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... Show moreThe 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. Show less
Hoogd, S. de; Goulooze, S.C.; Valkenburg, A.J.; Krekels, E.H.J.; Dijk M. van; Tibboel, D.; Knibbe, C.A.J. 2021
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.... Show moreBackground 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. Show less
Matic, M.; Hoogd, S. de; Wildt, S.N. de; Tibboel, D.; Knibbe, C.A.J.; Schaik, R.H. 2020
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... Show moreAim: 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. Show less
Hoogd, S. de; Valkenburg, A.J.; Dongen, E.P.A. van; Daeter, E.J.; Rosmalen, J. van; Dahan, A.; ... ; Knibbe, C.A.J. 2019
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... Show moreEarlier 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.\nBoth 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.\nThe study was registered at EudraCT (ref: 2013-000201-23) and ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT02031016).\nThe clinical relevance of the suggested hyperalgesic effects of remifentanil is still unclear, especially in the long term.\nThe current study evaluated the impact of remifentanil on thermal thresholds 3 days and 12 months after surgery, measured with Quantitative Sensory Testing.\nA single-blind, randomised controlled trial.\nA tertiary care teaching hospital in The Netherlands, from 2014 to 2016.\nA 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.\nPatients 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.\nWarm 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.\nCONCLUSION\nRESULTS\nTRIAL REGISTRATION\nBACKGROUND\nOBJECTIVE\nDESIGN\nSETTING\nPATIENTS\nINTERVENTIONS\nMAIN OUTCOME MEASURES Show less
Smit, C.; Hoogd, S. de; Bruggemann, R.J.M.; Knibbe, C.A.J. 2018
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... Show moreRemifentanil 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\nCONCLUSIONS Show less
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... Show moreObesity 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.\n for 1 h. Population pharmacokinetic modeling was performed using NONMEM 7.2.\nIn 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).\nMetabolism 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.\nINTRODUCTION\nMETHODS\nRESULTS\nCONCLUSION Show less
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... Show moreBACKGROUND: 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. Show less
