and reliable pain control ,28. ArguThe safety of MMA is a common concern among clinicians. Many clinicians believe NSAIDs are associated with an increased risk of postoperative bleeding. Several studies in the Otolaryngology literature show that with proper intraoperative hemostasis, perioperative NSAID use is not associated with increased postoperative bleeding ,26,31. COur study is limited by its retrospective design that inherently includes bias secondary to patient selection. The MMA protocol was a component of a head and neck ERAS care pathway that also included preoperative education, management of intraoperative fluid balance, and intraoperative temperature control. The other ERAS care elements were also part of the ongoing CHERP protocol and we, therefore, do not believe the differences between ERAS and CHERP influenced the results.This study is strengthened by its use of high-quality administrative data that was collected prospectively at the point of care. Such data are highly reliable, and we are confident in its accuracy and reliability. Another strength of this study is our analytical approach to the data which adjusted for variation within subjects and has improved our understanding of our patients’ postoperative pain experience using different treatment protocols. There are few published studies of MMA use in major head and neck cancer surgery with free flap reconstruction and none that incorporate the entire postoperative course. We have shown that MMA protocols are effective and are associated with reduced postoperative opioid consumption in head and neck cancer patients.We conclude that in a tertiary academic head and neck surgical oncology program MMA is a feasible method of postoperative pain management in patients undergoing major head and neck cancer surgery with free flap reconstruction. The use of MMA is associated with a significant decrease in the use of opioids and potentially decreased side effects associated with opioid use.


Our study showed that peripheral neuropathy was a common organ-specific complication in SS patients. In pSS patients, coexisting neurological involvement with symptoms such as pain and physical disability may be responsible for diminished HR-QOL.Sjögren’s syndrome (SS) is a chronic autoimmune disease with a wide spectrum of possible organ involvement. Peripheral (PNS) and central nervous system (CNS)-related symptoms may occur in the course of the disease. The aim of this study was to compare the health-related quality of life (HR-QOL) in SS patients with and without peripheral neuropathy. The study involved 50 patients with primary Sjögren’s syndrome (pSS). All patients underwent neurological clinical examination followed by nerve conduction studies (NCS) and rheumatological examination. Thirty-six-item Short Form Health Survey (SF-36) was used for evaluating HR-QOL. To assess pSS activity, the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) and EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) were used. For the assessment of clinical disability due to peripheral neuropathy, the Overall Disability Sum Score scale (ODSS) was used. Additional evaluation of pain was performed with the use of the Visual Analogue Scale (VAS) and a semistructured interview. Twenty-three (46%) patients were diagnosed with peripheral neuropathy. The most common PNS manifestation was sensorimotor neuropathy (47%). Neurological symptoms preceded the diagnosis of pSS in eight patients. The following domains of the SF-36 form were significantly lower scored by patients with peripheral nervous system involvement: role-physical [0 (0–100) vs. 75 (0–100)], role-emotional [67 (0–100) vs. 100 (0–100)], vitality [40 (10–70) vs. 50 (20–75)], bodily pain [45 (10–75) vs. 55 (0–100)], and general health [20 (5–50) vs. 30 (0–50)] ( Sjögren’s syndrome (SS) is a chronic inflammatory disease with an autoimmune background that mainly affects middle-aged women . It is characterized by the presence of lymphocytic infiltrates in the exocrine glands , which causes dryness of the eyes  and mouth (xerostomia). Sjögren’s syndrome may be primary (pSS)—it occurs then as an independent disease or secondary (sSS)—in the course of other systemic connective tissue diseases. Its prevalence is estimated at 0.1–1% of the population , 3. InvoThe study was approved by the Independent Bioethics Committee for Scientific Research of Medical University of Gdańsk, Poland (consent no. NKEBN/345/2011). All procedures were in accordance with the ethical standards of the 1964 Helsinki declaration and its later amendments. All patients gave their informed written consent.We studied a group of 50 unselected adult patients with the diagnosis of pSS who were under the care of the Department of Internal Diseases, Connective Tissue Diseases and Geriatrics of the Medical University of Gdańsk. Diagnosis of pSS was based on the 2002 American European Consensus Group criteria and Sjögren’s International Collaborative Clinical Alliance criteria published in 2012 , 9. ExclFor each patient, past and present systemic manifestations of pSS were recorded. Rheumatological assessment was carried out by one certified rheumatologist, and consisted of a detailed medical history, physical examination, pain evaluation, serological blood tests, assessment of disease activity, and functional outcomes.All patients underwent clinical neurological examination followed by nerve conduction studies (NCS) of nine peripheral nerves . The NCS studies were performed following our standard laboratory methods in accordance with the recommended protocol of the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) with the use of Medtronic’s Dantec Keypoint G4 . RecordiTo assess SS activity, the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) was used . The ESSTo assess irreversible damage to organs, Sjögren’s Syndrome Disease Damage Index (SSDDI) was used . SSDDI cAdditionally patients rated their disease activity using EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) . ESSPRI For the assessment of clinical disability due to peripheral neuropathy, the Overall Disability Sum Score scale (ODSS) was used . The ODSWe additionally asked patients to evaluate the pain that they have experienced in the previous 2 weeks with the Visual Analogue Scale (VAS). Based on a semistructured interview, the pain was categorized into the following types: neuropathic, muscular, or articular. Neuropathic pain was characterized as numbness, pins, and needles sensations or burning sensation. Muscular pain was described as aching or stiffness of the limb and girdle muscles or a feeling that muscles have been overworked. Articular pain  was characterized as pain or stiffness limited to joints. We have decided to use our own questionnaire focusing on pain to get one simple and comprehensive tool for gathering qualitative and quantitative information about patient’s pain. As the patients were filling in the questionnaire under supervision of experienced neurologist or rheumatologist, all potential interpretation problems were solved, especially in terms of differentiating neuropathic from muscular pain.Thirty-six-item Short Form Health Survey (SF-36) is the most widely used instrument for evaluating HR-QOL in patients with rheumatic diseases , 17. TheU test. Categorical variables were compared with the use of Chi-squared test. p value 0.05 or lower was considered significant.All statistical analyses were performed with Statistica version 13 (TIBCO Software Inc.). Normality distribution of the data was assessed with Shapiro–Wilk test. Continuous variables were compared using Mann–Whitney n = 27) were further referred to as PNS −. The most common PNS manifestation was sensorimotor neuropathy 11/23 (47%). Mononeuropathy was present in 6/23 (26%) patients, pure axonal sensory neuropathy in 1/23 (4.3%) patient, axonal motor neuropathy in 1/23 patient (4.3%), small-fiber neuropathy (SFN) in 1/23 (4.3%), and cranial nerve involvement was present in 4/23 (17.4%). One patient had both cranial and sensorimotor neuropathy. In one patient with normal NCS, the diagnosis of SFN was established on the basis of abnormal clinical and quantitative sensory testing (QST) findings performed in another laboratory.Our group consisted of 50 patients with a median age 57.5 years (33–74), 48 (96%) were female, and two were male (4%). The median age at diagnosis of pSS was 53.5 years (23–69). Detailed clinical data are presented in Table Neurological symptoms preceded the diagnosis of pSS in 8 (35%) of 23 PNS + patients.First, the two studied groups were compared in terms of clinical characteristics and results from laboratory tests. Details are presented in Table p = 0.229). Clinician’s assessment revealed that neuropathic type of pain was often observed in both subgroups. This type of pain was predominant in PNS + patients , while 11 of 27 PNS − patients (41%) suffered from neuropathic pain.Second, PNS + and PNS − groups were compared according to results obtained with the use of VAS-pain, the interview regarding type of pain and SF-36. The results are presented in Table p ≤ 0.05).In five domains of the SF-36 PNS + patients obtained significantly lower results than