LORAZEPAM

'Lorazepam' 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.^[1] It is a unique benzodiazepine insofar that 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. Compared to other benzodiazepines, lorazepam has relatively high addictive potential.

Uses

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.^[2]
Lorazepam's 'sedative/hypnotic' effects, and the duration of clinical effects from a single dose, makes it an appropriate choice for the short term treatment of insomnia, particularly in the presence of severe anxiety.
Its relatively potent amnesic effect^[1], with its anxiolytic and sedative effects, makes lorazepam useful as 'premedication'. It is given prior to 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.^[4]^[5]^[6]
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 after effects. 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.^[7]
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.^[8]
Where there is need for 'rapid sedation' of violent or agitated patients,^[9]^[10] including acute delirium, lorazepam may be used, but as it can cause paradoxical effects it is preferably given together with haloperidol.^[11] 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 occurring due to abrupt or over-rapid withdrawal from benzodiazepines, as part of the benzodiazepine withdrawal syndrome, should also respond to lorazepam treatment.^[12] As lorazepam can have paradoxical effects, haloperidol is sometimes given concomitantly.^[13]
Lorazepam is unique among benzodiazepines by having potent 'anti-emetic' properties. It is used as an adjunct antiemetic for treating the nausea and vomiting frequently associated with cancer chemotherapy, usually together with first-line antiemetics such as 5-HT₃ antagonists.^[14] It is also used as adjunct therapy for cyclic vomiting syndrome.

Formulation and Administration

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 either 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.^[15] Toxicity from propylene glycol has been reported in the case of a patient receiving a continuous lorazepam infusion.^[16] 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,^[17] which occur ten minutes after intravenous injection, up to one hour after intramuscular injection and about 120 minutes after oral administration^[18], but initial effects are noted before this. A clinically relevant lorazepam dose will normally be effective for 6 - 12 hours, making it unsuitable for regular once-daily administration; it is therefore usually prescribed as two to four daily doses when given regularly.

Pharmacology

Lorazepam is an intermediate acting benzodiazepine and its uniqueness^[19], 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^[20]^[21]).

Pharmacokinetics

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.^[22] 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 after-effects will be less than if a single dose lorazepam is given (diazepam anticonvulsant/sedative effects wear off after 15-30 minutes, but lorazepam effects last 12-24 hours.^[23]) 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,^[24], lorazepam is replacing diazepam as the ''intravenous'' agent of choice in status epilepticus.^[25]^[26]
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.^[27] A similar dose given intravenously will result in an earlier and higher peak serum level, with a higher proportion of unmetabolised (active) lorazepam.^[28] 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.

Pharmacodynamics

Relative to other benzodiazepines, lorazepam is thought to have high affinity for GABA receptors,^[29] which may also explain its marked amnesic effects. The main pharmacological effects of lorazepam are the enhancement of GABA at the GABA_A receptor.^[30]
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^[31].
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.^[32]

1987 Ativan advertisement. "In a world where certainties are few...no wonder Ativan® (lorazepam)C-IV is prescribed by so many caring clinicians."

Contraindications and Special Considerations

Contraindications

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. 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 oversedation is greater. Long term therapy may lead to cognitive deficits, especially in the elderly, but this is reversible after a period of discontinuation.

★ '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.^[33] 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 care-giver (parent, spouse, etc.) before 24 hours have elapsed, due to variable residual effects like sleepiness, vertigo, hypotension, amnesia, etc. Patients should also not drive a car or handle machines for 24 hours.

Tolerance, dependence and abuse

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 slower 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.^[34] 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. 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 stabilisation 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.^[35]
Prescribers of lorazepam must be alert to the possibility of abuse or diversion for illegitimate use when prescribing for unsupervised out-patients. 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 prior to committing crimes (which increases their potential for violence) or they may give them to unwitting victims as date rape drugs, notably with alcohol.

Adverse effects

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.^[1] 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 commonest 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. Ativan side effects

★ '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. The latter is relevant since frustrating stimuli - something which the drug may be prescribed to help the patient cope with - may in fact trigger such reactions. Since paradoxical effects are dose-related they usually subside on dose reduction or complete withdrawal of lorazepam.^[37]^[38]^[39]^[40]^[41]^[42]

★ '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.^[43] 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,^[44] 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.^[45] 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.

Interactions

★ '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,^[46] but such clear warnings are not universal.^[47]

Overdose

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.^[48] Opportunistic counseling has limited value here, as the patient is unlikely to recall this later due to drug-induced anterograde amnesia.

History and Legal status

Early lorazepam marketing, a 1977 direct-to-patient advertisement implying its positive effects: "Now it can be yours - The Ativan Experience."

