Spasmolytics
The generation of the neuronal signals in motor neurons that cause muscle contractions are dependent on the balance of synaptic excitation and inhibition that the motor neuron receives. Spasmolytic agents generally work by either enhancing the level of inhibition, or reducing the level of excitation. Inhibition is enhanced by mimicking or enhancing the actions of endogenous inhibitory substances, such as GABA. Because they may act at the level of the cortex, brain stem or spinal cord, or all three areas, they have traditionally been referred to as “centrally-acting” muscle relaxants. However, it is now known that not every agent in this class has CNS activity (e.g. dantrolene), so this name is inaccurate.
Because of the enhancement of inhibition in the CNS, most spasmolytic agents have the side-effects of sedation, drowsiness and may cause dependence with long term use. Several of these agents also have abuse potential, and their prescription is strictly controlled.
The benzodiazepines, such as diazepam, interact with the GABAA receptor in the central nervous system. While it can be used in patients with muscle spasm of almost any origin, it produces sedation in most individuals at the doses required to reduce muscle tone.
Baclofen is considered to be at least as effective as diazepam in reducing spasticity, and causes much less sedation. It acts as a GABA agonist at GABAB receptors in the brain and spinal cord, resulting in hyperpolarization of neurons expressing this receptor, most likely due to increased potassium ion conductance. Baclofen also inhibits neural function presynaptically, by reducing calcium ion influx, and thereby reducing the release of excitatory neurotransmitters in both the brain and spinal cord. It may also reduce pain in patients by inhibiting the release of substance P in the spinal cord as well.
Clonidine and other imidazoline compounds have also been shown to reduce muscle spasms by their central nervous system activity. Tizanidine is perhaps the most thoroughly studied clonidine analog, and is an agonist at α2-adrenergic receptors, but reduces spasticity at doses that result in significantly less hypotension than clonidine.
Neurophysiologic studies show that it depresses excitatory feedback from muscles that would normally increase muscle tone, therefore minimizing spasticity.Furthermore, several clinical trials indicate that tizanidine has a similar efficacy to other spasmolytic agents, such as diazepam and baclofen, with a different spectrum of adverse effects.
The hydantoin-derivative dantrolene is a spasmolytic agent with a unique mechanism of action outside of the CNS. Dantrolene reduces skeletal muscle strength by inhibiting the excitation-contraction coupling in the muscle fiber. In normal muscle contraction, calcium is released from the sarcoplasmic reticulum through the ryanodine receptor channel, which causes the tension-generating interaction of actin and myosin. Dantrolene interferes with the release of calcium by binding to the ryanodine receptor and blocking the endogenous ligand ryanodine by competitive inhibition. Muscle that contracts more rapidly is more sensitive to dantrolene than muscle that contracts slowly, although cardiac muscle and smooth muscle are depressed only slightly, most likely because the release of calcium by their sarcoplasmic reticulum involves a slightly different process. Major adverse effects of dantrolene include general muscle weakness, sedation, and occasionally hepatitis.
Other common spasmolytic agents include: methocarbamol, carisoprodol, chlorzoxazone, cyclobenzaprine, gabapentin, metaxalone, and orphenadrine.
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