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Journal of Clinical Medicine Research

Original Article

Volume 10, Number 6, June 2018, pages 499-507

Improved Outcomes Associated With the Use of Intravenous Acetaminophen for Management of Acute Post-Surgical Pain in Cesarean Sections and Hysterectomies

Post-surgical pain management is the key to successful surgical recovery [1]. Acute pain impacts short-term and long-term post-surgical outcomes since inadequate pain management can result in extended hospital length of stay (LOS) and increased risk of developing chronic pain [2, 3]. Population-based studies suggest that women may be more likely to experience chronic pain syndromes, and obstetric and gynecologic surgeries are among the most common surgeries in women [4-6].

The most commonly used analgesics for post-surgical pain are intravenous (IV) and oral opioids. While effective for pain relief, opioids are associated with a variety of costly opioid-related adverse events (ORADEs) [7, 8]. Opioid use can lead to addiction and abuse [9], and the overprescribing of opioids post-surgery is a contributor to the opioid epidemic in the United States [10]. Differences in opioid efficacy have also been reported between women and men [11, 12], and following Cesarean deliveries, additional concerns for postoperative pain management arise. For example, although breastfeeding while receiving opioid medications is generally permitted [13, 14], sedation associated with opioid-based analgesia following Cesarean sections can disrupt breastfeeding, infant care, and mother-infant bonding [15]; while suboptimal pain management or increased sedation may impair the mother’s ambulation, which increases the risk of thromboembolic disease [16].

New guidelines from the American Pain Society (APS), the American Society of Anesthesiologists (ASA), and the American Society of Regional Anesthesia and Pain Medicine (ASRA), as well as other professional societies, strongly recommend the use of multimodal therapies, incorporating non-opioid analgesics as foundational therapies to treat postoperative pain [17]. The American College of Obstetricians and Gynecologists (ACOG), the Society for Maternal-Fetal Medicine (SMFM), and the Academy of Breastfeeding Medicine (ABM) have specific guidelines and recommendations for breastfeeding mothers that include maximizing the use of multi-modal non-opioid analgesics, such as non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (APAP) if feasible and as appropriate [18]. Multimodal analgesia (MMA) regimens can generally reduce the use of opioids and consequent ORADEs [17]. Since most pain is multi-factorial in nature, owing to the physiology of pain transmission, the use of combinations of analgesics with differing mechanisms of action may also have additive or synergistic effects to reduce pain [19-22].

MMA regimens are well-established in guidelines for both Cesarean section and hysterectomy surgeries. In both surgical types, MMA has been associated with reduced hospital LOS and decreased opioid use [23-26]. A plethora of medications are utilized in MMA regimens, including NSAIDs, non-NSAIDs (e.g. APAP) and GABA analogs (gabapentin, pregabalin) [20, 21]. However, NSAIDS may be contra-indicated when certain comorbidities are present [27].

Oral APAP has been widely used for over 50 years. An intravenous (IV) APAP formulation appropriate for post-surgical patients who cannot take oral drugs due to sedation, nausea, vomiting, or slow gastrointestinal (GI) recovery became available in 2010. Use of IV APAP has expanded in several surgery types, including orthopedic and spine surgeries, but the overall impact of IV APAP on post-surgical pain remains relatively unstudied in non-clinical trials, real-world conditions, and especially in obstetric or gynecologic surgeries [2, 28, 29]. The primary objective for this retrospective analysis of electronic health records (EHR) was to evaluate the clinical and administrative outcomes associated with the utilization of oral APAP versus IV APAP in women undergoing a Cesarean section or hysterectomy.

This retrospective cohort study was conducted using data from the Cerner HealthFacts® dataset (Cerner HealthFacts®; Kansas City, MO) from January 1, 2011 to December 31, 2015. Cerner HealthFacts® is a large US electronic health database, based on patient records across the United States from over 600 hospitals. Patients receiving oral APAP versus IV APAP (verified through the selected National Drug Codes; NDC) and medication administration route in a post-surgical setting were evaluated. The study was granted an Institutional Review Board exemption from Western IRB.

The patient population was selected using International Classification of Diseases (ICD)-9-CM and ICD-10-CM codes for Cesarean section and hysterectomy surgeries (Fig. 1). Inclusion criteria selected adult patients (≥ 18 years) undergoing a qualifying Cesarean or hysterectomy procedure (see Supplementary Table 1, www.jocmr.org), with admission between January 1, 2011 and December 31, 2015, and administration of either oral APAP or IV APAP during the first 24 h post-surgery (day 0) (see medication criteria schematic in Supplementary Figure 1, www.jocmr.org). Oral APAP was defined as tablet or capsule formulations of APAP. Other formulations, such as liquid taken orally or suppositories, were not considered for inclusion. Combination APAP medications (e.g. acetaminophen/dextromethorphan/doxylamine succinate/pseudoephedrine HCl) were not regarded as oral APAP for inclusion purposes. Exclusion criteria included patients with < 6 months of history captured in the database prior to the index visit, missing information for age or gender, and in-hospital LOS > 90 days. The oral APAP and IV APAP cohorts were mutually exclusive. Patients in the oral APAP cohort could not have received IV APAP on days 0 - 3 and vice versa. Patients were excluded if they had received either oral or IV APAP on day 4 or after (see medication criteria schematic in Supplementary Figure 1, www.jocmr.org).

