Nonopioid pain management in otolaryngology—head and neck surgery: the pharmacist’s perspective





Introduction


With the setting of the opioid epidemic, a focus has been placed on understanding the prescribing patterns of physicians for postoperative surgery pain. A 2018 survey of 1770 members of the American Rhinologic Society was conducted regarding the prescribing patterns for pain management after endoscopic sinus surgery (ESS). The overall survey response rate was low at 9.49% ( N = 168). At least one kind of opioid was prescribed by 94.05% of respondents with an average of 27 pills. Those in private practice were less likely to prescribe oxycodone ( p = .000105). Private practice physicians were also less likely to refer patients to pain management ( p = .0117) and were more likely to refer patients to nontraditional forms of pain management ( p = .0164). There was no statistical difference between prescribing of acetaminophen between the groups. Academic physicians were less likely to prescribe nonsteroidal antiinflammatories (NSAIDs) ( p = .032). All across the country, regardless of practice setting, most providers prescribe opioids after ESS. Given this, multimodal pain strategies are essential to understand and implement perioperatively to decrease opioid use and more safely treat patients. Most data are for the (non-opioid) analgesics of acetaminophen, NSAIDs, and gabapentinoids, thus will be the focus of this chapter.


Acetaminophen


Overview


Acetaminophen (APAP) is a nonopioid analgesic that is available without a prescription and found both individually and in a wide variety of combination products (fixed dose with other analgesics, headache remedies, sleep aids, cold and flu preparations). Its full mechanism of action is not well understood. It is believed to provide analgesic effects through inhibiting descending serotonergic pathways in the central nervous system (CNS) in addition to possible interaction with other nociceptive systems. , It is commonly used for mild-to-moderate pain such as headaches and myalgia. It also provides antipyretic effects through inhibition of the hypothalamic heart-regulating center. It only weakly inhibits COX-1 and COX-2 enzymes in peripheral tissues and therefore has little antiinflammatory effects.


APAP is readily orally absorbed with an onset of action and peak effects reached within 60 min depending on gastric emptying time. It is also available in intravenous (IV) form, which may provide peak effects in as little as 15 min. APAP is widely distributed throughout the body. It has a 2–3 h half-life with a 4–6 h duration of effect (antipyretic effects may last longer). It is primarily metabolized through hepatic conjugation with glucuronic acid (∼60%) and sulfuric acid (∼35%). See Table 8.1 for specific dosing recommendations.



Table 8.1

Nonopioid pain medication overview. ,
































































Medication Preoperative dose Postoperative dose Maximum total daily dose Dose adjustments Adverse effects/Precautions
Acetaminophen (IV/PO) 500–1000 mg 500–1000 mg Q6-8 H 4000 mg Reduce dose for hepatic impairment GI upset, risk of severe hepatic impairment with excessive use
NSAIDs
Celecoxib (PO) 200–400 mg 100–200 mg twice daily 400 mg Avoid use with CrCl <30 mL/min GI upset, increased risk of CV events
Ketorolac (IV) 15–30 mg 15–30 mg Q6 H 120 mg 50% reduction for CrCl 30–50 mL/min, weight <50 kg or age >65 years;
Avoid use with CrCl <30 mL/min
Increased risk of bleeding/CV events with use greater than 5 days
Ibuprofen (PO) 400–800 mg 400–800 mg Q6-8 H 3200 mg Avoid use with CrCl <30 mL/min GI upset, increased risk of GI bleed and renal impairment with prolonged use
Naproxen (PO) 250–500 mg 250–500 mg Q8-12 H 1500 mg 50% reduction for CrCl 30–50 mL/min; avoid use with CrCl <30 mL/min GI upset, increased risk of GI bleed and renal impairment with prolonged use; potentially least risk of CV events
Gabapentinoids
Gabapentin (PO) 300–900 mg 300–900 mg Q8 H 3600 mg 50% dose reduction for CrCl 30–50 mL/min; 75% dose reduction for CrCl 15–30 mL/min Sedation, potential for abuse, potential for withdrawal with prolonged use or high dose if stopped abruptly
Pregabalin (PO) 150 mg 50–200 mg Q8-12 H 600 mg 50% reduction for CrCl 30–50 mL/min or age >65 years; 75% dose reduction and not more than Q12H interval for Sedation, potential for abuse, potential for withdrawal with prolonged use or high dose if stopped abruptly

CV , cardiovascular; CrCl , creatinine clearance, GI , gastrointestinal; H , hours; NSAIDs , nonsteroidal antiinflammatories; PO , oral; Q , every.


Common adverse effects include the following: nausea, vomiting, dizziness, mild hepatic enzyme elevation, and difficulty sleeping. At higher doses, a minor toxic metabolite ( N -acetyl- p -benzoquinone or NAPQI) can accumulate when normal metabolic pathways become saturated. The accumulation of NAPQI can lead to severe hepatotoxicity and acute renal impairment. It is recommended to avoid total daily doses of APAP greater than 4000 mg or single doses greater than 1000 mg in patients with normal hepatic function to reduce the risk of toxicity. Lower dosing cutoffs should be considered in patients with mild to moderate hepatic impairment and use should be avoided in patients with severe hepatic impairment. APAP has few clinically significant drug–drug interactions.


