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RFM - Revista Fluminense de Medicina ARTIGO FJM - Fluminense Journal of Medicine ARTICLE Clinical-Therapeutic Assessment of the Use of Lysine Clonixinate in the Treatment of Conditions in which Pain is a Present and Important Symptom Avaliação Clínico-Terapêutica do Uso de Clonixinato de Lisina no Tratamento Processos em que a Dor seja Sintoma Presente e Relevante de Marco Antonio Mibielli1, Carlos P Nunes2, Carlos Romualdo B Gama3, Marcia G Ribeiro4, Spyros GE Mezitis5, Lisa Oliveira6, Mauro Geller7 Professor and Chairman of Orthopedics – UNIFESO. Member of the Sociedade Brasileira de Ortopedia e Traumatologia. 2Associate Professor of Internal Medicine – UNIFESO. Associate Professor – IPGMCC. Member of the American College of Physicians. 3Professor and Chairman of Gynecology – UNIFESO. PhD in Gynecology – UNESP. Member of the Colégio Brasileiro de Cirurgiões. 4Associate Professor of Clinical Genetics – IPPMG – UFRJ. Head of the Clinical Genetics Service – IPPMG-UFRJ. 5Assistant Professor of Clinical Medicine – Weill Medical College of Cornell University. Endocrinology Consultant and Clinical Investigator, Division of Endocrinology, Diabetes and Metabolism – New York-Presbyterian Hospital/Weill-Cornell Medical Center. 6Researcher in Immunology and Microbiology – UNIFESO. 7Professor and Chairman of Immunology – UNIFESO. Post-PhD in Immunogenetics – Harvard University. Professor and Chairman of Clinical Immunology – IPGMCC. 1 ABSTRACT Objectives and Methods: This study evaluated the clinical efficacy and safety of the NSAID lysine clonixinate in the treatment of painful conditions. Efficacy was measured comparing the pretreatment to post-treatment results, using a 100 mm visual analog pain scale together with numerical scale assessments of overall condition as evaluated by the subject and the physician. Safety was monitored by incidence and severity of adverse effects, laboratory test alterations, and end of study overall tolerability assessment. Results: Based on the medical records of patients attended at UNIFESO, a total of 275 subjects were included. All subjects were treated with lysine clonixinate 125 mg, three times a day. There were no statistically significant changes in weight, BMI, and blood pressure. Mean heart rate decreased from 67.63bpm to 67.05 bpm from pretreatment to Assessment 2 (p = 0.004). A total of 53 subjects (19.3%) presented adverse events. Mean AE duration was 1.8 (± 0.77) days. With the exception of one case of flatulence that was classified as severe, all AEs were mild to moderate in severity. At pretreatment, total mean VAS value was 56.09 mm (± 12.04 mm). At Assessment 2, there was a statistically significant reduction in total mean VAS value to 9.17 mm (± 12.07 mm) in relation to those observed at pretreatment (t = 52.49; DF = 274; p < 0.0001). Improvements in VAS scores were seen in 273 (99.27%) patients, and 44% of subjects were completely pain-free (0 mm on VAS). Of the total subjects, 41.8% presented improvements ≥ 50 mm in VAS scores, while 57.4% presented improvements of up to 50 mm, and two subjects (0.7%) showed worsening of VAS scores. There was a statistically significant improvement in the scores of the Patient’s Overall Assessment (χ2 = 430.1; df = 9; p < 0.0001) as well as the Physician’s Overall Assessment scores (χ2 = 439.5; df = 9; p < 0.0001). Overall efficacy was classified as “Very Good” by the physician at Assessment 2 in 135 (49.1%) of subjects, while tolerability was classified as “Very Good” among 131 (47.6%) subjects. Conclusion: Treatment of painful conditions with lysine clonixinate was effective and safe, reducing pain and improving overall condition of the treated subjects. Keywords: Lysine clonixinate, analgesia, nonsteroidal anti-inflammatory drug Resumo Objetivos e Métodos: O estudo avaliou a eficácia clínica e segurança do AINE clonixinato de lisina no tratamento de condições de dor. A eficácia foi mensurada e os resultados do pré-tratamento foram comparados aos do pós-tratamento com o uso da escala analógica de