P0108 Total Knee Arthroplasty Pain Management With HTX-011 ...
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INTRODUCTION • Severe postoperative pain and resultant opioid use are common after total knee arthroplasty (TKA) 1,2 • ZYNRELEF (HTX-011) is an extended-release, dual-acting local anesthetic (DALA) formulation comprising bupivacaine and low-dose meloxicam in a controlled-diffusion polymer that allows for controlled delivery of active ingredients over 72 hours 3,4 – HTX-011 was approved in the European Union on September 24, 2020, and was approved in the United States on May 12, 2021 – The NSAID meloxicam in HTX-011 reduces surgery-related inflammation, thereby normalizing the local pH, which enhances penetration of bupivacaine into the nerve cell and potentiates its analgesic effect 5 – Neither the low dose of meloxicam contained in HTX-011 nor the addition of NSAID-containing multimodal analgesia (MMA) have been shown to increase NSAID-related adverse events 6-8 • HTX-011 has demonstrated superior postoperative pain management and limited opioid use compared with the standard of care local anesthetic bupivacaine hydrochloride (HCl) and saline placebo in randomized, controlled registration studies of patients undergoing bunionectomy, herniorrhaphy, and TKA 3,4,9 • Administration of HTX-011 during TKA is depicted in Figure 1 Figure 1. HTX-011 Is Administered Needle-free Using a Luer Lock Applicator. Top pictures illustrate administration to posterior capsule; bottom pictures illustrate administration to anterior capsule. HTX-011 was applied during surgery after cementation of components, placement of the tibial liner, and completion of irrigation and suction. OBJECTIVES • The objective of this study was to examine the efficacy and safety of HTX-011 as the foundation of a perioperative scheduled non-opioid MMA regimen after TKA • In this analysis, we examined the effect of HTX-011 + MMA on severe pain following TKA METHODS Study Design and Patients • This open-label, single-arm study enrolled patients undergoing primary unilateral TKA under bupivacaine spinal anesthesia (NCT03974932) – Patients were included if they had an American Society of Anesthesiologists Physical Status of I, II, or III and were able to walk ≥20 feet – Patients were excluded if they had used: – NSAIDs within 10 days (unless ≤100 mg daily acetylsalicylic acid for cardioprotection) – Bupivacaine within 5 days or any local anesthetic within 72 hours – Long-acting opioids within 3 days or any opioid within 24 hours • All patients received a single, intraoperative dose of HTX-011 (400 mg bupivacaine/12 mg meloxicam) via needle- free periarticular application into the surgical site prior to wound closure • All patients received a perioperative scheduled, NSAID-containing, non-opioid MMA regimen (Figure 2) – During the 72-hour inpatient period, opioid rescue medication was available upon patient request (oral oxycodone, intravenous [IV] morphine, or IV hydromorphone) Figure 2. Study Design and MMA Regimen Patients discharged Surgery Time: 0 Periarticular application of HTX-011 400 mg/12 mg (bupivacaine/meloxicam) 72 hours Follow-up: Day 11 Day 29 Inpatient period Bupivacaine spinal anesthesia Day 7 Acetaminophen 1 g PO Celecoxib 200 mg PO Pregabalin 300 mg PO Acetaminophen 1 g q8h PO Celecoxib 200 mg q12h PO Ibuprofen and/or acetaminophen as needed Postoperative MMA Preoperative MMA Ibuprofen 600 mg q6h PO Acetaminophen 1 g q6h PO Alternating so one analgesic is used every 3 hours MMA, multimodal analgesia; PO, oral; q6h, every 6 hours; q8h, every 8 hours; q12h, every 12 hours. Assessments and Endpoints • The primary endpoint was the area under the curve of visual analog scale of pain intensity (VAS) scores from 12-48 hours (AUC 12-48 ), adjusted for opioid use – In the 10 cm VAS, a pain score of <4.4 cm was considered “mild” and a score of ≥7.5 cm was considered “severe” • Additional pain endpoints included: – Pain control over the preceding 24 hours, evaluated using a 4-point Patient Global Assessment (PGA) scale in which 0 represents “poor” and 3 represents “excellent” 10 – Ability to participate in scheduled rehabilitation sessions • Discharge readiness was assessed using the Modified Postanesthetic Discharge Scoring System (MPADSS) criteria, which consider vital signs, ambulation, nausea/vomiting, pain, and surgical bleeding 11 – Patients were deemed “ready for discharge” if they had a MPADSS of ≥9 • Mean postoperative opioid consumption was measured in IV morphine milligram equivalents (MME) through 72 hours • Safety endpoints included the incidence of adverse events and serious adverse events Total Knee Arthroplasty Pain Management With HTX-011 as the Foundation of a Multimodal Analgesic Regimen Results in Low Incidence of Severe Pain Scott Hacker, 1 Peter Gerner, 2 Jia Hu, 3 Alan Rechter 4 1 Grossmont Orthopedic Medical Group, La Mesa, CA, USA; 2 Department of Anesthesiology, Critical Care and Pain Medicine, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria; 3 Heron Therapeutics, Inc., San Diego, CA, USA; 4 Orthopaedic Associates, L.L.P., Bellaire,TX, USA RESULTS • Fifty-one patients were included and received HTX-011 • Mean patient age was 65.4 years, and mean body mass index was 30.97 kg/m 2 • Most patients were female (60.8%) and white (92.2%) Pain Intensity • Mean pain scores remained in the mild range (VAS <4.4 cm) throughout the 72-hour postoperative period (Figure 3) – Mean (standard error [SE]) VAS AUC 12-48 was 145.4 (13.00) • Most patients (≥88%) did not experience severe pain (VAS ≥7.5 cm) at any individual time point (Figure 4) • On Day 2 (1 day after surgery), 88% of patients rated their pain control as “good” to “excellent;” this increased to 100% of patients by Day 4 (3 days after surgery) (Figure 5) • No patients missed rehabilitation sessions because of pain on Day 2, and only 2 patients (3.9%) missed a rehabilitation session because of pain on Day 3 (Table 1) Figure 3. Mean Pain Intensity Scores Through 72 Hours 0 1 2 3 4 5 6 7 8 9 10 12 6 4 8 12 24 36 48 60 72 VAS Score (cm) (mean ± SE) Hours After Study Drug Administration HTX-011 + MMA (N = 51) Severe Pain Mild Pain MMA, multimodal analgesia; SE, standard error;VAS, visual analog scale of pain intensity. Figure 4. Percentage of Patients With Severe Pain a Through 72 Hours 0 10 20 30 40 50 60 70 80 90 100 12 6 4 8 12 24 36 48 60 72 Percentage of Patients With Severe Pain, % Hours After Study Drug Administration HTX-011 + MMA (N = 51) MMA, multimodal analgesia; a Defined as VAS of pain intensity ≥7.5 cm. Figure 5. Percentage of Patients Rating Pain Control as “Good” or “Excellent” a 0 20 40 60 80 100 Percentage of Patients With PGA >1, % Day 2 Day 3 Day 4 88.2 90.2 100 HTX-011 + MMA (N = 51) PGA, patient global assessment; MMA, multimodal analgesia. a Good or excellent rating based on patient-reported PGA score of >1. Table 1. Proportion of Patients Unable to Participate in Rehabilitation Sessions Due to Pain a Timepoint N (%) HTX-011 + MMA (N = 51) Day 1 Session 1 7 (13.7) Day 2 Session 1 Session 2 0 (0) 0 (0) Day 3 Session 1 Session 2 1 (2.0) 1 (2.0) a Patients who were unable to participate in rehabilitation sessions more than once per day were only counted once. Discharge Readiness • Using MPADSS criteria, approximately half of patients were deemed ready for discharge by 8 hours after surgery, and >60% were ready for discharge by 12 hours after surgery (Figure 6) Figure 6. Percentage of Patients Designated Ready for Discharge a 0 20 40 60 80 100 Percentage of