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Prospective randomized trial of interventions for vincristine-related neuropathic pain.
Anghelescu, DL, Tesney, JM, Jeha, S, Wright, BB, Trujillo, L, Sandlund, JT, Pauley, J, Cheng, C, Pei, D, Pui, CH
Pediatric blood & cancer. 2020;(9):e28539
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Abstract
BACKGROUND To evaluate the efficacy of gabapentin at 20 mg/kg per day in the treatment of vincristine-related neuropathic pain. PROCEDURE Children aged 1-18 years who developed vincristine-induced neuropathy on a St Jude frontline acute lymphoblastic leukemia trial were prospectively enrolled on a randomized, double-blind, placebo-controlled, phase II trial with two treatment arms: gabapentin plus opioid versus placebo plus opioid. Daily evaluations of morphine dose (mg/kg per day) and pain scores were conducted for up to 21 days; the values of the two arms were compared to assess analgesic efficacy. RESULTS Of 51 study participants, 49 were eligible for analyses. Twenty-five participants were treated with gabapentin, with a mean (SD) dose of 17.97 (2.76) mg/kg per day (median 18.26, range 6.82-21.37). The mean (SD) opioid doses taken, expressed as morphine equivalent daily (mg/kg per day), were 0.26 (0.43) in the gabapentin group (25 patients, 432 days) and 0.15 (0.22) in the placebo group (24 patients, 411 days; P = .15). Only the risk classification of acute lymphoblastic leukemia was significantly associated with the daily morphine dosage (P = .0178): patients in the lower risk arm received higher daily morphine dosages. Multivariate analyses revealed a significant difference between the groups' average daily scores for the previous 24 h and "right now." CONCLUSION In this population of children with vincristine-related neuropathic pain, opioid consumption and pain scores were higher in the gabapentin group than in the placebo group. Future randomized, double-blind, placebo-controlled studies should test gabapentin given longer or at a higher dose.
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Dexketoprofen/tramadol: randomised double-blind trial and confirmation of empirical theory of combination analgesics in acute pain.
Moore, RA, Gay-Escoda, C, Figueiredo, R, Tóth-Bagi, Z, Dietrich, T, Milleri, S, Torres-Lagares, D, Hill, CM, García-García, A, Coulthard, P, et al
The journal of headache and pain. 2015;:541
Abstract
BACKGROUND Combination analgesics are effective in acute pain, and a theoretical framework predicts efficacy for combinations. The combination of dexketoprofen and tramadol is untested, but predicted to be highly effective. METHODS This was a randomised, double-blind, double-dummy, parallel-group, placebo-controlled, single-dose trial in patients with moderate or severe pain following third molar extraction. There were ten treatment arms, including dexketoprofen trometamol (12.5 mg and 25 mg) and tramadol hydrochloride (37.5 mg and 75 mg), given as four different fixed combinations and single components, with ibuprofen 400 mg as active control as well as a placebo control. The study objective was to evaluate the superior analgesic efficacy and safety of each combination and each single agent versus placebo. The primary outcome was the proportion of patients with at least 50 % max TOTPAR over six hours. RESULTS 606 patients were randomised and provided at least one post-dose assessment. All combinations were significantly better than placebo. The highest percentage of responders (72%) was achieved in the dexketoprofen trometamol 25 mg plus tramadol hydrochloride 75 mg group (NNT 1.6, 95% confidence interval 1.3 to 2.1). Addition of tramadol to dexketoprofen resulted in greater peak pain relief and greater pain relief over the longer term, particularly at times longer than six hours (median duration of 8.1 h). Adverse events were unremarkable. CONCLUSIONS Dexketoprofen trometamol 25 mg combined with tramadol hydrochloride 75 mg provided good analgesia with rapid onset and long duration in a model of moderate to severe pain. The results of the dose finding study are consistent with pre-trial calculations based on empirical formulae. TRIAL REGISTRATION EudraCT (2010-022798-32); Clinicaltrials.gov (NCT01307020).
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Catechol-O-methyltransferase genotype modulates opioid release in decision circuitry.
Mitchell, JM, O'Neil, JP, Jagust, WJ, Fields, HL
Clinical and translational science. 2013;(5):400-3
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Impulsivity, a risk factor for substance abuse disorders, is modulated by the Val158 variant of the catechol-O-methyltransferase (COMT) gene. Rodent studies have shown that opioids enhance impulsivity. Furthermore, alcohol consumption leads to endogenous opioid release in the cortex and nucleus accumbens (NAc), and this opioid release is correlated with greater positive hedonic effect. Using the selective mu opioid receptor radioligand [¹¹C] carfentanil, we find that, following alcohol consumption, individuals with the COMT Val158 allele have greater opioid release in the right NAc but less release in medial orbital frontal cortex (OFC). These data suggest that genetic regulation of dopamine levels can affect alcohol consumption in part by modulating endogenous opioid release in specific brain regions implicated in reward, which in turn promotes impulsive choice.
