Pharmacokinetics of morphine and oxycodone in frail elderly undergoing cardiac surgery

Opioid analgesics such as morphine and oxycodone are routinely used in the
treatment of moderate to severe pain after cardiac surgery. However, the
treatment of postoperative pain in elderly patients may be complicated by a
number of factors, such as an increased risk of age and disease related changes
in physiology, interactions between disease and medication, and polypharmacy,
resulting in variability in analgesic response. Age is a significant predictor
of opioid-related side effects, with patients older than 60 years having a two-
to eight-fold increased risk of respiratory de-pression and falls and
fractures. Frailty further increases this heterogeneity but its effects on
pha-macokinetics and pharmacodynamics of drugs and metabolites are relatively
poorly studied. Current treatment guidelines advocate a *start low and go slow*
approach to analgesic dosing in older patients, particularly in the treatment
of frail older patients, because of fear of sedation and respir-atory
depression. In practice, however, this dosing strategy is often interpreted as
"start low, stay low", giving the impression that this population is at risk
for inadequate analgesia, delirium and chronic pain. Despite increasing studies
examining the implications and consequences of frailty for a range of medical
outcomes, frail older people have been significantly underrepresented in
clinical trials, including those designed to investigate optimal pain
management strategies. Therefore, evidence-based management of postoperative
pain in the frail elderly patient is very limited.

Primary:
- To determine the pharmacokinetics and pharmacodynamics of morphine, oxycodone
and its metabolites in frail elderly undergoing cardiac surgery.
Secondary:
- To assess the influence of covariates such as frailty, serum creatinine,
Glomerular Filtration Rate (GFR) on the pharmacokinetics of morphine and
oxycodone.

Single center observational cohort study

Preoperative frailty screening is part of routine care for older cardiac
surgery patients at St. Antonius hospital and is no additional burden for study
patients. Patients will receive a standardized anesthetic regimen in which
routinely 10 mg intravenous morphine is administered at the end of surgery.
Blood samples will be taken from an intravenous catheter and an arterial line,
which are routinely inserted for drug/ fluid administration and invasive
continuous monitoring of arterial blood pressure during cardiac surgery. In
this study postoperative blood samples will be taken during postoperative stay
in the Intensive care Unit (phase 1) and thereafter in the general ward (phase
2) to determine the pharmacokinetics and pharmacodynamics of morphine,
oxycodone and its metabolites.
Phase 1: After cardiac surgery patients are admitted to the Intensive Care Unit
(ICU) where they routinely will receive continuous intravenous infusion of
morphine. During admission in the ICU blood samples will be taken from an
indwelling arterial line, which will be removed upon discharge to the general
ward. In total 10 samples with 5 ml extra blood will be taken to determine the
pharmacokinetics of morphine and metabolites.
Phase 2: After discharge from the ICU to the general ward patients will receive
2 times a day 5 mg oxycodone according to a standardized postoperative pain
protocol. Next, oxycodone blood samples will be taken up to 12 hours after the
last administration from an indwelling intravenous catheter. A total of 6
samples of 5 ml will be taken during admission to the ward. No extra punctures
are necessary to collect these blood samples. In total 80 ml extra blood will
be taken from patients, which leads to a minimal additional burden for
patients.
Furthermore, side effects of opioids such as nausea, vomiting, pruritus will be
noted. Vital signs (e.g. (SpO2, PR, RR) will continuously be monitored after
patients are discharged from the ICU to the general ward. Finally, a delirium
score will be done. This will lead to a minimal additional burden. There are no
further risks involved.