Use in otolaryngology surgery


APAP has been utilized for surgeries as both a single analgesic and as part of a multimodal pain medication approach. There is a large controversy around whether IV APAP is superior to oral. Most of the studies involving APAP use, either preoperatively or postoperatively, include IV APAP. There are conflicting data as a whole, but the proposed benefits include lower pain scores (VAS), less narcotic use, and longer time to rescue medication, as well as less nausea and vomiting compared to other analgesics. There are many studies involving APAP use in adenoidectomies, tonsillectomies, and ESS.


Most of the evidence for APAP use in otolaryngology involves pediatric patients undergoing adenoidectomies and tonsillectomies. APAP was reviewed in three studies, two for adenotonsillectomy and one for tonsillectomy. A double-blind randomized controlled trial of a single dose of IV APAP did not reduce pain scores in pediatric patients (ages 2–8) undergoing adenotonsillectomy ( N = 239). Patients received oral midazolam, propofol, and morphine before tracheal intubation. Intraoperatively IV APAP at 15 mg/kg ( n = 118) or saline placebo ( n = 121) was administered. Faces, Legs, Activity, Cry, Consolability (FLACC) scores and rescue analgesics did not differ at any postoperative time point between groups. Results were similar in a prospective trial of pediatric patients (ages 3–17) undergoing tonsillectomy or adenotonsillectomy ( N = 260). Patients either received IV APAP intraoperatively at 15 mg/kg ( n = 131) or did not. There were no differences in FLACC scores between the two groups up to 24 h postoperatively, but more incidences of nausea and vomiting with IV APAP. Lastly, a retrospective cohort study of 166 pediatric patients (age 1–16 years) evaluated the use of IV APAP ( n = 74) compared to none as the control group ( n = 92). Patients in the APAP cohort received a single dose of 15 mg/kg before anesthesia induction. Patients who received APAP received statistically significantly less morphine compared to the control cohort. Of note, this is a retrospective design compared to the prospective design of the previous two studies and they were assessing different outcomes.


APAP has also been utilized for postoperative pain control in ESS. Two double-blind, randomized controlled trials evaluated 1000 mg of IV APAP compared to placebo in adults undergoing ESS surgery. , In one study, there was a trend toward lower visual analog scores (VASs) in the APAP group at 1 h postoperatively, but also a trend toward the placebo at 12 and 24 h ( N = 62). However in the next study, significantly fewer patients in the APAP group required rescue analgesia and had less incidence of severe pain ( N = 74). The APAP dosing strategies were slightly different, with patients receiving APAP before surgery and then a second dose 4 h after versus right after completion of the surgery in the first and second studies, respectively. Another randomized, double-blind study evaluated 1000 mg of IV APAP 15 min before induction (Group I, n = 20) compared to at the end of surgery (Group II, n = 19) in adult ESS patients. Postoperative VAS pain scores were statistically significantly higher in Group II up to 6 h postoperatively, and the time to first analgesic was significantly longer in Group I. With conflicting results, it is hard to determine the optimal timing of APAP. Of note, the first trial had inconclusive results within the trial, possibly making a case that APAP should be dosed before surgery and continued throughout. , Lastly, a prospective study evaluated oral APAP at 665 mg modified-release tablets as either a scheduled regimen of three times daily for 5 days ( n = 38) versus on an as-needed basis ( n = 40). Although there was no difference between the scheduled and as-needed group in regards to recovery (average 9–10 days), there were significantly lower pain scores in the scheduled group. If using oral medication, due to the delay in absorption and peak effect, it is beneficial to schedule the medication rather than use as needed.


APAP has also been studied in combination with other analgesics. In a randomized, double-blind study, the efficacy of APAP alone was tested against the combination of APAP with codeine in pediatric patients (ages 3–12 years) undergoing outpatient tonsillectomy and adenoidectomy ( N = 51). Patients were transitioned to either APAP 15 mg/kg ( n = 31) or APAP/codeine 1 mg/kg ( n = 20), based on codeine dose. There was no difference in postoperative pain reported by the patients. APAP has also been reported to help with goal recovery (lower rates of severe pain) when used with remifentanil in ESS patients. A meta-analysis including 23 studies of otologic surgeries (myringotomy/tympanostomy, tympanomastoid, microtia reconstruction, middle ear surgeries) concluded that combination analgesics, such as APAP and codeine provided superior analgesia, while NSAIDs and α-agonists may be monotherapy options. Caution must be taken when using codeine in pediatric patients after tonsillectomy or adenoidectomy as there is now a Black Box Warning on the combination product. Due to a subset of the population being ultrarapid metabolizers of codeine, from a Cytochrome P450 2D6 polymorphism, codeine is converted to morphine at higher levels. The Black Box Warning came after pediatric deaths occurred with the use of APAP/codeine after tonsillectomies and adenoidectomies.


