Remifentanil

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Remifentanil
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Clinical data
Trade names Ultiva
Other namesmethyl 1-(2-methoxycarbonylethyl)-4-(phenyl-propanoyl-amino)-piperidine-4-carboxylate
AHFS/Drugs.com Monograph
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category
  • AU:C
Routes of
administration 		Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 0
Protein binding 70% (bound to plasma proteins)
Metabolism cleaved by non-specific plasma and tissue esterases
Elimination half-life 1-20 minutes
Identifiers
  • methyl 1-(3-methoxy-3-oxopropyl)-4-(N-phenylpropanamido)piperidine-4-carboxylate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
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KEGG
ChEBI
ChEMBL
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ECHA InfoCard 100.211.201 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C20H28N2O5
Molar mass 376.453 g·mol−1
3D model (JSmol)
Melting point 5 °C (41 °F)
  • O=C(OC)C2(N(c1ccccc1)C(=O)CC)CCN(CCC(=O)OC)CC2
  • InChI=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 Yes check.svgY
  • Key:ZTVQQQVZCWLTDF-UHFFFAOYSA-N Yes check.svgY
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Remifentanil, marketed under the brand name Ultiva is a potent, short-acting synthetic opioid analgesic 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.

Contents

Clinical use

Remifentanil is used as an opioid analgesic that has a rapid onset and rapid recovery time. [2] It has been used effectively during craniotomies, [3] spinal surgery, [4] cardiac surgery, [5] and gastric bypass surgery. [6] While opiates function similarly, with respect to analgesia, the pharmacokinetics of remifentanil [7] allows for quicker post-operative recovery. [8]

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). [9] 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 (µg/kg)/min. [10]

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 ng/ml are commonly used, but it generally varies between 3–8 ng/ml. For certain surgical procedures that produce particularly strong stimuli a level of up to 15 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. [11]

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. [12]

In combination with propofol, remifentanil is used for anesthesia of patients undergoing electroconvulsive therapy. [13]

Metabolism

Remifentanil is considered a metabolic soft drug, [14] 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 esterases. 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. [15]

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. [16] This leads often to more hemodynamic stability during surgery and a quicker post-operative recovery time.

Side-effects

Remifentanil is a specific μ-receptor agonist. [16] 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 sedatives 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 circulation once the infusion is terminated.

Potency

Comparing its analgesia-sedation effect in ventilated patients, remifentanil may be superior to morphine [17] but not to fentanyl. [18]

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-receptor agonist, functions like other μ-receptor agonists, such as morphine and codeine; it can cause euphoria and has the potential for abuse. [19] [20] 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. [21] [22]

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. [23]

Remifentanil was patented by Glaxo Wellcome Inc. [24] and was FDA approved on July 12, 1996. [25] Its patent ended on the 10th of September 2017.

Regulation

In Hong Kong, remifentanil is regulated under Schedule 1 of 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 HK$ 10,000 (US$ 1,550). The penalty for trafficking or manufacturing the substance is a HK$ 5,000,000 (US$ 775,000) fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a HK$ 1,000,000 (US$ 155,000) fine and/or 7 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 grams, unchanged from the prior year.

Related Research Articles

General anaesthetics are often defined as compounds that induce a loss of consciousness in humans or loss of righting reflex in animals. Clinical definitions are also extended to include an induced coma that causes lack of awareness to painful stimuli, sufficient to facilitate surgical applications in clinical and veterinary practice. General anaesthetics do not act as analgesics and should also not be confused with sedatives. General anaesthetics are a structurally diverse group of compounds whose mechanisms encompass multiple biological targets involved in the control of neuronal pathways. The precise workings are the subject of some debate and ongoing research.

<span class="mw-page-title-main">Anesthesia</span> State of medically-controlled temporary loss of sensation or awareness

Anesthesia or anaesthesia is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia, paralysis, amnesia, and unconsciousness. An individual under the effects of anesthetic drugs is referred to as being anesthetized.

