అధ్యాయము
ఆకారంయాక్షన్ యొక్క మెకానిజంఫార్మకోకైనటిక్స్ క్లినికల్ ఎఫిషియన్సీ సైడ్ ఎఫెక్ట్స్ దుర్వినియోగ 925 పొటెన్షియల్వ్యక్తిగత అస్థిపంజర కండరాలకు ఉపశమనం 925Carisoprodol (సోమ) Chlorzoxazone (Parafon ఫోర్టే DSC) సైక్లోబెంజప్రైన్ హైడ్రోక్లోరైడ్ (Flexeril) Metaxalone (Skelaxin) స్కెలాక్సిన్ Methocarbamol (Robaxin) రోబాక్సిన్ Orphenadrine ఒర్ఫెనద్రిం సిట్రేట్ (Norflex) Tizanidine టిజానిదిన్ హైడ్రోక్లోరైడ్ (Zanaflex) 926కండరాల అనియంత్రిత వ్యాకోచం చికిత్స మరియు పక్షవాతరోగి 926 లో వాడిన సంబంధం డ్రగ్స్డయాజెపామ్ (వాలీయమ్) Baclofenబ్యాక్లోఫెన్ (Lioresal) Dantrolene డాన్ట్రోలైన్ సోడియం (Dantrium) 927క్వినైన్ సల్ఫేట్ (Quinamm) తీర్మానం కండరాల అనియంత్రిత వ్యాకోచం సంబందించిన అనేక బాధాకరమైన పరిస్థితులు. ఈ తరచుగా పక్షవాతరోగి సంబంధం కండరాల మరియు అస్థిపంజర లోపాలు (ఉదా, కండర అలసట) లేదా కేంద్ర నాడీ వ్యవస్థ (CNS) క్రమరాహిత్యాలు. వివిధ చికిత్సలు, మందుల అధ్యయన ఎజెంట్ సహా తగ్గించేందుకు లేదా ఈ ద్వితీయ నొప్పి తగ్గించడానికి మరియు ఫంక్షన్ పెంచే విశ్వాసంతో కండరాల అనియంత్రిత వ్యాకోచం తుడుచు ఒక ప్రయత్నంగా వాడాడు చేశారు. 1234
ఔషధం యొక్క ఈ తరగతి యొక్క సామర్థ్యాన్ని సంబంధించి కేంద్ర అస్థిపంజర కండరం విశ్రాంతికారిణులు (SMRs) ఉన్నాయి కండరాల అనియంత్రిత వ్యాకోచం చికిత్స (టేబుల్ 125.1) కోసం తరచుగా సూచించిన మందులను నటనా వివాదం ఉంది. 5Studies ఈ మందులు, ప్రభావవంతమైన తట్టుకొలేక దుష్ప్రభావాలు కలిగి, మరియు కండరము ఆకస్మిక చైతన్యము తో బాధాకరమైన కండరాల పరిస్థితులు యొక్క చికిత్సలో సమ్మిళితంగా సూచించారు. 5678 వాటి ఉపయోగం నిద్రమత్తు 910111213 మరియు దుర్వినియోగం మరియు డిపెండెన్సీ కోసం సామర్ధ్యానికి పరిమితం. 14151617 SMRs న్యూరో జంక్షన్ ఫంక్షన్ బ్లాక్ మరియు సాధారణంగా శస్త్రచికిత్స అనస్థీషియా ఉపయోగించడానికి పరిమితమై ఇవి చదును నటన SMRs (ఉదా, క్యురేర్ మరియు pancuronium) తో తికమక పడకూడదు.టేబుల్ 125,1సాధారణంగా వాడే కేంద్రికముగా పనిచేసే అస్థిపంజర కండరాలకు ఉపశమనం కలిగించే మందులు
సాధారణ పేరు/వాణిజ్య పేరుCarisoprodolసోమChlorphenesinMaolateChlorzoxazoneParaflex, Parafon ఫోర్టే డీఎస్సీసైక్లోబెంజప్రైన్FlexerilMetaxaloneSkelaxinMethocarbamolRobaxinOrphenadrineNorflexTizanidineZanaflex
చర్య యొక్క మెకానిజం
