Lorazepam (also known by its brand name Ativan) is a benzodiazepine tranquilizer with short to medium duration of action. It has all five intrinsic benzodiazepine effects: anxiolytic, sedative/hypnotic, amnesic, anticonvulsant and muscle relaxant, to different extents. It is a unique benzodiazepine insofar as it has also found use as an adjunct antiemetic in chemotherapy. Since its introduction in 1971, lorazepam's principal use has been in treating the symptom of anxiety. One study concluded that, compared to other benzodiazepines, lorazepam has relatively high addictive potential.
Lorazepam has relatively potent anxiolytic effects and its best known indication is the short-term management of severe anxiety. It is less useful in panic disorder.
Lorazepam's sedative/hypnotic effects, and the duration of clinical effects from a single dose, make it an appropriate choice for the short term treatment of insomnia, particularly in the presence of severe anxiety.
Its relatively potent amnesic effect, with its anxiolytic and sedative effects, makes lorazepam useful as premedication. It is given before a general anaesthetic to reduce the amount of anaesthetic agent required, or before unpleasant awake procedures, such as dentistry or endoscopies, to reduce anxiety, increase compliance and produce varying degrees of amnesia for the procedure. Oral lorazepam is given 90 to 120 minutes before procedures and intravenous lorazepam as late as 10 minutes before procedures.
The marked anticonvulsant properties of lorazepam, and its pharmacokinetic profile, makes intravenous lorazepam a reliable agent for terminating acute seizures, but it has relatively prolonged sedation aftereffects. Oral lorazepam, and other benzodiazepines, have a role in long-term prophylactic treatment of resistant forms of petit mal epilepsy but not as first-line therapies, mainly because of the development of resistance to their effects.
Lorazepam's anticonvulsant, or CNS depressant, properties are useful for the prevention and treatment of alcohol withdrawal symptoms. In this setting it is relevant that impaired liver function is not a hazard with lorazepam since lorazepam does not require oxidation, hepatic or otherwise, for its metabolism.
Where there is need for rapid sedation of violent or agitated patients, including acute delirium, lorazepam may be used, but as it can cause paradoxical effects it is preferably given together with haloperidol. Lorazepam is absorbed relatively slowly if given intramuscularly, a common route in restraint situations.
Catatonia with inability to speak is responsive and sometimes controlled with a single 2 mg oral, or slow intravenous, dose of lorazepam. Symptoms may recur and treatment for some days may be necessary. Catatonia due to abrupt or too rapid withdrawal from benzodiazepines, as part of the benzodiazepine withdrawal syndrome, should also respond to lorazepam treatment. As lorazepam can have paradoxical effects, haloperidol is sometimes given concomitantly.
Pure lorazepam is an almost white powder that is nearly insoluble in water and oil. In medicinal form, lorazepam is mainly available as tablets and a solution for injection but in some locations it is also available as a skin patch, an oral solution and a sublingual tablet.
Lorazepam tablets and syrups are administered by mouth only. The tablets contain 0.5 mg, 1 mg, or 2 mg lorazepam, with some differences between countries. Lorazepam tablets of the Ativan brand also contain lactose, microcrystalline cellulose, polacrilin potassium, magnesium stearate and colouring agents (Blue tablets: indigo carmine, E132; Yellow tablets: tartrate, E102).
Lorazepam injectable solution is administered either by deep intramuscular injection or by intravenous injection. The injectable solution comes in 1 mL ampoules containing 2 mg or 4 mg lorazepam. The solvents used are polyethylene glycol 400 and propylene glycol. As a preservative, the injectable solution contains benzyl alcohol. Toxicity from propylene glycol has been reported in the case of a patient receiving a continuous lorazepam infusion. Intravenous injections should be given slowly and patients closely monitored for side-effects, such as respiratory depression, hypotension or loss of airway control.
Peak effects roughly coincide with peak serum levels, which occur ten minutes after intravenous injection, up to one hour after intramuscular injection and about 120 minutes after oral administration, but initial effects are noted before this. A clinically relevant lorazepam dose will normally be effective for 6 to 12 hours, making it unsuitable for regular once-daily administration; it is therefore usually prescribed as two to four daily doses when given regularly.
