Summary
Background
Enhanced recovery after surgery protocols increasingly use multimodal analgesia after major surgeries with intravenous acetaminophen and ketorolac, despite no documented cost-effectiveness of these strategies.
Aims
The goal of this prospective cohort study was to model cost-effectiveness of adding acetaminophen or acetaminophen + ketorolac to opioids for postoperative outcomes in children having scoliosis surgery.
Methods
Of 106 postsurgical children, 36 received only opioids, 26 received intravenous acetaminophen, and 44 received acetaminophen + ketorolac as analgesia adjuncts. Costs were calculated in 2015 US $. Decision analytic model was constructed with Decision Maker® software. Base-case and sensitivity analyses were performed with effectiveness defined as avoidance of opioid adverse effects.
Results
The groups were comparable demographically. Compared with opioids-only strategy, subjects in the intravenous acetaminophen + ketorolac strategy consumed less opioids (P = .002; difference in mean morphine consumption on postoperative days 1 and 2 was −0.44 mg/kg (95% CI −0.72 to −0.16); tolerated meals earlier (P < .001; RR 0.250 (0.112–0.556)) and had less constipation (P < .001; RR 0.226 (0.094–0.546)). Base-case analysis showed that of the 3 strategies, use of opioids alone is both most costly and least effective, opioids + intravenous acetaminophen is intermediate in both cost and effectiveness; and opioids + intravenous acetaminophen and ketorolac is the least expensive and most effective strategy. The addition of intra-venous acetaminophen with or without ketorolac to an opioid-only strategy saves $510–$947 per patient undergoing spine surgery and decreases opioid side effects.
Conclusion
Intravenous acetaminophen with or without ketorolac reduced opioid consumption, opioid-related adverse effects, length of stay, and thereby cost of care following idiopathic scoliosis in adolescents compared with opioids-alone postoperative analgesia strategy.
Keywords: cost-effectiveness, intravenous acetaminophen, ketorolac, multimodal analgesia, pain, spine fusion
1 | INTRODUCTION
The Healthcare Cost and Utilization Project identified 10 procedures with most rapidly increasing hospital costs between 2004 and 2007; the largest increase in costs was for spinal fusion (93.6%),1,2 a surgery associated with considerable hospital expenditures, estimated at $511.2 million annually (2007).3 Spinal fusion is commonly performed to correct adolescent idiopathic scoliosis, a condition which affects 2%–3% of children between the ages of 10 and 16 years. One of the largest contributors to overall cost of this surgery was inpatient hospital stay (22%).4 Hence, enhanced recovery after surgery (ERAS) protocols have been adopted after major surgeries including spine surgery, to hasten discharge, lower rates of morbidity and improve long-term outcomes.5,6 Most ERAS protocols for spine surgery utilize multimodal opioid-sparing strategies including intravenous (IV) acetaminophen and nonsteroidal anti-inflammatory drugs like ketorolac for postoperative pain management.6,7 The United States Food and Drug Administration approved IV acetaminophen in 2010.8 Since then, the use of IV acetaminophen has been growing rapidly in the postoperative setting; however, the drastic increase (140%) in its price since 2014 raises concerns about the cost-effectiveness of its routine use.
Overreliance on opioid therapy increases risk for opioid-related complications. Opioid use could result in adverse effects on the gastrointestinal system, including emesis and constipation, which can delay recovery and discharge from the hospital,3 resulting in significant increases in healthcare costs.9 Since the use of IV acetaminophen and ketorolac after invasive surgery decreases opioid consumption,10 we hypothesized that the use of IV acetaminophen (© Mallinckrodt Pharmaceuticals, Dublin, Ireland) and/or ketorolac (© Hospira, Lake Forest, IL, USA) as opioid adjuncts would be cost-effective compared with the use of opioids alone. To our knowledge, the cost-effectiveness of the use of these medications has never been evaluated before in the context of pediatric major surgery.
Using a decision analytic model, we evaluated the cost per opioid side-effects avoided, when subjects received only opioids, IV acetaminophen in addition to opioids, and IV acetaminophen + IV ketorolac, for postoperative analgesia, after spine fusion. We considered patient and surgical factors, perioperative opioid consumption, opioid-related adverse effects, treatment of adverse effects, and the cost of each strategy, in this analysis.
2 PATIENTS AND METHODS
After approval by the institutional review board at Cincinnati Children’s Hospital, a prospective study was conducted in 106 otherwise healthy, opioid naive subjects aged 10–18 years, undergoing spine fusion for correction of idiopathic scoliosis. Patients were excluded if they were pregnant or breastfeeding; if they had used opioids in the past 6 months or had a history of chronic pain, liver or renal disease. Hence, all recruited patients were otherwise healthy except for scoliosis. Standard physical therapy and discharge criteria were used over the time period of this study. Data were collected as part of a larger pharmacogenomic study registered with ClinicalTrials.gov (NCT01839461 and NCT01731873). Appropriate consent and assent were obtained from participants and legal guardians/parents. The surgeries were all performed by 2 surgeons.
