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| Trade names | Alodorm, Apodorm, Arem, Cerson, Insoma, Insomin, Mogadon, Nitrados, Nitrazadon, Nitrosun, Nitravet, Ormodon, Paxadorm, Remnos, Epam, and Somnite |
| AHFS/Drugs.com | International Drug Names |
| Dependence liability | Physical: HighPsychological: Moderate |
| Addiction liability | Moderate |
| Routes of administration | Oral |
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| Pharmacokinetic data | |
| Bioavailability | 53–94% |
| Metabolism | Hepatic |
| Eliminationhalf-life | 16–38 hours |
| Excretion | Renal |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.005.151 |
| Chemical and physical data | |
| Formula | C15H11N3O3 |
| Molar mass | 281.271 g·mol−1 |
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Nitrazepam, sold under the brand nameMogadon among others,[2][3] is ahypnotic drug of thebenzodiazepine class used for short-term relief from severe, disablinganxiety andinsomnia.[4] It also hassedative (calming) properties,[5] as well asamnestic (inducing forgetfulness),anticonvulsant, andskeletal muscle relaxant effects.
It was first synthesized in the late 1950s by a team of researchers atHoffmann-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 thanclonazepam in the treatment ofWest 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 significantlytolerance to anti-seizure effects typically develop with long-term treatment, generally limiting Nitrazepam to acute seizure management. Nitrazepam can also mitigate effects of alcohol withdrawal.[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, includingsomnolence,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 anelimination 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 andcognitive functions may persist into the next day, which may impair the ability of users to drive safely and increases the risk of falls andhip fractures.[13]
Less common side effects may include:Hypotension,[14] faintness,palpitation, rash orpruritus, gastrointestinal disturbances, and changes inlibido 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, anddelirium 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-peakedesophagealperistalsis,bronchospasm, delayed cricopharyngeal relaxation, and severerespiratory distress necessitating ventilatory support in children. Nitrazepam may promote the development ofparasympathetic overactivity orvagotonia, 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, andclonazepam are more toxic to the liver than other benzodiazepines as they are metabolically activated byCYP3A4 which can result incytotoxicity. This activation can lead to the generation offree 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 ofGABA incerebral tissue and alterations in the activity state of the serotonergic 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 withalcohol andbarbiturates. Common withdrawal symptoms includeanxiety,insomnia, concentration problems, andfatigue.[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 withcomorbidpsychiatric 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 deterioration invigilance performance combined with increased feelings of sleepiness.[32] Nitrazepam at doses of 5 mg or higher impairs driving skills[33] and like otherhypnotic drugs, it is associated with an increased risk of traffic accidents.[34] In the elderly, nitrazepam is associated with an increased risk of falls and hip fractures due to impairments of body balance.[35] Theelimination half-life of nitrazepam is 40 hours in the elderly and 29 hours in younger adults.[36][37] Nitrazepam is commonly taken inoverdose by drug abusers or suicidal individuals, sometimes leading to death.[38][39][40] Nitrazepam isteratogenic if taken in overdose during pregnancy with 30% of births showing congenital abnormalities.[41] It is a popular drug of abuse in countries where it is available.[42][43][44]
Doses as low as 5 mg can impair driving skills.[33] Therefore, people driving or conducting activities which require vigilance should exercise caution in using nitrazepam or possibly avoid it altogether.[45]