PNS − patients: role-physical [0 (0–100) vs. 75 (0–100)], role-emotional [67 (0–100) vs. 100 (0–100)], vitality [40 (10–70) vs. 50 (20–75)], bodily pain [45 (10–75) vs. 55 (0–100)], and general health [20 (5–50) vs. 30 (0–50)] . Delays in the diagnosis of pSS may contribute not only to the psychological distress, but also delay in starting the proper therapy and, therefore, may cause the development of systemic complications. Previous studies have shown large discrepancies in the prevalence and clinical picture of the nervous system involvement in pSS patients. Our study has clearly shown that peripheral nervous involvement is frequent, but remains under diagnosed in pSS patients, and it is correlated with worse HR-QOL. Patients with peripheral nervous system involvement obtained significantly lower scores in five domains of the SF-36: role-physical, role-emotional, vitality, bodily pain, and general health. There is an agreement in the literature that HR-QOL is impaired in pSS, but so far, it has been reported to be associated with fatigue, pain, sicca symptoms, and psychological distress , 18–20.Fatigue  and pain are the most common extraglandular symptoms reported by patients suffering from rheumatologic diseases –23. In pThe two items of bodily pain domain assess the frequency of pain and its impact on daily functioning, but does not distinguish the type of pain and its intensity. We suggest that additional evaluation of the intensity of pain according to VAS scale and using a semistructured interview to try to categorize the type of pain into neuropathic, muscular, or articular is vital in these patients’ group. Even if the pain is in the range of mild-to-moderate like in our group, it should be emphasized that we are considering chronic pain accompanying the patient every single day. Moreover, one should not assume that every pain suffered by a patient with a rheumatic disease is articular. According to clinicians’ assessment, many of our patients suffered from neuropathic pain. It should be emphasized that physician should strive to determine the nature of the pain and thus to start appropriate treatment.r = 0.53). The median score of pain on VAS in PNS + compared to PNS − patients was 3 (range 0–7) and 0 (range 0–7), respectively, while median score of pain on ESSPRI in PNS + compared to PNS − patients was 5 (0–8) and 4 (0–8), respectively. The possible scores on both scales range from 0 to 10, and in both, the same period of time was taken into account (2 weeks prior to the assessment). Previous surveys have indicated that ESSPRI correlates significantly with other patient-reported scales including VAS-pain. However, the ESSPRI index does not distinguish the type of pain and rating together with other components (fatigue and dryness) may cause an overstatement of the pain score. We hypothesize that more extensive pain assessment scale should be used in this group of patients to eliminate the negative effects of other symptoms on pain scoring and to distinguish the type of pain which is predominant to adjust the proper treatment.It is interesting to mention that in our study, there was a noticeable difference between pain scores on VAS scale and ESSPRI index, although the correlation between these two indicators was statistically significant  and systemic sclerosis (SSc). SS patients tend to be overlooked in this manner, because their disease is not “externally noticeable” like joint deformations in RA or contractures in SSc. However, concomitant neuropathy can significantly affect physical functioning in pSS patients. The median ODSS score determining the severity of disability due to peripheral neuropathy in our study was 1 (0–7) in PNS + group which reflects the worse every day functioning and may explain the low scores in role-physical domain. In PNS + patients, the neurological examination most often revealed sensory deficits and mild-to-moderate muscle weakness. However, in one patient, ataxic sensory neuropathy led to a significant disability due to severe loss of proprioception and kinesthesia.When a difficulty in performing certain activity occurs, many of the patients adapt by starting to choose alternative ones. Also in many of them, psychological adaptation occurs, because expectations are being reduced . This maThese two factors, i.e., neuropathic pain and disability due to neuropathy, may be two important components that affect the HR-QOL. Further research is needed in this field.Scores on SF-36 obtained from PNS + SS patients in our study are similar to those previously obtained from RA patients . HoweverPNS + SS patients tended to score lower in physical functioning, role-physical, bodily pain, vitality, and general health domains compared to systemic sclerosis (SSc) patients . In SSc SS patients in general tended to have lower scores in vitality domain than patients with RA, SLE, and SSc . This isDevelopment of medicine with extensive diagnostic options and new treatment possibilities has improved mean life expectancies, leading to an increased number of patients with chronic diseases , 27. DetPeripheral neuropathy in SS should be diagnosed and treated properly. Currently, there are no guidelines based on randomized trials regarding the treatment of patients with SS with nervous system involvement. Patients with oligosymptomatic and self-limiting course of the disease do not require pharmacological treatment. Immunosuppressive treatment is applied in case of high disease activity or progressive course of the nervous system involvement , 29. In In summary, these preliminary results suggest a large unmet health burden. SS patients are a very diverse group of patients with possible involvement of every organ and system, and therefore, the rheumatologists’ broad knowledge and interdisciplinary approach to these patients are relevant. We should remember that patients value their QOL more than disease activity indexes or laboratory parameters. This is the first study that emphasizes the relationship between PNS involvement and worse HR-QOL in pSS patients. An attempt to expand the pain assessment with its categorization into muscular, articular, and neuropathic is also a novelty in this group of patients. The above conclusions indicate the direction of future research in this group of patients, focused on the rapid detection of organ-specific complications with subsequent appropriate treatment. In addition, they indicate the need to pay more attention to the subjective symptoms reported by patients and their careful assessment. Further research seems to be needed on the pathomechanism of pain formation and its perception in pSS. Also the development of new scales to accurately assess pain and other patient-reported complaints seems necessary. It should be emphasized that pain in rheumatological patients is a much more complex problem than it seemed. As an attending physician, rheumatologist should take care of every aspect of the patient’s life, starting from controlling disease activity, effective pain treatment, through improvement of daily functioning, and finally mental well-being.Our study showed that peripheral nervous involvement is frequent in pSS patients and it is correlated with worse HR-QOL. We hypothesize that in pSS patients coexisting neurological complications with symptoms such as pain and physical disability, may be the reason for diminished HR-QOL. To get the complete picture of SS patients, a holistic approach starting with a comprehensive assessment of disease activity and PROs is needed. Combining personalized therapies, including immunosuppression, symptomatic pain management, physiotherapy, and psychological support, can improve compliance and treatment outcomes and patients’ HR-QOL.The study was conducted in a tertiary care university hospital, and thus, referral bias may have played a role in patient selection. Additionally, we did not have the possibility to conduct neurophysiological testing in cases where a pure small-fiber neuropathy was suspected.One of the weaknesses of our study was lack of unambiguous differentiation between SS-related neuropathy and other forms of neuropathy . To diagnose a neuropathy related to a disease, one should prove existence of a relation between the presence, course, and therapy of the disease, and the presence and course of neuropathy. In case of SS establishing direct link between the autoimmunological disease and a polyneuropathy (diagnosing “SS-related” polyneuropathy) would take years of observation. On the other hand, the aim of this study was to assess the association between involvement of peripheral nervous system and the quality of life of subjects with SS. For such an aim, the exact etiology of polyneuropathy is not decisive.The main advantage is the fact that study is a cross-sectional one with a thorough neurological and rheumatological assessment performed by one certified specialist. Much of the research in this topic was based on retrospective assessment. Additionally, only patients with pSS were included in the study. Patients with additional connective tissue diseases as well as patients with diabetes, degenerative disc disease, and other neurological conditions were excluded from the study.