Lorazepam is a "classical" benzodiazepine, other classical benzodiazepines include; diazepam, clonazepam, oxazepam, nitrazepam, flurazepam, bromazepam and clorazepate. Lorazepam is an intermediate acting benzodiazepine and its uniqueness, advantages and disadvantages are largely explained by its pharmacokinetic properties (poor water and lipid solubility, high protein binding and non-oxidative metabolism to a pharmacologically inactive glucuronide form) and by its high relative potency (lorazepam 1 mg is equal in effect to diazepam 10 mg). The half life of lorazepam is 10-20 hours. Lorazepam has an inhibitory effect on plasma cholinesterase of 40-50 per cent.
Because of its poor lipid solubility lorazepam is absorbed relatively slowly by mouth and is unsuitable for rectal administration. However, its poor lipid solubility and its high degree of protein binding (85-90%) means that lorazepam's volume of distribution is mainly the vascular compartment. This contrasts with the highly lipid soluble diazepam which, although speedily absorbed orally or rectally, soon redistributes from the serum to other parts of the body, particularly body fat. This explains why one lorazepam dose, despite lorazepam's shorter serum half-life, has longer duration of effect than one diazepam dose. On regular administration diazepam will however accumulate more, having a longer half-life and active metabolites with even longer half-lives.
Clinical Example: Diazepam has long been a drug of choice for status epilepticus: its high lipid solubility means it gets absorbed with equal speed whether given intravenously, orally or rectally (non-intravenous routes being convenient in non-hospital settings). But diazepam's high lipid solubility also means it does not remain in the vascular space but soon redistributes into other body tissues, and so it may be necessary to repeat diazepam doses to maintain anticonvulsant effects, resulting in excess body accumulation. Lorazepam is the opposite case: its low lipid solubility makes it relatively slowly absorbed by any route other than intravenously, but once given it does not get significantly redistributed beyond the vascular space. Therefore, lorazepam's anticonvulsant effects are more durable, reducing the need for repeated doses. If a patient is known to usually stop convulsing after only one or two diazepam doses, diazepam may be preferable because sedative aftereffects will be less than if a single dose of lorazepam is given (diazepam anticonvulsant/sedative effects wear off after 15-30 minutes, but lorazepam effects last 12-24 hours). Prolonged sedative effects from lorazepam may however be an acceptable trade-off for its reliable duration of effects, particularly if the patient needs to be transferred to another facility. Although lorazepam is not necessarily better than diazepam at initially terminating seizures,, lorazepam is replacing diazepam as the intravenous agent of choice in status epilepticus.
Lorazepam serum levels are proportional to the dose administered. Giving 2 mg oral lorazepam will result in a peak total serum lorazepam level of around 20 nanograms/ml around two hours later, half of which is lorazepam, half its inactive metabolite, lorazepam-glucuronide. A similar dose given intravenously will result in an earlier and higher peak serum level, with a higher proportion of unmetabolised (active) lorazepam. On regular administration, maximum lorazepam serum levels are attained after three days. Longer term use, up to six months, does not result in further accumulation. On discontinuation, lorazepam serum levels become negligible after 3 days and undetectable after about a week. Lorazepam is metabolised in the liver by conjugation into inactive lorazepam-glucuronide. This metabolism does not involve hepatic oxidation and therefore is relatively unaffected by reduced liver function. Lorazepam-glucuronide is more lipid-soluble than its precursor and therefore gets more widely distributed in the body leading to a longer half-life than lorazepam. Lorazepam-glucuronide is excreted by the kidneys and remains detectable - particularly in the urine - for substantially longer than lorazepam.
Relative to other benzodiazepines, lorazepam is thought to have high affinity for GABA receptors, which may also explain its marked amnesic effects. The main pharmacological effects of lorazepam are the enhancement of GABA at the GABAA receptor. Benzodiazepine drugs including lorazepam increase the inhibitory processes in the cerebral cortex.
The magnitude and duration of lorazepam effects are dose related, meaning that larger doses have stronger and longer-lasting effects. This is because the brain has spare benzodiazepine drug receptor capacity, with single, clinical doses leading only to an occupancy of some 3% of the available receptors.
The anticonvulsant properties of lorazepam 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 get limited, by the benzodiazepine effect of slowing recovery of sodium channels from inactivation.
Contraindications and special considerations
Lorazepam must be avoided in patients with the following conditions:
Allergy or hypersensitivity. Past hypersensitivity or allergy to lorazepam, to any benzodiazepine or to any of the ingredients in lorazepam tablets or injections.
