Continuing Education Activity

Drug-drug interactions (DDI) are a significant cause of adverse drug events (ADE) in palliative care. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions). It reviews the importance of the interprofessional team in identifying this issue.

Objectives:

• Review the pharmacokinetics and pharmacodynamics of drugs in palliative care.
• Identify serotonin syndrome using the Hunter criteria.
• Explain the importance of monitoring for drug-drug interactions in palliative care.
• Summarize the importance of improving drug-drug interactions education in palliative care.

Introduction

Drug-drug interactions (DDI) are a frequently encountered phenomenon in palliative care (PC) settings. To optimize management, clinicians should be aware of the pharmacokinetics and pharmacodynamics of the most commonly used drugs in this patient population. Based on a patient’s inherited alleles, age, sex, physiologic status, etc., pharmacotherapy will vary significantly from one patient to the next. Also, clinicians must be familiar with potential drug interactions.[1] Several studies have elucidated the prevalence of DDI in palliative care from 31 to 75% across various health care settings.[2] It is worth mentioning that palliative care medicine involves the concerted efforts of a multidisciplinary team to reduce disease burden for patients living with serious illnesses, whether provided concurrently with curative care or alone for comfort care.

Function

Pharmacotherapy consists of two processes: pharmacokinetics (effect the body has on the drug) and pharmacodynamics (physiological impact the drug has on the body). Pharmacokinetics involves four different steps: Absorption, distribution, metabolism, and excretion. These four individual processes vary greatly depending on the physiologic status of an individual. Drug absorption can be affected by the route of administration (e.g., gastroenteritis will result in minimal absorption via the oral route). Drug distribution varies according to the percentage of body fat per individual. The total area of distribution increases with fat, which then determines how much of the drug remains in circulation to interact with the desired receptors at target organs. Drug metabolism is the structural change that drugs undergo, most commonly seen in the liver, lungs, and kidneys. There are two phases of metabolism. For phase 1, the prodrug is biotransformed into an active or inactive metabolite via oxidation, reduction, and/or hydrolysis. During phase 2, the remaining compounds are metabolized into polar molecules allowing for future elimination. Lastly, drug excretion is dependent on how fast a drug and its metabolites get removed from the body.

A significant percentage of drug metabolism in the liver relies on the P450 family of isozymes, of which six are responsible for the metabolization of about 80% of all drugs: CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP2E1, and CYP3A4. Isozymes biotransform drugs into their active components.[3] When drugs are metabolized, their bioavailability increases as they reach maximum serum concentration (Cmax) levels. Some medications have active metabolites (intermediate products of metabolism) that can also add to the total physiologic effect of the drug. Drugs metabolized by the CYP450 system are divided into three categories: inducers, inhibitors, and substrates. Inducers are drugs that prompt an isozyme to metabolize other drugs faster, thus decreasing their total plasma concentration. Inhibitors will decrease the metabolism of a substrate by an isozyme, thereby increasing the substrate’s plasma concentration. Drugs metabolized by specific isozymes are called substrates. Increasing serum levels of unmetabolized substrates may not always cause an adverse drug event as some drugs require biotransformation to become biologically active.

Drug-drug interactions are particularly important as they will affect the onset of action, time to Cmax, half-life, and steady-state after roughly five half-lives of drug administration of a fixed-dose at regular intervals.[4] Please note that the following lists are not exhaustive and only include some of the most common culprits involved in drug-drug interactions:[1][4]

CYP450 Inducers

• Rifampin
• Barbiturates
• Carbamazepine
• Griseofulvin
• Primidone
• Phenytoin

CYP450 Inhibitors

• Amiodarone
• Cimetidine
• Diltiazem
• Grapefruit juice
• Omeprazole
• Macrolides (except azithromycin)
• Ketoconazole
• Verapamil

