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Identification
Name Butorphanol
Accession Number DB00611 (APRD00835)
Type small molecule
Groups illicit, approved
Description

A synthetic morphinan analgesic with narcotic antagonist action. It is used in the management of severe pain. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Butorfanol
  • Butorfanol [INN-Spanish]
  • Butorphanol Tartrate
  • Butorphanolum [INN-Latin]
Brand names
  • Beforal
  • Moradol
  • Stadol
  • Stadol NS
Brand name mixtures Not Available
Categories
  • Narcotics
  • Analgesics, Opioid
  • Antitussive Agents
  • Narcotic Antagonists
CAS number 58786-99-5
Weight Average: 327.4605
Monoisotopic: 327.219829177
Chemical Formula C21H29NO2
InChI Key InChIKey=IFKLAQQSCNILHL-PWRODBHTSA-N
InChI
InChI=1S/C21H29NO2/c23-17-7-6-16-12-19-21(24)9-2-1-8-20(21,18(16)13-17)10-11-22(19)14-15-4-3-5-15/h6-7,13,15,19,23-24H,1-5,8-12,14H2/t19-,20+,21+/m0/s1
Plain Text
IUPAC Name
(1S,9R,10S)-17-(cyclobutylmethyl)-17-azatetracyclo[7.5.3.0^{1,10}.0^{2,7}]heptadeca-2(7),3,5-triene-4,10-diol
SMILES
[H][C@@]12CC3=C(C=C(O)C=C3)[C@]3(CCCC[C@@]13O)CCN2CC1CCC1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Morphinans
  • Benzylisoquinolines
Substructures
  • Morphinans
  • Hydroxy Compounds
  • Naphthalenes
  • Phenols and Derivatives
  • Benzylisoquinolines
  • Benzene and Derivatives
  • Phenylpiperidines
  • Aliphatic and Aryl Amines
  • Alcohols and Polyols
  • Cyclobutane and Derivatives
  • Phenanthrenes
  • Phenethylamines
  • Heterocyclic compounds
  • Aromatic compounds
  • Phenylpropylamines
  • (Iso)quinolines and Derivatives
  • Cyclohexenes and Derivatives
  • Phenyl Esters
  • Amphetamines
  • Piperidines
Pharmacology
Indication For the relief of moderate to severe pain.
Pharmacodynamics Butorphanol is a synthetic opioid agonist-antagonist analgesic with a pharmacological and therapeutic profile that has been well established since its launch as a parenteral formulation in 1978. The introduction of a transnasal formulation of butorphanol represents a new and noninvasive presentation of an analgesic for moderate to severe pain. This route of administration bypasses the gastrointestinal tract, and this is an advantage for a drug such as butorphanol that undergoes significant first-pass metabolism after oral administration. The onset of action and systemic bioavailability of butorphanol following transnasal delivery are similar to those after parenteral administration. Butorphanol blocks pain impulses at specific sites in the brain and spinal cord.
Mechanism of action The exact mechanism of action is unknown, but is believed to interact with an opiate receptor site in the CNS (probably in or associated with the limbic system). The opiate antagonistic effect may result from competitive inhibition at the opiate receptor, but may also be a result of other mechanisms. Butorphanol is a mixed agonist-antagonist that exerts antagonistic or partially antagonistic effects at mu opiate receptor sites, but is thought to exert its agonistic effects principally at the kappa and sigma opiate receptors.
Absorption Rapidly absorbed after intramuscular injection and peak plasma levels are reached in 20-40 minutes. The absolute bioavailability is 60-70% and is unchanged in patients with allergic rhinitis. In patients using a nasal vasoconstrictor (oxymetazoline) the fraction of the dose absorbed was unchanged, but the rate of absorption was slowed. Oral bioavailability is only 5-17% because of extensive first-pass metabolism.
Volume of distribution
  • 305 to 901 L
Protein binding Serum protein binding is approximately 80%.
Metabolism

