Thoracic trauma results in multiple rib fractures (MRF), and surgical stabilisation of rib fractures (SSRF) can relieve fracture pain. Epigallocatechin-3-gallate (EGCG) is reported to exhibit beneficial effects in bone-related metabolic and differentiation processes. To study the clinical effect of EGCG on regional analgesia for pain relief in MRF patients after SSRF.2) were assessed day 10 after SSRF. Ninety-seven MRF patients  who were on epidural catheter analgesia after SSRF were recruited. They were randomly divided into: oral EGCG 100 mg  twice daily for 10 days and placebo groups. Pain scores, incentive spirometry (IS) volumes, respiratory rate and oxygen saturation , improved IS volume  and respiratory rate . However, no further enhancing effect on SpO2 was observed in the EGCG group . Comparing results from the placebo and EGCG group, in the 10-day intervention course, oral EGCG reduced pain score (8 at base line vs. 4 at end of intervention in EGCG group,  Although the study is limited by a relatively small sample size and lack of serum factor analysis, the key results and the study design, for the first time, nevertheless pave the way for trials with larger number of patients to understand the effect of EGCG in MRF patients that are undergoing SSRF. Thoracic trauma frequently results in multiple rib fractures (MRF), which occur in over 60% of all thoracic trauma incidences  as one of the most biologically potent components . The objective of the study was to assess the analgesic efficacy of oral EGCG in MRF patients who were on EPI catheter analgesia after SSRF.In the current clinical study, we recruited MRF patients, who were on EPI catheter analgesia after SSRF, and administered oral EGCG, followed by assessing their pain scores, incentive spirometry (IS) volumes, respiratory rates, and oxygen saturation . All recruited patients have given written informed consent forms, and their data were completely de-identified to keep their confidentiality.The study population consisted of 97 MRF patients who underwent complete evaluation including chest 3 D-computed tomography and met the inclusion and exclusion criteria for undergoing SSRF in Second Affiliated Hospital, Fujian Medical University from January 2017 to December 2018.Inclusion criteria were: 1) at least 18 years old; 2) MRF (4 or more fractured ribs) with bicortical displacement; 4) intractable pain with visual analogue scale >6 after conservative treatment  serious head trauma with a Glasgow coma scale <14; 2) multiple trauma at body regions outside the chest with an abbreviated injury scale score ≥3; 3) massive hemothorax or injury to the trachea or bronchus that required emergent surgery; 4) mechanically ventilated; 5) dementia; 6) coagulopathy.Our standard SSRF procedure combined video-assisted thoracoscopic surgery (VATS) and open reduction internal fixation (ORIF), using a muscle-sparing approach without thoracotomy  hold for 12 h before the procedure as a safe window, followed by PTP provided as 40 mg enoxaparin sodium once per day. EPI was administered as continuous infusion using a fixed electronic infusion device with portless tubing, with patients in a 25° head of bed elevation. EPI analgesia was achieved as a combination of 0.1% bupivacaine with 5 μg/mL fentanyl at 4 mL/h rate for approximately 3 h per day during the course of the study. IS was encouraged ten times per h while patients were awake.The 97 patients were divided using a permutated randomisation method stratified according to their baseline pain scores, with 49 in the EGCG group and 48 in the placebo group. In the EGCG group, patients were administered one capsule containing 100 mg EGCG , twice daily. In the placebo group, patients were administered one capsule containing 100 mg glucose (instead of EGCG), twice daily. Both types of capsules were identical in appearance to mask their contents to both the investigators and patients. Both interventions last for 10 days.2. All assessments were performed at the hospital admission  and at the end of intervention (day 10) by bedside nurses who were blind to the group assignment.Primary endpoint was pain score measured using a standard 0-10 numeric rating scale (NRS), with 0 indicating no pain at all and 10 indicating the worst possible pain. Secondary endpoints included IS volume, respiratory rate, and SpOp < 0.05 was considered to indicate statistically significant difference between groups.Statistical analysis was performed using the Graphpad software version 7. Data in the current study were found to be non-normally distributed therefore shown as median and interquartile range. P-value was calculated as two-sided and From January 2017 to December 2018, 97 patients with MRF who underwent SSRF and received EPI analgesia met the inclusion and exclusion criteria. As shown in p < 0.05), suggesting the general effectiveness of EPI analgesia in alleviating pain. Importantly, at the end of intervention, pain score of the EGCG group was significantly lower than that of the placebo group (p < 0.05), demonstrating the efficacy of EGCG in terms of additional pain relief on top of EPI analgesia.Pain score was the primary endpoint of the current study, which was assessed in the form of NRS. As shown in 2 were also measured (p < 0.05), and further improved IS volume was observed at the end of intervention in the EGCG group compared to that in the placebo group (p < 0.05). The same effect was also observed in terms of respiratory rate (2 (2 in both groups were greatly improved from baseline to the end of intervention (p < 0.05), no significantly different change was found in SpO2 at the end of intervention between the two study groups (p > 0.05).As the secondary endpoints, IS volume, respiratory rate and SpOmeasured . IS voluory rate , but not rate  It was a single centred study; therefore, our prospective results should be verified in a multi-centred study for generality considerations. 2) The sample size was relatively small; therefore, a larger sample pool would definitely bring more sophisticated statistical analysis and facilitate the identification of associated risk factors. 3) No serum factors known to be regulated by EGCG were assessed in the current study; future investigations are needed to identify the potential molecular mechanism underlying the observed benefits of EGCG in this setting.In this double-blind, placebo-controlled trial, we have demonstrated that oral EGCG administration could enhance pain management of EPI analgesia for MRF patients after SSRF operation. Our discovery warrants further investigations in order to compare the observed pain-relieving effect of EGCG with other analgesia techniques.