Nitrazepam, similar to other benzodiazepines andnonbenzodiazepines, causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. Combination with alcohol increases these impairments. Partial but incomplete tolerance develops to these impairments.[35] Nitrazepam has been found to be dangerous in elderly patients due to a significantly increased risk of falls.[46] This increased risk is probably due to the drug effects of nitrazepam persisting well into the next day.[47] Nitrazepam is a particularly unsuitable hypnotic for theelderly as it induces a disability characterised by general mental deterioration, inability to walk,incontinence, dysarthria,confusion,stumbling,falls, and disoriention which can occur from doses as low as 5 mg. The nitrazepam-induced symptomatology can lead to a misdiagnosis of brain disease in the elderly, for exampledementia, and can also lead to the symptoms ofpostural hypotension which may also be misdiagnosed. Ageriatric unit reportedly was seeing as many as seven patients a month with nitrazepam-induced disabilities and health problems. The drug was recommended to join the barbiturates in not being prescribed to the elderly.[48] Only nitrazepam andlorazepam were found to increase the risk of falls and fractures in the elderly.[49]CNS depression occurs much more frequently in the elderly and is especially common in doses above 5 mg of nitrazepam.[50] Both young and old patients report sleeping better after three nights' use of nitrazepam, but they also reported feeling less awake and were slower on psychomotor testing up to 36 hours after intake of nitrazepam. The elderly showed cognitive deficits, making significantly more mistakes in psychomotor testing than younger patients despite similar plasma levels of the drug, suggesting the elderly are more sensitive to nitrazepam due to increased sensitivity of the aging brain to it. Confusion and disorientation can result from chronic nitrazepam administration to elderly subjects. Also, the effects of a single dose of nitrazepam may last up to 60 hours after administration.[51]
Nitrazepam is not recommended for use in those under 18 years of age. Use in very young children may be especially dangerous. Children treated with nitrazepam for epilepsies may develop tolerance within months of continued use, with dose escalation often occurring with prolonged use. Sleepiness, deterioration in motor skills andataxia were common side effects in children withtuberous sclerosis treated with nitrazepam. The side effects of nitrazepam may impair the development of motor and cognitive skills in children treated with nitrazepam. Withdrawal only occasionally resulted in a return of seizures and some children withdrawn from nitrazepam appeared to improve. Development, for example the ability to walk at five years of age, was impaired in many children taking nitrazepam, but was not impaired with several other nonbenzodiazepineantiepileptic agents. Children being treated with nitrazepam have been recommended to be reviewed and have their nitrazepam gradually discontinued whenever appropriate.[52] Excess sedation,hypersalivation, swallowing difficulty, and high incidence ofaspiration pneumonia, as well as several deaths, have been associated with nitrazepam therapy in children.[9]
Nitrazepam is not recommended during pregnancy as it is associated with causing aneonatal withdrawal syndrome[53] and is not generally recommended in alcohol- or drug-dependent individuals or people with comorbid psychiatric disorders.[30] The Dutch, British and French system called the System of Objectified Judgement Analysis for assessing whether drugs should be included in drug formularies based on clinical efficacy,adverse effects,pharmacokinetic properties,toxicity, anddrug interactions was used to assess nitrazepam. A Dutch analysis using the system found nitrazepam to be unsuitable in drug-prescribing formularies.[54]
The use of nitrazepam during pregnancy can lead to intoxication of the newborn. A neonatal withdrawal syndrome can also occur if nitrazepam or other benzodiazepines are used during pregnancy with symptoms such as hyperexcitability, tremor, and gastrointestinal upset (diarrhea or vomiting) occurring.Breast feeding by mothers using nitrazepam is not recommended.[55] Nitrazepam is a long-acting benzodiazepine with a risk of drug accumulation, though no active metabolites are formed during metabolism. Accumulation can occur in various body organs, including the heart; accumulation is even greater in babies. Nitrazepam rapidly crosses the placenta and is present in breast milk in high quantities. Therefore, benzodiazepines including nitrazepam should be avoided during pregnancy.[56] In early pregnancy, nitrazepam levels are lower in the baby than in the mother, and in the later stages of pregnancy, nitrazepam is found in equal levels in both the mother and the unborn child.[57] Internationally benzodiazepines are known to cause harm when used during pregnancy and nitrazepam is a category D drug during pregnancy.
