Keywords
HTX-011 - multimodal analgesia - postoperative pain - total knee arthroplasty
Primary total knee arthroplasty (TKA) can be associated with significant postoperative
pain, which often requires the use of opioids.[1]
[2] Currently, postoperative pain after TKA is managed using a wide variety of multimodal
analgesic (MMA) regimens to reduce a patient's pain and avoid opioid use.[3]
[4]
[5] These regimens often include pre- and postoperative administration of analgesic
medications with distinct mechanisms of action, typically in combination with perioperative
administration of local anesthetics. Periarticular injections at the time of TKA have
been shown to reduce pain and opioid consumption when combined with a robust MMA protocol
following TKA.[6] Several studies have also shown periarticular injections to be as efficacious in
relieving pain as peripheral nerve blocks without the potential complications of neurovascular
nerve injury, motor dysfunction, or falls.[7] However, the duration and efficacy of these injections can be variable and often
limited to less than 24 hours. Extended-release formulations of local anesthetics
(i.e., liposomal bupivacaine) have failed to show superiority compared with conventional
bupivacaine in various randomized trials or to provide consistent pain relief beyond
24 hours compared with controls.[8]
[9]
Consequently, opioid consumption following TKA remains high, with opioid prescriptions
at discharge nearly universal in the United States.[2]
[10]
[11]
[12] Minimizing patient exposure to opioids at the time of surgery can have significant
personal and public health implications. Opioids are associated with opioid-related
adverse reactions and can result in worse patient outcomes and increased hospital
costs.[13]
[14] Postoperative use of opioid medications also increases the risk of long-term use,
misuse, and dependence.[15] In addition, in a recent analysis of an administrative database, Politzer et al
showed that 5% of opioid-naive patients undergoing TKA became chronic opioid users
2 years following TKA.[16] Therefore, there remains a need for an effective extended-release local anesthetic
that can provide longer term pain relief and minimize the need for the use of opioids.
HTX-011 (ZYNRELEF; Heron Therapeutics, San Diego, CA) is an extended-release, dual-acting,
local anesthetic formulation consisting of bupivacaine and low-dose meloxicam in a
novel, tri(ethylene glycol) poly(orthoester) polymer, which allows for the controlled
diffusion of active ingredients over 72 hours.[17]
[18] HTX-011 is a viscous solution that is applied without injection or needle directly
to the joint capsule, periosteum, and other pain generating tissues. It is applied
after irrigation and suction and prior to suturing. This direct coating of the joint
tissues during the procedure allows for extended release of the drug to all tissues
throughout the surgical site ([Fig. 1]). In an animal model, the anti-inflammatory effect of meloxicam in HTX-011 normalized
the local pH, allowing enhanced penetration of bupivacaine into the nerves and potentiation
of the analgesic effect.[17] Notably, the synergistic effect of local bupivacaine and meloxicam in HTX-011 was
observed in an animal model and confirmed in human clinical studies. This effect could
not be replicated by administering extended-release bupivacaine locally and meloxicam
systemically.[17]
Fig. 1 (A) HTX-011 is a viscous formulation administered without a needle. (B–D) HTX-011
application during total knee arthroplasty.
A prior randomized controlled trial (RCT) compared HTX-011 (400 mg bupivacaine and
12 mg meloxicam) with bupivacaine hydrochloride (HCl) and saline placebo in patients
undergoing primary unilateral TKA under general anesthesia.[19] In that study, HTX-011 was more effective than bupivacaine alone at reducing pain
and total opioid consumption over the first 72 hours; however, in the absence of other
nonopioid MMA agents, all patients treated with HTX-011 alone required the use of
rescue postoperative opioids. The objectives of this study were to assess postoperative
pain control and opioid consumption following primary TKA in patients administered
HTX-011 with a scheduled MMA regimen consisting of acetaminophen and a nonsteroidal
anti-inflammatory drug (NSAID), thereby addressing some limitations of the prior RCT.
Results from the prior RCT are presented here for comparison. Discharge readiness,
patient satisfaction, and safety were also assessed.
