|Systematic (IUPAC) name|
|Mol. mass||281.3 g/mol|
|Half life||16-38 hours|
Schedule IV (International)
WikiDoc Resources for Nitrazepam
Evidence Based Medicine
Guidelines / Policies / Govt
Patient Resources / Community
Healthcare Provider Resources
Continuing Medical Education (CME)
Experimental / Informatics
Nitrazepam is a type of benzodiazepine drug. It is a powerful hypnotic drug with strong sedative and motor impairing properties, anxiolytic, amnestic, anticonvulsant, and skeletal muscle relaxant properties. Nitrazepam is available in 5mg and 10mg tablets. In Australia, Israel and the United Kingdom it is only available in 5mg tablets.
It is long acting, is lipophilic and is metabolised hepatically via oxidative pathways. It acts on benzodiazepine receptors in the brain which are associated with the GABA receptors, causing an enhanced binding of GABA (gamma amino butyric acid) to GABAA receptors. GABA is a major inhibitory neurotransmitter in the brain, involved in inducing sleepiness, muscular relaxation and control of anxiety and seizures, and slows down the central nervous system. The mechanism of action of nitrazepam is the same as other benzodiazepine drugs and zopiclone. 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. The muscle relaxant properties of nitrazepam are produced via inhibition of polysynaptic pathways in the spinal cord. It is a full agonist of the benzodiazepine receptor. The endogenous opioid system may play a role in some of the pharmacological properties of nitrazepam in rats. Nitrazepam causes a decrease in the cerebral contents of the amino acids glycine and aspartic acid in the mouse brain. The decrease may be due to activation of benzodiazepine receptors. At high doses decreases in histamine turnover occur as a result of nitrazepam's action at the benzodiazepine-GABA receptor complex in mouse brain.  Nitrazepam possesses antipruritic properties. It possesses antipruritic properties, which are believed to be due to a central mechanism of action rather than a peripheral mechanism of action. Nitrazepam has demonstrated cortisol suppressing properties in man. Nitrazepam is an agonist for both central and peripheral type benzodiazepine receptors in rat neuroblastoma cells.
EEG and sleep
In sleep laboratory studies, nitrazepam decreased sleep onset latency. In psychogeriatric in-patients nitrazepam was found to be no more effective than placebo tablets in increasing total time spent asleep, was found to significantly impair trial subjects abilities to move and carry out everyday activities the next day and it was concluded that nitrazepam should not be used as a sleep aid in psychogeriatric in-patients.
Stage 2 NREM sleep is significantly increased by nitrazepam but SWS stage sleep is significantly decreased by nitrazepam. There is delay in the onset, and decrease in the duration of REM sleep. Following discontinuation of the drug, REM sleep rebound has been reported in some studies. Nitrazepam is reported to significantly affect stages of sleep: a decrease stage 1, 3 and 4 sleep and to increase stage 2. In young volunteers the pharmacological properties of nitrazepam was found to produce sedation, impaired psychomotor performance and standing steadiness. EEG tests showed a decrease of alpha activity and increased the beta activity. These effects increased according to blood plasma levels of nitrazepam. Performance was significantly impaired 13 hours after dosing with nitrazepam as was 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. An animal study demonstrated that nitrazepam induces a drowsy pattern of spontaneous EEG including high voltage slow waves and spindle bursts increase in the cortex and amygdala, while the hippocampal theta rhythm is desynchronized. Also low voltage fast waves occur particularly in the cortical EEG. The EEG arousal response to auditory stimulation and to electric stimulation of the mesencephalic reticular formation, posterior hypothalamus and centromedian thalamus is significantly suppressed. The photic driving response elicited by a flash light in the visual cortex is also suppressed by nitrazepam. Estazolam was found to be more potent however. 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. Benzodiazepines are therefore not good hypnotics in the treatment of insomnia. 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.
Nitrazepam is largely bound to plasma proteins. Benzodiazepines such as nitrazepam are lipid soluble and have a high cerebral uptake. The time for nitrazepam to reach peak plasma concentrations following oral administration is about 2 hours (0.5 to 5 hours).The half life which is the time taken for a dose to decrease by half is 16.5 to 48.3 (mean 28.8) hours. Both low dose (5 mg) and high dose (10 mg) of nitrazepam significantly increases growth hormone levels in humans. Nitrazepam has a much longer half life in the cerebrospinal fluid. The half life in the cerebrospinal fluid is 68 hours which indicates that nitrazepam is eliminated extremely slowly from the cerebrospinal fluid. Nitrazepam has a half life of about 29 hours in young people and a much longer half life in the elderly. In the elderly the half life is about 40 hours. 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.
Nitrazepam is most often used to treat short-term sleeping problems (insomnia), namely difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Nitrazepam is long acting and is sometimes used in patients who have difficulty in maintaining sleep. Nitrazepam shortens the time required to fall asleep and lengthens the duration of sleep. It is also useful for the management of myoclonic seizures and has been used in the management of seizure disorders in children and also for infantile spasms. However, the usefulness of nitrazepam is limited due to dose limiting sedative side effects. Nitrazepam is sometimes used for refractory epilepsies. However, long term prophylactic treatment of epilepsy has considerable drawbacks. Most importantly the loss of antiepileptic effects due to tolerance which renders prolonged nitrazepam therapy ineffective. Nitrazepam also has the draw back of significant side effects such as sedation, which is why nitrazepam and benzodiazepines in general are only prescribed in the acute management of epilepsies. Nitrazepam 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. However, as with other epilepies treated with benzodiazepines, long term therapy becomes ineffective with prolonged therapy and the side effects of hypotonia and drowsiness are troublesome with nitrazepam therapy, other antiepileptic agents are therefore recommended for long term therapy, possibly Corticotropin (ACTH) or vigabatrin.
Nitrazepam along with diazepam, oxazepam and temazepam 1993 represented 82% of the benzodiazepine market in Australia. The rate of benzodiazepine prescribing in Tasmania is higher than in other Australian states; Nitrazepam and flunitrazepam prescribing levels in Tasmania are disturbingly high. Prescribing of hypnotics in Norway is quite restrictive with only 4 hypnotics which are prescribable; nitrazepam, flunitrazepam, zolpidem and zopiclone. The usage of benzodiazepine hypnotics in local authority homes for the elderly 1982 in Edinburgh, established via a clinical survey, was that 34% of residents were taking sleeping medication. However, the number varied between the homes, with some homes reporting only 2.3% of residents to be on hypnotic medication and others up to 56.5% on hypnotic drugs. Nitrazepam was the most frequently prescribed hypnotic medication accounting for a third of hypnotic use in Edinburgh residential homes in 1982.
When used for treatment of insomnia, the usual dose for adults is 2.5mg to 10mg, taken at bedtime. Typically, it works within the hour and allows the individual to maintain sleep for 4 to 8 hours. When used for treatment of myoclonic seizures, the dose is based on body weight. The dose for children (30kg or less) is anywhere from 0.3mg/kg to 1mg/kg, daily in three divided doses.
