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      Worldwide research productivity on tramadol: a bibliometric analysis

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          Abstract

          Background

          Pain management and safe use of analgesics is an important medical issue. Tramadol is an old analgesic with controversial properties. Evaluation of worldwide scientific output on tramadol has not been explored. Therefore, the main objective of this study was to give a bibliometric overview of global research productivity on tramadol.

          Methods

          SciVerse Scopus was used to retrieve and quantitatively and qualitatively analyze worldwide publications on tramadol.

          Results

          A total of 2059 original and review research articles on tramadol were retrieved from Scopus. Forty-six documents (2.23 %) were published in Anesthesia and Analgesia Journal whereas 30 (1.46 %) were published in Arzneimittel Forschung Drug Research Journal. Retrieved tramadol documents were published from 71 countries and appeared in 160 peer reviewed journals. Although the United States of America (259; 12.86 %) had the largest contribution to tramadol publications; the contribution by other countries like Turkey (232; 11.27) India (189; 8.09 %) and Germany (176; 8.56 % was not far away from that of USA. The most productive institution was Grunenthal, Germany (47; 2.28 %) followed by Tehran University of Medical Sciences, Iran (29; 1.41 %), and, Ortho-McNeil Pharmaceutical Incorporated, USA (25; 1.21 %). Of the 2059 documents, there were 370 documents about dependence. The leading institution in documents pertaining to tramadol dependence was Grunenthal GmbH (18; 4.86 %) followed by Ortho-McNeil Pharmaceutical Incorporated (17; 4.59 %).

          Conclusions

          The current study showed that there is an obvious interest in tramadol research. More efforts are needed to clarify the abuse potential and safety profile of tramadol to help in determining the legal status of tramadol. Collaboration among pharmaceutical industry, clinical researchers and academic institutions can improve research quantity and quality on tramadol.

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          Most cited references 83

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          Clinical pharmacology of tramadol.

          Tramadol, a centrally acting analgesic structurally related to codeine and morphine, consists of two enantiomers, both of which contribute to analgesic activity via different mechanisms. (+)-Tramadol and the metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the mu opioid receptor. (+)-Tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake, enhancing inhibitory effects on pain transmission in the spinal cord. The complementary and synergistic actions of the two enantiomers improve the analgesic efficacy and tolerability profile of the racemate. Tramadol is available as drops, capsules and sustained-release formulations for oral use, suppositories for rectal use and solution for intramuscular, intravenous and subcutaneous injection. After oral administration, tramadol is rapidly and almost completely absorbed. Sustained-release tablets release the active ingredient over a period of 12 hours, reach peak concentrations after 4.9 hours and have a bioavailability of 87-95% compared with capsules. Tramadol is rapidly distributed in the body; plasma protein binding is about 20%. Tramadol is mainly metabolised by O- and N-demethylation and by conjugation reactions forming glucuronides and sulfates. Tramadol and its metabolites are mainly excreted via the kidneys. The mean elimination half-life is about 6 hours. The O-demethylation of tramadol to M1, the main analgesic effective metabolite, is catalysed by cytochrome P450 (CYP) 2D6, whereas N-demethylation to M2 is catalysed by CYP2B6 and CYP3A4. The wide variability in the pharmacokinetic properties of tramadol can partly be ascribed to CYP polymorphism. O- and N-demethylation of tramadol as well as renal elimination are stereoselective. Pharmacokinetic-pharmacodynamic characterisation of tramadol is difficult because of differences between tramadol concentrations in plasma and at the site of action, and because of pharmacodynamic interactions between the two enantiomers of tramadol and its active metabolites. The analgesic potency of tramadol is about 10% of that of morphine following parenteral administration. Tramadol provides postoperative pain relief comparable with that of pethidine, and the analgesic efficacy of tramadol can further be improved by combination with a non-opioid analgesic. Tramadol may prove particularly useful in patients with a risk of poor cardiopulmonary function, after surgery of the thorax or upper abdomen and when non-opioid analgesics are contraindicated. Tramadol is an effective and well tolerated agent to reduce pain resulting from trauma, renal or biliary colic and labour, and also for the management of chronic pain of malignant or nonmalignant origin, particularly neuropathic pain. Tramadol appears to produce less constipation and dependence than equianalgesic doses of strong opioids.
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            Bibliometric methods: pitfalls and possibilities.

