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

{{Short description|Synthetic opioid analgesic}}

{{cs1 config|name-list-style=vanc}}

| verifiedrevid = 464380644

| IUPAC_name = methyl 1-(3-methoxy-3-oxopropyl)-4-(''N''-phenylpropanamido)piperidine-4-carboxylate

| image = Remifentanil2DCSDS.svg

| width = 220px

| image2 = R-30490.png

| width2 = 220px

<!--Clinical data-->| tradename = Ultiva

| Drugs.com = {{drugs.com|monograph|remifentanil-hydrochloride}}

| pregnancy_AU = C

| pregnancy_US = N

| pregnancy_category =

| legal_AU = S8

| legal_BR = A1

| 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 I

| legal_DE = Anlage III

| legal_UK = Class A

| legal_US = Schedule II

| routes_of_administration = [[Intravenous]]

| ATC_prefix = N01

| ATC_suffix = AH06

| ATC_supplemental = <!--Pharmacokinetic data-->

| bioavailability = 0

| protein_bound = 70% (bound to plasma proteins)

| metabolism = cleaved by non-specific plasma and tissue esterases

<!--Identifiers-->| index2_label = as HCl

| IUPHAR_ligand = 7292

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 132875-61-7

| PubChem = 60815

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB00899

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 54803

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

| UNII = P10582JYYK

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D08473

| KEGG2_Ref = {{keggcite|correct|kegg}}

| KEGG2 = D01177

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

| ChEBI = 8802

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 1005

<!--Chemical data-->| C = 20

| H = 28

| N = 2

| O = 5

| smiles = O=C(OC)C2(N(c1ccccc1)C(=O)CC)CCN(CCC(=O)OC)CC2

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C20H28N2O5/c1-4-17(23)22(16-8-6-5-7-9-16)20(19(25)27-3)11-14-21(15-12-20)13-10-18(24)26-2/h5-9H,4,10-15H2,1-3H3

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = ZTVQQQVZCWLTDF-UHFFFAOYSA-N

| synonyms = methyl 1-(2-methoxycarbonylethyl)-4-(phenyl-propanoyl-amino)-piperidine-4-carboxylate

| melting_point = 5

'''Remifentanil''', marketed under the brand name '''Ultiva''' is a potent, short-acting synthetic [[opioid]] [[analgesic]] [[medication|drug]]. It is given to patients during surgery to relieve pain and as an adjunct to an [[anaesthetic]]. Remifentanil is used for [[sedation]] as well as combined with other medications for use in [[general anesthesia]]. The use of remifentanil has made possible the use of high-dose opioid and low-dose hypnotic anesthesia, due to synergism between remifentanil and various [[hypnotic]] drugs and volatile anesthetics.