dor de 100 mm associada à escala numérica das condições clínicas gerais, avaliadas tanto pelos pacientes quanto pelos médicos assistentes. A segurança foi monitorada pela incidência e severidade dos efeitos adversos, alterações dos testes laboratoriais, e uma avaliação global de tolerabilidade. Resultados: Com base nos prontuários médicos dos pacientes atendidos na UNIFESO, um total de 275 pacientes foi incluído. Todos os pacientes foram tratados com clonixinato de lisina 125 mg, três vezes ao dia. Não foram identificadas alterações estatísticas significativas no peso, IMC e na pressão arterial. Houve uma diminuição média do ritmo cardíaco de 67,63 bpm para 67,05 bpm, comparando o Pré-tratamento com a Avaliação (p = 0,004). Um total de 53 indivíduos (19,3%) apresentou eventos adversos. A duração média dos EA foi 1,8 (± 0,77) dia. Com a exceção de um caso de flatulência, que foi classificada como severa, todos os EAs foram de severidade branda a moderada. No prétratamento o valor total do VAS médio foi de 56,09 mm (± 12,04 mm). Na Avaliação 2 houve uma redução estatisticamente significativa no valor total do VAS médio para 9,17 mm (± 12,07 mm) em relação ao observado anteriormente (t = 52,49; GL = 274; p < 0,0001). Melhoras da pontuação do VAS foram observadas em 273 (99,27%) pacientes, e 44% dos pacientes estavam inteiramente livres de dor (0 mm no VAS). No total de pacientes, 41,8% apresentaram melhoras ≥ 50 mm, ao passo que 57,4% apresentaram melhoras de até 50 mm, e dois pacientes (0,7%) apresentaram piora da pontuação VAS. Houve uma melhora estatisticamente significativa na pontuação da Avaliação Global do Paciente (χ2 = 430,1; GL = 9; p < 0,0001), como também na pontuação da Avaliação Global do Médico (χ2 = 439,5; GL = 9; p < 0,0001). A eficácia geral foi classificada como “Muito Boa” pelo médico na Avaliação 2 em 135 (49,1%) dos pacientes, enquanto a tolerabilidade foi classificada como “Muito Boa” entre 131 (47,6%) pacientes. Conclusão: O tratamento de condições dolorosas com clonixinato de lisina foi eficaz e seguro, reduzindo a dor e melhorando a condição global dos pacientes tratados. Palavras-chave: clonixinato de lisina, analgesia, medicamento anti-inflamatório não esteroide Address to correspondence: MAURO GELLER Av. Alberto Torres, 111 – Alto – Teresópolis/RJ CEP: 25964-004 E-mail: [email protected] Received in: August 12, 2013 Approved in: October 25, 2013 RFM - Rev Flu Med 2014;78-79(2):4-10 - ISSN: 2238-9423 INTRODUCTION Lysine clonixinate is a nonsteroidal anti-inflammatory drug (NSAID), belonging to a group which is composed of several non-narcotic drugs that, while unrelated, share anti-inflammatory, analgesic, and antipyretic properties, and that are used in the treatment of mild to moderate pain. The therapeutic effects of the NSAIDs can be attributed to inhibition of the cyclooxygenase isoenzymes COX-1 and COX-2, thus they function as DOI: 10.5533/RFM-FJM-2238-9423-201478-79202 Clinical-Therapeutic Assessment of the Use of Lysine Clonixinate in the Treatment of Conditions in which Pain is a Present and Important Symptom direct inhibitors of prostaglandin and thromboxane synthesis through arachidonic acid. There is evidence to suggest that the NSAIDs may also have a mechanism of central action, which increases the peripheral mechanism1. COX-1 is the constitutive form of cyclooxygenase, and is found in platelets, vascular endothelial cells, as well as in the stomach and kidneys, where it is involved in the production of prostaglandins that are essential to protection of the stomach lining (prostaglandin E2), platelet aggregation (thromboxane A2), and renal function (prostaglandin I2)2. COX-2 is induced in the presence of inflammation, but can also be found in cerebral and renal tissue in the absence of inflammation. Upregulation of COX-2 in some areas of the central nervous system leads to production of prostaglandins, such as PGE2, which are involved in pain, fever, and inflammation1. The individual NSAIDs inhibit COX-1 and COX-2 in varying degrees, and when used in equipotent doses, the safety profiles