With increasing frequency, we encounter patients to whom, under the banners of enhanced recovery after surgery and multimodal analgesia, a multitude of drugs have been administered. At times, the melange can include a cyclooxygenase-2 inhibitor, dexamethasone, dexmedetomidine, fentanyl (and/or other opioids), gabapentin, ketamine, lidocaine, midazolam, magnesium, scopolamine (transdermal), and a volatile anesthetic. The recent articles by Beloeil et al., Shanthanna et al., and Kharasch and Clark have all presented timely and clinically pertinent discussions of the analgesic limitations of the multimodal analgesia regimens that have been implemented in the name of opiate sparing and opioid-free anesthesia.1–3  However, we suspect that the hazards of these regimens have not been given sufficient emphasis. While the enhanced recovery after surgery and multimodal analgesia banners may be worthy ones, and their benefits may be substantial, the potential harms have been underestimated.

The easy observation is that the multitude of potential drug interactions seems to be given little consideration and has most definitely received little systematic study.4,5  To highlight that point, consider the elaborate detail of our knowledge of the response face interactions of propofol and opioids and contrast that with the void that is our systematic knowledge of the interactions between the various agents administered during multimodal analgesia. Second, the zeal to pursue multimodal analgesia has led to the implementation of drugs, most notably lidocaine and ketamine, whose efficacies, ideal situations, and optimal regimens (if they are effective at all) are more dependent on speculation and best guess than science.6–8 

There is no question that opioids remain the most efficacious analgesics available. For the better part of the last half century, opioids have been a pillar of balanced anesthesia. Coupled with our sedative-hypnotics, opioids interact synergistically to increase sedation and control autonomic nervous system responses. These interactions are known and indisputable—response surface models describe this synergism specifically and elegantly.9,10  This two-drug, balanced anesthetic is simple, reliable, and scientifically sound.

In and of themselves, nonopioid analgesics do not have the same efficacy as opioids. One by one, the utility of these drugs as perioperative analgesics is being disproven as studies hypothesizing their efficacy are prematurely halted for futility.1,11 

Undeterred by the lack of efficacy of single nonopioid drug regimens, proponents of nonopioid analgesia have employed various combinations of these drugs, in varying concentrations, in the hope that additive or synergistic interactions will result in a clinical effect equal to that of opioids. Unfortunately, the exact nature of the interactions between nonopioid analgesics is poorly characterized.12  To date, there are no well-characterized, evidenced-based, opioid-free regimens to serve as guides for clinical application.13  In fact, many regimens are anecdote-based “recipes” employing a variety of combinations and doses.14–16  Uncharacterized interindividual variability in the relationships between drug concentration over time (pharmacokinetics) and physiologic response versus drug concentration (pharmacodynamics) has made rational selection of agents and dosing regimens difficult. Simply stated, we know very little to nothing about proper drug combinations or dosing regimens.

To ignore the potential harm of the polypharmacy associated with multimodal analgesia is hubristic. It is naive to assume that the side effects of these agents are benign or less severe than those of opioids.1,17–21  Furthermore, there is clear evidence that the incidence of adverse drug–drug interactions increases exponentially with the number of drugs administered. Approximately 40% of patients given 16 drugs during an anesthetic had an adverse drug interaction, compared to only 5% who were given 6 drugs.22,23 

The promises of multimodal analgesia are grand: provide analgesia equal to that offered by opioids with a side-effect profile that is comparably benign. Unfortunately, the side effects of these drugs are not benign, the analgesic efficacy of various combinations is unproven, and the optimal combinations and doses remain speculative or anecdote-based at best. Furthermore, as separate groups of well-intentioned care providers work in parallel to implement both enhanced recovery after surgery and multimodal analgesia strategies, the potential for drug interactions to intrude is further increased. To our habit of “Vigilance,” we should add caution and skepticism about incompletely studied drugs and drug combinations.

Dr. Ingrande currently receives grant support from Merck, Sharpe, and Dohme (all Kenilworth, New Jersey). Dr. Drummond declares no competing interests.

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