Drug-Drug Interactions Involving Pain Medications

Release Date: March 1, 2014

Expiration Date: March 31, 2016

FACULTY:

Donna M. Lisi, PharmD, BCPS, BCPP
Scholar, Geriatric Education Centers Faculty
Development Collaborative Program
New York Consortium of Geriatric
Education Centers
Independent Consultant/Medical Writer
Somerset, New Jersey

FACULTY DISCLOSURE STATEMENTS:

Dr. Lisi has no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy
acpePostgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 0430-0000-14-011-H01-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

FEE INFORMATION:

Payment of $6.50 required for exam to be graded.

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

GOAL:

To educate pharmacists about significant drug-drug interactions involving pain medications and to provide tools for avoiding or minimizing adverse outcomes.

OBJECTIVES:

After completing this activity, the participant should be able to:

  1. Identify the mechanisms of action associated with analgesic drug interactions, especially those involving the CYP450 enzyme system.
  2. Recognize the significance of pain medication drug interactions with respect to morbidity and mortality.
  3. List major drug interactions associated with pain relievers.
  4. Develop strategies to avoid or minimize potential analgesic drug interactions.

ABSTRACT: The mechanisms behind drug-drug interactions are complex. Genetic polymorphism can further predispose a patient to drug interactions. Major classes of pain medications include acetaminophen, nonsteroidal anti-inflammatory agents (NSAIAs; both conventional and cyclooxygenase-2 inhibitors), and opioids. Acetaminophen has been the focus of major concern, as liver damage can occur with therapeutic doses, especially in the presence of other hepatotoxic substances. The effects of many NSAIAs can be altered by the coadministration of drugs that inhibit or induce CYP2C9. The rise in opiate-related overdoses and deaths in the United States may be due in part to excessive dosing, drug-drug interactions, and adverse reactions. Pharmacists need to be aware of analgesic drug-drug interactions in order to provide optimal pharmacotherapy for patients living with pain.

Insight has been gained recently into the mechanisms associated with drug interactions. A drug interaction takes place when the pharmacokinetics or effects of a drug are altered by previous administration or coadministration of another drug.1 Drug interactions are further divided into pharmacokinetic interactions (in which one drug alters the rate or extent of absorption, distribution, or elimination [metabolism or excretion] of another drug) and pharmacodynamic interactions (in which one drug induces a change in a patient's response to a drug without altering the object drug's pharmacokinetics).1 A drug–disease state interaction refers to the positive or negative impact of one or more drugs on pre-existing medical conditions, pathologic processes, or disease states.2 This article will review mechanisms associated with pain medication drug interactions; significant drug interactions involving analgesics; and strategies to promote safe medication use. A discussion of drug-food, drug-laboratory, drug-alcohol, drug–dietary supplement/herbal product, and drug-disease interactions is beyond the scope of this article.

Mechanisms of Drug Interactions

The mechanisms behind drug-drug interactions are complex and involve major CYP450 enzymes (CYP1A2, -2B6, -2C8, -2C9, -2C19, -2D6, -3A4); uridine diphosphate glucuronosyltransferase (UGT) and sulfotransferase; monoamine oxidase (MAO); flavin monooxygenase (FMO); xanthine oxidase (XO); alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH); transporter-based interactions (P-glycoprotein, breast cancer resistance protein, hepatic uptake transporters organic anion-transporting polypeptide [OATP] 1B1 and 1B3 and renal transporters organic anion transporter [OAT] 1 and 3 or organic cation transporter 2); and therapeutic proteins.3 Hepatic metabolism occurs via phase I and phase II metabolizing enzymes. Phase I metabolizing enzymes, which include CYP enzymes, MAO, FMO, XO, ADH, and ALDH, are involved in oxidation, reduction, hydrolysis, cyclization, and decyclization. Phase II metabolizing enzymes are involved in conjugation reactions, typically with glucuronic acid, sulfonates, glutathione, or amino acids via UGTs. See TABLES 1 and 2.3-6


table1


table2

The field of pharmacogenomics is adding to our knowledge about drug interactions and about how extensive metabolizer or poor metabolizer status affects a drug's pharmacologic effects. Genetic polymorphism can further predispose a patient to drug interactions. Among the CYP enzymes most susceptible to genetic polymorphism are CYP2D6, CYP2C19, and CYP2C9; UGT1A1 and OATP1BI (SLCOIBI) are also subject to genetic polymorphism.3