All patients received standard anesthesia consisting of midazolam, fentanyl and total intravenous anesthesia (propofol and remifentanil) during the surgery. All patients also received dexamethasone 8 mg and ondansetron 0.1 mg/kg for anti-emesis prophylaxis during surgery. None received nitrous oxide in the intraoperative phase. After surgery, they received patient controlled analgesia (PCA) with morphine or hydromorphone and rescue doses available for severe pain. The PCA setting was standardized for weight. While PCA was ordered by the pain team for everyone after spine fusion, IV acetaminophen was per pain team discretion, and availability of the IV formulation; although literature has supported the use of ketorolac limited to 48 hours after surgery, with no increased risk for either adverse effect,11,12 ketorolac was avoided if the surgeon expressed concern regarding its use due to risk for bleeding/nonfusion in the particular subject. The doses administered were standard; IV acetaminophen was dosed at 15 mg/kg (maximum 1000 mg) every 6 hours for 3 days, with first dose given intraoperatively, and ketorolac at doses of 0.5 mg/kg (maximum 30 mg) every 6 hours for a total of 8 doses, starting either intraoperatively or on POD1 morning. For this study, subjects were grouped according to the following 3 strategies: patients receiving opioids alone (Strategy opioids only), opioids + IV acetaminophen (Strategy opioids + acetaminophen), and opioids + IV acetaminophen + ketorolac (Strategy opioids + acetaminophen + ketorolac).
Per hospital protocol, all patients receiving PCA were monitored using continuous electrocardiography/respiratory rate module by transthoracic impedance pneumography and pulse oximetry for oxygen saturation. The continuous monitor data were captured in real time on the Epic-based electronic medical record (Epic Systems Corporation, Verona, WI, USA) in 1-min intervals and available for review. The standard pain protocol also included diazepam as necessary for muscle spasms, and methocarbamol every 8 hours for 3 days. Ondansetron 0.1 mg/kg was made available to treat nausea/ vomiting. Oxycodone was started at 0.1 mg/kg every 4 hours once patients tolerated oral diet, and PCA was discontinued per pain physician order. Standard surgical orders for bowel regimen included Senna chewable tablets and polyethylene glycol 3350 two times daily to prevent constipation, and use of bisacodyl suppository as needed for constipation on postoperative days (POD) 1 and 2. A standing order required suppository to be administered on POD3 and every day beyond, and enema on POD4, if no bowel movement happened by then. Per os (PO) acetaminophen was started after discontinuation of PCA and only after oral intake was adequate in groups that did not receive IV acetaminophen and after IV acetaminophen course was completed in those who received IV acetaminophen.
2.1 | Data
We recorded patient demographics (age, race, and gender), weight, scoliosis curve and number of vertebral levels fused. Pain scores were recorded by nurses every 4 hours while patient was on PCA. Epic flowsheets and nursing notes were reviewed for respiratory rates, and intake output charts for episodes of emesis and the initial postoperative day on which 50% meals was tolerated orally (PO intake). Medical administration record was reviewed for use of ondansetron, naloxone, and suppository/enema. Opioid consumption was measured as PCA opioid doses (morphine/hydromorphone) in morphine equivalents. Oxycodone doses used in the postoperative period were also recorded. Date of hospital discharge was noted. Length of hospital stay (LOS) was calculated from the day of surgery through the day of hospital discharge. The postoperative opioid-related adverse effects studied were as follows: (i) postoperative nausea and vomiting (PONV), defined as at least one episode of emesis on POD1 and 2, (ii) respiratory depression (RD), defined as respiratory rate <8/min for >3 minutes on POD1 and 2, (iii) delayed PO intake, if first time after surgery that ≥50% meals were tolerated, was beyond POD2, and (iv) constipation, defined by the need for suppository/enema beyond 3 postoperative days. Occurrence of other complications such as pneumonia, surgical site infection, or critical care admission was noted. Data were collected using Research Electronic Data Capture (REDCap) hosted at Cincinnati Children’s Hospital Medical Center.13 Renal panel (Na+, K+, BUN, creatinine, glucose, CO2) and complete blood count were ordered by surgical team on POD 1 to 3 after surgery. Any abnormalities in creatinine and platelet counts were noted.
2.2 | Effectiveness
Effectiveness was defined as avoidance of any significant opioid side-effect. Since occurrence of opioid side-effects are nonmutually exclusive, the probability was calculated based on the following rule: P (A or B) = P (A) + P (B)−P (A and B), where the probability (P) of either side-effect A or B occurring is given by P (any/either side effect) = sum of P (of each side effect occurring) − P (side effects occurring together).
2.3 | Statistical analysis
The 3 groups were compared for surgical variables, perioperative opioid and diazepam consumption, pain scores, PONV, RD, PO intake, constipation, and LOS, using chi-square test for categorical variables and ANOVA or Kruskal-Wallis test for continuous variables as appropriate. Pairwise comparisons were conducted and 95% CI was reported when a statistical significant difference across the 3 treatment groups (P < .05) was indicated.
2.4 | Cost-effectiveness Analysis
We used Decision Maker software (Decision Maker, Boston, MA, USA) to construct and analyze a decision analytic model and to perform base-case and sensitivity analyses. The base-case analysis was evaluated using the initial set of parameter values. Sensitivity analyses were performed to test the stability of our results over a range of parameter estimates and to explore alternate scenarios. Incremental cost-effectiveness ratio (ICER), defined as the additional cost of the more effective strategy divided by the gain in effectiveness, was calculated at base-case and in sensitivity analyses of relevant parameters.