of these drugs vary individually, although there is little difference between them in terms of efficacy2. The NSAIDs with a greater affinity for COX-1 tend to be associated with higher rates of gastrointestinal side effects, while those that preferentially inhibit COX-2 may present a higher risk for cardiovascular adverse effects3,4. In this study, the clinical action of lysine clonixinate was evaluated in patients presenting painful conditions. Lysine clonixinate is an NSAID derived from nicotinic acid, a member of the non-salicylate family and belonging to the subgroup of anthranilic derivatives5. Its structural formula (2-(3-chloro-o-toluidine) piridino-3-carboxilate) allows for rapid absorption after oral ingestion. Following absorption, protein binding is 96-98%, and it undergoes hepatic metabolism, resulting in the formation of at least three inactive metabolites6. Excretion is primarily renal (75%) but fecal excretion also occurs (25%)7. As with many other NSAIDs, the mechanism of action of lysine clonixinate is not yet fully understood. However, in addition to its activity in cyclooxygenase inhibition8, it is very likely that the mechanism of action of lysine clonixinate includes preferential activity in attenuating the action of 5-lipoxygenase, reducing synthesis of pro-inflammatory 5-HETE (5-hydroxyeicosatetraenoic acid)9. Franchi et al. (2001) reported that lysine clonixinate exerts an inhibitory effect on the expression of the enzyme nitric oxide synthase (NOS) induced by lipopolysaccharides, which participate in the inflammatory process10. The preference towards 5-lipoxygenase may explain the absence of effects on platelet number and function, which are often observed during treatment with other NSAIDs11. Studies using animal models have demonstrated that lysine clonixinate and other NSAIDs can directly interact with the central serotonergic system and indirectly influence opioid receptor systems in the thalamic nucleus, dentate gyrus and in the layers of the parietal cortex6,12-14. OBJECTIVES 5 painful conditions, specifically in terms of visual analog pain scale scores, assessments in the form of questionnaires answered by the subjects and the study physician, results of physical examinations, incidence of adverse events, and incidence of clinically significant laboratory alterations. METHODS This was an open, qualitative and quantitative study carried out at FundaçãoEducacional Serra dos Órgãos – UNIFESO. The study protocol received approval of the university ethical committee (approval no. 604-11). Based on medical records, subjects who were attended at Hospital das Clínicas de Teresópolis, received a diagnosis of a painful condition and who were treated with lysine clonixinate (with a cutoff date of May 2011), were selected to be entered in the study. Each subject was designated a sequential three-digit study number, starting with 001, which was used to preserve the subject’s identity. Inclusion criteria for the study were for patients of both genders, over the age of 18, with a clinical presentation of mild to moderate pain (< 80mm on the 100 mm visual analog pain scale – VAS) resulting from headache, myalgias, non-infectious arthralgias, post-traumatic pain, and colics (menstrual, abdominal, and biliary). Exclusion criteria included pregnancy or lactation, hypersensitivity or intolerance to lysine clonixinate, severe pain (≥ 80 mm on the visual analog pain scale), treatment with other analgesic agents within 14 days of the first visit to the hospital, and any other disease or condition that in the opinion of the investigating physician should exclude the subject from the study. The Clinical Research Form included demographic data, medical history, and clinical evaluations (including physical examination data), dose of study medication and treatment duration, as well as results of laboratory tests, concomitant medications, adverse events (description, dates of onset and resolution, severity, relationship to study medication), and the efficacy and safety assessments. The efficacy and safety assessments were