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Figure 1. Patient selection in OB/GYN patients treated with oral vs. IV APAP. The study identified 30,198 unique Cesarean section and hysterectomy patients who were treated with oral APAP and 8,693 Cesarean section and hysterectomy patients who were treated with IV APAP. IV: intravenous; APAP: acetaminophen; OB/GYN: obstetrics and gynecology.

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Table 1. Demographics and Baseline Characteristics for Cesarean Section Surgery Patients

Baseline characteristics (e.g. age, gender, race, year of admission) and chronic comorbidities (based on the definitions of Elixhauser) at index admission and study outcomes were collected [30]. The Elixhauser comorbidities were calculated using the approach from Healthcare Cost and Utilization Project (HCUP), Elixhauser Comorbidity Software, Version 3.7 [30]. Hospital characteristics (e.g. bed size, urban/rural status, census region) at index admission and payer type were collected as reported. Additional information about procedure type for hysterectomies were incorporated into analytical models as open, laparoscopic, total vaginal hysterectomy, and total abdominal hysterectomy.

Study outcomes included length of hospital stay, presence of ORADEs, total daily opioid consumption (i.e. morphine (mg) equivalent; MME) and total pharmacy cost. Opioid consumption was calculated using the amounts administered to the patient, while taking into account any doses that were returned to the hospital pharmacy unused. The conversion to MME was performed as previously described [31, 32]. For outpatients, total, per patient, pharmacy cost was calculated by summing unit costs for all medications that were dispensed (unit cost represent cost per medication package), and for inpatients, it was calculated by summing unit cost of the medication multiplied by the number of medication units that were charged to the pharmacy (unit cost represents cost per unit). Missing body mass index (BMI) values were imputed with a univariate imputation sampling method from a regression model of known covariates [33]. To minimize the effect of outliers, total pharmacy costs were Winsorized at the 2.5% level, which means that values above the 97.5th percentile were set to the 97.5th percentile value and values below the 2.5th percentile were set to the 2.5th percentile value. Total morphine equivalent dosing had the following constraints to be deemed valid: No 4-day total from Day 0 to Day 3 could exceed 800 mg MME and each day after Day 0 could have no more than 200 mg MME.

The Cesarean and hysterectomy patients were analyzed separately using multivariable methods. The primary method to estimate the impact of IV APAP on the study outcomes (e.g. hospital LOS) was inverse probability weighted regression adjustment (IPW-RA) with covariates that included patient demographics, comorbidities, patient admission type (e.g. emergency admission), relevant surgical characteristics (e.g. a laparoscopic hysterectomy), and prior drug history up to the day of surgery [34, 35]. See Supplementary Tables 2, 3 (www.jocmr.org) for all variables used for multivariable adjustment. Hospital characteristics (e.g. the number of beds, teaching status, geographic location) were also used for adjustment.

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Table 2. Demographics and Baseline Characteristics for Hysterectomy Surgery Patients

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Table 3. Multivariable Results for Cesarean Sections and Hysterectomies

As a sensitivity analysis, generalized linear models (GLM) estimated the effect of IV APAP on the outcomes and were used with the same covariates that were used to estimate the propensities in the IPW-RA model. For continuous outcomes (e.g. LOS) a logarithmic link and a gamma distribution were used in the regression models. When the outcomes were binary, logistic regression models were utilized. Odds ratios (ORs) were converted to risk ratios (relative risks (RRs)) [36]. All GLM models used robust, Huber-White standard error estimators, clustered at the hospital level to account for potential serial correlation of patient outcomes among patients treated in the same hospital.

We identified 38,891 patients, with 9,767 (25.1%) undergoing hysterectomies and 29,124 (74.9%) patients undergoing Cesarean section surgery (Tables 1, 2). Overall, 8,693 (22.4%) of all Cesarean section and hysterectomy surgical patients received IV APAP (Tables 1, 2). However, the proportion varied by surgical type, with 15.5% of the Cesarean patients and 42.8% of hysterectomy patients receiving IV APAP (P < 0.001).

