Background. Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) (nabiximols or Sativex®) is an oromucosal spray formulation containing THC and CBD at an approximately 1:1 fixed ratio. Its administration for the treatment of pain in patients with multiple sclerosis (MS) has been established. MS patients generally complain of different kinds of pain, including spasticity-related and neuropathic pain. In this study, we compared and evaluated pain modulation and thermal/pain threshold of MS patients before and after THC/CBD administration. Methods. 19 MS patients underwent clinical examination, numerical rating scale (NRS), quantitative sensory testing (QST), and laser-evoked potentials (LEPs) before and after 1 month of therapy. Psychophysiological and neurophysiological data were compared to sex- and age-matched controls. Results. Patients reported a significant reduction in pain. We found statistically significant differences in LEP parameters between patients and controls but no significant change in LEP measures after THC/CBD therapy. Cold and heat detection thresholds were altered in patients but did not change after THC/CBD therapy. There was a significant increase in cold pain threshold by hand stimulation and a significant reduction in abnormal cold perception thresholds. Conclusions. Our results indicate that Sativex® therapy provides pain relief in MS patients and suggest that it might modulate peripheral cold-sensitive TRP channels. Pain is a key symptom in patients affected by multiple sclerosis (MS) ,2 and po®) have been demonstrated as effective in MS-related pain syndromes , LEP N2-P2 complex amplitude, and N2 latency were compared using one-way analysis of variance (ANOVA) with groups as between-subject factor. Bonferroni correction was then applied for post-hoc multiple comparisons. Patient data at T0 and T1 were compared with paired Student’s We also calculated the number of abnormal measurements of LEP and QST parameters in the patients. LEP latencies or amplitudes at T0 and T1 were classified as abnormal when they were either absent or their values were outside the normal limits for latencies (mean + 2SD) and/or amplitudes (mean − 2SD). CDT and HPT were considered abnormal when the values were under the 5th percentile of normal values; HDT and CPT were considered abnormal when they exceeded the 95th percentile. We compared the rate of abnormal measurements at T0 and T1 using the chi-square test to see whether there was a difference in frequency before and after therapy. Unlike QST, which can also assess small fibers related nociceptive pain , LEPs arp < 0.05 was considered significant.Statistical analysis was performed using SPSS ; n = 1, smoked marijuana abuse), relapse during 1-month Sativex® therapy (n = 1), lack of compliance with neurophysiological studies (n = 4), and intolerable adverse events (dizziness) ; among 19 MS patients who entered in the final analysis, 8 presented neuropathic pain, 6 nociceptive pain, and 5 mixed pain. In this group of 28 MS patients, 9 dropped out of the study because of drug abuse . Six patients reported mild side effects . A significant reduction in NRS score after drug therapy  was observed. If a 20% reduction in pain is considered clinically relevant, 14 patients (74%) responded to Sativex® therapy. All patients gradually increased their dose of oromucosal spray of Sativexp < 0.0001) or the feet (mean N2-P2 complex amplitude (SD) 24.95 uV (9.75) for C vs. 16.46 uV (7.63) for PT0; F = 6,502, p = 0.006)  37.48 uV (13.79) for C vs. 17.41 uV (8.22) for PT0, F = 26,814, = 0.006) . p < 0.0001) or the feet (mean N2 LEP latency (SD) 274.72 ms (34.12) for C vs. 321.67 ms (48.53) for PT0; F = 6,408, p = 0.002) (Significant differences were similarly found for N2 latency in either the dominant hand (mean N2 LEP latency (SD) 209.84 ms (14.70) for C vs. 261.18 ms (39.73) for PT0; F = 23,084, = 0.002) . LEPs were inelicitable at the upper limbs in 11% of patients and at the lower limbs in 32%. Conversely, no significant change in LEP parameters was noted after drug administration . p < 0.0001; mean N2 latency (SD) 209.84 ms (14.7) for C vs. 245 ms (36.76) for PT0; F = 573,622, p < 0.0001; feet: mean N2–P2 complex amplitude (SD) 24.95 uV (9.75) for C vs. 12.85 uV (4.77) for PT0; F = 293,020, p < 0.0001; mean N2 latency (SD) 274.72 ms (34.12) for C vs. 332.5 ms (59.87); F = 752,471; p < 0.0001).Similar results were observed in the patients with neuropathic/mixed pain, with a significant decrease of amplitude and increased latency of the ‘neuropathic’ group compared to control group, in either the dominant hand or feet (dominant hand: mean N2–P2 complex amplitude (SD) 37.48 uV (13.79) for C vs. 18.08 uV (8.96) for PT0; F = 911,374, ® therapy. Also in patients with neuropathic or mixed pain, no change in LEP parameters was observed after Sativexp < 0.0001; QST HDT median (5th–95th percentile) 34.07 °C (32.97–36.88) for C vs. 36.95 °C (33.96–47.54) for PT0; p < 0.0001; Feet: QST CDT median (5th–95th percentile) 29.77 °C (26.5–30.93) for C vs. 22.45 °C (4.66–29.83) for PT0; p < 0.0001; QST HDT median (5th–95th percentile) 36.48 °C (33.95–40.61) for C vs. 42 °C (36.84–47.12) for PT0; p < 0.0001; QST HPT median (5th–95th percentile) 44.94 °C (39.75–49.25) for C vs. 48.9 °C (43.6–51.5) for PT0; p < 0.0001] and did not change after THC/CBD therapy  30.67 °C (28.64–31.3) for C vs. 27.10 °C (15.77–30.9) for PT0;  therapy . p = 0016) (We observed a significant posttreatment difference between controls and patients in cold pain threshold as measured by hand stimulation (QST CPT median (5th–95th percentile) 8.67 (0–23.71) for C vs. 17.25 (0–27.8) for PT1;  = 0016) . p = 0.048) and a trend towards a reduction in abnormal CDT also in hands   . No diff® therapy is effective for relieving pain, as seen in the significant reduction in the NRS scores. Furthermore, a significant reduction in amplitude and increased latency, probably caused by conduction block and demyelination damage of the spinothalamic pathway, was observed in the MS patients as compared to controls. This observation is shared by other studies [Consistent with previous studies ,32, our  studies ,33. Conv studies , this laOther studies have demonstrated a significant decrease in the N2–P2 complex amplitude after tramadol injection in healthy volunteers  and a de®, and a significant percentage reduction in abnormal CDT after therapy, although the difference did not reach statistical significance between patients before and after treatment. Only one randomized, double-blind, placebo-controlled, crossover trial [Concerning QST, our results demonstrated a significant reduction in CDT and an increase in HDT in patients compared to controls. Intriguingly, there was a significant increase in the hand CPT of patients after Sativexer trial  comparedThermal sensation is known to be mediated by transient receptor potential (TRP) ion channels implicated in many physiological processes, including temperature sensation, pain, regulation of neurotransmitter release, and immune function. It is also established that THC and CBD may act as agonists of TRP channels, which is why they are also called ionotropic cannabinoid receptors to differentiate them from the classic CB1 and CB2 metabotropic receptors . The subThe mechanism of action of cannabinoids on TRP are multiple and complex, as some cannabinoids may indirectly suppress TRPV1 and TRPA effects on pain and inflammation by acting on CB1, but directly activate the TRP channel at higher concentrations ,46. FurtTRPM8, another member of the TRP superfamily, is also involved in thermosensation and has a role in the detection and transmission of cold stimuli ,48 and c® to modulate the more severely damaged nociceptive pathways, as suggested by the high number of abnormal thermal detections and sensory impairment evidenced on clinical examination of the feet. Furthermore, although the cold pain threshold was increased (from 9.55 °C to 17.25 °C) in the patients after Sativex® therapy, its value remained within the normal range (<23.71 °C) and they did not complain of thermal allodynia before or after drug intake. In our study, the increase in cold pain threshold in hands and the normalization of cold detection threshold in MS patients after therapy could reflect a cannabinoid-mediated modulation on either TRPA1 or TRPM8 channels, probably via activation (and consequent desensitization) of TRPA1 and inhibition of TRPM8, although the mechanisms of action of the single channels need to be elucidated . If cool® efficacy for the relief of both nociceptive and neuropathic pain has been demonstrated in some controlled studies [® relives pain symptoms in MS.We acknowledge several limitations of our study: first, the small sample size and high EDSS; second, the lack of a placebo group, although Sativex studies ,51; thir studies ,52. Furt® in reducing pain in MS patients. Furthermore, our findings suggest a possible direct effect of cannabinoids on TRP channels by modulating or desensitizing cold-channel functions, in particular TRPA1 and TRPM8. This underscores the importance of TRP channels as a therapeutic target by acting through peripheral desensitization and inhibition of sensory neurons [In summary, our study further corroborates evidence for the effectiveness of Sativex neurons . Several neurons .


