Postoperative breakthrough pain in paediatric cardiac surgery not reduced by increased morphine concentrations.

BACKGROUND: Morphine is commonly used for postoperative analgesia in children. Here we studied the pharmacodynamics of morphine in children after cardiac surgery receiving protocolized morphine. METHODS: Data on morphine rescue requirements guided by validated pain scores in children (n = 35, 3-36 months) after cardiac surgery receiving morphine as loading dose (100 µg kg-1) with continuous infusion (40 µg kg-1 h-1) from a previous study on morphine pharmacokinetics were analysed using repeated time-to-event (RTTE) modelling. RESULTS: During the postoperative period (38 h (IQR 23-46)), 130 morphine rescue events (4 (IQR 1-5) per patient) mainly occurred in the first 24 h (107/130) at a median morphine concentration of 29.5 ng ml-1 (range 7-180 ng ml-1). In the RTTE model, the hazard of rescue morphine decreased over time (half-life 18 h; P < 0.001), while the hazard for rescue morphine (21.9% at 29.5 ng ml-1) increased at higher morphine concentrations (P < 0.001). CONCLUSIONS: In this study on protocolized morphine analgesia in children, rescue morphine was required at a wide range of morphine concentrations and further increase of the morphine concentration did not lead to a decrease in hazard. Future studies should focus on a multimodal approach using other opioids or other analgesics to treat breakthrough pain in children. IMPACT: In children receiving continuous morphine infusion, administration of rescue morphine is an indicator for insufficient effect or an event. Morphine rescue events were identified at a wide range of morphine concentrations upon a standardized pain protocol consisting of continuous morphine infusion and morphine as rescue boluses. The expected number of rescue morphine events was found to increase at higher morphine concentrations. Instead of exploring more aggressive morphine dosing, future research should focus on a multimodal approach to treat breakthrough pain in children.

OPRM1 and COMT polymorphisms: implications on postoperative acute, chronic and experimental pain after cardiac surgery.

Aim: Investigate the potential role of OPRM1 (mu-opioid receptor) and COMT (catechol-O-methyltransferase enzyme) polymorphisms in postoperative acute, chronic and experimental thermal pain. Methods: A secondary analysis of 125 adult cardiac surgery patients that were randomized between fentanyl and remifentanil during surgery and genotyped. Results: Patients in the fentanyl group with the COMT high-pain sensitivity haplotype required less postoperative morphine compared with the average-pain sensitivity haplotype (19.4 [16.5; 23.0] vs 34.6 [26.2; 41.4]; p = 0.00768), but not to the low-pain sensitivity group (30.1 [19.1; 37.7]; p = 0.13). No association was found between COMT haplotype and other pain outcomes or OPRM1 polymorphisms and the different pain modalities. Conclusion:COMT haplotype appears to explain part of the variability in acute postoperative pain in adult cardiac surgery patients.

Severe pancytopenia and aspergillosis caused by thioguanine in a thiopurine S-methyltransferase deficient patient: a case report.

Azathioprine and mercaptopurine are widely used in the treatment of inflammatory bowel disease. However, its use is limited by adverse drug event related to the relatively narrow therapeutic index of the active metabolites. Several patients discontinue treatment because of intolerable adverse events or toxicity such as leucopenia and hepatotoxicity. High 6-thioguanine nucleotides and 6-methylmercaptopurine ribonucleotides levels are associated with toxicity. Variations in the thiopurine S-methyltransferase (TPMT) gene can lead to diminished TPMT enzyme activity and to an increased incidence of myelotoxicity due to high 6-methylmercaptopurine ribonucleotides levels after treatment with azathioprine and mercaptopurine. Unlike azathioprine and mercaptopurine, thioguanine is more directly metabolized to the active metabolites without formation of the toxic 6-methylmercaptopurine ribonucleotides. Taking this into account, it seems likely that thioguanine is less associated with myelotoxicity due to TPMT deficiency. However, we report the case of a Crohn's disease patient with life-threatening complications on 6TG treatment due to TPMT deficiency. Our patient developed a severe pancytopenia on thioguanine therapy, with 6-thioguanine nucleotides levels more than 10 times higher than the upper limit of the therapeutic window and was found to be a TPMT poor metabolizer (TPMT *3A/*3A). This case strongly illustrates that knowledge of TPMT enzyme activity is very important in the use of all thiopurines, including thioguanine. In conclusion, clinicians should be aware of the impact of TPMT deficiency on the metabolism of thioguanine and should consider performing preemptive TPMT genotyping in combination with frequent blood test monitoring when using thiopurines in general.