Severe respiratory failure. Benzodiazepines, including lorazepam, may depress central nervous system respiratory drive and are contraindicated in severe respiratory failure. An example would be the inappropriate use to relieve anxiety associated with acute severe asthma. The anxiolytic effects may also be detrimental to a patient's willingness and ability to fight for breath. However, if mechanical ventilation becomes necessary, lorazepam may be used to facilitate deep sedation.
Acute intoxication. Lorazepam may interact synergistically with the effects of alcohol, narcotics, or other psychoactive substances. It should therefore not be administered to a drunk or intoxicated person.
Ataxia. This is a neurological clinical sign, consisting of unsteady and clumsy motion of the limbs and torso, due to failure of gross muscle movement coordination, most evident on standing and walking. Benzodiazepines should not be administered to ataxic patients for the same reasons that they are not given alcohol.
Acute narrow-angle glaucoma. Lorazepam has pupil-dilating effects which may further interfere with the drainage of aqueous humour from the anterior chamber of the eye, thus worsening narrow-angle glaucoma.
Sleep apnoea. Sleep apnoea may be worsened by lorazepam's central nervous system depressant effects.
Myasthenia gravis. This condition is characterised by muscle weakness and a muscle relaxant may exacerbate symptoms.
Pregnancy and breast feeding. Lorazepam belongs to the Food and Drug Administration (FDA) pregnancy category D which means that it is likely to cause harm to the unborn baby if taken during the first trimester of pregnancy. Lorazepam given to pregnant women antenatally may cause floppy infant syndrome in the neonate, respiratory depression necessitating ventilation, and neonatal withdrawal symptoms. There is inconclusive evidence that lorazepam if taken early in pregnancy may result in reduced IQ, neurodevelopmental problems, physical malformations in cardiac or facial structure as well as other malformations in some new borns. Lorazepam when taken during late in pregnancy, the third trimester, causes a definite risk of a severe benzodiazepine withdrawal syndrome in the neonate with symptoms including hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth. Lorazepam may also inbibit foetal liver bilirubin glucuronidation, leading to neonatal jaundice. Lorazepam is present in breast milk; so caution must be exercised about breast feeding.
Special groups and situations
Children and the elderly. The safety and effectiveness of lorazepam is not well determined in children under 16 years of age, but it is used to treat serial seizures. Dose requirements have to be individualized, especially in the elderly and debilitated patients in whom the risk of over sedation is greater. Long-term therapy may lead to cognitive deficits, especially in the elderly, but this is reversible after a period of discontinuation. Benzodiazepines, including lorazepam, have been found to increase the risk of falls and fractures in the elderly.
Liver or Kidney failure. Lorazepam may be safer than most benzodiazepines in patients with impaired liver function. Like oxazepam it does not require hepatic oxidation, but only hepatic glucuronidation into lorazepam-glucuronide. Therefore, impaired liver function is unlikely to result in lorazepam accumulation to an extent causing adverse reactions. Lorazepam-glucuronide and a small amount of unchanged lorazepam are excreted by the kidneys, so in renal failure small increases in lorazepam levels may occur.
Premedication. Informed consent for medical or surgical procedures must be obtained before lorazepam is administered, or consent may be invalidated. Health workers should take sensible precautions (chaperoning, avoiding ambiguous language and gestures) against patients later making unfounded allegations of abuse during treatment, due to impaired memory and drug-induced disinhibition/misinterpretations. After a lorazepam injection, or a single oral premedication sized dose, patients should normally not be discharged from hospital settings without an accompanying caregiver (parent, spouse, etc.) before 24 hours have elapsed, owing to variable residual effects like sleepiness, vertigo, hypotension, amnesia, etc. Patients should also not drive a car or handle machines for 24 hours.
Pregnancy. Lorazepam rapidly penetrates membranes and therefore rapidly crosses over into the placenta with significant uptake of the drug. Use of benzodiazepines including lorazepam in late pregnancy especially high doses may result in floppy infant syndrome.