Genetic polymorphism also plays a significant role in drug pharmacokinetics. The hepatic isozyme CYP2D6 has been found to have the largest number of allelic variants. Interindividual variability response to CYP2D6 substrates is the result of high interethnic genetic variance. This genetic variance produces a spectrum ranging from poor metabolizers that have very little to no enzymatic CYP2D6 activity to ultra-fast metabolizers, as observed in the general population. Poor metabolizers are more likely to experience poor analgesic relief due to limited substrate biotransformation, thus increasing the risk for therapeutic failure and the need for rescue pain medications. Poor metabolizers get unevenly distributed amongst different ethnic populations: White race 6 to 10%, African Americans 2 to 5%, and Asians less than 1%. For example, poor metabolizers require increasing doses of the opioid analgesic codeine due to its decreased bioactivation into its far more potent metabolite, morphine. As a result, health workers may erroneously perceive poor metabolizers as drug-seekers. Conversely, ultra-fast metabolizers will experience heightened analgesic effects and are at higher risk of toxicity, even at labeled dosage regimens. Similar results are also observable with additional medications such as tramadol, which undergo CYP2D6 polymorphic drug metabolism; therefore, caution is necessary. Non-opioid analgesics and morphine are considered suitable alternatives in these instances. CYP2D6 ultra-fast metabolizers are also at risk for therapeutic failure with the selective serotonin-norepinephrine reuptake inhibitor (SSNRI) venlafaxine. The use of this antidepressant is prevalent in the palliative care setting for concurrent treatment of depressive disorders and neuropathic pain.[5] Diazepam, a long-acting benzodiazepine frequently used in patients with renal and hepatic dysfunction, is metabolized by CYP2C19 and CYP3A4. Poor metabolizers are more likely to experience prolonged sedation associated with the reduced metabolic activity of these isozymes. As an anticonvulsant, phenytoin can also carry a high risk for toxicity in the Asian population as a result of polymorphic variation. Phenytoin metabolism is via the isozymes CYP1A2, CYP2C9, and CYP2C19; therefore, it has the potential to achieve supra or subtherapeutic levels at lower doses depending on the individual’s phenotype.

Medications often found to have the highest number of drug-drug interactions in the PC setting include nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, anticonvulsants, anticholinergics, and methadone.[6][7]

NSAIDs: Used as an adjunct for pain management, they decrease renal perfusion via inhibition of prostaglandin synthesis, a critical arteriodilator. NSAIDs react synergistically with other agents such as clopidogrel, aspirin, and warfarin, thereby increasing the risk of cardiovascular adverse events, stroke, bleeding, and death.[4]

Warfarin: Oral anticoagulant used to prevent the formation of blood clots. Warfarin is a vitamin K antagonist that blocks the hepatic synthesis of several coagulation factors. It has the potential to interact with NSAIDs, acetaminophen, macrolides, quinolones, trimethoprim-sulfamethoxazole, and phenytoin, consequently increasing bleeding risk.

Anticonvulsants: Phenytoin and carbamazepine have significant drug-drug interactions due to their role as CYP450 inducers. Phenytoin is primarily used as an anticonvulsant, while carbamazepine is an option in managing neuropathic pain.

Anticholinergics: Atropine, scopolamine, and glycopyrrolate are primary agents used to decrease salivary, bronchial, and gastrointestinal secretions in the palliative care (PC) setting. Anticholinergic medications have a cumulative effect, manifesting as constipation, mydriasis, urinary retention, tachycardia, altered mental status, bowel obstruction, and decreased sweating.

Methadone: A potent, long-acting opioid agonist, is favored in PC due to its cost-effectiveness, convenient routes of administration, inactive metabolites, and relatively safe profile in end-stage-renal disease. Methadone is a racemic mixture of two stereoisomers. Its R-enantiomer has analgesic properties, while its S-enantiomer acts as an NMDA receptor antagonist, thereby preventing opioid tolerance with prolonged use. This drug is mostly metabolized in the liver by the CYP2B6 isozyme. Due to CYP2B6 polymorphism, diminished methadone N-demethylation may account for interindividual pharmacokinetic variability. Furthermore, several studies support allelic variations of the CYP2B6.6 gene, thereby predisposing African Americans to lower drug metabolic and clearance rates. Due to the potential association between methadone use and QTc prolongation and cardiac arrhythmia, ECG monitoring before initiation of methadone and during methadone dose changes is recommended. In the presence of risk factors for QTc interval prolongation such as electrolyte abnormalities, liver impairment, structural heart disease, use of drugs with QTc-prolonging properties, close ECG monitoring, and dose reduction are recommended as necessary.[8]

Additionally, antidepressants like selective serotonin reuptake inhibitors (SSRIs) and tricyclics vary in their anticholinergic effects; therefore, it is appropriate to replace drugs like paroxetine and amitriptyline with better-tolerated antidepressants such as sertraline and nortriptyline, respectively. Similarly, low-dose haloperidol has fewer anticholinergic effects when compared to other antipsychotics.

A severe adverse event often encountered and misdiagnosed when using serotonergic drugs is Serotonin Syndrome (SS). Clinicians may utilize the Hunter Criteria as a diagnostic aid, which requires that the patient be on a serotonergic agent and exhibit one of the following:[7]

• Spontaneous clonus
• Inducible clonus PLUS agitation or diaphoresis
• Ocular clonus PLUS agitation or diaphoresis
• Tremor PLUS hyperreflexia
• Hypertonia PLUS temperature above 38oC PLUS ocular clonus or inducible clonus

Many drugs can precipitate serotonin syndrome, including but not limited to fentanyl, tramadol, metoclopramide, ondansetron, lithium, buspirone, levodopa, SSRIs, SNRIs, and linezolid.[7]

It is worth noting that despite the side-effect profile of medications such as benzodiazepines, low- molecular-weight heparin, morphine, proton-pump inhibitors, and gabapentin, all were found to have the lowest risk for DDIs in the palliative care setting.

