Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Lormetazepam: Difference between pages

{{Short description|Benzodiazepine medication}}

{{Infobox drug

| Watchedfields = changed

| verifiedrevid = 461743593

| width = 200px

| width2 = 170px

| tradename = Noctamid, Loramet, others

| legal_BR = B1

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>

| legal_CA = Schedule IV

| legal_DE = Rx-only/Anlage III

| routes_of_administration = [[Oral administration|Oral]], [[intravenous]]<ref name="pmid32468272">{{cite journal |vauthors=Horowski R |title=Dependence liability of lormetazepam: are all benzodiazepines equal? The case of the new i.v. lormetazepam for anesthetic procedures |journal=Journal of Neural Transmission |volume=127 |issue=8 |pages=1107–1115 |date=August 2020 |pmid=32468272 |pmc=8823007 |doi=10.1007/s00702-020-02209-8}}</ref>

| class = [[Benzodiazepine]]

| ATC_prefix = N05

| ATC_suffix = CD06

| protein_bound =

| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 848-75-9

| IUPHAR_ligand = 7553

| DrugBank =

| UNII_Ref = {{fdacite|correct|FDA}}

| ChEBI_Ref = {{ebicite|correct|EBI}}

| NIAID_ChemDB =

| PDB_ligand =

| synonyms = Methyllorazepam; Methyl-lorazepam; N-Methyllorazepam; Ro 5-5516

| IUPAC_name = 7-Chloro-5-(2-chlorophenyl)-3-hydroxy-1-methyl-1''H''-benzo[''e''][1,4]diazepin-2(3''H'')-one

| C=16 | H=12 | Cl=2 | N=2 | O=2

| SMILES = ClC1=CC=CC=C1C2=NC(C(N(C)C3=C2C=C(C=C3)Cl)=O)O

<!-- Definition and medical uses -->

'''Lormetazepam''', sold under the brand name '''Noctamid''' among others, is a drug which is a short to intermediate acting 3-hydroxy<ref>{{cite journal | vauthors = Doenicke A, Dorow R, Täuber U | title = [The pharmacokinetics of lormetazepam following cimetidine] | language = German | journal = Der Anaesthesist | volume = 40 | issue = 12 | pages = 675–679 | date = December 1991 | pmid = 1685875 | trans-title = The pharmacokinetics of lormetazepam following cimetidine }}</ref> [[benzodiazepine]] derivative and [[temazepam]] analogue.<ref name="analogues"/> It possesses [[hypnotic]], [[anxiolytic]], [[anticonvulsant]], [[sedative]], and skeletal [[muscle relaxant]] properties.

<!-- History, society, and culture-->

It was patented in 1961 and came into medical use in 1980.<ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=537 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA537 |language=en}}</ref> Lormetazepam is not approved for sale in the United States or Canada. It is licensed in the UK as 0.5 and 1{{nbsp}}mg tablets for short-term treatment (2–4 weeks) of moderately severe insomnia. It is licensed in the [[Netherlands]] as 1 and 2{{nbsp}}mg tablets, under the brand names Loramet and Noctamid and as generic, available from several manufacturers. It is sold in Poland as Noctofer. A [[Netherlands|Dutch]] analysis stated that lormetazepam could be suitable to be included in drug prescribing formularies, although [[zolpidem]], [[zopiclone]], and [[temazepam]] appear better.<ref>{{cite journal | vauthors = Janknegt R, van der Kuy A, Declerck G, Idzikowski C | title = Hypnotics. Drug selection by means of the System of Objectified Judgement Analysis (SOJA) method | journal = PharmacoEconomics | volume = 10 | issue = 2 | pages = 152–163 | date = August 1996 | pmid = 10163418 | doi = 10.2165/00019053-199610020-00007 }}</ref>

==Medical uses==

Lormetazepam is considered a [[hypnotic]] benzodiazepine and is officially indicated for [[Insomnia#Benzodiazepines|moderate-to-severe insomnia]]. Lormetazepam is a short-acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep or falling asleep. Hypnotics should only be used on a short-term basis or, in those with chronic insomnia, on an occasional basis.<ref>{{cite journal | vauthors = Rickels K | title = The clinical use of hypnotics: indications for use and the need for a variety of hypnotics | journal = Acta Psychiatrica Scandinavica. Supplementum | volume = 332 | issue = S332 | pages = 132–141 | year = 1986 | pmid = 2883820 | doi = 10.1111/j.1600-0447.1986.tb08990.x | s2cid = 46560074 }}</ref>