<span class="mw-page-title-main">Fentanyl</span> Opioid medication

Fentanyl is a potent synthetic piperidine opioid primarily used as an analgesic. It is 50 times more potent than heroin and 100 times more potent than morphine; its primary clinical utility is in pain management for cancer patients and those recovering from painful surgeries. Fentanyl is also used as a sedative. Depending on the method of delivery, fentanyl can be very fast acting and ingesting a relatively small quantity can cause overdose. Fentanyl works by activating μ-opioid receptors. Fentanyl is sold under the brand names Actiq, Duragesic and Sublimaze, among others.

<span class="mw-page-title-main">General anaesthesia</span> Medically induced loss of consciousness

General anaesthesia (UK) or general anesthesia (US) is a method of medically inducing loss of consciousness that renders a patient unarousable even with painful stimuli. This effect is achieved by administering either intravenous or inhalational general anaesthetic medications, which often act in combination with an analgesic and neuromuscular blocking agent. Spontaneous ventilation is often inadequate during the procedure and intervention is often necessary to protect the airway. General anaesthesia is generally performed in an operating theater to allow surgical procedures that would otherwise be intolerably painful for a patient, or in an intensive care unit or emergency department to facilitate endotracheal intubation and mechanical ventilation in critically ill patients. Depending on the procedure, general anaesthesia may be optional or required. Regardless of whether a patient may prefer to be unconscious or not, certain pain stimuli could result in involuntary responses from the patient that may make an operation extremely difficult. Thus, for many procedures, general anaesthesia is required from a practical perspective.

<span class="mw-page-title-main">Propofol</span> Intravenous medication used in anesthesia

Propofol is the active component of an intravenous anesthetic formulation used for induction and maintenance of general anesthesia. It is chemically termed 2,6-diisopropylphenol. The formulation was approved under the brand name Diprivan. Numerous generic versions have since been released. Intravenous administration is used to induce unconsciousness after which anesthesia may be maintained using a combination of medications. It is manufactured as part of a sterile injectable emulsion formulation using soybean oil and lecithin, giving it a white milky coloration.

<span class="mw-page-title-main">Anesthetic</span> Drug that causes anesthesia

An anesthetic or anaesthetic is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into two broad classes: general anesthetics, which result in a reversible loss of consciousness, and local anesthetics, which cause a reversible loss of sensation for a limited region of the body without necessarily affecting consciousness.

<span class="mw-page-title-main">Carfentanil</span> Synthetic opioid analgesic

Carfentanil or carfentanyl, sold under the brand name Wildnil, is an extremely potent opioid analgesic used in veterinary medicine to anesthetize large animals such as elephants and rhinoceroses. It is typically administered in this context by tranquilizer dart. Carfentanil has also been used in humans to image opioid receptors. It has additionally been used as a recreational drug, typically by injection, insufflation, or inhalation. Deaths have been reported in association with carfentanil.

<span class="mw-page-title-main">Epidural administration</span> Medication injected into the epidural space of the spine

Epidural administration is a method of medication administration in which a medicine is injected into the epidural space around the spinal cord. The epidural route is used by physicians and nurse anesthetists to administer local anesthetic agents, analgesics, diagnostic medicines such as radiocontrast agents, and other medicines such as glucocorticoids. Epidural administration involves the placement of a catheter into the epidural space, which may remain in place for the duration of the treatment. The technique of intentional epidural administration of medication was first described in 1921 by Spanish military surgeon Fidel Pagés.

<span class="mw-page-title-main">Sufentanil</span> Synthetic opioid analgesic drug

Sufentanil, sold under the brand names Dsuvia and Sufenta, is a synthetic opioid analgesic drug approximately 5 to 10 times as potent as its parent drug, fentanyl, and 500 times as potent as morphine. Structurally, sufentanil differs from fentanyl through the addition of a methoxymethyl group on the piperidine ring, and the replacement of the phenyl ring by thiophene. Sufentanil first was synthesized at Janssen Pharmaceutica in 1974.

<span class="mw-page-title-main">Nalbuphine</span> Opioid analgesic

Nalbuphine, sold under the brand names Nubain among others, is an opioid analgesic which is used in the treatment of pain. It is given by injection into a vein, muscle, or fat.

