Despite advances in pain medicine, postoperative pain control remains problematic with over 5% of patients undergoing ambulatory surgery experiencing severe pain despite standard-of-care pain management. Pain is a frequently cited reason for delayed discharge following outpatient procedures.1 In anorectal surgery (ARS), almost all patients experience mild-to-moderate postoperative subjective pain,2 with 12% of patients reporting severe postoperative pain during their recovery.3 Preemptive analgesia (PEA) is a technique that involves premedicating patients with a regimen designed to target different points in the pain cascade with the goal of preventing central and peripheral sensitization to pain, also known as “windup.”4
Most pain control studies in the literature focus on postoperative rather than preemptive medication regimens for pain management, and there is no current standard of care recommending an effective regimen.5 , 6 This approach has not been well studied in the ARS patient population. To the best of our knowledge, this has only been addressed by Poylin et al,7 who demonstrated that perioperative gabapentin use is a cost-effective way to decrease posthemorrhoidectomy pain. Decreasing pain and opioid use for ARS is especially important because of the addictive and constipating effects of narcotics.
The purpose of this study is to evaluate the role of PEA in ARS. We hypothesize that there will be a statistically significant decrease in the amount of pain patients experience at predefined intervals and that those in the intervention group will require less narcotic pain management, therefore leading to fewer narcotic-related side effects.
MATERIALS AND METHODS
The Research Foundation of the American Society of Colon and Rectal Surgeons Eugene Salvati Grant funded this study and received interim progress reports. It is a single-center, prospective, randomized, double-blind, placebo-controlled trial designed to evaluate the primary outcome of changes in postoperative pain with PEA compared with those not receiving PEA. The study also assessed the following secondary outcomes: postoperative consumption of narcotic pain medication and narcotic-induced side effects. The University of Vermont Institutional Review Board approved of the protocol used in this study (CHRMS 13–226).
All patients seen at the University of Vermont Medical Center’s General Surgery Clinic in Burlington, VT, between June 2014 and April 2017, who presented with anal fistulas, anal fissures, hemorrhoids, or anal condyloma, were screened for participation in the study. All patients who were over 18 years of age undergoing surgery and had an ASA Physical Status Classification Score of I, II, or III were offered admission to the study by the study coordinator, with the exception of patients allergic to the study medications, taking chronic steroids, gabapentin/pregabalin, or narcotics, or experiencing chronic pain or hepatic or renal failure, or were currently pregnant.
After providing written informed consent, patients were randomly assigned to either the active or control group by using an en bloc randomization design, stratified by type of surgery to minimize intergroup variation of type of surgery. The statistician randomly assigned patients by using the SAS procedure PLAN (SAS Institute Inc, Cary, NC) with block sizes of 4. To ensure blinding of the patient, surgeons, and perioperative nursing staff, the statistician provided group assignment for the next patient to be enrolled to the study coordinator, and the study coordinator disclosed the group assignment only to the pharmacist and anesthesia staff. In addition, only the statistician knew that blocks of 4 were used within strata.
In the preoperative unit, patients rated their pain on a numerical rating scale (0–10) and answered screening questions to ensure that the patient had not taken any medications that would preclude them from participating in the study. Participants randomly assigned to the active group were given 1000 mg of acetaminophen and 600 mg of gabapentin, and those in the control group were given look-alike sugar placebos within 1 hour of the procedure. In the operating room, the nonblinded anesthesia team administered a bolus of 0.15 mg/kg ketamine and 8 mg of dexamethasone before the incision to the active group, but no additional medications to the control group, as outlined in Figure 1.
Surgical procedures were performed as indicated under conscious sedation utilizing combinations of propofol, midazolam, and fentanyl. The monitored anesthesia sedation was similar between the 2 groups with the exception of the low-dose ketamine in the active group. Standard perianal and inferior hemorrhoidal nerve blocks using a 50/50 mixture of 0.5% bupivacaine and 1% lidocaine with epinephrine were performed in all cases. Local anesthesia was supplemented as needed in the perianal region.
In the postanesthesia care unit (PACU), the nurse administered the first numerical rating scale and filled out the pertinent parts of the medication diary. Patients were discharged with a packet containing numerical scales and medication diaries to be filled out at 8 hours, 24 hours, 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, and 168 hours postoperatively. Following the 168-hour period, a side effects questionnaire was completed.
After surgery, patients were given instructions to alternate 1000 mg of acetaminophen and 600 mg of ibuprofen every 3 hours on a scheduled basis with 2 mg of hydromorphone for breakthrough pain every 3 hours as needed. To remind patients to complete their forms, a research associate called 8 hours after surgery and then Televox (Mobile, AL), an automated phone system, called patients at each time point.