==Side effects==

Side effects of lormetazepam are similar to those of other hypnotic benzodiazepines and can for the most part be regarded as a class effect.{{Citation needed|date=May 2020}} In a sleep study, 1{{nbsp}}mg lormetazepam increased total sleep time, reduced wakefulness, but did not alter [[REM sleep]]. However, at 2{{nbsp}}mg doses, there were significant increases in stage 3 sleep and reductions in REM sleep. [[Rebound effect]]s have been reported after chronic use including rebound REM.<ref name="analogues">{{cite journal | vauthors = Nicholson AN, Stone BM | title = Hypnotic activity and effects on performance of lormetazepam and camazepam--analogues of temazepam | journal = British Journal of Clinical Pharmacology | volume = 13 | issue = 3 | pages = 433–439 | date = March 1982 | pmid = 6120717 | pmc = 1402107 | doi = 10.1111/j.1365-2125.1982.tb01398.x }}</ref> In one clinical trial with patients who had prior experience with older hypnotics [[temazepam]] and [[nitrazepam]], most preferred lormetazepam due to less heavy sedation, amnesia, and residual effects.<ref>{{cite journal | vauthors = Hill RC, Harry TV | title = Lormetazepam (Lorámet): a multicentre assessment of its efficacy and acceptability as a hypnotic in out-patients with sleep disturbances | journal = The Journal of International Medical Research | volume = 11 | issue = 6 | pages = 325–332 | year = 1983 | pmid = 6360746 | doi = 10.1177/030006058301100601 | s2cid = 23167620 }}</ref> Some side effects, including drowsiness, [[amnesia]], and respiratory depression, are increased when lormetazepam is combined with other drugs with similar effects, e.g. [[alcohol (drug)|alcohol]] and [[nonbenzodiazepine]] drugs.

Although lormetazepam has been associated with adversely affecting immediate and delayed recall memory functions,<ref>{{cite journal | vauthors = Dorow R, Berenberg D, Duka T, Sauerbrey N | title = Amnestic effects of lormetazepam and their reversal by the benzodiazepine antagonist Ro 15-1788 | journal = Psychopharmacology | volume = 93 | issue = 4 | pages = 507–514 | year = 1987 | pmid = 2893417 | doi = 10.1007/bf00207244 | s2cid = 1680477 }}</ref> studies have shown that lormetazepam's amnesic properties may be lesser compared to other hypnotic benzodiazepines. For example, in a 1984 study comparing the amnesic effects of lormetazepam to temazepam and flurazepam showed that amnesia was smallest after lormetazepam and greatest after temazepam, which had produced greater amnesia than both lormetazepam and flurazepam by a significant margin.<ref>{{Cite book |chapter= Amnesic effects of lormetazepam |volume= 1 |issue= 1 |pages= 165–72 |year= 1984|pmid= 6147838 | vauthors = Roehrs T, McLenaghan A, Koshorek G, Zorick F, Roth T |title= Sleep, Benzodiazepines and Performance |doi= 10.1007/978-3-642-69659-6_14 |series= Psychopharmacology Supplementum |isbn= 978-3-642-69661-9 }}</ref>

Side effects of lormetazepam include:

* [[Somnolence]]

* Paradoxical increase in aggression

* [[Lightheadedness]]

* [[Confusion]]

* Muscle weakness

* [[Ataxia]] (particularly in the elderly)

* [[Anterograde amnesia]]

* [[Headache]]

* [[Vertigo (medical)|Vertigo]]

* [[Hypotension]]

* Salivation changes

* Gastrointestinal disturbances

* Visual disturbances

* [[Dysarthria]]

* [[Tremor]]

* Changes in [[libido]]

* [[Urinary incontinence]]

* [[Urinary retention]]

* [[Blood disorder]]s and [[jaundice]]

