Multimodal Analgesia for Management of Pain in Critically Ill Children

Jordan was a 10-year-old child with no past medical history who sustained polytrauma after an 18-foot fall. Their resultant injuries included abdominal trauma, pelvic fracture, left femur fracture, and left radial fracture. Following their initial exploratory laparotomy, bowel resection with anastomosis, and open reduction and internal fixation of their fractures, they were transferred to the pediatric critical care unit for mechanical ventilatory support and hemodynamic monitoring. Jordan was extubated on postoperative day 1.Adequate, timely management of pain reduces the numerous adverse physiologic and psychological effects associated with pain. Physiologic effects include cardiovascular (hypertension and increased oxygen demand), respiratory (tachypnea, shallow breathing, and atelectasis), immune (increased susceptibility to infection), endocrine (hyperglycemia and increased cortisol), gastrointestinal (slow gastrointestinal motility), musculoskeletal (guarding and muscle tension), and changes in central nervous system pain processing.1 Poorly controlled pain is also associated with impaired sleep, reduced quality of life, and impaired physical function. In a critically ill child, it is imperative to avoid the consequences of untreated pain, as the negative physiologic and psychological effects of pain may impede recovery from their underlying illness or injury.Following extubation, Jordan remained still and minimized movement. Their breathing was shallow and their respiratory rate was 24. Jordan intermittently experienced hypertension, with systolic measurements in the 130s and diastolic measurements in the 90s.Management of pain in the pediatric population presents unique challenges, given that age or developmental status may limit the clinician’s ability to assess, and, in turn, appropriately treat their pain. In the critically ill population, this challenge may be further compounded by sedation or delirium.Multiple validated tools (Table) exist for assessment of pain in infants and children, although most clinicians use the numeric rating scale, in which a patient assigns a value between 0 (no pain) and 10 (worst possible pain) to describe their pain.2 For children with developmental delays or cognitive impairments, or those who are too young to self-report or are medically sedated, it is crucial to use alternative tools to ensure appropriate assessment. The Faces, Legs, Activity, Cry, and Consolability–Revised Scale uses observable characteristics to assign a numeric value to the pain of a child who is otherwise unable to self-report.3 The Comfort Scale and Comfort–Behavior (Comfort-B) Scale assess distress in children who receiving ventilatory support or who are in the intensive care unit, and are most useful in assessing children who are sedated.4 For neonates, the Neonatal Pain Agitation Sedation Scale tool provides a validated assessment option that encompasses pain, agitation, and sedation.5In addition to validated tools, clinicians should use the following sequence in children who are unable to self-report pain: be aware of potential causes of pain, attempt to obtain self-report, observe patient behaviors, solicit proxy (parent/caregiver) report, and, finally, attempt an analgesic trial.8 Clinicians should also assess non–pain-related sources of discomfort or distress.9 In children, this may include fear or anxiety related to hospitalization. Additionally, the clinical team should attempt to obtain additional information about the patient’s pain through detailed symptom analysis, observation, and physical examination.While Jordan received ventilatory support and sedation, their pain was assessed using the Comfort-B Scale, producing a score of 17, indicating comfort; after extubation, they were able to self-report their pain using the numeric rating scale. Jordan consistently rated their pain 9/10 on the numeric rating scale on postoperative day 1. Jordan demonstrated anticipatory anxiety prior to any assessments or repositioning.Thorough assessment of pain helps clinicians to determine whether pain is present continuously versus intermittently. Treatment selection should be based upon the pattern of pain—that is, if pain is continuous, around-the-clock analgesia should be provided.10 If pain is intermittent or related to a procedure, analgesia can be planned around the time of the procedure. Rational polypharmacy, the intentional use of multiple medications with different mechanisms of action at lower doses, can help to reduce adverse effects and synergistically improve pain control.11Jordan described their pain as continuous; pain would increase with movement and with palpation of the abdomen. Pain in the abdomen was described as deep and aching; pain in the pelvis was described as sharp. Jordan also endorsed occasional tight, squeezing pain in the lower back and across the abdomen.Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common nonopioid analgesics and, when combined or alternated, have a similar efficacy to low potency opioid medications.11 Although the effects of acetaminophen are not fully elucidated, the analgesic effects are likely due to the activation of descending serotonergic pathways in the central nervous system.12 NSAIDs block the action of cyclooxygenase, which is an enzyme that converts arachidonic acid to prostaglandins responsible for inflammation and pain.11Acetaminophen provides modestly inferior pain control when compared to NSAIDs, although it has fewer considerations for patients with comorbidities. Specifically, NSAIDs must be used with caution in children with renal disease, coagulopathies, cardiovascular disease, and those at risk for gastrointestinal side effects.11 Additionally, NSAIDs are not recommended for children under 6 months of age, whereas acetaminophen can be used in the neonatal period. Both acetaminophen and NSAIDs may be administered intravenously (IV) if contraindications to enteral administration exist.11Jordan received IV acetaminophen every 6 hours beginning on postoperative day 0. The surgical team requested to hold initiation of ketorolac, an NSAID, until postoperative day 2 as they monitored Jordan’s hemodynamic status. Ketorolac was then initiated for a 5-day course; Jordan was later transitioned to ibuprofen every 6 hours once they were tolerating oral intake.Opioid agonists exert their effects by binding to the μ and κ opioid receptors within the central and peripheral nervous systems.11 There is significant variability in individual responsiveness to opioid medications related to genetic polymorphisms, as well as previous exposure to opioid medications and experiences with pain. Opioids remain an important intervention for pain management but should always be used for the shortest duration at the lowest possible dose due to the possibility of developing tolerance and dependence.Several IV opioids are commonly used within pediatric critical care: morphine, hydromorphone, and fentanyl. Selecting the appropriate opioid for treatment should include considerations regarding the desired pharmacokinetics and adverse effect profile.Morphine has a duration of action between 3 and 5 hours, providing a longer duration of coverage compared with other opioids.13 Morphine undergoes glucuronidation, a metabolic pathway in which glucuronic acid is added to the drug by the liver to help the drug clear renally; neurotoxic metabolites can accumulate in patients with reduced creatinine clearance. Use cautiously in children with significant renal or hepatic impairment. Morphine is also associated with relatively more histamine-related adverse effects effects, such as pruritis.13Hydromorphone has a duration of action between 3 to 4 hours, similar to morphine.14 It is also metabolized via glucuronidation and should be titrated cautiously in children with renal or hepatic impairment. Compared with morphine, it has fewer histamine-related adverse effects, making it a good option for patients experiencing pruritis with morphine administration.Fentanyl administered IV has a duration of action between 30 minutes and 1 hour, significantly shorter than morphine or hydromorphone.15 This is beneficial when providing analgesia during short procedures. Fentanyl is metabolized via CYP3A4, leading to substantial interactional potential with many medications. Inhibitors of CYP3A4, such as clarithromycin or ketoconazole, can increase opioid concentrations, while inducers for CYP3A4, such as phenobarbital, can reduce analgesic efficacy.16Within the critical care setting, opioids are often inappropriately used for sedation versus pain management. Exposure to high doses of opioids can lead to tolerance, dependence, and opioid-induced hyperalgesia—a paradoxical phenomenon in which an individual experiences increasing pain symptoms with escalating opioid doses. This phenomenon has been shown to occur even in healthy individuals without prior exposure to opioids.17 Patients may receive escalating doses of opioids that are, in fact, inadvertently increasing their pain. Opioids should be limited to managing pain, whereas α-adrenergic agonists should be used as first-line sedative agents.18Jordan initially received a combination of dexmedetomidine and fentanyl for sedation; in preparation for extubation, these medications were weaned. The fentanyl infusion was transitioned to a patient-controlled analgesia (PCA) pump delivering both demand and continuous morphine. The morphine PCA was changed to hydromorphone on postoperative day 2 due to significant pruritis with morphine.Ketamine is an N-methyl-D-aspartate receptor antagonist that blocks glutamate. Low, subanesthetic doses produce analgesia and modulate central sensitization, hyperalgesia, and opioid tolerance.19 Ketamine has a favorable safety profile, although it can increase myocardial oxygen demand and cause vivid dreams or hallucinations. In patients with increasing opioid requirements, refractory pain, or sedation needs, ketamine can serve as a helpful adjunctive agent.18 Some children and adolescents may report dysphoria and bad dreams while receiving ketamine therapy; it is imperative to routinely assess and adjust treatment based on their response.Jordan required significant opioid escalation on postoperative day 2 with attempts to increase in-bed mobility. With the escalation in dose, Jordan began to experience increased sedation and intermittently had a reduced respiratory rate. A subanesthetic ketamine infusion was initiated with the goal of reducing opioid requirements. On postoperative day 3, Jordan reported an improvement in pain control and less sedation; they experienced some vivid dreams that were manageable after receiving reassurance from family and clinical staff.Adjunctive medications including muscle relaxers, anticonvulsants, antidepressants, and topical agents address other symptoms that may contribute to ongoing discomfort or provide analgesia through alternate pathways. By addressing pain and discomfort with nonopioid medications, it is possible to reduce overall