Peringatan Keamanan

The reported LD50 for tramadol, when administered orally in mice, is 350 mg/kg.A174010

In carcinogenic studies, there are reports of murine tumors which cannot be concluded to be carcinogenic in humans. On the other hand, tramadol showed no evidence to be mutagenic in different assays and does not have effects on fertility. However, there are clear reports of embryotoxicity and fetotoxicity.L9257,F4679

Tramadol

DB00193

small molecule approved investigational

Deskripsi

Tramadol is a centrally acting synthetic opioid analgesic and SNRI (serotonin/norepinephrine reuptake-inhibitor) that is structurally related to codeine and morphine. Due to its good tolerability profile and multimodal mechanism of action, tramadol is generally considered a lower-risk opioid option for the treatment of moderate to severe pain. It is considered a Step 2 option on the World Health Organization's pain ladder and has about 1/10th of the potency of morphine.

Tramadol differs from other traditional opioid medications in that it doesn't just act as a ?-opioid agonist, but also affects monoamines by modulating the effects of neurotransmitters involved in the modulation of pain such as serotonin and norepinpehrine which activate descending pain inhibitory pathways.A182279 Tramadol's effects on serotonin and norepinephrine mimic the effects of other SNRI antidepressants such as duloxetine and venlafaxine.

Tramadol exists as a racemic mixture consisting of two pharmacologically active enantiomers that both contribute to its analgesic property through different mechanisms and are also themselves metabolized into active metabolites: (+)-tramadol and its primary metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the ? opioid receptor while (+)-tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake. These pathways are complementary and synergistic, improving tramadol's ability to modulate the perception of and response to pain.A4269,A183842

Tramadol has also been shown to affect a number of other pain modulators within the central nervous system as well as non-neuronal inflammatory markers and immune mediators.A183728,A183734,A183761,A17159,A182300 Due to the broad spectrum of targets involved in pain and inflammation, it's not surprising that the evidence has shown that tramadol is effective for a number of pain types including neuropathic pain, post-operative pain, lower back pain, as well as pain associated with labour, osteoarthritis, fibromyalgia, and cancer. Due to its SNRI activity, tramadol also has anxiolytic, antidepressant, and anti-shivering effects which are all frequently found as comorbidities with pain.A182300

Similar to other opioid medications, tramadol poses a risk for development of tolerance, dependence and abuse. If used in higher doses, or with other opioids, there is a dose-related risk of overdose, respiratory depression, and death.A183830,F4679 However, unlike other opioid medications, tramadol use also carries a risk of seizure and serotonin syndrome, particularly if used with other serotonergic medications.A183836,A179926

Struktur Molekul 2D

Berat 263.381
Wujud solid

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) Tramadol reported a half-life of 5-6 hours while the M1 metabolite presents a half-life of 8 hours.[A173980]
Volume Distribusi The volume of distribution of tramadol is reported to be in the range of 2.6-2.9 L/kg.[L9257,F4679] Tramadol has high tissue affinity; the total volume of distribution after oral administration was 306L and 203L after parenteral administration.[A182300] Tramadol crosses the blood-brain barrier with peak brain concentrations occurring 10 minutes following oral administration. It also crosses the placental barrier with umbilical concentrations being found to be ~80% of maternal concentrations.[A4269]
Klirens (Clearance) In clinical trials, the clearance rate of tramadol ranged from 3.73 ml/min/kg in renal impairment patients to 8.50 ml/min/kg in healthy adults.[L9257,F4679]

Absorpsi

Oral Administration Tramadol is administered as a racemate, with both the - and + forms of both tramadol and the M1 metabolite detected in circulation. Following administration, racemic tramadol is rapidly and almost completely absorbed, with a bioavailability of 75%. This difference in absorption and bioavailability can be attributed to the 20-30% first-pass metabolism. Peak plasma concentrations of tramadol and the primary metabolite M1 occur at two and three hours, respectively.F4679 Following a single oral dose of 100mg of tramadol, the Cmax was found to be approximately 300?g/L with a Tmax of 1.6-1.9 hours, while metabolite M1 was found to have a Cmax of 55?g/L with a Tmax of 3 hours.A4269,L9257 Steady-state plasma concentrations of both tramadol and M1 are achieved within two days of dosing. There is no evidence of self-induction.F4679 Following multiple oral doses, Cmax is 16% higher and AUC is 36% higher than after a single dose, demonstrating a potential role of saturable first-pass hepatic metabolism in increasing bioavailability.A4269 Intramuscular Administration Tramadol is rapidly and almost completely absorbed following intramuscular administration. Following injection of 50mg of tramadol, Cmax of 166?g/L was found with a Tmax of 0.75 hours.A4269 Rectal Administration Following rectal administration with suppositories containing 100mg of tramadol, Cmax of 294?g/L was found with a Tmax of 3.3 hours. The absolute bioavailability was found to be higher than oral administration (77% vs 75%), likely due to reduced first-pass metabolism with rectal administration compared to oral administration.A4269