Methods
This open-label study was conducted by eight surgeons at six sites across the United
States from May 2019 through November 2019. These six sites also participated in the
prior RCT. The study protocol, protocol amendments, and informed consent forms were
approved by Aspire, IRB (Santee, CA) and other relevant Institutional Review Boards
before patients were screened. Each patient was provided written informed consent
before undergoing any study-related procedures. The study design and entry criteria
for this study were similar to those of the prior RCT of HTX-011.[19] The MMA regimen and primary end point were selected based on a published phase 4
study of a long-acting liposomal bupivacaine with a scheduled MMA regimen in TKA.[20]
Patient Population
Patients were screened within 28 days before the scheduled surgery, and eligibility
was confirmed on the day of surgery.
The patient population mirrored the prior RCT of HTX-011 and included males and females
of at least 18 years of age who were scheduled to undergo their first unilateral TKA
and who had an American Society of Anesthesiologists Physical Status classification
of I, II, or III. Patients were excluded if they had planned concurrent surgical procedures
(e.g., bilateral TKA) or had preexisting conditions expected to require analgesic
treatment not related to TKA. Patients taking any of the following medications before
surgery were also excluded: NSAIDs (including meloxicam) within 10 days, long-acting
opioids within 3 days, any opioids within 24 hours, and bupivacaine HCl within 5 days.
In addition, patients with known or suspected daily use of opioids for 7 or more consecutive
days within 6 months before their scheduled surgery, known or suspected history of
drug abuse, a positive drug screen on the day of surgery, or a history of alcohol
abuse (within 10 years) were also excluded from the study.
Anesthesia and Surgical Considerations
All surgeries were performed under bupivacaine spinal anesthesia (≤20 mg). As in the
prior HTX-011 RCT, surgery was performed based on investigators' preferred surgical
techniques (including the use of drains, tourniquet time, and type of prosthesis).
Intraoperative pain control with intravenous (IV) fentanyl (≤4 µg/kg) was allowed.
All patients in the study received IV tranexamic acid (TXA) for antifibrinolysis and
oral (PO) acetylsalicylic acid for deep vein thrombosis prophylaxis.[21] TXA 1 g was administered before surgery, with a second dose up to 8 hours later,
and acetylsalicylic acid 325 mg was administered twice a day following surgery until
discharge.
Study Design and Treatments
The study design is presented in [Fig. 2]. All patients were administered a single 14-mL dose of HTX-011 (400 mg bupivacaine
and 12 mg meloxicam) during surgery after final irrigation and suction, just prior
to suture closure. HTX-011 was applied without a needle: 3.5 mL to the posterior capsule,
5.25 mL to the anteromedial tissues and periosteum, and 5.25 mL to the anterolateral
tissues and periosteum. All patients also received MMA while in the hospital. On the
day of surgery, patients were administered 1 g acetaminophen, 200 mg celecoxib, and
300 mg pregabalin (all PO) before surgery. For 72 hours following surgery, patients
received a scheduled MMA regimen consisting of 1 g acetaminophen PO every 8 hours
and 200 mg celecoxib PO every 12 hours.
Fig. 2 Follow-on study design. MMA, multimodal analgesia; PO, oral; q6h, every 6 hours;
q8h, every 8 hours; q12h, every 12 hours.
To allow for complete and rigorous data collection, patients were required to stay
in the treatment facility for at least 72 hours after surgery. Pain was assessed before
and at 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, and 72 hours after surgery using the visual
analog scale (VAS) and the numerical rating scale (NRS). Additional efficacy assessments
included patient global assessment (PGA) of pain control, ability to participate in
scheduled rehabilitation sessions (one on the night of surgery, then twice a day while
in the hospital), and discharge readiness based on the modified postanesthetic discharge
scoring system (MPADSS). Safety assessments included adverse event (AE) recording,
physical examinations, clinical laboratory tests (hematology and serum chemistry),
and vital signs.