Several predictors have been shown to be independently associated with chronic postsurgical pain for gastrointestinal surgery, but few studies have investigated the factors associated with acute postsurgical pain (APSP). The aim of this study was to identify the predictors of APSP intensity and severity through investigating demographic, psychological, and clinical variables.  We performed a prospective cohort study of 282 patients undergoing gastrointestinal surgery to analyze the predictors of APSP. Psychological questionnaires were assessed 1 day before surgery. Meanwhile, demographic characteristics and perioperative data were collected. The primary outcomes are APSP intensity assessed by numeric rating scale (NRS) and APSP severity defined as a clinically meaningful pain when NRS ≥4. The predictors for APSP intensity and severity were determined using multiple linear regression and multivariate logistic regression, respectively. β 0.05, 95% CI 0.03–0.07, p < 0.001), preoperative anxiety , and expected postsurgical pain intensity  were positively associated with APSP intensity. Furthermore, MME consumption , preoperative anxiety , and expected postsurgical pain intensity  were independently associated with APSP severity.  112 patients (39.7%) reported a clinically meaningful pain during the first 24 hours postoperatively. Oral morphine milligram equivalent (MME) consumption ( These results suggested that the predictors for APSP intensity following gastrointestinal surgery included analgesic consumption, preoperative anxiety, and expected postsurgical pain, which were also the risk factors for APSP severity. Acute postsurgical pain (APSP) is defined as pain within the first 24 hours postoperatively. Moderate or severe APSP is reported in 10% to 57% of patients undergoing various types of surgeries . FurtherEnhanced Recovery after Surgery (ERAS) is a multimodal perioperative care pathway designed to reduce perioperative stress, maintain postoperative physiological function, and accelerate recovery after surgery. Thus, major complications can be reduced while length of stay can be shortened after major gastrointestinal surgery –28. PainThe purpose of our study was to determine the predictors of APSP intensity and severity for gastrointestinal surgery by investigating demographic, psychological, and clinical variables. The primary outcome of interest is APSP intensity assessed using the 11-point numeric rating scale  , 35 and The protocol was registered at the Chinese Clinical Trial Registry (ChiCTR1900024837). This prospective cohort study was carried out at Zhongda Hospital, Southeast University. The study was approved by IEC for Clinical Research of Zhongda Hospital Affiliated to Southeast University (No. 2019ZDSYLL084-P01). Patients eligible for participation were those scheduled for gastrointestinal surgery between August 2019 and January 2020. The study recruited 345 patients to investigate the prediction of acute pain after gastrointestinal surgery. The written informed consent was obtained as a condition to participate in the study. Inclusion criteria included patients undergoing elective gastrointestinal surgery, aged ≥18 years old and physical status classification of the American Society of Anesthesiologists (ASA) ≤III. Patients with self-expression disorder and hearing or visual impairment were excluded.Demographic characteristics such as gender, age, height, weight, calculated body mass index (BMI), occupation status, education level, smoking , alcohol drinking , hypertension, diabetes, coronary heart disease, and physical status classification of ASA were collected on the day before surgery. Moreover, patients were asked to rate a history of preexisting pain. Patients who suffered from pain for more than 3 months were classified as having previous chronic pain. Simultaneously, a history of previous surgery was also attained and participants were classified as previous surgery and no previous surgery.During the preoperative visit, psychological factors were assessed with the respective standardized and validated questionnaires: Hospital Anxiety and Depression Scale (HADS)  and SurgSurgery was performed by 3 surgeons according to a standardized protocol. Data regarding type, site, duration of surgery, as well as number of drainage tube and length of hospital stay, were collected. Additionally, preoperative clinical factors were attained from the medical record. The primary sites of surgery included stomach, colorectum, and small bowel. The surgery was performed using either open or laparoscopic procedure.μg/kg of sufentanil, 2 to 2.5 mg/kg of propofol, and 0.6 mg/kg of rocuronium. Anesthesia was maintained with sevoflurane, remifentanil, and cisatracurium. During skin closure, sufentanil  was given.After standard monitoring , a standardized anesthetic protocol was carried out by the anesthesiologists who were members of the research team. General anesthesia was induced with intravenous (IV) administration of 0.3 The primary outcome was the maximum pain intensity assessed using NRS pain scores within the first 24 h after surgery. At 6–8, 14–16, and 22–24 hours after operation, patients were asked to report their level of pain during movement (changing position to either sitting up or standing), respectively. The maximum pain intensity was identified as the highest NRS pain score at three time points within the first 24 h postoperatively. We defined NRS ≥4 of the maximum pain as clinically meaningful pain, indicating moderate-to-severe pain intensity.After surgery, patients received routine postoperative pain management. In the postanesthesia care unit (PACU), patients received tramadol  or oxycodone  when NRS pain at rest ˃ 3. On the ward, patients received celecoxib 200 mg orally every 12 h, as well as a patient-controlled analgesia device with oxycodone or sufentanil. Furthermore, patients administered the breakthrough pain using tramadol intravenously only as needed. The analgesic consumption of 24 hours postoperatively was measured from arriving PACU. To compare the analgesic consumption, systemic opioid analgesics were converted to oral milligram morphine equivalent (MME). MME use was calculated using standard published conversion factors.p < 0.05 was considered statistically significant. Pearson's test was performed to investigate the correlation between preoperative anxiety and depression, expected postsurgical pain, SFQ-s, SFQ-l, and APSP intensity. Next, univariate linear regression and multiple linear regression models were used to examine whether MME consumption, preoperative anxiety, and expected postsurgical pain had an independent effect on APSP intensity. Furthermore, we also performed univariate logistic regression and multivariate logistic regression to identify whether MME consumption, preoperative anxiety, and expected postsurgical pain were independently associated with APSP severity. All analyses were performed with R (http://www.R-project.org) and EmpowerStats software .First, descriptive statistics were calculated on all variables. Mean ± standard deviation was used for normally distributed variables, medians (interquartile range) for nonnormally distributed variables, and number (percentage) for categorical data. 345 patients were approached for participation in this study. 31 declined participation, and 6 withdrew consent. There were 12 patients excluded owing to incomplete questionnaires, 8 patients for surgery cancellation, and 6 patients for transferring to intensive care unit. Thus, 282 patients (81.7%) were available for analysis .Demographic and clinical characteristics of patients are shown in Psychological characteristics of patients are shown in r = 0.63, p < 0.001), preoperative anxiety , preoperative depression , and expected postsurgical pain intensity . Meanwhile, it was also obviously correlated with SFQ-s  and SFQ-l  but negatively correlated with age .β 0.07, 95% CI 0.05–0.09, p < 0.001), preoperative anxiety , preoperative depression , and expected postsurgical pain . In addition, SFQ-s  and SFQ-l  were associated with APSP intensity. Meanwhile, age  and occupation  might also be associated with APSP intensity.As shown in β 0.12, 95% CI 0.08–0.15, p < 0.001), expected postsurgical pain , and MME consumption were positively associated with APSP intensity.To determine the predictors of postsurgical pain intensity, a multiple linear regression analysis was conducted . Preoperp < 0.001), preoperative anxiety , preoperative depression , and expected postsurgical pain . In addition, SFQ-s , SFQ-l , and age  were also associated with APSP severity (169 patients reported absence of pain or mild pain (NRS ≤3) on APSP severity, whereas 113 patients reported moderate-to-severe pain, regarded as clinically meaningful pain. The univariate logistic analysis showed that APSP severity was significantly correlated with MME consumption , preoperative anxiety , and expected postsurgical pain  were independently associated with APSP severity.After multivariable risk adjustment for potential confounding factors, a logistic regression was performed . MME conTo the best of our knowledge, there were few predictive prospective studies on APSP for gastrointestinal surgery. In this study, we assessed possible predictors for APSP after gastrointestinal surgery. We discovered that higher preoperative anxiety and higher expected postsurgical pain score were independently associated with stronger postsurgical pain intensity and severity. Moreover, the study showed that more analgesics were consumed in patients undergoing moderate or severe postoperative pain during the first 24 postoperative hours. Our results confirm and extend those of previous studies focused on patients undergoing other types of surgery.Despite uniform multimodal analgesic treatment, we discovered a large variability in pain intensity during movement. 59.9% of patients experienced moderate or severe pain during the first 24 postoperative hours, respectively. An important increase in opioid analgesic consumption was observed in the patients experiencing moderate or severe pain compared to those experiencing mild pain. Similar to previous studies on other surgery [We found that preoperative anxiety was significantly correlated with APSP intensity and became an independent predictor of APSP intensity and severity. These results are consistent with studies which suggested that presurgical anxiety can predict APSP intensity for hysterectomy , cesareaSimilar to previous studies on cesarean , 16 and Our results did not support an independent association between preoperative depression and APSP, although preoperative depression was correlated with APSP intensity by Pearson's test or univariable analysis. As previously stated, depression was not predictive of APSP severity at 2 days in women with breast cancer surgery, and only body image score emerged as an independent predictor . In addiA significant increase in postsurgical pain intensity was observed with the elevation of SFQ-s and SFQ-l. In addition, SFQ-s and SFQ-l could increase the incidence rate of the clinically meaningful postsurgical pain. However, after adjusting the confounding factors, they both could not independently predict the APSP intensity or severity. Unlike previous study , SFQ-s wPrevious trials showed that preoperative chronic pain was a clinical factor of interest in predicting APSP , 10, 22.According to our study, despite negative correlation with APSP intensity, age was not independently associated with APSP after controlling confounding factors. This may be explained by the uneven distribution of age, because most participants were elderly. In addition, there was no significant difference on APSP in different sites of surgery  and types of surgery (laparotomy and laparoscopy). However, in some studies for breast cancer, type of surgery could predict APSP, because axillary lymph nodes dissection caused potential injuries to the sensory intercostobrachial as compared with other types of surgery.Our study had several methodological limitations. First, our subjects were patients undergoing gastrointestinal surgery. Whether the results are applicable to other surgeries remains unknown. Second, all psychological predictor variables were assessed at the first day before surgery when the threatening surgical event might influence these variables and their relations to each other. Thus, the results should be considered with caution when compared with studies assessing the risk factors several days or even weeks before surgery. Third, the outcome variable, APSP intensity or severity, was assessed only within the first 24 hours after surgery. We did not frequently assess the pain over several days, so we did not make a clinically meaningful assessment of different pain trajectories among patients. Finally, as we investigated the predictors of APSP only in one single hospital, whether the results can be generalized to other countries should be considered cautiously. As a result, a larger multicenter study is needed.In conclusion, this study has shown that cumulative analgesic consumption, preoperative anxiety, and expected postsurgical pain were independently associated with APSP intensity following gastrointestinal surgery. Meanwhile, the predictors were highly associated with APSP severity. Further study is needed to confirm these findings in participants of multicenter clinical trials and different surgical procedures. Future strategies to relieve APSP may start from preoperative psychological interventions.


