Original Article 289

Authors

M. C. Magaa-Villa1, H. I. Rocha-Gonzlez2, C. Fernndez del Valle-Laisequilla2, V. Granados-Soto3,

J. Rodrguez-Silverio2, F. J. Flores-Murrieta2, 4, M. C. Carrasco-Portugal4, J. G. Reyes-Garca2

Aliations

Aliation addresses are listed at the end of the article

Key words
analgesia

osteoarthritis

B vitamins

diclofenac

inflammatory pain

Abstract

received 28.10.2012
accepted 08.02.2013
Bibliography
DOI http://dx.doi.org/
10.1055/s-0033-1334963
Published online:
March 22, 2013
Drug Res 2013;
63: 289292
Georg Thieme Verlag KG
Stuttgart New York
ISSN 2194-9379
Correspondence
J. G. Reyes-Garca, MD, PhD
Seccin de Estudios de
Posgrado e Investigacin
Escuela Superior de Medicina
Instituto Politcnico Nacional
Plan de San Luis y Daz Mirn s/n
Col. Casco de Santo Tomas
Del. Miguel Hidalgo
11340 Mxico, D.F.
MEXICO
Tel.: + 52/55/2138 3602
Fax: + 52/55/5665 4623
juangreyesgarcia@yahoo.com.mx

According to the high consumption of the mixture of B vitamins and diclofenac in several
countries, this combination has constituted a
frequently used option in pain therapy from
inflammatory origin. Although the evidence
obtained from inflammatory pain animal models has shown the existence of analgesic synergy
between diclofenac and the B vitamins mixture,
the corresponding clinical evidence is scarce. A
double-blind, randomized clinical trial study
was designed to characterize the analgesic eect
and safety of diclofenac and B vitamins against
diclofenac alone in patients with severe osteoarthritis. Forty eight patients programmed to

Introduction

Diclofenac is a non-steroidal anti-inflammatory

drug (NSAID) that has shown to be eective for
relieving pain in rheumatic and non-rheumatic
diseases from inflammatory origin [1, 2]. This
drug produces an eective analgesia mainly in
pain of moderate intensity, although produces
several adverse events that limit its use such as
mucosal irritation and ulcers in the gastrointestinal tract [3]. On the other hand, B vitamins are
normally used to treat the symptoms associated
with their own deficiencies [4]; however, in some
countries they have also been broadly and empirically utilized in combination with diclofenac, for
the treatment of several inflammatory painful
conditions, with the intention to improve its
analgesic profile [5].
Evidence obtained from inflammatory pain animal models including uric acid-induced pain [6],
formalin-induced pain [7, 8] and carrageenaninduced thermal hyperalgesia [9] have shown the
existence of analgesic synergy between sodium
diclofenac and the mixture of thiamine, pyridox-

total knee arthroplasty with a pain level 7 in

a 110 cm visual analogue scale were allocated
to receive a single intramuscular injection of
sodium diclofenac (75 mg) alone or combined
with thiamine (100 mg), pyridoxine (100 mg)
and cyanocobalamin (5 mg), and the pain level
was evaluated during 12 h post-injection.
Diclofenac + B vitamins mixture showed a superior analgesic eect during the assessed period
and also a better assessment of the pain relief
perception by patients than diclofenac alone.
This study constitutes a clinical support on the
improvement of the analgesic eect of diclofenac
by B vitamins in patients with osteoarthritis programmed to total knee arthroplasty, as a clinical
model of inflammatory pain.

ine and cyanocobalamin. Notwithstanding, the

corresponding clinical evidence on the ecacy
and safety of this combination is both scarce and
indirect.
In a recent study in post-surgery patients after
tonsillectomy, administration of i. v. diclofenac,
under requirement by patients, combined with
saline or a mixture of vitamins B1, B6 and B12
produced similar pain relief in both groups. However, a significant reduction in diclofenac consumption in patients treated with B vitamins was
observed, which constitute indirect evidence of
the analgesic synergy of diclofenac and B vitamins [10].
Several clinical reports are mainly related with
the assessment of the comparative ecacy of
diclofenac alone or combined with vitamins B1,
B6 and B12 in low back or cervical mixed pain
(i. e., inflammatory and neuropathic). These studies are clearly addressed to take advantage of the
potential anti-neuritic eects of B vitamins,
rather than to explore the possible analgesic synergy on clinical inflammatory pain models [1114].
Recently, a study was performed to compare the

Magaa-Villa MC et al. Diclofenac/B vitamins in arthritic pain Drug Res 2013; 63: 289292

Downloaded by: The University of Manchester Library. Copyrighted material.

