Clinical trial NCT03769714
Conditions: Pain
Keywords: laparoscopy supracervical hysterectomy Multimodal pain management bupivacaine liposome Exparel
Sponsor: Maimonides Medical Center
Start date: 2018-10-01; Completion date: 2019-06-30
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The aim of the of the study is a reduction in minimally invasive supracervical hysterectomy postsurgical pain, which may result in less need for supplemental opioid pain medications, fewer opioid related adverse events, and a better recovery experience for patients, which may offer an economic benefit to health care systems.

Intracervical preoperative dose of Exparel during minimally invasive (robotic--assisted or traditional laparoscopy) supracervical hysterectomy reduces cumulative pain scores for up to 24 hours and reduces overall requests for break through (additional) analgesia with opioid consumption compared with placebo.

Detailed description:
Exparel is a local analgesic that utilizes bupivacaine in combination with the proven product delivery platform, DepoFoam®. Exparel (bupivacaine liposome injectable suspension) is a liposome injection of bupivacaine, an amide-type local anesthetic, indicated (bupivacaine liposome injectable suspension) for administration into the surgical site to produce postsurgical analgesia. Liposomal drug- containing formulations can provide for controlled drug release over an extended period of time.

The overall length of hospital stay (LOS) for patients undergoing laparoscopic (robot- assisted or traditional laparoscopy) supracervical hysterectomy varies widely in published reports; typical durations range between 0 days and 4 days.

That is because in recent years there has been a trend toward use of enhanced or "fast- track" discharge protocols to reduce LOS in patients undergoing this procedure, predicated primarily on reducing the time to achieve tolerance of oral liquid/food intake and improved GI function. Most patients experience moderate to extreme pain after surgery and effective postsurgical pain management is a key factor affecting patient recovery. Multimodal analgesia techniques involving analgesics, such as local anesthetics, oral or parenteral nonsteroidal anti-inflammatory medications, and oral or parenteral opioids, are recommended as the safest and effective approach to postsurgical pain control. Local anesthetics administered during surgery are frequently used as part of multimodal analgesic regimens; however, the duration of analgesia with these agents is short (12 hours). Bupivacaine has a long history of use in the surgical setting, and the efficacy of bupivacaine HCl administered perioperatively via wound infiltration or acute postsurgical pain is well established. A novel formulation of bupivacaine, ie, liposome bupivacaine (Pacira Pharmaceuticals, Inc., Parsippany, NJ), has been developed to address the need for longer-acting local anesthetics that can be administered as a single dose. The question becomes whether this drug is effective for postsurgical analgesia if given preoperatively via the intracervical stroma during minimally invasive gynecologic surgical procedures, specifically laparoscopic (robot--assisted or traditional laparoscopy) supracervical hysterectomy.

Paracervical/intracervical injections are used for cervical/uterine manipulation in various obstetrical and gynecological procedures. Lukas et al used the intracervical/paracervical block prior to hysteroscopic polypectomy, with good pain scores following the procedure and no serious adverse effects were noted. In addition, Chauan et al also noted good pain control with intracervical injection with lidocaine in patients undergoing a hysterosalpingography, which involves distended the uterus and injecting dye. Mankowshi et al also studied both intracervical and paracervical injections of lidocaine for first trimester suction curettage and found no difference between the two forms ensuring that both effective means of analgesia.

In the U.S., surgical site infections (SSI) affect 1 in 24 patients that undergo inpatient surgery. Most surgical site infection take place after day 5 , which will be out of the scope of timeframe for conduct of the survey. However a SSI can make the differentiation of pain from the surgery itself and pain from a complication of surgery difficulty to differentiate. The patient will be asked to specify where the pain is and ask if they have any associated vaginal discharge, foul smelling odor, and difficulty urinating and or passing a bowel movement. These responses will be tracked, and if the participant shows signs of a SSI, the patients may warrant a closer followup in the office and or asked to go directly to the Emergency Department (ED). The patients will still be included in the study but special note will be made of how many participant had SSI in the discussion portion.

Methods:

Randomized double blind placebo controlled pilot study. After IRB approval, 52 subjects will be consented to participate in the study. The study includes subjects undergoing minimally invasive (robot--assisted or traditional laparoscopy) supracervical hysterectomy under general anesthesia. This study will include women (35 - 75 years) who have American Congress of Obstetricians and Gynecologists (ACOG) and American Association of Gynecologic Laparoscopists (AAGL) physical classification status for a minimally invasive (robotic- assisted or traditional laparoscopy)supracervical hysterectomy.

