A Review of Skeletal Muscle Relaxants for Pain Management
Although grouped under a single drug class, skeletal muscle relaxants are a heterogeneous group of structurally unrelated medications with variable pharmacologic and safety profiles.1-3 Skeletal muscle relaxants are used commonly for the treatment of 2 conditions: spasticity and local musculoskeletal spasms. Approximately 2 million Americans, including more than 300,000 people over 60 years of age, are prescribed muscle relaxants.3
Spasticity and spasms are distinct etiologies, and each condition responds differently to certain medications. Spasticity is a disorder of motor neurons that manifests as increased muscle tone and stiffness.4 Spasms are involuntary localized muscle contractions that arise from acute trauma or muscle strain.3,5 Although antispasmodics and antispasticity agents generally are not interchangeable, diazepam (Valium) is approved by the Food and Drug Administration (FDA) for both conditions.6,7
In this article, the authors review the etiologies of, and treatment options for, painful spasticity and muscle spasm.
Skeletal Muscle System
Table 1 highlights the basic differences between spasticity and spasms, including the etiology, symptoms, causes, and FDA-approved therapies.8
Two types of motor neurons regulate skeletal muscle excitability: upper motor neurons (UMNs), which originate from the cerebral cortex, and lower motor neurons (LMNs), which originate in the spinal cord and brain stem.9-11 UMNs innervate the LMNs in the spinal cord, where they directly innervate skeletal muscles, and in the brain stem (cranial nerves), where they innervate the facial muscles. UMNs can stimulate or inhibit skeletal muscle contraction by direct innervation to LMNs. UMN lesions can result in muscle weakness, spasticity, or both, but LMN lesions may develop into muscle weakness and paralysis.
How Skeletal Muscle Contracts
A single α-motor neuron can innervate up to 200 muscle fibers, forming a complex called motor unit (Figure 1).10 With movement, an action potential originates from the UMN in the motor cortex.9 This action potential depolarizes the motor neuron terminal, resulting in the opening of voltage-gated calcium (Ca2+) channels and the subsequent release of the neurotransmitter acetylcholine (Ach) into the synaptic cleft. In the synaptic cleft, Ach binds to nicotinic cholinergic receptors on the muscle fiber membrane, leading to an influx of sodium (Na+) and a discharge of potassium (K) across the muscle fiber’s membrane, which results in depolarization of the muscle fiber.11 This depolarization opens voltage-gated Ca2+ channels on the sarcoplasmic reticulum (via ryanodine and inositol triphosphate receptors), allowing for Ca2+ influx into the cytoplasm of striated muscle cells.12 The Ca2+ then binds to troponin C, which exposes myosin-binding sites on actin filaments. A cross-link forms between actin and myosin, leading to muscle contraction. The pumping of Ca2+ back into the sarcoplasmic reticulum, using adenosine triphosphate, leads to cessation of contraction.
There are 2 pathways that regulate skeletal muscle excitability and contraction: the monosynaptic and polysynaptic reflex pathways.8,10,13 In the monosynaptic reflex, afferent signals from muscle cells return to the spinal cord, resulting in negative feedback on motor movements. The Golgi tendon (Figure 2), a proprioceptive sensory receptor organ, senses muscle tension and sends an inhibitory signal to the spinal cord.9 In the polysynaptic reflex, type IA afferent neurons synapse on inhibitory neurons in the dorsal horn and inhibit contraction of the targeted area.8,10,13 For example, if a person touches a hot surface, the brain sends an excitatory signal to stimulate the bicep muscles to contract, allowing for the desired motion, and then sends an inhibitory signal.
Spasticity is defined as a velocity-dependent increase in muscle tone caused by the increased excitability of the muscle stretch reflex.4 Clinical manifestations include muscle stiffness, co-contraction of flexors and extensors, and increased resistance to muscle stretching. The etiology of spasticity is not fully known, but it is thought to be due to excessive stimulation or lack of inhibition of α-motor neurons, leading to increased muscle tone.2,4
Spasticity is associated with increased activity of excitatory neurotransmitters or decreased activity of inhibitory neurotransmitters (Table 2).13 Causes of spasticity include multiple sclerosis (MS), cerebral palsy, spinal cord injury, traumatic brain injury, and post-stroke syndrome.4,10,13
Antispasticity medications reduce muscle tone by acting either on the central nervous system (CNS) or directly on skeletal muscles (Figure 3).2 Agents that work on the CNS include baclofen (Gablofen, Lioresal, others), tizanidine (Zanaflex, others), gabapentinoids (gabapentin [Gralise, Horizant, others], pregabalin [Lyrica]), riluzole (Rilutek, others), and benzodiazepines (diazepam [Diazepam Intensol, Valium, others]), whereas peripheral agents include dantrolene (Dantrium, Revonto, others), and botulinum toxin (Table 3).14-16
Baclofen is a structural analogue of GABA that binds to GABAB receptors, which are coupled to presynaptic and postsynaptic Ca2+ and K+ channels.2,17 Therefore, baclofen acts presynaptically and postsynaptically to inhibit spinal reflexes. Presynaptic activation of GABAB receptors results in hyperpolarization and decreased Ca2+ influx, which reduces glutamate release, leading to a decrease in α-motor neuron activity. Postsynaptic activation of GABAB increases K+ conductance in the IA afferent neuron terminals, hyperpolarizing the membrane and enhancing presynaptic inhibition. Baclofen also is thought to inhibit substance P release into the spinal cord, which may reduce pain.18
Baclofen is available as an oral medication, as an intrathecal injection, or for use in an intrathecal pump; the latter form is reserved for cases of severe spasticity.19 Baclofen has been evaluated for other conditions, including cluster headache, intractable hiccups, and nicotine, cocaine, and alcohol dependence.20-24