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- Enteral absorption and haemodynamic response of clonidine in infants post-cardiac surgery. [JOURNAL ARTICLE]
- Br J Anaesth 2014 Jul 30.
Clonidine is a useful analgesic-sedative agent; however, few data exist regarding its use in infants after congenital heart disease surgery. We thus aimed to assess the absorption and safety of enterally administered clonidine in this setting.Sixteen infants (median age 6.7 months) received a single nasogastric dose of 3 μg kg(-1) clonidine 2-6 h after surgery. Blood samples were obtained at seven time intervals (up to 480 min). Plasma concentration profiles were obtained, and then pooled with a previous study (137 samples, 30 infants) for estimation of population pharmacokinetic parameters (NONMEM version 7.2).Enteral absorption showed considerable inter-individual variability, with clonidine Cmax ranging from 0.15 to 1.55 ng ml(-1) (median 0.73), and Tmax from 12 to 478 min (median 190). Although therapeutic sedative plasma concentrations were achieved in 94% of patients, only half had attained this by 70 min post-dose. Patients who did not receive inotropes exhibited a positive association between cumulative morphine dose and Tmax (interaction effect P=0.03); this was not seen among those receiving inotropes. The haemodynamic profile was favourable; few patients required fluid boluses, and this bore no relationship to plasma clonidine concentration. Population pharmacokinetic parameter estimation yielded results similar to previous paediatric studies: clearance 13.7 litre h(-1) 70 kg(-1) and Vd 181 litre 70 kg(-1).Early postoperative enteral clonidine produces favourable haemodynamic profiles and therapeutic plasma concentrations in the majority of cardiac surgical infants; however, the time to achieve this can be erratic. Thus, parenteral administration may be preferable if rapid analgo-sedative effects are needed.
- Nalbuphine for postoperative pain treatment in children. [JOURNAL ARTICLE]
- Cochrane Database Syst Rev 2014 Jul 31.:CD009583.
Several surveys over the past few years have demonstrated that postoperative pain in children is not treated appropriately. One pharmacological treatment option in a multimodal approach for postoperative pain treatment is the systemic administration of opioids. However, opioids are rarely used for postoperative pain treatment in children due to fear of adverse events. One long-standing opioid for systemic use is nalbuphine, a kappa-receptor agonist and µ-receptor antagonist. The efficacy of nalbuphine is believed to be similar to morphine. Increased dosing might result in a ceiling effect, and thus less analgesia than expected. In addition, there might be a lower risk for opioid-induced side effects (nausea, vomiting) and severe adverse events (respiratory depression) due to the antagonistic effect of the µ-receptor. Nalbuphine may be an useful opioid for postoperative use in children, but exact efficacy (e.g. compared to other commonly used opioids) has not been determined yet.To assess the efficacy and adverse events of nalbuphine for acute postoperative pain treatment in children undergoing surgery.We systematically searched the following databases: The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 7), MEDLINE via Pubmed (January 1966 to July 2013) and EMBASE via Ovid (January 1947 to July 2013). We did not impose any restrictions regarding language or publication date. We checked all reference lists of retrieved articles for additional references.All randomised controlled trials (RCTs) investigating nalbuphine compared with placebo or other opioids were included.Two review authors independently scanned the retrieved articles and made a decision regarding inclusion or exclusion of studies for this review. The same authors also performed the data extraction and the assessment of risk of bias.Ten RCTs including 658 patients were finally included in this systematic review. Five trials compared nalbuphine with placebo. Data from one out of five studies for the outcome moderate/severe pain following nalbuphine compared to placebo gave a risk ratio (RR) 1 hour postoperatively (postop) of 0.1 (95% confidence interval (CI) 0.01 to 0.71; low quality evidence) and a RR 2 hours postop of 0.14 (95% CI 0.02 to 1.06; low quality evidence). The estimated RR based on data from a single study indicated that nalbuphine reduced the requirement for analgesia two hours postop (RR 0.47; 95% CI 0.27 to 0.84; low quality evidence). Two included trials compared nalbuphine with morphine and showed a nonsignificant lower or comparable RR for moderate/severe pain at 1 hour postop (RR 0.84; 95% CI 0.12 to 5.74; low quality evidence), and 2 hours postop (RR 1.09; 95% CI 0.59 to 2.01; low quality evidence) for nalbuphine versus morphine. Four trials compared nalbuphine with tramadol for postoperative pain; data from one trial (per outcome) revealed a lower but nonsignificant RR for the need of