Editing Muscle relaxant (section)

==Spasmolytics==
{{main|Antispasmodic}}
[[File: Spasticity2.svg|thumb|right|250px|A view of the spinal cord and skeletal muscle showing the action of various muscle relaxants&nbsp;– black lines ending in arrowheads represent chemicals or actions that enhance the target of the lines, blue lines ending in squares represent chemicals or actions that inhibit the target of the line]]
The generation of the [[action potential|neuronal 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 as [[GABA]].

===Terminology===
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.<ref name=" MillerRD"/>

Most sources still use the term "centrally acting muscle relaxant". According to [[Medical Subject Headings|MeSH]], dantrolene is usually classified as a centrally acting muscle relaxant.<ref>{{MeshName|Dantrolene}}</ref> The [[World Health Organization]], in its [[Anatomical Therapeutic Chemical Classification System|ATC]], uses the term "centrally acting agents",<ref>{{cite web |url=http://www.whocc.no/atc_ddd_index/?code=M03B |title=M03B Muscle Relaxants, Centrally acting agents |work=ATC/DDD Index |publisher=WHO Collaborating Centre for Drug Statistics Methodology }}</ref> but adds a distinct category of "directly acting agents", for dantrolene.<ref>{{cite web |url=http://www.whocc.no/atc_ddd_index/?code=M03CA01 |title=M03CA01 Dantrolene |work=ATC/DDD Index |publisher=WHO Collaborating Centre for Drug Statistics Methodology }}</ref> Use of this terminology dates back to at least 1973.<ref name="pmid4712630">{{cite journal |vauthors=Ellis KO, Castellion AW, Honkomp LJ, Wessels FL, Carpenter JE, Halliday RP |title=Dantrolene, a direct acting skeletal muscle relaxant |journal=J Pharm Sci |volume=62 |issue=6 |pages=948–51 |date=June 1973 |pmid=4712630 |doi=10.1002/jps.2600620619 }}</ref>

The term "spasmolytic" is also considered a synonym for [[antispasmodic]].<ref name="urlDorlands Medical Dictionary:antispasmodic">{{cite web |url=http://www.mercksource.com/pp/us/cns/cns_hl_dorlands_split.jsp?pg=/ppdocs/us/common/dorlands/dorland/one/000006336.htm#000006336 |title=Dorlands Medical Dictionary:antispasmodic |archive-url=https://web.archive.org/web/20091001022542/http://www.mercksource.com/pp/us/cns/cns_hl_dorlands_split.jsp?pg=%2Fppdocs%2Fus%2Fcommon%2Fdorlands%2Fdorland%2Fone%2F000006336.htm#000006336 |archive-date=2009-10-01 |url-status=dead }}</ref>

