Ketamine as an Analgesic Adjunct for Opioid-Induced Hyperalgesia in a Patient With a Sickle Cell Pain Episode

CASE REPORT

A 35-year-old African American male with a medical history significant for asthma, previous tobacco abuse, and known sickle cell disease presented to the emergency department with severe generalized body aches, lower back pain, left flank and hip pain, and dyspnea, consistent with multiple prior sickle cell crises. His most recent admission for a similar episode was 6 months prior, at which time he was prescribed hydroxyurea 500 mg twice daily (180 capsules, 1 refill) and hydromorphone 4 mg orally every 4 hours as needed (42 tablets, no refills). He reportedly ran out of his hydroxyurea prescription 2 days prior to the current presentation because he did not establish care with a hematologist as had been recommended.

The patient complained of fatigue, arthralgias, and the myalgias mentioned above. His initial vital signs were within normal limits except for an oxygen saturation of 88% on room air that normalized with supplemental oxygen via nasal cannula. On physical examination, the patient was noted to be in distress, clutching his left hip, and was tender to palpation along the left flank and lower extremity. He was also noted to have scleral icterus. Abnormal admitting laboratory values included hemoglobin of 7.4 g/dL (reference range, 14.0-18.0 g/dL), reticulocyte count of 20.2% (reference range, 0.5%-2.2%), total bilirubin of 12.5 mg/dL (reference range, 0.2-1.2 mg/dL), and lactate dehydrogenase of 1,151 U/L (reference range, 84-246 U/L).

The patient's initial inpatient treatment regimen consisted of dextrose 5% with 0.45% normal saline maintenance IV fluids at 125 mL per hour, folic acid 1 mg per day, acetaminophen 325 mg every 4 hours, oral hydromorphone 4 mg every 6 hours scheduled, and IV hydromorphone 1 to 2 mg every 2 hours as needed for breakthrough pain. On hospital day 2, a hydromorphone patient-controlled analgesia infusion was initiated with a basal rate of 0.5 mg per hour and 0.4 mg every 10 minutes by demand dose. Despite aggressive treatment, the patient's anemia worsened, and he required 2 transfusions during the next week to maintain a hemoglobin concentration >6 mg/dL (nadir was 5.5 mg/dL on hospital day 3). By hospital day 3, the patient's flank pain was replaced by progressively worsening bilateral lower extremity pain, without associated skin changes, ulceration, erythema, or signs of obvious infection. Despite optimal nonopioid analgesics (celecoxib 200 mg twice daily and acetaminophen 325 mg every 4 hours), he required escalating doses of oral hydromorphone (from 4 mg per day on hospital day 2 to 16 mg per day by hospital day 3) and IV hydromorphone by patient-controlled analgesia (from an average of 35 mg per day on hospital day 3 to an average of 80 mg per day by hospital day 20). At the peak of the patient's inpatient opioid requirement, he used more than 1,200 mg morphine equivalent daily dose.¹⁴ Gabapentin 300 mg 3 times daily was added to the patient's nonopioid analgesic regimen with no improvement in his pain scores.

Extensive workup for his bilateral lower extremity pain included negative venous and arterial lower extremity Doppler ultrasound studies, negative bilateral knee and ankle joint synovial fluid analysis, and an equivocal magnetic resonance imaging scan suggestive of remote left tibial and fibular infarction vs chronic venous stasis.

By the third week of hospitalization, the patient's anemia and swelling had improved with IV furosemide 20 mg per day as needed, but he was unable to meet discharge criteria because of severe pain. The hospital Acute Pain Management Service was consulted on hospital day 29. On evaluation, the patient reported his pain level to be 10 of 10 on the visual analog scale in his bilateral ankles, radiating to his knees. Physical examination demonstrated bilateral ankle edema and tenderness to palpation in the bilateral lower extremities but otherwise no abnormalities (Figure). His pain was believed to be multifactorial, with the primary underlying cause being persistent swelling in his ankles that was complicated by opioid-related hyperalgesia from prolonged high-dose IV opioids during his hospital stay. His vaso-occlusive crisis was believed to be completely resolved and not contributing to his pain.

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Figure.

Chronic bilateral lower extremity cutaneous changes in the presence of sickle cell disease with edema noted on initial physical examination by Acute Pain Management Service.

A 5-day opioid weaning schedule was recommended to facilitate discharge, along with frequent Clinical Opiate Withdrawal Scale assessments to monitor for opioid withdrawal symptoms.¹⁵ Nonopioid analgesics were continued with slight dosage adjustments to optimize analgesia and minimize adverse effects, and a continuous ketamine infusion was initiated and titrated to a maximum dose of 0.4 mg/kg/h during the next 4 days (Table). IV furosemide 20 mg daily was also continued to facilitate diuresis and reduce edema. The patient tolerated the opioid-weaning schedule with improved pain and swelling. As planned, the patient was discharged on hospital day 34 with slight escalations of nonopioid analgesic doses and oral opioid dosage for breakthrough pain that was lower than the dose he had received after his prior hospitalization. His regimen included hydroxyurea 500 mg twice daily (180 capsules, 3 refills), folic acid 1 mg daily (90 tablets, 3 refills), acetaminophen 1,000 mg every 6 hours (over the counter), gabapentin 300 mg every 8 hours (90 capsules, no refills), and hydromorphone 2 mg every 6 hours as needed for breakthrough pain (60 tablets, no refills). His reported pain score at discharge was 0 of 10 on the visual analog scale. He was scheduled for 1-week follow-up to encourage improved chronic disease management in the outpatient setting.