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 

Safety and Efficacy of Bupivacaine HCl Collagen-Matrix Implant (INL-001) in Open Inguinal Hernia Repair: Results from Two Randomized Controlled Trials

Design

Analysis of two similar phase 3, multicenter, randomized, double-blind, placebo-controlled studies (MATRIX-1 and MATRIX-2)

(N= 524)

Objective

To examine the efficacy and safety of the bioresorbable bupivacaine HCl collagen-matrix implant (INL-001) for postsurgical pain after open inguinal hernia repair or placebo collagen-matrix implants

Study Groups

MATRIX-1

INL-001 (n= 204)

Placebo (n= 101)

MATRIX-2

INL-001 (n= 213)

Placebo (n= 106)

Combined modified intent-to-treat (mITT) population

Combined INL-001 (n= 404)

Combined placebo (n= 206)

Inclusion Criteria

Exclusion Criteria

Methods

Patients were randomized (2:1) to either three doses of INL-001 100 mg bupivacaine HCl collagen-matrix implants (total dose 300 mg bupivacaine HCl) or placebo collagen-matrix implants without bupivacaine. Providers were blinded unless patients develop an AE which then led to unblinding and revealing which treatment was assigned. Parenteral morphine was available for post-surgical pain as needed. All patients received acetaminophen PO 650 mg TID for 3 days along with immediate-release morphine as-needed. Pain intensity was recorded using a 11-point pain score at pre-determined points from 1 to 72 hours after study drug implantation.

The modified intent-to-treat population consisted of patients who were randomized and received any dose of study drug and reported at least one 11-point numerical rating scale pain intensity score.

Duration

MATRIX-1: August 2015 to April 2016

MATRIX-2: September 2015 to April 2016

Outcome Measures

Primary: Sum of pain intensity scores from 0 to 24 hours 

Secondary: Sum of pain intensity scores from 0 to 48 hours and 0 to 72 hours. Total use of opioid analgesia from times 0 to 24, 28, and 72 hours (measured as mg IV morphine equivalent). Safety

Baseline Characteristics

MATRIX-1

MATRIX-2

INL-001 (n= 204)

Age, years (SD)

Female

Male

8 (4%)

196 (96%)

4 (4%)

97 (96%)

5 (2%)

208 (98%)

3 (3%)

103 (97%)

Hispanic or Latino

Not Hispanic or Latino

Missing

77 (38%)

127 (62%)

0

38 (38%)

62 (61%)

1 (1%)

44 (21%)

169 (79%)

0

23 (22%)

83 (78%)

0

White

Black or African American

185 (91%)

15 (7%)

91 (90%)

7 (7%)

182 (85%)

23 (11%)

90 (85%)

12 (11%)

Body mass index, kg/m² (SD)

27.05 (3.899)

27.26 (4.596)

26.84 (4.025)

27.22 (5.062)

Previous ipsilateral hernia repair using mesh

Yes

No

Missing

20 (10%)

184 (90%)

0

12 (12%)

89 (88%)

0

22 (10%)

189 (89%)

2 (<1%)

10 (10%)

96 (91%)

0

Multiple hernias

Yes

No

Missing

13 (6%)

190 (93%)

1 (<1%)

4 (4%)

96 (95%)

1 (1%)

5 (2%)

204 (96%)

4 (2%)

4 (4%)

102 (96%)

0

Incision duration, hours (SD)

0.80 (0.432)

0.75 (0.379)

0.80 (0.327)

0.84 (0.352)

Results

Endpoint

Combined INL-001 (n= 404)

Placebo collagen-matrix (n= 206)

Sum of patient intensity from time 0 to 24 hours

Mean (standard error of mean)

Median

p-Value versus placebo

87.1 (2.34)

82.5

<0.0001

111.6 (3.22)

112.3

-

Sum of patient intensity from time 0 to 48 hours

Mean (standard error of mean)

Median

p-Value versus placebo

186.1 (4.65)

180.5

0.0033

209.2 (6.44)

208.8

-

Sum of patient intensity from time 0 to 72 hours

Mean (standard error of mean)