In addition to their scheduled MMA regimen, patients could receive opioid rescue medication
for pain control only upon request during the 72-hour inpatient period. Permitted
rescue medication included PO immediate-release oxycodone (≤10 mg within a 4-hour
period), IV morphine (2.5–5.0 mg within a 4-hour period), and/or IV hydromorphone
(0.5–1.0 mg within a 4-hour period). Other rescue medications and patient-controlled
analgesia were prohibited.
After completion of the 72-hour inpatient assessment, patients were discharged with
instructions to continue their scheduled MMA regimen, which consisted of 600 mg ibuprofen
every 6 hours alternating with 1 g acetaminophen every 6 hours (so that one analgesic
was taken every 3 hours), for the next 4 days. Only patients who received ≥10 mg of
oxycodone within 12 hours before discharge were eligible to receive a discharge prescription
for up to 30 5-mg PO immediate-release oxycodone tablets. All patients were provided
a daily diary to record whether they took any opioids between discharge and the day
11 follow-up assessment. Patients returned to the study site for follow-up assessments
on days 11 and 29.
Outcome Measures
All patients who received study drug were included in efficacy and safety analyses.
The primary efficacy end point was the mean area under the curve (AUC) of VAS pain
intensity scores from 12 through 48 hours after surgery (AUC12–48). Secondary efficacy end points included mean AUC of pain intensity scores through
72 hours using the NRS and VAS, the proportion of patients with severe pain at each
time point, mean total postoperative opioid consumption in IV morphine milligram equivalents
(MME) through 72 hours, and the proportion of patients who did not receive an opioid
prescription between discharge and the day 11 follow-up visit. Additional prespecified
end points included the proportion of patients achieving a PGA score of >1 (“good”
or “excellent” pain control over the preceding 24 hours),[22] the proportion of patients unable to participate in rehabilitation sessions because
of pain, and the proportion of patients considered ready for discharge (MPADSS score
of ≥9 on a 0–10 scale).[23]
[24]
For the primary end point analysis, pain intensity scores during periods of rescue
medication administration were replaced by the highest observed score before rescue
medication use to adjust for opioid use.[19]
[20] Prespecified secondary analyses of pain were performed using observed patient-reported
pain scores because these reflect the level of pain the patient is experiencing. All
end points were assessed using descriptive statistics. For total opioid consumption,
both arithmetic and log-transformed geometric means were analyzed.[8]
Safety end points included the incidence of AEs and serious AEs (SAEs). Safety data
were summarized using observed cases.
Results
Efficacy Findings—Primary and Secondary End Points
A total of 51 patients received study treatment, and all completed the study. All
patients had osteoarthritis. The mean age was 65 years and 60.8% were women ([Table 1]).
Table 1
Follow-on study demographics and baseline characteristics
|
HTX-011 + MMA
(N = 51)
|
|
Age, y, mean (min, max)
|
65.4 (39, 83)
|
|
Sex, n (%)
|
|
Female
|
31 (60.8)
|
|
Male
|
20 (39.2)
|
|
Race, n (%)
|
|
White
|
47 (92.2)
|
|
Black or African American
|
4 (7.8)
|
|
Body mass index, kg/m2, mean (min, max)
|
30.97 (24.0, 39.9)
|
Abbreviations: max, maximum; min, minimum; MMA, multimodal analgesia.
Throughout the 72-hour postoperative period, mean patient-reported pain scores remained
in the mild range when assessed using the VAS (VAS score of 5–44 mm) or NRS (NRS score
of ≤4). The mean AUC12–48 of the VAS score was 145.4 (standard error [SE], 13.00; primary end point). Mean
pain scores were lower at each time point over the 72-hour period compared with the
prior RCT ([Fig. 3A]). Although the difference in anesthesia between studies may have accounted for initially
lower pain scores, the mean AUC of the NRS scores was also lower in this study from
12 to 72 hours postoperatively compared with the RCT (177.4 vs. 214.2), respectively.
