Prospective Randomized Controlled Trial of an Enhanced Recovery Protocol for Anorectal Surgery
Phase: PHASE4
Conditions: Anorectal Disorder
Sponsor: Cedars-Sinai Medical Center

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PROSPECTIVE RANDOMIZED CONTROLLED STUDY 
OF AN ENHANCED RECOVERY PROTOCOL FOR 
ANORECTAL SURGERY 
 
 
Protocol Number: 
 
Version 5.0 (03 February 2020) 
 
 
Lead Investigator: 
 
Karen Zaghiyan, MD 
 
 
Division of Colorectal Surgery 
Cedars-Sinai Medical Center 
 
 
Co- Investigators:  
 
Phillip Fleshner, MD 
Division of Colorectal Surgery 
Cedars-Sinai Medical Center 
 
Aaron Parrish, MD  
Division of Colorectal Surgery 
Cedars-Sinai Medical Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol No./ Title: Prospective Randomized Controlled Study of an Enhanced Recovery Protocol 
for Anorectal Surgery 
Study Rationale: 
Anorectal surgery is primarily performed in an ambulatory setting (>90%) and 
has been shown to be safe and effective.1 
 
Postoperative pain control remains one of the largest impediments to excellent 
postoperative recovery. Mostly, pain is treated with opioids and these are his-
torically considered “safe” drugs as they do not impose an increased risk of 
bleeding, kidney, or stomach problems. However, many patients taking high 
dose opioids have a higher risk of constipation. In addition, rising concern over 
the opioid epidemic has piqued patients and provider interest in reduction of 
opioid use in the postoperative setting2 
 
Few studies exist regarding enhanced recovery after surgery (ERAS) in anorec-
tal surgery. Parrish et al. looked at an ERAS protocol for ambulatory anorectal 
surgery after a broad range of procedures in a retrospective analysis across mul-
tiple hospitals and found that given a 7 step ERAS protocol, patients had de-
creased postoperative pain and decreased returns to emergency care. However, 
there was low overall adherence to the protocol, significant variability across 
each patient’s care, and they did not look at postoperative pain after the patient 
left the hospital.3 
 
Toyonaga et al. showed that decreasing intravenous fluids (IVF) intraoperative-
ly, preoperative analgesia, and well-controlled postoperative pain can decrease 
postoperative urinary retention after anorectal surgery4 
 
Van Backer’s small randomized controlled trial (RCT) looked at preoperative 
analgesics and their effect on postoperative pain and found that there was sig-
nificantly less pain, and narcotic requirement in the immediate postoperative 
period.5 
 
To date, no prospective studies exists evaluating postoperative pain and narcot-
ic utilization in the postoperative period with multimodal ERAS pathway ver-
sus standard of care after anorectal surgery. 
 
We hypothesize that ERAS with a multimodal preoperative and postoperative 
pain management pathway can reduce narcotic utilization and pain during the 
first postoperative week after anorectal surgery. In this randomized clinical tri-
al, we will compare postoperative narcotic utilization, pain, complications, 
hospital readmission, and overall patient satisfaction after anorectal surgery.  
Study Population: 
80 patients undergoing either hemorrhoid or anal fistula surgery (up to 88 will 
be recruited as needed to account for any withdrawals). 

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Hypothesis: 
Multimodal ERAS pathway will result in decreased requirement of oral mor-
phine equivalents in the 1-week postop period (Arm 1) vs. anorectal surgery 
without ERAS pathway (Arm 2) 
 
Our secondary hypotheses are: 
 
The ERAS group will have decreased mean pain score and pain on defecation 
at 1 week postoperatively. There will be no significant difference in adverse 
events and analgesic related adverse events between the two groups. 
Study Design: 
Single center prospective randomized controlled trial performed in patients un-
dergoing elective hemorrhoid or anal fistula surgery.  
There will be 2 arms: Arm 1 will receive multimodal ERAS and Arm 2 anorec-
tal surgery without ERAS 
Arm1 (Multimodal ERAS):  
1) In preoperative care unit patients will be administered with a sip of wa-
ter oral gabapentin 600mg and oral acetaminophen 1,000mg 
2) Patients will be asked to void to empty their bladder in the 30 minutes 
prior to surgery 
3) Monitored anesthesia care will be the preferred anesthesia choice how-
ever, cases thought to benefit from general anesthesia will be allowed.  
4) Fluids will be minimized to < 500 ml during the operation and postop-
erative period 
5) Intraoperative: IV ketorolac 30mg will be administered by anesthesia 
6) Fentanyl IV will be administered in incremental doses of 25 mcg dur-
ing surgery based on anesthesiologist best judgment of pain response  
7) Perianal and bilateral pudendal nerve block using 30 ml total volume of 
0.25% bupivacaine with epinephrine 1:200,000 and dexamethasone 8 
mg  
8) Postoperative pain control: 
a. Gabapentin oral 300 mg qHS (#42, refill #1) 
b.  Acetaminophen oral 1000mg TID (#42, refill #1) 
c.  Ketorolac oral 10 mg TID (#15, refill #0)  
d. Oxycodone oral 5 mg PRN every 6 hours (#30, refill #0)  
9) Postoperative laxative regimen:  
a. Daily MiraLAX® 1 scoop in 1 glass of water for 15 days 
b. Daily milk of magnesia 1 tablespoon if no bowel movement by 
POD2 until regular bowel movements 
c. Daily mineral oil 1 table spoon if no bowel movement by 
POD2 until regular bowel movements 