Sample size estimates were based on detecting a 20% difference in pain rating between groups, which we judged to be a clinically meaningful difference. Conservatively using the largest standard deviation reported on the numerical rating scale for postoperative pain ratings in studies of PEA, the initial sample size calculation indicated that 37 participants per group would provide 80% power to detect a 20% difference, with a 2-sided type I error rate = 0.05. Sample size was reexamined using the observed standard deviation following enrollment of the first 20 patients, with the finding that 80% power to detect a 20% difference would be obtained with 30 participants per group. This was also found based on the standard deviation after enrollment of 40 patients, so 30 patients per group was used as the final target sample size.
The numerical rating scale was completed by the patient to rate his or her pain. The mean pain level from both study groups was compared using a nonparametric Wilcoxon rank-sum test. In addition, pain ratings were compared across all time points via a repeated-measures, mixed-model analysis, which uses all available data from each patient at each time point. The secondary outcomes were obtained from the Medication Diary forms. The percentage of patients utilizing breakthrough narcotic and narcotic-related side effects was evaluated via the Fisher exact test. A subgroup analysis was performed for patients undergoing hemorrhoidectomies, examining the mean pain level, narcotic pain medication requirement, and reported symptoms between the 2 groups utilizing the same statistical tests. The full protocol is available on request.
The goal accrual of 90 patients were enrolled between June 2014 and April 2017 with 61 patients completing the study and available for analysis (Table 1). Twenty-nine patients were excluded from the study because of patient withdrawal, canceled surgery, need for general anesthesia, and prior narcotic usage. There were 30 patients in the active group, with 13 fistulotomies, 8 hemorrhoidectomies, 6 lateral internal sphincterotomies, and 3 excision and fulguration of anal condyloma. There were 31 patients in the control group, which included 14 fistulotomies, 9 hemorrhoidectomies, 5 lateral internal sphincterotomies, and 3 anal condyloma excision and fulguration procedures.
Pain was first evaluated just before discharge from the PACU. Active group patients rated their pain at a mean level of 0.8 (interquartile range (IQR), 0–1) compared with the control group’s average of 1.6 (IQR, 0–2). The difference was statistically significant (p = 0.02). Similarly, at 8 hours following surgery, pain scores were 1.5 (IQR, 0–3) and 2.5 (IQR, 2–3) for the active and control groups. The active group also had significantly less pain than the control group (p = 0.007). Overall, pain control was excellent in both groups, and there was no significant difference in pain scores at any of the other time points (Fig. 2).
Patient use of breakthrough narcotic pain medication was also evaluated. As demonstrated in Figure 3, patients in the active group required breakthrough hydromorphone only 10% of the time, compared with 42% of patients in the control group (p = 0.008) while in the PACU. Risk reduction for narcotic use was therefore 76%. Eight hours after surgery, 3% of patients in the active group utilized narcotics, whereas 40% of patients in the control group required narcotics for adequate pain control. This difference was statistically significant, as well (p = 0.001). This results in a 92.5% relative risk reduction. There were also trends toward less use of narcotics in the active group at 24 hours postoperatively compared with the control group (21% vs 45%, p = 0.06) and overall narcotic usage in the active group compared with the control group (7.7 mg vs 15.5 mg, p = 0.12).
Both groups used similar amounts of ibuprofen and acetaminophen. Narcotic-related side effects were also similar in each group with an average of 1.4 adverse effects in the active group and 1.8 adverse effects in the control group (p = 0.75). There were no significant differences in reported side effects between the 2 groups.
Hemorrhoidectomies are traditionally the most painful anorectal procedures. We performed a subgroup analysis on patients undergoing hemorrhoidectomy and found that there were no statistically significant differences in pain control between the 2 groups at any time point (mean numerical rating scale score 2.4 vs 2.7, p = 0.77, in the active and control groups). However, our study was not powered to identify significant differences in surgical subgroups. Similarly, the breakthrough narcotic usage was not significantly different between the 2 groups.
However, significantly fewer patients utilized the breakthrough medication in the active group at the PACU time point (0% vs 56%, p = 0.03). There was a trend toward fewer patients requiring breakthrough hydromorphone at 8 hours after surgery, as well (0% vs 50%, p = 0.08). Similar to the full active versus control group comparison, the rest of the time points were not significantly different. However, in contrast to the overall group comparisons, the hemorrhoidectomy subgroup analysis revealed trends toward fewer average number of symptoms in the active group (1.5 vs 4.0, p = 0.08), as well as in patients experiencing nausea (0% vs 50%, p = 0.08).