opioid requirements and exposure.Both prolonged immobility and many surgical procedures can lead to increased muscle tension and/or muscle spasms. If a child endorses discomfort associated with a squeezing or tight sensation, they may benefit from the addition of a muscle relaxer. Benzodiazepines, which inhibit γ–aminobutyric acid receptors, are commonly used for muscle tension and spasm, as they are available in parenteral and enteral formulations and can be used in younger patients.11,20 Although effective, they are associated with high abuse potential and increase the risk of respiratory depression when used concurrently with opioids. Benzodiazepines have also been associated with the development of delirium. Cyclobenzaprine and tizanidine are skeletal muscle relaxants available only in enteral formulations; both are effective but are most studied in the adolescent and young adult populations, with limited evidence for younger patients.11,21,22 Baclofen, which inhibits the transmission of synaptic reflexes at the spinal cord level, is most commonly used for spasticity but can also be effective for muscle spasm or musculoskeletal pain.23 It is available in enteral and intrathecal formulations and is studied in children over 2 years of age.Anticonvulsants, namely gabapentinoids, can be helpful in managing neuropathic pain that can develop after procedures, secondary to a medical condition, or in the context of a primary pain disorder.11 If patients describe pain as burning, shooting, and/or tingling or have pain which is refractory to other analgesics, they may benefit from a gabapentinoid. Gabapentin and pregabalin dampen neuronal excitability, producing pain relief over time; it is important for patients and families to understand that maximum pain relief benefits from these medications occur over a period of days to weeks.24,25 As such, these medications are typically used when neuropathic pain is expected to persist beyond several days; they have less utility in providing immediate analgesia. Gabapentin is typically considered first-line treatment for neuropathic pain conditions due to its favorable adverse effect profile, effectiveness, and few major drug interactions. It does have decreased bioavailability with increasing doses.11 Pregabalin has better bioavailability but is associated with greater weight gain.11 Mood and behavioral changes can occur in some children and adolescents after initiation of gabapentinoids; patients should be monitored closely for these changes.24,25Antidepressants provide pain relief by blocking the presynaptic uptake of serotonin and norepinephrine in the central nervous system, which enhances descending inhibitory pain pathways.11 They are best used when pain is persistent or chronic in nature, as they must be administered over weeks to months in order to provide maximum pain relief benefits. Tricyclic antidepressants (eg, amitriptyline and nortriptyline) and serotonin-norephinephrine reuptake inhibitors (eg, duloxetine) are most commonly used for this indication, and are most studied in adolescents and young adults. They are generally not appropriate for infants and children. Tricyclics can be sedating and have anticholinergic side effects at increasing doses. Duloxetine is generally well tolerated, with nausea being the most common adverse effect.11Topical agents, such as lidocaine, are an excellent option for localized pain. Lidocaine is a local anesthetic that inhibits excitation of nerve endings by binding to and inactivating sodium channels.11,26 It is available in emollient (cream and ointment) and patch forms; it has a favorable safety profile in patch form. This may be helpful for localized pain, such as pain related to a chest tube or surgical incision site; lidocaine must be applied around the area but never on broken skin. Lidocaine can be used from the neonatal period onward.11Jordan demonstrated visible muscle tension and guarding and continued to describe intermittent squeezing and tightness throughout the lower back and abdomen. To manage these symptoms, diazepam IV every 6 hours as needed was added to the pain management plan to address muscle spasms. Additionally, a lidocaine 5% patch was applied to the lower back.Jordan’s pain was not adequately managed on a singular agent, but, rather, required a multimodal approach with multiple mechanisms of action. By using a multimodal approach, Jordan experienced fewer medication-related adverse effects and achieved more complete pain control. They also experienced less tolerance and physiologic opioid dependance, as pain was not controlled on an opioid medication alone. Aggressive management of their pain allowed them to mobilize quickly, reducing morbidity risks and leading to a timelier discharge.Critically ill pediatric patients often experience pain during the course of their treatment related to surgery, procedures, prolonged immobility, and/or the development of nociplastic pain. Children are at particular risk of under-treatment of pain because age or developmental status may impede their ability to communicate regarding their pain. It is imperative to support the delivery of multimodal pain management within the pediatric critical care population, with the goals of expediting recovery and minimizing harm or side effects related to treatment. Treatments should always be individualized to the child’s pain location, prior pain and treatment experiences, and treatment response; treatments should furthermore be dynamic and tailored to the patient’s ongoing clinical status.