== Clinical use ==

Remifentanil is used as an [[opioid]] [[analgesic]] that has a rapid onset and rapid recovery time.<ref name=":0">{{Cite web|title = Remifentanil, IV opioid analgesic, Remi {{!}} Ultiva|url = http://www.ultiva.com/|website = www.ultiva.com|access-date = 2015-11-30}}</ref> It has been used effectively during [[Craniotomy|craniotomies]],<ref name="pmid10553851">{{cite journal | vauthors = Gesztesi Z, Mootz BL, White PF | title = The use of a remifentanil infusion for hemodynamic control during intracranial surgery | journal = Anesthesia and Analgesia | volume = 89 | issue = 5 | pages = 1282–7 | date = November 1999 | pmid = 10553851 | doi = 10.1213/00000539-199911000-00038| doi-access = free }}</ref> spinal surgery,<ref name="pmid15502058">{{cite journal | vauthors = Grottke O, Dietrich PJ, Wiegels S, Wappler F | title = Intraoperative wake-up test and postoperative emergence in patients undergoing spinal surgery: a comparison of intravenous and inhaled anesthetic techniques using short-acting anesthetics | journal = Anesthesia and Analgesia | volume = 99 | issue = 5 | pages = 1521–1527 | date = November 2004 | pmid = 15502058 | doi = 10.1213/01.ANE.0000134684.25322.26 | s2cid = 45361690 | doi-access = free }}</ref> [[cardiac surgery]],<ref name="pmid16865075">{{cite journal | vauthors = Knapik M, Knapik P, Nadziakiewicz P, Misiołek H, Saucha W, Walaszczyk M, Dyaczyńska-Herman A | title = Comparison of remifentanil or fentanyl administration during isoflurane anesthesia for coronary artery bypass surgery | journal = Medical Science Monitor | volume = 12 | issue = 8 | pages = PI33–8 | date = August 2006 | pmid = 16865075 | doi = }}</ref> and [[gastric bypass surgery]].<ref name="pmid17606479">{{cite journal | vauthors = De Baerdemaeker LE, Jacobs S, Pattyn P, Mortier EP, Struys MM | title = Influence of intraoperative opioid on postoperative pain and pulmonary function after laparoscopic gastric banding: remifentanil TCI vs sufentanil TCI in morbid obesity | journal = British Journal of Anaesthesia | volume = 99 | issue = 3 | pages = 404–11 | date = September 2007 | pmid = 17606479 | doi = 10.1093/bja/aem164 | doi-access = free }}</ref> While opiates function similarly, with respect to analgesia, the [[pharmacokinetics]] of remifentanil<ref name="pmid8982900">{{cite journal | vauthors = Michelsen LG, Hug Jr CC | title = The pharmacokinetics of remifentanil | journal = Journal of Clinical Anesthesia | volume = 8 | issue = 8 | pages = 679–82 | date = December 1996 | pmid = 8982900 | doi = 10.1016/s0952-8180(96)00179-1 | url = }}</ref> allows for quicker post-operative recovery.<ref name="pmid9066316">{{cite journal | vauthors = Guy J, Hindman BJ, Baker KZ, Borel CO, Maktabi M, Ostapkovich N, Kirchner J, Todd MM, Fogarty-Mack P, Yancy V, Sokoll MD, McAllister A, Roland C, Young WL, Warner DS | display-authors = 6 | title = Comparison of remifentanil and fentanyl in patients undergoing craniotomy for supratentorial space-occupying lesions | journal = Anesthesiology | volume = 86 | issue = 3 | pages = 514–524 | date = March 1997 | pmid = 9066316 | doi = 10.1097/00000542-199703000-00002 | doi-access = free }}</ref>

==Administration==

It is administered in the form ''remifentanil hydrochloride'' and in adults is given as an [[intravenous infusion]] in doses ranging from 0.1 microgram per kilogram per minute to 0.5 (µg/kg)/min. Children may require higher infusion rates (up to 1.0 (µg/kg)/min).<ref>{{cite journal | vauthors = Weale NK, Rogers CA, Cooper R, Nolan J, Wolf AR | title = Effect of remifentanil infusion rate on stress response to the pre-bypass phase of paediatric cardiac surgery | journal = British Journal of Anaesthesia | volume = 92 | issue = 2 | pages = 187–194 | date = February 2004 | pmid = 14722167 | doi = 10.1093/bja/aeh038 | doi-access = free }}</ref> The clinically useful infusion rates are 0.025–0.1 (µg/kg)/min for sedation (rates adjusted to age of patient, severity of their illness and invasiveness of surgical procedure). Small amounts of other sedative medications are usually co-administered with remifentanil to produce sedation. Clinically useful infusion rates in [[general anesthesia]] vary but are usually 0.1–1&nbsp;(µg/kg)/min.<ref>{{cite web|url=http://www.fass.se/LIF/product?userType=0&nplId=20090807000024|title=Remifentanil Actavis|language=sv|access-date=21 Aug 2014}}</ref>

