DRUG DEVELOPMENT RESEARCH 66:36–39 (2006)
A B-Vitamin Mixture Reduces the Requirements of
Diclofenac After Tonsillectomy: A Double-Blind Study
and Francisco Javier Flores-Murrieta
´n de Estudios de Posgrado e Investigacio
´n, Escuela Superior de Medicina del Instituto
´cnico Nacional, Mexico City, Mexico
Instituto Nacional de Enfermedades Respiratorias, Secretarı´a de Salud, Mexico City, Mexico
Departamento de Farmacobiologı´a, Centro de Investigacio
´n y de Estudios Avanzados del Instituto
´cnico Nacional, Mexico City, Mexico
Strategy, Management and Health Policy
ABSTRACT Pain observed after tonsillectomy is often severe and frequently requires the use of opioid
analgesics. Non-steroidal anti-inﬂammatory drugs (NSAIDs) may reduce the need or avoid the use of
opioids, but gastrointestinal side effects may limit their use. Sparing analgesic agents may reduce the
requirement for NSAIDs and consequently their toxicity. It has been proposed that a B-vitamin mixture
produces analgesia in experimental pain models. The present study was carried out to establish if a
B-vitamin mixture was additive with the NSAID, diclofenac, in the treatment of postquirurgic pain. Two
groups of 20 subjects, participated in the study. Group 1 received a B-vitamin mixture infusion for 12 h
before the tonsillectomy, whereas Group 2 received vehicle. Both groups received a 50-mg diclofenac i.v.
8 h before surgery. Two hours after tonsillectomy, Group 1 received another B-vitamin mixture infusion for
12 h and Group 2 again received vehicle. Pain intensity was evaluated by a visual analog scale (VAS). Then
diclofenac (50 mg i.v.) was administered as required by the patient without exceeding 150 mg daily.
Diclofenac consumption was recorded and VAS was evaluated for 54 h. Group 1 exhibited a lower pain
intensity 2 h after tonsillectomy. Both groups showed similar analgesia. However, diclofenac consumption
was approximately 30% lower in the group treated with the B-vitamin mixture. These results indicate that
B vitamins can spare the use of analgesic agents. Drug Dev. Res. 66:36–39, 2006. c2006 Wiley-Liss, Inc.
Tonsillectomy is one of the most frequently
performed throat surgeries in adults and is associated
with severe pain, and in some cases bleeding,
protracted vomiting, and subsequent dehydration
[Maniglia et al., 1989; Reiner et al., 1990; Richmond
et al., 1987]. Very often, management of pain after this
surgery is inadequate, since side effects associated with
the use of opioids, such as emesis, excessive sedation,
and risk of respiratory depression, can limit their use.
Due to the side effects of opioid drugs, it has been
proposed that non-steroidal anti-inﬂammatory drugs
(NSAIDs) can reduce or even eliminate the need for
post-operative opioids [Nordbladh et al., 1991; Souter
et al., 1994; Saarnivaara et al., 1980]. However,
gastrointestinal or renal side effects can occur.
Additionally, the use of NSAIDs is contraindicated
Published online in Wiley InterScience (www.interscience.wiley.
com). DOI: 10.1002/ddr.20036
Received 10 October 2005; Accepted 30 October 2005
Correspondence to: Francisco J. Flores-Murrieta, PhD,
Unidad de Investigacio
´n, Instituto Nacional de Enfermedades
Respiratorias, SSA, Calz. De Tlalpan 4502, Col. Seccio
´xico, D.F, Mexico.
E-mail: fjﬂoresmurrieta@prodigy.net.mx; fjﬂoresmurrieta@yahoo.
c2006 Wiley-Liss, Inc.
during the surgery since they are able to prolong
the bleeding time by inhibiting the biosynthesis of
and they can increase blood loss
during and after surgery [Kam and See, 2000].
