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