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Zynrelef (bupivacaine and meloxicam) was approved by the FDA. How does it compare to Exparel (liposomal bupivacaine) with regards to cost, efficacy, pain control, opioid-sparing effects, and administration? What advantage if any does Zynrelef provide?

Comment by InpharmD Researcher

Overall, bupivacaine and meloxicam combination product seems to provide better pain reduction with less opioid consumption compared to bupivacaine alone. Although the data is limited as placebo is the primary comparator whereas bupivacaine is a secondary observation. There is a lack of cost analysis and ease of administration is not typically measured.
Background

A meta-analysis of RCTs was performed comparing the use of HTX-011 (former name of Zenrelef) with placebo and/or bupivacaine in patients undergoing abdominoplasty, bunionectomy, and herniorrhaphy. 24-hour pain scores reported HTX-011 lowering pain scores by 1.81 (95% Confidence interval [CI] 1.44 to 2.14; p=0.00) but were highly heterogenous between studies (I2=97.8%). Opioid-free consumption at 72 hours was also lower in the HTX-011 group with chance to be opioid free reported 2.39 times more likely (95% CI 1.54 to 3.7; p=0.00; I2=27.38%). Morphine consumption was also reduced at 72 hours with HTX-011 compared to bupivacaine but not significantly so (7.11 reduced morphine equivalents; 95% CI 0.12 to 14.35; p=0.05; I2=97.22%). [1]

References:

[1] Goudra B, Singh N, Xue L, Goyal A, Gouda D, Singh PM. Efficacy of New Long-Acting Bupivacaine HTX-011 in Providing Pain Relief for Patients Undergoing Elective Surgery - A Meta-analysis of Prospective Randomized Controlled Trials. Anesth Essays Res. 2020;14(2):288-294. doi:10.4103/aer.AER_34_20

Literature Review

A search of the published medical literature revealed 7 studies investigating the researchable question:

Zynrelef (bupivacaine and meloxicam) was approved by the FDA. How does it compare to Exparel (liposomal bupivacaine) with regards to cost, efficacy, pain control, opioid-sparing effects, and administration? What advantage if any does Zynrelef provide?

Please see Tables 1-7 for your response.


 

HTX-011 Reduced Pain Intensity and Opioid Consumption versus Bupivacaine HCl in Bunionectomy: Phase III Results from the Randomized EPOCH 1 Study

Design

Randomized, multi-center, double-blind, parallel group, active- and placebo-controlled Phase III clinical trial

N=412

Objective

To determine if HTX-011 (bupivacaine and meloxicam; Zynrelef), an extended-release dual-acting local anesthetic, reduces both post-operative pain over 72 hours and post-operative opioid use when compared with bupivacaine HCl and saline placebo.

Study Groups

Zynrelef (n=157)

Bupivacaine HCl (n=155)

Placebo (n=100)

Inclusion Criteria

Age ≥ 18 years; American Society of Anesthesiologists physical status of I, II, or III; undergoing a primary unilateral, distal, first metatarsal bunionectomy

Exclusion Criteria

Pre-existing, concurrent, acute, or chronic painful physical/restrictive condition(s); use of non-steroidal anti-inflammatory (NSAIDs, including meloxicam) ≥ 10 days prior to surgery; known or suspected daily use of opioids for ≥ 7 days within 6 months prior to surgery; long-acting opioids within 3 days prior to surgery; the use of any opioids < 24 hours prior to surgery; the administration of bupivacaine within 5 days prior to surgery; and the use of systemic steroids within five half-lives or 10 days prior to administration of study drug

Methods

Patients were randomized (3:2:2) to receive the study drug Zynrelef, 60 mg/1.8 mg (bupivacaine/meloxicam), 2.1 mL, applied into the surgical site without a needle; bupivacaine HCl 0.5%, 50 mg (10 mL), via injection into the surgical site; or saline placebo, 2.1 mL, applied into the surgical site without a needle.

Patients were prepared with 20 mL of 1% lidocaine without epinephrine as anesthesia. The observed agent was administered via local application into the surgical site.

Duration

Treatment: 72 hours

Follow-Up Intervals (post-surgery): Days 10, 28, and 42

Outcome Measures

Primary: Mean area under the curve (AUC) of the Numeric Rating Scale (NRS) of pain intensity scores through 72 hours for Zynrelef compared with saline placebo.