Calciphylaxis is a rare condition usually seen in patients with end-stage renal disease. Pain is a hallmark of this condition and can be extremely difficult to control. Anecdotal data suggests that pain management in calciphylaxis is challenging with variable approaches across the United Kingdom (UK) and internationally. A knowledge and practice survey was conducted to establish current practice in the management of pain in patients with calciphylaxis, in the UK. Based on the results and clinical experience the authors suggest a clinical practice guideline.An online questionnaire was circulated among physicians  involved in the management of pain in calciphylaxis. The questionnaire included a mix of open-ended questions and questions with drop down options.One hundred and six clinicians responded to the survey of which 60 (57%) respondents were from palliative medicine; the remaining 46 (43%) were from renal medicine. 31 (30%) respondents across both specialties had not encountered any patients with a diagnosis of calciphylaxis . A referral to the palliative care team was undertaken by 18% of renal physicians, 32% referred to the pain team and 50% referred to both. Only 3% of the palliative medicine respondents indicated that they had received a referral from the renal team at the time of diagnosis. Opioids were the preferred initial drug of choice for the management of all types of pain. Paracetamol was universally selected as the preferred first-choice adjuvant agent for management of all types of pain. The importance of advance care planning was highlighted with 72% undertaking advanced care planning discussions often or most of the time.There was wide variation in the current practice of pain management in patients with calciphylaxis, with variation between renal specialists and palliative care specialists. Referral to specialists in pain management is not universal despite the severe nature of the pain experienced by patients with calciphylaxis. The data generated has facilitated the development of a clinical practice guideline to support complex pain management in a group of patients with multiple comorbidities. Calcaemic uremic arteriolopathy or calciphylaxis is a rare but life-threatening condition usually seen in patients with end-stage renal disease (ESRD). The reported incidence in haemodialysis patients is variable and largely reliant on registry data with reported incidences of 0.04% in Germany and 0.35% in the United States. The mortality rate can be as high as 60–80% . It is cPain is a hallmark of this disease and can be extremely difficult to control. Pain resulting from calciphylaxis is classically an acute ischaemic pain resulting from tissue damage as a consequence of arteriolar occlusion causing hypoperfusion, ischaemia and infarction of tissues . As withCurrent management of calciphylaxis involves a multimodal approach including medical , surgical  and modification of dialysis regimens such as varying dialysate calcium concentrations and increasing dialysis frequency –8.Available evidence suggests that pain management in calciphylaxis is unsatisfactory with differing practice across the United Kingdom (UK) and internationally . A knowlhttps://www.gmann.co.uk/website/calciphylaxis-pain-management-survey.cfm). The survey was distributed to the palliative care physicians through the Association of Palliative Medicine, the only membership organisation in the UK and Republic of Ireland. The National Registry of Rare Kidney Diseases (RaDaR) distributed the survey to the renal physicians. A reminder was sent out once via both organisations. Questions included a mix of open-ended questions and questions with drop down options  were palliative medicine physicians and the remainder 46 (43%) were renal physicians. The respondents were predominantly (77%) working in acute care settings. Thirty percent of the respondents had not encountered any patients with calciphylaxis in the preceding 10 years, whilst 11 (10%) had managed more than 10 patients . For the management of pain in patients with calciphylaxis, 8 (18%) of renal physicians refer to the palliative care team, 14 (32%) refer to the pain team and 22 (50%) refer to both specialties. Palliative care physicians almost universally (97%) described late referral patterns whereby referrals were made when the renal team were struggling to manage pain or when a patient was approaching end of life; only 3% received a referral at the time of diagnosis.The 31 (30%) who had no experience of managing patients with calciphylaxis were excluded from the subsequent analysis. Results presented are from 75 respondents  opioid for all types of pain  with alfentanil and fentanyl being other popular choices Table . OxycodoBoth renal and palliative care physicians reported that modified release oral medications (73%) and continuous subcutaneous infusions of medications (51%) using a syringe driver were their preferred approaches to managing background pain. There was no clear drug preference for the management of breakthrough and procedure related pain with oral analgesia, subcutaneous analgesia or immediate release fentanyl preparations  being equally popular.Paracetamol was the preferred first-choice adjuvant agent for management of all types of pain, more so by renal physicians Fig. . Five ouThe perceived types of pain experienced by patients with calciphylaxis are illustrated in Fig. Calciphylaxis is a rare and life-threatening condition associated with a significant impact on quality of life; pain is a major contributor to this. Due to the rarity and high mortality associated with this condition, randomised control trial evidence on management has been a challenge and there is no uniform strategy for the management of calciphylaxis associated pain.Our survey demonstrated a wide variation in the management of pain in patients with Calciphylaxis. Notably the choice of medication varied depending on the speciality of the physician, indicating that familiarity with drugs and confidence in their use may be a factor in determining drug choice rather than an approach based on determining the nature of the pain and selecting the best choice of drug. Reported evidence in the literature on the management of pain in calciphylaxis is limited and variable. In a case series of three patients with Calciphylaxis, a cocktail approach of opioids, benzodiazepines and ketamine was used to manage refractory pain . Similarclinicaltrials.gov NCT03150420). The change in Pain Visual Analog Scale is a primary outcome measure in a Phase 3 randomised double-blind placebo-controlled trial investigating the effect of SNF472 on pain as well as wound healing . The use of these agents within pain guidelines has not been routinely recommended as trial data is awaited.Sodium thiosulphate (STS) has been widely reported as a potential treatment for calciphylaxis. The majority of the literature focuses on wound healing, however, Noureddine et al. reported that sodium thiosulphate attenuated pain in 71% of patients in a retrospective case series of 14 patients . In a reOur survey also showed a variable approach to specialist referral to the pain or palliative care team. These findings are similar to observations in the literature. A systematic review of 12 calciphylaxis studies concluded that there was no formal study of palliative care in patients with calciphylaxis, illustrating the need for the development of a calciphylaxis specific patient-reported outcome measure which would help to prompt earlier and more frequent palliative care consultations . The utiIn conclusion, there is wide variation in the current management of pain in calciphylaxis, amongst renal and palliative care physicians. The rarity of the condition and severity of pain are particularly challenging for non-pain specialists who have a tendency to revert to familiar drugs such as opioids. Moreover, there are no published guidelines or recommendations to support clinicians with decision-making.Pain caused by calciphylaxis is nociceptive, neuropathic and inflammatory in nature as it is a result of metastatic microcalcification and tissue necrosis . Choice Always refer to either the local palliative medicine team and / or pain team when calciphylaxis is suspected. This is because it is often a diagnosis of exclusion and pain control is difficult in this group and needs a specialist approach from the outset because of the additional morbidity associated with the use of inappropriate analgesia.Tissue viability service/wound care specialist referral is essential and daily serial medical photography with consent is advised.Ideally admit the patient to a renal unit or to a hospice for symptom control.Where the patient has capacity, start advance care planning conversations. If the patient does not have capacity and that capacity cannot be enabled, start planning care using the principles of best interests. This is because of the high mortality associated with this condition. It is important to discuss the considerable risk of dying and poor prognosis with the patient and their family.Consider enrolment in a clinical trial.The authors suggest the following pragmatic approach in this population.If the patient is opioid naïve, commence a safe opioid at the lowest effective dose  and titrate to effect. The authors recognise that opioids are not considered appropriate for chronic pain. However, this is an acute pain arising in response to tissue injury and death  and therIn opioid naïve patients who are starting an opioid for the first time a starting dose of alfentanil 0.5 mg continuous subcutaneous infusion (CSCI) over 24 h is proposed. This is approximately equivalent to morphine 7.5 mg/24 h by subcutaneous infusion. The authors recommend alfentanil as it is not removed by dialysis, it does not cause toxicity in an ESRD population and it occupies a low volume in syringe drivers. This guidance is drawn from literature on the use of opioids in cancer patients with severe and end stage terminal illness –21 and iWhere the patient is not opioid naïve, convert their existing opioid to alfentanil by CSCI. Palliative medicine team can help with conversions if this is outside of the usual scope of practice of the general clinician. Titrate daily