Tolerance and dependence
Tolerance to benzodiazepine effects develops with regular use. This is desirable with amnesic and sedative effects, undesirable with anxiolytic, hypnotic and anticonvulsant effects. Patients at first experience drastic relief from e.g. anxiety or sleeplessness, but symptoms gradually return, relatively soon in the case of insomnia but more slowly in the case of anxiety symptoms. After four to six months of regular benzodiazepine use, there is little evidence of continued efficacy. If regular treatment is continued for longer than this, dose increases may be necessary to maintain effects, but treatment resistant symptoms may in fact be benzodiazepine withdrawal symptoms.
On abrupt, or overly rapid discontinuation of lorazepam, anxiety and signs of physical withdrawal have been observed, similar to those seen on withdrawal from alcohol and barbiturates. Lorazepam as with other benzodiazepine drugs can cause physical dependence, addiction and what is known as the benzodiazepine withdrawal syndrome. The higher the dose and the longer the drug is taken for the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can however occur from standard dosages and also after short term use. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regime.
The likelihood of dependence is relatively high with lorazepam compared to other benzodiazepines. Because of lorazepam's relatively short serum half-life, confinement mainly to the vascular space and an inactive metabolite, with resultant interdose withdrawal phenomenon and next dose craving, which may reinforce psychological dependence. Because of lorazepam's high potency, the smallest tablet strength of 0.5 mg is also a significant dose reduction (in the UK, the smallest tablet strength is 1.0 mg, which accentuates this difficulty). To minimise the risk of physical/psychological dependence, lorazepam is best used only short-term and at the smallest effective dose. If a benzodiazepine has been used long-term, the recommendation is a gradual dose taper over a period of weeks, months or longer, according to dose and duration of use, degree of physical dependence and the individual. Coming off long-term lorazepam may be more realistically achieved by a gradual switch to an equivalent dose of diazepam, a period of stabilization on this and only then initiating dose reductions. The advantage of switching to diazepam is that dose reductions are felt less acutely, because of the longer half lives (20-200 hours) of diazepam and its active metabolites.
Withdrawal symptoms can occur after taking therapeutic doses of Ativan for as little as one week. Withdrawal symptoms include headaches, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating, dysphoria, dizziness, derealization, depersonalization, numbness/tingling of extremities, hypersensitivity to light, sound, and smell, perceptual distortions, nausea, vomiting, diarrhea, appetite loss, hallucinations, delirium, seizures, tremor, stomach cramps, myalgia, agitation, palpitations, tachycardia, panic attacks, short-term memory loss, and hyperthermia. 
Abuse and misuse
Prescribers of lorazepam must be alert to the possibility of abuse or diversion for illegitimate use when prescribing for unsupervised outpatients. This applies particularly to patients with past or present substance abuse disorders, as persons with addictive personalities are likelier to abuse medications such as lorazepam. In addition to recreational use, benzodiazepines may be diverted and used to facilitate crime: criminals may take them to deliberately seek disinhibition before committing crimes (which increases their potential for violence) or they may give them to unwitting victims as date rape drugs, notably with alcohol.
In Northern Ireland in cases where drivers had low or no alcohol readings but were thought to be impaired through drugs, benzodiazepines were found to be present in 87% of cases.
Any of the five intrinsic benzodiazepine effects possessed by lorazepam (sedative/hypnotic, muscle relaxant, anxiolytic, amnesic and anticonvulsant) may be considered as "adverse effects", or "side effects", if unwanted. Lorazepam's effects are dose-dependent, meaning that the higher the dose, the stronger the effects (and side effects) will be. Using the smallest dose needed to achieve desired effects lessens the risk of adverse effects.
Lorazepam has an advantage of being non-sedative relative to its potent anxiolytic effects, but sedation is still the most complained-of side effect. In a group of around 3500 patients treated for anxiety, the most common side-effects complained of from lorazepam were sedation (15.9%), dizziness (6.9%), weakness (4.2%), and unsteadiness (3.4%). Side-effects such as sedation and unsteadiness increased with age.
Paradoxical effects. In some cases there can be paradoxical effects with benzodiazepines, such as increased hostility and aggression, which is thought to be at least partially due to disinhibition. It is more likely to occur with higher doses, in patients with pre-existing personality disorders and those with a psychiatric illness. Frustrating stimuli may trigger such reactions — which is paradoxical, since the drug may have been prescribed to help the patient cope with such stimuli in the first place. Since paradoxical effects are dose-related, they usually subside on dose reduction or upon complete withdrawal of lorazepam.