===Clinical use===
Spasmolytics such as [[carisoprodol]], [[cyclobenzaprine]], [[metaxalone]], and [[methocarbamol]] are commonly prescribed for [[low back pain]] or [[neck pain]], [[fibromyalgia]], [[tension headaches]] and [[myofascial pain syndrome]].<ref name="pmid18448752">{{cite journal |vauthors=See S, Ginzburg R |title=Choosing a skeletal muscle relaxant |journal=Am Fam Physician |volume=78 |issue=3 |pages=365–370 |year=2008 |issn=0002-838X |pmid=18711953}}</ref> However, they are not recommended as first-line agents; in acute low back pain, they are not more effective than [[paracetamol]] or nonsteroidal anti-inflammatory drugs ([[NSAID]]s),<ref name="pmid17909209">{{cite journal | vauthors = Chou R, Qaseem A, Snow V, Casey D, Cross JT, Shekelle P, Owens DK | title = Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society | journal = Ann. Intern. Med. | volume = 147 | issue = 7 | pages = 478–91 | date = October 2007 | pmid = 17909209 | doi = 10.7326/0003-4819-147-7-200710020-00006| doi-access = free }}</ref><ref name="pmid12804507">{{cite journal | vauthors = van Tulder MW, Touray T, Furlan AD, Solway S, Bouter LM | title = Muscle relaxants for non-specific low back pain | journal = Cochrane Database Syst Rev | issue = 2 | pages = CD004252 | date = 2003 | volume = 2017 | pmid = 12804507 | doi = 10.1002/14651858.CD004252 | pmc = 6464310 }}</ref> and in fibromyalgia they are not more effective than [[antidepressants]].<ref name="pmid18448752"/> Nevertheless, some (low-quality) evidence suggests muscle relaxants can add benefit to treatment with NSAIDs.<ref name="pmid15767833">{{cite journal | vauthors = Beebe FA, Barkin RL, Barkin S | title = A clinical and pharmacologic review of skeletal muscle relaxants for musculoskeletal conditions | journal = Am J Ther | volume = 12 | issue = 2 | pages = 151–71 | date = 2005 | pmid = 15767833 | doi = 10.1097/01.mjt.0000134786.50087.d8 | s2cid = 24901082 }}</ref> In general, no high-quality [[evidence-based medicine|evidence]] supports their use.<ref name="pmid18448752"/> No drug has been shown to be better than another, and all of them have [[adverse drug effect|adverse effects]], particularly [[dizziness]] and [[drowsiness]].<ref name="pmid18448752"/><ref name="pmid12804507"/> Concerns about possible abuse and [[drug interaction|interaction]] with other drugs, especially if increased sedation is a risk, further limit their use.<ref name="pmid18448752"/> A muscle relaxant is chosen based on its adverse-effect profile, tolerability, and cost.<ref name="See-2008">{{cite journal | vauthors = See S, Ginzburg R | title = Skeletal muscle relaxants | journal = Pharmacotherapy | volume = 28 | issue = 2 | pages = 207–13 | date = February 2008 | pmid = 18225966 | doi = 10.1592/phco.28.2.207 | s2cid = 43152771 }}</ref>

Muscle relaxants (according to one study) were not advised for [[orthopedic]] conditions, but rather for [[neurological]] conditions such as spasticity in [[cerebral palsy]] and [[multiple sclerosis]].<ref name="pmid18448752"/> 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.<ref name="pmid15767833"/>

In general, muscle relaxants are not approved by [[FDA]] for long-term use. However, [[rheumatologists]] often prescribe [[cyclobenzaprine]] 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.<ref>{{cite web |url=http://arthritis.about.com/od/musclerelaxers/f/musclerelaxers.htm |title=When Are Muscle Relaxers Prescribed For Arthritis Patients? |access-date=2010-07-09 |archive-date=2010-12-05 |archive-url=https://web.archive.org/web/20101205111526/http://arthritis.about.com/od/musclerelaxers/f/musclerelaxers.htm |url-status=dead }}</ref>

Muscle relaxants such as [[tizanidine]] are prescribed in the treatment of [[tension headaches]].<ref>{{MedlinePlus|000797|Tension Headache}}</ref>

[[Diazepam]] and [[carisoprodol]] are not recommended for older adults, [[pregnant women]], or people who have [[Major depressive disorder |depression]] or for those with a history of drug or alcohol [[addiction]].<ref>{{cite web |url=http://www.webmd.com/back-pain/muscle-relaxants-for-low-back-pain |title=Muscle Relaxants |access-date=2010-07-09}}</ref>

===Mechanism===
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.<ref name="RangDale">{{cite book |last1=Rang |first1=H.P. |last2=Dale |first2=M.M. |chapter=Drugs Used in Treating Motor Disorders |title=Pharmacology |publisher=Churchill Livingston |year=1991 |isbn=0-443-04483-X |pages=684–705 |edition=2nd }}</ref><ref name="GnGStandaert">{{cite book |last1=Standaert |first1=D.G. |last2=Young |first2=A.B. |chapter=Treatment Of Central Nervous System Degerative Disorders |editor-first=L.S. |editor-last=Goodman |editor2-first=J.G. |editor2-last=Hardman |editor3-first=L.E. |editor3-last=Limbird |editor4-first=A.G. |editor4-last=Gilman |title=[[Goodman & Gilman's The Pharmacological Basis of Therapeutics]] |publisher=McGraw Hill |year=2001 |isbn=0-07-112432-2 |pages=550–568 |edition=10th |ref={{harvid|Goodman & Gilman's}}}}</ref><ref name="GnGCharney">{{cite book |last1=Charney |first1=D.S. |last2=Mihic |first2=J. |last3=Harris |first3=R.A. |chapter=Hypnotics and Sedatives |title={{harvnb|Goodman & Gilman's}} |year=2001 |pages=399–427 }}</ref>

