Rib fractures are present in up to 10% of injured patients, frequently occurring in the setting of multi-system trauma. They are a major cause of acute and chronic pain, which can lead to decreased quality of life and delay in return to routine activities. Current management strategies rely on aggressive pain control, pulmonary hygiene, and early mobilization. Rib fractures are associated with a mortality rate of up to 10% and a complication rate of 13%, with pain contributing to the subsequent morbidity (1). Almost half of complications are pulmonary, including atelectasis or lobar collapse, pneumonia, aspiration, pulmonary embolism, pleural effusions and acute respiratory distress syndrome (ARDS) (2). In addition, in a retrospective review, patients sustaining blunt trauma with moderate to severe rib cage injuries were associated with higher rates of reevaluation and readmission (3). Pain control in these patients is an often complex and challenging endeavor, and yet is essential to enhance recovery, optimize pulmonary hygiene and mitigate the worsening sequelae of disease.

Opioid analgesics remain the mainstay for pain management in patients with rib fractures despite multiple alternative analgesic options. In the United States, opioid prescriptions have nearly quadrupled from 1999 to 2014, without any measured difference in reported pain (4). Prescribing of opioids to opioid naïve patients has been shown to increase chronic opioid use five-fold compared with patients who did not receive opioids (5). The increase in opioid prescriptions has also been associated with a rapid rise in the number of drug overdoses. Opioid overdose is now the leading cause of injury-related death in over 30 states with more than 100 deaths per day in the United States (6).

In an effort to address this epidemic, many institutions have implemented the use of a multimodal approach to pain control relying on non-opioid analgesics including non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, skeletal muscle relaxants, alpha-2 agonists, mood stabilizers, neuropathic pain medications including gabapentinoids, N-methyl-D-aspartate (NMDA) receptor antagonists, topical analgesics as well as interventional therapies. Multimodal analgesia relies on synergistic combinations of medications to decrease dosing requirements and minimize adverse drug reactions for any single medication (7). In the setting of rib fractures, a multimodal approach has been suggested to address both pain control and respiratory performance(8). Numerous studies have addressed multimodal analgesia in the elective surgical patient population. Multimodal protocols have been less studied in the trauma population. The purpose of this study was to compare the effect of a multimodal pain regimen (MMPR) on inpatient opioid use and outpatient opioid prescribing practices in adult trauma patients with rib fractures.

During the study period, a total of 820 patients were assessed for eligibility based on presentation during either the PRE or POST study period with the presence of rib fractures. Mechanisms of injury were broad with the majority secondary to blunt trauma. 167 patients were excluded; 158 for continuous opioid infusions and 9 for chronic opioid use prior to admission.A total of 653 patients (323 PRE, 330 POST) met inclusion criteria for review. Of note, 4 patients in the PRE group and 5 patients in the POST group were excluded from data collection for pre-admission chronic opioid use. The majority of patients were male with approximately half of patients between 18–55 years old (Table 1). The most common injury mechanisms were motor vehicle crash and falls, and the injury mechanisms did not change significantly over the two time periods. Although the specific concomitant injuries and number of rib fractures were not tracked in this study, the ISS and Chest AIS were not significantly different over the two time periods. The admission lactate was also similar between the two time periods. The hospital LOS, ICU admission rate, ICU LOS, rate of mechanical ventilation and number of ventilator days were unchanged after implementation of MMPR.

There was no evidence for special cause variation in the for change in mean ISS or GCS in the post implementation period (Supplemental Figure 1a–b). Therefore, we did not adjust for ISS or GCS when analyzing the other outcomes of interest. There was evidence for special cause variation for percent gabapentanoid prescribed (higher in the implementation period) (Figure 2a). There was no evidence for special cause variation for the percent of patients receiving an opioid in the hospital. However, the 2 and 3 upper control limit lines cannot surpass 100%, which may have limited our ability for detection (Supplemental Figure 1c). Among patients prescribed inpatient opioids, there was evidence for special cause variation in the post-implementation period for average MME (decreased in post-implementation) (Figure 2b). Finally, there was evidence for special cause variation for percent of patients prescribed an opioid at discharge (higher in the post implementation period) (Figure 2c).