            Bibliometric studies are increasingly being used for research assessment. Bibliometric indicators are strongly methodology-dependent but for all of them, various types of data normalization are an indispensable requirement. Bibliometric studies have many pitfalls; technical skill, critical sense and a precise knowledge about the examined scientific domain are required to carry out and interpret bibliometric investigations correctly.
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              Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an 'atypical' opioid analgesic.

              Tramadol hydrochloride produced dose-related antinociception in mouse abdominal constriction [ED50 = 1.9 (1.2-2.6) mg/kg i.p.], hot-plate [48 degrees C, ED50 = 21.4 (18.4-25.3) mg/kg s.c.; 55 degrees C, ED50 = 33.1 (28.2-39.1) mg/kg s.c.] and tail-flick [ED50 = 22.8 (19.2-30.1) mg/kg s.c.] tests. Tramadol also displayed antinociceptive activity in the rat air-induced abdominal constriction [ED50 = 1.7 (0.7-3.2) mg/kg p.o.] and hot-plate [51 degrees C, ED50 = 19.5 (10.3-27.5) mg/kg i.p.] tests. The antinociceptive activity of tramadol in the mouse tail-flick test was completely antagonized by naloxone, suggesting an opioid mechanism of action. Consistent with this, tramadol bound with modest affinity to opioid mu receptors and with weak affinity to delta and kappa receptors, with Ki values of 2.1, 57.6 and 42.7 microM, respectively. The pA2 value for naloxone obtained with tramadol in the mouse tail-flick test was 7.76 and was not statistically different from that obtained with morphine (7.94). In CXBK mice, tramadol, like morphine, was devoid of antinociceptive activity after intracerebroventricular administration, suggesting that the opioid component of tramadol-induced antinociception is mediated by the mu-opioid receptor. In contrast to the mouse tail-flick test and unlike morphine or codeine, tramadol-induced antinociception in the mouse abdominal constriction, mouse hot-plate (48 degrees or 55 degrees C) or rat hot-plate tests was only partially antagonized by naloxone, implicating a nonopioid component. Further examination of the neurochemical profile of tramadol revealed that, unlike morphine, it also inhibited the uptake of norepinephrine (Ki = 0.79 microM) and serotonin (0.99 microM). The possibility that this additional activity contributes to the antinociceptive activity of tramadol was supported by the finding that systemically administered yohimbine or ritanserin blocked the antinociception produced by intrathecal administration of tramadol, but not morphine, in the rat tail-flick test. These results suggest that tramadol-induced antinociception is mediated by opioid (mu) and nonopioid (inhibition of monoamine uptake) mechanisms. This hypothesis is consistent with the clinical experience of a wide separation between analgesia and typical opioid side effects.
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                Author and article information

                Contributors
                waleedsweileh@yahoo.com , waleedsweileh@najah.edu
                shraim.n@gmail.com
                saedzyoud@yahoo.com
                samahjabi@yahoo.com
                Journal
                Springerplus
                Springerplus
                SpringerPlus
                Springer International Publishing (Cham )
                2193-1801
                19 July 2016
                19 July 2016
                2016
                : 5
                : 1
                Affiliations
                [ ]Department of Pharmacology/Toxicology, College of Medicine and Health Sciences, An-Najah National University, Nablus, 44839 Palestine
                [ ]Department of Pharmaceutical Chemistry and Technology, College of Medicine and Health Sciences, An-Najah National University, Nablus, 44839 Palestine
                [ ]Department of Clinical and Community Pharmacy, College of Medicine and Health Sciences, An-Najah National University, Nablus, 44839 Palestine
                Article
                2801
                10.1186/s40064-016-2801-5
                4949195
                27478725
                © The Author(s) 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                Categories
                Research
                Custom metadata
                © The Author(s) 2016

                Uncategorized

                bibliometric, tramadol, scopus, pain management

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