BUTORPHANOL

First approved in 1978

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C21H29NO2
Molecular Weight	327.4605
Optical Activity	UNSPECIFIED
Defined Stereocenters	3 / 3
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OC1=CC2=C(C[C@H]3N(CC4CCC4)CC[C@@]25CCCC[C@@]35O)C=C1

InChI

InChIKey=IFKLAQQSCNILHL-QHAWAJNXSA-N

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-/m1/s1

HIDE SMILES / InChI

Description
Sources: https://www.drugs.com/pro/butorphanol.html | https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19890s17lbl.pdf

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. Butorphanol has agonistic activity at the κ-receptor and antagonistic activity at the μ-receptor. It also exhibits partial agonistic activity at the σ-receptor.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Kappa opioid receptor 108 Target ID: CHEMBL237 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19890s17lbl.pdf \| https://www.ncbi.nlm.nih.gov/pubmed/21482470	Agonist 2678	0.12 nM [Ki]
Mu opioid receptor 221 Target ID: CHEMBL233 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19890s17lbl.pdf \| https://www.ncbi.nlm.nih.gov/pubmed/21482470	Partial Agonist 290	0.22 nM [Ki]
Delta opioid receptor 77 Target ID: CHEMBL236 Sources: https://www.drugbank.ca/drugs/DB00611 \| https://www.ncbi.nlm.nih.gov/pubmed/21482470	Agonist 2678	12.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Pain 614 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19890s17lbl.pdf	Palliative		Approved 8429	Butorphanol tartrate Approved Use Butorphanol tartrate injection is indicated as a preoperative or preanesthetic medication, as a supplement to balanced anesthesia, for the relief of pain during labor, and for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Launch Date 1978

C_max

Value	Dose	Co-administered	Analyte	Population
1376 pg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9113342/	1 mg 4 times / day steady-state, nasal dose: 1 mg route of administration: Nasal experiment type: STEADY-STATE co-administered:		BUTORPHANOL plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
1542 pg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9113342/	1 mg single, nasal dose: 1 mg route of administration: Nasal experiment type: SINGLE co-administered:		BUTORPHANOL plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
4130 pg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9113342/	1 mg 4 times / day steady-state, nasal dose: 1 mg route of administration: Nasal experiment type: STEADY-STATE co-administered:		BUTORPHANOL plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
4612 pg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9113342/	1 mg single, nasal dose: 1 mg route of administration: Nasal experiment type: SINGLE co-administered:		BUTORPHANOL plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
7.6 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9113342/	1 mg 4 times / day steady-state, nasal dose: 1 mg route of administration: Nasal experiment type: STEADY-STATE co-administered:	BUTORPHANOL plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
4.23 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9113342/	1 mg single, nasal dose: 1 mg route of administration: Nasal experiment type: SINGLE co-administered:	BUTORPHANOL plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
2.7 h REVIEW https://pubmed.ncbi.nlm.nih.gov/8031438	4 mg 1 times / day multiple, intramuscular dose: 4 mg route of administration: Intramuscular experiment type: MULTIPLE co-administered:	BUTORPHANOL plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
4 mg 1 times / day single, intramuscular Dose: 4 mg, 1 times / day Route: intramuscular Route: single Dose: 4 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/8031438	unhealthy Health Status: unhealthy Sources: https://pubmed.ncbi.nlm.nih.gov/8031438	Sources: https://pubmed.ncbi.nlm.nih.gov/8031438

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
Ca2+ channels 57 K+ channels 70	CYP 270

Drug as perpetrator

Target	Modality	Activity
L-type Ca2+ channels 30	activator 214 Sources: https://pubmed.ncbi.nlm.nih.gov/7556388/	likely
Ca2+ channels 60	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/11022297/	yes
K+ channels 70	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/11022297/	yes

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP 270	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/anda/98/75170_Butorphanol%20Tartrate.pdf Page: 5.0	likely

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:3242	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:3242
ZINC	ZINC000003812988	http://zinc15.docking.org/substances/ZINC000003812988
eMolecules	31229637	https://www.emolecules.com/cgi-bin/more?vid=31229637