Sufentanil has been widely used in epidural PCA, while its use in intravenous PCA has rarely been reported. Based on its use in target controlled infusion, we reckoned that the effect-site concentration of sufentanil would be steady if background infusion is given in intravenous PCA. This prospective, single center, randomized study with a three arm parallel group design aims to find out the appropriate dose of sufentanil when used in intravenous PCA with background infusion in abdominal surgeries.Patients diagnosed with gastrointestinal cancer and consented to the study were recruited. The analgesia pump with one of three different doses of sufentanil  was attached to the patient through peripheral venous line right after surgery. The primary endpoint was pain scale VAS up to 48 hours postoperatively.In our study 90 patients were analyzed. In group B (SF 2.0) and C (SF2.5), patients had better pain relief than in group A (SF 1.5). There was no difference between group B and C in pain intensity at rest. While in group C more patients got pain relived at activity than in group B. All three groups had low and similar incidence of adverse effects of sufentanil.The dose 2.5 μg/kg of sufentanil with background infusion is preferred because of better pain alleviation at activity without increase of adverse effects up to 48 hours after surgery. Many patients experienced acute postoperative pain, and approximately 86% had moderate, severe, or extreme pain. Although pain management system has been fully established in most institutions, yet there were still many patients complaining of inadequate pain control after acute pain care , which wSufentanil, one of the opioids with strong analgesic potency, is now widely used for surgery patients during anesthesia, has also been extensively used in postoperative pain control and labor pain relief, specifically in patient controlled epidural analgesia (PCEA) –5. AlthoThis is a prospective, single center, randomized study with a three arm parallel group design. No changes were made to methods after trial commencement.This trial was registered at ClinicalTrials.gov (NCT02503826). The study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki, approved by the Ethics Committee of the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China  on February 5, 2015. Written informed consent was obtained from all patients or a legal surrogate. It was a single center, randomized, double-blind, three arm parallel group study. It was conducted at the Second Affiliated Hospital of Xi’an Jiaotong University between February 11, 2015 and December 8, 2016. The authors confirm that all ongoing and related trials for this drug/intervention are registered. The delay in registering this study is due to: a. failed contact to the organization's PRS administrator to request a user login to the website for the registration (we requested repeatedly but had no reply), b. we had to finally apply a PRS account in person, c. we were not very familiar with the registration process on the website.Patients diagnosed with gastrointestinal cancer, aging from 20 to 75, BMI 18 to 28 kg/m^2, American Society of Anesthesiologists (ASA) grade I to II, anticipated surgery duration within 4 hours and agreed to sign the consent paper were scheduled for elective abdominal surgery including gastrectomy, colectomy, and rectectomy. Women participants in the study had to either be menopause or use routine contraceptive method.Patients with known allergy or contradiction to the treatment drugs, or severe respiratory, cardiovascular or neurological diseases, hepatic or renal dysfunction, psychiatric history or unstable mental state were excluded from the study. Patients with history of drug or alcohol abuse, chronic use of opioids and pregnancy or breast-feeding were excluded as well.2), end-tidal CO2 (ETCO2), blood loss, and transfusion were recorded during anesthesia. Cisatracurium and dexmedetomidine were discontinued until peritoneum closure, while propofol and remifentanil were stopped until the last stitch of skin.Patients were enrolled according to the inclusion and exclusion criteria by our nurse. All patients received general anesthesia. No premedication was given. Ten minutes before anesthesia induction a loading dose of dexmedetomidine with 1 μg/kg was infused over 10 minutes. Then anesthesia was induced with midazolam 2 mg, sufentanil 0.5 μg/kg, propofol 1–2 mg/kg. Cisatracurium 0.2 mg/kg was given to facilitate orotracheal intubation with a cuffed tube. Anesthesia was maintained with continuous infusion of propofol 3–7 mg/kg/h, remifentanil 0.1–0.25 μg/kg/min, cisatracurium 0.1 mg/kg/h and dexmedetomidine 0.2–0.5 μg/kg/h with positive pressure ventilation in a circle system. And the bispectral index (BIS) value was maintained between 40 and 60. Mean blood pressure (MAP), Heart rate (HR), pulse oxymetry . The randomization was generated by permuted block randomization with block size 6 manually. Briefly, there should be 2 patients assigned to A treatment, 2 assigned to B treatment and 2 assigned to C treatment in each block. Fifteen permutations and combinations were selected by a statistician based on random number table. The allocation sequence of patients was determined by the sequence of surgery. The allocation marks were sealed in 90 sequentially numbered envelopes and could only be opened 30 min before the end of surgery by the nurse who was responsible for the preparation of the pump. After checking up with the pump preparation and allocation mark, the allocation mark was concealed in envelop again by the nurse. And the allocation mark remained sealed till complete of last follow-up and start of data input. No changes were made for blinding.2, total pressing times, total consumption of sufentanil, rescue analgesic requirement, visual analogue scale (VAS), numerical rating scale (NRS) and Ramsay sedation scale (RSS) score were recorded. Side effects including nausea and vomiting, urinary retention, pruritus, respiratory depression were also recorded. Overall satisfaction index of the patients was recorded as well.The PCA pump was prepared with different doses of sufentanil and 10 mg tropisetron. The dose per body weight of sufentanil in the intravenous PCA pump was determined by which treatment arm the patient was allocated to, with 1.5 μg/kg sufentanil in arm A, 2.0 μg/kg sufentanil in arm B and 2.5 μg/kg sufentanil in arm C. The total volume of the pump was 100 ml. Immediately after surgery, the PCA pump was attached to the peripheral venous line by the investigator who was unaware of the formula of the PCA pump or the treatment arm. A loading dose of 10 μg sufentanil was administered right at the end of the surgery. And then 5 μg at a time according to the patients’ complaint of pain untill the pain relieved or the respiratory rate (RR) was less than 10 breaths per minute. The emergence and extubation time was recorded and emergence time was defined as the time from anesthesia discontinuation to eye opening on command. The background infusion of PCIA was set at 2 ml/h, the bolus volume of each PCA press was 0.5 ml and lockout interval was 10 min. All patients were monitored in the post-anesthesia care unit (PACU) for at least 30 min until the discharge criteria were met. All the patients were followed-up 2, 6, 24 and 48 hours after the surgery. Clinical evaluations including MAP, HR, RR, SpOThe overall study duration of each patient was less than 5 days, including the screening period (1 or 2 days before surgery), the treatment period (from surgery day to 48 hours after surgery) and the following-up period (from the end of the surgery to 48 hours after surgery).Patients, anesthesiologist, and data collectors involved in the study were unaware of which treatment arm the patients would be in. The double blind method was secured by putting no tag on the PCIA pump.Rescue analgesic of 5 μg sufentanil was administered intravenously by the investigators when the patient had maximal pressing times per unit time and the pain score was still above 5 at rest for more than 30 min.The efficacy of the PCIA pump was assessed based on the patients’ pain level of VAS and NRS at the time points of 2, 6, 24, 48 hours after surgery. VAS: the patient was presented with a horizontal 10-cm line (from 0 = no pain to 10 = worst pain) and was asked to mark the spot which indicated the current pain level. NRS: the patient was asked to describe the current pain level through an 11 points numerical scale from 0 = no pain to 10 = worst possible pain.The safety of the PCIA pump was evaluated based on the incidence, intensity, seriousness, and causality of pump-related adverse events (AEs) and the frequency of clinically significant changes in physical examination, HR, BP, laboratory safety tests , and 5-lead ECG.The primary endpoint was pain level assessed by VAS up to 48 hours after surgery. Secondary endpoints included NRS score of pain, nausea and vomiting, degree of sedation, hypotension, pruritus, urinary retention, respiratory depression and rescue analgesia. No changes were made to trial outcomes after the trial commenced.PASS 11  based on one-way ANOVA. And the calculated sample size was 29 in each group and we included 30 patients in each group. Comparisons of VAS or NRS for pain were performed by linear mixed model among groups using IBM SPSS Statistics 19.0. Ranked data of sedation degree and vomiting and nausea scale were analyzed with the Kruskal–Wallis tests. Probability values under 0.05 were considered significant. No interim analysis was planned and conducted.In order to find out the appropriate dose of sufentanil in PCIA after moderate surgery, the primary endpoint pain level assessed by VAS was analyzed. The expected standard deviation of means was 6.9 mm , and staNinety patients in our hospital were assigned to three treatment arms . The enrThe mean age of all patients was 60 (range 26–75) yrs old. There were 30 females and 60 males. Patient characteristics and baseline data were compared and no difference among three treatment arms . Other r1. The postoperative pain assessmentP<0.001), as well as the time effect (P = 0.001) and the interaction effect (P = 0.033). VAS scores at rest in both group SF 2.0 and SF 2.5 were decreased compared with group SF 1.5 respectively (P<0.001). But no difference between group SF 2.0 and group SF 2.5 was detected (P = 0.392). The fixed effect of group for VAS at activity was significant (P<0.001), as well as the time effect (P = 0.001). But no interaction effect was detected (P = 0.114). VAS at activity was decreased in group SF 2.0 compared with group SF 1.5 (P<0.001). And VAS at activity in group SF 2.5 was decreased as compared with group SF 2.0 (P = 0.038). The fixed effects of group for NRS at rest was significant (P<0.001), as well as the time effect (P<0.001), but not the interaction