Are there data to support the use of IV meloxicam for perioperative pain control in orthopedic surgery patients?
Background
Orthopedic surgeries are considered to be some of the most painful procedures patients undergo.1 In orthopedics and many other surgical specialties, the recommended strategy for achieving adequate postoperative analgesia involves a multi-modal approach–the simultaneous use of 2 or more agents that act on different targets of the pain pathway.1,2,3 This strategy has demonstrated synergistic effects compared to using agents individually, and has been shown to decrease the risk of drug-related adverse events (AEs) by allowing for reduced doses of individual analgesics.1
Opioid-sparing analgesics are an important component of postoperative pain management, especially when applying the multimodal approach.1,2,3 Opioid analgesics, while highly effective at managing pain, increase the risk of opioid-related AEs that can slow postoperative recovery.4 The growing opioid epidemic also warrants more judicious use opioids in an effort to reduce abuse and dependence. Commonly used non-opioid analgesics in orthopedic surgery are summarized in Table 1.1 Non-steroidal anti-inflammatory drugs (NSAIDs) are important players in this arena, and specifically recommended by national guidelines for postoperative pain management for patients without contraindications.2,3
| Table 1. Non-opioid analgesics used in orthopedic surgery.1 | |
|---|---|
| Drug | Route |
| Acetaminophen | IV/PO |
| Celecoxib | PO |
| Gabapentin/Pregabalin | PO |
| Ibuprofen | IV/PO |
| Ketamine | IV |
| Ketorolac | IN |
| Abbreviations: IN=intranasal; IV=intravenous; PO=by mouth. |
|
Meloxicam
Meloxicam is a NSAID with preferential cyclooxygenase-2 (COX2) inhibition; the agent is available as oral tablets and capsules, and a 30 mg/ml solution for intravenous (IV) push administration.5,6 Similar to other NSAIDs, meloxicam has analgesic, anti-inflammatory, and antipyretic actions.6 However, when compared to non-selective NSAIDs (ibuprofen, etc), meloxicam exhibits superior gastrointestinal tolerability with potentially improved renal protective properties. The IV formulation of meloxicam (Anjeso®) was Food and Drug Administration (FDA)-approved in February 2020 for the management of moderate-to-severe pain, making it the first and only IV, COX-2 preferential NSAID.7,8 While both oral and IV meloxicam are dosed once daily, the IV formulation has a faster onset of action (~15 minutes vs ~80 minutes).6
Of note, the initial approval of IV meloxicam was halted in 2018 when the FDA noted that the drug’s analgesic effects and selective secondary outcomes did not meet expectations.8 In the most recent approval documents, the FDA noted that the delayed onset of IV meloxicam would not meet prescriber expectations for its category of drugs. Nonetheless, meloxicam was granted FDA approval after an appeal by the manufacturer where evidence of effectiveness and safety was deemed appropriate for approval.
IV meloxicam in orthopedic surgery
Three randomized, double-blind, placebo-controlled trials provide data to support the safety and opioid-sparing effects of IV meloxicam in orthopedic surgery patients with moderate-to-severe postoperative pain (see Table 2).9-11 Two of these trials were published in 2018, and evaluated the efficacy and safety of IV meloxicam at doses of 30 and 60 mg in patients undergoing bunionectomy in the United States.10,11 In this population, IV meloxicam was well tolerated with generally mild AEs. In both trials, rescue oxycodone was required by >80% of patients in all groups during the first 24 hours after receiving the initial dose of study drug; however, the total number of doses of rescue therapy required was lower with IV meloxicam vs placebo. Furthermore, both trials found that IV meloxicam yielded significantly greater reductions in pain intensity over the first 48 hours vs placebo. However, the results for other analgesic outcomes, including differences in Patients’ Global Assessment (PGA) scores and proportions of patients with pain reduction of ≥30% and ≥50%, were not replicated across trials.
More recently, Sharpe et al published a subgroup analysis9 of orthopedic surgery patients from a larger multicenter trial.12 The subgroup included 379 orthopedic surgery patients; the most common procedures were total knee replacement, complex foot surgery, total hip replacement, and bunionectomy.9 Patients were randomized to IV meloxicam at a dose of 30 mg or placebo, and the most commonly used rescue agents were acetaminophen, gabapentin, and pregabalin. Similar to the trial by Gottlieb et al, IV meloxicam was well tolerated with mostly mild AEs. When compared to placebo, meloxicam demonstrated a 26.8% reduction in mean total opioid consumption (IV morphine equivalent dose, 50.3 mg vs 36.8 mg; p=0.0081). Likewise, mean opioid consumption was also significantly lower in the meloxicam vs placebo group during the first 24 hours (-28.9%; p=0.0033), and 24 to 48 hours (-25.5%; p=0.0362); the between group difference did not reach statistical significance at 48 to 72 hours (-38.4%; p=0.2178). Unlike the Gottlieb et al trial, this trial did not specifically evaluate analgesia.
