NALBUPHINE

First approved in 1964

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C21H27NO4
Molecular Weight	357.4434
Optical Activity	UNSPECIFIED
Defined Stereocenters	5 / 5
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[H][C@@]12OC3=C4C(C[C@H]5N(CC6CCC6)CC[C@@]14[C@@]5(O)CC[C@@H]2O)=CC=C3O

InChI

InChIKey=NETZHAKZCGBWSS-CEDHKZHLSA-N

InChI=1S/C21H27NO4/c23-14-5-4-13-10-16-21(25)7-6-15(24)19-20(21,17(13)18(14)26-19)8-9-22(16)11-12-2-1-3-12/h4-5,12,15-16,19,23-25H,1-3,6-11H2/t15-,16+,19-,20-,21+/m0/s1

HIDE SMILES / InChI

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/018024s041lbl.pdf
Curator's Comment: description was created based on several sources, including https://www.drugbank.ca/drugs/DB00844 | https://www.drugs.com/cdi/nalbuphine.html | http://reference.medscape.com/drug/nalbuphine-343329

Nalbuphine is a semi-synthetic opioid agonist-antagonist used commercially as an analgesic under a variety of trade names, including Nubain and Manfine. Nalbuphine is an agonist at kappa opioid receptors and an antagonist at mu opioid receptors. Nalbuphine analgesic potency is essentially equivalent to that of morphine on a milligram basis up to a dosage of approximately 30 mg. The opioid antagonist activity of Nalbuphine is one-fourth as potent as nalorphine and 10 times that of pentazocine. Nalbuphine is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Nalbuphine can also be used as a supplement to balanced anesthesia, for preoperative and postoperative analgesia, and for obstetrical analgesia during labor and delivery. The onset of action of Nalbuphine occurs within 2 to 3 minutes after intravenous administration, and in less than 15 minutes following subcutaneous or intramuscular injection. The plasma half-life of nalbuphine is 5 hours, and in clinical studies, the duration of analgesic activity has been reported to range from 3 to 6 hours. Like pure µ-opioids, the mixed agonist-antagonist opioid class of drugs can cause side effects with initial administration of the drug but which lessen over time (“tolerance”). This is particularly true for the side effects of nausea, sedation and cognitive symptoms. These side effects can in many instances be ameliorated or avoided at the time of drug initiation by titrating the drug from a tolerable starting dose up to the desired therapeutic dose. An important difference between nalbuphine and the pure mu-opioid analgesic drugs is the “ceiling effect” on respiration. Respiratory depression is a potentially fatal side effect from the use of pure mu opioids. Nalbuphine has limited ability to depress respiratory function.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Kappa opioid receptor 108 Target ID: CHEMBL237 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22204910	Partial Agonist 290		65.0 nM [EC50]
Mu opioid receptor 221 Target ID: CHEMBL233 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17407276	Antagonist 2778		110.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Pain 614 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/018024s041lbl.pdf	Primary		Approved 8429	NUBAIN Approved Use Indications and Usage Nalbuphine hydrochloride is indicated for the relief of moderate to severe pain. Nalbuphine hydrochloride can also be used as a supplement to balanced anesthesia, for preoperative and postoperative analgesia, and for obstetrical analgesia during labor and delivery. Launch Date 1979
Pruritus 29 Sources: https://clinicaltrials.gov/ct2/show/NCT00323154	Primary		Phase III 656	NUBAIN Approved Use Indications and Usage Nalbuphine hydrochloride is indicated for the relief of moderate to severe pain. Nalbuphine hydrochloride can also be used as a supplement to balanced anesthesia, for preoperative and postoperative analgesia, and for obstetrical analgesia during labor and delivery. Launch Date 1979

C_max

Value	Dose	Co-administered	Analyte	Population
7.3 μg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2758732	30 mg single, oral dose: 30 mg route of administration: Oral experiment type: SINGLE co-administered:		NALBUPHINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
24.8 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9107559	0.3 mg/kg single, rectal dose: 0.3 mg/kg route of administration: Rectal experiment type: SINGLE co-administered:		NALBUPHINE plasma	Homo sapiens population: HEALTHY age: CHILD sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Analyte	Population
139.9 μg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2758732	10 mg single, intravenous dose: 10 mg route of administration: Intravenous experiment type: SINGLE co-administered:	NALBUPHINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
25.8 μg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2758732	30 mg single, oral dose: 30 mg route of administration: Oral experiment type: SINGLE co-administered:	NALBUPHINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
58.2 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9107559	0.3 mg/kg single, rectal dose: 0.3 mg/kg route of administration: Rectal experiment type: SINGLE co-administered:	NALBUPHINE plasma	Homo sapiens population: HEALTHY age: CHILD sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Analyte	Population
2.28 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2758732	10 mg single, intravenous dose: 10 mg route of administration: Intravenous experiment type: SINGLE co-administered:	NALBUPHINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
10.6 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2758732	30 mg single, oral dose: 30 mg route of administration: Oral experiment type: SINGLE co-administered:	NALBUPHINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
2.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9107559	0.3 mg/kg single, rectal dose: 0.3 mg/kg route of administration: Rectal experiment type: SINGLE co-administered:	NALBUPHINE plasma	Homo sapiens population: HEALTHY age: CHILD sex: FEMALE / MALE food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
50% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2758732	10 mg single, intravenous dose: 10 mg route of administration: Intravenous experiment type: SINGLE co-administered:		NALBUPHINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Doses