Suicidality. Benzodiazepines in general may sometimes unmask suicidal ideation in depressed patients (indirectly, through disinhibition or fear reduction, rather than through any known direct effect). Though relatively non-toxic in themselves, the concern is that benzodiazepines may inadvertently become facilitators of suicidal behaviour. Lorazepam should therefore not be prescribed alone in depression but only together with an appropriate antidepressant and at the minimal dose required.
Amnesic effects. Among benzodiazepines, lorazepam has relatively strong amnesic effects, but patients soon develop tolerance to this with regular use. To avoid amnesia (or excess sedation) being a problem, the initial total daily lorazepam dose should not exceed 2 mg. This also applies to use for night sedation. Five participants in a sleep study were prescribed lorazepam 4 mg at night and the next evening three subjects unexpectedly volunteered memory gaps for parts of that day, an effect which subsided completely after 2-3 days use. Amnesic effects cannot be estimated from the degree of sedation present, since the two effects are unrelated.
For full lists of lorazepam side-effects, refer to the manufacturers' data sheets. Note that some may list side-effects for the entire benzodiazepine class, not the specific side-effect profile for lorazepam.
Alcohol. Lorazepam is not usually fatal in overdose, but may cause fatal respiratory depression if taken in overdose with alcohol. The combination also causes synergistic enhancement of the disinhibitory and amnesic effects of both drugs, with potentially embarrassing or forensic consequences. Some experts advise patients should be warned against taking alcohol while on lorazepam treatment, but such clear warnings are not universal.
Morphine. Benzodiazepines including lorazepam may inhibit the glucuronidation of morphine leading to increased levels of and prolongation of the effects of morphine.
In cases of a suspected lorazepam overdose, it is important to establish if the patient is a regular user of lorazepam or other benzodiazepines, since regular use causes tolerance to develop. Also, one must ascertain if other drugs were also ingested.
Signs of overdose range through mental confusion, dysarthria, paradoxical reactions, drowsiness, hypotonia, ataxia, hypotension, hypnotic state, coma, cardiovascular depression, respiratory depression and death.
Early management of alert patients includes emetics, gastric lavage and activated charcoal. Otherwise, management is by observation, including of vital signs, support and — only if necessary, considering the hazards of doing so — giving intravenous flumazenil.
Patients are ideally nursed in a kind, non-frustrating environment since, when given or taken in high doses, benzodiazepines are more likely to cause paradoxical reactions. If shown sympathy, even quite crudely feigned, patients may respond solicitously, but they may respond with disproportionate aggression to frustrating cues. Opportunistic counseling has limited value here, as the patient is unlikely to recall this later, owing to drug-induced anterograde amnesia.
History and legal status
Lorazepam was first introduced by Wyeth Pharmaceuticals in 1971 under the brand names of Ativan and Temesta. Wyeth's original patent on lorazepam is expired in the United States but the drug continues to be commercially viable. As a measure of its ongoing success, it has been marketed under more than seventy generic brands since then:
In 2000, the U.S. drug company Mylan agreed to pay $147 million to settle accusations by the F.T.C. that they had raised the price of generic lorazepam by 2600 percent and generic clorazepate by 3200 percent in 1998 after having obtained exclusive licensing agreements for certain ingredients.
Lorazepam is a Schedule IV drug under the Controlled Substances Act in the U.S. and internationally under the United Nations Convention on Psychotropic Substances. Lorazepam is a Schedule IV drug under the Controlled Drugs and Substances Act in Canada. In the United Kingdom, lorazepam is a Class 4 Controlled Drug under the Misuse of Drugs Regulations 2001.
In popular culture
Lorazepam has been mentioned in several contemporary media in recent years, with various clinical aspects highlighted. It is seen in medical situations, such as the TV series House, MD as the drug of choice for the cessation of seizures. A similar use is depicted in the movie Saw III where "Jigsaw" is being operated on and begins to convulse: the character performing the surgery yells many times for Ativan, but discovers that none is available in the limited operating area. Blue October mentions Lorazepam in their song "HRSA", where it is being prescribed in a psychiatric ward for a similar use. The dependency problem is portrayed in William Gibson's 2007 book Spook Country, in which the character Milgrim is addicted to Ativan and the character Brown exploits Milgrim's addiction, in order to control him, through a steady supply of Ativan and Rize (a brand of the benzodiazepine clotiazepam).
