Introduction
The two most common pediatric surgeries in the United States, tympanostomy tube insertion and tonsillectomy, are both performed by otolaryngologists. For this reason, a contemporary understanding of pediatric perioperative pain control is critical for otolaryngologists. The majority of these procedures are performed on an outpatient basis, with selected patients requiring one night of monitored observation after tonsillectomy. Anticipated postoperative pain and perioperative risks differ greatly between these two procedures, and the challenges of pain management usually take place after discharge. A variety of pharmacologic and nonpharmacologic strategies for perioperative pain management in children have been studied, with the goal of improving postoperative patient comfort while minimizing the likelihood of dangerous side effects. Commonly used medications include acetaminophen, nonsteroidal antiinflammatory drugs (NSAIDs), and opioids. This chapter discusses current issues and recommendations with the use of these analgesic classes and presents nonpharmacologic adjuncts for perioperative pain control in children. Although we focus on care after adenotonsillectomy or tympanostomy tube placement, the strategies discussed in this chapter can be adapted to other procedures in children, acknowledging that pharyngeal surgery usually causes significant pain with the need for aggressive management strategies. ,
Special considerations for pain management in children
Pain control in pediatric patients requires several special considerations. Unlike adult patients undergoing otolaryngologic procedures, young children are not usually able to perform their own pain assessments, communicate pain severity, or administer their own pain medications. Instead, it falls upon parents or caregivers to both assess the child’s pain level and administer appropriate types and dosages of analgesics. These caregivers must be educated to recognize the signs and symptoms of uncontrolled pain as well as early signs of overmedication to avoid potentially serious consequences from improper analgesic dosing.
The most obvious difference between pediatric and adult pain management is patient size. Given the variation in size and weight among children of all ages, ideal weight-based dosing is critical to achieving therapeutic effects. The smaller the patient, the narrower the margin of error to achieve levels within the therapeutic window. For example, a study of posttonsillectomy pain control in the United Kingdom, where over-the-counter acetaminophen and ibuprofen are dosed by age rather than weight, found that implementation of standardized weight-based dosing significantly improved the readmission rate for pain control without impacting postoperative hemorrhage rate.
Many opioid medications are dependent upon the cytochrome P450 2D6 (CYP2D6) pathway for breakdown into their active metabolites ( Table 5.1 ). Well-described variation in CYP2D6 activity exists, leading to four phenotypes of poor metabolizers, intermediate metabolizers, extensive metabolizers (considered “normal”), and ultrarapid metabolizers. Whereas ultrarapid metabolism and higher serum concentrations of an active metabolite may not exceed the wider therapeutic window in adults, this phenotype has been associated with respiratory depression and even death in young children after surgery.
| Opioid | Enzymes of metabolism | Metabolites | FDA warnings |
|---|---|---|---|
| Codeine | CYP 2D6; CYP 3A4; UGT 2B7 | Morphine (active); norcodine; codeine-6-glucuronide (active) | Box warning against use in posttonsillectomy pain; contraindicated for treatment of pain or cough in age <12; warning against use in age 12–18 with obesity, OSA, or severe lung disease |
| Tramadol | CYP 2D6; CYP 3A4 | O-desmethyl-tramadol (active) | Contraindicated for treatment of pain in age <12; Contraindicated for posttonsillectomy pain in age <18 |
| Morphine | UGT 2B7 | Morphine-6-glucuronide (active); morphine-3-glucuronide | |
| Hydromorphone | UGT 1A3; UGT 2B7 | Hydromorphine-6-glucuronide (active); hydromorphine-3-glucuronide | |
| Oxycodone | CYP 3A4; CYP 2D6 | Noroxycodone (active); oxymorphone (active) | |
| Hydrocodone | CYP 2D6; CYP 3A4 | Hydromorphone (active); norhydrocodone (active) |