Median

p-Value versus placebo

268.0 (6.91)

253.0

0.0441

291.3 (9.55)

274.9

-

Total use of opioid analgesia from time 0 to 24

Median

p-Value versus placebo

5.0

<0.0001

12.3

-

Total use of opioid analgesia from time 0 to 48

Median

p-Value versus placebo

7.0

<0.0001

15.0

-

Total use of opioid analgesia from time 0 to 72

Median

p-Value versus placebo

9.0

0.0004

17.0

-

Adverse Events

Any adverse events:

MATRIX-1

INL-001 (n= 203): 138 (68%)

Placebo (n= 101): 67 (66%)

MATRIX-2

INL-001 (n= 208): 118 (57%)

Placebo (n= 107): 76 (71%)

Commonly-reported adverse events consisted of incision-site swelling, somnolence, incision-site pain, dizziness, nausea, constipation, post-procedural discharge, dysgeusia, restlessness, incision-site complication, incision-site erythema, anxiety, vomiting, and tinnitus

Treatment-related adverse events:

Combined INL-001 (n= 441): 14 (3%)

Combined placebo (n= 208): 6 (3%)

Reported events in more than one patient possibly linked to treatment included dysgeusia, dizziness, and incision site complication

Study Author Conclusions

InpharmD Researcher Critique

The study was not a comparison between bupivacaine collagen matrix implant versus Exparel® (liposomal bupivacaine) or Zynrelef® (bupivacaine and meloxicam extended-release solution) but does illustrate its benefit compared to a placebo agent. As comparative studies are scarce, the data presented may prove useful and demonstrates the potentially reduced risk of local and systemic toxicity when bupivacaine was delivered via collagen technology as illustrated by the similar safety profile. Patients were predominantly white men which may limit the generalizability of results. 

Clinical Evaluation of XaraColl(®), a Bupivacaine-Collagen Implant, for Postoperative Analgesia in Two Multicenter, Randomized, Double-Blind, Placebo-Controlled Pilot Studies

Design

Two independent, multicenter, randomized, single-dose, double-blind, placebo-controlled, pilot studies

Study 1: N= 53 

Study 2: N= 50 

Objective

To evaluate the safety and efficacy of XaraColl at different doses (100 mg and 200 mg of bupivacaine hydrochloride; study 1 and 2, respectively)

Study Groups

Study 1: Bupivacaine 100 mg (n= 24), placebo (n= 29) 

Study 2: Bupivacaine 200 mg (n= 25), placebo (n= 25) 

Inclusion Criteria

Male, age ≥ 18, generally healthy, scheduled for a unilateral inguinal hernioplasty by open laparotomy.

Exclusion Criteria

Bilateral inguinal hernioplasty requiring more than one incision, previous hernia repair on the same side, concomitant illness that would significantly increase surgical risk, concomitant illness with tratment agents that could affect the analgesic response (central alpha agents, neuroleptic agents, other antipsychotic agents, monoamine oxidase inhibitors, systemic corticosteroids).

Methods

Two bupivacaine (or placebo) implants were administered to each patient. Patients in study one received two, 50 mg doses for a total of 100 mg and patients in study two received two, 100 mg doses for a total dose of 200 mg.  Initial administration time was denoted as 'time 0' and patients were followed up through 72 hours for postoperative pain intensity and supplemental opioid use. 

Efficacy endpoints are defined and calculated as follows:

Summed pain intensity (SPI): trapezoidal area under the visual analog scale curve from one hour through to 24, 48, or 72 hours after time 0, regardless of the actual time the assessments were recorded.

Total use of opioid analgesia (TOpA): patients in the combined treatment groups were ranked according to their SPI value; mean rank was subtracted from each patient’s SPI rank and expressed as a percentage of the mean rank (“% difference”); this yields positive values for patients having a higher SPI than the median and negative pain scores for patients having a lower SPI.

Integrated endpoint of SPI and TOpA (I-SPI-TOpA): the percent differences derived for the SPI and TOpA were summed to generate the summated percent difference.

