Poster Session II - 59
Oral Morphine in Treatment Resistant Obsessive Compulsive Disorder
Lorrin M. Koran, M.D.

Stanford University Medical Center, Stanford, CA

Method: We are conducting a placebo-controlled, double-blind trial to test the hypothesis that once weekly oral morphine is effective in treatment-resistant OCD. We recruited subjects with OCD for 3 years, who had failed at least 2 adequate SRI trials, and had Y-BOCS scores > 21. Current medications were continued. Subjects were randomized to random order, two-week blocks of once-weekly oral morphine sulfate, beginning at 30 mg; lorazepam, beginning at 1 mg; or placebo. The medication was administered in the clinic. Week 2 dosage was increased, decreased, or maintained depending on response and side effects.

Results: The first nineteen subjects, 14 men and 5 women, had a mean age (SD) of 39.8 (7.7), and had OCD for at least three years. They had failed from three to six SRI trials (mean = 3.3). The median Y-BOCS score at screening was 28.0 (range 20 to 38). After the highest morphine dose, the median Y-BOCS score was 24 (range 12 to 34) and the median decrease was 12.9% (range -70% to +43%). Six of the nineteen subjects were responders to morphine, with decreases in Y-BOCS score > 25%. In contrast, after the highest lorazepam dose, the median Y-BOCS score was 27 (range 15 to 33), and the median decrease was 6.2% (range -14% to +27%). Two subjects responded to lorazepam; one subject's Y-BOCS score decreased by 27% (compared to by 41% with morphine) and one by 25% (compared to by 70% with morphine). With placebo, the median Y-BOCS after the highest dose was 28, and the median decrease was 6.5%. No subject had a Y-BOCS decrease of >25%; one subject's Y-BOCS score increased 55%.

A Friedman two-way analysis of variance was significant (cr2 = 13.20, >p=.01) as was a Wilcoxon matched-pairs signed-ranks test for morphine vs. placebo (T=30.5, p=.015) but not for lorazepam. Several morphine responders maintained response for more than a year on twice weekly oral morphine without tolerance, euphoria, or drug seeking.

Discussion: Our results support the hypothesis that once- to twice-weekly doses of oral morphine can reduce symptoms in treatment-resistant OCD without creating tolerance or drug seeking behavior. Stimulation of mu-opoid receptors accelerates dopaminergic transmission in the striatum (Pieopponen et al., 1999) and inhibits glutamate release in cortical slices (Marek and Aghajanian, 1998). Most interestingly, acute stimulation of mu-opoid receptors disinhibits serotonergic neurons in the midbrain dorsal raphe nucleus by suppressing inhibitory GABAergic neurotransmission (Jolas et al., 2000). This could increase serotonergic tone in the basal ganglia and elsewhere just as does treatment with an SRI.Why some OCD sufferers are poorly responsive to treatment with SRIs or responsive to oral morphine is unknown.

Conclusion: Once-weekly oral morphine can substantially ameliorate OCD symptoms in some patients. Further research is indicated.

Source of Funding: National Center for Research Resources (NCRR) and Stanford University