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Pre-Emptive Analgesia in Ano-Rectal Surgery (PEAARS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02402543
Recruitment Status : Completed
First Posted : March 30, 2015
Last Update Posted : January 16, 2018
Sponsor:
Collaborator:
American Society of Colon and Rectal Surgeons
Information provided by (Responsible Party):
Peter Cataldo, MD, University of Vermont

Tracking Information
First Submitted Date  ICMJE March 25, 2015
First Posted Date  ICMJE March 30, 2015
Last Update Posted Date January 16, 2018
Study Start Date  ICMJE June 2014
Actual Primary Completion Date May 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 27, 2015)
Postoperative pain [ Time Frame: End of surgery up to 7 days postoperatively ]
Pain will be evaluated using numerical rating scales at specified intervals from the end of surgery up to 7 days postoperatively and mailed back to the investigators. The pain levels will be compared between groups.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 6, 2015)
  • Narcotic consumption [ Time Frame: End of surgery up to 7 days postoperatively ]
    Narcotic consumption will be recorded by the subject on medication diaries attached to the respective numerical rating scale. This helps to identify at which time point the patient took a narcotic. This will be compared between groups.
  • Interval for rescue pain medication [ Time Frame: End of surgery up to 7 days postoperatively ]
    On the aforementioned medication diaries, the patient will record when he or she first needed break through pain medication (i.e. the narcotic prescribed) beyond the scheduled pain medicines. This will help us evaluate the interval between end of the operation and first need for breakthrough pain medication. This number will be compared between groups.
  • Further pain requirements [ Time Frame: End of surgery up to 7 days postoperatively ]
    By examining the medication diaries, we will be able to evaluate if there were patients who required more than the scheduled pain medications and breakthrough narcotic. This number will be compared between groups.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 27, 2015)
  • Narcotic consumption [ Time Frame: End of surgery up to 7 days postoperatively ]
    Narcotic consumption will be recorded by the subject on medication diaries attached to the respective numerical rating scale. This helps to identify at which time point the patient took a narcotic. This will be compared between groups.
  • Interval for rescue pain medicaiton [ Time Frame: End of surgery up to 7 days postoperatively ]
    On the aforementioned medication diaries, the patient will record when he or she first needed break through pain medication (i.e. the narcotic prescribed) beyond the scheduled pain medicines. This will help us evaluate the interval between end of the operation and first need for breakthrough pain medication. This number will be compared between groups.
  • Further pain requirements [ Time Frame: End of surgery up to 7 days postoperatively ]
    By examining the medication diaries, we will be able to evaluate if there were patients who required more than the scheduled pain medications and breakthrough narcotic. This number will be compared between groups.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pre-Emptive Analgesia in Ano-Rectal Surgery
Official Title  ICMJE Pre-Emptive Analgesia in Ano-Rectal Surgery
Brief Summary

The perianal region is the region around the anus. Administering a pain medication before a surgery starts is called preemptive analgesia. In some studies, this technique has been shown to be an effective way to reduce the pain that a patient experiences in the post-operative timeframe to a greater extent than would be expected simply from the pain medications alone. One theory of why this occurs suggests that the preemptive analgesia desensitizes brain and nerves to pain, thereby decreasing the response to painful stimuli, like surgery when they occur. This leads to a decrease in the amount of narcotic pain medication required after the procedure, which leads to less side effects and a quicker return to normal functioning. As perianal surgeries do not usually include a long stay in the hospital, controlling post-procedure pain is a priority.

The use of preemptive analgesia is in other types of surgeries, such as orthopedics, is well established, but as the perianal region has not been well studied, its use is not the standard of care. This type of analgesia uses a combination of medications that are already in use for post-operative and non-operative pain control and administers them orally prior to the patient undergoing general anesthesia. The side effects of the medications are the same as if they had been given after surgery or for non-surgical pain.

The concept of preemptive analgesia is established in other types of surgeries and it has solid basic science to support its use. The purpose of this randomized, double-blind, placebo controlled study is to determine if patients undergoing perianal surgeries could benefit from preemptive pain control. The primary outcome will be whether patients experience less post-operative pain. Patient post-operative consumption and latency until use of narcotic pain medication will be the secondary outcomes. The investigators believe that the patients receiving pain medications before their operation will require less pain medication after surgery, with minimal increased risk to the patient.