Tolerance dependence and withdrawal
Tolerance to a drugs effects occurs after regular exposure to a drug. The mechanism of nitrazepam tolerance may be due to down-regulation of benzodiazepine receptors. When tolerance and habituation occurs to nitrazepam its pharmacokinetic profile changes with absorption of the drug slowing down, elimination time increasing and brain concentration of nitrazepam increasing significantly. Increased levels of GABA in cerebral tissue and alterations in the activity state of the serotoninergic system occurs as a result of nitrazepam tolerance.
After 6 days of use tolerance to nitrazepam's but not temazepams sleep inducing effects and performance impairing effects occurred in a study. One study demonstrated tolerance to the sleep promoting effects of nitrazepam and temazepam after 7 days nightly administration in 19 elderly inpatients. Self reported quality of sleep was found to be increased after the first nights administration of either nitrazepam or temazepam but by day 7 self reported quality of sleep was found to have returned to baseline in these patients, suggesting the development of tolerance after 7 days use. The effect was more pronounced in patients of lower intelligence.  In mice tolerance to the anticonvulsant properties of nitrazepam developed profoundly and rapidly over 6 days, and then did not proceed. Some anticonvulsant effects were still apparent after 6 days administration. In humans tolerance to the anticonvulsant effects of nitrazepam is a frequent occurrence.
Dependence and withdrawal
See also benzodiazepine withdrawal syndrome
Benzodiazepine drugs such as nitrazepam can cause dependence and addiction and is what is known as the benzodiazepine withdrawal syndrome. Withdrawal from nitrazepam or other benzodiazepines often leads to withdrawal symptoms which are similar to those seen with alcohol and barbiturates, including delirium tremens. The higher the dose and the longer the drug is taken the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can however occur at standard dosages and also after short term treatment. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regime.
Frequent use of nitrazepam may cause dependence and when the drug is reduced or stopped, withdrawal symptoms occur. Withdrawal symptoms including a worsening of insomnia compared to baseline typically occurs after discontinuation of nitrazepam even after short term single nightly dose therapy. Dependence on benzodiazepines such as nitrazepam or temazepam often occurs due to discharging patients from hospital on benzodiazepines who were started on benzodiazepine hypnotics in hospital. It is recommended that hypnotic use in hospital be limited to 5 days to avoid the development of drug dependence and withdrawal insomnia.
After discontinuation of nitrazepam a rebound effect may occur about 4 days after stopping medication. Nitrazepam has more side effects than other hypnotic drugs and tolerance to sedative properties and rebound insomnia after discontinuation occurs after only 7 days administration. Tolerance to the anticonvulsant and anxiolytic effects also develops rapidly during daily administration.
Abrupt withdrawal after long term use from therapeutic doses of nitrazepam may result in a severe benzodiazepine withdrawal syndrome. Reports in the medical literature report of two psychotic states developing after abrupt withdrawal from nitrazepam including delirium after abrupt withdrawal of 10 mg of nitrazepam and in another case auditory hallucinations and visual cognitive disorder developed after abrupt withdrawal from 5 mg of nitrazepam and 0.5 mg of triazolam. Gradual and careful reduction of the dosage was recommended to prevent severe withdrawal syndromes from developing. Antipsychotics increase the severity of benzodiazepine withdrawal effects with an increase in the intensity and severity of convulsions. Depersonalisation has also been reported as a benzodiazepine withdrawal effect from nitrazepam.
Nitrazepam may be carcinogenic in hamster cells under the influence of UV-light and has been found to be both photogenotoxic and photocytotoxic in hamster cells under UV light. Some studies on some animals have demonstrated teratogenic and also carcinogenic effects of nitrazepam and some other benzodiazepines in these animals and the wide spread use of these drugs world wide was of major concern for human health. A review and update of existing results was therefore attempted. However, since 1996 no further research for this concern has been carried out. Genotoxic drugs have the potential to cause genetic mutations, DNA damage and promote the development of cancer including tumors.
Nitrazepam has been reported in the medical literature by researchers as a drug which is well known for inducing testicular and reproductive toxicities. Nitrazepam decreases the number of motile sperm, curilinear velocity, beat cross frequency, maximum and mean amplitude of lateral head displacement and causes testicular lesions. Nitrazepam may result in low fertility.
In studies of Sprague-Dawley rats, nitrazepam induced reproductive toxicity has been demonstrated after 2 weeks of therapy, with significant decreases in fertility in nitrazepam treated male rats. Testicular signs of toxicity, decrease in number of sperm heads in the testis and increase in number of sperm with abnormal heads was found after 2 weeks treatment with the higher dose nitrazepam and after 4 weeks in the lower dosed rats. The doses used however in the toxicology tests were sigificantly higher than standard therapeutic doses. Nitrazepam has also been shown at high doses to affect sperm motion in laboratory tests via causing lesions in spermatids.
Nitrazepam has been shown in Sprague-Dawley rats to cause testicular damage. A decrease in the weight of the testis, weight of the epididymis, number of sperm in the testis and sperm motility was shown in very high dose of nitrazepam treated rats, i.e. 20mg/kg to 80mg/kg. Rats treated with such extreme doses of nitrazepam show a significant decrease in pregnancy rate. Localised necrosis in the seminiferous epithelium and Leydig cell hyperplasia occurs in the testis of rats treated with nitrazepam and morphological changes occur in spermatocytes with necrosis of the cytoplasm. Laboratory tests assessing the toxicity of nitrazepam, diazepam and chlordiazepoxide on mice spermatozoa found that nitrazepam produced the most toxicities on sperm including abnormalities involving both shape and size of the sperm head.
In female rats nitrazepam has been shown to inhibit ovulation.
In a rat study nitrazepam showed much greater damage to the fetus than other benzodiazepines, as did nimetazepam. High levels of nitrazepam were found in the maternal serum and in the whole fetus which may account for the increased toxicity. Diazepam showed relatively weak fetal toxicities. Rats treated with a single very high dose of nitrazepam on day 12 of gestation significant increase in malformation in rats. However, mice seem more resistant to the teratogenic effects which may be related to differences in metabolism of nitrazepam between the two species. Exencephaly, cleft palate, micrognathia, short or kinky tail and limb reduction defects occurred in rats treated with a single very high dose of nitrazepam, with limb buds revealing hemorrhage and mesenchymal cell necrosis. Another fetal toxicity study in rats at 100mg/kg demonstrated that nitrazepam has embryocidal activity in vitro and that nitrazepam is teratogenic in vivo in rats. Nitrazepam is much more teratogenic in rats, but not mice, than other benzodiazepines probably due to its extensive nitro reduction to 7-aminonitrazepam by rat intestinal microflora. Nitrazepam undergoes enterocyte metabolism to form oxidative free radicals. Superoxide is intracellularly produced during nitrazepam metabolism and this oxidative metabolism can lead to cellular dysfunction.
