Acetaminophen and ibuprofen are commonly used components of MMA regimens [13, 17]; however, there are limited data comparing dosing schedules. To our knowledge, this is the first study to evaluate the effectiveness of, and patient satisfaction with, the use of alternating versus concurrent ibuprofen/acetaminophen in an adult postoperative setting. In this study involving patients undergoing open inguinal herniorrhaphy with HTX-011, the alternating and the concurrent MMA regimens were similarly effective in managing postoperative pain with minimal use of opioids.
HTX-011, used with a scheduled non-opioid MMA regimen plus an opioid prescription algorithm for identifying individual patients who might require a discharge opioid prescription, enabled more than 90% of patients to be discharged without an opioid prescription, with no callbacks for pain management, and 95% of patients to recover opioid-free. The results of this study are similar to those observed in the EPOCH-2 single-arm follow-on study, in which 87% of patients who received HTX-011 and scheduled (alternating) acetaminophen/ibuprofen were managed opioid-free through postoperative day 10 . The results of the HOPE Hernia-1 study demonstrate the reproducibility of HTX-011 clinical trial data and prospectively confirm the clinical utility of a simple personalized algorithm to guide opioid prescribing in a real-world setting. Unlike EPOCH-2 and the EPOCH-2 single-arm follow-on study, in which patients were required per protocol to stay in the hospital for 72 hours, patients in the current study were discharged at a time determined by the investigator, which was an average of 2–3 hours after surgery.
Opioids are commonly used for postoperative pain but can result in opioid-related AEs and potential long-term dependence. As such, opioids should only be prescribed when necessary and at the lowest possible effective dose . Substantial progress has been made over the past 5 years regarding opioid-sparing postoperative protocols and decreased discharge prescription opioid quantities. Current literature recommends a discharge prescription range of 0 to 15 oxycodone (5 mg) pills for inguinal herniorrhaphy [2, 6, 18,19,20], with growing evidence that many patients may require at most only three pills [2, 6, 14, 21, 22]. In addition, limits on duration and/or doses of opioids have been enacted by state programs, large payers, and pharmacy chains and benefit managers .
Although this progress is notable, recent evidence suggests that clinical practice is lagging and opioids are still overprescribed after inguinal herniorrhaphy, possibly because of the inability to accurately predict which patients will need opioid-level analgesia. A retrospective study of administrative health claims from 60,000 patients undergoing inguinal hernia repair identified a median of approximately 210 oral morphine equivalents that were prescribed preoperatively (for use postoperatively), which equates to roughly 28 oxycodone pills . A recent meta-analysis of 44 studies in adult surgical populations estimated a total of 2,909,744 prescribed morphine milligram equivalents for 13,068 patients, with 61% of prescribed pills left over. This translates to an average of approximately 30 prescribed oxycodone (5 mg) pills per patient, with 18 unused . In addition, the initial results of opioid duration and/or dose limits by states and organizations have indicated that these programs have not resulted in decreased opioid prescribing for acute pain . Procedure-specific opioid prescribing recommendations and identification of risk factors for increased opioid consumption could help to avoid opioid overprescribing; however, additional guidance is needed for the individual patient [14, 19].
The use of scheduled non-opioid MMA alone for inguinal hernia repair (open and laparoscopic), based on current literature, results in approximately 15–64% of patients recovering opioid-free [2, 3, 6, 12, 14, 22]. Though the primary objective of the current study was not to assess the impact of HTX-011 on the rate of opioid-free patients, the use of HTX-011 in combination with scheduled non-opioid MMA resulted in 95% of patients overall with an opioid-free recovery through the 15-day follow-up period. Use of HTX-011 as the foundation of non-opioid MMA, in conjunction with an algorithm that distinguishes between patients who need or do not need a discharge opioid prescription, could further increase the proportion of opioid-free patients, decrease the amount of opioids required per patient, and decrease the total number of opioid pills prescribed. In combination, this could potentially result in several million fewer unused opioid tablets available for misuse or diversion.
