Codeine

Summary

Codeine (CHEMBL485) is an approved small-molecule opioid analgesic (ATC N02AA59) that acts as an opioid receptors; mu/kappa/delta agonist; investigated in clinical trials for 2 conditions including myopia and osteoarthritis.

At a glance

• Status: FDA-approved
• Modality: Small molecule
• ATC class: N02AA59 (+2 more)
• Targets: 1 (OPRM1)
• Indications: 8 conditions
• Clinical trials: 36
• Chemistry: 299.4 Da · C18H21NO3
• Target biology: 1 curated target implicated as cohort gene in 1 disease corpus-wide; indicated or in trials for 4 (0 on both)
• Competitive landscape: target OPRM1 is also targeted by 44 other curated drugs in the corpus

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: ubiquitous in the patent literature (a reference / commodity compound named in millions of filings — the raw count carries no drug-specific signal).

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

Mechanism of action (ChEMBL curated)

Mechanism of action	Action type	Target	Target type
Opioid receptors; mu/kappa/delta agonist	AGONIST	Opioid receptors; mu/kappa/delta	PROTEIN FAMILY

Broader ChEMBL bioactivity targets: 8 (assay-derived screening hits — not curated targets; per-target potencies are in the ChEMBL bioactivities table below).

Bioactivity

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

Protein	UniProt	Gene	pChembl	Type	Value	Activity ID
Mu-type opioid receptor	P35372	OPRM1	6.98	IC50	105 nM	CHEMBL_ACT_593224
Mu-type opioid receptor	P35372	OPRM1	6.27	AC50	540 nM	CHEMBL_ACT_25157652
Mu-type opioid receptor	P35372	OPRM1	6.14	Ki	727 nM	CHEMBL_ACT_2153547
Beta-1 adrenergic receptor	P08588	ADRB1	6.05	AC50	900 nM	CHEMBL_ACT_25122100
Mu-type opioid receptor	P35372	OPRM1	5.96	AC50	1100 nM	CHEMBL_ACT_25147120
cGMP-inhibited 3’,5’-cyclic phosphodiesterase 3A	Q14432	PDE3A	5.52	AC50	3000 nM	CHEMBL_ACT_25191032
Kappa-type opioid receptor	P41145	OPRK1	5.31	AC50	4942 nM	CHEMBL_ACT_25129736
Mu-type opioid receptor	P35372	OPRM1	5.21	EC50	6100 nM	CHEMBL_ACT_2149570
Mu-type opioid receptor	P35372	OPRM1	5.2	Ki	6300 nM	CHEMBL_ACT_2149578
Mas-related G protein-coupled receptor member X2	Q96LB1	MRGPRX2	5.17	EC50	6761 nM	CHEMBL_ACT_26241731
3’,5’-cyclic-AMP phosphodiesterase 4D	Q08499	PDE4D	5.14	AC50	7200 nM	CHEMBL_ACT_25185666
Delta-type opioid receptor (house mouse)	P32300		5	IC50	10000 nM	CHEMBL_ACT_1247320
Mas-related G protein-coupled receptor member X2	Q96LB1	MRGPRX2	5	EC50	10000 nM	CHEMBL_ACT_26241615

Target pathways

Aggregated over 1 target gene(s): OPRM1.

Top Reactome pathways

18 total, by targets touching each:

Pathway	Targets	Genes
Opioid Signalling	1	OPRM1
Cytokine Signaling in Immune system	1	OPRM1
Signal Transduction	1	OPRM1
Immune System	1	OPRM1
G-protein activation	1	OPRM1
Generic Transcription Pathway	1	OPRM1
Signaling by GPCR	1	OPRM1
Class A/1 (Rhodopsin-like receptors)	1	OPRM1
Peptide ligand-binding receptors	1	OPRM1
GPCR downstream signalling	1	OPRM1
G alpha (i) signalling events	1	OPRM1
Signaling by Interleukins	1	OPRM1
GPCR ligand binding	1	OPRM1
Interleukin-4 and Interleukin-13 signaling	1	OPRM1
RNA Polymerase II Transcription	1	OPRM1
Gene expression (Transcription)	1	OPRM1
Transcriptional Regulation by MECP2	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

Predicted targets — Sugi Predict

This molecule is SureChEMBL compound SCHEMBL1276342 — see its predicted protein targets + similar patent compounds on Sugi Predict.