Implementation of the MMPR reduced daily inpatient opioid administration during the first five days of hospitalization (23 MME PRE vs. 17 MME post, p=.007) (Table 2). There was a statistically significant increase in percentage of patients receiving inpatient opioids during their first five inpatient days after the MMPR implementation (291 patients, 90.1% PRE vs 315, 95.5% POST, p=0.008). However, there was a statically significant reduction in MME during each of days two through five of hospitalization (Table 2). At the time of discharge, there was no significant difference in the number of patients prescribed opioids (196 patients, 60.7% PRE vs. 220 patients, 66.7% POST, p=0.11) (Table 2). However, in patients who received opioids on discharge, there was a statistically significant reduction in the daily encounter MME (the daily quantity of opioids if taken as prescribed) for each prescription (median: 45, IQR (30.0–54.9) PRE MME vs. median: 32.1, IQR (24–49) POST MME, p=0.02) (Table 2). There was a corresponding decrease in total MME prescribed after the implementation of the MMPR.

A sub-group analysis was conducted on patients admitted with isolated rib fractures (an extra-thoracic AIS score of <=2). Within this subset, there were a total of 368 patients (167 PRE vs. 201 POST). These patients were also mostly men, with a similar age distribution, and with similar ISS and Chest AIS before and after the MMPR implementation (Table 3). Similar to the overall group, the hospital LOS, ICU admission rate, ICU LOS, rate of mechanical ventilation and number of ventilator days were unchanged after implementation of MMPR. When comparing isolated rib fracture patients, there was no statistically significant change in the overall median MME received during the first five days of admission (18 PRE vs. 16 POST, p=.11). However, when patients who received no inpatient opioids on days 1 through 5 were excluded, there was a statistically significant decrease in opioid consumption on inpatient days 2 and 3 (Table 4). At the time of discharge, there was no difference in the frequency of opioids prescriptions between the two groups (111 patients, 66.5% PRE vs. 137 patients, 68.2% POST, p=0.73). In this subgroup, there was a significant reduction in the total MME prescribed at discharge (median: 315.0, IQR (210–488) MME PRE vs median: 225, IQR(180–375) MME POST, p=0.03) (Table 4).

Although there was no effect on the use of NSAIDS, there was a statistically significant increase in use of gabapentinoids during the hospitalization after the initiation of the MMPR. In all rib fracture patients, there was a statistically significant increase in gabapentin after MMPR implementation (218, 67.5% PRE vs 282, 85.5% POST, p <.0001) (Table 1). In the subgroup-analysis of isolated rib fractures, there was also a statistically significant increase in gabapentinoid use (117, 70.1% PRE vs 172, 85.6% POST, p=0.0003) (Table 3). Of note, with the statistically significant increase in gabapentin use after the MMRP implementation, there were no changes in readmission or unplanned ICU admission rates.

In trauma patients with rib fractures, implementation of an MMPR significantly reduced inpatient opioid consumption and outpatient opioid prescriptions. While the use of NSAIDS was unchanged by the MMPR implementation, the use of gabapentinoids was significantly increased. This is one of only two studies to examine the effects of a multimodal pain regimen on inpatient and outpatient opioid use in patients with rib fractures.

Management of pain in trauma patients with rib fractures requires a careful balance of providing relief of suffering and optimizing pulmonary performance to decrease complications while limiting the use of opioids and minimizing the side effects of non-opioid analgesics. The opioid epidemic has necessitated the development of alternative strategies to managing rib fracture pain. Multimodal pain regimens, regional and neuraxial analgesia, non-pharmacologic therapies and operative stabilization have all been investigated as possible therapeutic interventions.

