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Nitrazepam

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Nitrazepam chemical structure
Nitrazepam

9-nitro-6-phenyl-2,5-diazabicyclo[5.4.0]undeca-
5,8,10,12-tetraen-3-one
IUPAC name
CAS number
146-22-5
ATC code

N05CD02

PubChem
4506
DrugBank
none
Chemical formula {{{chemical_formula}}}
Molecular weight 281.3 g/mol
Bioavailability 53-94%
Metabolism Hepatic
Elimination half-life 16-38 hours
Excretion Renal
Pregnancy category
Legal status Schedule IV (International)
Routes of administration Oral
File:Image047.jpg

Nitrazepam (marketed under the trade names Mogadon, Alodorm, Hypnotex, Remnos, Pacisyn, Eunoctin and Pelson) is a type of benzodiazepine drug. It is a powerful hypnotic drug which possesses strong sedative and motor impairing properties.[1] Nitrazepam also has anxiolytic, amnestic, anticonvulsant, and skeletal muscle relaxant properties.

Nitrazepam is most often used to treat short-term sleeping problems (insomnia). Insomnia can be described as a difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Nitrazepam is a long acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep. Intermediate half life benzodiazepines are also useful for patients with difficulty in maintaining sleep eg loprazolam, lormetazepam, temazepam. Hypnotics should only be used on a short term basis or in those with chronic insomnia on an occasional basis.[2] Nitrazepam shortens the time required to fall asleep and lengthens the duration of sleep. It is also useful for the management of myoclonic seizures.

Nitrazepam is available in 5mg and 10mg tablets. In Australia, Israel and the United Kingdom it is only available in 5mg tablets.

Pharmacology

Nitrazepam is categorised as a nitrobenzodiazepine. Other nitrobenzodiazepines include flunitrazepam and clonazepam. Nitrobenzodiazepines are metabolised to a 7-amino-metabolite.[3] Nitrazepam is classed as a 1,4 benzodiazepine, with the chemical name 1,3-Dihydro-7-nitro-5-phenyl-2H-1,4- -benzodiazepin-2-one.

It is a long acting benzodiazepine, is lipophilic and is metabolised hepatically via oxidative pathways. The main pharmacological effects of nitrazepam are the enhancement of GABA at the GABAA receptor.[4] It is a full agonist of the benzodiazepine receptor.[5] An opioid mechanism of action may play a role in some of the pharmacological properties of nitrazepam.[6] Nitrazepam causes a decrease in the cerebral contents of the amino acids glycine and aspartic acid. The decrease may be due to activation of benzodiazepine receptors.[7] At high doses decreases in histamine turnover occur as a result of nitrazepam's action at the benzodiazepine-GABA receptor complex.[8] Nitrazepam possesses antipruritic properties. The antipruritic properties of nitrazepam are believed to be due to a central mechanism of action rather than a peripheral mechanism of action.[9] Nitrazepam has demonstrated cortisol suppressing properties.[10] Nitrazepam is structurally related to quinazolines and is a hapten.[11]

Nitrazepam and other benzodiazepines may influence neurosteroid metabolism and progesterone levels which in turn may influence the functions of the brain and reproductive system. Nitrazepam and medazepam were found to have the strongest effects on neurosteroids and progesterone. The pharmacological actions of benzodiazepines at the GABAa receptor are similar to those of neurosteroids. Neuroactive steroids are positive allosteric modulators of the GABAa receptor, enhancing GABA function. Many benzodiazepines (diazepam, medazepam, estazolam, temazepam, flunitrazepam and nitrazepam) potently inhibit the enzymes involved in the metabolism of neurosteroids. Long-term administration of benzodiazepines may influence the concentrations of endogenous neurosteroids, and thereby would modulate the emotional state. Factors which effects the ability of individual benzodiazepines to alter neurosteroid levels depend on the molecular make up of the individual benzodiazepine drug. Presence of a substituent at N1 position of the diazepine ring and/or the chloro or nitro group at position 7 of the benzene ring contribute to potent inhibition of the isoenzymes, and in turn a bromo group at position 7 (for bromazepam) and additional substituents (3-hydroxy group for oxazepam and tetrahydroxazole ring for cloxazolam and oxazolam) decrease the inhibitory potency of benzodiazepines on neurosteroids.[12] Nitrazepam also induces melanogenesis in melanoma cells via modulating cell differentiation.[13]