Significant Pain Medication Drug Interactions

The risk of drug interactions versus the drug's benefits must be assessed when an analgesic is being considered, and the patient should play an active role in this discussion. The concomitant administration of drugs known to interact with analgesics heightens the risk of interactions. The drugs upon which CYP enzymes and other chemical mediators act are known as substrates. See TABLE 3.3


table3

A discussion of every drug interaction, or even every major drug interaction, is beyond the scope of this article. TABLE 4 is a compilation of major drug interactions identified in the prescribing information for each drug, American Hospital Formulary Service monographs, Facts & Comparisons eAnswers, and a search of two online drug-drug identification programs.7-107 The most serious drug-drug interactions listed in both identification programs are included. When the possibility of drug interactions is being researched, it is suggested that at least two sources be checked because of discordance between references.2


table4
table4

Class Effects

Salicylates: Numerous drug interactions are reported with salicylates. However, the most clinically significant interactions involve concomitant use with anticoagulants, thrombolytics, uricosurics, sulfonylureas, corticosteroids, methotrexate (MTX), and alcohol.10

NSAIAs: These drug interactions represent a class effect, although there may be individual differences among agents in the class in terms of the probability of the interaction. Coadministration of diuretics (thiazide or loop) with non-steroidal anti-inflammatory agents (NSAIAs) results in impaired response and increased risk of renal toxicity. This occurs secondary to inhibition of renal prostaglandin synthesis, which leads to increased sodium and water reabsorption and elevations in blood pressure. When NSAIAs are used with oral corticosteroids or anticoagulants or in patients who smoke or regularly consume alcohol, there is an increased risk of gastrointestinal (GI) bleeding. The response of ACE inhibitors and angiotensin II antagonists includes an impaired hypotensive effect and an increased risk of renal toxicity.

In addition to the antagonistic effect of NSAIAs on the antiplatelet function of low-dose aspirin, aspirin also increases the adverse effects associated with NSAIA use secondary to decreased protein binding. Coadministration of NSAIAs and MTX can result in enhanced toxicity of MTX. Use of NSAIAs with cyclosporine can result in decreased synthesis of renal prostaglandins and enhanced nephrotoxicity. The reaction between digoxin and NSAIAs is variable, but it can result in enhanced digoxin toxicity secondary to alterations in renal prostaglandins.13,14,108

A reaction with a potentially serious outcome is that between lithium and NSAIAs; NSAIAs reduce lithium clearance, which leads to lithium toxicity, with an increase in mean lithium concentration of 15% and a decrease in renal clearance of approximately 20%. Other highly significant class-related drug-drug interactions involve NSAIAs and apixaban, which can lead to increased anticoagulation, and other NSAIAs and ketorolac, which results in pharmacodynamic synergism and enhanced toxicity.13,14,108

Data are somewhat conflicting regarding the antagonistic effect of NSAIAs on low-dose aspirin's antiplatelet effect.109-111 Differences exist in study methodology (e.g., in vivo versus in vitro, open-label vs. randomized, placebo-controlled, small sample size). Regardless, it appears that NSAIAs, especially ibuprofen and naproxen, interfere with the antiplatelet activity of low-dose aspirin (81 mg, immediate-release) when the drugs are ingested concurrently.112-116 Other NSAIAs implicated in this drug interaction include flurbiprofen, mefenamic acid, oxaprozin, indomethacin, and piroxicam.113,116,117 NSAIAs that tend to interfere less with low-dose aspirin's antiplatelet effects include meloxicam, nabumetone, and diclofenac112,118-121; the effects of celecoxib have been mixed.116,122-124 The mechanism by which this interaction occurs may involve competitive inhibition of the acetylation site of cyclooxygenase (COX) in the platelet. NSAIAs other than salicylates are involved in reversible inhibition, whereas aspirin is involved in irreversible inhibition. There is competition to occupy nearby sites on COX, such that the presence of NSAIAs interferes with aspirin binding. This NSAIA-aspirin interference attenuates the expected aspirin-mediated irreversible inhibition of thromboxane B2 production and the expected inhibition of platelet aggregation, which may place cardiovascular patients at risk.114,125 The timing of NSAIA administration with regard to aspirin appears to be highly relevant.113,114