SMRs చర్య యొక్క ఖచ్చితమైన రీతిలో తెలియదు. SMRs ప్రాథాన్యపరంగా polysynaptic ప్రతిచర్యలు పోగొట్టడానికి కనిపిస్తాయి. అధిక మోతాదుల వద్ద, SMRs monosynaptic ప్రతిచర్యలు ప్రభావితం కావచ్చు. జంతువుల అధ్యయనాలు లో, ఈ మందులు interneuronal సూచించే నిరోధిస్తుందని మరియు వెన్నుపాము లో polysynaptic న్యూరాన్లు అడ్డుకున్న మెదడులో మెదడు కణజాల ఏర్పాటు అవరోహణ ద్వారా వారి కండరాల ఉపశమనాన్ని ప్రభావాలు ఉత్పత్తి కనిపిస్తాయి. 5, 10, 12 మానవుల్లో, SMRs నేరుగా అస్థిపంజర కండరం విశ్రాంతిని కనిపించవు. అయితే, వారు వారి ప్రభావాలు మత్తును ద్వారా, చికిత్సా మోతాదులో న్యూరాన్ సూచించే ఫలితంగా నిస్పృహ ఉత్పత్తి చేయవచ్చు. 6, 9, 12, 18ఫార్మకోకైనటిక్స్SMRs సాధారణంగా బాగా నోటిద్వారా తరువాత శోషించబడతాయి. వారు 1 గంట లోపల సాధారణంగా, చర్య యొక్క ఒక త్వరిత ప్రభావం. కొన్ని SMRs parenterally నిర్వహించబడుతుంది ఉండవచ్చు, మరియు ఈ మార్గం చర్య యొక్క మరింత వేగంగా ఆగమనం దిగుబడి. మందులు కాలేయంలో బయో ట్రాన్స్ఫర్మేషన్ చేయించుకోవడానికి మరియు జీవక్రియా వంటి మూత్రంలో ప్రధానంగా విడుదలవుతాయి. గణనీయంగా వైవిధ్యం వ్యక్తి మందులు మధ్య ఉంది, వారి ప్లాస్మా సగం జీవితం, మరియు చర్యా వ్యవధి (టేబుల్ 125.2).డ్రగ్యాక్షన్, ,ప్రారంభ
వ్యవధి (hr) మరియు హాఫ్-లైఫ్వ్యవధి అస్థిపంజర కండరాల సడలింపుకు ఆన్సెట్ *
హాఫ్-లైఫ్Carisoprodol30 min4-68 hrChlorphenesin30 minఎన్ ఆర్2.5-5 hrChlorzoxazone1 hr3-41-2 hrసైక్లోబెంజప్రైన్1 hr4-62-3 hrMetaxalone30 minఎన్ ఆర్1-2 hrMethocarbamol1 hr4-514 గంటలOrphenadrine1 hr12-241-3 రోజుల పూర్తి పరిమాణంలో వీక్షించండిఎన్ఆర్, చర్య యొక్క నిడివిని కాదు నివేదించారు.Basmajian జెవి నుండి: తీవ్రమైన వెన్నునొప్పి మరియు ఆకస్మిక చైతన్యము: కలిపి నొప్పి నివారిణి మరియు antispasm ఏజెంట్ల నియంత్రిత బహుళ కేంద్రం విచారణ, వెన్నెముక 14: 438, 1989.* డేటా నోటి ఆధారపడి ఉంటాయి.క్లినికల్ ఎఫిషియన్సీSMRs అసంఖ్యాక క్లినికల్ ట్రయల్స్ నిర్వహించిన చేశారు. దురదృష్టవశాత్తు, అధ్యయనం రూపకల్పన లోపాలు కష్టం అధ్యయనములు ఫలితాలు మరియు పోలికలు ఆయతుల చేశారు. ఈ లోపాలను లేనివి రోగి ఎంపిక ప్రమాణాలు, noncomparable కండరాల మరియు అస్థిపంజర లోపాలు అధ్యయనం, వ్యాధి తీవ్రత మరియు వ్యవధి యొక్క వైవిధ్యం మరియు మరియు చికిత్స రోగుల స్పందనలు ఆత్మాశ్రయ అంచనా ఉన్నాయి. 5, 18192021222324 ఈ కష్టాలు ఉన్నప్పటికీ, కొన్ని ముగింపులు సాధ్యమే. దాదాపు అన్ని అధ్యయనాలలో, SMRs అక్యూట్ బాధాకరమైన కండరాల మరియు అస్థిపంజర లోపాలు మరియు కండరాల అనియంత్రిత వ్యాకోచం చికిత్సలో ప్లేసిబో కంటే మరింత సమర్థవంతంగా మారాయి. సమర్ధతకు దీర్ఘకాలిక వ్యాధుల చికిత్సలో తక్కువ స్థిరంగా ఉంది. ఒంటరిగా ఉపయోగించినప్పుడు, SMRs నొప్పి ఉపశమనం లో సాధారణ అనాల్జేసిక్ (ఉదా, ఆస్ప్రిన్, ఎసిటమైనోఫెన్, మరియు స్టీరాయ్ద్ శోథ నిరోధక మందులు) కు స్థిరంగా ఉన్నతమైన కాదు. అయితే, SMRs అనాల్జేసిక్ కలిపి ఉపయోగించారు ఉన్నప్పుడు, నొప్పి ఉపశమనం ఒంటరిగా ఉపయోగిస్తారు మందు అని మేలైనదిగా గుర్తించారు. కంటే మరొక మందు ఆధిపత్యం పత్రబద్ధం SMR సమర్ధతకు తులనాత్మక అధ్యయనాలు విఫలమయ్యాయి. 