Amuscle relaxant is a drug that affectsskeletal muscle function and decreases themuscle tone. It may be used to alleviate symptoms such as musclespasms,pain, andhyperreflexia. The term "muscle relaxant" is used to refer to two major therapeutic groups:neuromuscular blockers andspasmolytics. Neuromuscular blockers act by interfering with transmission at the neuromuscular end plate and have nocentral nervous system (CNS) activity. They are often used during surgical procedures and inintensive care andemergency medicine to cause temporaryparalysis. Spasmolytics, also known as "centrally acting" muscle relaxant, are used to alleviatemusculoskeletal pain and spasms and to reducespasticity in a variety ofneurological conditions. While both neuromuscular blockers and spasmolytics are often grouped together as muscle relaxant,[1][2] the term is commonly used to refer to spasmolytics only.[3][4]
The earliest known use of muscle relaxant drugs was by natives of theAmazon Basin in South America who usedpoison-tippedarrows that produced death by skeletal muscle paralysis. This was first documented in the 16th century, when European explorers encountered it. This poison, known today ascurare, led to some of the earliest scientific studies inpharmacology. Its active ingredient,tubocurarine, as well as many synthetic derivatives, played a significant role in scientific experiments to determine the function ofacetylcholine inneuromuscular transmission.[5] By 1943, neuromuscular blocking drugs became established as muscle relaxants in the practice ofanesthesia andsurgery.[6]
The U.S.Food and Drug Administration (FDA) approved the use ofcarisoprodol in 1959,metaxalone in August 1962, andcyclobenzaprine in August 1977.[7]
Other skeletal muscle relaxants of that type used around the world come from a number of drug categories and other drugs used primarily for this indication includeorphenadrine (anticholinergic),chlorzoxazone,tizanidine (clonidine relative),diazepam,tetrazepam and otherbenzodiazepines,mephenoxalone,methocarbamol,dantrolene,baclofen.[7] Drugs once but no longer or very rarely used to relax skeletal muscles includemeprobamate,barbiturates,methaqualone,glutethimide and the like; some subcategories of opioids have muscle relaxant properties, and some are marketed in combination drugs with skeletal and/or smooth muscle relaxants such as wholeopium products, someketobemidone,piritramide andfentanyl preparations andEquagesic.
Muscle relaxation and paralysis can theoretically occur by interrupting function at several sites, including thecentral nervous system,myelinated somatic nerves, unmyelinated motor nerve terminals,nicotinic acetylcholine receptors, the motor end plate, and the muscle membrane or contractile apparatus. Most neuromuscular blockers function by blocking transmission at the end plate of theneuromuscular junction. Normally, a nerve impulse arrives at the motor nerve terminal, initiating an influx ofcalcium ions, which causes theexocytosis ofsynaptic vesicles containingacetylcholine. Acetylcholine then diffuses across the synaptic cleft. It may be hydrolysed byacetylcholine esterase (AchE) or bind to the nicotinic receptors located on the motor end plate. The binding of two acetylcholine molecules results in aconformational change in the receptor that opens the sodium-potassium channel of the nicotinic receptor. This allowsNa+ andCa2+ ions to enter the cell andK+ ions to leave the cell, causing a depolarization of the end plate, resulting in muscle contraction.[8] Following depolarization, the acetylcholine molecules are then removed from the end plate region and enzymatically hydrolysed by acetylcholinesterase.[5]
Normalend plate function can be blocked by two mechanisms. Nondepolarizing agents, such astubocurarine, block theagonist, acetylcholine, from binding to nicotinic receptors and activating them, thereby preventing depolarization. Alternatively, depolarizing agents, such assuccinylcholine, are nicotinic receptoragonists which mimic Ach, block muscle contraction by depolarizing to such an extent that itdesensitizes the receptor and it can no longer initiate anaction potential and cause muscle contraction.[5] Both of these classes of neuromuscular blocking drugs are structurally similar to acetylcholine, the endogenous ligand, in many cases containing two acetylcholine molecules linked end-to-end by a rigid carbon ring system, as inpancuronium (a nondepolarizing agent).[5]
The generation of theneuronal signals in motor neurons that cause muscle contractions is dependent on the balance of synaptic excitation and inhibition 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 asGABA.
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 not every agent in this class has CNS activity (e.g.,dantrolene), so this name is inaccurate.[5]
Most sources still use the term "centrally acting muscle relaxant". According toMeSH, dantrolene is usually classified as a centrally acting muscle relaxant.[9] TheWorld Health Organization, in itsATC, uses the term "centrally acting agents",[10] but adds a distinct category of "directly acting agents", for dantrolene.[11] Use of this terminology dates back to at least 1973.[12]
The term "spasmolytic" is also considered a synonym forantispasmodic.[13]
Spasmolytics such ascarisoprodol,cyclobenzaprine,metaxalone, andmethocarbamol are commonly prescribed forlow back pain orneck pain,fibromyalgia,tension headaches andmyofascial pain syndrome.[14] However, they are not recommended as first-line agents; in acute low back pain, they are not more effective thanparacetamol or nonsteroidal anti-inflammatory drugs (NSAIDs),[15][16] and in fibromyalgia they are not more effective thanantidepressants.[14] Nevertheless, some (low-quality) evidence suggests muscle relaxants can add benefit to treatment with NSAIDs.[17] In general, no high-qualityevidence supports their use.[14] No drug has been shown to be better than another, and all of them haveadverse effects, particularlydizziness anddrowsiness.[14][16] Concerns about possible abuse andinteraction with other drugs, especially if increased sedation is a risk, further limit their use.[14] A muscle relaxant is chosen based on its adverse-effect profile, tolerability, and cost.[18]
Muscle relaxants (according to one study) were not advised fororthopedic conditions, but rather forneurological conditions such as spasticity incerebral palsy andmultiple sclerosis.[14] Dantrolene, although thought of primarily as a peripherally acting agent, is associated with CNS effects, whereas baclofen activity is strictly associated with the CNS.