Short- and long-term impact of remifentanil on thermal detection and pain thresholds after cardiac surgery: A randomised controlled trial.

BACKGROUND: The clinical relevance of the suggested hyperalgesic effects of remifentanil is still unclear, especially in the long term. OBJECTIVE: The current study evaluated the impact of remifentanil on thermal thresholds 3 days and 12 months after surgery, measured with Quantitative Sensory Testing. DESIGN: A single-blind, randomised controlled trial. SETTING: A tertiary care teaching hospital in The Netherlands, from 2014 to 2016. PATIENTS: A total of 126 patients aged between 18 and 85 years, undergoing cardiothoracic surgery via sternotomy (coronary artery bypass grafts and/or valve replacement) were included. Exclusion criteria were BMI above 35 kg m, history of cardiac surgery, chronic pain conditions, neurological conditions, allergy to opioids or paracetamol, language barrier and pregnancy. INTERVENTIONS: Patients were allocated randomly to receive intra-operatively either a continuous remifentanil infusion or intermittent intra-operative fentanyl as needed in addition to standardised anaesthesia with propofol and intermittent intravenous fentanyl at predetermined time points. MAIN OUTCOME MEASURES: Warm and cold detection and pain thresholds 3 days and 12 months after surgery. In addition the use of remifentanil, presence of postoperative chronic pain, age, opioid consumption and pre-operative quality of life were tested as a predictor for altered pain sensitivity 12 months after surgery. RESULTS: Both warm and cold detection, and pain thresholds, were not significantly different between the remifentanil and fentanyl groups 3 days and 12 months after surgery (P > 0.05). No significant predictors for altered pain sensitivity were identified. CONCLUSION: Earlier reports of increased pain sensitivity 1 year after the use of remifentanil could not be confirmed in this randomised study using Quantitative Sensory Testing. This indicates that remifentanil plays a minor role in the development of chronic thoracic pain. Still, the relatively high incidence of chronic thoracic pain and its accompanying impact on quality of life remain challenging problems. TRIAL REGISTRATION: The study was registered at EudraCT (ref: 2013-000201-23) and ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT02031016).

Obesity and drug pharmacology: a review of the influence of obesity on pharmacokinetic and pharmacodynamic parameters.

INTRODUCTION: The rising prevalence of obesity confronts clinicians with dosing problems in the (extreme) overweight population. Obesity has a great impact on key organs that play a role in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs, however the ultimate impact of these changes on how to adapt the dose may not always be known. Areas covered: In this review, physiological changes associated with obesity are discussed. An overview is provided on the alterations in absorption, distribution, drug metabolism and clearance in (morbid) obesity focusing on general principles that can be extracted from pharmacokinetic studies. Also, relevant pharmacodynamic considerations in obesity are discussed. Expert opinion: Over the last two decades, increased knowledge is generated on PK and PD in obesity. Future research should focus on filling in the knowledge gaps that remain, especially in connecting obesity-related physiological changes with changes in PK and/or PD and vice versa. Ultimately, this knowledge can be used to develop physiologically based PK and PD models on the basis of quantitative systems pharmacology principles. Moreover, efforts should focus on thorough prospective evaluation of developed model-based doses with subsequent implementation of these dosing recommendations in clinical practice.

Randomized Controlled Trial on the Influence of Intraoperative Remifentanil versus Fentanyl on Acute and Chronic Pain after Cardiac Surgery.

