Is there literature supporting Exparel in hemorrhoidectomy as being superior to other agents for post-surgical pain management? If not, what agent has optimal outcomes?

Comment by InpharmD Researcher

Clinical trials comparing liposomal bupivacaine (Exparel®) to bupivacaine HCl in colon and rectal surgeries have produced conflicting results regarding the reduction of postoperative pain scores and opioid use. Some studies (specific to hemorrhoidectomy) report a significant decrease, while others report no significant differences. While meta-analyses and systematic reviews have demonstrated that long-acting nerve block agents are effective for reducing post-hemorrhoidectomy pain, there yet remains a comprehensive comparison analysis between the commonly-used agents: ropivacaine, bupivacaine, and liposomal bupivacaine.

  

Pubmed: liposomal bupivacaine hemorrhoidectomy = 14 results

Background

A 2022 systematic review explored pharmacological and non-pharmacological interventions aimed at reducing post-hemorrhoidectomy pain. The review encompassed a total of 157 randomized controlled trials (RCTs) and 15 meta-analyses. A referenced 2020 meta-analysis of seven RCTs, which included 440 patients undergoing excisional hemorrhoidectomy (222 receiving local anesthesia plus intravenous sedation and 218 receiving spinal anesthesia), revealed that the combination of local anesthesia and intravenous sedation led to significantly lower pain scores at 6 hours and 24 hours after the operation. The mean difference in the numerical pain rating scale was -2.25 (95% confidence interval [CI] −3.26 to −1.24) and -0.87 (95% CI −1.33 to −0.40) at 6 hours and 24 hours, respectively. Additionally, local anesthesia combined with intravenous sedation was associated with a significantly reduced risk of requiring rescue analgesia (risk ratio [RR] 0.18; 95% CI 0.06 to 0.53), experiencing urinary retention (RR 0.17; 95% CI 0.07 to 0.37), and developing headaches (RR 0.09; 95% CI 0.03 to 0.33) compared to spinal anesthesia. [1], [2]

Similarly, another 2020 meta-analysis encompassing 9 RCTs (six comparing local anesthesia versus regional anesthesia and the remaining three comparing local anesthesia versus general anesthesia; N= 727) demonstrated that hemorrhoidectomy under local anesthesia resulted in a significant reduction in postoperative pain intensity and length of hospitalization compared to procedures performed under regional or general anesthesia. Local anesthetic methods employed in the studies included pudendal nerve block, ischiorectal block, perianal block, posterior perineal block, and local anesthetic infiltration into the wound. While most researchers favored long-acting drugs such as ropivacaine, bupivacaine, and liposomal bupivacaine as local anesthetic agents, no conclusive evidence was provided to determine which agent would yield the most optimal pain management outcome. Regarding spinal anesthesia, it is noteworthy that the addition of midazolam or morphine to bupivacaine in spinal anesthesia resulted in improved pain control during the first 12 to 24 hours following hemorrhoidectomy. [1], [2], [3]

A 2022 single-center retrospective cohort study evaluated the use of spinal saddle block anesthesia (SBA) technique in anorectal procedures. A total of 859 SBA patients were included, with a mean age of 44.6 years, American Society of Anesthesia score of 1.9, and 609 (70.9%) being male. Eligible patients undergoing benign anorectal procedures at an outpatient setting generally received SBA using a spinal needle (25-27 gauge) and a single injection technique of a 1:1 ratio local anesthetic mixed with 10% dextrose solution. Individuals received 2.5-5 mg of hyperbaric anesthetic intrathecally in the sitting position and remained upright for 3-10 minutes, which provided analgesia for approximately 1-3 hours. Specifically, hemorrhoidectomy represented 24.7% of overall surgical indications, and the most common local anesthetics injected into the perianal tissue included liposomal bupivacaine (40.2%), bupivacaine (39.6%), ropivacaine (8.9%), lidocaine (2.3%), and combination of local anesthetics (0.8%). Though direct comparisons among different anesthetic agents regarding their efficacy in postoperative pain control were not performed, and liposomal bupivacaine was analyzed along with regular bupivacaine, univariate analysis found a significant difference in adverse anesthetic events (3.1% for bupivacaine, 3.6% for ropivacaine, and 12.9% other spinal anesthetic, p= 0.047). Additionally, ropivacaine was associated with a significantly shorter recovery time when used within the spinal block (median minutes of recovery time of 96 [range 45 to 335] for bupivacaine, 87 [46 to 341] for ropivacaine, and 108 [45 to 226] for other anesthetics, p<0.01). While SBA has been shown to provide an effective method of analgesia to avoid general anesthesia with a low rate of adverse events, the specific role of liposomal bupivacaine in this setting compared to other agents on analgesic outcomes needs further evaluation. [4]

