Project description:For over a millennium, mind-body interactions have fascinated scientists and doctors for their abilities to shape human perceptions of the external world 1,2. Placebo effects are striking demonstrations of mind-body interactions in which, in the absence of any treatment, a positive expectation of pain relief can reduce or even abolish the experience of pain 3–6. However, despite widespread recognition of the strength of placebo effects and their impact on everyday human experience and clinical trials for new analgesics, the neural circuit basis of the placebo effect has remained a mystery. Here, we show that analgesia from the expectation of pain relief is mediated by a distinct population of rostral anterior cingulate cortex (rACC) neurons that project to the pontine nuclei (rACC→Pn), a pair of brainstem pre-cerebellar nuclei with no established function in pain processing. To do this, we created a behavioral assay that models placebo analgesia by conditioning mice to expect pain relief when moving from a chamber with a heated floor to a second chamber. In this assay, an expectation of pain relief induces an analgesic effect that, like placebo analgesia in humans, is mediated by endogenous opioids. Calcium imaging of neural activity in freely moving mice and electrophysiological studies in cingulate cortical brain slices showed that expectations of pain relief boost the activity of rACC→Pn neurons and potentiate neurotransmission in this pathway. Transcriptomic studies of Pn neurons revealed an unusual abundance of opioid receptors in these cells, further suggesting a role in pain modulation. Selective inhibition of either the rACC→Pn pathway or of opioid-receptor-expressing Pn neurons disrupted placebo analgesia and decreased pain thresholds. Finally, a subset of cerebellar Purkinje cells exhibits activity patterns resembling those of rACC→Pn neurons during pain relief expectation, providing cellular-level evidence of a role for the cerebellum in cognitive pain modulation. Altogether, these findings elucidate longstanding mysteries surrounding the placebo effect by identifying a specific neural pathway that mediates expectation-based pain relief. This discovery opens the possibility of targeting this novel pathway with drugs or neurostimulation methods to treat pain. More broadly, our studies provide a framework for investigating the neural circuit basis of other mind-body interactions beyond those involving pain, and point to prefrontocortical-cerebellar communication as a potential basis for such effects.

Project description:BackgroundChronic postoperative pain (CPSP) is one of the common complications of breast cancer patients, which can seriously affect the quality of life and long-term prognosis of patients. The purpose of this study was to investigate whether perioperative intravenous lidocaine infusion could reduce the incidence of CPSP in patients with breast cancer.MethodsFemale patients undergoing radical breast cancer surgery were randomly assigned to the 2% lidocaine group (L) and the control group (S). group L received an intravenous infusion of 1.5 mg/kg lidocaine 10 minutes prior to induction, followed by a continuous infusion of 2 mg/kg/h until the end of surgery. The control group received an equal amount of saline. The primary outcome was the incidence of CPSP at 3 months. Secondary outcomes included VAS pain scores and frequency of remedial analgesia within 24 hours postoperatively; incidence of CPSP at 1 and 6 months; and scores on the Brief Pain Inventory (BPI), Simplified McGill Pain Questionnaire (SF-MPQ), and Neuropathic Pain Score (DN-4) at 1, 3, and 6 months postoperatively.ResultsEighty-two patients participated in this study. A total of 78 patients completed the 3-month postoperative follow-up (39 in group S and 39 in group L). At 3 months, the incidence of CPSP was significantly lower in the L group than in the S group (33.3% in the S group and 12.8% in the L group, P=0.032). Pain scores at rest and during exercise were significantly lower in the L group than in the S group at different time points (P≤0.001 and P<0.001). The need for remedial analgesia at 24 hours postoperatively also differed significantly between the two groups (P=0.036). At 6 months, the incidence of CPSP was also lower in the L group than in the S group (29.7% in the S group and 10.5% in the L group, P=0.038). The differences in SF-MPQ scores were statistically significant at both 3 and 6 months postoperatively (P=0.022, P=0.037).ConclusionsIntravenous infusion of lidocaine reduces the incidence of CPSP in breast cancer patients at 3 and 6 months and is effective in relieving acute postoperative pain.Trial registrationChinese Clinical Trial Registry ChiCTR2100050445.

