Worldwide research productivity on tramadol: a bibliometric analysis

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.


Background
Search for best methods of pain management is as old as mankind (Gildenberg 1997;Greenblatt et al. 1997). However, only in the past several decades did research about pain management showed great momentum and became a cornerstone in the medical field. The initiation of several international peer reviewed journals specialized in the field of pain/anesthesia has contributed to this positive momentum in pain research. Furthermore, the discovery and development of potent and unique analgesics have also increased attention to pain research. No doubt that the increase in prevalence of chronic pain has also stimulated many pharmaceutical companies to search for new analgesic medications those bear ideal characteristics. Despite the ongoing research and development in the field of pain, no ideal analgesic drug has been found yet. A study that discussed the characteristics of more than 50 analgesics introduced in the past 50 years concluded that despite intense research efforts, there is no real novel analgesic drug discovery and an ideal analgesic is not yet available (Kissin 2010). In 1977, tramadol, a new and atypical opioid analgesic medication, was introduced and marketed by the German pharmaceutical company, Grünenthal GmbH. Since that time, many articles have been published about tramadol and its unique pharmacology and toxicology. Tramadol is unique in that it affects serotonin and norepinephrine systems in addition to its weak μ-opioid receptor agonist activity (Dayer et al. 1994(Dayer et al. , 1997Grond and Sablotzki 2004;Epstein et al. 2006;Raffa 2008;Reeves and Burke 2008). Therefore, tramadol has dual mechanism of action; µ opioid agonist and a serotonin/norepinephrine reuptake inhibitor (Raffa 2013;Vazzana et al. 2015). That is why tramadol causes adverse effects pertaining to elevated brain serotonin levels (serotonin syndrome) especially when coadministered with selective serotonin reuptake inhibitors (SSRI) drug class (Nelson and Philbrick 2012;Beakley et al. 2015). Another important pharmacological aspect of tramadol is its metabolism by CYP2D6 which exhibits wide polymorphism leading to variation in toxic and therapeutic effects of tramadol (Lassen et al. 2015;Ibrahim et al. 2016).
The abuse potential of tramadol is still an ongoing controversy (Friderichs et al. 1978;Murano et al. 1978;Richter et al. 1985;Ehrenreich and Poser 1993;Liu et al. 1999;Aknine et al. 2000;Yates et al. 2001;Brinker et al. 2002;Ripamonti et al. 2004;Naslund and Dahlqvist 2003;Woody et al. 2003;Skipper et al. 2004;Soyka et al. 2004). Understanding progress made in pain management research in general and about tramadol in particular requires periodic assessment of how scientific research in this topic is advancing. Bibliometric analysis, a statistical method for literature evaluation, is commonly used for assessment of research activity in any particular filed (Wallin 2005). Several bibliometric studies on pain related topics have been recently published (Robert et al. 2008a, b;Dubner 2009;Mogil et al. 2009;Onyeka and Chukwuneke 2014). However, based on author's best knowledge, no bibliometric analysis has been published about analgesic drugs, particularly about a controversial medication like tramadol. In this study we planned to give a bibliometric overview of tramadol publications through analysis of temporal research productivity and analysis of highly cited articles in tramadol field. This study is important for those in the field of clinical pharmacology and medicine since it will give them a comprehensive look on current research trends on tramadol and future status of pain management in general and role of tramadol in pain management guidelines.

Methods
In this study, traditional bibliometric indicators were applied and presented. Such indicators have been explained in previous studies by the same authors. Standard competition ranking (SCR) was used to rank productive journals, countries, authors and institutions. The h-index (Hirsch 2005) was used to assess quantity and quality of research productivity by authors, countries and institutions. The journal impact factor (IF) obtained from the Journal Citation Report (JCR; Web of Knowledge) 2014 science edition by Thomson Reuters and the SCImago Journal Rank (SJR) indicator (available at: http://www.scimagojr.com/SCImagoJournalRank.pdf ) were used as a quality indicator for journal strength and reputation. The adjustment index (AI) was used to stratify productivity with income and population size and was obtained using the following equation: "AI = [total number of publications for the country/gross domestic product (GDP) per capita of the country] × 1000, where the GDP per capita = GDP/population of the country" (Sweileh et al. 2013;Zyoud et al. 2014e, 2015a. In this study, the keyword entered into Scopus search engine was "tramadol" in the "Article Title". All subject areas were selected and the time interval of the analysis was set up to December 31st, 2013. Analysis was restricted to original and review articles. Citation analysis was completed within 1 day on July 29th, 2015 to avoid bias due to daily in database update. The extracted data were tabulated and analyzed according to the indicators found in previous bibliometric studies (Sweileh et al. 2014;Zyoud et al. 2014bZyoud et al. , c, e, f, 2015a.