Randomization will be done prior to recruitment of patient via computer software. There will be two groups with numbers 1-52, no numbers will be repeated. Each patient that is recruited will be assigned a number from 1-52 (in sequential order); the master list will be kept with the pharmacy director. Group A (control, n=26) to receive 20ml of saline while Group B (study, n=26) to receive 20ml of liposomal bupivacaine (EXPAREL) into the stroma of the cervix at the 4 and 8 o'clock positions (innervation insertion points of the cervix).

The MMC Pharmacy will prepare an individualized numbered bubble wrapped amber package accordingly to the randomization. It will be prepared prior to the recruitment and kept in the fridge in 4th floor PACU pharmacy. After the patient is consented and given a subject number, the package with the corresponding number will be picked up from the pharmacy and given to either the resident/attending (not involved in the study) who will share the contents of the package with the anesthesia team. While prepping, the same individual will inject the contents. The syringe will covered as to disguise the contents of the syringe.

The investigators will show a short video on how to prepare the Exparel as well the injection component in order to diminish the differences between the individuals.

Measurements:

The severity of pain will be assessed preoperatively in the holding area, PACU arrival, 12, 24, and 48 hours postoperatively using a numeric rating scale (NRS) at rest for pain with 0 = no pain and 10 = worst possible pain. Pain inquiries will assess low pelvic/suprapubic area and lower abdominal pain, type of pain (dull, achy, sharp, stabbing, etc.) and radiation of pain to a surrounding area. Other endpoints will include number of patients who required break through (additional) opioid analgesic medications, median time to first break through opioid use, total opioid analgesic requirement. The time, day and number of requests for break through (additional) analgesia will be noted by gynecologic surgery team (Resident or Fellow) participating in this study.

When the patient is home the patient will have a Pain Medication Diary that the investigators will provide for the patient prior to discharge. The patient will bring at the post-operative visit and or mail it in.

Arms: arm 1: Group A (control, n=26) to receive 20ml of saline while prepping. The syringe will covered as to disguise the contents of the syringe. arm 2: Group B (study, n=26) to receive 20ml of liposomal bupivacaine (EXPAREL) into the stroma of the cervix at the 4 and 8 o'clock positions (innervation insertion points of the cervix).
Interventions: intervention 1: Saline Solution for Injection intervention 2: Exparel
Intervention descriptions: intervention 1: Injection of 20mL of 0.9%Normal Saline intervention 2: Exparel (bupivacaine liposome injectable suspension) is a liposome injection of bupivacaine, an amide-type local anesthetic, indicated (bupivacaine liposome injectable suspension) for administration into the surgical site to produce postsurgical analgesia.

Protocol documents:
Prot_000.pdf: 
 
 
 
TITLE:  
A Placebo-controlled, Double-blinded, Randomized Pilot Study of Bupivacaine Liposome 
Injectable Suspension (EXPAREL) for Minimally Invasive Supracervical Hysterectomies 
Postsurgical Analgesia   
 
 
 
