Details of the Drug Combination

General Information of Drug Combination (ID: DCSACKG)

• Drug Combination Name: Morphine + Tramadol
• Indication: Postoperative Pain; Status: Phase 4 [1]
• Component Drugs:
  Morphine (DMRMS0L): Small molecular drug
  Tramadol (DMRQD04): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Morphine

Disease Entry	ICD 11	Status	REF
Advanced cancer	2A00-2F9Z	Approved	[2]
Chronic pain	MG30	Approved	[3]
Pain	MG30-MG3Z	Approved	[2]
Diarrhea	ME05.1	Investigative	[2]

Morphine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Opioid receptor mu (MOP)	TTKWM86	OPRM_HUMAN	Modulator	[9]

Morphine Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[10]
Multidrug resistance-associated protein 3 (ABCC3)	DTQ3ZHF	MRP3_HUMAN	Substrate	[11]

Morphine Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[12]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[13]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[14]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[15]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[16]
UDP-glucuronosyltransferase 1A3 (UGT1A3)	DEF2WXN	UD13_HUMAN	Metabolism	[17]

Morphine Interacts with 47 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Affects Chemical Synthesis	[18]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Response	[19]
Mu-type opioid receptor (OPRM1)	OT16AAT8	OPRM_HUMAN	Increases Response	[19]
Toll-like receptor 4 (TLR4)	OTP7ML3S	TLR4_HUMAN	Affects Binding	[20]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[21]
LIM homeobox transcription factor 1-beta (LMX1B)	OTM8145D	LMX1B_HUMAN	Increases Expression	[22]
Krueppel-like factor 7 (KLF7)	OTS3YVA0	KLF7_HUMAN	Increases Expression	[23]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Increases Expression	[24]
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Increases Expression	[25]
Apolipoprotein B-100 (APOB)	OTH0UOCZ	APOB_HUMAN	Increases Expression	[25]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[26]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[22]
Interleukin-4 (IL4)	OTOXBWAU	IL4_HUMAN	Increases Expression	[27]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Increases Secretion	[26]
Coagulation factor VII (F7)	OTGNJ97M	FA7_HUMAN	Increases Expression	[25]
Fibroblast growth factor 2 (FGF2)	OT7YUJ9F	FGF2_HUMAN	Decreases Secretion	[26]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[28]
C-C motif chemokine 5 (CCL5)	OTSCA5CK	CCL5_HUMAN	Decreases Expression	[29]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Increases Expression	[24]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[27]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[27]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Expression	[30]
Kappa-type opioid receptor (OPRK1)	OTXCZF4L	OPRK_HUMAN	Increases Activity	[31]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[28]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[21]
Interleukin-2 (IL2)	OTGI4NSA	IL2_HUMAN	Decreases Expression	[27]
Eukaryotic translation initiation factor 5A-1 (EIF5A)	OTQ8DJX5	IF5A1_HUMAN	Increases Expression	[22]
C-C motif chemokine 8 (CCL8)	OTCTWYN8	CCL8_HUMAN	Increases Secretion	[26]
Cytochrome c (CYCS)	OTBFALJD	CYC_HUMAN	Increases Secretion	[21]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Increases Phosphorylation	[24]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[28]
Beclin-1 (BECN1)	OT4X293M	BECN1_HUMAN	Increases Expression	[32]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Decreases Expression	[30]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Increases Expression	[33]
DNA damage-binding protein 2 (DDB2)	OTO8HVVB	DDB2_HUMAN	Increases Expression	[22]
Ninjurin-1 (NINJ1)	OTLRZ1EU	NINJ1_HUMAN	Increases Expression	[22]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[22]
Acetylcholinesterase (ACHE)	OT2H8HG6	ACES_HUMAN	Increases Chemical Synthesis	[34]
Interleukin-1 receptor antagonist protein (IL1RN)	OT308CBE	IL1RA_HUMAN	Affects Response To Substance	[35]
Protein kinase C alpha type (PRKCA)	OT5UWNRD	KPCA_HUMAN	Increases ADR	[36]
Beta-arrestin-2 (ARRB2)	OTAEJZCI	ARRB2_HUMAN	Affects Response To Substance	[37]
Cocaine esterase (CES2)	OTC647SQ	EST2_HUMAN	Increases Chemical Synthesis	[38]
Signal transducer and activator of transcription 6 (STAT6)	OTCKMP49	STAT6_HUMAN	Affects Response To Substance	[37]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases ADR	[36]
Mitogen-activated protein kinase 8 (MAPK8)	OTEREYS5	MK08_HUMAN	Increases ADR	[36]
Platelet-derived growth factor subunit B (PDGFB)	OTMFMFC3	PDGFB_HUMAN	Decreases Response To Substance	[39]
Cholinesterase (BCHE)	OTOH3WQ9	CHLE_HUMAN	Increases Chemical Synthesis	[34]

