Oxazepam

Oxazepam (marketed under brand names Alepam, Murelax, Oxascand, Serax, Serepax, Seresta, Sobril) is a drug which is a benzodiazepine derivative. It possesses relatively weak anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties.

Pharmacology
Oxazepam is an intermediate acting benzodiazepine. Oxazepam acts on benzodiazepine receptors resulting in an enhancement of the binding of GABA to the GABAA receptor which results in inhibitory effects on the central nervous system. The half life of oxazepam is 4-15 hours. Oxazepam has been shown to suppress cortisol levels.

Oxazepam is an active metabolite formed during the breakdown of diazepam, nordazepam, and certain similar drugs. Oxazepam may be safer than many other benzodiazepines in patients with impaired liver function because it does not require hepatic oxidation, but rather it is simply metabolized via glucuronidation. This means that oxazepam is less likely to accumulate and cause adverse reactions in the elderly or people with liver disease. Oxazepam is similar to lorazepam in this respect. (1) There is preferential storage of oxazepam in some organs including the heart. Absorption by any administered route and the risk of accumulation is significantly increased in the neonate and there is clinical justification to recommend the withdrawal of oxazepam during pregnancy and breast feeding as oxazepam is excreted in breast milk.

Indications
It is an intermediate acting benzodiazepine with a slow onset of action, so it is usually prescribed to individuals who have trouble staying asleep, rather than falling asleep. It is commonly prescribed for anxiety disorders with associated tension, irritability, and agitation. It is also prescribed for drug and alcohol withdrawal, and for anxiety associated with depression. Also prescribed for sleepwalking before a neurologist is involved when the sleepwalker may be a problem or danger to themselves.

Tolerance
When tolerance and habituation occurs brain concentration of oxazepam increase according to degree of tolerance.

Dependence
Oxazepam as with other benzodiazepine drugs can cause physical dependence, addiction and what is known as the benzodiazepine withdrawal syndrome. Withdrawal from oxazepam or other benzodiazepines often leads to withdrawal symptoms which are similar to those seen during alcohol and barbiturate withdrawal. The higher the dose and the longer the drug is taken the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can however occur at standard dosages and also after short term use. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regime.

The Committee on the Review of Medicines
The Committee on the Review of Medicines (UK) carried out a review into benzodiazepines due to significant concerns of tolerance, drug dependence and benzodiazepine withdrawal problems and other adverse effects. The committee found that benzodiazepines do not have any antidepressant or analgesic properties and are therefore unsuitable treatments for conditions such as depression, tension headaches and dysmenorrhoea. Benzodiazepines are also not beneficial in the treatment of psychosis due to a lack of efficacy. The committee also recommended against benzodiazepines being used in the treatment of anxiety or insomnia in children. The committee was in agreement with the Institute of Medicine (USA) and the conclusions of a study carried out by the White House Office of Drug Policy and the National Institute on Drug Abuse (USA) that there was little evidence that long term use of benzodiazepine hypnotics were beneficial in the treatment of insomnia due to the development of tolerance. Benzodiazepines tended to lose their sleep promoting properties within 3 - 14 days of continuous use and in the treatment of anxiety the committee found that there was little convincing evidence that benzodiazepines retained efficacy in the treatment of anxiety after 4 months continuous use due to the development of tolerance. The committee found that the regular use of benzodiazepines caused the development of dependence characterised by tolerance to the therapeutic effects of benzodiazepines and the development of the benzodiazepine withdrawal syndrome including symptoms such as anxiety, apprehension, tremor, insomnia, nausea, and vomiting upon cessation of benzodiazepine use. Withdrawal symptoms tended to develop within 24 hours on the cessation of a short acting benzodiazepine and within 3 - 10 days after the cessation of a more short acting benzodiazepine. Withdrawal effects could occur after treatment lasting only 2 weeks at therapeutic dose levels however withdrawal effects tended to occur with habitual use beyond 2 weeks and were more likely the higher the dose. The withdrawal symptoms may appear to be similar to the original condition. The committee recommended that all benzodiazepine treatment be withdrawn gradually and recommended that benzodiazepine treatment be used only in carefully selected patients and that therapy be limited to short term use only. It was noted in the review that alcohol can potentiate the central nervous system depressant effects of benzodiazepines and should be avoided. The central nervous system depressant effects of benzodiazepines may make driving or operating machinery dangerous and the elderly are more prone to these adverse effects. In the neonate high single doses or repeated low doses have been reported to produce hypotonia, poor sucking, and hypothermia in the neonate and irregularities in the fetal heart. Benzodiazepines should be avoided in lactation. Withdrawal from benzodiazepines should be gradual as abrupt withdrawal from high doses of benzodiazepines may cause confusion, toxic psychosis, convulsions, or a condition resembling delirium tremens. Abrupt withdrawal from lower doses may cause depression, nervousness, rebound insomnia, irritability, sweating, and diarrhoea.

