Considering the increased use of central nervous system (CNS) stimulants for narcolepsy and other daytime sleep disorders, we need to have a better understanding of the impact that eugeroics (drugs that specifically improve wakefulness and alertness) like modafinil have on the response to anesthetics. This case report describes how a patient taking modafinil demonstrated resistance to a general anesthetic induction with propofol, and the possible mechanisms of this alteration. The author obtained written consent from the patient to publish anonymous information regarding the events of this case.
I encountered a 58-year-old woman (height: 173 cm and weight: 62 kg) scheduled for eye muscle surgery in the holding area of our ambulatory surgery center. Pertinent medical history included well-controlled hypertension and a 5-year history of narcolepsy for which the patient was taking modafinil at a dose of 200 mg orally each morning. Her last dose of modafinil was approximately 4 hours before arrival. The patient did not recall unusual events during previous general anesthetics, although her use of modafinil began several months after her last one. Anesthetic records for those cases were not available. In addition, the patient began using modafinil several months after her last general anesthetic.
On the way to the operating room, I administered sedation with 2 mg of IV midazolam. The patient remained awake but felt more relaxed. In the operating room, I began inducing general anesthesia with 2 mg/kg IV propofol. After waiting approximately 45 seconds, the patient was still responding to verbal stimulation. Over the next 3 minutes, I incrementally administered an additional 4 mg/kg IV propofol, but the patient remained responsive to tactile stimulation and it was impossible to open her mouth. A Bispectral Index (BIS) monitor showed an index of 72. Because of the already high dose of propofol the patient had received (6 mg/kg), and a desire to avoid opioids, I administered 0.3% sevoflurane by facemask. Approximately 2 minutes later, the patient’s motor tone decreased, and I was able to insert a laryngeal mask airway.
At that point the BIS index was 53. General anesthesia was maintained with sevoflurane at approximately 2.1% end-tidal concentration for the remainder of the procedure. Toward completion of surgery, I slowly reduced the inhaled sevoflurane concentration to 0.25% and easily removed the laryngeal mask airway when the patient demonstrated airway reflexes. The stay in the postanesthesia care unit was uneventful. The patient reached an Aldrete score of 10 within 15 minutes of arrival. The patient was discharged from the postanesthesia care unit 70 minutes after arrival.
Because modafinil was the only CNS medication the patient was taking, I considered the possibility of an association between this medication and her need of a higher dose of propofol.
Researchers in France initially discovered modafinil in the 1970s and found it to possess properties useful as an eugeroic treatment for narcolepsy. It has since been approved by the FDA for the treatment of sleepiness that occurs related to narcolepsy, sleep apnea, and shift work sleep disorder. The exact mechanism by which modafinil works is not totally well understood, but it produces changes in neurotransmitters in multiple areas of the brain, including glutamine, Gamma-aminobutyric acid (GABA), dopamine, histamine, and norepinephrine. Modafinil also directly inhibits the transporters of central dopamine and norepinephrine uptake and causes an elevation in catecholamine levels.1 Concentrations of serotonin, glutamate, histamine, and orexin increase in the extracellular space while concentrations of GABA decrease.2 Thus, the proarousal and prowakefulness actions of modafinil are thought to originate from these increases in dopaminergic and adrenergic transmission along with interactions with the orexin/hypocretin axis.3 The result of these changes is an increase in wakefulness.
Despite modafinil’s similarity to cocaine and other medications that inhibit catecholamine reuptake, modafinil appears to more specifically target the hypothalamic nuclei involved in sleep/awake control. However, modafinil may have some similarity to CNS stimulants such as methylphenidate in that it also enhances arousal after administration of either isoflurane or propofol in animal models.4,5 As the authors allude to in these reports, the difference between methylphenidate and modafinil may reside in the effects on various subtypes of GABA receptors. In contrast to modafinil, propofol activates sleep-producing neurons, and may be the mechanism responsible for GABA-associated propofol-induced sedation.6 Thus, in effect, modafinil can theoretically counteract the hypothalamic and other CNS effects of propofol. Corroborating the potential of changes in GABA on the response to propofol, animal studies indicate a large effect of artificially enhancing GABA concentrations on improving the anesthetizing actions of propofol. In contrast, changes in GABA concentrations have little effect on the response to sevoflurane.7
Regarding the potential effects of modafinil on response to anesthetics, case reports help provide some information. A case report described an uneventful induction of anesthesia using propofol 150 mg and fentanyl 75 µg for day surgery in a patient on chronic modafinil medication for narcolepsy. However, the patient had not taken her modafinil for at least 36 hours before her surgery.8
Another case report described the administration of typical doses of propofol and remifentanil to a patient taking modafinil for narcolepsy who underwent cardiac surgery.9 The authors, however, did not report on the timing of the patient’s last preoperative use of modafinil. No difficulties with induction and maintenance of anesthesia using propofol and remifentanil were reported in a patient who took modafinil on the morning of surgery.10 The authors used BIS-directed titration of anesthetic administration; however, they did not report the infusion rate of propofol or remifentanil. In contrast, induction of anesthesia with sevoflurane and remifentanil with maintenance guided by BIS monitoring were unremarkable in a patient taking modafinil until the day of surgery.11
It is possible that certain characteristics of this patient enhanced the effect of modafinil. Although the half-life of modafinil generally is in the 10- to 12-hour range, it is subject to differences in liver or renal function or cytochrome genotypes. However, the patient’s liver and renal functions were normal as suggested by blood chemistry obtained 5 months before. Her cytochrome P-450 (CYP) genotype was unknown. However, non–CYP-related pathways are the
most rapid in metabolizing modafinil. Because of this it is thought that medications that impact CYP activity likely have no significant effects on the pharmacokinetics of modafinil.12
In conclusion, modafinil is the most likely cause of resistance to propofol in this patient. Multiple factors point to this determination: (1) in the brain, modafinil counteracts what likely are the mechanisms involved in the induction of sleep by propofol; (2) case reports indicate that the response to volatile anesthetics does not appear to be affected by modafinil; and (3) modafinil was the only CNS-altering medication the patient was taking at the time of this anesthetic.
Name: Timothy N. Harwood, MD.
Contribution: This author wrote the manuscript.
This manuscript was handled by: Hans-Joachim Priebe, MD, FRCA, FCAI.
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