The cytochrome P450 (CYP) system is the principal phase I metabolic pathway for most drugs.¹² The main role of the CYP system is to convert parent drugs to inactive metabolites for elimination and to convert prodrugs to active metabolites for utilization.¹² Drugs interacting with the CYP system are classified as substrates, inhibitors, or inducers.^12,13 Substrates are further classified as weak, moderate, or strong affinity substrates for a specific CYP isoenzyme.^12,13 Substrates sharing the same isoenzyme interact such that the stronger affinity substrate (or perpetrator drug) competitively inhibits the weaker affinity substrate (or victim drug). This type of competitive inhibition cannot be overcome because substrate affinity for a CYP isoenzyme is constant; however, it may be mitigated by separating times of drug administration. Substrates with similar affinities sharing the same isoenzyme also interact; the substrate with the higher dose competitively inhibits the substrate with the lower dose. This type of competitive inhibition can be overcome by increasing the dose of the victim drug to surpass the dose of the perpetrator drug.^12-14 However, higher opioid doses pose greater risks for opioid use disorders and overdoses. 

Substrates of a CYP isoenzyme are potential competitive inhibitors; however, not all inhibitors of a CYP isoenzyme are substrates. Unlike substrates, inhibitors bind to an allosteric site, changing the conformational structure of a CYP isoenzyme. As a result, substrates of the inhibited CYP isoenzyme cannot interact with that isoenzyme to be metabolized. An inhibitor renders the metabolic activity of a CYP isoenzyme nonfunctional, occurring immediately upon interaction. This action is known as noncompetitive inhibition, which cannot be overcome unless the inhibitor is removed. In contrast, inducers bind to certain receptors and increase the synthesis of a CYP isoenzyme. Unlike inhibition, induction takes days to weeks to occur.^12,15 

Drug interactions involving opioids are mediated by the CYP system. The CYP2D6 isoenzyme, in particular, mediates the metabolism of approximately 25% of drugs used in practice.¹⁶ This includes activation of the prodrug opioids codeine, hydrocodone, oxycodone, and tramadol from relatively inert drugs to pharmacologically active metabolites.¹⁷ Altered activity of the CYP2D6 isoenzyme is one of the most studied scenarios of genetic variants influencing the CYP system.^17-19 For example, activation of tramadol by the CYP2D6 isoenzyme is a prerequisite for its analgesic effects. Patients expressing the poor metabolizer phenotype have little to no CYP2D6 isoenzyme activity, resulting in adequate pain control when using tramadol.^20,21 Although CYP3A4 plays a role in metabolizing many opioids, studies have not consistently linked altered activity of this isoenzyme to a clinically significant response from the prodrug opioids.^17,22 We believe relatively few prescribers are knowledgeable about the impact of altered CYP2D6 activity on response to prodrug opioids. Because a surge in prescriptions for prodrug opioids has contributed to the present-day opioid epidemic, understanding the role of the CYP2D6 isoenzyme in opioid metabolism and response is paramount. 

Depicted in Figure 1, the CYP2D6 isoenzyme metabolizes the prodrug opioids into active metabolites. These metabolites are much more potent for the µ-opioid receptor target than the prodrug opioids and are primarily responsible for their analgesic response.^24,26 For example, the µ-opioid receptor affinities of morphine and O-desmethyl-tramadol are 200 times greater than the affinities of the parent opioids, codeine and tramadol, respectively.^24,26 Hydromorphone has a 10- to 30-fold greater affinity and oxymorphone has a 40-fold greater affinity for the µ-opioid receptor than their respective parent opioids.²⁶ Therefore, CYP2D6 activity is required to produce the highly potent µ-opioid receptor agonists of the prodrug opioids. 

