Diazepam: Encyclopedia - Diazepam

Diazepam

Diazepam, market under brand names of: Valium, Seduxen; and in Europe Apozepam, Diapam, is a 1,4-benzodiazepine derivative, which possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. Diazepam is used to treat anxiety and tension, and is the most effective benzodiazepine for treating muscle spasms. It is also used as a sedative premedication for various medical procedures, and to treat alcohol and opiate withdrawal symptoms. Occasionally, diazepam is used by military and paramilitary snipers to relax muscles and slow breathing for increased firing accuracy. Diazepam is a Schedule IV drug under the Convention on Psychotropic Substances[1]. Diazepam is one of the 'standard benzodiazepines' most often used in clinics and for outpatients. It is enrolled in the WHO List of 'Essential Drugs'.

When introduced in 1963, it was the best of the new alternatives to barbiturates, drugs that could be deadly with an overdose. Diazepam (like the other benzodiazepines) did not have this danger, nor immediately obvious side effects, and became in widespread use to treat chronic anxiety. Diazepam was America's top-selling drug from 1969 to 1982. In the 70s, the peak period for the use of the drug, The Roche Group, sold two billion Valium pills a year (for $US600 million). It is the subject of a Rolling Stones song, "Mother's Little Helper."

However, it is now recognised that the drug is not as harmless as was first assumed. In the autumn of 1973, a report aired on the television show 60 Minutes attesting to the drug's addictiveness. This can occur in as little as four weeks. Following controversial and often polemic discussion prescriptions declined by nearly half in the 1980's and 1990's. Surprisingly, psychiatrists and neurologists have recently discovered new therapeutic fields for this 'old' drug diazepam (e.g. adjunctive treatment of extrapyramidal disorders, some forms of anxiety in children, and adjunctive treatment of spastic paresis); a process still ongoing.

Diazepam - Mode of action

In animals, diazepam appears to act on parts of the limbic system, the thalamus and hypothalamus, and induces calming effects. It binds in to specific benzodiazepine receptors, which are part of the GABA-receptors. When diazepam binds to this receptor, it causes an increase in the inhibitory effects of GABA. It is redistributed into tissues and fat deposits, and there is an adaptation of benzodiazepine receptors. In humans, tolerance to the sedative effects may develop within weeks, but tolerance to the anxiolytic efficiacy usually does not develop. Lorazepam, clonazepam and alprazolam show stronger anxiolytic effects compared to diazepam, but the former 3 drugs carry a particular high risk of abuse, misuse and psychological dependence.

Diazepam - Pharmacokinetics

Diazepam can be administered orally, intravenously or intramuscularly, or as a suppository. When taken orally, diazepam is rapidly absorbed and shows a fast onset of action. Absorption is much slower and more erratic when diazepam is given as an intramuscular injection. Diazepam is highly lipid-soluble and therefore crosses the blood-brain barrier easily. Diazepam is metabolised in the liver and it has a biphasic half-life. The half-life (t1/2α) is 20-100 hours, and its main active metabolite, desmethyldiazepam, has a half-life of 2-5 days. Diazepam's other active metabolites include, among others, temazepam and oxazepam. Diazepam and its metabolites are excreted into the urine.

Diazepam - Experimentation

Roche Labs found they could induce anxiety in rats by performing brain surgery, creating lesions in the animal's limbic system. The rats behaved as if they were very nervous and jumpy. When given drugs such as Librium® or Valium®, the rats behaved normally.

Diazepam - Half-Life

The half-life of a drug is measured as the amount of time, following a single dose, that it takes for the drug to reach half the concentration in the blood that it did at its peak level. Chrystal Ashton DM, FRCP, Emeritus Professor of Clinical Psycho-pharmacology, the University of Newcastle upon Tyne, England, gives the half-life of diazepam as 20-100 hours and the active metabolite as 36-200. A daily dose will quickly build up to a high concentration in the body (mainly in fatty tissues), which will be far in excess of the actual dose for that day.

Diazepam - Indications

Diazepam as a very broad spectrum of indications as follows:

• short-term treatment of insomnia
• treatment of anxiety, panic attacks, and states of agitation
• pre-/postoperative sedation
• treatment of status epilepticus, adjunctive treatment of other forms of epilepsy
• Tetanus together with other measures of intensive-treatment
• adjunctive treatment of painful muscle conditions
• adjunctive treatment of spastic muscular paresis (para-/tetraplegia) caused by cerebral or spinal cord conditions such as stroke, multiple sclerosis, spinal cord injury (long-term treatment together with other rehabilitative measures)
• initial management of mania, together with firstline drugs like Lithium, Valproate or neuroleptics
• adjunctive treatment of overdosage with hallucinogens or central stimulants
• alleviation of the symptoms of alcohol- and opioid-withdrawal, under close clinical supervision
• initial treatment of patients with depression developing suicidal thoughts to decrease the risk of suicide until remission of depression is evident. The antidepressant therapy must be continued.
• adjunctive treatment of patients also treated with neuroleptics, who develop early extrapyramidal side-effects
• experimental treatment of children with anxiety due to separation from their parents (long-term hospitilizations, treatment in rehabiliative institutions far away from home etc.) and their normal social connections (also known under German term 'Trennungsangst')

In the treatment of status epilepticus and tetanus the use of diazepam may be life-saving.

