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NEW THERAPY TARGETS PSEUDOBULBAR AFFECT IN MS

Stratmoen, Jo

News From the Aan Annual Meeting

MIAMI BEACH—A drug combining dextromethorphan and quinidine (AVP-923) was effective in treating pseudobulbar affect in patients with multiple sclerosis (MS), investigators reported in April here at the AAN Annual Meeting. Pseudobulbar affect is a fairly common condition in several neurological disorders, including MS, amyotrophic lateral sclerosis (ALS), Alzheimer disease, stroke, and traumatic brain injury.

“The hallmark symptoms are involuntary crying, laughing, or both,” according to Hillel Panitch, MD, Professor of Neurology at the University of Vermont in Burlington. “Pseudobulbar affect is also known as pathological laughing and crying, emotional lability, and emotional incontinence.”

“Pseudobulbar affect affects approximately 10 percent of patients with MS,” Dr. Panitch, who was the lead investigator on the current study, added. “It can be quite disabling to patients, caregivers, and family members.”

Dr. Hillel noted that antidepressants such as amitriptyline had been used for years to treat pseudobulbar effect, but they had unpleasant side effects.

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PATHOPHYSIOLOGY OF PSEUDOBULBAR AFFECT

Although the pathophysiology of this disorder is not well understood, it is thought to result from disruption of cortico-ponto-cerebellar pathways, resulting in uninhibited brainstem responses to emotional stimuli.

AVP-923 combines dextromethorphan – an ingredient commonly found in cough syrup – and a very low dose of quinidine, which is a cardiac anti-arrhythmic agent.

“Quinidine inhibits the metabolism of dextromethorphan,” Dr. Panitch said. “This results in increased and sustained plasma dextromethorphan levels allowing greater penetration into the CNS. Once in the CNS, dextromethorphan decreases glutamatergic signaling by acting on sigma-1 and NMDA receptors in the cerebellum and brainstem.”

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STUDY PROTOCOLS

In this double-blind, placebo-controlled multinational study, patients were randomized to receive either AVP-923 or placebo for three months. The primary endpoint was a patient-completed questionnaire called the Center for Neurologic Studies Lability Scale (CNS-LS). Secondary endpoints included the number of episodes of uncontrollable laughing and weeping, quality of life (QoL) and quality of relationships (QoR) measured by visual analog scales, and a pain intensity rating scale.

The CNS-LS is a seven-item instrument, in which each item is rated by the patient on a 1 to 5 scale, ranging from “never” to “most of the time.” The resulting scores range from 7 to 35.

Significantly more patients treated with AVP-923 experienced a decrease in their CNS-LS scores than those treated with placebo, Dr. Panitch said. In addition, AVP-923-treated patients achieved a 46 percent reduction in the number of episodes.

Significantly more patients treated with AVP-923 experienced no episodes for the duration of the trial. The effect was maintained over time, with a considerable difference between groups seen at all time points, Dr. Panitch noted.

QoL and QoR were also greatly improved with AVP-923.

Results on the pain intensity scale were also promising. “This measure was not part of the initial trial design, thus, there were no specific entry criteria relating to pain intensity,” Dr. Panitch said. “However, there was a significant reduction in perception of pain among patients treated with AVP-923.”

On the whole, the incidence of adverse events was similar between groups, with headache being the most prevalent event. “However, significantly more patients in the AVP-923 group experienced dizziness,” Dr. Panitch added.

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EXPERTS COMMENT

According to Benjamin Rix Brooks, MD, Professor of Neurology at the University of Wisconsin Medical School in Madison, the positive effects seen in the MS study were reflected in a trial of AVP-923 he led in patients with ALS (Neurology 2004;63(8):1364–1370).

A higher proportion of patients with ALS – approximately 40- to 50 percent – experience pseudobulbar affect than those with MS, he said. In addition, patients with ALS probably have a more severe form of the disorder.

“After a few doses, patients noticed an improvement. They said they felt able to control the onset of pseudobulbar affect,” Dr. Brooks said. “My sense is that this agent has a quicker onset of action than selective serotonin uptake inhibitors (SSRIs), which have also been used to treat pseudobulbar affect.”

If a patient is not fully controlled with an SSRI, it may be possible to add AVP-923 to achieve greater control. “However,” Dr. Brooks added, “there is a potential for dextromethorphan to increase serotonin levels.”

When asked how it was recognized that the combination of dextromethorphan and quinidine might be effective, Dr. Brooks said that many years ago dextromethorphan was being studied as a treatment for ALS and it was noted that emotionality appeared to be controlled. However, this agent alone had no effect on the course of the disease itself.

“Now that it appears that quinidine enhances the effects of dextromethorphan, studies are in the planning stage to examine the effect of this combination on other aspects of ALS.”

In the ALS study of AVP-923, some patients experienced an increase in spasticity. “Patients with MS who are taking this agent on an open-label basis also have had an increase in spasticity,” Dr. Brooks noted.

Figure. D

Figure. D

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REFERENCE

• Brooks BR, Thisted RA, Appel SH, Bradley WG, Olney RK, Berg JE, Pope LE, Smith RA; AVP-923 ALS Study Group. Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial. Neurology 2004;63(8):1364–1370.
©2005 American Academy of Neurology