<span class="mw-page-title-main">Dexmedetomidine</span> Anxiolytic, sedative, and pain medication

Dexmedetomidine, sold under the trade name Precedex among others, is a drug used in humans for sedation. Veterinarians use dexmedetomidine for similar purposes in treating cats, dogs, and horses. It is also used in humans to treat acute agitation associated with schizophrenia or bipolar I or II disorder.

<span class="mw-page-title-main">Dihydroetorphine</span> Opioid analgesic drug

Dihydroetorphine was developed by K. W. Bentley at McFarlan-Smith in the 1960s and is a potent opioid analgesic used mainly in China. It is a derivative of the better-known opioid etorphine, a very potent veterinary painkiller and anesthetic medication used primarily for the sedation of large animals such as elephants, giraffes, and rhinos.

Veterinary anesthesia is a specialization in the veterinary medicine field dedicated to the proper administration of anesthetic agents to non-human animals to control their consciousness during procedures. A veterinarian or a Registered Veterinary Technician administers these drugs to minimize stress, destructive behavior, and the threat of injury to both the patient and the doctor. The duration of the anesthesia process goes from the time before an animal leaves for the visit to the time after the animal reaches home after the visit, meaning it includes care from both the owner and the veterinary staff. Generally, anesthesia is used for a wider range of circumstances in animals than in people not only due to their inability to cooperate with certain diagnostic or therapeutic procedures, but also due to their species, breed, size, and corresponding anatomy. Veterinary anesthesia includes anesthesia of the major species: dogs, cats, horses, cattle, sheep, goats, and pigs, as well as all other animals requiring veterinary care such as birds, pocket pets, and wildlife.

<span class="mw-page-title-main">Medetomidine</span> Chemical compound

Medetomidine is a synthetic drug used as both a surgical anesthetic and analgesic. It is often used as the hydrochloride salt, medetomidine hydrochloride, a crystalline white solid. It is an α2 adrenergic agonist that can be administered as an intravenous drug solution with sterile water.

<span class="mw-page-title-main">Twilight anesthesia</span> Anesthetic technique

Twilight anesthesia is an anesthetic technique where a mild dose of sedation is applied to induce anxiolysis, hypnosis, and anterograde amnesia. The patient is not unconscious, but sedated. During surgery or other medical procedures, the patient is under what is known as a "twilight state", where the patient is relaxed and "sleepy", able to follow simple directions by the doctor, and is responsive. Generally, twilight anesthesia causes the patient to forget the surgery and the time right after. It is used for a variety of surgical procedures and for various reasons. Just like regular anesthesia, twilight anesthesia is designed to help a patient feel more comfortable and to minimize pain associated with the procedure being performed and to allow the medical practitioner to practice without interruptions.

<span class="mw-page-title-main">Patient-controlled analgesia</span> Administration of pain relief medication by a patient

Patient-controlled analgesia (PCA) is any method of allowing a person in pain to administer their own pain relief. The infusion is programmable by the prescriber. If it is programmed and functioning as intended, the machine is unlikely to deliver an overdose of medication. Providers must always observe the first administration of any PCA medication which has not already been administered by the provider to respond to allergic reactions.

<span class="mw-page-title-main">Coinduction (anesthetics)</span>

Coinduction in anesthesia is a pharmacological tool whereby a combination of sedative drugs may be used to greater effect than a single agent, achieving a smoother onset of general anesthesia. The use of coinduction allows lower doses of the same anesthetic agents to be used which provides enhanced safety, faster recovery, fewer side-effects, and more predictable pharmacodynamics. Coinduction is used in human medicine and veterinary medicine as standard practice to provide optimum anesthetic induction. The onset or induction phase of anesthesia is a critical period involving the loss of consciousness and reactivity in the patient, and is arguably the most dangerous period of a general anesthetic. A great variety of coinduction combinations are in use and selection is dependent on the patient's age and health, the specific situation, and the indication for anesthesia. As with all forms of anesthesia the resources available in the environment are a key factor.

Total intravenous anesthesia (TIVA) refers to the intravenous administration of anesthetic agents to induce a temporary loss of sensation or awareness. The first study of TIVA was done in 1872 using chloral hydrate, and the common anesthetic agent propofol was licensed in 1986. TIVA is currently employed in various procedures as an alternative technique of general anesthesia in order to improve post-operative recovery.