B-vitamin Mixture Improves the Analgesic Eect of

Diclofenac in Patients with Osteoarthritis: A Double
Blind Study

290 Original Article

ecacy of diclofenac alone or combined with B vitamins in

patients with lower limb fracture and surgery showing that the
addition of B vitamins to diclofenac increased its analgesic eect
[15]. Notwithstanding, further studies in other inflammatory
diseases are necessary to confirm the therapeutic potential of
this combination.
Osteoarthritis is a degenerative joint disease caused by gradual
loss of cartilage resulting in the development of bony spurs and
cysts at the margins of the joints [16]. In severe cases, complete
loss of cartilage cushion causes friction between bones and
intense inflammatory pain at rest or pain with limited motion,
which tend to require joint replacement surgery as treatment
[17]. Thus, osteoarthritis in patients programmed to total knee
arthroplasty was thought as a proper clinical inflammatory
model to assess the potential synergistic analgesic eect of the
combination between diclofenac and B vitamins.

Table 1 Demographic data.

Characteristic
Sex (male/ female)
Age (years)
Height (cm)
Weight (Kg)

Diclofenac alone

Diclofenac + B Vitamins

(n = 24)

(n = 24)

7/17
65.6 3.1
161.8 1.5
70.5 2.8

9/15
61.2 1.8
157.6 1.5
74.4 1.7

Data are expressed as mean S.E.M. There were no significant dierences between
studied groups by the 2 test (sex) or Students t test (age, height and weight)

words no pain and worst imaginable pain at its left and right
ends, respectively. After this, patients were asked to score their
pain relief on a visual Lickert scale as none, mild, moderate
or complete. Adverse events reported by patients were also
recorded.

Subjects
To determine whether B vitamin complex improved preoperative analgesic profile of diclofenac in patients with osteoarthritis
programmed to total knee arthroplasty, 48 patients (24 males
and 24 females) with severe osteoarthritis and pain level 7
were recruited 48 h before surgery to perform a double-blind
and randomized clinical trial study. All patients included in the
current study were being treated with 500 mg of paracetamol
every 8 h before starting the study. A comparison of the demo Table 1. All subjects
graphic data of the volunteers is shown in
were healthy according to a medical history, clinical examination and suitable laboratory tests. Patients with a history of
allergic reactions to NSAIDs, thiamine, pyridoxine or cyanocobalamin, NSAIDs-induced asthma, kidney or liver dysfunction,
gastrointestinal ulceration, bleeding disorders or diabetes were
excluded from the study. This study was carried out following
the recommendations of the latest version of the World Medical
Association Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects [18]. All participants
read the protocol, which was approved by the Institutional
Research and Ethics Committees of the Hospital de Ortopedia
Magdalena de las Salinas (Mexico, Distrito Federal), and provided written informed consent for their participation in the
study.

Study design
After obtaining written informed consent, patients were randomly allocated to one of 2 groups, 48 h before the programmed
surgery to receive a single intramuscular injection of sodium
diclofenac (75 mg) alone or combined with thiamine (100 mg),
pyridoxine (100 mg) and cyanocobalamin (5 mg). A high dose of
cyanocobalamin was used in the current study since preclinical
studies show that B-vitamin complex in a 100:100:5 proportion
has a greater synergistic antinociceptive interaction with nonsteroidal anti-inflammatory drugs than 100:100:1 proportion of
B1, B6 and B12, respectively [19]. In addition, it seems that
cyanocobalamin is the most eective vitamin in the B vitamin
complex [20, 21]. Both formulations were provided by Merck,
S.A. de C.V. (Naucalpan de Juarez, Mexico). The pain level in
patients was evaluated at 0, 0.5, 1, 2, 4, 6, 8 and 12 h post-injection. Pain measurements were done by using a visual analogue
scale (VAS) on a 10-cm horizontal line paper sheet that had the

Data were grouped by treatment. Potential dierences of demographic data between groups were assessed by the Student
t-test or 2 test. Statistical analysis of the time-course VAS values
was performed by 2-way analysis of variance followed by the
Tukeys test. Area under the curve (AUC) values were calculated
by the trapezoidal rule and assessed by Students t-test. Patient
perception of global assessment of pain relief was evaluated by
the 2 test. Dierences were considered statistically significant
when P < 0.05.

