NMDA‐receptor Antagonism in Pediatric Pancreatitis

Pancreatitis can be associated with severe and complex pain, which requires a comprehensive strategy with broad therapeutic options (1). This is a problem in pediatrics where pain is generally under-recognized and inadequately treated (2). This is, in part, due to a dearth of evidence, safety data, and approved indications for the use of many analgesic medications, which can limit the therapeutic options of medical prescribers. Opioids remain the mainstay of therapy for severe pain, although these agents carry significant adverse effects including, paradoxically, opioid-induced hyperalgesia which may manifest as abdominal pain that is challenging to distinguish from pancreatic pain. The pathophysiology of pancreatic pain is incompletely understood. There are anatomic and clinical indicators of neuropathic pain in patients with chronic pancreatic pain, including pancreatic neuritis, pancreatic neural hypertrophy and hyperplasia, as well as hyperalgesia and allodynia (1). Pediatric neuropathic pain can be successfully treated using N-methyl-D-aspartate (NMDA)-receptor antagonist medications, such as ketamine (3) and methadone (4), and accordingly, emerging evidence from adults with acute and chronic pancreatic pain can demonstrate a favorable response to ketamine (5,6). These medications, however, lack indications and safety data for use as analgesia in pediatrics. There is increasing evidence demonstrating opioid-sparing effects of ketamine at subanesthetic doses (7–9), including its use in children with toxic megacolon (10) and acute injuries (11). Ketamine may be administered via oral, intranasal, subcutaneous, or intravenous routes. Dosing may be intermittent or, for the latter 2 routes, as a continuous infusion. Possible adverse effects include dissociation, hallucinations, blurred vision, nausea, tachycardia, hypertension, transaminitis, and animal studies suggest a risk of toxicity to the developing brain (12). No studies were identified that describe the use of NMDA-receptor antagonists in pediatric pancreatitis. Here, we report the off-label use of ketamine and methadone in a teenager with refractory pain due to pancreatitis. In this case, the use of these medications resulted in dramatically improved pain control with substantially reduced opioid requirements. CASE DESCRIPTION A 13-year-old, 90-kg boy presented with severe pain secondary to acute necrotizing pancreatitis and pseudocyst formation. His mother experienced chronic pancreatitis, suggesting a genetic predisposition. Genetic testing is negative for mutations in SPINK1, PRSS1, CFTR (common mutations), and CTRC genes. IgG4 subclass levels were normal. The patient's lipase at first presentation was >1200 units/L. He required intravenous then oral hydromorphone during his first admission, but was weaned off all opioids by discharge 4 weeks later. Following discharge, however, the patient continued to experience episodes of sudden onset, severe pain causing extreme distress and had intermittent spikes in his lipase. One month after his initial discharge, and on his fourth emergency department visit, the patient was re-admitted and re-started on intravenous hydromorphone. This was insufficient to treat his pain despite escalating doses over 2 weeks’ time; he reached a peak total daily oral morphine equivalent (OME) of 1375 mg. After discussion with the patient and his family, a subanesthetic ketamine infusion (2–2.5 μg · kg−1 · min−1) was initiated for adjunctive pain management. This infusion resulted in a rapid reduction in his pain scores (on a numeric pain scale from 0 to 10) from an average of 8.3 to 4.4 by day 5 of infusion. While receiving ketamine, the patient's mood, energy, and activity level improved dramatically, and he experienced no associated adverse effects. Because the institutional policy requires intensive care unit admission for ketamine, weaning was a priority and the infusion was discontinued given his excellent progress. Although pain scores increased with ketamine weaning, opioid use continued to decline reaching a nadir of 375 mg OME/day following the 9-day ketamine infusion (Fig. 1).FIGURE 1: Addition of ketamine. Hydromorphone usage (solid line, mg of oral morphine equivalents/day) and average daily pain scores (dotted line, out of 10) over time during his second admission days 0 to 30. Ketamine infusion from day 13 to 21 (solid horizontal line, turning into dotted line when ketamine dose was weaned).Unfortunately, the patient plateaued in pain scores and opioid use (∼600 mg OME/day) and declined again in mood and activity. For 1 month, no further weaning was achieved, despite extensive pharmacologic strategies, including acetaminophen, ibuprofen, gabapentin, duloxetine, clonazepam, and pancreatic enzymes, and nonpharmacologic strategies, including diet, distraction, deep breathing, child life intervention, mindfulness, meditation, and guided imagery (Fig. 2).FIGURE 2: No NMDA-receptor antagonist. Hydromorphone usage (solid line, mg of oral morphine equivalents/day) and average daily pain scores (dotted line, out of 10) over time during admission days 31 to 60. Nonpharmacologic interventions and pharmacologic adjuncts were unsuccessful in weaning overall opioid dose during this period.Given his persistent symptoms, the patient underwent drainage of his peripancreatic pseudocyst (9.3 × 5 × 4.5 cm) via endoscopic fine-needle aspiration with ultrasound guidance. Approximately 390 mL of sterile fluid was removed. The procedure did not resolve his pain. Two weeks following the drainage, his opioid use began to rise again, and so he was transitioned from hydromorphone to methadone (300 mg OME/day), given his success with previous NMDA-receptor antagonism. The patient again achieved rapidly decreasing pain scores (Fig. 3). He was discharged 2 weeks later, and was subsequently weaned off methadone over 2 months. As of 7 months after discharge, his only regular medication was duloxetine. He continued to experience pain occasionally but employs many nonpharmacologic coping strategies. He has since been discharged from the chronic pain clinic. He has been seen in the emergency department 3 times in the 18 months since his second discharge, but has not required admission or treatment. He has not met criteria for pancreatitis during any of these return visits.FIGURE 3: Rotation to methadone. Hydromorphone usage (solid line, mg of oral morphine equivalents/day) and average daily pain scores (dotted line, out of 10) over time during admission days 61 to discharge on day 84. Transition to methadone began on day 73. Methadone was weaned off over the course of the subsequent 2 months as an outpatient. Overall, treatment with both ketamine and methadone was associated with a substantive reduction in opioid use.DISCUSSION This case demonstrates the benefits of the NMDA-receptor antagonists ketamine and methadone in providing analgesia for a pediatric patient with refractory pancreatic pain. There is increasing evidence for the use of NMDA-receptor antagonist medications for use in pediatric analgesia, particularly in settings of severe neuropathic pain (13). These medications are not without inherent short- and long-term risks, and the decision to use them cannot be made lightly. Opioids, surgeries, interventional procedures, and prolonged hospital stays, however, carry their own risks (including hyperalgesia and abdominal pain), and the detrimental impact of severe pain on the developing brain cannot be underestimated. Further studies are required to confirm the findings in this case and to better understand this risk/benefit relationship. Pancreatic pain is an example of pediatric pain that may be undertreated as a result of being understudied. Children may benefit from access to a wider variety of analgesic medications, such as methadone and ketamine; however, the use of these medications is limited by insufficient evidence. Further studies are required regarding pancreatic pain and the use of NMDA-receptor antagonists in pediatric patients.

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