effect (P = 0.138). NRS scores at rest in both group SF 2.0 and SF 2.5 were decreased compared with group SF 1.5 respectively (P<0.001), while there was no difference between group SF 2.0 and SF 2.5 (P = 0.694). The fixed effect of group for NRS at activity was significant (P<0.001) as well as the interaction effect (P = 0.028). But no time effect was detected (P = 0.980). NRS scores at activity in both group SF 2.0 and SF 2.5 were decreased compared with group SF 1.5 respectively (P<0.001). But no difference between group SF 2.0 and group SF 2.5 was detected (P = 0.214). In order to further clarify the difference between group SF 2.5 and SF 2.0, we analyzed patients with VAS or NRS scores at activity less than 5.0 [The postoperative pain of VAS and NRS was analyzed by mixed linear model. The included factor was group, subjects was set as random effect, repeated effect was time and covariance structure was unstructured. The fixed effect of group for VAS at rest was significant  with continuous background infusion for the first time. Meanwhile we explored the optimal dose of sufentanil for PCIA in abdominal surgeries from three incremental doses.As to PCA pump parameters, we set background infusion rate at 2 ml/h, bolus volume at 0.5 ml and the lockout time at 10 min. The dose of sufentanil in PCA pump was calculated by the body weight of the patient and the parameters were set based on the sufentanil TCI system of Gepts . After iBackground infusion is not recommended when morphine or fentanyl is used in PCA pump because it won’t improve pain relief and may increase the risk of delayed respiratory depression. The latter is mostly due to the accumulation of opioids during continuous infusion ,15. And It has been reported that the wake-up concentration of sufentanil is around 0.1 ng/ml or higher . Using tA report about the comparison of continuous infusion and bolus administration of sufentanil during anesthesia for cardiac valve surgery showed that there was no benefit in continuous infusion except for the simplicity in clinical practice. The continuous infusion group consumed 26% more of sufentanil than bolus administration, while both groups had stable hemodynamics . In our Even though there was no difference in pain relief at rest in arm B and arm C, we considered that dose 2.5 μg/kg would be the preferred optimal dose. On one hand with 2.5 μg/kg sufentanil more patients experienced pain relief when they were at activity (pain intensity score less than 5 when coughing) 24 hours after surgery. On the other hand, with 2.5 μg/kg sufentanil it didn’t increase side effects compared to 2 μg/kg sufentanil. Theoretically, a higher dose of sufentanil will lead to more significant pain relief because sufentanil has no ceiling effect, as long as the side effects of sufentanil are acceptable. In our study the patients were encouraged to walk in the ward after abdominal surgery as early as possible, and most patients could manage to walk at about 24 hours postoperatively. Therefore, we only observed the pain intensity at activity 24 hours and 48 hours after surgery.The efficacy of sufentanil PCIA was proved and the safety of its use was preliminarily testified. However, how sufentanil would influence the recovery of patients after 48 hours was not discussed in this study, including physical recovery, the gastrointestinal function and hospital stays. Another question was whether the development of chronic postoperative pain would be influenced by sufentanil PCIA.Finally, in light of sufentanil TCI we found that sufentanil PCIA with continuous background infusion could provide effective pain relief with less side effects. The optimal dose of sufentanil was 2.5 μg/kg in this study, which is more preferred to the other two lower doses.PASS 11 on basis of one-way ANOVA but not the linear mixed model. This would cause incorrect power. We run the linear mixed model analysis and both the effects of treatment and time were significant except for the interaction. Other biases may come from the education backgrounds, personalities and pain sensitivities of all subjects.This study has several limitations. For a dose-effect study, 30 subjects each group is enough. But if patient safety is to be evaluated, a study with more cases and more centers might be more convincing. The biases of the study were inevitable. The sample size calculation was conducted by a software program S1 File(DOC)Click here for additional data file.S2 File(DOCX)Click here for additional data file.S3 File(DOC)Click here for additional data file.S4 File(RAR)Click here for additional data file.S1 Table(DOC)Click here for additional data file.S2 Table(DOC)Click here for additional data file.


Pain due to oral mucositis (OM) is a major problem during concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) patients.n = 27) and a severe pain group (n = 29) according to the degree of pain reported  score 4–6 or severe = NRS score 7–10) at initiation of controlled-release oxycodone (CRO) treatment.We enrolled 56 NPC patients receiving CCRT and allocated them into two groups: moderate pain group (P = 0.015). Moderate pain patients had significantly better quality of life (P = 0.037), lower weight loss (P = 0.030) and more active CCRT response . Although 24-h pain control rate was comparable in the two groups , the moderate pain group score eventually stabilized at ~ 2 vs. 3 in the severe pain group (P < 0.001); the titration time to reach bearable pain (NRS ≤ 3) was also significantly shorter in moderate pain patients . Incidence of adverse events was comparable in both groups.Total dose of CRO was significantly higher in severe pain patients than in moderate pain patients (791.60 ± 332.449 mg vs. 587.27 ± 194.940 mg; The study findings suggest that early introduction of low-dose CRO at the moderate pain stage could help reduce the total dose required, provide better pain control, improve quality of life, and enhance CCRT response. Nasopharyngeal carcinoma (NPC) is usually > 70%) diagnosed at a locoregionally advanced stage –3, when 0% diagnoCurrently, the primary strategies for preventing or reducing OM pain include nutritional supplementation, oral cleaning, promotion of local mucosal recovery, and use of antibiotics and analgesics , 11–13. According to the WHO Three-Step Treatment of Cancer Pain principles, it is recommended to give short-acting opioids in patients with severe cancer pain to achieve the goal of analgesia and then converted to long-acting opioids maintenance. The National Comprehensive Cancer Network (NCCN) and the European Association for Palliative Care (EAPC) guidelines recommend long-acting opioids  as the first-line treatment for cancer pain , 15. WhiSince 1995, controlled-release oxycodone (CRO) has been widely used for treatment of moderate to severe cancer pain and non-cancer pain –21. In cTrails.gov NCT03045484. The key raw data was uploaded onto the Research Data Deposit (RDD) public platform (www.researchdata.org.cn), with the approval RDD number as RDDA2018000731.The study population was comprised of NPC patients without distant metastasis receiving CCRT at Sun Yat-Sen University Cancer Center in China between May 19, 2015, and January 23, 2018. The study protocol was approved by the institutional review board of Sun Yat-sen University Cancer Center and written informed consent was obtained from all enrolled patients. The study was registered at Clinical First, to evaluate the exact time of introduction of CRO, we conduct a preliminary experiment of 10 patients: 1 patient needed pain intervention at 12F of radiotherapy, 1 at 14F, 5 at 15F, 2 at 16F, and 1 at 17F. Considering the result of the preliminary experiments, the majority of patients (5/10) require pain relief at 15F of radiotherapy; we define 15F as the time node to introduce CRO. Patients were eligible for inclusion if they 1) were aged 18–65 years, 2) had been newly diagnosed with NPC without distant metastasis and were receiving CCRT, 3) need pain intervention and experienced moderate to severe OM pain  score ≥ 4) at 15F of radiotherapy, 4) had not received opioid analgesics previously, 5) were able to understand the application of the NRS for assessing pain level, 6) had normal hematology examination results, and 7) were willing to give written informed consent. Patients were excluded if they 1) refused treatment with CRO, 2) need pain intervention before or after 15F, 3) had only mild oral mucosal pain (NRS score < 4) at 15F, and 4) had any mental illness. The enrolled patients were separated into two groups according to the degree of pain experienced at 15F of radiotherapy (the best pain intervention time node) when CRO was initiated: a moderate pain group (NRS score 4–6) or a severe pain group (NRS score 7–10).The CCRT schedule comprised 100 mg/m2 cisplatin given intravenously every 3 weeks concurrently with intensity-modulated radiation therapy. Total cumulative doses were > 66 Gy to the primary tumor and > 50 Gy to the bilateral cervical lymph nodes and potential sites of local infiltration. The radiation dose was 2.0–2.27 Gy per fraction with five daily fractions per week for 6–7 weeks, administered as megavoltage photons.CRO treatment was initiated with dose of 20 mg/day  [The primary efficacy endpoint was the total dose of CRO from baseline to the end of week 3. Secondary endpoints were 1) 24-h pain effective rate (ER), which was defined as pain remission of ≥ 25% over 24 h; the remission rate was calculated using the formula: (predose NRS − NRS after 24 h/predose NRS) × 100%); 2) weight loss from baseline to week 3; and 3) change in QOL from baseline to week 3, as assessed by the WHO QOL-100) plus an additional question (question 101) on appetite in which the responses were scored as follows: 1 = very bad, 2 = bad, 3 = average, 4 = good, 5 = very good); 3) CCRT response based on nasopharyngoscopic examination and MRIs, completely response (CR) defined as the complete resolution of assessable nasopharyngeal primary tumors.AEs—defined as any undesirable and unintended sign, symptom, or disease temporally and possibly associated with the use of CRO—were graded using the Common Terminology Criteria for Adverse Events v 3.0 . Clinicat test was used for comparison of continuous variables. The chi-square test and Fisher’s exact test were used for categorical variables. The percentage of patients experiencing at least one AE was calculated for each group. All statistical tests were two-sided. P ≤ 0.05 was considered statistically significant.Statistical analysis was performed using SPSS software, version 19.0 . A total of 56 patients received the same treatment. The safety analysis/adverse events analysis was performed on all 56. But 9 patients dropped out of the study for various reasons and so final analysis to establish efficacy of treatment was performed only the data of 47 