Both MMA regimens resulted in high levels of patient satisfaction in all three domains (effectiveness, convenience, and global satisfaction) of the validated TSQM-9 survey (Table 2). Because similar efficacy, tolerability, and high patient satisfaction were demonstrated in the two cohorts, applying these findings to clinical practice could allow the patient and provider to determine the preferred MMA schedule, which could improve convenience and medication adherence. Increasing patient autonomy in medical decision-making has been shown to increase patient satisfaction . In the second part of the HOPE Hernia study (HOPE Hernia-2), currently ongoing, the alternating or concurrent MMA schedule is selected for each patient by the investigator, and may reflect patient preference .
We formulated an algorithm to guide discharge opioid prescriptions for individual patients based on an analysis of the EPOCH-2 single-arm follow-on study, which revealed that patients who required postoperative opioids had an NRS pain score of ≥ 6 at 2 hours after surgery and/or received an opioid rescue medication within the first 2 hours after surgery. In the current study, we prospectively evaluated the effectiveness of the algorithm in a real-world setting. Application of the algorithm successfully differentiated patients who needed an opioid prescription from those who did not, enabling more than 90% of patients to be discharged without an opioid prescription. The algorithm was not overly restrictive; of the seven patients who met algorithm-specified criteria and received a discharge opioid prescription, four did not take any opioids after discharge. More importantly, the algorithm did not wrongly withhold an opioid prescription; there were no callbacks for pain management from anyone discharged without a prescription, and no patients discharged without a prescription reported taking opioids from any other source.
Though decreasing opioid use can decrease opioid-related AEs, the scheduled use of acetaminophen and NSAIDs, especially long-term use, is also not without risk. In single-arm follow-on studies involving HTX-011 as the foundation of non-opioid MMA, coadministration of HTX-011 with scheduled NSAIDs and acetaminophen for a minimum of 3 days did not impact safety; there was no evidence of NSAID- or acetaminophen-related toxicity based on treatment-emergent AEs or clinical laboratory test results [11, 15]. The current study confirmed these findings for a 5-day MMA regimen. Although these data provide confidence in the safety of real-world use of HTX-011 with scheduled acetaminophen and ibuprofen, clinicians should not dismiss the common drug-class–related AEs for these OTC medications.
The 2019 American Society for Enhanced Recovery and Perioperative Quality Initiative Joint Consensus Statement on Perioperative Opioid Minimization in Opioid-Naive Patients recommends that clinicians provide patients with individually tailored education, including information about postoperative pain management . In this study, before surgery, all patients were shown a short educational video describing their assigned MMA protocol. We believe that patient education is a key component to setting appropriate expectations regarding postoperative pain and ensuring adherence to a scheduled non-opioid MMA regimen after discharge.
This study is not without limitations. In the HOPE Hernia-1 study, the alternating and concurrently administered acetaminophen and ibuprofen regimens were similarly effective; as such, the study may have been underpowered to show a statistically significant difference between the two regimens. However, these results indicate that alternating or concurrent administration of ibuprofen and acetaminophen appear to offer similar clinical benefit.
This study did not contain a non-HTX-011 control arm, for two reasons: first, the superiority of HTX-011 compared with bupivacaine hydrochloride in pain reduction and reduced opioid consumption was previously established in the phase 3 EPOCH-2 study , and second, the primary objective was to determine which of two postoperative non-opioid (MMA) regimens, with intraoperative administration of HTX-011 as the foundation, would result in a higher proportion of patients not requiring a prescription for opioid medication following unilateral open inguinal herniorrhaphy.
A wide variety of non-opioid MMA regimens are commonly used in clinical practice, so it is not known whether use of a different non-opioid MMA regimen could have affected the results presented herein. However, because MMA regimens comprising the two most commonly used OTC analgesics were evaluated, the results should be applicable to a large number of patients .
Lastly, although this study provided evidence of the feasibility of a personalized opioid prescription algorithm to identify which patients required or did not require an opioid prescription, the algorithm was used only with HTX-011 as the foundation of non-opioid MMA. Because of the sustained pain control provided by HTX-011 over 72 hours, applicability of the algorithm to regimens not containing HTX-011 is not known. Future research into HTX-011 with additional non-opioid MMA in other surgical models and confirmation of the generalizability of the algorithm, as well as exploration of different algorithms, are desirable.