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Arm 2 (Anal surgery without multimodal ERAS pathway):  
No preoperative pain medications will be administered 
1)   Monitored anesthesia care will be the preferred anesthesia choice how-
ever, cases thought to benefit from general anesthesia will be allowed.  
2)   Patients will be asked to void to empty their bladder in the 30 minutes 
prior to surgery 
3)  Fluids will be minimized to < 500 ml during the operation and postop-
erative period 
4)  Fentanyl IV will be administered in incremental doses of 25 mcg during 
surgery based on anesthesiologist best judgment of pain response  
5) Perianal and bilateral pudendal nerve block using 30 cc total volume of 
0.25% bupivacaine with epinephrine 1:200,000 
6) Postoperative pain control: 
a. Oxycodone oral 5 mg PRN every 6 hours (#30, refill #0) 
b. Patients will be allowed to take oral acetaminophen and ibu-
profen over the counter if needed but active narcotic-sparing 
pain management regimen will not be implemented 
7) Postoperative laxative regimen:  
c. Daily MiraLAX® 1 scoop in 1 glass of water for 15 days 
d. Daily milk of magnesia 1 tablespoon if no bowel movement by 
POD2 until regular bowel movements 
Daily mineral oil 1 table spoon if no bowel movement by POD 2 until regular 
bowel movements 
Randomization: 
Randomization will be performed via online randomization program: sealeden-
velope.com 
80 patients will be randomized in blocks of 4 and stratified by treatment (hem-
orrhoid or fistula surgery). NOTE: Up to 88 subjects may be recruited in order 
to account for any withdrawn subjects). 
Primary Endpoint: 
Total narcotic use in the 1-week period postoperatively in oral morphine equiv-
alents 
Secondary End-
points: 
1. Total narcotic use in the 1-week period postoperatively in oral morphine 
equivalents 
2. Postoperative pain score on arrival to postoperative care unit (PACU) and 
upon discharge from PACU  
3. Postoperative nausea 
4. Maximum daily pain score recorded by patient daily log (mean of days 1-7)  
5. Maximum daily pain score recorded by patient log (mean of days 8-14) 

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6. Mean pain on defecation score (days 1-7 and days 8-14) 
7. Urinary retention and urinary function as measured by the international 
prostate symptom score 
8. Presence of adverse events requiring return to emergency care (urinary re-
tention, pain, nausea, constipation, infection, bleeding) 
9. Adverse events possibly related to medication use assessed at 1 and 2-week 
postoperative visits (nausea, vomiting, dizziness, drowsiness, light headed-
ness, amnesia, tremor, shortness of breath, chest pain, or any other adverse 
event reported by patient) 
10. Time to first bowel movement 
Data collection and 
measurement of 
endpoints 
Patient demographics and preoperative characteristics will be collected from 
the patient medical record 
1) Patient identifiers: medical record number, date of birth 
2) Patient demographics; age at the time of surgery, gender, height and 
weight, race, ethnicity 
3) Prior anorectal surgical history 
4) Prior history of constipation and average standard interval between un-
assisted (if no laxative used) bowel movements 
5) Presence of comorbid disease 
6) Prior narcotic utilization and duration since last use 
7) American Society of Anesthesiologist (ASA) classification 
Preoperative baseline pain will be measured in the preoperative care unit using 
VAS pain scale (0-10; 10 being worst imaginable pain) 
Preoperative baseline nausea will be measured in the preoperative care unit us-
ing a scale 0-2, 0 (no nausea), 1 (Nausea without vomiting), 2 (active vomiting) 
Preoperative urinary function will be assessed using validated instrument (In-
ternational Prostate Symptom Score (I-PSS)  
Surgical characteristics 
1) Type of surgery performed 
2) Size of wound 
3) Estimated blood loss 
4) Type of anesthesia 
5) Total narcotic dose in morphine equivalents administered in the OR 
6) Volume of intravenous fluids administered 
Postoperative outcomes (PACU) 
1) Pain (VAS) score on arrival and discharge from PACU 
2) Nausea score (0-2) on arrival and discharge from PACU 