Indications & clinical

Indications

2 diseases in clinical trials (phase 2–3, investigational — not approved indications). Highest ChEMBL trial phase per disease; a non-cancer approved use is occasionally logged at phase 3 here.

Disease (in trials)	Phase	MONDO	EFO
myopia	3	MONDO:0001384
osteoarthritis	2	MONDO:0005178

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

Regulatory approval & mechanism (DrugCentral)

Approved: FDA. Curated mechanism: AGONIST · 1 MOA target of 3 total (P35372).

DrugCentral (CC BY-SA): authoritative regulatory-approval status + curated mechanism. The drug’s full target set is in Targets above.

Clinical trials

Total trials: 36.

Phase distribution

Phase	Trials
Phase 4	15
Phase 1	6
Not specified	6
Phase 3	5
Phase 2	3
Phase 1/2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00324038	Phase 4	COMPLETED	Buprenorphine in the Treatment of Osteoarthritis (OA) in the Elderly
NCT00386269	Phase 4	COMPLETED	Double Blind Randomized Study Into the Efficacy of Codeine Phosphate Analgesia After Cleft Palate Repair in Infants
NCT00513864	Phase 4	WITHDRAWN	Assessment of Opioid Analgesia in Sickle Cell
NCT00784810	Phase 4	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	Phase 4	COMPLETED	Analgesic Effect of Paracetamol, Paracetamol + Codeine, Ibuprofen and Their Combination
NCT01055704	Phase 4	COMPLETED	Effect of Methylnaltrexone on GI Transit in Healthy Volunteers
NCT01189773	Phase 4	COMPLETED	Combined Analgesia to Control Pain in Children Seen in Emergency Department (ED) for a Trauma of a Limb
NCT01672112	Phase 4	COMPLETED	Comparison of the Efficacy of Oral Oxycodone and Oral Codeine in the Treatment of Postcraniotomy Pain
NCT02032927	Phase 4	WITHDRAWN	Treatment of Chronic Pain From Osteoarthritis
NCT02455518	Phase 4	COMPLETED	Comparative Efficacy of 4 Oral Analgesics
NCT02547896	Phase 4	COMPLETED	Effectiveness of Diclofenac and Its Association to Codeine After Lower Third Molar Extraction.
NCT02647788	Phase 4	COMPLETED	Acetaminophen/Codeine vs Acetaminophen/Ibuprofen for Pain Control and Patient Satisfaction After Hand Surgery
NCT03049878	Phase 4	COMPLETED	Efficacy of Preoperative Administration of Paracetamol-codeine on Pain Following Impacted Mandibular Third Molar Surgery
NCT04066426	Phase 4	COMPLETED	Efficacy of Naproxen-codeine, Naproxen+Dexamethasone, and Naproxen on Myofascial Pain
NCT06907355	Phase 4	COMPLETED	CHAO Tos: Codeina, HederA Helix, LevOdropropizina Para la TOS
NCT00694369	Phase 3	COMPLETED	A Study to Asses the Effect of MK0663 in the Treatment of Patients With Postoperative Dental Pain (0663-092)
NCT01676493	Phase 3	TERMINATED	A Study of Oral Codeine Sulfate in Pediatric Patients With Post-procedural Pain
NCT02625753	Phase 3	COMPLETED	Codeine Plus Paracetamol Versus Placebo for PRK Post-operative Pain
NCT04641338	Phase 3	COMPLETED	Fixed Combination of Dipyrone and Codeine for Controlling Pain After Pelvic-abdominal Surgery
NCT05229965	Phase 3	COMPLETED	Paracetamol Vs Caffeine Vs Codeine in the Management of Post Traumatic Pain in Emergencies
NCT00174538	Phase 1/2	COMPLETED	Codeine in Sickle Cell Disease
NCT02845271	Phase 2	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	Phase 2	COMPLETED	Comparing Five Oral Analgesics for Treatment of Acute Pain in the Emergency Department (ED)
NCT05477875	Phase 2	COMPLETED	Cannabinoid vs Opioid for Photorefractive Keratectomy Pain Control
NCT00456898	Phase 1	COMPLETED	Study Evaluating the Potential of DVS SR to Inhibit the CYP2D6 Pathway
NCT01322204	Phase 1	COMPLETED	Codeine in Mechanically Ventilated Neonates
NCT01788254	Phase 1	COMPLETED	Open Label Study for the Functional Characterization of Drug Metabolism and Transport
NCT01845194	Phase 1	COMPLETED	Repeated Dose Study for the Investigation of Heritability of and Genetic Influences on Drug Pharmacokinetics
NCT02737059	Phase 1	COMPLETED	Effect of Naloxegol on Gastric, Small Bowel, and Colonic Transit in Healthy Subjects
NCT03335423	Phase 1	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