Results

Demographic data
Table 1.
Demographic data on the patients are shown in
Diclofenac and diclofenac plus B vitamins groups resulted equilibrated regarding treatment, sex, age, weight and height variables. There were no violations to the protocol that may have
interfered with the study variables. No patients were withdrawn
from the study.

Ecacy and safety of diclofenac plus B vitamins against

diclofenac alone
Baseline mean VAS pain scores were 8.04 0.18 cm for diclofenac
and 7.87 0.20 cm for the mixture of diclofenac plus B vitamins.
Both treatments produced a gradual reduction of VAS pain values until the 12th h, but the time course of the group treated
with diclofenac plus B vitamins showed a significant better profile than the diclofenac alone group. Thus, treatment with
diclofenac plus B vitamins produced a significant reduction of
VAS pain score (P 0.05 by 2-way analysis of variance with
repeated measures, followed by the Tukeys test) starting at 0.5 h
and finishing 12 h later with a score of 1.41 0.35 cm, while
treatment with diclofenac alone started until the first hour, with
Fig. 1). Concordantly,
a final 12th h score of 3.66 0.17 cm (
mean areas under the VAS values against time curve, a measure
of global pain condition of patients during the 12 h period,
resulted significantly lower (P 0.05 by Students t-test) in the
group medicated with the combination of diclofenac plus B vitamins mixture compared to the group treated with diclofenac
alone, 34.5 3.97 cm/h vs. 60.65 1.65 cm/h, respectively.
The global profile of pain relief perception favored to the group
treated with the combination. A significant greater number of
patients under treatment with diclofenac plus B vitamins

Magaa-Villa MC et al. Diclofenac/B vitamins in arthritic pain Drug Res 2013; 63: 289292

Downloaded by: The University of Manchester Library. Copyrighted material.

Data analysis
Patients and Methods

Fig. 1 Time course of visual analogue pain scale (VAS) obtained during
12 h in patients that received either diclofenac alone (black circles) or diclofenac + B vitamins mixture (white circles) 48 h before to be submitted a
total knee arthroplasty. Data are expressed as mean S.E.M. *Significantly
dierent from respective baseline value at time 0 and #significantly dierent between groups at the same time (p < 0.05), as determined by 2-way
analysis of variance with repeated measures, followed by the Tukeys test.

Table 2 Pain relief perception after 12 h of the intramuscular administration

of diclofenac alone or combined with B vitamins.
Pain relief percep-

Diclofenac alone

Diclofenac +

tion by patients

(n = 24)

B Vitamins (n = 24)

None
Mild
Moderate
Complete

1
6
14
3

0
2
10
12*

Data are expressed as frequencies. *Statistically dierent from the diclofenac alone
group by the 2 test, p < 0.05

perceived a complete pain relief (12) in comparison with patients

Table 2). Both treatments
treated with diclofenac alone (3) (
were well tolerated, since patients only reported mild to moderate pain during injection.

Discussion

Besides of its demonstrated ecacy in reducing pain in rheumatic and non-rheumatic diseases [1, 2], in several countries
diclofenac has been broadly used in combination with thiamine,
pyridoxine and cyanocobalamin as intent to improve its analgesic profile. However, direct evidence on the positive analgesic
interaction of these drugs in clinical inflammatory models is
scarce.
In this study, a single injection of i.m. 75 mg diclofenac produced
a gradual reduction of pain in patients programmed to total
knee arthroplasty, which resulted statistically significant from
the first hour to the 12th h post-injection. Our results agree with
previous observations about the ecacy of diclofenac in the oral
treatment of patients with osteoarthritis [22, 23]. However, the
mixture of 75 mg diclofenac plus 100 mg vitamin B1, 100 mg
vitamin B6 and 5 mg vitamin B12 produced a better profile to
reduce pain than diclofenac alone. Diclofenac plus vitamin B
produced a significantly better pain relief in comparison with
diclofenac alone, from the 0.5 h to the 12th h post-injection. The