Duration

Study 1: March 2008 to January 2009 

Study 2: December 2010 to May 2011 

Outcome Measures

Mean SPI, Mean TOpA, I-SPI-TOpA, each at 24, 48, and 72 hour intervals

Baseline Characteristics

Mean age, years

White

Mean body mass index, kg/m²

Results

Mean SPI/mm • hour ± standard deviation

Mean TOpA/mg IV morphine equivalent ± standard deviation

 I-SPI-TOpA

Treatment

Placebo

p-Value

Treatment

Placebo

p-Value

p-Value

24 hours post time 0

Study 1

Study 2

Pooled

670 ± 401

996 ± 504

833

1191 ± 602

1270 ± 567

1231

<0.001

0.080

<0.001 

18.5 ± 12.6

20.6 ± 19.9

19.5

24.6 ± 15.3

36.9 ± 17.6

30.8

0.123

0.004

0.001

0.013

0.005

<0.0001 

48 hours post time 0

Study 1

Study 2

Pooled

1351 ± 857

2018 ± 1093

1684 

2130 ± 1288

2457 ± 1157

2293

0.012

0.178

0.006

30.6 ± 19.9

36.3 ± 34.7

33.4 

36.5 ± 25.5

56.4 ± 32.8

46.5

0.359

0.042

0.024 

0.097

0.039

0.008

72 hours post time 0

Study 1

Study 2

Pooled

1864 ± 1239

2842 ± 1722

2337 

2838 ± 1807

3485 ± 1807

3161

0.030

0.184

0.014 

37.2 ± 29.3

48.7 ± 46.1

42.9 

44.9 ± 35.0

70.8 ± 44.3

57.8 

0.3960

0.094

0.058 

0.136

0.078

0.021 

Adverse Events

Common Adverse Events:

Study 1: constipation, nausea, headache (occurred in ≥ 10% of patients)

Study 2: constipation, nausea, scrotal swelling, vomiting, dizziness, chills, pyrexia, and incision site infection (occurred in ≥ 5% of patients)

Serious Adverse Events:

Study 1: hypotension (n= 1, bupivacaine group), hiccups (n= 1, placebo group)

Study 2: none

Percentage that Discontinued due to Adverse Events: none

Study Author Conclusions

Through use of I-SPI-TOpA in addition to those traditional endpoints [SPI and TOpA], we have demonstrated that XaraColl, a perioperative bupivacaine-collagen implant, significantly reduces pain and use of opioid medication over at least 48 hours after hernioplasty, as based on two independent pilot studies performed at safe and well tolerated doses of bupivacaine. Furthermore, a pooled analysis of both studies indicates a statistically significant treatment effect over 72 hours after surgery. These findings suggest that XaraColl offers great potential for the management of postoperative pain and warrants definitive clinical trials with larger sample sizes.

InpharmD Researcher Critique

Values for TOpA in study 1 were not statistically significant at 24-, 48-, and 72-hour intervals; the authors suspected this was due to a patient dosing his medication per the maximum allowed amount rather than as needed for pain control. When looking at the pooled data sets, the significance of bupivacaine was more apparent versus looking at either individual study. 

A Randomized, Multicenter, Pilot Study Comparing the Efficacy and Safety of a Bupivacaine-Collagen Implant (XaraColl®) with the ON-Q PainBuster® Post-op Pain Relief System Following Open Gynecological Surgery

Design

Randomized, multicenter, pilot study

N= 27

Objective

To compare the efficacy and safety of XaraColl for the prevention of postsurgical pain versus a slow postoperative perfusion of bupivacaine to the wound environment via the ON-Q PainBuster^® Post-op Pain Relief System (ON-Q)

Study Groups

XaraColl^® (n=14)

ON-Q (n=13)

Inclusion Criteria

Women at least 18 years of age, generally healthy, scheduled to receive an elective total abdominal hysterectomy or other nonlaparoscopic gynecological procedure for reasons other than malignancy (e.g., adenocarcinoma, cervical cancer, or leiomyosarcoma) under general anesthesia.