In the prior RCT, HTX-011 in the absence of an MMA regimen reduced the proportion
of patients with severe pain compared with bupivacaine HCl and saline placebo, and
the addition of an MMA regimen in this study provided further improvement ([Fig. 4]). More than 82% of patients who received the HTX-011–based MMA regimen did not experience
severe pain (NRS score of ≥7) at any individual time point.
Fig. 3 An HTX-011–based MMA regimen reduced mean (SE) patient-reported pain scores (A) and
total opioid consumption (B) over 72 hours. Opioid consumption presented in intravenous
MME. HCl, hydrochloride; MMA, multimodal analgesia; MME, morphine milligram equivalents;
NRS, numeric rating scale of pain intensity; RCT, randomized controlled trial; SE,
standard error.
Fig. 4 An HTX-011–based MMA regimen reduced the proportion of patients with severe pain
(NRS ≥7) at each time point through 72 hours. HCl, hydrochloride; MMA, multimodal
analgesia; NRS, numerical rating scale of pain intensity; RCT, randomized controlled
trial.
Reduction in pain with the HTX-011–based MMA regimen was achieved without an increase
in opioid consumption ([Fig. 3B]). Mean total opioid consumption was lower over 24, 48, and 72 hours compared with
the RCT ([Table 2]). Almost half of patients (47.1%) receiving HTX-011 with an MMA regimen took ≤20 MME
(≤4 oxycodone 10 mg tablets) over the 72-hour postoperative period. The geometric
mean total opioid consumption through 48 and 72 hours after surgery was 3.0 MME (SE,
1.97) and 3.7 MME (SE, 2.5), respectively. The proportion of patients who did not
require the use of a postoperative opioid (i.e., were opioid free) through 72 hours
was 11.8%. Additionally, 39.2% of patients were discharged without an opioid prescription
and did not call the study site for additional pain medication through the day 11
follow-up visit.
Table 2
An HTX-011–based MMA regimen reduced total opioid consumption
|
Total opioid consumption (MME)
|
Randomized controlled trial
|
Follow-on study
|
|
Saline placebo (N = 53)
|
Bupivacaine HCl 125 mg (N = 55)
|
HTX-011 400 mg/12 mg (N = 58)
|
HTX-011 + MMA (N = 51)
|
|
0–24 h
|
|
Mean (SE)
|
39.1 (2.64)
|
32.6 (2.05)
|
28.8 (1.84)
|
10.6 (1.30)
|
|
Median
|
38.0
|
30.0
|
27.8
|
7.5
|
|
Min, max
|
5.0, 82.0
|
0.0, 71.0
|
2.5, 74.0
|
0.0, 35.0
|
|
0–48 h
|
|
Mean (SE)
|
58.5 (3.84)
|
52.6 (3.05)
|
48.8 (2.870)
|
19.4 (2.46)
|
|
Median
|
56.0
|
50.0
|
48.5
|
15.8
|
|
Min, max
|
5.0, 114.0
|
0.0, 108.0
|
2.5, 105.0
|
0.0, 93.3
|
|
0–72 h
|
|
Mean (SE)
|
73.6 (4.73)
|
68.4 (3.93)
|
64.4 (3.66)
|
24.8 (3.18)
|
|
Median
|
73.0
|
70.0
|
63.3
|
21.7
|
|
Min, max
|
10.0, 158.0
|
0.0, 147.5
|
2.5, 123.0
|
0.0, 118.3
|
Abbreviations: HCl, hydrochloride; max, maximum; min, minimum; MMA, multimodal analgesia;
MME, morphine milligram equivalents; SE, standard error.
Patient's satisfaction was high; 88.2, 90.2, and 100% of patients reported a PGA score
of >1 (“good” or “excellent” pain control) at 24, 48, and 72 hours, respectively.
No patient missed rehabilitation sessions because of pain on the day after surgery
(day 2), and only two patients (3.9%) missed a rehabilitation session because of pain
on day 3. Approximately half of patients (49.0%) were considered ready for discharge
(had an MPADSS score of ≥9) by 8 hours, 60.8% were ready for discharge by 12 hours,
and 68.6% by 24 hours after surgery.