improved eect of diclofenac plus B vitamins was confirmed by

the significant lesser areas under the VAS values against time
curve respect to diclofenac alone. It is fair to say that this parameter give us a measure of the duration and intensity pain suffered by patients during the 12 h period of the study. Likewise, a
better global profile of pain relief perception of patients was
observed, with a significant higher number of patients treated
with diclofenac plus B vitamins considering a complete pain
relief after 12 h of treatment. These data provides direct evidence that the combination of diclofenac plus B vitamins is better in the inflammatory pain relief than diclofenac alone.
Our results agree with previous observations showing the existence of a synergistic analgesia between oral diclofenac and B
vitamins in rodents [69]. Likewise, several clinical reports
including comparisons of diclofenac alone or combined with B
vitamins, in terms of duration of therapy in mixed [1114], and
inflammatory pain models [15], or spare analgesic drug usage as
outcome measures in inflammatory models [10] have favored to
the combination diclofenac plus B vitamin mixture therapy.
The better analgesic profile of diclofenac plus B vitamin mixture
therapy vs. diclofenac alone to reduce the inflammatory pain
could be related to the dierent action mechanisms of the drugs.
In the case of diclofenac, there is evidence that this drug produces mainly its antinociceptive eect through the inhibition of
cyclooxygenases 1 and 2 [22, 24]. In addition, other observations
suggest that diclofenac could activate the nitric oxide-cyclic
GMP-K + channel pathway, inhibits the thromboxane-prostanoid
receptor, decreases release and reuptake of arachidonic acid,
inhibits lipoxygenase enzymes, inhibits peroxisome proliferator
activated receptor gamma, blockages acid-sensing ion channels,
reduces interleukin-6 production, and inhibits N-methyl-Daspartate receptors in order to reduce pain in the rat [2527]. On
the other hand, several mechanisms have been proposed to
explain the potential analgesic activity of B vitamins, including
increases on the availability and/or eectiveness of norepinephrine and 5-HT acting as inhibitory transmitters in the nociceptive system [28]. Moreover, it has been reported that the
B-vitamin mixture eect could be due to the activation of an
opioid mechanism as well as nitric oxide release, since administration of naloxone and L-NAME are able to inhibit the antinociceptive eect of the B-vitamin mixture in rodents, as well as,
reduction of free radicals [5, 29].
Although our results suggest a potential acute synergy on the
analgesic eect of diclofenac, induced by the B vitamins mixture, on the basis of the present results we cannot discard a simple additive interaction. On the same way, other design study
could be needed to assess if B vitamin mixture is able to enhance
the analgesic ecacy of diclofenac.
In summary, our data give direct evidence that the combination
of diclofenac plus B vitamins produces both a significantly
greater reduction of pain and a significantly better pain relief
patient perception than diclofenac alone in patients with osteoarthritis programmed to total knee arthroplasty. Data indicate
that the combination of diclofenac and B vitamins could be a
better option than diclofenac alone in the treatment of osteoarthritis and other inflammatory pain conditions. However, larger
double-blind clinical trials are needed to confirm this possibility.

Magaa-Villa MC et al. Diclofenac/B vitamins in arthritic pain Drug Res 2013; 63: 289292

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Original Article 291

Acknowledgments

Authors kindly acknowledge Merck, S.A. de C.V., Naucalpan de

Juarez, Mexico for the formulations gifted in this study.

Conflict of Interest

Authors declare that there is no conflict of interest.

Aliations
Hospital de Ortopedia Magdalena de las Salinas, Instituto Mexicano del
Seguro Social, Mexico City, Mexico
2
Seccin de Estudios de Posgrado e Investigacin, Escuela Superior de
Medicina, Instituto Politcnico Nacional, Mexico City, Mexico
3
Departamento de Farmacobiologa, Cinvestav, Sede Sur, Mexico City,
Mexico
4
Instituto Nacional de Enfermedades Respiratorias, Secretara de Salud,
Mexico City, Mexico
1

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Magaa-Villa MC et al. Diclofenac/B vitamins in arthritic pain Drug Res 2013; 63: 289292

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292 Original Article