Indication(s) of Tramadol

Disease Entry	ICD 11	Status	REF
Osteoarthritis	FA00-FA05	Approved	[4]
Pain	MG30-MG3Z	Approved	[5]
Chronic pain	MG30	Investigative	[4]
Premature ejaculation	HA03.0Z	Investigative	[4]

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	[40]

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	[41]

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	[42]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[43]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[42]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[42]

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	[44]
L-lactate dehydrogenase A chain (LDHA)	OTN7K4XB	LDHA_HUMAN	Decreases Expression	[45]
Creatine kinase B-type (CKB)	OTUCKOTT	KCRB_HUMAN	Decreases Expression	[45]
NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1)	OTTIZDFR	NDUS1_HUMAN	Decreases Expression	[45]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Affects Activity	[45]
kinase isozyme 3, mitochondrial (PDK3)	OTCPSTID	PDK3_HUMAN	Increases Expression	[45]

References

• [1] ClinicalTrials.gov (NCT05956275) USG-Guided Infiltration Popliteal Artery Capsule Knee Block Versus Adductor Canal Block Application as Postoperative Analgesia
• [2] Morphine FDA Label
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] Tramadol 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: 8286).
• [6] Genetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268: ethnic diversity of alleles and potential clinical significance. Pharmacogenetics. 2000 Nov;10(8):679-85. doi: 10.1097/00008571-200011000-00002.
• [7] Isoform selectivity and kinetics of morphine 3- and 6-glucuronidation by human udp-glucuronosyltransferases: evidence for atypical glucuronidation kinetics by UGT2B7. Drug Metab Dispos. 2003 Sep;31(9):1086-9. doi: 10.1124/dmd.31.9.1086.
• [8] Inhibition of NF-B by opioids in T cells. J Immunol. 2013 Nov 1;191(9):4640-7. doi: 10.4049/jimmunol.1300320. Epub 2013 Sep 25.
• [9] Antianalgesia: stereoselective action of dextro-morphine over levo-morphine on glia in the mouse spinal cord.J Pharmacol Exp Ther.2005 Sep;314(3):1101-8.
• [10] Genetic variability and clinical efficacy of morphine. Acta Anaesthesiol Scand. 2005 Aug;49(7):902-8.
• [11] Multidrug resistance-associated proteins 3, 4, and 5. Pflugers Arch. 2007 Feb;453(5):661-73.
• [12] Modulation of UDP-glucuronosyltransferase 2B7 function by cytochrome P450s in vitro: differential effects of CYP1A2, CYP2C9 and CYP3A4. Biol Pharm Bull. 2005 Oct;28(10):2026-7.
• [13] Contribution of UDP-glucuronosyltransferase 1A1 and 1A8 to morphine-6-glucuronidation and its kinetic properties. Drug Metab Dispos. 2008 Apr;36(4):688-94.
• [14] 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. J Pharmacol Exp Ther. 2004 Feb;308(2):547-54.
• [15] In vitro metabolism study of buprenorphine: evidence for new metabolic pathways. Drug Metab Dispos. 2005 May;33(5):689-95.
• [16] Molecular cloning of the baboon UDP-glucuronosyltransferase 2B gene family and their activity in conjugating morphine. Drug Metab Dispos. 2010 Apr;38(4):545-53.
• [17] Glucuronidation of amines and other xenobiotics catalyzed by expressed human UDP-glucuronosyltransferase 1A3. Drug Metab Dispos. 1998 Jun;26(6):507-12.
• [18] Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med. 2004 Dec 30;351(27):2827-31. doi: 10.1056/NEJMoa041888.
• [19] Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin Pharmacol Ther. 2008 Apr;83(4):559-66.
• [20] Possible involvement of toll-like receptor 4/myeloid differentiation factor-2 activity of opioid inactive isomers causes spinal proinflammation and related behavioral consequences. Neuroscience. 2010 May 19;167(3):880-93. doi: 10.1016/j.neuroscience.2010.02.011. Epub 2010 Feb 21.