EEG and sleep

In sleep laboratory studies, nitrazepam decreased sleep latency. However, in a clinical study 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.[14]

Stage 2 NREM sleep is significantly increased by nitrazepam but SWS stage sleep is significantly decreased by nitrazepam.[15] 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.[16] Nitrazepam is reported to significantly affect stages of sleep: a decrease stage 1, 3 and 4 sleep and to increase stage 2.[17] 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.[18] 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.[19] 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.[20] 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.[21]

Nitrazepam produces a decrease in delta activity and an increase in the total non-REM sleep time and a decrease in delta activity during non-REM sleep. The effect of benzodiazepine drugs on delta however may not be mediated via benzodiazepine receptors. Delta activity is an indicator of depth of sleep within non-REM sleep. Delta activity is thought to reflect sleep quality with lower levels of delta sleep reflecting poorer quality of sleep. Thus nitrazepam and other benzodiazepines cause a deterioration in sleep quality. Cyproheptadine may be superior to nitrazepam in the treatment of insomnia.[22]

Pharmacokinetics

Nitrazepam is largely bound to plasma proteins.[23] Benzodiazepines such as nitrazepam are lipid soluble and have a high cerebral uptake.[24] The time for nitrazepam to reach peak plasma concentrations following oral administration is about 2 hours (0.5 to 5 hours). Nitrazepam breaks down into a nitro benzophenone and quinolone compound.[25] 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.[26] 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.[27] 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.[28][29] 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.[30]

Mechanism of action

Nitrazepam belongs to a group of medicines called benzodiazepines. 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.[31] GABA is a major inhibitory neurotransmitter in the brain, involved in inducing sleepiness, muscular relaxation and control of anxiety and fits, and slows down the central nervous system. The mechanism of action of nitrazepam is the same as other benzodiazepine drugs and zopiclone.[32] 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.[33] The muscle relaxant properties of nitrazepam are produced via inhibition of polysynaptic pathways in the spinal cord.[34]

Uses

Nitrazepam possesses potent anti-epileptic properties and has been used in the management of seizure disorders in children and also for infantile spasms. Clonazepam has also been used for the same indications. However, the usefulness of nitrazepam and clonazepam is limited due to their deliterious effect on neurological function, especially their negative effect on cognition. Clobazam a 1,5-benzodiazepine has shown to be less neurotoxic than 1,4-benzodiazepines such as nitrazepam and clonazepam.[35][36]

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.[37] 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.[38]

Utilisation

Nitrazepam along with diazepam, oxazepam and temazepam represent 82% of the benzodiazepine market in Australia.[39] The rate of benzodiazepine prescribing in Tasmania is higher than in Australia. Nitrazepam and flunitrazepam prescribing levels in Tasmania are disturbingly high.[40] Prescribing of hypnotics in Norway is quite restrictive with only 3 hypnotics which are prescribable; nitrazepam, flunitrazepam and zopiclone.[41] The usage of benzodiazepine hypnotics in local authority homes for the elderly established via a clinical survey 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.[42]

Dosage

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.

Nitrazepam is chemically similar to Nimetazepam, with 10mg approximately equating to a 5mg dosage respectively.[1]

Tolerance

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.[43] When tolerance and habituation occurs to nitrazepam its pharmacokinteic profile changes with absorption of the drug slowing down, elimination time increasing and brain concentration of nitrazepam increasing significantly.[44] Increased levels of GABA in cerebral tissue and alterations in the activity state of the serotoninergic system occurs as a result of nitrazepam tolerance.[45]

Although tolerance to the sleep inducing properties of nitrazepam develops within a matter of days so to does tolerance to the residual performance impairment. After 6 days of use tolerance to nitrazepam's sleep inducing effects and performance impairing effects occurs.[46] One study demonstrated tolerance to the sleep promoting effects of nitrazepam and temazepam after 7 days nightly administration. Quality of sleep was found to be increased after the first nights administration of either nitrazepam or temazepam but by day 7 quality of sleep was found to have returned to baseline suggesting the development of complete tolerance after 7 days use.[47] In mice tolerance to the anticonvulsant properties of nitrazepam developed profoundly and rapidly over 6 days, although some anticonvulsant effects were still apparent after 6 days administration.[48] In humans tolerance to the anticonvulsant effects of nitrazepam is a frequent occurance.[49]

Nitrazepam shares cross tolerance with barbiturates. Barbiturates can easily be substituted for nitrazepam in those who are habituated to barbiturate sedative hypnotics.[50]