In the current study, we saw a significant increase in the use of gabapentin after the implementation of our MMPR. Gabapentin is a structural analogue of γ-aminobutyric acid (GABA), although it does not appreciably interact with GABA receptors(11). Gabapentin inhibits the α₂δ subunit of voltage-gated calcium channels in the brain and reduces presynaptic release of excitatory neurotransmitters that are associated with pain perception(11). Gabapentin is labeled for postherpetic neuralgia and is used in an off-label fashion for neuropathic, post-operative, and chronic pain.

Gabapentin is associated with neurologic and respiratory adverse drug reactions and requires dose reduction in the setting of renal impairment. In December 2019, the FDA(12) warned of serious, life-threatening, and fatal respiratory depression in patients receiving gabapentinoids. This risk may be increased with concomitant use of opioids and other central nervous system depressants, conditions such as chronic obstructive pulmonary disease, and in elderly patients. Furthermore, gabapentin misuse and withdrawal have been described and must be considered as potential complications, especially in at-risk populations(13,14). As a result of these potential risks, the use of gabapentin in patients with multisystem trauma should be done with caution.

While there are more studies investigating the use of gabapentin in surgical patients, there remains limited data on its benefit in the trauma population. A meta-analysis of pre-operative gabapentin administration to patients in the setting of abdominal, orthopedic, gynecological, thyroid, breast, prostatectomy, caesarean section and thoracotomy surgery was associated with lower post-operative opioid use(15). However, in critically ill patients with rib fractures, there was no difference in numeric pain scores, oxygen requirement, or opioid consumption between gabapentin and placebo(16).

NSAIDs are another non-opioid analgesic option for managing trauma patients with rib fractures. Complications from NSAIDs are considerable and include gastrointestinal and renal adverse drug reactions. Gastrointestinal complications range from mild dyspepsia and heartburn to life threatening bleeding and perforation. Consistent use of NSAIDS for greater than 4 days is associated with increased risk of severe complications including bleeding, clinically significant ulceration and perforation(17). In our study, no cases of clinically significant upper gastrointestinal hemorrhage were identified either before or after implementation of the MMPR.

NSAIDs decrease prostaglandin synthesis and therefore affect intraglomerular hemodynamics by decreasing the ability of the afferent arteriole to vasodilate(18). As, such, renal blood flow is altered. NSAIDs are also associated with interstitial nephritis(18). Risk factors for drug-induced kidney disease include older age and chronic kidney disease, with a 3–4 fold increased risk of worsening renal function for patients with abnormal baseline renal function who use ibuprofen(19). Given the advanced age of many patients with rib fractures, the risk of high-dose NSAID use remains significant. Despite 30% of our patients being >65 year of age, the rate of acute kidney injuries was low and remained unchanged by the implementation of the MMPR. However, it is possible that some of the adverse effects of NSAIDS may have been delayed and unrecognized on initial admission.

There have been conflicting results for the use of non-opioid analgesics in patients with rib fractures. Lidocaine patches have been shown to have minimal impact on pain control in a randomized controlled trial when compared with standard therapy (20). However, some studies examining the effect of non-opioid medications in patients with rib fractures have demonstrated success in minimizing opioid use. In one small retrospective cohort study, scheduled intravenous (IV) ibuprofen was associated with decreased opioid use and decreased hospital length of stay(21). Another retrospective cohort study showed IV ketorolac was associated with a decreased incidence of pneumonia in patients with rib fractures(22). These studies did not explore the impact of a multimodal pain protocol on the quantity of opioids prescribed at the time of discharge. In addition, the studies did not evaluate the effect of multimodal regimens on adverse drug reactions, including stress ulcer bleeding and acute kidney injury, or polypharmacy effects, such as unplanned ICU admission.