References:

[1] Lohsiriwat V, Jitmungngan R. Strategies to Reduce Post-Hemorrhoidectomy Pain: A Systematic Review. Medicina (Kaunas). 2022;58(3):418. Published 2022 Mar 12. doi:10.3390/medicina58030418
[2] Mohamedahmed AYY, Stonelake S, Mohammed SSS, et al. Haemorrhoidectomy under local anaesthesia versus spinal anaesthesia: a systematic review and meta-analysis. Int J Colorectal Dis. 2020;35(12):2171-2183. doi:10.1007/s00384-020-03733-5
[3] Xia W, MacFater HS, MacFater WS, et al. Local Anaesthesia Alone Versus Regional or General Anaesthesia in Excisional Haemorrhoidectomy: A Systematic Review and Meta-Analysis. World J Surg. 2020;44(9):3119-3129. doi:10.1007/s00268-020-05555-6
[4] ​​Peterson KJ, Dyrud P, Johnson C, et al. Saddle block anesthetic technique for benign outpatient anorectal surgery. Surgery. 2022;171(3):615-620. doi:10.1016/j.surg.2021.08.066
Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

Is there literature supporting Exparel in hemorrhoidectomy as being superior to other agents for post-surgical pain management? If not, what agent has optimal outcomes?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→


Please see Tables 1-4 for your response.

A Double-Blind, Randomized, Active-Controlled Study for Post-Hemorrhoidectomy Pain Management with Liposome Bupivacaine, a Novel Local Analgesic Formulation

Design

Double-blind, randomized, dose-finding study 

N= 100

Objective

To assess three dose levels of liposomal bupivacaine compared with bupivacaine HCl with respect to the extent and duration of analgesia as reflected in pain intensity scores and postsurgical consumption of opioid rescue medication, after single-dose administration via local infiltration in patients undergoing excisional hemorrhoidectomy. 

Study Groups

Liposomal bupivacaine 66 mg (n= 24)

Liposomal bupivacaine 199 mg (n= 25)

Liposomal bupivacaine 266 mg (n= 25)

Bupivacaine HCl (n= 26)

Inclusion criteria

Men and nonpregnant women ≥18 years of age with an American Society of Anesthesiologists (ASA) physical status classification of 1 to 3 scheduled to undergo 2- or 3-column excisional hemorrhoidectomy (with a cumulative incision length of ≥3 cm) under general anesthesia 

Exclusion criteria

Patients who weigh less than 50 kg, had clinically significant abnormal laboratory results, history of clinically significant medical conditions (including cardiovascular, hepatic, renal, neurologic, psychiatric, or metabolic disease; alcohol/substance abuse), previously taken a long-acting opioid within 3 days or any opioid within 24 hours before surgery

Methods

Participants were randomized to receive either liposomal bupivacaine 66 mg, liposomal bupivacaine 199 mg, liposomal bupivacaine 266, or bupivacaine HCl 75 mg with epinephrine. The study medication was administered in 5-mL increments via infiltrative moving needle technique in a fan-like fashion to the perianal tissues just outside the external sphincter. At the end of the surgery, patients also received a single 30 mg dose of intravenous ketorolac.