Common misconceptions


As seen in the evidence presented in this section, there is conflict in the data about whether APAP should be given IV or orally when used perioperatively. In adult clinical practice, IV APAP has a specific place in therapy for a patient that cannot take APAP via an enteral route and there is significant rectal pathology or a history of sexual abuse or trauma where administering rectal APAP could cause a psychological disturbance for the patient. Patients that are neutropenic (absolute neutrophil count less than 500) and do not have enteral access would be another reason to use IV APAP. We have created this type of restriction criteria at our institution to help curb unnecessary use of IV APAP, especially in the historical setting of the significant increased cost compared to the oral and rectal suppository formulations.


As of April 2021, the cost of generic APAP IV (10 mg/mL, 100 mL bottle) is ∼$0.45 per mL. With the IV route typically dosed at 1000 mg per dose, that is almost $50 per dose, whereas an oral APAP tablet (500 mg dose per tablet) and a rectal APAP suppository (650 mg dose per suppository) are roughly the same cost as 1 mL (10 mg) of IV APAP ($0.45 per tablet or suppository). If a patient is on scheduled APAP 1000 mg every 6 h for multimodal pain management, the cost of administering this regimen via an IV route definitely adds up and can generate thousands of dollars of unnecessary yearly drug spend for a hospital.


Another question that often comes up when putting together postoperative multimodal pain regimens is how to best utilize APAP with NSAID medications in patients where both medication classes are deemed safe for use. You may have heard before that alternating timing of NSAIDs with APAP can improve the effectiveness of pain control more than taking the medications together at the same time or even alone but is there evidence to support this strategy?


A retrospective chart review described outcomes in pain relief in children who received alternating regimens of APAP and ibuprofen after tonsillectomy or adenoidectomy. Out of 583 patients that were 1–18 years of age, only 56 (9.6%) reported inadequate pain control with this regimen. Overall, the incidence of postoperative bleeding and bleeding requiring surgical intervention was low at 24 patients (4.1%) and 9 patients (1.5%), respectively. Although this review was conducted in children, it is reasonable to say an alternating regimen of APAP and ibuprofen at doses appropriate for adults would also allow for improved pain control with little risk of postoperative bleeding concerns.


In contrast, a randomized controlled trial described a combined regimen of APAP 500 mg and ibuprofen 150 mg per tablet (studying the British prescription product Maxigesic), two tablets by mouth preoperatively, and then two tablets every 6 h for up to 48 h postoperatively in patients undergoing dental molar removal. This was compared to monotherapy of either APAP 500 mg by mouth every 6 h or ibuprofen 150 mg by mouth every 6 h. Of general relevance was the secondary endpoint of global pain rating, a subjective patient report, with the favored group being the combined regimen (68.4% of patients reported “none” or “mild” pain scores compared to 37.5% of patients taking APAP alone and 54.3% of patients taking ibuprofen alone). To note, only the APAP group had a statistically significant difference compared to the combined regimen ( p = .008). Also, patients on the combined therapy required less use of rescue pain medication, though this was not statistically significant. This example shows the potential of combined APAP/ibuprofen providing greater pain control compared to monotherapy with either of these agents. Although there is little evidence looking at a combined regimen versus an alternating regimen of these two medications, from a patient adherence standpoint a combined regimen, either in a combined tablet (not available in the United States as of May 2021) or taking these medications at the same time with equal frequency, will allow for better patient medication adherence and less confusion in trying to stagger medications and higher risk of potentially exceeding recommended maximum daily doses.


Nonsteroidal antiinflammatory drugs


Overview


NSAIDs are a large class of nonopioid analgesics. NSAIDs as a whole have analgesic, antiinflammatory, and antipyretic effects through both nonselective COX inhibition and selective COX-2 inhibition depending on the agent. They are particularly effective at treating pain when inflammation is involved in triggering pain perception. , Many NSAIDs are available without a prescription and can commonly be found as individual agents and in multiple combination products similar to APAP. A few NSAIDS are available in formulations other than oral (i.e., topical diclofenac gel; IV and ophthalmic ketorolac).


Most NSAIDs have rapid absorption after oral intake with the onset of action within 30–60 min and peak effects generally in 1–3 h. , They are widely distributed throughout the body including relatively high concentrations in the CNS providing central analgesic effects. They are primarily metabolized through hepatic pathways and renally excreted. Half-life and duration of effect can vary greatly depending on the specific agent used. See Table 8.1 for specific dosing recommendations.


Common adverse effects include the following: abdominal pain and cramping, nausea, vomiting, dizziness, headache, and fluid retention. , More serious adverse effects include the following: severe gastrointestinal events (including inflammation, ulceration, and bleeding), rash (including Stevens-Johnson Syndrome and toxic epidermal necrosis), bleeding (through inhibition of platelet adhesion and aggregation), hepatic and renal impairment, and cardiovascular events (including myocardial infarction and stroke). The risk of gastrointestinal adverse effects increases significantly when NSAIDs are taken in combination with aspirin or other antiplatelet agents, anticoagulants, selective serotonin reuptake inhibitors, or prolonged use of corticosteroids. The risk of renal impairment is significantly increased when NSAIDs are taken in combination with ACE inhibitors. NSAIDs are also highly protein bound and may displace other protein-bound medications increasing the risk of toxicity of these agents (such as methotrexate or warfarin).


