Review Tramadol hydrochloride: Pharmacokinetics, pharmacodynamics, adverse side effects, co-administration of drugs and new drug delivery systems M. Vazzana a , T. Andreani b,c , J. Fangueiro d , C. Faggio a , C. Silva e , A. Santini f , M.L. Garcia g,h , A.M. Silva b,c , E.B. Souto d,i, * a Department of Biological and Environmental Sciences, University of Messina, Viale Fernando Stagno d’ Alcontres, 31, 98166 S. Agata-Messina, Italy b Department of Biology and Environment, University of Tra ´s-os Montes e Alto Douro, Quinta de Prados, P-5001-801, Vila Real, Portugal c Centre for Research and Technology of Agro-Environmental and Biological Sciences (CITAB, UTAD), Vila Real, Portugal d Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), Po ´lo das Cieˆncias da Sau ´de, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal e Center for Nanotechnology and Smart Materials, Rua Fernando Mesquita, 2785, 4760-034 Vila Nova de Famalica˜o, Portugal f Department of Pharmacy, University of Napoli ‘‘Federico II’’, Via D. Montesano 49, 80131 Napoli, Italy g Department of Physical Chemistry, Faculty of Pharmacy, University of Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain h Institute of Nanoscience and Nanotechnology, University of Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain i Center for Neuroscience and Cell Biology & Institute for Biomedical Imaging and Life Sciences (CNC-IBILI), University of Coimbra, Po ´lo das Cieˆncias da Sau ´de, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal 1. Introduction Tramadol hydrochloride (TrHC) is a synthetic analgesic drug showing opioid and non-opioid properties, acting mainly on the central nervous system (CNS). This drug is structurally related to codeine and morphine, but it is 6000-times less potent than morphine and 10-times less potent than codeine [1–3]. It appeared in the 1970s, but only approved by the Food and Drug Administra- tion (FDA) in 1995 for the management, treatment and relief of moderate to severe pain conditions [4–6]. The anti-nociceptive effects are due to a double (opioid and non-opioid) mechanism of action. In fact, TrHC acts on m-opioid and k-opioid receptors with low affinity, exerting a weak agonist effect, and it affects monoamine receptor systems by blocking norepinephrine (NE) and serotonin (5-HT) reuptake, responsible for the inhibition of pain transmission in the spinal cord [7,8]. TrHC is more advantageous than other typical opioid agents for its unique pharmacological profile, since it exhibits a lower incidence of side effects and abuse potential [8,9]. Table 1 summarizes the physicochemical properties of this drug. Biomedicine & Pharmacotherapy 70 (2015) 234–238 A R T I C L E I N F O Article history: Received 10 January 2015 Accepted 23 January 2015 Keywords: Tramadol hydrochloride Solid lipid nanoparticles Polyacrylates Drug delivery Pain relief A B S T R A C T Tramadol hydrochloride (TrHC) is a synthetic analgesic drug exhibiting opioid and non-opioid properties, acting mainly on the central nervous system. It has been mostly used to treat pain, although its use to treat anxiety and depression has also been documented. These properties arise from the fact that they inhibit serotonin (5-HT) reuptake augmenting 5-HT concentration on the synaptic cleft. Despite this, TrHC has also been described to have several side effects which are mainly due to its fast metabolization and excretion which in turn requires multiple doses per day. To surpass this limitation, new pharmaceutical formulations are being developed intending the protection, target and sustained delivery as well as a reduction on daily dose aiming a reduction on the side effects. In the present work we have revised the efficacy, safety, biological and adverse effects of TrHC, and the added value of developing a novel drug delivery system for topical administration. ß 2015 Elsevier Masson SAS. All rights reserved. Abbreviations: 5-HT, serotonin; BBB, blood brain barrier; CNS, central nervous system; FDA, Food and Drug Administration; GABA, gamma aminobutyric acid; M1, O-desmethyltramadol; M2, N-desmethyltramadol; NA, noradrenaline; NE, norepinephrine; NET, norepinephrine transporter; NMDA, N-methyl-D-aspartate; NMDAR, N-methyl-D-aspartate receptor; NSAIDs, non-steroidal anti-inflammatory drugs; P-gp, P-glicoprotein; SERT, serotonin (5-HT) transporters; TrHC, tramadol hydrochloride. * Corresponding author at: Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), Po ´ lo das Cie ˆncias da Sau ´ de, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal. Tel.: +351 239 488 400; fax: +351 239 488 503. E-mail address: ebsouto@ff.uc.pt (E.B. Souto). Available online at ScienceDirect www.sciencedirect.com http://dx.doi.org/10.1016/j.biopha.2015.01.022 0753-3322/ß 2015 Elsevier Masson SAS. All rights reserved.