* [[Skin]] reactions

* Dependence and withdrawal reactions

Residual "hangover" effects after nighttime administration of lormetazepam 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 increase risks of falls and [[hip fracture]]s.<ref>{{cite journal | vauthors = Vermeeren A | title = Residual effects of hypnotics: epidemiology and clinical implications | journal = CNS Drugs | volume = 18 | issue = 5 | pages = 297–328 | year = 2004 | pmid = 15089115 | doi = 10.2165/00023210-200418050-00003 | s2cid = 25592318 }}</ref>

Benzodiazepines require special precaution if used during pregnancy, in children, in alcohol- or drug-dependent individuals and individuals with [[comorbid]] [[psychiatric disorder]]s.<ref>{{cite journal | vauthors = Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, Vennat B, Llorca PM, Eschalier A | display-authors = 6 | title = Benzodiazepine dependence: focus on withdrawal syndrome | journal = Annales Pharmaceutiques Françaises | volume = 67 | issue = 6 | pages = 408–413 | date = November 2009 | pmid = 19900604 | doi = 10.1016/j.pharma.2009.07.001 }}</ref> Lormetazepam may be unsuitable for the elderly due to residual effects on memory and body sway which may result in falls.<ref>{{cite journal | vauthors = Allain H, Bentué-Ferrer D, Tarral A, Gandon JM | title = Effects on postural oscillation and memory functions of a single dose of zolpidem 5 mg, zopiclone 3.75 mg and lormetazepam 1 mg in elderly healthy subjects. A randomized, cross-over, double-blind study versus placebo | journal = European Journal of Clinical Pharmacology | volume = 59 | issue = 3 | pages = 179–188 | date = July 2003 | pmid = 12756510 | doi = 10.1007/s00228-003-0591-5 | s2cid = 13440208 }}</ref>

Lormetazepam causes impaired driving skills, thus caution is required in individuals who drive or operate machinery.<ref>{{cite journal | vauthors = Staner L, Ertlé S, Boeijinga P, Rinaudo G, Arnal MA, Muzet A, Luthringer R | title = Next-day residual effects of hypnotics in DSM-IV primary insomnia: a driving simulator study with simultaneous electroencephalogram monitoring | journal = Psychopharmacology | volume = 181 | issue = 4 | pages = 790–798 | date = October 2005 | pmid = 16025317 | doi = 10.1007/s00213-005-0082-8 | s2cid = 26351598 }}</ref>

===Tolerance, dependence, and withdrawal===

{{See also|Benzodiazepine withdrawal syndrome}}

The risks of tolerance, dependence, and withdrawal are very low when the drug is used for 2–4 weeks only, and lormetazepam is generally a safe and effective drug when used for no longer than 2–4 weeks. Some sleep disturbance in the form of rebound insomnia can, however, occur even after short-term usage of 7 days.<ref>{{cite journal | vauthors = Kales A, Bixler EO, Soldatos CR, Mitsky DJ, Kales JD | title = Dose-response studies of lormetazepam: efficacy, side effects, and rebound insomnia | journal = Journal of Clinical Pharmacology | volume = 22 | issue = 11–12 | pages = 520–530 | date = 12 November 1982 | pmid = 6131080 | doi = 10.1002/j.1552-4604.1982.tb02645.x | s2cid = 694106 }}</ref> Those with a history of [[substance dependence|addiction]] may be at increased risk of problems of tolerance and dependence especially those with a past history of dependency on sedative hypnotic drugs.