MeSH pharmacological classification

Definition (MeSH): An opioid analgesic related to MORPHINE but with less potent analgesic properties and mild sedative effects. It also acts centrally to suppress cough.

Pharmacological action: Analgesics, Opioid; Antitussive Agents; Narcotics.

Broader MeSH heading: Morphine Derivatives.

MeSH descriptor D003061 “Codeine” — exact-name match.

Pharmacogenomics

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

4 guidelines:

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

PGx drug labels — PharmGKB annotations of regulatory drug labels (FDA / EMA / PMDA / Health Canada (HCSC) / Swissmedic) that carry pharmacogenomic information, ordered by the label’s PGx level (Testing Required strongest → No Clinical PGx; — = no level recorded). Label guidance = the label gives PGx prescribing / dosing / alternate-drug information.

4 label annotations:

Agency	PGx level	Gene(s)	Label guidance	PharmGKB
FDA	Actionable PGx	CYP2D6	prescribing, alternate drug	PA166104916
PMDA	Actionable PGx	CYP2D6		PA166160226
HCSC	Actionable PGx	CYP2D6	prescribing, alternate drug	PA166127654
Swissmedic	Actionable PGx	CYP2D6	prescribing, alternate drug	PA166184126

Pharmacogenomic clinical annotations (13) — variant × gene × association × phenotype, ranked by PharmGKB evidence level (1 strongest → 4):

Gene	Variant	Association	Phenotype	Level
CYP2D6	CYP2D6*1, CYP2D6*1xN, CYP2D6*2, CYP2D6*2xN	Toxicity	Pain	1A
CYP2D6	CYP2D6*1, CYP2D6*1xN, CYP2D6*2, CYP2D6*2xN, CYP2D6*3, CYP2D6*4, CYP2D6*5, CYP2D6*6, CYP2D6*10, CYP2D6*17, CYP2D6*29, CYP2D6*36, CYP2D6*41	Metabolism/PK		1A
CYP2D6	CYP2D6*1, CYP2D6*4, CYP2D6*5, CYP2D6*6, CYP2D6*17, CYP2D6*40	Efficacy	Pain	1A
ABCB1	rs1045642	Toxicity		3
ABCB1	rs1128503	Toxicity	Pain	3
CYP2D6	CYP2D6*1, CYP2D6*24	Metabolism/PK		3
CYP2D6	CYP2D6*1, CYP2D6*3, CYP2D6*4	Toxicity	Opioid-Related Disorders	3
OPRM1	rs1799971	Dosage		3
OPRM1	rs62436463	Toxicity	adverse events	3
SEPTIN3	rs739296	Toxicity	adverse events	3
UGT2B7	rs7439366	Dosage		3
WBP2NL	rs739296	Toxicity	adverse events	3
WBP2NL	rs9620007	Toxicity	adverse events	3

Published variant annotations — per-publication pharmacogenomic findings for this drug (significant associations only), each from a curated PharmGKB literature annotation:

40 published findings:

Gene	Variant	Category	Finding	PMID
ABCB1	rs1045642	Toxicity, Metabolism/PK	Allele A is associated with increased likelihood of CNS depression in breast-feeding infants when treated with codeine in women with Pain as compared to allele G.	PMID:22398969
ABCB1	rs1128503	Toxicity, Metabolism/PK	Allele A is associated with increased likelihood of CNS depression in breast-feeding infants when treated with codeine in women with Pain as compared to allele G.	PMID:22398969
ABCB1	rs2032582	Toxicity, Metabolism/PK	Genotype AA is associated with increased likelihood of CNS depression in breast-feeding infants when treated with codeine in women with Pain.	PMID:22398969
CYP1B1	rs1056836	Efficacy	Allele C is associated with decreased clinical benefit to codeine or tramadol in men with Pain as compared to allele G.	PMID:35102242
CYP1B1	rs1056837	Efficacy	Allele A is associated with decreased clinical benefit to codeine or tramadol in men with Pain as compared to allele G.	PMID:35102242
CYP2D6	CYP2D6 intermediate metabolizer	Efficacy	CYP2D6 intermediate metabolizer and poor metabolizer is associated with increased likelihood of Emergencies and Pain when treated with codeine, hydrocodone or tramadol in people with Pain as compared to CYP2D6 normal metabolizer and ultrarapid metabolizer.	PMID:40720122
CYP2D6	CYP2D6 poor and ultrarapid metabolizers	Efficacy, Toxicity, Metabolism/PK	CYP2D6 poor and ultrarapid metabolizers is associated with increased likelihood of discontinuation when treated with codeine or tramadol in people with Pain as compared to CYP2D6 normal metabolizer.	PMID:30784356
CYP2D6	CYP2D6 poor metabolizer	Efficacy	CYP2D6 poor metabolizer is associated with increased likelihood of Pain when treated with codeine or tramadol in people with Pain as compared to CYP2D6 normal metabolizer.	PMID:30784356
CYP2D6	CYP2D6 poor metabolizer	Efficacy	CYP2D6 poor metabolizer is associated with decreased clinical benefit to codeine, hydrocodone, oxycodone or tramadol in people with Pain as compared to CYP2D6 normal metabolizer.	PMID:40816377
CYP2D6	CYP2D6 poor metabolizers	Toxicity	CYP2D6 poor metabolizer is associated with decreased risk of adverse events due to codeine in children with Pain, Postoperative as compared to CYP2D6 normal metabolizer and intermediate metabolizer.	PMID:24122716
CYP2D6	CYP2D6 poor metabolizers	Metabolism/PK	CYP2D6 poor metabolizer is associated with decreased metabolism of codeine.	PMID:24747667
CYP2D6	CYP2D6 poor metabolizers and intermediate metabolizers	Efficacy	CYP2D6 intermediate metabolizer and poor metabolizer are associated with decreased response to codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone or tramadol in people with Neoplasms and Pain as compared to CYP2D6 normal metabolizer.	PMID:34423496
CYP2D6	CYP2D6*1	Efficacy, Metabolism/PK	CYP2D6 *1/*1 is associated with inhibition of metabolism when treated with acetaminophen, codeine and levomepromazine in people with Back Pain.	PMID:19308365
CYP2D6	CYP2D6*1, CYP2D6*10	Metabolism/PK	CYP2D6 *1/*10 + *10/*10 is associated with decreased plasma levels of morphine, M3G and M6G levels but not those of codeine when treated with codeine in healthy individuals as compared to CYP2D6 *1/*1.	PMID:24077935
CYP2D6	CYP2D6*1, CYP2D6*17	Efficacy	CYP2D6 *17 is associated with decreased response to codeine in children with Anemia, Sickle Cell as compared to CYP2D6 *1.	PMID:17517247
CYP2D6	CYP2D6*1, CYP2D6*1x2, CYP2D6*2, CYP2D6*2x2, CYP2D6*2xN, CYP2D6*4, CYP2D6*9, CYP2D6*10, CYP2D6*41, CYP2D6*41x2	Other	CYP2D6 *1/*1x2 + *1/*2x2 + *1x2/*41 + *2/*2x2 + *2xN/*4 + *1/*1 + *1/*10 + *1/*2 + *1/*41 + *1/*41x2 + *1/*9 + *2/*2 + *2/*41 + *2/*9 (assigned as normal metabolizer and ultrarapid metabolizer phenotype) is associated with increased likelihood of Opioid-Related Disorders when exposed to codeine.	PMID:37940651
CYP2D6	CYP2D6*1, CYP2D6*1xN, CYP2D6*10	Metabolism/PK	CYP2D6 *1xN/*10 (assigned as ultrarapid metabolizer phenotype) is associated with increased metabolism of codeine in healthy individuals as compared to CYP2D6 normal metabolizer.	PMID:16819548
CYP2D6	CYP2D6*1, CYP2D6*1xN, CYP2D6*3, CYP2D6*4, CYP2D6*6	Metabolism/PK	CYP2D6 *1xN/*1 (assigned as ultrarapid metabolizer phenotype) is associated with increased metabolism of codeine in healthy individuals as compared to CYP2D6 normal metabolizer.	PMID:16819548