to either pain relief or toxicity. Increases in background analgesia are usually of the order of 30–50% every 24 h having checked for any signs or symptoms of opioid neurotoxicity. Symptoms of neurotoxicity include troublesome confusion or cognitive slowing, misperceptions or visual hallucinations. If neurotoxicity occurs reduce the dose of opioids by 30% and add adjuvant analgesics e.g. gabapentinoid.Thirty percentage of patients will experience nausea for 3–5 days on starting an opioid. Ensure that an antiemetic is available for use as and when needed e.g. metoclopramide 10 mg per oral (PO) or subcutaneously (SC) three times a day. Patients will experience constipation and need to be prescribed a regular daily laxative. Senna 7.5 mg twice a day is recommended as a starting dose.Avoid morphine, oxycodone, tramadol or codeine as background analgesia as they can rarely be titrated to effect in this population without opioid-induced neurotoxicity. Once pain is stable, transdermal fentanyl or buprenorphine may be used in place of opioids by continuous subcutaneous infusion. If the lesions heal and pain resolves it is important to reduce the opioids step by step and aim to withdraw them fully.To address the neuropathic element of pain secondary to calciphylaxis, gabapentin 100 mg after each haemodialysis session or pregabalin 25 mg after each haemodialysis session may be used in conjunction with opioids. If the patient is not on haemodialysis, start with a dose of 100 mg of gabapentin on alternate days or 25 mg of pregabalin on alternate days. Caution is needed as gabapentinoids accumulate in ESRD though they are removed by dialysis , 23.Discuss the use of a non-steroidal anti-inflammatory drug (NSAID) with the nephrology team as they are very effective for the management of the inflammatory aspect of pain secondary to calciphylaxis. If residual renal function is not important, use an oral or parenteral NSAID (e.g. ketorolac) by continuous subcutaneous infusion for pain that is not controlled with the measures outlined above. Cover with a proton pump inhibitor is recommended. In general, NSAIDs are best used at the minimally effective dose and for a short duration but their harms are weighed against their opioid sparing effect .If background pain remains problematic or dose-limiting toxicity is encountered, consider the addition of methadone as a co-analgesic or rotation to methadone from the current opioid. This step may require hospice inpatient care and should only be undertaken with specialist palliative care guidance.Even when background pain control is achieved, the patient may continue to experience spontaneous breakthrough pain. Oxycodone 1-2 mg may be used by oral or by subcutaneous injection on a four hourly to 6 hourly basis. In countries where hydromorphone is available, 0.5 mg of hydromorphone sublingually four hourly is useful.Short-acting transmucosal fentanyl preparations have a quick onset and offset of action, which makes them a potentially useful option for dressing changes in patients with calciphylaxis. However, in the UK they are licenced for breakthrough cancer pain and contra-indicated in patients who are opioid naïve. They should be used with caution and with careful patient selection and under the guidance of local pain or palliative medicine teams. An alternative to transmucosal fentanyl, is subcutaneous fentanyl or alfentanil, which have short duration of action. There is a mismatch between the time-action relationship of oral opioids and the time course of breakthrough pain such as that precipitated by dressing changes – the patient may be sleepy for some hours after the procedure.Step1. Short-acting fentanyl preparation .Step 2. SC fentanyl or alfentanil (short duration of action).Step 3. SC opioid and sedation with subcutaneous midazolam.Step 4. Anaesthesia with propofol and fentanyl under anaesthetic supervision in theatre.For dressing changes, use a stepwise approach as follows:The use of a pain tool to record patient reported outcome measures is recommended. The integrated palliative care outcome scale (IPOS) renal is a useful tool though not validated for use in calciphylaxis.Additional file 1. Survey Questionnaire.Additional file 2. Salient responses to free text questions.


Background and objectives: For the treatment of chronic unilateral radicular syndrome, there are various methods including three minimally invasive computed tomography (CT)-guided methods, namely, pulsed radiofrequency (PRF), transforaminal oxygen ozone therapy (TFOOT), and transforaminal epidural steroid injection (TFESI). Despite this, it is still unclear which of these methods is the best in terms of pain reduction and disability improvement. Therefore, the purpose of this study was to evaluate the short and long-term effectiveness of these methods by measuring pain relief using the visual analogue scale (VAS) and improvement in disability (per the Oswestry disability index (ODI)) in patients with chronic unilateral radicular syndrome at L5 or S1 that do not respond to conservative treatment. Materials and Methods: After screening 692 patients, we enrolled 178 subjects, each of whom underwent one of the above CT-guided procedures. The PRF settings were as follows: pulse width = 20 ms, f = 2 Hz, U = 45 V, Z ˂ 500 Ω, and interval = 2 × 120 s. For TFOOT, an injection of 4–5 mL of an O2-O3 mixture (24 μg/mL) was administered. For the TFESI, 1 mL of a corticosteroid (betamethasone dipropionate), 3 mL of an anaesthetic (bupivacaine hydrochloride), and a 0.5 mL mixture of a non-ionic contrast agent (Iomeron 300) were administered. Pain intensity was assessed with a questionnaire. Results: The data from 178 patients  who submitted correctly completed questionnaires in the third month of the follow-up period were used for statistical analysis. The median pre-treatment visual analogue scale (VAS) score in all groups was six points. Immediately after treatment, the largest decrease in the median VAS score was observed in the TFESI group, with a score of 3.5 points (a decrease of 41.7%). In the PRF and TFOOT groups, the median VAS score decreased to 4 and 5 points . The difference in the early (immediately after) post-treatment VAS score between the TFESI and TFOOT groups was statistically significant (p = 0.0152). At the third and sixth months after treatment, the median VAS score was five points in all groups, without a statistically significant difference (p > 0.05). Additionally, there were no significant differences in the Oswestry disability index (ODI) values among the groups at any of the follow-up visits. Finally, there were no significant effects of age or body mass index (BMI) on both treatment outcomes . Conclusions: Although the three methods are equally efficient in reducing pain over the entire follow-up, we observed that TFESI  proved to be the most effective method for early post-treatment pain relief. Minimally invasive treatment methods are important therapeutic options for patients suffering from chronic lumbar radicular syndrome, and these methods involve the use of computed tomography (CT) or fluoroscopy to ensure accurate needle placement and to prevent adverse reactions ,2.Three methods that are commonly used to treat lumbar radicular syndrome are epidural steroid injection (ESI), pulsed radiofrequency (PRF), and oxygen-ozone therapy (OOT). Epidural steroid injection (ESI) of corticosteroids is one of the most commonly used minimally invasive interventions for the management of chronic spinal pain . CorticoPulsed radiofrequency (PRF) was developed, in part, as a less invasive alternative to conventional continuous radiofrequency . Althoug2-O3 gas mixture, which can be applied intradiscally, to the epidural space or to the paravertebral muscle [2-O3 gas mixture to the root ganglion is thought to normalize the levels of cytokines and prostaglandins, increase superoxide dismutase levels, minimize reactive oxidant species levels, and improve local peri-ganglionic circulation, and this mixture has an eutrophic effect on the nerve root [2-O3 mixture [Oxygen-ozone therapy (OOT) is based on the injection of an Ol muscle . The prorve root . Complic mixture ,16. Howe mixture .2-O3 therapy to that of TFESI in patients with acute and chronic low back pain (LBP) and sciatic nerve pain. The authors reported complete pain remission in most patients, regardless of the type of treatment. At the six-month follow-up, the differences in favour of O2-O3 treatment were significant in patients with disc disease but not in those without disc disease.In a previous retrospective study, Ding et al.  comparedPRF treatment is increasingly being used in the management of chronic pain syndromes ,20. The These data indicate that there is still confusion about the choice of the most appropriate method for the treatment of chronic lumbar unilateral radicular syndrome. The choice of the method must be based on certain criteria including effectiveness in terms of pain reduction and improvement of disability. In this regard, to our knowledge, a comparison of these parameters among these three methods is not yet available. Thus, the aim of this study was to compare the efficacies of PRF, transforaminal oxygen ozone therapy (TFOOT), and transforaminal epidural steroid injection (TFESI) in relieving pain and improving disability in patients with chronic unilateral radicular syndrome. To this end, we used the same CT-guided minimally invasive approach to administer PRF, TFOOT, and TFESI and assessed the levels of pain relief ) and improvement in disability (per the Oswestry disability index (ODI)) of patients over a period of six months following treatment.This study was a prospective, randomized, single-blinded, monocentric trial and was approved by the Institutional Ethics Committee of the University Hospital Hradec Kralove , and no registration was required according to the State Institute for Drug Control, as it does not evaluate a new active substance or any new therapies. The study was conducted in the Department of Radiology of the University Hospital Hradec Kralove in the Czech Republic. Patient recruitment started in December 2014 and ended in September 2017. The follow-up period for each patient was six months (questionnaire