Stefan
Schraag, MD PhD
Department
of Perioperative Medicine
Golden
Jubilee National Hospital
Clydebank,
UK
New aspects in opioid pharmacology
Traditionally,
opioids are widely used in modern anaesthesia and recent pharmaceutical
developments have added a variety of suitable agents for different anaesthetic
indications. A fundamental achievement of pain research during the last decade
is the understanding that the molecular physiology of pain and analgesia is
rather complex than simple and involves a variety of anatomical and biochemical
pathways. Only recently, the clinical implication of opioid-induced tolerance
and the development of hyperalgesia and chronic pain in response to high doses
of opioids have been evaluated and understood. Contemporary infusion devices
incorporating drug-specific pharmacokinetic data can now be used to improve the
accuracy of intravenous opioid administration, based on previous experience
with target-controlled infusion (TCI) of propofol
This
lecture will give an overview of current aspects using TCI for opioids and its
impact on both research and clinical anaesthesia.
What is the rationale for opioid TCI?
Even
with short acting drugs like remifentanil, it remains difficult to titrate a
manual controlled infusion to the variable requirements of modern surgical
anaesthesia, and studies who were designed to administer opioids manually to
certain clinical endpoints, have struggled to achieve their goals and mostly
experienced quite a high degree of side effects. The principle of TCI takes the
pharmacokinetic variations away and allows a controlled and individualized
administration. Furthermore, the incorporation of population-related
co-variates reduces the apparent disparities among different patient groups
even more. The first studies on opioid TCI have been performed in the middle of
the 1980s. These have demonstrated the benefit of this administration mode to
ensure a better hemodynamic control during the perioperative period. The
conclusions of a review performed by en expert group of the Cochrane Library
included:
·
Faster therapeutic
control
·
Lower risk to reach
toxic levels
·
Fewer incidence of
adverse effects
·
Reduction in hospital
stay
Which clinical benefits are envisaged by TCI opioids?
Intraoperative
analgesia with opioids administered by TCI has been investigated in several
studies. They could demonstrate a well controlled titration
of the drugs to a stable blood concentration. Favourable clinical effects have
been reported with alfentanil TCI for major abdominal surgery, whereas
sufentanil TCI appeared to offer only a minor benefit compared with manual
controlled infusion as its effect site equilibration time (t ½ ke0
= 5.7 min) is considerably longer. However, remifentanil, the latest fentanyl congener,
is ideally suited to be used by infusion, although there are few published
studies of its use in TCI. Although a manual remifentanil infusion gives
acceptable stability once it became equilibrated to a steady-state, it remains
difficult to modify the blood concentration to different levels of analgesia in
a controlled fashion and infusion rates are likely to be chosen arbitrarily in
clinical practice. The advantages of TCI for analgesia include:
·
rapid achievement of analgesic
blood concentrations of drug;
·
ability to use drugs with short
blood-brain equilibration half-lives, ensuring rapid onset of analgesia;
·
ability to use drugs with a short
duration of action to prevent accumulation, while ensuring long-lasting
analgesia by maintaining the target concentration over time;
·
ability to alter the level of
analgesia rapidly.
The use
of the TCI technique in the postoperative phase for analgesia provides a
rational approach for the continuation of the analgesic used intra-operatively.
The first reported study of TCI for postoperative analgesia involved the
administration of alfentanil to 14 patients following major aortic surgery.
Postoperatively, an alfentanil concentration was chosen for each patient to
provide good analgesia with minimal respiratory depression. Nursing staff were
then allowed to increase or decrease the concentration by 5 ng ml-1
if required. The system was used for an average of 39 h and for 96% of the time
the patients experienced little or no pain. The median target blood
concentration was 71 ng ml-1 (range 34-150 ng ml-1).
Meanwhile, a couple of studies in patients undergoing different surgical
procedures have proven the safety and efficacy of a patient-controlled
administration of alfentanil using a demand button hand-set similar to that
known from standard PCA devices. All studies have been reported to be associated with
a high level of patient satisfaction. Recently, remifentanil has been studied
as a patient-maintained TCI system to overcome the problems in analgesia known
to be an issue in the immediate postoperative period after remifentanil based
anaesthesia. The authors report a smooth transition to early postoperative
analgesia in 30 patients after major orthopaedic surgery without respiratory
side effects.
Conclusion
Previously
used as a research tool to facilitate pharmacokinetic/pharmacodynamic
experiments in a more controlled fashion, TCI for opioids with alfentanil,
sufentanil and remifentanil has now become widely available commercially and
will undoubtedly influence the practice of anaesthetists in their ability to
administer these important drugs more precise and rational.
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