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Do the potential benefits outweigh the risks? An update on the use of ziconotide in clinical practice.
Bäckryd, E
European journal of pain (London, England). 2018;(7):1193-1202
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Abstract
Ziconotide is a selective and potent blocker of N-type voltage-gated calcium channels. It was approved by the Food and Drug Administration in 2004 and by the European Medicines Agency in 2005 for the treatment of severe chronic pain in patients needing intrathecal analgesia (ITA). The aim of this paper is to provide a practitioner-oriented, educational, narrative, up-to-date review on the use of ziconotide in clinical pain medicine. Of special concern regarding safety is the partial incongruity between dosing statements in the Summary of Product Characteristics and novel low-dosage, slow uptitration recommendations. Even though ziconotide has obvious advantages compared to opioids, pain practitioners pondering the use of ziconotide nonetheless have to balance its proved potential analgesic effect against its neurological side effects, with special consideration being given to dosing and neuropsychiatric dangers. Using a seesaw analogy, the paper discusses what factors pain physicians should weigh in when considering ziconotide as ITA drug, the non-opioid advantages of ziconotide being counterbalanced by its potential psychiatric side effects. Ziconotide is an important part of the armamentarium of modern interventional pain medicine. If ITA is deemed necessary, ziconotide is a rational alternative, at least in chronic (neuropathic) non-cancer pain. However, in many European countries, ziconotide treatment is only available in a few (if any) centres. The safety profile of ziconotide is not fundamentally more worrying than that of opioids or cannabinoids; it is just different. This paper provides a concise, up-to-date and clinically-oriented summary of the use of ziconotide in clinical practice, not least concerning safety and dosage issues.
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Understanding Phase Behavior of Nearly Energetically Equivalent Polymorphs To Achieve Controlled Crystallization for a Nav1.7 Pain Inhibitor Compound.
Chakravarty, P, DiPasquale, AG, Stumpf, A, Lubach, JW, Nagapudi, K
Molecular pharmaceutics. 2018;(11):5072-5080
Abstract
GENE-A, a Nav1.7 inhibitor compound with analgesic activity, was developed as a crystalline anhydrate, for which two polymorphic forms, I and II, were discovered. The two forms were found to possess very similar free energies as determined experimentally with Form II being thermodynamically stable above 25 °C based on solubility measurements. A detailed solid-state characterization was conducted to determine the relative stability of these solid forms, and both thermodynamic and kinetic pathways (slurry bridging and crystallization) were evaluated. Form II was obtained as the final form in competitive slurries at RT. The outcome of crystallization experiments in terms of the solid form obtained was complicated and yielded variable results depending on the form of the starting material and that of the seeds. Form II was reproducibly obtained as the end product in unseeded experiments and in those with Form II as seeds and starting material, while Form I was obtained in all other seeded experiments. On the basis of the experimental data, a controlled crystallization strategy was developed, wherein Form II was used both as starting material and seeds to reproducibly obtain the desired form upon scale-up.
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Pregabalin and Dexmedetomidine Combined for Pain After Total Knee Arthroplasty or Total Hip Arthroplasty Performed Under Spinal Anesthesia.
Lee, C, Lee, J, Lee, G, Lee, H, Koh, E, Hwang, J
Orthopedics. 2018;(6):365-370
Abstract
Pregabalin and dexmedetomidine have been introduced to manage postoperative pain. This study evaluated the effect of the 2 drugs combined on pain in patients undergoing total knee or hip arthroplasty. A total of 124 patients undergoing total knee or hip arthroplasty under spinal anesthesia were randomly assigned to either group C (n=31, placebo), group P (n=33, pregabalin), group PD (n=29, pregabalin and dexmedetomidine), or group D (n=31, dexmedetomidine). One hour before spinal anesthesia, patients received 150 mg of pregabalin or placebo orally, and a bolus dose of 0.5 µg/ kg of intravenous dexmedetomidine was given over 10 minutes before induction of spinal anesthesia. This was followed by a continuous infusion of 0.5 µg/kg/h or the same calculated volume of normal saline until completion of the surgery. Clinically relevant pain for 24 hours postoperatively, including time to first analgesic request, visual analog scale score, ketorolac dose, and volume of patient-controlled analgesia consumed, was recorded. Group C had significantly longer time to first analgesic request, higher visual analog scale scores at rest and on movement, higher ketorolac dose, and higher volume of patient-controlled analgesia for the first 24 hours postoperatively compared with the other groups. Although group PD and group D had less clinically relevant pain than group P, group PD and group D were not significantly different. Dexmedetomidine was more effective than pregabalin for clinically relevant pain. Pregabalin and dexmedetomidine combined had no synergic effect compared with dexmedetomidine alone. [Orthopedics. 2018; 41(6):365-370.].