Remifentanil can be administered as part of an anesthesia technique called TIVA ([[total intravenous anesthesia]]) using computer controlled infusion pumps in a process called TCI ([[target controlled infusion]]). A target plasma concentration is entered as ng/ml into the pump, which calculates its infusion rate according to patient factors like age and weight. Induction levels of 40&nbsp;ng/ml are commonly used, but it generally varies between 3–8&nbsp;ng/ml. For certain surgical procedures that produce particularly strong stimuli a level of up to 15&nbsp;ng/ml might be needed. The relatively short [[context-sensitive half-life]] of remifentanil allows the desired [[blood plasma]] level to be achieved quickly, and also for the same reason, recovery occurs quickly. This allows remifentanil to be used in unique circumstances such as cesarean section.<ref>{{cite journal | vauthors = White LD, Hodsdon A, An GH, Thang C, Melhuish TM, Vlok R | title = Induction opioids for caesarean section under general anaesthesia: a systematic review and meta-analysis of randomised controlled trials | journal = International Journal of Obstetric Anesthesia | volume = 40 | pages = 4–13 | date = November 2019 | pmid = 31230994 | doi = 10.1016/j.ijoa.2019.04.007 | doi-access = free | hdl = 10072/416502 | hdl-access = free }}</ref>

Remifentanil's short context-sensitive half-life makes it ideal for intense pain of short duration. As such, it has been used for analgesia in labor successfully; however, it is not as effective as epidural analgesia.<ref>{{cite journal | vauthors = Stocki D, Matot I, Einav S, Eventov-Friedman S, Ginosar Y, Weiniger CF | title = A randomized controlled trial of the efficacy and respiratory effects of patient-controlled intravenous remifentanil analgesia and patient-controlled epidural analgesia in laboring women | journal = Anesthesia and Analgesia | volume = 118 | issue = 3 | pages = 589–597 | date = March 2014 | pmid = 24149580 | doi = 10.1213/ANE.0b013e3182a7cd1b | s2cid = 4844447 | doi-access = free }}</ref>

In combination with [[propofol]], remifentanil is used for anesthesia of patients undergoing [[electroconvulsive therapy]].<ref name=" pmid = 24398757 ">{{cite journal | vauthors = Ulusoy H, Cekic B, Besir A, Geze S, Hocaoglu C, Akdogan A | title = Sevoflurane/remifentanil versus propofol/remifentanil for electroconvulsive therapy: comparison of seizure duration and haemodynamic responses | journal = The Journal of International Medical Research | volume = 42 | issue = 1 | pages = 111–119 | date = February 2014 | pmid = 24398757 | doi = 10.1177/0300060513509036 | doi-access = free }}</ref>

==Metabolism==

Remifentanil is considered a metabolic [[retrometabolic drug design|soft drug]],<ref>{{cite journal | vauthors = Bodor N, Buchwald P | title = Soft drug design: general principles and recent applications | journal = Medicinal Research Reviews | volume = 20 | issue = 1 | pages = 58–101 | date = January 2000 | pmid = 10608921 | doi = 10.1002/(SICI)1098-1128(200001)20:1<58::AID-MED3>3.0.CO;2-X | s2cid = 25119421 }}</ref> one that is rapidly metabolized to an inactive form. Unlike other synthetic opioids which are hepatically metabolized, remifentanil has an [[ester]] linkage which undergoes rapid hydrolysis by non-specific tissue and plasma [[esterase]]s. This means that accumulation does not occur with remifentanil and its [[context-sensitive half-life]] remains at 4 minutes after a 4-hour infusion.

Remifentanil is metabolized to a compound (remifentanil acid) which has 1/4600th the potency of the parent compound.<ref>{{cite journal | vauthors = Hoke JF, Cunningham F, James MK, Muir KT, Hoffman WE | title = Comparative pharmacokinetics and pharmacodynamics of remifentanil, its principle metabolite (GR90291) and alfentanil in dogs | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 281 | issue = 1 | pages = 226–232 | date = April 1997 | pmid = 9103501 }}</ref>