Detailed Description

Despite advances in pain medicine, postoperative pain control remains problematic with over 5% of patients experiencing severe pain despite standard of care pain management, and is a frequently cited reason for delayed discharge in outpatient procedures [1]. In anorectal surgeries, almost all patients experience mild-to-moderate postoperative subjective pain [2], and as an example 12% of patients report severe postoperative pain during their recovery from hemorrhoidectomy surgery [3]. Control of postoperative pain is an important goal. Preemptive analgesia is a technique that involves premedicating the patient with a regimen of medications designed to target different points in the pain cascade to prevent central and peripheral sensitization to pain, also known as "wind-up" [4]. The activation of N-methyl-D-aspartate (NMDA) receptors is an identified process that occurs in 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 hyperalgesic, or exaggerated pain response, that some patients experience [5]. Peripheral sensitization is a similar concept and occurs due to 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 analgesia focusing on the effect of single medications on pain control has shown promising results, however some studies appear to lend themselves to practice [6-19] better than others [20-26]. On the other hand, multimodal pain control regimens might be more promising. A search of the literature reveals that preemptive pharmacological blockade of wind up has been effectively used in both surgical and nonsurgical patients (burn patients [27]). In patients undergoing hip arthroplasty, or hip replacement surgery, under general anesthesia, blocking both central and peripheral sensitization results in significantly decreased subjective pain, and a trend toward less postoperative use of analgesics [28]. Similarly, patients undergoing multilevel spinal surgeries [29] and those undergoing prostatic surgery [30] under general anesthesia consume less postoperative analgesics when undergoing multimodal preemptive pain control by blocking both sensitization pathways. Finally, preemptive central sensitization blockade alone has been used with trends in improved pain control for gynecological surgeries under both general [31] and regional anesthesia [32]. The preemptive use of such medications has not been studied for anorectal surgeries and it is what we are suggesting in this study. Most pain control studies in the literature focus on postoperative rather than preemptive medication regimens for pain management [33-35], and there is no current standard of care as to an effective regimen. The studies effective in decreasing postoperative pain in other surgical contexts, such as for patients undergoing hip arthroplasty, have used the same combination of medications proposed for the Treatment Group. Finally, the added benefit of the anorectal patient population in terms of the putative decreased use of opioids for postoperative pain control revolves around the opioid-related adverse effects on bowel function. In fact, return of bowel movements and regularity is one criterion for healing after surgery.

Based on this existing literature, we propose in our current study to preemptively block both central sensitization through the use of intravenous ketamine perioperatively and peripheral sensitization through the use of intravenous dexamethasone administered perioperatively and oral gabapentin and acetaminophen administered preoperatively. Ketamine is a noncompetitive NMDA receptor antagonist acting centrally in the dorsal horn of the spinal cord to decrease the release of glutamate, reducing the transmission of pain messages centrally [36]. Intravenous ketamine has been shown to decrease 24-hour opioid requirements, and preemptive use of ketamine was part of the medications used in most of the studies mentioned in the literature review above. As it currently stands, use of ketamine in anorectal surgeries as an added analgesic has been proven safe. Among Nigerian surgery patients having received regional anesthesia and preemptive ketamine, postoperative pain levels have been shown to decrease, however it is unclear if this patient cohort included anorectal surgery patients [37]. No other studies have been conducted regarding postoperative pain in these patients [38]. By utilizing ketamine as one of the medications in our study, we hope to show similar effects resulting in patients experiencing decreased postoperative pain after common anorectal surgeries.

Dexamethasone is a corticosteroid with potent anti-inflammatory effects that is also used as an anti-emetic. The proposed mechanism of action of dexamethasone is not completely known, but it is thought to involve inhibition of prostaglandin synthesis and an increased release of endorphins. Endorphins are endogenous peptides that bind to pain receptors in the body to decrease pain. In addition, endorphins can facilitate mood elevation and a sense of well-being. Intravenous dexamethasone was part of the medications used in studies mentioned in the literature review above. One study investigating the prophylactic use of dexamethasone for its anti-emetic properties, in combination with sevoflurane, a general anesthetic, during anorectal surgery found a significant decrease in maximal postoperative VAS pain scores in patients administered dexamethasone compared to those given placebos [2]. The use of dexamethasone as a preemptive analgesic has not been fully studied in anorectal surgery patients.

Gabapentin acts by binding to receptors on voltage-gated calcium channels on presynaptic nerves, reducing the entry of calcium into presynaptic nerve terminals. The subsequent decreased release of excitatory neurotransmitters such as glutamate, aspartate, substance P, and norepinephrine into the synaptic cleft is linked to a diminished postsynaptic transmission of neural pain messages [36]. It is usually used for neuropathic pain control, and has been used in some of the studies mentioned in the literature review above. A systemic review of the perioperative effects of gabapentin found that it is an effective means of reducing post-operative pain, opioid consumption, and opioid-related adverse effects in surgical patients. In fact, administration of a single dose of gabapentin was found to be equivalent to a reduction of 30 mg of morphine in the first 24 hours after surgery [39]. No studies have been conducted, to the best of our knowledge, regarding preemptive use of gabapentin in anorectal surgeries.