Drug interactions can mimic genetic variants and similarly contribute to variability in opioid response.^19,27-29 For example, patients receiving CYP2D6 inhibitors have exhibited lower plasma concentrations of O-desmethyl-tramadol after a dose of tramadol compared with patients in whom the CYP2D6 isoenzyme was not inhibited.²⁰ Similar effects of inhibition have been exhibited for the other prodrug opioids.^27-30 Additionally, lack of pain control and opioid-related adverse events in patients with CYP2D6 genetic variants receiving prodrug opioids suggest a significant impact of altered CYP2D6 activity on opioid response; albeit, conflicting data exist with oxycodone.^{17,22,23,29,30} 

Prodrug opioids are weak affinity substrates of the CYP2D6 isoenzyme.¹⁶ Consequently, they are usually victims of competitive inhibition.^14,16 Examples of commonly prescribed substrates with moderate-to-strong affinity of the CYP2D6 isoenzyme include citalopram, metoprolol, and risperidone. These drugs reduce the CYP2D6-mediated activation of prodrug opioids to their most potent metabolites. Similarly, drugs with relatively weak affinity for the CYP2D6 isoenzyme, such as amitriptyline, trazodone, and venlafaxine, are usually perpetrators of competitively inhibiting prodrug opioids because they are often administered at higher doses. When concurrently administered with prodrug opioids, they, too, reduce the CYP2D6-mediated activation of the opioids. Additionally, several drugs are inhibitors of the CYP2D6 isoenzyme; those commonly used include amiodarone, diphenhydramine, and paroxetine. These inhibitors completely prevent the CYP2D6-mediated activation of prodrug opioids to their most potent metabolites. A selected list of CYP2D6 substrates and inhibitors is provided in the Table. 

In the absence of drug interactions, patients are expected to experience the analgesic effects and possibly the side effects of opioids. In the presence of drug interactions involving prodrug opioids, patients are likely to experience reduced analgesic effects and probably side effects. Thus, the 2 main consequences of opioid-involved drug interactions are reduced benefits and increased risks. These consequences are depicted in Figure 2. 

When a patient experiences reduced analgesic effects or absence of pain relief, the patient and/or prescriber typically increases opioid use (eg, dose, frequency). We refer to this as “unintentional misuse.” Unintentional misuse often precipitates opioid tolerance and dependence, potentially leading to opioid abuse. Additionally, increased use of prescribed opioids increases overdose risk, including death.^32,33 Patients who use higher opioid doses also are at greater risk for poor functional status, increased pain sensitivity, prolonged opioid use, falls and fractures, and motor vehicle accidents.^34,35 

Drug interactions involving opioids are associated with additional risks, particularly, side effects, opioid withdrawal, and accidental overdose. A drug interaction that leads to side effects often results in prescribing 1 or more other drugs for their treatment. This is referred to as a “prescribing cascade.”³⁶ In the case of a drug interaction involving a prodrug opioid, the concentrations of the active metabolite decrease. Consequently, this interaction can precipitate opioid withdrawal in a patient who is opioid dependent.¹⁰ The onset of opioid withdrawal may trigger abuse of opioids or other illicit substances (eg, heroin) and/or resumption of high-risk behaviors.¹⁰ If the opioid-involved drug interaction in the aforementioned case is circumvented, the patient may experience an accidental and, potentially, fatal overdose. 

Health care professionals can integrate various therapies, including nonpharmacologic, into their treatment of patients with chronic pain to avoid drug interactions involving opioids. Knowledge of potential drug interactions, especially prior to prescribing, better equips prescribers with selecting opioids and other drugs for their many patients requiring pharmacologic management.^11,14 Because opioids will likely continue to be used for chronic pain management in the foreseeable future, health care professionals should particularly understand strategies to mitigate drug interactions in their practices. 