Duration

 Up to 96 hours after medication administration

Outcome Measures

 Pain intensity, rescue opioid medication, difference in cumulative pain score through 96 hours, median time to first use of postsurgical rescue opioid medication

Baseline Characteristics

  

Liposomal bupivacaine 66 mg (n= 24)

Liposomal bupivacaine 199 mg (n= 25)

Liposomal bupivacaine 266 mg (n= 25)

Bupivacaine HCl 75 mg (n= 26)

Age, years

  42 42 46 44

Male

 17 (71%) 16 (64%) 22 (88%) 15 (58%)

White

 21 (88%) 25 (100%) 24 (96%) 24 (92%)

Weight, kg

 85 77 82 80

ASA physical status

1-2

3-4

NR



18 (75%)

4 (17%)

2 (8%)



23 (92%)

2 (8%)

0



22 (88%)

2 (8%)

1 (4%)



19 (73%)

2 (8%)

5 (19%)

ASA=American Society of Anesthesiologists; NR=not reported

Results

 

  

Liposomal bupivacaine 66 mg (n= 24)

 Liposomal bupivacaine 199 mg (n= 25) Liposomal bupivacaine 266 mg (n= 25) Bupivacaine HCl 75 mg (n= 26)

95% confidence interval (CI) difference in cumulative pain score compared to bupivacaine HCl through 96 hours (p-Value)

 -302 to 11 (0.023) -363 to -52 (0.001) -373 to -60 (p< 0.001) --

Median time to first use of postsurgical rescue opioid medication, hours (range)

 9 (0.1 to 96.0) 11 (0.2 to 96.0) 19 (0.1 to 96.0)* 8 (0.3 to 96)

Data was primarily presented as a graph.

Pain intensity was significantly lower in the liposomal bupivacaine 199 mg and 266 mg groups compared with the bupivacaine HCl group through 72 hours after administration of study medication. The greatest between-group difference occurred in the liposomal bupivacaine 266 mg group compared with the bupivacaine HCl 75 mg group. Differences in cumulative pain scores remained statistically significant for the liposomal bupivacaine 199 mg and 266 mg groups compared with bupivacaine HCl through 96 hours.

A smaller proportion of patients in each of the three liposomal bupivacaine groups required rescue opioid medication
compared with the bupivacaine HCl group between 8 and 72 hours after surgery. The between-group differences did not reach statistical significance for any of the liposomal bupivacaine groups compared with bupivacaine HCl at any time point.

*p= 0.005 vs bupivacaine HCl

Adverse Events

Constipation (12.5% vs 20% vs 0% vs 15.4%), nausea (12.5% vs 16% vs 0% vs 11.5%), and vomiting (12.5% vs 12% vs 0% vs 11.5%)

Study Author Conclusions

Liposomal bupivacaine has the potential to offer important clinical advantages over bupivacaine HCl for pain relief in the setting of hemorrhoidectomy, including a longer duration of analgesia, less use of opioid analgesic medications, and fewer opioid-related adverse events. 

InpharmD Researcher Critique

Limitations include a relatively small sample size of healthy patients in each treatment group. Additionally, the age range of the patient population was limited to individuals between 21 to 69 years old, so the findings of the study may not be generalizable to very young or elderly patients. Another limitation is that the use of general anesthetic technique was not strictly standardized across all the participating centers in the study, which resulted in the use of prophylactic and rescue antiemetic drugs being left to the discretion of the investigator at each site.

 

References:

Haas E, Onel E, Miller H, Ragupathi M, White PF. A double-blind, randomized, active-controlled study for post-hemorrhoidectomy pain management with liposome bupivacaine, a novel local analgesic formulation. Am Surg. 2012;78(5):574-581. doi:10.1177/000313481207800540

 

Liposomal compared to 0.25% bupivacaine in patients undergoing hemorrhoidectomy: A pre- and post-implementation quality improvement evaluation

Design

Pre- and post-intervention quality improvement cohort evaluation

N= 94

Objective

 To evaluate the analgesic efficacy, patient satisfaction, and side effects of liposomal bupivacaine compared to bupivacaine during hemorrhoidectomy procedures. 

Study Groups

Bupivacaine 125 mg (n= 47)

Liposomal bupivacaine 266 mg (n= 47)

Inclusion Criteria

 Adult patients, undergoing hemorrhoid surgery, received 0.25% bupivacaine (Marcaine®) or liposomal bupivacaine (Exparel®)

Exclusion Criteria

 N/A

Methods

Patient data was collected and divided into 2 comparator arms depending on whether they received 0.25% bupivacaine between October 1, 2019 and June 17, 2020 or liposomal bupivacaine between June 23, 2020 and November 31, 2020.

