Pregnancy Category D

Uses. This quick-acting drug's common medical uses are to reduce anxiety, calm people, and help them sleep. Naturalists use the substance to knock out wildlife ranging from foxes to aardvarks. Effects do not last a long time, typically making the substance a good choice for weakened persons or animals who would be strained by a longer-acting drug. For example, weary mountaineers climbing Mt. Everest have used the drug to improve quality of sleep.

One study found the drug could help workers who must alter their sleep schedules for reporting to different work shifts. Experiments show the drug having potential for treating muscle spasms. Midazolam has been used successfully to alleviate status epilepticus, in which people have continual seizures, and to control seizures caused by high fevers in children. The U.S. Army has tested midazolam experimentally, but with limited success, to counteract seizures and other poisonous effects from the chemical warfare substance soman. A case report about treating a cobra snake bite victim notes that midazolam worked when another drug faltered. Midazolam reduces blood pressure. The compound is routinely given to people before surgical, dental, or uncomfortable medical procedures and is used to relieve pain in afflictions and after surgery. Midazolam can produce amnesia about events that occurred while under the drug's influence and may be able to interfere with remembering things that occurred shortly before the drug was received. That amnesia action can be beneficial in reducing stress from medical treatments but might also be used by unscrupulous persons wanting to exploit someone.

Drawbacks. When injected intravenously the drug can be so hazardous that in some instances a resuscitation specialist must be on hand with the exclusive duty of monitoring the patient's condition at all times. Without that precaution people have suffered crippling brain damage or death from respiratory arrest caused by the drug while a medical procedure was being performed. Respiratory emergencies have also occurred from oral dosage. Midazolam is not recommended for persons suffering from breathing trouble. Nonetheless, despite the drug's potential hazards, examination of 5,439 records of patients receiving the drug at one hospital revealed only 3 instances of respiratory arrest. Examination of 9,842 medical records of persons who received midazolam in 14 hospitals did not reveal serious respiratory events caused by the drug; indeed, the study concluded that people were more likely to die from diazepam. That conclusion, of course, was based on administration of the drugs in a medical setting, not misuse on the street.

A rat study found the drug to have "minimal" ability to cause brain damage, and then only in older rats, even after four months of daily dosing. In a subsequent and related report investigators stated flatly that the drug does not cause brain damage, although once again slight differences were observed when older rats were compared to others.

Researchers have noted that midazolam harms white blood cells. Other unwanted effects include headache, coughing and hiccups, nausea, and vomiting. Less commonly, the drug can prompt euphoria, hallucinations, tremor, rapid heartbeat, discomposure, and aggression. Two researchers tracking violent deaths in Finland concluded that the drug was found in victims more often than would be expected through chance occurrence. Hallucinations by surgical patients have occurred often enough and can be realistic enough (such as patients perceiving imaginary sexual assault by medical personnel) that medical staff have been advised to have someone witness all contact with patients receiving the drug.

Midazolam lengthens reaction times, although two experiments found that users performed normally 4 hours after a dose such as a patient would receive for outpatient surgery. Those findings are supported by other studies as well, including one using test equipment to measure performance of commercial airline pilots. Nonetheless, persons are supposed to avoid activity requiring careful vigilance (such as driving) for at least 24 hours after taking midazolam.

A small study found that a dose of midazolam produces higher blood levels of the drug and lasts longer in ethnic Mexicans than in ethnic whites.

Abuse factors. Among monkeys dependence has been established with the drug after 5 to 10 weeks of steady dosage. Sudden cessation of dosage can provoke a withdrawal syndrome: perspiration, tremors and cramps, vomiting, convulsions, and hallucinations. The syndrome can be avoided by gradually reducing drug use instead of stopping all at once. Some researchers believe tolerance has been demonstrated. The substance is considered to have at least the same addiction potential as diazepam, which is three or four times weaker than midazolam.

Drug interactions. In some circumstances midazolam can lower blood pressure drastically and cause seizures; administering the drug with fentanyl or other opiates can increase the likelihood of such severe actions. Rat experiments unexpectedly found that the stimulant caffeine boosts difficulties in movement caused by midazolam, and cocaine also worsened that performance. Opiates or alcohol can deepen some midazolam effects in humans, and rat experiments find that midazolam makes alcohol more appealing. The HIV/AIDS (human immunodeficiency virus/acquired immunodeficiency syndrome) drug saquinavir and the antibiotic erythromycin increase midazolam levels in the body and make effects last longer. The antacid and ulcer medication cimetidine (such as Tagamet) can lengthen sedation from a midazolam dose. Some research indicates that drinking grapefruit juice increases midazolam's ability to act upon a person, but other research does not support that finding. The tuberculosis medicine rifampin and the epilepsy drugs phenytoin and carbamazepine diminish midazolam's effectiveness.

Cancer. Rat and mice experiments have produced no cancer even when midazolam was given daily for two years at 25 times the recommended human dose. The same usage of the drug at about 225 times the recommended human dose, however, produced liver and thyroid tumors. Relevance of the latter outcome to human medical use, involving normal dosage and typically using the drug for one day, is unclear. Gene mutations are considered an element in causing cancer, and midazolam did not produce mutations in assorted standard tests, nor were they observed in a study of patients receiving the drug.

Pregnancy. The drug has been given to mice, rats, and rabbits at 5 to 32 times the normal human dose without producing birth defects. Researchers conducting one experiment concluded, however, that the drug altered behavior of mice after fetal exposure (making males more uneasy and females less uneasy) while slowing their development. Tests indicate that the drug will pass from a pregnant woman into the fetus. The substance has been successfully used to treat eclampsia, a serious disease of late pregnancy involving convulsions, but midazolam is generally not desirable for pregnant women. The drug passes into the milk supply of nursing mothers, and caution is recommended about breast-feeding in such circumstances.

Additional scientific information may be found in:

Curran, H.V., and B. Birch. "Differentiating the Sedative, Psychomotor and Amnesic Effects of Benzodiazepines: A Study with Midazolam and the Benzodiazepine Antagonist, Flumazenil." Psychopharmacology 103 (1991): 519-23. Dundee, J.W. "Fantasies during Sedation with Intravenous Midazolam or Diazepam."

Medico-Legal Journal 58 (1990, pt. 1): 29-34. Gupta, A., et al. "The Effects of Midazolam and Flumazenil on Psychomotor Function."

Journal of Clinical Anesthesia 9 (1997): 21-25. Kelly, D.J., et al. "The Effects of Midazolam on Pure Tone Audiometry, Speech Audiometry, and Audiological Reaction Times in Human Volunteers." Anesthesia and Analgesia 88 (1999):1064-68. Langlois, S., et al. "Midazolam: Kinetics and Effects on Memory, Sensorium, and Hemodynamics." British Journal of Clinical Pharmacology 23 (1987): 273-78. "Midazolam." Medical Letter on Drugs and Therapeutics 28 (1986): 73-74. Nordt, S.P., and R.F. Clark. "Midazolam: A Review of Therapeutic Uses and Toxicity." Journal of Emergency Medicine 15 (1997): 357-65.

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