| Table 2. Efficacy and safety data for IV meloxicam in orthopedic surgery patients.9-11 | ||||
|---|---|---|---|---|
| Citation/Design/Population | Interventions/Background analgesia/Rescue therapy | Outcomes | ||
| Analgesia | Opioid-use | Safety | ||
| Sharpe 20209 Post-hoc subgroup analysis of a MC, DB, PC, RCT12 N=379 orthopedic surgery patients with moderate-to-severe pain (the most common procedures were total knee replacement, complex foot surgery, total hip replacement, and bunionectomy) | IV meloxicam 30 mg once daily (n=20) Placebo (n=19) Maximum of 7 doses of study medication No background analgesia Standard of care rescue medications allowed, excluding NSAIDS. Most commonly used agents included acetaminophen, gabapentin, and pregabalin. | Not reported | Mean total opioid consumption was 26.8% lower in the meloxicam vs placebo group (IV morphine equivalent dose, 36.8 mg vs 50.3 mg; p=0.0081) Mean opioid consumption was significantly lower in the meloxicam vs placebo group during the first 24 hours (-28.9%; p=0.0033), and 24 to 48 hours (-25.5%; p=0.0362); between group difference did not reach significance at 48 to 72 hours (-38.4%; p=0.2178) | Occurrence of AEs: meloxicam, 64.7%; placebo, 68.8% Nausea, constipation, and vomiting were the most common AEs and most AEs were mild in severity |
| Gottlieb 201810 Phase 2, RCT, DB, SC in the US N=59 adults with moderate- to-severe pain following a unilateral bunionectomy | IV meloxicam 30 mg once daily (n=20) IV meloxicam 60 mg once daily (n=20) Placebo (n=19) Maximum of 3 doses of study medication No background analgesia Rescue oral oxycodone 5 mg administered as needed up to every 2 hours | Both doses of meloxicam yielded significantly greater reductions in summed pain intensity differences over the first 48 hours vs placebo (p≤0.01) There were no statistically significant differences in PGA scores between groups at 24 or 48 hours after administration of the first dose of study medication Results for the proportions of patients with pain reduction of ≥30% and ≥50% were discordant between analyses | Rescue oxycodone during the first 24 hours after receiving the initial dose of study medication was required by ≥90% of patients in each group At hours 24 to 48, oxycodone was required by more patients who received placebo (77.8%) vs meloxicam 30 mg or 60 mg (55.0% and 52.6%, respectively) Median time to first use of oxycodone: meloxicam 60 mg, 3.10 hours; placebo, 1.57 hours (p<0.05) The difference in median time to first use of oxycodone was not significant between the meloxicam 30 mg dose and placebo Average number of rescue oxycodone doses: meloxicam 30 mg, 8.2; 60 mg, 6.9; placebo, 11.1 (between-group differences were not statistically significant) | AEs occurred in 12, 10, and 10 patients randomized to meloxicam 30 mg, 60 mg, and placebo, respectively Nausea, headache, and dizziness were the most common AEs, and most AEs were mild in severity |
| Pollak 201811 Phase 3, RCT, DB, MC in the US N=201 adults with moderate-to-severe pain following a unilateral bunionectomy | IV meloxicam 30 mg once daily (n=97) Placebo (n=97) Maximum of 3 doses of study medication No background analgesia Rescue oral oxycodone 5 mg was allowed | Meloxicam yielded significantly greater reductions in summed pain intensity differences over the first 48 hours vs placebo (p=0.0034) Median time to meaningful pain relief: meloxicam, 2.16 hours; placebo, 3.19 hours The percentage of patients who reported “good” or “better” pain control (PGA assessment score ≥2) was significantly higher in the meloxicam vs placebo group at both 24 hours (57.9% vs. 43.3%, p=0.0452) and 48 hours (84.2% vs. 65.6%)(p=0.0043) The percentage of patients with a ≥30% improvement in pain was significantly higher in the meloxicam vs placebo group at 6 hours (32% vs. 19.8%; p=0.0451) and 24 hours (37% vs. 20.9%; p=0.0107) The percentage of patients with a ≥50% improvement in pain was significantly higher in the meloxicam vs placebo group at 24 hours (13% vs. 5%, respectively; p=0.0430); the difference at 6 hours was not statistically significant | Rescue oxycodone use during the first 24 hours after receiving the initial dose of study medication: meloxicam, 83%; placebo, 98% Median time to first use of oxycodone: ~2 hours in both groups Mean number of oxycodone doses: meloxicam, 5.45; placebo, 7.49 (p=0.0014) | Occurrence of AEs: meloxicam, 44 patients; placebo, 54 patients Nausea, headache, and pruritis were the most common AEs, and most AEs were mild in severity |
| Abbreviations: AE=adverse events; DB=double blind; IV=intravenous; MC=multicenter; NSAID=non-steroidal anti-inflammatory drug; PC=placebo controlled; PGA=Patients’ Global Assessment; RCT=randomized controlled trial; SC=single center; US=United States. | ||||
Discussion
In orthopedic surgery, NSAIDs are an important component of postoperative pain management and are often used as part of a multimodal analgesic regimen.1 In patients with moderate-to-severe pain after orthopedic surgery, 3 randomized, placebo-controlled trials have demonstrated good tolerability and safety with IV meloxicam at doses of 30 and 60 mg.9-11 Positive analgesic and opioid-sparing effects with IV meloxicam were also demonstrated across trials. However, the clinical significance and applicability of these results to practice require careful evaluation.