In 2005, Fall Out Boy member Pete Wentz overdosed on lorazepam; he included references to the episode in the songs "I've Got a Dark Alley and a Bad Idea That Says You Should Shut Your Mouth (Summer Song)" and "7 Minutes in Heaven (Atavan Halen)", on the album From Under the Cork Tree. In the novel "Absurdistan", the main character Misha Vainberg is a regular user of prescription Ativan, which he often combines with alcohol. His manservant usually carries his Ativan for him.
^ abcdef Hindmarch, Ian (January 30 1997). Benzodiazepines and their effects. benzo.org.uk. Retrieved on 2007-05-13.
^ Kemper N; Poser W, Poser S. (5). "[Benzodiazepine dependence: addiction potential of the benzodiazepines is greater than previously assumed (author's transl)]". Deutsche medizinische Wochenschrift (1946).105 (49): 1707-12. PMID 7439058.
^ Lader M (1984). "Short-term versus long-term benzodiazepine therapy". Current Med Res Opin8 Suppl 4: 120–6. PMID 6144459.
^ Maltais F, Laberge F, Laviolette M (1996). "A randomized, double-blind, placebo-controlled study of lorazepam as premedication for bronchoscopy".PDFChest109 (5): 1195–8. PMID 8625666.
^ Heisterkamp DV, Cohen PJ (1975). "The effect of intravenous premedication with lorazepam (Ativan), pentobarbitone or diazepam on recall". Br J Anaesth47 (1): 79–81. PMID 238548.
^ Milligan DW, Howard MR, Judd A (1987). "Premedication with lorazepam before bone marrow biopsy". J Clin Pathol40 (6): 696–8. PMID 3611398. Full text at PMC: 1141067.
^ 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.
^ ab Peppers MP (1996). "Benzodiazepines for alcohol withdrawal in the elderly and in patients with liver disease". Pharmacotherapy16 (1): 49–57. PMID 8700792.
^ Bird RD, Makela EH (1994). "Alcohol withdrawal: what is the benzodiazepine of choice?". Ann Pharmacother28 (1): 67–71. PMID 8123967.
^ Alexander J, Tharyan P, Adams C, John T, Mol C, Philip J (2004). "Rapid tranquillisation of violent or agitated patients in a psychiatric emergency setting. Pragmatic randomised trial of intramuscular lorazepam v. haloperidol plus promethazine".PDFBr J Psychiatry185 (1): 63–9. PMID 15231557.
^ McAllister-Williams RH (2005). "Intramuscular haloperidol-promethazine sedates violent or agitated patients more quickly than intramuscular lorazepam". Evidence-Based Mental Health8 (1): 7. PMID 15671498.
^ ab Bieniek SA, Ownby RL, Penalver A, Dominguez RA (1998). "A double-blind study of lorazepam versus the combination of haloperidol and lorazepam in managing agitation". Pharmacotherapy18 (1): 57–62. PMID 9469682.
^ Rosebush PI, Mazurek MF (1996). "Catatonia after benzodiazepine withdrawal". Journal of clinical psychopharmacology16 (4): 315-9. PMID 8835707.
^ Van Dalfsen AN, Van Den Eede F, Van Den Bossche B, Sabbe BG (2006). "[Benzodiazepines in the treatment of catatonia]" (in Dutch; Flemish). Tijdschrift voor psychiatrie48 (3): 235–9. PMID 16956088.
^ Herrstedt J, Aapro MS, Roila F, Kataja VV (2005). "ESMO Minimum Clinical Recommendations for prophylaxis of chemotherapy-induced nausea and vomiting (NV)".PDFAnn Oncol16 Suppl 1: i77–9. PMID 15888767. doi:10.1093/annonc/mdi805
^ Yaucher NE, Fish JT, Smith HW, Wells JA (2003). "Propylene glycol-associated renal toxicity from lorazepam infusion.". Pharmacotherapy23 (9): 1094-9. PMID 14524641.
^ abc Greenblatt DJ, Schillings RT, Kyriakopoulos AA, Shader RI, Sisenwine SF, Knowles JA, Ruelius HW (1976). "Clinical pharmacokinetics of lorazepam. I. Absorption and disposition of oral 14C-lorazepam". Clin Pharmacol Ther20 (3): 329–41. PMID 8232.