Secondary: Mean AUC of the NRS pain intensity scores for Zynrelef compared with bupivacaine HCl within 72 hrs post-surgery; mean total post-operative opioid consumption (in morphine mg equivalents) through 72 hours for Zynrelef compared with saline placebo; the proportion of subjects who were opioid free through 72 hours for Zynrelef compared with bupivacaine HCl; the mean total post-operative opioid consumption (in morphine equivalents) through 72 hours for Zynrelef compared with bupivacaine HCl.

Baseline Characteristics

 

Zynrelef

(n=157)

Bupivacaine

(n=155)

Placebo

(n=100)

Age, years

48.0 ± 14.47 45.5 ± 14.79 47.3 ± 12.83

Female

138 (87.9%) 132 (85.2%) 86 (86%)

White

Black

123 (78.3%)

24 (15.3%)

128 (82.6%)

22 (14.2%)

86 (86%)

12 (12.0%)

Results

 

Zynrelef

(n=157)

Bupivacaine

(n=155)

Placebo

(n=100)

P-value

Mean AUC0-72 NRS Pain Score

323.3 ± 182.6

--

445.3 ± 155.8

<0.001

Mean AUC0-72 NRS Pain Score

Opioid Consumption vs placebo

Opioid Consumption vs bupivacaine

Opioid free for 72 H

323.3 ± 182.6

18.8 ± 19.8

18.8 ± 19.8

45 (28.7%)

393.5 ± 153.8

25.09 ± 21.55

17 (11%)

-

30.06 ± 21.01

-

2 (2%)

0.0002

<0.0001

0.0022

<0.0001

Adverse Events

Common Adverse Events: Nausea (37.6%, 45.5%, 43.6) and dizziness (21.7%, 23.4%, 17.8%)

Serious Adverse Events: Zynrelef (1.9%), bupivacaine (1.9%), placebo (1%)

Percentage that Discontinued due to Adverse Events: 0.6 % (Zynrelef group)

Study Author Conclusions

Zynrelef demonstrated a significant reduction in postoperative pain through 72 hours with a significant reduction in opioid consumption and a significant increase in the proportion of opioid-free subjects compared with saline placebo and the most widely used local anesthetic, bupivacaine HCl.

InpharmD Researcher Critique

Bupivacaine dosing was based on surgeon consensus due to the lack of an approved dose form. Typical discharge after surgery is 1-2 hours but patients were retained for 72 hours which may not reflect real-world outcomes. 

 

References:

Viscusi E, Gimbel JS, Pollack RA, Hu J, Lee GC. HTX-011 reduced pain intensity and opioid consumption versus bupivacaine HCl in bunionectomy: phase III results from the randomized EPOCH 1 study [published online ahead of print, 2019 May 21]. Reg Anesth Pain Med. 2019;rapm-2019-100531. doi:10.1136/rapm-2019-100531

 

HTX-011 Reduced Pain Intensity and Opioid Consumption versus Bupivacaine HCl in Herniorrhaphy: Results from the Phase 3 EPOCH 2 Study

Design

Phase 3, randomized, multi-center, double-blind, parallel-group, active- and placebo-controlled clinical trial

N=446

Objective

To assess the safety and efficacy of HTX-011 (bupivacaine and meloxicam in Biochronomer® polymer technology), a long-acting investigational anesthetic, in reducing both postoperative pain over 72 h and postoperative opioid use compared to bupivacaine hydrochloride (HCl)

Study Groups

Zynrelef (n=164)

Bupivacaine HCl (n=172)

Saline placebo (n=82)

Inclusion Criteria

Age ≥ 18 years; American Society of Anesthesiologists physical status of I, II, or III; undergoing unilateral open inguinal herniorrhaphy

Exclusion Criteria

Pre-existing, concurrent, acute, or chronic painful physical/restrictive condition(s); planned or concurrent surgical procedures; and those with a history of prior inguinal herniorrhaphy, except during childhood; use of non-steroidal anti-inflammatory (NSAIDs, including meloxicam) ≥ 10 days prior to surgery; known or suspected daily use of opioids for ≥ 7 days within 6 months prior to surgery; long-acting opioids within 3 days prior to surgery; the use of any opioids < 24 hours prior to surgery; the administration of bupivacaine within 5 days prior to surgery; and the use of systemic steroids within 10 days prior to administration of study drug

Methods

Subjects were randomized (2:2:1) to the following groups: (a) Zynrelef, 300 mg/9 mg (bupivacaine/meloxicam), 10.3 mL, via instillation into the surgical site; (b) bupivacaine HCl 0.25%, 75 mg (30 mL), via injection into the surgical site; (c) saline placebo, 10.3 mL, via instillation into the surgical site. 