Preemptive analgesia works to decrease pain by preventing hyperalgesia related to the sensitization of pain fibers in the central and peripheral nervous systems. We sought to preemptively block central sensitization through the use of intravenous ketamine perioperatively and peripheral sensitization through the use of preoperative oral gabapentin and acetaminophen and intravenous dexamethasone.
This is the first randomized, double-blind, placebo-controlled trial to evaluate the efficacy of PEA for ARS. We have demonstrated that patients utilizing preoperative acetaminophen, gabapentin, ketamine and dexamethasone experience less postoperative pain as measured by a patient-completed pain scale in PACU and 8 hours postoperatively. Patients who were in the active group were also significantly less likely to use narcotics in PACU and 8 hours postoperatively. There was also a trend toward fewer patients requiring narcotics at the 24-hour time point, as well. For the PACU and 8-hour time points, the relative risk reductions were 76% and 92.5%. These findings are particularly significant because they demonstrate the ability of PEA to reduce patients’ exposure to narcotics.
When we performed a subgroup analysis of patients undergoing hemorrhoidectomy (traditionally the most painful anorectal surgery), we did not find a difference in pain scores between the 2 groups. However, only 17 total patients underwent hemorrhoidectomy, so it is likely that this is related to a type II error, considering the differences in pain control seen in the combined groups between the active and control arms. The study was only powered to identify significant differences in the entire operative group, not for individual procedures. Despite this study being powered to determine significant differences in the entire operative group, not for individual procedures, we were able to demonstrate that PEA led to a significant reduction in the number of patients undergoing hemorrhoidectomy who required breakthrough narcotics.
The activation of N-methyl-D-aspartate receptors by glutamate has been identified as a process that leads to central sensitization after a noxious stimulus. By pharmacologically blocking these receptors, it may be possible to prevent or suppress the degree of central sensitization, which can prevent the hyperalgesia experienced by some patients.8 Peripheral sensitization is a similar concept and occurs because of noxious stimuli in the periphery, such as a surgical incision. This type of sensitization has typically been prevented with regional anesthesia and by increasing the nociceptive threshold of the neurons with different medications.
Preemptive pharmacological blockade of windup has been effectively used in both surgical and nonsurgical patients.9 In patients undergoing hip arthroplasty, blocking both central and peripheral sensitization results in significantly decreased subjective pain and a trend toward less postoperative use of analgesics.10 Similarly, patients undergoing multilevel spinal surgery and those undergoing prostatic surgery consume fewer postoperative analgesics when undergoing multimodal PEA by blocking both sensitization pathways.11 , 12 Preemptive central sensitization blockade alone has also shown trends toward improved pain control for gynecological surgery under both general and regional anesthesia.13 , 14
Poylin et al7 gave patients undergoing hemorrhoidectomy 1000 mg of gabapentin daily, beginning 1 day preoperatively, and continued it daily for a total of 9 days. In their prospective, open-labeled study, they demonstrated that the group taking gabapentin had less postoperative pain and had a trend toward less narcotic usage. They concluded that perioperative gabapentin was a cost-effective way to possibly decrease narcotic usage, but that this required further study.
Dexamethasone is a corticosteroid with potent anti-inflammatory effects that is also used as an antiemetic. The proposed mechanism of action of dexamethasone is not completely known, but it is thought to involve the inhibition of prostaglandin synthesis and an increased release of endorphins. Wu et al2 demonstrated that, combined with sevoflurane, patients who received dexamethasone during ARS reported lower postoperative pain scores than with placebo.
Local, peripheral sensitization has also been minimized through the use of nonsteroidal anti-inflammatory drugs due to decreased production of prostaglandins and kinins because acetaminophen and nonsteroidal anti-inflammatory drugs block the enzyme required to make these molecules. Acetaminophen is a weak analgesic that forms the most basic component of a multimodal analgesia regimen.15 Oral preemptive use of acetaminophen has been shown to decrease postoperative narcotic use in surgical patients and has been used in some of the studies mentioned in the literature review above.16 Ketorolac has also been used preemptively among patients undergoing ARS with good pain control.17
In the context of the current opioid epidemic, decreasing the number of patients who require narcotics is particularly important and beneficial. Our results demonstrate that PEA is successful and safe for patients undergoing outpatient ARS. We believe that preemptive analgesic pathways should be part of routine management for patients undergoing ambulatory ARS and that our results are generalizable to the majority of patients undergoing ARS.