performed based on the data collected before treatment (Pretreatment, Assessment 1) and after treatment (Post-Treatment, Assessment 2). The efficacy evaluations included a visual analog pain scale (VAS), which was measured by the distance from the left side of a 100 mm line (ranging from 0mm – no pain, to 100 mm – most severe pain) to the subject’s vertical mark along the line corresponding to pain severity at the time of the assessment. The Patient’s Overall Assessment and the Physician’s Overall Assessment ranked the subject’s overall condition on a scale of 1 (worst possible score) to 10 (best possible score). At Assessment 2, subjects also rated their willingness to continue treatment on a scale of 1-10 (from 1 – less willing to 10 – most willing). Additionally, the physician assessed overall efficacy and tolerability at Assessment 2, assigning a rating of “Very Good”, “Good”, “Fair” or “Poor”. The primary efficacy measures were symptomatic improvement of pain (VAS scores), as well as the Patient’s Overall The objective of this study was to evaluate the efficacy and Assessment, Physician’s Overall Assessment and the physician tolerability of the use of lysine clonixinate in the treatment of assessment of efficacy. Clinical tolerability and safety were asRFM - Rev Flu Med 2014;78-79(2):4-10 6 MIBIELLI et al. sessed taking into account the incidence of all adverse effects, serious adverse effects and/or hospitalizations, incidence of clinically significant laboratory test alterations, as well as the physician assessment of tolerability. Table 2 – Clinical Evaluations Variable Total Weight (kg) Pretreatment 67.85 (± 14.41) the software GraphPad Prism 5.1. Continuous variables were Assessment 2 67.83 (± 14.43) analyzed using the student’s T-test or ANOVA, while categorical BMI (kg/cm ) The CRF was filled, coded, and the data analyzed using variables were analyzed using the χ2 or Fisher’s exact test. The results were compared pre- and post-treatment. The efficacy endpoints were: the percentage of subjects presenting reductions on the VAS in relation to pretreatment; the percentage of 2 Pretreatment 24.83 (± 3.65) Assessment 2 24.81 (± 3.66) Heart rate (bpm) Pretreatment 67.63 (± 4.73) the percentage of subjects pain-free at Assessment 2. The safety Assessment 2 67.05 (± 4.45) endpoints of this study were: percentage of patients presenting Systolic blood pressure (mmHg) subjects presenting ≥ 50mm reduction in pain on the VAS; and changes to the physical exam; the percentage of subjects presenting adverse events; the percentage of subjects presenting changes to laboratory tests; and the percentage of subjects evaluated with “Very Good” in the overall tolerability assessment. RESULTS A total of 275 subjects were included in the analysis, of whi- Pretreatment 121.1 (± 5.26) Assessment 2 120.8 (± 5.52) Diastolic blood pressure (mmHg) Pretreatment 78.07 (± 8.21) Assessment 2 77.89 (± 7.88) Data are means (± SD). ch 177 (64.36%) were female and 98 (35.64%) were male. Table 1 summarizes the demographic and pretreatment characteristics of the total study population. All subjects were treated for pain with lysine clonixinate 125 mg, three times per day. Treatment duration ranged from 2 to 5 days, with amean treatment duration of 4.82 (± 0.54) days. Table 2 summarizes the results of the physical examinations. There were no statistically significant changes in weight (p = 0.406), BMI (p = 0.249), and blood pressure (p = 0.106 for systolic blood pressure; p = 0.258 for diastolic blood pressure) between pretreatment and Assessment 2. Mean heart rate decreased from 67.63 bpm to 67.05 bpm from pretreatment to Assessment 2 (p = 0.004). Table 1 – Demographic and Pretreatment Characteristics Variable Total Age (years) 39.11 (± 11.45) Ethnicity Asian 2 Black 75 Caucasian 110 Mulatto 88 Height (cm) 164.7 (± 8.66) Pain type Abdominal colic 38 Biliary colic 7 Dysmenorrhea 86 Headache 33 Myalgia 50 Non-infectious arthralgia 38 Post-traumatic pain 23 Data are n or means (± SD). RFM - Rev Flu Med 2014;78-79(2):4-10 A total of 53 subjects (19.3%) presented