Extensively metabolized in the liver. The pharmacological activity of butorphanol metabolites has not been studied in humans; in animal studies, butorphanol metabolites have demonstrated some analgesic activity.
Route of elimination Butorphanol is extensively metabolized in the liver. Elimination occurs by urine and fecal excretion.
Half life The elimination half-life of butorphanol is about 18 hours. In renally impaired patients with creatinine clearances <30 mL/min the elimination half-life is approximately doubled. After intravenous administration to patients with hepatic impairment, the elimination half-life of butorphanol was approximately tripled.
Clearance
  • 99 +/- 23 L/h [Young with IV 2 mg]
  • 82 +/- 21 [Eldery with IV 2 mg]
Toxicity The clinical manifestations of butorphanol overdose are those of opioid drugs in general. The most serious symptoms are hypoventilation, cardiovascular insufficiency, coma, and death.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Bedford laboratories div ben venue laboratories inc
  • Claris lifesciences ltd
  • Hikma farmaceutica (portugal) sa
  • Hikma farmaceutica sa
  • Hospira inc
  • Apothecon inc div bristol myers squibb
  • Mylan pharmaceuticals inc
  • Novex pharma
  • Roxane laboratories inc
  • Bristol myers squibb co pharmaceutical research institute
Packagers
Dosage forms
Form Route Strength
Liquid Nasal
Spray Nasal
Prices
Unit description Cost Unit
Butorphanol Tartrate 10 mg/ml Solution 2.5ml Bottle 56.99 USD bottle
Butorphanol 10 mg/ml spray 39.63 USD ml
Stadol 2 mg/ml vial 10.11 USD ml
Butorphanol 2 mg/ml vial 7.2 USD ml
Butorphanol 1 mg/ml vial 3.6 USD ml
Patents Not Available
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
water solubility Moderate PhysProp
logP 3.3 PhysProp
Predicted Properties
Property Value Source
water solubility 1.60e-01 g/l ALOGPS
logP 3.65 ALOGPS
logP 2.86 ChemAxon Molconvert
logS -3.31 ALOGPS
pKa 13.73 ChemAxon Molconvert
hydrogen acceptor count 3 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 43.70 ChemAxon Molconvert
rotatable bond count 2 ChemAxon Molconvert
refractivity 95.92 ChemAxon Molconvert
polarizability 37.94 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Gear RW, Miaskowski C, Gordon NC, Paul SM, Heller PH, Levine JD: The kappa opioid nalbuphine produces gender- and dose-dependent analgesia and antianalgesia in patients with postoperative pain. Pain. 1999 Nov;83(2):339-45. Pubmed
  2. Fan LW, Tanaka S, Tien LT, Ma T, Rockhold RW, Ho IK: Withdrawal from dependence upon butorphanol uniquely increases kappa(1)-opioid receptor binding in the rat brain. Brain Res Bull. 2002 Jun;58(2):149-60. Pubmed
External Links
Resource Link
KEGG Drug D00837 Link_out
PubChem Compound 6916249 Link_out
PubChem Substance 46507553 Link_out
ChemSpider 4514667 Link_out
BindingDB 50240437 Link_out
ChEBI 3242 Link_out
ChEMBL 3242 Link_out
Therapeutic Targets Database DAP000214 Link_out
PharmGKB PA448703 Link_out
Drug Product Database 844977 Link_out
RxList http://www.rxlist.com/cgi/generic2/butor.htm Link_out
Drugs.com http://www.drugs.com/cdi/butorphanol-solution.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Butorphanol Link_out
ATC Codes
  • N02AF01
AHFS Codes
  • 28:08.12
PDB Entries Not Available
FDA label show (319.5 KB)
MSDS show (60.6 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • Avoid alcohol.
Targets

1. Kappa-type opioid receptor

Pharmacological action: yes
Actions: agonist

Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Receptor for dynorphins. May play a role in arousal and regulation of autonomic and neuroendocrine functions