^ abcde Lorzem Data Sheet. New Zealand Medicines and Medical Devices Safety Authority (June 4 1999). Retrieved on 2007-05-13.
^ Braestrup C; Squires RF. (Apr 1978). "Pharmacological characterization of benzodiazepine receptors in the brain.". Eur J Pharmacol48 (3): 263-70. PMID 639854.
^ Pompéia S, Manzano GM, Tufik S, Bueno OF (2005). "What makes lorazepam different from other benzodiazepines?"PDFJ Physiol569 (2): 709. PMID 16322061. doi:10.1113/jphysiol.2005.569005. Letter.
^British Medical Association and Royal Pharmaceutical Society of Great Britain (March 2007). British National Formulary, v53. ISBN 0-85369-731-0.
^ Nimmo, Ray; C. Heather Ashton (March 2007). Benzodiazepine Equivalence Table. benzo.org.uk. Retrieved on 2007-05-13.
^ Professor heather Ashton (April 2007). BENZODIAZEPINE EQUIVALENCY TABLE. Retrieved on Sept 23, 2007.
^ Holmes JH; Kanfer I, Zwarenstein H. (Aug 1978). "Effect of benzodiazepine derivatives on human blood cholinesterase in vitro.". Res Commun Chem Pathol Pharmacol21 (2): 367-70. PMID 29327.
^ Funderburk FR, Griffiths RR, McLeod DR, Bigelow GE, Mackenzie A, Liebson IA, Nemeth-Coslett R (1988). "Relative abuse liability of lorazepam and diazepam: an evaluation in 'recreational' drug users.". Drug and alcohol dependence22 (3): 215-22. PMID 3234245.
^ Lackner TE (2002). "Strategies for optimizing antiepileptic drug therapy in elderly people". Pharmacotherapy22 (3): 329–64. PMID 11898891. Free full text with registration at Medscape
^ Choudhery V, Townend W (2006). "Best evidence topic reports. Lorazepam or diazepam in paediatric status epilepticus". Emergency Medicine Journal23 (6): 472–3. doi:10.1136/emj.2006.037606. PMID 16714516.
^ Henry JC, Holloway R (2006). "Review: lorazepam provides the best control for status epilepticus".PDFEvid Based Med11 (2): 54. PMID 17213084. doi:10.1136/ebm.11.2.54.
^ Cock HR, Schapira AH (2002). "A comparison of lorazepam and diazepam as initial therapy in convulsive status epilepticus". QJM95 (4): 225–31. PMID 11937649.
^ Papini O, Bertucci C, da Cunha SP, dos Santos NA, Lanchote VL (2006). "Quantitative assay of lorazepam and its metabolite glucuronide by reverse-phase liquid chromatography-tandem mass spectrometry in human plasma and urine samples". Journal of pharmaceutical and biomedical analysis40 (2): 389–96. doi:10.1016/j.jpba.2005.07.033. PMID 16243469.
^ Herman RJ, Van Pham JD, Szakacs CB (1989). "Disposition of lorazepam in human beings: enterohepatic recirculation and first-pass effect". Clin Pharmacol Ther46 (1): 18–25. PMID 2743706.
^ Matthew E, Andreason P, Pettigrew K, et al (1995). "Benzodiazepine receptors mediate regional blood flow changes in the living human brain". Proc. Natl. Acad. Sci. U.S.A.92 (7): 2775–9. PMID 7708722. Full text at PMC: 42301.
^ Oelschläger H. (4). "[Chemical and pharmacologic aspects of benzodiazepines]". Schweiz Rundsch Med Prax.78 (27-28): 766-72. PMID 2570451.
^ Zakusov VV; Ostrovskaya RU, Kozhechkin SN, Markovich VV, Molodavkin GM, Voronina TA. (Oct 1977). "Further evidence for GABA-ergic mechanisms in the action of benzodiazepines." 229 (2): 313-26. PMID 23084.
^ Sybirska E, Seibyl JP, Bremner JD, et al (1993). "[123I]iomazenil SPECT imaging demonstrates significant benzodiazepine receptor reserve in human and nonhuman primate brain". Neuropharmacology32 (7): 671–80. PMID 8395663.
^ 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.
