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10 Articles in Volume 12, Issue #7
August 2012 Pain Research Updates
Cash Patient: A Clinical Dilemma
Common Opioid-Drug Interactions: What Clinicians Need to Know
Compliance in Pain Patients: Balancing Need to Test With Need to Treat
Cytochrome P450 Testing In High-dose Opioid Patients
Discharging a Patient Suspected of Diversion
Examining the Safety of Joint Injections In Patients on Warfarin
Genomic Medicine
Letters to the Editor from August 2012
Minimally Invasive Spine Surgery— Who Can it Help?

Common Opioid-Drug Interactions: What Clinicians Need to Know

The overall prevalence of drug–drug interactions in patients on long-term opioids is 27%. Good pain management practice should include knowledge of potential interactions, and well as ways to avoid and ameliorate them.

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).

Figure: The most common sites of DDIs.

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

Figure: The approximate % of current drugs metabolized by each indicated CYP450 isozyme.

Opioids, CYP450, and 
Drug–Drug Interactions
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

CYP450 isozymes have been especially well characterized in terms of clinically relevant drug metabolism. For example, CYP-3A catalyzes the metabolism of the largest number of currently marketed drugs and many commonly used drugs can inhibit this enzyme. CYP-2D6 also metabolizes many current drugs, including many opioid analgesics.21 Several commonly used drugs inhibit or induce CYP-3A and CYP-2D6 (Table 1).8,19,21,22

Table: Some common inducers and inhibitors of the CYP450 isozymes involved in the metabolism of opioid drugsTable 1: Some common inducers and inhibitors of the CYP450 isozymes involved in the metabolism of opioid drugs

CYP450 Polymorphisms
Polymorphic differences in CYP450 enzymatic activity account for numerous interindividual variations in drug metabolism. It has been estimated that nearly 60% of drugs most commonly implicated in ADEs are metabolized by enzymes affected by inherited DNA variations.23

Some CYP450 isozymes are highly polymorphic, such as the CYP-2D6 gene locus, which has at least 100 known allelic variants with more than 30 subvariants.24 As just one example of the clinical relevance, an allelic variant in CYP-2D6 is associated with an ultraslow (“poor”) metabolizer phenotype that results in poor conversion of codeine to its active metabolite morphine and, thus, has a significantly less analgesic response to codeine.24 More details about the implications of CYP450 polymorphisms on opioid metabolism are available in recent reviews.

Pharmacogenomic testing can assess the activity of a CYP450 isozyme, such a CYP-2D6, prior to administration to a particular patient in order to predict a poor (or exaggerated) response, but this is currently relatively time consuming and expensive, and of questionable value when other opioids are available whose analgesic activity is not so susceptible to metabolism by the isozyme.24

Drug–Drug Interactions
Tables 2 and 3 list commonly used opioid medications and potential DDIs encountered with prescription and OTC medications, including herbs and food. The tables are intentionally inclusive of a very broad listing of drugs and other substances that are substrates, inducers, or inhibitors of CYP450, even if their activity at a particular site is low or normally subclinical in most patients. Likewise, the tables provide a very inclusive listing of CYP450 isozymes that participate in the metabolism of specific opioid drugs, even if metabolism of the opioid occurs primarily via only one or a few of these pathways. Thus, it provides a theoretical maximal potential for DDIs based on known metabolic routes and CYP450 activities. For the majority of patients, many of these possible DDIs remain only a hypothetical possibility, but it is important to list them because polymorphisms in any aspect of drug pharmacokinetics or pharmacodynamics can put an individual patient at increased risk.