Patients Achieving MPADSS ≥9, % 4 8 12 48 72 24 31.4 49.0 60.8 82.4 86.3 68.6 HTX-011 + MMA (N = 51) Hours After Study Drug Administration MMA, multimodal analgesia; MPADSS, Modified Postanesthetic Discharge Scoring System. a MPADSS score ≥9. Opioid Use • Mean total opioid consumption was 24.8 MME within the 72-hour postoperative period (<2 10 mg oxycodone tablets/day) (Table 2) • 22% of patients did not require opioids (ie, they remained opioid-free) through 24 hours after surgery; 12% remained opioid-free throughout the 72-hour postoperative period • 39% of TKA patients treated with HTX-011 plus a scheduled non-opioid MMA regimen were discharged without an opioid prescription and did not call the study site for additional pain medication through Day 11 – Only patients who received ≥10 mg of oxycodone within 12 hours before discharge were eligible to receive a discharge prescription for opioids Table 2.Total Opioid Consumption (MME) HTX-011 + MMA (N = 51) 0-24 hours Mean (SE) Median (range) 10.6 (1.30) 7.5 (0.0-35.0) 0-48 hours Mean (SE) Median (range) 19.4 (2.46) 15.8 (0.0-93.3) 0-72 hours Mean (SE) Median (range) 24.8 (3.18) 21.7 (0.0-118.3) MMA, multimodal analgesia; MME, morphine milligram equivalents; SE, standard error. Safety and Tolerability • HTX-011 was well-tolerated; most adverse events were rated mild or moderate (Table 3) • No serious adverse events were reported • There was no evidence of NSAID-related toxicity Table 3. Adverse Events N (%) HTX-011 + MMA (N = 51) ≥1 AE Mild Moderate Severe a 42 (82.4) 17 (33.3) 24 (47.1) 1 (2.0) AE possibly related to study drug b 7 (13.7) AEs leading to study withdrawal 0 SAE 0 AE, adverse event; MMA, multimodal analgesia; SAE, serious adverse event. a Severe postoperative pain in left knee. b AEs reported by the investigator as possibly related to study drug were nausea (5 patients), vomiting (3 patients), dizziness (1 patient), and intermittent elevated blood pressure (1 patient). CONCLUSIONS • HTX-011, as the foundation of a perioperative scheduled non-opioid MMA regimen, has the potential to keep most patients out of severe pain, maintain mean pain in the mild range, minimize opioid consumption, provide high patient satisfaction, and allow most patients to be discharged within 12 hours following TKA REFERENCES 1. Zlotnicki JP et al. J Arthroplasty. 2018;33:2460-2464. 2. Cook DJ et al. J Arthroplasty. 2019;34:638-644 e631. 3. Viscusi E et al. Reg Anesth Pain Med. 2019;44:700-706. 4. Viscusi E et al. Hernia. 2019;23:1071-1080. 5. Ottoboni T et al. Reg Anesth Pain Med. 2019;45:117-123. 6. Pollak R et al. J Am Podr Med Assoc. 2021;111:Article 15. 7. Singla N et al. Surgery. 2020;168:915-920. 8. Minkowitz H et al. Pain Ther. 2021; doi: 10.1007/s40122-021-00289-2. 9. Lachiewicz PF et al. J Arthroplasty. 2020;35:2843-2851. 10. Rothman M et al. Curr Med Res Opin. 2009;25:1433-1443. 11. Chung F. Can J Anaesth. 1995;42:1056-1058. ACKNOWLEDGMENTS Funding for this research was provided by Heron Therapeutics, Inc. (San Diego, CA, USA). Medical writing assistance was provided by ApotheCom (San Diego, CA, USA) and funded by Heron Therapeutics, Inc. Prepared for the American Academy of Orthopaedic Surgeons (AAOS) Annual Meeting; San Diego, CA; August 31, 2021-September 3, 2021 P0108
Transcript of P0108 Total Knee Arthroplasty Pain Management With HTX-011 ...
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An electronic version of the poster can be viewed by scanning the QR code. The QR code is intended to provide scientific information for individual reference. The PDF should not be altered or reproduced in any way. All copyrights remain those of the copyright holder. This page will not be available after September 3, 2021. https://bit.ly/3qWW6Ki (This URL is case sensitive.)