252627దుష్ప్రభావాలుSMRs చాలా సామాన్యంగా నివేదించారు దుష్ప్రభావాన్ని మగత ఉంది. ఈ ఏజెంట్ల తయారీదారులు t (ఉదా, డ్రైవింగ్, ఆపరేటింగ్ యంత్రాలు) మానసిక చురుకుదనం అవసరమైన చర్యలు హెచ్చరించడమే
Centrally Acting Skeletal Muscle Relaxants and Associated Drugs
Pain Management, Chapter 125, 924-928
Chapter outline
- Mechanism of Action 924
- Pharmacokinetics 924
- Clinical Efficacy 924
- Side Effects 925
- Potential for Abuse 925
- Individual Skeletal Muscle Relaxants 925
- Carisoprodol (Soma) 925
- Chlorzoxazone (Parafon Forte DSC) 925
- Cyclobenzaprine Hydrochloride (Flexeril) 926
- Metaxalone (Skelaxin) 926
- Methocarbamol (Robaxin) 926
- Orphenadrine Citrate (Norflex) 926
- Tizanidine Hydrochloride (Zanaflex) 926
- Associated Drugs Used in the Treatment of Muscle Spasm and Spasticity 926
- Diazepam (Valium) 927
- Baclofen (Lioresal) 927
- Dantrolene Sodium (Dantrium) 927
- Quinine Sulfate (Quinamm) 928
- Conclusion 928
Numerous painful conditions have associated muscle spasm. These are most frequently musculoskeletal disorders (e.g., muscle strain) or central nervous system (CNS) disorders associated with spasticity. Various therapeutic interventions, including pharmacologic agents, have been used in an attempt to reduce or obliterate muscle spasm in the belief that this will secondarily alleviate pain and improve function.
Although there is controversy regarding the efficacy of this class of drug, centrally acting skeletal muscle relaxants (SMRs) are the most frequently prescribed drugs for the treatment of muscle spasm ( Table 125.1 ). Studies have suggested that these drugs are effective, have tolerable side effects, and can be an adjunct in the treatment of painful musculoskeletal conditions with associated muscle spasm. Their use is limited by somnolence and the potential for abuse and dependency. The SMRs should not be confused with peripherally acting SMRs (e.g., curare and pancuronium), which block neuromuscular junction function and are generally confined to use in surgical anesthesia.