Dose	Population	Adverse events
40 mg single, intravenous Dose: 40 mg Route: intravenous Route: single Dose: 40 mg Sources: https://pubmed.ncbi.nlm.nih.gov/3769586	healthy, 37 years n = 1 Health Status: healthy Age Group: 37 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/3769586	Other AEs: Pulmonary edema... Other AEs: Pulmonary edema (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/3769586
10 mg single, intramuscular Recommended Dose: 10 mg Route: intramuscular Route: single Dose: 10 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018024s042lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018024s042lbl.pdf	Other AEs: Respiratory depression... Other AEs: Respiratory depression (serious\|grade 5) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018024s042lbl.pdf
10 mg single, intravenous Recommended Dose: 10 mg Route: intravenous Route: single Dose: 10 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018024s042lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018024s042lbl.pdf	Other AEs: Respiratory depression... Other AEs: Respiratory depression (serious\|grade 5) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018024s042lbl.pdf
10 mg single, subcutaneous Recommended Dose: 10 mg Route: subcutaneous Route: single Dose: 10 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018024s042lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018024s042lbl.pdf	Other AEs: Respiratory depression... Other AEs: Respiratory depression (serious\|grade 5) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018024s042lbl.pdf
160 mg multiple, intramuscular (total) Studied dose Dose: 160 mg Route: intramuscular Route: multiple Dose: 160 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018024s042lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018024s042lbl.pdf	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018024s042lbl.pdf
160 mg multiple, intravenous (total) Studied dose Dose: 160 mg Route: intravenous Route: multiple Dose: 160 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018024s042lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018024s042lbl.pdf	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018024s042lbl.pdf
160 mg multiple, subcutaneous (total) Studied dose Dose: 160 mg Route: subcutaneous Route: multiple Dose: 160 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018024s042lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018024s042lbl.pdf	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018024s042lbl.pdf
15 mg single, oral Dose: 15 mg Route: oral Route: single Dose: 15 mg Sources: https://pubmed.ncbi.nlm.nih.gov/6690170	unhealthy n = 39 Health Status: unhealthy Population Size: 39 Sources: https://pubmed.ncbi.nlm.nih.gov/6690170	Other AEs: Dizzy, Sleepy... Other AEs: Dizzy (1 patient) Sleepy (4 patients) Headache (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/6690170

AEs

AE	Significance	Dose	Population
Pulmonary edema	1 patient	40 mg single, intravenous Dose: 40 mg Route: intravenous Route: single Dose: 40 mg Sources: https://pubmed.ncbi.nlm.nih.gov/3769586	healthy, 37 years n = 1 Health Status: healthy Age Group: 37 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/3769586
Respiratory depression	serious\|grade 5	10 mg single, intramuscular Recommended Dose: 10 mg Route: intramuscular Route: single Dose: 10 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018024s042lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018024s042lbl.pdf
Respiratory depression	serious\|grade 5	10 mg single, intravenous Recommended Dose: 10 mg Route: intravenous Route: single Dose: 10 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018024s042lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018024s042lbl.pdf
Respiratory depression	serious\|grade 5	10 mg single, subcutaneous Recommended Dose: 10 mg Route: subcutaneous Route: single Dose: 10 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018024s042lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018024s042lbl.pdf
Dizzy	1 patient	15 mg single, oral Dose: 15 mg Route: oral Route: single Dose: 15 mg Sources: https://pubmed.ncbi.nlm.nih.gov/6690170	unhealthy n = 39 Health Status: unhealthy Population Size: 39 Sources: https://pubmed.ncbi.nlm.nih.gov/6690170
Headache	1 patient	15 mg single, oral Dose: 15 mg Route: oral Route: single Dose: 15 mg Sources: https://pubmed.ncbi.nlm.nih.gov/6690170	unhealthy n = 39 Health Status: unhealthy Population Size: 39 Sources: https://pubmed.ncbi.nlm.nih.gov/6690170
Sleepy	4 patients	15 mg single, oral Dose: 15 mg Route: oral Route: single Dose: 15 mg Sources: https://pubmed.ncbi.nlm.nih.gov/6690170	unhealthy n = 39 Health Status: unhealthy Population Size: 39 Sources: https://pubmed.ncbi.nlm.nih.gov/6690170

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
	substrate 1037	substrate 1217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP2C19 991

Drug as victim

Target	Modality	Activity
CYP2C19 991	substrate 3367 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0928098719303665 Page: 31.0	yes
CYP2C9 1037	substrate 3367 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0928098719303665 Page: 31.0	yes
CYP2D6 1217	substrate 3367 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0928098719303665 Page: 31.0	yes