INTRODUCTION• Severe postoperative pain and resultant opioid use are common after total knee arthroplasty (TKA)1,2
• ZYNRELEF (HTX-011) is an extended-release, dual-acting local anesthetic (DALA) formulation comprising bupivacaine and low-dose meloxicam in a controlled-diffusion polymer that allows for controlled delivery of active ingredients over 72 hours3,4
– HTX-011 was approved in the European Union on September 24, 2020, and was approved in the United States on May 12, 2021
– The NSAID meloxicam in HTX-011 reduces surgery-related inflammation, thereby normalizing the local pH, which enhances penetration of bupivacaine into the nerve cell and potentiates its analgesic effect5
– Neither the low dose of meloxicam contained in HTX-011 nor the addition of NSAID-containing multimodal analgesia (MMA) have been shown to increase NSAID-related adverse events6-8
• HTX-011 has demonstrated superior postoperative pain management and limited opioid use compared with the standard of care local anesthetic bupivacaine hydrochloride (HCl) and saline placebo in randomized, controlled registration studies of patients undergoing bunionectomy, herniorrhaphy, and TKA3,4,9
• Administration of HTX-011 during TKA is depicted in Figure 1
Figure 1. HTX-011 Is Administered Needle-free Using a Luer Lock Applicator. Top pictures illustrate administration to posterior capsule; bottom pictures illustrate administration to anterior capsule.
HTX-011 was applied during surgery after cementation of components, placement of the tibial liner, and completion of irrigation and suction.
OBJECTIVES• The objective of this study was to examine the efficacy and safety of HTX-011 as the foundation of a perioperative
scheduled non-opioid MMA regimen after TKA• In this analysis, we examined the effect of HTX-011 + MMA on severe pain following TKA
METHODSStudy Design and Patients • This open-label, single-arm study enrolled patients undergoing primary unilateral TKA under bupivacaine spinal
anesthesia (NCT03974932) – Patients were included if they had an American Society of Anesthesiologists Physical Status of I, II, or III and
were able to walk ≥20 feet – Patients were excluded if they had used:
– NSAIDs within 10 days (unless ≤100 mg daily acetylsalicylic acid for cardioprotection) – Bupivacaine within 5 days or any local anesthetic within 72 hours – Long-acting opioids within 3 days or any opioid within 24 hours
• All patients received a single, intraoperative dose of HTX-011 (400 mg bupivacaine/12 mg meloxicam) via needle-free periarticular application into the surgical site prior to wound closure
• All patients received a perioperative scheduled, NSAID-containing, non-opioid MMA regimen (Figure 2) – During the 72-hour inpatient period, opioid rescue medication was available upon patient request (oral
oxycodone, intravenous [IV] morphine, or IV hydromorphone)
Figure 2. Study Design and MMA Regimen
Patientsdischarged
Surgery
Time: 0Periarticular application ofHTX-011 400 mg/12 mg(bupivacaine/meloxicam)
72 hours
Follow-up:Day 11Day 29
Inpatient period
Bupivacainespinalanesthesia
Day 7
Acetaminophen 1 g POCelecoxib 200 mg POPregabalin 300 mg PO
Acetaminophen 1 g q8h POCelecoxib 200 mg q12h PO
Ibuprofen and/oracetaminophen as needed
Postoperative MMA Preoperative MMA
Ibuprofen 600 mg q6h POAcetaminophen 1 g q6h POAlternating so one analgesic
is used every 3 hours
MMA, multimodal analgesia; PO, oral; q6h, every 6 hours; q8h, every 8 hours; q12h, every 12 hours.