^ McElhatton PR. (Nov-Dec 1994). "The effects of benzodiazepine use during pregnancy and lactation.". Reprod Toxicol.8 (6): 461-75. PMID 7881198.
^ 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.
^ Kanto JH. (May 1982). "Use of benzodiazepines during pregnancy, labour and lactation, with particular reference to pharmacokinetic considerations.". Drugs.23 (5): 354-80. PMID 6124415.
^ Longo LP, Johnson B (2000). "Addiction: Part I. Benzodiazepines--side effects, abuse risk and alternatives". American Family Physician61 (7): 2121–8. PMID 10779253. Free full text
^ 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. PMID 6133446.
^ Heather Ashton, C (April 2001). Reasons for a diazepam (Valium) taper. benzo.org.uk. Retrieved on 2007-06-01.
^ FDA (April 2007). Labeling Revision. fda.gov. Retrieved on 2007-10-03.
^ ab Michel L, Lang JP (2003). "[Benzodiazepines and forensic aspects]" (in French). L'Encéphale29 (6): 479–85. PMID 15029082.
^ Cosbey SH. (Dec 1986). "Drugs and the impaired driver in Northern Ireland: an analytical survey.". Forensic Sci Int.32 (4): 245-58. PMID 3804143.
^ Ativan side effects. RxList (2007). Retrieved on 2007-08-10.
^ Bond A, Lader M (1988). "Differential effects of oxazepam and lorazepam on aggressive responding". Psychopharmacology (Berl.)95 (3): 369–73. PMID 3137624.
^ Pietras CJ, Lieving LM, Cherek DR, Lane SD, Tcheremissine OV, Nouvion S (2005). "Acute effects of lorazepam on laboratory measures of aggressive and escape responses of adult male parolees". Behav Pharmacol16 (4): 243–51. PMID 15961964.
^ Kalachnik JE, Hanzel TE, Sevenich R, Harder SR (2002). "Benzodiazepine behavioral side effects: review and implications for individuals with mental retardation". Am J Ment Retard107 (5): 376–410. PMID 12186578.
^ Mancuso CE, Tanzi MG, Gabay M (2004). "Paradoxical reactions to benzodiazepines: literature review and treatment options". Pharmacotherapy24 (9): 1177–85. PMID 15460178. Free full text with registration
^ Goldney RD (1977). "Paradoxical reaction to a new minor tranquilizer". Med. J. Aust.1 (5): 139-40. PMID 15198.
^ Edwards RA, Medlicott RW (1980). "Advantages and disadvantages of benzodiazepine prescription". N Z Med J92 (671): 357–9. PMID 6109269.
^ Izaute M, Bacon E (2005). "Specific effects of an amnesic drug: effect of lorazepam on study time allocation and on judgment of learning". Neuropsychopharmacology30 (1): 196–204. doi:10.1038/sj.npp.1300564. PMID 15483562. Free full text
^ Scharf MB, Kales A, Bixler EO, Jacoby JA, Schweitzer PK (1982). "Lorazepam-efficacy, side effects, and rebound phenomena.". Clin. Pharmacol. Ther.31 (2): 175-9. PMID 6120058.
^ Sorel L; Mechler L, Harmant J. (1981). "Comparative trial of intravenous lorazepam and clonazepam im status epilepticus.". Clin Ther.4 (4): 326-36. PMID 6120763.
^ Genus Pharmaceuticals (January 21 1998). Lorazepam: Patient Information Leaflet, UK, 1998. benzo.org.uk. Retrieved on 2007-05-14.
^ Lorazepam. Patient UK (October 25 2006). Retrieved on 2007-05-14.
^ 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.
^ Coundil of Europe, Pompidou Group (Strassbourg, 2002) Contribution to the sensible use of benzodiazepines.ISBN 9789287147516.
^ Labaton, Stephen. "Generic-Drug Maker Agrees to Settlement In Price-Fixing Case", The New York Times, July 13 2000. Retrieved on 2007-05-14.
^International Narcotics Control Board (August 2003). List of psychotropic substances under international control: Green ListPDF (1.63 MiB), 23rd ed., Vienna: International Narcotics Control Board, p.7.
^ Derogatis, Jim. "Falling in: North Shore heroes Fall Out Boy are as surprised as you are by their success", Chicago Sun-Times, April 8 2007. Retrieved on 2007-05-14.