Mean ages within surgical categories were similar between the oral and IV APAP groups (Cesarean mean age = 29.6 vs. 30.9 years; hysterectomy mean age = 47.1 vs. 47.4 years) (Tables 1, 2). The majority of hysterectomy patients (90.5% of oral APAP and 64.3% of IV APAP) were treated at urban facilities. In contrast, 76.0% of Cesarean section patients in the oral APAP cohorts were treated at urban facilities and only 33.2% of the IV APAP cohorts were treated at urban facilities. Regardless of procedure type (Cesarean section or hysterectomy) or APAP cohort (oral or IV), the majority of patients were treated at teaching hospitals, with a greater percentage of IV APAP cohorts treated at a teaching hospital versus the oral APAP cohorts.

Adjusted results (see (Supplementary Table 4, www.jocmr.org) for unadjusted outcomes) were derived using IPW-RA estimators based on covariates that included demographics, comorbidities, patient clinical characteristics, and hospital characteristics. In the IPW-RA analyses (Table 3), Cesarean section patients receiving IV APAP (versus oral APAP) showed an 11.7% shorter LOS. In the IV APAP cohort, the total (marginal) mean adjusted LOS was 3.40 days (95% CI 3.29, 3.51) for IV APAP versus 3.85 days (95% CI 3.60, 4.10) for oral APAP. This 0.45 day shorter LOS for IV APAP patients (95% CI -0.72, -0.17) was statistically significant (P < 0.001). Similarly, in patients undergoing hysterectomies, IV APAP was associated with an 11.8% shorter LOS, with a total adjusted 2.01 days (95% CI 1.89, 2.13) for IV APAP versus LOS of 2.28 days (95% CI 1.14, 2.43) for oral APAP. This 0.27 day shorter LOS for IV APAP patients (95% CI -0.46, -0.08) was also statistically significant (P < 0.001). The results in the GLM sensitivity analyses (Table 3) showed similar reductions in LOS associated with the receipt of IV APAP.

Total MME consumption per day observed from Day 0 to Day 3 was statistically significantly lower for IV APAP patients in both Cesarean section and hysterectomy surgeries (-1.6 mg; 95% CI -2.5, -0.8; P < 0.001 for Cesarean section and -1.7 mg; 95% CI -3.1, -0.3; P < 0.014 for hysterectomy) (Table 3). However, these differences in total MME consumption per day were not significantly different by APAP route in the GLM sensitivity analysis for either surgery type.

IV APAP was associated with fewer potential ORADEs [37] than oral APAP in Cesarean section surgeries (relative risk = 0.45; 95% CI 0.26, 0.78; P < 0.001). However, there was no significant association between the route of APAP administration and the adjusted risk of potential ORADEs in hysterectomy surgeries (relative risk = 1.09; 95% CI 0.77, 1.41; P = 0.57). The findings in the GLM sensitivity analyses were also concordant, with significant risk reduction for Cesarean section, and no significant association for hysterectomy.

IV APAP and oral APAP showed no significant difference in pharmacy costs for hysterectomy patients. The IPW-RA model did not converge for Cesarean section patients, possibly due to some predictors being uncommon but correlated with both treatment and costs. Moreover, total pharmacy costs were not significantly different for IV APAP and oral APAP in either surgery in the GLM sensitivity analysis. We also examined other known cost drivers, including 90-day readmissions, ICU admissions and mortality. ICU admissions showed no significant differences between IV APAP and oral APAP use in both surgery types and the other outcomes were too rare to model reliably in these populations (data not reported).

Using a large, multi-center, retrospective database, we demonstrated that IV APAP use is associated with significantly shorter LOS (by approximately 12%) in Cesarean section and hysterectomy patients when compared to oral APAP. This analysis is one of the first to assess the clinical outcomes and costs of oral APAP versus IV APAP from EHRs, from a robust database of over 600 hospitals and over 62 million patients. Our study focused on Cesarean sections and hysterectomies, where reductions in LOS may be most impactful for hospital costs and resources, given that these patients generally have consistent LOS, with less variation when compared to other surgeries requiring hospitalization. Additionally, research indicates that pain management may differ by gender [5], but the potential for confounding by sex is eliminated by focusing on Cesarean sections and hysterectomies.

A previous claims-based study of Cesarean section and hysterectomy surgeries showed significantly less daily opioid use and lower hospitalization costs in patients receiving IV APAP as part of MMA versus patients receiving IV opioid-only analgesia in Cesarean section and a non-significant trend towards less opioid use and lower cost in hysterectomy; however, the claims-based analysis did not show reductions in LOS in the IV APAP cohort following adjustment [24]. The current study demonstrates statistically significant reductions in LOS and opioid consumption for both Cesarean section and hysterectomy patients. The LOS reductions approached 12%, translating to a reduction of approximately 8 to 12 h, or potentially one nursing shift per day. In the Cesarean group, IV APAP patients also had lower risk of developing an ORADE. There were no statistically significant differences in total pharmacy costs between oral APAP and IV APAP, despite cost differences between these formulations.