Due to its quick metabolism and short effects, remifentanil has opened up new possibilities in anesthesia. When remifentanil is used together with a hypnotic (i.e. one that produces sleep) it can be used in relative high doses. This is because remifentanil is rapidly eliminated from the blood plasma on termination of the remifentanil infusion; hence the effects of the drug quickly dissipate even after very long infusions. Owing to synergism between remifentanil and hypnotic drugs (such as [[propofol]]) the dose of the hypnotic can be substantially reduced.<ref name = Patel>{{cite journal | vauthors = Patel SS, Spencer CM | title = Remifentanil | journal = Drugs | volume = 52 | issue = 3 | pages = 417–27; discussion 428 | date = September 1996 | pmid = 8875131 | doi = 10.2165/00003495-199652030-00009 | s2cid = 265900417 }}</ref> This leads often to more hemodynamic stability during surgery and a quicker post-operative recovery time.

==Side-effects==

Remifentanil is a specific [[Μ-opioid receptor|μ-receptor]] agonist.<ref name = Patel/> Hence, it causes a reduction in [[sympathetic nervous system]] tone, [[respiratory depression]] and [[analgesia]]. The drug's effects include a dose-dependent decrease in [[heart rate]] and [[arterial pressure]] and [[respiratory rate]] and [[tidal volume]]. [[Muscle rigidity]] is sometimes noted.

The most common side effects reported by patients receiving this medication are a sense of extreme "dizziness" (often short lived, a common side effect of other fast-acting synthetic phenylpiperidine narcotics such as [[fentanyl]] and [[alfentanil]]) and intense itching ([[pruritus]]), often around the face. These side effects are often controlled by either altering the administered dose (decreasing or in some cases, increasing the dose) or by administering other [[sedative]]s that allow the patient to tolerate or lose awareness of the side effect.

Because pruritus is partially due to excessive serum histamine levels, antihistamines such as [[diphenhydramine]] (Benadryl) are often co-administered. This is done with care, however, as excessive sedation may occur.

Nausea can occur as a side effect of remifentanil, however, it is usually transient in nature due to the drug's short half-life which rapidly removes it from the patient's [[Circulatory system|circulation]] once the infusion is terminated.

==Potency==

Comparing its analgesia-sedation effect in ventilated patients, remifentanil may be superior to morphine<ref>{{cite journal | vauthors = Dahaba AA, Grabner T, Rehak PH, List WF, Metzler H | title = Remifentanil versus morphine analgesia and sedation for mechanically ventilated critically ill patients: a randomized double blind study | journal = Anesthesiology | volume = 101 | issue = 3 | pages = 640–646 | date = September 2004 | pmid = 15329588 | doi = 10.1097/00000542-200409000-00012 | s2cid = 17192694 | doi-access = free }}</ref> but not to fentanyl.<ref>{{cite journal | vauthors = Spies C, Macguill M, Heymann A, Ganea C, Krahne D, Assman A, Kosiek HR, Scholtz K, Wernecke KD, Martin J | display-authors = 6 | title = A prospective, randomized, double-blind, multicenter study comparing remifentanil with fentanyl in mechanically ventilated patients | journal = Intensive Care Medicine | volume = 37 | issue = 3 | pages = 469–476 | date = March 2011 | pmid = 21165734 | doi = 10.1007/s00134-010-2100-5 | doi-access = free }}</ref>

==Circumventing naltrexone==

Remifentanil has been used with some success to circumvent [[naltrexone]] in patients who are in need of pain management.

