Skeletal Muscle Relaxers
Skeletal muscle relaxants as a class
Skeletal muscle relaxants constitute a heterogeneous group of drugs. As a class, they are structurally and pharmacologically diverse.
The goal of muscle relaxants is to normalize muscle excitability, decrease pain, and improve motor function. They exert their pharmacologic effect centrally at the level of the spinal cord, the brainstem, or the cerebrum. They have an insignificant, if any effect, at the muscle fiber level.
Muscle relaxants can be divided into two main categories:
Although muscle relaxants have by convention been classified into one group, the FDA has approved only a few members in this class for treatment of spasticity. The remainder are approved for treatment of musculoskeletal conditions.
Drugs classified as skeletal muscle relaxants include:
Only baclofen, dantrolene, and tizanidine are approved for treatment of spasticity. Carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, and orphenadrine have been approved for treatment of musculoskeletal disorders, but not for spasticity.
Treatment of spasticity
Spasticity is a state of increased muscular tone with exaggeration of the tendon reflexes. Some of the more common conditions associated with spasticity and requiring treatment include multiple sclerosis, spinal cord injury, traumatic brain injury, cerebral palsy, and poststroke syndrome. In many patients with these conditions, spasticity can be disabling and painful with a marked effect on functional ability and quality of life.
The upper motor neuron syndrome is a complex of signs and symptoms that can be associated with exaggerated cutaneous reflexes, autonomic hyperreflexia, dystonia, contractures, paresis, lack of dexterity, and fatigability. Spasticity from the upper motor neuron syndrome can result from a variety of conditions affecting the cortex or spinal cord.
Baclofen, dantrolene, tizanidine, and diazepam are used for treatment of spasticity.
Diazepam appears to reduce spasticity by enhancing the inhibitory effects of neurotransmitter GABA. It also exerts some supraspinal sedative effect. Diazepam has efficacy in patients with spinal cord injury, hemiplegia, and multiple sclerosis.
Baclofen is a GABA agonist, and its primary site of action is the spinal cord. It improves muscle contraction, flexor spasm frequency, and joint range of motion, resulting in improved mobility and functioning.
Baclofen may be used intrathecally in the management of severe spasticity of spinal cord origin, spasticity secondary to severe chronic disorders such as multiple sclerosis and other spinal diseases. The clinical goal of intrathecal baclofen therapy is to maintain muscle tone as close to normal as possible and to minimize the frequency and severity of spasms, and minimize intolerable adverse effects.
Tizanidine is a centrally acting α2-agonist that exerts its antispastic effect by causing presynaptic inhibition of motor neuron hyperactivity. It decreases the number and severity of spasms, alleviates clonus, and improves mobility.
Patients usually experience less muscle weakness from tizanidine than from other antispastic agents (e.g. baclofen, diazepam).
According to the research data, the efficacy of tizanidine in reducing muscle tone is comparable to that of baclofen and better than that of diazepam. When combined with baclofen, tizanidine presents the opportunity to maximize therapeutic effects and minimize adverse effects by reducing the amounts of both relaxants. If tizanidine is used in conjunction with baclofen or benzodiazepines, the combination increases the likelihood of sedation and liver toxicity.
Dantrolene is the only peripherally acting muscle relaxant. It seems to work directly on the muscle cell, affecting the sarcoplasmic reticulum within the cell, which stores calcium. When the electrical signal through the nerve releases an excitatory neurotransmitter the sarcoplasmic reticulum releases calcium, which brings on the contraction of the muscle. Dantrolene seems to prevent the release of calcium, and thus short-circuits the muscle contraction.
Dantrolene is indicated for treatment of spasticity in upper motor neuron disorders. The main concern is the risk of hepatotoxicity.
The evidence does not support a difference between the comparative efficacies of baclofen, dantrolene, or tizanidine for spasticity associated with chronic neurological conditions.
Treatment of musculoskeletal conditions
Muscle spasm is defined as a sudden involuntary contraction of one or more muscle groups and is usually an acute condition associated with muscle strain (partial tear of a muscle) or sprain (partial or complete rupture of a ligament).
Common musculoskeletal conditions causing tenderness and muscle spasms include fibromyalgia, tension headaches, myofascial pain syndrome, and mechanical low back or neck pain. If muscle spasm is present in these conditions, it is related to local factors involving the affected muscle groups. There is no hypertonicity or hyperreflexia, and the other symptoms associated with the upper motor neuron syndrome are not present. These conditions are commonly encountered in clinical practice and can cause significant functional disability and pain in some people.
The skeletal muscle relaxants used for the management of musculoskeletal disorders include carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, and orphenadrine.
Cyclobenzaprine, closely related to the tricyclic antidepressants, produces its effects within the CNS, primarily at the brainstem level. It causes the expected lethargy and anticholinergic side effects, and may have some toxicity in overdose and in combination with other substances.
Carisoprodol is a carbamate derivative. It inhibits interneuronal transmission in the descending reticular formation and spinal cord and is thought to act via sedation rather than by direct skeletal muscle relaxation.
Metaxalone suppresses the polysynaptic spinal cord reflexes, while leaving the monosynaptic (sensorimotor) pathways intact. It has no direct action on the contractile mechanism of striated muscle, or the nerve fiber. The advantages of metaxalone over other skeletal muscle relaxants include reduced sedation, lack of abuse potential, and limited accumulation because of its short elimination half-life.
Methocarbamol is a carbamate derivative of guaifenesin. It has no direct effect on the contractile mechanism of striated muscle, the motor endplate, or the nerve fiber. It is used for relief of painful, acute musculoskeletal conditions, and control of neuromuscular manifestations of tetanus.
Chlorzoxazone works primarily in the spinal cord and in the subcortical areas of the brain, where it inhibits multisynaptic reflex arcs involved in producing and maintaining skeletal muscle spasm. The exact mode of action, although not clearly identified, may be related to the sedative properties.
Orphenadrine is closely related to diphenhydramine. It possesses anticholinergic actions and acts on brain stem and does not act directly on muscles. Orphenadrine is used to treat skeletal muscle tension, rigidity secondary to afflictions such prolapsed discs, and degenerative soft tissue disease.
Clinical studies show, that cyclobenzaprine, carisoprodol, orphenadrine, and tizanidine are effective compared to placebo in patients with musculoskeletal conditions (primarily acute back or neck pain). Cyclobenzaprine has been evaluated in the most clinical trials and has consistently been found to be effective.
References & Resources
Published: May 05, 2007