Primum Non Nocere: Even a Little High Is Still High

One of the unresolved critical issues in opioid safety is defining the risk of developing a long-term opioid use syndrome, such as opioid abuse, opioid use disorder (e.g., addiction, dependence), or opioid-induced hyperalgesia. The existing risk assessment tools do not fare well, and while data point to the duration of the initial oral opioid prescription as the greatest risk contributor,1 less is known about the influence of the dose and the specific agent involved. Whereas most of the previous research has highlighted the risk of discharge prescriptions, insight into the risk of developing one of these syndromes after acute opioid administration in the emergency department (ED) remains murky. Early in the opioid epidemic, emergency physicians were criticized for being liberal prescribers of opioid analgesics and were told we were being targeted by “drug seekers” looking for a quick supply (which is likely not true). In response, we created prescribing guidelines, responded to regulations about dosing limitations, and checked our state’s prescription drug monitoring programs. As the data accumulated, we noted that while we were in fact prescribing opioids to many patients, as would be expected, we prescribed only very limited quantities and we became increasingly shrewd to whom we offered opioids. At the same time, we continued to administer opioids in the ED liberally. Despite our prescribing changes, we continued to use intravenous (IV) opioids for patients with migraine headache or renal colic or offer an opioid bolus to patients with exacerbation of their chronic back pain. With time, efforts to find alternatives to administering opioids in the ED gained footing, and we found ourselves relegating opioids to second or often third line for many patients with painful syndromes by using lidocaine patches, subdissociative-dose ketamine, or even lowly nonsteroidal anti-inflammatories and acetaminophen in their place.2 The goal of pain relief became clear, and our attempts to disentangle this from short-term euphoria and long-term harm became a guiding light. In the study “Opioid-induced Euphoria Among Emergency Department Patients With Acute Severe Pain: An Analysis of Data From a Randomized Trial” by Abril Ochoa et al, the authors examined opioid-induced euphoria in ED patients receiving parenteral hydromorphone for acute abdominal pain.3 The authors concluded that although hydromorphone-induced euphoria was measurable, it was less important, and therefore less consequential, for patients than relief of pain.3 We applaud the authors for studying this important topic, but we would like to further examine their interpretation. The authors evaluated opioid-naïve ED patients who presented with acute abdominal pain and received a 10-minute IV infusion of 1 mg of hydromorphone. The investigators questioned the subjects about pleasurable experiences after receiving the medication and this was compared to the experiences of individuals who received an infusion of the nonopioid lidocaine. They found that there was opioid-induced euphoria, even after accounting for relief of pain but felt that “opioid-induced euphoria did not seem to be important for these ED patients with acute abdominal pain.” Many, including us, would consider euphoria as an adverse effect related to opioid use and one that may be directly responsible for the development of long-term use or recreational use. The choice of hydromorphone is important because it is more euphoric than other opioids, both in opioid-naïve individuals and in those with opioid use disorder.4 This is due to its lipophilicity, which is 10-fold that of morphine, allowing it to cross the blood–brain barrier much more rapidly.5 Studies comparing parenteral morphine to hydromorphone found significantly more euphoria and reinforcement with hydromorphone.4 Hydromorphone in healthy volunteers demonstrated increased “pleasant bodily sensations” and “liking of the drug” compared to morphine.4 While immediate-release oral hydromorphone was less likely to be used recreationally compared to several other opioid formulations, there were higher rates of such use by injection.6 Additionally, hydromorphone has been used as a heroin substitute in safe consumption sites and through “heroin” vending machines that are being trialed in Canada.7 The rate of administration of hydromorphone also significantly affects its euphoric potential. In this study hydromorphone was administered as a short infusion over 10 minutes, which does not reflect real-world practice and may have underestimated the euphoric effect of hydromorphone. In many EDs, hydromorphone is administered as an IV bolus over 1 minute or less. Administering hydromorphone in a faster manner leads to higher initial central nervous system concentrations, causing a “rush,” which is more reinforcing. Despite the limitations, the study by Abril Ochoa et al. highlights important areas for future study and has significant implications for opioid administration in the ED.3 It is the first study of its kind that evaluates how the acute, parenteral administration of an opioid analgesic in the ED leads to euphoric effects. This is important because opioid analgesics, particularly hydromorphone, are commonly administered in the ED and many consider the various opioid interchangeable (which they are not). At the same time, much of the current research surrounding opioid utilization in the ED has focused not on the actual administration but rather on the subsequent adverse effects of the discharge prescription. Future studies should examine how the acute administration of parenteral opioids in the ED impacts long-term outcomes mentioned earlier; this has been increasingly scrutinized for postoperative pain management.8 These studies should include opioid-naïve individuals, those who are use opioids chronically, and those with a history of opioid use disorder. The fact that hydromorphone was associated with euphoria should cause emergency medicine as a specialty to pause and reevaluate our opioid utilization practices. Hydromorphone is one of the most commonly administered opioids in U.S. EDs and its use has been on the rise.9 While euphoria is indeed a surrogate marker for risk, important areas of future study include evaluating the comparative euphoric effects of different opioids in the ED setting, under real-world conditions, so that we may identify the least likely to risk harm. EDs and professional organizations should consider evaluating their current opioid policies to limit the use of more abuse-liable opioids, particularly hydromorphone, in favor of less euphoric opioids, such as morphine.10 The analgesic efficacy of morphine and hydromorphone are equivalent when dosed appropriately.11 When a parenteral opioid is indicated, hydromorphone should be reserved for patients who have refractory pain despite adequate treatment with a less euphoric opioid, during times of opioid shortages, or perhaps in select conditions, such as end-of-life care. When parenteral hydromorphone is indicated, we can implement ways to limit the euphoric effects, such as administering it by infusion as opposed to a rapid bolus and limiting the concurrent administration of the “potentiator” diphenhydramine. Furthermore, perhaps due to its high potency and thus low dose requirement (1 mg is equal to about 7 mg of morphine), there is an increased incidence of adverse drug effects and error associated with hydromorphone.4 Safe utilization practices, which are already in place for this high-risk class of opioids, need to be enforced to assure that these never events do not occur. The study by Abril Ochoa et al. represents an important first step in identifying that the acute parenteral administration of hydromorphone is associated with euphoric effects. This will hopefully stimulate additional research examining the downstream effects of acute ED administration of parenteral opioids and promote opioid stewardship,2 particularly the use of opioid alternatives, in the ED. While we all agree that pain reduction is a key principle of compassionate emergency care, imparting risk through the use of euphoric medication, no matter how little the high, does not satisfy the perhaps most important principle: primum non nocere—above all, do no harm.

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