Near the completion of surgery and following irrigation and suction of each fascial layer, a single dose of study drug (Zynrelef, bupivacaine HCl, or saline placebo) was administered intraoperatively via local administration into the surgical site. Subjects remained in the hospital/research facility for a minimum of 72 h following surgery to be evaluated for the primary and secondary endpoints.

Duration

Treatment: 72 hours

Follow-Up Intervals (post-surgery): Days 10 and 28

Outcome Measures

Primary: Mean area under the curve (AUC) of the Numeric Rating Scale (NRS) of pain intensity scores through 72 hours for Zynrelef compared with saline placebo.

Secondary: Mean AUC of the NRS pain intensity scores for Zynrelef compared with bupivacaine HCl within 72 hrs post-surgery; mean total post-operative opioid consumption (in morphine mg equivalents) through 72 hours for Zynrelef compared with saline placebo; the proportion of subjects who were opioid-free through 72 hours for Zynrelef compared with bupivacaine HCl; the mean total post-operative opioid consumption (in morphine equivalents) through 72 hours for Zynrelef compared with bupivacaine HCl.

Baseline Characteristics

 

Zynrelef (n=164)

Bupivacaine (n=172)

Placebo (n=82)

Age, years

48.9 (13.29%) 49.4 (11.26%) 48 (14.59%)

Female

12 (7.3%) 8 (4.7%) 3 (3.7%) 

White

139 (84.8%) 153 (89%) 78 (95.1%)

Results

 

Zynrelef

(n = 164)

Bupivacaine

(n = 172)

Placebo

(n = 82)

Mean AUC0-72 NRS Pain Score

p-value versus placebo

p-value versus bupivacaine

269.4 ± 173.72

0.0004

<0.0001

341.9 ± 158.3

-

-

350.8 ± 171.22

-

-

Opioid Consumption, mg of morphine equivalents

p-value versus placebo

p-value versus bupivacaine

10.9 ± 17.06

0.0001

0.0240

14.5 ± 18.19

-

-

17.5 ± 18.91

-

-

Opioid free for 72 H

84 (51.2%)

69 (40.1%)

18 (22%)

Adverse Events

(Zynrelef, bupivacaine, placebo)

Common Adverse Events: Nausea: (18.4%, 21.4%, 34.1%); Constipation: (17.2%, 23.7%, 18.3%); Dizziness: (14.7%, 24.3%, 15.9%); Headache: (12.9%, 13.9%, 12.2%)

Serious Adverse Events (SAEs): Zynrelef (1.2%), bupivacaine (0.6%), placebo (1.2%)

Percentage that Discontinued due to Adverse Events: None (0%) in all 3 groups

Study Author Conclusions

Zynrelef demonstrated significant improvement in postoperative pain control and a clinically meaningful reduction in opioid consumption when compared to the most widely used local anesthetic, bupivacaine HCl.

InpharmD Researcher Critique

An extensive inclusion/exclusion criteria makes it difficult to apply in a general surgical population. Typical discharge would occur in a few hours but patients remained for 72 hours to collect data. Patients would also possibly be discharged with opioid prescriptions which could not be measured in the study due to the 72-hour timeframe.