Project description:IntroductionOrthopedic procedures have been associated with increased pain, making perioperative analgesia a major clinical concern. We assessed the efficacy and safety of intravenous parecoxib administration during the perioperative period for postoperative pain relief after orthopedic surgery in adults.MethodsPubMed, Cochrane Library, EMBASE, and clinicaltrial.gov were searched from inception to 23 August 2021 without language restrictions. Randomized controlled trials comparing intravenous parecoxib with placebo or another active treatment for acute postoperative pain in adults after orthopedic surgery were included. The primary outcomes were the pain scores and cumulative morphine consumption. The secondary outcomes included the proportion of patients requiring rescue analgesics and the incidence of adverse events. The meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and was registered on the International Prospective Register of Systematic Reviews Registration (PROSPERO).ResultsTwenty-seven trials (n = 2840) from more than 20 countries involving six types of orthopedic surgery met the inclusion criteria. Compared with placebo, intravenous parecoxib administration led to reductions in postoperative resting pain scores at 6, 12, 24, and 48 h [mean difference (MD) -0.87, 95% confidence interval [CI] -1.71 to -0.03; MD -0.86, 95% CI -1.26 to -0.46; MD -0.57, 95% CI -0.84 to -0.31; MD -0.40, 95% CI -0.69 to -0.11, respectively], postoperative movement pain scores at 24 and 48 h (MD -0.66, 95% CI -1.14 to -0.19; MD -0.78, 95% CI -1.16 to -0.39, respectively), cumulative morphine consumption (MD -11.30 mg, 95% CI -14.79 to -7.81 mg), and the proportion of patients requiring rescue analgesia (relative risk 0.83, 95% CI 0.77-0.89). There was no difference in the incidence of adverse events between groups.ConclusionLow to moderate evidence indicates that parecoxib might be an effective and safe analgesic in perioperative orthopedic settings. It relieves postoperative orthopedic pain while sparing opioid analgesic consumption without increasing the incidence of adverse events.Prospero registrationCRD42021274939.

Project description:BackgroundPain is one of the main reasons to present to emergency departments (EDs). Opioids are indispensable for acute pain management but are associated with side effects, misuse, and dependence. The aim of this study was to test whether a single dose of intravenous (IV) acetaminophen (paracetamol) can reduce the use of morphine for pain relief and/or morphine-related adverse events (AEs).MethodsED patients >18 years with acute pain (i.e., Numeric Rating Scale [NRS] > 4) were screened for eligibility. Patients with analgesia in the past 6 h, chronic pain, or clinical instability were excluded. Patients were randomized in a 1:1 ratio to receive either morphine 0.1 mg/kg and 1 g acetaminophen IV or morphine 0.1 mg/kg and placebo IV. The intervention was double-blinded. Additional morphine 0.05 mg/kg IV was administered every 15 minutes until pain relief (defined as NRS < 4) and whether the pain recurred. The primary outcome was the mean morphine dose for pain relief. Secondary outcomes were the total amount of morphine given, time to achieve pain relief, and AEs.ResultsA total of 220 patients were randomized and 202 evaluated for the primary outcome. The mean morphine dose for pain relief was similar in both groups (acetaminophen 0.15 mg ± 0.07 mg/kg, placebo 0.16 ± 0.07 mg/kg). There were no differences in the total amount of morphine given (acetaminophen 0.19 ± 0.09 mg/kg, placebo 0.19 ± 0.1 mg/kg), the time to achieve pain relief (acetaminophen 30 min [95% CI 17-31 min], placebo 30 min [95% CI 30-35 min]), and the frequency of AEs (overall 27.4%). Time to pain recurrence did not differ significantly between the groups (hazard ratio 1.23 [0.76-1.98], p = 0.40).ConclusionsIn ED patients, acetaminophen had no additional effect on pain control or morphine-sparing effect at the time of first morphine administration. Titrated morphine with the algorithm used was highly effective, with 80% of all patients reporting pain relief within 60 min of starting therapy.