Metabolisme

Tramadol undergoes extensive first-pass metabolism in the liver by N- and O- demethylation and conjugation. From the extensive metabolism, there have been identified at least 23 metabolites. There are two main metabolic pathways: the O-demethylation of tramadol to produce O-desmethyl-tramadol (M1) catalyzed by CYP2D6 and the N-demethylation to N-desmethyl-tramadol (M2) catalyzed by CYP3A4 and CYP2B6.A4269,L9257,F4679 The wide variability in the pharmacokinetic properties between patients can partly be ascribed to polymorphisms within the gene for CYP2D6 that determine its enzymatic activity. CYP2D6\*1 is considered the wild-type allele associated with normal enzyme activity and the "extensive metabolizer" phenotype; 90-95% of Caucasians are considered "extensive metabolizers" (with normal CYP2D6 function) while the remaining 5-10% are considered "poor metabolizers" with reduced or non-functioning enzyme.A182294 CYP2D6 alleles associated with non-functioning enzyme include *3, *4, *5, and *6 while alleles associated with reduced activity include *9, *10, *17, and *41.A183812 Poor metabolizers have reduced activity of the CYP2D6 enzyme and therefore less production of tramadol metabolites M1 and M2, which ultimately results in a reduced analgesic effect as tramadol interacts with the ?-opioid receptor primarily via M1.A4269 There are also large differences in the frequency of these alleles between different ethnicities: \*3, \*4, \*5, \*6, and \*41 are more common among Caucasians while \*17 is more common in Africans for example.A183812 Compared to 5-10% of Caucasians, only ~1% of Asians are considered poor metabolizers, however Asian populations carry a much higher frequency (51%) of the CYP2D6\*10 allele, which is relatively rare in Caucasian populations and results in higher exposure to tramadol.A182294 Some individuals are considered "ultra-rapid metabolizers", such as those carrying CYP2D6 gene duplications (CYP2D6*DUP) or multiplications. These individuals are at risk of intoxication or exaggerated effects of tramadol due to higher concentrations of its active metabolite (M1).A182297 The occurrence of this phenotype is seen in approximately 1% to 2% of East Asians (Chinese, Japanese, Korean), 1% to 10% of Caucasians, 3% to 4% of African-Americans, and may be >10% in certain racial/ethnic groups (ie, Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). The FDA label recommends avoiding the use of tramadol in these individuals.L9257,F4679

Rute Eliminasi

Tramadol is eliminated primarily through metabolism by the liver and the metabolites are excreted primarily by the kidneys, accounting for 90% of the excretion while the remaining 10% is excreted through feces.L9257,F4679,A173980 Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites.A174010 The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 are 6.3 ± 1.4 and 7.4 ± 1.4 hours, respectively. The plasma elimination half-life of racemic tramadol increased from approximately six hours to seven hours upon multiple dosing.L9257,F4679

Interaksi Makanan

2 Data
  • 1. Avoid alcohol. Co-administration of alcohol may potentiate the CNS effects of tramadol.
  • 2. Take with or without food. Co-administration of food does not affect pharmacokinetics.