CYP2D6	CYP2D6*1, CYP2D6*1xN, CYP2D6*41	Metabolism/PK	CYP2D6 *1xN/*41 (assigned as ultrarapid metabolizer phenotype) is associated with increased metabolism of codeine in healthy individuals as compared to CYP2D6 normal metabolizer.	PMID:16819548
CYP2D6	CYP2D6*1, CYP2D6*2, CYP2D6*2xN	Metabolism/PK	CYP2D6 *1/*2xN (assigned as ultrarapid metabolizer phenotype) is associated with increased metabolism of codeine in healthy individuals as compared to CYP2D6 normal metabolizer.	PMID:16819548
CYP2D6	CYP2D6*1, CYP2D6*3, CYP2D6*4	Toxicity	CYP2D6 *3/*3 + *4/*4 are associated with decreased risk of Opioid-Related Disorders due to codeine, hydrocodone or oxycodone as compared to CYP2D6 *1/*1 + *1/*3 + *1/*4.	PMID:9352573
CYP2D6	CYP2D6*1, CYP2D6*3, CYP2D6*4, CYP2D6*5	Other	CYP2D6 *1/*1 + *1/*4 is associated with increased oroceccal transit time when treated with codeine in healthy individuals.	PMID:9129563
CYP2D6	CYP2D6*1, CYP2D6*36	Metabolism/PK	CYP2D6 *36 is associated with decreased codeine metabolism and morphine and glucuronides formation when treated with codeine in healthy individuals as compared to CYP2D6 *1/*1.	PMID:8823235
CYP2D6	CYP2D6*1, CYP2D6*4	Metabolism/PK	CYP2D6 *4/*4 is associated with decreased metabolism of codeine in people with Kidney Failure, Chronic as compared to CYP2D6 *1/*1 + *1/*4.	PMID:19940985
CYP2D6	CYP2D6*1, CYP2D6*4	Efficacy	CYP2D6 *4 is associated with decreased response to codeine in children with Anemia, Sickle Cell as compared to CYP2D6 *1.	PMID:17517247
CYP2D6	CYP2D6*1, CYP2D6*40	Efficacy	CYP2D6 *40 is associated with decreased response to codeine in children with Anemia, Sickle Cell as compared to CYP2D6 *1.	PMID:17517247
CYP2D6	CYP2D6*1, CYP2D6*5	Efficacy	CYP2D6 *5 is associated with decreased response to codeine in children with Anemia, Sickle Cell as compared to CYP2D6 *1.	PMID:17517247
CYP2D6	CYP2D6*1, CYP2D6*5, CYP2D6*17	Metabolism/PK	CYP2D6 *5/*17 is associated with decreased metabolism of codeine, debrisoquine, dextromethorphan or metoprolol in healthy individuals as compared to CYP2D6 *17/*17 + *1/*1.	PMID:11823760
CYP2D6	CYP2D6*1, CYP2D6*6	Efficacy	CYP2D6 *6 is associated with decreased response to codeine in children with Anemia, Sickle Cell as compared to CYP2D6 *1.	PMID:17517247
CYP2D6	CYP2D6*17	Metabolism/PK	CYP2D6 *17 is associated with decreased metabolism of codeine in people with Anemia, Sickle Cell.	PMID:19357842
CYP2D6	CYP2D6*2, CYP2D6*2xN, CYP2D6*41	Metabolism/PK	CYP2D6 *2xN/*41 (assigned as ultrarapid metabolizer phenotype) is associated with increased metabolism of codeine in healthy individuals as compared to CYP2D6 normal metabolizer.	PMID:16819548
OPRM1	rs1799971	Dosage	Genotype AA is associated with decreased dose of codeine in women as compared to genotype AG.	PMID:25752520
OPRM1	rs1799971	Toxicity	Genotype AA is associated with increased likelihood of Urinary Retention, Constipation, Nausea, Vomiting, Abdominal Pain, Exanthema, Wheezing or adverse events when treated with codeine, morphine or oxycodone in people with Neoplasms and Pain as compared to genotypes AG + GG.	PMID:40873551
OPRM1	rs62436463	Toxicity	Allele T is associated with decreased risk of adverse events when treated with codeine, hydrocodone, oxycodone or tramadol as compared to allele C.	PMID:34061827
SEPTIN3	rs739296	Toxicity	Allele A is associated with decreased risk of adverse events when treated with codeine, hydrocodone, oxycodone or tramadol as compared to allele G.	PMID:34061827
SLC22A1	SLC22A1 low activity	Toxicity	SLC22A1 low activity is associated with increased likelihood of Dizziness, Drug Toxicity, Headache, Nausea and sedation when exposed to codeine in healthy individuals as compared to SLC22A1 high activity.	PMID:23835420
UGT2B7	rs73823859	Efficacy	Allele A is associated with increased Pain when treated with codeine, morphine or tramadol in children with Anemia, Sickle Cell as compared to allele G.	PMID:37248824
UGT2B7	rs7439366	Dosage	Genotype TT is associated with decreased dose of codeine in women as compared to genotype CC.	PMID:25752520
WBP2NL	rs739296	Toxicity	Allele A is associated with decreased risk of adverse events when treated with codeine, hydrocodone, oxycodone or tramadol as compared to allele G.	PMID:34061827
WBP2NL	rs9620007	Toxicity	Allele G is associated with decreased risk of adverse events when treated with codeine as compared to allele C.	PMID:34061827