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Imaging human cerebral pain modulation by dose-dependent opioid analgesia: a positron emission tomography activation study using remifentanil.
Wagner, KJ, Sprenger, T, Kochs, EF, Tölle, TR, Valet, M, Willoch, F
Anesthesiology. 2007;(3):548-56
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BACKGROUND Previous imaging studies have demonstrated a number of cortical and subcortical brain structures to be activated during noxious stimulation and infusion of narcotic analgesics. This study used O-water and positron emission tomography to investigate dose-dependent effects of the short-acting mu-selective opioid agonist remifentanil on regional cerebral blood flow during experimentally induced painful heat stimulation in healthy male volunteers. METHODS Positron emission tomography measurements were performed with injection of 7 mCi O-water during nonpainful heat and painful heat stimulation of the volar forearm. Three experimental conditions were used during both sensory stimuli: saline, 0.05 microg x kg x min remifentanil, and 0.15 microg x kg x min remifentanil. Cardiovascular and respiratory parameters were monitored noninvasively. Across the three conditions, dose-dependent effects of remifentanil on regional cerebral blood flow were analyzed on a pixel-wise basis using a statistical parametric mapping approach. RESULTS During saline infusion, regional cerebral blood flow increased in response to noxious thermal stimulation in a number of brain regions as previously reported. There was a reduction in pain-related activations with increasing doses of remifentanil in the thalamus, insula, and anterior and posterior cingulate cortex. Increasing activation occurred in the cingulofrontal cortex (including the perigenual anterior cingulate cortex) and the periaqueductal gray. CONCLUSIONS Remifentanil induced regional cerebral blood flow increases in the cingulofrontal cortex and periaqueductal gray during pain stimulation, indicating that mu-opioidergic activation modulates activity in pain inhibitory circuitries. This provides direct evidence that opioidergic analgesia is mediated by activation of established descending antinociceptive pathways.
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Analgesic transition after remifentanil-based anesthesia in neurosurgery. A comparison of sufentanil and tramadol.
Cafiero, T, Burrelli, R, Latina, P, Mastronardi, P
Minerva anestesiologica. 2004;(1-2):45-52
Abstract
AIM: Transition from the end of remifentanil infusion and postoperative analgesia must be planned carefully owing to remifentanil's (R) rapid offset. Intraoperative morphine has been used for the transition to postoperative analgesia following remifentanil-based anesthesia. Sufentanil (S) is a very potent opioid with high micro-receptor affinity, a much wider therapeutic index and a lower fractional receptor occupancy. These pharmacological and dynamics features make sufentanil an interesting alternative to morphine for immediate postoperative analgesia. EXPERIMENTAL DESIGN perspective, randomized, single blinded and comparative study. Institution: neurosurgical operating theatre at University. PATIENTS 96 patients, aging from 25 to 67 years, ASA class I-III, undergoing neurosurgical operations, were studied. INTERVENTIONS AND MEASUREMENTS the anesthetic management was: premedication: atropine 0.01 microg kg(-1) + remifentanil 0.20 microg kg(-1) min(-1); induction: propofol 2.0 microg kg(-1) + cisatracurium 0.15 microg kg(-1); maintenance: sevoflurane 0.8% + remifentanil (titrated infusion) cisatracurium. All patients received ketorolac 30 mg i.v. 1 hour before the end of surgery and ketorolac (60-90 mg) + tramadol (200-300 mg) by elastomeric pump; patients were divided into 2 groups: group T receiving tramadol 100 mg and group S receiving a bolus dose of sufentanil 0.10 microg kg(-1), 30 and 15 minutes before the end of surgery respectively. Recovery time, postoperative analgesia evaluated by VAS, cardiocirculatory parameters and side effects like nausea, vomiting, shivering, muscle rigidity, sedation and respiratory depression were recorded. RESULTS VAS was significantly lower in Group S. Recovery time was shorter in Group T than in Group S (8.8 +/- 3.6 vs 11.6 +/- 4.6 min), no statistically significant differences between groups as regards nausea, vomiting and shivering. Short-lasting respiratory depression was detected in 3 cases in Group S. CONCLUSION At the emergence much better control of the transition phase in patients treated with sufentanil: smooth recovery with better tolerability of the endotracheal tube; efficacious analgesia along with cardiocirculatory stability.