The Journal of Clinical Sleep Medicine published a paper which had carried out a systematic review of the medical literature concerning insomnia medications and raised concerns about benzodiazepine receptor agonist drugs, the benzodiazepines and the Z-drugs that are used as hypnotics in humans. The review found that almost all trials of sleep disorders and drugs are sponsored by the pharmaceutical industry. It was found that the odds ratio for finding results favorable to industry in industry-sponsored trials was 3.6 times higher than non-industry-sponsored studies and that 24% of authors did not disclose being funded by the drug companies in their published paper when they were funded by the drug companies. The paper found that there is little research into hypnotics that is independent from the drug manufacturers. Also of concern was the lack of focus in industry sponsored trials on their own results showing that use of hypnotics is correlated with depression. The author was concerned that there is no discussion of adverse effects of benzodiazepine agonist hypnotics discussed in the medical literature such as significant increased levels of infection, cancers and increased mortality in trials of hypnotic drugs and an overemphasis on the positive effects. No hypnotic manufacturer has yet tried to refute the epidemiology data that shows that use of their product is correlated with excess mortality. The author stated that "major hypnotic trials is needed to more carefully study potential adverse effects of hypnotics such as daytime impairment, infection, cancer, and death and the resultant balance of benefits and risks." The author concluded that more independent research into daytime impairment, infection, cancer, and shortening of lives of sedative hypnotic users is needed to find the true balance of benefits and risks of benzodiazepine agonist hypnotic drugs in the treatment of insomnia. Chronic use of benzodiazepines seemed to cause significant immunological disorders in a study of selected outpatients attending a psychopharmacology department.
Benzodiazepine usage for more than 1 - 6 months at prescribed doses is associated with an increased risk of the development of ovarian cancer. There have been 15 epidemiologic studies which have shown that hypnotic drug use is associated with increased mortality, mainly due to increased cancer deaths in humans. The cancers included cancer of the brain, lung, bowel, breast, and bladder, and other neoplasms. Not only are benzodiazepines associated with an increased risk of cancer, the benzodiazepine receptor agonist Z-drugs also are associated with cancer in humans in these studies. Initially FDA reviewers did not want to approve the Z drugs due to concerns of cancer but ultimately changed their mind and approved the drugs despite the concerns. The data shows that trial subjects receiving hypnotic drugs had an increased the risk of developing cancer. The review author concluded saying; "the likelihood of cancer causation is sufficiently strong now that physicians and patients should be warned that hypnotics possibly place patients at higher risk for cancer". It has to be seen if other reviewers and the FDA come to the same result.
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.  Nitrazepam may cause sudden death in children. Nitrazepam therapy 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.
Nitrazepam is a drug which is very frequently involved in drug intoxication. Nitrazepam was the most commonly detected benzodiazepine in urine samples in the UK in 1997 suggesting a high liking and preference amongst drug abusers. However, it has been superseded by temazepam, despite the fact that temazepam is much more highly regulated in the UK. Temazepam is Class B drug, while nitrazepam is a Class C drug. In Nepal, nitrazepam is a major drug of abuse as is codeine, heroin, buprenorphine and cannabis.
Nitrazepam in animal studies has been shown to increase reward seeking which may suggest increased risk of addictive behavioural patterns. A study found that nitrazepam caused significant euphoria as against placebos and was identified as an active drug by freshly detoxified experienced drug abusers of heroin and other drugs. Nitrazepam resembled diazepam (Valium), however, on certain parameters the effects produced by nitrazepam were more pronounced in these drug abusers. Nitrazepam was found to be an abusable drug and has similar abuse liability like diazepam, if not slightly higher in these drug abusers. Treatment with nitrazepam should usually not exceed 7 to 10 consecutive days. Use for more than 2 to 3 consecutive weeks requires complete re-evaluation of the patient. Prescriptions for nitrazepam should be written for short-term use (7 to 10 days) and it should not be prescribed in quantities exceeding a 1-month supply. Dependence can occur in as little as four weeks.
Benzodiazepines, including diazepam, nitrazepam and flunitrazepam account for the largest volume of forged drug prescriptions in Sweden, a total of 52% of drug forgeries being for benzodiazepines, suggesting benzodiazepines are a major prescription drug class of abuse.
Nitrazepam is detected frequently in cases of people suspected of driving under the influence of drugs in Sweden. Other benzodiazepines and zolpidem and zopiclone are also found in high numbers in suspected impaired drivers. Many drivers have blood levels far exceeding the therapeutic dose range suggesting a high degree of abuse potential for benzodiazepines and zolpidem and zopiclone. In Northern Ireland in cases where drugs were found in tests on impaired drivers, benzodiazepines were found to be present in 87% of cases.
Common Side Effects
CNS depression including, somnolence, dizziness, depressed mood, rage, violence, fatigue, ataxia, headache, vertigo, impairment of memory, impairment of motor functions, hangover feeling in the morning, slurred speech, decreased physical performance, numbed emotions, reduced alertness, muscle weakness, double vision and inattention have been reported. Unpleasant dreams and rebound insomnia has also been reported. High levels of confusion, clumsiness also occurs after administration of nitrazepam. Increased reaction time, co-ordination problems and impaired learning and memory.
Impaired learning and memory occurs due to the action of the drug on benzodiazepine receptors which causes a dysfunction in the cholinergic neuronal system. Nitrazepam causes a reduced output of serotonin which is closely involved in regulating mood and may be the cause of feelings of depression in users of nitrazepam or other benzodiazepines.
Nitrazepam is a long acting benzodiazepine with an elimination half life of 15-38 (mean elimination half life 26 hours). 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. Significant impairment of visual perception and sedative effects persisting into the next day typically occurs with nitrazepam administration as was demonstrated in a human clinical trial assessing the effect of nitrazepam on peak saccade velocity.
Impairment of psychomotor function may especially occur after repeated administration, with the elderly being more vulnerable to this adverse effect. Overall accuracy of completing tasks is impaired after repeated administration of nitrazepam and is due to drug accumulation of nitrazepam. The elderly are more vulnerable to these side effects.
Less Common Side Effects
Hypotension, faintness, palpitation, rash or pruritus, gastrointestinal disturbances, changes in libido. Very infrequently, paradoxical reactions may occur, e.g. excitement, stimulation, hallucinations, hyperactivity and insomnia. Also depressed or increased dreaming, disorientation, severe sedation, retrograde amnesia, headache, hypothermia, delirium tremens. Acroparaesthesia has been reported as a side effect from nitrazepam with symptoms including, pins and needles in hands and loss of power of fingers and clumsiness of the fingers.
Nitrazepam interacts with the antibiotic erythromycin which is a strong inhibitor of CYP3A4, which affects concentration peak time. This interaction is not to believed to be clinically important. However, anxiety, tremor and depression have been documented in a case report following administration of nitrazepam and triazolam. Following administration of erythromycin to the patient, repetitive hallucinations and abnormal bodily sensations developed. The patient had however acute pneumonia and renal failure. Co-administration of benzodiazepine drugs at therapeutic doses with erythromycin may cause serious psychotic symptoms especially in those with other significant physical complications. Oral contraceptive pills, reduce the clearance of nitrazepam which may lead to increased plasma levels of nitrazepam and accumulation. Rifampin increases the clearance of nitrazepam significantly and probenecid decreases the clearance of nitrazepam significantly. Cimetidine slows down the elimination rate of nitrazepam leading to more prolonged effects of nitrazepam and increased risk of accumulation. Alcohol (ethanol) in combination with nitrazepam may cause a synergistic enhancement of the hypotensive properties of both benzodiazepines and alcohol. Benzodiazepines including nitrazepam may inhibit the glucuronidation of morphine leading to increased levels of and prolongation of the effects of morphine in rat experiments.
