DIHYDROCODEINE PHOSPHATE

First approved in 1956

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C18H23NO3.H3O4P
Molecular Weight	399.3753
Optical Activity	UNSPECIFIED
Defined Stereocenters	5 / 5
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OP(O)(O)=O.[H][C@@]12OC3=C(OC)C=CC4=C3[C@@]15CCN(C)[C@H](C4)[C@]5([H])CC[C@@H]2O

InChI

InChIKey=HFBYLYCMISIEMM-FFHNEAJVSA-N

InChI=1S/C18H23NO3.H3O4P/c1-19-8-7-18-11-4-5-13(20)17(18)22-16-14(21-2)6-3-10(15(16)18)9-12(11)19;1-5(2,3)4/h3,6,11-13,17,20H,4-5,7-9H2,1-2H3;(H3,1,2,3,4)/t11-,12+,13-,17-,18-;/m0./s1

HIDE SMILES / InChI

Molecular Formula	C18H23NO3
Molecular Weight	301.3801
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	5 / 5
E/Z Centers	0
Optical Activity	UNSPECIFIED

Molecular Formula	H3O4P
Molecular Weight	97.9952
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: http://www.drugbank.ca/drugs/DB01551
Curator's Comment: Description was created based on several sources, including

Dihydrocodeine is an opioid analgesic used as an alternative or adjunct to codeine to treat moderate to severe pain, severe dyspnea, and cough. It is semi-synthetic, and was developed in Germany in 1908 during an international search to find a more effective antitussive agent to help reduce the spread of airborne infectious diseases such as tuburculosis. It was marketed in 1911. Dihydrocodeine is metabolized to dihydromorphine -- a highly active metabolite with a high affinity for mu opioid receptors. Dihydrocodeine is used for the treatment of moderate to severe pain, including post-operative and dental pain. It can also be used to treat chronic pain, breathlessness and coughing. In heroin addicts, dihydrocodeine has been used as a substitute drug, in doses up to 2500mg/day to treat addiction.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Mu opioid receptor 221 Target ID: CHEMBL233 Sources: http://www.genome.jp/dbget-bin/www_bget?D07831	Agonist 2678		0.3 µM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Pain 614 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/011483s027lbl.pdf	Palliative		Approved 8429	SYNALGOS-DC Approved Use For the relief of moderate to moderately severe pain. Launch Date 1958

C_max

Value	Dose	Analyte	Population
487 pmol/g EXPERIMENT https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1046/j.1365-2125.1999.00042.x	60 mg 2 times / day multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DIHYDROCODEINE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
341 nM EXPERIMENT https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1046/j.1365-2125.1999.00042.x	60 mg single, oral dose: 60 mg route of administration: Oral experiment type: SINGLE co-administered:	DIHYDROCODEINE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
739 nM EXPERIMENT https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1046/j.1365-2125.1999.00042.x	90 mg 1 times / day multiple, oral dose: 90 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DIHYDROCODEINE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
918 nM EXPERIMENT https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1046/j.1365-2125.1999.00042.x	120 mg 1 times / day multiple, oral dose: 120 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DIHYDROCODEINE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
60.089 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4885392/	20 mg single, oral dose: 20 mg route of administration: Oral experiment type: SINGLE co-administered:	DIHYDROCODEINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
18 nM EXPERIMENT https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1046/j.1365-2125.1999.00042.x	120 mg 1 times / day multiple, oral dose: 120 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DIHYDROMORPHINE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
8.7 nM EXPERIMENT https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1046/j.1365-2125.1999.00042.x	60 mg 1 times / day multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DIHYDROMORPHINE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
4.7 pmol/g EXPERIMENT https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1046/j.1365-2125.1999.00042.x	60 mg single, oral dose: 60 mg route of administration: Oral experiment type: SINGLE co-administered:	DIHYDROMORPHINE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
13 nM EXPERIMENT https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1046/j.1365-2125.1999.00042.x	90 mg 1 times / day multiple, oral dose: 90 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DIHYDROMORPHINE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED

AUC

Value	Dose	Analyte	Population
3367 nM × h EXPERIMENT https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1046/j.1365-2125.1999.00042.x	60 mg 2 times / day multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DIHYDROCODEINE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
3415 nM × h EXPERIMENT https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1046/j.1365-2125.1999.00042.x	60 mg single, oral dose: 60 mg route of administration: Oral experiment type: SINGLE co-administered:	DIHYDROCODEINE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
5118 nM × h EXPERIMENT https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1046/j.1365-2125.1999.00042.x	90 mg 1 times / day multiple, oral dose: 90 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DIHYDROCODEINE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
6566 nM × h EXPERIMENT https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1046/j.1365-2125.1999.00042.x	120 mg 1 times / day multiple, oral dose: 120 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DIHYDROCODEINE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
301.643 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4885392/	20 mg single, oral dose: 20 mg route of administration: Oral experiment type: SINGLE co-administered:	DIHYDROCODEINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
132 nM × h EXPERIMENT https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1046/j.1365-2125.1999.00042.x	120 mg 1 times / day multiple, oral dose: 120 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DIHYDROMORPHINE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
65 nM × h EXPERIMENT https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1046/j.1365-2125.1999.00042.x	60 mg 1 times / day multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DIHYDROMORPHINE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
70 nM × h EXPERIMENT https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1046/j.1365-2125.1999.00042.x	60 mg single, oral dose: 60 mg route of administration: Oral experiment type: SINGLE co-administered:	DIHYDROMORPHINE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
99 nM × h EXPERIMENT https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1046/j.1365-2125.1999.00042.x	90 mg 1 times / day multiple, oral dose: 90 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DIHYDROMORPHINE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED

T_1/2

Value	Dose	Co-administered	Analyte	Population
3.146 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4885392/	20 mg single, oral dose: 20 mg route of administration: Oral experiment type: SINGLE co-administered:		DIHYDROCODEINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
32 mg 6 times / day multiple, oral Recommended Dose: 32 mg, 6 times / day Route: oral Route: multiple Dose: 32 mg, 6 times / day Co-administed with:: aspirin(356.4 mg) caffeine(30 mg) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/011483s033lbl.pdf	unhealthy, > 18 years Health Status: unhealthy Age Group: > 18 years Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/011483s033lbl.pdf	Other AEs: Respiratory depression... Other AEs: Respiratory depression (grade 5) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/011483s033lbl.pdf
240 mg 2 times / day multiple, oral Overdose Dose: 240 mg, 2 times / day Route: oral Route: multiple Dose: 240 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/26479786	unhealthy Health Status: unhealthy Sources: https://pubmed.ncbi.nlm.nih.gov/26479786	Other AEs: Hypercapnic respiratory failure... Other AEs: Hypercapnic respiratory failure Sources: https://pubmed.ncbi.nlm.nih.gov/26479786

AEs

AE	Significance	Dose	Population
Respiratory depression	grade 5	32 mg 6 times / day multiple, oral Recommended Dose: 32 mg, 6 times / day Route: oral Route: multiple Dose: 32 mg, 6 times / day Co-administed with:: aspirin(356.4 mg) caffeine(30 mg) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/011483s033lbl.pdf	unhealthy, > 18 years Health Status: unhealthy Age Group: > 18 years Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/011483s033lbl.pdf
Hypercapnic respiratory failure		240 mg 2 times / day multiple, oral Overdose Dose: 240 mg, 2 times / day Route: oral Route: multiple Dose: 240 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/26479786	unhealthy Health Status: unhealthy Sources: https://pubmed.ncbi.nlm.nih.gov/26479786

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737	substrate 1037	substrate 1217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP1A2 1054 CYP2A6 543 CYP2C19 991 UGT2B7 389

Drug as victim

Target	Modality	Activity
CYP1A2 1054	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042888/pdf/bcp_0626.pdf#page=5 Page: 5.0	likely
CYP2A6 543	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042888/pdf/bcp_0626.pdf#page=5 Page: 5.0	likely
CYP2C19 991	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042888/pdf/bcp_0626.pdf#page=5 Page: 5.0	likely
CYP2C9 1037	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042888/pdf/bcp_0626.pdf#page=5 Page: 5.0	likely
CYP2D6 1217	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042888/pdf/bcp_0626.pdf#page=5 Page: 5.0	yes
CYP3A4 1737	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/14597688/ Page: 3.0	yes
UGT2B7 389	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/14597688/ Page: 3.0	yes

