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Diazepam

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Diazepam
Systematic (IUPAC) name
7-chloro-1-methyl-
5-phenyl-1,3-dihydro-2H-
1,4-benzodiazepin-2-one
Identifiers
CAS number 439-14-5
ATC code N05BA01 N05BA17
PubChem 3016
DrugBank APRD00642
Chemical data
Formula C16H13N2ClO 
Mol. weight 284.7 g/mol
Pharmacokinetic data
Bioavailability 93%
Metabolism Hepatic
Half life 20-100 hours
Excretion Renal
Therapeutic considerations
Pregnancy cat.

C(AU) D(US)

Legal status

Schedule IV (International)
Schedule IV (CA)

Routes Oral, IM, IV, suppository

Diazepam (IPA: [daɪˈæzɪpæm]), marketed under brand names Valium, Stesolid, Diazemuls, Seduxen, Bosaurin, Diapam, Antenex and Apozepam)<ref name="DrugBank">Wishart, David (2006). Diazepam. DrugBank. Retrieved on 2006-03-10.</ref> is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative, skeletal muscle relaxant and amnestic properties. This makes it a useful drug for treating anxiety, insomnia, seizures, alcohol withdrawal, and muscle spasms. It is also used before certain medical procedures (such as endoscopies) to reduce tension and anxiety, and in some surgical procedures to induce amnesia.<ref name="PubChem">Diazepam. PubChem. National Institute of Health: National Library of Medicine (2006). Retrieved on 2006-03-11.</ref><ref name="NLM">Diazepam. Medical Subject Headings (MeSH). National Library of Medicine (2006). Retrieved on 2006-03-10.</ref>

Diazepam is a core medicine in the World Health Organization's "Essential Drugs List", which is a list of minimum medical needs for a basic health care system.<ref name="essentialWHO">WHO Model List of Essential Medicines (PDF). World Health Organization (March 2005). Retrieved on 2006-03-12.</ref> Diazepam is used to treat a wide range of conditions and is one of the most frequently prescribed benzodiazepines.

Contents

[edit] Benzodiazepine

Diazepam is a benzodiazepine that binds to a specific subunit on the GABAA receptor at a site that is distinct from the endogenous GABA molecule.<ref name="Barondes2">Barondes, Samuel H. (MONTH 1999). Molecules and Mental Illness. New York: Scientific American Library, 190-194. ISBN 0-7167-6033-9.</ref><ref name="Pharma">Sieghart, W. (January 1994). "Pharmacology of benzodiazepine receptors: an update". Journal of Psychiatry and Neuroscience 19 (1): 24-29. PubMed. Retrieved on 2006-03-10.</ref>The GABAA receptor is an inhibitory channel which, when activated, decreases neurologic activity.

Due to the role of diazepam as a positive allosteric modulator of GABA, when it binds to benzodiazepine receptors it causes inhibitory effects. This arises from the hyperpolarization of the postsynaptic membrane, due to the control exerted over negative chloride ions by GABAA receptors.<ref name="Barondes2" /><ref name="Drugs.com">Thomson Healthcare (Micromedex) (March 2000). Diazepam. Prescription Drug Information. Drugs.com. Retrieved on 2006-03-11.</ref>

Diazepam appears to act on areas of the limbic system, thalamus and hypothalamus, inducing anxiolytic effects. Its actions are due to the enhancement of GABA activity.<ref name="PubChem" /><ref name="Barondes2">Barondes, Samuel H. (MONTH 1999). Molecules and Mental Illness. New York: Scientific American Library, 190-194. ISBN 0-7167-6033-9.</ref>

[edit] History

Diazepam was the second benzodiazepine to be invented by Leo Sternbach of Hoffmann-La Roche, and was approved for use in 1963. It is five times more potent than its predecessor, chlordiazepoxide, which it quickly surpassed in terms of sales. After this initial success, other pharmaceutical companies began to introduce other benzodiazepine derivatives.<ref name="Obituary">Sample, Ian. "Leo Sternbach's Obituary", The Guardian (Guardian Unlimited), Monday October 3, 2005. Retrieved on 2006-03-10.</ref>