BACKGROUND: Remifentanil has been associated with increased acute and potentially chronic postoperative pain. The objective of this prospective randomized controlled trial was to investigate the influence of intraoperative remifentanil on acute and chronic postoperative pain after cardiac surgery. METHODS: Patients (N = 126) receiving standardized anesthesia with propofol and intermittent intravenous fentanyl at predetermined times for cardiac surgery were randomized to intraoperatively receive either a continuous remifentanil infusion or additional intermittent intraoperative fentanyl as needed. The primary endpoint was chronic thoracic pain at 12 months after surgery. Secondary endpoints were pain at 3 and 6 months after surgery and analgesic requirements and pain levels in the first 72 hours. RESULTS: There was no significant difference in incidence of chronic thoracic pain between the remifentanil and fentanyl groups, respectively (20% vs. 18%; P = 0.817). At 3 months, however, significantly more patients in the remifentanil group reported chronic thoracic pain (51% vs. 33%; P = 0.047). This effect was more pronounced in younger patients and in patients receiving a higher dose of remifentanil (both P < 0.05). The first 24 and 48 hours postoperatively, morphine consumption in the remifentanil group was significantly higher than in the fentanyl group (34.3 mg [interquartile range (IQR) 25.3 to 48.2] vs. 30.2 mg [IQR 19.2 to 38.1], P = 0.028; and 46.8 mg [IQR 33.8 to 59.2] vs. 39.0 mg [IQR 6.2 to 51.4], P = 0.047, respectively). CONCLUSIONS: Intraoperative use of remifentanil during cardiac surgery does not impact chronic postoperative pain 1 year after surgery. Nevertheless, remifentanil increases analgesic requirements and thoracic pain until 3 months after surgery, and its use is therefore less favorable during cardiac surgery.

Influence of Morbid Obesity on the Pharmacokinetics of Morphine, Morphine-3-Glucuronide, and Morphine-6-Glucuronide.

INTRODUCTION: Obesity is associated with many pathophysiological changes that may result in altered drug metabolism. The aim of this study is to investigate the influence of obesity on the pharmacokinetics of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) through a combined analysis in morbidly obese patients and non-obese healthy volunteers. METHODS: In this analysis, data from 20 morbidly obese patients [mean body mass index 49.9 kg/m2 (range 37.6-78.6 kg/m2) and weight 151.3 kg (range 112-251.9 kg)] and 20 healthy volunteers [mean weight 70.6 kg (range 58-85 kg)] were included. Morbidly obese patients received 10 mg of intravenous (I.V.) morphine after gastric bypass surgery, with additional morphine I.V. doses as needed. Healthy volunteers received an I.V. bolus of morphine of 0.1 mg/kg followed by an infusion of 0.030 mg kg-1 h-1 for 1 h. Population pharmacokinetic modeling was performed using NONMEM 7.2. RESULTS: In morbidly obese patients, elimination clearance of M3G and M6G was decreased substantially compared with healthy volunteers (p < 0.001). Regarding glucuronidation, only a slight decrease in the formation of M6G and a delay in the formation of M3G was found (both p < 0.001). Obesity was also identified as a covariate for the peripheral volume of distribution of morphine (p < 0.001). CONCLUSION: Metabolism of morphine is not altered in morbidly obese patients. However, decreased elimination of both M3G and M6G is evident, resulting in a substantial increase in exposure to these two metabolites. A rational explanation of this finding is that it results from alterations in membrane transporter function and/or expression in the liver. ClinicalTrials.gov identifier: NCT01097148.

Is Intraoperative Remifentanil Associated With Acute or Chronic Postoperative Pain After Prolonged Surgery? An Update of the Literature.

OBJECTIVE: Remifentanil is an ultra-short-acting opioid that is used commonly during both short-term and prolonged surgery. This review investigated associations of intraoperative remifentanil administration with acute postoperative pain, hyperalgesia, and chronic postoperative pain, with emphasis on the perioperative coanesthetic drug regimen used. METHODS: Medline and Embase databases were searched for randomized studies, evaluating the intraoperative use of remifentanil (>2 h) versus another analgesic or a different dosage of remifentanil, and reporting acute postoperative pain parameters such as postoperative pain scores, hyperalgesia, acute opioid tolerance, or analgesics requirements. Furthermore, all studies in which remifentanil was used intraoperatively and parameters for chronic postoperative pain were measured were included (pain levels after a prolonged period of time after surgery). RESULTS: From the 21 studies that were identified, less than half of the studies found higher acute postoperative pain, higher postoperative analgesic requirements after intraoperative remifentanil use, or both. Coanesthetics to some extent determined this incidence, with mainly studies using volatile agents reporting increased pain levels. There was less evidence when remifentanil was combined with total intravenous anesthesia or a combination of anesthetics. The limited number of studies (n=4) evaluating chronic pain suggested a potential association with the intraoperative use of remifentanil. DISCUSSION: Although studies are diverse and sample sizes small, coanesthetics used in combination with remifentanil may influence the occurrence of postoperative hyperalgesia. No firm conclusions could be made regarding acute and chronic pain, indicating that further research with the goal to investigate the effect of volatile or intravenous anesthetics along with simultaneous remifentanil infusion on acute and chronic postoperative pain is needed.