patients. All analyses were conducted using available data, and no imputation was performed for missing data, except for the analysis of the QOL, where missing data were handled using mean/mode imputation. Student’s n = 2), refusal to accept CRO after relief of pain (n = 1)) and 6 because they had serious AEs. Thus, for the full analysis, there were only 47 patients (22 in the moderate pain group and 25 in the severe pain group). Table Figure pain n = ) and 6 bP = 0.015).The mean total dose of CRO in the FAS was 695.96 ± 292.63 mg. The mean total dose of CRO was significantly lower in the moderate pain group than in the severe pain group . As Fig. P < 0.001). The titration time to achieve bearable pain (NRS ≤ 3) was significantly shorter in the moderate pain group than in the severe pain group .Among all 56 patients, the 24-h ER (proportion achieving ≥ 25% reduction in pain) was 85.7% (48/56). There was no significant difference in the 24-h ER between the moderate pain and severe pain groups  and at week 3 . Mean weight loss from baseline to week 3 in the full analysis population was 4.11 ± 2.64 kg. Weight loss was significantly lower in the moderate pain group than in the severe pain group .The appetite score was significantly better in the moderate pain group than in the severe pain group at baseline .We compare the CCRT treatment effect of the two group at 30F according the nasopharyngoscopic and MRI examination. Mean CR (complete response) rate in the full analysis population was 76.6% (36/47). CR rate was significantly higher in the moderate pain group than in the severe pain group (90.9% (20/22) vs. 64.0% (16/25); P > 0.99) and serious AEs (P > 0.99). During the study, 23/27 (85.2%) moderate pain group patients experienced 31 AEs, and 25/29 (86.2%) severe pain group patients experienced 33 AEs  and also greatly increase patient compliance with treatment.In our sample, the NRS score in the moderate pain group remained significantly lower than that in the severe pain group. Furthermore, the 24-h ER was higher and the titration time to stable pain control less in the moderate pain group. Rapid, stable, and effective pain control will lead to increased food intake and decreased weight loss in NPC patients during CCRT and, overall, improve the QOL of patients.According to clinical practice, OM pain can interfere with eating and adversely affect the quality of life of patients , and mayThe main factor countering the benefits of early introduction of CRO is the probability of adverse events such as constipation, vomiting, anorexia, dizziness, and nausea . GeneralOur trail results revealed that early induction of CRO at the moderate pain had better analgesic qualities and more active CCRT response of NPC patients. The results provide a promising way to guide treatment strategy for OM of NPC patients. Our study has several strengths. First, this is the first time to confirm the efficacy and rational medication time of CRO for OM in NPC patients. Second, we first found that CRO may promote better overall effect of CCRT treatment in NPC patients.Due to ethical reasons , this experiment was designed as an uncontrolled experiment. Besides above, this study has some limitations. First, this was a single-center trial, and the sample size was small, therefore, we are still proceeding the trail and seeking help from other centers. Second, because of the short duration of observation, we do not have information on long-term prognosis and the occurrence of late AEs; in view of this, we decided to make a long-time follow-up of 2 to 5 years hoping to get a comprehensive prognosis data. Despite these limitations, our study throws some light on strategies for control of OM pain in NPC patients.Early introduction of CRO at the moderate pain stage may help reduce the total dose of CRO required, provide better pain relief, reduce weight loss during CCRT, improve the quality of life, and eventually enhance overall effect of CCRT in NPC patients.


We also found a significant negative correlation between the improvement rate and functional connectivity strength between the mPFC and precuneus. These findings suggest that subanesthetic-dose ketamine is effective in patients with chronic pain whose brain functional connectivity between the mPFC and precuneus is low. We believe that the current study explored for the first time the correlation between brain functional connectivity and the effect of subanesthetic-dose ketamine for chronic pain and indicated the possibility of use of the predictive marker in pharmacological treatment of chronic pain.Ketamine has been used to treat chronic pain; however, it is still unknown as to what types of chronic pain is ketamine effective against. To identify the effect of administration of subanesthetic-dose ketamine in patients with chronic pain and to clarify the mechanism of the effect, we retrospectively investigated brain functional connectivity using resting-state functional magnetic resonance imaging (rs-fMRI). Patients were divided into responders  and non-responders (Group NR). We compared the differences in terms of brain functional connectivity by seed-to-voxel correlation analysis. Two-sample  In these cases, brain imaging studies5 using functional MRI (fMRI) to evaluate blood flow dynamic responses related to human and animal central nervous system activities were conducted. Changes in central nervous system activity following ketamine administration have been observed in healthy adults and patients with depression. However, to the best of our knowledge, no previous study has examined the relationship between brain activity in patients with chronic pain and their responses to subanesthetic-dose ketamine.In recent years, the rapid and sustained antidepressant effect of subanesthetic-dose ketamine has received considerable attention8. In a study involving a neuropathic pain animal model, it was reported that the spared nerve injury model of neuropathic pain induced depressive behavior in rats and a single subanesthetic dose of ketamine successfully treated this depressive behavior9. Ketamine has been used to treat chronic pain; however, it is still not known what kind of chronic pain ketamine is effective against. Identification of patients who respond to ketamine by noninvasive examination can provide substantial clinical benefits to treatment of patients with chronic pain.Ketamine is a general anesthetic used as an N-methyl-d-aspartate receptor (NMDA) antagonist since the 1960s10; it is also used in the field of pain research, and many studies have been conducted on subjects with chronic pain11.fMRI is a noninvasive examination for brain activity. Resting-state fMRI (rs-fMRI) is a research method for targeting baseline brain activity at rest. The rs-fMRI signal displays spontaneous fluctuations associated with the temporal patterns of neural activity. The correlation of these spontaneous fluctuations in distant brain regions is called brain functional connectivity, and it is believed to be the basis of communication within the brain network. Brain functional connectivity is used in many different clinical applicationsIn this study, to identify the effect of administration of subanesthetic-dose ketamine to patients with chronic pain and to clarify the mechanism of the effect, we examined the differences between patients who responded to the treatment and those who did not based on brain functional connectivity using fMRI. By assessing rs-fMRI images prior to the treatment, we managed to identify the key region of therapeutic response to subanesthetic-dose ketamine in patients with chronic pain.A convenience sample of patients with chronic pain was included in this study Fig. . The cri12), and Pain Catastrophizing Scale (PCS13) prior to ketamine administration and 60 min following the end of ketamine infusion. Further, they were divided into two groups according to their pain response: responders  and non-responders (Group NR)14.Eligible patients completed structural MRI and rs-fMRI following medical assessment. Within 30 min after MRI imaging, ketamine (0.3 mg/kg) was administered intravenously to all patients for 30 min. Ketamine treatment is usual care at our facility for the types of chronic pain that is resistance to treatment such as nerve block and medication. Three physicians who examined the patient at outpatient department decided to treat patient with subanesthetic-dose ketamine. The dosage and administration method of ketamine were based on the conventionally method in our facility. The patients were then asked to complete pain ratings, including NRS, Hospital Anxiety and Depression Scale  with a 20-channel head coil. Prior to performing rs-fMRI, the patients were given the following instructions: “Close your eyes, relax, and do not think of anything in particular. Do not fall asleep.” Scans were then acquired using single-shot gradient-recalled echoplanar imaging. The acquisition parameters were set as follows: TR: 2000 ms, TE: 30 ms, flip angle: 90°, voxel size: 3.75 × 3.75 × 3.0 mm3 with 0.6 mm gap, field of view: 240 × 240 mm, matrix size: 64 × 64, number of slices: 40, number of scans: 300, and scan time: 10 min. High-resolution 1-mm isotropic T1-weighted images of the entire brain were also collected to provide anatomical information to superimpose functional activation maps.Neuroimaging was performed on a 3-Tesla Siemens Skyra scanner (www.nitrc.org/projects/conn) and SPM12 (www.fil.ion.ucl.ac.uk/spm/). Briefly, images of each patient were first realigned (motion corrected) and corrected for slice timing. Structural images were normalized to a Montreal Neurological Institute’s echoplanar imaging template with affine registration, followed by nonlinear transformation. Then, the normalization parameters determined for the structural volume were applied to the corresponding functional image volumes for each subject. Finally, the images were smoothed with a Gaussian kernel of 8 mm at full width at half maximum. Before averaging of individual voxel data, the denoising processes were performed. CONN implements the component-based noise correction method (CompCor) strategy for physiological and other noise source reduction, additional removal of movement, and temporal covariates, temporal filtering and windowing of the residual blood oxygen level-dependent (BOLD) contrast signal15. One of the denoising processes is the removal of the effect of low-frequency drift and high-frequency noise by a band pass filter (0.008–0.09 Hz). The other is removal of non-neural activity effect from the ventricular regions, the white matter, and head motion by multiple regression. Individual correlation maps were generated in the CONN by extracting the mean BOLD time course from each region of interest (ROI) and calculating correlation coefficients with the BOLD time course of each voxel throughout the