Details of the Drug Combination

General Information of Drug Combination (ID: DC69S9M)

• Drug Combination Name: Tramadol + Oxycodone
• Indication: Osteo Arthritis Knee; Status: Phase 1 [1]
• Component Drugs:
  Tramadol (DMRQD04): Small molecular drug
  Oxycodone (DMXLKHV): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Tramadol

Disease Entry	ICD 11	Status	REF
Osteoarthritis	FA00-FA05	Approved	[2]
Pain	MG30-MG3Z	Approved	[3]
Chronic pain	MG30	Investigative	[2]
Premature ejaculation	HA03.0Z	Investigative	[2]

Tramadol Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
5-HT 2C receptor (HTR2C)	TTWJBZ5	5HT2C_HUMAN	Modulator	[7]

Tramadol Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[8]

Tramadol Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[10]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[9]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[9]

Tramadol Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1)	OTZKVLVJ	CP17A_HUMAN	Decreases Activity	[11]
L-lactate dehydrogenase A chain (LDHA)	OTN7K4XB	LDHA_HUMAN	Decreases Expression	[12]
Creatine kinase B-type (CKB)	OTUCKOTT	KCRB_HUMAN	Decreases Expression	[12]
NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1)	OTTIZDFR	NDUS1_HUMAN	Decreases Expression	[12]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Affects Activity	[12]
kinase isozyme 3, mitochondrial (PDK3)	OTCPSTID	PDK3_HUMAN	Increases Expression	[12]

Indication(s) of Oxycodone

Disease Entry	ICD 11	Status	REF
Osteoarthritis	FA00-FA05	Approved	[4]
Pain	MG30-MG3Z	Approved	[5]
Back pain	ME84.Z	Phase 3	[6]

Oxycodone Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Opioid receptor mu (MOP)	TTKWM86	OPRM_HUMAN	Modulator	[13]
Opioid receptor delta (OPRD1)	TT27RFC	OPRD_HUMAN	Agonist	[14]

Oxycodone Interacts with 5 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1)	OTM0GDTP	IF2A_HUMAN	Increases Phosphorylation	[15]
Endoplasmic reticulum chaperone BiP (HSPA5)	OTFUIRAO	BIP_HUMAN	Increases Expression	[15]
Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	OTRFV19J	ATF4_HUMAN	Increases Expression	[15]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Affects Metabolism	[16]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Affects Response To Substance	[17]

References

• [1] ClinicalTrials.gov (NCT04003350) The Effect of Prolonged Multimodal Analgesic Regimen on Post Hospital Discharge Opioid Use and Pain Control After Primary Total Knee Arthroplasty
• [2] Tramadol FDA Label
• [3] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8286).
• [4] Oxycodone FDA Label
• [5] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7093).
• [6] ClinicalTrials.gov (NCT01427283) A Study of Oxycodone/Naloxone Controlled-release Tablets (OXN) to Assess Analgesic Efficacy and Management of Opioid-induced Constipation (OIC) in Opioid-experienced Subjects With Moderate to Severe Chronic Low Back Pain. U.S. National Institutes of Health.
• [7] The inhibitory effects of tramadol on 5-hydroxytryptamine type 2C receptors expressed in Xenopus oocytes. Anesth Analg. 2004 May;98(5):1401-6, table of contents.
• [8] Tramadol hydrochloride: pharmacokinetics, pharmacodynamics, adverse side effects, co-administration of drugs and new drug delivery systems. Biomed Pharmacother. 2015 Mar;70:234-8.
• [9] Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879-923.
• [10] Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004 Nov;32(11):1201-8.
• [11] Steroidogenic disruptive effects of the serotonin-noradrenaline reuptake inhibitors duloxetine, venlafaxine and tramadol in the H295R cell assay and in a recombinant CYP17 assay. Toxicol In Vitro. 2018 Mar;47:63-71.
• [12] Comparative study of the neurotoxicological effects of tramadol and tapentadol in SH-SY5Y cells. Toxicology. 2016 Jun 1;359-360:1-10. doi: 10.1016/j.tox.2016.06.010. Epub 2016 Jun 15.
• [13] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 319).
• [14] Oxycodone: a pharmacological and clinical review. Clin Transl Oncol. 2007 May;9(5):298-307.
• [15] Chronic oxycodone induces integrated stress response in rat brain. BMC Neurosci. 2015 Sep 16;16:58. doi: 10.1186/s12868-015-0197-8.
• [16] Evaluation of Recombinant CYP3A4 Variants on the Metabolism of Oxycodone In Vitro. Chem Res Toxicol. 2021 Jan 18;34(1):103-109. doi: 10.1021/acs.chemrestox.0c00361. Epub 2021 Jan 4.
• [17] Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety. Br J Pharmacol. 2010 Jun;160(4):919-30. doi: 10.1111/j.1476-5381.2010.00709.x.