The benzodiazepines gained popularity among medical professionals as an improvement upon barbiturates, which have a comparatively narrow therapeutic index, and are far more sedating at therapeutic doses. The benzodiazepines are also far less dangerous; death rarely results from diazepam overdose, except in cases where it is consumed with large amounts of other depressants (such as alcohol or other sedatives).<ref name="Barondes1">Barondes, Samuel H. (2003). Better Than Prozac. New York: Oxford University Press, 47-59. ISBN 0-19-515130-5.</ref>

Diazepam was the top-selling pharmaceutical in the United States from 1969 to 1982, with peak sales in 1978 of 2.3 billion pills.<ref name="Obituary" /> In 1966, The Rolling Stones released the song "Mother's Little Helper", which is about a mother needing the "little yellow pill" to get through the day.<ref name="RollingStones">Chuck Ayoub. Mother's Little Helper Lyrics - The Rolling Stones. The Rolling Stone Lyrics. Retrieved on 2006-09-09.</ref>

Over the years, physicians, psychiatrists and neurologists have discovered many new off-label uses for diazepam, such as treatment of spastic paresis and palliative treatment of stiff-person syndrome.<ref name="RXL.Indications">Diazepam: indications. Rxlist.com. RxList Inc. (January 24, 2005). Retrieved on 2006-03-11.</ref> Diazepam is also found in nature. Several plants, such as potato and wheat, contain trace amounts of naturally occurring diazepam and other benzodiazepines.<ref name="Natural_sources">Wildmann J, Vetter W, Ranalder UB, Schmidt K, Maurer R, Mohler H (1988). "Occurrence of pharmacologically active benzodiazepines in trace amounts in wheat and potato". Biochem Pharmacol 37 (19): 3549-59. PubMed. Retrieved on 2006-04-12.</ref>

[edit] Pharmacokinetics

Diazepam can be administered orally, intravenously, intramuscularly, or as a suppository.<ref name="Inchem">Pere Munne/M. Ruse, Ed. (1990/1998 Ed.). Diazepam. Inchem.org. Inchem.org. Retrieved on 2006-03-11.</ref>

When diazepam is administered orally, it is rapidly absorbed and has a fast onset of action. The onset of action is 1-5 minutes for IV administration and 15-30 minutes for IM administration. The duration of the diazepam's main pharmacological effects is 15 minutes to 1 hour for both routes of administration.<ref name="Cuny.edu">Langsam, Yedidyah. DIAZEPAM (VALIUM AND OTHERS). Brooklyn College (Eilat.sci.Brooklyn.CUNY.edu). Retrieved on 2006-03-23.</ref>

Peak plasma levels are achieved 30 minutes to 2 hours after oral administration. When diazepam is administered as an intramuscular injection, absorption is slow, erratic and incomplete.<ref name="DrugBank" /><ref name="ElephantCare">Mikota, Susan K. and Plumb, Donald C. (2005). Diazepam. The Elephant Formulary. Elephant Care International.</ref>

Diazepam is highly lipid-soluble, and is widely distributed throughout the body after administration. It easily crosses both the blood-brain barrier and the placenta, and is excreted into breast milk. After absorption, diazepam is redistributed into muscle and adipose tissue. Continual daily doses of diazepam will quickly build up to a high concentration in the body (mainly in adipose tissue), which will be far in excess of the actual dose for any given day.<ref name="Inchem" /><ref name="ElephantCare" />

Diazepam is metabolised in the liver via the cytochrome P450 enzyme system. It has a biphasic half-life of 1-2 and 2-5 days, and has several pharmacologically active metabolites. The main active metabolite of diazepam is desmethyldiazepam (also known as nordazepam or nordiazepam). Diazepam's other active metabolites include temazepam and oxazepam. These metabolites are conjugated with glucuronide, and are excreted primarily in the urine. Because of these active metabolites, the serum values of diazepam alone are not useful in predicting the effects of the drug.<ref name="DrugBank" /><ref name="ElephantCare" />

Diazepam has a half-life (t1/2α) of 20-50 hours, and desmethyldiazepam has a half-life of 30-200 hours.<ref name="ElephantCare" />

Most of the drug is metabolised; very little diazepam is excreted unchanged.<ref name="Inchem" />

In humans, the protein binding of diazepam is around 98.5%.<ref name="DrugBank" />