Use in otolaryngology surgery


NSAIDs are a cornerstone for opioid-sparing regimens in otolaryngology. In 2013, a survey was published of Danish patients who underwent tonsillectomies and their number of days absent from work or school along with their pain score for the first 14 days postoperative time period. A total of 549 patients returned the survey, with 30% dissatisfied with the information provided about postoperative complications and risks. The daily pain score was significantly higher in adults (>15 years) compared to children ( p < .0001). Days missed were significantly higher in patients greater than 16 years (12 versus 9 days; p < .0001). Pain medications prescribed for the first week were a combination of paracetamol (APAP) and NSAIDs, according to age and weight. While the survey did find that most patients were satisfied with their outpatient tonsillectomy procedure, postoperative pain management warrants review. Unfortunately, no specifics on the dosing, frequency, and selection of NSAIDs were provided in the study.


A survey of parents of 324 children who underwent adenotonsillectomy was conducted to assess the opioid-sparing effects of postoperative ibuprofen use. The pain regimen included the combination of APAP and ibuprofen or the combination hydrocodone/APAP and ibuprofen. Oral APAP was prescribed at 15–20 mg/kg every 6 h, ibuprofen was dosed at 7.5–10 mg/kg every 6 h, and hydrocodone/APAP was dosed at 0.1 mg/kg of hydrocodone every 6 h. The two groups (opioid and nonopioid) were equally matched in gender, race/ethnicity, and insurance status. Most parents filling out the survey ranked their child’s pain control as excellent or good/adequate, while only 9% without opioids ranked it as poor/inadequate and 5% with opioids. The authors concluded that nonopioid analgesic regimens following pediatric adenotonsillectomy did not result in worse parental satisfaction or poor/inadequately controlled pain in children.


Various studies have investigated whether adults could have their pain adequately managed without the use of opioids. In a randomized controlled study of adults undergoing thyroidectomy or parathyroidectomy surgery, 127 patients were randomized to either a narcotic arm ( n = 53) or nonnarcotic arm ( n = 73) for postoperative pain management. The groups had some differences in baseline demographics with more patients in the nonnarcotic arm reporting alcohol use (10.9% versus 5% in narcotic arm; p = .009), while more patients in the nonnarcotic arm had an active illicit drug use (9.5% versus 0% in narcotic arm; p = .03). All patients received 1000 mg APAP alternating with 800 mg of ibuprofen every 4 h as needed for pain, along with ice packs on the incision (15 min on, 15 min off) and dyclonine throat lozenge to dissolve in the mouth every 2 h as needed for throat pain. Breakthrough pain while inpatient could be treated with 5 mg of oxycodone every 6 h as needed. Upon discharge, the nonnarcotic arm received 1000 mg APAP alternating with 800 mg of ibuprofen every 4 h as needed for pain, but no oxycodone for rescue. Upon discharge, the narcotic arm received the same APAP and ibuprofen instructions and prescriptions along with a prescription for 5 mg of oxycodone every 6 h as needed for breakthrough pain. Only 10 oxycodone tablets were prescribed in the narcotic arm. Patients were surveyed at postoperative days (POD) 0 and 5. When reviewing patients who received a narcotic after discharge from the PACU, either in the hospital or after discharge, there was no difference in age, sex, race, or history of chronic pain between the groups. The narcotic group had a larger percentage reporting alcohol consumption (15.1% vs. 2.8%; p = .01), active illicit drug use (9.6% vs. 1.4%; p = .03), previous opioid misuse (7.7% vs. 0%; p = .02), and smoking (41.5% vs. 15.1%; p = .001), while 98.6% in the narcotic-free group were opioid naïve and 86.8% ( p = .007) in the narcotic group. Opioid naïve was defined as not having received narcotic within 3 months of surgery. The median pain score on POD 0 was 7 and 7.5 for narcotic versus nonnarcotic ( p = .1), respectively. Each day until POD 5, the median pain score decreased by 1 and was evenly matched between the groups. On POD 5, it was 2.5 for the narcotic group and 2 for the nonnarcotic group ( p = .8). The authors concluded that an opioid-sparing pain regimen provides effective analgesia for patients after a thyroidectomy or a parathyroidectomy. As a result of this study, the authors created a standardized approach to postoperative pain management after thyroidectomy and parathyroidectomy. The approach involves patient education regarding expectations for postoperative pain and where the pain is most likely to occur (incision site, throat, and neck, headache due to anesthesia, sometimes chest wall, and shoulder, jaw, and ear pain), no longer routinely prescribing narcotics at discharge, and the use of ice and dyclonine as adjuncts to APAP and ibuprofen. If the pain is uncontrolled with this regimen, three narcotic tablets are prescribed for rescue.