with 56 adverse events (three subjects presenting 2 AEs each and 50 subjects presenting 1 AE each). Mean AE duration was 1.8 (± 0.77) days, with a minimum duration of 1 day and a maximum duration of 4 days. With the exception of one case of flatulence that was classified as severe, all AEs were mild to moderate in severity. The AEs observed are summarized in Table 3. One subject (0.36%) presented an altered laboratory test result (elevated transaminases). At pretreatment, total mean VAS value was 56.09 mm (±12.04 mm). At Assessment 2, there was a statistically significant reduction in total mean VAS value to 9.17 mm (±12.07 mm) in relation to those observed at pretreatment (t = 52.49; DF = 274; p < 0.0001). Improvements in VAS scores were seen in 273 (99.27%) of subjects at Assessment 2 in relation to pretreatment values. At Assessment 2, 44% of subjects were completely pain-free (0 mm on VAS). Of the total subjects, 41.8% presented improvements ≥ 50 mm in VAS scores, while 57.4% presented improvements of up to 50 mm, and two subjects (0.7%) showed worsening of VAS scores. Figure 1 shows the VAS score changes at Assessment 2 divided by pain type. Figure 2 summarizes the results of the overall assessment performed by the patient and the physician. There was a statistically significant improvement in the scores of the Patient’s Overall Assessment recorded at Assessment 2 in relation to pretreatment values (χ2 = 430.1; df = 9; p < 0.0001). The Physician’s Overall Assessment scores also improved significantly at Assessment 2 in relation to pretreatment (χ2 = 439.5; df = 9; p < 0.0001). Overall efficacy was classified as “Very Good” by the physician at Assessment 2 in 135 (49.1%) of subjects, while tolerability was classified as “Very Good” among 131 (47.6%) subjects (Figure 3). Clinical-Therapeutic Assessment of the Use of Lysine Clonixinate in the Treatment of Conditions in which Pain is a Present and Important Symptom 7 to a faster improvement of nausea as compared to treatment Table 3 – Adverse Events with metamizole17. Adverse Event Severity Abdominal distension Mild 1 125 mg lysine clonixinate resulted in analgesia comparable Abdominal distension Moderate 1 to that achieved using 500 mg paracetamol18. Noronha et al. Bronchial asthma Moderate 1 (2009) evaluated the analgesic efficacy of lysine clonixinate Constipation Moderate 1 (125 mg) among patients undergoing extraction of the lower Constipation Mild 1 Diarrhea Moderate 3 Elevated transaminases Mild 1 Epigastralgia Mild 5 ced menstrual pain, premenstrual pain and intramenstrual pain Epigastralgia Moderate 6 in a placebo-controlled study of patients presenting with pri- Flatulence Severe 1 mary dysmenorrhea20. The analgesic efficacy of oral treatment Flatulence Moderate 1 Headache Mild 1 Hiccoughs Mild 1 Inappetence Mild 2 faster onset in relation to treatment with paracetamol and bu- Insomnia Moderate 1 tylscopolamine21. Hernandéz-Bueno et al. (1998) also reported Meteorism Moderate 1 therapeutic efficacy of lysine clonixinate in combination with Nausea Mild 11 Nausea Moderate 4 Photophobia Moderate 1 with 125 mg lysine clonixinate was compared with that of a Pyrosis Mild 4 combination of paracetamol 125 mg and codeine 30 mg, and Pyrosis Moderate 2 both treatments were reported to be equally effective in re- Somnolence Moderate 3 Somnolence Mild 1 Vertigo Mild 1 Vomiting Mild 1 Number of Affected Subjects Data are n. In patients undergoing dental surgery, administration of third molar, as compared to metamizole (500 mg) and paracetamol (750 mg); the authors reported comparable analgesic efficacy among the three medications19. Oral administration of lysine clonixinate significantly redu- of dysmenorrheic subjects at a dose of 125 mg in combination with propinox was reportedly comparable to treatment with paracetamol (500 mg) in combination with butylscopolamine (10 mg). However, the analgesic effect of lysine clonixinate had a butylscopolamine in the treatment of the signs and symptoms associated with primary or secondary dysmenorrhea22. In a study of post-episiostomy