PharmGKB pathway — curated pharmacokinetic / pharmacodynamic pathway diagrams for this drug:

• Codeine and Morphine Pathway, Pharmacokinetics — pharmacokinetic

Adverse-event reports (FAERS)

36,331 reports across 3 FAERS drug-name records; 3,617 distinct MedDRA reactions.

openFDA FAERS — spontaneous post-marketing reports. Co-occurrence, not causation: reports are voluntary, unverified, and confounded by indication and reporting bias (the drug’s own indication often appears as a ‘reaction’). PRR is a disproportionality heuristic (reaction rate for this drug vs the FAERS background), NOT a risk estimate. Counts are pooled across the drug’s name records.

Most-reported events

Serious = reports flagged serious (death / life-threatening / hospitalisation / disability / other medically important).

50 reactions by report volume:

Reaction (MedDRA PT)	Reports	Serious	PRR
drug hypersensitivity	8,329	3,607 (43%)	25.8×
drug ineffective	4,551	4,356 (96%)	2.0×
pain	3,991	3,913 (98%)	3.8×
off label use	3,699	3,628 (98%)	2.5×
rash	3,492	3,320 (95%)	4.7×
nausea	3,450	3,147 (91%)	2.5×
rheumatoid arthritis	3,438	3,431 (100%)	18.1×
fatigue	3,433	3,328 (97%)	2.6×
arthralgia	3,303	3,246 (98%)	4.6×
toxicity to various agents	3,206	3,158 (99%)	11.2×
headache	3,203	3,091 (97%)	3.0×
diarrhoea	2,925	2,815 (96%)	2.6×
drug intolerance	2,897	2,857 (99%)	17.9×
hypersensitivity	2,739	2,589 (95%)	8.7×
joint swelling	2,702	2,689 (100%)	13.2×
infusion related reaction	2,672	2,667 (100%)	24.3×
dyspnoea	2,573	2,482 (96%)	2.6×
vomiting	2,563	2,380 (93%)	3.2×
hypertension	2,377	2,362 (99%)	6.5×
condition aggravated	2,373	2,356 (99%)	4.6×
peripheral swelling	2,352	2,336 (99%)	9.0×
malaise	2,299	2,247 (98%)	3.0×
pyrexia	2,289	2,271 (99%)	3.8×
hepatic enzyme increased	2,214	2,212 (100%)	19.4×
drug abuse	2,144	2,134 (100%)	15.2×
pruritus	2,039	1,901 (93%)	3.1×
dizziness	1,989	1,886 (95%)	2.3×
contraindicated product administered	1,980	1,974 (100%)	40.5×
abdominal discomfort	1,936	1,865 (96%)	6.8×
arthropathy	1,897	1,895 (100%)	20.3×
musculoskeletal stiffness	1,856	1,850 (100%)	12.5×
synovitis	1,851	1,850 (100%)	65.8×
overdose	1,845	1,824 (99%)	5.0×
treatment failure	1,840	1,835 (100%)	13.2×
alopecia	1,837	1,814 (99%)	5.4×
insomnia	1,784	1,729 (97%)	3.9×
infection	1,781	1,768 (99%)	7.2×
pneumonia	1,774	1,773 (100%)	3.2×
ill-defined disorder	1,766	1,764 (100%)	17.2×
product use issue	1,764	1,737 (98%)	5.5×
confusional state	1,749	1,731 (99%)	6.3×
decreased appetite	1,688	1,664 (99%)	4.2×
nasopharyngitis	1,665	1,641 (99%)	5.2×
swelling	1,649	1,631 (99%)	10.4×
abdominal pain upper	1,645	1,610 (98%)	4.7×
abdominal pain	1,627	1,610 (99%)	4.1×
weight increased	1,569	1,545 (98%)	4.1×
general physical health deterioration	1,559	1,557 (100%)	7.9×
asthenia	1,556	1,523 (98%)	2.4×
hypoaesthesia	1,553	1,533 (99%)	6.0×