2.5 | Decision analytic model
The decision model assessed the choice between using opioids only, opioids + acetaminophen, and opioids + acetaminophen + ketorolac (Figure 1). Chance events following the decision node are dependent on morphine doses per weight required in the postoperative period. Hence, for each strategy, patients may require high-dose morphine (HDM) or low-dose morphine (LDM) (defined as > or ≤1.2 mg/kg morphine consumption on POD1 and 2, respectively; cut-off 1.2 mg/kg was used as this is the average value for the entire cohort). Based on our inter-group analyses, we modeled the occurrence of PONV, delay in PO intake and constipation, as the gastrointestinal side effects of opioids are known to delay hospital discharge, as well as LOS is an important component of costs from surgery. Pain scores were not included as opioid consumption is a surrogate for pain. Finally, the outcome avoidance of opioid side effects was calculated for side effects that were significantly different among the 3 strategies.
FIGURE 1.
Decision analytical model for determining cost-effectiveness of the use of 3 strategies for postoperative analgesia after spine fusion surgery: opioids alone, opioids + intravenous (IV) acetaminophen (APAP), and opioids + IV acetaminophen + ketorolac. The decision node is denoted by the filled square, while the chance events following the 3 strategies were similar and are indicated by filled circles following the brackets. The decision tree evaluated each strategy based on probabilities of occurrence opioid side effects/outcomes in high-dose and low-dose morphine subgroups (cut-off of morphine requirement 1.2 mg/kg/d, which was the average for the cohort). The base values included for probabilities of postoperative nausea vomiting (PONV), delayed per os (PO) intake, constipation, and hospital length of stay are detailed in Table 3. Cost-effectiveness was defined as the cost of the strategy to avoid significant opioid side effects
2.6 | Costs
Costs were based on a health-care system perspective. Cost data obtained from hospital purchasing based on 2015 U.S. dollars represent costs to the institution. They include in-hospital costs of facilities, medications, supplies, and labor on postoperative days. We modeled costs of treatment of adverse effects, for example, use of ondansetron for emesis, suppository for constipation, oxygen/respiratory therapy/naloxone for respiratory depression. Of note, we did not include surgery, surgical supplies, pharmacy, laboratory testing, radiology, blood, and respiratory therapy charges that were delivered on the day of surgery, or professional costs for physicians—as these costs would be the same for all strategies, and thus would not impact the calculation of the incremental C/E ratio (ICER). Each chargeable item is given a charge description master (CDM) code within the hospital billing system. These CDM codes can then be categorized based on detailed revenue codes such that all charges can be separated. Charges may reflect varied policies for reimbursement, making them an arbitrary representation of true resource use.14 Hence, costs and no charges were used to represent the consumption of resources.
3 | RESULTS
3.1 | Demographics and cohort variables
The overall mean age for the cohort was 14.4 ± 2 years. 68.4% were female, average weight was 56.7 ± 15.2 kg, and 84.2% were White. The opioids only, opioids + acetaminophen, and opioids + acetaminophen + ketorolac strategies included 36, 26, and 44 patients, respectively. Demographics and perioperative cohort variables are presented in Table 1. The groups were comparable demographically. First dose of ketorolac was administered starting on POD1 in 66% of those who received ketorolac.
TABLE 1.
Comparison of patient and surgical data, postoperative opioid analgesia, and incidence of side effects by strategy
| Strategy | Inter group comparisons | ||||||
|---|---|---|---|---|---|---|---|
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| Variable | Opioids + IV acetaminophen (N = 26) | Opioids + IV acetaminophen + ketorolac (N = 44) | Opioids only (N = 36) | P-value (all 3 strategies) | b Difference between means or RR (95% CI), P-value Opioids + IV acetaminophen vs Opioids + IV acetaminophen + ketorolac | b Difference between means or RR (95% CI), P-value; Opioids + IV acetaminophen vs Opioids only | b Difference between means or RR (95% CI), P-value Opioids + IV acetaminophen + ketorolac vs Opioids only |
| Demographics and baseline variables | |||||||
|
| |||||||
| a Age in years | 14.2 (1.9) | 14.3 (2.1) | 14.4 (1.7) | – | – | – | – |
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| Gender (female %) | 76.9% | 66.0% | 69.4% | – | – | – | – |
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| Race (White %) | 80.8% | 91% | 77.8% | – | – | – | – |
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| a Weight (kg) | 54.9 (14.7) | 56.3 (15.6) | 59.1 (16.5) | – | – | – | – |
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| a Number of vertebral levels fused | 11.4 (2.0) | 11.7 (1.9) | 11.3 (2.3) | – | – | – | – |
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| a Scoliosis curve | 57.5 (11.2) | 58.9 (14.8) | 55.1 (10.8) | – | – | – | – |
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| Perioperative variables | |||||||