Organism class: human
UniProt ID: P41145 Link_out
Gene: OPRK1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Vivian JA, DeYoung MB, Sumpter TL, Traynor JR, Lewis JW, Woods JH: kappa-Opioid receptor effects of butorphanol in rhesus monkeys. J Pharmacol Exp Ther. 1999 Jul;290(1):259-65. Pubmed
  2. Park Y, Jang CG, Ho IK, Ko KH: kappa-opioid agonist stimulated regional distribution of [(35)S]GTPgammas binding in butorphanol continuously infused rat. Brain Res Bull. 2000 May 1;52(1):17-20. Pubmed
  3. Fan LW, Tanaka S, Tien LT, Ma T, Rockhold RW, Ho IK: Withdrawal from dependence upon butorphanol uniquely increases kappa(1)-opioid receptor binding in the rat brain. Brain Res Bull. 2002 Jun;58(2):149-60. Pubmed
  4. Fan LW, Tanaka S, Park Y, Sasaki K, Ma T, Tien LT, Rockhold RW, Ho IK: Butorphanol dependence and withdrawal decrease hippocampal kappa 2-opioid receptor binding. Brain Res. 2002 Dec 27;958(2):277-90. Pubmed
  5. Commiskey S, Fan LW, Ho IK, Rockhold RW: Butorphanol: effects of a prototypical agonist-antagonist analgesic on kappa-opioid receptors. J Pharmacol Sci. 2005 Jun;98(2):109-16. Epub 2005 Jun 8. Pubmed
  6. Picker MJ, Benyas S, Horwitz JA, Thompson K, Mathewson C, Smith MA: Discriminative stimulus effects of butorphanol: influence of training dose on the substitution patterns produced by Mu, Kappa and Delta opioid agonists. J Pharmacol Exp Ther. 1996 Dec;279(3):1130-41. Pubmed
  7. Wakabayashi H, Tokuyama S, Ho IK: Simultaneous measurement of biogenic amines and their metabolites in rat brain regions after acute administration of and abrupt withdrawal from butorphanol or morphine. Neurochem Res. 1995 Oct;20(10):1179-85. Pubmed
  8. Narita M, Feng Y, Makimura M, Hoskins B, Ho IK: Repeated administration of opioids alters characteristics of membrane-bound phorbol ester binding in rat brain. Eur J Pharmacol. 1994 Dec 27;271(2-3):547-50. Pubmed
  9. Ohta S, Niwa M, Nozaki M, Tsurumi K, Shimonaka H, Tanahashi T, Uematsu H, Yamamoto M, Fujimura H: [Kappa-type opioid receptor in human placental membrane] Masui. 1989 Oct;38(10):1293-300. Pubmed
  10. Walsh SL, Chausmer AE, Strain EC, Bigelow GE: Evaluation of the mu and kappa opioid actions of butorphanol in humans through differential naltrexone blockade. Psychopharmacology (Berl). 2008 Jan;196(1):143-55. Epub 2007 Oct 2. Pubmed

2. Delta-type opioid receptor

Pharmacological action: yes
Actions: agonist

Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Highly stereoselective. receptor for enkephalins

