Background    Pharmacokinetics is the science of what the body does to a drug after administration, in contrast to pharmacodynamics — the effect of a drug on the body.  Knowledge of opioid pharmacokinetics parameters is critical for the safe and effective administration. 

Absorption    The proportion of active drug (whether given intravenously or absorbed from the gastrointestinal, respiratory, or cutaneous system) that enters the systemic circulation is defined as bioavailability.  The wide bioavailability range amongst different opioids is partially attributable to differences in first pass metabolism, when the drug is metabolized directly by the liver from the gastrointestinal tract before it reaches the systemic circulation.  Clinicians should be aware of the bioavailability for the opioid being prescribed because it indirectly affects PO: IV conversion ratios. 

Distribution    refers to the movement of drug between the blood and various tissues in the body. The parameter used to describe this movement is the volume of distribution (Vd). The targeted tissue for opioids is the central nervous system (CNS). To activate the targeted receptors, opioids must cross the blood-brain-barrier (1). Those opioids with a higher Vd are usually more lipophilic, and more likely to distribute faster and more strongly both into and out of the blood-brain-barrier.  In clinical practice these opioids also tend to have a quicker onset, and shorter duration of analgesic action.

Metabolism    The most important area of opioid pharmacokinetics is metabolism. The metabolism process may involve the Cytochrome (CYP) P-450 enzymes, particularly CYP 2D6 and 3A4, or other enzymes such as UDP-glucuronyltransferase (2).  The spectrum of interpatient analgesic variability and clinically significant drug interactions of opioids are mostly due to the CYP enzymes.

Interpatient Variability  CYP 2D6 influences the metabolism of codeine, hydrocodone, oxycodone, and tramadol, and has been found to have many genetic polymorphisms. Based on phenotypic profiles, patients can be poor, intermediate, or extensive metabolizers (3). This can potentially lead to inadequate analgesia or over-sedation. Fentanyl and methadone are primary metabolized by CYP 3A4. Although CYP 3A4 also has many genetic polymorphisms, none have be shown to be of major clinical relevance (4). UDP-glucuronyltransferase, the primary enzyme responsible for the metabolism of morphine, hydromorphone, oxymorphone, and tapentadol, does not possess significant interpatient variability.

Clinically Significant Drug Interactions  There are three types of CYP P-450 enzyme subcategories: substrates, inhibitors, and inducers. Substrates require P-450 enzymes for metabolism. When enzyme inhibitors or inducers are concomitantly administered with substrates, the serum levels of these substrates are altered. Enzyme inhibitors may increase opioid serum levels leading to over-sedation; enzyme inducers may decrease opioid serum levels leading to inadequate analgesia. Table 1 summarizes drug interactions between opioids and commonly prescribed medications (5).

Excretion    The vast majority of opioids are excreted as metabolites through the kidneys, with the exception of methadone which is primarily excreted via bile.  Patients with renal and/or liver dysfunction may have altered drug clearance (see Fast Facts #161 and #260). Clinicians should be aware of opioid-individual terminal elimination half-lives (T ½), as these dictate the speed of opioid titrations. When given consistently, opioids reach steady state after four T½. Opioid titrations should be avoided until the opioid regimen has reach steady state.

Summary    Table 2 summarizes the pharmacokinetic parameters of commonly used oral opioids. These parameters are critical for the safe and effective use of these medications, as they commonly translate into individual pharmacodynamics properties (6-17).

References

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Authors Affiliations: University of Pittsburgh Medical Center, Pittsburgh, PA.

Conflict of Interest: The authors have disclosed no relevant conflicts of interest.

Version History: First electronically published November 2015.