It has been recommended in the medical literature that 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 the higher the dosage that is prescribed. Nitrazepam in doses of 5 mg or more causes significant deterioration in vigilance performance combined with increased feelings of sleepiness. Doses as low as 5 mg of nitrazepam can impair driving skills. Therefore people driving or conducting activities which require vigilance should exercise caution in using nitrazepam or possibly avoid it all together.
Caution in the elderly. Nitrazepam has been found to be dangerous in elderly patients due to a significant increased risk of falls. This increased risk is probably due to the persisting drug effects of nitrazepam well into the next day. Nitrazepam is a particularly unsuitable hypnotic for the elderly as it induces a disability characterised by general mental deterioration, inability to walk, incontinence, dysarthric, confusion, prone to 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 eg dementia and can also lead to the symptoms of postural hypotension which may also get misdiagnosed. It was reported that a geriatric unit was seeing as many as 7 patients a month with nitrazepam induced disabilities and health problems. It was recommended that nitrazepam should join the barbiturates in not being prescribed to the elderly. Only nitrazepam and lorazepam were found to increase the risk of falls and fractures in the elderly. CNS depression occurs much more frequently in the elderly and is especially common in doses above 5 mg of nitrazepam. Both young and old patients report sleeping better after 3 nights use of nitrazepam however they also report feeling less awake and are 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 that the elderly are more sensitive to nitrazepam due to increased sensitivity of the aging brain to nitrazepam. 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.
Caution in children. Nitrazepam is not recommended for use in those under 18. Use in very young children may be especially danagerous. 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 and ataxia were common side effects in children with tuberous sclerosis treated with nitrazepam. The side effects of nitrazepam may impair the development of motor and cognitive skills in children treated with nitrazepam. Withdrawal of nitrazepam only occasionally resulted in a return of seizures and some children withdrawn from nitrazepam appeared to improve. Development, eg able to walk at 5 years was impaired in many children taking nitrazepam but was not impaired with several other non benzodiazepine antiepileptic agents. It has been recommended that children being treated with nitrazepam should be reviewed and have their nitrazepam gradually discontinued whenever appropriate.
Caution in hypothyroidism. Caution should be exercised by people who have hypothyroidism as this condition may cause a long delay in the metabolism of nitrazepam leading to significant drug accumulation.
Nitrazepam is a long acting benzodiazepine and there is a risk of drug accumulation, even 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 also is present in breast milk in high quantities. Therefore nitrazepam and benzodiazepines should be avoided during pregnancy and breast feeding. 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. 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 and therefore rapidly penetrate the placenta with significant uptake of the drug. Use of benzodiazepines eg nitrazepam in late pregnancy especially high doses may result in floppy infant syndrome. Use in the third trimester stage of pregnancy may result in the development of a severe benzodiazepine withdrawal syndrome in the neonate. Withdrawal symptoms from benzodiazepines in the neonate may include hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. These symptoms may persist for hours or months after birth.
Nitrazepam should be avoided in patients with chronic obstructive pulmonary disease (COPD), especially during acute exacerbations of COPD, due to the fact that serious respiratory depression may occur in patients who are receiving hypnotics.
Nitrazepam should be avoided in patients who drive or operate machinery. A study assessing driving skills of sedative hypnotic users found that users of nitrazepam were found 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.
Nitrazepam overdose may result in stereotypical symptoms of benzodiazepine 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 opiates, as was highlighted in a review of deaths of users of the opiate buprenorphine. 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.
Benzodiazepines were implicated in 39% of suicides by drug poisoning in Sweden, with nitrazepam and flunitrazepam 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 Swedish death 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. 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.
In a retrospective study of deaths, when benzodiazepines were implicated in the deaths, the benzodiazepines nitrazepam and flunitrazepam were the most common benzodiazepines involved. Benzodiazepines were a factor in all deaths related to drug addiction in this study of causes of deaths. Nitrazepam and flunitrazepam 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. In Australia, nitrazepam and temazepam were the benzodiazepines most commonly detected in overdose drug related deaths. In a third of cases benzodiazepines were the sole cause of death.
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.
Mogadon, Alodorm, Apodorm, Remnos, Somnite, Apodorm, Arem, Cavodan, Dima, Dormalon, Dormigen, Dormo-Puren, Dumolid, Eatan N, Eunoctin, Hypnotex, Imeson, Insoma, Insomin, Ipersed, Mitidin, Mogadan, Nilandron, Nitavan, Nitepam, Nitrados, Nitrapan, Nitravet, Nitrazadon, Nitrazep, Nitrazepan, Nitrazepol, Nitredon, Nitrosun, Novanox, Numbon, Onirema, Ormodon, Pacisyn, Paxadorm, Pelson, Pelsonfilina, Protraz, Radedorm, Remnos, Serenade, Somnibel N, Somnipar, Somnite, Sonebon, Sonotrat, Surem, Tri, Unisomnia, Nitrazepam Capsules BP 1993, Nitrazepam Oral Suspension BP 1993, Nitrazepam Tablets BP 1993.
In Popular Culture
- Marillion refers to the drug in the song Punch & Judy on their second album Fugazi, with lyricist Fish writing Curling tongs, mogadons, "I got a headache baby, don't take so long"
- Porcupine Tree reference the drug in their song Fear of a Blank Planet from the album of the same name with the line "My face is Mogadon."
- Yasui M; Kato A, Kanemasa T, Murata S, Nishitomi K, Koike K, Tai N, Shinohara S, Tokomura M, Horiuchi M, Abe K. (Jun 2005). "[Pharmacological profiles of benzodiazepinergic hypnotics and correlations with receptor subtypes]" 25 (3): 143-51. PMID 16045197.
- Robertson MD; Drummer OH. (May 1995). "Postmortem drug metabolism by bacteria.". J Forensic Sci. 40 (3): 382-6. PMID 7782744.
- Danneberg P; Weber KH (1983). "Chemical structure and biological activity of the diazepines". Br J Clin Pharmacol 16 (Suppl 2): 231S-244S. PMID 6140944.
- Skerritt JH; Johnston GA. (6). "Enhancement of GABA binding by benzodiazepines and related anxiolytics.". Eur J Pharmacol. 89 (3-4): 193-8. doi:10.1016/0014-2999(83)90494-6. PMID 6135616.
- Sato K; Hong YL, Yang MS, Shibuya T, Kawamoto H, Kitagawa H. (Apr 1985). "Pharmacologic studies of central actions of zopiclone: influence on brain monoamines in rats under stressful condition.". Int J Clin Pharmacol Ther Toxicol. 23 (4): 204-10. PMID 2860074.
- McLean MJ; Macdonald RL. (Feb 1988). "Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture.". J Pharmacol Exp Ther. 244 (2): 789-95. PMID 2450203.
- Date SK; Hemavathi KG, Gulati OD. (Nov 1984). "Investigation of the muscle relaxant activity of nitrazepam.". Arch Int Pharmacodyn Ther. 272 (1): 129-39. PMID 6517646.
- Podhorna J; Krsiak M. (2000). "Behavioural effects of a benzodiazepine receptor partial agonist, Ro 19-8022, in the social conflict test in mice.". Behavioural pharmacology. 11 (2): 143-51. PMID 10877119.
- Nowakowska E; Chodera A. (Feb 1991). "Studies on the involvement of opioid mechanism in the locomotor effects of benzodiazepines in rats.". Pharmacology, biochemistry, and behavior. 38 (2): 265-6. doi:10.1016/0091-3057(91)90276-8. PMID 1676167.