analgesia, oral treatment ducing mild to moderate pain23. In another study of patients who had undergone inguinal hernioplasty, the same authors compared the analgesic efficacy of the same two treatments, reporting similar efficacy between the treatment groups24. Cayetti et al. (1995) reported anti-inflammatory and analgesic superiority of lysine clonixinate over aspirin in the treatment of patients with gonarthrosis25. Additionally, treatment of patients presenting gonarthrosis using 125 mg lysine DISCUSSION In this study, the use of lysine clonixinate was evaluated in the treatment of several different types of painful conditions: arthralgia, headache, post-traumatic pain, dysmenorrhea, abdominal colic, biliary colic, and myalgias. The results obtained in terms of efficacy in pain relief and tolerability are similar to those previously reported in the literature. Lysine clonixinate has been evaluated in the clinical setting for the treatment of several painful conditions. In the treatment of headaches, oral or intravenous therapy using lysine clonixinate resulted in analgesia within one hour of administration6. Oral administration of lysine clonixinate (125 mg) was superior to placebo in the treatment of patients presenting with headache15. The analgesic efficacy of lysine clonixinate (at a dose of 250 mg) was compared with that of naproxen (550 mg) in patients presenting with headache, and equivalent analgesic action between the two drugs was reported16. Intravenous administration of 200 mg lysine clonixinate was superior to metamizole (dipirone) (1 g) in pain relief among patients presenting with headache, in addition clonixinate three times daily was found to be comparable in efficacy compared to thrice daily treatment with 400 mg ibuprofen26. Lysine clonixinate was also reported to be effective in the treatment of swelling caused by ankle sprains at a daily dose of 300 mg27. Lysine clonixinate has been considered well-tolerated, though previous studies have reported adverse effects similar to those we report in this study18,26-30. As with other members of the NSAID class of therapeutics, gastrointestinal side effects are the most commonly reported adverse reaction to lysine clonixinate therapy. These include nausea, epigastric pain, vomiting, flatulence, pyrosis, and changes in bowel function. Adverse effects affecting the nervous system have also been reported, including headache, dizziness, insomnia, and somnolence. CONCLUSION Treatment of painful conditions with lysine clonixinate was effective and safe, reducing pain and improving overall condition of the treated subjects. RFM - Rev Flu Med 2014;78-79(2):4-10 8 MIBIELLI et al. Percentage of subjects Post-treatment VAS pain score reductions 100 80 60 40 20 pa ic m at tr au t Po s ec nf N on -i in a ra l th ar tio us H ys D Ab gi a M ea d ya l ac gi he he a m en or r ry Bi lia do m in al co lic co lic 0 Pain Type VAS reduction < 50 mm VAS reduction ≥ 50 mm Figure 1 – VAS pain score reductions at Assessment 2 in relation to pretreatment values. Patient and phisician overall assessment scores Number of subjects 120 100 80 Pretreatment patient 60 Pretreatment physician 40 Post-treatment patient 20 Post-treatment physician 0 1 2 3 4 5 6 7 8 Assessment scores Figure 2 – Overall Assessment scores at pre- and post-treatment. RFM - Rev Flu Med 2014;78-79(2):4-10 9 10 Clinical-Therapeutic Assessment of the Use of Lysine Clonixinate in the Treatment of Conditions in which Pain is a Present and Important Symptom 9 Overall efficacy and safety evaluation Number of subjects 140 120 100 80 60 Overall efficacy 40 Overall tolerability 20 Po or le ab oo d G pt ce Ac Ve r y go od 0 Figure 3 – Physician’s overall Assessment of efficacy and safety performed at Assessment 2. Conflict of interest There is no conflict of interest to declare. Acknowledgements The authors would like to thank Daiane Bergamim, Flavia Kuperman and Renata Kuperman for data management, as well as Natasha Cytrynbaum and Silvia Maciel for CRF and record verification. 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