Calciphylaxis is characterized by marked vascular calcification and painful skin ulcers, and it has a poor prognosis.The patient was a 72‐year‐old male. He was referred for penile pain. He had a 4‐year history of dialysis therapy under a diagnosis of diabetic nephropathy. Black and yellow necrosis was observed involving the entire glans, accompanying severe pain. Computed tomography revealed marked calcification involving the thoracoabdominal aorta to iliac arteries, the dorsal artery of the penis and the corpus cavernosum, leading to a diagnosis of calciphylaxis. Penile pain gradually exacerbated and partial penectomy was performed. After surgery, penile pain promptly subsided. Pathological examination confirmed marked calcification of the microvascular wall and narrowing of the lumen.We reviewed 15 Japanese patients with calciphylaxis who had undergone penile surgery. Surgical treatment was considered to be effective at relieving penile pain, but the prognosis remained poor. CacalciumCRPC‐reactive proteinHbhemoglobin1cHbA1chemoglobin AIPinorganic phosphorusI‐PTHintact parathyroid hormonePLTplateletWBCwhite blood cellPartial penectomy was performed on a patient with diabetic nephropathy for severe calciphylaxis‐related penile pain. After surgery, penile pain promptly subsided. In the reviewed 15 Japanese patients with calciphylaxis, penile surgery was considered to be effective at relieving penile pain, but the prognosis remained poor.Calciphylaxis is a refractory disease characterized by marked vascular calcification and painful skin ulcers that primarily develop in dialysis patients, and it has a poor prognosis. It frequently develops in the limbs/trunk/fingers/toes.The patient was a 72‐year‐old male. He was referred for penile pain. He had a 4‐year history of dialysis therapy under a diagnosis of diabetes mellitus, which had been made 11 years previously. No urine production was observed, and 4‐hour hemodialysis was performed three times a week. He also had a history of acute myocardial infarction, lacunar infarction, hypothyroidism and diabetic retinal detachment. Insulin glargine, aspirin, furosemide, amezinium metilsulfate, levothyroxine sodium hydrate and allopurinol were administered for the respective diseases.Pain of the glans had persisted for 10 days, but the patient was unable to confirm the site of pain due to blindness. On consultation at the previous hospital, necrosis of the glans was observed and he was referred to our department for treatment.His height, body weight, blood pressure, pulse rate, and body temperature were 160 cm, 64 kg, 142/74 mmHg, 77/min, and 36.8°C, respectively.Yellow and black necrosis of the entire glans with severe pain was noted Fig. , and pur1c, WBC, Hb, and PLT levels of  9.7 mg/dL,    7.4 mg/dL, 97 pg/mL, 11.5 mg/dL, 7.3%,  13 500/μL, 18.3 g/dL and 23.4 × 104/μL, respectively.Laboratory examination on admission demonstrated corrected Ca, IP, I‐PTH, CRP, HbAPlain computed tomography of the thorax and abdomen revealed marked calcification involving the thoracoabdominal aorta to external/internal iliac arteries. Calcification of the dorsal artery of the penis and ectopic calcification of the corpus cavernosum were also observed Fig. . On uretAfter admission, lavage and debridement were performed based on a diagnosis of calciphylaxis or necrosis related to intravascular thrombus at the department of dermatology. However, pain control of the glans was poor and there was no reduction of necrosis. Partial penectomy was performed 8 days after admission. The glans was dissected at an area proximal to the coronary sulcus. There was no hemorrhage. The external urethral meatus was created by a standard procedure. After surgery, penile pain promptly subsided. Paleness in a portion of the surgical wound, purulent discharge and fever were observed, but perineal care, debridement and antimicrobial drug administration were carried out.Pathological macroscopic findings included ulceration, necrosis and abscess formation. Microscopy demonstrated marked calcification of the media in the small arteries, and thickening of the intima and lumen stenosis was noted, suggesting calciphylaxis Fig. .The patient was transferred to his previous dialysis hospital 34 days postoperatively, with improvement in his general condition. The course had been favorable based on postoperative follow‐up, but he died of pneumonia 11 months after surgery.Calciphylaxis primarily develops in dialysis patients. It is characterized by purpura/induration of the skin and severe pain, rapidly causing ulcers and necrosis. Histopathologically, ischemia associated with arterial stenosis related to marked calcification of small arteries and soft tissue is primarily observed. This condition is considered to be different from arteriosclerosis, which is generally defined as atherosclerosis related to hypertension, diabetes mellitus or dyslipidemia.The annual incidence of calciphylaxis in Europe and the United States is 3.5 per 1000 patients chronically receiving dialysis.It frequently develops in the lower limbs/trunk. Calciphylaxis of the penis accounts for approximately 3%.No treatment has been established. In addition to conservative treatment, surgery is sometimes performed to ameliorate pain or remove the source of infection, but few case reports have been published.et al.In Japan, 14 patients treated by surgery for calciphylaxis‐related necrosis of the penis have been reported. We reviewed 15 patients, including ours (Table We reported a patient in whom partial penectomy for calciphylaxis‐related necrosis of the penis reduced pain. Based on a review of 15 Japanese patients with calciphylaxis treated by penile surgery, surgery was considered to be effective at relieving penile pain due to calciphylaxis, but the prognosis was poor.The authors declare no conflict of interest.


Prefrontal repetitive transcranial magnetic stimulation is an established add-on treatment for major depressive disorder and is increasingly feasible with protocols of short duration, such as intermittent theta burst stimulation (iTBS). The most common and limiting side effect is pain at the site of application. Our objective was to investigate how pain develops over time in patients with depression receiving iTBS compared to sham stimulation.This is a subsample from a randomized clinical trial. Patients received daily sessions of 2400 pulses of dorsomedial prefrontal iTBS or sham stimulation with transcutaneous electric stimulation during 2 to 3 weeks. After unmasking of treatment allocation, patients receiving sham treatment were offered active iTBS in an open phase. Patients rated pain on a scale from 0 to 10 after the last train of stimulation on the first, fifth and final treatment day. A Mann-Whitney U-test was conducted to test for group differences and related-samples Friedman’s tests to analyze changes in pain ratings over time.p = 0.035) and fifth day  but not on the final day . The pain decreased mainly during the first 5 days of treatment . In the open phase the pain decreased from the first day to the final day .The scalp pain in the group receiving iTBS was rated higher than sham treatment on the first (U = 263.5, The subjective pain perception of active dorsomedial iTBS was higher than sham treatment but decreased over time, indicating an analgesic effect, or habituation. The result from this study can be used to inform patients about what to expect regarding pain during an iTBS treatment course.NCT02905604. Registered 19 September 2016.Clinicaltrials.gov,  Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) is considered an established add-on alternative for treatment resistant depressive disorders and there is also evidence for an analgesic effect when delivered over the primary motor cortex contralateral to the pain .Apart from the DLPFC, new targets for depression treatment have been under investigation, such as the dorsomedial prefrontal cortex (DMPFC) .When targeting the left DLPFC or DMPFC in depression, theta burst stimulation (TBS) is delivered intermittently, in 2 s trains delivered at 10 s intervals. This is believed to increase excitability in the targeted region similar to the traditional high frequency (10 Hz) protocols but with a shorter duration, just over 3 min, compared to almost 38 min .RTMS is an overall well tolerated treatment with scalp pain or discomfort on the application site being the most common issue . In the The aim of this study was to investigate and compare the pain perception of active and sham iTBS of the DMPFC in patients with depression. The main objective was to study how the pain develops over time and if any differences could be observed between patients receiving active or sham treatment.This study includes a subset of patients from a double-blind randomized clinical trial at Uppsala University Hospital, Unit for brain stimulation, investigating the effect of iTBS over the DMPFC on negative symptoms. Recruitment of the patients in this subset with depression was from September 29 in 2016 to October 1 in 2018.Patients were recruited from the academic psychiatric clinic in Uppsala, Sweden, and enrolled by author RB. For the present subset we only included the patients with a depressive disorder diagnosis verified through a Mini International Neuropsychiatric Interview version 6.0 (M.I.N.I.) . FurtherThe first visit was a screening visit where patients were investigated and scheduled for a baseline visit if they fulfilled all inclusion criteria. The baseline visit included structured psychiatric symptom interviews, self-rating of depressive symptoms with the Montgomery Asberg Depression Rating Scale (MADRS-S) , a neuroThe stimulator operating nurse received a randomization code in an envelope prepared by a contract research organization, which was entered in the rTMS machine to obtain correct treatment allocation. Sham or active treatment was given daily during 10–15 weekdays depending on the patients’ ability to reach the target intensity, which was 90% of the individual RMT. During each session at least 50% of the trains had to reach the predetermined treatment intensity to be regarded as a complete treatment session. If a session did not meet these criteria the treatment course was prolonged with 1 day at a time, with a maximum of 15 days for the whole treatment course.The day after the final treatment, the psychiatric and neurophysiological examinations made on the baseline visit were repeated. The operator and patients were unmasked 4 weeks after baseline. During the open phase, patients allocated in the sham group received active iTBS treatment with the same titration procedure and treatment protocol as described above.Treatment was applied to the DMPFC which was located with an MRI-based neuronavigational system . The brain target used for navigation was defined as the coordinates x = 0, y = 30, z = 30 in Montreal Neurological Institution (MNI) . The magTo the active group, rTMS with theta-burst frequency was applied at 90% of resting motor threshold, 80 trains of stimulation , each train consisting of ten bursts at 5 Hz and each burst consisting of three biphasic pulses at 50 Hz, a