- Tomono S; Kuriyama K. (Dec 1985). "Effect of 450191-S, a 1H-1,2,4-triazolyl benzophenone derivative, on cerebral content of neuroactive amino acids.". Jpn J Pharmacol. 39 (4): 558-61. doi:10.1254/jjp.39.558. PMID 2869172.
- Oishi R; Nishibori M, Itoh Y, Saeki K. (27). "Diazepam-induced decrease in histamine turnover in mouse brain.". Eur J Pharmacol. 124 (3): 337-42. doi:10.1016/0014-2999(86)90236-0. PMID 3089825.
- Krause L; Shuster S. (22). "Mechanism of action of antipruritic drugs." (pdf). Br Med J (Clin Res Ed). 287 (6400): 1199-200.. PMID 6138120.
- Christensen P; Lolk A, Gram LF, Kragh-Sørensen P. (1992). "Benzodiazepine-induced sedation and cortisol suppression. A placebo-controlled comparison of oxazepam and nitrazepam in healthy male volunteers.". Psychopharmacology. 106 (4): 511-6. PMID 1349754.
- Watabe S; Yoshii M, Ogata N, Tsunoo A, Narahashi T (26). "Differential inhibition of transient and long-lasting calcium channel currents by benzodiazepines in neuroblastoma cells". Brain Res 606 (2): 244-50. PMID 8387860.
- Linnoila, M; Viukari M. (Jun 1976). "Efficacy and side effects of nitrazepam and thioridazine as sleeping aids in psychogeriatric in-patients.". British Journal of Psychiatry 128: 566-9. PMID 776314.
- Nakazawa Y; Kotorii M, Oshima M, Horikawa S, Tachibana H. (31). "Effects of thienodiazepine derivatives on human sleep as compared to those of benzodiazepine derivatives.". Psychopharmacologia. 44 (2): 165-71. doi:10.1007/BF00421005. PMID 709.
- Adam K; Oswald I. (Jul 1982). "A comparison of the effects of chlormezanone and nitrazepam on sleep.". Br J Clin Pharmacol. 14 (1): 57-65. PMID 7104168.
- Mizuki Y; Suetsugi M, Hotta H, Ushijima I, Yamada M. (May 1995). "Stimulatory effect of butoctamide hydrogen succinate on REM sleep in normal humans.". Prog Neuropsychopharmacol Biol Psychiatry. 19 (3): 385-401. doi:10.1016/0278-5846(95)00020-V. PMID 7624490.
- Tazaki T; Tada K, Nogami Y, Takemura N, Ishikawa K. (1989). "Effects of butoctamide hydrogen succinate and nitrazepam on psychomotor function and EEG in healthy volunteers.". Psychopharmacology (Berl). 97 (3): 370-5. doi:10.1007/BF00439453. PMID 2497487.
- Malpas A; Rowan AJ, Boyce CR, Scott DF. (27). "Persistent behavioural and electroencephalographic changes after single doses of nitrazepam and amylobarbitone sodium." (pdf). Br Med J. 2 (5712): 762-4.
- Watanabe S; Ohta H, Sakurai Y, Takao K, Ueki S. (Jul 1986). "[Electroencephalographic effects of 450191-S and its metabolites in rabbits with chronic electrode implants]". Nippon Yakurigaku Zasshi. 88 (1): 19-32. PMID 3758874.
- Noguchi H; Kitazumi K, Mori M, Shiba T. (Mar 2004). "Electroencephalographic properties of zaleplon, a non-benzodiazepine sedative/hypnotic, in rats." (pdf). J Pharmacol Sci. 94 (3): 246-51. doi:10.1254/jphs.94.246. PMID 15037809.
- Tokola RA; Neuvonen PJ (1983). "Pharmacokinetics of antiepileptic drugs". Acta neurologica Scandinavica. Supplementum 97: 17-27. PMID 6143468.
- Hertz MM; Paulson OB. (May 1980). "Heterogeneity of cerebral capillary flow in man and its consequences for estimation of blood-brain barrier permeability.". J Clin Invest. 65 (5): 1145-51. doi:10.1172/JCI109769. PMID 6988458.
- Kangas L; Kanto J, Syvälahti E. (Jul 1977). "Plasma nitrazepam concentrations after an acute intake and their correlation to sedation and serum growth hormone levels.". Acta Pharmacol Toxicol (Copenh). 41 (1): 65-73. PMID 331868.
- Kangas L; Kanto J, Siirtola T, Pekkarinen A. (Jul 1977). "Cerebrospinal-fluid concentrations of nitrazepam in man.". Acta Pharmacol Toxicol (Copenh). 41 (1): 74-9. PMID 578380.
- Kangas L; Iisalo E, Kanto J, Lehtinen V, Pynnönen S, Ruikka I, Salminen J, Sillanpää M, Syvälahti E. (Apr 1979). "Human pharmacokinetics of nitrazepam: effect of age and diseases.". Human pharmacokinetics of nitrazepam: effect of age and diseases. 15 (3): 163-70. PMID 456400.
- Vozeh S. (21). "[Pharmacokinetic of benzodiazepines in old age]". Schweiz Med Wochenschr. 111 (47): 1789-93. PMID 6118950.
- Holm V; Melander A, Wåhlin-Boll E. (1982). "Influence of food and of age on nitrazepam kinetics.". Drug-nutrient interactions. 1 (4): 307-11. PMID 6926838.
- Isojärvi, JI; Tokola RA. (Dec 1998). "Benzodiazepines in the treatment of epilepsy in people with intellectual disability.". J Intellect Disabil Res. 42 (1): 80-92. PMID 10030438.
- Djurić M; Marjanović B, Zamurović D. (May-Jun 2001). "[West syndrome--new therapeutic approach]". Srp Arh Celok Lek. 129 (1): 72-7. PMID 15637997.
- Mant A; Whicker SD, McManus P, Birkett DJ, Edmonds D, Dumbrell D. (Dec 1993). "Benzodiazepine utilisation in Australia: report from a new pharmacoepidemiological database.". Aust J Public Health. 17 (4): 345-9. PMID 7911332.
- Jacobson GA; Friesen WT, Peterson GM, Rumble RH, Polack AE. (6). "Psychoactive drug prescribing in the Tasmanian community.". Med J Aust. 157 (1): 20-4. PMID 1353603.
- Kayed K. (30). "[Insomnia and hypnotics]". Tidsskr Nor Laegeforen. 115 (9): 1087-90. PMID 7725291.
- Morgan K; Gilleard CJ, Reive A. (Nov 1982). "Hypnotic usage in residential homes for the elderly: a prevalence and longitudinal analysis.". Age Ageing. 11 (4): 229-34. doi:10.1093/ageing/11.4.229. PMID 7180725.
- Szczawińska K; Cenajek-Musiał D, Nowakowska E, Chodera A. (16). "Decrease in [3H]flunitrazepam receptor binding in rats tolerant to the effects of nitrazepam." 147 (1): 7-11. PMID 2836221.
- Chodera A; Szczawińska K, Cenajek D, Nowakowska E. (Jul-Aug 1984). "Pharmacokinetic aspects of habituation to benzodiazepines.". Pol J Pharmacol Pharm. 36 (4): 353-60. PMID 6152051.