Table 125.1
Commonly Used Centrally Acting Skeletal Muscle Relaxants
| Generic Name | Trade Name |
|---|---|
| Carisoprodol | Soma |
| Chlorphenesin | Maolate |
| Chlorzoxazone | Paraflex, Parafon Forte DSC |
| Cyclobenzaprine | Flexeril |
| Metaxalone | Skelaxin |
| Methocarbamol | Robaxin |
| Orphenadrine | Norflex |
| Tizanidine | Zanaflex |
Mechanism of Action
The exact mode of action of the SMRs is not known. The SMRs appear to depress polysynaptic reflexes preferentially. At higher dosages, the SMRs may influence monosynaptic reflexes. In animal studies, these drugs appear to produce their muscle relaxation effects by inhibiting interneuronal activity and blocking polysynaptic neurons in the spinal cord and descending reticular formation in the brain. In humans, the SMRs do not appear to relax skeletal muscle directly. Rather, they may produce their effects through sedation, with resultant depression of neuronal activity at therapeutic doses.
Pharmacokinetics
The SMRs are generally well absorbed after oral ingestion. They have a rapid onset of action, generally within 1 hour. Some SMRs may be administered parenterally, and this route yields a more rapid onset of action. The drugs undergo biotransformation in the liver and are excreted primarily in the urine as metabolites. Significant variability exists among individual drugs, their plasma half-lives, and their duration of action ( Table 125.2 ).
Table 125.2
Skeletal Muscle Relaxant Onset of Action, Duration, and Half-Life *
| Drug | Onset | Duration (hr) | Half-Life |
|---|---|---|---|
| Carisoprodol | 30 min | 4–6 | 8 hr |
| Chlorphenesin | 30 min | NR | 2.5–5 hr |
| Chlorzoxazone | 1 hr | 3–4 | 1–2 hr |
| Cyclobenzaprine | 1 hr | 4–6 | 2–3 hr |
| Metaxalone | 30 min | NR | 1–2 hr |
| Methocarbamol | 1 hr | 4–5 | 14 hr |
| Orphenadrine | 1 hr | 12–24 | 1–3 days |
NR, duration of action not reported.
From Basmajian JV: Acute back pain and spasm: a controlled multicenter trial of combined analgesic and antispasm agents,Spine 14:438, 1989.
Clinical Efficacy
Numerous clinical trials of SMRs have been conducted. Unfortunately, study design deficiencies have made interpretation of results and comparisons among studies difficult. These deficiencies include ill-defined patient selection criteria, noncomparable musculoskeletal disorders studied, variability of disease severity and duration, and subjective assessment of patients' responses to therapy. Despite these difficulties, certain conclusions are possible. In almost all studies, SMRs were more effective than placebo in the treatment of acute painful musculoskeletal disorders and muscle spasm. Efficacy was less consistent in the treatment of chronic disorders. When used alone, SMRs were not consistently superior to simple analgesics (e.g., aspirin, acetaminophen, and nonsteroidal anti-inflammatory medications) in pain relief. However, when SMRs were used in combination with an analgesic, pain relief was superior to that of either drug used alone. Comparative studies of SMR efficacy failed to document superiority of one drug over another.
Side Effects
The most commonly reported side effect of the SMRs is drowsiness. Manufacturers of these agents warn against activities that require mental alertness (e.g., driving, operating machinery) while taking these medications. Other CNS side effects include dizziness, blurred vision, confusion, hallucinations, agitation, and headaches. Gastrointestinal (GI) side effects have also been frequently reported, including anorexia, nausea, vomiting, and epigastric distress. Allergic reactions, including skin rash, pruritus, edema, and anaphylaxis, have also been observed. SMRs are generally not recommended for use in children or in pregnant or lactating women. Because SMRs undergo hepatic metabolism and renal excretion, they must be used cautiously in patients with compromised hepatic or renal function. SMRs should be used with caution in combination with alcohol and other CNS depressants because the effects of these substances may be cumulative. Excessive doses of SMRs may result in significant toxicity, with CNS depression consisting of stupor, coma, respiratory depression, and even death. Abrupt cessation of some SMRs may cause withdrawal symptoms similar to those seen in barbiturate or alcohol withdrawal.
Potential for Abuse
The SMRs have the potential for abuse and dependence. Although the abuse potential of the SMRs is lower than that for benzodiazepines or opioids, numerous incidences have been reported in the medical literature.
