Pronunciation: klor-dye-az-uh-POX-ide

Chemical Abstracts Service Registry Number: 58-25-3. (Hydrochloride form 43841-5)

Formal Names: Libritabs, Librium, Limbitrol Informal Names: Libs

Type: Depressant (benzodiazepine class). See page 21 Federal Schedule Listing: Schedule IV (DEA no. 2744) USA Availability: Prescription Pregnancy Category: D

Uses. Chlordiazepoxide was the first benzodiazepine tranquilizer and has been commonly used since 1960. It is considered one of the safer psychiatric drugs and has actions comparable to those of barbiturates and alcohol.

This classic benzodiazepine is used mainly for calming anxiety and for treating symptoms of alcohol withdrawal, including delirium tremens. Studies have found, however, that alcoholics receiving this drug to help them through withdrawal are about three times more likely to resume drinking than alcoholics who receive a placebo. The substance is also used to overcome convulsions and to treat insomnia, migraine headache, gastric ulcers, and irritable bowel syndrome (persistent cramps and diarrhea). Actions from a dose of this drug take longer to appear than actions from a dose of lorazepam or diazepam, so those latter substances are sometimes preferred when faster results are needed.

Researchers have used rats and mice to demonstrate partial cross-tolerance between pentobarbital, alcohol, and chlordiazepoxide, and that relationship may contribute to the latter's therapeutic role in treating alcohol withdrawal. An argument has been made that when clinical signs of alcohol withdrawal can be treated as well with chlordiazepoxide as with lorazepam, the former is preferable because of cheaper cost. Chlordiazepoxide can be substituted for alprazolam to wean someone from that drug, although one study found chlor-diazepoxide to be about 86 times weaker than alprazolam (consistent with animal experiments, where large doses of chlordiazepoxide are needed to produce dependence). Chlordiazepoxide can be used in place of most benzodi-azepines if someone who stops taking one of those drugs is troubled by withdrawal. An experiment found chlordiazepoxide to be as effective as methadone in easing opiate withdrawal symptoms experienced by heroin addicts.

Drawbacks. Chlordiazepoxide is one of the longer-lasting benzodiazepines, which can have advantages—but it can also have disadvantages; for example, the drug is associated with higher chance of hip fractures in older persons, perhaps because it makes them unsteady longer and more likely to fall.

Blood disorders can be an unusual unwanted effect, and a case is reported in which long-term use produced purpura, tiny purple spots in the skin caused by bleeding under the skin surface. Although the drug is used to relieve anxiety, studies conflict on whether it increases users' hostility. The drug reduces aggression in animal experiments, and human aggression is certainly not a typical result of a dose; perhaps lowered anxiety among resentful persons also lowers inhibitions, allowing those angry individuals to engage in aggression they had been afraid to attempt. That outcome is more likely when a person using chlordiazepoxide has also been drinking alcohol, and alcohol definitely can lower inhibitions. Chlordiazepoxide can make people weary, degrade verbal communication ability, and raise or lower interest in sex. Among alcoholics, measurements find that chlordiazepoxide reduces rapid eye movement (REM) sleep and delta (deep) sleep; those types are considered important for maintaining normal mental functioning. A case report indicates that the substance may worsen symptoms of Parkinson's disease, possibly due to untoward reaction with the Parkinson's drug levodopa. Another case report notes a diabetic whose blood sugar levels rose substantially while taking chlor-diazepoxide. An instance is known of continual hiccups starting soon after a person started taking the drug and stopping soon after the drug dosage stopped. Still another case report associated the drug with gout.

Persons who receive chlordiazepoxide by injection should avoid hazardous activity (such as driving a car) for several hours; a test of the oral format showed that it lowered driving ability as well. Drivers can be unaware that chlordiazepoxide is affecting them. A study of bronchitis patients found that the drug worsened their breathing, and in general the compound impairs respiration. Chlordiazepoxide is also suspected of worsening porphyria, a disease involving body chemistry and that makes a person extremely sensitive to light. Porphyria caused the madness of George III, king of Great Britain during the American Revolution.

Abuse factors. Sudden stoppage of chlordiazepoxide dosage can produce symptoms similar to those of alcohol or barbiturate withdrawal: tremors and cramps, vomiting, perspiring, and even convulsions.

Drug interactions. When delta-9-tetrahydrocannabinol (also called THC, the main psychoactive chemical in marijuana) was given to pregnant mice in an experiment, administering chlordiazepoxide along with THC raised the blood level of THC. Another mice experiment showed an increase in THC's cataleptic effect when chlordiazepoxide was administered. In mice chlordiazepoxide can increase potency of the anticancer drug ifosfamide, and in both mice and humans alcohol can boost chlordiazepoxide's potency (though a rat experiment did not find that effect). In humans monoamine oxidase inhibitors (MAOIs) boost chlordiazepoxide actions, and the antacid-heartburn medicine cimetidine lengthens the effect of a chlordiazepoxide dose. Cigarette smoking reduces chlordiazepoxide actions, and morphine and meperidine each make oral dosage of chlordiazepoxide less effective. The drug is suspected of affecting blood clotting and is known to constrain the healing abilities of the anticoagulant medicine warfarin.

Cancer. Chlordiazepoxide has produced DNA damage in experiments designed to reveal potential for such defects. Under certain laboratory conditions the drug can promote DNA damage in rats, which theoretically might encourage development of cancer, but that outcome has not been observed in practice.

Pregnancy. "Nitrosatable" drugs, of which chlordiazepoxide is one, cause birth defects in animal experiments. Some studies suggest that using chlordiazepoxide during pregnancy may cause human birth defects, but confirmation is elusive. For example, a study of 50,000 pregnancies published in 1975, including many women who used chlordiazepoxide, found no difference in outcome regardless of whether women used the drug. In contrast, a study of almost 20,000 pregnancies (published in 1974) compared women who took chlordiazepoxide to those who took assorted other antianxiety drugs or none at all in early pregnancy. In the chlordiazepoxide group birth defects were more than two times as frequent compared to the "other drugs" group and over four times as frequent compared to the "no drug" group. Some researchers believe chlordiazepoxide may cause infant skull deformities if a pregnant woman uses the drug.

Combination products. Limbitrol is a combination product using chlordi-azepoxide to reduce anxiety and amitriptyline as a tricyclic antidepressant. Taking a tricyclic antidepressant along with an MAOI can be fatal. Tricyclics are not recommended for persons with glaucoma or urinary difficulties. An experiment with hamsters showed that the drug combination is more likely to produce birth defects than either drug alone. Amitriptyline is Pregnancy Category C and passes into a nursing mother's milk supply.

Additional scientific information may be found in:

Giri, A.K. and S. Banerjee. "Genetic Toxicology of Four Commonly Used Benzodiazepines: A Review." Mutation Research 340 (1996): 93-108. Harmatz, J.S., et al. "Differential Effects of Chlordiazepoxide and Oxazepam on Hostility in a Small Group Setting." American Journal of Psychiatry 132 (1975): 861-63.

Palva, E.S., and M. Linnoila. "Effect of Active Metabolites of Chlordiazepoxide and Diazepam, Alone or in Combination with Alcohol, on Psychomotor Skills Related to Driving." European Journal of Clinical Pharmacology 13 (1978): 345-50. Salzman, C., et al. "Chlordiazepoxide-Induced Hostility in a Small Group Setting."

Archives of General Psychiatry 31 (1974): 401-5. Sternbach, L.H. "The Discovery of Librium." Agents and Actions 43, nos. 3-4 (1994): 8285.

Continue reading here: Pregnancy Category D

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