additional rescue analgesics in children receiving nalbuphine (RR 2 hours postop 0.75; 95% CI 0.39 to 1.43; low quality evidence) (RR 12 hours postop 0.33; 95% CI 0.04 to 2.77; low quality evidence). One out of three trials comparing nalbuphine with pethidine demonstrated that the RR was not significantly lower following nalbuphine administration compared to pethidine (RR 2 hours postop 1.07; 95% CI 0.52 to 2.23; low quality evidence) (RR 24 hours postop 1.13; 95% CI 0.52 to 2.44; very low quality evidence). The most common adverse event was postoperative nausea and vomiting (PONV). Only one included trial reported that the RR for PONV in the postoperative care unit (PACU) was not significantly higher following nalbuphine compared to placebo (RR 1.00; 95% CI 0.16 to 6.42; low quality evidence) nor to morphine (RR 1.33; 95% CI 0.64 to 2.77; low quality evidence).Because the overall quality of available evidence was low, this systematic review could not definitively show that the analgesic efficacy of nalbuphine is superior compared to placebo. Furthermore, due to the lack of significant results the comparison with other common opioids is also unclear. The same holds true for the evidence focusing on adverse events following nalbuphine compared to placebo or other opioid administration. The evidence is limited, because studies did not report conclusively all important postoperative pain outcomes (e.g. number of patients with the need for rescue analgesia, postoperative pain scores). Thus, a quantitative analysis was not possible for many major aspects (e.g. rescue analgesia, pain scores) and heterogeneity could not be further explored.
- Effect of intravenous lignocaine on perioperative stress response and post-surgical ileus in elective open abdominal surgeries: a double-blind randomized controlled trial. [JOURNAL ARTICLE]
- ANZ J Surg 2014 Jul 31.
Perioperative stress response can be detrimental if excessive and prolonged. Intravenous (i.v.) lignocaine, while being an effective analgesic, has the added benefit of anti-inflammatory activity. This study was done to assess the effect of i.v. lignocaine on operative stress response and post-surgical ileus after elective open abdominal surgeries.Patients (n = 134) were randomized into two groups (n = 67 each) to receive an i.v. infusion of lignocaine (group L) or saline (group S) as a bolus of 1.5 mg/kg at intubation followed by an infusion of 1.5 mg/kg/h throughout the surgery until 1 h post-surgery. Total leukocyte count (TLC), C-reactive protein (CRP) and interleukin-6 (IL-6) levels immediately and 24 h after surgery were compared with preoperative levels. Time to first passage of flatus and stools post-operatively was noted. Post-operative pain scores, analgesic requirements, and incidence of post-operative nausea and vomiting (PONV) were assessed in the two groups.Post-operative surge in TLC, CRP and IL-6 was attenuated in group L as compared to group S (P < 0.001, 0.018, <0.001). Time to passage of flatus and stools was earlier in group L (P = 0.04, 0.02). PONV was lesser in group L at 6 and 18 h post-surgery (<0.001, 0.28). Post-operative pain scores and post-operative morphine requirement were significantly less in group L at each point of time post-operatively (P < 0.001, <0.001).Perioperative i.v. lignocaine infusion attenuates the operative stress response, provides effective analgesia and reduces the need for opioids post-operatively. Through these effects, it reduces post-operative ileus and the incidence of PONV.
- Pharmacologic Management of Pain at the End of Life. [JOURNAL ARTICLE]
- Am Fam Physician 2014 Jul 1; 90(1):26-32.
Although many patients experience debilitating pain at the end of life, there are many options to improve analgesia and quality of life. Pain assessment using a validated tool, with attention to patient function and specific goals, helps tailor individual treatment plans. The World Health Organization pain ladder offers a stepwise guideline for approaching pain management. However, for many patients with terminal illness, strong opioids are necessary for efficient and effective analgesia. Equianalgesic dosing tables and expert guidelines aid in initiating, monitoring, and adjusting doses of oral and parenteral opioids. Clinicians should feel comfortable administering a repeat dose after the time to peak analgesic effect if the patient is still in pain. In patients with constant pain, using scheduled long-acting opioids may significantly improve pain control. Among pain subtypes, visceral pain management usually requires multiple drugs. Neuropathic pain responds well to adjuvant pharmacotherapies, such as anticonvulsants or antidepressants, in addition to opioids. Opioid-induced hyperalgesia can occur with any dose of an opioid, but is more common with higher doses of parenteral morphine and hydromorphone. With appropriate counseling, most patients with a history of substance abuse will comply with a pain treatment plan.