survey), and the final six-month follow-up dates were in March 2018.A total of 692 patients were screened for eligibility, and 189 of them were deemed eligible. The enrolled patients were then randomized to one of the three treatment groups and given the indicated treatment. The data from 178 patients  were used for the statistical analysis at baseline, as 11 patients dropped out at the third month of the follow-up period. The data from 154  patients were used for the analysis at the six month. A flow diagram showing the patient inclusion process, including reasons for exclusion, is shown in A total of 178 patients with chronic unilateral radicular syndrome who were advised to undergo minimally invasive therapy by specialized clinicians  were included in the study. The patients were informed of the purpose of the study, principles of treatment, possible complications, and post-treatment regimen. The possibility that the study may be interrupted due to the need for retreatment or another reason was emphasized. Written informed consent was required. The patients were randomly divided into the experimental groups and were blinded to the treatment group to which they were assigned. The study was conducted as part of regular shifts aimed at treating patients with back pain. Prior to each of these shifts, the order of execution of the individual methods was determined by lot . Patients who met the criteria for inclusion in the study and agreed to be treated by the method according to the pre-drawn lot order were included. Thus, 0–5 patients were enrolled in the study during one shift.Doctors were directly involved in the treatment of patients . Personal data and data from the obtained questionnaires were recorded by persons not directly involved in the treatment .The inclusion criteria were as follows: non-progressive, clearly dominant mono-segmental radicular pain in the unilateral dermatome L5 or S1, insufficient response to conservative therapy, the absence of indications for surgical treatment, a duration of pain of >3 months, a VAS score ≥ 3/10, morphologic correlate depicted by magnetic resonance imaging (MRI) or CT , international normalized ratio (INR) ≤ 1.2, and age ≥ 18 years. The exclusion criteria were as follows: leg paresis or paralysis; sphincter insufficiency; local infections or sepsis; oncologic diseases; haemorrhagic diathesis or anticoagulation (INR > 1.2); uncontrolled diabetes or other severe internal comorbidities; allergies to the medication or materials used; glucose-6-phosphate dehydrogenase deficiency; pregnancy; or uncooperativeness.For CT, the Somatom Definition AS + scanner  was used. For PRF, the RFG˗1B radiofrequency generator , a dispersive electrode, a thermocouple electrode, and a 22G SMK RF cannula  were used. For TFOOT, the OZO2 FUTURA ozone generator , 22G Spinocan needles , a 10 mL syringe, and a source of medical oxygen were used. For TFESI, 22G Spinocan needles, a 5 mL syringe, a corticosteroid solution (betamethasone dipropionate), a local anaesthetic solution (bupivacaine hydrochloride), and a non-ionic contrast agent solution (Iomeron 300) were used.All therapies were performed in an outpatient setting. Prior to the intervention, patients were instructed to expect different feelings in the area of the intervention site and in the treated lower limb during the needle insertion and treatment themselves, as well as to communicate these feelings to the medical staff on their regular inquiries. In all three groups , the loading technique and size (22G) were identical. Feelings when inserting the same needle/radiofrequency (RF) cannula in patients are usually markedly individual. Similarly, in the case of the application of drug mixtures and stimulation and the actual effect of the RF treatment, the feelings of the treated patients  are not the same within the individual types of treatment. We therefore consider the possibility of unambiguous identification of the method by patients on the basis of emotion to be considerably limited and unreliable. Auditory perceptions were masked by music played in the CT scanner room. Visual identification was excluded by the patient’s position. During the procedure, the patients were placed in the prone position. The generators were set and the drug mixtures prepared outside of the view of the patients. The sounds of all the procedures were masked by music being played in the CT scanner room. CT navigation utilizing a low-dose protocol was used. The entry point and needle trajectory were identified by axial CT scan measurements. After aseptic preparation, the needle (RF cannula) was introduced with a few steps into the chosen neuroforamen, and each time the needle needed to be repositioned, the position was graphically verified.For PRF, the dispersive electrode was placed on the thigh of the limb contralateral to the treated side. After proper RF cannula insertion, the stylet was replaced by the thermocouple electrode. The distance of the electrode tip position to the DRG was subsequently verified and corrected by sensory and motor nerve stimulation when possible. The patients were expected to confirm a change in feeling  to the sensory stimulation at a frequency of f = 50 Hz and voltage of U = 0.3–0.5 V. Similarly, a reaction to the motor stimulation was expected at a frequency of f = 2 Hz and voltage of U = 0.5–0.7 V. The PRF settings used were as follows: pulse width = 20 ms, f = 2 Hz, U = 45 V, Z ˂ 500 Ω, and interval = 2 × 120 s.2-O3 mixture was created by an ozone generator and transferred to a syringe. A total of 4–5 mL (24 μg/mL) of the O2-O3 mixture was injected gradually and slowly through the inserted needle. For TFESI, a mixture of a corticosteroid (1 mL), local anaesthetic (3 mL), and contrast agent (0.5 mL) was utilized. In the TFOOT and TFESI procedures, negative blood aspiration always preceded the injection. The distribution of the gas/drug mixtures used was imaged , and patient disability was measured by means of the ODI (0–50 points). Before treatment and at 3 and 6 months after treatment, we used a printed questionnaire containing the VAS and the Czech translation of the Oswestry disability questionnaire, which addresses 10 aspects of daily life activities for the calculation of the ODI. The early (result within 30 min after treatment) post-treatment VAS score of each patient was obtained via interview after the procedure.The patients were randomly assigned to the treatment groups, and the data from the questionnaire were recorded by medical staff members not directly involved in the treatment. The maximum time to enrol patients into the study was set to three years. The minimum number of patients was set at 30/group.p-values less than 0.05 (p < 0.05) indicated statistical significance. Statistical analyses were performed with NCSS software, version 11.0.7 .Semi-quantitative data  are presented as the median (interquartile range). The VAS and ODI scores were compared among groups by means of the Kruskal–Wallis ANOVA with the post hoc Dunn test and Bonferroni correction. The correlations between the VAS or ODI score and age and body mass index (BMI) were assessed by correlation analysis (Spearman’s rank correlation coefficient). Only complete sets of data from correctly completed questionnaires were used. The presented data do not have a “normal” distribution. The statistical methods used were chosen with this in mind.p = 0.50970). Patients with failed back surgery syndrome (FBSS) accounted for 30.9% of all patients, with no significant differences among the groups (p = 0.13578). The demographic characteristics of the patients are summarized in The age range of the patients was 20–84 years (median age: 56 years), and there were 63 males and 115 females. The median BMI was 27.5. No statistically significant correlations were found between age, or BMI and the pre-treatment VAS or ODI score or the post-treatment changes in the scores over the follow-up period . There were no significant differences in the distribution of sides or levels of the treated nerve roots (The VAS and ODI scores (median and interquartile range) are shown in p = 0.0152). The median VAS scores at the third and sixth months after treatment were comparable among groups (five points), and these values were lower than the pre-treatment values. The persistent decrease in the median VAS score, therefore, was approximately 16.7% with respect to the pre-treatment state. There were no statistically significant differences in the VAS score among groups at three or six months after treatment.The median pre-treatment VAS score of all groups was six points. At the early post-treatment time points, the largest reduction in the median VAS score (to 3.5 points) was observed in the TFESI group (a decrease of 41.7%); in the PRF and TFOOT groups, the VAS score decreased to 4 points (a decrease of 33%) and 5 points (a decrease of 16.7%), respectively. There was a significant difference in the early post-treatment VAS score between the TFESI and TFOOT groups  were observed in the TFOOT group immediately after the procedure. Both patients fully recovered within 15 min, with no residual complaints. An early post-treatment increase in the VAS score was noted in 45 patients: 15 (26.3%) in the PRF group, 20 (29%) in the TFOOT group, and 10 (19%) in the TFESI group.This study was performed to compare the changes in pain and disability following three minimally invasive CT-guided methods, PRF, TFOOT and TFESI, in patients with chronic unilateral radicular syndrome at L5 or S1 who are resistant to conservative treatment.Based on the published literature, we expected that the therapeutic efficacy of the newer mini-invasive methods (PRF and TFOOT) would be better than that of TFESI ,23,24. IThe discrepancy of the effect of TFESI between previous studies and our study may be explained by the differences in the drug mixtures used. Another difference between these studies is the duration of pain before the mini-invasive treatment. Nonetheless, our data are in line with previous reports showing the greater efficacy of TFESI in the short term. In their systematic review, Abdi et al. summarized the effects of lumbar TFESI in managing lumbar radicular pain, showing that the evidence