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 Volume 63, Number 8, October 26, 2004
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NEUROLOGY 2004;63:1364-1370
© 2004 American Academy of Neurology

Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine

A randomized trial

B. R. Brooks, MD, R. A. Thisted, PhD, S. H. Appel, MD, W. G. Bradley, DM FRCP, R. K. Olney, MD, J. E. Berg, BA, L. E. Pope, PhD and R. A. Smith, MD for the AVP-923 ALS Study Group*

From the University of Wisconsin (Dr. Brooks), Madison; University of Chicago (Dr. Thisted), IL; Baylor College of Medicine (Dr. Appel), Houston, TX; University of Miami (Dr. Bradley), FL; University of California San Francisco (Dr. Olney); and Avanir Pharmaceuticals (Dr. Pope, J.E. Berg), San Diego; and Center for Neurologic Study (Dr. Smith), La Jolla, CA.

Address correspondence to Dr. B.R. Brooks, University of Wisconsin, 600 Highland Ave., Rm. H6/563 CSC, Madison, WI 53792-5132, e-mail: brooks{at}neurology.wisc.edu; and reprint requests to Dr. L.E. Pope, Avanir Pharmaceuticals, 11388 Sorrento Valley Rd., Suite 200, San Diego, CA 92121, e-mail: LPope{at}avanir.com

Background: Patients with ALS commonly exhibit pseudobulbar affect.

Methods: The authors conducted a multicenter, randomized, double-blind, controlled, parallel, three-arm study to test a defined combination of dextromethorphan hydrobromide (DM) and quinidine sulfate (Q) (AVP-923) for the treatment of pseudobulbar affect in ALS. Q inhibits the rapid first-pass metabolism of DM. The effects of AVP-923 (30 mg of DM plus 30 mg of Q) given twice daily for 28 days were compared with those of its components. Patients were evaluated on days 1, 15, and 29. The primary efficacy variable was the change from baseline in the Center for Neurologic Study Lability Scale (CNS-LS) score. Secondary efficacy variables were laughing/crying episode rates and changes in Visual Analog Scales for Quality of Life (QOL) and Relationships (QOR). Efficacy was evaluated in intention-to-treat subjects who were not poor metabolizers of DM (n = 65 for AVP-923, n = 30 for DM, and n = 34 for Q). Safety was assessed in all randomized subjects (n = 140).

Results: AVP-923 patients experienced 3.3-point greater improvements in CNS-LS than DM patients (p = 0.001) and 3.7-point greater improvements than Q patients (p < 0.001). AVP-923 patients exhibited lower overall episode rates, improved QOL scores, and improved QOR scores (p < 0.01 for all endpoints). Adverse effects were mostly mild or moderate; treatment-related discontinuation was 24% for AVP-923, 6% for DM, and 8% for Q.

Conclusions: AVP-923 palliates pseudobulbar affect in ALS. Overall benefits of treatment are reflected in fewer episodes of crying and laughing and improvements in overall quality of life and quality of relationships.

Received August 28, 2003. Accepted in final form June 3, 2004.

See Commentary, page 1345

*See the Appendix on page 1370 for a list of Group members.

Drs. Appel, Bradley, Brooks, and Olney received grants and/or honoraria from Avanir Pharmaceuticals (the sponsor). Dr. Thisted received compensation for statistical consulting from the sponsor. Dr. Smith is paid as a medical consultant to Avanir Pharmaceuticals and will receive royalties if the product is successfully marketed. Mr. Berg and Dr. Pope are employees of Avanir Pharmaceuticals. The amount of compensation for all authors was in excess of $10,000.


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