== Abuse potential ==

Remifentanil, being a [[Μ-opioid receptor|μ-receptor]] [[agonist]], functions like other μ-receptor agonists, such as [[morphine]] and [[codeine]]; it can cause euphoria and has the potential for abuse.<ref>{{cite journal | vauthors = Ternes JW, O'Brien CP | date = 1990 | title = The opioids: Abuse liability and treatments for dependence. | journal = Advances in Alcohol & Substance Abuse | volume = 9 | issue = 1–2 | pages = 27–45 | doi = 10.1300/J251v09n01_03| pmid = 2198785 | url = https://www.ojp.gov/ncjrs/virtual-library/abstracts/opioids-abuse-liability-and-treatments-dependence-addiction }}</ref><ref name="pmid10867977">{{cite journal | vauthors = Panlilio LV, Schindler CW | title = Self-administration of remifentanil, an ultra-short acting opioid, under continuous and progressive-ratio schedules of reinforcement in rats | journal = Psychopharmacology | volume = 150 | issue = 1 | pages = 61–6 | date = May 2000 | pmid = 10867977 | doi = 10.1007/s002130000415 | s2cid = 21623038 }}</ref> However, due to its rapid metabolism and short-acting half-life the likelihood of abuse is quite low. Nevertheless, there have been some documentations of remifentanil abuse.<ref name="pmid11106130">{{cite journal | vauthors = Baylon GJ, Kaplan HL, Somer G, Busto UE, Sellers EM | title = Comparative abuse liability of intravenously administered remifentanil and fentanyl | journal = Journal of Clinical Psychopharmacology | volume = 20 | issue = 6 | pages = 597–606 | date = December 2000 | pmid = 11106130 | doi = 10.1097/00004714-200012000-00002 }}</ref><ref name="pmid19917624">{{cite journal | vauthors = Levine AI, Bryson EO | title = Intranasal self-administration of remifentanil as the foray into opioid abuse by an anesthesia resident | journal = Anesthesia and Analgesia | volume = 110 | issue = 2 | pages = 524–5 | date = February 2010 | pmid = 19917624 | doi = 10.1213/ANE.0b013e3181c5f069 | doi-access = free }}</ref>

== Development and marketing ==

Prior to the development of remifentanil, most short-acting hypnotics and amnestics faced issues with prolonged use, where accumulation would result in unfavorable lingering effects during post-operative recovery. Remifentanil was designed to serve as a strong anesthetic with an ultra-short and predictable duration that would not have accumulation issues.<ref>{{cite journal | vauthors = Feldman PL, Chorghade MS | veditors = Chorghade MS | title = Discovery and development of the ultrashort-acting analgesic remifentanil. | journal = Drug Discovery and Development. | publisher = Wiley Online Library | date = July 2006 | volume = 18 | pages = 339–342 | doi = 10.1002/0471780103 | isbn = 9780471398486 }}</ref>

Remifentanil was patented by [[GlaxoSmithKline|Glaxo Wellcome Inc.]]<ref>{{cite patent | inventor = Gatlin LA, Heiman SA, Lewis JS | title = Stable formulations of remifentanil | country = US | number = 5866591 | gdate = 2 February 1999 }}</ref> and was FDA approved on July 12, 1996.<ref>{{cite book | publisher = US Food and Drug Administration. | date = 2010 | title = Orange book: approved drug products with therapeutic equivalence evaluations. | location = Silver Spring, MD }}</ref> Its patent ended on the 10th of September 2017.

==Regulation==

In [[Hong Kong]], remifentanil is regulated under Schedule 1 of [[Hong Kong|Hong Kong's]] Chapter 134 ''Dangerous Drugs Ordinance''. It can only be used legally by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without prescription can be fined {{Currency|10000|HKD}} ({{Currency|{{To USD|10000|China|r=-1}}|USD}}). The penalty for trafficking or manufacturing the substance is a {{Currency|5000000|HKD}} ({{Currency|{{To USD|5000000|China|r=-3}}|USD}}) fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a {{Currency|1000000|HKD}} ({{Currency|{{To USD|1000000|China|r=-3}}|USD}}) fine and/or 7{{nbs}}years of jail time.

Remifentanil is a Schedule II narcotic controlled substance in the United States with a DEA ACSCN of 9739 and a 2013 annual aggregate manufacturing quota of 3,750{{nbs}}grams, unchanged from the prior year.

== References ==

{{Reflist}}

== External links ==

* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/remifentanil | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Remifentanil }}

* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/remifentanil%20hydrochloride | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Remifentanil Hydrochloride }}

{{General anesthetics}}

{{Analgesics}}

{{Opioidergics}}

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