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:
''Almazine, Alzapam, Anxiedin, Anxira, Anzepam, Aplacasse, Aplacassee, Apo-Lorazepam, Aripax, Azurogen, Bonatranquan, Bonton, Control, Donix, Duralozam, Efasedan, Emotion, Emotival, Idalprem, Kalmalin, Larpose, Laubeel, Lopam, Lorabenz, Loram, Lorans, Lorapam, Lorat, Lorax, Lorazene, Lorazep, Lorazepam, Lorazin, Lorazon, Lorenin, Loridem, Lorivan, Lorsedal, Lorzem, Lozepam, Merlit, Nervistop L, Nervistopl, NIC, Novhepar, Novolorazem, Orfidal, Piralone, Placidia, Placinoral, Punktyl, Quait, Renaquil, Rocosgen, Securit, Sedarkey, Sedatival, Sedizepan, Sidenar, Silence, Sinestron, Somnium, Stapam, Tavor, Titus, Tolid, Tranqil, Tranqipam, Trapax, Trapaxm, Trapex, Upan, Wintin'' and ''Wypax''.
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.^[49]
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.^[50] 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. Lorazepam, as an anxiolytic, is portrayed in the 2006 movie ''The Departed'', where Vera Farmiga's character, Madolyn prescribes it to Leonardo DiCaprio's character, Billy. 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)",^[51] on the album ''From Under the Cork Tree''.

★ In Gym Class Hero's "Pillmatic", the chorus refers to the drug as part of a chemical escape cocktail: "This world is crazy so I stay medicated / Percocet, Ativan, and Klonopin."

★ Minus the Bear mentions the drug in their song "Get Me Naked 2: Electric Boogaloo"

