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Supplements Improving Outcomes With Opioid Use: Focus on Drug-Drug Interactions

Opioid Pharmacokinetic Drug-Drug Interactions

Brian R. Overholser, PharmD and David R. Foster, PharmD, FCCP

Pharmacokinetic drug-drug interactions (DDIs) involving opioid analgesics can be problematic. Opioids are widely used, have a narrow therapeutic index, and can be associated with severe toxicity. The purpose of this review is to describe pharmacokinetic DDIs associated with opioids frequently encountered in managed care settings (morphine, codeine, oxycodone, oxymorphone, hydrocodone, hydromorphone, fentanyl, tramadol, and methadone). An introduction to the pharmacokinetic basis of DDIs is provided, and potential DDIs associated with opioids are reviewed. Opioids metabolized by the drug metabolizing enzymes of the cytochrome P450 (CYP450) system (codeine, oxycodone, hydrocodone, fentanyl, tramadol, and methadone) are associated with numerous DDIs that can result in either a reduction in opioid effect or excess opioid effects. Conversely, opioids that are not metabolized by that system (morphine, oxymorphone, and hydromorphone) tend to be involved in fewer CYP450-associated pharmacokinetic DDIs.

(Am J Manag Care. 2011;17:S276-S287)

Adverse drug reactions (ADRs) are a significant problem, resulting in substantial morbidity, mortality, and healthcare expenses.1 In 2004, 1.2 million hospitalized patients experienced an ADR, 90% of which were due to a medication that was properly administered.2 Drug-drug interactions (DDIs) are an important and potentially preventable source of ADRs. DDIs can be broadly categorized as pharmacokinetic or pharmacodynamic; pharmacokinetic DDIs occur when a drug (the “precipitant drug”) causes a change in the absorption, distribution, metabolism, and/or elimination (“ADME”) of another drug (the “object drug”). These interactions can lead to either loss of efficacy or toxicity of the object drug. Pharmacodynamic DDIs result when 2 drugs are coadministered and the concentration-response curve of 1 or both drugs is altered without a change in the object drug’s pharmacokinetics.3

Opioid analgesics are widely used in the treatment of both cancer-related and noncancer-related pain. In consensus guidelines, chronic opioid therapy is proposed as an option for patients with moderate to severe chronic noncancer pain, where the pain is impacting their quality of life, and the potential benefits of opioids are expected to outweigh the risks.4 Similarly, in elderly patients, consideration of opioid therapy is recommended for all patients with moderate to severe pain, pain-related functional impairment, or pain-related diminished quality of life.5

As a drug class, opioids are associated with a narrow therapeutic index, wide interindividual variability in response (eg, doses used in an opioid-tolerant patient can be fatal to an opioid-naïve patient), and potentially life-threatening toxicity. As the prevalence of opioid use has increased, serious adverse reactions and deaths associated with opioids have also increased.6 Although there have been substantial efforts to improve the safety of opioids in clinical practice, much of this effort has been directed to prevention of misuse and diversion, and management of chronic adverse effects.7 In contrast, the importance of pharmacokinetic DDIs related to opioids has received little attention. For example, in a systematic review of publications that described “opioid related problems,” 105 publications including 156 patients were identified; of these, approximately 30% described opioid-associated DDIs.8 Moreover, in a series of analyses evaluating opioid users with chronic low back pain and osteoarthritis in a managed care database, approximately 30% of patients identified were taking opioids metabolized by the cytochrome P450 (CYP450) system and were also exposed to other CYP450 substrates, including potentially interacting drugs.9,10 Consequences of pharmacokinetic DDIs associated with opioids can include excess opioid effects (including fatal toxicity), loss of analgesic efficacy, predisposition to other adverse effects, relapse to illicit or inappropriate drug use, and misinterpretation of opioid screening results.

Purpose and Scope

The purpose of this review is to describe potential DDIs associated with opioids that are frequently encountered in managed care (morphine, codeine, oxycodone, oxymorphone, hydrocodone, hydromorphone, fentanyl, tramadol, and methadone). The focus will be on pharmacokinetic DDIs involving the CYP450 system where the opioid is the object drug (ie, we will not address the potential for some opioids to impact the disposition of other drugs, nor will we address pharmacodynamic interactions such as excessive sedation when an opioid is used with a benzodiazepine; although each of these categories of interactions can be clinically important, they are beyond the scope of this review). We will first provide a brief overview of the pharmacokinetic basis of opioid drug interactions, and then will review potential DDIs associated with opioids. Where relevant, we will also briefly address the impact of genetic factors (ie, “pharmacogenetics”) on predisposition to drug interactions. A complete review of the pharmacogenetics of opioids is outside of the scope of this manuscript.

Pharmacokinetic Basis of Opioid Drug Interactions

The manifestation of opioid toxicity or lack of efficacy can occur due to several clinical consequences including pharmacokinetic DDIs. In general, opioids share common metabolic pathways, many through the CYP450 enzymatic system. Therefore, clinicians have the tools to avoid potential DDIs by switching the precipitating drug or altering the opioid dose. However, given the common use of opioids, many patients are concurrently prescribed drugs that could precipitate a DDI.9,10 The focus of this section is to review fundamental concepts of drug metabolism as they relate to the opioid analgesics. Additionally, this section will introduce pharmacogenetic concepts as they relate to variability in DDIs with opioids.