Issues of Concern

Due to the widespread misuse of prescription opioids in recent years, the CDC previously released explicit practice recommendations for primary care clinicians who prescribe opioids for chronic pain. The CDC later released a statement clarifying that their guidelines for prescribing opioids intended to guide primary care practitioners treating patients with “chronic pain outside of active cancer treatment, palliative care, and end-of-life care.''[9] This is particularly important because 70 to 90% of cancer patients will experience significant pain near the end-of-life that will require around-the-clock opioids and adjuvant medications. Over half of these patients will experience breakthrough pain, especially those with neuropathic and bone pain.[10] Adequate pain control is an integral part of palliative care as many patients believe unrelieved pain to be a key attribute eroding dignity towards the end of life.[11][12][13]

Pain should be assessed, quantified, and documented often. The FDA’s definition of opioid tolerance can help the clinician distinguish opioid naïve patients from opioid-tolerant patients. The WHO’s analgesic ladder can be employed and supplemented with analgesic adjuvant therapy with agents such as NSAIDs, corticosteroids, antidepressants, anticonvulsants, and ketamine.[7][12] Optimizing drug therapy in the earlier stages of disease should include careful documentation of any over-the-counter supplements, recognition of critical drug-nutrition interactions (e.g., herbal supplements), and potential polypharmacy.[8] An accurate history and thorough documentation are particularly important when as many as 25% of U.S. adults endorse taking herbal supplements in conjunction with their medications for serious illness. These herbal supplements have the potential of altering pharmacokinetics (e.g., therapeutic dose) and or pharmacodynamics by enhancing or negating prescription medications. The two most commonly used herbal supplements are St. John’s wort and goldenseal.[3]

Clinical Significance

Aligning the treatment plan with goals of care, optimizing symptom management, maximizing the patient's level of comfort, facilitating safe discharge planning, and helping with the transition of care for concerned family members are at the heart of palliative medicine. However, DDIs are an unfortunate type of adverse drug event that becomes more frequent in later stages of diseases as patients begin to experience progressive organ function decline and increased symptoms, thus requiring polytherapy and increasing doses of analgesics. Ultimately, the type of pain, choice of drug, optimal dose, and route to achieve appropriate symptom control for each patient will depend on the prescriber's clinical judgment and will vary considerably based on individual patient response.[13] Nonpharmacologic interventions and spiritual/psychological guidance are an essential part of palliative medicine and, in conjunction with routine pain assessments, can help optimize palliation and increase the quality of life. 

Enhancing Healthcare Team Outcomes

Symptoms commonly encountered in palliative care may include dyspnea, air hunger, constipation, uncontrolled bleeding, excessive respiratory tract secretions, delirium, depression, insomnia, refractory nausea, vomiting, pruritus, urinary retention, and uncontrolled pain require continuous and frequent reassessments as patients transition to comfort-focused care near the end of life. Management of these symptoms will always involve nonpharmacologic therapy in addition to pharmacotherapy, yet knowledge of significant DDI, interpatient variability and drug-nutrient interactions by interprofessional team members is critical for safe and effective care. Existing literature encourages the utilization of mobile and online equianalgesic tables, opioid rotation guidelines, drug interaction checker apps, and clinical decision support (CDS) alerts in electronic medical record systems as they have all been critical in decreasing DDIs and potential adverse drug reactions.[14] Furthermore, increasing drug-drug interaction awareness in prescribers improves deprescribing skills, thus decreasing the frequency of adverse drug events.[15][16][17][18][19]

This is where a pharmacist consult is necessary, so a thorough medication reconciliation can take place, looking for interactions, verifying dosing, and communicating with the prescriber as well as the palliative care nursing staff, so that all members of the interprofessional team are on the same page. Advance care planning should be discussed early in the disease process to understand individual patient preferences, needs, and values and to ensure the designation of a surrogate decision-maker. Only through an interprofessional team model involving clinicians, nursing, pharmacy, nursing assistants, other palliative care providers, as well as the patient and their family caregivers, can DDI in palliative cases be avoided. [Level 5]

Patients facing serious illness with complex symptom management value medication-specific optimization conversations and medication reviews by members of the interprofessional palliative team. Comprehensive palliative care assessment and goal setting through shared decision-making must align treatment plans with patients’ known goals and values and ensure transparency due to the delicate nature of this particular healthcare setting.[17]