Benzodiazepines are lipophilic and rapidly penetrate membranes, so rapidly penetrate the placenta with significant uptake of the drug. Use of benzodiazepines such as nitrazepam in late pregnancy in especially high doses may result infloppy infant syndrome.[58] Use in thethird trimester of pregnancy may result in the development of a severe benzodiazepine withdrawal syndrome in theneonate. Withdrawal symptoms from benzodiazepines in the neonate may includehypotonia, and reluctance to suckle, toapnoeic spells,cyanosis, and impaired metabolic responses to cold stress. These symptoms may persist for hours or months after birth.[53]
Caution in those suffering fromhypotension, nitrazepam may worsen hypotension.[14]
Caution should be exercised by people who havehypothyroidism, as this condition may cause a long delay in the metabolism of nitrazepam leading to significant drug accumulation.[59]
Nitrazepam should be avoided in patients withchronic obstructive pulmonary disease (COPD), especially during acute exacerbations of COPD, because serious respiratory depression may occur in patients receiving hypnotics.[60]
As with other hypnotic drugs, nitrazepam is associated with an increased risk of traffic accidents.[34] Nitrazepam is recommended to be avoided in patients who drive or operate machinery. A study assessing driving skills of sedative hypnotic users found the users of nitrazepam to be significantly impaired up to 17 hours after dosing, whereas users of temazepam did not show significant impairments of driving ability. These results reflect the long-acting nature of nitrazepam.[61]
Nitrazepam interacts with the antibioticerythromycin, a strong inhibitor of CYP3A4, which affects concentration peak time. Alone, this interaction is not believed to be clinically important.[62] However, anxiety, tremor, and depression were documented in a case report involving a patient undergoing treatment for acute pneumonia and renal failure. Following administration of nitrazepam, triazolam, and subsequently erythromycin, the patient experienced repetitive hallucinations and abnormal bodily sensations. Coadministration of benzodiazepine drugs at therapeutic doses with erythromycin may cause serious psychotic symptoms, especially in persons with other, significant physical complications.[63]
Oral contraceptive pills reduce the clearance of nitrazepam, which may lead to increased plasma levels of nitrazepam and accumulation.[64]Rifampin significantly increases the clearance of nitrazepam, whileprobenecid significantly decreases its clearance.[65]Cimetidine slows down the elimination rate of nitrazepam, leading to more prolonged effects and increased risk of accumulation.[66] Alcohol in combination with nitrazepam may cause a synergistic enhancement of the hypotensive properties of both benzodiazepines and alcohol.[67] Benzodiazepines including nitrazepam may inhibit theglucuronidation ofmorphine, leading to increased levels and prolongation of the effects of morphine in rat experiments.[68]
Nitrazepam is a nitrobenzodiazepine.[69][70] It is a 1,4 benzodiazepine, with the chemical name1,3-Dihydro-7-nitro-5-phenyl-2H-1,4- benzodiazepin-2-one.
It is long acting,lipophilic, and metabolised hepatically by oxidative pathways. It acts on benzodiazepine receptors in the brain which are associated with the GABA receptors, causing an enhanced binding of GABA to GABAA receptors.[71] GABA is a major inhibitoryneurotransmitter in the brain, involved in inducing sleepiness, muscular relaxation, and control of anxiety and seizures, and slows down the central nervous system. Nitrazepam is similar in action to the z-drugzopiclone prescribed for insomnia.[72] The anticonvulsant properties of nitrazepam and other benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems to be limited by benzodiazepines effect of slowing recovery of sodium channels from inactivation in mouse spinal cord cell cultures.[73] The muscle relaxant properties of nitrazepam are produced via inhibition of polysynaptic pathways in the spinal cord of decerebrate cats.[74] It is afull agonist of the benzodiazepine receptor.[75] The endogenous opioid system may play a role in some of the pharmacological properties of nitrazepam in rats.[76] Nitrazepam causes a decrease in thecerebral contents of theamino acidsglycine andalanine in themouse brain. The decrease may be due to activation of benzodiazepine receptors.[77] At high doses decreases in histamine turnover occur as a result of nitrazepam's action at the benzodiazepine-GABA receptor complex in mouse brain.[78] Nitrazepam has demonstrated cortisol-suppressing properties in humans.[79]It is an agonist for both central benzodiazepine receptors and to the peripheral-type benzodiazepine receptors found in rat neuroblastoma cells.[80]
In sleep laboratory studies, nitrazepam decreasedsleep onset latency. In psychogeriatric inpatients, it was found to be no more effective than placebo tablets in increasing total time spent asleep and to significantly impair trial subjects' abilities to move and carry out everyday activities the next day, and it should not be used as a sleep aid in psychogeriatric inpatients.[81]