- Nowakowska E; Chodera A, Szczawińska K, Cenajek D. (May-Jun 1983). "Development of tolerance to benzodiazepines. I. Changes in the systems of central nervous system neurotransmitters during long-term administration of nitrazepam." 34 (3): 345-51. PMID 6202092.
- Griffiths AN; Tedeschi G, Richens A. (1986). "The effects of repeated doses of temazepam and nitrazepam on several measures of human performance.". Acta Psychiatrica Scandinavica. Supplementum. 332: 119-26. PMID 2883819.
- Cook PJ; Huggett A, Graham-Pole R, Savage IT, James IM. (8). "Hypnotic accumulation and hangover in elderly inpatients: a controlled double-blind study of temazepam and nitrazepam." (pdf). Br Med J (Clin Res Ed). 286 (6359): 100-2.. PMID 6129914.
- Garratt JC; Gent JP, Feely M, Haigh JR. (5). "Can benzodiazepines be classified by characterising their anticonvulsant tolerance-inducing potential?". Eur J Pharmacol. 145 (1): 75-80. doi:10.1016/0014-2999(88)90351-2. PMID 2894998.
- Loiseau P (1983). "[Benzodiazepines in the treatment of epilepsy]". Encephale 9 (4 Suppl 2): 287B-292B. PMID 6373234.
- Darcy L (19). "Delirium tremens following withdrawal of nitrazepam". Med J Aust 2 (8): 450. PMID 5086307.
- Berezak A; Weber M, Hansmann J, Tulasne PA, Laporte B, Ould Ouali A (1984). "[Physical dependence on benzodiazepines in traumatology]". Ann Fr Anesth Reanim 3 (5): 383-4. PMID 6149713.
- MacKinnon GL; Parker WA. (1982). "Benzodiazepine withdrawal syndrome: a literature review and evaluation.". The American journal of drug and alcohol abuse. 9 (1): 19-33. doi:10.3109/00952998209002608. PMID 6133446.
- Kales A; Scharf MB, Kales JD, Soldatos CR. (20). "Rebound insomnia. A potential hazard following withdrawal of certain benzodiazepines.". JAMA : the journal of the American Medical Association. 241 (16): 1692-5. doi:10.1001/jama.241.16.1692. PMID 430730.
- Hecker R; Burr M, Newbury G. (1992). "Risk of benzodiazepine dependence resulting from hospital admission.". Drug Alcohol Rev. 11 (2): 131-5. doi:10.1080/09595239200185601. PMID 16840267.
- Hindmarch I. (Nov 1977). "A repeated dose comparison of three benzodiazepine derivative (nitrazepam, flurazepam and flunitrazepam) on subjective appraisals of sleep and measures of psychomotor performance the morning following night-time medication.". Acta Psychiatrica Scandinavica 56 (5): 373-81. PMID 22990.
- Viukari M; Linnoila M, Aalto U. (Jan 1978). "Efficacy and side effects of flurazepam, fosazepam, and nitrazepam as sleeping aids in psychogeriatric patients.". Acta Psychiatrica Scandinavica 57 (1): 27-35. PMID 24980.
- Nowakowska E; Chodera A, Cenajek-Musiał D, Szczawińska K. (May-Jun 1987). "Differences in the development of tolerance to various benzodiazepines.". Pol J Pharmacol Pharm. 39 (3): 245-52. PMID 2894019.
- Terao T; Tani Y. (1). "[Two cases of psychotic state following normal-dose benzodiazepine withdrawal]". J UOEH. 10 (3): 337-40. PMID 2902678.
- Tagashira E; Hiramori T, Urano T, Nakao K, Yanaura S. (Oct 1981). "Enhancement of drug withdrawal convulsion by combinations of phenobarbital and antipsychotic agents.". Jpn J Pharmacol. 31 (5): 689-99. doi:10.1254/jjp.31.689. PMID 6118452.
- Terao T; Yoshimura R, Terao M, Abe K. (15). "Depersonalization following nitrazepam withdrawal.". Biol Psychiatry. 31 (2): 212-3. PMID 1737083.
- Kersten B; Kasper P, Brendler-Schwaab SY, Müller L. (26). "Use of the photo-micronucleus assay in Chinese hamster V79 cells to study photochemical genotoxicity.". Mutation Research. 519 (1-2): 49-66. PMID 12160891.
- Giri AK; Banerjee S. (Jun 1996). "Genetic toxicology of four commonly used benzodiazepines: a review.". Mutation Research. 340 (2-3): 93-108. PMID 8692185.
- Ban Y; Naya M, Nishimura T, Kaneto M, Kishi K, Inoue T, Yoshizaki H, Ooshima Y. (Feb 2001). "Collaborative study on rat sperm motion analysis using CellSoft Series 4000 semen analyzer." (pdf). J Toxicol Sci. 26 (1): 9-24. doi:10.2131/jts.26.9. PMID 11255794.
- Kishi K; Kanamori S, Maruyama T, Sasaki K, Hara K, Kawai M, Ikeuchi K. (Aug 1995). "Potential parameters of male reproductive toxicity: reproductive performance, histopathology and sperm evaluation in SD rats given nitrazepam.". J Toxicol Sci. 20 (3): 329-39. PMID 8667457.
- Kaneto M; Kanamori S, Hara K, Kishi K. (1999). "Characterization of epididymal sperm motion and its correlation with stages of target cells in rats given alpha-chlorohydrin, cyclophosphamide or nitrazepam.". The Journal of toxicological sciences. 24 (3): 187-97. PMID 10478333.
- Sanbuissho A; Terada S, Suzuki K, Masuda N, Teranishi M, Masuda H. (Aug 1995). "Male reproductive toxicity study of nitrazepam in rats.". J Toxicol Sci. 20 (3): 319-28. PMID 8667456.
- Kar RN; Das RK. (1983). "Induction of sperm head abnormalities in mice by three tranquilizers.". Cytobios. 36 (141): 45-51. PMID 6132780.
- (22) "Effects of psychotropic drugs on aldo-keto reductase activity in rat ovary and adrenal gland". Biochem Pharmacol biochemistry 52 (10): 1585-91. PMID 8937474.
- Saito H; Kobayashi H, Takeno S, Sakai T. (1984). "Fetal toxicity of benzodiazepines in rats.". Res Commun Chem Pathol Pharmacol. 46 (3): 437-47. PMID 6151222.
- Takeno S; Hirano Y, Kitamura A, Sakai T. (Aug 1993). "Comparative developmental toxicity and metabolism of nitrazepam in rats and mice.". Toxicol Appl Pharmacol. 121 (2): 233-8. doi:10.1006/taap.1993.1150. PMID 8346540.
- Takeno S; Nakagawa M, Sakai T. (Jul 1990). "Teratogenic effects of nitrazepam in rats.". Res Commun Chem Pathol Pharmacol. 69 (1): 59-70. PMID 2218071.
- Saito H; Kobayashi H, Takeno S, Sakai T, Ishii H (Jun 1986). "In vivo and in vitro studies on fetal toxicity of benzodiazepines in rats". Res Commun Chem Pathol Pharmacol 52 (3): 295-304. PMID 2874598.
