Provigil (Modafinil) Anesthesia and Perioperative Interaction: What Patients and Clinicians Need to Know

Does modafinil change how much anesthetic you need?

A 2017 case report describes a patient taking modafinil who was sedated with midazolam and then given propofol for induction. After a total of 6 mg/kg of propofol intravenously the patient still responded to tactile stimulation, and the bispectral index was 72. Sevoflurane by facemask at a low concentration then produced a depth that allowed a laryngeal mask airway to be inserted without difficulty, and the concentration of sevoflurane needed to induce or maintain anesthesia remained unaltered. The authors suggested modafinil may have caused resistance to propofol [2].

A single case cannot establish a dose requirement. The one randomized trial identified was designed to test functional recovery, not anesthetic dose. That double-blind pilot trial enrolled 102 patients with obstructive sleep apnea and gave them 200 mg of modafinil or placebo before general anesthesia. It was terminated for futility. Post-anesthesia care unit length of stay did not differ between groups, and neither did the interval from stopping the volatile anesthetic to extubation, intraoperative bispectral index values, postoperative pain scores or narcotic consumption measured in morphine equivalents. In the recovery unit, respiratory rate was higher and mean arterial pressure was lower in the modafinil group [3].

A second case report describes a 22-year-old with narcolepsy who took his morning modafinil dose on the day of endoscopic sinus surgery. Anesthesia was induced with 5% sevoflurane and maintained with sevoflurane plus a remifentanil infusion, with sevoflurane titrated using bispectral index monitoring (values 47 to 58). Surgery lasted 150 minutes, he emerged within 10 minutes and was extubated, and recovery was uneventful [5].

Taken together, the human record is one case of apparent propofol resistance, one uneventful sevoflurane-remifentanil case, and one randomized trial that did not significantly change BIS values, extubation time or recovery-unit stay [2][3][5]. None of these studies measured the minimum alveolar concentration of a volatile anesthetic.

What is known about how modafinil works

The Provigil label states that the mechanism by which modafinil promotes wakefulness is unknown. It has wake-promoting actions similar to sympathomimetics such as amphetamine and methylphenidate, although the pharmacologic profile is not identical. In vitro it binds the dopamine transporter and inhibits dopamine reuptake, and in mice lacking the dopamine transporter it had no wake-promoting activity [1].

Label interactions to know before surgery

Modafinil induces CYP3A4/5. The label says clearance of drugs that are CYP3A4/5 substrates, specifically steroidal contraceptives, cyclosporine, midazolam and triazolam, may be increased, lowering systemic exposure, and that dosage adjustment of these drugs should be considered. Cyclosporine blood levels may fall, and monitoring of circulating concentrations is advised [1].

Modafinil also inhibits CYP2C19. The label says elimination of CYP2C19 substrates, naming phenytoin, diazepam, propranolol, omeprazole and clomipramine, may be prolonged, with higher systemic exposure and possible dose adjustment. In people deficient in CYP2D6, levels of CYP2D6 substrates that are also cleared partly by CYP2C19, such as tricyclic antidepressants and selective serotonin reuptake inhibitors, may rise [1].

For warfarin, the label advises considering more frequent monitoring of prothrombin time and INR whenever modafinil is coadministered. It also advises caution when modafinil is given with a monoamine oxidase inhibitor [1].

The label states that the effectiveness of steroidal contraceptives may be reduced during modafinil treatment and for one month after it is stopped, and it recommends alternative or concomitant methods of contraception over that period [1].

Blood pressure and heart rate

In pooled placebo-controlled trials of 934 patients on modafinil and 567 on placebo, hypertension occurred in 3% vs 1%, palpitation in 2% vs 1% and chest pain in 3% vs 1% [1]. A larger share of modafinil patients needed new or increased treatment with an antihypertensive medicine: 2.4% vs 0.7% with placebo, and 3.4% vs 1.1% in the obstructive sleep apnea studies [1]. Three subjects with mitral valve prolapse or left ventricular hypertrophy developed chest pain, palpitations, dyspnea and transient ischemic T-wave changes. The label states that use is not recommended in left ventricular hypertrophy or in mitral valve prolapse syndrome previously triggered by CNS stimulants [1].

Not every measurement points the same way. In the 102-patient surgical trial the mean arterial pressure in the recovery unit was lower in the modafinil group, alongside a higher respiratory rate [3].

Modafinil after anesthesia: the recovery trials

Two small randomized studies tested modafinil as a recovery drug rather than a perioperative hazard. In a double-blind trial of 34 patients recovering from general anesthesia, a single 200 mg dose of modafinil or placebo was given once patients tolerated oral intake and met discharge criteria. At 24 hours the placebo group reported significantly more postoperative fatigue (4.8 vs 1.4 on a 0 to 10 scale), more exhaustion and a greater feeling of being worn out. Moderate to severe fatigue was reported by 65% of the placebo group versus 12% of the modafinil group [7].

In a second trial, 67 patients who completed the study had extracorporeal shock wave lithotripsy under fentanyl with midazolam or remifentanil with propofol, each with modafinil 200 mg or placebo given one hour before sedation. The tiredness score was lower with modafinil in the fentanyl and midazolam groups (1.3 vs 3.8, P=0.02) but not in the remifentanil and propofol groups (modafinil 3.1 vs placebo 2.6, P>0.05). There was no significant difference in the digital symbol substitution test, trail making test, observer sedation scores or Aldrete scores, and dizziness was greater with modafinil in the remifentanil and propofol group (1.7 vs 0.0) [8].

Both are small studies of a single dose, so they describe how patients felt after anesthesia and do not amount to a treatment protocol.

Medication details for a surgical history

The Provigil label's dosage section gives 200 mg once daily in the morning for narcolepsy or obstructive sleep apnea, 200 mg about one hour before the work shift for shift work disorder, half the usual dose in severe hepatic impairment, and lower doses with closer monitoring in geriatric patients. The half-life is about 15 hours after multiple doses, and steady state takes 2 to 4 days [1].

Details a surgical team may ask about are the dose and timing of the last dose, the condition being treated, whether continuous positive airway pressure is used for sleep apnea, any left ventricular hypertrophy or mitral valve prolapse, and other medicines such as a contraceptive, warfarin, cyclosporine, a benzodiazepine or phenytoin.

Sleep apnea and narcolepsy

In obstructive sleep apnea the label is explicit that modafinil treats the excessive sleepiness, not the airway obstruction, and that a maximal effort to treat with continuous positive airway pressure should be made before and during treatment [1]. The randomized surgical trial described above was conducted in patients with this diagnosis [3].

The label also says that wakefulness may not return to normal on modafinil, that sleepiness should be reassessed frequently, and that, if appropriate, patients should be advised to avoid driving or other potentially dangerous activity [1].