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| a Intraoperative remifentanil dose μg/kg | 1.14 (0.35) | 1.25 (0.51) | 1.42 (0.45) | 0.053 | – | – | – |
|
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| Intraoperative Crystalloid/kg | 42.6 (18.2) | 40.1 (12.2) | 49.9 (18.8) | 0.184 | – | – | – |
| Intraoperative Albumin/kg | 15.6 (2.5) | 11.5 (4.3) | 12.5 (4.4) | 0.202 | – | – | – |
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| * Intraoperative PRBC/kg | 12.3 (10.4) | 7.6 (7.8) | 5.1 (2.3) | 0.321 | – | – | – |
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| a Length of stay in days | 4.5 (1.0) | 4.5 (1.7) | 5.1 (1.4) | 0.138 | – | – | – |
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| Opioid and diazepam consumption in the postoperative period | |||||||
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| |||||||
| a Morphine dose mg/kg | 1.6 (0.6) | 1.6 (0.6) | 2.0 (0.7) | 0.011 | 0.008 (−0.30, 0.31) 0.957 |
−0.45 (−0.77, −0.13) 0.006 |
−0.44 (−0.72, −0.16) 0.002 |
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| a Oxycodone dose mg/kg | 1.7 (1.2) | 1.9 (1.5) | 2.4 (1.9) | 0.190 | – | – | – |
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| a Diazepam doses mg/kg | 0.19 (0.15) | 0.14 (0.12) | 0.16 (0.14) | 0.328 | – | – | – |
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| Postoperative analgesia and opioid side effects | |||||||
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| a Pain score (NRS) POD 1 and 2 | 3.8 (1.5) | 4.5 (1.4) | 4.3 (1.3) | 0.130 | – | – | – |
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| Respiratory depression (%) | 30.8 | 20.5 | 25 | 0.623 | – | – | – |
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| Emesis (%) | 34.6 | 38.6 | 36.1 | 0.940 | – | – | – |
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| Number of emesis events | 1.3 (1.6) | 0.9 (1.3) | 0.7 (1.2) | 0.351 | – | – | – |
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| a Mean POD when 50% meals tolerated | 2.4 (1.2) | 1.7 (1.0) | 3 (1.2) | <0.001 | 0.73 (0.17 to 1.30) 0.012 |
−0.56 (−1.17 to 0.05) 0.072 |
−1.29 (−1.84 to −0.75) <0.001 |
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| |||||||
| % subjects with delayed oral intake # | 40% | 15% | 59% | 0.001 | RR 2.733 (1.132–6.601) 0.020 |
RR 0.682 (0.386, 1.207) 0.172 |
RR 0.250 (0.112–0.556) <0.001 |
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| % subjects with constipation @ | 37% | 14% | 63% | 0.001 | RR 2.579 (0.946, 7.027) 0.087 |
RR 0.583 (0.295, 1.153) 0.105 |
RR 0.226 (0.094–0.546) <0.001 |
Numerical variables are presented as mean (SD); categorical variables are presented as %.
For significant P-values (<.05), 95% CI or relative risk-10 (RR) with 95% CI are presented.
Pain was measured using the 0–10 Numerical Rating Scale.
PO, per os; POD, postoperative day;
Delayed oral intake defined as initial postoperative day on which 50% meals was tolerated >2 d;
Constipation defined as needing enema/suppository after POD 3;
Missing values.
3.2 | Opioid consumption and comparison of analgesia and opioid side effects
All patients received morphine as the PCA drug per the pain team; hence, no conversion to morphine equivalents was required. Mean morphine use on POD1, LOS, time to PO intake, and mean postoperative day for suppository use for the cohort were 1.2 ± 0.45 mg/kg, 4.76 ± 1.40 days, 2.3 ± 1.26 days, and 3.57 ± 2.88 days, respectively. Data and results of comparison of strategies for opioid consumption, pain scores, and side effects are provided in Table 1. None of the subjects in the cohort required admission to intensive care units or use of naloxone. Compared with those who received only opioids, subjects receiving the opioids + acetaminophen had decreased opioid consumption (P = .006) but no significant differences in opioid side effects. Compared with those who received only opioids, subjects in the opioids + acetaminophen + ketorolac strategy had significantly less opioid consumption (P = .002), earlier tolerance of meals (P < .001) and less constipation (<0.001). The strategies did not differ in pain scores, occurrence of respiratory depression, emesis or LOS in days, although the LOS was on average, approximately 0.5 days shorter in the strategies that included IV acetaminophen. None of the reported creatinine or platelet level laboratory values were noted to be abnormal (out of acceptable clinical range), and hence, have not been presented.
3.3 | Cost data
The costs of facilities, medications, supplies, and labor used in the model are summarized in Table 2. The cost of hospital stay per day includes room/board (64.5%), pharmacy (9.0%), occupational and physical therapy (OT/PT) (10/8%), radiology, respiratory, supplies, blood bank, research lab, and other costs. We analyzed the average costs each day from POD 1 to POD 6 for every patient, for each of the categories mentioned above (Table 2). The total cost per day decreased slightly from POD 1 to 3 as would have been expected, but peaked on POD 4. Excluding POD4, the total costs per day per patient fell within a narrow range of $2549.30 to $2941.82. Average direct costs per hospital day amounted to $1639.32 Average indirect hospital overhead costs were $1015.37/d and included administrative and general costs, linen and laundry, housekeeping, dietary, cafeteria, nursing administration, medical records, social services, intern, and resident expenses.
TABLE 2.