Lormetazepam as with other [[benzodiazepine]]s is generally only recommended for short-term use (2–4 weeks) due to tolerance and loss of [[efficacy]]. Tolerance to and loss of the [[sedative]] effects of [[benzodiazepine]] [[hypnotic]]s can occur within 14 days of regular use.<ref>{{cite web | vauthors = Smith AE | date = 1989 | url = http://www.benzo.org.uk/bznz.htm | title = Benzodiazepines - Use & Abuse - A Guide for Prescribers | work = New Zealand Department of Health }}</ref> Some studies however suggest such treatments retain their effectiveness in the long term<ref>{{cite journal | vauthors = Oswald I, French C, Adam K, Gilham J | title = Benzodiazepine hypnotics remain effective for 24 weeks | journal = British Medical Journal | volume = 284 | issue = 6319 | pages = 860–863 | date = March 1982 | pmid = 6121605 | pmc = 1496323 | doi = 10.1136/bmj.284.6319.860 }}</ref><ref>{{cite journal | vauthors = Vogel GW, Morris D | title = The effects of estazolam on sleep, performance, and memory: a long-term sleep laboratory study of elderly insomniacs | journal = Journal of Clinical Pharmacology | volume = 32 | issue = 7 | pages = 647–651 | date = July 1992 | pmid = 1640005 | doi = 10.1002/j.1552-4604.1992.tb05776.x | s2cid = 44857913 }}</ref><ref>{{cite journal | vauthors = Walsh JK, Krystal AD, Amato DA, Rubens R, Caron J, Wessel TC, Schaefer K, Roach J, Wallenstein G, Roth T | display-authors = 6 | title = Nightly treatment of primary insomnia with eszopiclone for six months: effect on sleep, quality of life, and work limitations | journal = Sleep | volume = 30 | issue = 8 | pages = 959–968 | date = August 2007 | pmid = 17702264 | pmc = 1978384 | doi = 10.1093/sleep/30.8.959 }}</ref> - such a lack of consistency in the findings of many studies could be due to the variation of responses to benzodiazepine treatment.

Dependence is the medical term for [[substance dependence|addiction]]. Dependence can either be psychological and/or physical.

Psychological dependence can manifest itself as a reliance on a drug to cope with everyday life or in the form of craving.

Physical dependence occurs due to physiological adaptations occurring as the body attempts to overcome the drugs effects which is known as tolerance and the continuing need to take the drug to avoid or suppress withdrawal symptoms which can sometimes resemble the original condition being treated. When the dose or the drug is discontinued withdrawal symptoms typically occur. Lormetazepam as with all other benzodiazepines produces both physical and psychological dependence but the main problem of concern is physical dependence which appears in the form of the [[benzodiazepine withdrawal syndrome]] after the dosage is reduced or the drug is stopped completely.<ref>{{cite journal | vauthors = Ashton CH | journal = Psychiatr Ann. | date = 1995 | volume = 25 | pages = 158–165 | url = http://www.bcnc.org.uk/protracted.html | title = Protracted Withdrawal Symptoms From Benzodiazepines | doi = 10.3928/0048-5713-19950301-09 | archive-url = https://web.archive.org/web/20060821162913/http://www.bcnc.org.uk/protracted.html | archive-date = 21 August 2006 }}</ref> The dependence induced by lormetazepam is related to changes in the sensitivity of the GABA-BZD receptor complex.<ref>{{cite journal | vauthors = Gerra G, Giucasto G, Zaimovic A, Fertonani G, Chittolini B, Avanzini P, Caccavari R, Delsignore R | display-authors = 6 | title = Intravenous flumazenil following prolonged exposure to lormetazepam in humans: lack of precipitated withdrawal | journal = International Clinical Psychopharmacology | volume = 11 | issue = 2 | pages = 81–88 | date = June 1996 | pmid = 8803645 | doi = 10.1097/00004850-199611020-00002 }}</ref>

Withdrawal symptoms typically subside after 4–8 weeks but in approximately 10-15% of individuals symptoms can persist for many months<ref>{{cite web | vauthors = Ashton CH | url = http://www.benzo.org.uk/manual/bzcha01.htm | title = Benzodiazepines: How They Work And How To Withdraw }}</ref> and in rare cases years.<ref name="pmid22291380">{{cite journal | vauthors = Lader MH, Morton SV | title = A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal | journal = Journal of Psychopharmacology | location = Oxford, England | volume = 6 | issue = 3 | pages = 357–63 | date = January 1992 | pmid = 22291380 | doi = 10.1177/026988119200600303 | s2cid = 23530701 | url = http://www.bcnc.org.uk/flumazenil.html |archive-url = https://web.archive.org/web/20070611180344/http://www.bcnc.org.uk/flumazenil.html | archive-date = 11 June 2007 }}</ref> Some "Withdrawal Symptoms" can emerge despite a constant dosage with the body needing extra dosage in order to feel normal. This is sometimes associated with dosage escalation.