Table 2: Potential DDIs with prescription medicationsTable 2: Potential DDIs with prescription medicationsTable 2: Potential DDIs with prescription medicationsTable 2: Potential DDIs with prescription medicationsTable 2: Potential DDIs with prescription medicationsTable 2: Potential DDIs with prescription medicationsTable 2: Potential DDIs with prescription medications

Assessing for DDIs associated with common OTC medications presents more of a gray area for the physician when writing a prescription for an opioid medication. Physicians do not necessarily have control over what type or how much of OTC products a patient is taking (eg, other analgesics such as nonsteroidal anti-inflammatory drugs [NSAIDs] or acetaminophen, proton pump inhibitors, vitamins, herbals, dietary supplements, weight-loss products). Because some of these products can be substrates, inducers, or inhibitors of CYP450 enzymes, it is very important for the prescriber to take a careful history that includes inquiring about all the OTC products a patient might be taking. Prescribers can then counsel the patient to cease the OTC product or prescribers can select the most appropriate (compatible) opioid medication based on the medication history.

As noted, it is not uncommon for patients with pain to present with one or more comorbidities. When a physician writes a prescription for an opioid, he or she might or might not have some control over what other prescription medications that patient is taking. Table 4 is a sample listing of some of the most commonly encountered prescription and OTC medications that a patient with pain might be on that would have the greatest potential to cause a DDI when coadministered with an opioid.9,19,25-33

Table: Potential Drug-Herb and Drug Food InteractionsTable: Potential Drug-Herb and Drug Food InteractionsTable: Potential Drug-Herb and Drug Food InteractionsTable 3: Potential Drug-Herb and Drug Food Interactions

A prescriber can do several practical things to lower a patient’s risk for DDIs—specifically, knowing which agents to avoid or when to switch to a different opioid:

  • Take a complete history of all prescription medications the patient is currently taking
  • Take a complete history of all OTC products the patient is currently taking
  • Determine (using the tables in this article and other sources) potential sources of metabolic DDIs
  • Recommend changes to avoid potential DDIs when possible and medically appropriate (eg, eliminate a potential DDI involving an OTC product)
  • When choosing an opioid analgesic, consider using/substituting an opioid that is not metabolized by a potential DDI pathway

Special Populations
Patients With Liver Disease
Drug metabolism in patients with hepatic dysfunction has been reviewed recently.34 CYP450 activity is differentially affected by the presence of liver disease. For example, the clearance of drugs metabolized by CYP-3A decreases in patients with cirrhosis. In early-stage hepatic disease, the clearance of a drug metabolized by CYP-2C19 is reduced but the clearance of a drug metabolized by CYP-1A2, CYP-2D6, or CYP-2E1 remains normal. At an intermediate level of severity of liver disease, clearance of a drug is more or less reduced according to the specific CYP450 isozyme involved in its elimination, and in end-stage liver disease, clearance of a drug by CYP-1A2, CYP-2C19, CYP-2D6, or CYP-2E1 is reduced. In general, most conjugation reactions have been considered to be less affected by liver disease than are CYP450 reactions, but recent studies have reported impaired glucuronidation of drugs, including morphine, in patients with advanced cirrhosis.34

Table: Commonly encountered prescription and over-the-counter medicationsTable 4: Commonly encountered prescription and over-the-counter medications

The Elderly
Drug metabolism in the elderly population has also been reviewed recently.35 No significant age-related changes in hepatic microsomal protein content or in CYP450 enzyme activity in vivo were reported. Likewise, neither the content nor the activity of CYP450 enzymes in hepatic biopsy were found to differ with age (10 to 80 years). Regarding the possible influence of donor age on CYP isozyme activities (eg, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, and 4A11), investigators found no significant difference between the group aged 20 to 60 years compared to the group older than 60 years. These findings suggest that drug metabolism remains well preserved in the elderly, at least up to 80 years. Similar conclusions emerge from studies in vivo.36 Thus, conversion to potential metabolite-associated ADEs can occur to the same extent in this generally more frail population. Table 2 provides an extensive list of potential opioid DDIs.8,21,22

Conclusion
An understanding and appreciation of the sites, mechanisms, and processes related to DDIs is an initial step in decreasing preventable DDIs in the pain populations that require opioid medications and is an integral and integrated part of a rational polypharmacy regimen for the management of their pain. It would, thus, seem reasonable and prudent that, when physicians select a specific opioid, they consider the potential for metabolic DDIs.

Last updated on: September 27, 2017
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