Muscle relaxants are thought to be useful in painful disorders based on the theory that pain induces spasm and spasm causes pain. However, considerable evidence contradicts this theory.[17]
In general, muscle relaxants are not approved byFDA for long-term use. However,rheumatologists often prescribecyclobenzaprine nightly on a daily basis to increase stage 4 sleep. By increasing this sleep stage, patients feel more refreshed in the morning. Improving sleep is also beneficial for patients who have fibromyalgia.[19]
Muscle relaxants such astizanidine are prescribed in the treatment oftension headaches.[20]
Diazepam andcarisoprodol are not recommended for older adults,pregnant women, or people who havedepression or for those with a history of drug or alcoholaddiction.[21]
Because of the enhancement of inhibition in the CNS, most spasmolytic agents have the side effects of sedation and drowsiness and may cause dependence with long-term use. Several of these agents also have abuse potential, and their prescription is strictly controlled.[22][23][24]
Thebenzodiazepines, such asdiazepam, interact with theGABAA 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.[5]
Baclofen is considered to be at least as effective as diazepam in reducing spasticity, and causes much less sedation. It acts as a GABAagonist 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 ofsubstance P in the spinal cord, as well.[5][25]
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 atα2-adrenergic receptors, but reduces spasticity at doses that result in significantly lesshypotension than clonidine.[26] Neurophysiologic studies show that it depresses excitatory feedback from muscles that would normally increase muscle tone, therefore minimizing spasticity.[27][28] 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.[29]
Thehydantoin derivativedantrolene is a spasmolytic agent with a unique mechanism of action outside of the CNS. It reduces skeletal muscle strength by inhibiting the excitation-contraction coupling in themuscle fiber. In normal muscle contraction, calcium is released from thesarcoplasmic reticulum through theryanodine receptor channel, which causes the tension-generating interaction ofactin andmyosin. Dantrolene interferes with the release of calcium by binding to the ryanodine receptor and blocking the endogenous ligand ryanodine bycompetitive inhibition. Muscle that contracts more rapidly is more sensitive to dantrolene than muscle that contracts slowly, althoughcardiac muscle andsmooth 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 occasionallyhepatitis.[5]
Other common spasmolytic agents include:methocarbamol,carisoprodol,chlorzoxazone,cyclobenzaprine,gabapentin,metaxalone, andorphenadrine.
Thiocolchicoside is a muscle relaxant withanti-inflammatory andanalgesic effects and an unknown mechanism of action.[30][31][32][33] It acts as acompetitive antagonist atGABAA andglycine receptors with similarpotencies, as well as atnicotinic acetylcholine receptors, albeit to a much lesser extent.[34][35] It has powerfulproconvulsant activity and should not be used inseizure-prone individuals.[36][37][38]
Patients most commonly reportsedation as the main adverse effect of muscle relaxants. Usually, people become less alert when they are under the effects of these drugs. People are normally advised not to drivevehicles or operateheavy machinery while under muscle relaxants' effects.
Cyclobenzaprine produces confusion andlethargy, as well asanticholinergic side effects. When taken in excess or in combination with other substances, it may also betoxic. While the body adjusts to this medication, it is possible for patients to experiencedry mouth,fatigue, lightheadedness,constipation orblurred vision. Some serious but unlikely side effects may be experienced, including mental or mood changes, possible confusion andhallucinations, and difficulty urinating. In a very few cases, very serious but rare side effects may be experienced: irregular heartbeat, yellowing of eyes or skin,fainting,abdominal pain includingstomach ache,nausea orvomiting,lack of appetite, seizures, dark urine or loss of coordination.[39]
Patients taking carisoprodol for a prolonged time have reporteddependence,withdrawal and abuse, although most of these cases were reported by patients with addiction history. These effects were also reported by patients who took it in combination with other drugs with abuse potential, and in fewer cases, reports of carisoprodol-associated abuse appeared when used without other drugs with abuse potential.[40]
Common side effects eventually caused by metaxalone include dizziness,headache, drowsiness, nausea,irritability,nervousness,upset stomach andvomiting. Severe side effects may be experienced when consuming metaxalone, such as severeallergic reactions (rash,hives,itching, difficulty breathing, tightness in the chest, swelling of the mouth, face, lips, or tongue),chills,fever, andsore throat, may require medical attention. Other severe side effects include unusual or severe tiredness or weakness, as well as yellowing of the skin or the eyes.[41] When baclofen is administeredintrathecally, it may cause CNS depression accompanied with cardiovascular collapse andrespiratory failure. Tizanidine may lowerblood pressure. This effect can be controlled by administering a low dose at the beginning and increasing it gradually.[42]