Lormetazepam has a short to intermediate [[biological half-life|half-life]] of approximately 10–12 hours. Shorter acting benzodiazepine compounds are generally associated with a more intense and immediate withdrawal reaction compared to longer acting benzodiazepines. For this reason it is generally recommended to cross from lormetazepam to an equivalent dose of [[diazepam]] to gradually taper the dosage.<ref>{{cite web | work = Roche Products (UK) Ltd | date = 1990 | url = http://www.benzo.org.uk/roche1.htm | title = Benzodiazepines and Your Patients: A Management Programme }}</ref>

==Pharmacology==

The [[bioavailability]] of lormetazepam was found to be 80%.<ref>{{cite journal | vauthors = Hümpel M, Stoppelli I, Milia S, Rainer E | title = Pharmacokinetics and biotransformation of the new benzodiazepine, lormetazepam, in man. III. Repeated administration and transfer to neonates via breast milk | journal = European Journal of Clinical Pharmacology | volume = 21 | issue = 5 | pages = 421–425 | year = 1982 | pmid = 6122580 | doi = 10.1007/BF00542330 | s2cid = 19327058 }}</ref>

Lormetazepam and other benzodiazepine drugs act as positive modulators at the [[GABA receptor|GABA_A benzodiazepine receptor complex]]. Lormetazepam binds to the benzodiazepine receptor which in turn enhances the effect of the GABA_A receptor producing its therapeutic effects as well as adverse effects. When lormetazepam binds to the benzodiazepine receptor sites in sufficient quantities it produces sedation which is used clinically as a therapeutic treatment for insomnia. Lormetazepam alters the brain electrical activity which has been studied via EEG readings.<ref>{{cite journal | vauthors = Kurowski M, Ott H, Herrmann WM | title = Relationship between EEG dynamics and pharmacokinetics of the benzodiazepine lormetazepam | journal = Pharmacopsychiatria | volume = 15 | issue = 3 | pages = 77–83 | date = May 1982 | pmid = 6124982 | doi = 10.1055/s-2007-1019513 }}</ref> Lormetazepam appears to be more selective in the type of benzodiazepine receptor it binds to showing a higher affinity for the omega 1 receptor which is responsible for sedation.<ref>{{cite journal | vauthors = Ozawa M, Nakada Y, Sugimachi K, Akai T, Yamaguchi M | title = [Interaction of the hypnotic lormetazepam with central benzodiazepine receptor subtypes omega 1, omega 2 and omega 3] | journal = Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica | volume = 98 | issue = 5 | pages = 399–408 | date = November 1991 | pmid = 1687574 | doi = 10.1254/fpj.98.5_399 | doi-access = free }}</ref> Changes in EEG can therefore be used to measure the sedative sleep promoting properties of lormetazepam.

==Chemistry==

===Stereochemistry===

Lormetazepam has a [[stereocenter]] and two [[enantiomers]]. Medications are [[racemates]].<ref name="Rote Liste">Rote Liste Service GmbH (Hrsg.): ''Rote Liste 2017 – Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte)''. Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, {{ISBN|978-3-946057-10-9}}, S. 196.</ref>

{| class="wikitable" style="text-align:center"

|-

! colspan="2"| Enantiomers of lormetazepam

|-

| [[File:(R)-Lormetazepam Structural Formula V1.svg|200 px]]<br/>(''R'')-lormetazepam<br/><small> CAS number: 113679-56-4</small>

| [[File:(S)-Lormetazepam Structural Formula V1.svg|200 px]]<br/>(''S'')-lormetazepam<br/><small> CAS number: 113679-54-2</small>

|}

==Industry==

===Brand names===

Trade names include Aldosomnil, Dilamet, Ergocalm, Loramet, Loretam, Metatop, Minias, Noctamid, Noctamide, Noctofer, Nocton, Pronoctan, Sedaben, Sedalam, and Stilaze.

== References ==

{{Reflist}}

== External links ==

* {{cite web | url = http://www.inchem.org/documents/pims/pharm/pim929.htm | work = Inchem.org | title = Lormetazepam }}

{{Benzodiazepines}}

{{Hypnotics and sedatives}}

{{GABAAR PAMs}}

[[Category:Benzodiazepines]]

[[Category:Chloroarenes]]

[[Category:Lactams]]

[[Category:Lactims]]