total of 2400 pulses/session.In the group allocated to sham treatment the magnetic stimulator automatically prompted the user to place the insulated side of the coil towards the patient. For all patients, two TENS electrodes were placed medially on the forehead under the coil. However only in the sham group, patients received a mild TENS with a maximum current of 4 mA, synchronous with the magnetic pulses and scaled to magnetic stimulation intensity to mimic the sensation of active treatment. No TENS was given in the active group. The TENS application is a built-in software within the TMS device, which is activated depending on the entered randomization code, enabling blinding of the operating nurse.Patients were asked to rate the pain they were experiencing directly after the last train of stimulation. Patients decided for themselves if they preferred pain rating with Visual Analogue Scale (VAS) or Numeric Rating Scale (NRS), on a scale from 0 to 10, where 0 is no pain and 10 is worst imaginable pain.days to target.During the first treatments the intensity was individually titrated up aiming to reach 90% of RMT. In the sham group the TENS intensity was automatically scaled to the magnetic stimulation intensity by the built-in software within the TMS device, which enabled titration to reach a TENS intensity corresponding to 90% of RMT. The titration was employed to reduce the discomfort by letting the patients get used to the sensation of the stimulation. The intensity was slowly increased if the patient found the pain manageable, i.e. not rating the pain higher than seven. When at least 50% of the trains reached the predetermined treatment intensity (90% of RMT) the session was regarded as a complete session. The number of days to reach the first complete session was defined as Shapiro-Wilks test of normality implied that the pain rating data was not normally distributed. Since the data was skewed and pain is measured in ordinal scale, median was chosen as central tendency measure and non-parametric tests were chosen for the analysis.Baseline demographic and clinical data were assessed with Mann-Whitney U-tests  or Chi-square tests .To account for the fact that patients received different degrees of stimulation intensity due to variations in titration rate and RMT (which in turn affected the target stimulator intensity), an adjusted pain score was created by dividing the original pain score by actual magnetic stimulator intensity at train 80.First, a Mann-Whitney U-test was conducted to test for group differences in pain rating on the first, fifth, and final day. Second, a related-samples Friedman’s test of differences among repeated measures was conducted in order to analyze changes of the pain scores over time. Dunn-Bonferroni post hoc tests were carried out, with significance values adjusted by the Bonferroni correction for multiple tests. Finally, the pain score from the open phase was analyzed with a related-samples Friedman’s test of differences among repeated measures and Dunn-Bonferroni post hoc tests.To explore if treatment response might explain the differences between the two treatment groups a non-parametric ANCOVA was conducted with treatment day as repeated measures and treatment arm as between-groups effect. The covariate was the difference in total MADRS-S rating scores between baseline and follow-up.A second Mann-Whitney U-test was conducted to test for groups differences in days to target intensity due to titration.Additional analysis were conducted without adjusting the pain score for stimulator intensity in the titration phase as described above.Statistical analyzes were conducted IBM SPSS Statistics 25.0.A total of 42 patients with depression were included in the study and 36 completed the blind phase. Two declined before randomization, and 21 were allocated to sham and 19 to active iTBS. Three dropped out during the blind phase, two in the sham group between fifth and final day, one due to a serious adverse event, and the other due to poor subjective effect, one in the active group before the fifth day due to practical issues to attend the treatments, and one patient in the active group had missing data on pain rating on the first treatment day. Consequently, for the first and fifth treatment day, 18 patients receiving active and 21 patients receiving sham treatment were available for analysis. Thereafter, one patient in the active group was excluded from analysis of the final day due to unblinding of operator and patient because of faulty magnetic stimulator. Thus, for the final treatment day data was analyzed on 17 patients receiving active and 19 receiving sham treatment. Two of the 21 patients from the sham group did not enter the open phase. One of the remaining 19 patients dropped out before the fifth treatment day.p = 0.175). These MADRS-S change scores have been reported elsewhere [There were no differences between groups in baseline demographic and clinical characteristics Table . Both grlsewhere .Table 1p = 0.054). Median (IQR) treatment duration was 11 (2) days in the active group, and 10 (5) days in the sham group.Due to titration, there was a trend towards the group allocated to sham treatment reaching target intensity faster , compared to the group receiving active treatment . However, there was no statistically significant group difference  and the sham (N = 21) group on the first  and fifth day , but not between the active (N = 17) and the sham (N = 19) group on the final day .An Independent-Samples Mann-Whitney U test showed a statistically significant difference in pain scores between the active (N = 16), there was a statistically significant difference in pain score over time (χ2(2) = 9.855, p = 0.007), with an effect size of w = 0.3. There were significant differences between the first and the fifth day  and the first and the final day  with decreasing pain rating scores. There was no significant difference between the fifth and the final day . In the group receiving sham treatment (N = 19), there was a significant difference in pain score over time (χ2(2) = 6.880, p = 0.032). However, when values were adjusted by the Bonferroni correction for multiple tests there was no significant post hoc tests .A related-samples Friedman’s test of differences among repeated measures was conducted in order to analyze the pain scores over time. When analyzing the pain rating score in the active group  and no significant time x symptom change interaction .A non-parametric ANCOVA with change in MADRS-S rating as covariate was conducted to control for treatment effect on depressive symptoms. There was no main effect of symptom change  pain ratings, not adjusted for titration of stimulation intensity, for the active/sham group were 4 (2) / 2 (4) on the first day, 3 (2) / 1 (2) on the fifth day, and 2.5 (4) / 2 (2) on the final day, respectively.The group allocated to sham iTBS received active iTBS in a subsequent open phase. There, the pain ratings were higher in the beginning of treatment, showing a similar trend of decreasing pain as the group receiving active rTMS during the blind phase Fig. . Median N = 18), showed a significant difference in pain scores over time . Dunn-Bonferroni post hoc tests were conducted with adjustments by the Bonferroni correction for multiple tests showing a significant difference between the first and the final day  but not between the first and the fifth day  or the fifth and the final day .A related-samples Friedman’s test of differences among repeated measures comparing pain rating in the open phase . A meta-analysis exploring the activation and localization of cortical areas involved in pain processing showed that the right ACC had the highest likelihood of being activated when painful stimuli were applied . A studyA study by Fox et al. 2012) suggests that the antidepressant effect of rTMS over the DLPFC may partly be explained by a decreased activity in the sgACC and other limbic regions, as a result of the treatment . Further12 suggesThe fact that patients in our study, especially in the active group, overall received higher intensity of stimulation towards the end of the treatment course, may have affected the pain rating scores. We do not know how a supposed habituation would have affected the pain rating scores if the individually predetermined target magnetic stimulator intensity was applied on the first day without titration. However, one could expect that tolerability would decrease and drop-out rates would probably have been considerably higher due to more discomfort.For a session to be regarded as a complete treatment session at least 50% of the trains had to reach target treatment intensity. If a session was not complete, the treatment course was prolonged with a maximum of five additional days, which might be a good way to increase tolerability. However, longer treatment courses mean higher costs, potentially limiting accessibility. A pilot study on strategies to reduce rTMS-related pain showed a considerable reduction in pain by injections of lidocaine (with or without epinephrine). They also showed a smaller reduction in rTMS-related pain by applying foam padding between coil and scalp, but no effect by applying topical local anesthetics cream . StudiesOne of the limitations of this study was the instruments used for pain rating. Patients decided for themselves if they preferred pain rating with VAS or NRS, and therefore both scales were used inconsistently, and without any recording which scale was used. However, the importance of the limitation remains uncertain. A review investigating pain assessment in 54 papers showed that the NRS and VAS scores overall corresponded, with only few exceptions where higher scores were reported with VAS . AnotherA strength of our methodology was the study sham-controlled parallel group design and that the pain scores were adjusted for titration in both groups. By doing this, comparisons between active group and sham group, where target intensity was reached to a greater extent, were more accurate than analyzing the original pain score. However, we do not know if the assumption of a linear relation between stimulation intensity and subjective pain rating is met. By allowing inclusion of patients with concomitant diagnoses such as autism spectrum disorders or personality disorder, the patients in this study adequately represented the general clinical patient where multi-morbidity is common, which promotes generalizability of the findings.To conclude, active iTBS was more painful than sham in the beginning of the treatment course. The painfulness of active iTBS decreased over time and converged on sham iTBS, with the two being equally tolerable towards the end. When the group allocated to sham iTBS received active iTBS in a subsequent open phase there was a similar trend of decreasing pain. Further research on how to best reduce pain of depression treatment with iTBS could enable faster titration and shorter protocols and increase tolerability.The outcome of this study can be used clinically to inform patients that during treatment of depression with iTBS, the pain decreases throughout the treatment course.


