Abstract
-
Objective
Emergency physicians have become hesitant to treat patients with opioids because of downstream sequelae related to opioid use disorder. We enrolled a prospective cohort to determine whether the experience of a patient receiving an intravenous (IV) opioid was associated with multiple opioid prescriptions. Specifically, we tested whether greater improvements in pain and a larger euphoric response could predict which previously opioid-naive patients exposed to IV opioids would fill at least two opioid prescriptions in the subsequent 6 months.
-
Methods
We recorded pain scores (range, 0–10) before and 15 minutes after opioid-naive emergency department patients were given IV opioids to manage severe pain. We also determined opioid-induced euphoria (range, 0–10 points) by querying how good, how high, how much euphoria the opioid caused, and how likely the participant was to want the opioid again. Six-month outcomes were ascertained using the state prescription monitoring database.
-
Results
Among 506 patients, 32 (6.3%) filled at least two prescriptions during the 6 months following the emergency department visit. There were no differences between those who filled ≥2 prescriptions and those who did not with regard to pain relief (P=0.54), how good the medication made participants feel (P=0.91), how high the medication made participants feel (P=0.97), how much euphoria the opioid caused (P=0.23), or how likely the participant was to want the medication again (P=0.37).
-
Conclusion
Filling at least two opioid prescriptions was uncommon after initial exposure to therapeutic IV opioids and was unrelated to either analgesic efficacy or opioid-induced euphoria.
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Keywords: Opioids; Opioid-induced euphoria; Analgesia; Persistent opioid use
Capsule Summary
What is already known
The frequency of persistent opioid use may have reached as high as 14% among opioid-naive emergency department (ED) patients exposed to opioids, though increased awareness of the potential harms of opioid prescribing and secular trends in the management of pain have lowered this rate to 1%. Nevertheless, because of the very frequent use of opioids in the ED, it is important to understand who is at risk of persistent opioid use.
What is new in the current study
Neither the analgesic efficacy of an opioid nor opioid-induced euphoria is associated with a patient filling at least two opioid prescriptions during the 6 months following an ED visit, though both a history of chronic pain and older age are associated with this outcome.
INTRODUCTION
Two-thirds of emergency department (ED) patients present to an ED because of pain [
1]. While disease-specific treatments are available for some painful disorders, including migraine [
2], gout [
3], and gastritis [
4], emergency physicians are forced to use nonspecific analgesics for many other patients. Opioids have long been used as nonspecific yet potent analgesics. Over the last decade, however, emergency physicians have become increasingly reluctant to treat patients with opioids because of fears of downstream sequelae related to opioid use disorder [
5–
7]. The frequency of persistent opioid use among ED patients exposed to opioids may have reached as high as 14% [
8], though increased awareness of the potential harms of opioid prescribing and secular trends in the management of pain have lowered this rate to <2% [
9,
10]. Nevertheless, because of the very frequent use of opioids in the ED, it is important to understand who is at risk of persistent opioid use.
Risk factors associated with the development of opioid use disorder include past or current substance abuse, larger prescribed opioid doses, and longer exposure to opioids [
11–
13]. However, the risk can vary from patient to patient and depends in part on hereditary and social factors as well as experiential factors related to euphoria and pain [
14,
15]. Furthermore, there is a substantial amount of interindividual variability in response to therapeutic use of opioids, with some patients reporting minimal pain relief, some reporting dysphoric reactions, and many experiencing side effects like dizziness and nausea [
16]. We hypothesized that this interindividual variability observed with opioid use could be used to predict who might be at risk of persistent opioid use. Specifically, we wished to determine whether opioid-induced analgesia or opioid-induced euphoria are associated with persistent opioid use.
We conducted a prospective cohort study to determine whether a patient’s experience after receiving an intravenous (IV) opioid for the first time was associated with repeated prescription opioid use during the subsequent 6 months. Specifically, we tested whether greater improvements in pain and a larger euphoric response could predict which previously opioid-naive patients exposed to IV opioids would fill at least two opioid prescriptions in the subsequent 6-month period.
