The synergistic antinociceptive effect of lornoxicam in combination with tramadol

© 2013 Amela Saraèeviæ, Fahir Beèiæ; licensee University of Sarajevo Faculty of Health Studies. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. UNIVERSITY OF SARAJEVO FACULTY OF HEALTH STUDIES ABSTRACT


INTRODUCTION
Pain is defi ned by the International Association for the Study of Pain as "unpleasant sensory and emotional experience associated with actual or potential tissue damage", and it is caused by nociceptive stimulus.Although pain is a reaction of the body to harmful stimuli and is therefore a protective early warning system, the sensation of pain in postoperative patients has little positive eff ect.Hence, the term pain, derived from the Latin poena for punishment, refl ects the deleterious eff ects that can be infl icted upon the body (1).Th e goal of postoperative pain relief is to achieve optimal analgesia, facilitating a quick return to normal physiological organ function with minimal side eff ects (2).Many diff erent groups of drugs are being used in pain control, primarily opioid analgesics and nonsteroidal anti-infl ammatory drugs (NSAIDs).Tramadol, a centrally acting analgesic, consists of two enantiomers, both of which contribute to analgesic activity via diff erent mechanisms.Tramadol is eff ective as analgesics and seems to have a better profi le of adverse eff ects than most opioids.Its analgesic effi cacy can further be improved by combination with a non-opioid analgesic (3)(4)(5).Lornoxicam is a new NSAID belonging to the oxicam class.Compared to the other NSAIDs, lornoxicam demonstrates strong analgesic and anti-infl ammatory eff ects, along with an improved gastrointestinal toxicity profi le.Its analgesic activity is comparable to that of opioids.High therapeutic potency is indicated in low doses, with a reduced risk of side eff ects (6)(7)(8).Preliminary research, which requires further confi rmation, suggest that lornoxicam may be a better alternative or adjunctive therapy to opioid analgesics in the treatment of moderate to severe pain (9,10).Studies have also shown that opioids may act in synergy with some NSAIDs, and that such combinations may have therapeutic benefi t in the clinical treatment of infl ammatory pain (11).Th is eff ect is expected when combining analgesics that act at different areas along the route of painful stimulus, for example by combining nonsteroidal anti-infl ammatory drug (NSAID), which operates mainly in the periphery, and opioid, which operates centrally.Th e objective of development of analgesics combination is to achieve effi cacy, that is, to improve therapeutic eff ect while using lower dosages and having less side eff ects.(11,12).Th e use of combination of oral analgesics as opposed to an individual therapy off ers potential benefi ts for the patients.Combining analgesics into a single product may facilitate prescribing and compliance by reducing the number of medicines that a patient must take during the pain control therapy.Combining products with diff erent mechanism of action may provide multimodal approach in pain therapy, and, in addition, enable the individual agents potentially to act synergistically.Furthermore, with regard to safety, lower doses of each individual analgesic, used in combination, may result in a lower incidence of individual adverse events (13).Th e data obtained in one study indicated that the combination of atypical opioid tramadol and atypical NSAID propacetamol had more potent antinociceptive eff ects that those of tramadol and propacetamol, in mouse and rat models with acute and persistent pain.Study suggests that it is possible to increase the antinociceptive eff ects and decrease the undesirable side eff ects of tramadol, by coadministrating propacetamol (14).Th e fundamental concept that underlies the appropriate and successful management of pain by the use of opioid and nonopioid analgesics is individualization of analgesic therapy (15).During the development of multimodal analgesia, apart from increasing antinociception which was the primary goal, clinical evaluation of combinations' benefi ts should be based on the benefi ts coming from reduction of adverse eff ects of opioids in comparation to the side eff ects of non-opioids involved in such combination.Th e aim of this study was to examine whether the coadministration of tramadol and lornoxicam change the threshold of sensitivity to painful stimuli and to examine the relationship between analgesia and method of application of the tested substances.

METHODS
Analgesic eff ects of lornoxicam in combination with tramadol was analysed on female albino mice, weighing 25-30 g.Four groups were formed, each consisting of ten mice.Th e sense of pain was induced by thermal stimulus by the method of hot plate.Th e temperature of the plate was constantly 55°C during the experiment.Analgesic eff ect was measured after a single intraperitoneal (i.p.) and subcutaneous (s.c.) administration of lornoxicam (in a dose of 10 mg/kg body weight), tramadol (in a dose of 10 mg/kg body weight) and their combination (lornoxicam and tramadol each in a dose of 10 mg/kg body weight) in time intervals of 30, 60, 90 and 120 minutes.Physiological solution in the same volume was administered to a control group.Th e study was conducted on animal models (in vivo), in accordance with OECD, EPA regulation and European convention for the protection of vertebrate animals used for experimental and other scientifi c purposes.

