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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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