The drug causes a delay in the onset, and decrease in the duration ofREM sleep. Following discontinuation of the drug, REM sleep rebound has been reported in some studies.[82] Nitrazepam is reported to significantly affectstages of sleep - a decrease in stage 1, 3, and 4 sleep and an increase in stage 2.[83] In young volunteers, the pharmacological properties of nitrazepam were found to produce sedation and impaired psychomotor performance and standing steadiness. EEG tests showed decreased alpha activity and increased the beta activity, according to blood plasma levels of nitrazepam.[84] Performance was significantly impaired 13 hours after dosing with nitrazepam, as were decision-making skills. EEG tests show more drowsiness and light sleep 18 hours after nitrazepam intake, more so than amylobarbitone. Fast activity was recorded via EEG 18 hours after nitrazepam dosing.[85] An animal study demonstrated that nitrazepam induces a drowsy pattern of spontaneous EEG including high-voltage slow waves and spindle bursts increase in thecortex andamygdala, while thehippocampal theta rhythm is desynchronized. Also low-voltage fast waves occur particularly in thecortical EEG. The EEG arousal response toauditory stimulation and to electric stimulation of the mesencephalic reticular formation,posteriorhypothalamus and centromedianthalamus is significantly suppressed. Thephotic driving response elicited by a flash light in thevisual cortex is also suppressed by nitrazepam.Estazolam was found to be more potent however.[86] Nitrazepam increases the slow wave light sleep (SWLS) in a dose-dependent manner whilst suppressing deep sleep stages. Less time is spent in stages 3 and 4 which are the deep sleep stages, when benzodiazepines such as nitrazepam are used. The suppression of deep sleep stages by benzodiazepines may be especially problematic to the elderly as they naturally spend less time in the deep sleep stage.[87]
Nitrazepam is largely bound to plasma proteins.[88] Benzodiazepines such as nitrazepam arelipid-soluble and have a high cerebral uptake.[89] The time for nitrazepam to reach peak plasma concentrations following oral administration is about 2 hours (0.5 to 5 hours). Thehalf-life of nitrazepam is between 16.5 and 48.3 hours. In young people, nitrazepam has a half-life of about 29 hours and a much longer half-life of 40 hours in the elderly.[36][37] Both low dose (5 mg) and high dose (10 mg) of nitrazepam significantly increasesgrowth hormone levels in humans.[90]
Nitrazepam's half-life in thecerebrospinal fluid, 68 hours, indicates that nitrazepam is eliminated extremely slowly from the cerebrospinal fluid.[91] Concomitant food intake has no influence on the rate of absorption of nitrazepam nor on its bioavailability. Therefore, nitrazepam can be taken with or without food.[92]
Nitrazepam overdose may result in stereotypical symptoms ofbenzodiazepine overdose including intoxication, impaired balance and slurred speech. In cases of severe overdose this may progress to a comatose state with the possibility of death. The risk of nitrazepam overdose is increased significantly if nitrazepam is abused in conjunction with opioids, as was highlighted in a review of deaths of users of the opioidbuprenorphine.[93] Nitrobenzodiazepines such as nitrazepam can result in a severe neurological effects.[94] Nitrazepam taken in overdose is associated with a high level of congenital abnormalities (30 percent of births). Most of the congenital abnormalities were mild deformities.[41]
Severe nitrazepam overdose resulting in coma causes the central somatosensory conduction time (CCT) after median nerve stimulation to be prolonged and the N20 to be dispersed. Brain-stem auditory evoked potentials demonstrate delayed interpeak latencies (IPLs) I-III, III-V and I-V. Toxic overdoses therefore of nitrazepam cause prolonged CCT and IPLs. An alpha pattern coma can be a feature of nitrazepam overdose with alpha patterns being most prominent in the frontal and central regions of the brain.[95][96]
Benzodiazepines were implicated in 39% of suicides by drug poisoning inSweden, with nitrazepam andflunitrazepam accounting for 90% of benzodiazepine implicated suicides, in the elderly over a period of 2 decades. In three quarters of cases death was due to drowning, typically in the bath. Benzodiazepines were the predominant drug class in suicides in this review of Swedishdeath certificates. In 72% of the cases benzodiazepines were the only drug consumed. Benzodiazepines and in particular nitrazepam and flunitrazepam should therefore be prescribed with caution in the elderly.[40] In a brain sample of a fatal nitrazepam poisoning high concentrations of nitrazepam and its metabolite were found in the brain of the deceased person.[97]
In a retrospective study of deaths in Sweden, when benzodiazepines were implicated in the deaths, the benzodiazepines nitrazepam andflunitrazepam were the most common benzodiazepines involved. Benzodiazepines were a factor in all deaths related to drug addiction in this study of causes of deaths. In Sweden, nitrazepam andflunitrazepam were significantly more commonly implicated in suicide related deaths than natural deaths. In four of the cases benzodiazepines alone were the only cause of death.[38] In Australia, nitrazepam andtemazepam were the benzodiazepines most commonly detected in overdose drug related deaths. In a third of cases benzodiazepines were the sole cause of death.[39]
Individuals with chronic illnesses are much more vulnerable to lethal overdose with nitrazepam, as fatal overdoses can occur at relatively low doses in these individuals.[98]
Reaction of 2-amino-5-nitrobenzophenone (1) withbromoacetyl bromide forms the amide2. Ring closure inliquid ammonia affords nitrazepam (3). More simply,diazepinone (4) can be nitrated directly at the more reactive C7 position withpotassium nitrate insulfuric acid.