- Relief of Cancer Pain by Glycine Transporter Inhibitors. [JOURNAL ARTICLE]
- Anesth Analg 2014 Jul 29.
Recent studies have revealed the antinociceptive effects of glycine transporter (GlyT) inhibitors in neuropathic pain models such as sciatic nerve-injured and diabetic animals. Bone cancer can cause the most severe pain according to complex mechanisms in which a neuropathic element is included. Bone cancer modifies the analgesic action of opioids and limits their effectiveness, and thus novel medicament for bone cancer pain is desired.For the femur bone cancer model, NCTC 2472 tumor cells were injected into the medullary cavity of the distal femur of C3H/HeN mice. Effects of GlyT2 inhibitors, ORG 25543 and ALX 1393, and GlyT1 inhibitors, ORG 25935, and knockdown of the expression of spinal GlyTs protein by GlyTs siRNA on pain-like behaviors, such as allodynia, withdrawal threshold, guarding behavior, and limb-use abnormality, were examined in the femur bone cancer model mice. Effects of morphine in combination with GlyT inhibitor were examined.GlyT2 inhibitors, ORG 25543 and ALX 1393, and GlyT1 inhibitor ORG 25935 by IV or oral administration or knockdown of the expression of spinal GlyTs protein improved pain-like behaviors at 11 days after tumor transplantation. The pain-relief activity was potent and long lasting. Morphine at a dose with no analgesic activity combined with ORG 25543 further promoted the ORG 25543-induced pain-relief activity. Injection of ORG 25543 on the second day after tumor implantation caused 3 phases of pain responses; pain-like behaviors were initially accelerated (at 2-4 days) and subsequently almost disappeared (5-7 days) and then reappeared. Intrathecal injection of strychnine 1 day after injection of ORG 25543 transiently antagonized the pain-relief activity of ORG 25543. In control mice, strychnine improved pain-like behaviors 4 days after tumor implantation and aggravated the behaviors between 4 and 5 days. The evidence suggests that the different mechanisms are phase-dependently involved.GlyT inhibitors with or without morphine may be a new strategy for the treatment of bone cancer pain and lead to further investigations of the mechanisms underlying the development of bone cancer pain.
- Erratum to: CB1 antagonism: interference with affective properties of acute naloxone-precipitated morphine withdrawal in rats. [JOURNAL ARTICLE]
- Psychopharmacology (Berl) 2014 Jul 31.
- Using drug combinations to assess potential contributions of non-GABAA receptors in the discriminative stimulus effects of the neuroactive steroid pregnanolone in rats. [JOURNAL ARTICLE]
- Physiol Behav 2014 Jul 26.
Neuroactive steroids are increasingly implicated in the development of depression and anxiety and have been suggested as possible treatments for these disorders. While neuroactive steroids, such as pregnanolone, act primarily at γ-aminobutyric acid (GABAA) receptors, other mechanisms might contribute to their behavioral effects and could increase their clinical effectiveness, as compared with drugs acting exclusively at GABAA receptors (e.g., benzodiazepines). The current study examined the role of non-GABAA receptors, including n-methyl-D-aspartate (NMDA) and serotonin3 (5-HT3) receptors, in the discriminative stimulus effects of pregnanolone. Separate groups of rats discriminated either 3.2mg/kg pregnanolone from vehicle or 0.32mg/kg of the benzodiazepine midazolam from vehicle while responding under a fixed ratio 10 schedule for food pellets. When administered alone in both groups, pregnanolone and midazolam produced ≥80% drug-lever responding, the NMDA receptor antagonists dizocilpine and phencyclidine produced ≥60 and 30% drug-lever responding, respectively, and the 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide (CPBG) and morphine produced <20% drug-lever responding up to doses that markedly decreased response rates. When studied together, neither dizocilpine, phencyclidine, CPBG nor morphine significantly altered the midazolam dose-effect curve in either group. Given that CPBG is without effect, it is unlikely that 5-HT3 receptors contribute substantially to the discriminative stimulus effects of pregnanolone. Similarities across groups in effects of dizocilpine and phencyclidine suggest that NMDA receptors do not differentially contribute to the effects of pregnanolone. Thus, NMDA and 5-HT3 receptors are not involved in the discriminative stimulus effects of pregnanolone.