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3) Volume of PACU intravenous fluids administered 
4) Narcotic dose (morphine equivalents) administered in PACU 
5) Ability to void prior to discharge home  
6) Any patient reported adverse events  
Postoperative outcomes  
1) Total narcotic utilization in the 1-week postoperative period will be 
calculated in oral morphine equivalents by asking the patient to bring 
in their pills for measurement of total used at their 1-week postopera-
tive visits 
2) Compliance with additional pain medications used will be performed in 
a similar fashion at 1 week 
3) Compliance with laxative regimen will be assessed at 1-week postop-
erative visits 
4) Patients assigned to standard of care will be asked if they used any ad-
ditional over the counter medications 
5) Any new prescriptions prescribed in the 1-week postoperative period 
will be recorded 
6) Any refills on prescription medications will be recorded 
7) Patient reported pain and nausea at the first 1-week postop period will 
be collected by asking the patient to fill out a pain and nausea daily log 
for the first 1-week postoperative period and bring the log to their 1 
week and 1-week postop visits  
8) A pain at defecation questionnaire will also be collected for 1 week af-
ter surgery and patients will be asked to bring this to their postop visit 
at 1 week. 
9) The patient will be asked to log the day of their first postoperative 
bowel movement 
10) A study investigator will assess the patient’s postoperative urinary 
function (I-PSS) modified to include the previous 24 hours and previ-
ous week on POD 1 and 7 respectively 
11) At 1-month postoperative visit, any additional adverse events or com-
plications, urgent care, emergency department visits or hospital admis-
sions will be collected 
Subgroup Analy-
sis: 
Subgroup analysis will be performed for the following patient groups: 
1. Patients undergoing hemorrhoid surgery 
2. Patients undergoing anal fistula surgery 
Safety Endpoints:  
Number of adverse events related to gabapentin, acetaminophen, dexame-
thasone 

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Sample size: 
With a sample size of 17 patients per arm for a total of 34 patients, this study 
will have 80% power to detect a statistically significant difference between the 
standard of care and multimodal ERAS assuming a mean oral morphine 
equivalent requirement of 60mg (SD 30mg) in the first postoperative week for 
the standard of care group, a 50% reduction total oral morphine equivalent re-
quirement for the ERAS group to 30mg, with alpha less than 0.05. Due to lack 
of normality we will increase each group to 20 patients. 
 
In order to have enough power to analyze hemorrhoid surgery and anal fistula 
surgery patients separately in our subgroup analysis, we plan to include 80 pa-
tients total in our analysis with stratified randomization based on type of sur-
gery.  
 
To allow for dropouts, 4 additional patients will be recruited per arm for a total 
of 88 patients.  
Interim analysis: 
An interim safety analysis will be performed at 50% subject accrual.  
Key Inclusion  
Criteria: 
1. Able to freely give written informed consent to participate in the study and 
have signed the Informed Consent Form; 
2. Males or females, age 18 to 70 years old at the time of study screening; 
3. American Society of Anesthesiologists (ASA) Class I-III (Appendix III) un-
dergoing elective anorectal surgery 
4. Patients undergoing the following hemorrhoid surgeries will be included: 
a. Excisional single column or multiple column hemorrhoidectomy in-
cluding internal and external component 
b. Stapled hemorrhoidpexy (aka procedure for prolapsed hemorrhoids 
with or without excision of external hemorrhoid or skin tag) 
c. Trans anal hemorrhoidal dearterialization with mucopexy (THD) 
with or without excision of external hemorrhoid or skin tag 
5. Patients undergoing the following anal fistula surgery will be included: 
a. Anal fistulotomy or fistulectomy of intersphincteric or transphincter-
ic fistula with wound > 1 cm  
b. Endorectal or anocutaneous advancement flap for anal fistula repair 
c. Ligation of intersphincteric fistula tract (LIFT) 