Diazepam - Veterinary Uses

Diazepam is very useful as short term sedative and anxiolytic for cats and dogs. It can also be used for preoperative sedation of cats and dogs and as an anticonvulsive suitable for shortterm and longterm treatment, if sedation is tolerated. To terminate status epilepticus in cats as much as 5mg rectally or slow i.v., repeated as needed, may be necessary.

Diazepam - Contraindications

• myasthenia gravis
• acute intoxications with alcohol, narcotics, and psychoactive drugs
• ataxia
• severe respiratory insufficiency
• acute narrow-angle glaucoma
• severe liver insufficiency (hepatitis and liver cirrhosis decrease elimination by a factor of 2)
• severe sleep apnea
• hypersensitivity or allergy to any drug in the benzodiazepine class

• children and adolescents (< 18 yrs. of age) : treatment usually not indicated, except treatment of epilepsy, and pre-/postoperative treatment; extended clinical experience in this group of age is lacking. Try pschyotherapeutic methods first.
• patients with a history of drug- or alcohol misuse or dependence : monitor these patients closely.
• I.V.-injections in hypotensive patients or those in shock

Diazepam - Side effects

Diazepam has a range of side effects (in common with other benzodiazepines). Most frequently encountered are:

• drowsiness
• depression
• impaired motor function / coordination
• impaired balance
• dizziness
• nervousness
• anterograde amnesia (especially pronounced in higher doses)

Paradoxical effects like irritability, insomnia, muscle cramps, and in extreme cases, even rage and violence may be seen (these require immediate withdrawal of the drug). It can lead to physiological tolerance and psychological addiction. It should be noted that up to 30% treated on a long-term basis develop a form of dependence known as 'low-dose-dependence', i.e. these patients do not need increasing doses to experience the feeling of 'well-being' caused by the drug. Withdrawal can only be accomplished with difficulty by a slow programme (see below).

Ambulatory patients should be warned that Diazepam may impair the ability to drive vehicles and to operate machinery. The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants. During the course of therapy tolerance to the sedative effects usually develops.

Organic changes such as leukopenia and liver-damage of the cholostatic type with or without jaundice (icterus) have been seen in a few cases.

N.B. Patients with attacks of apnea during sleep may suffer respiratory depression leading to respiratory arrest and death.

Diazepam - Routine examinations needed under long-term treatment

Normally not indicated (EKG, EEG, laboratory tests).

Diazepam - Interactions

• Diazepam increases the central depressive effects of alcohol, other hypnotics/sedatives (e.g. barbiturates), narcotics, and other muscle relaxants. The euphoriant effects of opioids may be increased, leading to increased risk of psychological dependence.
• cimetidine (Tagamet®), omeprazol, ketoconazol, and fluoxetine prolong the action of diazepam by inhibiting its elimination. Disulfiram may act in the same way. Dose reductions during long-term therapy may be necessary.
• Hormonal contraceptives ('the pill') significantly decrease the elimination of a major metabolite of diazepam (desmethyldiazepam).
• Cisapride may enhance the absorption of diazepam and therefore increase the sedative activities of diazepam.
• Smoking can enhance the elimination of diazepam and decrease its action.
• Small doses of theophylline (asthma medication) inhibit the action of Diazepam
• Diazepam may block the action of levodopa used in the treatment of Morbus Parkinson.
• Diazepam may infrequently block the matabolism of phenytoin and therefore increase its actions and side-effects.

Diazepam - High Risk patients for abuse and dependence

At a particular high risk are:

• patients with a history of alcohol or drug abuse or dependence
• emotionally unstable patients
• patients with severe personality disorders like Borderline Personality Disorder
• patients with chronic pain or possible other forms of physical disorders

Patients from the aforementioned groups should be monitored very closely during therapy regarding signs of abuse and the development of dependence. Discontinue therapy, if any of these signs are noted. Long-term therapy in these patients is seldom, if ever, wanted or necessary.

Diazepam - Withdrawal procedure after long-term treatment

After continued therapy in excess of a few weeks, diazepam should never be stopped abruptly, but withdrawn gradually.

It is necessary to withdraw diazepam over a course of weeks, sometimes of months. The first 50% of the usual daily dose may be withdrawn quite rapidly, the next 25% fairly slow and the last quarter very slow to avoid unpleasant and sometimes serious withdrawal effects. Sometimes a temporary halt after withdrawal of the first 50% is indicated.