 

References:

Viscusi E, Minkowitz H, Winkle P, Ramamoorthy S, Hu J, Singla N. HTX-011 reduced pain intensity and opioid consumption versus bupivacaine HCl in herniorrhaphy: results from the phase 3 EPOCH 2 study [published correction appears in Hernia. 2020 Jun;24(3):679]. Hernia. 2019;23(6):1071-1080. doi:10.1007/s10029-019-02023-6

 

HTX-011 Reduced Pain and Opioid Use After Primary Total Knee Arthroplasty: Results of a Randomized Phase 2b Trial

Design

Phase 2b, double-blind, placebo-controlled and active-controlled trial 

N=222

Objective

To determine the efficacy and safety of one application of HTX-011 (bupivacaine and meloxicam in Biochronomer® polymer technology; Zynrelef) with or without ropivacaine in patients undergoing a primary unilateral total knee arthroplasty (TKA)

Study Groups

Saline Placebo (n=53)

Bupivacaine (n=55)

Zynrelef  (n=58)

Zynrelef and ropivacaine (n=56)

Inclusion Criteria

Patient's scheduled for a unilateral TKA, ≥18 years old and demonstrated an American Society of Anesthesiologists (ASA) physical status of I, II, or III.

Exclusion Criteria

Patient's known/suspected of daily opioid use for ≥ 7 consecutive days within 6 months before their scheduled surgery

Use of the following medications within the listed times before surgery: nonsteroidal anti-inflammatory medications (NSAIDs) (including meloxicam) within 10 days, long-acting opioids within 3 days, any opioids within 24 hours and bupivacaine HCl within 5 days.

Methods

Patients were randomized (1:1:1:1) to receive Zynrelef alone (400 mg bupivacaine/12 mg meloxicam, 14 mL) via periarticular application; Zynrelef (14 mL of 400 mg bupivacaine/12 mg meloxicam) via periarticular application plus seperate dose of 0.5% ropivacaine 0.5% (50 mg, 10 mL) injected into the posterior capsule; Bupivacaine HCl 0.25% alone (125 mg, 50 mL) administered through multiple periarticular injections; 14 mL saline placebo, administered via multiple periarticular injections.

All patients were also given 150 mg of oral pregabalin, ≤1000 mg of intravenous acetaminophen and 1 gram of intravenous tranexamic acid (TXA) before surgery. Patients also received a second dose of TXA 1 gram up to 8 hours after surgery. Following surgery, patients were required to stay in the hospital or a treatment facility for a minimum of 72 hours for observation. During the post-operative observation period, patients had the option of receiving pain medications upon request. 

After 72 hours, patients return to their prospective study sites and must complete a daily diary of their opioid use upon discharge.  

Duration

72 hours

Outcome Measures

Primary and Secondary efficacy: Area under the curve (AUC) of the Numeric Rating Scale (NRS) of pain intensity scores over 48 hours and 72 hours.

Other secondary efficacy endpoints: Evaluations of total postoperative opioid consumption and discharge readiness evaluated by the Modified Postanesthetic Discharge Scoring System (MPADSS) criteria.

Baseline Characteristics

 

Saline Placebo (n=53)

Bupivacaine (n=55)

Zynrelef (n=58)

Zynrelef and ropivacaine (n=56)

Age, years

61.5 61.4 

62.5

63.2

Male

 28 (52.8%)  20 (36.4%)  32 (55.2%)  29 (51.8%)

White 

Black

45 (84.9%)

8 (15.1%) 

47 (85.5%)

7 (12.7%)

51 (87.9%)

6 (10.3%)

49 (87.5%)

5 (8.9%)

Body mass index, kg/m2

32.1 32.4  31.7

31.2

Results

Primary Analysis (adjusted for opioid use)

Saline placebo (n= 53)   

Zynrelef (n= 58)

Zynrelef and ropivacaine (n= 56)

bupivacaine

AUC0-48 of NRS (SD)

P-value vs saline placebo

396.4 (77.5)

-

322.1 (99.7)

0.0002

307.3 (127.7)

<.0001

 

AUC 0-72 of NRS (SD)

P-value vs saline placebo

577.9 (125.1)

-

471.2 (149.4)

0.0004

452.5 (194.1)

<0.0001

 

AUC 0-48 of NRS (SD)

P-value vs saline placebo

P-value vs bupivacaine

267.3 (81.3)

-

-

188.9 (81.6)

<.0001

0.0070

194.5 (99.6)

<.0001

0.0190

233.7 (85.5)

-

-

AUC 0-72 of NRS (SD)

P-value vs saline placebo

P-value vs bupivacaine 

365.4 (127.2)

-

-

264.56 (123.2)

<0.0001

0.0269

269.51 (144.8)

0.0002

0.0456

269.5 (144.8)

-

-

SD= Standard deviation

Adverse Events

Any AE: Saline placebo (94.3%), bupivacaine (92.7%), Zynrelef (94.8%), Zynrelef + ropivacaine (92.9%)

Severe AEs possibly related to study drug: Saline placebo (0%), bupivacaine (0%), Zynrelef (0%), Zynrelef + ropivacaine (1.8%)

The three most common AEs in the Zynrelef groups were nausea, constipation, and vomiting. Incidence were lower or comparable to the bupivacaine group.