[edit] Indications

Diazepam is mainly used to treat anxiety, insomnia, and symptoms of acute alcohol or opiate withdrawal. It is also used as a premedication for inducing sedation, anxiolysis or amnesia prior to certain medical procedures (e.g. endoscopy).<ref name="DrugBank" />

Diazepam is rarely used as a primary drug for the long-term treatment of epilepsy. This is due to the fact that tolerance to the anticonvulsant effects of diazepam usually develops within 6 to 12 months of treatment, effectively rendering it useless for this purpose.<ref name="Inchem" />

Diazepam has a broad spectrum of indications (most of which are off-label), including:

  • Treatment of status epilepticus, adjunctive treatment of other forms of epilepsy<ref name="DrugBank" />
  • Treatment of the symptoms of alcohol and opiate withdrawal<ref name="DrugBank" />
  • Short-term treatment of insomnia<ref name="DrugBank" />
  • Treatment of tetanus, together with other measures of intensive-treatment<ref name=tetanus>Okoromah, C. N., F. E. Lesi (2004). "Diazepam for treating tetanus". Cochrane database of systematic reviews (Online) (1). PubMed.</ref>
  • Adjunctive treatment of painful muscle conditions<ref name="RXL.Indications" />
  • 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 is coupled with other rehabilitative measures)<ref name="RXL.Indications" />
  • Pre-/postoperative sedation, anxiolysis and/or amnesia (e.g. before endoscopic or surgical procedures)<ref name="RXL.Indications" />

[edit] Veterinary uses

Diazepam is used as a short term sedative and anxiolytic for cats and dogs. It is also used for short-term treatment of seizures in dogs and short-term and long-term treatment of seizures in cats. For emergent treatment of seizures, the typical dose is 0.5 mg/kg intravenously or 1-2 mg/kg per rectum of the injectable solution.<ref>Hines, Ron DVM PhD (January 14, 2006). Epilepsy In Your Dog Or Cat. 2nd Chance Sanctuary Pet Health Center. Retrieved on May 18, 2006.</ref>

[edit] Dosage

Dosages should be determined on an individual basis, depending upon the condition to be treated, the severity of symptoms, the body weight of the patient, and any comorbid conditions the patient may have.<ref name="Inchem" />

Elderly patients and those with liver disorders experience decreased metabolism of diazepam; therefore the dosage for these patients should be reduced. General guidelines for this group of patients: initial doses of 2mg to 2.5mg, 1 or 2 times daily; increase gradually as required/tolerated.<ref name="Drugs.com" />