Opiates: Opiates are associated with numerous drug-drug interactions, which can result in a heightened pharmacodynamic effect. When opiates are used with central nervous system (CNS) depressants (e.g., alcohol, other opioids, phenothiazines, sedative/hypnotics, antihistamines, anti-psychotics, antianxiolytics, general anesthetics, antiemetics, skeletal muscle relaxants, illicit drugs), there can be an additive or synergistic effect; this can cause respiratory depression, hypotension, profound sedation, coma, or death. The concomitant use of opiates and anticholinergics may result in an additive risk of urinary retention and paralytic ileus or severe constipation, which may be particularly problematic in elderly patients or patients taking other anticholinergic-type medications (e.g., drugs for urinary incontinence).13,14,126

Concomitant use of antidepressants can result in excessive sedation, acute hypotension, and excessive anticholinergic effects. When an opiate is administered with a monoamine oxidase inhibitor (MAOI; e.g., isocarboxazid, phenelzine, tranylcypromine) and a tricyclic antidepressant (TCA), the MAOI may markedly potentiate the action of the opiate. This is most prominent with meperidine. Opiates should not be used in patients taking MAOIs or within 14 days of stopping an MAOI. The use of opiate antagonists and partial opiate agonists (e.g., pentazocine, nalbuphine, butorphanol, buprenorphine) plus an opiate agonist may precipitate withdrawal.13,14,126

Amphetamines such as dextroamphetamine may enhance opioid-induced analgesia. The effect of diuretics may be decreased in heart failure patients because opiates induce the release of antidiuretic hormone. The use of opiates (both full agonist and agonist/antagonist opiates) with alvimopan is contraindicated because alvimopan competes with opiate binding sites. Opioids must be discontinued at least 7 days before alvimopan is administered. Other drugs implicated in opiate-related class drug-drug interactions include procarbazine, which inhibits MAO in the GI tract; sodium oxybate, which results in pharmacodynamic synergy and enhanced CNS depressant effects; and tramadol, whose diverse effects include precipitation of withdrawal in opiate-dependent patients and possible reinitiation of drug use in formerly opiate-dependent patients.13,14,126

Opiate Agonists/Antagonists: These drugs have a ceiling effect for analgesia, which may result in inadvertent coadministration with full agonist opioids. Opiate agonists/antagonists display a pattern of class-related drug-drug interactions that is similar to that of full opiate agonist drugs. In narcotic-dependent patients, opiate agonists/antagonists can precipitate withdrawal or loss of pain control. When used concomitantly with CNS depressants, these drugs carry the risk for increased CNS-depressant effects. The interaction between MAOIs and opiate agonists/antagonists may not be as defined as that occurring with full opiate agonists, but most drug references recommend avoiding concomitant use. Use of this class of analgesics with antipsychotics can result in enhanced hypotensive effect. More than one mixed agonist/antagonist should not be used at the same time.13,14,126

Strategies to Avoid Potential Drug Interactions With Pain Medications

During oxidation via CYPE1, which accounts for a small portion of acetaminophen (APAP) metabolism, a reactive intermediate toxic metabolite—N-acetyl-p-benzoquinone imine (NAPQI)—is formed. High doses of APAP deplete glutathione, which is needed to inactivate the toxic metabolite. A lack of glutathione and resultant high levels of NAPQI increase the risk of hepatotoxicity.7,8,127 Strategies to help minimize APAP-induced hepatotoxicity include avoiding the use, or limiting the dosage, of other hepatotoxic medications and alcohol whenever possible.