Local, peripheral sensitization has also been minimized through the use of non-steroidal anti-inflammatory drugs (NSAIDs) due to the decreased production of certain molecules such as prostaglandins and kinins. The enzyme required to make these molecules is blocked by acetaminophen and NSAIDs, which is why acetaminophen is included in this study in hopes of demonstrating better pain control among anorectal surgery patients. Acetaminophen is a weak analgesic that forms the most basic component of a multimodal analgesia regimen [36]. Oral preemptive use of acetaminophen has been proven to decrease postoperative narcotic use in surgical patients [40], and has been used in some of the studies mentioned in the literature review above. A related intramuscular NSAID, namely Toradol, has been used preemptively among anorectal surgical patients with good pain control [41]. No other studies are reported in this patient population.

Of importance, the combinations of the medications used in this study have been used in other studies before with similar or higher doses and no significant differences in terms of hemodynamic variables (such as vital signs) or adverse side effects have been noted compared to control groups [31]. In fact, these medications are safely used at UVM Medical Center by the collaborating surgeons as part of their care for other surgeries such as abdominal surgeries.

*References 1-41 available upon request

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Hemorrhoids
  • Fissure in Ano
  • Rectal Fistula
  • Anal Condyloma
Intervention  ICMJE
  • Drug: Gabapentin
    Other Name: Neurontin, Gralise, Fanatrex
  • Drug: Ketamine
    Prior to the incision in the operating room, the anesthesiologist administers 0.15 mg/kg of ketamine IV push in patients randomized to the experimental arm, only.
    Other Name: Ketalar
  • Drug: Acetaminophen
    Other Name: Tylenol, panadol, mapap, ofirmev, tempra
  • Drug: Dexamethasone
    Prior to the incision in the operating room, the anesthesiologist administers 8 mg of dexamethasone IV push in patients randomized to the experimental arm, only.
    Other Name: Decadron,
  • Drug: Placebo
Study Arms  ICMJE
  • Placebo Comparator: Control Arm
    In pre-op, the subject is administered four placebo pills PO containing confectioners sugar, which are matched in color, size, and shape to the active pills.
    Intervention: Drug: Placebo
  • Experimental: Experimental Arm
    In pre-op, the subject is administered four pills PO containing a total of 1000 mg of acetaminophen and 600 mg of gabapentin, which are matched in color, size, and shape to the placebo pills.
    Interventions:
    • Drug: Gabapentin
    • Drug: Ketamine
    • Drug: Acetaminophen
    • Drug: Dexamethasone
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 27, 2015)
90
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE May 2017
Actual Primary Completion Date May 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients having anal fistula repairs for anal fistulas recalcitrant to non-surgical management at the University of Vermont Medical Center or Fanny Allen Campuses OR
  • Patients having anal sphincterotomies for chronic anal fissures recalcitrant to non-surgical management at the University of Vermont Medical Center or Fanny Allen Campuses OR
  • Patients having hemorrhoidectomies for hemorrhoids recalcitrant to non-surgical management at the University of Vermont Medical Center or Fanny Allen Campuses OR
  • Patients having anal condyloma excisions for anal condylomas recalcitrant to non-surgical management at the University of Vermont Medical Center or Fanny Allen Campuses
  • Patients undergoing these surgeries must be American Society of Anesthesiologists (ASA) Physical Status Classification System scores of I (normal, healthy patient), II (patient with mild, systemic disease), or III (patients with more significant disease)

Exclusion Criteria:

  • Allergies to any study medications;
  • Patient history and chart review for existence of hepatic or renal failure;
  • Chronic pain syndrome;
  • Inability to understand or utilize the Numerical Rating Scale (NRS);
  • Pregnancy;
  • Patients currently on gabapentin, pregabalin or narcotics
  • Patients taking chronic steroids, unable to taper off before surgery
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02402543
Other Study ID Numbers  ICMJE CHRMS: M13-226
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Peter Cataldo, MD, University of Vermont
Study Sponsor  ICMJE University of Vermont
Collaborators  ICMJE American Society of Colon and Rectal Surgeons
Investigators  ICMJE Not Provided
PRS Account University of Vermont
Verification Date January 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP