Common Opioid-Drug Interactions: What Clinicians Need to Know
Patients who require opioid medications often present with comorbidities or disease sequelae related to their pain condition. These patients frequently require medications in addition to their opioid pain medications. A recent study showed that 67% of patients who required opioid medications were also receiving one or more other prescription drugs.1 This type of multi-drug regimen is even more prevalent in the older pain population. For example, one survey reported that nearly 60% of people older than 65 years take five or more different medications per week and, remarkably, nearly 20% of them take 10 or more different medications per week.2
Even if all of the medications are warranted, adverse drug events (ADEs) are linked to such polypharmacy.3 A likely outcome of increased drug–drug exposure (DDE) is drug–drug interactions (DDIs), which can hinder achieving optimal analgesic effect or precipitate ADEs that prompt discontinuation of therapy and less than favorable outcomes. A recent retrospective analysis that evaluated DDIs among chronic low back pain patients on long-term opioid analgesics reported that the overall prevalence of DDIs was 27%.4 Such DDIs are a particularly important type of ADE, and ADEs affect millions of patients each year (estimated at up to 5% of hospital admissions).5-7
Metabolic DDIs, particularly those involving the cytochrome P450 (CYP450) system, are among the most common, most clinically relevant,8 and most potentially avoidable.9 Individual differences among patients affect the disposition and clinical profile of drugs, especially when CYP450 enzymes are involved in the metabolism of a drug.10
Good pain management practice should include consideration of the potential for metabolic DDIs. The purpose of this review is to highlight for clinicians potential DDIs so they can develop strategies to avoid or ameliorate them.
Sites of Drug–Drug Interactions
DDIs can occur at all levels of drug passage and action in the body: pharmacokinetic (absorption, distribution, metabolism, or elimination) or pharmacodynamic (molecular mechanism of action). They can occur somewhere along the gastrointestinal (GI) tract; in the bloodstream; at transporters (membrane proteins involved in the influx of needed substances and the efflux of toxic substances, one of the most important of which is P-glycoprotein [P-gp, encoded by the gene MDR1])11; and during metabolism, which is the most common mechanism of DDIs (Figure 1).
The liver—strategically located in the portal circulation and containing a large quantity of “drug-metabolizing” enzymes—is the major site of drug metabolism in humans; but almost all cells, including those in the GI tract, lungs, kidneys, and brain, can metabolize drugs to some extent.
Most drugs are suitable substrates for multiple metabolizing enzymes and therefore undergo multiple “biotransformations” and produce multiple metabolites. In the case of most opioids, multiple metabolites do not contribute significantly or at all to pain relief, but represent potential sources of ADEs. In some cases, both the “parent” drug and a metabolite are analgesic (such as hydrocodone and hydromorphone, respectively). In the case of a “prodrug,” the parent drug is inactive, but is biotransformed to an active metabolite (an example is codeine, which is generally considered to be a prodrug of morphine).12
Many metabolic DDIs occur as a result of changes in drug metabolism brought about by other drugs that are metabolized through the same biochemical pathway(s) and by inducers or inhibitors of the same metabolic pathways.13
Metabolism of Medications
The two major types of chemical reactions involved in the metabolism of drugs are termed “Phase 1” and “Phase 2.” Phase 2–type reactions involve conjugation of a drug to a substance that is usually available in excess in well-nourished cells, so these reactions are rarely rate-limiting steps in metabolic pathways; thus, they are rarely involved in DDIs.
In contrast, Phase 1–type metabolic reactions involve CYP450 enzymes, flavin monooxygenases (FMOs), and reductases that are more frequently the rate-limiting steps in metabolic pathways and, thus, are more commonly the basis of clinically significant DDIs.14-16
Phase 1–type reactions commonly are catalyzed by the actions of CYP-450 enzymes. The name “cytochrome” (colored cell) derives from the fact that CYP450 enzymes contain iron, which gives (liver) cells a red color. The “450” derives from the fact that the enzymes absorb a characteristic wavelength (450 nm) of ultraviolet light when exposed to carbon monoxide.
The CYP450 superfamily comprises several members (called “isozymes”), each with several genetic polymorphisms.16 Importantly, the great majority of currently used drugs are substrates for one or more CYP450 isozymes. An approximation of the distribution of CYP450 involvement in current drug metabolism is shown in Figure 2.10,17,18
Opioids, CYP450, and
Most opioid medications are metabolized by one or more of the CYP450 isozymes, and this process typically results in the generation of multiple metabolites. In addition, other prescription medications, over-the-counter (OTC) medications, “herbals,” dietary supplements, etc, can inhibit or induce the activity of CYP450 enzymes involved in the metabolic pathways of opioid medications. A clinically significant DDI can result from such an action.19
The inhibition of a drug’s metabolism results in an increase in the blood level of the parent drug and a decrease in its metabolites. This can lead to an increase in the drug’s therapeutic effect and an increase or decrease in ADEs. In the special case of inhibition of metabolism of a prodrug, conversion of a parent drug to its active metabolite(s) diminishes its therapeutic effect.
In contrast to inhibition, induction of a drug’s metabolizing enzymes results in a decreased blood level of a parent drug and increase in its metabolite(s). This decreases the drug’s therapeutic effect (except in the case of a prodrug).
ADEs will either increase or decrease depending on whether they are caused by the parent drug or by its metabolite(s). The overall effect of metabolic interaction can be a complex interplay of properties of a large number of metabolites and potential for a clinically significant DDI. If different medications are metabolized via the same CYP450 isozyme pathway, competitive inhibition between or among the drugs can lead to higher than intended levels of one or more of the drugs. If a medication is metabolized by a specific CYP450 isozyme and is administered with an inhibitor or inducer of that same isozyme, an interaction is possible.20