PubMed

Title	Date	PubMed
Tolerance to the analgesic effect of buprenorphine, butorphanol, nalbuphine, and cyclorphan, and cross-tolerance to morphine.	2001	14569437
Noninvasive drug delivery.	2001 Winter	11765687
Analysis of synovial fluid from clinically normal alpacas and llamas.	2002 Apr	11939322
Comparison of transdermal administration of fentanyl versus intramuscular administration of butorphanol for analgesia after onychectomy in cats.	2002 Apr 1	12420780
Effect of medetomidine-butorphanol-ketamine anaesthesia and atipamezole on heart and respiratory rate and cloacal temperature of domestic pigeons.	2002 Aug	12227468
Effects of morphine, butorphanol, buprenorphine, and U50488H on the minimum alveolar concentration of isoflurane in cats.	2002 Aug	12171176
Nasal administration of opioids for pain management in adults.	2002 Aug	12139528
In vitro effects of oxytocin, acepromazine, detomidine, xylazine, butorphanol, terbutaline, isoproterenol, and dantrolene on smooth and skeletal muscles of the equine esophagus.	2002 Dec	12492290
Effects of medetomidine-midazolam, acepromazine-butorphanol, and midazolam-butorphanol on induction dose of thiopental and propofol and on cardiopulmonary changes in dogs.	2002 Dec	12492281
Focal kappa-opioid receptor-mediated dependence and withdrawal in the nucleus paragigantocellularis.	2002 Dec	12376173
Effect of acepromazine and butorphanol on isoflurane minimum alveolar concentration in goats.	2002 Feb	11874529
Effects of gonadal steroid hormone treatments on opioid antinociception in ovariectomized rhesus monkeys.	2002 Jan	11862360
Butorphanol and nalbuphine in opioid-dependent humans under a naloxone discrimination procedure.	2002 Jan-Feb	11812511
The effects of xylazine, detomidine, acepromazine and butorphanol on equine solid phase gastric emptying rate.	2002 Jul	12358052
Age-related differences in sensitivity to the antinociceptive effects of kappa opioids in adult male rats.	2002 Jul	12122483
Evaluation of the perioperative stress response in dogs administered medetomidine or acepromazine as part of the preanesthetic medication.	2002 Jul	12118677
Effects of medetomidine-midazolam, midazolambutorphanol, or acepromazine-butorphanol as premedicants for mask induction of anesthesia with sevoflurane in dogs.	2002 Jul	12118664
Validation and application of a sensitive assay for butorphanol in human plasma by high-performance liquid chromatography with tandem mass spectrometry detection.	2002 Jul 25	12101060
Withdrawal from dependence upon butorphanol uniquely increases kappa(1)-opioid receptor binding in the rat brain.	2002 Jun	12127012
Effects of preoperative administration of ketoprofen on whole blood platelet aggregation, buccal mucosal bleeding time, and hematologic indices in dogs undergoing elective ovariohysterectomy.	2002 Jun 15	12092955
Simultaneous determination of in total 17 opium alkaloids and opioids in blood and urine by fast liquid chromatography-diode-array detection-fluorescence detection, after solid-phase extraction.	2002 Jun 15	12015270
Evaluation of the bispectral index as an indicator of degree of central nervous system depression in isoflurane-anesthetized horses.	2002 Mar	11911581
Characterization of the discriminative stimulus effects of buprenorphine in pigeons.	2002 Mar	11875630
Effects of mu-opioid agonists on cocaine- and food-maintained responding and cocaine discrimination in rhesus monkeys: role of mu-agonist efficacy.	2002 Mar	11861822
Laparoscopic cryptorchidectomy using electrosurgical instrumentation in standing horses.	2002 Mar-Apr	11884956
Postoperative pain control in cats: clinical trials with medetomidine and butorphanol.	2002 Mar-Apr	11884953
A pharmacokinetic interaction study between butorphanol and sumatriptan nasal sprays in healthy subjects: importance of the timing of butorphanol administration.	2002 May	12100090
Quantitative electroencephalography of medetomidine, medetomidine-midazolam and medetomidine-midazolam-butorphanol in dogs.	2002 May	12069256
Stadol nasal spray for headache.	2002 May	12047344
Butorphanol decreases edema following carrageenan-induced paw inflammation in rats.	2002 Nov	12456153
Activation profiles of opioid ligands in HEK cells expressing delta opioid receptors.	2002 Nov 18	12437765
A comparison of thiopental, propofol, and diazepam-ketamine anesthesia for evaluation of laryngeal function in dogs premedicated with butorphanol-glycopyrrolate.	2002 Nov-Dec	12428879
Sex-related differences in mechanical nociception and antinociception produced by mu- and kappa-opioid receptor agonists in rats.	2002 Oct 4	12354566
The bindings of [3H]muscimol and [3H]flunitrazapam are elevated in discrete brain regions of butorphanol-withdrawal rats.	2002 Sep	12396105
Influence of gonadectomy on the antinociceptive effects of opioids in male and female rats.	2002 Sep	12202965
Effects of two preanesthetic regimens for ophthalmic surgery on intraocular pressure and cardiovascular measurements in dogs.	2002 Spring	12050831
WHO Expert Committee on Drug Dependence.	2003	12772439
Agonist/antagonist properties of nalbuphine, butorphanol and (-)-pentazocine in male vs. female rats.	2003 Apr	12759132
Sensitivity to the effects of opioids in rats with free access to exercise wheels: mu-opioid tolerance and physical dependence.	2003 Aug	12709780
Comparison of electroacupuncture and butorphanol on respiratory and cardiovascular effects and rectal pain threshold after controlled rectal distention in mares.	2003 Feb	12602580
Postoperative hypoxemia and hypercarbia in healthy dogs undergoing routine ovariohysterectomy or castration and receiving butorphanol or hydromorphone for analgesia.	2003 Feb 1	12564595
Evaluation of the sedative and cardiorespiratory effects of dexmedetomidine, dexmedetomidine-butorphanol, and dexmedetomidine-ketamine in cats.	2003 Jan 1	12523477
Reduction and stabilization of hip luxation by the transposition of the ligamentum sacrotuberale in dogs: an in vivo study.	2003 Jan-Feb	12520489
Postoperative analgesia in children undergoing myringotomy and placement equalization tubes in ambulatory surgery.	2003 Jun	12760984
Comparison of the cardiorespiratory effects of medetomidine-butorphanol-ketamine and medetomidine-butorphanol-midazolam in patas monkeys (Erythrocebus patas).	2003 Mar	12723799
Progressive changes in ophthalmic blood velocities in Beagles with primary open angle glaucoma.	2003 Mar	12641848
Interactions between opioids and cocaine on locomotor activity in rats: influence of an opioid's relative efficacy at the mu receptor.	2003 May	12669175
The competitive N-methyl-D-aspartate receptor antagonist (-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959) potentiates the antinociceptive effects of opioids that vary in efficacy at the mu-opioid receptor.	2003 Nov	12975489
Dose ratio is important in maximizing naloxone enhancement of nalbuphine analgesia in humans.	2003 Nov 6	14550900
Physicians and the pharmaceutical industry: a dysfunctional relationship.	2003 Spring	12721524