Costs used in the model and average daily costs per postoperative day per patient in US $categorized by hospital service
| Variable (unit) | Unit cost estimate ($) | |||||
|---|---|---|---|---|---|---|
| Cost of ketorolac vial (30 mg/mL) | 6.00 | |||||
| Cost of IV ondansetron (4 mg/2 mL) | 1.14 | |||||
| Cost of IV fluids (5% dextrose + 0.45% normal saline, 1000 mL) | 5.03 | |||||
| Cost of IV tubing | 7.00 | |||||
| Cost of IV acetaminophen (1000 mg/100 mL bottle) | 42.50 | |||||
| Cost of oxycodone (5 mg) | 0.54 | |||||
| Cost of PCA morphine (30 mg/30 mL syringes) | 16.00 | |||||
| Average cost of hospital stay per postoperative daya | 2691.00 | |||||
| Bisacodyl suppository (each) | 0.20 | |||||
| Enema (each) | 2.50 | |||||
| Cost category per hospital services | Costs per postoperative day (POD) in US $ | |||||
| POD1 | POD2 | POD3 | POD4 | POD5 | POD6 | |
| Blood bank | 12.35 | 35.67 | 27.74 | 0.00 | 0.00 | 0.00 |
| Laboratory | 45.96 | 45.33 | 57.38 | 20.58 | 14.10 | 0.00 |
| Other ancillaryb | 120.14 | 110.72 | 119.59 | 543.75 | 285.26 | 350.51 |
| Occupational/physical therapy | 438.18 | 405.12 | 216.41 | 851.42 | 235.47 | 210.98 |
| Pharmacy | 449.36 | 357.67 | 173.52 | 153.98 | 164.04 | 108.86 |
| Profee | 1.65 | 8.54 | 49.72 | 34.20 | 18.86 | 0.00 |
| Radiology | 6.45 | 26.16 | 126.02 | 90.95 | 33.66 | 0.00 |
| Research Lab | 3.35 | 2.18 | 0.00 | 0.00 | 0.00 | 0.00 |
| Respiratory therapy | 34.98 | 10.46 | 8.46 | 16.03 | 7.52 | 0.00 |
| Room/board | 1742.59 | 1713.54 | 1742.40 | 2285.57 | 2009.34 | 1931.35 |
| Supply | 86.82 | 36.99 | 28.05 | 92.72 | 8.36 | 375.69 |
| Total | 2941.82 | 2752.38 | 2549.30 | 4089.22 | 2776.61 | 2977.39 |
IV, intravenous; PCA, patient controlled analgesia.
Includes room/board (64.5%), pharmacy (9.0%), occupational and physical therapy (OT/PT) (10.8%), radiology, respiratory, supplies, blood bank, research lab, and other costs.
Nutrition Therapy and Vascular Access Team.
3.4 | Base-case analysis
The base case values for key model parameters are shown for each strategy in Table 3. They are stratified by the need for either low-or high-dose morphine (HDM). The probability of needing HDM was highest for those receiving opioids only (89%), compared with opioids + acetaminophen (58%) and opioids + acetaminophen + ketorolac (52%) strategies. The risk of needing HDM relative to the strategy opioids + acetaminophen + ketorolac was 1.12 and 1.71 for the opioids + acetaminophen and the opioids only strategies, respectively. The probability of opioid side effects was lower in the LDM compared with HDM subgroups in opioids + acetaminophen and opioids + acetaminophen + ketorolac strategy and lower in the HDM subgroup in the opioid-only strategy. Probabilities of occurrence of both delayed PO intake and constipation occurring together in every subgroup were used to model effectiveness, as they were significantly different among the strategies. Hence, probability of any significant opioid side effect was calculated as (Pboth (delayed PO intake) + P (constipation)) − Pboth(delayed PO intake and constipation) (Table 3). Effectiveness was defined as freedom from opioid side effects (ie, 1 – the probability of any significant opioid side effect) in each subgroup.
TABLE 3.
Base-case probabilities and results based on cost-effectiveness decision analytic modeling
| Base-case probabilities | ||||||
|---|---|---|---|---|---|---|
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| Opioids + IV acetaminophen strategy | Opioids + IV acetaminophen + ketorolac strategy | Opioids-only strategy | ||||
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| LDM | HDM | LDM | HDM | LDM | HDM | |
| Probability of receiving HDM (SE) | 0.58 (0.096) | 0.52 (0.075) | 0.89 (0.052) | |||
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| Relative risk for needing HDM | 1.12 | 1 | 1.71 | |||
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| Mean morphine dose (mg/kg), mean (SD) | 1.11 (0.34) | 2.10 (0.47) | 1.08 (0.19) | 1.92 (0.47) | 0.88 (0.26) | 2.16 (0.63) |
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| Mean oxycodone dose (mg/kg), mean (SD) | 1.25 (0.63) | 2.24 (1.51) | 1.45 (0.67) | 2.34 (1.82) | 4.12 (2.56) | 2.16 (1.74) |
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| LOS (days), mean (SD) | 3.8 (0.53) | 5.3 (0.89) | 4.1 (0.74) | 5.1 (1.97) | 5.1 (1.21) | 5.7 (2.40) |
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| Probability of LOS > 4 d | 0.18 | 0.6 | 0.16 | 0.48 | 0.25 | 0.71 |
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| Probability of PONV (95% CI) | 0.3 (0.1–0.61) | 0.4 (0.17–0.69) | 0.3 (0.1–0.61) | 0.5 (0.24–0.76) | 0.3 (0.1–0.61) | 0.4 (0.17–0.69) |
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| Probability of delayed PO intake (PPO) (95% CI) | 0.18 (0.12–0.27) | 0.53 (0.43–0.62) | 0.21 (0.14–0.30) | 0.17 (0.11–0.26) | 0.33 (0.25–0.43) | 0.61 (0.51–0.70) |
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| Probability of constipation (PConst) (95% CI) | 0 (0–0.83) | 0.64 (0.54–0.73) | 0.06 (0.03–0.13) | 0.21 (0.14–0.30) | 1 (0.17–1) | 0.59 (0.49–0.68) |
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| Probability of both “delayed PO intake and constipation” occurring together (Pboth)(95% CI) | 0 (0–0.83) | 0.50 (0.24–0.76) | 0 (0–0.83) | 0 (0–0.83) | 0.50 (0.24–0.76) | 0.60 (0.31–0.83) |
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| Probability of any significant opioid side effect (PSE)(95% CI) | 0.18 (0.12–0.27) | 0.67 (0.57–0.75) | 0.27 (0.19–0.36) | 0.38 (0.29–0.48) | 0.83 (0.74–0.89) | 0.61 (0.51–0.70) |
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| Effectiveness = Probability of avoidance of any significant opioid side effect = 1 − PSE (95% CI) | 0.82 (0.73–0.88) | 0.33 (0.25–0.43) | 0.73 (0.64–0.80) | 0.62 (0.52–0.71) | 0.17 (0.11–0.26) | 0.39 (0.30–0.49) |
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| Strategy | Cost (US $) | Effectiveness (free of opioid side effects) | Incremental cost (US $) | Incremental effectiveness (free of opioid side effects) | Incremental C/E ($/free of opioid side effects) | |
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| Opioids + IV acetaminophen + Ketorolac | 14 527.36 | 0.694 | Dominant | |||
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| Opioids + IV acetaminophen | 14 963.81 | 0.612 | 436.45 | −0.082 | Dominated | |
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| Opioids only | 15 474.43 | 0.315 | 947.07 | −0.379 | Dominateda | |
IV, intravenous; LDM, low-dose morphine; LOS, length of stay; HDM, high-dose morphine; PO, per os/oral; PONV, postoperative nausea and vomiting.