Safety
Over the course of the study, 82.4% of patients reported at least one AE ([Table 3]). The most common AEs were nausea, vomiting, constipation, and dizziness. AEs considered
possibly related to study drug were reported for 13.7% of patients, and all were mild
or moderate in severity. There was no evidence of NSAID-related toxicity or local
anesthetic systemic toxicity. No SAEs were reported.
Table 3
Summary of AEs with an HTX-011–based MMA regimen
|
AE, n (%)
|
HTX-011 + MMA
(N = 51)
|
|
At least 1 AE
|
42 (82.4)
|
|
Mild
|
17 (33.3)
|
|
Moderate
|
24 (47.1)
|
|
Severe
|
1 (2.0)
|
|
AE possibly related to study drug[a]
|
7 (13.7)
|
|
SAE
|
0
|
|
AE leading to study withdrawal
|
0
|
|
Most common AEs
|
|
Nausea
|
29 (56.9)
|
|
Vomiting
|
14 (27.5)
|
|
Constipation
|
10 (19.6)
|
|
Dizziness
|
6 (11.8)
|
Abbreviations: AE, adverse event; MMA, multimodal analgesia; SAE, serious adverse
event.
a AEs reported by the investigator as possibly related to study drug were nausea, vomiting,
dizziness, and intermittently elevated blood pressure.
Discussion
TKA can be associated with significant postoperative pain. Despite MMA protocols,
which include periarticular injections, reproducible pain relief beyond the first
24 hours remains inconsistent, and a significant proportion of patients undergoing
TKA still requires the use of opioids postoperatively.[1]
[9]
[25]
[26] In a phase 4 study (PILLAR), the use of liposomal bupivacaine 266 mg admixed with
bupivacaine HCl 100 mg plus an MMA regimen resulted in a mean VAS AUC12–48 score of 180.8 (primary end point).[20] More than 80% received >20 mg of opioid medication; the geometric mean total opioid
consumption over 48 hours was 18.7 mg.[20]
HTX-011, an extended-release dual-acting local anesthetic, is designed to provide
analgesia for up to 72 hours and to reduce postoperative opioid consumption; it has
been shown to provide superior pain relief compared with bupivacaine HCl following
TKA.[19] The purpose of this study was to evaluate HTX-011 with an MMA regimen in TKA.
HTX-011 with a scheduled MMA regimen (pregabalin, acetaminophen, and celecoxib preoperatively
and acetaminophen and celecoxib postoperatively) resulted in substantial and durable
pain control. Mean patient-reported pain scores remained in the mild range throughout
the 72-hour postoperative period, with a mean AUC12–48 of the VAS score of 145.4 (primary end point). Most patients (≥82%) did not have
severe pain at any individual time point. Prior reports of patients undergoing TKA
with other MMA protocols noted severe pain in up to 60% of patients.[27]
[28] This is a meaningful observation because the potential consequences of severe, poorly
controlled postoperative pain include delayed postoperative ambulation, an increase
in cardiopulmonary complications, prolonged hospital stay, decreased patient satisfaction,
and the development of chronic postoperative pain.[29]
[30]
[31] In this study, the pain levels were lower compared with the observed pain scores
in the prior RCT in patients receiving HTX-011 without MMA undergoing primary TKA.
Although differences in anesthesia (general anesthesia in the RCT and spinal anesthesia
in the current study) contributed to lower initial pain scores in this study, subsequent
pain scores remained lower for the HTX-011–based MMA regimen. Notably, opioid consumption
was substantially lower as well. Over the 72-hour period, mean total consumption for
HTX-011 with MMA was 24.8 MME (approximately one to two 10-mg oxycodone tablets per
day) and the geometric mean was 3.7 MME (less than one-third of a 10-mg oxycodone
tablet per day).
Despite the minimal use of opioids in the current study, HTX-011 with MMA provided
sufficient pain control for early mobilization and was associated with high patient
satisfaction. Adelani and Barrack surveyed prospective TKA patients and reported that
54.8% had concerns with pain control postoperatively.[32] In this study, more than 88% of patients reported “good” or “excellent” pain control,
and ∼60% of patients were ready for discharge by 12 hours after surgery and up to
70% by 24 hours per the MPADSS.
A total of 39.2% of patients were discharged without an opioid prescription and did
not call back to the study site to request additional pain medication between discharge
at 72 hours and the day 11 follow-up visit. This result contrasts with data indicating
that from 72 to 96% of patients receive an opioid prescription following TKA, with
86 to 126 oxycodone (5-mg) pills routinely prescribed.[2] Given that studies have found that up to 70% of prescribed opioids remain unused
and available for misuse and abuse,[10]
[11]
[33] the ability to avoid opioid prescriptions in nearly 40% of patients receiving HTX-011
and a scheduled MMA regimen will not only avoid opioid-related complications in individual
patients but could also have a profound societal impact by reducing the number of
leftover opioid pills available for diversion and abuse.
Study treatment was well tolerated. HTX-011 with an MMA regimen had an overall safety
profile similar to that for HTX-011 alone.[19]
[34]
[35] The use of HTX-011 400 mg/12 mg in patients undergoing TKA with bupivacaine spinal
anesthesia did not identify any safety concerns, and there was no evidence of NSAID-related
toxicity, suggesting that MMA regimen did not impact the safety profile of HTX-011.
This study is not without limitations. No control arm was included in this current
study, which was designed as a follow-on to an RCT of HTX-011 in TKA. However, the
eligibility criteria and study assessments were similar to the prior RCT facilitating
cross-study comparisons. General anesthesia was used in the RCT, while spinal anesthesia
was used in this study, which may have contributed to differences in pain scores and
the need for postoperative pain medications between studies. In addition, all patients
were required to stay in the hospital for 72 hours following surgery to allow for
data collection. This requirement contrasts with the recent shift toward outpatient
TKA surgeries[36] and highlights the need for more real-world studies of postoperative pain and opioid
use following TKA. It is possible that the number of opioid prescriptions provided
at discharge may have differed from earlier patient discharge. Furthermore, the six
study sites and eight surgeons in this study also participated in the RCT. In the
RCT, pain scores for HTX-011–treated patients at the six sites were indistinguishable
from those of the entirety of the HTX-011 group, supporting the use of the prior RCT
as context when interpreting results from this follow-on study. Another limitation
is that this study evaluated HTX-011 in combination with only one MMA regimen, although
there are many postoperative MMA regimens currently in use for TKA. The MMA regimen
selected for this study is commonly used and was evaluated in the phase 4 liposomal
bupivacaine study (PILLAR study)[20] and, as in that study, did not include other periarticular infiltration medications
or femoral and adductor canal blocks.[37] Further investigation will be needed to understand the benefits of HTX-011 in combination
with the diverse options currently in place for MMA regimens used today. Finally,
our study design excluded patients with recent prior opioid use. Additional studies
that include patients with current and chronic opioid use are needed to see whether
these patients will experience similar opioid reductions as observed in this study.
Conclusion
As TKA transitions to the outpatient setting, a pain protocol that is effective and
well tolerated is critical to successful and safe patient discharge. HTX-011 and an
MMA regimen provided substantial pain control, maintaining mean pain in the mild range
after TKA, with only a minority of patients (<18%) experiencing severe pain at any
individual time point through 72 hours. Notably, this effect was achieved with low
opioid consumption, and nearly 40% of patients did not require a discharge opioid
prescription in this study. Pain scores and opioid consumption were lower than those
observed in the prior RCT in which HTX-011 alone was superior to bupivacaine HCl.
HTX-011 was well tolerated when used with bupivacaine-based spinal anesthesia and
in conjunction with an NSAID-containing MMA regimen. These results suggest that HTX-011
in combination with an MMA regimen may be a promising new option for the management
of postoperative pain in patients undergoing TKA.