The [[benzodiazepine]]s, such as [[diazepam]], interact with the [[GABAA receptor|GABA<sub>A</sub> 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.<ref name="MillerRD"/>

[[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 GABA<sub>B</sub> 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.<ref name="MillerRD"/><ref name="pmid9928310">{{cite journal |vauthors=Cazalets JR, Bertrand S, Sqalli-Houssaini Y, Clarac F |title=GABAergic control of spinal locomotor networks in the neonatal rat |journal=Ann. N. Y. Acad. Sci. |volume=860 |pages=168–80 |date=November 1998 |issue=1 |pmid=9928310 |doi=10.1111/j.1749-6632.1998.tb09047.x |bibcode=1998NYASA.860..168C |s2cid=33042651}}</ref>

[[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 [[Adrenergic receptor|α<sub>2</sub>-adrenergic receptors]], but reduces spasticity at doses that result in significantly less [[hypotension]] than clonidine.<ref name="YoungRR">{{cite journal |editor=Young, R.R. |title=Symposium: Role of tizanidine in the treatment of spasticity |journal=Neurology |volume=44 |issue=Suppl 9 |year=1994 |pages=S1-80 | pmid =7970005}}</ref> Neurophysiologic studies show that it depresses excitatory feedback from muscles that would normally increase muscle tone, therefore minimizing spasticity.<ref name="pmid12106064">{{cite journal | vauthors = Bras H, Jankowska E, Noga B, Skoog B | title = Comparison of Effects of Various Types of NA and 5-HT Agonists on Transmission from Group II Muscle Afferents in the Cat | journal = Eur. J. Neurosci. | volume = 2 | issue = 12 | pages = 1029–1039 | date = 1990 | pmid = 12106064 | doi = 10.1111/j.1460-9568.1990.tb00015.x | s2cid = 13552923 }}</ref><ref name="pmid10712650">{{cite journal | vauthors = Jankowska E, Hammar I, Chojnicka B, Hedén CH | title = Effects of monoamines on interneurons in four spinal reflex pathways from group I and/or group II muscle afferents | journal = Eur. J. Neurosci. | volume = 12 | issue = 2 | pages = 701–14 | date = February 2000 | pmid = 10712650 | doi = 10.1046/j.1460-9568.2000.00955.x | s2cid = 21546330 }}</ref> 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.<ref name="YoungRR2">{{cite journal | vauthors = Young RR, Wiegner AW | title = Spasticity | journal = Clin. Orthop. Relat. Res. | issue = 219 | pages = 50–62 | date = June 1987 | pmid = 3581584 }}</ref>

The [[hydantoin]] derivative [[dantrolene]] 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 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]].<ref name=" MillerRD"/>

Other common spasmolytic agents include: [[methocarbamol]], [[carisoprodol]], [[chlorzoxazone]], [[cyclobenzaprine]], [[gabapentin]], [[metaxalone]], and [[orphenadrine]].