Exclusion Criteria

Laparoscopic procedures, supraumbilical or Maylard incisions, or concomitant vaginal procedures (e.g., anterior and posterior colporrhaphy), any additional surgical procedures either related or unrelated to abdominal hysterectomy during the same hospitalization, neuraxial opioid analgesics during the surgery, use of an adhesion barrier, chronic painful conditions or other concomitant illness with agents that could affect the analgesic response (e.g., central alpha agents, neuroleptic agents, and other antipsychotic agents, monoamine oxidase inhibitors, or systemic corticosteroids), unreliable or incapable of complying with the requirements of the protocol. 

Methods

Eligible patients undergoing open gynecological surgery were randomized (1:1) to receive either three XaraColl implants (each containing 50 mg bupivacaine hydrochloride) or ON-Q (900 mg bupivacaine hydrochloride perfused over 72 hours). Following surgery, patients had access to intravenous (IV) morphine via a patient-controlled analgesia (PCA) pump as rescue analgesia for the first 24 hours and to oral opioid medication thereafter. 

Duration

September 2008 to December 2008

Outcome Measures

Primary: Total use of opioid analgesia through 24, 48, 72, and 96 hours after surgery.

Secondary: Time to first use of opioid rescue analgesia, patients' overall pain control over the 96-hour period using a five-point numeric rating scale, adverse events.

Baseline Characteristics

XaraColl^® 

(n=14)

ON-Q

(n=13)

Age, years

Mean (standard deviation [SD])

Median (minimum, maximum)

43.3 (11.5)

39.0 (28, 63)

43.4 (6.2)

41.0 (36, 59)

Race

Asian

Black or African American

White or Caucasian

1 (7.1%)

2 (14.3%)

11 (78.6%)

0 (0.0%)

5 (38.5%)

8 (61.5%)

Ethnicity

Hispanic or Latino

Not Hispanic or Latino

3 (21.4%)

11 (78.6%)

0 (0.0%)

13 (100.0%)

Weight, kg

Mean (SD)

Median (minimum, maximum)

71.7 (12.8)

77.0 (53.6, 90.5)

73.3 (11.0)

74.1 (56.4, 93.6) 

Height, cm

Mean (SD)

Median (minimum, maximum)

162.1 (6.4)

161.3 (150.0, 171.0)

160.2 (8.6)

162.6 (139.7, 175.0)

Body mass index, kg/m²

Mean (SD)

Median (minimum, maximum)

27.1 (3.8)

27.6 (21.4, 32.5)

28.7 (4.6)

29.0 (22.9, 37.0)

Surgical procedure performed

Abdominal hysterectomy

Myomectomy

Abdominal hysterectomy with right salpingo-oophorectomy

Right salpingo-oophorectomy (adnexal only)

10 (71.4%)

3 (21.4%)

1 (7.1%)

0 (0.0%)

11 (84.6%)

1 (7.7%)

0 (0.0%)

1 (7.7%)

Results

Treatment group

Non-inferiority and superiority statistics

The time to first use of opioid analgesia was significantly delayed in patients treated with XaraColl (p=0.024). Fifty percent of patients took their first opioid medication at 0.78 and 0.57 hours after time 0 in the XaraColl and ON-Q groups, respectively. 

Overall, there was no significant difference in the patients’ rating of pain control (p=0.847).

Adverse Events

Common Adverse Events: Constipation (14.3% XaraColl^® vs. 0.0% ON-Q), flatulence (14.3% vs. 0.0%), nausea (7.1% vs. 15.4%), pyrexia (7.1% vs. 15.4%), headache (14.3% vs. 7.7%), rash (14.3% vs. 0.0%)

Serious Adverse Events: 0%

Percentage that Discontinued due to Adverse Events: 0%

Study Author Conclusions

Despite using only 17% of the ON-Q dose, XaraColl is as effective as ON-Q in providing postoperative analgesia for 4 days after open gynecological surgery. These preliminary findings suggest that XaraColl offers great potential for the management of postoperative pain and warrants further definitive studies.

