Preoperative Intravenous Meloxicam for Moderate-To-Severe Pain in the Immediate Post-Operative Period: A Phase IIIB Randomized Clinical Trial in 55 Patients Undergoing Primary Open or Laparoscopic Colorectal Surgery with Bowel Resection and/or Anastomosis

Figures & data

Table 1. Enhanced recovery after surgery protocol.

Period	Intervention
Preoperative
	Patient education:
	• Subject education (which may include discussion and a written handout) describing pre-, peri- and postoperative care and expectations
	Diet:
	• Encourage hydration 2 days prior to surgery • Encourage carbohydrate loading preoperatively up to 2–6 h prior to surgery
	Bowel prep:
	• Clear liquids with mechanical bowel prep as indicated by surgery type • Antibiotics as indicated by surgeon
	Motility:
	• Use of alvimopan is prohibited
	Analgesia:
	• Gabapentin 300 mg orally once, approximately 30–90 min preoperatively • Acetaminophen 650 mg orally or IV once, approximately 30–90 min preoperatively • Study drug IV administered within 30 min prior to start of surgery
	Anxiolysis:
	• Midazolam 2 mg IV once as needed
Perioperative
	Epidural:
	• No epidural medication will be utilized
	Analgesia:
	• Perioperative analgesia should be maintained using IV opioids • Prohibited therapies include NSAIDS, ketamine, TAP blocks, lidocaine and/or local instillation
	Nausea prophylaxis:
	• Dexamethasone IV up to 4 mg once and ondansetron IV once or promethazine IV 25 mg once and a scopolamine transdermal patch 0.5 mg
	Fluids:
	• Target fluids 5–7 mL/kg/h, as medical condition and intraoperative physiological status permits
	Anesthesia:
	• Acceptable agents include nitrous oxide, isoflurane, sevoflurane or desflurane • Total intravenous anesthesia is also acceptable
	NMB:
	• Institution-specific standard of care for NMB and reversal agents
Postoperative
	Diet:
	• Clear liquids on DOS • Advance diet to solids as tolerated starting on POD1 • Liquid protein supplements available with each meal
	Ambulation:
	• OOB and ambulating on DOS • OOB ≥6 h with ambulation four-times daily starting on POD1
	Analgesia:
	• All subjects will receive acetaminophen 650 mg orally every 8 h as tolerated until 24 h following the last study dose • Patient-controlled analgesia morphine 1 mg bolus with 6-min lockout; supplement with 1–2 mg IV morphine every hour as needed OR intravenous morphine bolus as needed; dose should not exceed 12 mg/h • Convert to oral oxycodone 5 mg every 4 h as needed; supplement with intravenous morphine 1–4 mg up to every hour if needed
	Pyrexia:
	• Cooling blankets (acetaminophen should not be used to manage pyrexia until 24 h following the last study dose while subject is receiving routine acetaminophen)
	Postoperative nausea and vomiting:
	• Ondansetron 4 mg IV or 8 mg orally as needed (avoid prophylactic use)
	Fluids:
	• Fluids to be managed per subjects’ individual needs
	Motility:
	• Gum chewing is prohibited • Use of alvimopan is prohibited
	Tubes/drains:
	• Orogastric/nasogastric tubes should be removed in the operating room or on DOS • Urinary catheters should be removed on or before POD1

DOS: Day of surgery; NMD: Neuromuscular blockade; OOD: Out of bed; POD: Postoperative day 1; TAP: Transverse abdominis plane.

Figure 1. Consolidated Standards of Reporting Trials patient flow diagram.

Table 2. Subject demographics, baseline characteristics and surgical characteristics.

Characteristic	Meloxicam IV 30 mg (n = 27)	Placebo (n = 28)	Overall (n = 55)
Mean age (years)	58.8 (11.2)	60.6 (11.1)	59.7 (11.1)
– ≥65 years, n (%)	9 (33.3)	12 (42.9)	21 (38.2)
– Female, n (%)	12 (44.4)	11 (39.3)	23 (41.8)
Race, n (%)
– White	22 (81.5)	23 (82.1)	45 (81.8)
– Black or African–American	4 (14.8)	5 (17.9)	9 (16.4)
– Asian	1 (3.7)	0	1 (1.8)
Mean baseline BMI (kg/m^2)	28.9 (5.7)	27.5 (4.7)	28.2 (5.2)
Primary indication for surgery, n (%)
– Colon cancer	13 (48.1)	9 (32.1)	22 (40.0)
– Diverticular disease	4 (14.8)	9 (32.1)	13 (23.6)
– Intestinal polyps	5 (18.5)	1 (3.6)	6 (10.9)
– Crohn’s disease	1 (3.7)	1 (3.6)	2 (3.6)
– Colostomy reversal	1 (3.7)	0	1 (1.8)
– Ulcerative colitis	0	1 (3.6)	1 (1.8)
– Other	3 (11.1)	7 (25.0)	10 (18.2)
Actual incision type, n (%)
– Open	3 (11.1)	2 (7.1)	5 (9.1)
– Laparoscopic	20 (74.1)	23 (82.1)	43 (78.2)
– Laparoscopic converted to open	4 (14.8)	3 (10.7)	7 (12.7)
Mean time from first dose to surgery start, min (SD)	37.4 (17.4)	31.2 (13.9)	34.3 (15.9)
Mean surgery duration, h (SD)	2.6 (1.3)	2.4 (0.96)	2.5 (1.1)
Mean time in PACU, min (SD)	98.0 (67.0)	110.0 (56.0)	104.1 (61.4)

BMI: Body mass index; PACU: Post anesthesia care unit; SD: Standard deviation.