Duration

 Data collection period: October 1, 2019 to November 31, 2020

Outcome Measures

Primary: frequency and dose of postoperative opioids in the post-anesthesia care unit (PACU), patient-reported pain scores (11-point numerical pain score from 0 [no pain] to 10 [worst pain imaginable])

Secondary: post-discharge refill requests for pain medication, opioid-related side effects, patient satisfaction with pain management on day 3, constipation, opioid prescription refill requests

Baseline Characteristics

  

Bupivacaine 125 mg (n= 47)

Liposomal bupivacaine 266 mg (n= 47)

p-value

Age, years

 53 49 Not significant

Male

 22 17 Not significant

Body mass index, kg/m2

 28.9 28.8 Not significant

American Society of Anesthesiology (ASA) score

 2 2 Not significant

Charlson Comorbdiity Scale

 0 0 Not significant

Preoperative opioid use

 3 5 Not significant

Preoperative adjunctive care

Acetaminophen

Gabapentin

 

35

32

 

46

45

 

< 0.01

< 0.01

Intraoperative adjunctive care

Midazolam

Fentanyl

Dexmedetomidine

Ketorolac

Methocarbamol

Dexamethasone

Ondansetron

 

38

29

11

9

16

20

31

 

38

36

8

11

13

21

35

 

Not significant

Not significant

Not significant

Not significant

Not significant

Not significant

Not significant

Results

Endpoint

Bupivacaine 125 mg (n= 47)

Liposomal bupivacaine 266 mg (n= 47)

p-Value

Recovery time, min (interquartile range [IQR])

80 (64 to 105)

67 (54 to 78)

0.01

Preoperative pain score (IQR)

First PACU pain score (IQR)

Peak PACU pain score (IQR)

Last PACU pain score (IQR)

0 (0 to 0)

0 (0 to 4)

3 (0 to 6)

2 (0 to 4)

0 (0 to 0)

0 (0 to 0)

0 (0 to 4)

0 (0 to 4)

0.69

0.02

0.03

0.09

Rescue opioids (PACU 1st dose)

Time to first opioid, min (IQR)

Oxycodone use

Hydromorphone use

1st rescue MME dose (IQR)

18 (38.3%)

45 (38 to 62)

9 (19.1%)

9 (19.1%)

10 (10 to 15)

12 (25.5%)

40 (34 to 49)

10 (21.2%)

2 (4.3%)

15 (15 to 15)

0.18

0.08

0.08

0.08

0.06

Total PACU opioid MME (IQR)

 15 (10 to 23) 15 (15 to 25) 0.39

Rescue anti-emetics in recovery

 2 (4.3%) 0 0.49

Opioid refill requested

 5 (10.6%) 6 (12.8%) 0.75

Pain control effective

 28 (76.1%) 26 (76.7%) 0.94

Reported constipation on day 3

8 (17.4%)

15 (34.1%)

0.07

Study Author Conclusions

 Liposomal bupivacaine compared to a bupivacaine perianal block reduces early PACU pain scores without affecting opioid refill requests, has a similarly low incidence of complications, and high satisfaction in both groups.

InpharmD Researcher Critique

 Limitations are characterized by a lack of randomization, potential management changes during the evaluation period, and the reliance on pre- and post-implementation data. Additionally, the study did not evaluate the details of post-discharge pain scores, and the actual number of tablets consumed may be less than prescribed in either group.