RESULTS
Latency period of lornoxicam was increased as compared to the control group after intraperitoneal administration (i.p.) and after subcutaneous administration (s.c.) as well.Lornoxicam applied intraperitoneally in dose of 10 mg/kg showed an analgesic eff ect, statistically diff erent compared to the control group 60, 90 and 120 minutes after application (p<0.05).However, 30 minutes after the i.p. application, the latency period of lornoxicam was increased, as compared to the control group, but with no statistically signifi cant diff erence (p = 0.053).Subcutaneously applied lornoxicam showed analgesic effect compared to control group, in all observed time intervals (p<0.05).Th e results have shown that lornoxicam in combination with tramadol, applied intraperitoneally, increase the threshold of sensitivity to painful stimuli, which was not the case with subcutaneous administration.Latency period of lornoxicam itself was 8.

DISCUSSION
Studies have shown that the use of the combinations of opioids and nonsteroidal anti-infl ammatory drugs (NSAIDs) can increase their antinociceptive activity and improve the therapeutic eff ect, and lead to the use of lower doses of opioids, resulting in a reduction of side eff ects.Data obtained in the study carried out by Zhang et al (14) indicated that the combination of atypical opioid, tramadol and atypical NSAIDs, propacetamol had more potent antinociceptive eff ects than those of tramadol and propacetamol, in mouse and rat models, in the treatment of acute persistent pain.If propacetamol is used together with tramadol clinically, the dose of tramadol could be minimized and then enhance the analgesic eff ect.Th e study suggests that it is possible to increase the antinociceptive eff ects and decrease the undesirable adverse eff ects of tramadol by coadministrating propacetamol.Fernández -Dueñas et al. ( 16) investigated a synergistic interaction between fentanyl, tramadol and paracetamol, or whether the analgesic eff ect of this mixture has increased activity compared to the very strong opioid fentanyl, and whether it leads to a reduction in the dose of fentanyl, and consequently reduced side eff ects.Th e results showed that there is a synergistic interaction between these three drugs in reducing nociception induced by acetic acid in mice.Such a multimodal approach also permits reducing the dose of fentanyl, and reduced the incidence of adverse eff ects, primarily gastrointestinal inhibition passage, which is a common side eff ect of opioid therapy.
Combinations of two analgesic drugs of the same or diff erent class are widely used in clinical therapy to enhance its antinociceptive eff ects and reduce the side eff ects.Moreno-Rocha et al. (17) were evaluating a possible antinociceptive synergistic interaction of metamizol (NSAID) and tramadol (an atypical opioid, opioid receptor agonist), when administered alone or in combination, as well as the possible development of pharmacological tolerance produced by such combination.Th e results of the study showed that both metamizol and tramadol produced antinociceptive eff ects with a low rate trend towards tolerance development at the end of the treatment.Th e antinociceptive effi cacy of tested combination gradually decreased after the second injection.Th ese data suggested that when the combination is given in a unique administration it results in an important potentiation of their individual antinociceptive eff ects.But, the repeated coadministration of tramadol and metamizol results in a development of tolerance.Th e experimental part of our study presents the similar results.Application of individual substances lornoxicam and tramadol showed the expected results.Both, tramadol and lornoxicam produced a signifi cant analgesic eff ect in applied doses, which was statistically diff erent compared to the control group, for each method of application.Th e combination of tramadol and lornoxicam, after i.p. application, produced increased pain reaction (enhanced antinociception) when compared to lornoxicam alone under the same conditions (p<0.05).Th ese results confi rm the literature data on combining opioids and drugs from the group of NSAIDs.Subcutaneous administration of tested combination showed some diff erent results.Just in the fi rst observed time interval after application, the combination of tramadol and lornoxicam produced signifi cantly better analgesic eff ect compared to lornoxicam alone (p < 0.05).At later time points (60, 90 and 120 minutes), the eff ect of this combination is almost the same as the eff ect of lornoxicam, thus, increased latency was demonstrated, but with no statistically signifi cant diff erence.

CONCLUSIONS
After intraperitoneal administration, latency period of lornoxicam was increased as compared to the control group, with signifi cant diff erence after 60, 90 and 120 minutes of test.Lornoxicam also showed increased latency when administered subcutaneously.
Lornoxicam signifi cantly increases analgesic eff ect when applied intraperitoneally in combination with tramadol.On the other hand, lornoxicam in combination with tramadol, did not increase the threshold of sensitivity to painful stimuli with signifi cant difference, after subcutaneous administration.Th e fi ndings of the combination that includes opioid and nonopioid reveal that it has potential for development as one of the new strategies of analgesics.Any clinical decision of using such multimodal approach in pain therapy, in addition to increasing the antinociception which has been experimentally demonstrated in our study, should also be based on the benefi ts coming from reduction of adverse effects of opioids in comparation to the side eff ects of non-opioids involved in such combination.
Statistical analysisStatistical analysis was done using Microsoft Excel (Microsoft Corporation, Redmond, WA, USA) and SPSS for Windows (version 20.0, SPSS Inc, Chicago, Illinois, USA).Th e Student's t-test was used in order to determine if two sets of data are significantly diff erent from each other by calculating statistically signifi cant diff erence between the two arithmetic means.Th e results are presented in the diagram, showing the calculated mean (average of ten measurements), standard deviation and standard error (the ratio of the standard deviation and the square root of the number of measurements).Calculated p value is based on a two-tailed distribution, comparing two sets of measurements of unequal variances.Level of signifi cance was set at p<0.05.