was strong for pain relief in the short term (six weeks or less) and moderate for pain relief in the long term (six weeks or longer) . Moreove2-O3 therapy. This approach can be supplemented by a periforaminal O2-O3 injection [Regarding OOT, a number of studies evaluating OOT for treatment of LBP have focused on intradiscal Onjection ,29,30,31njection  evaluatenjection  stated t2-O3 therapy are insomnia, itching, papules around the point of infiltration, gastritis, dizziness, tachycardia, and hot flashes [In our study, there were no clinically severe periprocedural complications. However, two patients in the TFOOT group complained of transient nausea and mild headache immediately after the procedure. The commonly reported minor complications of O flashes . Severe  flashes .Moreover, Vanni et al.  describeOne limitation of this study is its inclusion of a relatively small and heterogeneous population. We recruited patients primarily on the basis of their anamnesis and clinical symptomatology when unilateral radicular syndrome was the strictly dominant complaint. A range of degenerative or postoperative spinal changes was observed on the pre-treatment MR and CT images. The use of more specific selection criteria for patients based on imaging findings may have limited the possibility of selecting a large number of patients for the study. We are also aware of the fact that the extent of blinding of this study may have been limited by the capacity of our workplace.In summary, we found that TFESI  was the most effective procedure among the examined treatments for reducing early post-treatment pain in patients with chronic lumbar radicular syndrome. However, contrary to our expectations, there were no significant differences in efficacy among the three evaluated methods over the long term (three and six months’ follow-up). Thus, the CT-guided mini-invasive methods PRF, TFOOT and TFESI are equally effective and can be used as complementary treatments in the management of patients suffering from chronic lumbar radicular syndrome at L5 or S1.


To determine the effects of foot massage on pain severity during in unconscious trauma patients admitted to the intensive care unit (ICU).  In this randomized clinical trial (RCT), 80 unconscious trauma patients admitted in the ICU of a hospital in an urban area of Iran were included using the convenience sampling method. They were randomly assigned to the intervention and control groups (n=40 in each group). In both groups, the intensity of pain was measured immediately, 10 minutes after the first change position and without any intervention before the change of position using the Critical Care Pain Observation Tool (CCPOT). In the intervention group, before the second position change, classic foot massage was performed for 20 minutes, but the control group received routine care. Pain was re-evaluated after the change position at desired times. The pain intensity was compared between the two study groups. The baseline characteristics were comparable between the two study groups and no difference was found. There was no statistically significant difference between the mean scores of pain after the change of position (immediately and ten minutes later) before the intervention in the groups . However, after the intervention, the pain intensity was significantly lower in the intervention groups compared to the control group (p<0.001).Foot massage decreases the pain intensity related to the change of position in unconscious trauma patients admitted in the ICU. Due to its simplicity and low cost, this method can be used along with analgesic drugs to reduce pain in patients. Pain as a symptom is reported by the individual . HoweverOne of the methods for pain control in the ICU is the use of medications. While drugs can relieve pain, they may delay the patient’s separation from the ventilator, increase ventilator-dependent infection and increase costs , 8. Theret al., [Massage as one of the methods of complementary medicine is one part of the non-invasive relaxing treatments and aims at reducing unwanted symptoms. Various studies have indicated the effect of massage on the reduction of anxiety, muscle sprain, heart rate and blood pressure in patients . Short-tet al.,  stated tThe samples of most studies conducted on the effect of massage on pain were conscious patients , 18-21. Study population and samplingThis was a double-blinded clinical trial with two groups, before and after design a time series. This study was performed in the ICU ward of a hospital in an urban area of Iran for 8 months. Inclusion criteria were adult patients with a GCS between 5 and 8 (coma state), receiving no muscle relaxant drugs, age 18-65 years, severity of pain 3+, no peripheral nervous system neuropathy, deep vein thrombosis (DVT), foot fracture, spinal cord injury and drug abuse, and at least 4 hours passed since receiving pain killers. Exclusion criteria included the patient's lack of satisfaction to continue with the intervention, changes in the patient's GCS, initiation of analgesic or sedative medications, and transfer to other wards or death. The samples were randomly assigned to two groups using a randomized block method. Data collection instrumentset al., [The data gathering tool was a two-part questionnaire consisting of demographic data about gender, age, type of the disease, duration of hospitalization, GCS score, etc and Critical Care Pain Observation Tool (CPOT) for assessing the severity of pain in patients with communication disabilities. The score for this tool was between 0 and 8 as the minimum and maximum pain, respectively . Jelinezet al.,  reportedThis tool was validated in Iran with a high interclass correlation coefficient (0.887) and content and criterion validities with a coefficient reported as 0.91 . Pain caInterventionAfter assigning the samples to the groups, the severity of pain caused by the change in the position of the patient in both groups was assessed before any intervention, immediately and ten minutes after the intervention. After two hours, in the second change of position, pain was assessed in both groups again. In the intervention group, 20 minutes before the change of position and assessment of pain, foot massage was performed using classical massage techniques. Massage was performed using petrissage, effleurage, vibration, friction movements for 10 minutes for each leg, including the sole and the dorsum of the legs from the ankle to the tip of toes . Foot maEthical considerationsThis study was approved by the Ethics Committee affiliated with Hamadan University of Medical Sciences (decree code: IR.UMSHA.REC.1395.218) and the Iranian Center for Clinical Trials Registration (No. IRCT2016121031327N1). The written informed consent form was signed by the family members of the patients for participation in the study.Statistical analysisIn this study, the required sample size was calculated using a comparison of means, α = 5% and β = 20%, and a 95% confidence interval, the mean and standard deviation from previous studies  and a saDuring the study, 300 patients were hospitalized in the ICU. Among them, 110 patients had the inclusion criteria and were divided into two groups. From the intervention and control groups, 16 patients and 14 patients were excluded. Therefore, 40 patients in each group were available .The result of the comparison showed that no statistically significant differences between the groups in terms of demographic variables  were reported. Therefore, the groups were homogeneous for these variables .p<0.001). Not such a difference was reported in the control group (p=0.256 and p=0.781)  before and after the intervention in the intervention group (p=0.781) .p=0.915). However, after the intervention, a statistically significant difference between the two groups was reported (p< 0.001)  before the intervention in the groups (p=0.660 and < 0.001) . The treet al., [et al., [et al., [et al., [The results of this study showed that foot massage reduced the severity of pain caused by changes in the position of patients with decreased consciousness. Therefore, the research hypothesis was confirmed. While the comparison of the severity of pain immediately and ten minutes after the change in the position showed no significant difference between the mean score of pain intensity in the groups before the intervention, it was significant after the intervention. Despite the presence of pain during the change in the position of the patients in the ICU in most healthcare centers, pain control during painful procedures is not taken seriously and it is not prevented , 6, 33. et al.,  study sh[et al.,  also sta[et al.,  in a stu[et al.,  to inveset al. to investigate the effect of massage therapy on pain, anxiety and stress after the cardiac surgery in the United States showed a significant reduction in the severity of pain, anxiety and stress in groups (p<0.001) [et al., [et al., [et al., [Also, the results of the study by Cutshall p<0.001) , which w[et al.,  examined[et al., , 40. How[et al.,  showed t[et al.,  stated t[et al., . We note some limitations to this study. Due to the time limitation for conducting this study, we were unable to measure the effect of massage for several consecutive days on the pain of patients during the change of position. The patients may have impaired motor and sensory functions due to injury and trauma that might have affected the outcome of the intervention. Other factors such as heart rate, respiration rate, and blood pressure and cortisol levels could be studied to increase the validity of the study.In conclusion, the results of this study showed that foot massage decreases the pain intensity in change position in unconscious patients hospitalized in the ICU. Due to its simplicity, low cost and availability, this method can be used as an adjunct to the use of analgesic drugs to reduce the side effects of drugs. The results of this study showed that despite the presence of pain relief, pain relief due to massage was not clinically significant and it was necessary to use other pharmaceutical and non-pharmaceutical methods along with massage therapy.None declared.This study was funded by a grant from the Hamadan University of Medical Sciences.