A study was conducted evaluating the effect of celecoxib added to the postoperative pain regimen. In a retrospective matched cohort study of patients undergoing head and neck cancer surgery with free tissue reconstruction, the amount of morphine equivalents per patient per day postoperative was measured in those who received celecoxib ( N = 51) and the control group ( N = 51). The celecoxib group received 200 mg twice daily through a feeding tube for a minimum of 5 days starting on POD 1. Celecoxib use was associated with decreased use of opioids (30.9 mg mean morphine equivalents (MME) per day) compared to the control (44.9 mg MME/day; 14 mg of morphine equivalents per day difference (95% confidence interval: 2.6–25.4)). The reduction in MME is clinically significant, as the Center for Disease Control has shown that 50 mg MME (equivalent to 33 mg of oxycodone) more than doubles the risk of overdose and other opioid-related complications. There were no statistically significant differences in complications between the two groups; flap dehiscence/surgical site infection (16% vs. 13% in control), hematomas (1.9% vs. 4.0% in control), free flap failure rate (4% in both groups), gastrointestinal complications (4% vs. 5.8% in control), cardiovascular complications (4% in both groups), and no difference in 30-day mortality (1.9% in both groups). The authors concluded that in head and neck cancer surgery patients that oral celecoxib helped to reduce morphine equivalent use in patients without increasing surgery and microvascular flap-related complications.


Common misconceptions


As discussed in the literature review earlier in this section, a significant increase in postoperative bleeding risk is not a clinically relevant concern in patients without risk factors like concomitant anticoagulation or antiplatelet therapy or significantly low hemoglobin, hematocrit, or platelet values. This should not be a concern when considering scheduled NSAID therapy, especially with the antiinflammatory properties of this drug class that often help with pain relief for patients.


In addition to the questions on bleeding risk, concern for immediate risk of perioperative acute kidney injury (AKI) due to NSAID use is also not a significant concern in patients without underlying kidney insufficiency, though ketorolac specifically can cause acute AKI even with short term use (can be seen within the first 7 days of use). Remembering to keep patients hydrated and regularly monitoring renal labs while inpatient is important to catch any developing AKI quickly and decrease unintended morbidity associated with this drug class.


In reviewing the role of IV ketorolac as part of a postoperative multimodal pain regimen, a common intervention that pharmacists make is the dose recommendation. There is evidence that there is a ceiling effect for ketorolac dosing that supports a lower dose of 15 mg (vs. 30 mg that is often ordered especially for younger patients with excellent renal function). In a randomized controlled trial ( N = 240), patients were divided evenly into three groups where a single dose of IV ketorolac, either 10 mg, 15 mg, or 30 mg was given in the emergency department for acute pain. The reduction in pain scores after 30 min between the three groups was similar and the differences were not statistically significant. Patients that had complete resolution of the pain also did so with ketorolac only and did not require an available rescue dose of IV morphine, which also shows the possibility of opioid-sparing effects in a multimodal pain regimen. This support for the lower dose of ketorolac in the setting of similar efficacy will also help more safely use this specific NSAID that can lead to AKI concerns more quickly as previously mentioned. Given this, the general recommendation is not to use scheduled ketorolac IV for more than five consecutive days—the approval studies did not study consecutive use for longer than this in human subjects, and there could be an increased risk of AKI development. That being said, if your patients cannot take medications orally after 5 days (and can be switched to an oral NSAID), risk versus benefit of extending therapy beyond 5 days should be considered, with a focus specifically on younger, healthy patients with no baseline or new renal insufficiency and no prior history of gastrointestinal (GI) ulcers or bleeding ulcers; daily checks of renal function and hemoglobin, hematocrit, and platelet counts are also recommended for safety monitoring.


Another side effect often discussed for NSAIDs is GI ulcer development and whether stress ulcer prophylaxis with a proton pump inhibitor (PPI) is required for scheduled NSAID therapy for postoperative pain control. To answer this question, we really should look at the patient’s risk factors for gastrointestinal toxicity with NSAID use. Joint guidelines from the American College of Cardiology, American College of Gastroenterology, and American Heart Association listed the following factors as high risk for GI toxicity and stress prophylaxis should be considered with NSAID use: history of ulcer disease or ulcer complication, patients on dual antiplatelet therapy, patients on anticoagulant therapy, and patients who meet two or three of the following criteria: age ≥60 years, glucocorticoid use, or dyspepsia or gastroesophageal reflux disease symptoms. Patients meeting these criteria may warrant stress ulcer prophylaxis. In this scenario, PPIs are preferred for improved effectiveness regarding ulcer prevention over histamine H2 receptor antagonists, such as famotidine or ranitidine. Additionally, the ease of once-daily dosing with PPIs is helpful for improving patient adherence. Duration of NSAID use should also be considered as short durations of use (<1 week) are considered relatively low risk regardless of the presence of other risk factors. If stress ulcer prophylaxis is warranted, an important piece to remember is to ensure that the PPI is stopped when the scheduled NSAID therapy is stopped. This can often be overlooked leading to possible long-term polypharmacy with an unnecessary PPI increasing the risk for significant adverse events ( Clostridium difficile infections, electrolyte/nutrient deficiencies, and osteoporosis-related bone fractures).


