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Pharmgkb Summary: Tramadol Pathway Li Gonga, Ulrike M

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Pharmgkb Summary: Tramadol Pathway Li Gonga, Ulrike M View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Bern Open Repository and Information System (BORIS) 374 PharmGKB summary PharmGKB summary: tramadol pathway Li Gonga, Ulrike M. Stamerc,d, Mladen V. Tzvetkove, Russ B. Altmana,b and Teri E. Kleina Pharmacogenetics and Genomics 2014, 24:374–380 Correspondence to Teri E. Klein, PhD, Department of Genetics, Stanford University Medical Center, 318 Campus Drive, Clark Center Room S221A, MC Keywords: analgesic, CYP2D6, OCT1, opioids, OPRM1, pathway, 5448, Stanford, CA 94305, USA pharmacogenomics, pharmacokinetics, tramadol Tel: + 1 650 725 0659; fax: + 1 650 725 3863; e-mail: [email protected] a b Departments of Genetics, Bioengineering, Stanford University, Stanford, Received 14 January 2014 Accepted 5 April 2014 California, USA, cDepartment of Anaesthesiology and Pain Medicine, Inselspital, dDepartment of Clinical Research, University of Bern, Bern, Switzerland and eInstitute of Clinical Pharmacology, University Medical Center, Göttingen, Germany Background (tramadol : morphine) and 10 : 1 to 12 : 1 ratio parenterally Tramadol is a mixed centrally acting opioid analgesic [13–16]. Some patients experience inadequate pain relief used to relieve moderate to severe pain. It is commonly or adverse effects with tramadol. The main reported used alone or in combination with nonopioid analgesics, adverse drug reactions (ADRs) for tramadol are nausea, for example, paracetamol (acetaminophen) in the treat- vomiting, sweating, itching, constipation, headache, and ment for postoperative, dental, cancer, neuropathic, and central nervous system stimulation. Most of these reac- acute musculoskeletal pain [1–3]. It can also be used as tions are dose dependent. Neurotoxicity to tramadol may an adjuvant to NSAID therapy in osteoarthritis patients manifest as seizures, which have been reported in [4]. Tramadol exerts its analgesic effect through at least patients receiving tramadol both at the recommended two complementary and synergistic mechanisms: by and the high dosage ranges in animal and human stu- activating the µ-opioid receptor and inhibiting the neu- dies [17]. rotransmitter reuptake. The opioid receptor-mediated Tramadol metabolism to its major active metabolite M1 analgesic effects are mainly attributed to the active is predominantly mediated through CYP2D6 [18–20]; metabolite M1 (O-desmethyltramadol), whereas the thus, CYP2D6 plays a significant role in tramadol phar- inhibition of the neurotransmitter reuptake is caused by macokinetics and variability in drug responses [21,22]. the parent drug, thus enhancing the inhibitory effects on The influence of the CYP2D6 genotype on plasma levels pain transmission in the spinal cord [1,5,6]. Therefore, of tramadol and its metabolites as well as tramadol effi- both the parent drug and especially the M1 metabolite cacy and ADR have been reported [18,21,23–25] (see the contribute toward the overall analgesic activity of Pharmacogenomics section). This review briefly sum- tramadol. marizes the metabolism and transport of tramadol (Fig. 1) | downloaded: 13.3.2017 and discusses genetic variations affecting the pharmaco- Tramadol is administered as a racemic mixture of kinetics, efficacy, and toxicity of tramadol. Knowledge of (+ )-tramadol and (− )-tramadol enantiomers (also known genetic variants mediating the diverse pharmacological as R, R and S, S tramadol, respectively). Tramadol is a profile of tramadol may help optimize opioid therapy to synthetic opioid belonging to the class of weak opioid achieve better control of pain and less adverse effects for receptor agonists [step 2 analgesics according to the the patients. WHO ladder (http://www.who.int/cancer/palliative/painlad der/en/)]. In comparison with typical opioid agonists such as morphine at equivalent doses, tramadol shows similar Pharmacodynamics overall analgesic efficacy, and yet appears to have a lower Tramadol consists of two enantiomers [(+ )-tramadol and potential for respiratory depression or physical depen- (− )-tramadol], both of which, along with metabolite M1, dence as well as a lower incidence of constipation contribute toward overall analgesic activity by distinct [1,3,7–9]. However, cases of physical dependence and but complementary mechanisms [1,6]. In-vitro and clin- withdrawal syndrome have been reported, especially ical studies showed that the parent drug is only a weak µ- with long-term use of high tramadol doses [10–12]. The opioid receptor agonist, whereas the metabolite M1 is dose requirements for tramadol are variable and interac- significantly more potent than tramadol µ-opioid receptor tions