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Key Exclusion  
Criteria: 
1. Unable or unwilling to provide informed consent or comply with study pro-
cedures 
2. American Society of Anesthesiologists (ASA) Class IV or V; emergency 
surgeries 
3. Children <18  
4. Patients over age 70 due to small risk of altered mental status with gabapen-
tin in elderly6 
5. Patients with impaired renal clearance (baseline creatinine 1.5mg/dL, creati-
nine clearance < 60ml/min or known renal dysfunction) 
6. Patients with known liver dysfunction (Childs class A, B, or C)   
7. Patients with prior liver or kidney transplant 
8. Pregnant patients 
9.Patients requiring emergency surgery 
10. Patients taking narcotics or steroids at the time of surgery  
11. Patients having external hemorrhoidectomy or skin anal tag excision only  
12. Patients having anal abscess drainage, seton placement without definitive 
fistula repair, subcutaneous fistulotomy or fistulotomy with wound <1 cm 
Treatment Dura-
tion and proce-
dures: 
• 
Screening: Patients will be screened and enrolled in the study after re-
view of their, demographics, medical history and physical exam. 
• 
Day of Surgery: Patients will be randomized to either of the 2 study 
arms: Arm1 (Anal Surgery with multimodal ERAS), or Arm2 (Anal 
surgery without multimodal ERAS pathway).  
• 
Follow-Up Clinic Visit (7 days) from surgery will be scheduled per 
standard of care.  
• 
Follow-Up Clinic Visit (30 days) from surgery will be scheduled per 
standard of care.  
Patients will be followed during the 1-month postoperative period. At their pre-
operative, 1 week, 2 week, and 30-day postoperative visits they will answer a 
subjective questionnaire.  
The preoperative questionnaire (Appendix B) will include any pain meds they 
currently use, average bowel movements per week, any baseline anorectal pain, 
presence of nausea, and IPSS,  
The postoperative PACU questionnaire (Appendix C) will include Pain (VAS) 
score post-surgery to discharge from PACU. Nausea score (0-2) post-surgery to 
discharge from PACU. Volume of PACU intravenous fluids administered. Nar-
cotic dose (morphine equivalents) administered in PACU. Ability to void prior 
to discharge home, and any patient reported adverse events. 
The postoperative questionnaire (Appendix D) will include questions regarding 
medication taken for pain, nausea, and any meds not directly given postopera-
tively for pain. Adverse effects of any of the medications taken will be record-

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ed. Any prolonged urinary retention requiring return to emergency care. Con-
stipation requiring a secondary agent (laxative other than the first line). Overall 
satisfaction with their care (0-10). 
They will then be followed up for 30-days after surgery and any complications 
occurring during that study period will be recorded. Any visits to the outpatient 
service, urgent care, or emergency department of issues relating to the surgery 
or medications, Any admissions to the hospital for related issues  
Patient participation in this study will end after 1 month.  
Treatment Failure/ 
Discontinuation 
Criteria: 
Patients will be discontinued from the trial at any time as a result of any other 
event (e.g., treatment-emergent serious adverse event, surgery) that in the opin-
ion of the investigator warrants discontinuation from the trial. 
These include: 
• 
Drug allergy 
• 
Evidence of AKI, Bleeding, or other adverse events from the drugs. These 
events would be recorded but the patient would not be included in the 
postop pain analysis. 
• 
Patients with significant postoperative pain in the control group that is not 
adequately controlled with opioids and require additional pain medications. 
This would be recorded but the patient would be disqualified from the 
analysis 
• 
Any patient requiring an additional procedure during the study period  
 
 
 
 
 
 
 
 
 
 

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References 
 
1. Smith LE. Ambulatory surgery for anorectal diseases: an update. 
1986. South Med J 79:163–166 
 
2. Tan WH et al. Opioid medication use in the surgical patient: an 
assessment of prescribing patterns and use in the surgical patient. 
JACS 2018;epub ahead of print 
 
3. Parrish et al. An Enhanced Recovery After Surgery (ERAS) Pro-
tocol for Ambulatory Anorectal Surgery Reduced Postoperative 
Pain and Unplanned Returns to Care After Discharge. World J 
Surg (2018) 42:1929–1938) 
 
4. Toyonaga. Postoperative urinary retention after surgery for benign 
anorectal disease: potential risk factors and strategy for preven-
tion. Int J Colorectal Dis. 2006 Oct;21(7):676-82) 
 
5. van Backer et al. Preemptive Analgesia Decreases Pain Following 
Anorectal Surgery: A Prospective, Randomized, Double-Blinded, 
Placebo-Controlled Trial. Dis Colon Rectum 2018; 61: 00-00) 
 
6. Fleet JL et al. Gabapentin dose and the 30-day risk of altered men-
tal status in older adults: a retrospective population-based study. 
PLoS One.2018;13:e0193134