Given the role of caregivers in managing postoperative pediatric pain in the outpatient setting, education of these caregivers before discharge, and perhaps at the time of presurgical counseling, is essential. Parents can be taught to use behavioral pain scales to assess pain levels at routine intervals. Studies demonstrate that although caregivers are able to recognize pain in children, they often underdose analgesics. , Pain management education starts preoperatively and should be incorporated into the discussion of risks and benefits of surgery. Perioperative staff, such as preoperative and postanesthesia care unit (PACU) nurses, play a central role in parental education and should reinforce analgesic dosing recommendations, teach parents the signs of pain, and detail the side effects of the prescribed medications. A standardized program including teaching in the PACU with an educational booklet, use of a timer to adhere to the analgesic regimen, instructions on how to accurately measure doses, use of a pain management diary, and reinforcement/coaching through telephone calls can be effective for parental education. An educational booklet or video has been shown to increase parental knowledge about managing their children’s pain. ,
Caregiver education is particularly critical when opioids are prescribed. Evidence suggests that parents may not understand the risk of oversedation in children with obstructive sleep apnea syndrome (OSAS), and half of the parents in one study would give an opioid medication when their child exhibited signs of oversedation, demonstrating the need for improved education to recognize and manage signs of opioid toxicity. Implementation of provider education to use nonopioid analgesics first in conjunction with a guideline reducing the number of oxycodone doses prescribed after tonsillectomy resulted in both decreased opioid prescription quantity and higher odds of good pain control. Otolaryngologists should also recognize that cultural factors such as ethnicity may affect how caregivers assess and treat pain. Such education should balance our efforts to improve pain control after uncomfortable procedures like tonsillectomy with the imperative to avoid adverse drug reactions.
Tympanostomy tube placement
Myringotomy with insertion of tympanostomy tubes is the most commonly performed pediatric surgical procedure in the United States. Pain following tympanostomy tube placement is neither severe nor long lasting. Given the short duration and limited nature of the procedure, inhalational anesthetics are typically used and intravenous (IV) access is often not required. However, inhalational anesthetics are associated with higher rates of emergence delirium, which typically lasts 5–15 min. While this is usually limited in time and severity, it may result in injury to self or others. The mechanism of emergence delirium is not clear; however, pain, anxiety, and anesthetic choice are all thought to contribute.
Studies have evaluated varying approaches to preoperative, intraoperative, and postoperative analgesia for tympanostomy tube placement, both with regards to pain control and reduction of emergence delirium. No obvious benefit has been observed with one analgesic regimen compared to another, and most patients are managed postoperatively with acetaminophen and/or ibuprofen as needed. Prescription pain medications are typically not required. A randomized controlled trial (RCT) found no benefit in postoperative pain control when children were premedicated with acetaminophen and ibuprofen before tympanostomy tube placement. A large retrospective study found superior analgesia when a combination of intramuscular fentanyl and ketorolac were administered. However, another retrospective study found that choice of intraoperative analgesic among fentanyl, ketorolac, or a combination had no impact on postoperative pain control or time to discharge. Intraoperative acupuncture has been shown to reduce postoperative pain and agitation following tympanostomy tube insertion; however, this has not been widely adopted or studied.
Emergence delirium was reduced with the administration of a single IV dose of propofol and ketorolac at the conclusion of sevoflurane anesthetic for tympanostomy tube placement in a prospective observational study. However, most children undergoing tympanostomy tube placement do not require IV access and such intervention may be neither practical nor time- and cost-effective. Although dexmedetomidine is used both in the management and prevention of pediatric emergence delirium, a retrospective study of intranasal dexmedetomidine before tympanostomy tube placement found no reduction in emergence delirium scores or duration of PACU stay with its use.
Tonsillectomy and adenoidectomy
After myringotomy with insertion of tympanostomy tubes, tonsillectomy is the second most common pediatric surgical procedure performed in the United States. Tonsillectomy and adenotonsillectomy, like other pharyngeal procedures, are associated with severe pain that is often poorly controlled. Pain after tonsillectomy has a stereotypic course with worsening later in the first postoperative week. Pain after tonsillectomy appears to be more severe and long lasting than after orchiopexy or inguinal hernia repair in children. In general, adenoidectomy alone causes significantly less pain than tonsillectomy, and our discussion in this chapter, like the bulk of the research, is focused on tonsillectomy or adenotonsillectomy.