There was no significant difference in the neck disability index and EuroQol-5Dimension scores after four weeks and eight weeks of follow-up. Adverse events were reported by four patients (20.0%) in the opioid-only group and five patients (26.3%) in the pregabalin add-on group (p = 0.716). However, over time, the occurrence of side effects and dropouts increased in the pregabalin add-on group. This exploratory pilot study suggests that pregabalin add-on treatment is more efficient than the use of opioids alone at the beginning of NP treatment in cervical myelopathy patients. However, prescribing pregabalin add-on treatment for more than four weeks should be done cautiously.Among patients with cervical myelopathy who were diagnosed with neuropathic pain (NP) by the LANSS test, the study participants were randomly assigned to one of the two study groups. The participants in one study group received opioids only, while those in the other group received opioids and pregabalin. Thirty-nine patients were analyzed in the study . The LANSS, neck pain, and arm pain scores in the pregabalin add-on group improved significantly compared with those in the opioid-only group after the first 4 weeks ( Although some medications are available for NP, including opioids, tramadol, antidepressants, and different antiepileptic drugs (AEDs), a systematic review suggests that considering the balance between efficacy and tolerability, pregabalin may be recommended as a first-line treatment for NP5. Pregabalin is an AEDs prescribed for the treatment of various diseases such as epilepsy, spasticity, anxiety, and NP6. The use of AEDs in the treatment of NP is based on several similarities in the pathophysiology and biochemical mechanisms of epilepsy and NP. It is frequently used for the treatment of several NP syndromes, and it has been approved by the Food and Drug Administration for the treatment of post-herpetic neuralgia, fibromyalgia, diabetic peripheral neuropathy, and spinal cord injury11. In post-herpetic neuralgia, significantly more patients in the pregabalin group were responders (> or =50% decrease in mean pain scores from baseline to endpoint) than in the placebo group11. Additionally, pregabalin significantly reduced weekly mean sleep interference scores. Health-related quality-of-life measurements using the SF-36 Health Survey have demonstrated improvement in the mental health, bodily pain and vitality domains in pregabalin groups. Pregabalin is safe and effective for decreasing pain associated with diabetic peripheral neuropathy and also improves mood, sleep disturbances, and quality of life10. In central NP associated with spinal cord injury, the mean endpoint pain score was found to be lower in the pregabalin group than in the placebo group8. Pregabalin was associated with improvements in sleep disturbances and anxiety, and more patients reported global improvement at the endpoint in the pregabalin group. The off-label use of pregabalin for various pain syndromes, especially for NP, is widespread. However, there is little literature supporting this practice, and the cost is likely astronomical. On 1 April 2019, pregabalin and gabapentin were reclassified as class C controlled substances in the UK. The reclassification was prompted by a growing number of deaths associated with misuse of the two drugs: the number of deaths linked to pregabalin increased sharply from four in 2012 to 136 in 2017, and those related to gabapentin rose from eight in 2012 to 59 in 201612. In the previous five years, prescribing pregabalin has increased by 350% and gabapentin by 150%13.Neuropathic pain (NP) is defined as pain caused by a lesion or dysfunction of the central or peripheral nervous system14. Cervical myelopathy is the most common form of spinal cord injury in adults in North America, with an incidence of 76 per million15. The present definition of cervical myelopathy is both the presence of long-tract signs and high signal changes on T2 MRI in the cervical spinal cord17. There is also little information on the effect of pregabalin in patients with NP in cervical myelopathy under routine clinical practice.Spinal cord injury guidelines recommend pregabalin as the first choice of first-line medications for the reduction of NP intensity among people with spinal cord injuryThe current clinical trial was developed to provide pilot data regarding the efficacy of pregabalin add-on treatment for NP in cervical myelopathic patients and to provide enough positive data to support the conduct of a subsequent large definitive randomized placebo-controlled trial.This study was a randomized, open-label, pilot trial. The study was approved by an institutional review board (H-1609-118-795) and was registered with clinicaltirals.gov (NCT-03618589). Informed consent was obtained from the study participants after explaining the off-label use of pregabalin and its possible adverse effects.No previous studies have reported the effect of pregabalin on NP in cervical myelopathy patients. Since this was a pilot study, the calculation of sample size was not performed. It was determined by the possible number of patients within the study period. The study participants were selected with strict criteria Table . Patient18. The LANSS scale has two parts; a pain questionnaire with five items  and a sensory component assessing allodynia and altered pin-prick threshold (two items). Skin sensitivity was examined by comparing the painful area with a contralateral or adjacent nonpainful area for the presence of allodynia and an altered pin-prick threshold. Allodynia was assessed by investigating the response to the light stroking of cotton wool across the nonpainful area followed by the painful area. The altered pin-prick threshold was determined by comparing the response to a 23-gauge (blue) needle mounted inside a 2 ml syringe barrel placed gently onto the skin in the nonpainful followed by the painful areas. If the LANSS pain scale score was ≥ 12, then neuropathic mechanisms were likely to contribute to the patient’s pain. In this study, only patients with a LANSS pain scale score of 12 points or more were included. The secondary outcomes of changes in disability level and patient satisfaction with treatment were evaluated by using the neck disability index (NDI) and EuroQol-5Dimension (EQ-5D) 5 L, respectively. The EQ-5D evaluates patient-perceived health19. The EQ-5D comprises five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The scores of the five items can be used to calculate a utility index that ranges from −0.6 to 1.0, where a higher score means better patient health. After completing the 4-week and 8-week medication regimens, the study participants visited the outpatient clinic and completed the questionnaires.The study participants completed the baseline questionnaires (including sensory testing) before taking the medicine. The effects of treatment were evaluated in three areas: pain, disability, and health-related quality of life. The primary outcome, pain changes, was assessed using the Leeds assessment of neuropathic symptoms and signs scale (LANSS) and visual analogue scale (VAS) for the neck and arm. The LANSS pain scale is used to screen for the presence of pain of neuropathic origin because of its high sensitivity and specificityp-value of <0.05 was considered significant. Data analysis was performed using SPSS for Windows, version 22 .The Mann-Whitney U test was used to compare pain, disability, and health-related quality of life between the two groups. The Wilcoxon signed-rank test was used to analyze changes in pain, disability, and health-related quality of life within each group. The Bonferroni correction was utilized to compare the clinical results, which included scores for the LANSS, VAS-N, VAS-A, ODI, and EQ-5D, between both groups at each time point. A generalized linear mixed-effects model was applied to analyze the clinical outcomes. The fixed effects were group, time, the interaction between group and time, and confounding factors such as age, sex, weight, smoking status, diagnosis, and the baseline measurements corresponding to the outcomes for each linear mixed model. A two-sided We screened 263 cervical myelopathy patients for the study between November 2017 and June 2019 .The baseline characteristics of the study participants are summarized in Table p < 0.001). The treatment effect  was −3.9 ± 1.3 (p = 0.005) at the 4-week follow-up and −5.8 ± 1.5 (p = 0.003) at the 8-week follow-up. The VAS-N and VAS-A scores improved after 8 weeks in both groups, with significant differences. The treatment effect of the VAS-N was statistically significant at the 4-week and 8-week follow-ups . The treatment effect of the VAS-A was also statistically significant at the 4-week follow-up (p = 0.035), but there was no significant difference at the 8-week follow-up (p = 0.125). The NDI and the EQ-5D scores improved in both groups without significant differences at the 8-week follow-up, and the treatment effect was not significant at the 4-week and 8-week follow-ups.The baseline and treatment responses of the opioid-only and pregabalin add-on groups measured in terms of the