Strongest disproportionality

Reactions over-reported for this drug vs the FAERS background (PRR), among those with ≥ 10 reports (a high PRR off a few reports is noise, not signal).

50 reactions by disproportionality:

Reaction (MedDRA PT)	Reports	Serious	PRR
granuloma skin	467	467 (100%)	756.7×
optic nerve operation	14	14 (100%)	723.8×
grip strength	115	115 (100%)	573.7×
synovial fluid analysis	38	38 (100%)	450.2×
red blood cell sedimentation rate	121	121 (100%)	438.3×
blood parathyroid hormone decreased	562	562 (100%)	350.1×
deep vein thrombosis postoperative	717	717 (100%)	333.7×
duodenal ulcer repair	10	10 (100%)	284.4×
c-reactive protein	294	294 (100%)	278.2×
stoma site dermatitis	11	11 (100%)	272.0×
anti-cyclic citrullinated peptide antibody	207	207 (100%)	260.4×
blood ethanol	12	12 (100%)	227.5×
adjustment disorder with depressed mood	542	542 (100%)	212.6×
lupus vulgaris	317	317 (100%)	209.4×
swollen joint count	65	65 (100%)	207.7×
subcutaneous drug absorption impaired	143	143 (100%)	205.9×
pancreatic fibrosis	13	13 (100%)	205.4×
swollen joint count increased	790	790 (100%)	195.3×
panniculitis	570	570 (100%)	178.7×
x-ray abnormal	395	395 (100%)	164.2×
dislocation of vertebra	489	489 (100%)	162.7×
rheumatoid factor positive	1,239	1,239 (100%)	157.7×
rheumatic fever	931	931 (100%)	156.1×
muscle tension dysphonia	16	16 (100%)	144.4×
rheumatoid nodule	542	542 (100%)	140.1×
duodenal ulcer perforation	1,392	1,392 (100%)	134.5×
anti-cyclic citrullinated peptide antibody positive	1,323	1,323 (100%)	131.4×
postmortem blood drug level	11	11 (100%)	130.3×
drug tolerance decreased	505	505 (100%)	127.2×
facet joint syndrome	556	556 (100%)	123.8×
c-reactive protein abnormal	1,050	1,050 (100%)	113.1×
retinitis	265	265 (100%)	109.0×
sleep disorder due to general medical condition, hypersomnia type	15	15 (100%)	101.6×
overlap syndrome	98	98 (100%)	95.4×
helicobacter infection	1,420	1,420 (100%)	93.3×
hepatic enzyme	19	19 (100%)	90.8×
peripheral venous disease	543	543 (100%)	90.6×
sleep disorder due to general medical condition, insomnia type	872	870 (100%)	90.3×
hypocholesterolaemia	41	41 (100%)	88.7×
muscle injury	1,084	1,083 (100%)	87.5×
postmortem blood drug level abnormal	19	19 (100%)	86.4×
neuropathic muscular atrophy	12	12 (100%)	80.3×
temperature regulation disorder	254	253 (100%)	75.9×
tender joint count	10	10 (100%)	75.8×
hand deformity	1,496	1,496 (100%)	74.4×
pemphigus	1,421	1,421 (100%)	74.2×
porphyria acute	157	157 (100%)	74.2×
amaurosis fugax	121	121 (100%)	73.6×
folliculitis	1,160	1,160 (100%)	72.8×
gastrointestinal stoma output abnormal	15	15 (100%)	67.2×