whole brain. The resulting coefficients were converted to normally distributed scores using Fisher’s transformation to give maps of voxel-wise functional connectivity for each ROI for each subject. The value of each voxel throughout the whole brain represents the relative degree of functional connectivity with each seed. These maps were subsequently used for second-level analysis of relative functional connectivity using a two-sided independent t test, implemented in the CONN, to investigate differences in seed-to-voxel connectivity between groups.Preprocessing procedures were performed with the CONN functional connectivity toolbox  and that resting state network such as DMN is involved in its treatment effect18. A previous study reported that chronic pain alters brain functional connectivity from nociceptive circuits to emotional circuits19, in addition, glutamatergic NMDA receptors are abundant in the subcortical region20; thus, we also defined the seed in the amygdala and nucleus accumbens. These seeds are provided in the CONN. Subcortical seeds, the amygdala and nucleus accumbens, are from FSL Harvard-Oxford Atlas maximum likelihood subcortical atlas (HarvardOxford-sub-maxprob-thr25-1mm.nii). Seeds as the network defined from CONN’s Independent Component analyses of healthy control dataset (497 subjects). These seeds were 10 mm diameter spheres. The spatial coordinate of these network seeds were presented here; mPFC , PCC , anterior cingulate cortex , left anterior insula cortex , right anterior insula cortex. The reasoning for identification and use of these seeds is described in greater detail by the originators of CONN15. We performed voxel-wise statistical analysis over the whole brain using an uncorrected level (p < 0.001) before a familywise error rate (FWE) correction was applied at the cluster level (p < 0.05)21.Seed-to-voxel correlation analysis was performed to investigate the difference in brain functional connectivity between Group R and Group NR. The seeds used for analysis were the medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC), anterior cingulate cortex, and anterior insular cortex as the specific regions of the default mode network (mPFC–PCC) and the salience network (anterior cingulate cortex–anterior insular cortex) because there is a link between these networks and the chronicity of painBased on the results of the seed-to-voxel correlation analysis described below, we also performed independent component analysis (ICA). ICA has been widely used to identify brain networks in resting-state and task-based fMRI data. The fMRI data were submitted to a subject-wise group ICA implemented in the CONN. The group ICA was performed with 20 factors and a dimensionality reduction of 64 as a default setting of CONN.t-test to examine the effect of ketamine treatment on pain severity and other scores between pre- and post-ketamine infusion. All clinical data were also compared using two-sample t-test between Group R and Group NR.We used paired t-test was performed. The statistical results were used to determine the brain regions showing significant differences in terms of correlation to each region defined as the seed. The average of the Z-values from all the voxels in the correlated regions as the functional connectivity strength and NRS reduction rate between pre- and post-ketamine infusion were analyzed using Spearman’s rank correlation test. All statistical analyses were performed using MATLAB R2017b. (https://jp.mathworks.com/products/matlab.html) p < 0.05 was considered statistically significant.To examine changes in brain functional connectivity between the groups, a random effect, two-sample Between January 2015 and December 2017, 33,286 patients visited our outpatient clinic. A total of 30 patients agreed to undergo pre-treatment fMRI, and 24 patients met the inclusion criteria. Patient details are summarized in Table t-test revealed a significant effect of treatment on NRS, HADS-A, HADS-D, and PCS. Twelve  patients showed an improvement on NRS of ≥50% following ketamine treatment and were classified into Group R, and the remaining 12  were classified into Group NR. There was no significant difference in terms of age, dosage of ketamine, pre-treatment NRS, HADS, and PCS between the two groups  and compared these values between the two groups by two sample t-test. We found no significant differences in any parameter.We compared both study groups as for potential head motion. There are some studies that head motion during MRI acquisition affects the analysis result of brain functional connectivityThe result of functional connectivity analysis between Group R and Group NR is shown in Fig. p < 0.001, uncorrected).The average of the Z-values of each patient extracted as the functional connectivity strength between MPFC and precuneus are shown in Fig. 27. To consider the possibility that our result relates to alterations of DMN, we performed group ICA. We identified 20 independent components within the fMRI data, and we selected two independent components (ICs) corresponding to DMN according to spatial matching between extracted independent components by group ICA and templates of resting state networks implemented in CONN  for 6 hour/day for 5 consecutive days33. They reported that approximately 50% of patients had a reduction in NRS of 30% or greater at 1 month after intravenous ketamine infusion, and the relationship between temporal summation of pain and pain relief is mediated by default mode network–descending antinociceptive pathway dynamic functional connectivity. In our study, we revealed that in patients with chronic pain who responded to subanesthetic-dose ketamine, the brain functional connectivity between the mPFC and precuneus was significantly lower on rs-fMRI images, suggesting that subanesthetic-dose ketamine is effective in patients with chronic pain whose brain functional connectivity between the mPFC and precuneus is low.In recent years, ketamine has been used as a remarkable research target and a promising drug for multiple psychiatric disorders. Several neuroimaging techniques have been used to examine the effects of ketamine at the local and whole-brain levels. Among these techniques, fMRI is characterized by higher spatial and temporal resolution without risk of radiation exposure and has proven invaluable to the studies of ketamine34. On the other hand, the precuneus is important for supporting complex cognition and behavior36, but the complete function of the precuneus is still unknown. Kucyi reported that the brain functional connectivity between the mPFC and PCC/precuneus was enhanced in patients with chronic pain and reported a positive correlation of the mPFC and PCC/precuneus brain functional connectivity with pain rumination37. Rikandi reported that the functional connectivity between the mPFC and PCC/precuneus increased in psychotic disorders38. The mPFC and precuneus are cortical midline structures (CMS) related to processing self-related information40. The CMS are regions that respond not only to physical pain stimuli but also to emotional pain stimuli41. Meerwijk et al. reported in their review of psychological pain that regions of the CMS play important roles in the recognition of psychological pain42. In our study, the HADS-D score tended to be higher in Group R than in Group NR, suggesting that ketamine is more effective for pain related to emotion or psychology.Regarding the mPFC and precuneus, wherein the change in connectivity was observed in our study, the mPFC is considered to be a brain region related to human decision-making process and the descending pain suppression pathway27, and many studies have reported that DMN alters in various chronic pain patients44. To consider the possibility that our result relates to alterations of DMN, we performed group ICA, but we were not able to find any group differences. Because this result is probably due to ICs mainly consisted of the posterior part of DMN  and did not contain most part of the mPFC, we also compared an additional IC containing mPFC between the two groups. Nevertheless, group differences were not significant. Considering the discrepancy between results of seed-to-voxel correlation analysis and that of group ICA, lower functional connectivity between mPFC and precuneus should be explained according to specific functions of these two regions rather than the alteration of DMN at this time. However, the sample size of this study was the minimum to perform group comparisons, regarding the statistical power. Therefore, further studies are needed to fully understand the relationship between the therapeutic effect of ketamine and the changes of resting-state networks, in particular, DMN.Both mPFC and precuneus are the core brain regions of DMNThe present study has a number of limitations. First, this study was a single-center retrospective study, so many potential confounders are not well controlled, and for example, the use of medication may change the connectivity patterns. Second, the number of patients was small, so further examination of larger patient populations is necessary to verify our findings. Third, the pain site and diseases were not unified, and this confounding factor is not ruled out in this study. In future studies, it may be possible to predict the effect of ketamine on individual diseases and pain site by unifying the subjects. Fourth, all subject received ketamine, but there was no placebo control in this study. This result may be a brain functional connectivity change in association with placebo in patients with chronic pain. Based on the present results, it is necessary to carry out a follow-up study using a placebo control group in the future. Lastly, we divided the patients based on a short time pain response to ketamine. The long-term effects of ketamine treatment are recognized in psychiatry, and some patients with chronic pain respond to ketamine in the long term. If we can reveal the marker that can predict long-term pain response to ketamine, it will be a notable contribution to chronic pain therapy.In this study, we revealed that the brain functional connectivity of the mPFC and precuneus was significantly lower in patients with chronic pain who responded to subanesthetic-dose ketamine. In addition, we found that there was a significant negative correlation between the improvement rate for pain by ketamine administration and the functional connectivity strength between the mPFC and precuneus. Ketamine may be effective in patients with chronic pain whose brain functional connectivity between the mPFC and precuneus is low. The current study is the first to explore the correlation between brain functional connectivity and the effect of subanesthetic-dose ketamine for chronic pain, and it indicates the possibility of a biomarker for the pharmacological treatment of chronic pain.