Study Author Conclusions

Patients treated with Zynrelef demonstrated a significant reduction in pain intensity compared to patients treated with saline placebo for the first 48-hr and 72 hours post-operative (total knee arthroplasty) periods.

InpharmD Researcher Critique

The primary endpoints were focused on the p-value versus placebo rather than comparisons between 



References:

Lachiewicz PF, Lee GC, Pollak RA, Leiman DG, Hu J, Sah AP. HTX-011 Reduced Pain and Opioid Use After Primary Total Knee Arthroplasty: Results of a Randomized Phase 2b Trial. J Arthroplasty. 2020;35(10):2843-2851. doi:10.1016/j.arth.2020.05.044

 

Liposomal Bupivacaine Versus Traditional Periarticular Injection for Pain Control After Total Knee Arthroplasty

Design

Retrospective, pre-post study

N=150

Objective

To assess the efficacy of liposomal bupivacaine versus a traditional periarticular injection in minimizing opiate consumption and postoperative pain levels following primary total knee arthroplasty (TKA)

Study Groups

Liposomal Bupivicaine (n=65)

Ropivicaine Injection (n=85)

Inclusion Criteria

Patients who underwent unilateral primary TKA

Exclusion Criteria

Not reported

Methods

Intraoperatively, all patients received a periarticular injection consisting of ropivacaine, morphine, and epinephrine, or liposomal bupivacaine. During the first six months of the study (January to June), patients who underwent TKA got a periarticular injection of 400 mg ropivacaine, 5 mg morphine, and 0.4 mg epinephrine in 100 mL solution. From July to September, patients got a periarticular injection consisted of liposomal bupivacaine per the manufacturer-recommended dose.

Duration

January to September 2013

Outcome Measures

Pain control

Baseline Characteristics

 

Liposomal Bupivicaine (n=65)

Ropivicaine Injection (n=85)

 

Age, years

63.13±10.32 65.19±9.21   

BMI, kg/m2

34.64±7.81 35.25±8.49   

Length of stay

2.32±0.53 2.31±0.93   

Female

47 (72.3%) 

61 (70.9%) 

 

Side

Left

Right

 

34 (52.3%)

31 (47.7%)

 

49 (57.0%)

37 (43.0%)

 

Results

 

Liposomal Bupivicaine (n=65)

Ropivicaine Injection (n=85)

P-values

Pain Scores during the first 24 h

None

Mild

Moderate

Severe

1.94±2.10

14 (21.54%)

38 (58.46%)

12 (18.46%)

1 (1.54%)

1.93±2.14 

21 (25.0%)

46 (54.76%)

12 (15.48%)

4 (4.76%)

0.97

Pain Scores during the remaining stay

None

Mild

Moderate

Severe

4.89±1.35

0

11 (16.92%)

49 (75.38%)

5 (7.69%)

 4.38±1.60

0

40 (47.62%)

39 (46.43%)

5 (5.95%)

0.04

Final Pain Scores

None

Mild

Moderate

Severe

4.11±1.86

3 (4.62%)

17 (26.15%)

38 (58.46%)

7 (10.77%)

3.62±2.09

9 (10.71%)

26 (30.95%)

31 (36.90%)

8 (9.52%)

0.14

Adverse Events

Not studied

Study Author Conclusions

This study demonstrates that a periarticular injection of liposomal bupivacaine in primary TKA patients is not associated with a significant improvement in postoperative pain or narcotic usage. This study found no benefit to intra-articular injection of liposomal bupivacaine, with the possible negative effect of increased pain throughout the remaining hospital course after the initial 24 h. Based on the results of this study, the authors conclude that pain control after TKA with a multimodal pain management protocol is not improved with the addition of liposomal bupivacaine compared to a traditional injection of ropivacaine and epinephrine. In addition, the additional cost of liposomal bupivacaine does not appear to be warranted over the less expensive ropivacaine injection.

