Principles of dosing intervals
In order to prescribe opioids safely and effectively it is important to understand the principles of prescribing intervals.
The duration of a drug’s effect on the body depends on its half life. This is the time it takes for the drug’s plasma concentration to decrease to half its value when it entered the bloodstream. It is determined by how quickly the drug is eliminated from the plasma through the processes of metabolism, distribution and excretion.
Clearance describes the removal of a drug from the plasma. It is the volume of plasma from which the drug is completely removed per unit of time. Morphine, like most opioids, has a high clearance and as a result the half life is short (2-4 hours in most individuals). These drugs must therefore be given at regular intervals for therapeutic effect.
Volume of distribution
This is the volume of fluid that would be required to contain the same amount of drug present in the body at the same concentration as in the plasma. Morphine rapidly distributes to the body tissues, including the brain, and therefore has a large volume of distribution. The volume of distribution of fentanyl is larger still.
Also known as the therapeutic index, this is the range of plasma concentrations of a drug between efficacy (below which no effect is seen) and toxicity (above which adverse effects outweigh benefit). Opioids characteristically have a narrow therapeutic index.
This is when the amount of a drug entering the plasma is in balance with the amount that is being cleared. It takes 4 to 5 half lives for a drug to reach steady state. For a drug to be efficacious, the steady state must sit within the therapeutic window and is influenced by factors which affect its absorption or delivery into the plasma. This includes modified-release oral preparations and first pass metabolism.
For immediate-release morphine (and most commonly-prescribed IR oral opioids) it takes between 10 - 20 hours to achieve steady state. Time to steady state is increased for modified-release (MR) preparations, up to approximately 48 to 72 hours. There should be 2 to 3 days between dose titrations using MR formulations. Patients should still be reviewed after 24 hours to monitor analgesic and adverse effects.
Due to the short half life of most opioids, loading doses are not recommended outside of specialist acute pain management.
In order to maintain a drug in steady state within its therapeutic window, dosing intervals must be considered.
When an opioid is administered continuously, plasma levels rise smoothly over time to reach steady state. This is the case for continuous subcutaneous infusions (CSCI) and transdermal patches. Fentanyl patches take 72 hours to reach steady state due to the transdermal route. This must be taken into consideration when switching a patient from an oral or subcutaneously infused opioid. It also explains why fentanyl patches are not suitable for unstable pain.
When an opioid is administered intermittently, plasma levels rise sharply. Opioids have a narrow therapeutic index, meaning peak plasma concentrations can easily rise above the toxic threshold, particularly if given intravenously. Plasma concentrations then decline more gradually and if they fall below the efficacy threshold the therapeutic effect is lost. At steady state, these peaks and troughs oscillate around the continuous infusion curve.
It is not ideal for patients to be at risk of toxicity or loss of analgesic effect (or both) with each dose of opioid. Peaks and troughs can be smoothed by lower doses administered more frequently. The opioid is given when the plasma concentration is declining but before it falls below the efficacy threshold. Sufficient drug is given to maintain plasma concentrations within the therapeutic window without exceeding the toxicity threshold.
Oral administration avoids steep rises in plasma levels because of the time taken to absorb the drug is longer than for injections. Modified release preparations increase this time further, whilst also offering convenience acceptable to most patients. This is why opioids should be given orally wherever possible.
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