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Non-steroidal Anti-inflammatory Drugs in Newborns and Infants.
Aranda, JV, Salomone, F, Valencia, GB, Beharry, KD
Pediatric clinics of North America. 2017;(6):1327-1340
Abstract
Nonsteroidal antiinflammatory drugs (NSAIDs) and acetaminophen are used in young infants and newborns for pain and fever control, patent ductus closure, prevention of intraventricular hemorrhage, and potentially for prevention of retinopathy of prematurity. These drugs inhibit cyclooxygenase 1 (COX-1), COX-2, and peroxidases, thus, blocking prostaglandin (PG) synthesis. PGs are eicosanoids that regulate several physiologic, pathologic, and cellular processes, including vasomotor tone, platelet aggregation, sensitization of neurons to pain, and many molecular events critical to physiologic homeostasis. NSAIDs inhibit caspases and cell death. Increasing knowledge of these molecular entities may allow targeted drug development to prevent or minimize neonatal morbidities.
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Alpha Lipoic Acid Plus Omega-3 Fatty Acids for Vestibulodynia Associated With Painful Bladder Syndrome.
Murina, F, Graziottin, A, Felice, R, Gambini, D
Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC. 2017;(3):131-137
Abstract
OBJECTIVE This study assessed the effectiveness of alpha lipoic acid (ALA) plus omega-3 polyunsaturated fatty acids (n-3 PUFAs) in combination with amitriptyline therapy in patients with vestibulodynia/painful bladder syndrome (VBD/PBS). METHODS Women with VBD/PBS were randomly assigned to receive amitriptyline or amitriptyline plus a commercially available preparation (ALAnerv Age; Alfa Wassermann, Bologna, Italy) containing, in 2 capsules, ALA 600 mg plus docosahexaenoic acid 250 mg and eicosapentaenoic acid 16.67 mg. Symptoms of burning and pain were assessed using a 10-cm visual analog scale and the short form of the McGill-Melzack Pain Questionnaire. RESULTS Among 84 women who were randomized, the mean ± standard deviation dose of amitriptyline was 21.7 ± 6.6 mg/day, without statistical difference between the two groups. Pain, as assessed using both the pain rating index of the visual analog scale and the short-form McGill Pain Questionnaire, decreased significantly in both trial groups, with a greater effect seen with the addition of ALA and n-3 PUFAs. The addition of ALA/n-3 PUFAs to amitriptyline treatment was also associated with improvements in dyspareunia and pelvic floor muscle tone. The overall incidence of adverse events was low, and none led to treatment discontinuation. CONCLUSIONS The addition of ALA/n-3 PUFAs to amitriptyline treatment in patients with VBD/PBS appears to improve outcomes and may allow for a lower dosage of amitriptyline, which may lead to fewer adverse effects.
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The role of oxidative stress, inflammation and acetaminophen exposure from birth to early childhood in the induction of autism.