InpharmD Researcher Critique

This could be considered an underpowered hypothesis-generating pilot study. Participants and investigators were non-blinded due to fundamentally different treatment modalities. The principal efficacy endpoint was patient use of opioid analgesia which can be readily influenced by confounding factors such as patient attitudes and educations. 

Pharmacokinetics and Safety of INL-001 (Bupivacaine HCl) Implants Compared with Bupivacaine HCl Infiltration After Open Unilateral Inguinal Hernioplasty

Design

Multicenter, single-blind, pharmacokinetics and safety study

N= 52

Objective

Study Groups

INL-100 bupivacaine (n= 35)

0.25% bupivacaine HCl infiltration (n= 17)

Inclusion Criteria

Exclusion Criteria

Known hypersensitivity to amide local anesthetics, morphine, acetaminophen, or bovine products; scheduled for bilateral inguinal hernia repair or another concomitant surgical procedure; underwent major surgery within 3 months of initial treatment; planned laparotomy within 30-day postsurgical period; known history of alchohol/drug abuse within 3 years of screening; clinically significant unstable cardiac, neurologic, immunologic, renal, hepatic, hematologic disease, or any other significant condition.

Methods

Duration

Outcome Measures

Primary: pharmacokinetic assessment of INL-100 bupivacaine

Secondary: safety

Baseline Characteristics

INL-001 (n= 34)

0.25% Bupivacaine HCl infiltration (n= 17)

Age, years (SD)

Female

Male

1 (2.9%)

33 (97.1%)

0

16 (100%)

White

Non-hispanic or Latino

Hispanic or Latoni

27 (79.4%)

7 (20.6%)

13 (81.3%)

3 (18.8%)

Body mass index, kg/m² (SD)

27.4 (5.0)

27.8 (4.9)

Results

Endpoint

INL-001 (n= 34)

0.25% Bupivacaine HCl infiltration (n= 16)

Pharmacokinetic parameter

Median T_max, hours (min, max)

Mean t_1/2, hours (SD)

Mean C_max, ng/mL (SD; range)

AUC: time 0 to last quantifiable plasma concentration

AUC: time from 0 to infinity

3.0 (1.5, 24.0)

19.0 (5.9)

663.4 (263.8; 274 to 1230)

18,186.9

19,012.5

1.0 (0.5, 4.0)

9.1 (3.8)

641.0 (262.7; 275 to 1140)

8,836.9

8,920.1

Any treatment-emergent adverse events

Nervous system disorders

Somnolence

Dizziness

Tremor

Dysgeusia

Headache

26 (76.5%)

19 (55.9%)

12 (35.3%)

6 (17.6%)

4 (11.8%)

4 (11.8%)

13 (81.3%)

10 (62.5%)

7 (43.8%)

3 (18.8%)

4 (25.0%)

1 (6.3%)

Gastrointestinal disorders

Constipation

Oral hypoesthesia

Nausea

Oral paresthesia

12 (35.3%)

8 (23.5%)

3 (8.8%)

3 (8.8%)

3 (8.8%)

4 (25.0%)

1 (6.3%)

2 (12.5%)

2 (12.5%)

2 (12.5%)

Eye disorders

Vision blurred

10 (29.4%)

8 (23.5%)

3 (18.8%)

3 (18.8%)

Psychiatric disorders

Restlessness

Anxiety

7 (20.6%)

6 (17.6%)

2 (5.9%)

4 (25.0%)

2 (12.5%)

1 (6.3%)

Injury, poisoning, and procedural complications

Incision site complications

6 (17.6%)

3 (8.8%)

1 (6.3%)

0

Ear and labyrinth disorders

Tinnitus

3 (8.8%)

3 (8.8%)

1 (6.3%)

1 (6.3%)

Cardiac disorders

Bradycardia

2 (5.9%)

2 (5.9%)

2 (12.5%)

1 (6.3%)

Study Author Conclusions

These findings demonstrate that INL-001 provides immediate and extended delivery of bupivacaine and is well tolerated in patients undergoing open inguinal hernioplasty with no adverse effect on wound healing.

InpharmD Researcher Critique