A Comparison of Tertiary Drug Resources’ Consistency Regarding Drug-Drug Interactions of Adjunctive Analgesics

Abstract

Background: Health care providers routinely rely on tertiary drug information resources to affirm knowledge or proactively verify the safety and efficacy of medications. Though all patient care areas are affected, the reliability of these resources is perhaps nowhere as poignant as it is in high-acuity settings, including the emergency department and the intensive care unit. As providers seek to identify adjunctive analgesics for acute pain in these areas, they must be able to rely on the integrity to whichever resource their institution has granted access. Objective: To determine the congruency of drug-drug interaction information found on 3 tertiary drug resources. Methods: A drug-drug interaction analysis was conducted on Micromedex, Lexicomp, and Medscape. Adjunctive analgesics included dexmedetomidine and ketamine, which were compared with the intravenous opioid products morphine, fentanyl, and hydromorphone. Results: Significant discrepancies were appreciated with regard to the severity of drug-drug interactions. In addition, the heterogeneity in which reaction severity and likelihood are described by each respective resource makes direct comparisons difficult. Interaction warnings for dexmedetomidine and fentanyl included a “major interaction” from Micromedex, whereas Lexicomp did not identify a risk and Medscape only recommended increased monitoring on the grounds of respiratory and central nervous system depression. Conclusions: Health care providers must remain vigilant when reviewing tertiary drug information resources. Pharmacists possess the training and skills necessary to assist interdisciplinary medical teams in providing optimal patient care through evaluating and applying the information gleaned from these resources.

Background

While opioids have traditionally been the selected analgesic for acute pain in hospitalized patients, adjunctive agents are being utilized extensively in an effort to reduce both opioid doses and prescriptions.¹ Legislative and deprescribing initiatives over the past decade have been effective in limiting the number of opioid doses dispensed from pharmacies; however, these actions have also made managing pain in high-acuity settings, such as in emergency departments and intensive care units, a more difficult process in which numerous medications are employed.^2-4 Though many different classes of drugs are used, including nonsteroidal anti-inflammatories and those used for neuropathic pain, 2 increasingly common medications that are used as adjuncts to opioids are dexmedetomidine and ketamine.⁵

Dexmedetomidine is a centrally acting α₂-agonist that has sedative, anxiolytic, and analgesic properties.⁶ Though traditionally used in the intensive care unit for light levels of sedation, an increasing number of emergency medicine practitioners are relying on this drug to provide anxiolysis and as an adjunct to intravenous opioids as it can be easily titrated to effect.⁶ Ketamine is a N-methyl-d-aspartate receptor agonist in the central nervous system (CNS) that also boasts sedating, anxiolytic, and analgesic properties.⁷ Historically used for subprocedural sedation, it is now more frequently being administered in conjunction with opioids, with or without benzodiazepines, to provide a holistic approach to patient management in high-acuity settings.⁷

Pharmacists are uniquely qualified to provide drug information and therapy recommendations to other health care providers in high-acuity settings, and their comprehensive training in pharmacotherapy has demonstrated better patient outcomes and lower health care costs in a variety of clinical areas.^8-10 Despite these facts, not all health care systems employ emergency department pharmacists, and the intimate drug knowledge required to make an appropriate recommendation in the emergency setting is not possessed by all pharmacists.¹¹ Regardless of training, level of expertise, or years in the profession, pharmacists and other health care providers alike rely on tertiary drug resources as a tool to provide up-to-date information in a rapid fashion.¹² Alarmingly, discrepancies have been found to exist between tertiary resources, thus putting the health of patients and the confirmation of knowledge by health care providers at the mercy of whatever service is contracted by the health system in which they are treated or employed, respectively.

The objective of this study was to describe the discrepancies that exist between tertiary drug information resources as applied to drug-drug interactions between dexmedetomidine, ketamine, and intravenous opioid medications.

Methods

An analysis was conducted on 3 different, widely available and utilized tertiary drug resources, in an attempt to quantify the results of drug-drug interaction screening between dexmedetomidine, ketamine, and various intravenous opioids. A drug interaction search comparing ketamine with fentanyl, morphine, and hydromorphone was conducted using Lexicomp (Wolters-Kluwer Health), Micromedex (IBM Analytics), and Medscape.^13-15 The drug interaction search was then repeated, substituting dexmedetomidine for ketamine, in each of the 3 tertiary references. Following the results of each independent drug-drug interaction search, the authors reviewed severity indexes as well as any primary literature made available through the respective tertiary resource.

