Codeine

Summary

Codeine (CHEMBL485) is an approved small-molecule opioid analgesic (ATC N02AA59) targeting OPRM1; indicated across 8 conditions including myopia and osteoarthritis.

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: N02AA59 (+2 more)
• Targets: 1 (OPRM1)
• Indications: 8 conditions
• Clinical trials: 36
• Chemistry: 299.4 Da · C18H21NO3

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL485
Name	Codeine
Type	Small molecule
Max phase	4
FDA approved	yes
PubChem CID	5284371
ChEBI	CHEBI:16714
ATC	N02AA59, N02AA79, R05DA04
Molecular formula	C18H21NO3
Molecular weight	299.4
InChIKey	OROGSEYTTFOCAN-DNJOTXNNSA-N

SMILES: CN1CC[C@]23[C@@H]4[C@H]1CC5=C2C(=C(C=C5)OC)O[C@H]3[C@H](C=C4)O

IUPAC name: (4R,4aR,7S,7aR,12bS)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-ol

ChEBI definition: A morphinane alkaloid found in the opium poppy, Papaver somniferum var. album; has analgesic, anti-tussive and anti-diarrhoeal properties.

Pharmacological roles (ChEBI): opioid analgesic, antitussive, opioid receptor agonist, prodrug, drug allergen.

Other ChEBI roles (chemical / environmental): xenobiotic, environmental contaminant.

Also known as: Codeine, Codeine monohydrate, Codeinum, Codeinum monohydricum, Dea no. 9050, IDS-NC-005(SECT.-2), codeine, CODEINE, SID144207280, (-)-Codeine

Parent form; salt/anhydrous children: CHEMBL284671, CHEMBL369475, CHEMBL1201463, CHEMBL1257022, CHEMBL4297091, CHEMBL6067642

Patent coverage: 19,305 distinct patent families (73,486 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 73,476 (100%) of the total. Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.

Targets

Targets

Primary targets (GtoPdb curated mechanism): the Cancer dependency column is the DepMap CRISPR fitness signal (% of screened cell lines dependent on the target).

Gene	Target	Action	pAffinity	Cancer dependency	UniProt
OPRM1	μ receptor	Full agonist	6.9	0%	P35372

Broader ChEMBL bioactivity targets: 8 (assay-derived). Sample: Opioid receptor, Beta-1 adrenergic receptor, Mu-type opioid receptor, Delta-type opioid receptor, Kappa-type opioid receptor, cGMP-inhibited 3’,5’-cyclic phosphodiesterase 3A, 3’,5’-cyclic-AMP phosphodiesterase 4D, Mas-related G-protein coupled receptor member X2.

Bioactivity

ChEMBL activities: 13 potent at pChembl ≥ 5 of 16 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
OPRM1	6.98	IC50	105	nM	CHEMBL_ACT_593224
OPRM1	6.27	AC50	540	nM	CHEMBL_ACT_25157652
OPRM1	6.14	Ki	727	nM	CHEMBL_ACT_2153547
ADRB1	6.05	AC50	900	nM	CHEMBL_ACT_25122100
OPRM1	5.96	AC50	1100	nM	CHEMBL_ACT_25147120
PDE3A	5.52	AC50	3000	nM	CHEMBL_ACT_25191032
OPRK1	5.31	AC50	4942	nM	CHEMBL_ACT_25129736
OPRM1	5.21	EC50	6100	nM	CHEMBL_ACT_2149570
OPRM1	5.2	Ki	6300	nM	CHEMBL_ACT_2149578
MRGPRX2	5.17	EC50	6761	nM	CHEMBL_ACT_26241731
PDE4D	5.14	AC50	7200	nM	CHEMBL_ACT_25185666
P32300	5	IC50	10000	nM	CHEMBL_ACT_1247320
MRGPRX2	5	EC50	10000	nM	CHEMBL_ACT_26241615

Target pathways

Aggregated over 1 target gene(s): OPRM1.