Sourcing

Vendor/Aggregator	ID	URL
BioSynth	D-3270
Compound Cloud	46174078
Compound Cloud	5284543
Compound Cloud	5492624
Compound Cloud	5493302
NovoSeek	5284543
Parchem	56756	https://www.parchem.com/chemical-supplier-distributor/Pseudomorphine-056756.aspx
Sigma Aldrich	D-019
Sigma Aldrich	D-019\|CERILLIAN
Smolecule	S526105	http://www.smolecule.com/products/s526105
THE BioTek	bt-264832	https://www.thebiotek.com/product/inhibitors/bt-264832
Tetrahedron	TS81021
Toronto Research Chemicals	KIT2290
Yick-Vic Chemicals & Pharmaceuticals (HK) Ltd.	PH-0343A
ZINC	ZINC000004215736	http://zinc15.docking.org/substances/ZINC000004215736
eMolecules	303498464

PubMed

Title	Date	PubMed
Randomized placebo controlled trial of lofexidine hydrochloride for chronic pelvic pain in women.	2001 Aug	11473971
Postmortem diffusion of drugs from the bladder into femoral venous blood.	2001 Dec 1	11728758
Contribution of dihydrocodeine and dihydromorphine to analgesia following dihydrocodeine administration in man: a PK-PD modelling analysis.	2001 Jul	11453888
Head-column field-amplified sample stacking in presence of siphoning. Application to capillary electrophoresis-electrospray ionization mass spectrometry of opioids in urine.	2001 Jul 27	11521903
Time of drug elimination in chronic drug abusers. Case study of 52 patients in a "low-step" detoxification ward.	2001 Jun 15	11376991
Dihydrocodeine--drug of use or misuse?	2001 May	11360709
Capillary electrophoresis-electrospray ionization ion trap mass spectrometry for analysis and confirmation testing of morphine and related compounds in urine.	2001 May 4	11382295
Predictors for completing an inpatient detoxification program among intravenous heroin users, methadone substituted and codeine substituted patients.	2001 Oct 1	11543987
Capillary electrophoresis and capillary electrophoresis-ion trap multiple-stage mass spectrometry for the differentiation and identification of oxycodone and its major metabolites in human urine.	2002 Apr 25	12013227
Diclofenac does not interact with codeine metabolism in vivo: a study in healthy volunteers.	2002 Feb 27	11943073
A rapid GC-MS method for the determination of dihydrocodeine, codeine, norcodeine, morphine, normorphine and 6-MAM in urine.	2002 Jun 25	12098538
Interpretation of GC-MS opiate results in the presence of pholcodine.	2002 Jun 25	12098537
Prolonged erections produced by dihydrocodeine and sildenafil.	2002 Jun 29	12089093
[Paliative treatment: Treatment of chronic cancer pain (ii): the use of opiates].	2002 May 15	12031226
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
Alcohol consumption in heroin users, methadone-substituted and codeine-substituted patients--frequency and correlates of use.	2003 Jan	12566797
Hair analysis for opiates: evaluation of washing and incubation procedures.	2003 Jun 5	12726847
Enzyme immunoassay validation for the detection of buprenorphine in urine.	2003 Mar	12670004
The role of active metabolites in dihydrocodeine effects.	2003 Mar	12665158
Effects of second generation of histamine H1 antagonists, cetirizine and ebastine, on the antitussive and rewarding effects of dihydrocodeine in mice.	2003 Mar	12536265
The cholecystokinin antagonist proglumide enhances the analgesic effect of dihydrocodeine.	2003 May-Jun	12792559
Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality, Part II.	2003 Nov-Dec	14597688
Putting an Ecstasy test kit to the test: harm reduction or harm induction?	2003 Oct	14594341
The Leeds Evaluation of Efficacy of Detoxification Study (LEEDS) project: an open-label pragmatic randomised control trial comparing the efficacy of differing therapeutic agents for primary care detoxification from either street heroin or methadone [ISRCTN07752728].	2004 Apr 29	15117415
Activation of G-proteins by morphine and codeine congeners: insights to the relevance of O- and N-demethylated metabolites at mu- and delta-opioid receptors.	2004 Feb	14600248