Neuropathic pain has a prevalence of 2–17% in the general population. Diagnosis and treatment of neuropathic pain are not fully described in different populations. The aim was to determine the treatment patterns and direct costs of care associated with the management of neuropathic pain from the onset of the first symptom to up to two years after diagnosis.  From a drug-claim database, a cohort of randomly selected outpatients diagnosed with neuropathic pain was obtained from an insurer in Colombia and followed up for two years after diagnosis. The clinical records were reviewed individually to identify the study variables, including the time needed to make the diagnosis, the medical and paraclinical resources used, the pharmacological therapy for pain management, and the direct costs associated with care.  We identified 624 patients in 49 cities, with a mean age of 50.3 ± 14.1 years, of which 324 were men (51.9%). An average of 90 days passed from the initial consultation until the diagnosis of neuropathic pain, the most frequent being lumbosacral radiculopathy (57.9%). 34.5% of the cohort had at least one diagnostic imaging procedure, and 16% had an electromyography. On average, they were treated by a general practitioner twice. 91.7% received initial treatment with tramadol, carbamazepine, amitriptyline, imipramine, or pregabalin, and 60.4% received combined therapy. The mean cost of care for two years for each patient was US$246.3.  Patients with neuropathic pain in Colombia are being diagnosed late, are using therapeutic agents not recommended as first-line treatment by clinical practice guidelines, and are being treated for short periods of time. Neuropathic pain has a prevalence of 2 to 17% in the general population according to different studies . NeuropaDifferent therapeutic strategies are available to deal with neuropathic pain, including both pharmacological and nonpharmacological interventions , 6. The Occasionally, patients are treated with other types of treatments, such as analgesics, which have not proved efficacy for this specific condition. Also, some patients could be receiving suboptimal doses or at inappropriate intervals. Consequently, adherence of these treatments may be poor, which can lead to a low therapeutic response and persistence of symptoms , 11.On the other hand, accurate diagnosis is challenging due to the heterogeneity of positive and negative sensorineural symptoms; thus, developing simple protocols for pain classification and correct treatment sometimes is not plausible, which leads to unnecessary use of health system resources and administration of inappropriate treatments , 13. In In Colombia, the annual cost of chronic pain is unknown. Some statistics indicate that about 35 to 50% of the general population suffers chronic pain,  suggestiDue to the implications of pain for the quality of life of patients, complexity involved in diagnosing the neuropathic pain, and the potential budget impact to the Health Care System, our objective was to determine the treatment patterns and direct costs for medications, consultations, and diagnostic aids associated with the management of neuropathic pain. We analyzed these factors from the onset of a first diagnosis of any type of pain until the patient was actually diagnosed with neuropathic pain and then during a two year follow-up. Additionally, we analyzed persistence, changes, and combinations used for the treatment of neuropathic pain.This was a longitudinal retrospective study. Patients diagnosed with neuropathic pain who were attended by a health insurer  in Colombia between 2002 and 2017 were identified from a drug-claim database. This database includes more than 2 million people from the HMO of this study. Two periods of time were evaluated. The initial period began from the appearance of the first diagnosis of pain for each patient to the time of the diagnosis of neuropathic pain (the index date). The second period comprised the following two years after the diagnosis of neuropathic pain was established. From the patients identified in the drug-claim database, a random sample was calculated to select those who participated in the study.Subsequently, the drug-claim database, electronic medical records (EMRs) of each selected case, and billing information were used to extract the study variables. Using the EMRs, the clinical course was evaluated from the first diagnosis of pain until the diagnosis of neuropathic pain was made. This evaluation comprised identification of the resources associated with care, including medical appointments with specialists and general practitioners, the medications dispensed, and the laboratory and imaging services provided. The variables were parameterized based on the data in EMRs and the published clinical studies.During the two-year follow-up period after diagnosis, the treatment patterns were identified, considering the drugs used, their dosages, persistence, or changes in medication, the current cost of the drugs, and the use of health resources. The International Association for the Study of Pain (IASP) diagnostic guidelines were used to evaluate the symptoms of neuropathic pain . FinallyWe included patients older than 18 years with complete medical records and the diagnoses associated with neuropathic pain according to the International Classification of Diseases (ICD-10), G54.1, G53, G54, and G56-G62, who were receiving medications approved by the National Institute for the Surveillance of Drugs and Foods of Colombia  for this indication prior to 2015 and who had been diagnosed and treated in the health insurer network. We also included the code for fibromyalgia (M79.7), which is not formally defined as a neuropathic pain, but it is a condition in which many of the medications used to treat neuropathic pain can be useful .Patients with the following diagnoses were excluded: acute and transient psychotic disorders (F23), depressive episode (F32), recurrent depressive disorder (F33), persistent mood (affective) disorders (F34), epilepsy (G40), seizures not classified elsewhere (R56), phobic anxiety disorders (F40), and other anxiety disorders (F41).A simple random sample of 646 patients was estimated, based on a total of 49,321 patients affiliated with the HMO who had the diagnoses of the study. An expected proportion of 18.9% (according to treatment persistence), accuracy of 3%, and a confidence level of 95% were used.Sociodemographic: age, sex, city of residence, and insurance regimeClinical: main diagnosis considered in the inclusion criteria, diagnostic images related to the diagnosis of neuropathic pain, specific tests for the diagnosis of neuropathic pain, date of the diagnosis of neuropathic pain, comorbidities, and interventionsPharmacological: medications for the management of neuropathic pain, dosages, dates of beginning and end of treatment, route and frequency of administration, cause of suspension of study drugs, proportion of days covered, use of combination therapy, start and end dates for combination therapy and concomitant medicationsUse of resources: costs of study treatment, number of visits to medical specialists, type of medical specialists, type and number of laboratory and imaging services, and appointment costs for medical specialistsThe following groups of variables were considered:The costs of medical care  and of each paraclinical diagnostic test were evaluated during the second period of the study. The payer's perspective from a microcosting approach was used to determine gross costs using the Colombian pesos and US dollars for quantification, according to the representative exchange rate given by the Central Bank of Colombia, 1 US = COP$2,984.Medical care and paraclinical costs were assessed using the Colombian Social Security Institute's 2001 fee manual, with an additional 30% added to compensate for 2018 prices, as recommended by the Institute of Health Technology Evaluations of Colombia .The costs of the drugs were obtained from the invoicing prices of the logistic operator (Audifarma SA) for the corresponding HMO. The price of each medication was considered according to the average cost for the treatment year during the two-year follow-up.For the data analysis, the statistical package SPSS Statistics, version 24.0  for Windows was used. The information was collected by physicians following a data extraction template developed in Microsoft Excel. The template was parameterized according to the possible responses and the availability of information. It was validated in a pilot test of randomly selected medical records with the aim of standardizing criteria and concepts. Frequency and proportion analyses were performed for categorical variables, and measures of central tendency, position, and dispersion were conducted for quantitative variables according to the data normality determined using the Kolmogorov–Smirnov test.The study was approved by the Bioethics Committee of the Universidad Tecnológica de Pereira (Code : CBE-SYR-162016) under the “no risk” research category. The ethical principles established by the Declaration of Helsinki were respected. In no case was personal data collected for the patients.A total of 624 randomly selected patients were evaluated after excluding 22 due to identification of a concomitant diagnosis of anxiety disorder or depressive episodes during the EMR review. The mean age at the beginning of the cohort was 50.3 ± 14.1 years, 324 were men (51.9%), and all patients were followed for 24 months. The patients were from 49 different cities in Colombia.We found a median of 7 days (interquartile range: 0–82 days) and an average of 90.6 ± 214 days between the pain-related diagnosis and neuropathic pain diagnosis. The most frequent diagnosis was lumbar radiculopathy . n = 194, 31.1%), dyslipidemia , diabetes mellitus , migraine , obesity , and peripheral vascular disease . A total of 236 patients were receiving concomitant medications for any of these conditions, the most common of which were losartan , atorvastatin , omeprazole , enalapril , acetylsalicylic acid , gemfibrozil , insulin , and metformin .Comorbidities were identified in 367 patients (58.8%). The most frequent comorbidities were arterial hypertension , and the most commonly used therapies were tramadol plus acetaminophen , carbamazepine plus acetaminophen with codeine , and amitriptyline plus acetaminophen with codeine , although 70 other combinations were identified.The