A B S T R A C T An examination of the metabolic fate of the R and the S isomers of warfarin revealed that the two isomers were metabolized by different routes. R warfarin was oxidized to 6-hydroxywarfarin and was reduced to the (R,S) warfarin alcohol. In contrast, S warfarin was oxidized to 7-hydroxywarfarin and was reduced to the (S,S) warfarin alcohol. S warfarin was also oxidized to 6-hydroxywarfarin.These observations suggested that interactions between warfarin and other drugs might be manifest stereospecifically, i.e., have a different effect on the isomers of warfarin, so a series of experiments were conducted with each isomer of warfarin, before and after phenylbutazone. The plasma clearance of S warfarin was slowed from 3.1 to 1.1% per h in one subject and from 2.3 to 1.6% per h in another. In contrast, the clearance of R warfarin was increased from 1.5 to 3.0% per h and from 0.9 to 1.6% per h in two subjects after phenylbutazone. The rate of clearance of racemic warfarin was unaffected by phenylbutazone; the depression of the rate of clearance of the S isomer masked the stimulation of the clearance of the R isomer. Since S warfarin is five times more potent an anticoagulant than R warfarin, it is concluded that inhibition of the metabolism of S warfarin provides one mechanism for the augmented anticoagulation which follows phenylbutazone.

Behavioral treatment of comorbid insomnia in individuals with CM produced large reductions in headache frequency, though some improvement in headache occurred with a behavioral intervention not focused on modifying sleep. Among the CBTi group only, both headache frequency and sleep parameters continued to improve after treatment, suggesting the presence of enduring effects over time. Directly treating insomnia using components of stimulus control and sleep restriction holds promise for reducing comorbid migraine. Development of and comparison to a truly inert pseudotherapy control presents unique challenges that future studies should address.

Paralleling results from the broader chronic pain literature, pain acceptance and values-based action play significant roles in headache pain and disability. Further study of interventions targeting these processes may enhance existing treatments.

Items that assess headache-related disability, use of combination medications, and fear of pain help identify patients who are currently overusing acute headache medications and may serve as indicators of treatment progress. Future studies should apply similar analytic approaches longitudinally to identify headache sufferers at risk for medication-overuse headache prior to headache progression.