Interaksi Obat

1966 Data
Doxylamine Doxylamine may increase the central nervous system depressant (CNS depressant) activities of Tramadol.
Hydroxyzine Hydroxyzine may increase the central nervous system depressant (CNS depressant) activities of Tramadol.
Magnesium sulfate The therapeutic efficacy of Tramadol can be increased when used in combination with Magnesium sulfate.
Metyrosine Tramadol may increase the sedative activities of Metyrosine.
Minocycline Minocycline may increase the central nervous system depressant (CNS depressant) activities of Tramadol.
Pramipexole Tramadol may increase the sedative activities of Pramipexole.
Ropinirole Tramadol may increase the sedative activities of Ropinirole.
Suvorexant Tramadol may increase the central nervous system depressant (CNS depressant) activities of Suvorexant.
Thalidomide Tramadol may increase the central nervous system depressant (CNS depressant) activities of Thalidomide.
Zolpidem Tramadol may increase the central nervous system depressant (CNS depressant) activities of Zolpidem.
Alvimopan The therapeutic efficacy of Tramadol can be decreased when used in combination with Alvimopan.
Carbamazepine The therapeutic efficacy of Carbamazepine can be decreased when used in combination with Tramadol.
Cyclobenzaprine The risk or severity of serotonin syndrome and seizure can be increased when Cyclobenzaprine is combined with Tramadol.
Desmopressin The risk or severity of hyponatremia can be increased when Tramadol is combined with Desmopressin.
Aclidinium The risk or severity of adverse effects can be increased when Tramadol is combined with Aclidinium.
Mirabegron The risk or severity of urinary retention can be increased when Tramadol is combined with Mirabegron.
Potassium chloride The risk or severity of gastrointestinal ulceration can be increased when Tramadol is combined with Potassium chloride.
Pramlintide The risk or severity of reduced gastrointestinal motility can be increased when Pramlintide is combined with Tramadol.
Secretin porcine The therapeutic efficacy of Secretin porcine can be decreased when used in combination with Tramadol.
Tiotropium The risk or severity of adverse effects can be increased when Tramadol is combined with Tiotropium.
Topiramate The risk or severity of hyperthermia and oligohydrosis can be increased when Tramadol is combined with Topiramate.
Umeclidinium The risk or severity of adverse effects can be increased when Tramadol is combined with Umeclidinium.
Methadone The risk or severity of adverse effects can be increased when Methadone is combined with Tramadol.
Glycopyrronium The risk or severity of adverse effects can be increased when Tramadol is combined with Glycopyrronium.
Memantine The risk or severity of adverse effects can be increased when Tramadol is combined with Memantine.
Linezolid The risk or severity of serotonin syndrome and seizure can be increased when Linezolid is combined with Tramadol.
Furazolidone The risk or severity of serotonin syndrome and seizure can be increased when Furazolidone is combined with Tramadol.
Tranylcypromine The risk or severity of serotonin syndrome and seizure can be increased when Tranylcypromine is combined with Tramadol.
Phenelzine The risk or severity of serotonin syndrome and seizure can be increased when Phenelzine is combined with Tramadol.
Minaprine The risk or severity of serotonin syndrome and seizure can be increased when Minaprine is combined with Tramadol.
Selegiline The risk or severity of serotonin syndrome and seizure can be increased when Selegiline is combined with Tramadol.
Procarbazine The risk or severity of serotonin syndrome and seizure can be increased when Procarbazine is combined with Tramadol.
Moclobemide The risk or severity of serotonin syndrome and seizure can be increased when Moclobemide is combined with Tramadol.
Isocarboxazid The risk or severity of serotonin syndrome and seizure can be increased when Isocarboxazid is combined with Tramadol.
Rasagiline The risk or severity of serotonin syndrome and seizure can be increased when Rasagiline is combined with Tramadol.
Pargyline The risk or severity of serotonin syndrome and seizure can be increased when Pargyline is combined with Tramadol.
Clorgiline The risk or severity of serotonin syndrome and seizure can be increased when Clorgiline is combined with Tramadol.
Iproniazid The risk or severity of serotonin syndrome and seizure can be increased when Iproniazid is combined with Tramadol.
Nialamide The risk or severity of serotonin syndrome and seizure can be increased when Nialamide is combined with Tramadol.
Safinamide The risk or severity of serotonin syndrome and seizure can be increased when Safinamide is combined with Tramadol.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline The risk or severity of serotonin syndrome and seizure can be increased when 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline is combined with Tramadol.
Hydracarbazine The risk or severity of serotonin syndrome and seizure can be increased when Hydracarbazine is combined with Tramadol.
Pirlindole The risk or severity of serotonin syndrome and seizure can be increased when Pirlindole is combined with Tramadol.
Toloxatone The risk or severity of serotonin syndrome and seizure can be increased when Toloxatone is combined with Tramadol.
Benmoxin The risk or severity of serotonin syndrome and seizure can be increased when Benmoxin is combined with Tramadol.
Mebanazine The risk or severity of serotonin syndrome and seizure can be increased when Mebanazine is combined with Tramadol.
Octamoxin The risk or severity of serotonin syndrome and seizure can be increased when Octamoxin is combined with Tramadol.
Pheniprazine The risk or severity of serotonin syndrome and seizure can be increased when Pheniprazine is combined with Tramadol.
Phenoxypropazine The risk or severity of serotonin syndrome and seizure can be increased when Phenoxypropazine is combined with Tramadol.