Assessments and Endpoints• The primary endpoint was the area under the curve of visual analog scale of pain intensity (VAS) scores from
12-48 hours (AUC12-48), adjusted for opioid use – In the 10 cm VAS, a pain score of <4.4 cm was considered “mild” and a score of ≥7.5 cm was considered “severe”
• Additional pain endpoints included: – Pain control over the preceding 24 hours, evaluated using a 4-point Patient Global Assessment (PGA) scale in
which 0 represents “poor” and 3 represents “excellent”10
– Ability to participate in scheduled rehabilitation sessions• Discharge readiness was assessed using the Modified Postanesthetic Discharge Scoring System (MPADSS) criteria,
which consider vital signs, ambulation, nausea/vomiting, pain, and surgical bleeding11
– Patients were deemed “ready for discharge” if they had a MPADSS of ≥9 • Mean postoperative opioid consumption was measured in IV morphine milligram equivalents (MME) through 72 hours• Safety endpoints included the incidence of adverse events and serious adverse events
Total Knee Arthroplasty Pain Management With HTX-011 as the Foundation of a Multimodal Analgesic Regimen Results in Low Incidence of Severe Pain
Scott Hacker,1 Peter Gerner,2 Jia Hu,3 Alan Rechter4
1Grossmont Orthopedic Medical Group, La Mesa, CA, USA; 2Department of Anesthesiology, Critical Care and Pain Medicine, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria; 3Heron Therapeutics, Inc., San Diego, CA, USA; 4Orthopaedic Associates, L.L.P., Bellaire, TX, USA
RESULTS • Fifty-one patients were included and received HTX-011• Mean patient age was 65.4 years, and mean body mass index was 30.97 kg/m2
• Most patients were female (60.8%) and white (92.2%)
Pain Intensity• Mean pain scores remained in the mild range (VAS <4.4 cm) throughout the 72-hour postoperative period
(Figure 3) – Mean (standard error [SE]) VAS AUC12-48 was 145.4 (13.00)
• Most patients (≥88%) did not experience severe pain (VAS ≥7.5 cm) at any individual time point (Figure 4)• On Day 2 (1 day after surgery), 88% of patients rated their pain control as “good” to “excellent;” this increased
to 100% of patients by Day 4 (3 days after surgery) (Figure 5)• No patients missed rehabilitation sessions because of pain on Day 2, and only 2 patients (3.9%) missed a
rehabilitation session because of pain on Day 3 (Table 1)
Figure 3. Mean Pain Intensity Scores Through 72 Hours
0
1
2
3
4
5
6
7
8
9
10
12 64 8 12 24 36 48 60 72
VA
S S
core
(cm
) (m
ean
± S
E)
Hours After Study Drug Administration
HTX-011 + MMA (N = 51)
Severe Pain
Mild Pain
MMA, multimodal analgesia; SE, standard error; VAS, visual analog scale of pain intensity.
Figure 4. Percentage of Patients With Severe Paina Through 72 Hours
0
10
20
30
40
50
60
70
80
90
100
12 64 8 12 24 36 48 60 72
Per
cent
age
of P
atie
nts
Wit
hS
ever
e P
ain,
%
Hours After Study Drug Administration
HTX-011 + MMA (N = 51)
MMA, multimodal analgesia; aDefined as VAS of pain intensity ≥7.5 cm.
Figure 5. Percentage of Patients Rating Pain Control as “Good” or “Excellent”a
0
20
40
60
80
100
Per
cent
age
of P
atie
nts
Wit
h P
GA
>1,
%
Day 2 Day 3 Day 4
88.2 90.2
100
HTX-011 + MMA (N = 51)
PGA, patient global assessment; MMA, multimodal analgesia.aGood or excellent rating based on patient-reported PGA score of >1.
Table 1. Proportion of Patients Unable to Participate in Rehabilitation Sessions Due to Paina
Timepoint N (%)
HTX-011 + MMA (N = 51)
Day 1Session 1 7 (13.7)
Day 2Session 1Session 2
0 (0)0 (0)
Day 3Session 1Session 2
1 (2.0)1 (2.0)
aPatients who were unable to participate in rehabilitation sessions more than once per day were only counted once.