Another common misconception is that COX-2 selective inhibitors, such as celecoxib, are safer to use than nonspecific NSAIDs. While COX-2 selective inhibitors tend to carry a lower risk of gastroduodenal ulcer than nonspecific NSAIDs, the use of concomitant aspirin (including low-dose aspirin) negates this benefit. Additionally, COX-2 specific inhibitors have a similar to higher risk of myocardial infarction compared to other NSAIDs. This has led to the removal of rofecoxib and valdecoxib from the market. There is some data to suggest the risk of adverse cardiovascular events is dose dependent and can be mitigated by limiting celecoxib to a dose of no more than 200 mg per day. Alternatively, naproxen may carry some cardioprotective properties and therefore be the preferred agent in patients with risk factors for cardiovascular disease (prior history of cardiovascular event, diabetes, hypertension, hyperlipidemia, and obesity). Based on this increased cardiovascular risk, a general higher cost (more than $4 per 100 mg tablet of celecoxib vs. less than $1 per 500 mg tablet of naproxen) and typically more difficulty with obtaining insurance coverage for COX-2 selective inhibitors, we suggest using naproxen as the NSAID of choice when patients have cardiovascular risk factors.


Gabapentinoids


Overview


Gabapentinoids consist of a group of gamma aminobutyric acid (GABA) analogs, gabapentin and pregabalin. Although these agents have a close structural resemblance to GABA, they do not directly act on GABA receptors. However, they bind to voltage-gated calcium channels within the CNS to inhibit the release of excitatory neurotransmitters such as glutamate, norepinephrine, serotonin, and dopamine. , Both agents were originally designed to treat seizures but have become more commonly used for the treatment of neuropathic pain and potential synergistic effects when paired with other analgesics.


Gabapentin has a dose-dependent nonlinear absorption, while pregabalin exhibits linear absorption. Peak effects are reached within 1–2 h in a fasting state and 3–4 h when taken with food. Neither agent is hepatically metabolized and both are primarily eliminated unchanged through renal excretion. Half-life ranges from 4 to 8 h in the setting of normal renal function. See Table 8.1 for specific dosing recommendations.


Common adverse effects include the following: somnolence, dizziness, ataxia, headache, and tremor. Pregabalin is classified as a schedule V controlled substance due to increased reports of euphoria compared to placebo in clinical trials (4% vs. 1%, respectively). While gabapentin does not carry a controlled designation, misuse and abuse have increased significantly over the past several years as regulations on opioids have become more stringent. There are minimal clinically significant drug–drug interactions.


Use in otolaryngology surgery


Gabapentinoids, including gabapentin and pregabalin, have been studied as part of a multimodal analgesia regimen as well as in randomized, placebo-controlled trials in otolaryngology surgeries including sinonasal, head and neck, tonsillectomy, and adenotonsillectomy. Studies including meta-analyses have conflicting conclusions on whether gabapentinoids dosed either perioperatively or postoperatively are efficacious for reduced postoperative pain control or decreased analgesic rescue. However, most studies reported less nausea and vomiting with gabapentinoids, but increased incidence of dizziness and somnolence.


A meta-analysis evaluated randomized controlled trials to determine the efficacy of perioperative gabapentinoids for the management of postoperative acute pain in adults. Although 281 trials with over 24,000 patients were included, only 32 (10%) of trials with 2431 patients underwent ophthalmologic, maxillofacial, oral, and otolaryngologic surgeries. Gabapentinoids (including gabapentin and pregabalin) were administered as a single dose in 192 (68%) trials and multiple doses in 87 trials (31%). They were administered perioperatively, postoperatively, or both in 71%, 4%, and 25% of trials, respectively. For subgroup analysis, doses were considered high dose at 300 mg/day and above for pregabalin and at least 900 mg/day for gabapentin. Although there was slightly lower postoperative pain intensity at 6, 12, 24, and 48 h with gabapentinoids, this did not appear to be clinically significant. Gabapentinoids were associated with less postoperative nausea and vomiting but with more dizziness and visual disturbances. It was concluded that there was no clinically significant analgesic effect for perioperative gabapentinoids and use was not recommended.


Although the previous meta-analysis with a range of surgeries did not conclude benefit with gabapentin and pregabalin use, a systematic review of 15 randomized controlled trials with perioperative use of gabapentin in surgeries including tonsillectomy ( n = 4), rhinologic surgery ( n = 3), and thyroidectomy ( n = 3) did show benefit. Gabapentin doses ranged from 600 to 1200 mg for adults and 10–20 mg/kg for pediatric patients. Of the 15 trials, 13 used a single preoperative dose administered 1–2 h before anesthesia. The systematic review reported inconsistent results regarding gabapentin for perioperative pain control in tonsillectomies. Reductions in VASs were inconsistent. Of note, gabapentin was considered effective pain control for nasal surgery, with statistically significant reduction in VAS compared to control up to 24 h postoperatively ( p < .05). This was not demonstrated in a retrospective comparison of sinonasal surgery patients receiving either gabapentin 600 mg 1 h preoperatively or no gabapentinoid. Of note, approximately 6% of patients in the study were on chronic opioids. There was no significant difference in morphine equivalent doses or VAS scores between those that received gabapentin and those that did not. The authors concluded that perioperative gabapentin did not have an effect on postoperative pain or morphine equivalent doses. Lastly in a meta-analysis, four randomized, placebo-controlled trials reported reduced VAS pain scores with gabapentin administered perioperatively in thyroidectomies. Studies also reported less nausea and vomiting, with a higher incidence of dizziness and somnolence.