Pivhydrazine The risk or severity of serotonin syndrome and seizure can be increased when Pivhydrazine is combined with Tramadol.
Safrazine The risk or severity of serotonin syndrome and seizure can be increased when Safrazine is combined with Tramadol.
Caroxazone The risk or severity of serotonin syndrome and seizure can be increased when Caroxazone is combined with Tramadol.
Harmaline The risk or severity of serotonin syndrome and seizure can be increased when Harmaline is combined with Tramadol.
Brofaromine The risk or severity of serotonin syndrome and seizure can be increased when Brofaromine is combined with Tramadol.
Methylene blue The risk or severity of serotonin syndrome and seizure can be increased when Methylene blue is combined with Tramadol.
Dicoumarol The risk or severity of adverse effects can be increased when Tramadol is combined with Dicoumarol.
Phenindione The risk or severity of adverse effects can be increased when Tramadol is combined with Phenindione.
Coumarin The risk or severity of adverse effects can be increased when Tramadol is combined with Coumarin.
Tioclomarol The risk or severity of adverse effects can be increased when Tramadol is combined with Tioclomarol.
Phenprocoumon The risk or severity of adverse effects can be increased when Tramadol is combined with Phenprocoumon.
4-hydroxycoumarin The risk or severity of adverse effects can be increased when Tramadol is combined with 4-hydroxycoumarin.
Ethyl biscoumacetate The risk or severity of adverse effects can be increased when Tramadol is combined with Ethyl biscoumacetate.
Fluindione The risk or severity of adverse effects can be increased when Tramadol is combined with Fluindione.
Clorindione The risk or severity of adverse effects can be increased when Tramadol is combined with Clorindione.
Diphenadione The risk or severity of adverse effects can be increased when Tramadol is combined with Diphenadione.
Desogestrel The metabolism of Tramadol can be increased when combined with Desogestrel.
Zidovudine The metabolism of Tramadol can be increased when combined with Zidovudine.
Ethinylestradiol The metabolism of Tramadol can be increased when combined with Ethinylestradiol.
Testosterone propionate The metabolism of Tramadol can be increased when combined with Testosterone propionate.
Tedizolid phosphate The risk or severity of serotonin syndrome can be increased when Tedizolid phosphate is combined with Tramadol.
Botulinum toxin type A The risk or severity of adverse effects can be increased when Tramadol is combined with Botulinum toxin type A.
Glucagon Tramadol may increase the gastrointestinal motility reducing activities of Glucagon.
Mirtazapine The risk or severity of serotonin syndrome can be increased when Mirtazapine is combined with Tramadol.
Eluxadoline The risk or severity of constipation can be increased when Tramadol is combined with Eluxadoline.
Ethanol Tramadol may increase the central nervous system depressant (CNS depressant) activities of Ethanol.
Azelastine Tramadol may increase the central nervous system depressant (CNS depressant) activities of Azelastine.
Methylenedioxyethamphetamine Methylenedioxyethamphetamine may increase the analgesic activities of Tramadol.
Phendimetrazine Phendimetrazine may increase the analgesic activities of Tramadol.
Pentolinium The risk or severity of adverse effects can be increased when Pentolinium is combined with Tramadol.
Trimethaphan The risk or severity of adverse effects can be increased when Trimethaphan is combined with Tramadol.
Dihydro-2-thioxo-5-((5-(2-(trifluoromethyl)phenyl)-2-furanyl)methyl)-4,6(1H,5H)-pyrimidinedione The risk or severity of adverse effects can be increased when Dihydro-2-thioxo-5-((5-(2-(trifluoromethyl)phenyl)-2-furanyl)methyl)-4,6(1H,5H)-pyrimidinedione is combined with Tramadol.
Fenoterol The risk or severity of adverse effects can be increased when Fenoterol is combined with Tramadol.
Profenamine The risk or severity of adverse effects can be increased when Profenamine is combined with Tramadol.
Oxyphenonium The risk or severity of adverse effects can be increased when Oxyphenonium is combined with Tramadol.
Benzatropine The risk or severity of adverse effects can be increased when Benzatropine is combined with Tramadol.
Disopyramide The risk or severity of adverse effects can be increased when Disopyramide is combined with Tramadol.
Metixene The risk or severity of adverse effects can be increased when Metixene is combined with Tramadol.
Buclizine The risk or severity of adverse effects can be increased when Buclizine is combined with Tramadol.
Trihexyphenidyl The risk or severity of adverse effects can be increased when Trihexyphenidyl is combined with Tramadol.
Oxyphencyclimine The risk or severity of adverse effects can be increased when Oxyphencyclimine is combined with Tramadol.
Procyclidine The risk or severity of adverse effects can be increased when Procyclidine is combined with Tramadol.
Hyoscyamine The risk or severity of adverse effects can be increased when Hyoscyamine is combined with Tramadol.
Methscopolamine bromide The risk or severity of adverse effects can be increased when Methscopolamine bromide is combined with Tramadol.
Tridihexethyl The risk or severity of adverse effects can be increased when Tridihexethyl is combined with Tramadol.
Anisotropine methylbromide The risk or severity of adverse effects can be increased when Anisotropine methylbromide is combined with Tramadol.
Atropine The risk or severity of adverse effects can be increased when Atropine is combined with Tramadol.
Pirenzepine The risk or severity of adverse effects can be increased when Pirenzepine is combined with Tramadol.
Homatropine methylbromide The risk or severity of adverse effects can be increased when Homatropine methylbromide is combined with Tramadol.
Benzquinamide The risk or severity of adverse effects can be increased when Benzquinamide is combined with Tramadol.
Propantheline The risk or severity of adverse effects can be increased when Propantheline is combined with Tramadol.