Organism class: human
UniProt ID: P41143 Link_out
Gene: OPRD1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Fan LW, Tanaka S, Tien LT, Ma T, Rockhold RW, Ho IK: Withdrawal from dependence upon butorphanol uniquely increases kappa(1)-opioid receptor binding in the rat brain. Brain Res Bull. 2002 Jun;58(2):149-60. Pubmed
  2. Fan LW, Tanaka S, Park Y, Sasaki K, Ma T, Tien LT, Rockhold RW, Ho IK: Butorphanol dependence and withdrawal decrease hippocampal kappa 2-opioid receptor binding. Brain Res. 2002 Dec 27;958(2):277-90. Pubmed
  3. Commiskey S, Fan LW, Ho IK, Rockhold RW: Butorphanol: effects of a prototypical agonist-antagonist analgesic on kappa-opioid receptors. J Pharmacol Sci. 2005 Jun;98(2):109-16. Epub 2005 Jun 8. Pubmed
  4. Picker MJ, Benyas S, Horwitz JA, Thompson K, Mathewson C, Smith MA: Discriminative stimulus effects of butorphanol: influence of training dose on the substitution patterns produced by Mu, Kappa and Delta opioid agonists. J Pharmacol Exp Ther. 1996 Dec;279(3):1130-41. Pubmed
  5. Wakabayashi H, Tokuyama S, Ho IK: Simultaneous measurement of biogenic amines and their metabolites in rat brain regions after acute administration of and abrupt withdrawal from butorphanol or morphine. Neurochem Res. 1995 Oct;20(10):1179-85. Pubmed
  6. Narita M, Feng Y, Makimura M, Hoskins B, Ho IK: Repeated administration of opioids alters characteristics of membrane-bound phorbol ester binding in rat brain. Eur J Pharmacol. 1994 Dec 27;271(2-3):547-50. Pubmed
  7. Walsh SL, Chausmer AE, Strain EC, Bigelow GE: Evaluation of the mu and kappa opioid actions of butorphanol in humans through differential naltrexone blockade. Psychopharmacology (Berl). 2008 Jan;196(1):143-55. Epub 2007 Oct 2. Pubmed
  8. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

3. Mu-type opioid receptor

Pharmacological action: yes
Actions: partial antagonist

Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Receptor for beta-endorphin

Organism class: human
UniProt ID: P35372 Link_out
Gene: OPRM1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Vivian JA, DeYoung MB, Sumpter TL, Traynor JR, Lewis JW, Woods JH: kappa-Opioid receptor effects of butorphanol in rhesus monkeys. J Pharmacol Exp Ther. 1999 Jul;290(1):259-65. Pubmed
  2. Fan LW, Tanaka S, Tien LT, Ma T, Rockhold RW, Ho IK: Withdrawal from dependence upon butorphanol uniquely increases kappa(1)-opioid receptor binding in the rat brain. Brain Res Bull. 2002 Jun;58(2):149-60. Pubmed
  3. Fan LW, Tanaka S, Park Y, Sasaki K, Ma T, Tien LT, Rockhold RW, Ho IK: Butorphanol dependence and withdrawal decrease hippocampal kappa 2-opioid receptor binding. Brain Res. 2002 Dec 27;958(2):277-90. Pubmed
  4. Commiskey S, Fan LW, Ho IK, Rockhold RW: Butorphanol: effects of a prototypical agonist-antagonist analgesic on kappa-opioid receptors. J Pharmacol Sci. 2005 Jun;98(2):109-16. Epub 2005 Jun 8. Pubmed
  5. Picker MJ, Benyas S, Horwitz JA, Thompson K, Mathewson C, Smith MA: Discriminative stimulus effects of butorphanol: influence of training dose on the substitution patterns produced by Mu, Kappa and Delta opioid agonists. J Pharmacol Exp Ther. 1996 Dec;279(3):1130-41. Pubmed
  6. Wakabayashi H, Tokuyama S, Ho IK: Simultaneous measurement of biogenic amines and their metabolites in rat brain regions after acute administration of and abrupt withdrawal from butorphanol or morphine. Neurochem Res. 1995 Oct;20(10):1179-85. Pubmed
  7. Picker MJ: Discriminative stimulus effects of the mixed-opioid agonist/antagonist dezocine: cross-substitution by mu and delta opioid agonists. J Pharmacol Exp Ther. 1997 Dec;283(3):1009-17. Pubmed
  8. Narita M, Feng Y, Makimura M, Hoskins B, Ho IK: Repeated administration of opioids alters characteristics of membrane-bound phorbol ester binding in rat brain. Eur J Pharmacol. 1994 Dec 27;271(2-3):547-50. Pubmed
  9. Walsh SL, Chausmer AE, Strain EC, Bigelow GE: Evaluation of the mu and kappa opioid actions of butorphanol in humans through differential naltrexone blockade. Psychopharmacology (Berl). 2008 Jan;196(1):143-55. Epub 2007 Oct 2. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on April 19, 2011 15:05

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.