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

Female

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 AUC_0-72 NRS Pain Score

323.3 ± 182.6

--

445.3 ± 155.8

<0.001

Mean AUC_0-72 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. 

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

Female

White

Results

Zynrelef

(n = 164)

Bupivacaine

(n = 172)

Placebo

(n = 82)

Mean AUC_0-72 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

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)

Age, years

62.5

63.2

Male

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

31.2

Results

Primary Analysis (adjusted for opioid use)

Saline placebo (n= 53)   

Zynrelef (n= 58)

Zynrelef and ropivacaine (n= 56)

bupivacaine

AUC_0-48 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 

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

Baseline Characteristics

Liposomal Bupivicaine (n=65)

Ropivicaine Injection (n=85)

Age, years

BMI, kg/m²

Length of stay

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

InpharmD Researcher Critique

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

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

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

Women

BMI, kg/m²

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

Time to ambulate 100 feet, hours

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. 

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

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)

Age, years

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)

Least squares mean (SE)*

Least squares mean difference (SE)*

95% CI for difference*

P value for treatment*

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. 

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

Inclusion Criteria

Exclusion Criteria

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

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

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.

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

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.

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

Design

Prospective, double-blind, randomized study where 96 total knee arthroplasty (TKA) patients into a control group and treatment

N= 96

Objective

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

Study Groups

Ropivacaine  n= 49

Liposomal bupivacaine n= 47

Inclusion Criteria

Patients Age ≥ 18 years; diagnosis of degenerative osteoarthritis of the knee; determination that the patient was opioid-naive prior to surgery.

Exclusion Criteria

Patients with prior knee replacement, inflammatory arthritis, unicompartmental knee replacement, bilateral TKA, opioid tolerance

Methods

Patients (N= 96) were randomized into two groups-control group that received standard periarticular “pain cocktail” injection, consisting of ropivacaine, ketorolac, morphine, and epinephrine mixed with saline into a 100 mL preparation and treatment group that received a similar periarticular injection consisting of bupivacaine, ketorolac, morphine, and epinephrine mixed with saline into a 80 mL preparation as well as an injection of liposomal bupivacaine, 20 mL of 1.3% Exparel, to total 100 mL.

A 22-gauge spinal needle was used to inject the periarticular soft tissue envelope with the 100 mL preparation divided between the superficial and deep soft tissue structures. The deep soft tissue envelope was injected with a 50 mL suspension distributed throughout the posterior capsule, medial and lateral capsule, and the collateral ligaments. The synovial tissue and periosteum were also injected circumferentially on the femur and the tibia. Before wound closure, 50 mL was infiltrated into the subcutaneous tissue divided equally on each side of the incision.

 Patients in both groups were treated with the same postoperative pain management protocol as well as the same physical therapy post-operation.

Duration

Treatment and control groups were followed from the time of TKA procedure to the point in time from surgery they were able to ambulate 100 feet and their time of discharge from the hospital, approximately 60 hours.

Outcome Measures

The post-operative use of opioids by the treatment and control groups after a TKA procedure 

 The time to ambulate 100 feet and the time to discharge (from hospital) was measured.

Baseline Characteristics

Ropivacaine

n= 49

Liposomal Bupivacaine

n= 47

P-Value

Age, years

67.7 (+/- 9)

31.5 (+/- 6.5)

p< 0.292

Female

28

27

p< 0.976

Male

21

20

BMI

31.9 (+/- 5.9)

31.5 (+/- 6.5)

p< 0.788

Results

Endpoint

Postoperative Opioid Use (mg)

Ropivacaine

Liposomal Bupivacaine

p-Value

Percocet

49.1

35.2

p< 0.154

Norco

28.8

44.7

p< 0.043

Ultram

54.0

26.6

p< 0.984

Dilaudid

0.85

0.84

p< 0.978

Postoperative NSAID Consumption

p< 0.641

Length of Hospital Stay (hours)

Time to Ambulate 100 ft

60.3

26.4

59.0

27.3

p< 0.978

p<0.757

The per hour mean use of narcotics (mg) was measured.

The data in the Ultram group were not normally distributed, despite the appearance there was a great difference between the control and treatment groups. Kruskal-Wallis ranked test was used for the Ultram group.

Serious Adverse Events: None stated

Percentage that Discontinued due to Adverse Events: None stated 

Study Author Conclusions

When liposomal bupivacaine was compared to ropivacaine in periarticular injection as part of multimodal pain management, there was no significant difference in opioid use per hour or in total opioid use during hospital stay. In addition, there was no difference in the NSAID consumption postoperatively. There was no difference in the amount of time to mobilize or length of stay.

InpharmD Researcher Critique

Liposomal bupivacaine appears equivalent to ropivacaine with standard multimodal pain management.