Discharge Readiness• Using MPADSS criteria, approximately half of patients were deemed ready for discharge by 8 hours after surgery,
and >60% were ready for discharge by 12 hours after surgery (Figure 6)
Figure 6. Percentage of Patients Designated Ready for Dischargea
0
20
40
60
80
100
Per
cent
age
of P
atie
nts
Ach
ievi
ng M
PA
DS
S ≥
9, %
4 8 12 48 7224
31.4
49.0
60.8
82.486.3
68.6
HTX-011 + MMA (N = 51)
Hours After Study Drug Administration
MMA, multimodal analgesia; MPADSS, Modified Postanesthetic Discharge Scoring System. aMPADSS score ≥9.
Opioid Use• Mean total opioid consumption was 24.8 MME within the 72-hour postoperative period (<2 10 mg oxycodone
tablets/day) (Table 2)• 22% of patients did not require opioids (ie, they remained opioid-free) through 24 hours after surgery; 12%
remained opioid-free throughout the 72-hour postoperative period• 39% of TKA patients treated with HTX-011 plus a scheduled non-opioid MMA regimen were discharged without
an opioid prescription and did not call the study site for additional pain medication through Day 11 – Only patients who received ≥10 mg of oxycodone within 12 hours before discharge were eligible to receive a
discharge prescription for opioids
Table 2. Total Opioid Consumption (MME) HTX-011 + MMA
(N = 51)
0-24 hoursMean (SE)Median (range)
10.6 (1.30)7.5 (0.0-35.0)
0-48 hoursMean (SE)Median (range)
19.4 (2.46)15.8 (0.0-93.3)
0-72 hoursMean (SE)Median (range)
24.8 (3.18)21.7 (0.0-118.3)
MMA, multimodal analgesia; MME, morphine milligram equivalents; SE, standard error.
Safety and Tolerability • HTX-011 was well-tolerated; most adverse events were rated mild or moderate (Table 3)• No serious adverse events were reported• There was no evidence of NSAID-related toxicity
Table 3. Adverse Events
N (%)HTX-011 + MMA
(N = 51)
≥1 AEMildModerateSeverea
42 (82.4)17 (33.3)24 (47.1)1 (2.0)
AE possibly related to study drugb 7 (13.7)
AEs leading to study withdrawal 0
SAE 0
AE, adverse event; MMA, multimodal analgesia; SAE, serious adverse event. aSevere postoperative pain in left knee. b AEs reported by the investigator as possibly related to study drug were nausea (5 patients), vomiting (3 patients), dizziness (1 patient), and intermittent elevated blood pressure (1 patient).
CONCLUSIONS• HTX-011, as the foundation of a perioperative scheduled non-opioid MMA regimen, has the potential to keep
most patients out of severe pain, maintain mean pain in the mild range, minimize opioid consumption, provide high patient satisfaction, and allow most patients to be discharged within 12 hours following TKA
REFERENCES1. Zlotnicki JP et al. J Arthroplasty. 2018;33:2460-2464.2. Cook DJ et al. J Arthroplasty. 2019;34:638-644 e631.3. Viscusi E et al. Reg Anesth Pain Med. 2019;44:700-706.4. Viscusi E et al. Hernia. 2019;23:1071-1080.5. Ottoboni T et al. Reg Anesth Pain Med. 2019;45:117-123.6. Pollak R et al. J Am Podr Med Assoc. 2021;111:Article 15.
7. Singla N et al. Surgery. 2020;168:915-920.8. Minkowitz H et al. Pain Ther. 2021; doi: 10.1007/s40122-021-00289-2.9. Lachiewicz PF et al. J Arthroplasty. 2020;35:2843-2851.
10. Rothman M et al. Curr Med Res Opin. 2009;25:1433-1443.11. Chung F. Can J Anaesth. 1995;42:1056-1058.
ACKNOWLEDGMENTSFunding for this research was provided by Heron Therapeutics, Inc. (San Diego, CA, USA). Medical writing assistance was provided by ApotheCom (San Diego, CA, USA) and funded by Heron Therapeutics, Inc.
Prepared for the American Academy of Orthopaedic Surgeons (AAOS) Annual Meeting; San Diego, CA; August 31, 2021-September 3, 2021
P0108
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