Dependence

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. 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.[51]

Frequent use of nitrazepam may cause dependence and when the drug is reduced or stopped, withdrawal symptoms. Withdrawal symptoms including a worsening of insomnia compared to baseline typically occurs after discontinuation of nitrazepam even after short term single nightly dose therapy.[52] 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.[53]

After discontinuation of nitrazepam a rebound effect may occur about 4 days after stopping medication.[54] 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.[55] Tolerance to the anticonvulsant and anxiolytic effects also develops rapidly during daily administration.[56]

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.[57] Antipsychotics increase the severity of benzodiazepine withdrawal effects with an increase in the intensity and severity of convulsions.[58] Depersonalisation has also been reported as a benzodiazepine withdrawal effect from nitrazepam.[59]

Abrupt withdrawal from very high doses is even more likely to cause severe withdrawal effects. Withdrawal from very high doses of nitrazepam may cause severe hypoperfusion of the whole brain with diffuse slow activity on EEG. After withdrawal, abnormalities in hypofrontal brain wave patterns may persist beyond the withdrawal syndrome suggesting that organic brain damage may occur from chronic high dose abuse of benzodiazepines.[60]

The Committee on the Review of Medicines

The Committee on the Review of Medicines (UK) carried out a review into benzodiazepines due to significant concerns of tolerance, drug dependence and benzodiazepine withdrawal problems and other adverse effects. The committee found that benzodiazepines do not have any antidepressant or analgesic properties and are therefore unsuitable treatments for conditions such as depression, tension headaches and dysmenorrhoea. Benzodiazepines are also not beneficial in the treatment of psychosis due to a lack of efficacy. The committee also recommended against benzodiazepines being used in the treatment of anxiety or insomnia in children. The committee was in agreement with the Institute of Medicine (USA) and the conclusions of a study carried out by the White House Office of Drug Policy and the National Institute on Drug Abuse (USA) that there was little evidence that long term use of benzodiazepine hypnotics were benefitial in the treatment of insomnia due to the development of tolerance. Benzodiazepines tended to lose their sleep promoting properties within 3 - 14 days of continuous use and in the treatment of anxiety the committee found that there was little convincing evidence that benzodiazepines retained efficacy in the treatment of anxiety after 4 months continuous use due to the development of tolerance. The committee found that the regular use of benzodiazepines caused the development of dependence characterised by tolerance to the therapeutic effects of benzodiazepines and the development of the benzodiazepine withdrawal syndrome including symptoms such as anxiety, apprehension, tremor, insomnia, nausea, and vomiting upon cessation of benzodiazepine use. Withdrawal symptoms tended to develop within 24 hours on the cessation of a short acting benzodiazepine and within 3 - 10 days after the cessation of a more long acting benzodiazepine. Withdrawal effects could occur after treatment lasting only 2 weeks at therapeutic dose levels. However, withdrawal effects tended to occur with habitual use beyond 2 weeks and were more likely the higher the dose. The withdrawal symptoms may appear to be similar to the original condition. The committee recommended that all benzodiazepine treatment be withdrawn gradually and recommended that benzodiazepine treatment be used only in carefully selected patients and that therapy be limited to short term use only. It was also noted in the review that alcohol can potentiate the central nervous system depressant effects of benzodiazepines and should be avoided. The central nervous system depressant effects of benzodiazepines may make driving or operating machinery dangerous. The elderly are more prone to these adverse effects. In the neonate high single doses or repeated low doses have been reported to produce hypotonia, poor sucking, and hypothermia and irregularities in the fetal heart. Benzodiazepines should be avoided in lactation. Withdrawal from benzodiazepines should be gradual as abrupt withdrawal from high doses of benzodiazepines may cause confusion, toxic psychosis, convulsions, or a condition resembling delirium tremens. Abrupt withdrawal from lower doses may cause depression, nervousness, rebound insomnia, irritability, sweating, and diarrhoea. In the case of nitrazepam it was recommended that nitrazepam only be used for the short term treatment of insomnia where day time sedation was acceptable.[61]

