Randomized clinical trial of the optimization of procedural pain control in ICU patients

In 2006, in the Intensive Care Unit (ICU) of the St. Antonius Hospital an
analgesia improvement program has been implemented. This program consisted of
training of ICU nurses and intensivists using a hospital based standardized
pain protocol, and three times daily mandatory measurements of pain levels in
rest, rated by the patient himself whenever possible or otherwise by the
attending nurse. This program has resulted in a reduction of severe pain levels
(NRS>=4) in ICU patients in rest from 41% to 22%. In order to further reduce
this percentage, a pain titration protocol is introduced in 2007. As no
attention has yet been paid to intervention-related pain levels in these
patients, in this prospective study pain control will be studied using
different analgesic dosages of morphine around unavoidable painful
interventions within a pain titration protocol for pain control in rest.

The primary objective of this study is to determine the influence of morphine
dosage (2.5 mg vs 7.5 mg) on the percentage of patients with a rated NRS of >= 4
during an painful and unavoidable intervention.
The secondary objectives are to evaluate NRS scores, safety and other aspects
of both the intervention related pain protocol (morphine 2.5 mg vs 7.5 mg) as
well as the standard pain titration protocol aiming at pain control in rest
(paracetamol and morphine), such as nausea, constipation, respiratory
depression, length of ICU and hospital stay, duration of ventilation,
hallucinations, delirium, Glascow Coma Scale, endorphins, stress hormones
(epinephrine, norepinephrine and/or cortisol), liver function tests and renal
function. Additionally, a population pharmacokinetic and pharmacodynamic model
of morphine and its metabolites will be developed using population
pharmacokinetics and/or pharmacodynamics (PK/PD) modelling and covariate
analysis in order to develop rational individualized dosing schemes for
morphine in ICU patients. Whenever possible the level of sedation or
concentration of sedative will be incorporated in the model leading to an
analgo-sedative model. Studied covariates will include body weight, age, renal
function (ureum, creatinin concentrations and creatinin clearance), liver
function, diagnose, Sequential Organ Failure Assessment (SOFA) scores, DNA
polymorphisms (µ-opioid receptor, COMT etc) and (perioperative) endorphins and
stress hormones (epinephrine, norepinephrine and/or cortisol).

Prospective, randomized, double blind, clinical trial

150 patients will be randomized into two groups, one group will be given 2.5 mg
morphine and the other group will be given 7.5 mg morphine, half an hour before
the intervention (turning of the patient) Before, during and after the
intervention, the patients will be asked to rate the pain using NRS. When the
patient is not capable to communicate verbally, the pain ratings are scored by
the attending nurse using NRS. For basic pain relief, a standard pain titration
protocol is used in all patients, which is current practice in the ICU since
2007.

Participation in this study has minimal burden and risks for the patient, as
the two different doses of morphine (2.5 and 7.5 mg) administrated before the
unavoidable and painful intervention, both are within the therapeutic range.
In daily practice doses between 0 to 10 mg morphine are considered to be
standard, depending on the attending nurse and physician. Scoring NRS after
intervention may be a burden to the patient, because this may lead to a focus
of the patient to his pain.
The total amount of blood taken from the patient for this study is 28 ml per
day, with an additional 23 ml on the second day of admission to the ICU, and an
additional 19.5 ml for patients undergoing cardio- thoracic surgery before
admission to the ICU. These amounts are not expected to influence the recovery
of the patient. Moreover, all of the blood samples are taken from an existing
arterial line, so no invasive interventions are therefore needed. All the other
procedures (NRS scores, Pain titration protocol) are part of the standard care.