The SMRs may be the primary drug of abuse, presumably for their sedative or mood-altering effects. More frequently, SMRs are used in combination with other CNS depressants, such as opioids or alcohol. These combinations may be taken to prolong the effect of the opioid or benzodiazepines or to achieve the same effect with a lesser amount of the primary drug of abuse. Prescriptions for the SMRs are more readily obtainable than are prescriptions for opioids or benzodiazepines, and prescriptions for SMRs elicit less suspicion when they are frequently refilled. Because of the potential for abuse, investigators have recommended that SMRs be prescribed only for acute conditions and for short periods of time. The SMRs should be used cautiously in known or suspected drug abusers, especially if these patients are already using other CNS depressants.
Individual Skeletal Muscle Relaxants
Carisoprodol (Soma)
Carisoprodol is a precursor of meprobamate (Miltown and Equanil). Meprobamate is one of the three primary metabolites produced by hepatic biotransformation of carisoprodol. Meprobamate dependency secondary to carisoprodol use has been reported with associated drug-seeking behavior and withdrawal symptoms. Withdrawal symptoms are similar to those seen in withdrawal from barbiturates and include restlessness, anxiety, insomnia, anorexia, and vomiting. Severe withdrawal symptoms have included agitation, hallucinations, seizures, and, rarely, death. Because of this potential for physical dependency, carisoprodol should be tapered rather than abruptly discontinued following long-term use. Idiosyncratic adverse effects include weakness, speech disturbances, temporary visual loss, ataxia, and transient paralysis.
The onset of action of carisoprodol is 30 minutes. The plasma half-life is 8 hours, and the duration of action is 4 to 6 hours. The drug is supplied as 350-mg tablets, and the recommended dose is one tablet taken four times daily. Carisoprodol is also available in combination with aspirin (Soma Compound) or aspirin and codeine (Soma Compound with Codeine).
Chlorzoxazone (Parafon Forte DSC)
Chlorzoxazone is similar to the other SMRs, except for some reported cases of significant hepatotoxicity in individuals taking this drug. Chlorzoxazone has an onset of action within 1 hour and a plasma half-life of 1 to 2 hours. The duration of action is 3 to 4 hours. The drug is available in 250- and 500-mg caplets, and the recommended adult dose is 250 to 750 mg taken three to four times daily. A pediatric dose of 20 mg/kg divided into three or four doses is suggested by the manufacturer.
Cyclobenzaprine Hydrochloride (Flexeril)
Cyclobenzaprine is related structurally and pharmacologically to the tricyclic antidepressants (TCAs). Like other SMRs, cyclobenzaprine produces its effects within the CNS, primarily at the brainstem level. Like the TCAs, cyclobenzaprine has anticholinergic properties and may cause dry mouth, blurred vision, increased intraocular pressure, urinary retention, and constipation. The drug should therefore be used with caution in individuals with angle-closure glaucoma or prostatic hypertrophy. As with the TCAs, cyclobenzaprine should not be used in patients with cardiac arrhythmias, conduction disturbances, or congestive heart failure or during the acute phase of recovery from myocardial infarction. Cyclobenzaprine may interact with monoamine oxidase inhibitors and should not be used concurrently or within 14 days of discontinuation of these drugs. Withdrawal symptoms consisting of nausea, headache, and malaise have been reported following abrupt cessation of cyclobenzaprine after prolonged use.
Cyclobenzaprine has an onset of action within 1 hour. The plasma half-life is 1 to 3 days, and the duration of action is 12 to 24 hours. Cyclobenzaprine is supplied as 10-mg tablets and has a recommended dose of 10 mg three times per day. Up to 40 mg daily in divided doses may be prescribed.
A long-acting formulation of cyclobenzaprine has been introduced and is believed by some clinicians to have a lower side effect profile than the immediate-release formulation of this drug.
Metaxalone (Skelaxin)
Metaxalone is comparable in effect to the other SMRs. Adverse effects are also similar, with the exception of drug-associated hemolytic anemia and impaired liver function. Hepatotoxicity associated with metaxalone has not been as severe as that reported with chlorzoxazone. Monitoring of liver function is recommended with long-term usage. Metaxalone has an onset of action of 1 hour, a plasma half-life of 2 to 3 hours, and a duration of action of 4 to 6 hours. This drug is supplied as 400-mg tablets and has a recommended dose of 800 mg three to four times daily.