Toxicity

Aromatic nitro-containing compounds such as nitrazepam produce superoxide free radicals during cellular metabolism by endothelial cells.[62] Nitrazepam is much more toxic than other benzodiazepines probably due to its extensive nitro reduction to 7-aminonitrazepam free radical by intestinal microflora.[63] Nitrazepam a nitro-containing benzodiazepine is reduced by NADPH-cytochrome c (P-450) reductase to a nitro anion free radical and in the presence of oxygen, superoxide is generated. It was found that nitrazepam produced superoxide intracellularly but not extracellulary. Free radicals such as superoxide injure and degenerate the cell integrity of cells.[64] 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.[65] Superoxide is generated by the one electron reduction of nitrazepam to its corresponding nitro anion free radical during drug metabolism.[66]

Genotoxicity

Nitrazepam is carcinogenic and has been found to be both photogenotoxic and photocytotoxic.[67] Studies on animals have demonstrated teratogenic and also carcinogenic effects of nitrazepam and some other benzodiazepines and the wide spread use of these drugs world wide is of major concern for human health.[68]

Genotoxic drugs have the potential to cause genetic mutations, DNA damage and promote the development of cancer including tumors.[2]

Reproductive Toxicity

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.[69]

In studies of 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 high dose nitrazepam and after 4 weeks in the lower dosed rats.[70] Nitrazepam has also been shown at high doses to affect sperm motion in laboratory tests via causing lesions in spermatids.[71]

Nitrazepam has been shown in 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 moderate and high dose nitrazepam treated rats. Rats treated with high 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.[72] 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.[73]

In female rats nitrazepam has been shown to inhibit ovulation.[74]

Fetal Toxicity

In a rat study Nitrazepam showed much greater damage to the fetus, as did nimetazepam and temazepam than other benzodiazepines. 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.[75] 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.[76] 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.[77] Another fetal toxicity study in rats demonstrated that nitrazepam has embryocidal activity in vitro. Nitrazepam possesses both embryotoxicity and teratogenicity toxicities in vivo.[78]

Fatality

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 with intractable epilepsy.[79] Nitrazepam may cause sudden death. Nitrazepam therapy can cause swallowing incoordination, high-peaked esophageal peristalsis, bronchospasm, delayed cricopharyngeal relaxation and severe respiratory distress necessitating ventilatory support. Nitrazepam may promote the development of parasympathetic overactivity or vagotonia leading to potentially fatal respiratory distress.[80]

Abuse potential

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.[81][82] In Nepal, nitrazepam is a major drug of abuse as is codeine, heroin, buprenorphine and cannabis.[83]

Nitrazepam in animal studies has been shown to increase reward seeking which may suggest increased risk of addictive behavioural patterns.[84] Studies suggest that nitrazepam caused significant euphoria as against placebos and was identified as an active drug by the subjects. Nitrazepam resembled diazepam (Valium), however, on certain parameters the effects produced by nitrazepam were more pronounced. Nitrazepam was found to be an abusable drug and has similar abuse liability like diazepam, if not slightly higher. 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.[3][4]

Benzodiazepines, including diazepam, temazepam, 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.[85]

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.[86] In Northern Ireland in cases where drugs were found in tests on impaired drivers, benzodiazepines were found to be present in 87% of cases.[87]

Cognitive Behavioural Therapy

Nitrazepam, temazepam and zopiclone are the most frequently prescribed hypnotics in the United Kingdom. Hypnotic drugs are of poor value for the management of chronic insomnia. Hypnotic drug consumption has been shown to reduce work performance, increase absenteeism, increase road traffic accidents, increased morbidity, increase mortality and is associated with an increased incidence of deliberate self harm. In the elderly, increases in falls and fractures associated with sedative hypnotic drug use has been found. It is widely accepted that hypnotic drug usage beyond 4 weeks is undesirable for all age groups of patients. Many continuous hypnotic users exhibit disturbed sleep as a consequence of tolerance but experience worsening rebound or withdrawal insomnia when the dose is reduced too quickly which compounds the problem of chronic hypnotic drug use. Cognitive behavioural therapy has been found to be more effective for the long term management of insomnia than sedative hypnotic drugs. No formal withdrawal programs for benzodiazepines exists with local providers in the UK. Meta-analysis of published data on psychological treatments for insomnia show a success rate between 70 and 80%. A large scale trial utilising cognitive behavioural therapy in chronic users of sedative hypnotics including nitrazepam, temazepam and zopiclone found CBT to be a significantly more effective long term treatment for chronic insomnia than sedative hypnotic drugs. Persisting improvements in sleep quality, sleep latency, increased total sleep, improvements in sleep efficiency, significant improvements in vitality, physical and mental health at 3, 6 and 12 month follow up was found in those receiving cognitive behavioural therapy. A marked reduction in total sedative hypnotic drug use was found in those receiving CBT, with 33% reporting zero hypnotic drug use. Age has been found not to be a barrier to successful outcome of CBT. It was concluded that CBT for the management of chronic insomnia was flexible, practical and a cost effective treatment and it was also concluded that CBT leads to a reduction of benzodiazepine drug intake in a significant number of patients.[88]

