Pharmacokinetic Optimisation of Opioid Treatment in Acute Pain Therapy

Abstract

Traditionally, opioids have been administered as fixed doses at fixed dose intervals. This approach has been largely ineffective. Patient-controlled analgesia (PCA) and upgraded traditional approaches incorporating flexibility in dose size and dose interval, and titration for an effect in individual patients with the monitoring of pain and sedation scores, can greatly improve the efficacy of opioid administration. Optimising opioid use, therefore, entails optimising the titration process. Opioids have similar pharmacodynamic properties but have widely different kinetic properties. The most important of these is the delay between the blood concentrations of an opioid and its analgesic or other effects, which probably relate to the delay required for blood and brain and spinal cord (CNS) equilibrium. The half-lives of these delays range from approximately 34 minutes for morphine to 1 minute for alfentanil. The titration is influenced by the time needed after an initial dose before it is safe to administer a second dose and the duration of the effects of a single dose, which varies widely between opioids, doses and routes of administration. To compare opioids and routes of administration, we examined the relative CNS concentration profiles of opioids - the CNS concentration expressed as a percentage of its maximum value. The relative onset was the defined as the time the relative CNS concentration first rose to 80% of maximum, while the relative duration was defined as the length of time the concentration was above 80%. For an intravenous bolus dose, the relative onset varies from approximately 1 for alfentanil to 6 minutes for morphine, while their relative durations are approximately 2 and 96 minutes, respectively. Although all of the common opioids, perhaps with the exception of alfentanil, have kinetic and dynamic properties suitable for use in PCA with intravenous bolus doses, the long relative duration of morphine makes it particularly suited to an upgraded traditional approach using staff administered intramuscular or subcutaneous doses. There is a clear kinetic preference for regimens with a rapid onset and short duration (e.g. intravenous PCA) for coping with incident pain. It is shown that, in general, titration is improved by the more frequent administration of smaller doses, but it is important to use additional doses to initially 'load' a patient. The titration of opioids should always be accompanied by the monitoring of pain and sedation scores and ventilation.

Cerebral kinetics of oxycodone in conscious sheep

“…Simultaneous blood samples of 2 mL volume were collected from the arterial and sagittal sinus catheters at 0.5, 1, 1.5, 2, 3, 4, 4.5, 5, 5. 5,6,8,10,15,20,30,45, 60 and 75 min after start of drug infusion. The blood samples were collected in 10 mL tubes with heparin as an anticoagulant.…”

“…2-5 As reported for other opioids and anaesthetics, this delay in effect has been proposed to be similar in magnitude to the time required for equilibration of blood and central nervous system (CNS) concentrations. 6 For some opioids, particularly when used parenterally, the delay in cerebral equilibration means that the cerebral kinetics of the opioid become an important factor in dictating their optimal clinical use.…”

Translational pain research: Evaluating analgesic effect in experimental visceral pain models

“…A pronounced delay between the plasma concentrations and analgesia will produce hysteresis when the analgesic effect is plotted against plasma concentration. This is characteristic for opioids and has been shown previously to be caused partially by the rate of transport of the opioid into the CNS (across the blood-brain barrier) [26] , but also by receptor-mediated cascades [13,27] . Traditionally, hysteresis is collapsed by the implementation of a theoretical effect compartment between the plasma compartment and effect (i.e.…”

Randomized Clinical Trial of Efficacy and Safety of a Single 2‐mg Intravenous Dose of Hydromorphone Versus Usual Care in the Management of Acute Pain

“…physiologic variation in opioid receptor sites, their type, regulation, saturation kinetics, and relationship to analgesia, in addition to broad variation in other aspects of opioid pharmacokinetics, including rate of drug metabolism. [30][31][32][33] The marked natural variation in opioid requirement is well illustrated by a study of morphine titration in 621 ED patients by Lvovschi et al 3 Patients received 2-to 3-mg boluses of morphine every 5 minutes administered by nurses until patients reported a visual analog scale (VAS) score of 30 or less, the study's prespecified definition of adequate analgesia. The mean (AESD) dose needed to achieve this level of analgesia was 11 (AE6) mg morphine.…”