Evaluation of the One-Step ELISA kit for the detection of buprenorphine in urine, blood, and hair specimens.	2004 Jul 16	15240036
ECG abnormalities in co-proxamol (paracetamol/dextropropoxyphene) poisoning.	2005	16035201
Simultaneous analysis of thebaine, 6-MAM and six abused opiates in postmortem fluids and tissues using Zymark automated solid-phase extraction and gas chromatography-mass spectrometry.	2005 Aug 5	15993661
Replacement of immunoassay by LC tandem mass spectrometry for the routine measurement of drugs of abuse in oral fluid.	2005 Jul	15989728
The prescribing of methadone and other opioids to addicts: national survey of GPs in England and Wales.	2005 Jun	15970068
Dihydrocodeine tartrate.	2005 May 3-9	15892502
Palliative management of refractory dyspnea in COPD.	2006	18046866
Hyperinflation and its management in COPD.	2006	18044095
Simultaneous determination of psychoactive drugs and their metabolites in aqueous matrices by liquid chromatography mass Spectrometry.	2006 Dec 1	17180984
[Transient sick sinus syndrome by oral intake of high dose dehydrocodeine for postherpetic neuralgia].	2007 Apr	17441449
Interrupted time-series analysis of regulations to reduce paracetamol (acetaminophen) poisoning.	2007 Apr	17407385
London audit of drug-related overdose deaths: characteristics and typology, and implications for prevention and monitoring.	2007 Feb	17222287
Substitution treatment for opioid addicts in Germany.	2007 Feb 2	17270059
The Leeds Evaluation of Efficacy of Detoxification Study (LEEDS) prisons project pilot study: protocol for a randomised controlled trial comparing dihydrocodeine and buprenorphine for opiate detoxification.	2007 Jan 8	17210080
A mixed methods study to investigate needs assessment for knee pain and disability: population and individual perspectives.	2007 Jul 4	17610732
The enantiomers of tramadol and its major metabolite inhibit peristalsis in the guinea pig small intestine via differential mechanisms.	2007 Mar 16	17367519
"Me's me and you's you": Exploring patients' perspectives of single patient (n-of-1) trials in the UK.	2007 Mar 19	17371593
Pharmacokinetic-pharmacodynamic modeling of the miotic effects of dihydrocodeine in humans.	2007 Nov	17786418
The role of tramadol in current treatment strategies for musculoskeletal pain.	2007 Oct	18472996
Factors that help injecting drug users to access and benefit from services: A qualitative study.	2007 Oct 30	17971204
Hemodynamic effects of methadone and dihydrocodeine in overdose.	2007 Oct-Nov	17852162
Hepatotoxicity associated with sulfasalazine in inflammatory arthritis: A case series from a local surveillance of serious adverse events.	2008 Apr 11	18405372
Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study.	2008 Jan 26	18182416
Differentiation between drug use and environmental contamination when testing for drugs in hair.	2008 Mar 21	17980987
Primary care incidence and treatment of four neuropathic pain conditions: a descriptive study, 2002-2005.	2008 May 6	18460194

Patents

Sample Use Guides

In Vivo Use Guide

The usual dose of dihydrocodeine is 1 tablet every 4 to 6 hours

Route of Administration: Oral

In Vitro Use Guide

Dihydrocodeine inhibited paracetamol glucuronidation with Ki value 4.02 mmol/l in human liver microsomes

Substance Class	Chemical Created by `admin` on `Fri Dec 15 19:01:57 GMT 2023` Edited by `admin` on `Fri Dec 15 19:01:57 GMT 2023`
Record UNII	5D9XI60ASE
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

DIHYDROCODEINE PHOSPHATE

Common Name

English

MORPHINAN-6-OL, 4,5-EPOXY-3-METHOXY-17-METHYL-, (5.ALPHA.,6.ALPHA.)-, PHOSPHATE (1:1) (SALT)

Systematic Name

English

DIHYDROCODEINE PHOSPHATE [MART.]

Common Name

English

Dihydrocodeine phosphate [WHO-DD]

Common Name

English

4,5-ALPHA-EPOXY-3-METHOXY-17-MORPHINAN-6-OL PHOSPHATE (1:1)

Common Name

English

DIHYDROCODEINE PHOSPHATE [JAN]

Common Name

English

Code System Code Type Description

CAS

24204-13-5