Side Effects

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.[89] Increased reaction time, co-ordination problems and impaired learning and memory.[90]

Impaired learning and memory occurs due to the action of the drug on benzodiazepine receptors which causes a dysfunction in the cholinergic neuronal system.[91] 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.[92]

Nitrazepam is a long acting benzodiazepine with an elimination half life of 15-38 (mean elimination half life 26 hours).[5] 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.[93] 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.[94]

Impairment of psychomotor function may especially occur after repeated administration, with the elderly being more vulnerable to this adverse effect.[95] 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.[96]

Less Common Side Effects

Hypotension,[97] 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.[98] 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.[99]

Interactions

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.[100] 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.[101] Oral contraceptive pills, reduce the clearance of nitrazepam which may lead to increased plasma levels of nitrazepam and accumulation.[102] Rifampin increases the clearance of nitrazepam significantly and probenecid decreases the clearance of nitrazepam significantly.[103] Cimetidine slows down the elimination rate of nitrazepam leading to more prolonged effects of nitrazepam and increased risk of accumulation.[104] Alcohol (ethanol) in combination with nitrazepam may cause a synergistic enhancement of the hypotensive properties of both benzodiazepines and alcohol.[105] Benzodiazepines including nitrazepam may inhibit the glucuronidation of morphine leading to increased levels of and prolongation of the effects of morphine.[106]

Special precautions

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.[107] Nitrazepam in doses of 5 mg or more causes significant deterioration in vigilance performance combined with increased feelings of sleepiness.[108] Doses as low as 5 mg of nitrazepam can impair driving skills.[109] Therefore people driving or conducting activities which require vigilance should exercise caution in using nitrazepam or possibly avoid it all together.[110]

Caution in the elderly. Nitrazepam has been found to be dangerous in elderly patients due to a significant increased risk of falls.[111] This increased risk is probably due to the persisting drug effects of nitrazepam well into the next day.[112] 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.[113] Only nitrazepam and lorazepam were found to increase the risk of falls and fractures in the elderly.[114] CNS depression occurs much more frequently in the elderly and is especially common in doses above 5 mg of nitrazepam.[115] 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.[116]

Caution in children. Nitrazepam is not recommended for use in those under 18. Use in very young children may be especially danagerous. Nitrazepam was implicated, along with the drugs diphenylhydantoin and clonazepam, in the death of a 7 and a half month old girl. She developed inclusions consisting of lamellar profiles, situated in membrane-bound cytosomes which were found mainly in astrocytes, but also in neurones and in the axons of peripheral nerves before dying. Lipofuscin bodies were also found to be increased in number.[117] 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.[118]

Caution in hypotension. Caution in those suffering from hypotension, nitrazepam may worsen hypotension.[97]

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.[119]

Pregnancy

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.[120] 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.[121] 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.[122] 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.[123]

Contraindications

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.[124]

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.[125]

Overdose

Nitrazepam is a drug which is very frequently involved in drug intoxication, including overdose.[126] 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.[127] 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.[128]

Benzodiazepines were implicated in 39% of suicides by drug poisoning in Sweden, with nitrazepam, temazepam 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 temazepam, nitrazepam and flunitrazepam should therefore be prescribed with caution in the elderly.[129] 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.[130]

In a retrospective study of deaths, when benzodiazepines were implicated in the deaths, the benzodiazepines nitrazepam, temazepam, 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, temazepam, 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.[131] 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.[132]

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.[133]

Trade names

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.[6]

In Popular Culture

See also

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Further reading

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  • Ballinger, B. R., Presly, A., Reid, A. H., & Stevenson, I. H. (1974). The effects of hypnotics on imipramine treatment: Psychopharmacologia Vol 39(3) 1974, 267-274.
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  • Beyer, K. H., & Sadee, W. (1969). Spectrophotometric determination of 5-phenyl-1, 4-benzodiazepine derivatives and investigations on the metabolism of nitrazepam: Arzneimittel-Forschung Vol 19(12) Dec 1969, 1929-1931.
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