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Comparative study of analgesic efficacy and morphine-sparing effect of intramuscular dexketoprofen trometamol with ketoprofen or placebo after major orthopaedic surgery.
Hanna, MH, Elliott, KM, Stuart-Taylor, ME, Roberts, DR, Buggy, D, Arthurs, GJ
British journal of clinical pharmacology. 2003;(2):126-33
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AIMS: Multimodal analgesia is thought to produce balanced and effective postoperative pain control. A combined therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) and opiates could result in synergistic analgesia by acting through different mechanisms. Currently there are very few parenterally administered NSAIDs suitable for the immediate postoperative period. Therefore, this study was undertaken to assess the analgesic efficacy, relative potency, and safety of parenteral dexketoprofen trometamol following major orthopaedic surgery. METHODS One hundred and seventy-two patients elected for prosthetic surgery, were randomized to receive two intramuscular injections (12 hourly) of either dexketoprofen 50 mg, ketoprofen 100 mg or placebo in a double-blind fashion. Postoperatively, the patient's pain was stabilized, then they were connected to a patient- controlled analgesia system (PCA) of morphine for 24 h (1 mg with 5 min lockout). RESULTS The mean cumulative amount of morphine (CAM) used was of 39 mg in the dexketoprofen group and 45 mg in the ketoprofen group vs 64 mg in the placebo group. (Reduction in morphine use was approximately one-third between the active compounds compared with placebo (adjusted mean difference of -25 mg between dexketoprofen and placebo and -23 mg between ketoprofen and placebo. These differences were statistically significant: P ≤ 0.0003; 95% CI -35, -14. Pain-intensity scores were consistently lower with the active compounds, the lowest corresponded to the dexketoprofen-treated patients. Regarding sedation, there were statistically significant differences between the two active compounds and placebo only at the 2nd and 13th hours. Wound bleeding was specifically measured with no statistically significant differences found between all the groups. CONCLUSIONS Intramuscular administration of dexketoprofen trometamol 50 mg has good analgesic efficacy both in terms of opioid-sparing effect and control of pain after major orthopaedic surgery.
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A randomized study of the effect of oral lamotrigine and hydromorphone on pain and hyperalgesia following heat/capsaicin sensitization.
Petersen, KL, Maloney, A, Hoke, F, Dahl, JB, Rowbotham, MC
The journal of pain. 2003;(7):400-6
Abstract
In this randomized double-blind placebo-controlled study, the analgesic effect of oral lamotrigine (400 mg) on cutaneous sensitization induced with the heat/capsaicin sensitization model was compared with the effect of oral hydromorphone (8 mg) in healthy volunteers. In a separate session, intravenous remifentanil (0.10 microg.kg(-1).min(-1)) and placebo were administered. This session was used as an additional reference comparator. Outcome measures were the areas of secondary hyperalgesia to brush and von Frey hair stimulation and the painfulness of noxious thermal stimulation in nonsensitized skin. Compared with placebo, both intravenous remifentanil and oral hydromorphone significantly suppressed secondary hyperalgesia and acute thermal nociception. Oral lamotrigine did not reduce secondary hyperalgesia or acute thermal nociception but produced side effects of severity comparable with that of oral hydromorphone. Although lamotrigine is efficacious in the management of some types of chronic neuropathic pain, the lack of effect of this agent on human experimental pain suggests that its analgesic effects depend on nerve injury-associated abnormalities, which cannot be simulated in healthy human volunteers.
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Effect of perioperative administration of dexketoprofen on opioid requirements and inflammatory response following elective hip arthroplasty.
Iohom, G, Walsh, M, Higgins, G, Shorten, G
British journal of anaesthesia. 2002;(4):520-6
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BACKGROUND In this double-blind, randomized, placebo-controlled trial, the safety and analgesic efficacy of perioperative dexketoprofen were evaluated. METHODS Thirty ASA I or II patients undergoing elective hip arthroplasty were randomized to one of two groups. One group (D) received dexketoprofen 25 mg tds for 24 h before and 48 h after surgery; the second group (P) received placebo tablets at equivalent times. Hyperbaric 0.5% bupivacaine (17.5 mg if greater than 70 kg and 15 mg if less than 70 kg) and preservative-free morphine (0.6 mg) were administered intrathecally. Postoperatively, PCA was provided (bolus morphine sulphate 1 mg; lockout 5 min; no continuous infusion). RESULTS The two groups were similar in terms of age, gender, weight, height, ASA class, duration of operation, and level of sensory block on arrival to the recovery room. Groups were also similar in terms of blood loss, transfusion requirements, ventilatory frequency, and haemodynamic variables. According to visual analogue pain scores patients in group D experienced less pain at 15 h (P=0.02) postoperatively. Cumulative morphine consumption was also less in group D compared with group P at 6 (0.06 (0.2) vs 0.85 (1.4) mg, P=0.04) and 48 h postoperatively (10.1 (8) vs 26.2 (20) mg, P<0.01). Plasma interleukin 6 concentrations increased postoperatively to a significantly lesser extent in group D than in group P (P=0.02). Nausea and vomiting were less (P<0.01) in group D compared with group P at 18 h postoperatively. Sedation scores were less (P=0.03) in group D. CONCLUSIONS Perioperative administration of dexketoprofen 25 mg 8 hourly markedly improves analgesia and decreases opioid requirements (and associated adverse effects) following hip arthroplasty. It appears that this regimen decreases the postoperative pro-inflammatory response.