Table 3. Adverse events occurring in ≥2 subjects in either study group.

Preferred term	No. of subjects (%)
	Meloxicam IV 30 mg (n = 27)	Placebo (n = 28)
Subjects with ≥1 event	23 (85.2)	26 (92.9)
Nausea	9 (33.3)	14 (50.0)
Vomiting	5 (18.5)	5 (17.9)
Hypokalemia	2 (7.4)	7 (25.0)
Hypophosphatemia	2 (7.4)	6 (21.4)
Ileus	1 (3.7)	5 (17.9)
Hypertension	2 (7.4)	3 (10.7)
Anxiety	1 (3.7)	3 (10.7)
Insomnia	1 (3.7)	3 (10.7)
Oliguria	1 (3.7)	3 (10.7)
Pyrexia	2 (7.4)	2 (7.1)
Constipation	1 (3.7)	2 (7.1)
Hypomagnesemia	1 (3.7)	2 (7.1)
Hypotension	1 (3.7)	2 (7.1)
Musculoskeletal pain	1 (3.7)	2 (7.1)
Gastroesophageal reflux disease	0	2 (7.1)
Paranasal sinus hypersecretion	2 (7.4)	0
Urinary retention	2 (7.4)	0
Wound dehiscence	2 (7.4)	0
Wound infection	2 (7.4)	0

Table 4. Adverse events of special interest occurring in ≥1 subject in either study group.

AEOSI category/preferred term (MedDRA 20.1)	No. of subjects (%)
	Meloxicam IV 30 mg (n = 27)	Placebo (n = 28)
Subjects with ≥1 AEOSI	8 (29.6)	6 (21.4)
Bleeding
– Incision-site hematoma	0	1 (3.6)
– Post-procedural hemorrhage	1 (3.7)	0
Cardiovascular
– Hypertension	2 (7.4)	3 (10.7)
Hepatic
– Abnormal liver function test	1 (3.7)	1 (3.6)
Injection-site reactions
– Injection-site pain	1 (3.7)	0
Renal
– Hypercreatinemia	0	1 (3.6)
Wound healing
– Cellulitis	0	1 (3.6)
– Incision-site cellulitis	1 (3.7)	0
– Incision-site swelling	0	1 (3.6)
– Wound dehiscence	2 (7.4)	0
– Wound infection	2 (7.4)	0

AEOSI: Adverse event of special interest.

Table 5. Summary of total opioid consumption (in mg of IV morphine equivalent dose) by time interval.

Total opioid consumption (least square mean [standard error]) by time interval	Meloxicam IV30 mg(n = 27)	Placebo(n = 28)	Group mean difference (%)	p-value
Hour 0–discharge	29.2 (5.2)	45.2 (5.2)	35.3%	0.0339
Hour 0–24	17.5 (5.7)	19.1 (2.5)	8.4%	0.6500
Hour 24–48	6.7 (1.7)	13.1 (1.7)	49.1%	0.0106
Hour 48–72	4.3 (1.5)	8.3 (1.3)	48.0%	0.0540
Hour 0–48	24.1 (3.8)	32.1 (3.8)	25.0%	0.1393
Hour 0–72	27.5 (4.5)	39.9 (4.5)	31.0%	0.0567
Hour 0–EOT	27.2 (4.5)	38.6 (4.4)	29.6%	0.0730
Overall (total in study)	49.3 (5.7)	66.1 (5.7)	25.5%	0.0403

EOT: End of treatment; IVMED: IV morphine equivalent dose.

Table 6. Economic and healthcare resource data.

	Meloxicam IV 30 mg(n = 27)	Placebo(n = 27)^†	p-value
Time from EOS to discharge, h (SD)	77.0 (7.7)	104.6 (9.0)	0.0301
Total hospital LOS, h^‡ (SD)	86.2 (42.4)	111.7 (48.5)	0.0162
Total hospital costs^§ (SD)	$23,115 ($19,013)	$22,682 ($14,828)	0.3370

† Missing data from one subject.

‡ Reported as number of h from hospital admission to discharge.

§ A cost-to-charge ratio of 0.477 was applied to convert charges to cost.

EOS: End of surgery; LOS: Length of stay; SD: Standard deviation.

Data sharing statement

The authors certify that this manuscript reports original clinical trial data, NCT03323385. Individual, de-identified participant data will not be available. Data will be available to the public at https://clinicaltrials.gov/ct2/show/NCT03323385 for the duration of 2020.