pain, disability, and satisfaction associated with treatment are presented in Table p = 0.005 and 0.615, respectively). The VAS-N score in the pregabalin add-on group decreased more significantly than that in the opioid-only group during the first 4 weeks, but there was no significant difference between the two groups over the next four weeks . The VAS-A score in the pregabalin add-on group also decreased more significantly than that in the opioid-only group during the first 4 weeks (p = 0.035), but the VAS-A score in the opioid-only group decreased more than that in the pregabalin add-on group over the next four weeks (p = 0.716). The NDI score improved during the first four weeks and over the next four weeks in both groups, but there was no significant difference between the two groups . The EQ-5D score also improved in the first four weeks and over the next four weeks in both groups, but there was no significant difference between the two groups.The interval changes of the LANSS, VAS-N, VAS-A, NDI, and EQ-5D scores are summarized in Table p = 0.716). Two patients with dizziness, one patient with nausea, and one patient with constipation were reported in the opioid-only group. In the pregabalin add-on group, two patients complained of somnolence, 2 of dizziness and 1 of dry mouth. A total of 2 (10.0%) patients in the opioid-only group and 3 (15.8%) in the pregabalin add-on group discontinued treatment due to adverse events (p = 0.661).The incidences of adverse events and discontinuation are described in Fig. 24. In a systemic review, in only two of seven studies reporting useful efficacy data was amitriptyline significantly better than placebo25. For nortriptyline, only one study reported the primary outcome of people with at least a 50% reduction in pain26. For venlafaxine, four of the six studies reported some positive benefit27. In the largest study by Rowbotham, 56% of participants achieved at least a 50% reduction in pain intensity versus 34% of participants in the placebo group28. However, this study was subject to significant selection bias. In a survey of opioids for NP in adults, at least 50% pain intensity reduction was reported in three studies 29. Using a random-effects analysis, 70/132 (53%) had at least 50% pain relief with opioids and 40/133 (30%) with placebo. Opioid drugs, including oxycodone, are commonly used to treat NP, and they are considered effective by some professionals. A systematic review assessed the analgesic efficacy of oxycodone for chronic NP in adults30. There was only very low-quality evidence that oxycodone was of value in the treatment of painful diabetic neuropathy or postherpetic neuralgia. There was no evidence for other NP conditions, including cancer-related neuropathy, central NP, type II complex regional pain syndrome, human immunodeficiency virus neuropathy, painful diabetic neuropathy, phantom limb pain, postherpetic neuralgia, postoperative or traumatic NP, spinal cord injury, and trigeminal neuralgia. However, there have been no studies regarding NP in cervical myelopathic patients.The currently recommended first-line pharmacological treatments for NP include anticonvulsants , tricyclic antidepressants (amitriptyline and nortriptyline), serotonin-noradrenalin reuptake inhibitors (duloxetine and venlafaxine), and opioidsIn this study, among patients with cervical myelopathy, the proportion of NP patients with a LANSS pain score of 12 points or more was higher than expected (28.1%). However, a large number of patients (more than 36.5%) refused to participate in the study. Therefore, we could only recruit 39 patients for 20 months. Our study population was composed of a small but relatively homogeneous target group of patients with NP and cervical myelopathy.p = 0.005). However, there was no significant difference in the change in LANSS scores between the two groups over the next four weeks (p = 0.615). The VAS-N and VAS-A scores also showed similar changes after medication. These results suggest that the use of pregabalin add-on treatment for NP in patients with cervical myelopathy is useful in the early stages (approximately four weeks), but after that, the effect is negligible. The present study also analyzed the satisfaction of patients (EQ-5D) after medication. In this study, the opioid-only group and the pregabalin add-on group did not show significant differences in the changes in EQ-5D scores at the beginning of the treatment (p = 0.645) or over the next four weeks (p = 0.765); the same results were observed for the NDI. It is noteworthy that pregabalin add-on treatment was effective for reducing pain but did not significantly affect disability or satisfaction. It is thought that the NDI and EQ-5D scores did not improve because cervical myelopathy did not improve. The modified Japanese Orthopaedic Association score has been found to have a moderately strong negative correlation with the NDI31. Another study has shown a decrease in EQ-5D scores in patients with cervical myelopathy32.In Table 33. In a systematic review of pregabalin for acute and chronic pain, side effects were reported to occur in 3–5% of cases34. The duration of therapy is one of the predictive factors for adverse events associated with pregabalin administered for NP35. Although it is not possible to give a precise period, long-term administration of pregabalin may cause more side effects. Although some studies have reported that opioids are ineffective for NP, other studies show that NP can be improved by opioids38. Even though the treatment with pregabalin was of short duration, and the patients were followed for only a brief period, the results of this study are meaningful.In the opioid-only group, during the first four weeks, two patients complained of side effects, one of whom stopped taking the medicine due to dizziness. During the next four weeks, two patients complained of side effects, one of whom stopped taking the medicine due to nausea. There was no difference in the occurrence of side effects or dropouts between the two periods. In the pregabalin add-on group, during the first four weeks, two patients complained of side effects, one of whom stopped taking the medicine due to somnolence. During the next four weeks, three patients complained of side effects, two of whom stopped taking the medicine due to dizziness and dry mouth. Over time, the occurrence of side effects and dropouts increased. In a nationwide study of opioids, 0.60% of patients experienced severe opioid-related adverse eventsOur study had several limitations, including a small sample size, which resulted in low statistical power. Another limitation was that our study did not evaluate pharmacological effects. Moreover, there was also no systematic assessment of the tolerability of treatment. However, the high percentage of patients who completed treatment and the low frequency of dropouts due to side effects means that opioids could represent a useful treatment option for patients with NP and cervical myelopathy. The third limitation was the open‐label design of the study, introducing possible sources of bias in terms of the patients. A double-blind and double-dummy design could minimize such bias. However, due to ethical issues and practical situations, such models could not be used. The fourth limitation was that cervical myelopathy is a condition of chronic progressive atraumatic spinal cord compression that, over time, may cause a decline in physical function and quality of life. All of the diagnoses included in this study  can progress even after surgical treatment. However, all of these conditions would have had a similar impact on the primary endpoint. The fifth limitation of our study was that repeated use of a questionnaire could impact its validity. Finally, patients in neither of the groups were taking pregabalin alone.Despite its limitations, this study is important for several reasons. First, we were able to randomly assign patients with NP and cervical myelopathy to receive treatment with opioids only or pregabalin add-on treatment since the study recruited patients before the use of pregabalin and gabapentin had become common. To our knowledge, this study is the first randomized, open-label, pilot trial in which the impact of pregabalin add-on treatment is examined explicitly for NP in cervical myelopathy patients. However, the now increasingly common prescription of these medications by primary care providers may preclude a large-scale study in the future, or a wash-out period may be needed for the discontinuation of pregabalin. Second, the results of this study will lead to a larger, well-controlled, randomized clinical trial regarding the efficacy of pregabalin for the treatment of NP in cervical myelopathy patients before such use becomes permanently engrained among pain physicians.We demonstrated that pregabalin add-on treatment was effective for the treatment of NP in the short term. There remains a persistent need to evaluate the excessive practice of pregabalin use in a large proportion of patients with NP and cervical myelopathy. Replication with a larger sample size is recommended to confirm the results of this study.