Each invited participant presented on a specific aspect of the opioid crisis and/or pain management as it relates to total hip or knee arthroplasty. Representing orthopedics, anesthesiology, psychiatry, bioethics, health information technology, and law, this group crafted a consensus statement on appropriate pain management for total hip or knee arthroplasty. Many have also contributed to this special issue of HSS Journal on “Opioid Prescribing and Pain Management” (February 2019)  but also an increased possibility of complications .Improve risk assessment by educating clinical staff on issues related to substance use disorder.Implement risk-mitigation strategies, such as providing naloxone rescue kits for patients requiring high opioid doses and limiting initial dosage of discharge prescriptions.Institute an opioid-responsible pain-management strategy for each patient. This involves identifying a single prescriber who uses evidence-based recommendations for prescribing opioids conservatively—i.e., for the shortest duration and at the lowest dose to manage that individual’s peri-operative pain—and a plan for weaning while avoiding withdrawal symptoms.Provide easy-to-understand fact sheets for patients that review the risks and benefits of opioid use, weaning, and safe storage and disposal .Commit to patient and family to reduce the risks of opioid use and manage withdrawal symptoms should they arise. Provide contact information of the prescriber whom patient, family members, or team members may call with questions.Establish institutional standards to guide the use of opioids, ensuring quality improvement and monitoring in clinical practice and in the education and training of physicians, pharmacists, nurses, and other professional staff.Refer patients when indicated for appropriate treatment of substance use disorder.Script uniform messages for clinicians to use when discussing patients’ expectations for surgery, pain management, rehabilitation, and opioid use, and when responding to patients’ concerns about pain, dependency, hyperalgesia, and addiction.Maintain open communication with patients post-surgically to oversee pain management and opioid weaning. A patient who requests refills or reports increased or persistent pain deserves in-depth re-evaluation for additional pain relief or behavioral health assessment.Establish clear protocols and lines of communication for patient handoff among clinicians and settings.Review the execution of each patient’s pain-management plan as part of routine quality improvement. Team members can discuss successes and failures, and data analysts can evaluate metrics on successful weaning, referrals, and other data.Make use of an opioid agreement, which delineates the expectations and responsibility of both provider and patient, ensuring that the pain-management plan is thoroughly explained and understood.Multimodal and regional anesthesia strategies are strongly recommended for total joint arthroplasty. These approaches have been shown to decrease opioid use, increase patient satisfaction, and shorten lengths of stay.Incorporate innovative technologies to measure both patient-reported outcomes and clinicians’ prescribing patterns. Such data are to be used for continuous quality improvement.Identify gaps in the evidence on post-arthroplasty pain management and alternatives to opioids.Develop comparative research studies on the methods for enhancing the quality and extending the duration of opioid-free post-arthroplasty analgesia.Determine the risk factors of and methods for preventing long-term opioid use in opioid-naïve patients and/or escalation of opioid use in opioid-tolerant patients undergoing hip or knee arthroplasty.Investigate the use of “comfort menus”—alternatives to opioids for pain relief such as massage therapy, aromatherapy, music, or visualization—in post-arthroplasty pain management.Establish opioid-use and pain-management protocols for all orthopedic surgical procedures.Is there a legitimate medical need for a prescribed opioid? If yes, state the need.Have appropriate non-opioid measures been implemented? If yes, list them.The state prescription drug monitoring program (PDMP) database has been checked.The patient’s history of substance use, mental health conditions, and sleep apnea has been documented.Toxicology reports, if indicated, have been reviewed.Has the patient’s risk been assessed?Has the prescriber referred to the service-specific guideline when choosing a medication and dosage, adhering to the adage “start low, go slow”?Has the patient been educated on the risks and benefits of opioid use, including safe storage, disposal, and tapering?Has the patient received the name and phone number of the prescribing clinician?Have the patient and prescriber signed an opioid agreement?Has all of the above been documented?ESM 1(PDF 1.19 mb)ESM 2(PDF 1.19 mb)ESM 3(PDF 1.19 mb)ESM 4(PDF 1.19 mb)ESM 5(PDF 1.19 mb)ESM 6(PDF 1.19 mb)ESM 7(PDF 1.19 mb)ESM 8(PDF 1.19 mb)ESM 9(PDF 1.21 mb)ESM 10(PDF 1.19 mb)ESM 11(PDF 1.19 mb)ESM 12(PDF 1.19 mb)


Trigeminal postherpetic neuralgia (TPHN) often presents with moderate to severe pain, hyperalgesia, and allodynia. Conventional analgesic treatments are poorly effective, which seriously affects the quality of life. This retrospective study aimed to evaluate the efficacy of pulsed radiofrequency (PRF) for the treatment of TPHN.n = 45 per group): group A, peripheral nerve  PRF; group B, gasserian ganglion PRF. Follow-up assessments of visual analogue scale (VAS) pain assessment, SF-36 health status questionnaire, total efficiency rate, and drug dosage of anticonvulsants and opioid analgesics were performed at time points of 1 week, 1 month, 3 months, 6 months, and 1 year after surgery.A total of 90 TPHN patients were selected between January 2014 and December 2016 in the Department of Pain Management, Shengjing Hospital, China Medical University. Patients were randomly divided into two groups according to the order of enrollment (P < 0.05). Compared with group A, VAS decreased, SF-36 increased, and dosage of anticonvulsants and opioids analgesics decreased significantly in group B (P < 0.05). The total efficiency rates one year after surgery in group A and group B were 68.9 and 86.7%, respectively. The total efficiency rate of group B was statistically higher than that of group A (P < 0.05).At each postsurgery time point, the VAS decreased, SF-36  increased, and drug dosage of anticonvulsants and opioids analgesics decreased in both treatment groups; values at each time point were significantly different from presurgery values (PRF relieved TPHN, and gasserian ganglion PRF was more effective than peripheral nerve PRF. The method was effective and improved the quality of life of the patients. PRF is recommended as a treatment for TPHN. Postherpetic neuralgia (PHN) is a persistent neuropathic pain that remains after a herpes zoster rash has healed. It is the most common complication of herpes zoster infection. The incidence and treatment costs of PHN increase with age . Herpes Trigeminal postherpetic neuralgia is a severe neuropathic pain that occurs when varicella-zoster virus infection affects the trigeminal gasserian ganglion or its divisions. Of the three divisions of the trigeminal nerve, the most commonly involved is the ophthalmic division (V1), which is 20 times more likely to be involved than the other two divisions, the maxillary (V2) division and the mandibular (V3) division . The incIn this study, PRF treatment of the gasserian ganglion was compared with PRF treatment of peripheral nerves  for evaluation of its clinical efficacy and satisfaction in TPHN patients.n = 45): group A, peripheral nerve PRF ; group B, gasserian ganglion PRF. The distribution area of posterior herpes pigments or lesions were unilateral. After the PRF treatment, both groups received steroid injections. Patients were supplemented with anticonvulsants and opioid analgesics. Nutritional supplements that promote nerve recovery and other therapeutic drugs were the same in both groups. The study was approved by the Ethics Committee of Shengjing Hospital, China Medical University. All patients were informed of the risks and complications before surgery, and written informed consents were obtained.A total of 90 TPHN patients were selected between January 2014 and December 2016 in the Department of Pain Management, Shengjing Hospital, China Medical University . The pat(1) Average pain intensity score  ≥5 points in 24 h before enrollment. (2) Skin lesions had healed, but there was still persistent, intense and intractable pain, local skin hyperalgesia, numbness, and sensory abnormalities. (3) Natural course more than 3 months and conservative treatment was ineffective. (4) Age > 50 years old.(1) Epilepsy, trigeminal neuralgia, or intracranial space-occupying lesion. (2) Hematologic disease or abnormal coagulation, (3) Severe liver and kidney dysfunction or severe cardiopulmonary disease, (4) Drug abuse, (5) Mental illness/unable to cooperate with treatment.The patient was placed in the supine position. Under CT guidance, the ipsilateral shoulder was positioned and attached to the electrode plate of the radiofrequency apparatus. In group A, PRF of peripheral nerves  was performed. The point of supraorbital nerve puncture was located in the supraorbital orifice, immediately above the orbital ridge, using the medial line through the pupil as a reference for the supraorbital nerve; The point of infraorbital nerve puncture was located in the infraorbital foramen, can be approximated by having the patient look straight ahead and imagining a line down from the pupil to the inferior border of the infraorbital ridge, bicuspid teeth, and mental foramen; The point of mental nerve puncture was located in the mental foramen, located halfway between the upper  and the lower edge of the mandible in direct line with the second bicuspid (premolar). In Group B, the Hartel anterior approach to access the gasserian ganglion was performed. The puncture point was positioned 2.5–3 cm from the corner of the mouth. After 0.5% lidocaine was used to anesthetize the ipsilateral-affected side of the mouth, the sterilized radiofrequency needle  was guided along the established puncture angle until it reached the site of the foramen ovale. The needle was then guided to the gasserian ganglion. The radio frequency meter was tested to assure coverage of affected area: (1) 50 Hz, 0.1–0.3 V test sensation, to induce pain sensation in the herpes area. (2) 2 Hz, 0.1 V test exercise, jaw tremor will be induced when V3 division is affected. The radiofrequency stimulation tests determined whether the herpes area was covered. The position of the needle tip was adjusted until the movement and sensation determined that the affected area was completely covered and that normal areas were avoided. When the position was satisfactory, each point was treated with 42°C PRF for 300 s, and then 2 ml of an analgesic solution  was administered. ceftriaxone sodium was given 30 min before surgery to prevent infection. Vital signs were monitored during surgery. The patient’s reaction was observed during the operation and adjustments made, if needed. The patients were restricted to absolute bed rest for 24 h post treatment.Presurgery data were recorded: gender, age, pain duration, presurgery VAS, pain location and divisions affected, and drug dosage of anticonvulsants and opioid analgesics. Follow-up assessments were performed at 1 week, 1 month, 3 months, 6 months, and 1 year after surgery. The non-surgical medical staff used a double-blind method to assess patients at follow-ups.1.Visual analogue scale: used to evaluate the degree of pain. No pain = 0 points; intense pain = 10 points.2.SF-36 evaluation : the qua3.Total efficiency rate: according to subjective symptoms and clinical signs, the efficiency rate was divided into three grades: excellent, effective, and ineffective. Excellent – pain, numbness and hyperalgesia disappeared, and labor levels returned to premorbid levels, effective – pain and numbness were relieved, quality of life improved and ability to work increased, and ineffective – no improvement in symptoms. The total