In 2009, the FDA required that manufacturers of APAP include the following warning on their product's label: "Liver warning: This product contains acetaminophen. Severe liver damage may occur if you take more than 4000 mg of acetaminophen in 24 hours with other drugs containing acetaminophen, or with 3 or more alcoholic drinks every day while using this product."128 In January 2011, the FDA recommended that prescription products containing acetaminophen contain no more than 325 mg per dose.129 In January 2014, the FDA went even further, recommending that healthcare professionals discontinue prescribing and dispensing prescription combination drug products containing more than 325 mg of acetaminophen.130

Concomitant ingestion of multiple products (prescription or OTC) containing acetaminophen can result in excessive doses and toxicity. Additionally, patients must be assessed for pain, since concomitant administration of CYP enzyme inducers may decrease the therapeutic effect of APAP. In patients receiving warfarin, limiting the APAP dosage to less than 1,950 mg weekly reduces the likelihood of a significant drug interaction. When high dosages of APAP are used, the prothrombin time and international normalized ratio should be monitored once or twice weekly until bleeding times are stabilized. It is especially important to closely monitor bleeding times upon therapy initiation and discontinuation. The warfarin dosage may be adjusted as needed. The dosage of lamotrigine may need to be increased with chronic APAP use.7-9

Drug interactions may contribute to aspirin resistance.131,132 The FDA has issued a black box warning for ticagrelor, a reversible antiplatelet agent, to avoid the use of maintenance doses of aspirin exceeding 100 mg per day because of concerns over reduced effectiveness of ticagrelor; the aspirin dosage should therefore be limited to 75 to 100 mg per day.17 However, some researchers have challenged this recommendation, citing reductions in major adverse cardiovascular events, 30-day all-cause mortality, and 30-day vascular mortality in diabetic patients receiving ticagrelor and aspirin at dosages of 300 to 325 mg per day.133

The FDA has recommended the following for the safe and effective administration of salicylates and NSAIAs: "With occasional use of ibuprofen, there is likely to be minimal risk from any attenuation of the antiplatelet effect of low dose aspirin, because of the long-lasting effect of aspirin on platelets. Patients who use immediate release aspirin (not enteric coated) and take a single dose of ibuprofen 400 mg should dose the ibuprofen at least 30 minutes or longer after aspirin ingestion, or more than 8 hours before aspirin ingestion to avoid attenuation of aspirin's effect. Recommendations about the timing of concomitant use of ibuprofen and enteric-coated low dose aspirin cannot be made based upon available data. Other nonselective OTC NSAIDs should be viewed as having the potential to interfere with the antiplatelet effect of low-dose aspirin unless proven otherwise. Prescribe analgesics that do not interfere with the antiplatelet effect of low dose aspirin for high risk populations."134

The FDA has noted that aspirin and salicylates should not be used by children and teens who have or are recovering from chickenpox or flulike symptoms. Children should be monitored for behavior changes accompanied by nausea and vomiting, which may be signs of Reye syndrome. Other warnings include GI bleeding and severe allergic reactions to aspirin or NSAIAs. The FDA considers the following patient populations to be at greatest risk: those aged 60 years and older; those with stomach ulcers or bleeding problems; those taking anticoagulants, corticosteroids, or other OTC or prescription NSAIAs; those consuming three or more alcoholic drinks per day; and those who take more medication than directed or take the medication for longer than directed.135

Opiates: The most problematic opiates are methadone, oxycodone, meperidine, fentanyl, codeine, and tramadol.

Methadone has high interpatient variability and a long half-life, making dosing difficult. The duration of activity is shorter than the plasma half-life, so accumulation can occur. Full analgesic effects are not seen until 3 to 5 days after therapy initiation; this may cause the prescriber to add additional pain medications to the patient's regimen, thereby increasing the risk of drug interactions and adverse effects. Methadone has a narrow therapeutic index, and deaths have occurred in opioid-tolerant patients during conversion to methadone. Coadministration of CYP3A4 and CYP2C9 inhibitors can lead to methadone toxicity, whereas concomitant methadone administration with CYP inducers can precipitate withdrawal. Drug-drug interactions play a significant role in the development of QTc prolongation, especially when the dosage and administration of other arrhythmogenics are considered.74-77