<span class="mw-page-title-main">Remifentanilic acid</span> Inactive metabolite of remifentanil

Remifentanilic acid is a metabolite of the potent short-acting synthetic opioid analgesic drug remifentanil. It is an analog of fentanyl and remifentanil, but is not active as an opioid in its own right.

<span class="mw-page-title-main">Talmage Egan</span> American academic

Talmage D. Egan is an anesthesiologist, academic, entrepreneur, and author. He is a professor and chair in the department of anesthesiology, and an adjunct professor in the departments of pharmaceutics, bioengineering, and neurosurgery at the University of Utah School of Medicine.

References

  1. ↑ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  2. ↑ "Remifentanil, IV opioid analgesic, Remi | Ultiva". www.ultiva.com. Retrieved 2015-11-30.
  3. ↑ Gesztesi Z, Mootz BL, White PF (November 1999). "The use of a remifentanil infusion for hemodynamic control during intracranial surgery". Anesthesia and Analgesia. 89 (5): 1282–7. doi: 10.1213/00000539-199911000-00038 . PMID   10553851.
  4. ↑ Grottke O, Dietrich PJ, Wiegels S, Wappler F (November 2004). "Intraoperative wake-up test and postoperative emergence in patients undergoing spinal surgery: a comparison of intravenous and inhaled anesthetic techniques using short-acting anesthetics". Anesthesia and Analgesia. 99 (5): 1521–1527. doi: 10.1213/01.ANE.0000134684.25322.26 . PMID   15502058. S2CID   45361690.
  5. ↑ Knapik M, Knapik P, Nadziakiewicz P, Misiołek H, Saucha W, Walaszczyk M, Dyaczyńska-Herman A (August 2006). "Comparison of remifentanil or fentanyl administration during isoflurane anesthesia for coronary artery bypass surgery". Medical Science Monitor. 12 (8): PI33–8. PMID   16865075.
  6. ↑ De Baerdemaeker LE, Jacobs S, Pattyn P, Mortier EP, Struys MM (September 2007). "Influence of intraoperative opioid on postoperative pain and pulmonary function after laparoscopic gastric banding: remifentanil TCI vs sufentanil TCI in morbid obesity". British Journal of Anaesthesia. 99 (3): 404–11. doi: 10.1093/bja/aem164 . PMID   17606479.
  7. ↑ Michelsen LG, Hug Jr CC (December 1996). "The pharmacokinetics of remifentanil". Journal of Clinical Anesthesia. 8 (8): 679–82. doi:10.1016/s0952-8180(96)00179-1. PMID   8982900.
  8. ↑ Guy J, Hindman BJ, Baker KZ, Borel CO, Maktabi M, Ostapkovich N, et al. (March 1997). "Comparison of remifentanil and fentanyl in patients undergoing craniotomy for supratentorial space-occupying lesions". Anesthesiology. 86 (3): 514–524. doi: 10.1097/00000542-199703000-00002 . PMID   9066316.
  9. ↑ Weale NK, Rogers CA, Cooper R, Nolan J, Wolf AR (February 2004). "Effect of remifentanil infusion rate on stress response to the pre-bypass phase of paediatric cardiac surgery". British Journal of Anaesthesia. 92 (2): 187–194. doi: 10.1093/bja/aeh038 . PMID   14722167.
  10. ↑ "Remifentanil Actavis" (in Swedish). Retrieved 21 Aug 2014.
  11. ↑ White LD, Hodsdon A, An GH, Thang C, Melhuish TM, Vlok R (November 2019). "Induction opioids for caesarean section under general anaesthesia: a systematic review and meta-analysis of randomised controlled trials". International Journal of Obstetric Anesthesia. 40: 4–13. doi: 10.1016/j.ijoa.2019.04.007 . hdl: 10072/416502 . PMID   31230994.
  12. ↑ Stocki D, Matot I, Einav S, Eventov-Friedman S, Ginosar Y, Weiniger CF (March 2014). "A randomized controlled trial of the efficacy and respiratory effects of patient-controlled intravenous remifentanil analgesia and patient-controlled epidural analgesia in laboring women". Anesthesia and Analgesia. 118 (3): 589–597. doi: 10.1213/ANE.0b013e3182a7cd1b . PMID   24149580. S2CID   4844447.