efficiency rate was calculated as the number of patients scoring as “excellent” and “effective” divided by the total number of patients in the group.4.Drug dosage of anticonvulsants and opioid analgesics: anticonvulsants drugs included carbamazepine, gabapentin, and pregabalin; the opioid analgesic oxycontin was used.P < 0.05 was statistically significant.The data were processed using SPSS18.0 analysis software. The measurement data was first tested for normality, and the single-sample Kolmogorov–Smirnov test was used in non-parametric tests. The normal distribution variables were expressed as mean ± standard deviation  or the foramen ovale, respectively. Three-dimensional CT (3D-CT) was performed to further clarify the path and position of the needle .P > 0.05)  .P < 0.05). VAS decreased gradually in both groups, with the lowest values reached at 3 months, after which the VAS values increased slightly at 6 months and 1 year but still remained significantly lower than presurgery levels. VAS values in group B were significantly lower than group A at each time point (P < 0.05)  and were significantly different from presurgery values ( < 0.05) .P < 0.05). PCS and MCS increased gradually in both groups. PCS and MCS values were the highest at 3 months, and decreased thereafter at 6 months and 1 year but still remained significantly higher than presurgery levels. Compared with group A, PCS and MCS increased significantly in group B (P < 0.05) , and were significantly different from the preoperative values ( < 0.05) .P < 0.05)  .P < 0.05). The decrease in the dosage of anticonvulsants and opioid analgesic in group B was significantly different from the decrease observed in group A (P < 0.05)  and opioid analgesic (oxycontin) used postsurgery decreased to varying degrees (or were even discontinued) in both treatment groups, and were significantly different from presurgery usage ( < 0.05) .Postherpetic neuralgia is a chronic neuropathic pain resulting from re-activation of the herpes zoster virus. The condition is persistent and unresolvable. Its etiology and mechanism are not fully known, and there are no completely effective therapeutic drug or treatment regimens. This study found that after PRF treatment, pain was relieved, quality of life was improved, and the dosage of anticonvulsants and opioid analgesics were reduced in both treatment groups . Gasserian ganglion PRF therapy was superior to peripheral nerve PRF in the relief of pain; the total efficiency rate and patient satisfaction was significantly higher.The trigeminal nerve is the dominate sensory nerve of the face. After the initial infection of herpes zoster, the virus lies latent in the trigeminal gasserian ganglion. With a decrease in the body’s immune system, the latent herpes zoster virus can reactivate and replicate. Peripheral nerves associated with the infected ganglion will exhibit lesions . Severe Neurodestructive therapy is not recommended for PHN because of an increased chance for neurological damage and aggravation of neuropathic pain . PRF is The incidence of V1 division involvement is high. Due to the particular anatomy of V1, special care is required during treatment. Therefore, it is necessary to select a treatment method with less side effect. PRF has been shown to cause transient endoneural edema and collagen deposition without structural changes . The ultThe analgesic mechanism of PRF is unclear . The PRFOur study showed that PRF effectively relieved the pain of TPHN in both peripheral nerve and gasserian ganglion treatment groups. The neuromodulation effect was relatively slow; the analgesic effect occurred gradually, becoming maximal at the 3 months follow-up. Although VAS increased slightly at the 6 months and 1 year time point, they stayed significantly lower than presurgery levels. The finding that pain was recurring in the latter time points may explain reports that PRF treatment needed to be repeated and combined with drugs and other therapies for optimal analgesia.In summary, PRF is a recommend treatment to relieve the pain of TPHN. PRF treatment of gasserian ganglion was more effective than treatment of the associated peripheral nerves. The method was effective. PRF reduced VAS, significantly relieved PHN, increased the total efficiency rate, reduced the dosage of anticonvulsants and opioids analgesics, and improved the quality of life for the patients.dingyy81@163.com.The datasets for this manuscript are not publicly available because this article contains personal information about the patient, so is not publicly available. Requests to access the datasets should be directed to GZ and PY designed and conducted the study, and contributed to patient recruitment, data collection, and data analysis. HL collected the data. TH analyzed the data. YD prepared the manuscript. All authors approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In this study we are aiming to evaluate the changes of serum serotonin and its association with pain in patients suffering from chronic low back pain before and after lumbar discectomy surgery. A prospective study was performed on the patients referring to the outpatient clinic in Besat hospital, Hamadan University of Medical Sciences, Hamadan, Iran, during 2016. A 2 mL fasting blood sample was collected from each patient at preoperative day 1 and postoperative day 14 and they were measured for level of serum serotonin. Besides, all patients were asked for severity of their low back pain in preoperative day 1 and postoperative day 14 and scored their pain from zero to ten using a Numerical Rating Scale. Forty patients with the mean age of 47 ± 13 yrs/old (range 25–77) including 15 (37.5%) males were enrolled into the study. The overall mean score of preoperative pain was significantly decreased from 7.4 ± 2.18 (range 4–10) to the postoperative pain score 3.87 ± 2.92 (range 0–10) (P < .001). The overall levels of pre- and postoperative serum serotonin were 3.37 ± 1.27 (range 1.1–6.4) and 3.58 ± 1.32 (range .94–7.1) ng/mL, respectively, with no significant difference (P = .09). The levels of pre- and postoperative serum serotonin were significantly higher in males and patients older than 50 yrs/old compared to the females and patients younger than 50 yrs/old, respectively . A significant inverse correlation between the postoperative levels of pain and serum serotonin was observed (r = -.36 and P = .02). A negative medium strength linear relationship may exist between the postoperative serum serotonin and low back pain. Low back pain is one the most common health care issues causing enormous financial and social costs globally. Chronic low back pain with duration of pain greater than three months is the second most frequent complaint in physician visits which is related to disability of one-fourth of working populations and significant loss of working days , 2. LumbAlthough the role of some mechanical, thermal, and chemical agents have been studied in pain regulation, the mechanism of pain induction and perception has not been completely elucidated yet . RecentlIn this study we are aiming to evaluate the effectiveness of lumbar discectomy with either laminectomy or laminotomy surgery on chronic low back pain, changes of pre- and postoperative serum serotonin, and the association of serum serotonin and pain of the patients.A prospective study was performed on the patients referring to the outpatient clinic in Besat hospital, Hamadan University of Medical Sciences, Hamadan, Iran, during 2016. Inclusion criteria were the patients suffering from chronic low back pain due to lumbar disk herniation who were candidates for surgical treatment. The pain of the patients was disabling even with full medical treatment and was associated with radiculopathy, neurologic deficit, and physical status of class two or less based on the American Society of Anesthesiology classification system. The diagnosis of lumbar disk herniation was made based on the related signs and symptoms of the patients and magnetic resonance imaging findings. Patients with major depression, neurological disorders, diabetes mellitus, and history of using antidepressant or antipsychotic medications were excluded from the study.A 2 mL fasting blood sample was collected from each patient at preoperative day 1 and postoperative day 14 and was kept at -20°C under the same condition. All samples were measured for level of serum serotonin on the same day using Enzyme-linked immunosorbent assay kit . Besides, all patients were asked for severity of their low back pain at preoperative day 1 and postoperative day 14 and scored their pain from zero to ten using a Numerical Rating Scale with score of zero indicating having no pain and ten indicating the most severe experienced pain. These data in addition to the demographics and status of smoking and opium use were recorded prospectively. All patients underwent lumbar discectomy with either laminectomy or laminotomy surgery by the same surgeon. Also, all postoperative visits were done by the same surgeon.The approval of the Ethics Committee of Hamadan University of Medical Sciences was granted prior to patient recruitment and once the aims and procedures of the study were explained, a written informed consent was granted from all participants.Analysis of data was performed by using the SPSS statistical software . Data were expressed as mean ± standard deviation and were compared by using independent or paired samples t-tests. Correlation between the level of serum serotonin and the Numerical Rating Scale score was assessed by using Pearson correlation coefficient. P value less than .05 was considered statistically significant.Forty patients with the mean age of 47 ± 13 yrs/old (range 25–77) including 15 (37.5%) males were enrolled into the study. Laminectomy surgery alone has been performed in 18 (45%) patients while laminectomy and lumbar pedicle screw fixation has been performed in the others. Frequencies of the patients who were current cigarette smoker and opium addict were 6 (15%) and 4 (10%), respectively.The overall mean score of preoperative pain was significantly decreased from 7.4 ± 2.18 (range 4–10) to the postoperative pain score 3.87 ± 2.92 (range 0 – 10) (P < .001). The detailed data about scores of pre- and postoperative pain are shown in A significant inverse correlation between the postoperative levels of pain and serum serotonin was observed (r = -.36 and P = .02). However, there was no significant correlation between the preoperative levels of pain and serum serotonin (r = .08 and P = .6).In our study, pain of the patients was significantly reduced from the pre- to the postoperative period regardless of the type of surgery, age, and gender of the patients. Consistent with our data, it has been shown that there is no significant difference between lumbar discectomy surgery with either laminectomy or laminotomy in reducing low back pain . HoweverSerotonin synthesis is controlled by sex hormones; therefore, the alteration of serum serotonin can be expected by difference in ethnicity, gender, and advancement of age , 19. TesIn our study, the level of serum serotonin was not significantly changed from the pre- to the postoperative period, in contrast to the level of the pain. Besides, in the postoperative period, the level of serum serotonin was inversely associated with the level of the pain. There is much debate over the association of levels of serum serotonin and chronic low back pain. Similar to ours, an inverse relationship between serum serotonin and pain was reported in healthy individuals and patients performing lumbar exercise for treatment of their low back pain , 23. In Chronic low back pain associated with lumbar disk herniation may be related to inflammatory process and mediators such as tumor necrosis factor-alpha and serotonin which are released from mast cells and platelets as a consequence of tissue injury . SerotonIn summary, preoperative chronic low back pain of our patients reduced in postoperative period; however the level of serum serotonin was not significantly changed. Moreover, a negative medium strength linear relationship between the postoperative serum serotonin and pain was observed in our study.