main drugs initiated for pain management and those used at any time during follow-up are shown in n = 63, 10.1%), orthopedics , psychiatry , occupational medicine , neurosurgery , and internal medicine . A total of 143 (22.9%) patients had more than one specialized consultation.All patients had an average of two consultations with a general practitioner per year during the follow-up period, with 228 (36.8%) visiting a specialist, particularly a family doctor  were the most frequently prescribed initial drugs (68% vs 34.1% in this study), followed by opioids (25% vs 33.5% for tramadol in Colombia) and tricyclic antidepressants (17% vs 27.4% in Colombia) , 19. In Tramadol was the most commonly used as initial therapeutic analgesic, and one-third of the patients were receiving it. However, a high proportion underwent a suspension or change to another medication. Opioids are used for the management of low back pain with radiculopathy only in acute episodes according to current recommendations, although studies have supported their effectiveness in reducing pain and improving activity, especially for peripheral neuropathic pain , 8, 20. Carbamazepine, amitriptyline, and imipramine accounted for approximately half of the prescriptions used as initial therapy; these have some evidence of their effectiveness in the treatment of long-term neuropathic pain. Nevertheless, a significant proportion of treatment discontinuation was found during the follow-up, with persistence of use in approximately 10% of cases. This situation may be associated with poor tolerability due to the appearance of adverse effects or therapeutic failure , 22–24; Pregabalin and gabapentin were prescribed with low frequencies as an initial therapy . However, their use increased throughout the follow-up period. These drugs were used in 34.2% of the patients at any time during follow-up and were the group of drugs that were most often used at the end of the study period (the last month). The persistence was also high for these drugs, with almost half of the patients who started with them continuing the therapy, alone or combined with another drug, after the first three months; in contrast, the persistence of use of all of the other analgesics was only approximately 10%. These results are similar to those of a study conducted in the United States, which found that these two drugs showed the greatest persistence .The predominance in the use of pregabalin in the male population is striking; previous reports have shown that women with ages similar to those reported in this study use it more frequently . The aveDuring the observation time were frequent the combinations in the treatment, with periods of acute and chronic use or changes and moments without therapy. This finding might suggest some type of difficulty in the management of this group of pathologies, in which drugs not approved for these indications were being chosen and prescribed at suboptimal doses or with different efficacy/tolerability ratios . In addiThe cost of pharmacological therapy was approximately $62 per year, particularly for generic drugs that generally had lower prices. The lowest cost therapies were those that included commonly used analgesics, such as acetaminophen or different nonsteroidal anti-inflammatories, whereas opioids, such as codeine or hydrocodone, and anticonvulsant drugs had higher costs , 30.This study has some limitations as a descriptive study, such as the inclusion of patients diagnosed with neuropathic pain from a single HMO in the country and the exclusion of those who have not been diagnosed or are not being treated pharmacologically. Also, we could not evaluate the medical records of the consultations of some patients attended by a group of specialist doctors who were outside the HMO's network and could not establish the use of resources and the costs associated with emergency care and during hospitalization. Finally, the calculated costs are a general estimate at the current prices, but each service provider may have different rates established for interventions, consultations, and diagnostic tests. Thus, conclusions should be applied to populations with similar demographic and insurance characteristics.Multiple strengths are also recognized, such as the size of the sample for an observational study of this type, the rigor of data collection, the different sources of information for monitoring the medicines used, and the associated costs based on a population of more than 2 million insured patients.With the above findings, this study concludes that patients with neuropathic pain are being diagnosed on average 90 days after their initial consultation, using significant imaging resources, general medical care, and different specialties. Additionally, these patients are initially treated with drugs that are not considered first-line for this type of pain according to clinical practice guidelines and are prescribed at doses lower than recommended for relatively short periods, with multiple suspensions and substitutions with new drugs over a two-year follow-up .These results suggest that making the diagnosis and undertaking and maintaining adequate therapy is difficult, and thus, an effort needs to be made to ensure that those responsible for healthcare take measures to guarantee the opportunity and quality of the service. Studies must be carried out to establish the effectiveness of neuropathic pain treatments and develop clinical practice guidelines that seek to improve diagnostic processes and provide adequate, effective, and safe treatment in these patients.


Material and Methods.  Proprioceptive training is popularly applied as a therapeutic exercise method in physiotherapy. Its effects on pain and range of motion are only poorly evaluated. Therefore, this study assesses the effectiveness of proprioceptive training with an Eye-Cervical Re-education Program to decrease pain and increase the joint range in chronic neck pain patients. Setting. Physiotherapy consultation. Participants. 44 people were divided into two groups. Interventions. All patients were treated with a multimodal physiotherapy intervention. The experimental group was supplemented with an exercise program that included eye-cervical proprioception. Outcomes. The primary outcomes included pain pressure thresholds  and cervical range of motion. The secondary outcomes included pain measured by the Visual Analogical Scale and the McGillSpv Questionnaire.  A randomized, no-blinded, controlled clinical trial. p=0.001), left upper trapezius (p=0.001), left upper trapezius (p=0.001), left upper trapezius (p=0.001), left upper trapezius (p=0.001), left upper trapezius ( The proprioception treatment was effective in reducing the pain pressure threshold in the right upper trapezius (NCT03197285 (retrospective registration). The Eye-Cervical Re-education Program is effective at relieving pain pressure thresholds in the upper trapezius, right levator scapula, and left splenius capitis and especially effective for increasing the cervical range of motion. This trial is registered with  This study assesses chronic neck pain (CNP), a common problem in modern and industrialized countries  and amonAdults with neck pain commonly experience hyperalgesia of cervical muscles, as evidenced by a reduced pressure pain threshold (PPT) . Pain syProprioceptive function accuracy has recently gained considerable attention in the description and assessment of CNP , 10. TheConsidering these findings, the goal of the present study focuses on proprioceptive training at the cervical level, a therapeutic option that targets maladaptive changes in patients suffering from neck pain; however, its effects on pain and function have been poorly evaluated .The Eye-Cervical Re-education Program (ECRP) is a specific proprioceptive training program that includes head relocation exercise practice, gaze stability, eye follow, and eye/head coordination exercises . This prTo the best of our knowledge, the effect of the ECRP versus that of the multimodal physiotherapy intervention (MPI) efficacy has not been analyzed. Thus, this clinical trial aims to verify the effectiveness of the ECRP against an isolated multimodal physiotherapy intervention in increasing the pressure pain threshold and range of motion in the cervical area.NCT03197285) (retrospective registration).This study was a no-blinded, randomized controlled clinical trial, with parallel groups and a blinded assessor. It was guided according to the CONSORT Statement guidelines. This research received approval from the Ethics Committee of the University of Seville (ref. 30062010). The authors confirm that all research was performed in accordance with the relevant guidelines of the Ethics Committee of the University of Seville. Participation in the study was voluntary. Patients were informed orally and in writing regarding the procedure to be conducted, and informed consent was obtained from all participants. The study was registered at clinicaltrials.gov (All participants were recruited in a private physiotherapy consultation in Cadiz (Spain) by a specialized physician in traumatology with more than 12 years of experience. The inclusion criteria were as follows: patients of both sexes, age between 20 and 50 years, with neck pain diagnosed by their physician greater than 3 months in duration and active or latent myofascial trigger points (MTrPs) in at least one of the following muscles: upper trapezius, levator scapulae, or splenius capitis. Both active and latent MTrPs were considered because latent MTrPs have been associated with the development of sensory-motor dysfunction and may contribute to different chronic musculoskeletal pain disorders . RegardiTwo groups of subjects were established; the control group (CG) received multimodal physiotherapy intervention (MPI) as subsequently described, and the experimental group (EG) was treated with the MPI and an Eye-Cervical Re-education Program (ECRP) developed by Revel et al. . All proA trained and blinded physiotherapist performed the initial and final assessments. This professional had more than 10 years of clinical experience. In the first session, self-reported outcomes were collected via the McGillQSpV and the Visual Analogue Scale (VAS). The following clinical tests were subsequently performed: range of motion (ROM) and pressure pain threshold (PPT). These clinical tests will be described in detail and show acceptable reliability, construct and discriminative validity.