References:

Chitty L, Ridley B, Johnson B, Ibrahim M, Mongan PD, Hoefnagel AL. Liposomal compared to 0.25% bupivacaine in patients undergoing hemorrhoidectomy: A pre- and post-implementation quality improvement evaluation. J Clin Anesth. 2022;80:110868. doi:10.1016/j.jclinane.2022.110868

Liposomal Bupivacine Transversus Abdominis Plane Block Versus Epideural Analgesia in a Colon and Rectal Surgery Enhanced Recovery Pathway: A Randomized Clinical Trial 
Design

Randomized, open-label, single-center trial

N= 200

Objective

To compare liposomal bupivacaine transversus abdominis plane (TAP) block with epidural analgesia in patients undergoing colorectal surgery

Study Groups

Liposomal bupivacaine TAP block, 20 mL (133 mg) (n=99)

Epidural Analgesia, 0.0625% bupivacaine with fentanyl (n=101)

Inclusion criteria

Patients ≥ 18 years of age, undergoing elective colorectal surgery for benign and malignant colorectal disease

Exclusion criteria

Contraindications to epidural analgesia (spinal stenosis, spinal fusion, elevated international normalized ratio) or TAP block, history of chronic opioid use, urgent or emergent operations, systemic infections precluding epidural or TAP block options

Methods

Epidural catheters and liposomal TAP blocks were administered in the preoperative suite. Patients randomized to the epidural group were infused with 0.0625% bupivacaine with fentanyl was typically started toward the end of the operative procedure at 6 to 8 mL/h. Patient randomized to the TAP group were given 20 mL (133 mg) of liposomal bupivacaine in the fascial plane between the internal oblique and transversus abdominis in the midaxillary line and repeated on the contralateral side with ultrasound guidance.

No attempt was made to supplement the block with a subcostal oblique or rectus sheath approach. Anesthesia induction was typically done with 1 to 2 mg/kg propofol, 1 to 2 μg/kg fentanyl, and 1 to 2 mg/kg succinylcholine or 0.25 to 0.5 mg/kg rocuronium.

Duration

Follow-up: 4 to 7 days after discharge

Outcome Measures

Primary Outcomes: numeric pain scale (NPS) and validated overall benefit of analgesia score (OBAS) 

Secondary Outcomes: perioperative epidural, intravenous, and oral opioid requirements measured in intravenous morphine equivalents (mg), time to first flatus, time to first bowel movement, hospital length of stay, postoperative complications, 30-day readmissions, 30-day reoperations, and cost 

Baseline Characteristics

  

Epidural Analgesia (n= 87)

Liposomal bupivacaine TAP block (n= 92)

P-Value

Age, years

 62.06 ± 11.12 62.05 ± 11.79 0.999

Female

 34 (39.08%) 42 (45.65%) 0.461

White

 77 (89.53%) 85 (92.39%) 0.79
Previous abdominal surgery 30 (34.48%) 41 (44.57%) 0.22

Surgical approach

Laparoscopic colectomy

Laparoscopic converted

Open colectomy

Robot colectomy

Robot converted

Robot rectal resection

 

2 (2%)

4 (5%)

6 (7%)

65 (76%)

4 (5%)

5 (6%)

 

3 (3%)

4 (4%)

3 (3%)

61 (67%)

6 (7%)

12 (14%)

 0.473

Results

  

Epidural Analgesia (n= 101)

Liposomal bupivacaine TAP block (n= 99)

 P-Value

Mean pain score up to POD 3

 2.12 ± 1.44 2.32 ± 2.65 0.387

Mean OBAS score up to POD 3

0.48 ± 0.52

0.37 ± 0.31

 0.091

Total opioids up to POD 3, MME

Not including fentanyl from epidural

206.84 (173.73-246.25)

54.70 (46.33-64.58)

98.29 (86.70-111.43)

98.29 (86.70-111.43)

<0.001

<0.001

MME= morphine milligram equivalents

There were no significant differences in the Numeric Pain Scale and Overall Benefit of Analgesia Score between groups.

There were no statistically significant differences observed in time to first flatus, time to first bowel movement, hospital length of stay, postoperative complications, 30-day readmissions, and 30-day reoperations.

The average index hospitalization cost for the TAP population in this study was $581.16 compared to $838.05 for the epidural analgesia group. 

Adverse Events

None reported

Study Author Conclusions

Liposomal bupivacaine TAP blocks in an enhanced recovery pathway provide pain management equal to epidural analgesia but with significantly less opioid needs and cost, especially for patients undergoing minimally invasive surgery.

InpharmD Researcher Critique

 Limitations of this study include the single-center, open-label design, and possible variation between the comparison groups due to the technique differences. 