Top Reactome pathways

6 total, by targets touching each:

Pathway	Targets	Genes
Opioid Signalling	1	OPRM1
G-protein activation	1	OPRM1
Peptide ligand-binding receptors	1	OPRM1
G alpha (i) signalling events	1	OPRM1
Interleukin-4 and Interleukin-13 signaling	1	OPRM1
MECP2 regulates neuronal receptors and channels	1	OPRM1

Dominant GO biological processes

GO term	Targets
G protein-coupled receptor signaling pathway	1
G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger	1
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1
adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway	1
phospholipase C-activating G protein-coupled receptor signaling pathway	1
neuropeptide signaling pathway	1
sensory perception	1
negative regulation of cell population proliferation	1
sensory perception of pain	1
G protein-coupled opioid receptor signaling pathway	1
negative regulation of nitric oxide biosynthetic process	1
behavioral response to ethanol	1
positive regulation of neurogenesis	1
negative regulation of cytosolic calcium ion concentration	1
negative regulation of Wnt protein secretion	1

Indications & clinical

Indications

8 indications (2 at ChEMBL trial phase 4). Phase below is the highest clinical-trial phase recorded for this drug against each disease — not the molecule’s overall approval status (that is in the Summary).

Indication	Trial phase	MONDO	EFO
myopia	3	MONDO:0001384	HP:0000545
osteoarthritis	2	MONDO:0005178	MONDO:0005178
constipation disorder	1	MONDO:0002203	HP:0002019
sickle cell disease	1	MONDO:0011382	MONDO:0011382

4 further indication records had no mapped disease name (EFO/MeSH-only) or were duplicates, and are omitted.

Clinical trials

Total trials: 36.

Phase distribution

Phase	Trials
PHASE4	15
PHASE1	6
Not specified	6
PHASE3	5
PHASE2	3
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00324038	PHASE4	COMPLETED	Buprenorphine in the Treatment of Osteoarthritis (OA) in the Elderly
NCT00386269	PHASE4	COMPLETED	Double Blind Randomized Study Into the Efficacy of Codeine Phosphate Analgesia After Cleft Palate Repair in Infants
NCT00513864	PHASE4	WITHDRAWN	Assessment of Opioid Analgesia in Sickle Cell
NCT00784810	PHASE4	COMPLETED	A Study to Compare Oxycodone/Naloxone Prolonged Release Against Codeine/Paracetamol in the Treatment of Moderate to Severe Chronic Low Back Pain or Pain Due to Osteoarthritis
NCT00921700	PHASE4	COMPLETED	Analgesic Effect of Paracetamol, Paracetamol + Codeine, Ibuprofen and Their Combination
NCT01055704	PHASE4	COMPLETED	Effect of Methylnaltrexone on GI Transit in Healthy Volunteers
NCT01189773	PHASE4	COMPLETED	Combined Analgesia to Control Pain in Children Seen in Emergency Department (ED) for a Trauma of a Limb
NCT01672112	PHASE4	COMPLETED	Comparison of the Efficacy of Oral Oxycodone and Oral Codeine in the Treatment of Postcraniotomy Pain
NCT02032927	PHASE4	WITHDRAWN	Treatment of Chronic Pain From Osteoarthritis
NCT02455518	PHASE4	COMPLETED	Comparative Efficacy of 4 Oral Analgesics
NCT02547896	PHASE4	COMPLETED	Effectiveness of Diclofenac and Its Association to Codeine After Lower Third Molar Extraction.
NCT02647788	PHASE4	COMPLETED	Acetaminophen/Codeine vs Acetaminophen/Ibuprofen for Pain Control and Patient Satisfaction After Hand Surgery
NCT03049878	PHASE4	COMPLETED	Efficacy of Preoperative Administration of Paracetamol-codeine on Pain Following Impacted Mandibular Third Molar Surgery
NCT04066426	PHASE4	COMPLETED	Efficacy of Naproxen-codeine, Naproxen+Dexamethasone, and Naproxen on Myofascial Pain
NCT06907355	PHASE4	COMPLETED	CHAO Tos: Codeina, HederA Helix, LevOdropropizina Para la TOS
NCT00694369	PHASE3	COMPLETED	A Study to Asses the Effect of MK0663 in the Treatment of Patients With Postoperative Dental Pain (0663-092)
NCT01676493	PHASE3	TERMINATED	A Study of Oral Codeine Sulfate in Pediatric Patients With Post-procedural Pain
NCT02625753	PHASE3	COMPLETED	Codeine Plus Paracetamol Versus Placebo for PRK Post-operative Pain
NCT04641338	PHASE3	COMPLETED	Fixed Combination of Dipyrone and Codeine for Controlling Pain After Pelvic-abdominal Surgery
NCT05229965	PHASE3	COMPLETED	Paracetamol Vs Caffeine Vs Codeine in the Management of Post Traumatic Pain in Emergencies
NCT00174538	PHASE1/PHASE2	COMPLETED	Codeine in Sickle Cell Disease
NCT02845271	PHASE2	COMPLETED	Proof-of-concept Study to Assess the Efficacy, Tolerability and Safety of a Single Intraarticular Dose of GZ389988 Versus Placebo in Patients With Painful Osteoarthritis of the Knee
NCT03173456	PHASE2	COMPLETED	Comparing Five Oral Analgesics for Treatment of Acute Pain in the Emergency Department (ED)
NCT05477875	PHASE2	COMPLETED	Cannabinoid vs Opioid for Photorefractive Keratectomy Pain Control
NCT00456898	PHASE1	COMPLETED	Study Evaluating the Potential of DVS SR to Inhibit the CYP2D6 Pathway
NCT01322204	PHASE1	COMPLETED	Codeine in Mechanically Ventilated Neonates
NCT01788254	PHASE1	COMPLETED	Open Label Study for the Functional Characterization of Drug Metabolism and Transport
NCT01845194	PHASE1	COMPLETED	Repeated Dose Study for the Investigation of Heritability of and Genetic Influences on Drug Pharmacokinetics
NCT02737059	PHASE1	COMPLETED	Effect of Naloxegol on Gastric, Small Bowel, and Colonic Transit in Healthy Subjects
NCT03335423	PHASE1	COMPLETED	Inter- and Intra-individual Variations in Metformin Pharmacokinetics - The Importance of Genes and Drug Interactions
NCT01605240	Not specified	UNKNOWN	Ibuprofen Versus Codeine. Is One Better for Post-operative Pain Relief Following Reduction of Paediatric Forearm Fractures?
NCT02295280	Not specified	COMPLETED	A Cost Effective Treatment for Headache in Pregnancy When Acetaminophen Alone is Ineffective.
NCT02883569	Not specified	COMPLETED	Comparative Effectiveness Study for Surgery vs. Non-Surgery in Patients With Low Back Pain
NCT03478423	Not specified	TERMINATED	Opioid Analgesics for Acute Fracture Pain in Adults Discharged From the ED
NCT04202406	Not specified	COMPLETED	Preoperative Acetaminophen- Caffeine- Codeine Combination and Anaesthetic Success in Patients With Acute Pulpitis
NCT04874675	Not specified	SUSPENDED	An Randomized Control Trial Comparing Two Drug Combinations for Pain Management After Third Molars Surgery