µs width pulse, and a frequency of 1 Hz for 10 minutes. The patient should notice a slight vibration, without it being painful).The treatment was performed by a different physiotherapist than the evaluator. In this case, she could not be blinded because she had to apply the ECRP. The subjects received ten sessions on alternate days. All patients were treated with an MPI that consisted of thermotherapy (70 W continuous microwave 10 minutes), therapeutic massage , and the application of analgesic currents  using 4 × 4 cm self-adhesive silicone electrodes, symmetrical biphasic rectangular current, a 200 The ECRP developed by Revel et al.  had beenTo stimulate ocular mobility without including the cervical movement: the patient was placed in the supine position, with the physiotherapist seated at the height of the head.Exercise 1. Activation of ocular muscles. Without moving the head, analytical exercises on the maximum amplitude of ocular movement towards the right, left, front, and feet were actively performed. The exercise was repeated 3 times, first with the eyes open and then with closed eyes.Exercise 2. The physiotherapist performed a passive mobilization of the cervical spine in rotation and flexo-extension, while the patient maintained the eyes at a fixed point located in the vertical direction. After memorizing this point, the exercise was repeated with eyes closed.To exercise cervical mobility with restricted eye movement. the patient is placed on a rotating stool. The ocular mobility is excluded with opaque glasses that exclusively allowed the foveal vision.Exercise 3. Analytical exercises on cervical mobility were actively performed. The goal was to keep the gaze on a target as far as possible in each of the directions. Each movement was repeated 3 times.Exercise 4. Global exercise of cervical movement. The patient follows with his eyes a complex geometric path or a graphic painted on the wall.Exercise 5. Cervical mobility work with the trunk. The patient fixed his gaze on a target on the wall, while the physiotherapist destabilized the trunk in all directions in a combined manner.Exercise 6. Head reposition exercise (first degree). The patient was placed in front of a mirror in the correct position. After memorizing this position, he had to make movements with his eyes closed . Without opening his eyes, the patient should try to return to the starting position. This exercise is repeated 10 times.Exercise 7. Head reposition exercise (second degree). This exercise is the same as the previous exercise except the physiotherapist destabilized the patient.Finally, we stimulate eye and neck movement coordination. The patient continued to sit on the stool, in this case, without the glasses.Exercise 8. Free coordination exercise. The physiotherapist stood in front of the patient with an object in his hand. The patient fixed his eyes on this object, which was directed by the physiotherapist with the intention of reaching the maximum amplitude in each of the movements. The duration of this exercise was one minute, and it was repeated twice. The amplitude of the movements performed by the physiotherapist depended on the condition of the patient but was applied throughout the joint range available.Exercise 9. Manual resistance coordination exercise. The physiotherapist stood behind the patient. The subject had to move in a requested direction and, in turn, the physiotherapist offered manual resistance to the movement. As in exercise 8, the amplitude and resistance depended on the physical condition of the patient. The duration was 2 minutes.Exercise 10. Oculocervical coordination and multidirectional manual stimuli work. Exercise 9 was repeated; however, instead of offering manual resistance, the physiotherapist performed soft imbalances on the patient's head. The duration was two minutes.This program includes 10 exercises that have proprioceptive reprogramming in the cervical area with the following phases:At the end of the last session, the same blinded evaluator performed the measurements in all subjects. Registered computerized medical records were used to collect demographic and clinical information on the patients.The primary outcome measures reported in this study included the cervical pressure pain threshold and cervical range of motion.2 at the round tip. To ensure the repeatability of the location for the subsequent assessment sessions, the PPT measurements were performed at the splenius capitis sites near the upper insertion of the trapezius muscle 2 cm lateral to the spinous process of the axis and on the levator scapulae muscle 2 cm above the lower insertion located in the upper medial border of the scapulae while patients were lying prone. Finally, measurements were obtained on the upper border of the trapezius muscle half-away between the midline and lateral border of the acromion [2) turned into a pain sensation, at which point compression was terminated. After a rest of approximately 30 seconds, the next measurement was obtained [Pressure pain threshold (PPT) is a reliable outcome measure to measure pain . The PPTacromion . The patobtained . Measureobtained .Range of motion (ROM) was examined using a bubble inclinometer  for flexion/extension and lateral flexion and neck rotation. This test has satisfactory psychometric properties and may be recommended for clinical use  with ICCThe neck pain intensity measured on VAS and McGillQSpV was considered as secondary outcomes.VAS reproducibility has been recognized in individual subjects (ICC = 0.97) . On the 2 and with a size of effect d of 0.80 [α = 0.05 and β = 0.20, and a ratio between groups N2/N1 = 1. The calculations indicated a sample size of 42 subjects, with 21 subjects per group. After the estimation and given the characteristics of our convenience sampling, we considered it appropriate to include 22 subjects per group , which indicated an increase in the power of the study up to 82% (β = 0.18).The sample size was calculated using the free Gpower3.1.9.2 software for a clinical trial. The sample used for the calculation was obtained from a pilot study with similar characteristics to the present study, considering as outcome measure “pressure pain threshold in the right trapezius” with a difference between groups of 0.15 kg/cm of 0.80  and repr of 0.80 , an α = Data were analyzed with SPSS Version 25.00 for Windows . Shapiro–Wilk test was used to verify the normality of the main variables. This statistic was calculated by first considering all subjects together, followed by considering each group separately. A description of our data was provided, which includes the means and standard deviations of normally distributed variables and the medians and interquartile ranges for nonnormally distributed variables. In the case of the qualitative gender variable, the absolute frequencies and percentages of each category were calculated.t-test was used for independent samples.The initial homogeneity of the two intervention groups was subsequently checked for the age and pretest variables of all dependent variables. Student's t-test was used for related samples and the Wilcoxon signed-rank test for pretest and posttest values. When we considered two groups, Student's t-tests were used; for the variables that did not fit the normal, the Mann–Whitney U test was used. We complemented the significance test with effect size calculation using Cohen's d  [To determine the effectiveness of MPI the Student's freedom) . The varfreedom) .p < 0.05).An intention to treat analysis was performed. Statistical tests were conducted considering a 95% confidence interval (CI)  and left (p=0.014) upper trapezius, right levator scapula (p=0.040), and the left splenius capitis (p=0.021), whereas for the left levator scapulae and the right splenius capitis, our results indicated no significant differences (p ≥ 0.05). For the ROM, statistically significant differences were observed in all ranges (p < 0.05). . .There was no significant effect of ECRP on secondary outcomes compared with MPI.p values in a range between 0.05 and 0.98.In the case of the McGillQSpv, all items showed nonsignificant p=0.07 was obtained with a mean difference of 6.32. These values cannot be considered significant  [2), left tibialis (0.9 kg/cm2), C5 right (0.07 kg/cm2), and C5 left (0.48 kg/cm2) in a chronic neck pain population but not in the trapezius, levator scapulae, and splenius capitis. These values are far from the values established for PPTs in general (2.04 kg/cm2). In future investigations, it is necessary to establish the MCID for the PPT typically measured in the chronic neck pain population. Then, we should return to the present analysis.Considering the minimum clinically important difference (MCID) established in general for the PPT (a difference of at least 2.04 kg/cme means) , our rese means)  determinThe cervical ROM was statistically significant in all movements measured with a large effect size and showed a substantially beneficial difference . DetericThe values obtained in the VAS were not statistically significant and did not show a substantially beneficial difference. This instrument may be less sensitive with respect to measuring pain after cervical proprioception training alone . This maAfter assessing the study, one limitation is the lack of follow-up in the medium and long term to assess the duration of the results obtained. Consequently, these data will be incorporated into future research. In addition, pathologies such as whiplash may be prospectively included because these patients present a greater number of alterations in the eye-cervical proprioception . It woulThe results of the study show some improvement in ROM . In addition, the study has failed to demonstrate improvement in neck pain and function. More research is needed, including variables to measure function such as the Neck Disability Index.The method of sealed envelopes for randomization may add a risk of bias in favour of the experimental group. In future research methods that achieve better randomization should be used.In conclusion, the ECRP is effective for increasing the pressure pain threshold in the right and left upper trapezius and left splenius capitis and especially effective for increasing joint cervical mobility. The ECRP implies a significant increase in the range of motion compared to the isolated application of a multimodal physiotherapy intervention.


