A randomised clinical trial evaluating the effect of remifentanil vs fentanyl
during cardiac surgery on the incidence of chronic thoracic pain.

Chronic thoracic pain after cardiac surgery via sternotomy is a serious
condition affecting many patients. Recent studies report incidences one year
after surgery varying from 11% to 56%(1-6), depending on the definition and the
study population. Patients suffering from chronic thoracic pain experience a
significantly lower physical and mental health status compared with patients
without chronic thoracic pain.(1,5,7,8) Since 2006, in the Intensive Care Unit
(ICU) of the St. Antonius Hospital, efforts were made to improve postoperative
pain management in patients after cardiac surgery (9,10). As part of this
research, a follow-up study (11) was performed including cardiac ICU patients,
in order to identify predictors for the development of chronic thoracic pain
one year after cardiac surgery. In this study, intraoperative use of
remifentanil appeared to be a major predictor for chronic thoracic pain.(11)
This association appeared to be dose dependent.
The association between the use of remifentanil and the development of chronic
pain was also suggested in a prospective, non-randomised study (12) designed to
evaluate allodynie after thoracotomy. Furthermore, it is suggested that higher
intraoperative remifentanil consumption correlates with an increase in early
postoperative hyperalgesia(13-15), which may eventually lead to the development
of chronic thoracic pain. It is unknown whether this development of
postoperative hyperalgesia is related to changes in pain thresholds.
Nowadays, in the St. Antonius Hospital the use of remifentanil or fentanyl
depends on the attending anaesthetist. No randomised controlled trials are yet
available evaluating the influence of intraoperative remifentanil during
cardiac surgery on the incidence of chronic thoracic pain. In this clinical
trial, the effect of the intra-operative use of remifentanil versus fentanyl
during cardiac surgery on the development of chronic thoracic pain will be
investigated. Within this context, it is of interest to investigate pain
thresholds pre- and postoperatively using quantitative sensory testing, in
order to evaluate changes in pain sensitivity of the patient due to cardiac
surgery or intraoperative use of remifentanil. Also, the role of pain
biomarkers measured with metabolomics will be investiged as well as the
influence of genetic variances involved in pain sensitivity and in
pharmacokinetics and pharmacodynamics of opiates. The results of this
randomised trial may be used to optimise perioperative options and thereby
improve the quality of life of patients after cardiac surgery.
Bearing in mind the increasing pressure on health care budgets and the growing
interest in cost-effective and evidence-based health care, this study will
analyze the cost-effectiveness of remifentanil versus fentanyl. The
cost-effectiveness of remifentanil in cardiac surgery patients has hardly been
studied before, so it can only be speculated upon whether it provides good
value for money.

The primary objective of this study is to determine the influence of
intra-operative use of remifentanil versus fentanyl on the percentage of
patients with chronic thoracic pain one year after cardiac surgery.

The secondary objectives are to evaluate the influence of intra-operative use
of remifentanil versus fentanyl on the percentage of patients with chronic
thoracic pain and their mean NRS scores (pain score 0-10 using the Numeric
Rating Scale) three months and six months after cardiac surgery. Also, the
effect on the quality of life (QoL) and the use of analgesics three months, six
months and one year after surgery will be evaluated. Moreover, total
administered amount of remifentanil and fentanyl will be taken into account.
Furthermore, pain thresholds and variability in pain scoring will be measured,
evaluating the difference in postoperative pain threshold (three days and one
year after surgery) compared to preoperative pain threshold (baseline), using
quantitative sensory testing.
Also other aspects in the postoperative period will be investigated, such as
postoperative NRS scores, postoperative analgesics consumption (e.g.
paracetamol, morphine), length of ICU- and hospital stay, and safety parameters
of remifentanil, such as nausea, rigidity of skeletal muscles, hypotension,
constipation, respiratory depression, duration of ventilation, hallucinations,
delirium and Glascow Coma Scale. In addition, the influence of different
genetic variances (e.g. COMT, UGT, GCH-1, MC1R) involved in pain sensitivity
and involved in pharmacokinetics and pharmacodynamics of remifentanil, fentanyl
and morphine are evaluated. In addition to genetic research, biomarkers for
chronic pain are also investigated with the help of metabolomics. Metabolomics
is an emerging approach and used as a novel approach do research in the field
of biomarkers. Finally, with the aim of demonstrating whether the effects of
remifentanil are worth the costs, a cost-effectiveness analysis alongside the
randomised controlled trial (RCT) with a 12 month follow-up will be performed.

Prospective, randomised, single-blind clinical trial

126 patients will be randomised into two groups before cardiac surgery.
During cardiac surgery, group A will be given remifentanil, starting with 0.15
ug/IBW(kg)/min, next to fentanyl bolus (200 - 500 ug) injections on
predetermined times; before incision, at sternotomy, at aorta canulation and at
opening of the pericard.
Group B will be given fentanyl bolus injections on an *as needed* base, next to
the fentanyl bolus injections on predetermined times. Both interventions are
daily practice in the St. Antonius Hospital.

Participation in this study has minimal burden and risks for the patient as
both treatment options (remifentanil or fentanyl) are considered daily practice
in our hospital. Nowadays the choice between these two treatment options
depends on the attending anaesthetist.
The questionnaire considering chronic pain and quality of life (appendices I
and J) may be a burden to the patient, because they are time-consuming.
The amount of blood taken from the patient during hospitalization for this
study is eight millilitres once after induction of the cardiac surgery. These
amounts are not expected to influence the recovery of the patient. This blood
sample is taken from an existing arterial line, so no invasive interventions
are therefore needed. The second blood sample, also eight millilitres is taken
one year after surgery when patients are fully recovered. All the other
procedures are part of the standard care.

Pain thresholds will be measured one day before surgery, three days and one
year after the surgery. This may be a burden to these patients. Although the
measurements are non-invasive and are also successfully used in children(16),
they are time-consuming.(17,18) Analyzing pain thresholds (cold detection
limit, warm detection limit, cold pain threshold, hot pain threshold) and
measuring pain variability using quantitative sensory testing takes about 40
minutes per patient.(19)The third pain threshold measurement will be done one
year after surgery. Most patients will be visiting the St. Antonius Hospital
one year after surgery for routine check. So only for few patients an extra
hospital visit one year after surgery is required for measuring pain
thresholds. Therefore, only patients from region Utrecht and surroundings will
be asked to participate the REFLECT-trial; in case an extra hospital visit is
required for measuring pain thresholds one year after surgery, the time needed
to travel to the hospital will be acceptable.