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
Survey of pain management therapy provided for children with sickle cell disease.	1992 Apr	1373356
Tolerance to the analgesic effect of buprenorphine, butorphanol, nalbuphine, and cyclorphan, and cross-tolerance to morphine.	2001	14569437
Investigation of 4,5-epoxymorphinan degradation during analysis by HPLC.	2002 Aug 22	12151069
The analgesic effect of nalbuphine and its long-acting prodrug, nalbuphine pivalate, in rats.	2002 Dec	12596618
Minidose lidocaine-fentanyl spinal anesthesia in ambulatory surgery: prophylactic nalbuphine versus nalbuphine plus droperidol.	2002 Dec	12456423
Differences in systemic opioid use do not explain increased fever incidence in parturients receiving epidural analgesia.	2002 Jul	12131117
The UK pre-hospital management of burn patients: current practice and the need for a standard approach.	2002 Mar	11900936
Self-administration of cocaine, alfentanil, and nalbuphine under progressive-ratio schedules: consumer demand and labor supply analyses of relative reinforcing effectiveness.	2002 Nov	12498333
Nalbuphine reverses urinary effects of epidural morphine: a case report.	2002 Nov	12477591
Hitting them where it hurts? Low dose nalbuphine therapy.	2002 Nov	12421793
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
Sex-related differences in mechanical nociception and antinociception produced by mu- and kappa-opioid receptor agonists in rats.	2002 Oct 4	12354566
Influence of gonadectomy on the antinociceptive effects of opioids in male and female rats.	2002 Sep	12202965
[Nalbuphine (Nubain) dependence: 2 cases].	2002 Sep-Oct	12611206
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
A review of emergency equipment carried and procedures performed by UK front line paramedics.	2003 Aug	12909377
Pharmacogenetic analysis of sex differences in opioid antinociception in rats.	2003 Dec	14659521
Opioid interactions in rhesus monkeys: effects of delta + mu and delta + kappa agonists on schedule-controlled responding and thermal nociception.	2003 Dec	14557380
Differential effects of agonists on adenylyl cyclase superactivation mediated by the kappa opioid receptors: adenylyl cyclase superactivation is independent of agonist-induced phosphorylation, desensitization, internalization, and down-regulation.	2003 Dec	14557376
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
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
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
The antinociceptive effect of nalbuphine and its long-acting esters in rats.	2003 Sep	12933406
Sub-Tenon infiltration or classical analgesic drugs to relieve postoperative pain.	2004 Apr	15068431
[Medical termination of pregnancy at 9-14 weeks gestation. Prospective study of 105 cases in Saint-Laurent-du-Maroni (French Guyana)].	2004 Apr	15052177
[National survey of emergency management of acute pain in prehospital setting].	2004 Dec	15589354
Modulation of the discriminative stimulus effects of mu opioid agonists in rats: II. Effects of dopamine D2/3 agonists.	2004 Feb	15075629
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
Effects of opioids in morphine-treated pigeons trained to discriminate among morphine, the low-efficacy agonist nalbuphine, and saline.	2004 Jul	15044559
Nalbuphine and slow release morphine.	2004 Jun 12	15191981
Experimental pain models reveal no sex differences in pentazocine analgesia in humans.	2004 May	15114226
Less IS less: a randomised controlled trial comparing cautious and rapid nalbuphine dosing regimens.	2004 May	15107384
Antinociceptive effect of a novel long-acting nalbuphine preparation.	2004 May	15003978
Reducing cardiovascular responses to laryngoscopy and tracheal intubation: a comparison of equipotent doses of tramadol, nalbuphine and pethidine, with placebo.	2004 Oct	15651510
In vitro evaluation of the potential role of sulfite radical in morphine-associated histamine release.	2004 Oct 6	15469613
In rats, acute morphine dependence results in antagonist-induced response suppression of intracranial self-stimulation.	2004 Sep	15024547
[Analgesic alternatives for the control of postoperatory pain in radical mastectomy].	2004 Sep-Oct	15550223
Using mixed agonist-antagonists.	2005 Feb	15706252
Dextromethorphan differentially affects opioid antinociception in rats.	2005 Feb	15655510
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
Self-Administration of cocaine-opioid combinations by rhesus monkeys: evaluation of the role of mu receptor efficacy using labor supply analysis.	2005 Mar	15550572

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