 

References:

Felling DR, Jackson MW, Ferraro J, et al. Liposomal Bupivacaine Transversus Abdominis Plane Block Versus Epidural Analgesia in a Colon and Rectal Surgery Enhanced Recovery Pathway: A Randomized Clinical Trial. Dis Colon Rectum. 2018;61(10):1196-1204. doi:10.1097/DCR.0000000000001211

Effectiveness of Liposomal Bupivacaine in Colorectal Surgery: A Pragmatic Nonsponsored Prospective Randomized Double Blinded Trial in a Community Hospital

Design

Randomized, double-blind, single-center, comparative trial

N= 57

Objective

To determine whether liposomal bupivacaine reduced the need for opioid analgesia as compared to standard bupivacaine following colon resection

Study Groups

Bupivacaine HCl (n= 30)

Liposomal bupivacaine (n= 27)

Inclusion criteria

Patients undergoing elective colon resection for any pathology at a single center

Exclusion criteria

Age <18 years, emergent cases, cases performed by non-colorectal surgeons, bupivacaine use within 96 hours prior to surgery

Methods

Patients were randomized to receive 20 mL of liposomal bupivacaine (266 mg) diluted in 10 mL of saline or 30 mL of 0.5% bupivacaine with epinephrine at completion of surgery. After completion of the procedure and facial closure, the attending surgeon left the operating room and subfascial peri-incisional injection of the local anesthetic was completed by the resident surgeon. 

As there were differences in appearance of the two drugs, the resident surgeons could not be blinded; however, the attending colorectal surgeon was not notified of the type of local anesthetic that would be used.

Duration

Follow-up: up to 17 days post-operative

Outcome Measures

Primary: use of opioid analgesia after surgery

Secondary: length of stay (LOS), need for administration of antiemetic medication, pain levels

Baseline Characteristics

  

Bupivacaine HCl (n= 30)

Liposomal bupivacaine (n= 27)

 P-value

Age, years

 67.9±11.2 66.2±15.7 0.85

Women

 15 (50%) 12 (44%) 0.68

ASA physical status

ASA class 2

ASA class 3

ASA class 4

 

9 (30%)

20 (67%)

1 (3%)

 

12 (44%)

14 (52%)

1 (3%)

 0.51

IV acetaminophen usage

 6 (20%) 12 (44%) 0.05

ASA=American Society of Anesthesiologists

Results

  

Bupivacaine HCl (n= 30)

Liposomal bupivacaine (n= 27)

P-value

Postoperative opioid use

IV hydromorphone in first 48 hours, mg

Total opioid use in the first 48 hours, hydromorphone-equivalent mg

Total opioid use in the first 7 days, hydromorphone-equivalent mg

 

11.3 ± 8.9

12.8 ± 8.7

25.1 ± 40.9

 

13.3 ± 11.9

15.0 ± 11.6

21.1 ± 20.2

 

0.58

0.54

0.64

Length of stay, days

 6.2 ± 12.2 4.1 ± 2.8 0.62

Antiemetic use

 14 (47%) 9 (33%) 0.62

Pain score

At post-op day 4

At post-op day 14

 

5.3 ± 1.8

2.8 ± 1.4

 

6.3 ± 2.0

3.2 ± 1.8

 

0.08

0.35

Adverse Events

 Not reported

Study Author Conclusions

Liposomal bupivacaine did not change the amount of opioid use postoperatively. Based on this study, liposomal bupivacaine does not provide any added benefit over conventional bupivacaine after colon resection.

InpharmD Researcher Critique

Limitations of this study revolve around the small sample size, which greatly limits the analysis of secondary outcomes. This study was also limited to efficacy of peri-incisional subfascial infiltration without use of transverse abdominis (TAP) block. Assessment of pain scores and oral analgesic use after discharge from the hospital were conducted at points after the surgery, allowing the possibility of recall bias.

 

References:

Knudson RA, Dunlavy PW, Franko J, Raman SR, Kraemer SR. Effectiveness of Liposomal Bupivacaine in Colorectal Surgery: A Pragmatic Nonsponsored Prospective Randomized Double Blinded Trial in a Community Hospital. Dis Colon Rectum. 2016;59(9):862-9.