Fundamental Concepts of Pharmacokinetics and Opioid Metabolism

Drugs that interfere with the pharmacokinetics of opioids generally do so by altering their elimination.11 The overall elimination of opioids from the systemic circulation refers to the irreversible removal from the body by all routes. The concept of drug elimination can be divided into 2 major physiologic components, metabolism and excretion.3 Excretion refers to the removal of drug from the body, commonly through the kidney or biliary secretion. Clearance describes the efficiency of irreversible drug elimination from the body through metabolism or excretion.3

In general, the clinically significant DDIs that involve opioids occur through modulation of drug metabolism. The major metabolizing organ in the body is the liver, although the gastrointestinal tract and other organs also have metabolizing capacity.3 Drug metabolism can be broken down into 2 fundamental elements termed Phase I and Phase II metabolism.3

Phase I Opioid Metabolism

Phase I metabolism refers to the modulation of a molecular structure of endogenous or exogenous substances (eg, drugs) through chemical reactions such as oxidation, reduction, or hydrolysis. The predominant catalysts for Phase I metabolism of drugs are found in the CYP450 enzymatic system.3 The opioids that are metabolized by CYP450 include codeine, hydrocodone, oxycodone, methadone, tramadol, and fentanyl.12 The CYP450 system comprises distinct isozymes that are responsible for drug metabolism. Of these isoenzymes, CYP3A and CYP2D6 are primarily responsible for opioid metabolism through the CYP450 system, with CYP2B6 also contributing to methadone metabolism. The metabolic pathways of the opioids are presented in Table 1.

The CYP3A isoenzyme is responsible for the metabolism of approximately 50% of all drugs currently available. The functional component of the CYP3A enzyme that is most likely relevant to opioid metabolism is CYP3A4.13 In general, CYP3A4 is responsible for opioid metabolism but the capability of CYP3A5 to metabolize opioids has not been thoroughly assessed for many of the drugs. CYP3A5 is polymorphically expressed, and some patients do not have functional CYP3A5 alleles.13 This is important because many CYP3A4 substrates have overlap with CYP3A5 and catalyze the formation of the same metabolites. Therefore, patients without functional CYP3A5 alleles may appear to have decreased CYP3A4 activity and this may influence the degree of DDI.

The CYP2D6 isoenzyme is also an important CYP450 enzyme that metabolizes several opioid analgesics.12 The CYP2D6 enzyme is polymorphically expressed and patients have varying degrees of CYP2D6 activity with a small percentage of the population having no enzyme activity.14,15

The CYP2D6 metabolizing phenotypes can be described as ultrarapid metabolizer (UM), extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM). CYPD6 PMs have little to no CYP2D6 function and therefore do not metabolize opioid substrates through this pathway. This can greatly diminish the analgesic effects of opioid prodrugs (as discussed below) that require CYP2D6 to form active metabolites, such as hydrocodone and codeine.

Phase II Opioid Metabolism

Phase II metabolism refers to a chemical reaction in which a drug is conjugated with a chemical moiety such as a glucuronide, which promotes drug excretion though the kidneys.3 In almost all cases, the conjugated drug is rendered inactive and loses biological activity. However, morphine represents an important exception and is an example of a conjugated compound (morphine-6-glucuronide) that maintains its analgesic effect. The most abundant Phase II enzyme to metabolize the opioid analgesic class is UDPglucuronosyltransferase-2B7 (UGT2B7).16 This enzyme is the primary route of elimination for morphine, hydromorphone, and oxymorphone.


A drug that is administered in a biologically inactive form and is biotransformed into an active metabolite is termed a prodrug. Hydrocodone and tramadol are prodrugs that are converted to active forms by CYP450 isoenzymes.12 Additionally, codeine is metabolized into morphine through CYP2D6, which contributes a greater analgesic effect than codeine.17-19 The consideration of drug interactions involving opioid prodrugs is important because they can be clinically manifested in the opposite manner from an active parent drug. For example, the decreased metabolism of a prodrug would result in a decreased analgesic effect and potential treatment failure, whereas the decreased metabolism of an active parent drug would enhance an analgesic effect and potentially lead to opioid toxicity.

CYP450 Inhibition vs Induction—Potential DDIs and Clinical Manifestations

Drugs that are metabolized by CYP450 enzymes are considered substrates for that system. In general, the coadministration of an opioid that is metabolized by the CYP450 system and another substrate of the same enzyme will not result in a drug interaction. The metabolic capacity of the P450 system can maintain the burden of 2 substrates in most situations. However, when a substrate has a high affinity for the CYP450 isoenzyme and is at a concentration that can occupy most or all of the enzyme’s catalytic sites, there can be competition. This drug would be considered a substrate and also a competitive inhibitor of the CYP450 isoenzyme. Some drugs can inhibit CYP450 isoenzymes by other mechanisms and even without being substrates. For the purposes of this review drugs that inhibit CYP450 by any mechanism will be referred to as CYP450 inhibitors. Drugs that can inhibit CYP3A or CYP2D6 and are most likely to interact with certain opioids are presented in Table 2.

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