To help end the opioid epidemic, a paradigm shift in our current strategies for managing chronic pain is needed. As described in a 2017 article,⁶ the necessary paradigm shift should be built on the foundation of the core osteopathic tenets. These tenets are as follows: The body is a unit, and the person is a unit of body, mind, and spirit…. The body is capable of self-regulation, self-healing, and health maintenance…. Structure and function are reciprocally interrelated…. Rational treatment is based upon an understanding of the basic principles of body unity, self-regulation, and the interrelationship of structure and function.³⁷ 

A cornerstone of osteopathic care is nonpharmacologic therapies.³⁸ Those with fair-to-good evidence of effectiveness for chronic pain management include exercise, yoga, massage, progressive relaxation, acupuncture, functional restoration, spinal manipulation, and transcutaneous nerve stimulation.^5,38-40 In addition to these broad-based therapies, osteopathic physicians may use osteopathic manipulative treatment (OMT).⁶ A substantial body of evidence supports the effectiveness of OMT as an adjunctive therapy for chronic pain management, particularly for low back pain.^41,42 In 2016, the American Osteopathic Association published their updated guidelines⁴² for OMT, further strengthening the evidence for using OMT alone or with other nonpharmacologic therapies. If after examining the patient and assessing the pain, health care professionals choose to prescribe a drug, they should first consider nonopioid therapies, such as acetaminophen, nonsteroidal anti-inflammatory drugs, anticonvulsants, and antidepressants.^5,6,40 

Overall, the biopsychosocial model recognizes that chronic pain management is complex and requires a combination of therapies to manage pain.⁶ In aggregate, these therapies may prevent, or at least lessen, the need to use opioids. This strategy has the potential to avoid opioid-involved drug interactions; however, when opioids are necessary, other mitigating tactics can be used. 

In institutional settings in particular, health care professionals commonly administer drugs to patients at specific times of day. These administration times are usually based on staffing schedules, not drug pharmacology. Similarly, in noninstitutional settings, patients usually administer drugs based on their personal schedules. Patients taking multiple drugs commonly administer most of them concomitantly, such as in the morning with breakfast. These practices, while convenient, markedly increase the risk of exposing patients to potential clinically significant drug interactions. 

To mitigate drug interactions between competing substrates, those with weaker affinity should be administered at least 2 to 4 hours before those with stronger affinity. This strategy allows weaker-affinity substrates to bind to CYP isoenzymes unoccupied by stronger-affinity substrates and, therefore, be preferentially metabolized. This strategy can also be effective for mitigating drug interactions between 2 or more substrates with similar affinities for the same CYP isoenzyme. In this case, substrates with the lower dose should be administered at least 2 to 4 hours before substrates with the higher dose. While this strategy of altering times of administration works for mitigating competitive inhibition, it is not effective for noncompetitive inhibition, which can only be mitigated by changing either the perpetrator drug or victim drug. 

Though effective, this strategy is challenging, because many commonly used opioids are prodrugs that have weak affinity for CYP isoenzymes, such as CYP2D6. As a result, these opioids are typically the victim drug, which should be administered before substrates with stronger affinity. However, because opioids are usually administered multiple times a day, changing their times of administration poses a medically complicated scenario. Therefore, for these patients, other strategies may need to be used. 

As previously described, drugs interacting with prodrug opioids mainly interfere with activating these opioids, primarily through competitive and noncompetitive inhibition of the CYP2D6 isoenzyme. In contrast to prodrug opioids, the opioids hydromorphone, morphine, and oxymorphone are already in their active form and undergo phase II metabolism via glucuronidation (Figure 1).^13,25 As a result, these opioids are not subject to CYP-mediated drug interactions; albeit, drug interactions and genetic variants can occur with the UGT2B7 isoenzyme.¹³ 

Health care professionals should consider prescribing an opioid that undergoes phase II metabolism for opioid-naive patients who use concomitant drugs that rely on the CYP system, especially the CYP2D6 isoenzyme. For opioid-tolerant patients who experience a consequence of a clinically significant drug interaction, health care professionals should consider changing the victim opioid to one with an alternative metabolic pathway, empirically reducing the calculated dose requirement of the alternative opioid by at least 50%. Additionally, health care professionals should consider the intermittent use of a short-acting formulation of the alternative opioid, preferable to the around-the-clock use of a long-acting formulation, particularly during the early conversion period. Together, these strategies will significantly reduce the risk for an accidental opioid overdose. 