[edit] Adult dosage recommendations

  • Insomnia - Up to 30mg orally, as a single dose, at bedtime.<ref name="Inchem" />
  • Anxiety/panic attacks - Dosage differs depending upon severity of symptoms. For panic attacks, diazepam is taken "as needed".
    • Oral - 2mg to 10mg oral, 2 to 4 times daily.<ref name="Drugs.com" />
    • IV/IM - 2mg to 10mg. Repeat in 3 to 4 hours, if necessary.<ref name="RXL.Indications" />
  • Pre-/postoperative sedation - If other premedications are used, they must be administered separately.<ref name="RXL.Indications" />
    • Oral - Up to 20mg as a single dose.<ref name="Inchem" />
    • IV/IM - 2mg to 10mg, repeated at intervals of at least 5 to 10 minutes, until adequate sedation and/or anxiolysis is achieved.<ref name="Inchem" />
  • Status epilepticus
    • Oral - 2mg to 10mg, 2 to 4 times daily.<ref name="Drugs.com" />
    • IV/IM - 5mg to 10mg. May be repeated every 5 to 10 minutes until termination of seizures. Maximum dose of 40mg to 60mg can be used; if this dose is ineffective, other anticonvulsant drug therapy should be instituted.<ref name="Inchem" />
    • Rectal solution - 10mg as a single dose. May be repeated after 5 minutes, if necessary. The oral solution can also be administered rectally.<ref name="Inchem" />
  • Painful muscle conditions or muscle spasms
    • Oral - Up to 15mg daily, in divided doses. In severe spasticity associated with cerebral palsy, doses may be increased gradually up to 60mg daily.<ref name="Inchem" />
    • IV/IM - 5mg to 10mg initially, then 5mg to 10mg in 3 to 4 hours, if necessary.<ref name="RXL.Indications" />
  • Tetanus - 100 to 300µg/kg intravenously, repeated every 1 to 4 hours.<ref name="Inchem" />
  • Spastic paresis - Usually starting with 3 times daily 2mg, increasing to up to 3 times 20mg in slow increments, taking care to avoid ataxia.[citation needed]
  • Alcohol/opioid withdrawal - For symptomatic relief of agitation, tremor, delirium tremens and hallucinosis.
    • Oral - 10mg, 3 or 4 times during the first 24 hours. Reduce to 5mg, 3 or 4 times a day, or as needed.<ref name="Drugs.com" />
    • IV/IM - 10mg initially, 5mg to 10mg in 3 to 4 hours, if necessary.<ref name="RXL.Indications" />
  • Initial treatment of mania - 30 to 40mg daily oral or rectal, rarely more.[citation needed]
  • Overdosage with hallucinogens/CNS stimulants - Normally a single intravenous dose of 10 to 20mg is sufficient.[citation needed]
  • Adjunctive treatment of 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.[citation needed]
  • Adjunctive treatment of extrapyramidal side-effects - Depends on the individual. Effective dose(s) unknown. Do not administer for more than 4 weeks.<ref name=EPS>Director, K. L., C. E. Muniz (April 1982). "Diazepam in the treatment of extrapyramidal symptoms: a case report.". Journal of Clinical Psychiatry 43 (4): 160-161. PubMed.</ref>
  • Cardioversion - To relieve anxiety/tension and to reduce recall of procedure. 5mg to 15mg IV, 5 to 10 minutes prior to the procedure.<ref name="RXL.Indications" />
  • Prophylactic treatment of oxygen toxicity during hyperbaric therapy - 5mg to 10mg.<ref name="Hyperbaric" />

[edit] Pediatric dosage recommendations

  • Patients over 6 months of age:
    • Initiate therapy with the lowest effective dose.<ref name="Drugs.com" />
    • Oral: Initial dose of 40 to 200µg/kg of bodyweight. Can be repeated as tolerated, up to 4 times daily.<ref name="Inchem" />
    • Rectal suppository: 40 to 200µg/kg of bodyweight, which can be repeated as tolerated up to 4 times daily.<ref name="Inchem" />
      • Sedation or muscle relaxation<ref name="Inchem" />
        • IV/IM - 200µg/kg of bodyweight.
      • Status epilepticus<ref name="Inchem" />
        • IV/IM - 200 to 300µg/kg of bodyweight. May be repeated after 5 to 10 minutes, if required.
        • Rectal solution - 5mg (for patients 1 to 3 years of age); repeat after 5 to 10 minutes, if necessary.
      • Tetanus<ref name="RXL.Indications" />
        • Patients 30 days to 5 years of age - 1mg to 2mg IV/IM, slowly; repeat every 3 to 4 hours, as necessary.
        • Patients 5 years of age or older - 5mg to 10mg IV/IM, slowly; repeat every 3 to 4 hours, as necessary.
      • Convulsive disorders<ref name="RXL.Indications" />
        • Patients 30 days to 5 years of age - 0.2mg to 0.5mg IV/IM, slowly, every 2 to 5 minutes. Maximum dose of 5mg.
        • Patients 5 years of age or older - 1mg IV/IM, slowly, every 2 to 5 minutes. Maximum of dose of 10mg. Repeat in 2 to 4 hours, if necessary.
    • Patients under 6 months of age:
      • Diazepam should not be given to children under 6 months of age or younger.<ref name="Drugs.com" />

[edit] Availability

Diazepam is supplied in the following forms:

  • For oral administration:
    • Tablets - 2mg, 5mg, 10mg<ref name="Drugs.com" />. Generic versions available.
    • Capsules, time-release - 15mg (marketed by Roche as Valrelease®)<ref name="ElephantCare" />
    • Liquid solution - 1mg/ml in 500ml containers and unit-dose (5mg & 10mg); 5mg/ml in 30 ml dropper bottle (marketed by Roxane as Diazepam Intensol®)<ref name="ElephantCare" />
  • For parenteral administration:
    • Solution for IV/IM injection - 5mg/ml. 2ml ampoules and syringes; 1ml, 2ml, 10ml vials; 2 ml Tel-E-Ject; also contains 40% propylene glycol, 10% ethyl alcohol, 5% sodium benzoate and benzoic acid as buffers, and 1.5% benzyl alcohol as a preservative.<ref name="RXL.Description">Diazepam: description. Rxlist.com. RxList Inc. (January 24, 2005). Retrieved on 2006-03-10.</ref><ref name="ElephantCare" />
  • For rectal administration:
    • Solution<ref name="Inchem" />
    • Suppositories - 5mg and 10mg<ref name="Suppositories">Kaewnopparat, N., Kaewnopparat, S., Rojanarat, W., Ingkatawornwong, S. (July/August 2004). "Enhanced Release of Diazepam From Hollow-Type Suppositorie". International Journal of Pharmaceutical Compounding. Retrieved on 2006-03-10.</ref><ref name="Inchem" />
  • For inhalation administration:This method uses heating diazepam to form a vapor later producing an aerosol. This allows the drug to be passed through an inhalation route during an inhalation therapy.Provided in doses 2mg-20mg either in a single inhalation or multiple small inhalations <ref>Pharmaceutical Patents. http://www.pharmcast.com/Patents100/Yr2004/Oct2004/101904/6805853_Diazepam101904.htm </ref>

[edit] Side effects

Diazepam has a range of side effects which are common to most benzodiazepines. Most common side effects include:

Rare paradoxical side effects can include: nervousness, irritability, insomnia, muscle cramps, and in extreme cases, rage, and violence.<ref name=rage>Marrosu, F., G. Marrosu, M. G. Rachel, G. Biggio (July-September 1987). "Paradoxical reactions elicited by diazepam in children with classic autism.". Functional Neurology 2 (3): 355-361. PubMed. Retrieved on 2006-09-24.</ref><ref name=next_three>Diazepam: Side Effects. RxList.com. Retrieved on September 26, 2006.</ref><ref name=violence>Michel, L., J. P. Lang (November-December 2003). "Benzodiazépines et passage à l'acte criminel / Benzodiazepines and forensic aspects". L'Encéphale 29 (6): 479-85. PubMed.</ref> If these side effects are present, diazepam treatment should be immediately terminated.

Up to 30% of individuals treated on a long-term basis develop a form of dependence known as "low-dose-dependence". These patients do not develop a tolerance, and do not need increasingly large doses to experience the euphoric side effects of the drug.[citation needed]

Diazepam may impair the ability to drive vehicles or operate machinery. The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants.<ref name="Drugs.com" />

During the course of therapy, tolerance to the sedative effects usually develops, but not to the anxiolytic and myorelaxant effects.<ref name=sedative_effect_tolerance>Hriscu, A., F. Gherase, V. Nastasa, and E. Hriscu (October-December 2002). "[An experimental study of tolerance to benzodiazepines]". Revista Medico-Chirurgicală̆ a Societă̆ţ̜ii de Medici ş̧i Naturaliş̧ti din Iaş̧i 106 (4): 806-811. PubMed.</ref>

Patients with severe attacks of apnea during sleep may suffer respiratory depression (hypoventilation) leading to respiratory arrest and death.

Organic changes such as leukopenia<ref name=leukopenia>Haerten, K., W. Pottgen (September 19, 1975). "[Leukopenia following benzodiazepine derivatives]". Die Medizinische Welt 26 (38): 1712-1714. PubMed.</ref> and liver-damage of the cholostatic type with or without jaundice (icterus) have been observed in a few cases.[citation needed]

[edit] Interactions

If diazepam is to be administered concomitantly with other drugs, attention should be paid to the possible pharmacological interactions. Particular care should be taken with drugs that enhance the effects of diazepam, such as barbiturates, phenothiazines, narcotics and antidepressants.<ref name="Drugs.com" />

Diazepam does not increase or decrease hepatic enzyme activity, and does not alter the metabolism of other compounds. There is no evidence which would suggest that diazepam alters its own metabolism with chronic administration.<ref name="Inchem" />

