DINALBUPHINE SEBACATE

First approved in 1964

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C52H68N2O10
Molecular Weight	881.1037
Optical Activity	UNSPECIFIED
Defined Stereocenters	10 / 10
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[H][C@@]12OC3=C(OC(=O)CCCCCCCCC(=O)OC4=C5O[C@@]6([H])[C@@H](O)CC[C@@]7(O)[C@@]8([H])CC(C=C4)=C5[C@@]67CCN8CC9CCC9)C=CC%10=C3[C@@]1%11CCN(CC%12CCC%12)[C@]([H])(C%10)[C@]%11(O)CC[C@@H]2O

InChI

InChIKey=ALOIOAGKUOQNID-ITCIXCFHSA-N

InChI=1S/C52H68N2O10/c55-35-19-21-51(59)39-27-33-15-17-37(45-43(33)49(51,47(35)63-45)23-25-53(39)29-31-9-7-10-31)61-41(57)13-5-3-1-2-4-6-14-42(58)62-38-18-16-34-28-40-52(60)22-20-36(56)48-50(52,44(34)46(38)64-48)24-26-54(40)30-32-11-8-12-32/h15-18,31-32,35-36,39-40,47-48,55-56,59-60H,1-14,19-30H2/t35-,36-,39+,40+,47-,48-,49-,50-,51+,52+/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
Nalbuphine is better than naloxone for treatment of side effects after epidural morphine.	1992 Nov	1416128
Advantages of intrathecal nalbuphine, compared with intrathecal morphine, after cesarean delivery: an evaluation of postoperative analgesia and adverse effects.	2000 Sep	10960384
The use of intravenous nitroglycerin in a case of spasm of the sphincter of Oddi during laparoscopic cholecystectomy.	2001 Apr	11379694
Enadoline discrimination in squirrel monkeys: effects of opioid agonists and antagonists.	2001 Apr	11259547
New advances in the treatment of sickle cell disease: focus on perioperative significance.	2001 Aug	11759366
Controlled release of nalbuphine propionate from biodegradable microspheres: in vitro and in vivo studies.	2001 Jun 4	11376971
The effects of chronic morphine on behavior reinforced by several opioids or by cocaine in rhesus monkeys.	2001 May 1	11295322
The analgesic effect of nalbuphine and its long-acting prodrug, nalbuphine pivalate, in rats.	2002 Dec	12596618
Pharmacological treatment of postoperative shivering: a quantitative systematic review of randomized controlled trials.	2002 Feb	11812718
Relationship between rate and extent of G protein activation: comparison between full and partial opioid agonists.	2002 Jan	11752111
Butorphanol and nalbuphine in opioid-dependent humans under a naloxone discrimination procedure.	2002 Jan-Feb	11812511
Age-related differences in sensitivity to the antinociceptive effects of kappa opioids in adult male rats.	2002 Jul	12122483
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
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
Activation profiles of opioid ligands in HEK cells expressing delta opioid receptors.	2002 Nov 18	12437765
Comparison of the discriminative and neuroendocrine effects of centrally penetrating kappa-opioid agonists in rhesus monkeys.	2002 Oct	12373425
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
Pharmacogenetic analysis of sex differences in opioid antinociception in rats.	2003 Dec	14659521
The analgesic effect of interscalene block using clonidine as an analgesic for shoulder arthroscopy.	2003 Jan	12505963
Activity of opioid ligands in cells expressing cloned mu opioid receptors.	2003 Jan 4	12513698
Nalbuphine versus ondansetron for prevention of intrathecal morphine-induced pruritus after cesarean delivery.	2003 Jun	12761013
Response of neuropathic trigeminal pain to the combination of low-dose nalbuphine plus naloxone in humans.	2003 Jun 5	12759184
Bilateral interpleural versus lumbar epidural bupivacaine-morphine analgesia for upper abdominal surgery.	2003 Oct	14740589
A comparison of morphine and nalbuphine for intraoperative and postoperative analgesia.	2003 Sep	14620312
The antinociceptive effect of a long-acting nalbuphine preparation in rabbits.	2003 Sep	14601195
[Medical termination of pregnancy at 9-14 weeks gestation. Prospective study of 105 cases in Saint-Laurent-du-Maroni (French Guyana)].	2004 Apr	15052177
Modulation of the discriminative stimulus effects of mu opioid agonists in rats: I. Effects of dopamine D2/3 antagonists.	2004 Feb	15075628
Undocumented drug utilization and drug waste increase costs of pediatric anesthesia care.	2004 Feb	14748762
[Analgesic alternatives for the control of postoperatory pain in radical mastectomy].	2004 Sep-Oct	15550223

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

DINALBUPHINE SEBACATE

Official Name

English

NALDEBAIN

Brand Name

English

SEBACOYLDINALBUPHINE

Common Name

English

NALBUPHINE SEBACATE

Official Name

English

dinalbuphine sebacate [INN]

Common Name

English

BIS(17-(CYCLOBUTYLMETHYL)-4,5.ALPHA.-EPOXY-6.ALPHA.,14-DIHYDROXYMORPHINAN-3-YL) DECANEDIOATE

Systematic Name

English

MORPHINAN-3,6,14-TRIOL, 17-(CYCLOBUTYLMETHYL)-4,5-EPOXY-, 3,3'-DECANEDIOATE, (5.ALPHA.,6.ALPHA.)-(5'.ALPHA.,6'.ALPHA.)-

Systematic Name

English

Nalbuphine sebacate [WHO-DD]

Common Name

English

Code System Code Type Description

SMS_ID

300000020471