METHODS
Ethics statement
This study was approved by the Institutional Review Board of Albert Einstein College of Medicine (No. 2019-10482). All participants provided written informed consent.
Study design and setting
This prospective cohort study was conducted in the two academic EDs at Montefiore-Einstein in the Bronx, NY, USA. Patients presenting to the ED with severe pain were enrolled during their visit and followed up by telephone interview 6 months later. We supplemented patient interviews with a review of medical records, including the New York State prescription monitoring program database.
Participants
We included adults aged ≥18 years who were administered IV opioids during their ED visit for treatment of pain and who could speak English or Spanish. We excluded patients who required hospital admission or who had used opioids within the previous 6 months, as determined through patient interviews supplemented with a review of the state prescription database. We also excluded patients who were unavailable for follow-up.
Outcomes
The primary outcome was filling at least two prescriptions for opioids during the 6 months following the index ED visit. The risk of persistent opioid use more than doubles among opioid-naive acute pain patients who receive a second opioid prescription [
17,
18]. The US Centers for Disease Control and Prevention has recommended discussion about the risk of long-term opioid use upon prescription of the first refill [
17,
18].
Our hypothesized predictors included opioid-induced analgesia and opioid-induced euphoria. Opioid-induced analgesia was assessed as pain relief in response to an IV opioid. We measured pain intensity on a scale of 0–10 points immediately prior to IV opioid administration and again 15 minutes later. We calculated percent improvement as (baseline pain – 15-minute pain) / baseline pain. We assessed euphoria using the following four items, each of which was assessed on a scale of 0–10 points, with 0 points signifying “not at all” and 10 points signifying “very much”: (1) How good did the opioid medication make you feel?; (2) How high did the opioid medication make you feel?; (3) How much euphoria, joy, or happiness did the opioid medication give you?; and (4) how much would you like to use the medication again? These instruments were originally developed as part of the Addiction Research Center Inventory, a comprehensive questionnaire used to determine the subjective effects of psychoactive substances [
19]. The items we used were validated for use among recreational opioid users [
20,
21] and then refined in work among ED patients with acute pain [
22–
24].
Other baseline variables of interest included age, sex, and presence of chronic pain. For this analysis, we defined chronic pain as pain in any body part for more than 50% of days over the previous 6 months. This was assessed during the baseline interview.
Statistical analysis
We reported the baseline variables using frequencies and percentages, mean±standard deviation, or median (interquartile range) as appropriate. Also, the primary outcomes are reported as frequencies and percentages with 95% confidence interval (CI). We used IBM SPSS ver. 29 (IBM Corp) for all analyses.
To determine the associations between percent pain relief and euphoria variables and the filling of at least two opioid prescriptions, we performed t-tests and reported the P-values. P<0.05 was considered statistically significant. To determine the impact of chronic pain on our primary outcome, we first built bivariate and then multivariable logistic regression models in which filling of at least two opioid prescriptions was the dependent variable. We forced chronic pain and percent pain relief into the model to determine whether chronic pain or pain relief resulting from IV opioid use was associated with the primary outcome. We included sex and age in the multivariable model to determine if these variables impacted the associations of interest. We reported the model output using odds ratio and 95% CIs.
Our sample size calculation was built around the point estimate of the primary outcome. A sample size of 500 patients allows us to report the point estimate of the primary outcome with a precision of ±2%. We enrolled an extra 50 patients (10%) to account for missing data.
RESULTS
Enrollment commenced in February 2021 and concluded in August 2022. During this period, we screened 1,555 patients for inclusion and enrolled 550. We excluded 38 patients retrospectively because a review of the prescription monitoring program database at the time of the 6-month follow-up revealed opioid use during the 6 months prior to the ED visit. Six participants were also excluded due to incomplete data (
Fig. 1).
Baseline features of our population are summarized in
Table 1. Of the 506 included patients, morphine was the opioid most frequently prescribed in the ED (n=478, 94.5%), followed by hydromorphone (n=20, 4.0%). Eight patients (1.6%) received both morphine and hydromorphone.