Postoperative pain after breast cancer surgery remains a major challenge in patient care. Local infiltration analgesia is a standard analgesic technique used for pain relief after surgery. Its application in patients who underwent mastectomy requires more clear elucidation. This study aimed to investigate the effect of ropivacaine infiltration of drainage exit site in ameliorating the postoperative pain after mastectomy.n = 37) or 10 ml normal saline (Group B) (n = 37). Pain scores were recorded in post-anesthesia care unit (PACU), at 6 h, 12 h, 24 h and 36 h after operation by using a visual analogue scale (VAS). Postoperative nausea and vomiting (PONV) incidence, postoperative analgesic and antiemetic requirements, the incidence of chronic pain, as well as the quality of recovery were recorded.A prospective randomized controlled study was conducted in 74 patients who were scheduled for unilateral mastectomy by standardized general anesthesia. Both intervention group and control group were given infiltration of the two entry points of drainage catheters with 10 ml 0.5% ropivacaine (Group A) (p < 0.0005), at 6 h (p < 0.0005), 12 h (p < 0.0005), and 24 h after surgery (p < 0.05) when compared to those in Group B. There were more postoperative analgesic requirements in Group B (p < 0.05). With regard to the quality of recovery, Group A was shown to be much superior over Group B (p < 0.05).The patients in Group A showed a significant reduction in postoperative pain in PACU .retrospectively registered in  Postoperative pain is one of the most common challenges in women following breast cancer surgeries, which impairs rehabilitation and increases the length of hospital stay. About 50% of patients who receive mastectomy might experience persistent postoperative pain , 2. SensAlthough multimodal analgesic strategies including opioids, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), peripheral regional techniques, patient-controlled modalities as well as local anesthetic techniques such as wound infiltration are available, postoperative pain still has been poorly managed. Analgesia-related side-effects such as nausea and vomiting, dizziness, constipation and itching are commonly observed, impairing patients’ satisfaction and delaying their discharge time , 8. PostThis prospective randomized controlled study aimed to investigate if infiltration of ropivacaine at the insertion sites of the two drain catheters in mastectomy would reduce postoperative acute pain, postoperative nausea and vomiting (PONV), and chronic pain.Chictr.org.cn registry system on 24 February 2020 (ChiCTR2000030139). This study was conducted in Cancer Hospital, Chinese Academy of Medical Sciences between September and November 2019, and has been approved by the institutional ethics committee . All patients were followed up until 3 months after discharge from the hospital.This prospective, randomized controlled trial was designed in adherence to the CONSORT guidelines and was registered in Patients who underwent unilateral mastectomy with axillary lymph node dissection (ALND) or sentinel lymph node biopsy (SLNB) were enrolled in this study. Written informed consent was obtained from patients. The patients aged 20 ~ 70 years, and with the American Society of Anesthesiologists physical status of I to III were included. Patients with the following conditions were excluded from the study: history of severe cardiovascular or pulmonary, hepatic, renal, neurologic, and psychiatric or metabolic diseases; history of allergy to any of the potential study medications; active drug abuse; intake of NSAIDs, opioids, or other analgesics in the 24 h before surgery; pregnancy; breastfeeding, active menstruation.Prior to study initiation, 80 sequentially numbered envelopes containing the allocation were prepared. The involved patients were randomly assigned to 10 ml 0.5% ropivacaine infiltration (Group A) or 10 ml normal saline infiltration (Group B) groups. A physician independent of the study randomly inserted 40 anesthesia strategies for each group into the envelopes. The random allocation sequence was generated using computer-generated random numbers. The researchers opened the envelope to determine as to which anesthesia strategy to implement before the induction of general anesthesia. All perioperative data were collected by an investigator who was blinded to the patient’s allocation, and was responsible for measuring the outcome.Standard general anesthesia was induced using sufentanil 0.3 ~ 0.6 μg/kg, propofol 1 ~ 2 mg/kg and cis-Atracurium 0.2 ~ 0.4 mg/kg in the two groups. After laryngeal mask airway insertion, the patients were mechanically ventilated to maintain the end-tidal carbon dioxide concentration at 35 ~ 45 mmHg with a fresh gas flow of 2 L/min 60% oxygen. Anesthesia was maintained by constant inhalation of 1.5 ~ 2.5% sevoflurane and constant infusion of remifentanil at a rate of 0.1 ~ 0.2 μg/kg/min. Sufentanil 0.1 μg/kg was added intraoperatively as required. At the end of the surgery all patients received 100 mg of flurbiprofen (an NSAID). Dexamethasone 8 mg (given after induction) and ondansetron 4 mg (given at the end of surgery) were used for prevention of postoperative nausea and vomiting (PONV). All surgical procedures were finished by the same surgical team with the same standardized technique. The two drainage catheters were placed by the surgeon before closing the surgical incision. Before the placement, the subcutaneous tissue of the two entry points of the catheters received local infiltration, which included intervention group (Group A) by 10 ml 0.5% ropivacaine and control group (Group B) by 10 ml normal saline (5 ml for each point). After operation, all patients were extubated and transferred to the post-anesthesia care unit (PACU). Flurbiprofen 100 mg was provided by intravenous injection daily to control the postoperative pain within 3 days after operation. If the pain visual analogue scale (VAS) was ≥3, 100 mg tramadol was administered as a rescue analgesic. For postoperative antiemetic treatment, metoclopramide was intravenously administrated if the nausea VAS was ≥5 or episodes of vomiting ≥2. All patients received standard postoperative therapies according to the pathological characteristics.The pain was immediately assessed after returning to PACU and at 6 h, 12 h, 24 h, and 36 h after operation using a VAS (0 = no pain to 10 = most severe pain). The incidence of PONV was recorded simultaneously, using a three-point ordinal scale , and nausea was evaluated by VAS. The number of patients who received postoperative analgesic or antiemetic drugs was recorded.The status of chronic pain in patients was collected using the breast cancer pain questionnaire, which was first developed by Gartner et al. . A Pain The quality of recovery including 40 questions (QoR-40), which is used as a measure of quality of recovery, was distributed to patients for collecting data 24 h after operation. This included five factors of emotional state, physical comfort, psychological support, physical independence, and pain. In all, the highest score was 200 while the lowest being 40 and the more score, the better the results.Also the remaining data, including the consumption of sufentanil during the surgery, types of surgical procedures, operation and anesthesia time, age, body mass index (BMI), history of smoking and PONV were collected,p < 0.05.The sample size was calculated based on our preliminary experiment that enrolled 10 cases in each group. The mean pain VAS at 12 h after the surgery was 1.2 ± 2.1 for Group A and 2.9 ± 2.2 for Group B. Using standard sample size calculation formula to achieve a power of 0.8 at α = 0.05, there should be at least 29 patients included in each group to detect a significant difference. Considering the possibility of data censored, a total of 40 patients in each group were recruited to guarantee the sample size. SPSS 23.0 for windows  was used for data analysis. Normally distributed continuous data were expressed as means (SD), and were analyzed using analysis of variance (ANOVA), independent-sample t-test or paired t-test. Nonparametric data were analyzed by Mann-Whitney and Wilcoxon text. Two-sided tests were performed to declare statistical significance at The random assignment of the participants into the two groups and analysis of the outcome was presented in Fig. 6. Although whether surgical drains increase opioid consumption after mastectomy has not been investigated, pain originating from the insertion sites of the two drainage catheters constitutes a major part of acute postoperative pain. In this study, we found that ropivacaine infiltration of the two drainage exit sites have significantly reduced the postoperative pain in PACU , at 6 h , 12 h , and 24 h after operation   .Surgical drains were reported to be associated with high postoperative opioid use after breast-conserving surgeryWe did not collect pain scores of restricted movement of the shoulder and values of arm abduction angle. Because the operated arm was tightly bound and forbidden to move by surgeons within 3 days after the operations, in case of wound dehiscence, subcutaneous effusion and hematoma.p < 0.05).The intervention showed no effect on the incidence of chronic pain within 3 months, and PBI in the two groups showed similar results Table . No signTo our knowledge, this is the first prospective randomized controlled study to reveal ropivacaine infiltration of the two drainage exit sites, which significantly reduced postoperative pain and analgesic requirements and improved the quality of recovery after mastectomy.Park’s study  reportedTo compare with the previous similar studies, in Table The incidence of PONV in the two groups remained similar. However, from 6 h to 12 h after operation, PONV occurred in 6 patients in Group A and 12 in Group B. This difference might due to the side-effects of higher tramadol requirement in Group B. At 3-months follow-up, no significant differences were discovered with regard to the incidence of chronic pain. The mechanism of chronic pain is complicated, and it is still poorly controlled. Although our intervention decreased the postoperative pain more effectively, no surgical, demographic, and psychosocial factors that influenced chronic pain after breast surgery considered . It has However, there are certain limitations in this study that require consideration. Firstly, the sample size is small, and so it is not sufficient to perform subgroup analysis. Secondly, follow-up of the patient’s pain after 3-months was not evaluated.In conclusion, ropivacaine infiltration of two drainage exit sites effectively decreased the degree of postoperative acute pain and analgesic requirements within 24 h, and meanwhile improved patients’ quality of recovery. Further large scale studies are warranted to study the outcomes in the future, and explore efficient approach that relieve pain after mastectomy in long run.