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:7454	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:7454
MolPort	MolPort-047-151-516	https://www.molport.com/shop/molecule-link/MolPort-047-151-516
ZINC	ZINC000003812989	http://zinc15.docking.org/substances/ZINC000003812989

PubMed

Title	Date	PubMed
Advantages of intrathecal nalbuphine, compared with intrathecal morphine, after cesarean delivery: an evaluation of postoperative analgesia and adverse effects.	2000 Sep	10960384
Age-related differences in sensitivity to the antinociceptive effects of opioids in male rats. Influence of nociceptive intensity and intrinsic efficacy at the mu receptor.	2001 Aug	11498722
Efficacy and safety of patient-controlled opioid analgesia for acute postoperative pain. A quantitative systematic review.	2001 Aug	11472277
"Invisible" synthetic opiates and acute psychosis.	2001 Aug 9	11496869
[Opioid tolerance and dependence--pharmacological aspects].	2001 Jul-Sep	12092171
Pharmacological control of opioid-induced pruritus: a quantitative systematic review of randomized trials.	2001 Jun	11412287
Elective laparoscopic cholecystectomy.	2001 Mar	11344434
Neither nalbuphine nor atropine possess special antishivering activity.	2001 Sep	11524329
Intravesical morphine analgesia is not effective after bladder surgery in children: results of a randomied double-blind study.	2002 Aug	12131352
Butorphanol and nalbuphine in opioid-dependent humans under a naloxone discrimination procedure.	2002 Jan-Feb	11812511
Differences in systemic opioid use do not explain increased fever incidence in parturients receiving epidural analgesia.	2002 Jul	12131117
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
Nalbuphine reverses urinary effects of epidural morphine: a case report.	2002 Nov	12477591
Dexamethasone 8 mg in combination with ondansetron 4 mg appears to be the optimal dose for the prevention of nausea and vomiting after laparoscopic cholecystectomy.	2002 Nov	12419717
Summary version of the Standards, Options and Recommendations for the use of analgesia for the treatment of nociceptive pain in adults with cancer (update 2002).	2003 Aug	12915905
Opioid interactions in rhesus monkeys: effects of delta + mu and delta + kappa agonists on schedule-controlled responding and thermal nociception.	2003 Dec	14557380
The sedative and behavioral effects of nalbuphine in dogs.	2003 Jul	12906398
An optimal dose study of intrathecal morphine in gynecological patients.	2003 Jun	12930007
Effect of nalbuphine on the motility of the sphincter of Oddi in patients with suspected sphincter of Oddi dysfunction.	2003 Mar	12612509
Sexual dimorphism in very low dose nalbuphine postoperative analgesia.	2003 Mar 13	12618286
Dose ratio is important in maximizing naloxone enhancement of nalbuphine analgesia in humans.	2003 Nov 6	14550900
The antinociceptive effect of a long-acting nalbuphine preparation in rabbits.	2003 Sep	14601195
[National survey of emergency management of acute pain in prehospital setting].	2004 Dec	15589354
Experimental pain models reveal no sex differences in pentazocine analgesia in humans.	2004 May	15114226
Reducing cardiovascular responses to laryngoscopy and tracheal intubation: a comparison of equipotent doses of tramadol, nalbuphine and pethidine, with placebo.	2004 Oct	15651510
Using mixed agonist-antagonists.	2005 Feb	15706252
The preoperative administration of ketoprofen improves analgesia after laparoscopic cholecystectomy in comparison with propacetamol or postoperative ketoprofen.	2005 Mar	15619603
In vitro and in vivo evaluation of the metabolism and pharmacokinetics of sebacoyl dinalbuphine.	2005 Mar	15608131
Effects of the mixed mu/kappa opioid nalbuphine on cocaine-induced changes in subjective and cardiovascular responses in men.	2005 Mar	15602503

Patents

Sample Use Guides

In Vivo Use Guide

Non-opioid-tolerant patients: 10-20 mg/70kg IV/IM/SC q3-6hr PRN; individual dose not to exceed 20 mg Opioid-dependent patients: Administer ¼ dose, and observe for withdrawal signs Not to exceed 160 mg/day

Route of Administration: Other

In Vitro Use Guide

Bac 1.2F5 P2 membranes were incubated with [N-methyl-3H]morphine in the presence and absence of Nalbuphine (0.1 nM–10 mkM). Mixtures were filtered and washed, and binding was determined by measuring the radioactivity retained on the filter discs.

Name

Type

Language

NALBUPHINE

Official Name

English

17-(CYCLOBUTYLMETHYL)-4,5.ALPHA.-EPOXYMORPHINAN-3,6.ALPHA.,14-TRIOL

Systematic Name

English

NALBUPHINE [MI]

Common Name

English

INTAPAN

Brand Name

English

NALBUPHINE [VANDF]

Common Name

English

nalbuphine [INN]

Common Name

English

Nalbuphine [WHO-DD]

Common Name

English

MORPHINAN-3,6,14-TRIOL, 17-(CYCLOBUTYLMETHYL)-4,5-EPOXY-

Systematic Name

English

Classification Tree Code System Code

NDF-RT

N0000175685