InpharmD Researcher Critique

This was not a randomized, prospective study. The patient's self-reported pain might be subjective.



References:

Bagsby DT, Ireland PH, Meneghini RM. Liposomal bupivacaine versus traditional periarticular injection for pain control after total knee arthroplasty. J Arthroplasty. 2014;29(8):1687-1690. doi:10.1016/j.arth.2014.03.034

 

Effectiveness of Bupivacaine Liposome Injectable Suspension for Postoperative Pain Control in Total Knee Arthroplasty: A Prospective, Randomized, Double Blind, Controlled Study

Design

Prospective, randomized, double-blinded, controlled trial

N=96

Objective

To compare the effectiveness of liposomal bupivacaine to ropivacaine, each as part of multimodal pain management, in total knee arthroplasty (TKA) postoperative pain control

Study Groups

Ropivacaine cocktail (n=49)

Liposomal bupivacaine cocktail (n=47)

Inclusion Criteria

Age >18, unilateral TKA, diagnosis of degenerative osteoarthritis of the knee, determination that the patient was opioid-naive before surgery

Exclusion Criteria

Prior knee replacement, inflammatory arthritis, unicompartmental knee replacement, bilateral TKA, opioid tolerance as defined by FDA

Methods

The control group was administered a periarticular injection of ropivacaine, ketorolac, morphine, and epinephrine mixed with saline in a 100 mL preparation. The treatment group was administered a periarticular injection of bupivacaine, ketorolac, morphine, and epinephrine mixed with saline in an 80 mL preparation and a 20 mL injection of 1.3% liposomal bupivacaine (Exparel) to total 100 mL. 

The method of injection was standardized between the groups. A 22-gauge spinal needle was used to inject the periarticular soft tissue envelope, and 50 mL was distributed throughout the posterior capsule, medial and lateral capsule, and the collateral ligaments and 50 mL was infiltrated into the subcutaneous tissue before wound closure. Patients were also treated with the same postoperative pain management protocol as well as the same postoperative physical therapy program in the hospital. 

Duration

Mean hospital stay of 60.3 hours

Outcome Measures

Postoperative narcotic use during hospital stay, length of hospital stay, time to ambulate 100 feet, visual analog scales (VAS) for pain.

Baseline Characteristics

 

Ropivacaine cocktail (n=49)

Liposomal bupivacaine cocktail (n=47)

 

Age, years

67.7 ± 9 69.7 ± 8.6  

Women

58% 56.5%  

BMI, kg/m2

31.9 ± 5.9 31.5 ± 6.5  

Results

 

Ropivacaine cocktail (n=49)

Liposomal bupivacaine cocktail (n=47)

P-value

Postoperative hydrocodone use, mg*

Oxycodone use, mg

Hydrocodone use, mg

Tramadol use, mg

89.6 ± 58.57

49.1

28.8

54.0

97.7 ± 42.84

35.2

44.7

26.6

<0.443

Not significant

<0.043

Not significant

Length of hospital stay, hours

60.3 59 Not significant

Time to ambulate 100 feet, hours

26.4 27.3 Not significant

Visual analog scale pain score

Day 1

Day 2

 

34.1

45.7

 

41.0

44.4

 

<0.823

<0.657

*Weighted sum of hydrocodone equivalents

Adverse Events

N/A

Study Author Conclusions

Compared to a standard ropivacaine cocktail, there was no benefit in using liposomal bupivacaine for pain control following TKA. 

InpharmD Researcher Critique

Limitations of this study include the small sample size. The use of multiple different postoperative medications led to a non-normalized distribution. Because blinding the medications is impossible during surgery (Exparel is milky, whereas the control solution is not), a blinded independent reviewer conducted the postoperative assessments and statistics. Another limitation is the relatively short-term follow-up. 

