Anesth Analg 2001;93:213-214
© 2001 International Anesthesia Research Society
REGIONAL ANESTHESIA
The Reversal of Fentanyl-Induced Tolerance by Administration of "Small-Dose" Ketamine
Helge Eilers, MD,
Lisa A. Philip, MD,
Philip E. Bickler, MD, PhD,
Warren R. McKay, MD, and
Mark A. Schumacher, PhD, MD
Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California
Address correspondence and reprint requests to Mark A. Schumacher, PhD, MD, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94143-0648. Address e-mail to schumac{at}itsa.ucsf.edu
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Introduction
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The development of opioid analgesic-induced tolerance leading to escalating opioid requirement remains a significant problem in the treatment of severe pain. We describe a patient that continued to have severe unremitting pain despite receiving exceptionally large doses of the opioid analgesic fentanyl. The administration of subanesthetic doses of the N-methyl-D-aspartic acid (NMDA) receptor antagonist ketamine is effective in preventing and reversing morphine-induced tolerance in animals and humans (1–3). We therefore undertook the adjunctive use of ketamine in an attempt to reduce tolerance induced by fentanyl and improve analgesia.
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Case Report
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A 22-yr-old female patient with the history of acute myeloid leukemia was admitted with graft-versus-host disease (GVHD) after a donor lymphocyte transfusion. Despite aggressive immunosuppression therapy, her GVHD progressed rapidly, requiring increasing amounts of opioid analgesics for pain control. Five days after hospital admission her medication included hydromorphone 28 mg, fentanyl 350 µg, and lorazepam 6 mg per day. She was transferred to the intensive care unit (ICU) for pain management and sedation for worsening manifestations of her GVHD, which included severe skin desquamation involving more than 85% of her body surface area and gastrointestinal mucosal breakdown with diarrhea progressing to massive gastrointestinal bleeds. After admission to the ICU, the dose of opioid analgesics the patient required rapidly escalated (Fig. 1) and endotracheal intubation for airway protection became necessary. On ICU day 15, the patient was receiving 7000 µg/h of fentanyl and 10 mg/h of midazolam in addition to 100 mg methadone per day. Despite this regimen her pain control was inadequate and she complained of severe pain by nodding her head, grimacing, and fighting the ventilator. To facilitate dressing changes twice daily, an intermittent propofol (Diprivan; AstraZeneca, Sodertalje, Sweden) infusion was used. However, increased plasma concentrations of triglycerides prevented the continuous use of propofol to achieve adequate sedation.
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Figure 1. Daily doses of midazolam (open circles), fentanyl (closed circles), and ketamine (black bar, indicating continuous infusion at 0.1 mg · kg-1 · hr-1) during the patient’s intensive care unit (ICU) stay. The x-axis shows the number of ICU days. The fentanyl dose on ICU day 15 just before the start of the ketamine infusion (*) is inclusive of 2065 mg of hydromorphone that was converted to an equipotent dose of fentanyl. We used a conversion factor of 20.
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On ICU day 15, the pain management service was consulted to provide alternative strategies to reduce her fentanyl infusion volume (3.4 L/day) and possibly stop the escalation of opioid requirements. An initial attempt to convert fentanyl to an equipotent dose of hydromorphone failed. At this point (ICU day 16) the patient was receiving 7000 µg/h of fentanyl and 20 mg/h of midazolam in addition to 150 mg methadone per day. In an attempt to reduce opioid tolerance and improve analgesia, a ketamine infusion was started (Fig. 1, black bar) at 0.1 mg · kg-1 · hr-1 (8 mg/hr based on admission weight of 80 kg). Although the patient was intubated and mechanically ventilated, over the first 12 h after initiation of the ketamine infusion she progressed from complaining of unremitting pain to becoming sedated and minimally responsive. A taper of the fentanyl and midazolam infusions was initiated. Despite a lack of improvement of her overall medical condition, she progressively awoke over the next 5 days and on ketamine infusion day 6 (ICU day 21) she followed commands and indicated that she was comfortable by nodding her head appropriately to questions. Given the patient had concurrent renal and mild hepatic dysfunction, ketamine plasma levels were obtained on ICU day 25 (21 ng/mL) and ICU day 29 (77 ng/mL) (National Medical Services, Willow Grove PA). Gradually, the patient’s GVHD improved and it was therefore possible to continue the fentanyl and midazolam taper after the ketamine infusion had been discontinued on ICU day 31. The patient was transferred to the ward on ICU day 45 receiving only methadone at 300 mg/day. Although her condition showed some improvement, she remained critically ill and died approximately 5 wk later from fungal pneumonia.
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Discussion
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It is well established that chronic administration of µ-opioid agonists produces tolerance, and more recent findings suggest that acute administration of large doses of opioid agonists can also produce tolerance and hyperalgesia (4–6). Although the mechanism of opioid-induced tolerance is unknown, it is believed to involve an interaction between NMDA receptors, the nitric oxide pathway, and µ-opioid receptors (2). Ketamine, a noncompetitive NMDA receptor antagonist, given as a bolus of 2 mg/kg, can produce a dissociative anesthetic state that includes loss of consciousness, analgesia, sympathetic stimulation–excessive salivation and, when used alone, emergence phenomenon including vivid dreams and other psychomimetic effects (7). However, when ketamine is administered at subanesthetic doses (0.3 mg · kg-1 · hr-1), it produces analgesia (8,9). Moreover, the use of "small-dose" ketamine, has been described in the treatment of patients with chronic benign or cancer pain that have developed tolerance to opioids after the continuous use of oral, IV, or intrathecal morphine (9–11). The use of ketamine 1 mg · kg-1 · 24h-1 (0.042 mg · kg-1 · hr-1) in these cases resulted in superior analgesia and reversal of opioid tolerance leading to the dramatic reduction of the total daily dose of opioids (10). Other NMDA antagonists, such as dextromethorphan and opioids, with possible antagonistic effects at NMDA receptors, are also being studied and clinically tested for their potential to improve pain management by reducing tolerance (12,13). Although the presence of side effects was difficult to assess in our patient, there was especially no indication of unwanted psychomimetic effects. This is not surprising given the very small dose of ketamine and the large doses of midazolam used. The plasma levels observed in our patient were well below the concentrations reported by other authors who found only minimal side effects or none at all (14,15).
There is growing evidence that adjunctive use of a very small-dose ketamine infusion is a successful approach to reduce opioid tolerance and improve analgesia. Previous reports have focused on the treatment of terminally ill patients suffering from tumor pain. These patients have usually been treated with large doses of opioids for prolonged times. Our case report illustrates the effective use of the same strategy to reverse escalating dose requirements of fentanyl while maintaining analgesia in a more acute setting of an ICU patient suffering from severe unremitting pain. The described patient had not been using opioids regularly before admission but had rapidly escalating opioid requirements because of the acute exacerbation of her chronic illness. We believe that our case report serves as an example of a patient population in critical care medicine that would benefit from an early use of a small-dose ketamine infusion. Although apparently successful in this patient, controlled clinical studies are necessary to demonstrate efficacy and safety before such a practice can be recommended for routine use.
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References
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Accepted for publication March 28, 2001.
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Introduction
Case Report