All 3 trials evaluated in this review were placebo-controlled, and studies comparing IV meloxicam to other NSAIDs or non-opioid analgesics in patients undergoing orthopedic surgery were not identified.9-11 The majority of patients in 2 of the 3 trials required rescue opioids during the first 24 hours after receiving the initial dose of study medication.10,11 Likewise, the time to first use of an opioid was short in both trials (approximately 2 to 3 hours postoperatively). The opioid-sparing effects of IV meloxicam observed in these trials were arguably not clinically significant based on the number of oxycodone doses or total opioid consumption.9-11 For example, the statistically significant difference in total rescue oxycodone doses found by Pollak et al equated to a between-group difference of approximately 2 doses.11 Similarly, the statistically significant difference in total opioid consumption between meloxicam and placebo groups found by Sharpe et al equated to a difference of only 13.5 morphine equivalents.9
Other limitations of the reviewed data include the relatively small sample size across trials when considering the frequency at which orthopedic procedures are performed.9-11 None of the trials evaluated IV meloxicam as part of a traditional multimodal approach that uses ≥2 therapies simultaneously, and 2 of the 3 trials were exclusively in patients undergoing bunionectomy.10,11 Interpatient variability must also be considered, as intraoperative events may have led to deviations from standard operative procedures, which may impact patient recovery. Lastly, since most orthopedic procedures are done on an outpatient basis, the extended duration of hospital stay required for clinical assessment in these trials may not reflect the current practice.
Conclusion
Overall, IV meloxicam at doses of 30 and 60 mg appears to be a safe and effective for moderate-to-severe pain post orthopedic surgery.9-11 Comparative efficacy of this agent over other NSAIDs or non-opioid agents used for analgesia in orthopedics are lacking and warrant further research. If choosing this agent for postoperative pain management, rescue analgesic therapies should be available as well.
References
- Pitchon DN, Dayan AC, Schwenk ES, Baratta JL, Viscusi ER. Updates on multimodal analgesia for orthopedic surgery. Anesthesiol Clin. 2018;36(3):361-373. doi:10.1016/j.anclin.2018.05.001
- American Society of Anesthesiologists Task Force on Acute Pain Management. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012;116(2):248-273. doi:10.1097/ALN.0b013e31823c1030
- Chou R, Gordon DB, de Leon-Casasola OA, et al. Management of postoperative pain: a clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain. 2016;17(2):131-157. doi:10.1016/j.jpain.2015.12.008
- Martinez L, Ekman E, Nakhla N. Perioperative opioid-sparing strategies: utility of conventional NSAIDs in adults. Clin Ther. 2019;41(12):2612-2628. doi:10.1016/j.clinthera.2019.10.002
- Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. Food and Drug Administration. Accessed July 22, 2020. https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm
- Bekker A, Kloepping C, Collingwood S. Meloxicam in the management of post-operative pain: narrative review. J Anaesthesiol Clin Pharmacol. 2018;34(4):450-457. doi:10.4103/joacp.JOACP_133_18
- Anjeso. Package insert. Baudax Bio, Inc.; 2020.
- Rosenfeld S. FDA approves IV meloxicam for pain management. HCP live. February 20, 2020. Accessed July 22, 2020. https://www.mdmag.com/medical-news/fda-approves-iv-meloxicam-pain-management
- Sharpe KP, Berkowitz R, Tyndall WA, et al. Safety, tolerability, and effect on opioid use of meloxicam IV following orthopedic surgery. J Pain Res. 2020;13:221-229. Published 2020 Jan 21. doi:10.2147/JPR.S216219
- Gottlieb IJ, Tunick DR, Mack RJ, et al. Evaluation of the safety and efficacy of an intravenous nanocrystal formulation of meloxicam in the management of moderate-to-severe pain after bunionectomy. J Pain Res. 2018;11:383-393. Published 2018 Feb 16. doi:10.2147/JPR.S149879
- Pollak RA, Gottlieb IJ, Hakakian F, et al. Efficacy and safety of intravenous meloxicam in patients with moderate-to-severe pain following bunionectomy: a randomized, double-blind, placebo-controlled trial. Clin J Pain. 2018;34(10):918-926. doi:10.1097/AJP.0000000000000609
- Bergese SD, Melson TI, Candiotti KA, et al. Aphase 3, randomized, placebo-controlled evaluation of the safety of intravenous meloxicam following major surgery. Clin Pharmacol Drug Dev. 2019;8(8):1062-1072. doi:10.1002/cpdd.666
Prepared by:
Katherine Sarna, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
August 2020
The information presented is current as July 20, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.