These findings are consistent with prior studies of MMA protocols including IV APAP, demonstrating a reduced LOS in orthopedic and spine surgery patients [38, 39]. Retrospective studies in orthopedic and other surgery types have found similar associations [24, 40-42]. MMA is thought to improve surgical outcomes by reducing opioid dosing, resulting in decreased ORADEs and complications, and creating synergies that result in pain reductions. APAP exerts its effects in the central nervous system, and versus oral APAP, IV APAP has a faster T max and a higher C max, with pharmacokinetics that achieve greater concentration in cerebrospinal fluid, suggesting better analgesia from this formulation [43, 44]. Our results support these findings and suggest that IV APAP use may be cost-effective for Cesarean section and hysterectomy surgeries through the reduction of LOS, opioid consumption, and ORADEs.

Other studies have also found that MMA following Cesarean sections or hysterectomies can help to minimize/manage postoperative pain and drive positive clinical outcomes [26, 45]. MMA after Cesarean section has been shown to provide better clinical outcomes with less reliance on opioid pain medications [45, 46]. Supplemental uses of non-opioid medications have been associated with superior pain relief, improved analgesia, and opioid sparing (reduced morphine consumption) [47, 48].

Similar to Cesarean section surgeries, MMA in hysterectomy surgeries is associated with reduced hospital LOS following both open abdominal surgeries and minimally invasive/laparoscopic surgeries [23, 26]. Likewise, MMA in hysterectomy surgeries decreased total opioid utilization perioperatively on postoperative days 1 and 2 [25]. Furthermore, this reduced opioid consumption via MMA does not reduce the efficacy of pain relief [25].

While our results demonstrate an association between IV APAP and shorter LOS, further studies should examine other aspects of efficacy, including pain reduction. Additionally, multimodal therapy including IV APAP may help to reduce sedation associated with opioids to promote mother-baby bonding, caretaking, breast-feeding, and ambulation [15, 16]. Furthermore, reducing the LOS and ORADEs could also help mothers return to their families earlier and perform their daily activities normally. Therefore, using IV APAP in Cesarean section surgeries may benefit both the mother and the newborn infant.

Using IV APAP in a multimodal pain management approach after Cesarean sections or hysterectomies may also reduce the risk of postoperative opioid-related complications by decreasing the amount of opioids used. In fact, a previous study found that, compared with IV opioid-only analgesia, managing pain after Cesarean sections or hysterectomies with the addition of IV APAP decreased both opioid use and hospitalization costs [24].

The study’s strengths include the large, multi-center nature of the database and the breadth of variables used to adjust for potential confounding. Another strength is the statistical methodology; IPW-RA is a more sophisticated method than related approaches like propensity score matching. With IPW-RA, one model is used to derive probabilities (propensities) for treatment and another uses these probabilities in a weighted regression model to estimate average treatment effects. Because IPW-RA estimators are doubly robust, only one of the two models must be correctly specified for the IPW-RA estimator to be consistent. IPW-RA models may not produce a solution with a large number of rare predictors. To address this possibility, we used a more traditional regression model approach as a sensitivity analysis and found generally similar findings.

One limitation of this study is that these findings may not be generalizable to Cesarean or hysterectomy patients that differ substantially from those observed in the Cerner HealthFacts database. It is also unknown how oral APAP versus IV APAP correlates with hospital LOS in other surgical populations. Another study limitation is unmeasured confounding. Laboratory results and acuity measures were not analyzed, and the chronic comorbidities defined by Elixhauser were not developed specifically for the Cesarean section and hysterectomy populations [30]. Specific Cesarean section and hysterectomy variables like pre-eclampsia were not available for this analysis. Nevertheless, a large number of covariates were used for multivariable adjustment. Finally, total cost data could not be reported, as the percentage of patients missing unadjusted data was too high.

Overall, this study provides further evidence supporting the preferential use of IV APAP as part of MMA regimens in Cesarean section and hysterectomy surgeries by demonstrating decreases in LOS, opioid consumption, and ORADE rate.

Acknowledgments

This study was supported by Mallinckrodt Pharmaceuticals. The authors thank Jeffrey R. Skaar and Anna K. Talaga at Boston Strategic Partners, Inc. for editorial support.

Conflict of Interest

EAB, RF, GJW, and JC are employees of Mallinckrodt Pharmaceuticals, and BL and ATP were employees of Mallinckrodt Pharmaceuticals at the time of the study. VK and XZ are consultants with Boston Strategic Partners, Inc., which contracted with Mallinckrodt Pharmaceuticals for this study. BHN is an employee of OptiStatim, LLC and was contracted for this study by Boston Strategic Partners, Inc.

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