In head and neck surgery, a randomized controlled trial and retrospective cohort review examined patients undergoing head and neck mucosal surgery and free flap reconstruction. , Ninety adult patients received either gabapentin 300 mg twice daily before surgery and up to 72 h after surgery ( n = 44) or placebo ( n = 46). Oral morphine equivalents were similar between gabapentin and placebo groups. VAS scores were lower in the gabapentin group (after adjusting for differences in comorbidity and self-reported baseline pain levels). Patients reported higher satisfaction and less pain with gabapentin. There was less reported nausea in the gabapentin group, but again more dizziness. In the retrospective cohort study, patients received either gabapentin 600 mg before surgery ( n = 43) or did not (control, n = 43). Gabapentin was administered at 300 mg twice daily until postoperative day 5. APAP was also administered perioperatively and postoperatively. There was a statistically significant decrease in opioid consumption 5 days postoperatively and in daily pain scores. No adverse events occurred. The authors concluded that gabapentin is safe and effective.


A meta-analysis compared studies assessing preoperative gabapentinoids at a single dose from 300 to 1200 mg for postoperative pain after tonsillectomy. A total of eight articles were included. Like previous meta-analyses, there was significant heterogeneity between trials. The meta-analysis included both adult and pediatric patients. Gabapentinoids resulted in statistically lower postoperative resting pain at four and 8 h, but not 12 and 24 h. The same trend was determined for swallowing pain, with differences at 2 and 8 h postoperative (compared to control) but not at 12 and 24 h. The time to analgesic administration and analgesic requirements were lower for gabapentinoids compared to controls during the first 24 h. While the incidence of postoperative nausea and vomiting were lower in the postoperative period (first 24 h) compared to control, there was no significant difference in dizziness or sedation.


Two trials compared APAP to gabapentinoids in adenotonsillectomy and ESS. , In a double-blind randomized study, children either received gabapentin 10 mg/kg orally or paracetamol (APAP) 20 mg/kg orally 2 h before anesthesia. The gabapentin group had significantly lower pain scores (VAS scale) up to 8 h postoperatively, longer time to first analgesic, and less pethidine (meperidine) use compared to the APAP group. In the other randomized controlled trial, patients with nasal polyps received either pregabalin 50 mg three times daily or APAP 500 mg orally every 6 h for a total of 3 days. The VAS score was significantly lower in the pregabalin group at 12–72 h postoperatively compared to the APAP group. Adverse events such as nausea, vomiting, headache, and bleeding were less in the pregabalin group as well. This lead to the conclusion that gabapentinoids may have advantages over oral APAP for pain control in otolaryngologic surgeries.


Lastly, a head-to-head randomized controlled trial was performed comparing gabapentin to APAP. In a double-blind randomized control trial ( N = 60), children 7–15 years old undergoing adenotonsillectomy were assigned to receive either gabapentin at 10 mg/kg ( n = 30) or rectal APAP at 40 mg/kg ( n -30) preoperatively. There was no difference between groups at any time point up to 24 h after surgery in regards to pain, and both had a statistically significant decrease in pain intensity ( p < .001 for both groups). There was also no difference in the incidence of nausea and vomiting.


Common misconceptions


As seen in the literature review in this section, there are a few studies that showed no difference between gabapentin and placebo, but more studies indicated that the use of gabapentin in a multimodal pain regimen could reduce the use of opioids and may lead to improved subjective pain score reporting from patients. With this mixed literature on reduction in postoperative opioid use, there are multiple meta-analyses in various surgical specialties that have shown some clinically significant reduction in 24-h postoperative opioid consumption, though with varying doses of gabapentin and different opioids studied.


In clinical practice, the usual starting dose of gabapentin is 300 mg by mouth at bedtime, where dose and frequency titration (up to three times daily) should not occur more than every 3–4 days to allow the current dosing regimen to reach a steady state. This is important as gabapentinoids are known to cause somnolence and dizziness and should be dosed cautiously, especially in patients with renal impairment as well as older adults, where a lower starting dose of 100 mg by mouth at bedtime is common.


To note, pregabalin is often used in preoperative pain regimens given its longer half-life compared to gabapentin to help with immediate 24-h postoperative opioid sparing. That being said, in clinical practice the general recommendation is to trial gabapentin first for postoperative scheduled regimens as part of a multimodal pain plan. It is much less costly than pregabalin, which often requires prior authorization and proven failure after trialing gabapentin before insurance companies will assist with drug cost coverage.