Incremental cost and effectiveness for opioid-only strategy was calculated against opioids + IV acetaminophen + ketorolac, due to dominance.
In the base case, opioids + acetaminophen + ketorolac strategy dominated the other 2 strategies by being the least costly and most effective strategy (Table 3). Opioids only was the most expensive and least effective strategy. The strategy opioids + acetaminophen had an intermediate cost and effectiveness compared with the other 2 strategies, but was still dominated by opioids + IV acetaminophen + ketorolac.
3.5 | Sensitivity analyses
We performed sensitivity analyses to determine the impact of uncertainty on a variety of parameter values. In Figure 2, we examined the ICER between opioids + acetaminophen vs opioids + acetaminophen + ketorolac to assess the impact of (i) probability of needing HDM and (ii) probability of significant opioid side effect with HDM. The opioids-only group was not included in this analysis, since it was dominated in the base case. As shown in panel A, as the probability of requiring HDM in the opioids + acetaminophen strategy increases from 0 to 0.16, the ICER increases, meaning the opioids + acetaminophen strategy becomes increasingly more costly per significant side effect avoided. Beyond a probability of 0.18, the opioids + acetaminophen + ketorolac strategy dominates by being less costly and more effective than opioids + acetaminophen. The base-case value of this parameter is 0.58. The one-way sensitivity analysis in panel B examines the probability of significant opioid side effects in the opioids + acetaminophen strategy. As the probability increases, the ICER increases, meaning opioids + acetaminophen becomes increasingly costly for the benefit provided. At a probability exceeding 0.47, opioids + acetaminophen + ketorolac dominates by being less costly and more effective than opioids + acetaminophen. The base-case value of this parameter is 0.67.
FIGURE 2.
One-way sensitivity analysis examining the incremental cost-effectiveness ratio of the opioids + intravenous (IV) acetaminophen (APAP) strategy compared with the opioids + IV acetaminophen + ketorolac strategy as a function of the probability of requiring high-dose morphine for adequate analgesia (Panel A), and the probability of any significant opioid side effect from high dose-morphine in the opioids + IV acetaminophen strategy (Panel B). In the first panel, as the probability of requiring HDM in the opioids + IV acetaminophen increases from 0 to 0.16, the ICER increases, meaning the opioids + IV acetaminophen strategy becomes increasingly more costly for the benefit of opioid side effects avoided. Beyond a probability of 0.18, the opioids + IV acetaminophen + ketorolac strategy dominates by being less costly and more effective. The base-case value is 0.58. The opioids-only strategy was not included since it was a dominated strategy in the base-case analysis. Panel B shows that as the probability of significant side effects in the opioids + acetaminophen strategy increases from 0 to 0.47, the ICER increases, meaning the opioids + acetaminophen strategy becomes increasingly costly for the achieved benefit. At a probability exceeding 0.47, the opioids + acetaminophen + ketorolac strategy dominates (less costly and more effective at avoiding side effects) and the base-case value is 0.67
In a second set of sensitivity analyses (Figure 3), we examined the impact of changes in the cost of IV acetaminophen. Since this parameter has a similar effect on both strategies containing IV acetaminophen, in these one-way sensitivity analyses, we compared the opioids + acetaminophen + ketorolac strategy to the opioids-only strategy. In panel A, the ICER of opioids + acetaminophen + ketorolac increases as the cost of a 1000 mg bottle of IV acetaminophen increases. Below a per bottle cost of $121 (~3-fold higher than the current cost of $42.50), the opioids + IV acetaminophen + ketorolac strategy is dominant, being both less costly and more effective than the opioids-only strategy. Panel B examines the cost of each of the 3 strategies as a function of the per bottle cost of IV acetaminophen. At the base case cost of $42.50, opioids + acetaminophen + ketorolac is the least expensive.
FIGURE 3.