Poorly controlled oropharyngeal pain is the primary cause of morbidity after tonsillectomy in children, and this may lead to a reduction in oral intake with subsequent dehydration or weight loss. Studies have found that dehydration, hemorrhage, and throat pain are the three most common reasons for unplanned posttonsillectomy emergency room (ER) presentations. , Additional reasons for presentation included nausea and vomiting, respiratory issues, and fever. , Poor pain control and choice of analgesic regimen are likely involved with each of these potential complications.
Opioids
OSAS represents the most common indication for tonsillectomy (or adenotonsillectomy) in children. Patients with sleep apnea have a unique sensitivity to opioids with regard to respiratory depression, and this is further complicated by impaired upper airway function from postoperative swelling as well as the effects of general anesthesia. Administration of opioids, given their dose-dependent risk of sedation and respiratory depression, is particularly fraught in this high-risk population. Although tonsillectomy usually improves and often cures OSAS in children, the improvement is not immediate, and in fact sleep-related airway obstruction may worsen transiently in the immediate postoperative period.
This risk of respiratory depression with opioid use in “typical” OSAS patients after tonsillectomy is further compounded by the known variation in the rate of metabolism of certain opioid preparations. Several commonly used opioids, including codeine, are metabolized by the CYP2D6 pathway into active morphine metabolites ( Table 5.1 ). Ultrarapid metabolizer phenotypes with duplication of the CYP2D6 allele can cause rapid accumulation of active metabolites to supratherapeutic levels, leading to accelerated sedation and respiratory depression even with standard opioid dosing.
Although respiratory depression is the most severe risk associated with opioid use in children, other side effects may make opioids intolerable for some. Gastrointestinal side effects such as nausea, vomiting, or constipation can compound pain-related difficulties with reduced oral intake and worsen dehydration. Additional bothersome adverse effects include lightheadedness/dizziness, dry mouth, itching, and rash.
Prescription opioids also have the potential for misuse and abuse in adolescents, who are thought to be even more susceptible than adults due to the sensitivity of reward centers in the adolescent brain. , An analysis of a large commercial claims database found that 4.8% of opioid-naïve patients aged 13–21 continued to refill opioid prescriptions 90–180 days after tonsillectomy. Although older children and adolescents may be less vulnerable to respiratory depression, habit formation and potential for opioid misuse is an important consideration in this age group. Opioid prescriptions, even for children, should be accompanied by education regarding appropriate secure storage, cessation of medication when pain abates, and methods for disposal of unused medication.
Codeine
Historically, codeine, usually combined with acetaminophen, was the most commonly prescribed medication used for the management of posttonsillectomy pain. However, in 2009, a report of the codeine-related posttonsillectomy death of a 2-year-old with obstructive sleep apnea (OSA) who had a duplication of the CYP2D6 allele raised awareness of the risk of codeine administration in patients with this ultrarapid metabolizer phenotype. In 2013, after a review of similar cases, the FDA issued a new box warning (its strongest warning) against the use of codeine for posttonsillectomy pain management in children. In 2017, the FDA expanded this advisory to a contraindication against the use of codeine for the treatment of pain or cough in children under 12, and a warning against its use in adolescents age 12–18 with obesity, OSA, or severe lung disease. A review of the FDA Adverse Event Reporting System (FAERS) from 1969 to 2015 identified 24 codeine-related deaths in children under 18, 21 of which occurred in children under the age of 12. Many of these patients were ultrarapid or extensive metabolizers, leading to supratherapeutic morphine levels that can be especially dangerous in the posttonsillectomy OSAS population. Unfortunately, preprocedural screening for CYP2D6 polymorphisms would be impractical and has not been shown to correlate with clinical phenotype.
On the other end of the spectrum, the subset of patients belonging to the “poor metabolizer” phenotype is unable to metabolize codeine to its active metabolite and therefore derive minimal analgesia from its administration. RCTs have found no difference in pain control with acetaminophen with codeine compared to either acetaminophen or ibuprofen alone in children after tonsillectomy. Codeine use was associated with increased nausea and decreased tolerance of a normal diet in these studies. , All of these data taken together indicate that the risks of codeine far outweigh the benefits in children, and codeine administration has decreased substantially in recent years. However, despite the strongest FDA warnings, 1 in 20 children who underwent a tonsillectomy in 2015 still received a prescription for codeine.