Project description:Importance:Intravenous acetaminophen is a commonly prescribed analgesic for the prevention and treatment of postsurgical pain. Its efficacy in the context of endoscopic sinus surgery (ESS) has yielded mixed results. Objective:To compare the efficacy of perioperative intravenous acetaminophen (IVAPAP) with that of placebo in improving early postoperative pain after endoscopic sinus surgery (ESS). Design, Setting, and Participants:A prospective, randomized clinical trial including 62 patients undergoing ESS for chronic rhinosinusitis in a single tertiary referral hospital. Interventions:Participants were randomized to receive 1 g of IVAPAP or 100 mL of placebo consisting of saline infusions immediately before the start of surgery and 4 hours after the initial dose. Main Outcomes and Measures:The primary outcome was postoperative pain measured by visual analog scale (VAS) scores up to 24 hours after surgery by blinded observers. Secondary endpoints included postoperative opioid (intravenous and oral) use and adverse events in the 24-hour postoperative period. Results:Of the 62 enrolled adult participants, 60 were randomized (31 to IVAPAP intervention and 29 to placebo). The mean (SD) age of participants was 53.7 (14.7) years and 35 (58%) of the participants were men and 25 (42%) were women. Within the first hour, mean pain scores were reduced in the IVAPAP group compared with the control group, reaching a maximum difference of 7.7 mm on a VAS scale favoring the treatment group with a true difference possibly as high as 22 mm, and the data are compatible with a clinically meaningful difference. At 12- and 24-hours, average pain scores were less in the placebo group and the data are compatible with a clinically meaningful difference of 5.8 (-5.2 to 16.8) and 8.2 (-1.9 to 18.4), respectively, favoring the placebo group. However, at all time points the CIs included the null value and were wide, thus preventing definitive conclusions. Inspection of the secondary outcomes favored IVAPAP, but the wide range of the CIs and inclusion of the null value prevent definitive conclusions. Conclusions and Relevance:The results of this study are inconclusive. The data suggest that perioperative intravenous acetaminophen may reduce immediate postoperative pain and opioid requirements compared with placebo and these differences could be clinically meaningful. Unfortunately, the imprecision of the estimates prevents definitive conclusion. Use of IVAPAP does not seem to increase adverse events. Trial Registration:clinicaltrials.gov Identifier: NCT01608308.

Project description:Many women experience pain during hysterosalpingogram (HSG). This prospective, randomized, double-blinded, placebo-controlled study assessed whether the use of benzocaine spray during HSG is associated with reduced pain as compared with placebo. Thirty women presenting for HSG were enrolled and randomized to either benzocaine or saline spray. Treatment groups were similar in age, race, parity, pre-procedure oral analgesic use and history of dysmenorrhoea and/or chronic pelvic pain. Median change in pain score from baseline to procedure was 50.6mm (-7.4 to 98.8mm) in the benzocaine group and 70.4mm (19.8 to 100mm) in the placebo group. There was no difference between groups after adjusting for history of dysmenorrhoea. There was no difference in resolution of pain in benzocaine versus placebo groups at 5 min post procedure--median pain score difference -11.1 (-90.1 to 18.5) versus -37.0 (-100 to 1.2)--or at 30 min post procedure. Satisfaction scores did not differ by treatment and did not correlate with pain score during the procedure (rho=0.005). The use of benzocaine spray does not significantly improve pain relief during HSG nor does it hasten resolution of pain post HSG. Of interest, patient satisfaction was not correlated with pain. Many women experience pain during hysterosalpingogram (HSG), which is a test used to evaluate the uterine cavity and fallopian tube. We conducted a prospective, randomized, double-blinded, placebo-controlled study to assess whether the use of benzocaine spray during HSG is associated with reduced pain as compared with placebo. Thirty women presenting for HSG were enrolled and randomized to either benzocaine or saline spray. Treatment groups were similar in age, race, previous pregnancies, pre-procedure oral analgesic use and history of dysmenorrhoea (painful periods) and/or chronic pelvic pain. There was no difference in pain scores or resolution of pain between the two groups. Satisfaction scores did not differ by treatment group and did not correlate with the pain score during the procedure. We conclude that the use of benzocaine spray does not significantly improve pain relief during HSG nor does it hasten resolution of pain post HSG. Of interest, patient satisfaction was not correlated with pain.

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The efficacy of intravenous ketorolac for pain relief in single-stage adjustable strabismus surgery: a prospective, randomized, placebo-controlled trial.

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