Results
A total of 2429 research articles on tramadol were retrieved. Of the 2429 articles, there were 1958 (80.61 %) original journal articles, 101 (4.16 %) review articles, 146 (6.01 %) letters, 67 (2.76 %) conference papers, and 157 (6.47 %) other types of publications such as editorial, notes, book chapters, erratum and undefined. Analysis in this manuscript was based on 2059 documents that were original research articles and reviews. The 2059 articles were written in 23 different languages. The main language encountered was English (n = 1687; 80.68 %) followed distantly by Turkish (n = 87; 4.16 %), Chinese (n = 72; 3.44 %), German (n = 62; 2.97 %), Spanish (n = 56; 2.68 %), French (n = 24; 1.15 %), Italian (n = 21; 1.00 %), and 16 other languages (82; 3.92 %). The number of published documents about tramadol in the past 5 years (2008-2013) has increased by approximately 15-folds compared with the time interval from 1978 to 1988 (Table 1). The first article on tramadol was published in 1978. Retrieved tramadol articles were published from 71 countries and appeared in 160 peer reviewed journals. Top ten productive countries on tramadol research are shown in Table 2. Tramadol research and publications were produced by countries from different world regions and even from countries outside Europe and North America. Although the largest number of articles about tramadol was produced by the USA (259; 12.58 %); 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 the USA (Table 2). It is noteworthy that Turkey surpassed Germany and other European countries in tramadol research.
The total citations of retrieved articles was 36,275, with an average of 17.62 citations per article as recorded in Scopus on July 29th, 2015. The h-index of tramadol publications was 74. List of most commonly cited articles on tramadol is shown in Table 3 (Raffa et al. 1992(Raffa et al. , 1993Vickers et al. 1992;Lee et al. 1993;Poulsen et al. 1996;Harati et al. 1998;Sindrup et al. 1999;Scott and Perry 2000;Xia et al. 2000;Grond and Sablotzki 2004). Those about the potential mechanism of action and potential role of tramadol in treatment of neuropathic pain were most commonly cited. Two of the top 10 cited articles were published from the same research group, the Raffa et al., group present in the USA. Table 4 shows top 10 productive journals involved in tramadol research. Fortysix articles (2.24 %) were published in Anesthesia and Analgesia whereas 30 (1.46 %) were published in Arzneimittel Forschung: Drug Research. Of the top 10 journals, six were in the field of anesthesia and pain, three in the field of pharmacology, therapeutics and drug research and one in the field of clinical pharmacology and anesthesia. Of the top 10 journals, two were Turkish journals while the others were based either in USA or Europe. When the journals were screened for IF, three journals of the top productive ones were not listed in ISI JCR and the remaining were listed and had an IF <5.  Table 7 presents the top 10 productive authors on about tramadol, along with their affiliations. Half of the top prolific authors were from USA and seven were affiliated with academic institutions.

Discussion
Evidence-based pain management requires exploration of efficacy and safety of various analgesics as presented in literature. Our study analyzed 2059 research articles retrieved from Scopus, a large databases equipped  Although tramadol is unique in having dual mechanism of action, its introduction to the worldwide market was slow and cautious. A possible reason for this slow introduction was the uncertainty regarding safety and abuse potential. However, reports and clinical trials have shown that tramadol has lesser toxic profile and better tolerability than oral traditional nonsteroidal anti-inflammatory drugs (NSAIDs) or commonly used opioids (Preston et al. 1991;Adams et al. 2006;Epstein et al. 2006). A study carried out to compare the abuse potential among NSAIDs, codeine, placebo and tramadol has found that abuse potential for tramadol is significantly lower than that of codeine (Adams et al. 2006). On the other hand, reports about other serious side effects like seizure have been reported (Tobias 1997;Raffa and Stone 2008;Sen    In our study, bibliometric techniques were applied to give an overview on worldwide published research on tramadol. The first publication about tramadol appeared in 1978 followed by rapid increase, particularly after 1995 which coincide with the year of introduction in the US market. The first article about tramadol as analgesic was published by Rost, A., Schenck, E.G. in Arzneimittel-Forschung/Drug Research in 1978 as a comparative clinical study (Rost and Schenck 1978). The discovery and identification of tramadol and its unique mechanism of action lead to the development of a newer tramadollike agent named tapentadol which is currently available in the market and promoted to have better safety profile than tramadol (Giorgi et al. 2012;Mercadante et al. 2012Mercadante et al. , 2013Cepeda et al. 2013;Gohler et al. 2013;Lee et al. 2013;Schwittay et al. 2013;Singh et al. 2013;Fejos et al. 2014).
An average of 17.62 (median = 6) citations per article was obtained in this study. This finding means that tramadol is an interesting topic for scientific research community. Furthermore, the fact that the top 10 productive countries and top 10 productive institutions in tramadol research included countries and institutes outside the Americas and Europe suggest that tramadol research is of interest to many nations. It was obvious that non-academic institutions, particularly pharmaceutical companies, were involved heavily in tramadol   (Wu et al. 2001;Teppema et al. 2003;Giorgi et al. 2009a, b). In addition, research about tramadol and its potential use in premature ejaculation gave further momentum to tramadol research (Safarinejad and Hosseini 2006;Salem et al. 2008;Bar-Or et al. 2012). At the official level, research interest in tramadol was motivated by the debate about the legal status and whether to schedule or un-schedule tramadol. In Sweden and in several states in the USA, including New York, Arkansas, Illinois, Kentucky, Mississippi, North Dakota, Oklahoma, Tennessee, Wyoming, and West Virginia have categorized tramadol as a schedule IV controlled substance. In most countries of the world, the legal status of tramadol is currently under re-evaluation. Finally, the authors believe that this study, like all other bibliometric studies, has few limitations that have been explained in previous bibliometric studies (Li et al. 2011;Sweileh et al. 2013;Zyoud et al. 2014aZyoud et al. , d, 2015bZyoud 2015). Such limitations include the use of Scopus database; the use of "tramadol" word as a title keyword in the search engine; and the restriction of analysis to original articles and article reviews. However, despite all this, the current study will be of great value for people in pain management policy and those involved in research pertaining to analgesia.

Conclusions
Tramadol is an analgesic with controversial properties which made it an appealing topic for researchers from different scientific disciplines. Research output about tramadol was not confined to particular country. More research efforts are needed to shed light on the abuse potential and the non-analgesic therapeutic benefits of tramadol. Research activity about tramadol needs to be directed toward minimizing its side effects. Such research activity can be achieved through collaboration among people in pharmaceutical industry, clinical practice and academic institutions.