Tramadol
Tramadol is a synthetic codeine analog that is a weak opioid receptor agonist and has been proposed as a safer alternative to codeine for pediatric posttonsillectomy pain. However, in a review of its FAERS database from 1969 to 2016, the FDA identified nine reports of respiratory depression in children under 18 including three deaths in children under 6. Based on this data, in 2017, the FDA released a contraindication against tramadol use for the treatment of all types of pain in children under 12 and against its specific use for posttonsillectomy pain in children under 18. Similar to codeine, tramadol is also dependent upon CYP2D6 for conversation to its active metabolite, and ultra-rapid metabolizer status may contribute to tramadol-associated respiratory depression.
Hydrocodone, oxycodone, and morphine
Oxycodone is metabolized largely by pathways other than CYP2D6, and morphine is an active agent without metabolism, and therefore these drugs have been proposed as safer opioids for treating posttonsillectomy pain in children. However, these narcotics are stronger opioid receptor agonists than codeine or tramadol, and they may cause serious side effects regardless of methods of metabolic breakdown and pharmacogenomic effects. Stronger opioid receptor stimulation may lead to more severe respiratory depression in high-risk OSAS patients. An RCT comparing oral morphine to ibuprofen found increased desaturation events on the night of tonsillectomy/adenotonsillectomy in the morphine group, with improved oxygen saturations in only 14% of the morphine group compared to 68% of the ibuprofen group, and no difference in other side effects. Brown et al. found that children with OSAS are more sensitive to both respiratory depression and analgesic effect of opioids, and therefore urge caution when dosing opioids in this group.
There is no such thing as a “safe narcotic” for all children undergoing tonsillectomy. Each child’s particular risk factors, such as the severity of OSAS, young age, and presence of comorbidities such as obesity or lung disease must be considered when making decisions regarding the use and dosing of opioids after tonsillectomy. Additionally, high-risk patients who appear to require opioids for successful pain control should have therapy started in a monitored setting with conservative dosing. These risks must be weighed against the ability to provide equivalent analgesia with nonopioid medications.
Acetaminophen
Acetaminophen is the most commonly used medication in children. Although generally considered to be one of the safest analgesics, acetaminophen is associated with the risk of hepatic injury with prolonged use, high doses, or in patients with preexisting liver conditions. Although acetaminophen is commonly used after tonsillectomy, it is often inadequate to provide satisfactory pain control when used on its own. The 2019 American Academy of Otolaryngology-Head and Neck Surgery (AAOHNS) clinical practice guideline on tonsillectomy in children included a strong recommendation for “ibuprofen, acetaminophen, or both for pain control after tonsillectomy.” Although IV acetaminophen is expensive, its use in the immediate postoperative period has been shown to reduce overall costs by decreasing side effects and time spent in PACU.
Nonsteroidal antiinflammatory drugs
Ibuprofen is now commonly used as an effective alternative to opioids for posttonsillectomy analgesia, especially with the recognition of the risks of opioids in this setting. However, concerns regarding potential increased bleeding risk with NSAID use continue to stimulate debate. The 2019 AAOHNS guideline strongly supports ibuprofen use after tonsillectomy but describes ketorolac use as controversial. Both a Cochrane review and a meta-analysis of 18 RCTs found no association between NSAID use and posttonsillectomy hemorrhage. , Systematic reviews have also identified decreased risk of nausea and vomiting with NSAIDs compared to opioids. , , Several single-center studies compared their tonsillectomy patients historically treated with codeine with those more recently treated with ibuprofen and found no change in the incidence of bleeding complications.
On the other hand, a recent multicenter noninferiority RCT of 688 children randomized to ibuprofen or acetaminophen could not exclude a higher rate of severe bleeding requiring operative intervention in the ibuprofen group. A meta-analysis of RCTs and cohort studies found a possible increased tendency to bleeding with ibuprofen use, and a systematic review observed more reoperations due to bleeding in patients treated with NSAIDs.
It has been suggested that dosing intervals may play a role in the risk of posttonsillectomy hemorrhage with NSAID use. A retrospective study found a reduction in posttonsillectomy hemorrhage rate and posttonsillectomy ER visits after spacing out alternating doses of acetaminophen and ibuprofen from every 3 h to every 4 h, without an increase in phone calls regarding pain.