While the effects of multimodal pain regimens in elective surgical patients has been well documented, their impact in trauma patients is less clear. Several studies note decreased opioid usage after implementation of a multimodal regimen. In a recent retrospective study of more than 6000 trauma patients over an 8-year period, the authors found a significant reduction in inpatient opioid consumption as well as the quantity of outpatient opioid prescriptions in patients with at least one rib fracture(23). While this is the only study to date to examine the effect of a multimodal pain regimen on inpatient and outpatient opioid use in rib fracture patients, this study does have notable limiting factors. At the start of the study, the opioid epidemic came into national focus, substantially changing the culture regarding opioid use, resulting in both providers and patients having a better understanding of the dangers of opioid use. Thus, provider and patient awareness regarding the opioid epidemic were likely a significant confounding factor that may have obscured the true impact of a multimodal regimen on inpatient and outpatient opioid use in that study. In addition, scheduled tramadol, an opioid derivative, was used as part of the MMPR in this study, raising concerns for the significant opioid exposure in the MMPR itself, which may have increased the total inpatient MME requirement. Indeed, the outpatient prescription rate of tramadol increased significantly during the duration of the study. This would not only expose patients to the risk of tramadol addiction, abuse, and misuse, but also to other adverse effects specified in the US Boxed Warning for this agent(24). These include, but are not limited to, life-threatening respiratory depression, complex effects resulting from interactions with drugs affecting cytochrome P450 isoenzymes, and potential for profound sedation, coma, and death when used concomitantly with benzodiazepines or other CNS depressants.

In a smaller retrospective cohort study of critically ill trauma patients, the authors found a significant decrease in inpatient opioid use following MMPR implementation (25). Additionally, they found a corresponding decrease in inpatient opioid consumption with each successive number of pharmaceutical adjuncts used. Interestingly, Hamrick, et al.(25) also found that a majority of patients were prescribed a higher daily opioid dose on discharge than they had used during the preceding 24 hours of hospitalization, suggesting opportunities for customizing prescriptions to more closely match inpatient opioid requirements. However, this study was a small heterogenous group of polytrauma patients, which represents quite a variable spectrum. There was a significant difference in injury mechanisms pre and post multimodal regimen implementation. The researchers also compared time periods two years apart, which again raises the possibility that changes in patient and provider awareness of the growing opioid epidemic during the study, distorted the actual impact of the multimodal regimen.

In the current retrospective study, we evaluated a brief time period before and after the implementation of an MMPR to minimize the impact of changes in provider and patient perspective over the course of the study. Like the previous retrospective studies, we did see a statistically significant reduction in the quantity of opioids administered during the inpatient setting for polytrauma patients with rib fractures. However, we did not observe the same reduction in inpatient opioid consumption in patients with isolated rib fractures. We did see a reduction of inpatient MME for days 2 and 3 in isolated rib fracture patients who required inpatient opioids. It is unclear whether the lack of a statistical difference in the inpatient MME of this subgroup was related to an overall lower injury burden, as suggested by the lower ISS, and thus decreased opioid requirements, or the lower power of this subset analysis. Notably, after the implementation of the MMPR, there was no change in NSAID use, suggesting that some individual elements of MMPR were already being used prior to the protocol. There was a statistically significant increase in gabapentin use after the implementation of the protocol, which may have contributed to the reduction in the opioid consumption during the study period. However, we cannot conclude that this alone was responsible for the reduction in MME. Consideration must also be given to the risk-benefit profile of this agent and its place in pain management closely scrutinized given its potential for adverse drug reactions. There was a significant decrease in the MME prescribed at discharge to patients after implementation of the MMPR, although no difference was seen in percentile of patients prescribed opioids on discharge. This was also true for the subset of isolated rib fracture patients.