- Takeno S; Sakai T. (Aug 1991). "Involvement of the intestinal microflora in nitrazepam-induced teratogenicity in rats and its relationship to nitroreduction.". Teratology. 44 (2): 209-14. doi:10.1002/tera.1420440209. PMID 1925980.
- Mansbach CM 2nd; Rosen GM, Rahn CA, Strauss KE. (29). "Detection of free radicals as a consequence of rat intestinal cellular drug metabolism.". Biochim Biophys Acta. 888 (1): 1-9. PMID 3017439.
- Kripke DF (15). "Who should sponsor sleep disorders pharmaceutical trials?". J Clin Sleep Med 3 (7): 671-3. PMID 18198797. “major hypnotic trials is needed to more carefully study potential adverse effects of hypnotics such as daytime impairment, infection, cancer, and death and the resultant balance of benefits and risks.”
- Lechin F; van der Dijs B, Vitelli-Flores G, Báez S, Lechin ME, Lechin AE, Orozco B, Rada I, León G, Jiménez V (Feb 1994). "Peripheral blood immunological parameters in long-term benzodiazepine users". Clin Neuropharmacol 17 (1): 63-72. PMID 7908607.
- Harlow BL; Cramer DW (Mar 1995). "Self-reported use of antidepressants or benzodiazepine tranquilizers and risk of epithelial ovarian cancer: evidence from two combined case-control studies (Massachusetts, United States)". Cancer Causes Control 6 (2): 130-4. doi:10.1007/BF00052773. PMID 7749052.
- Kripke, Daniel F (2008). "Evidence That New Hypnotics Cause Cancer" (PDF). Department of Psychiatry, UCSD. University of California. “the likelihood of cancer causation is sufficiently strong now that physicians and patients should be warned that hypnotics possibly place patients at higher risk for cancer.”
- Rintahaka PJ; Nakagawa JA, Shewmon DA, Kyyronen P, Shields WD. (Apr 1999). "Incidence of death in patients with intractable epilepsy during nitrazepam treatment.". Epilepsia. 40 (4): 492-6. doi:10.1111/j.1528-1157.1999.tb00746.x. PMID 10219277.
- Lim HC; Nigro MA, Beierwaltes P, Tolia V, Wishnow R. (Sep 1992). "Nitrazepam-induced cricopharyngeal dysphagia, abnormal esophageal peristalsis and associated bronchospasm: probable cause of nitrazepam-related sudden death." 14 (5): 309-14. PMID 1456385.
- Zevzikovas A; Kiliuviene G, Ivanauskas L, Dirse V. (2002). "[Analysis of benzodiazepine derivative mixture by gas-liquid chromatography]". Medicina (Kaunas). 38 (3): 316-20. PMID 12474705.
- Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
- Garretty DJ; Wolff K, Hay AW, Raistrick D. (Jan 1997). "Benzodiazepine misuse by drug addicts.". Annals of clinical biochemistry. 34 (Pt 1): 68-73. PMID 9022890.
- Chatterjee A; Uprety L, Chapagain M, Kafle K. (1996). "Drug abuse in Nepal: a rapid assessment study.". Bull Narc. 48 (1-2): 11-33..
- Thiébot MH; Le Bihan C, Soubrié P, Simon P. (1985). "Benzodiazepines reduce the tolerance to reward delay in rats.". Psychopharmacology (Berl). 86 (1-2): 147-52. doi:10.1007/BF00431700. PMID 2862657.
- Bergman U; Dahl-Puustinen ML. (1989). "Use of prescription forgeries in a drug abuse surveillance network.". Eur J Clin Pharmacol. 36 (6): 621-3. doi:10.1007/BF00637747. PMID 2776820.
- Jones AW; Holmgren A, Kugelberg FC. (Apr 2007). "Concentrations of scheduled prescription drugs in blood of impaired drivers: considerations for interpreting the results.". Ther Drug Monit. 29 (2): 248-60. doi:10.1097/FTD.0b013e31803d3c04. PMID 17417081.
- Cosbey SH. (Dec 1986). "Drugs and the impaired driver in Northern Ireland: an analytical survey.". Forensic Sci Int. 32 (4): 245-58. doi:10.1016/0379-0738(86)90201-X. PMID 3804143.
- Sanders LD; Yeomans WA, Rees J, Rosen M, Robinson JO. (Nov 1988). "A double-blind comparison between nitrazepam, lorazepam, lormetazepam and placebo as preoperative night sedatives.". Eur J Anaesthesiol. 5 (6): 377-83. PMID 2907315.
- Liljequist R; Mattila MJ. (May 1979). "Acute effects of temazepam and nitrazepam on psychomotor skills and memory.". Acta Pharmacol Toxicol (Copenh). 44 (5): 364-9. PMID 38627.
- Nabeshima T; Tohyama K, Ichihara K, Kameyama T. (Nov 1990). "Effects of benzodiazepines on passive avoidance response and latent learning in mice: relationship to benzodiazepine receptors and the cholinergic neuronal system.". J Pharmacol Exp Ther. 255 (2): 789-94. PMID 2173758.
- Antkiewicz-Michaluk, L; Grabowska M, Baran L, Michaluk J. (1975). "Influence of benzodiazepines on turnover of serotonin in cerebral structures in normal and aggressive rats.". Arch Immunol Ther Exp (Warsz). 23(6): 763-7. PMID 1241268.
- Vermeeren A. (2004). "Residual effects of hypnotics: epidemiology and clinical implications.". CNS Drugs. 18 (5): 297-328. PMID 15089115.
- Richens A; Mercer AJ, Jones DM, Griffiths A, Marshall RW. (Jul 1993). "Effects of zolpidem on saccadic eye movements and psychomotor performance: a double-blind, placebo controlled study in healthy volunteers.". British journal of clinical pharmacology. 36 (1): 61-5. PMID 8373713.
- Morgan K. (1985). "Effects of repeated dose nitrazepam and lormetazepam on psychomotor performance in the elderly.". Psychopharmacology (Berl). 86 (1-2): 209-11. PMID 3927357.
- Morgan K. (1984). "Effects of two benzodiazepines on the speed and accuracy of perceptual-motor performance in the elderly.". Psychopharmacology Suppl. 1: 79-83. PMID 6147843.
- Hossmann V; Maling TJ, Hamilton CA, Reid JL, Dollery CT. (Aug 1980). "Sedative and cardiovascular effects of clonidine and nitrazepam.". Clin Pharmacol Ther. 28 (2): 167-76. PMID 7398184.
- Impallomeni M; Ezzat R. (24). "Letter: Hypothermia associated with nitrazepam administration.". Br Med J. 1 (6003): 223-4. PMID 1247796.
- MacLean H. (24). "Nitrazepam: another interesting syndrome." (pdf). Br Med J. 1 (5851): 488.
- Luurila H; Olkkola KT, Neuvonen PJ. (Apr 1995). "Interaction between erythromycin and nitrazepam in healthy volunteers.". Pharmacol Toxicol. 76 (4): 255-8. PMID 7617555.
- Tokinaga N; Kondo T, Kaneko S, Otani K, Mihara K, Morita S. (Dec 1996). "Hallucinations after a therapeutic dose of benzodiazepine hypnotics with co-administration of erythromycin." 50 (6): 337-9. PMID 9014234.