Pain is a universal issue and is of particular concern in mechanically ventilated patients, as they require intensive nursing care and multiple invasive procedures, while being unable to communicate verbally. The aim of this study was to assess the effect of music on pain experienced by mechanically ventilated patients during morning bed bathing.Of the 60 mechanically ventilated patients enrolled in this single-center pilot study between March 2013 and October 2015, the first 30 received no music and the next 30 the music intervention, during the morning bed bath. The Behavioral Pain Scale (BPS) score was determined during and at the end of the bath then 30, 60, and 120 minutes after the bath. BPS score changes over time were assessed and the proportions of bath times spent with a BPS score ≥5 and with the maximal BPS score were determined.P = 0.43). After bed bath initiation, 88% of patients experienced pain. The maximum BPS value during the bath was lower in the music group . Proportions of total bath time spent with BPS≥5 and with the maximum BPS were significantly lower in the music group than in the control group . Two hours after the end of the bath, the BPS values had returned to baseline in both groups.At baseline, no patient had pain (defined as a BPS score <5) and the median BPS score was 3  in both groups (In our population, music significantly decreased pain intensity and duration during the morning bed bath in mechanically ventilated patients. These results warrant further assessment in a large multicenter randomized controlled trial.NCT02883959ClinicalTrials.gov  Among critically ill patients who are able to communicate, over 60% report pain , 2. PainPain control in ICU patients relies mainly on pharmacotherapy . HoweverThe aim of this study was to assess the potential effect of a music intervention on pain experienced during morning bed bathing by patients receiving MV in the ICU. We conducted a prospective, comparative, single-center, nonrandomized pilot study to compare bed bathing with and without music.Comité de Protection des Personnes, Paris–Ile de France VI, 5 October 2012, #12044). When the first patient was enrolled on March 2013, which is 6 months after registration of the study protocol by the French health authorities, it was 3 years before clinicaltrials.gov registration . The authors confirm that not a single change was made in the study protocol during this time. The authors also confirm that all ongoing and related trials for this drug/intervention are registered. According to French law, written informed consent from a relative or surrogate was obtained for each participant before study inclusion. Written informed consent was then requested from all included patients as soon as they regained competence, and before ICU discharge. All procedures involving the patients complied with the ethical standards of the institutional and national research committees and with the 1964 Declaration of Helsinki and its later amendments.Our local ethics committee approved this prospective pilot study   [13] scoThis single-center study was performed at the university-affiliated Versailles hospital ICU. The physicians and a clinical research nurse and/or assistant were in charge of daily patient screening and inclusion, ensuring compliance with the study protocol available in the data supplement as We included 60 patients. The first 30 patients were included in the control group and the next 30 patients in the intervention group. As bed bathing is performed in all patients and in a standardized manner, we evaluated the potential effects of music during the morning bed bath. The Transparent Reporting of Evaluations with Nonrandomized Designs developed to guide standardized reporting of nonrandomized controlled trials is available in the data supplement as the Morning bed bathing was performed once a day at 8 AM by a nurse and nursing assistant. First, the anterior aspect of the body was washed with soap-based products. Ocular, nasal, and oral care was given. If needed, the patient was shaved and the endotracheal tube suctioned. Then, the patient was lateralized and the posterior aspect of the body and genitals were washed with soap-based products, a massage was given for pressure-sore prevention, and the sheets were changed.All patients received analgesia and sedation as needed, according to the standard protocol in our unit, which involves various titrated combinations of midazolam, propofol, morphine, and/or sufentanil.In the intervention group, patients were exposed to music during the morning bed bath, using headphones connected to an MP3 converter via a Bluetooth connection. The same selection of passages by Mozart was used in all patients, 15. TheThe primary outcome was the proportion of total bath time spent with a BPS score ≥5, computed as the time spent with a BPS score ≥5 during the bath divided by the total bath time. The secondary outcome was the proportion of total bath time spent with the highest BPS score, computed as the time spent with the highest BPS score during the bath divided by the total bath time.BPS scores  16] wer wer16] wDemographic and clinical data were collected prospectively at the bedside on a standardized form. BPS scores were assessed as described above. Physiologic and respiratory parameters were collected automatically by a monitor  and central monitoring report system . Sedation and analgesia, and physiologic parameters  were assessed in both groups at baseline; during bed bathing; at the end of the bath, and 30, 60, and 120 minutes after the end of the bath.Acute illness severity at ICU admission was assessed using the Simplified Acute Physiology Score II (SAPS-II),. Length Quantitative parameters were described as median (interquartile range [IQR]) and qualitative parameters as number (%). Categorical variables were compared between treatment groups using Fisher’s exact test and continuous variables using the Wilcoxon test.P<0.10). These variables were gender, age, SAPS II score, diastolic blood pressure, and number of invasive devices.To test the robustness of our results, an exploratory analysis was carried out using a propensity score approach based on 1:1 pair matching when estimating associations between variables in the music intervention and control groups. We performed exact matching for each variable, with no replacement, using a specified caliper distance of 0.2. The variables included in the propensity score were selected among the demographic and baseline characteristics associated with treatment group by univariate statistical analysis *. *P = .43). After bed bath initiation, 88% of patients experienced pain (as defined by a BPS score ≥5). The maximum BPS value during bathing was lower in the music group . P < .0001) and ; respectively. Two hours after the end of the bath, the BPS values had returned to baseline in both groups.P = .0005), the proportion spent with the maximum BPS was not significantly different between the two groups .Tables To our knowledge, this study provides the first information on the effects of a music intervention on pain during a potentially painful nursing care procedure in critically ill patients receiving mechanical ventilation (MV). Of the 60 prospectively included patients, 88% had pain, defined as a Behavioral Pain Scale (BPS) score ≥5, during bed bathing. Total times spent with a BPS score ≥5 and with the maximal BPS score were significantly shorter in the music intervention group compared to the controls.Pain control in ICU patients is a major but challenging treatment objective that is receiving increasing attention . Pain inOur findings are consistent with previous studies of pain during nursing care in the ICU. In keeping with these data, 88% of our patients experienced pain during bed bathing. The heterogeneity of previously published studies of pain in ICU patients hinders comparisons. Among unselected critically ill patients, including 37% on MV and 65 able to communicate, 63% experienced pain and 15% severe pain during the ICU stay . In a poWe believe our findings provide a new contribution that may have clinical and scientific implications. The authors of a 2014 Cochrane review concludeP<0.10). Second, the nurse who conducted the BPS score assessments was not blinded to the treatment group, potentially leading to confirmatory bias. Third, the music was selected by the researchers and may not have matched patient preferences. Fourth, although our endpoint of pain was assessed by having a specifically trained and experienced nurse apply a well-validated and reproducible pain scale, the BPS, neuromonitoring was not used as a tool for comparing pain in the two groups.[Our study has several limitations. The single-center design mandates caution regarding the applicability of our findings to the full spectrum of nursing care procedures. Moreover, several potential sources of biases must be acknowledged. First, for this pilot study, randomization was not used, and bias in patient selection may therefore have occurred. Thus, the two groups differed significantly regarding gender distribution, diastolic blood pressure, and number of invasive devices. To minimize the consequences of potential patient selection bias, we performed a sensitivity analysis after matching patients in the music intervention and control groups on a propensity score based on the demographic and baseline characteristics associated with treatment group by univariate statistical analysis Click here for additional data file.S2 File(PDF)Click here for additional data file.S3 File(PDF)Click here for additional data file.