Patents

Sample Use Guides

In Vivo Use Guide

Preoperative Medication: Initial dose: 2 mg intramuscularly 60 to 90 minutes before surgery Balanced Anesthesia: Initial dose: 2 mg intravenously shortly before induction and/or 0.5 mg to 1 mg in increments during anesthesia. The increments may be higher, up to 0.06 mg/kg (4 mg/70 kg) depending on the previous sedative, analgesic, and hypnotic drugs administered. The total dose needed will vary. However, patients have generally been reported to have needed between a total dosage of 4 mg to 12.5 mg (approximately 0.06 to 0.18 mg/kg). Usual Adult Dose for Labor Pain For use In the treatment of patients at full term early in labor: Initial dose: 1 or 2 mg intravenously or intramuscularly once. This dose may be repeated in 4 hours if necessary. Usual Adult Dose for Pain Initial dose: 1 mg intravenously once. Depending on the severity of the pain, effective intravenous doses range from 0.5 to 2 mg.

Route of Administration: Other

In Vitro Use Guide

At high concentration (100 uM) butorphanol greatly inhibited the depolarization of the rat cerebrocortical brain slices by veratrine as determined by the reduced release of K+.

Name

Type

Language

BUTORPHANOL

Official Name

English

(-)-17-(CYCLOBUTYLMETHYL)MORPHINAN-3,14-DIOL

Systematic Name

English

MORPHINAN-3,14-DIOL, 17-(CYCLOBUTYLMETHYL)-

Systematic Name

English

BUTORPHANOL [USAN]

Common Name

English

LEVO-BC-2627

Code

English

butorphanol [INN]

Common Name

English

BUTORPHANOL [MI]

Common Name

English

BUTORPHANOL [VANDF]

Common Name

English

Butorphanol [WHO-DD]

Common Name

English

Classification Tree Code System Code

NDF-RT

N0000175692