Remifentanil versus fentanyl during cardiac surgery on the incidence of chronic thoracic pain (REFLECT): study protocol for a randomized controlled trial.

BACKGROUND: Chronic thoracic pain after cardiac surgery is prevalent (11 to 56%) and may affect patients' physical and mental health status. Despite its favorable pharmacokinetic and pharmacodynamic properties, high doses of remifentanil administered during surgery are reported to cause acute postoperative pain and increased requirements for analgesics. Recently, an association between remifentanil use and the incidence of chronic thoracic pain in the long term was also reported. Our objective is to investigate the influence of the intraoperative remifentanil on chronic postoperative pain in a prospective randomized controlled trial. METHODS/DESIGN: In this prospective, randomized, single-blind clinical trial, all patients (N = 126) between 18 and 85 years undergoing cardiac surgery via sternotomy receive a continuous infusion of propofol together with intermittent intravenous fentanyl at predetermined times perioperatively. Patients are randomized to receive either an additional continuous infusion of remifentanil (0.15 µg(-1)kgIBW(-1) min(-1)) or additional fentanyl (200 to 500 µg) as needed during surgery.The primary end point is the prevalence of chronic thoracic pain 12 months after surgery. Secondary end points include acute postoperative pain; postoperative analgesic use; chronic thoracic pain 3 and 6 months after surgery; quality of life (SF-12) at 3, 6 and 12 months after surgery; work productivity; and use of health care. In addition, thermal detection and pain thresholds are measured preoperatively, 3 days after surgery and 12 months after surgery using quantitative sensory testing (QST). Finally, the influence of several genetic variances on the different outcomes will be measured. DISCUSSION: Chronic thoracic pain is prevalent after cardiac surgery, and research is needed to minimize the risk of chronic persistent postoperative pain, which is an invalidating, long-term complication of surgery. The objective of this trial is to determine the influence of perioperative remifentanil on long-term pain outcomes for cardiac patients in a prospective randomized trial. The results may be used to optimize perioperative analgesia techniques and, thereby, improve quality of life after cardiac surgery. TRIAL REGISTRATION: Clinicaltrials.gov NCT02031016 on 13 December 2013.

Differences in body mass index z-scores and weight status in a Dutch pediatric psychiatric population with and without use of second-generation antipsychotics.

OBJECTIVE: Weight gain and metabolic adverse effects of second-generation antipsychotics (SGAs) have become a major concern, particularly in youth. However, the specific contribution of SGAs versus other medications or the underlying illness is unclear. METHODS: In a chart review study of psychiatric outpatients aged ≤ 18 years treated with SGAs and psychiatric controls without lifetime SGA, use body mass index (BMI) z-scores between patients and controls were compared in the entire sample, patients without co-medications, diagnostic subgroups, and age subgroups. In patients with follow-up data, weight z-score change was calculated. RESULTS: Altogether, 592 Caucasian patients aged 4-18 (mean: 10.0) years with a psychiatric diagnosis were included. BMI z-scores in 96 youth treated with SGAs for 9.0 ± 6.1 months were significantly higher than in 496 patients without lifetime SGA use (0.81 ± 1.1 vs. 0.05 ± 1.2; p<0.0001). BMI z-score differences remained significant in all age groups <16 years old. In sub-analyses, results remained the same after eliminating patients on any co-medication (0.82 ± 1.2 vs. 0.23 ± 1.2; p<0.0001) and in patients with (0.75 ± 1.2 vs. 0.17 ± 1.1, p<0.0001) or without autism spectrum disorders (1.1 ± 1.0 vs. -0.02 ± 1.2, p<0.0001). Significantly more SGA-treated youth were obese (27.1% vs. 9.5%, odds ratio [OR]: 3.55, 95% confidence interval [CI]:2.07-6.08) or overweight (21.9% vs. 8.3%, OR: 3.11, 95%CI: 1.75-5.52). In 24 patients (92.3% antipsychotic-naïve) with 6.6 months follow-up, weight z-score increased significantly from -0.17 ± 1.5 to 0.25 ± 1.4 (p<0.0001) with 12.5% transitioning to overweight or obese status. CONCLUSION: These data show robust and significant differences in sex- and age-adjusted body weight and weight status in young pediatric Caucasian samples with and without use of SGAs independent of Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR) (American Psychiatric Association 2000 ) diagnosis and nonantipsychotic medications. Weight status and metabolic effects of SGAs require careful attention, especially in youth.