Each adjunctive agent was input to the drug-drug interaction search engine on Lexicomp, Micromedex, and Medscape, in combination with fentanyl, morphine, and hydromorphone, between March and April 2020. The interactions of both dexmedetomidine and ketamine were each reviewed for a total of 9 interaction screens.

Results

Micromedex displayed results with a severity rating (major vs minor), level of documentation (ie, fair), and a brief description. Lexicomp similarly displayed a severity rating; however, it differed from Micromedex by using an alphabetized scale to demonstrate risk (A = minimal/none through E = severe). Data from Medscape differed from the other 2 tertiary resources, in that the severity of an interaction was quantified by the level of monitoring necessary rather than by a scale. A full list of results can be viewed in Table 1.

Table 1.

Scoping Study of Drug-Drug Interactions Between Dexmedetomidine, Ketamine, and Select Opioids.

Opioid and adjunct	Micromedex	Lexicomp	Medscape
Dexmedetomidine and fentanyl	Severity: Major. Documentation: Fair. Concurrent use of fentanyl and CNS depressants may result in increased risk of CNS depression.	No interactions of risk level A or greater identified	No interactions found
Dexmedetomidine and Morphine	Severity: Major. Documentation: Fair. Concurrent use of morphine and CNS depressants may result in increased risk of CNS depression.	Risk Rating C: Monitor therapy. Blood pressure lowering agents may enhance the hypotensive effect of Hypotension-Associated Agents. Severity Moderate Reliability Rating Fair	Monitor closely: dexmedetomidine and morphine both increase sedation. Use caution/monitor.
Dexmedetomidine and hydromorphone	Severity: Major. Documentation: Fair. Concurrent use of hydromorphone and CNS depressants may result in increased risk of CNS depression.	No interactions of Risk Level A or greater identified	Monitor closely: Dexmedetomidine and hydromorphone both increase sedation. Use caution/monitor.
Ketamine and morphine	Severity: Major. Documentation: Fair. Concurrent use of morphine and CNS depressants may result in increased risk of respiratory and CNS depression.	Risk Rating D: Consider therapy modification. CNS depressants may enhance the CNS depressant effect of Opioid Agonists. Severity Major Reliability Fair	Monitor closely: Ketamine and morphine both increase sedation. Use caution/monitor.
Ketamine and fentanyl	Severity: Major. Documentation: Fair. Concurrent use of fentanyl and CNS depressants may result in increased risk of CNS depression.	Risk Rating D: Consider therapy modification. CNS depressants enhance the CNS depressant effect of opioid agonists. Severity Major Reliability Rating Fair.	Serious-use alternative. Fentanyl, ketamine. Either increases effects of the other by pharmacodynamic synergism. Avoid or use alternate drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.
Ketamine and hydromorphone	Severity: Major. Documentation: Fair. Concurrent use of hydromorphone and CNS depressants may result in increased risk of respiratory and CNS depression.	Risk Rating D: Consider therapy modification. CNS depressants may enhance the CNS depressant effect of opioid agonists. Severity Major Reliability Fair	Monitor closely: ketamine and hydromorphone both increase sedation. Use caution/monitor.

Abbreviation: CNS, central nervous system.

All combinations of dexmedetomidine or ketamine with any of the opioids reviewed were ranked as a “major” interaction in Micromedex. This severe warning was issued due to an increased risk of respiratory depression and negative CNS effects. Conversely, Lexicomp stated that one of the “major” interactions between dexmedetomidine and fentanyl did not pose a risk, which was further validated by Medscape that did not identify a reaction. Similarly, where Micromedex found an interaction of ketamine and morphine to be “major,” Lexicomp only assigned a “Risk Rating D,” though both cite respiratory and CNS depression as the reason for concern. Medscape identified this interaction, though only recommended to “monitor closely” as both agents have sedative properties.

Primary or supporting literature referenced by the tertiary resource in conjunction with the drug-drug interaction ranking were reviewed by the authors. As with the heterogeneity of results and ranking systems employed by the 3 resources reviewed, the primary literature associated with each drug-drug interaction result was specific to each resource. Whereas documentation was provided detailing the predicted adverse effect on all platforms, though the articles sourced varied.

