Nitrazepam, sold under the brand name Mogadon among others,[2][3] is a hypnotic drug of the benzodiazepine class used for short-term relief from severe, disabling anxiety and insomnia.[4] It also has sedative (calming) properties,[5] as well as amnestic (inducing forgetfulness), anticonvulsant, and skeletal muscle relaxant effects.
It was first synthesized in the late 1950s by a team of researchers at Hoffmann-La Roche in Switzerland.[6] It was patented in 1961 and came into medical use in 1965.[7]
Nitrazepam is used to treat short-term sleeping problems (insomnia),[8] namely difficulty falling asleep, frequent awakening, early awakening, or a combination of each.
Nitrazepam is sometimes tried to treat epilepsy when other medications fail. It has been found to be more effective than clonazepam in the treatment of West syndrome, which is an age-dependent epilepsy, affecting the very young. In uncontrolled studies, nitrazepam has shown effectiveness in infantile spasms and is sometimes considered when other anti-seizure drugs have failed.[9] However, drowsiness, hypotonia, and most significantly tolerance to anti-seizure effects typically develop with long-term treatment, generally limiting Nitrazepam to acute seizure management.[10]
A light-activated derivative of nitrazepam (fulgazepam) has been developed for research purposes.[11]
More common side effects may include: central nervous system depression, including somnolence, dizziness, depressed mood, fatigue, ataxia, headache, vertigo, impairment of memory, impairment of motor functions, a "hungover" feeling in the morning, slurred speech, decreased physical performance,[clarification needed] numbed emotions, reduced alertness, muscle weakness, double vision, and inattention have been reported. Unpleasant dreams and rebound insomnia have also been reported.
Nitrazepam is a long-acting benzodiazepine with an elimination half-life of 15–38 hours (mean elimination half-life 26 hours).[12] Residual "hangover" effects after nighttime administration of nitrazepam such as sleepiness, impaired psychomotor and cognitive functions may persist into the next day, which may impair the ability of users to drive safely and increases the risk of falls and hip fractures.[13]
Less common side effects may include: Hypotension,[14] faintness, palpitation, rash or pruritus, gastrointestinal disturbances, and changes in libido are less common. Very infrequently, paradoxical reactions may occur, for example, excitement, stimulation, hallucinations, hyperactivity, and insomnia. Also, depressed or increased dreaming, disorientation, severe sedation, retrograde amnesia, headache, hypothermia, and delirium tremens are reported.[15] Severe liver toxicity has also been reported.[16]
Benzodiazepine use is associated with an increased risk of developing cancer.[17]However, conflicting evidence implies that further research is needed in order to conclude that products of this class really do induce cancer.[18]
Nitrazepam therapy, compared with other drug therapies, increases risk of death when used for intractable epilepsy in an analysis of 302 patients. The risk of death from nitrazepam therapy may be greater in younger patients (children below 3.4 years in the study) with intractable epilepsy. In older children (above 3.4 years), the tendency appears to be reversed in this study.[19] Nitrazepam may cause sudden death in children. It can cause swallowing incoordination, high-peaked esophageal peristalsis, bronchospasm, delayed cricopharyngeal relaxation, and severe respiratory distress necessitating ventilatory support in children. Nitrazepam may promote the development of parasympathetic overactivity or vagotonia, leading to potentially fatal respiratory distress in children.[20]
Nitrazepam has been associated with severe hepatic disorders, similar to other nitrobenzodiazepines. Nitrobenzodiazepines such as nitrazepam, nimetazepam, flunitrazepam, and clonazepam are more toxic to the liver than other benzodiazepines as they are metabolically activated by CYP3A4 which can result in cytotoxicity. This activation can lead to the generation of free radicals and oxidation of thiol, as well as covalent binding with endogenous macromolecules; this results, then, in oxidation of cellular components or inhibition of normal cellular function. Metabolism of a nontoxic drug to reactive metabolites has been causally connected with a variety of adverse reactions.[16]
Long-term use of nitrazepam may carry mental and physical health risks, such as the development of cognitive deficits. These adverse effects show improvement after a period of abstinence.[21][22]Some other sources however seem to indicate that there is no relation between the use of benzodiazepine medication and dementia.[23] Further research is needed in order to assert that this class of medication does really induce cognitive decline.
Recreational use of nitrazepam is common.[citation needed]
A monograph for the drug says: "Treatment with nitrazepam should usually not exceed seven to ten consecutive days. Use for more than two to three consecutive weeks requires complete re-evaluation of the patient. Prescriptions for nitrazepam should be written for short-term use (seven to ten days) and it should not be prescribed in quantities exceeding a one-month supply. Dependence can occur in as little as four weeks."[24]
Tolerance to nitrazepam's effects often appears with regular use. Increased levels of GABA in cerebral tissue and alterations in the activity state of the serotoninergic system occur as a result of nitrazepam tolerance.[citation needed]Tolerance to the sleep-inducing effects of nitrazepam can occur after about seven days;[citation needed] tolerance also frequently occurs to its anticonvulsant effects.[citation needed]
However, other sources indicate that continuous use does not necessarily lead to reduced effectiveness,[25][26][27] which implies that tolerance is not automatic and that not all patients exhibit tolerance to the same extent.
Nitrazepam can cause dependence, addiction, and benzodiazepine withdrawal syndrome. Withdrawal from nitrazepam may lead to withdrawal symptoms which are similar to those seen with alcohol and barbiturates. Common withdrawal symptoms include anxiety, insomnia, concentration problems, and fatigue.[28] Discontinuation of nitrazepam produced rebound insomnia after short-term single nightly dose therapy.[29]
Benzodiazepines require special precautions if used in alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders.[30] Caution should be exercised in prescribing nitrazepam to anyone who is of working age due to the significant impairment of psychomotor skills; this impairment is greater when the higher dosages are prescribed.[31]
Nitrazepam in doses of 5 mg or more causes significant de