Anesth Analg 2004;99:1876-1877
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000137452.25564.0A
LETTERS TO THE EDITOR
Does Modafinil Improve Recovery?
Keith E. Frazer, DO,
Jose Valle, MD, and
Henry L. Bennett, PhD
Department of Anesthesiology, University of Medicine and Dentistry of New Jersey, Newark, NJ, bennethl@umdnj.edu
To the Editor:
In the April, 2004 issue, Larijani et al. (1) reported that modafinil significantly improved recovery after anesthesia. A pilot questionnaire study provided baseline data, while the study involving modafinil used a randomized, double-blind, placebo-controlled design. Modafinil is indicated for the use to improve wakefulness in patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome (OSA/HS), and shift work sleep disorder (2).
Both studies used a self-designed questionnaire that did not undergo validation procedures. The sample size, with 17 patients receiving modafinil, is small for the claims made that patients can "significantly benefit," and without any data, "multiple dosing may be needed." The numerical scale (not a VAS) that was used is a nonparametric scale and "Student’s t-test" is inappropriate. While a power analysis is reported in the Study 2 methods, the results or description are not provided.
Adding to the difficulties of the study, moderate to severe "fatigue" and "feeling worn out" were less with modafinil, while moderate to severe "exhaustion" was equivalent to placebo. We cannot find a semantic reason for this inconsistency, adding to the difficulty of using an invalid instrument. An ad hoc term, "postoperative distress," does not report a statistical test despite claiming a significant finding.
In the discussion, the authors claim placebo patients had more difficulty remaining asleep on the first night, but the ratings for "ease of sleep" show no difference. In conclusion, the authors state modafinil improves feelings of alertness and energy, but alertness was not measured by their scale and the "energy" scale shows no difference between the groups (modafinil change = –1.3; placebo change = –1.6, not significant).
Finally, and of some concern, 12% of modafinil patients complained of "restlessness," whereas the difference with placebo in the modafinil Phase III trial is only 2% (2). As severe paranoid reactions have been reported with modafinil, an increase in side effects following residual chemically induced unconsciousness for general anesthesia provides ample opportunity for study but hardly prescriptions for use or "multiple doses."
References
- Larijani GE, Goldberg ME, Hojat M, et al. Modafinil improves recovery after general anesthesia. Anesth Analg 2004; 98: 976–81.[Abstract/Free Full Text]
- Provigil (modafinil)[package insert], West Chester, PA, Cephalon, Inc, 1999.
Response
Ghassem E. Larijani, PharmD, and
Michael E. Goldberg, MD
Department of Anesthesiology, University of Medicine and Dentistry of New Jersey, Cooper University Hospital, Camden, NJ, larijani-ghassem@cooperhealth.edu
In Response:
Few data are available regarding postdischarge symptoms in patients recovering from general anesthesia. Recovery from general anesthesia can resemble narcolepsy with respect to tiredness, sleepiness, and the general feeling of "being down." As stated in the article, this was a proof of a concept study with its own limitations. Furthermore, we believe in the face validity of subjective symptoms reported by the patients. Prior to performing our study, we evaluated the face validity of the items in the questionnaire by asking a group of five patients to read each question and judge whether they had any problem understanding the meaning of the questions. While fatigue, worn-out, and exhaustion are similar, they are qualitatively different. A patient may feel fatigue and worn-out without being exhausted.
Frazer et al. question the validity of the last two sentences of our study. They question why we stated in our article "patients recovering from general anesthesia can significantly benefit from modafinil." This sentence was supported by the previous sentences stating, "Modafinil significantly reduces the degree of fatigue, incidence of moderate to severe fatigue, and postoperative distress." We believe that a significant reduction in the degree of fatigue, exhaustion, or feeling worn out signifies significant improvement and benefit. In addition, as has been stated in the article, content analysis of the patient’s description of recovery from general anesthesia demonstrates improved feelings of alertness and energy in those receiving modafinil. We do understand that there is much to learn about recovery from general anesthesia. We also believe that the effect of modafinil on recovery from anesthesia is measurable and that its effect on drug-induced central nervous system (CNS) depression warrants further evaluation.
The Methods section of the study states that both parametric and nonparametric statistics were used to analyze data. In addition, our recalculation shows that 11.3 (9.1) is significantly different than 21.0 (13.8) (The difference between sample means = 9.7, standard error of the difference = 4.01, df = 32, t = 2.04, 95% confidence interval for the difference between means is 1.53 to 17.9.)
We have seen many patients with a history of exaggerated postoperative CNS depression; many of them require a few days to recover to their preoperative cognitive states. These patients may be the group that would benefit the most from modafinil. We understand that much more work needs to be done if modafinil is to be recommended for this new indication. We also understand that thorough dose-response evaluation, including different doses or multiple dosing, will be needed before such recommendations are made. We stand behind our findings, statements, and interpretations of our results.
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