Does it still hurt?: Perioperative opioid analgesia in different patient populations

The last decades it is increasingly recognized that acute as well as chronic postoperative pain is an important problem. Treatment and prevention of postoperative pain is a challenge, especially in special patient populations where there is only limited guidance on how to optimally use opioids. In this thesis we focused on the perioperative use of opioids in three different populations. First, the influence of the opioids remifentanil versus fentanyl on acute and chronic postoperative pain was investigated in adult cardiac surgery patients. Second, pharmacodynamic modelling methods were applied to analyze the postoperative use of morphine in children after cardiac surgery. Finally, a pharmacokinetic model was developed to investigate the influence of obesity on the pharmacokinetics of morphine and its metabolites. Pain remains a complex puzzle among biological, psychological, behavioral and social-cultural factors. The high inter-individual variation in all of these factors results in postoperative pain still being a major issue while the ultimate goal is to stay without pain after a surgical procedure. Therefore, the answer to the question: “Does it still hurt?” is: YES unfortunately. This thesis adds pieces to this complex puzzle by focusing on the use of opioids in three different patient populations.</p

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

Perioperative Medicine: Efficacy, Safety and Outcom

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

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.\nPatients (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.\nThere 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).\nIntraoperative 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.\nBACKGROUND\nMETHODS\nRESULTS\nCONCLUSIONSPharmacolog

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

Contains fulltext : 190521.pdf (publisher's version ) (Closed access)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

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

Item does not contain fulltextOBJECTIVE: 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-naive) 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

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 mu g kg(-1)) with continuous infusion (40 mu g 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. ImpactIn 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.Pharmacolog

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

Pharmacolog