Clinical evidence (CIViC)

No CIViC predictive evidence (expected for non-precision-medicine drugs).

Pharmacology

Pharmacogenomics

PharmGKB dosing guidelines (4) — CPIC / DPWG genotype-guided dosing for this drug (drug × pharmacogene):

Guideline	Source	Gene(s)	Dosing	Recommendation
Annotation of DPWG Guideline for codeine and CYP2D6	DPWG	CYP2D6	yes	yes
Annotation of CPIC Guideline for codeine and CYP2D6	CPIC	CYP2D6		yes
Annotation of CPNDS Guideline for codeine and CYP2D6	CPNDS	CYP2D6		yes
Annotation of CPIC Guideline for alfentanil, buprenorphine, codeine, f	CPIC	COMT;OPRM1

PharmGKB also curates 12 clinical and 92 variant annotation(s) for this drug (gene-keyed; see PharmGKB).

Related molecules

Related molecules

Molecules sharing ≥1 of this drug’s curated primary targets, merged from two biobtree sources and ranked by shared-target count, then clinical phase: ChEMBL clinical-stage candidates (development phase ≥2) and PubChem drug-class bioactivity (approved / known drugs acting on the target). Deduplicated by drug name; the drug’s own salt forms are excluded. Note: for a drug with few primary targets a shared-target match can reflect off-target / promiscuous binding rather than the same therapeutic mechanism — the phase ordering surfaces bona-fide therapeutics first.

400 molecules share ≥1 primary target. Top 60 by shared-target count:

Molecule	Source	Status	Shared targets
Dihydroergotamine	ChEMBL + PubChem	Phase 4 (approved)	OPRM1
ELUXADOLINE	ChEMBL + PubChem	Phase 4 (approved)	OPRM1
GENTIAN VIOLET	ChEMBL + PubChem	Phase 4 (approved)	OPRM1
MAVORIXAFOR	ChEMBL + PubChem	Phase 4 (approved)	OPRM1
PIMAVANSERIN	ChEMBL + PubChem	Phase 4 (approved)	OPRM1
PROPOXYPHENE	ChEMBL + PubChem	Phase 4 (approved)	OPRM1
REGORAFENIB	ChEMBL + PubChem	Phase 4 (approved)	OPRM1
VORAPAXAR	ChEMBL + PubChem	Phase 4 (approved)	OPRM1
ALFENTANIL	ChEMBL	Phase 4 (approved)	OPRM1
ALOGLIPTIN	ChEMBL	Phase 4 (approved)	OPRM1
ALPIDEM	ChEMBL	Phase 4 (approved)	OPRM1
ALVIMOPAN	ChEMBL	Phase 4 (approved)	OPRM1
AMBENONIUM	ChEMBL	Phase 4 (approved)	OPRM1
AMILORIDE	ChEMBL	Phase 4 (approved)	OPRM1
AMIODARONE	ChEMBL	Phase 4 (approved)	OPRM1
AMITRIPTYLINE	ChEMBL	Phase 4 (approved)	OPRM1
AMLODIPINE	ChEMBL	Phase 4 (approved)	OPRM1
AMODIAQUINE	ChEMBL	Phase 4 (approved)	OPRM1
AMOXAPINE	ChEMBL	Phase 4 (approved)	OPRM1
ANTAZOLINE	ChEMBL	Phase 4 (approved)	OPRM1
ARIPIPRAZOLE	ChEMBL	Phase 4 (approved)	OPRM1
ASTEMIZOLE	ChEMBL	Phase 4 (approved)	OPRM1
ATOMOXETINE	ChEMBL	Phase 4 (approved)	OPRM1
AZELASTINE	ChEMBL	Phase 4 (approved)	OPRM1
BAZEDOXIFENE	ChEMBL	Phase 4 (approved)	OPRM1
BENFLUOREX	ChEMBL	Phase 4 (approved)	OPRM1
BENZBROMARONE	ChEMBL	Phase 4 (approved)	OPRM1
BENZIODARONE	ChEMBL	Phase 4 (approved)	OPRM1
BENZTROPINE	ChEMBL	Phase 4 (approved)	OPRM1
BENZYDAMINE	ChEMBL	Phase 4 (approved)	OPRM1
BEPRIDIL	ChEMBL	Phase 4 (approved)	OPRM1
BEXAROTENE	ChEMBL	Phase 4 (approved)	OPRM1
BITHIONOL	ChEMBL	Phase 4 (approved)	OPRM1
BOSUTINIB	ChEMBL	Phase 4 (approved)	OPRM1
BROMOCRIPTINE	ChEMBL	Phase 4 (approved)	OPRM1
BROMODIPHENHYDRAMINE	ChEMBL	Phase 4 (approved)	OPRM1
BROMPERIDOL	ChEMBL	Phase 4 (approved)	OPRM1
BUPRENORPHINE	ChEMBL	Phase 4 (approved)	OPRM1
BUTORPHANOL	ChEMBL	Phase 4 (approved)	OPRM1
CANDESARTAN CILEXETIL	ChEMBL	Phase 4 (approved)	OPRM1
CANNABIDIOL	ChEMBL	Phase 4 (approved)	OPRM1
CARVEDILOL	ChEMBL	Phase 4 (approved)	OPRM1
CASPOFUNGIN	ChEMBL	Phase 4 (approved)	OPRM1
CETRORELIX	ChEMBL	Phase 4 (approved)	OPRM1
CHLORHEXIDINE	ChEMBL	Phase 4 (approved)	OPRM1
CHLORPROMAZINE	ChEMBL	Phase 4 (approved)	OPRM1
CHLORPROTHIXENE	ChEMBL	Phase 4 (approved)	OPRM1
CINACALCET	ChEMBL	Phase 4 (approved)	OPRM1
CINNARIZINE	ChEMBL	Phase 4 (approved)	OPRM1
CITALOPRAM	ChEMBL	Phase 4 (approved)	OPRM1
CLEMASTINE	ChEMBL	Phase 4 (approved)	OPRM1
CLOMIPHENE	ChEMBL	Phase 4 (approved)	OPRM1
CLOMIPRAMINE	ChEMBL	Phase 4 (approved)	OPRM1
CLOPIDOGREL	ChEMBL	Phase 4 (approved)	OPRM1
CLOTRIMAZOLE	ChEMBL	Phase 4 (approved)	OPRM1
COBIMETINIB	ChEMBL	Phase 4 (approved)	OPRM1
CYCLIZINE	ChEMBL	Phase 4 (approved)	OPRM1
CYPROHEPTADINE	ChEMBL	Phase 4 (approved)	OPRM1
DANAZOL	ChEMBL	Phase 4 (approved)	OPRM1
DARIFENACIN	ChEMBL	Phase 4 (approved)	OPRM1