Another strategy that health care professionals can use to mitigate opioid-involved drug interactions is to reduce pharmacologic intake by avoiding prescribing multidrug regimens or by discontinuing perpetrator drugs.³⁶ An alternative strategy is to change the perpetrator drug. For example, metoprolol has moderate affinity for the CYP2D6 isoenzyme, whereas atenolol does not undergo CYP-mediated metabolism. Replacing metoprolol with atenolol in a patient using a prodrug opioid not only mitigates but also avoids a CYP2D6-mediated drug interaction. When changing the perpetrator drug, though, the dose of the current opioid must be empirically reduced by approximately 25% to 50% to avoid an accidental overdose because the prodrug opioid would be fully activated in the absence of a CYP-mediated drug interaction. 

Pharmacists can play a critical role in identifying and rectifying opioid-involved drug interactions, owing to their extensive education in clinical pharmacology and training in drug optimization. In various practice settings, pharmacists have demonstrated the ability to use drug interaction data to provide recommendations to health care professionals and intervene directly with patients.^43-45 Including pharmacists in a team-based care model for managing chronic pain helps health care professionals create a plan for safely prescribing opioids.⁴⁶ 

The unique role of pharmacists as drug experts on the interdisciplinary care team should complement that of other health care professionals. Many health care professionals recognize their knowledge gap in understanding and interpreting drug interaction data, and studies have shown that health care professionals fail to recognize a substantial portion of clinically meaningful drug-drug interactions.^47,48 It is also plausible that health care professionals do not fully comprehend how other drugs influence the benefits and risks of opioids as discussed in this article, underscoring the importance of using pharmacists in the treatment of patients with chronic pain. 

In addition to drug-drug interactions, there is an abundance of evidence showing that genetic variants and drug-gene interactions may also influence opioid response.^17,23,31 Variants in genes encoding for opioid-metabolizing CYP isoenzymes (eg, CYP2D6), opioid-sensitive transporters (eg, ABCB1), and opioid-target receptors (eg, OPRM1) can alter opioid-related analgesia and side effects.^17,23,49 For example, variants in the CYP2D6 gene result in several phenotypes: poor metabolizer, intermediate metabolizer, and ultra-rapid metabolizer; these are in addition to the nonvariant (ie, wild type) phenotype, normal metabolizer. The poor metabolizer phenotype results in the inability to convert prodrug opioids to their active metabolites, thus making pain relief negligible. In contrast, the ultra-rapid metabolizer phenotype results in increased conversion of prodrug opioids to active metabolites, resulting in higher plasma concentrations of the active opioid.^18,25 Superimposed on genetic variants, multidrug interactions can change the genetically encoded CYP metabolic status (eg, normal metabolizer to poor metabolizer); a process known as phenoconversion.^12,31 Multidrug interactions resulting in phenoconversion of the CYP2D6 isoenzyme commonly occur in populations with complex medical conditions, such as those with chronic pain and depression.⁵⁰ Therefore, it may be useful for health care professionals to know a patient's genotype and phenotype to avoid prescribing an opioid that likely is ineffective or unsafe. 

The well-characterized variation in opioid response is partly due to the individualistic nature of drug metabolism and drug interactions. The effectiveness and safety of prodrug opioids are largely dependent on the activity of the CYP2D6 isoenzyme. Drug interactions interfering with this activity are an important but preventable source of altered opioid response; therefore, they should be of constant concern for health care professionals who care for patients with chronic pain. This article serves as a way for health care professionals to better understand and recognize these interactions. Using osteopathic principles for chronic pain management alongside other strategies to avoid and/or mitigate opioid-involved drug interactions can aid health care professionals in obtaining a favorable balance in the risk-benefit ratio associated with opioid use. 

We acknowledge Heather Vorselen, MA, and David Wensel, DO, for proofreading the manuscript for grammar and content, respectively.