Limitations of this study include its retrospective design. While exposure to NSAIDs and gabapentin were assessed, dosing strategies and adherence to the MMPR were not. We also do not have data regarding the use of neuraxial or regional anesthesia techniques or surgical stabilization of the rib fractures in our patient population, which may impact the inpatient and outpatient opioid requirement. However, given the stability of our performance of regional anesthesia and surgical stabilization over time as well as their use in the minority of our total rib fracture patients, the effect on our outcomes is likely to be relatively small. Given the variable reasons for opioid infusions for mechanically ventilated patients other than pain control, patients requiring opioid infusions were excluded. In addition, this exclusion likely eliminated some of the moderate traumatic brain injury (TBI) patients and all severe TBI patients as these patients were intubated and supported with opioid infusions as part of their TBI therapy. This occurrence can be seen in the median admission GCS of 15 in both PRE and POST groups. This exclusion eliminated the falsely low estimate of oral opioid consumption in these patients, but also excluded many of the more severely injured patients. This exclusion did minimize the effect of TBI on the perception and management of rib fracture pain. Another limitation of our study is the lack of information on number of ribs fractured and characteristics of the rib fractures. While this information was beyond the scope of our review, we do know that the chest AIS was similar PRE and POST MMPR, suggesting no significant change in the severity of the chest injuries over the study period. Lastly, the development of the MMPR at our institution was largely in response to the growing opioid epidemic. It is possible that providers’ attitudes regarding opioid prescriptions changed during the study period and that this contributed to the observed decrease in outpatient opioid prescriptions. The majority of inpatient orders and discharge prescriptions were written by rotating residents and trauma advanced practice providers. Although the use of the MMPR order set was advised and encouraged, rotating personnel could have contributed to variability in compliance with the use of the order set. While the Hawthorne effect could be responsible for some participant bias and enhanced compliance with MMPR order set usage, this effect on provider behavior was likely modest given the frequent order set modifications and guideline development within our trauma program. Since the MMPR order set was imbedded within our trauma admission order sets, its use was likely robust as it became the least labor-intensive method to enter orders, including pain medication. It is also unclear if the North Carolina Strengthen Opioid Misuse Prevention (STOP) Act legislation, passed in 2017, had any impact on our results (26). This legislation limits opioid prescriptions to a 5-day supply after injury or trauma and 7-day supply after surgical procedures. One might postulate that the decrease in inpatient opioid use and outpatient prescriptions were due to this legislation, the implementation of this MMPR, or a combination of both.

The impact of the opioid epidemic cannot be overstated. While we search to find solutions to minimize opioid consumption, we must also refrain from overly optimistic, simplistic solutions without evidence of their effectiveness. MMPRs have become a common solution to minimize opioid consumption in most trauma centers, despite minimal evidence of the effectiveness in doing so. When establishing guidelines and protocols, as important as the implementation phase is the subsequent review of the effectiveness. Adherence to and assessment of outcomes after a new guideline has been implemented is crucial to a strong performance improvement program. Our intent was to review an institutional performance improvement initiative in the form of an MMPR. In our review, we have concluded that our MMPR did result in a statistically significant reduction in both inpatient opioid consumption and outpatient prescription quantity. In addition to continued use of the MMPR, we will continue to search for which combinations of which medications are the most effective and to find mechanisms to mirror an outpatient prescription with a patient’s inpatient opioid requirement. It is unknown whether these results are generalizable beyond level 1 trauma centers or at other hospitals or regions with different ongoing interventions or legislation surrounding opioid prescribing. Next steps should include dissemination of this intervention to other settings to determine generalizability.

In trauma patients with rib fractures, implementation of an MMPR significantly reduced inpatient opioid consumption and outpatient opioid prescriptions. We are witnessing an advance in the use of various non-opioid analgesics as well as procedural techniques to aid in the treatment of pain. Future efforts will likely be directed at expanding regional and neuraxial analgesia techniques, non-pharmaceutical adjunct usage, and developing a tool to determine the appropriate quantity of opioids for discharge, using the patient’s inpatient requirement as a guide. With a growing number of options now available for pain control, it is crucial to determine which methods, and in which combinations, are most effective at reducing pain, with the least complications and in the most cost effective way, as we continue to treat rib fractures in trauma patients.