Ketorolac is not commonly used after tonsillectomy due to even greater concerns regarding hemorrhage risk. Bleeding rates of 4.4%–18% after tonsillectomy were observed in trials of ketorolac use, leading the 2011 AAOHNS clinical practice guideline to recommend against its use in children after tonsillectomy. Although children have a smaller increase in bleeding risk with ketorolac use after tonsillectomy than adult patients, and the 2019 updated guideline no longer explicitly recommends against ketorolac, its use remains highly controversial.
Steroids
Steroids have been proposed as a nonnarcotic adjunct for pain control after tonsillectomy. The 2019 AAOHNS clinical practice guideline on tonsillectomy in children strongly recommends the administration of a single intraoperative dose of IV dexamethasone. This practice decreases postoperative nausea and vomiting, which can contribute to postoperative dehydration. An observed elevated bleeding risk with dexamethasone use in one study has not been replicated in a number of other studies or substantiated by meta-analyses. , , Although intraoperative steroid administration has become standard of care, there is conflicting evidence supporting postoperative steroid use. Two randomized double-blind, placebo-controlled trials found no benefit to a postoperative course of oral prednisolone, , whereas one nonblinded nonplacebo-controlled randomized trial found improved pain scores with its use. A recent blinded RCT found improved pain control and fewer ER visits and phone calls with a single oral dose of dexamethasone administered on postoperative day 3, suggesting that choice of steroid and timing of administration may influence efficacy.
Opioid sparing regimens
Most major centers have adopted NSAIDs and acetaminophen as the centerpiece of posttonsillectomy pain management in children. A retrospective review of 583 patients who received alternating doses of ibuprofen and acetaminophen after tonsillectomy found a 90.4% rate of adequate pain control without an increase in postoperative hemorrhage rate. An RCT comparing oral morphine and acetaminophen to ibuprofen and acetaminophen found no difference in pain control. Evaluation of oral morphine for breakthrough pain in addition to acetaminophen and ibuprofen also found no added benefit. RCTs have shown no difference in pain control in children treated with acetaminophen with codeine compared with either acetaminophen or ibuprofen alone. A parental survey found no difference in parental satisfaction or inadequate pain control with acetaminophen and ibuprofen compared to hydrocodone and acetaminophen. Interestingly, in an RCT of 152 children the combination of ibuprofen and acetaminophen did not provide superior pain control compared to either medication alone. All of these studies indicate that equivalent pain control can be achieved with opioid-sparing regimens, while avoiding the known risks of opioid administration. Experienced clinicians recognize that some of the “equivalence” of opioid and opioid-sparing regimens may actually reflect inadequate pain relief for some of the postoperative periods no matter what medications are prescribed.
Enhanced recovery after surgery pathways have been implemented in a variety of settings to optimize perioperative outcomes in adults, but have not been widely used in pediatric perioperative management. However, studies have demonstrated the advantages of standardized multimodal protocols for posttonsillectomy pain management. A recent study of discharge order set implementation demonstrated a significant reduction in opioid prescriptions, ER visits for posttonsillectomy dehydration, and pain with a standardized regimen of acetaminophen, ibuprofen, and opioid. An increase in readmission for posttonsillectomy hemorrhage was observed in this study; however, this finding has not been replicated in other studies of nonopioid regimens. ,
At the Johns Hopkins Children’s Center, we primarily use opioid-sparing protocols for children after tonsillectomy and adenotonsillectomy ( Table 5.2 ). The decision to prescribe opioids is based on (1) age , where children younger than 6 years are prescribed acetaminophen and ibuprofen, and children 6 years and older can receive also an opioid prescription, and (2) plan for postoperative care , where any child who is scheduled for overnight observation or hospital admission does not receive opioids after the immediate perioperative period in the PACU. The decision to admit or observe after adenotonsillectomy is made based on the known clinical risk factors for respiratory compromise, and thus is a proxy for the severity of obstructive sleep apnea in a given patient. , We use oxycodone when an opioid is prescribed, to avoid combination medications and to provide an opioid that is not primarily metabolized with the CYP2D6 pathway.
