Pre-Emptive Analgesia in Ano-Rectal Surgery
Pre-Emptive Analgesia in Ano-Rectal Surgery
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.
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
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