 

References:

DeClaire JH, Aiello PM, Warritay OK, Freeman DC. Effectiveness of Bupivacaine Liposome Injectable Suspension for Postoperative Pain Control in Total Knee Arthroplasty: A Prospective, Randomized, Double Blind, Controlled Study. J Arthroplasty. 2017;32(9S):S268-S271.

 

A Phase 3, Randomized, Placebo-Controlled Trial of DepoFoam® Bupivacaine (Extended-Release Bupivacaine Local Analgesic) in Bunionectomy

Design

Phase 3, multicenter, parallel-group, placebo-controlled, randomized, double-blind study

N=193

Objective

To determine the safety and efficacy of 120 mg of liposomal bupivacaine on wound infiltration

Study Groups

Liposomal bupivacaine 120 mg (n=97)

Placebo (n=96)

Inclusion Criteria

Age ≥18 years, scheduled to undergo primary unilateral first metatarsal osteotomy without hammertoe; receive Mayo block for intraoperative local analgesia and propofol and/or midazolam for intraoperative sedation. Criteria for Women: surgically sterile, at least 2 years menopausal, using an acceptable method of birth control, or if of childbearing age, have a documented negative blood or urine pregnancy test within 24 hours before surgery

Exclusion Criteria

Pregnant, Nursing, or planning to become pregnant during the study or within 1 month after receiving the study drug; Chronic users of analgesic medications (i.e using opioid medications >14 days in the last 3 months or non-opioid pain medications > 5 times/week); Use of acetaminophen within 24 hours of surgery, any NSAID or selective serotonin reuptake inhibitors, gabapentin, pregabalin, or duloxetine within 3 days of surgery, or systemic glucocorticosteroids within 1 month of study enrollment; Peripheral neuropathy; Hepatitis, Alcohol or Drug abuse within the past 2 years; Peripheral ischemic disease; Diabetes; Hypersensitive to amide-type local anesthetics or to opioid medication

Methods

Patients were randomized to receive Liposomal bupivacaine 120mg through a wound infiltration before closing the skin or matching placebo. Afterwards, a numeric rating scale (NRS) from 0-72 hours after surgery

Duration

Not disclosed

Outcome Measures

Primary efficacy: Measure the area under the curve (AUC) of numeric rating scale (NRS) scores through 24 hours. Other efficacy: AUC of NRS at other time points, proportion of patients who were painfree, time to first opioid use and total postsurgical consumption of supplemental opioid medication.

Baseline Characteristics

 

Liposomal bupivacaine (n=97)

Placebo (n=96)

Total (N=193)

Age, years

42.4 ±12.7  43.3 ± 13.4 42.8 ± 13.0

Male 

Female 

22 (22.7%)

75 (77.3%) 

12 (12.5%)

84 (87.5%)

34 (17.6%)

159 (82.4%)

Black or African American 

White or Caucasian

25 (25.8%)

66 (68%)

21 (21.9%)

72 (75.0%)

46 (23.8%)

138 (71.5%)

Body mass index, kg/m2

 

28.1 ± 5.8 

27.6 ± 5.7 

27.9 ± 5.8

Results

Endpoint

Liposomal bupivacaine (n=97)

Placebo (n= 96)

Liposomal bupivacaine vs. Placebo 

Mean pain scores (SD)

124.9 (±48.3) 146.4 (±42.9) -

Least squares mean (SE)*

123.9 (4.5) 146.2 (4.6)

Least squares mean difference (SE)*

- -  -22.3 (6.3)

95% CI for difference*

- -  (-34.8, -9.794)

P value for treatment*

- -  0.0005

SD= Standard deviation AUC= area under the curve using trapezoidal method; CI= confidence interval; LSM= least squares mean; NRS= numeric rating scale (0= no pain, 10=worst possible pain); wWOCF+LOCF=imputation using the worst observation prior to use of rescue medication within a medication window and last-observation-carried-forward for missing values. 

Adverse Events

Common Adverse Events: Nausea (40.2% vs. 37.5%), Vomiting (27.8% vs. 17.7%), Dizziness (11.3% vs. 26%), Headache (5.2% vs. 8.3%) and generalized Pruritus ( 5.2% vs. 6.3%)

Serious Adverse Events: Fungal infections (2.1% vs 1%), Increased Alanine aminotransferase (ALT) (3.1% vs. 3.1%), Increased Aspartate aminotransferase (AST) (3.1% vs. 2.1%), Muscle spasms (1% vs. 2.1%), Blood creatinine increased (2.1% vs. 0%), Hot flush (0% vs. 2.1%), Pyrexia (2.1% vs. 0%), Syncope (2.1% vs. 0%)

Percentage that Discontinued due to Adverse Events: 1%

Study Author Conclusions

DepoFoam bupivacaine, a long-acting local analgesic, provided extended pain relief and decreased opioid use after bunionectomy, compared with placebo.No patients had any evidence of malunion or non-union on their routine podiatric follow-up visits. This investigational, long-acting local analgesic provided extended pain relief and decreased opioid use after bunionectomy, compared with placebo. DepoFoam bupivacaine, therefore, may offer clinically meaningful advantages in postsurgical pain relief.

InpharmD Researcher Critique

The extensive inclusion/exclusion criteria makes it difficult to extrapolate the results beyond a limited surgical patient population. Patients with comorbidities and taking multiple medications were also excluded which leaves the population somewhat sterile. 



References:

Golf M, Daniels SE, Onel E. A phase 3, randomized, placebo-controlled trial of DepoFoam® bupivacaine (extended-release bupivacaine local analgesic) in bunionectomy. Adv Ther. 2011;28(9):776-788. doi:10.1007/s12325-011-0052-y

 

Liposomal bupivacaine infiltration into the transversus abdominis plane for postsurgical analgesia in open abdominal umbilical hernia repair: results from a cohort of 13 patients

Design

Cohort study

N=13

Objective

To evaluate the analgesic efficacy and safety of liposomal bupivacaine infiltration into the TAP in patients undergoing open abdominal umbilical hernia repair

Study Groups

Study participants (N=13)

Inclusion Criteria

Age 18 to 75 years undergoing open abdominal umbilical hernia repair under general anesthesia

Exclusion Criteria

None reported

Methods

Patients included were administered liposomal bupivacaine at the end of open abdominal umbilical hernia repair using a standardized infiltration protocol and administered vial TAP infiltration. Short-acting fentanyl was permitted for intraoperative analgesia.

Duration

120 hours post-surgery. 30 days post-surgery for AEs.

Outcome Measures

Primary outcome: Effect of postsurgical analgesia based on 11-point numeric rating scale (NRS) from patient-reported pain intensity.

Secondary outcome: Required supplemental analgesia up to 72 hours postsurgery.

Baseline Characteristics

 

Study participants (N=13)

Age, years

46 ± 13

White

African American

Asian

10 (77%)

2 (15%)

1 (8%)

Results

 

Study participants (N=13)

Mean NRS prior to infiltration

Mean NRS 120 hours after infiltration

0.6

0.9

Required supplemental analgesia 72 hours postsurgery

10 (77%)

Reported extreme satisfaction (5 on 5-point Likert scale) at time of discharge

54%

Reported extreme satisfaction (5 on 5-point Likert scale) at day 10.

62%

Data was reported via a bar graph with no exact numbers provided aside from baseline and 120 hours after infiltration.

Throughout the 120 hours, pain intensity remained below 2.3.

TAP infiltration failed in the first patient, no analgesia was reported and the patient was hospitalized overnight for pain control.

Adverse Events

There were no adverse events or serious AEs reported during the study

Study Author Conclusions

Although the current study was limited by both its lack of a control group and its small size, to our knowledge, it is the first published report on use of liposomal bupivacaine for TAP infiltration. In this cohort, liposomal bupivacaine was observed to be well tolerated with encouraging analgesic efficacy.

InpharmD Researcher Critique

The study revolved around a specific surgery procedure (abdominal umbilical hernia repair). It may not be reflective of those undergoing other types of hernia repair surgeries. The lack of control group also makes comparisons against other therapies in this setting uncertain; although a constant pain score below 2.3 meant there was minimal pain during the 120 hours.

 

References:

Feierman DE, Kronenfeld M, Gupta PM, Younger N, Logvinskiy E. Liposomal bupivacaine infiltration into the transversus abdominis plane for postsurgical analgesia in open abdominal umbilical hernia repair: results from a cohort of 13 patients. J Pain Res. 2014;7:477-482. Published 2014 Aug 16.