Parker, W, Hornik, CD, Bilbo, S, Holzknecht, ZE, Gentry, L, Rao, R, Lin, SS, Herbert, MR, Nevison, CD
The Journal of international medical research. 2017;(2):407-438
Abstract
The wide range of factors associated with the induction of autism is invariably linked with either inflammation or oxidative stress, and sometimes both. The use of acetaminophen in babies and young children may be much more strongly associated with autism than its use during pregnancy, perhaps because of well-known deficiencies in the metabolic breakdown of pharmaceuticals during early development. Thus, one explanation for the increased prevalence of autism is that increased exposure to acetaminophen, exacerbated by inflammation and oxidative stress, is neurotoxic in babies and small children. This view mandates extreme urgency in probing the long-term effects of acetaminophen use in babies and the possibility that many cases of infantile autism may actually be induced by acetaminophen exposure shortly after birth.
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The Effect of Intravenous Acetaminophen on Postoperative Pain and Narcotic Consumption After Vaginal Reconstructive Surgery: A Double-Blind Randomized Placebo-Controlled Trial.
Crisp, CC, Khan, M, Lambers, DL, Westermann, LB, Mazloomdoost, DM, Yeung, JJ, Kleeman, SD, Pauls, RN
Female pelvic medicine & reconstructive surgery. 2017;(2):80-85
Abstract
OBJECTIVE This study aimed to determine the effect of intravenous acetaminophen versus placebo on postoperative pain, satisfaction with pain control, and narcotic use after vaginal reconstructive surgery. METHODS This was an institutional review board-approved, double-blind placebo-controlled randomized trial. Women scheduled for reconstructive surgery including vaginal hysterectomy and vaginal vault suspension were enrolled. Subjects received 1000 mg of intravenous acetaminophen or 100 mL placebo every 6 hours for 24 hours. Pain and satisfaction with pain control were assessed using visual analog scales and a numeric rating scale. Visual analog scales were collected at 18 and 24 hours postoperatively and at discharge. A sample size calculation determined 90 subjects would be required to detect a 30% reduction in postoperative narcotic use with 80% power and significance level of 0.05. RESULTS One hundred subjects were enrolled. There were no differences in demographics or surgical data and no difference in narcotic consumption at multiple evaluation points. At 18 hours postoperative, median pain scores at rest were 27.0 (interquartile range, 35.0) for acetaminophen and 35.0 (interquartile range, 44.5) for placebo, finding no difference (P = 0.465). Furthermore, pain with activity and numeric rating scale-assessed pain scales were similar (P = 0.328; P = 0.597). Although satisfaction with pain control was high overall (91.5), no difference was noted. CONCLUSIONS Patients undergoing vaginal reconstructive surgery receiving perioperative intravenous acetaminophen did not experience a decrease in narcotic requirements or postoperative pain when compared with placebo. Reassuringly, pain scores were low and satisfaction with pain control was high for all subjects. The general use of this medication is not supported in these surgical patients.
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Postoperative Multimodal Analgesia Pain Management With Nonopioid Analgesics and Techniques: A Review.
Wick, EC, Grant, MC, Wu, CL
JAMA surgery. 2017;(7):691-697
Abstract
IMPORTANCE Amid the current opioid epidemic in the United States, the enhanced recovery after surgery pathway (ERAS) has emerged as one of the best strategies to improve the value and quality of surgical care and has been increasingly adopted for a broad range of complex surgical procedures. The goal of this article was to outline important components of opioid-sparing analgesic regimens. OBSERVATIONS Regional analgesia, acetaminophen, nonsteroidal anti-inflammatory agents, gabapentinoids, tramadol, lidocaine, and/or the N-methyl-d-aspartate class of glutamate receptor antagonists have been shown to be effective adjuncts to narcotic analgesia. Nonsteroidal anti-inflammatory agents are not associated with an increase in postoperative bleeding. A meta-analysis of 27 randomized clinical trials found no difference in postoperative bleeding between the groups taking ketorolac tromethamine (33 of 1304 patients [2.5%]) and the control groups (21 of 1010 [2.1%]) (odds ratio [OR], 1.1; 95% CI, 0.61-2.06; P = .72). After adoption of the multimodal analgesia approach for a colorectal ERAS pathway, most patients used less opioids while in the hospital and many did not need opioids after hospital discharge, although approximately 50% of patients received some opioid during their stay. CONCLUSIONS AND RELEVANCE Multimodal analgesia is readily available and the evidence is strong to support its efficacy. Surgeons should use this effective approach for patients both using and not using the ERAS pathway to reduce opioid consumption.