Methocarbamol (Robaxin)
Methocarbamol is available in oral and parenteral form for intravenous (IV) or intramuscular (IM) injection. Subcutaneous injection is not recommended. Taken orally, this drug is similar to the other SMRs. Parenteral use of methocarbamol has been associated with pain, sloughing of skin, and thrombophlebitis at the injection site. Additionally, overly rapid IV injection has been associated with syncope, hypotension, bradycardia, and convulsions. Because of the risk of convulsion, parenteral use of the drug is not recommended for use in patients with epilepsy.
The onset of action is 30 minutes following oral ingestion and is almost immediate following parenteral administration. The plasma half-life of the drug is 1 to 2 hours. The duration of action has not been reported. Methocarbamol is produced in 500- and 750-mg tablets and has a recommended dosage range of 4000 to 4500 mg daily in three to four divided doses. For severe conditions, a dose as high as 6 to 8 g may be given for the first 48 to 72 hours. This drug is available for IV or IM injection in 10-mL single-dose vials containing 10 mg/mL. Methocarbamol tablets are also available in combination with aspirin (Robaxisal).
Orphenadrine Citrate (Norflex)
Orphenadrine is an analogue of the antihistamine diphenhydramine (Benadryl). Orphenadrine shares some of the antihistaminic and anticholinergic effects of diphenhydramine. Unlike the other SMRs, orphenadrine produces some independent analgesic effects that may contribute to its efficacy in relieving painful skeletal muscle spasm. In addition to adverse effects commonly associated with other SMRs, dry mouth, blurred vision, and urinary retention may occur as a result of the drug's anticholinergic activity. Rare instances of aplastic anemia have been reported. Like methocarbamol, orphenadrine is available for IV or IM injection. Anaphylactoid reactions have been reported following parenteral administration.
Orphenadrine has an onset of action of 1 hour following oral administration. The onset of action is approximately 5 minutes after IM injection and is almost immediate with IV administration. The drug's plasma half-life is 14 hours, and the duration of action is 4 to 6 hours. Orphenadrine is available in 100-mg tablets with a recommended dose of one tablet twice daily. Orphenadrine is available for parenteral use in 2-mL ampules containing 60 mg of the drug and is also administered once every 12 hours. Orphenadrine tablets are also produced in combination with aspirin and caffeine (Norgesic and Norgesic Forte, respectively).
Tizanidine Hydrochloride (Zanaflex)
Tizanidine hydrochloride is a centrally acting alpha 2 -adrenergic agonist. Tizanidine is thought to exert its antispasticity properties by increased presynaptic inhibition of motoneurons; this action reduces facilitation of spinal motoneuron firing. Tizanidine does not appear to have any direct effect on the neuromuscular junction or on skeletal muscle fibers. The drug is well absorbed after oral administration and has a half-life of approximately 2.5 hours. Tizanidine is metabolized by the liver, and 95% is excreted in the urine and feces. The drug is available in 2-mg and 4-mg tablets for oral administration.
Because of the drug's short half-life, it must be administered every 6 to 8 hours. Because of the common side effects of weakness and sedation, it is best to start the patient on a 2-mg bedtime dose and then titrate upward every 4 to 6 days in 2-mg doses given every 6 to 8 hours. Faster upward titration is best accomplished in an inpatient setting. The maximum daily divided dose should not exceed a total of 36 mg.
Associated Drugs Used in the Treatment of Muscle Spasm and Spasticity
Two additional drugs with muscle relaxant effects, specifically the benzodiazepine diazepam and the antispasmodic agent baclofen, may be useful in the treatment of pain. A third drug, dantrolene sodium, a peripherally acting spasmolytic agent, is limited to controlling chronic spasticity associated with upper motoneuron disorders. Finally, the cinchona alkaloid quinine sulfate may help to reduce nocturnal leg cramps. A discussion of each drug follows.
Diazepam (Valium)
Diazepam is the most frequently prescribed benzodiazepine used in the treatment of muscle spasm and pain. Other available benzodiazepines have not been proven superior to diazepam for this use. Diazepam has anxiolytic, hypnotic, and antiepileptic properties in addition to its antispasmodic actions.
