Opioid Analgesics Pharmacokinetics

Some properties of clinically important opioids are summarized in following table:

Common Opioid Analgesics.

Generic Name Receptor Effects1   Approximately Equivalent Dose (mg) Oral:Parenteral Potency Ratio Duration of Analgesia (hours) Maximum Efficacy delta mu kappa Morphine2   +++ + 10 Low 4–5 High Hydromorphone +++ 1.5 Low 4–5 High Oxymorphone +++ 1.5 Low 3–4 High Methadone +++ 10 High 4–6 High Meperidine +++ 60–100 Medium 2–4 High Fentanyl +++ 0.1 Low 1–1.5 High Sufentanil +++ + + 0.02 Parenteral only 1–1.5 High Alfentanil +++ Titrated Parenteral only 0.25–0.75 High Remifentanil +++ Titrated3   Parenteral only 0.054   High Levorphanol +++ 2–3 High 4–5 High Codeine ± 30–60   High 3–4 Low Hydrocodone5   ± 5–10 Medium 4–6 Moderate Oxycodone2,6   ± 4.57   Medium 3–4 Moderate Propoxyphene (+, very weak) 60–1207   Oral only 4–5 Very low Pentazocine ± + 30–507   Medium 3–4 Moderate Nalbuphine –– ++ 10 Parenteral only 3–6 High Buprenorphine ± –– –– 0.3 Low 4–8 High Butorphanol ± +++ 2 Parenteral only 3–4 High

¹+++, ++, +, strong agonist; ±, partial agonist; –, ––, antagonist.

²Available in sustained-release forms, morphine (MSContin); oxycodone (OxyContin).

³Administered as an infusion at 0.025–0.2 mcg/kg/min.

⁴Duration is dependent on a context-sensitive half-time of 3–4 minutes.

⁵Available in tablets containing acetaminophen (Norco, Vicodin, Lortab, others).

⁶Available in tablets containing acetaminophen (Percocet); aspirin (Percodan).

⁷Analgesic efficacy at this dose not equivalent to 10 mg of morphine

Absorption

Most opioid analgesics are well absorbed when given by subcutaneous, intramuscular, and oral routes. However, because of the first-pass effect, the oral dose of the opioid (eg, morphine) may need to be much higher than the parenteral dose to elicit a therapeutic effect. Considerable interpatient variability exists in first-pass opioid metabolism, making prediction of an effective oral dose difficult. Certain analgesics such as codeine and oxycodone are effective orally because they have reduced first-pass metabolism. Nasal insufflation of certain opioids can result in rapid therapeutic blood levels by avoiding first-pass metabolism. Other routes of opioid administration include oral mucosa via lozenges, and transdermal via transdermal patches. The latter can provide delivery of potent analgesics over days.

Distribution

The uptake of opioids by various organs and tissues is a function of both physiologic and chemical factors. Although all opioids bind to plasma proteins with varying affinity, the drugs rapidly leave the blood compartment and localize in highest concentrations in tissues that are highly perfused such as the brain, lungs, liver, kidneys, and spleen. Drug concentrations in skeletal muscle may be much lower, but this tissue serves as the main reservoir because of its greater bulk. Even though blood flow to fatty tissue is much lower than to the highly perfused tissues, accumulation can be very important, particularly after frequent high-dose administration or continuous infusion of highly lipophilic opioids that are slowly metabolized, eg, fentanyl.

Metabolism

The opioids are converted in large part to polar metabolites (mostly glucuronides), which are then readily excreted by the kidneys. For example, morphine, which contains free hydroxyl groups, is primarily conjugated to morphine-3-glucuronide (M3G), a compound with neuroexcitatory properties. The neuroexcitatory effects of M3G do not appear to be mediated by receptors but rather by the GABA/glycinergic system. In contrast, approximately 10% of morphine is metabolized to morphine-6-glucuronide (M6G), an active metabolite with analgesic potency four to six times that of its parent compound. However, these relatively polar metabolites have limited ability to cross the blood-brain barrier and probably do not contribute significantly to the usual CNS effects of morphine given acutely. Nevertheless, accumulation of these metabolites may produce unexpected adverse effects in patients with renal failure or when exceptionally large doses of morphine are administered or high doses are administered over long periods. This can result in M3G-induced CNS excitation (seizures) or enhanced and prolonged opioid action produced by M6G. CNS uptake of M3G and, to a lesser extent, M6G can be enhanced by coadministration with probenecid or with drugs that inhibit the P-glycoprotein drug transporter. Like morphine, hydromorphone is metabolized by conjugation, yielding hydromorphone-3-glucuronide (H3G), which has CNS excitatory properties. However, hydromorphone has not been shown to form significant amounts of a 6-glucuronide metabolite.

The effects of these active metabolites should be considered in patients with renal impairment before the administration of morphine or hydromorphone, especially when given at high doses.

Esters (eg, heroin, remifentanil) are rapidly hydrolyzed by common tissue esterases. Heroin (diacetylmorphine) is hydrolyzed to monoacetylmorphine and finally to morphine, which is then conjugated with glucuronic acid.

Hepatic oxidative metabolism is the primary route of degradation of the phenylpiperidine opioids (meperidine, fentanyl, alfentanil, sufentanil) and eventually leaves only small quantities of the parent compound unchanged for excretion. However, accumulation of a demethylated metabolite of meperidine, normeperidine, may occur in patients with decreased renal function and in those receiving multiple high doses of the drug. In high concentrations, normeperidine may cause seizures. In contrast, no active metabolites of fentanyl have been reported. The P450 isozyme CYP3A4 metabolizes fentanyl by N-dealkylation in the liver. CYP3A4 is also present in the mucosa of the small intestine and contributes to the first-pass metabolism of fentanyl when it is taken orally. Codeine, oxycodone, and hydrocodone undergo metabolism in the liver by P450 isozyme CYP2D6, resulting in the production of metabolites of greater potency. For example, codeine is demethylated to morphine. Genetic polymorphism of CYP2D6 has been documented and linked to the variation in analgesic response seen among patients. Nevertheless, the metabolites of oxycodone and hydrocodone may be of minor consequence because the parent compounds are currently believed to be directly responsible for the majority of their analgesic actions. In the case of codeine, conversion to morphine may be of greater importance because codeine itself has relatively low affinity for opioid receptors. As a result, patients may experience either no significant analgesic effect or an exaggerated response based on differences in metabolic conversion. For this reason, routine use of codeine, especially in pediatric age groups, is being reconsidered.

Excretion

Polar metabolites, including glucuronide conjugates of opioid analgesics, are excreted mainly in the urine. Small amounts of unchanged drug may also be found in the urine. In addition, glucuronide conjugates are found in the bile, but enterohepatic circulation represents only a small portion of the excretory process.

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