Unique Protocol ID: 2018-0-12 
 
 
Document Date:  December 12, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Description  
All patients who are scheduled for a robot-assisted or traditional laparascopic supracervical 
hysterectomy will be identified in the beginning of the week (Sunday) through the OR scheduler.  
All patients go to pre-admission testing, where they meet with a nursing staff who will coordinate 
their blood work and take a history.  The co-investigators will be able to prescreen them in this 
fashion and on the day of the surgery confirm that they are eligible for the study.  
After obtaining informed consent, participants will be assigned to the intervention or placebo group 
randomly. Randomization will be performed based computer-based random number generator 
(www.randomizer.org) which would generate two sets of random numbers containing 26 numbers 
from 1 to 52 with each number in a set remaining unique, which will be given to the pharmacy 
assistant director. The master list will be only accessible by pharmacy personnel. Hospital pharmacy 
staff will prepare the numbered package of either Exparel or normal saline (based on the 
randomization) in bubbled wrapped amber bag that will be given to the resident/attending who will 
proceed to inject the given medication during the prepping. Unlike normal saline which will be used 
as placebo, EXPAREL is milky in color, therefore to ensure adequate blinding of study investigators 
and surgeons an independent resident will unpack the package prior to the surgery and administer it 
to the patient in the absence of study investigators and surgeons during the prepping. All OB-GYN 
residents will be instructed about the proper injection procedure prior to the start of the study. All 
resident are equally capable, however senior residents (PGY3/PGY4) are assigned to do 
hysterectomies ( a total of 12 residents). We expect performance bias but will rehearse with a model 
cervix in the simulation lab in order to diminish it. Only the pharmacy staff and independent 
residents will have access to the random generated list; all other staff including the investigators, 
surgeons, anesthesiologists, and nurses as well as patients will be kept blinded to the assigned 
treatments.  
Subjects in the intervention arm will receive paracervical block with 20 ml of extended-release 
liposomal bupivacaine (EXPAREL) at the 4 and 8o’clock positions. Subjects in the placebo arm will 
receive paracervical/intracervical block with 20 ml of saline at the 4 and 8 o’clock positions.  In 
both study arms the injection will be administered preoperatively.  
Post operative pain management will be the same for both study groups. Immediately after surgery 
in the recovery room they will be able to receive ketorolac 30mgIV and/or acetominophen 1000mg 
IV, and if needed narcotics (as requested by the patient).  This will all be recorded in the anesthesia 
record which is accessible to the co-investigators. Robot-assisted and traditional laparoscopic 
supracervical hysterectomy are ambulatory cases and we expect same day discharge. At home or in 
the hospital, all study participants will have oral acetaminophen 650mg q4-6 hr and NSAIDS 600mg 
q4-6 hours, as needed. If needed they will also have percocet 5-325mg q4-6 hours, the first dose of 
which will be recorded as the median time to narcotics.   
Post operative pain management for both groups will include a combination of oral or parenteral 
nonsteroidal anti-inflammatory medications, and oral or parenteral opioids to be used as needed. 
Since most patients who undergo minimally invasive hysterectomy are discharged few hours after 
the surgery, data regarding the time, type and dose of postoperative analgesics used by the patient 
will be collected by providing the patient with a pain diary before discharge. Patient will be 
instructed to record use of any analgesics (including NSAIDS) for 72 hours whether the analgesic 
was prescribed by the surgeon or was taken at patient's own discretion. These data regarding the 
time, number and type of breakthrough analgesia will be used for evaluation of median time to first 


break through opioid use and total opioid analgesic requirement. 
The severity of pain will be assessed preoperatively in the holding area, at the time of PACU arrival, 
and at 12, 24, and 48 hours postoperatively using a numeric rating scale (NRS) from 0 to 10 with 10 
being the worst pain the patient has ever experienced. The first two assessments will be performed 
in the hospital by the principal investigators and the remaining assessments will happen through a 
phone conversation with the patient after discharge from hospital. The NRS has been found to be a 
simple and valid alternative to the visual analog scale, and has been validated by Paice and Cohen in 
1997. Based on this study which examined the validity of a verbally administered NRS using 
convergence methods, the correlation between the VAS and the NRS was strong and statistically 
significant (r = 0.847, p < 0.001), supporting the validity of the verbally administered NRS. Type of 
pain (characterized as sharp, dull, stabbing, aching), location of pain (categorized as right upper 
quadrant, epigastric, left upper quadrant, right lumbar, umbilical, left lumbar, right iliac, hypogastric, 
left iliac ) and radiation of pain will also be evaluated and recorded. 
Based on the available evidence EXPAREL's adverse effects includes QT interval prolongation.  
The long QT prolongation syndrome usually does not manifest in any symptoms however one 
reported symptom is fainting, and if left persistent can lead to seizure activity and or death. To 
assess the incidence and severity of adverse events, patients’ heart activity will be monitored during 
the surgery and any abnormal findings in the electrocardiogram pattern will be recorded. 
Additionally, before patient's discharge from hospital, the investigator will seek information on 
adverse event of the intervention by specific questioning and, as appropriate, by examination. 
Questions will include, do you feel faint and/or dizzy, do you have difficulty breathing. Information 
on all adverse events will be recorded immediately and the clinical course of each event will be 
followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause. Any adverse event that occurs after patient discharge and is considered 
to be possibly related to the study intervention will also be recorded. Adverse events can include re-
admission, signs and symptoms of infection, and bleeding.   
The Data Safety and Monitoring Board (DSMB) will include 3 doctors, who are independent of the 
study. Members of DSMB will meet every 2 months at Maimonides hospital to carry out a regular 
assessment of the number and type of serious adverse events. They will report their findings or 
recommendations to the principal investigator and representatives from Maimonides Institutional 
Review Board (IRB). The DSMB will recommend whether to continue the study or stop it early 
considering the objectives of the study and subjects safety.