Because of overall excellent pain control, our study was limited by a “floor effect” making it more difficult to demonstrate differences between the 2 groups. With only 61 patients completing enrollment, it is possible that we have encountered a type II error and missed significant differences in some parameters. Despite minor limitations, we have demonstrated, for the first time, the benefits of PEA before outpatient ARS. Large multi-institutional studies could further confirm these findings.
Preemptive analgesia before outpatient ARS decreases early postoperative pain, reduces the number of patients who require narcotics in the early postoperative period, and does not increase medication-related side effects. Administration of PEA, including acetaminophen, gabapentin, ketamine, and dexamethasone, is safe and effective, and it should be implemented for appropriate patients undergoing ARS.
The authors thank Dr Krista Evans for her contributions to the study. We also thank the Office of Clinical Trials and Research at the University of Vermont Medical Center, especially Karen Lepuschenko, for their efforts and dedication to this study. We also thank the Department of Anesthesiology, as well as the Investigational Pharmacists, and preoperative and PACU nursing staff for their contributions to the study.
Required Copyright Statement: Author M.R.J. is a military service member. This work was prepared as part of my official duties. Title 17 U.S.C. 105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17 U.S.C. 101 defines a United States Government work as a work prepared by a military service member or employee of the United States Government as part of that person’s official duties.
1. Chung F, Ritchie E, Su JPostoperative pain in ambulatory surgery. Anesth Analg. 1997;85:808–816.
2. Wu JI, Lu SF, Chia YY, Yang LC, Fong WP, Tan PHSevoflurane with or without antiemetic prophylaxis of dexamethasone in spontaneously breathing patients undergoing outpatient anorectal
surgery. J Clin Anesth. 2009;21:469–473.
3. Labas P, Ohradka B, Cambal M, Olejnik J, Fillo JHaemorrhoidectomy in outpatient practice. Eur J Surg. 2002;168:619–620.
4. Mendell LM, Wall PDResponses of single dorsal cord cells to peripheral cutaneous unmyelinated fibres. Nature. 1965;206:97–99.
5. Vinson-Bonnet B, Coltat JC, Fingerhut A, Bonnet FLocal infiltration with ropivacaine improves immediate postoperative pain control after hemorrhoidal surgery. Dis Colon Rectum. 2002;45:104–108.
6. Tegon G, Pulzato L, Passarella L, Guidolin D, Zusso M, Giusti PRandomized placebo-controlled trial on local applications of opioids after hemorrhoidectomy. Tech Coloproctol. 2009;13:219–224.
7. Poylin V, Quinn J, Messer K, Nagle DGabapentin significantly decreases posthemorrhoidectomy pain: a prospective study. Int J Colorectal Dis. 2014;29:1565–1569.
8. Stubhaug A, Breivik H, Eide PK, Kreunen M, Foss AMapping of punctuate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery. Acta Anaesthesiol Scand. 1997;41:1124–1132.
9. Richardson P, Mustard LThe management of pain in the burns unit. Burns. 2009;35:921–936.
10. Rasmussen ML, Mathiesen O, Dierking G, et alMultimodal analgesia
with gabapentin, ketamine and dexamethasone in combination with paracetamol and ketorolac after hip arthroplasty: a preliminary study. Eur J Anaesthesiol. 2010;27:324–330.
11. Mathiesen O, Dahl B, Thomsen BA, et alA comprehensive multimodal pain treatment reduces opioid consumption after multilevel spine surgery. Eur Spine J. 2013;22:2089–2096.
12. Trabulsi EJ, Patel J, Viscusi ER, Gomella LG, Lallas CDPreemptive multimodal pain regimen reduces opioid analgesia
for patients undergoing robotic-assisted laparoscopic radical prostatectomy. Urology. 2010;76:1122–1124.
13. Kwok RF, Lim J, Chan MT, Gin T, Chiu WKPreoperative ketamine improves postoperative analgesia
after gynecologic laparoscopic surgery. Anesth Analg. 2004;98:1044–1049.
14. Menkiti ID, Desalu I, Kushimo OTLow-dose intravenous ketamine improves postoperative analgesia
after caesarean delivery with spinal bupivacaine in African parturients. Int J Obstet Anesth. 2012;21:217–221.
15. Tang R, Evans H, Chaput A, Kim CMultimodal analgesia
for hip arthroplasty. Orthop Clin North Am. 2009;40:377–387.
16. Khalili G, Janghorbani M, Saryazdi H, Emaminejad AEffect of preemptive and preventive acetaminophen on postoperative pain score: a randomized, double-blind trial of patients undergoing lower extremity surgery. J Clin Anesth. 2013;25:188–192.
17. Richman IMUse of Toradol in anorectal
surgery. Dis Colon Rectum. 1993;36:295–296.