Multimodal analgesia


Many surgery centers are contemplating an opioid-free postoperative approach to pain management. A retrospective chart review was conducted of adult patients undergoing thyroid and parathyroid operations, before and after implementation of an opioid-free analgesia protocol. The primary outcome was new postoperative opioid prescriptions, secondary outcomes were prescription characteristics (daily MME and days supply), as well as predictors of new opioid prescriptions. There were 240 patients in the preintervention group (May through October 2017) and 275 patients in the postintervention group (May through October 2018). The preintervention prescribing was traditionally hydrocodone/APAP (5/325 mg) 1–2 tablets every 6 h as needed for pain, for up to 10 days. This was at the discretion of the surgeon and practice differed among surgeons. In February 2018, the endocrine surgery group at the University of Kentucky implemented an opioid-sparing analgesia practice where patients would no longer receive opioid prescriptions postoperatively. Opioids were not discussed with or offered to patients and patients were instructed to take APAP 1000 mg every 6 h with ibuprofen up to 600 mg every 6 h. The time periods were selected to allow for an adequate 3-month washout period before and after the practice change. The opioid discharge prescriptions for the primary endpoint included buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, tapentadol, or tramadol. The only statistically significant demographic between the two groups was preoperative opioid use, which was higher (12.5%) in the control (preimplementation) compared to the intervention (2.9%; p < .001). Patients were less likely to receive opioids postoperatively in the intervention group (12.0% vs. 59.6%; p < .001). Those patients that did receive a prescription postoperatively had lower doses and shorter durations, but it was not statistically significant. Hydrocodone/APAP accounted for 75.8% of all new prescriptions pre- and postimplementation. The patients in the intervention cohort were prescribed significantly fewer pills per prescription (21 vs. 64; p < .001). The authors concluded that a simple practice change of utilizing APAP and NSAIDs is effective for analgesia after thyroid or parathyroid operations. They also noted that the study adds to existing evidence that opioid-free surgeries may be possible even in environments with high baseline opioid utilization.


While the use of both NSAIDs and APAP could be considered in multimodal approaches, more investigation to refine multimodal pathways has been underway. A review of perioperative multimodal nonopioid alternatives for sinus and skull base surgery demonstrated that opioids should be reserved for breakthrough pain management. Short-acting opioids are preferred over long-acting opioids for acute pain and the lowest reasonable dose to adequately control pain should be used to decrease misuse and overdose. Sinus surgery algorithms should begin with a preoperative assessment for medical and psychiatric comorbidities, medication review, history of chronic pain or substance abuse, postpostoperative pain plan, and checking the prescription drug monitoring program. Preoperative pain control should begin with anesthesia and the use of preoperative APAP, gabapentinoids, and α-2 agonists. Intraoperative pain control should involve tissue infiltration/nerve block with a local anesthetic. Postoperative pain control should include scheduled IV/PO APAP, scheduled IV/PO NSAIDs, a gabapentinoid, and oral opioids only for breakthrough pain. Discharge medication regimens should include scheduled APAP and NSAID, and if opioids are necessary the smallest dose and duration necessary should be used. Traditional NSAIDs utilized are ibuprofen, ketorolac, and celecoxib. Gabapentin is the most commonly used gabapentinoid.


An evidence-based review evaluated the studies behind specific multimodal agents and the benefit-harm assessment of their use in endoscopic sinus surgery. The review utilized many elements of a Cochrane review. A total of 32 studies with 1812 patients were included in the review. APAP has a preponderance of benefit over harm and may adequately control postoperative pain and reduce the immediate need for opioid rescue. NSAIDs require consideration of benefit versus harm as many patients undergoing sinus surgery have asthma or nasal polyposis and are NSAID intolerant. They may also help reduce postoperative opioid consumption and manage mild-to-moderate pain. α-2 agonists, such as dexmedetomidine or clonidine, also require careful analysis of benefit versus harm as there is a possibility of hypotension, bradycardia, and dry mouth. Their use has been associated with reduced anesthetic requirements and can help with anxiolysis, sedation, and attenuation of sympathoadrenal response to laryngoscopy and intubation as well as postoperative analgesia. Regional sinonasal analgesia via a peripheral nerve block or local anesthetic-soaked sinus packs also have a preponderance of benefit over harm. They can reduce the need for any additional rescue analgesia, have a quick onset, and are simple to administer. Finally, gabapentin also has a preponderance of benefit over harm and also has a role in the treatment of chronic pain. In conclusion, the authors recommend scheduling agents rather than prescribing “as-needed” administration can increase efficacy, especially with medications such as APAP.


Conclusion


In light of the growing opioid epidemic in the United States, the need to find new ways to manage pain while minimizing opioid use and prescribing is greater than ever. Multimodal pain management strategies are one avenue for combating this problem. As demonstrated in this chapter, the use of nonopioid analgesic combinations has the potential to improve perioperative pain management and decrease opioid utilization. However, definitive conclusions on the optimal combination, dosing, and duration of medications cannot be made due to a paucity of high-quality data. There is a continued need for more large-scale, well-designed clinical studies to evaluate pain management using robust multimodal focused perioperative protocols to fill this gap in knowledge.



References

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Feb 19, 2022 | Posted by in OTOLARYNGOLOGY | Comments Off on Nonopioid pain management in otolaryngology—head and neck surgery: the pharmacist’s perspective
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