A serious concern regarding methadone is its potential to cause QTc prolongation via inhibition of cardiac potassium channels. Although the development of QTc prolongation and torsades de pointes is more common when the dosage exceeds 200 mg per day, patient-specific risk factors include the presence of cardiac hypertrophy, diuretic use, hypokalemia, hypomagnesemia, a history of cardiac abnormalities, and avoidance of methadone in patients taking other QTc-prolonging medications or drugs that inhibit methadone metabolism. QT prolongation has been reported in patients with no prior cardiac history who were taking high dosages of methadone. A baseline ECG should be obtained prior to methadone initiation. The drug-drug interaction between methadone and antiretrovirals is more complex. Concurrent use of protease inhibitors with CYP3A4 inhibitory activity results in increased clearance or a decreased plasma methadone level, which may also induce withdrawal. On the other hand, methadone decreases the bioavailability and peak effects of didanosine and stavudine, with a greater effect on didanosine levels, and it increases the bioavailability of zidovudine, possibly resulting in zidovudine toxicity.74-77

Oxycodone is the opiate with the greatest jump in usage from the year 2000 to 2010, increasing by 69.7%.136 Oxycodone is extensively metabolized via CYP3A4 and CYP2D6, which are often associated with drug-drug interactions. In 2009, approximately 16,000 people in the United States died from opiate-related overdoses. It is estimated that 11% of opiate-related events were due to excessive dosing, drug-drug interactions, and adverse reactions.137

Meperidine interacts with numerous psychotropic medications, possibly resulting in serotonin syndrome. However, it also interacts with linezolid, an anti-infective agent. If linezolid is indicated, meperidine must be discontinued immediately and the patient monitored for CNS toxicity. Meperidine may be restarted 24 hours after the last linezolid dose or after 2 weeks of monitoring, whichever comes first.13,14 To avoid the serious, sometimes fatal, reaction that can result from concomitant administration of an MAOI with meperidine or opioids, the patient must be off his or her antidepressant for at least 14 days.71-73

Because of substantial differences in pharmacokinetic profiles, different formulations of fentanyl should not be interchanged. Fentanyl also is associated with numerous drug-drug interactions. Patients need to be instructed on the proper use of the fentanyl patch, since overdoses have been associated with this route of administration.138

Codeine metabolism is subject to genetic polymorphism. The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5% to 1% in Chinese and Japanese, 0.5% to 1% in Hispanic, 1% to 10% in white, 3% in African American, and 16% to 28% in North African, Ethiopian, and Arab populations. Death has occurred in children who received codeine following tonsillectomy and/or adenoidectomy and were ultrarapid metabolizers of codeine (owing to CYP2D6 polymorphism) or who had received high morphine concentrations. Mortality has occurred in nursing infants who were exposed to high levels of morphine in breast milk from mothers who were ultrarapid metabolizers of codeine. This rapid conversion results in higher than expected serum morphine levels. Children with obstructive sleep apnea who are treated with codeine for posttonsillectomy and/or postadenoidectomy pain may be particularly sensitive to the respiratory depressant effects of codeine. As a result of these deaths, codeine is contraindicated for postoperative pain management in all pediatric patients who undergo tonsillectomy and/or adenoidectomy.57,58

Tramadol, a weak reuptake inhibitor of norepinephrine and serotonin, is extensively metabolized via CYP2D6 and CYP3A4 and undergoes conjugation. In poor metabolizers of CYP2D6, tramadol concentrations are 20% higher than in extensive metabolizers, and concentrations of the metabolite are 40% lower. Seizure risk associated with tramadol use is increased in patients taking selective serotonin reuptake inhibitors (SSRIs), anorectics, TCAs, other opioids, MAOIs, neuroleptics, or other drugs that lower the seizure threshold. The combination of tramadol and an epileptogenic should be avoided, if possible. Patients receiving tramadol with an SSRI, serotonin norepinephrine reuptake inhibitor (SNRI), TCA, MAOI, or triptan should be monitored for signs of serotonin syndrome, including mental-status changes (i.e., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).93,94

Opiate agonists/antagonists (i.e., partial agonists) have a ceiling effect on pain relief. The sublingual form of buprenorphine is not an analgesic; it is indicated only for the treatment of opioid dependence.139 Pentazocine is available with either naloxone or acetaminophen. Pentazocine is on the Beer's list, as it is associated with increased adverse CNS reactions in the elderly, including confusion and hallucinations.105-107

Conclusion

By increasing their knowledge about analgesic drug interactions, pharmacists can play a major role in helping patients and prescribers avoid potentially harmful adverse events that may be associated with the use of these medications.

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