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Neonatal Maturation of Paracetamol (Acetaminophen) Glucuronidation, Sulfation, and Oxidation Based on a Parent-Metabolite Population Pharmacokinetic Model.
Cook, SF, Stockmann, C, Samiee-Zafarghandy, S, King, AD, Deutsch, N, Williams, EF, Wilkins, DG, Sherwin, CM, van den Anker, JN
Clinical pharmacokinetics. 2016;(11):1395-1411
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Abstract
OBJECTIVES This study aimed to model the population pharmacokinetics of intravenous paracetamol and its major metabolites in neonates and to identify influential patient characteristics, especially those affecting the formation clearance (CLformation) of oxidative pathway metabolites. METHODS Neonates with a clinical indication for intravenous analgesia received five 15-mg/kg doses of paracetamol at 12-h intervals (<28 weeks' gestation) or seven 15-mg/kg doses at 8-h intervals (≥28 weeks' gestation). Plasma and urine were sampled throughout the 72-h study period. Concentration-time data for paracetamol, paracetamol-glucuronide, paracetamol-sulfate, and the combined oxidative pathway metabolites (paracetamol-cysteine and paracetamol-N-acetylcysteine) were simultaneously modeled in NONMEM 7.2. RESULTS The model incorporated 259 plasma and 350 urine samples from 35 neonates with a mean gestational age of 33.6 weeks (standard deviation 6.6). CLformation for all metabolites increased with weight; CLformation for glucuronidation and oxidation also increased with postnatal age. At the mean weight (2.3 kg) and postnatal age (7.5 days), CLformation estimates (bootstrap 95% confidence interval; between-subject variability) were 0.049 L/h (0.038-0.062; 62 %) for glucuronidation, 0.21 L/h (0.17-0.24; 33 %) for sulfation, and 0.058 L/h (0.044-0.078; 72 %) for oxidation. Expression of individual oxidation CLformation as a fraction of total individual paracetamol clearance showed that, on average, fractional oxidation CLformation increased <15 % when plotted against weight or postnatal age. CONCLUSIONS The parent-metabolite model successfully characterized the pharmacokinetics of intravenous paracetamol and its metabolites in neonates. Maturational changes in the fraction of paracetamol undergoing oxidation were small relative to between-subject variability.
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Different interventions in preventing opioid-induced cough: a meta-analysis.
Shuying, L, Ping, L, Juan, N, Dong, L
Journal of clinical anesthesia. 2016;:440-7
Abstract
BACKGROUND Cough is one of the most common complications of opioids. Many studies have evaluated the effect of various drugs in preventing opioid-induced cough (OIC). However, there is existing controversy about those reports. The present study was performed to assess the efficacy of different interventions on OIC. METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, and Embase to identify randomized controlled trials on the efficacy of different drugs in the prevention of OIC. Opioids included fentanyl, sufentanil, and remifentanil. We mainly investigated the incidence and severity of OIC after different interventions. RESULTS Thirty-four trials including 9906 patients were analyzed in this study. Twenty different drugs were reported, and 10 drugs were indentified in more than 2 articles. These drugs, including lidocaine, ketamine, dexmedetomidine, priming of fentanyl, propofol, dezocine, dexamethasone, dextromethorphan, and magnesium sulfate (MgSO4), showed a significant efficacy compared with controls. There were insufficient numbers of trials for salbutamol, clonidine, tramadol, pentazocine, rocuronium, midazolam, atropine, terbutaline, sodium chromoglycate, beclomethasone, and ephedrine. From these data, we found that salbutamol, tramadol, midazolam, and atropine were ineffective. CONCLUSIONS This meta-analysis suggested that the prophylactic administration of lidocaine, ketamine, dexmedetomidine, priming of fentanyl, propofol, and dezocine was effective in preventing OIC.