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.

399 molecules share ≥1 primary target. Top 100 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
DAUNORUBICIN	ChEMBL	Phase 4 (approved)	OPRM1
DELAVIRDINE	ChEMBL	Phase 4 (approved)	OPRM1
DEQUALINIUM	ChEMBL	Phase 4 (approved)	OPRM1
DESERPIDINE	ChEMBL	Phase 4 (approved)	OPRM1
DESOGESTREL	ChEMBL	Phase 4 (approved)	OPRM1
DESVENLAFAXINE	ChEMBL	Phase 4 (approved)	OPRM1
DEXTROMETHORPHAN	ChEMBL	Phase 4 (approved)	OPRM1
DEZOCINE	ChEMBL	Phase 4 (approved)	OPRM1
DIBENZEPIN	ChEMBL	Phase 4 (approved)	OPRM1
DIETHYLSTILBESTROL	ChEMBL	Phase 4 (approved)	OPRM1
DIPHENHYDRAMINE	ChEMBL	Phase 4 (approved)	OPRM1
DIPHENIDOL	ChEMBL	Phase 4 (approved)	OPRM1
DIPHENOXYLATE	ChEMBL	Phase 4 (approved)	OPRM1
DIPHENYLPYRALINE	ChEMBL	Phase 4 (approved)	OPRM1
DISULFIRAM	ChEMBL	Phase 4 (approved)	OPRM1
DOBUTAMINE	ChEMBL	Phase 4 (approved)	OPRM1
DOMPERIDONE	ChEMBL	Phase 4 (approved)	OPRM1
DOXAZOSIN	ChEMBL	Phase 4 (approved)	OPRM1
DRONEDARONE	ChEMBL	Phase 4 (approved)	OPRM1
DULOXETINE	ChEMBL	Phase 4 (approved)	OPRM1
ECONAZOLE	ChEMBL	Phase 4 (approved)	OPRM1
EDROPHONIUM	ChEMBL	Phase 4 (approved)	OPRM1
ELETRIPTAN	ChEMBL	Phase 4 (approved)	OPRM1
ELIGLUSTAT	ChEMBL	Phase 4 (approved)	OPRM1
EMETINE	ChEMBL	Phase 4 (approved)	OPRM1
ENASIDENIB	ChEMBL	Phase 4 (approved)	OPRM1
EPINASTINE	ChEMBL	Phase 4 (approved)	OPRM1
ERLOTINIB	ChEMBL	Phase 4 (approved)	OPRM1
ERYTHROMYCIN PROPIONATE	ChEMBL	Phase 4 (approved)	OPRM1
ESCITALOPRAM	ChEMBL	Phase 4 (approved)	OPRM1
ESTRADIOL	ChEMBL	Phase 4 (approved)	OPRM1
ESTRONE	ChEMBL	Phase 4 (approved)	OPRM1
ETHINYL ESTRADIOL	ChEMBL	Phase 4 (approved)	OPRM1
ETHOPROPAZINE	ChEMBL	Phase 4 (approved)	OPRM1
ETONOGESTREL	ChEMBL	Phase 4 (approved)	OPRM1
ETRAVIRINE	ChEMBL	Phase 4 (approved)	OPRM1
EZETIMIBE	ChEMBL	Phase 4 (approved)	OPRM1
FEDRATINIB	ChEMBL	Phase 4 (approved)	OPRM1
FENOLDOPAM	ChEMBL	Phase 4 (approved)	OPRM1
FENOTEROL	ChEMBL	Phase 4 (approved)	OPRM1