  13. ↑ Ulusoy H, Cekic B, Besir A, Geze S, Hocaoglu C, Akdogan A (February 2014). "Sevoflurane/remifentanil versus propofol/remifentanil for electroconvulsive therapy: comparison of seizure duration and haemodynamic responses". The Journal of International Medical Research. 42 (1): 111–119. doi: 10.1177/0300060513509036 . PMID   24398757.
  14. ↑ Bodor N, Buchwald P (January 2000). "Soft drug design: general principles and recent applications". Medicinal Research Reviews. 20 (1): 58–101. doi:10.1002/(SICI)1098-1128(200001)20:1<58::AID-MED3>3.0.CO;2-X. PMID   10608921. S2CID   25119421.
  15. ↑ Hoke JF, Cunningham F, James MK, Muir KT, Hoffman WE (April 1997). "Comparative pharmacokinetics and pharmacodynamics of remifentanil, its principle metabolite (GR90291) and alfentanil in dogs". The Journal of Pharmacology and Experimental Therapeutics. 281 (1): 226–232. PMID   9103501.
  16. 1 2 Patel SS, Spencer CM (September 1996). "Remifentanil". Drugs. 52 (3): 417–27, discussion 428. doi:10.2165/00003495-199652030-00009. PMID   8875131. S2CID   265900417.
  17. ↑ Dahaba AA, Grabner T, Rehak PH, List WF, Metzler H (September 2004). "Remifentanil versus morphine analgesia and sedation for mechanically ventilated critically ill patients: a randomized double blind study". Anesthesiology. 101 (3): 640–646. doi: 10.1097/00000542-200409000-00012 . PMID   15329588. S2CID   17192694.
  18. ↑ Spies C, Macguill M, Heymann A, Ganea C, Krahne D, Assman A, et al. (March 2011). "A prospective, randomized, double-blind, multicenter study comparing remifentanil with fentanyl in mechanically ventilated patients". Intensive Care Medicine. 37 (3): 469–476. doi: 10.1007/s00134-010-2100-5 . PMID   21165734.
  19. ↑ Ternes JW, O'Brien CP (1990). "The opioids: Abuse liability and treatments for dependence". Advances in Alcohol & Substance Abuse. 9 (1–2): 27–45. doi:10.1300/J251v09n01_03. PMID   2198785.
  20. ↑ Panlilio LV, Schindler CW (May 2000). "Self-administration of remifentanil, an ultra-short acting opioid, under continuous and progressive-ratio schedules of reinforcement in rats". Psychopharmacology. 150 (1): 61–6. doi:10.1007/s002130000415. PMID   10867977. S2CID   21623038.
  21. ↑ Baylon GJ, Kaplan HL, Somer G, Busto UE, Sellers EM (December 2000). "Comparative abuse liability of intravenously administered remifentanil and fentanyl". Journal of Clinical Psychopharmacology. 20 (6): 597–606. doi:10.1097/00004714-200012000-00002. PMID   11106130.
  22. ↑ Levine AI, Bryson EO (February 2010). "Intranasal self-administration of remifentanil as the foray into opioid abuse by an anesthesia resident". Anesthesia and Analgesia. 110 (2): 524–5. doi: 10.1213/ANE.0b013e3181c5f069 . PMID   19917624.
  23. ↑ Feldman PL, Chorghade MS (July 2006). Chorghade MS (ed.). "Discovery and development of the ultrashort-acting analgesic remifentanil". Drug Discovery and Development. 18. Wiley Online Library: 339–342. doi:10.1002/0471780103. ISBN   9780471398486.
  24. ↑ US 5866591,Gatlin LA, Heiman SA, Lewis JS,"Stable formulations of remifentanil",issued 2 February 1999
  25. ↑ Orange book: approved drug products with therapeutic equivalence evaluations. Silver Spring, MD: US Food and Drug Administration. 2010.
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