Topic: Reduction in Pain Intensity in Multiple Sclerosis Patients with Involuntary Emotional Expression Disorder Treated with AVP-923
By Kristin Jenkins

Results from a double-blind, placebo-controlled study of 150 multiple sclerosis (MS) patients with involuntary emotional expression disorder (IEED), shows that treatment with AVP-923 appears to give MS patients with IEED a significant benefit in pain control (Panitch H. et al, Annals of Neurology May 2006; 59 (5): 780-7).

Patients treated with AVP-923 experienced significant improvement in clinical study endpoints, reported James P. Wymer MD of Upstate Neurology, Albany, NY. These endpoints included a decreased CNS-LS score—a validated measure of IEED severity—and, when compared to patients on placebo, a significant improvement in the level of pain intensity.

AVP-923 is a proprietary combination of dextromethorphan (DM) and quinidine (Q), which inhibits metabolism of DM, resulting in increased and sustained plasma DM levels. The Q levels used to block DM metabolism are 10-20 fold lower than those used to treat cardiac arrhythmias, noted Dr. Wymer.

DM acts as an uncompetitive antagonist of NMDA and a sigma-1 receptor agonist, which suppresses the release of excitatory neurotransmitters, including glutamate. This decreased glutamatergic signaling may help alleviate pain, said Dr. Wymer.

During the course of treatment, MS patients often experience disabling levels of pain. Involuntary emotional expression disorder (IEED), which occurs as a result of neurological disease or injury, can also be seen in patients with ALS, Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke and traumatic brain injury (TBI). It is characterized by sudden swings of emotion for no apparent reason. Hallmark symptoms include uncontrollable crying and/or laughing or related facial expressions, which have no relation to underlying mood. In the past, IEED as been referred to as pathological laughing or crying, emotional lability, emotional incontinence or pseudobulbar affect.

In the study, which was carried out at 18 sites in the U.S. and four in Israel, patients were asked to select a number that best described the amount of pain they had experienced in the past 24 hours. ‘0’ represented no pain, ‘1’ was mild pain, ‘2’ indicated moderate pain, ‘3’ was severe pain and ‘4’ was extreme pain. Then, pain was assessed at baseline and again on days 15, 29, 57 and 85.

Patients in both groups were permitted to take OTC analgesics during the course of the study or stronger meds if required, including gabapentin, fentanyl, lidocane, oxycodone, tramadol and Vicodin.

At baseline, patients in the treatment group (n=76) had an average age of 46.3 years versus 43.7 years in the placebo group (n=74). Most patients were female (81.6% in the AVP-923 group versus 83.8% in the placebo group) and both groups had a mean of 9 years or more of MS (an average of 10.3 years for the AVP-923 group and 9.6 years for the placebo group).

CNS-LS scores at baseline were slightly higher for the placebo group: 21.4 versus 20.3 f0r the treatment group; similarly, the mean estimated episodes of pain each week were somewhat higher for the untreated group (17.3 versus 14.1 for the treatment group). Self-reported ratings on the pain intensity rating scale were the same in both groups, however (1.4).

When asked about the amount of pain experienced in the previous 24 hours, patients in the placebo group reported an adjusted mean improvement in pain in intensity of 0.2. By comparison, patients on AVP-923 reported an improvement of 0.4. This represents a P value of .0271, said Dr. Wymer.

The reduction in CNS-LS score was more than double for patients in the AVP-923 group as it was for patients in the placebo group: greater than 7.0 for treated patients versus greater than 3.0 for patients on placebo.

The more severe a patient’s pain, the more he or she appeared to benefit from treatment, noted Dr. Wymer. Patients with moderate to extreme pain at baseline (greater than or equal to 2), for instance, experienced significantly more improvement in pain intensity than did patients with mild pain (less than 2) at baseline. “This may be attributed to a floor effect as patients with mild pain scores also experienced improvements from baseline during scheduled study visits,” noted Dr. Wymer.

Plans are now underway to look at the effect of AVP-923 in more specific components of pain. “We want to further quantitate the impact of different kinds of pain, whether it is a burning pain, a stabbing pain and so on,” said Dr. Wymer in an interview. “We also need to look at the impact of pain on other quality of life measures such as sleep as well as the impact of pain on quality of life in other types of diseases.”

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