Agents which have an effect on hepatic cytochrome P450 pathways or conjugation can alter the rate of diazepam metabolism. These interactions would be expected to be most significant with long-term diazepam therapy, and their clinical significance is variable.<ref name="Inchem" />

  • Oral contraceptives ("the pill") significantly decrease the elimination of desmethyldiazepam, a major metabolite of diazepam.<ref name="PDRhealth" />
  • Nefazodone can cause increased blood levels of benzodiazepines.<ref name="PDRhealth" />
  • Cisapride may enhance the absorption, and therefore the sedative activity, of diazepam.<ref name="Cisapride">Bateman, D.N. (1986). "The action of cisapride on gastric emptying and the pharmacodynamics and pharmacokinetics of oral diazepam.". Eur J Clin Pharmacol. 30 (2): 205-8. PMID 3709647.</ref>
  • Small doses of theophylline may inhibit the action of diazepam.<ref name=theophylline>Mattila, M. J., E. Nuotto (1983). "Caffeine and theophylline counteract diazepam effects in man". Medical Biology 61 (6): 337-343. PubMed.</ref>
  • Diazepam may alter digoxin serum concentrations.<ref name="Inchem" />
  • Smoking tobacco can enhance the elimination of diazepam and decrease its action.<ref name="Holt" />
  • Foods that acidify the urine can lead to faster absorption and elimination of diazepam, reducing drug levels and activity.<ref name="Holt" />
  • Foods that alkalinize the urine can lead to slower absorption and elimination of diazepam, increasing drug levels and activity.<ref name="Inchem" />
  • There are conflicting reports as to whether food in general has any effects on the absorption and activity of orally administered diazepam.<ref name="Holt" />

[edit] Contraindications

Use of diazepam should be avoided, when possible, in individuals with the following conditions:

[edit] Special caution needed

  • Pediatric patients
    • Less than 18 years of age - Treatment usually not indicated, except treatment of epilepsy, and pre-/postoperative treatment. The smallest possible effective dose should be used for this group of patients.<ref name="PDRhealth" />
    • Under 6 months of age - Safety and effectiveness have not been established; diazepam should not be given to individuals in this age group.<ref name="Drugs.com" /><ref name="PDRhealth" />
  • Elderly and very ill patients - Possibility that apnea and/or cardiac arrest may occur. Concomitant use of other central nervous system depressants increases this risk. The smallest possible effective dose should be used for this group of patients..<ref name="Drugs.com" /><ref name="PDRhealth" /><ref name="RXL.Caution">Diazepam: precautions. Rxlist.com. RxList Inc. (January 24, 2005). Retrieved on 2006-03-10.</ref>
  • I.V. or I.M. injections in hypotensive individuals or those in shock should be administered carefully and vital signs should be monitored.<ref name="RXL.Caution" />

[edit] Patients at a high risk for abuse and dependence

Diazepam can lead to physiological tolerance, and psychological and/or physical dependence[citation needed]. At a particularly high risk for diazepam misuse, abuse, and dependence are:

Patients from the aforementioned groups should be monitored very closely during therapy for signs of abuse and development of dependence. Discontinue therapy if any of these signs are noted. Long-term therapy in these patients is not recommended.<ref name="Drugs.com" /><ref name="RXL.Abuse" /> The American Society of Addiction Medicine has policy indicating that patients with addictive disease should not be presecribed benzodiazepines such as diazepam.

[edit] Withdrawal

Administration of therapeutic doses of diazepam for 6 weeks or longer can result in physical dependence, characterized by a withdrawal syndrome when the drug is discontinued. With larger doses, physical dependence develops more rapidly.<ref name="Inchem" />

After continued therapy in excess of a few weeks, diazepam should never be stopped abruptly. The dose should instead be lowered gradually, over a period of 2 to 4 weeks, in order to minimize withdrawal symptoms.<ref name="Inchem" /><ref name="RXL.Abuse" />

Withdrawal symptoms are initially minimal, and increase in severity over the first 5 to 9 days after ingestion of the drug is stopped. Diazepam's long half-life and active metabolites delay the onset of such symptoms.<ref name="Inchem" />

The withdrawal symptoms for diazepam are similar to those of other CNS depressants (e.g. alcohol, barbiturates), and can include<ref name="Inchem" />:

  • Anxiety
  • Dysphoria
  • Irritability
  • Insomnia
  • REM Rebound
  • Confusion
  • Tremors
  • Muscle spasms
  • Abdominal and muscle cramps
  • Anorexia (i.e. lack of appetite)
  • Nausea/vomiting
  • Hyperthermia/sweating
  • Hypotension

In severe cases of diazepam withdrawal, symptoms can include:

  • Convulsions (i.e. seizures)
  • Death

The more severe side effects usually only develop for patients who were treated with excessive doses for extended periods of time. Usually only the milder symptoms develop in patients terminating therapeutic-level treatment after several months.<ref name="Drugs.com" />

[edit] Overdose

An individual who has consumed too much diazepam will display one or more of the following symptoms<ref name="Drugs.com" /><ref name="RXL.Overdose">Diazepam: overdose. Rxlist.com. RxList Inc. (January 24, 2005). Retrieved on 2006-03-10.</ref>:

  • Somnolence/difficulty staying awake
  • Mental confusion
  • Hypotension
  • Impaired motor functions
    • Impaired reflexes
    • Impaired coordination
    • Impaired balance
    • Dizziness
  • Coma

Although not usually fatal when taken alone, a diazepam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. The antidote for an overdose of diazepam (or any other benzodiazepine) is flumazenil (Anexate®). This drug is only used in cases with severe respiratory depression or cardiovascular complications. Because flumazenil is a short-acting drug and the effects of diazepam can last for days, several doses of flumazenil may be necessary. Artificial respiration and stabilization of cardiovascular functions may also be necessary. Although not routinely indicated, activated charcoal can be used for decontamination of the stomach following a diazepam overdose. Emesis is contraindicated. Dialysis is minimally effective. Hypotension may be treated with levarterenol or metaraminol.<ref name="Inchem"/><ref name="Barondes1"/><ref name="Drugs.com"/><ref name="RXL.Overdose"/>

The oral LD50 (lethal dose in 50% of the population) of diazepam is 720mg/kg in mice and 1240mg/kg in rats.<ref name="Drugs.com"/> D. J. Greenblatt and colleagues reported in 1978 on two patients who had taken 2000 and 500 mg of diazepam, respectively, went into moderately deep comas, and were discharged within 48 hours without having experienced important complications in spite of having high concentrations of diazepam and its metabolites—desmethyldiazepam, oxazepam, and temazepam—according to samples taken in the hospital and as follow-up.<ref name=Greenblatt_et_al_1978>Greenblatt, D. J., E. Woo, M. D. Allen, P. J. Orsulak, and R. I. Shader (October 20, 1978). "Rapid recovery from massive diazepam overdose". Journal of the American Medical Association 240 (17): 1872-4. PubMed.</ref>

Overdoses of diazepam with alcohol and/or other depressants may be fatal.<ref name="Barondes1"/>

[edit] Recreational use

Generally, diazepam is not used as a recreational drug as frequently as alprazolam or flunitrazepam.

Diazepam is often found as an adulterant in heroin.<ref name=heroin_adulterant>International Narcotics Control Board (1996). CHAPTER II. OPERATION OF THE INTERNATIONAL DRUG CONTROL SYSTEM (English). REPORT OF THE INTERNATIONAL NARCOTICS CONTROL BOARD FOR 1996. Retrieved on September 25, 2006.</ref> This may be because diazepam greatly amplifies the effects of opioids.

Sometimes diazepam is used by stimulant abusers to 'come down' and sleep and to help control the urge to binge<ref name=with_meth>Overclocker. Methamphetamine and Benzodiazepines: Methamphetamine & Benzodiazepines. Erowid Experience Vaults. Retrieved on September 26, 2006.</ref> and also by users of LSD and other hallucinogens to help ease their trip without unpleasant after-effects.[citation needed]

[edit] Popular culture references

[edit] Legal status

Internationally, diazepam is a Schedule IV drug under the Convention on Psychotropic Substances.<ref name="Legal">International Narcotics Control Board (2003). List of psychotropic substances under international control. Green list. Retrieved on 2006-03-11.</ref>

