Are there any new calcium channel modulators in the pipeline?
There are several N-type calcium channel blockers (intrathecal ziconotide) and modulators (pregabalin and gabapentin) currently on the market. Clinical effectiveness has been mixed with both positive and negative clinical trials. Mirogabalin is a new promising N-type calcium channel modulator. Pregabalin and gabapentin bind the alpha-2-delta subunit of the N-type calcium channel and reduce the amount of time the channel is in the open state. This reduces the amount of calcium influx, resulting in less presynaptic neurotransmitter release and dampening of pain signaling. Whereas pregabalin and gabapentin are nonspecific alpha-2-delta subunit ligands, mirogabalin is specific to the alpha-2-delta type II subunit. It is thought that the type I subunit is responsible for the side effects seen with N-type calcium channel modulators. Thus there appears to be fewer side effects with mirogabalin, resulting in the ability to achieve higher doses and improved efficacy. A recent study in painful diabetic neuropathy showed significant pain reductions at 15, 20, and 30 mg doses versus placebo. In the same study, an active comparator (pregabalin 300 mg) was not effective.
T-type Ca 3.2 calcium channels are thought to play a crucial role in pain signaling at central and peripheral endings of primary afferent neurons. Unlike antagonism of the T-type Ca 3.1 and 3.3 subtypes, the 3.2 subtype does not produce any sedation and is likely better tolerated. Preclinical studies have demonstrated efficacy in capsaicin-induced pain, models of arthritis, and neuropathic pain models. However, a recent study in a healthy volunteer pain model failed to show any effect whereas an active comparator (pregabalin) was effective. This discrepancy may be due to different locations of action between the two drugs. Pregabalin is thought to act mainly at the level of the spinal cord dorsal horn, whereas the T-type calcium channels antagonists may work at the thalamic level. Therefore, the T-type calcium channel antagonists may act through modulation of the affective component of pain.