In our study, we found pain level in all groups decreased early in minute 5. However, patients who received morphine experienced their lowest pain level after 15 minutes of intervention and then the analgesic effect of morphine decreased. The maximum effect of ibuprofen was observed after 30 minutes and interestingly the effect of ibuprofen-acetaminophen combination maintained after 60 minutes. Therefore, the findings show that, the effect of ibuprofen and its combination with acetaminophen initiate as early as morphine and moreover can affect for a longer period of time. However, considering minimum clinically important difference, we will get in another conclusion about initiation of effects.
We know there were statistically significant changes in pain level between all the time points in each group, but some of these changes were not clinically important. In previous studies, a difference of 1.3 in pain levels between two time points has been considered clinically significant(18). Using this criterion, we observed a plateau in the morphine group regarding mean pain level after 30 minutes from injection, while in the other two groups, the analgesia effect initiates 15 minutes post-injection and all the changes after that are significant rather than previous time. Although this difference is clinically significant, pain intensity is typically categorized into three levels in pain management guidelines, and pain scores under 4 points are categorized as mild pain that can be managed with non-pharmacologic treatment or a low-dose oral analgesic, if requested by the patient. (23, 24). So, while the mean VAS score increased in the ibuprofen and morphine groups, it did not require invasive intervention, because their pain score consistently after 15 minutes from injection was categorized as mild pain. The pain score in the ibuprofen-acetaminophen group was consistently categorized as mild pain from 30 minutes after injection until the end of the study.
In recent years, there has been a growing trend towards replacing opioids with non-opioid drugs, and various studies have compared the efficacy of these drugs in trauma patients. While these studies have used different drugs, doses, and surveyed patients at different time periods and age categories, they have focused on the effect of non-opioids, especially ibuprofen and acetaminophen, versus opioids.
Furthermore, most of these studies have been conducted in the field of pediatric medicine(18, 25–27). In one of these studies, the combination of ibuprofen and acetaminophen was found to be as effective as acetaminophen with oxycodone, hydrocodone, or codeine, which are three types of opioids, in patients with acute extremity pain after two hours of treatment. In this study, the drugs were administered orally, and the doses were 400 mg of ibuprofen and 1000 mg of acetaminophen, 5 mg of oxycodone and 325 mg of acetaminophen, 5 mg of hydrocodone and 300 mg of acetaminophen, or 30 mg of codeine and 300 mg of acetaminophen(18), Other studies have also demonstrated that ibuprofen or acetaminophen, or their combinations, are as effective as opioids (26, 27). These studies have focused on patients with limb pain or extremity trauma, however, it should be noted that the pain experienced by patients with a fractured limb can be significantly greater than other types of pain(28).
Morphine is considered the gold standard opioid for the management of severe pain, but it has several side effects in fracture physiology (10) and is a short-acting analgesic in fracture pain management as we saw in this study(29). In contrast, ibuprofen and acetaminophen have longer periods of action than morphine, which is consistent with our result (30, 31). Additionally, several studies have shown that the combination of acetaminophen with ibuprofen has a synergistic effect that is greater than the prescription of each drug alone in post-operative patients, which may be due to different analgesic pathways (32–34).
The national opioid crisis is a pressing issue concerning public health policies, as increasing opioid abuse has become a great burden for countries worldwide(35). Prescribing opioids for patients with pain chief complaint not only increases the risk of opioid abuse, but also has side effects from one-time consumption(36). While our data only discusses morphine alternatives in the first hour of admission, it can prompt physicians to consider continuing treatment with non-opioids during admission or after discharge. Moreover, it can help increase society's acceptance of non-opioids as effective even in emergency departments, ultimately protecting patients from their first encounter with opioids and potentially contributing to the fight against the opioid crisis.
Limitations
Our study had some limitations. First, we followed patients for one hour after injection of the drugs. Although further follow-up could provide more data about pain and side effects, our study was limited to one hour after drug injection as we aimed to determine whether a non-opioid drug can relieve pain during the patients' stay in the emergency department, where most patients are referred to orthopedic services or discharged quickly, making it challenging to follow them and consider rescue analgesic drugs.
Second, our study only focused on moderate to severe side effects due to the limited one-hour follow-up period, which is a relatively short time frame to assess the incidence of mild or long-term side effects(10, 14, 25, 26, 34).
Third, there are various forms of opioid and non-opioid drugs, and while this study focused on the parenteral form of three drugs, other studies and pain management guidelines recommend different drugs and doses, indicating the need for further research(25, 26).
Fourth, the target population in this study consisted of patients with simple extremity fractures. While our findings may apply to other types of trauma, it is possible that different types of fractures could result in different pain patterns. In addition, it is important to assess pain with different origins, such as post-surgical pain or visceral pain, separately from the findings of this study.