One-way sensitivity analysis examining the incremental cost-effectiveness of the opioids + intravenous (IV) acetaminophen (APAP) + ketorolac strategy compared with the opioids-only strategy (Panel A) as a function of cost of the 1000 mg (100 mL) IV acetaminophen bottle (shown on the x-axis). Present cost (2015 US $) is $42.50. The opioids + IV acetaminophen + ketorolac strategy continues to be the dominant strategy up to a cost of $121 per bottle. Beyond that cost, the strategy of opioids + IV acetaminophen + ketorolac has an increasing ICER. At per bottle costs exceeding $1200 (not shown in the figure), the opioids-only strategy becomes dominant. Panel B shows the costs for each of the 3 strategies at different costs per 1000 mg bottles of IV acetaminophen. At a cost exceeding $121 per bottle, the opioid-only strategy becomes the least costly
4 | DISCUSSION
In the current setting of rising healthcare expenditures, it is increasingly important to deliver safe healthcare in a cost-effective manner. Multimodal analgesia strategies using IV acetaminophen and ketorolac decrease opioid overreliance following major surgery. To assess the cost-effectiveness of including these analgesia adjuncts, we compared cost per significant opioid side effect avoided for 3 strategies commonly employed for managing postoperative pain after spine fusion, in otherwise healthy adolescents. Our results show that the use of opioids alone is both more costly and less effective than strategies using adjuvant IV pain medications. Opioids plus IV acetaminophen is intermediate in both cost and effectiveness, while opioids plus IV acetaminophen and ketorolac is the least expensive and most effective of the 3 strategies. The addition of IV acetaminophen to an opioid-only strategy with or without ketorolac saves at least $510 per patient undergoing spine surgery and decreases opioid side effects. The addition of both IV acetaminophen and ketorolac results in an even greater net savings and improved effectiveness. Thus, the strategy of opioids + acetaminophen + ketorolac strategy dominants the other 2 by being the least costly and most effective at avoiding significant opioid side effects on the gastrointestinal system (delayed oral intake and constipation). Generalizing our results to the 38 000 spine fusions performed annually in the United States for patients with idiopathic scoliosis,15 using pain adjuncts IV acetaminophen and ketorolac could result in substantial cost savings.
ERAS protocols are increasingly used following spinal fusion in patients with idiopathic scoliosis to facilitate early discharge; however, the cost efficacy of the therapeutic components used has not been studied in detail.16 Our results are consistent with prior research findings in adults undergoing orthopedic surgeries, where use of IV acetaminophen was found to decrease costs and lower LOS.17,18 In adults undergoing obstetric, cardiovascular, colorectal, and orthopedic surgeries, authors report decreased opioid-related complications by 28.7% and LOS by 18.5% by the use of IV acetaminophen, with estimated cost savings of $4.5 million.19 Another retrospective study evaluating the use of IV acetaminophen after spinal surgery reported decrease in postoperative opioid use, but they did not find decreased subsequent antiemetic or laxative use.8 However, their study size was small (n = 34), and the acetaminophen doses were not standardized. Unlike the studies mentioned above, our study has the advantage of being prospective and uses standardized weight-based acetaminophen dosing. We show that opioid consumption and side effects, as well as LOS, are reduced by 0.5 days and the IV acetaminophen strategies are more effective and less costly than using opioids alone. Subjects receiving only opioids had the largest relative risk of needing high-dose morphine and a correspondingly higher probability of both delayed PO intake and constipation from opioid use, with a tendency to longer LOS. These results substantiate the well-known opioid adverse effects on the gastrointestinal system.20 Although we did not evaluate the effect of side effects on LOS, our results are consistent with previous report of a relationship between the number of opioid induced adverse effects per patient and increased LOS.23
Our study is also the first to formally evaluate cost-effectiveness of combined IV acetaminophen and ketorolac pain management strategies in pediatric subjects undergoing major surgery. Prior studies of ketorolac as a sole adjunct after pediatric orthopedic procedures reported decreased morphine use,21 decreased gastrointestinal side effects, enhanced early mobility, and shortened LOS after spine surgery.22,23 However, concerns have been raised regarding the negative effects of ketorolac on platelet function, gastric ulceration, renal toxicity, and osteoblastic proliferation after spine fusion.24 There is increasing evidence over the past few years that impaired bone healing happens with higher doses (120–240 mg/d)25 and longer duration (>14 days) of treatment with ketorolac.26 Therefore, we can safely advocate the use of ketorolac for 8 doses along with IV acetaminophen as cost-effective opioid adjuncts, especially in patients at risk for requiring high doses of opioids.
This study does not address the optimum number of postoperative doses of IV acetaminophen and whether to switch to oral acetaminophen when patients start eating. Pharmacokinetic studies have consistently shown that mean plasma concentrations are significantly higher with IV rather than oral administration of acetaminophen as it avoids first-pass hepatic metabolism27 and 100% of patients achieved therapeutic plasma concentrations (66 μmol/L) in the IV group compared with only 35% in the oral group, which lasts longer.28–30 A recent meta-analysis concluded that for patients who can take an oral dosage form, no clear indication exists for preferential prescribing of IV acetaminophen, and decision making must take into account other considerations such as convenience and cost.31 Since the average time to tolerating PO was 2.3 days in our study, it is more relevant to ask whether IV acetaminophen would remain cost-effective if switched to PO formulation on the second POD—this needs further study.
Our study is timely and significant for the following reasons: (i) increasing use of IV acetaminophen in the United States has resulted in substantial increases in costs for the drug, and (ii) the anticipated transition from traditional “fee-for-service” models to “bundled payment,” whereby health care providers are encouraged to deliver care more efficiently and to improve quality, cost, and outcomes.32 Increase in medication costs makes it necessary for physicians to justify the use of medications based on their costs vs efficacy and makes cost-effectiveness studies very relevant. Sensitivity analyses (Figure 3) showed that even if IV acetaminophen costs increased 3-fold (~$121 per 100 mL), the opioids + IV acetaminophen + ketorolac strategy would dominate the opioid-only strategy.