Of the 506 included patients, 32 (6.3%; 95% CI, 4.3%–8.4%) filled at least two prescriptions during the 6 months following their ED visit. Among the 478 study participants who received only IV morphine, 28 (5.9%; 95% CI, 3.8%–8.0%) filled a second prescription. Among the 20 who received just IV hydromorphone, 2 (10%; 95% CI, 0%–23%) filled a second prescription. Among the eight who received both medications, two (25%; 95% CI, 0%–55%) filled a second prescription. Neither pain relief in response to IV opioids nor markers of euphoria were associated with filling at least two prescriptions versus less than two prescriptions (
Table 2).
Of the 506 included patients, 392 (77.5%) did not fill an opioid prescription during the 6 months following their ED visit. Meanwhile, 57 patients (11.3%) filled their first opioid prescription within 1 week of their ED visit (
Table 3).
In a multivariable logistic regression model, only age and history of chronic pain were associated with filling at least two opioid prescriptions (
Table 4).
DISCUSSION
In this prospective cohort study of opioid-naive patients exposed to therapeutic IV opioids during an ED visit, 6.3% filled at least two opioid prescriptions during the subsequent 6 months. We hypothesized that the individual patient experience with opioids in the ED might be associated with subsequent filling of multiple opioid prescriptions. However, this did not prove to be true. Neither markers of opioid-induced euphoria nor pain relief experienced with IV opioids were associated with filling opioid prescriptions. We did identify two variables, age and history of chronic pain, associated with filling at least two opioid prescriptions, though neither of these are measures of the opioid experience itself.
While frequent opioid use is associated with opioid use disorder, these are not interchangeable terms. Opioid use disorder implies a use of opioids in a manner that impairs an individual’s ability to function normally in society [
25]. Frequent use of opioids may be appropriate for some patients with stable chronic or recurrent pain. For emergency physicians, we believe it is appropriate to counsel patients about the small risk of persistent opioid use after initial exposure.
It is interesting that neither pain relief afforded by IV opioids nor opioid-induced euphoria were associated with filling at least two prescriptions. Addiction is thought to be mediated by the activation of reward pathways in the brain among genetically or environmentally susceptible individuals [
25]. For many patients with opioid use disorder, the reward offered by opioids is relief from functionally impairing pain or euphoria that allows escape from difficult environmental or social struggles. Our data demonstrate that neither pain relief itself nor opioid-induced euphoria is sufficient to cause opioid-naive ED patients to progress to frequent use.
It is important to contextualize these data with reports linking use of parenteral opioids with adverse outcomes among patients with recurrent pain disorders such as migraine and low back pain. Among ED patients with migraine, treatment with opioids has been linked to repeated ED visits [
26]. Further, among ED patients with low back pain, treatment with opioids has been associated with persistent use [
27]. While the risk of persistent opioid use is low among opioid-naive patients, the risk may be higher among patients more frequently exposed to parenteral opioids. Therefore, for patients with recurrent pain disorders, we urge use of opioid alternatives or coordinated analgesic strategies.
It is not surprising that chronic pain was associated with filling at least two opioid prescriptions, as opioids are often used to treat chronic pain. It is also not surprising that age was associated with filling at least two opioid prescriptions because chronic pain is more prevalent among older adults than younger adults. Only 8.5% of adults ages 18–29 years experience chronic pain compared to 14.6% of adults ages 30–44 years, 25.8% of adults ages 45–64 years, and 30.8% of adults ages ≥65 years [
28].
Based on our results, we believe that emergency physicians need not be apprehensive about using IV opioids in the ED among patients who are opioid-naive due to concerns over opioid-induced euphoria or opioid-induced analgesia leading to later opioid use disorder.
Several limitations must be mentioned. All study data originated from two EDs in the Bronx. However, the participants in this study reported a diverse array of racial and ethnic backgrounds. It should also be noted that our primary outcome for this study, filling at least two opioid prescriptions during the subsequent 6 months, is a surrogate for the outcome truly of interest—opioid use disorder. Opioid use disorder itself is such a rare outcome after exposure to opioids in the ED that it would be impractical to conduct this type of analysis if we had relied on that outcome. Finally, the study only followed patients for 6 months after their ED visit, and we do not know longer-term outcomes.