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Effects of caffeine as an adjuvant to morphine in advanced cancer patients. A randomized, double-blind, placebo-controlled, crossover study.
Mercadante, S, Serretta, R, Casuccio, A
Journal of pain and symptom management. 2001;(5):369-72
Abstract
Psychomotor abnormalities are one of the complications of opioid therapy in advanced cancer patients. Caffeine has potential properties to counteract the central effects of morphine. Twelve patients receiving stable doses of slow release morphine with adequate pain relief were scheduled for this double-blind placebo-controlled crossover trial. The treatment consisted of an intravenous dose of 1/6 of the daily morphine dose, using an intravenous/oral conversion ratio of 1:3. The dose calculated was administered in 5 minutes. Patients were randomly divided to received in a double-blind manner an infusion of 200 mg of caffeine or saline solution intravenously over one hour. A crossover took place after 2-3 days. Patients were assessed immediately before the infusion and once at the end (one hour after). Each assessment included pain, nausea, confusion, and drowsiness intensity. Psychomotor tests, including tapping speed with 10-30 seconds trials, arithmetic tests, memory for digits, and visual memory were also performed. Caffeine infusion induced a significant decrease in pain intensity (from 25.3 to 16.3, p =0.003), but this was no different from the placebo. Caffeine increased both tapping speed tests (p = 0.041 and 0.010, respectively) in comparison with placebo treatment. No other significant differences were found in the other parameters examined. Caffeine showed a partial effect on the cognitive performance of advanced cancer patients on chronic morphine treatment who received a bolus of intravenous morphine. Further studies are necessary to evaluate whether higher doses of caffeine may be more effective and to establish the role of tolerance to caffeine in this group of patients.
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Morphine plus bupivacaine vs. morphine peridural analgesia in abdominal surgery: the effects on postoperative course in major hepatobiliary surgery.
Barzoi, G, Carluccio, S, Bianchi, B, Vassia, S, Colucci, G, Mangiante, GL
HPB surgery : a world journal of hepatic, pancreatic and biliary surgery. 2000;(6):393-9
Abstract
Anaesthesia and surgical procedures lead to a reduction of intestinal motility, and opioids may produce a postoperative ileus, that might delay postoperative feeding. The aim of this prospective randomised study is to test whether or not different kinds of epidural analgesia (Group A: morphine 0.0017 mg/kg/h and bupivacaine 0.125%-0.058 mg/kg/h; Group B: morphine alone 0.035 mg/kg/12h in the postoperative period) allow earlier postoperative enteral feeding, enhance intestinal motility a passage of flatus and help avoid complications, such as nausea, vomiting, ileus, diarrhoea, pneumonia or other infective diseases. We included in the study 60 patients (28 males and 32 females) with a mean age of 61.2 years (range 50-70) and with an ASA score of 2 or 3. All patients had hepato-biliary-pancreatic neoplasm and were candidates for major surgery. We compared two different pharmacological approaches, i.e., morphine plus bupivacaine (30 patients, Group A) versus morphine alone (30 patients, Group B). Each medication was administered by means of a thoracic epidural catheter for the control of postoperative pain. In the postoperative course we recorded every 6 hours peristaltic activity. We also noted morbidity (pneumonia, wound sepsis) and mortality. Effective peristalsis was present in all patients in Group A within the first six postoperative hours; in Group B, after 30 hours. Six patients in Group A had bowel motions in the first postoperative day, 11 in the second day, 10 in the third day and 3 in fourth day, while in Group B none in the first day, two in the second, 7 in the third, 15 in the fourth, and 6 in the fifth: the difference between the two groups was significant (p<0.05 in 1st, 2nd, 4th and 5th days). Pneumonia occurred in 2 patients of Group A, and in 10 of Group B (p < 0.05). We conclude that epidural analgesia with morphine plus bupivacaine allowed a move rapid return to normal gut activity and early enteral nutrition compared with epidural analgesia with morphine alone.