- Back DJ; Orme ML. (Jun 1990). "Pharmacokinetic drug interactions with oral contraceptives.". Clin Pharmacokinet. 18 (6): 472-84. PMID 2191822.
- Brockmeyer NH; Mertins L, Klimek K, Goos M, Ohnhaus EE. (Sep 1990). "Comparative effects of rifampin and/or probenecid on the pharmacokinetics of temazepam and nitrazepam.". Int J Clin Pharmacol Ther Toxicol. 28 (9): 387-93. PMID 2228325.
- Ochs HR; Greenblatt DJ, Gugler R, Müntefering G, Locniskar A, Abernethy DR. (Aug 1983). "Cimetidine impairs nitrazepam clearance.". Clin Pharmacol Ther. 34 (2): 227-30. PMID 6872417.
- Zácková P; Kvĕtina J, Nĕmec J, Nĕmcová J. (Dec 1982). "Cardiovascular effects of diazepam and nitrazepam in combination with ethanol.". Pharmazie. 37 (12): 853-6. PMID 7163374.
- Pacifici GM; Gustafsson LL, Säwe J, Rane A. (Apr 1986). "Metabolic interaction between morphine and various benzodiazepines.". Acta Pharmacol Toxicol (Copenh). 58 (4): 249-52. PMID 2872767.
- Lahtinen U; Lahtinen A, Pekkola P. (Feb 1978). "The effect of nitrazepam on manual skill, grip strength, and reaction time with special reference to subjective evaluation of effects on sleep.". Acta Pharmacol Toxicol (Copenh). 42 (2): 130-4. PMID 343500.
- Kozená L; Frantik E, Horváth M. (May 1995). "Vigilance impairment after a single dose of benzodiazepines.". Psychopharmacology (Berl). 119 (1): 39-45. PMID 7675948.
- Törnros J; Laurell H. (Jul 1990). "Acute and carry-over effects of brotizolam compared to nitrazepam and placebo in monotonous simulated driving.". Pharmacol Toxicol. 67 (1): 77-80. PMID 2395820.
- Hindmarch I; Parrott AC. (1980). "The effects of combined sedative and anxiolytic preparations on subjective aspects of sleep and objective measures of arousal and performance the morning following nocturnal medication. I: Acute doses.". Arzneimittelforschung. 30 (6): 1025-8. PMID 6106498.
- Shats V; Kozacov S. (1). "[Falls in the geriatric department: responsibility of the care-giver and the hospital]". Harefuah 128 (11): 690-3. PMID 7557666.
- Borland RG; Nicholson AN. (Feb 1975). "Comparison of the residual effects of two benzodiazepines (nitrazepam and flurazepam hydrochloride) and pentobarbitone sodium on human performance.". Br J Clin Pharmacol. 2 (1): 9-17. PMID 10941.
- Evans JG; Jarvis EH. (25). "Nitrazepam and the elderly." (pdf). Br Med J. 4 (5838): 487.
- Trewin VF; Lawrence CJ, Veitch GB. (Apr 1992). "An investigation of the association of benzodiazepines and other hypnotics with the incidence of falls in the elderly.". J Clin Pharm Ther. 17 (2): 129-33. PMID 1349894.
- Greenblatt DJ; Allen MD. (May 1978). "Toxicity of nitrazepam in the elderly: a report from the Boston Collaborative Drug Surveillance Program.". British journal of clinical pharmacology. 5 (5): 407-13. PMID 656280.
- Castleden CM; George CF, Marcer D, Hallett C. (1). "Increased sensitivity to nitrazepam in old age." (pdf). Br Med J. 1 (6052): 10-2.
- Dennis J; Hunt A. (14). "Prolonged use of nitrazepam for epilepsy in children with tuberous sclerosis." (pdf). Br Med J (Clin Res Ed). 291 (6497): 692-3. PMID 3929902.
- Kenny RA; Kafetz K, Cox M, Timmers J, Impallomeni M. (Apr 1984). "Impaired nitrazepam metabolism in hypothyroidism.". Postgrad Med J. 60 (702): 296-7. PMID 6728755.
- Olive G; Dreux C. (Jan 1977). "Pharmacologic bases of use of benzodiazepines in peréinatal medicine.". Arch Fr Pediatr. 34 (1): 74-89.. PMID 851373.
- Kangas L; Kanto J, Erkkola R. (16). "Transfer of nitrazepam across the human placenta.". Eur J Clin Pharmacol. 12 (5): 355-7. doi:10.1007/BF00562451. PMID 598407.
- Kanto JH. (May 1982). "Use of benzodiazepines during pregnancy, labour and lactation, with particular reference to pharmacokinetic considerations.". Drugs. 23 (5): 354-80. doi:10.2165/00003495-198223050-00002. PMID 6124415.
- McElhatton PR. (Nov-Dec 1994). "The effects of benzodiazepine use during pregnancy and lactation.". Reprod Toxicol. 8 (6): 461-75. doi:10.1016/0890-6238(94)90029-9. PMID 7881198.
- Midgren B; Hansson L, Ahlmann S, Elmqvist D. (1990). "Effects of single doses of propiomazine, a phenothiazine hypnotic, on sleep and oxygenation in patients with stable chronic obstructive pulmonary disease.". Respiration. 57 (4): 239-42. PMID 1982774.
- O'Hanlon JF; Volkerts ER. (1986). "Hypnotics and actual driving performance.". Acta Psychiatrica Scandinavica Suppl. 332: 95-104. PMID 3554901.
- Lai SH; Yao YJ, Lo DS. (Oct 2006). "A survey of buprenorphine related deaths in Singapore.". Forensic Sci Int. 162 (1-3): 80-6. doi:10.1016/j.forsciint.2006.03.037. PMID 16879940.
- Rumpl E; Prugger M, Battista HJ, Badry F, Gerstenbrand F, Dienstl F. (Dec 1988). "Short latency somatosensory evoked potentials and brain-stem auditory evoked potentials in coma due to CNS depressant drug poisoning. Preliminary observations." 70 (6): 482-9. PMID 2461282.
- Carlsten, A; Waern M, Holmgren P, Allebeck P. (2003). "The role of benzodiazepines in elderly suicides.". Scand J Public Health. 31 (3): 224-8. PMID 12850977.
- Moriya F; Hashimoto Y. (28). "Tissue distribution of nitrazepam and 7-aminonitrazepam in a case of nitrazepam intoxication.". Forensic Sci Int. 131 (2-3): 108-12. doi:10.1016/S0379-0738(02)00421-8. PMID 12590048.
- Ericsson HR; Holmgren P, Jakobsson SW, Lafolie P, De Rees B. (10). "[Benzodiazepine findings in autopsy material. A study shows interacting factors in fatal cases]". Läkartidningen. 90 (45): 3954-7. PMID 8231567.
- Drummer OH; Ranson DL. (Dec 1996). "Sudden death and benzodiazepines.". Am J Forensic Med Pathol. 17 (4): 336-42. doi:10.1097/00000433-199612000-00012. PMID 8947361.
- Brødsgaard I; Hansen AC, Vesterby A. (Jun 1995). "Two cases of lethal nitrazepam poisoning.". Am J Forensic Med Pathol. 16 (2): 151-3. PMID 7572872.