[[Thiocolchicoside]] is a muscle relaxant with [[anti-inflammatory]] and [[analgesic]] effects and an unknown mechanism of action.<ref name="pmid14563464">{{cite journal | vauthors = Tüzün F, Unalan H, Oner N, Ozgüzel H, Kirazli Y, Içağasioğlu A, Kuran B, Tüzün S, Başar G | title = Multicenter, randomized, double-blinded, placebo-controlled trial of thiocolchicoside in acute low back pain | journal = Joint, Bone, Spine | volume = 70 | issue = 5 | pages = 356–61 | date = September 2003 | pmid = 14563464 | doi = 10.1016/S1297-319X(03)00075-7 }}</ref><ref name="pmid19780000">{{cite journal | vauthors = Ketenci A, Basat H, Esmaeilzadeh S | title = The efficacy of topical thiocolchicoside (Muscoril) in the treatment of acute cervical myofascial pain syndrome: a single-blind, randomized, prospective, phase IV clinical study | journal = Agri | volume = 21 | issue = 3 | pages = 95–103 | date = July 2009 | pmid = 19780000 | url = http://www.journalagent.com/pubmed/linkout.asp?ISSN=1300-0012&PMID=19780000 }}</ref><ref name="pmid18839644">{{cite journal | vauthors = Soonawalla DF, Joshi N | title = Efficacy of thiocolchicoside in Indian patients suffering from low back pain associated with muscle spasm | journal = Journal of the Indian Medical Association | volume = 106 | issue = 5 | pages = 331–5 | date = May 2008 | pmid = 18839644 }}</ref><ref name="pmid15963201">{{cite journal | vauthors = Ketenci A, Ozcan E, Karamursel S | title = Assessment of efficacy and psychomotor performances of thiocolchicoside and tizanidine in patients with acute low back pain | journal = International Journal of Clinical Practice | volume = 59 | issue = 7 | pages = 764–70 | date = July 2005 | pmid = 15963201 | doi = 10.1111/j.1742-1241.2004.00454.x | s2cid = 20671452 | doi-access = free }}</ref> It acts as a [[Receptor antagonist|competitive antagonist]] at [[GABA receptor|GABA<sub>A</sub>]] and [[Glycine receptor|glycine receptors]] with similar [[potency (pharmacology)|potencies]], as well as at [[nicotinic acetylcholine receptor]]s, albeit to a much lesser extent.<ref name="pmid16806306">{{cite journal | vauthors = Carta M, Murru L, Botta P, Talani G, Sechi G, De Riu P, Sanna E, Biggio G | title = The muscle relaxant thiocolchicoside is an antagonist of GABAA receptor function in the central nervous system | journal = Neuropharmacology | volume = 51 | issue = 4 | pages = 805–15 | date = September 2006 | pmid = 16806306 | doi = 10.1016/j.neuropharm.2006.05.023 | s2cid = 11390033 }}</ref><ref name="pmid17234181">{{cite journal | vauthors = Mascia MP, Bachis E, Obili N, Maciocco E, Cocco GA, Sechi GP, Biggio G | title = Thiocolchicoside inhibits the activity of various subtypes of recombinant GABA(A) receptors expressed in Xenopus laevis oocytes | journal = European Journal of Pharmacology | volume = 558 | issue = 1–3 | pages = 37–42 | date = March 2007 | pmid = 17234181 | doi = 10.1016/j.ejphar.2006.11.076 }}</ref> It has powerful [[convulsant|proconvulsant]] activity and should not be used in [[seizure]]-prone individuals.<ref name="pmid11554898">{{cite journal | vauthors = De Riu PL, Rosati G, Sotgiu S, Sechi G | title = Epileptic seizures after treatment with thiocolchicoside | journal = Epilepsia | volume = 42 | issue = 8 | pages = 1084–6 | date = August 2001 | pmid = 11554898 | doi = 10.1046/j.1528-1157.2001.0420081084.x | s2cid = 24017279 | doi-access =  }}</ref><ref name="pmid19707540">{{cite journal | vauthors = Giavina-Bianchi P, Giavina-Bianchi M, Tanno LK, Ensina LF, Motta AA, Kalil J | title = Epileptic seizure after treatment with thiocolchicoside | journal = Therapeutics and Clinical Risk Management | volume = 5 | issue = 3 | pages = 635–7 | date = June 2009 | pmid = 19707540 | pmc = 2731019 | doi = 10.2147/tcrm.s4823 | doi-access = free }}</ref><ref name="pmid12967581">{{cite journal | vauthors = Sechi G, De Riu P, Mameli O, Deiana GA, Cocco GA, Rosati G | title = Focal and secondarily generalised convulsive status epilepticus induced by thiocolchicoside in the rat | journal = Seizure | volume = 12 | issue = 7 | pages = 508–15 | date = October 2003 | pmid = 12967581 | doi = 10.1016/S1059-1311(03)00053-0 | s2cid = 14308541 | doi-access = free }}</ref>