Target Protein

Mu-type opioid receptor OPRM1
Sodium-dependent noradrenaline transporter SLC6A2
Sodium-dependent serotonin transporter SLC6A4
Sodium channel protein type 2 subunit alpha SCN2A
NMDA receptor GRIN1
Adenosine receptor A1 ADORA1
Alpha-2 adrenergic receptors ADRA2A
5-hydroxytryptamine receptor 2C HTR2C
Kappa-type opioid receptor OPRK1
Delta-type opioid receptor OPRD1
Neuronal acetylcholine receptor subunit alpha-7 CHRNA7
Muscarinic acetylcholine receptor M3 CHRM3
Muscarinic acetylcholine receptor M1 CHRM1
Substance-P receptor TACR1
Transient receptor potential cation channel subfamily V member 1 TRPV1

Referensi & Sumber

Synthesis reference: Wolfgang Reimann, "Combination preparation containing tramadol and a calcium channel antagonist." U.S. Patent US5929122, issued March, 1993.
Artikel (PubMed)
  • PMID: 9190321
    Dayer P, Desmeules J, Collart L: Pharmacology of tramadol. Drugs. 1997;53 Suppl 2:18-24.
  • PMID: 9633738
    Harati Y, Gooch C, Swenson M, Edelman S, Greene D, Raskin P, Donofrio P, Cornblath D, Sachdeo R, Siu CO, Kamin M: Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology. 1998 Jun;50(6):1842-6.
  • PMID: 10959067
    Harati Y, Gooch C, Swenson M, Edelman SV, Greene D, Raskin P, Donofrio P, Cornblath D, Olson WH, Kamin M: Maintenance of the long-term effectiveness of tramadol in treatment of the pain of diabetic neuropathy. J Diabetes Complications. 2000 Mar-Apr;14(2):65-70.
  • PMID: 9190323
    Gobel H, Stadler T: Treatment of post-herpes zoster pain with tramadol. Results of an open pilot study versus clomipramine with or without levomepromazine. Drugs. 1997;53 Suppl 2:34-9.
  • PMID: 12855342
    Boureau F, Legallicier P, Kabir-Ahmadi M: Tramadol in post-herpetic neuralgia: a randomized, double-blind, placebo-controlled trial. Pain. 2003 Jul;104(1-2):323-31.
  • PMID: 26218943
    Beakley BD, Kaye AM, Kaye AD: Tramadol, Pharmacology, Side Effects, and Serotonin Syndrome: A Review. Pain Physician. 2015 Jul-Aug;18(4):395-400.
  • PMID: 28953949
    Shin HW, Ju BJ, Jang YK, You HS, Kang H, Park JY: Effect of tramadol as an adjuvant to local anesthetics for brachial plexus block: A systematic review and meta-analysis. PLoS One. 2017 Sep 27;12(9):e0184649. doi: 10.1371/journal.pone.0184649. eCollection 2017.
  • PMID: 25636495
    Martyn-St James M, Cooper K, Kaltenthaler E, Dickinson K, Cantrell A, Wylie K, Frodsham L, Hood C: Tramadol for premature ejaculation: a systematic review and meta-analysis. BMC Urol. 2015 Jan 30;15:6. doi: 10.1186/1471-2490-15-6.
Menampilkan 8 dari 27 artikel.

Contoh Produk & Brand

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International Brands
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