• [21] Chronic high-dose morphine treatment promotes SH-SY5Y cell apoptosis via c-Jun N-terminal kinase-mediated activation of mitochondria-dependent pathway. FEBS J. 2009 Apr;276(7):2022-36. doi: 10.1111/j.1742-4658.2009.06938.x.
• [22] Morphine induces DNA damage and P53 activation in CD3+ T cells. Biochim Biophys Acta. 2009 Aug;1790(8):793-9. doi: 10.1016/j.bbagen.2009.04.011. Epub 2009 May 3.
• [23] Identification of opioid-regulated genes in human lymphocytic cells by differential display: upregulation of Krppel-like factor 7 by morphine. Exp Cell Res. 2003 Dec 10;291(2):340-51. doi: 10.1016/s0014-4827(03)00408-7.
• [24] Mechanisms of the inhibition of nuclear factor-B by morphine in neuronal cells. Mol Pharmacol. 2012 Apr;81(4):587-97. doi: 10.1124/mol.111.076620. Epub 2012 Jan 18.
• [25] Effect of opium addiction on new and traditional cardiovascular risk factors: do duration of addiction and route of administration matter?. Lipids Health Dis. 2008 Nov 3;7:42. doi: 10.1186/1476-511X-7-42.
• [26] Morphine treatment of human monocyte-derived macrophages induces differential miRNA and protein expression: impact on inflammation and oxidative stress in the central nervous system. J Cell Biochem. 2010 Jul 1;110(4):834-45. doi: 10.1002/jcb.22592.
• [27] opioid receptor agonist-selective regulation of interleukin-4 in T lymphocytes. J Neuroimmunol. 2013 Oct 15;263(1-2):35-42. doi: 10.1016/j.jneuroim.2013.07.012. Epub 2013 Jul 25.
• [28] Morphine promotes apoptosis in Jurkat cells. J Leukoc Biol. 1999 Oct;66(4):650-8. doi: 10.1002/jlb.66.4.650.
• [29] Morphine inhibits human microglial cell production of, and migration towards, RANTES. J Psychopharmacol. 2000;14(3):238-43. doi: 10.1177/026988110001400307.
• [30] beta-arrestin2 inhibits opioid-induced breast cancer cell death through Akt and caspase-8 pathways. Neoplasma. 2009;56(2):108-13. doi: 10.4149/neo_2009_02_108.
• [31] In vivo and in vitro evaluation of novel -opioid receptor agonist compounds. Eur J Pharmacol. 2015 Nov 15;767:193-200. doi: 10.1016/j.ejphar.2015.10.025. Epub 2015 Oct 20.
• [32] Morphine induces Beclin 1- and ATG5-dependent autophagy in human neuroblastoma SH-SY5Y cells and in the rat hippocampus. Autophagy. 2010 Apr;6(3):386-94. doi: 10.4161/auto.6.3.11289. Epub 2010 Apr 25.
• [33] Morphine induces apoptosis of human endothelial cells through nitric oxide and reactive oxygen species pathways. Toxicology. 2009 Feb 4;256(1-2):83-91. doi: 10.1016/j.tox.2008.11.015. Epub 2008 Nov 25.
• [34] Kinetic characterization of cholinesterases and a therapeutically valuable cocaine hydrolase for their catalytic activities against heroin and its metabolite 6-monoacetylmorphine. Chem Biol Interact. 2018 Sep 25;293:107-114.
• [35] A role for proinflammatory cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine. J Neurosci. 2004 Aug 18;24(33):7353-65. doi: 10.1523/JNEUROSCI.1850-04.2004.
• [36] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [37] Clinical response to morphine in cancer patients and genetic variation in candidate genes. Pharmacogenomics J. 2005;5(5):324-36. doi: 10.1038/sj.tpj.6500327.
• [38] Metabolism of cocaine and heroin is catalyzed by the same human liver carboxylesterases. J Pharmacol Exp Ther. 1996 Nov;279(2):713-7.
• [39] A growth factor attenuates HIV-1 Tat and morphine induced damage to human neurons: implication in HIV/AIDS-drug abuse cases. PLoS One. 2011 Mar 24;6(3):e18116. doi: 10.1371/journal.pone.0018116.
• [40] 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.
• [41] Tramadol hydrochloride: pharmacokinetics, pharmacodynamics, adverse side effects, co-administration of drugs and new drug delivery systems. Biomed Pharmacother. 2015 Mar;70:234-8.
• [42] Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879-923.
• [43] 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.
• [44] 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.
• [45] 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.