- Short Term Morphine Exposure In Vitro Alters Proliferation and Differentiation of Neural Progenitor Cells and Promotes Apoptosis via Mu Receptors. [Journal Article]
- PLoS One 2014; 9(7):e103043.
Chronic morphine treatment inhibits neural progenitor cell (NPC) progression and negatively effects hippocampal neurogenesis. However, the effect of acute opioid treatment on cell development and its influence on NPC differentiation and proliferation in vitro is unknown. We aim to investigate the effect of a single, short term exposure of morphine on the proliferation, differentiation and apoptosis of NPCs and the mechanism involved.Cell cultures from 14-day mouse embryos were exposed to different concentrations of morphine and its antagonist naloxone for 24 hours and proliferation, differentiation and apoptosis were studied. Proliferating cells were labeled with bromodeoxyuridine (BrdU) and cell fate was studied with immunocytochemistry.Cells treated with morphine demonstrated decreased BrdU expression with increased morphine concentrations. Analysis of double-labeled cells showed a decrease in cells co-stained for BrdU with nestin and an increase in cells co-stained with BrdU and neuron-specific class III β-tubuline (TUJ1) in a dose dependent manner. Furthermore, a significant increase in caspase-3 activity was observed in the nestin- positive cells. Addition of naloxone to morphine-treated NPCs reversed the anti-proliferative and pro-apoptotic effects of morphine.Short term morphine exposure induced inhibition of NPC proliferation and increased active caspase-3 expression in a dose dependent manner. Morphine induces neuronal and glial differentiation and decreases the expression of nestin- positive cells. These effects were reversed with the addition of the opioid antagonist naloxone. Our results demonstrate the effects of short term morphine administration on the proliferation and differentiation of NPCs and imply a mu-receptor mechanism in the regulation of NPC survival.
- The clinical analgesic efficacy of buprenorphine. [JOURNAL ARTICLE]
- J Clin Pharm Ther 2014 Jul 29.
Based on in vitro assays and select animal models, buprenorphine is commonly called a 'partial agonist'. An implication is that it should produce less analgesic effect in humans than so-called 'full agonists' such as morphine or fentanyl. However, buprenorphine has a multimechanistic pharmacology, and thus partial agonism at a specific receptor is not particularly relevant to its overall analgesic action. We review published clinical trials that directly compared the magnitude of buprenorphine's analgesic effect to analgesics commonly considered full agonists.Due to different signal transduction pathways, a drug can be a full agonist on one endpoint and a partial agonist on another. Therefore, we limited the present review to buprenorphine's analgesic effect.Twenty-four controlled clinical trials were identified, plus a case report and dose-response curve. Based on complete or comparable pain relief, in buprenorphine had full clinical analgesic efficacy in 25 of the 26 studies.
- A Multicenter Cohort Study of Treatments and Hospital Outcomes in Neonatal Abstinence Syndrome. [JOURNAL ARTICLE]
- Pediatrics 2014 Jul 28.
To compare pharmacologic treatment strategies for neonatal abstinence syndrome (NAS) with respect to total duration of opioid treatment and length of inpatient hospital stay.We conducted a cohort analysis of late preterm and term neonates who received inpatient pharmacologic treatment of NAS at one of 20 hospitals throughout 6 Ohio regions from January 2012 through July 2013. Physicians managed NAS using 1 of 6 regionally based strategies.Among 547 pharmacologically treated infants, we documented 417 infants managed using an established NAS weaning protocol and 130 patients managed without protocol-driven weaning. Regardless of the treatment opioid chosen, when we accounted for hospital variation, infants receiving protocol-based weans experienced a significantly shorter duration of opioid treatment (17.7 vs 32.1 days, P < .0001) and shorter hospital stay (22.7 vs 32.1 days, P = .004). Among infants receiving protocol-based weaning, there was no difference in the duration of opioid treatment or length of stay when we compared those treated with morphine with those treated with methadone. Additionally, infants treated with phenobarbital were treated with the drug for a longer duration among those following a morphine-based compared with methadone-based weaning protocol. (P ≤ .002).Use of a stringent protocol to treat NAS, regardless of the initial opioid chosen, reduces the duration of opioid exposure and length of hospital stay. Because the major driver of cost is length of hospitalization, the implications for a reduction in cost of care for NAS management could be substantial.