Diazepam - Dose Recommendations

Strictly individual, depending upon the condition to be treated, severity of symptoms, and weight of the patient. The elderly and those with preexisting liver disease experience an intensified and prolonged action of the drug; in elderly the elimination of Diazepam and its major metabolites is decreased by a factor of 2 to 4. Therefore, the single doses should be reduced and/or the dosing intervalls spaced. General recommenations are:

• insomnia : 5 to 10mg bedtime dose (sometimes 2 to 2,5mg suffice), rarely 20mg is needed
• anxiety states and panic attacks : single doses of 5 to 10mg oral, rectal or slowly i.v., in severe cases sometimes regular treatment wíth 3 times 5mg up to 4 times 10mg is required
• pre- and postoperative sedation : 5 to 10mg oral, rectal or slowly i.v., depending on other drugs used concomittantly. Postoperatively, 5 to 10mg can be given once or repeatedly.
• status epilepticus : 10 to 20mg i.v. initially, additional doses of 10mg i.v. may be given every 10 to 20 minutes, as long as seizures persist. In long-term treatment 5 to 15 mg orally per day together with primary therapy will normally suffice
• tetanus : to save the life of the patient high i.v. doses (as continous infusion) of up to 210mg daily are usually necessary
• painful muscle conditions : individually, 4 to 40mg daily oral or rectal
• spastic paresis : usually starting with 3 times 2mg daily, increasing to up to 3 times 20mg in slow increments. Take care that ataxia does not worse the clinical state of the patient!
• initial mangement of mania : 30 to 40mg daily oral or rectal, rarely more
• overdosage with hallucinogens or central stimulants : normally a single i.v. dose of 10 to 20mg is sufficient
• alcohol-/opioid-wihdrawal : individually, high initial doses (40 to 60mg daily oral), later decreasing. Therapy should be terminated after 10 to 14 days to avoid development of addiction in this high risk group of patients.
• adjunctive therapy in depression : usually 10 to 30mg daily oral, the greater part of the dose given at bedtime. The doses should be decreased and the medication stopped as soon as the clinical situation allows.
• adjunctive treatment of patient extrapyramidal side-effects : individually, most effective doses not known so far. Do not treat for more than 4 weeks.

Doses in hospitalized patients are usually higher than in ambulatory patients.

Diazepam - Dose Forms

• tablets 2mg, 5mg, 10mg
• injection 10mg
• suppositories 5mg and 10mg
• Controlled Release (Valrelease®) Capsules of 15mg
• liquid concentrate (Valiquid®), generics available

Diazepam - Recreational Use

Diazepam is often used as an adulterant in the heroin sold as street drug (so called 'street lore'). This is because diazepam amplifies greatly the euphoriant effects of heroin. Often users are not aware that they are also taking diazepam and that dependence on diazepam may have developed with chronic use leading to far greater withdrawal problems than with heroin alone.

Sometimes diazepam is used by stimulant abusers to 'come down' and sleep and also by LSD users (or those using other hallucinogens) to help ease their trip without unpleasant after-effects.

Generally, its recreational use is not as frequent as with alprazolam or flunitrazepam.

Diazepam - Overdose

A person who has consumed too much diazepam will have the following symptoms: difficulty staying awake, mental confusion, coma, and diminished reflexes. Overdose of diazepam constitutes a medical emergency and requires the immediate attention of emergency medical personnel. Its antidote is flumazenil (Anexate®). Because flumazenil is a short-acting drug and the effects of Diazepam can last for days, repetitive doses of flumazenil may be necessary. Artificial respiration and stabilization of cardiovascular functions should be done as indicated.

The oral lethal dose of Diazepam in humans, if taken as sole drug, is estimated to be 500mg or more. A case where a patient took 300mg resulted only in prolonged sleep and consecutive drowsiness for the next days without serious involvement of vital functions. Overdoses of diazepam with alcohol or other central depressants may be fatal.

Diazepam - Fatal Reaction

In April 1975, a young New Jersey woman named Karen Ann Quinlan allegedly took a small dose of Valium along with alcohol, became unconscious and stopped breathing. She became comatose and was declared to be in a persistent vegetative state. Her right to die case ended up in the US Supreme Court. The Life Support System was not unplugged, however, and she was weaned from her respirator by doctors in 1976. She never woke up and died 9 years later.

Diazepam - Occurrence in plants

Several plants, such as potato herbs (Solanum tuberosum), contain small amounts of naturally occurring diazepam and temazepam.

Diazepam - Inventor

Chemist Leo Sternbach created diazepam in the 1950s. He was inducted into the National Inventors Hall of Fame in 2005.

Adapted from the Wikipedia article "Diazepam", under the G.N U Free Docmentation License. Please also see http://en.wikipedia.org/wiki