The muscle relaxant effects of this drug are thought to result from enhancement of γ-aminobutyric acid (GABA)–mediated presynaptic inhibition at spinal and supraspinal sites. Numerous studies have been performed comparing diazepam with placebo and with other SMRs in the treatment of painful musculoskeletal disorders. Results have been inconsistent; in general, however, diazepam has been found to be superior to placebo, but not consistently superior to other SMRs in the relief of muscle spasm and pain. Diazepam appears to offer greater relief of associated anxiety than the other SMRs tested. Diazepam is superior, however, to other SMRs in the treatment of spasticity associated with CNS disorders such as spinal cord injury and cerebral palsy. Efficacy is similar to that of baclofen and dantrolene sodium for CNS disorders. Diazepam's long-term use in these disorders is limited primarily by sedation, abuse potential, and dependence.
Diazepam is well absorbed from the GI tract, although it may also be administered by IV or IM injection. The drug undergoes biotransformation in the liver and is excreted in the urine. Diazepam is highly lipid soluble and rapidly crosses the blood-brain barrier. The onset of action is rapid following oral and parenteral administration. Diazepam's plasma half-life is 20 to 50 hours, and active metabolites of the drug have plasma half-lives ranging from 3 to 200 hours. The duration of action is variable, depending on rate and extent of drug distribution and elimination.
Abuse and dependence have been reported with the use of diazepam and the other benzodiazepines. The incidence of these problems is somewhat controversial. The potential for abuse varies among individuals and also varies with doses and length of therapy. Withdrawal symptoms may occur with abrupt cessation of the drug and are similar to symptoms of barbiturate or alcohol withdrawal, including anxiety, dysphoria, insomnia, diaphoresis, vomiting, diarrhea, tremor, and seizures. Diazepam may have an additive effect when taken with other CNS depressants. Diazepam may have reduced plasma clearance and an increased half-life when taken in combination with disulfiram (Antabuse) or cimetidine (Tagamet).
Diazepam's most common adverse effects are related to its CNS-depressant activity: sedation, impairment of psychomotor performance, cognitive dysfunction, confusion, dizziness, and behavioral changes. Paradoxical CNS stimulation has also been reported. Other reported adverse effects include GI complaints, skin rash, blood dyscrasias, and elevation of liver enzymes. Parenteral administration has been associated with pain and thrombophlebitis at the injection site. IV and IM administration has produced more serious side effects, especially in seriously ill or geriatric patients; these side effects include cardiopulmonary depression, apnea, hypotension, bradycardia, and cardiac arrest.
Diazepam is available in 2-, 5-, and 10-mg tablets. The recommended dose for relief of painful musculoskeletal conditions is 2 to 10 mg three to four times daily. An extended-release 15-mg capsule (Valrelease) is produced and has a daily single dose of 1 to 2 capsules. Diazepam is available for parenteral administration in 2-mL ampules or 10-mL vials with 5 mg/mL. The recommended IM or IV dose is 5 to 10 mg every 3 to 4 hours as necessary.
Baclofen (Lioresal)
Baclofen is a chemical analogue of GABA, which is an inhibitory neurotransmitter. The drug produces its effects primarily by inhibiting monosynaptic and polysynaptic transmission in the spinal cord, although some supraspinal activity may also occur. Baclofen is used chiefly in the management of spasticity associated with CNS disorders such as spinal cord lesions and multiple sclerosis. The drug is reported to be equal or superior in efficacy when compared with diazepam and dantrolene sodium. It is less sedating than diazepam and has fewer serious side effects than dantrolene sodium. Baclofen may be administered intrathecally to manage severe spasticity in patients who are intolerant or unresponsive to oral therapy.
Baclofen has been useful in the treatment of trigeminal neuralgia. Because the a more favorable side effect profile, some researchers consider baclofen to be the drug of first choice in the treatment of this condition. The coadministration of baclofen and carbamazepine may be more effective than either drug used singly owing to a synergistic effect; however, adverse effects may be cumulative. l -Baclofen has been reported to be more effective and to have fewer side effects than racemic baclofen.