[edit] Physical properties

Diazepam occurs as solid white or yellow crystals and has a melting point of 131.5 to 134.5°C. It is odorless, and has a slightly bitter taste. The British Pharmacopoeia lists diazepam as being very slightly soluble in water, soluble in alcohol and freely soluble in chloroform. The United States Pharmacopoeia lists diazepam as soluble 1 in 16 of ethyl alcohol, 1 in 2 of chloroform, 1 in 39 of ether, and practically insoluble in water. The pH of diazepam is neutral (i.e. 7). Diazepam has a shelf-life of 5 years for oral tablets and 3 years for IV/IM solution.<ref name="Inchem">Pere Munne/M. Ruse, Ed. (1990/1998 Ed.). Diazepam. Inchem.org. Inchem.org. Retrieved on 2006-03-11.</ref>

Diazepam should be stored at room temperature (15°-30°C). The solution for parenteral injection should be protected from light and kept from freezing. The oral forms should be stored in air-tight containers and protected from light.<ref name="ElephantCare">Mikota, Susan K. and Plumb, Donald C. (2005). Diazepam. The Elephant Formulary. Elephant Care International.</ref>

Diazepam can absorb into plastic, and therefore diazepam solution is not stored in plastic bottles or syringes. It can absorb into plastic bags and tubing used for intervenous infusions. Absorption appears to be dependent on several factors such as temperature, concentration, flow rates and tube length. Diazepam should not be administered if a precipitate has formed and will not dissolve.<ref name="ElephantCare" />

[edit] External links

[edit] References

  • Fachinformationen (German) for Valium, provided by Roche Pharmaceuticals
  • Bandelow, Borwin et al. Handbuch der Arzneimitteltherapie, Bd.1, Psychopharmaka, 2nd edition. Enke, 2004. ISBN 3-13-113041-5.
  • Benkert, Otto et al. Kompendium der Psychiatrischen Pharmakotherapie, 5th edition. Springer, 2003. ISBN 3-540-21893-9.

[edit] Footnotes

<references/>


Benzodiazepines edit

Adinazolam, Alprazolam, Bentazepam, Bromazepam, Brotizolam, Camazepam, Chlordiazepoxide, Cinolazepam, Clobazam, Clonazepam, Clorazepate, Clotiazepam, Cloxazolam, Cyprazepam, Diazepam, Doxefazepam, Estazolam, Ethyl loflazepate, Etizolam, Fludiazepam, Flunitrazepam, Flurazepam, Flutazolam, Flutoprazepam, Gidazepam, Halazepam, Haloxazolam, Ketazolam, Loprazolam, Lorazepam, Lormetazepam, Medazepam, Mexazolam, Midazolam, Nimetazepam, Nitrazepam, Nordazepam, Oxazepam, Oxazolam, Phenazepam, Pinazepam, Prazepam, Quazepam, Temazepam, Tetrazepam, Tofisopam, Triazolam


Anticonvulsants (N03) edit

Barbiturates: Barbexaclone, Metharbital, Methylphenobarbital, Phenobarbital, Primidone

Hydantoins: Ethotoin, Fosphenytoin, Mephenytoin, Phenytoin -- Oxazolidinediones: Ethadione, Paramethadione, Trimethadione

Succinimides: Ethosuximide, Mesuximide, Phensuximide

Benzodiazepines: Clobazam, Clonazepam, Clorazepate, Diazepam, Lorazepam, Midazolam, Nitrazepam, Temazepam

Carboxamides: Carbamazepine, Oxcarbazepine, Rufinamide -- Fatty acid derivatives: Valpromide, Valnoctamide

Carboxylic acids: Valproic acid (Sodium valproate & Valproate semisodium), Tiagabine -- GABA analogs: Gabapentin, Pregabalin, Progabide, Vigabatrin

Others:- Monosaccharides: Topiramate -- Aromatic allylic alcohols: Stiripentol -- Ureas: Phenacemide, Pheneturide -- Phenyltriazines: Lamotrigine

Carbamates: Emylcamate, Felbamate, Meprobamate -- Pyrrolidines: Brivaracetam, Levetiracetam, Nefiracetam, Seletracetam

Sulfa drugs: Acetazolamide, Ethoxzolamide, Sultiame, Zonisamide -- Propionates: Beclamide -- Aldehydes: Paraldehyde -- Bromides: Potassium bromide, Sodium bromide

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