Imaging the Effects of Savella
The pain inhibitory system is the suspected area where Savella (milnacipran) works to reduce pain in people with fibromyalgia. A companion study showed that fibromyalgia patients have decreased activity in the brain regions believed to be involved in the pain inhibitory system, such as the thalamus and the anterior cingulate cortex.1 So when pain signals enter the spinal cord, the brain areas that should be actively releasing pain-fighters, such as opioids, serotonin and norepinephrine, actually become less active. This is the opposite of what happens in people without pain and provides an objective basis for why fibromyalgia patients hurt all over.
Savella increases the amount of norepinephrine and serotonin at the nerve junctions in the central nervous system, which theoretically should boost the activity of the pain inhibitory system. In turn, this should raise a fibromyalgia patient’s pain threshold. Using functional MRI (fMRI), Yves Mainguy, Ph.D., of France, evaluated a small group of fibromyalgia patients before and after a nine-week trial who took either Savella (100 mg twice daily) or placebo.2 He measured their pressure pain threshold at the thumbnail and their fMRI to a subjectively determined pressure pain rating of 5 on a scale of 0 to 10. The pressure required was determined for each individual in the study at week nine, just before the end of the blinded, placebo-controlled trial.
Patients responding with a greater than a 30 percent reduction in subjective pain ratings over the treatment period were defined as pain responders (this group included mostly patients taking Savella but also some placebo responders as well). However, these two groups were easily differentiated. The patients on the active drug (i.e., Savella) were found to have a significant increase in pressure pain threshold when the stimulus was applied to the thumbnail, but this was not the case for the placebo responders. Mainguy notes that “the mechanism of drug response appears to be different from that of placebo response, indicating a true pharmacological effect of the drug.”
What about fibromyalgia patients who took Savella but did not reap any improvements? The non-responders to the drug typically had their symptoms for twice as long as the Savella responder group. In addition, patients who did not respond to this drug also did not display a significant improvement in pressure pain threshold.
A random subgroup of fibromyalgia patients in the trial underwent fMRI while a pressure pain stimulus was applied to their thumbnail. Those who took Savella showed significantly greater brain activity than the placebo group in the anterior cingulate cortex and a region of the brainstem … both areas involved in the pain inhibitory control. Activity in the thalamus also increased for the patients taking Savella, but the results were not quite significant.
Mainguy states that the lower pain threshold in fibromyalgia is due to decreased activity in the brain areas controlling the spinal pain inhibitory system, and the results of the Savella study support this claim. He also comments that fMRI may be a useful tool to demonstrate the objective effects of drugs to treat fibromyalgia and provide a better understanding of how they work.
- Jensen KB, et al. Pain 144:95-100, 2009.
- Mainguy Y. Human Psychopharmacol Clin Exp 24:S19-S23, 2009.