Discussion

This analysis of drug-drug interactions between dexmedetomidine, ketamine, and select intravenous opioids on Micromedex, Lexicomp, and Medscape highlighted notable and clinically significant discrepancies. These discrepancies between resources were appreciated not only in the type, rating, or severity of the warning but also in the way in which explanatory information was summarized and presented to the reader.

In order to appreciate the discrepancies noted, it is important to note the source of information found in Micromedex, Lexicomp, and Medscape. Micromedex is a composite of more than 30 individual drug information resources, including over-the-counter, toxicology, laboratory sciences, drug pricing, calculators, and components of the Physician’s Desk Reference.¹⁶ Lexicomp has a slightly smaller arsenal in its 25-item repository, which has functionality in all of the same areas as Micromedex in addition to some nuances, including 6 different external sources utilized to compile drug monographs.¹⁶ Finally, Medscape pulls information directly from MEDLINE, and it has been freely available on the internet since the early 1990s.¹⁷

While Medscape may not initially be considered a drug resource that is appropriate for health care providers when compared with Micromedex or Lexicomp, it remains an important comparator for 3 reasons. First, it is an easily accessible tool that can be accessed from any internet-connected device; second, it is free of charge, compared with relatively expensive individual or institutional access fees for other drug resources; and finally, it boasts an intuitive and user-friendly interface. It is beyond plausible that health care providers who lack the experience with a more comprehensive drug resource, or those who are having difficulty accessing an institutional resource, may turn to Medscape as a drug-drug interaction resource.

The consideration between a robust drug information resource with a free and user-friendly comparator is not without precedent. In their review, Hunter et al¹⁸ compared Lexicomp to Wikipedia with regard to each platforms’ content and supporting references. Doses and dose directions, medication indication, and adverse effects were compared for levothyroxine, atorvastatin, pantoprazole, acetylsalicylic acid, and metformin.¹⁸ In every category, Lexicomp was unquestionably the more comprehensive resource, making it apparent that free resources may not have the same quantity or quality of information in the health information sector.¹⁸ This conclusion is further validated by the work of Clauson et al,¹⁹ who compared Medscape to Wikipedia in 8 domains of drug information inquiries. Though Medscape outperformed Wikipedia in answers to drug information questions (40% vs 82.5%, P ≤ .001), and information completeness (76% vs 95.5%, P ≤ .001), it is important to note that Lexicomp scored at 100% across all domains in the previously discussed Hunter article.^18,19 The discrepancies between Micromedex and Lexicomp have more dangerous implications than the discrepancies of Medscape in comparison to either database. Though Lexicomp demonstrated favoritism over Micromedex in an analysis of pharmacists by Mountford et al,¹² there were no questions raised as to the quality or quantity of the content on either database.

The medications chosen for this evaluation were specifically selected due to their frequent use in high-acuity environments in an effort to highlight the danger of conflicting information in this setting. The ramifications of this conflicting information are incalculable in many ways, but at surface value, may influence the care received simply based on whatever tertiary drug resources has been provided by an institution. Providers must remain judicious in interpreting drug information, specifically the severity and likelihood of drug-drug interactions, from tertiary resources. Pharmacists continue to play a crucial role as an integrative member of the patient care team, and possess the training and skills necessary to mitigate the uncertainty described in this report.

Several limitations in this report exist that warrant discussion. First, though Micromedex and Lexicomp are arguably 2 of the most commonly available tertiary drug information resources available in US health care institutions, Clinical Pharmacology is also widely utilized and was not included in this evaluation due to limitations of institutional access. Second, only a single free resource was evaluated, whereas others, such as Wikipedia, could have been in an effort to lend credence to the notion that both Micromedex and Lexicomp are superior databases. Third, the heterogeneity between tertiary resources’ severity indices made direct comparison of risk difficult to interpret. Finally, our drug selection for the drug-drug interaction exercise only included 5 drugs, which may have inadvertently skewed the results due to the small sample size.

Conclusions

Caution must be exercised when interpreting drug-drug interaction data provided by tertiary drug resources. Health care providers must be cognizant of the inherent differences of these resources, and rely on clinical judgement in order to provide optimal patient care. In addition, bedside clinicians should always use a comprehensive drug reference as opposed to a free, internet-based search. As drug information experts, pharmacists are prepared to assist in the provision of pharmaceutical care that is both safe and efficacious.