In conclusion, filling at least two opioid prescriptions was uncommon after initial exposure to therapeutic IV opioids and was unrelated to either analgesic efficacy or opioid-induced euphoria.
NOTES
-
Author contributions
Conceptualization: SB, BWF; Data curation: EI, AW, MD, JB, BWF; Formal analysis: SB, BWF; Funding acquisition: BWF; Investigation: EI, AW, MD, JB, BWF; Methodology: EI, BWF; Project administration: EI, BWF; Supervision: EI, BWF; Writing–original draft: SB; Writing–review & editing: all authors. All authors read and approved the final manuscript.
-
Conflicts of interest
The authors have no conflicts of interest to declare.
-
Funding
This study was supported in part by a grant from the National Center for Advancing Translational Sciences (No. UM1TR004400).
-
Data availability
Data analyzed in this study are available from the corresponding author upon reasonable request.
Fig. 1.Flow diagram of patient inclusion.
Table 1.Baseline characteristics (n=506)
Table 1.
|
Characteristic |
Value |
|
Age (yr) |
46.3±15.3 |
|
Sex |
|
|
Female |
320 (63.2) |
|
Male |
186 (36.8) |
|
Chronic pain |
|
|
Yes |
61 (12.1) |
|
No |
438 (86.6) |
|
Unknown |
7 (1.4) |
|
Pain score prior to medication (range, 0–10) |
10 (9–10) |
|
First IV opioid received |
|
|
Morphine |
485 (95.8) |
|
Hydromorphone |
21 (4.2) |
|
First IV opioid received dose (mg) |
|
|
Morphine |
4 (1.8–6.2) |
|
Hydromorphone |
2 (1.4–2.6) |
|
Discharge diagnosis |
|
|
Abdominal |
202 (39.9) |
|
Urogenital |
131 (25.9) |
|
Musculoskeletal |
78 (15.4) |
|
Multiple diagnoses |
56 (11.1) |
|
Infection |
31 (6.1) |
|
Other |
8 (1.6) |
Table 2.Pain relief and euphoria scores among study participants with and without repeated opioid prescription fills
Table 2.
|
Variable |
≥2 Prescriptions |
<2 Prescriptions |
P-value |
|
No. of patients |
Score |
No. of patients |
Score |
|
|
Pain relief (%) |
32 |
46±32 |
474 |
49±32 |
0.54 |
|
How good |
32 |
5.4±3.7 |
469 |
5.5±3.9 |
0.91 |
|
How high |
32 |
2.7±3.9 |
473 |
2.8±3.5 |
0.97 |
|
Euphoria, joy, or happiness |
32 |
2.3±3.4 |
470 |
1.6±2.9 |
0.23 |
|
Take again |
32 |
5.4±3.9 |
470 |
6.1±4.0 |
0.37 |
Table 3.Time elapsed before first opioid prescription fill after the emergency department visit
Table 3.
|
Time elapsed |
No. of patients (%) |
|
No prescription filled |
392 (77.5) |
|
≤3 days |
46 (9.1) |
|
4–7 days |
11 (2.2) |
|
8–30 days |
11 (2.2) |
|
31–90 days |
16 (3.2) |
|
>90 days |
30 (5.9) |
Table 4.Logistic regression models of pain predictors on repeated opioid prescription
Table 4.
|
Independent variable |
Bivariate analysis |
Multivariable analysis |
|
OR (95% CI) |
P-value |
OR (95% CI) |
P-value |
|
Age (yr) |
1.04 (1.01–1.06) |
<0.01 |
1.03 (1.00–1.05) |
0.03 |
|
Sex |
1.37 (0.66–2.81) |
0.40 |
1.56 (0.73–3.29) |
0.25 |
|
Chronic pain |
3.27 (1.43–7.49) |
<0.01 |
2.58 (1.09–6.15) |
0.03 |
|
Improvement in pain (%) |
0.70 (0.23–2.16) |
0.54 |
0.73 (0.22–2.38) |
0.60 |
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