with other drugs are common. Depending on the binding and in producing analgesia [22,26,27]. (+ )-M1 https://doi.org/10.7892/boris.69119 duration of treatment and settings, there might be certain has a significantly higher affinity for the µ-opioid receptor variance in the equipotent use of tramadol and morphine. (encoded by gene OPRM1)(Ki = 0.0034 µmol/l) than the Tramadol has been shown to be approximately equipo- parent drug (+ / − )-tramadol (Ki = 2.4 µmol/l) as well as source: tent to morphine in the range of 4 : 1 to 5 : 1 ratio orally (+ / − )-M5 (Ki = 0.1 µmol/l) and (− )-M1 (Ki = 0.24 µmol/l) 1744-6872 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/FPC.0000000000000057 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. PharmGKB summary: tramadol pathway Gong et al.375 Fig. 1 Tramadol O-desmethyl tramadol (M1) SLC22A1 Tramadol CYP3A4 CYP2D6 Liver cell CYP2B6 N-desmethyl O-desmethyl tramadol (M2) CYP3A4 tramadol (M1) CYP3A4 CYP2D6 CYP2B6 CYP2B6 UGT2B7 N,N-didesmethyl tramadol (M3) N,O-didesmethyl tramadol (M5) UGT1A8 © PharmGKB O-desmethyl N,N,O-tridesmethyl tramadol glucuronide tramadol (M4) N,O-didesmethyl tramadol conjugates N,N,O-tridesmethyl ABCC2 tramadol conjugates O-desmethyl N,N,O-tridesmethyl tramadol glucuronide tramadol conjugates N,O-didesmethyl tramadol conjugates Stylized liver cell showing candidate genes involved in the metabolism and transport of tramadol. A fully interactive version is available online at http:// www.pharmgkb.org/pathway/PA165946349. [26], suggesting that it is the compound primarily [by binding to transporter hSERT (encoded by gene responsible for opioid receptor-mediated analgesia. The SLC6A4)] and norepinephrine [by binding to transporter (+ / − )-tramadol also contribute toward analgesia by hNET (encoded by gene SLC6A2)]. The racemic tra- inhibiting reuptake of the neurotransmitters serotonin madol binds to hNET and hSERT with Ki values at 14.6 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 376 Pharmacogenetics and Genomics 2014, Vol 24 No 7 and 1.19 µmol/l, respectively (reviewed by Raffa et al. lesser extent N,O-didesmethyltramadol (M5), are phar- [28]). Studies with the enantiomers showed that macologically active. Following bioactivation in the liver, (− )-tramadol is more potent in inhibiting norepinephrine M1 is released into the blood, enters the central nervous uptake (Ki = 1.08 µmol/l) and stimulating α-adrenergic system, and activates µ-opioid receptors. In the phase II receptors. In contrast, the (+ )-tramadol is more potent metabolism, M1 is inactivated by glucuronidation in the than (− )-tramadol for inhibiting serotonin uptake liver, mostly through UGT2B7 and UGT1A8 [35]. The (Ki = 0.87 µmol/l) and enhancing serotonin release major route of excretion for tramadol and its metabolites is [28,29]. Both enantiomers act synergistically to enhance through the kidneys, with about 30% of the dose excreted tramadol efficacy. These properties of tramadol may also in the urine as the parent drug and the rest excreted as contribute toward an increased risk of serotonin toxicity metabolites. Capillary electrophoresis assay showed that with concomitant use of serotoninergic drugs such as in healthy volunteers administered 150 mg oral tramadol, serotonin reuptake inhibitors (SSRIs) (e.g. fluoxetine, about 11.4% of the dose was excreted as (− )-tramadol, paroxetine, sertraline). SSRIs can not only inhibit tra- 16.4% as (+ )-tramadol, and 23.7% as O-desmethyl- madol metabolism by inhibiting CYP2D6 but also tramadol glucuronide in the urine [36]. This study also increase serotonin levels in the central nervous system, observed a four-fold higher excretion of (− )-O-desmethyl- an effect also mediated by tramadol. Therefore, con- tramadol glucuronide than the (+ )-O-desmethyltramadol comitant use of an SSRI and tramadol can lead to ser- glucuronide. otonin syndrome, and should be avoided [1,13,14,30]. As tramadol metabolism is primarily mediated through The FDA-approved tramadol drug label now states: ‘In CYP2D6, CYP3A4, and CYP2B6, drugs that inhibit vitro drug interaction studies in human liver microsomes CYP2D6 or induce or inhibit CYP3A4 and CYP2B6 indicates that inhibitors of CYP2D6 such as fluoxetine function should be used with caution in patients taking and its metabolite norfluoxetine, amitriptyline, and qui- tramadol because of a potential risk of drug interaction nidine inhibit the metabolism of tramadol to various [37,38]. For example, carbamazepine, a potent inducer of degrees. The full pharmacological impact of these CYP3A4, may increase tramadol metabolism through alterations in terms of either efficacy or safety is CYP3A4 to inactive metabolites and therefore reduce its unknown. Concomitant use of SEROTONIN re-uptake analgesic effect [39] (TRAMADOL
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