Baclofen is well absorbed from the GI tract and undergoes limited hepatic biotransformation. Most of the drug is excreted unchanged in the urine. The onset of action is highly variable, ranging from hours to weeks. The drug has a plasma half-life of 2.5 to 4 hours. The onset of action following intrathecal injection is 0.5 to 1 hour.
The most frequent side effects associated with the use of baclofen are drowsiness, dizziness, weakness, confusion, nausea, and hypotension. Side effects may be minimized by starting the drug at a low dose and gradually increasing it to the desired level. Abrupt discontinuation of the drug has been associated with hallucinations, psychiatric disturbances, and seizures; therefore, the drug should be gradually withdrawn. Baclofen is produced in 10- and 20-mg tablets. The recommended starting dose is 5 mg three times daily for 3 days with an incremental increase of 5 mg per dose every 3 days. The therapeutic range is 40 to 80 mg daily.
Dantrolene Sodium (Dantrium)
Dantrolene sodium is a peripherally acting skeletal muscle relaxant that produces its effect on skeletal muscle by interfering with the release of calcium ions from the sarcoplasmic reticulum. The primary indication for this drug is reduction of spasticity associated with upper motoneuron disorders, including spinal cord injury, stroke, multiple sclerosis, and cerebral palsy. This drug is also used in the treatment of malignant hyperthermia by reducing the hypometabolic processes associated with this disorder. Dantrolene sodium is not indicated in the treatment of other painful musculoskeletal disorders.
Dantrolene sodium is incompletely absorbed from the GI tract. It is metabolized by the liver and is excreted in the urine primarily as metabolites. The onset of action may require a week or more in the treatment of CNS-associated spasticity. The drug's plasma half-life is 8.7 hours. The most frequent side effects associated with its use are muscle weakness, drowsiness, dizziness, malaise, and diarrhea, which may be severe. Serious idiosyncratic and hypersensitive hepatocellular injury may occur that may be fulminant and fatal. This adverse effect has occurred most frequently in women more than 35 years old. The drug is supplied in 25-mg, 50-mg, and 100-mg tablets. For treatment of spasticity, the recommended starting dose is 25 mg, which is gradually increased to a maximum daily dose of 400 mg.
Quinine Sulfate (Quinamm)
Quinine sulfate is a cinchona alkaloid best known for its use as an antimalarial agent. Although the use of this drug for the treatment of nocturnal leg cramps is controversial, many clinicians believe that the drug is useful in this setting. The drug reportedly produces its effect on skeletal muscle by an increased refractory period, reduced excitability of the motor end plate to acetylcholine, and redistribution of calcium within the muscle fiber. After oral ingestion, the drug is well absorbed, metabolized by the liver, and excreted in the urine. Quinine sulfate has a plasma half-life of 4 to 5 hours.
Some individuals are hypersensitive to quinine sulfate and develop thrombocytopenic purpura, which may be life-threatening. Visual disturbances, nausea, vomiting, and skin rash have also been reported. The drug may increase plasma levels of digoxin and may potentiate the effects of neuromuscular blocking agents owing to its curariform-like effects. Cinchonism does not usually occur at doses used to treat leg cramps. The drug is supplied as 260-mg tablets, and the recommended dose is one or two tablets nightly.
Conclusion
The SMRs are efficacious in the treatment of painful musculoskeletal disorders. They are generally more effective in combination with analgesics and may potentiate the effects of other CNS depressants. The use of these drugs may be limited by sedation and other undesirable side effects, as well as by their potential for abuse and dependence. Diazepam may also be useful as a muscle relaxant and an anxiolytic, but it also causes sedation and has potential for abuse. Baclofen is used primarily to treat spasticity resulting from CNS lesions. It is also useful in the treatment of trigeminal neuralgia and may be the drug of first choice for this condition. Dantrolene sodium is a peripherally acting agent used to treat spasticity. It is not useful in the treatment of other painful musculoskeletal disorders. Quinine sulfate is an antimalarial agent that may be useful in the treatment of nocturnal leg cramps. Numerous evaluations have failed to demonstrate clear superiority of one SMR over another. Practitioners should base their choice of an agent on careful consideration of individual variables in a given clinical situation.
No comments:
Post a Comment