The cost impact to decreasing postoperative LOS has been suggested to be minimal.33 In our study, we found that costs following spine fusion in relatively healthy adolescents were mainly driven by room/board, OT/PT and pharmacy costs, as has been previously described.17 Observed increase in costs on POD4 was unexpected and is partly explained by 4-fold higher costs for OT/PT on POD4 than POD3. Room/board costs on POD4 were also high, which we believe might have been inaccurate as variable direct costs attributable to nursing were not included for many patients on POD 1–3, while 100% of nursing costs had been included on POD4. While this billing structure presumes nursing staff adjusts with patient turnover, given the staffing levels large hospitals are committed to, it might be beneficial to treat them as direct fixed costs to prevent such oversights. Our findings that subjects in the strategies that included IV acetaminophen were discharged on average 0.5 day earlier could be extrapolated to 63 fewer hospital days for the 106 patients in this study. Indirect benefits relating to quicker return to familiar settings for the child, and decreased disruption of life quality for the parents, especially if they have other children to care for, and earlier return to work were not included in our cost-effectiveness analysis, but would only add to the ICER of multimodal analgesia.
The cost-effectiveness of the intraoperative combination of IV acetaminophen and IV opioids vs IV opioids alone after tonsillectomy has been evaluated in a pediatric ambulatory setting. Similar to our results that focuses on the cost-effectiveness of IV acetaminophen over the range of hospital stay after major surgery in an inpatient setting, IV acetaminophen in combination with opioids was both less costly ($17.12) and more effective (3.3% fewer rescue events), and hence reduced overall costs after tonsillectomy.34 The price of IV acetaminophen has, however, increased drastically since the publication of the tonsillectomy study.
Our study is limited by the lack of randomization, and absence of an adequate “ketorolac-only” treatment group for comparison. The groups, however, were based on real-world clinical scenarios and the decision to use acetaminophen or ketorolac was based on drug availability, cost concerns and surgeon preference, and not deliberate bias by the pain physician. Since the only variation to standardized pain management involved the drugs being studied, this provided a convenience sample for us to conduct this study. Treatment groups were comparable demographically; surgical variation was minimal, and the dosing of acetaminophen and ketorolac was standardized; however, the study is limited by the fact that the phase of care in which ketorolac dosing was started was not standardized. We did not collect laboratory evidence of liver function. Acetaminophen overdoses have been associated with cases of acute liver failure, at times resulting in liver transplant and death. However, most of the cases of liver injury are associated with doses that exceed the maximum daily limits, and often involve more than one acetaminophen-containing product, and not clinically appropriate doses.35 We would like to emphasize that although this is a small, nonrandomized study, we not only report results from our study, we have also constructed a model that allows us to study the impact of uncertainty around parameter values and that our conclusions are robust within reasonable bounds around these base case values. Moreover, a recent editorial described why efficacy and costs measured in randomized clinical trials, while being essential to evidence-based medicine, may not capture cost-effectiveness of treatment strategies in less controlled, real-world clinical settings.2
5 | CONCLUSIONS
In conclusion, the addition of IV acetaminophen + ketorolac to opioids for postoperative analgesia in adolescents undergoing major spine surgery is more effective at decreasing opioid side-effects at lower costs, when compared with the use of IV acetaminophen alone as an adjunct or only opioids. Sensitivity analyses suggest that in patients who have a low risk for needing high morphine doses (lower pain response, minor surgery), or opioid side effects (genetics affecting opioid pharmacokinetics or pharmacodynamics), the opioids + acetaminophen strategy may be a reasonable alternative. Finally, opioids + acetaminophen + ketorolac strategy continues to be cost-effective within a range of potential future cost increases for IV acetaminophen. Use of only opioids as mainstay analgesia after major surgery is least effective at decreasing opioid side effects and is the most expensive strategy.
What is already known
Enhanced recovery after surgery protocols increasingly use multimodal analgesia with intravenous acetaminophen and intravenous ketorolac as opioid adjuncts, which are known to be opioid-sparing.
What this article adds
The cost-effectiveness of multimodal strategies has not been studied before. Our study shows that the use of a combination of acetaminophen and ketorolac in multimodal postoperative analgesia protocols for major pediatric spine surgery is less costly and more effective than opioids or acetaminophen alone as an adjunct.
Acknowledgments
Funding information: The project described was supported by the 5K23HD082782 through the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (PI: Chidambaran), National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant 8 UL1 TR000077 through the T1 Junior Faculty Award and Clinical Research Feasibility Funds (PI: Chidambaran). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. It was also supported by the APSF/ASA Safety Scientist Career Development Award by the Anesthesia Patient Safety Foundation (PI: Chidambaran).
We thank our prior research coordinators for their help in subject recruitment: Hope Esslinger, CRC IV, and Kayla Stallworth, BS. We also thank John Hingl R.Ph. MBA, Director of Pharmacy Operations; Teresa M Meyer, Pharmacy Buyer; Carol Laux, Cost Reporting and Account Manager; and Priscilla Murray, Business Director, Patient services Finance, for providing the data on costs.
Footnotes
CONFLICT OF INTEREST
The authors report no conflict of interest.
References
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