References

1. Benzodiazepines and their effects
2. Short-term versus long-term benzodiazepine therapy, Lader M, , , Current Med Res Opin, 1984
3. Benzodiazepines and their effects
4. Maltais F, Laberge F, Laviolette M (1996). ''Chest'' '109' (5): 1195–8. PMID 8625666.
5. The effect of intravenous premedication with lorazepam (Ativan), pentobarbitone or diazepam on recall, Heisterkamp DV, Cohen PJ, , , Br J Anaesth, 1975
6. Premedication with lorazepam before bone marrow biopsy, Milligan DW, Howard MR, Judd A, , , J Clin Pathol, 1987 .
7. Benzodiazepines in the treatment of epilepsy in people with intellectual disability., , JI, Isojärvi, J Intellect Disabil Res., 1998
8. Alcohol withdrawal: what is the benzodiazepine of choice?, Bird RD, Makela EH, , , Ann Pharmacother, 1994
9. Alexander J, Tharyan P, Adams C, John T, Mol C, Philip J (2004). ''Br J Psychiatry'' '185' (1): 63–9. PMID 15231557.
10. Intramuscular haloperidol-promethazine sedates violent or agitated patients more quickly than intramuscular lorazepam, McAllister-Williams RH, , , Evidence-Based Mental Health, 2005
11. A double-blind study of lorazepam versus the combination of haloperidol and lorazepam in managing agitation, Bieniek SA, Ownby RL, Penalver A, Dominguez RA, , , Pharmacotherapy, 1998
12. Catatonia after benzodiazepine withdrawal, Rosebush PI, Mazurek MF, , , Journal of clinical psychopharmacology, 1996
13. [Benzodiazepines in the treatment of catatonia], Van Dalfsen AN, Van Den Eede F, Van Den Bossche B, Sabbe BG, , , Tijdschrift voor psychiatrie, 2006
14. Herrstedt J, Aapro MS, Roila F, Kataja VV (2005). ''Ann Oncol'' '16 Suppl 1': i77–9. PMID 15888767.
15. baxter.com - Lorazepam Injection Data Sheet
16. Propylene glycol-associated renal toxicity from lorazepam infusion., Yaucher NE, Fish JT, Smith HW, Wells JA, , , Pharmacotherapy, 2003
17. Clinical pharmacokinetics of lorazepam. I. Absorption and disposition of oral 14C-lorazepam, Greenblatt DJ, Schillings RT, Kyriakopoulos AA, Shader RI, Sisenwine SF, Knowles JA, Ruelius HW, , , Clin Pharmacol Ther, 1976
18. Lorzem Data Sheet
19. Pompéia S, Manzano GM, Tufik S, Bueno OF (2005). ''J Physiol'' '569' (2): 709. PMID 16322061. . Letter.
20. British National Formulary, British Medical Association and Royal Pharmaceutical Society of Great Britain, , , , 2007,
21. Benzodiazepine Equivalence Table
22. Relative abuse liability of lorazepam and diazepam: an evaluation in 'recreational' drug users., Funderburk FR, Griffiths RR, McLeod DR, Bigelow GE, Mackenzie A, Liebson IA, Nemeth-Coslett R, , , Drug and alcohol dependence, 1988
23. Strategies for optimizing antiepileptic drug therapy in elderly people, Lackner TE, , , Pharmacotherapy, 2002 Free full text with registration at Medscape
24. Best evidence topic reports. Lorazepam or diazepam in paediatric status epilepticus, Choudhery V, Townend W, , , Emergency Medicine Journal, 2006
25. Henry JC, Holloway R (2006). ''Evid Based Med'' '11' (2): 54. PMID 17213084. .
26. A comparison of lorazepam and diazepam as initial therapy in convulsive status epilepticus, Cock HR, Schapira AH, , , QJM, 2002
27. Quantitative assay of lorazepam and its metabolite glucuronide by reverse-phase liquid chromatography-tandem mass spectrometry in human plasma and urine samples, Papini O, Bertucci C, da Cunha SP, dos Santos NA, Lanchote VL, , , Journal of pharmaceutical and biomedical analysis, 2006
28. Disposition of lorazepam in human beings: enterohepatic recirculation and first-pass effect, Herman RJ, Van Pham JD, Szakacs CB, , , Clin Pharmacol Ther, 1989
29. Benzodiazepine receptors mediate regional blood flow changes in the living human brain, Matthew E, Andreason P, Pettigrew K, ''et al'', , , Proc. Natl. Acad. Sci. U.S.A., 1995 .
30. [Chemical and pharmacologic aspects of benzodiazepines], Oelschläger H., , , Schweiz Rundsch Med Prax., 1989
31. [123I]iomazenil SPECT imaging demonstrates significant benzodiazepine receptor reserve in human and nonhuman primate brain, Sybirska E, Seibyl JP, Bremner JD, ''et al'', , , Neuropharmacology, 1993
32. Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture., McLean MJ, , , J Pharmacol Exp Ther., 1988
33. Benzodiazepines for alcohol withdrawal in the elderly and in patients with liver disease, Peppers MP, , , Pharmacotherapy, 1996
34. Addiction: Part I. Benzodiazepines--side effects, abuse risk and alternatives, Longo LP, Johnson B, , , American Family Physician, 2000 Free full text
35. Reasons for a diazepam (Valium) taper
36. Benzodiazepines and their effects
37. Differential effects of oxazepam and lorazepam on aggressive responding, Bond A, Lader M, , , Psychopharmacology (Berl.), 1988
38. Acute effects of lorazepam on laboratory measures of aggressive and escape responses of adult male parolees, Pietras CJ, Lieving LM, Cherek DR, Lane SD, Tcheremissine OV, Nouvion S, , , Behav Pharmacol, 2005
39. Benzodiazepine behavioral side effects: review and implications for individuals with mental retardation, Kalachnik JE, Hanzel TE, Sevenich R, Harder SR, , , Am J Ment Retard, 2002
40. [Benzodiazepines and forensic aspects], Michel L, Lang JP, , , L'Encéphale, 2003
41. Paradoxical reactions to benzodiazepines: literature review and treatment options, Mancuso CE, Tanzi MG, Gabay M, , , Pharmacotherapy, 2004 Free full text with registration
42. Paradoxical reaction to a new minor tranquilizer, Goldney RD, , , Med. J. Aust., 1977
43. Advantages and disadvantages of benzodiazepine prescription, Edwards RA, Medlicott RW, , , N Z Med J, 1980
44. Specific effects of an amnesic drug: effect of lorazepam on study time allocation and on judgment of learning, Izaute M, Bacon E, , , Neuropsychopharmacology, 2005 Free full text
45. Lorazepam-efficacy, side effects, and rebound phenomena., Scharf MB, Kales A, Bixler EO, Jacoby JA, Schweitzer PK, , , Clin. Pharmacol. Ther., 1982
46. Lorazepam: Patient Information Leaflet, UK, 1998 Genus Pharmaceuticals
47. Lorazepam
48. Coundil of Europe, Pompidou Group (Strassbourg, 2002) ''Contribution to the sensible use of benzodiazepines.'' ISBN 9789287147516.
49. Generic-Drug Maker Agrees to Settlement In Price-Fixing Case Stephen Labaton
50. International Narcotics Control Board (August 2003). , 23^rd ed., Vienna: International Narcotics Control Board, p.7.
51. Falling in: North Shore heroes Fall Out Boy are as surprised as you are by their success Jim Derogatis

External links

★ inchem.org - Lorazepam data sheet

★ rxlist.com - Lorazepam data sheet

★ drugs.com - Lorazepam data sheet

★ baxter.com - Lorazepam Injection Data Sheet

★ NZ medsafe.govt.nz - Lorzem Data Sheet

★ benzo.org.uk - Genus/Wyeth 1998 UK Lorazepam Data Sheet

★ benzo.org.uk - Ashton H. Benzodiazepines: How They Work And How to Withdraw. August 2002 (The "Ashton Manual").

★ ndaa.org - Drummer, OH. 'Benzodiazepines: Effects on Human Performance and Behavior'(Central Police University Press, 2002).

This article provided by Wikipedia. To edit the contents of this article, click here for original source.

psst.. try this: add to faves

	Hotel Valley Ho (Caf� ZuZu, VH Spa)
	Scottsdale CVB
	Interpro Travel Services Inc.
	traverse jamaica
	Pelican Executive Suites
	Time Out for Touring Inc.
	Travelonly - Dave Corless
	Travelonly - Allan Jenkins
	Heavenly Paradise Getaways
	Temptation Resort Spa Cancun