Dosage

 * Mild/moderate anxiety - 10 to 15mg, 3 to 4 times daily
 * Severe anxiety - 15 to 30mg, 3 to 4 times daily
 * Symptoms related to alcohol withdrawal - 15 to 30mg, 3 to 4 times daily

Availability
In the United Kingdom, oxazepam is available generically in the form of 10mg, 15mg and 30mg tablets.

Side effects
The side effects of oxazepam are similar in nature to those of other benzodiazepines.

Side effects from oxazepam are common and include: drowsiness, dizziness, tiredness, weakness, dry mouth, diarrhea, upset stomach, changes in appetite, heart palpitations, anxiety, trouble breathing, shortness of breath, angry outbursts, trouble sleeping, tremors

Internal tremors have been alleviated by using 15mg of oxazepam as required, usually approximately four hourly.

Interactions
As oxazepam is an active metabolite of diazepam, there is likely an overlap in possible interactions with other drugs or food, with exception of the pharmacokinetic CYP450 interactions (e.g. with cimetidine). Take precautions, and follow closely the prescription of your doctor, when taking oxazepam (or other benozodiazepines) in combinations with potent painkillers (opioids, e.g. morphine, oxycodone or methadone). Avoid drinking alcoholic beverages when taking oxazepam; alcohol and oxazepam (as well as other benzodiazepines) are interacting in a way, that is difficult to pre-estimate, concomitant use of oxazepam and alcohol can lead to increased sedation, severe problems with coordination (ataxiae), decreased muscle tone and in severe cases or in predisposed patients even to life-threatening intoxications with coma and collapse. Concomitant use of alcohol and oxazepam (as well as other benzodiazepines) also increases the risk of an addiction. Benzodiazepines including oxazepam may inhibit the glucuronidation of morphine leading to increased levels of and prolongation of the effects of morphine.

Special precautions
Benzodiazepines including oxazepam are lipophilic drugs and rapidly penetrate membranes and therefore rapidly cross over into the placenta with significant uptake of the drug. Use of benzodiazepines in late pregnancy especially high doses may result in floppy infant syndrome.

Pregnancy
There is inconclusive evidence that benzodiazepines including oxazepam if taken early in pregnancy may result in reduced IQ, neurodevelopmental problems, physical malformations in cardiac or facial structure as well as other malformations in some new borns. Oxazepam when taken during late in pregnancy, the third trimester, causes a definite risk to the neonate including a severe benzodiazepine withdrawal syndrome in the neonate with symptoms including hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Floppy infant syndrome and sedation in the new born may also occur. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth.

Carcinogenicity
Oxazepam is listed a possible carcinogen (Group 2b) by the IARC.

Overdose
Oxazepam is a drug which is very frequently involved in drug intoxication, including overdose. Oxazepam overdose has been involved in fatal overdoses in an Australian study of drug related deaths. Benzodiazepines were found to be the sole cause of death in one third of cases.

Symptoms of overdose include:
 * Somnolence
 * Confusion
 * Impaired motor function
 * Coma
 * Hypoventilation (respiratory depression)
 * Hypotension

Abuse
Benzodiazepines, including diazepam, oxazepam, nitrazepam, temazepam, and flunitrazepam account for the largest volume of forged drug prescriptions in Sweden, a total of 52% of drug forgeries being for benzodiazepines, suggesting benzodiazepines are a major prescription drug class of abuse.

Legal Status
Oxazepam is a Schedule IV drug under the Convention on Psychotropic Substances.

Usage
Oxazepam along with diazepam, nitrazepam and temazepam represent 82% of the benzodiazepine market in Australia.