In order to reduce the requirements of NSAIDs
and, consequently, the risk of toxicity associated with
their use, it is desirable to combine them with analgesic
adjuvants. A B-vitamin mixture (thiamine, piridoxine,
and cyanocobalamin) can produce analgesic effects in
several experimental pain models [Jurna et al., 1990;
Reyes-Garcia et al., 2001, 2002], and can increase the
antinociceptive effect of diclofenac [Bartoszyk and
Wild, 1989; Jurna, 1998]. Moreover, several clinical
trials have suggested that the use of diclofenac plus a
B-vitamin mixture provides more effective pain relief
than treatment with diclofenac alone [Bruggemann
et al., 1990; Kuhlwein et al., 1990]. Additionally, a
combination of diclofenac with a B-vitamin mixture,
instead of diclofenac alone, can shorten the duration of
treatment of painful osteoarticular syndromes [Vetter
et al., 1988]. To assess the possible use of this
combination in severe pain, a comparison between
diclofenac alone or combined with a B-vitamin mixture
was carried out in adult patients with post-surgery pain
MATERIALS AND METHODS
This randomized, double-blind study was ap-
proved by the Institutional Research and Ethics
Committees of the Instituto Nacional de Enferme-
dades Respiratorias Hospital and the study was carried
out following the recommendations of the Declaration
of Helsinki. After obtaining written, informed consent,
40 patients were studied, undergoing elective tonsil-
lectomy, allocated randomly to one of two groups of
equal size. Demographic data on the patients are
shown in Table 1. Patients with a history of allergic
reactions to NSAIDs, thiamine, pyridoxine or cyano-
cobalamin, NSAIDs-induced asthma, kidney or liver
dysfunction, gastrointestinal ulceration, or bleeding
disorders were excluded from the study.
A standardized anesthetic technique was used,
consisting of the administration of a combination of
propofol 5 mg/kg, Diprivan
hydrochloride 2 mg/kg, Fentanest
vacuronium bromide 200 mg/kg, and Norcuron
non). Sevoﬂurane (Sevorane
, Abbott) was adminis-
tered by inhalation and dosage was adjusted according
to patient requirements.
Patients in the group of the combination of
diclofenac–B-vitamin mixture received an infusion of
100 mg of thiamine, 100 mg pyridoxine, and 5 mg
cyanocobalamin (Merck, S.A. de. C.V) in 500 ml of
isotonic saline solution for a period of 12 h prior
to surgery; 8 h before the beginning of the surgery,
both groups received an intravenous dose of 50 mg
of diclofenac. Two hours after the end of the surgery
(mean time of surgery was 1.5–2 h), upon recovery
from anesthesia, patients were evaluated in order to
establish the pain level using a visual analogue scale
(VAS). Patients were asked to score pain on a 10-cm
horizontal line on a paper sheet that had the words ‘‘no
pain’’ and ‘‘worst imaginable pain’’ at its left and right
Once the pain levels were known, both groups
received diclofenac (50 mg i.v.), and the group
pretreated with the B-vitamin mixture received another
infusion of thiamine 100 mg, pyridoxine 100 mg, and
cyanocobalamin 5 mg for a 12-h period, whereas the
other group received vehicle.
The pain level was evaluated at 2, 6, 10, 14, 18,
22, 26, 30, 38, 46, and 54 h after surgery, and additional
doses of diclofenac (50 mg, i.v.) were given to the
patients on demand, without exceeding the maximal
daily dose recommended (150 mg). If pain was not
controlled 2 h after diclofenac administration, patients
received rescue treatment with morphine.
Patients were discharged 54 h after surgery when
they had no or mild pain, were able to tolerate clear
ﬂuids and soft food, had no bleeding, and had no
nausea or vomiting.
Statistical analysis of VAS was performed by two-
way analysis of variance followed by the Tukey’s test.
Diclofenac consumption was compared by the Stu-
dent’s t-test. Differences were considered statistically
signiﬁcant when the Po0.05.
Patient characteristics are shown in Table 1.
There were no violations to the protocol that may have
interfered with the study variables. No patients were
withdrawn from the study.
A statistically signiﬁcant difference in VAS 2 h
after surgery was observed between the groups. A
lower VAS was observed in the group that was
TABLE 1. Patients and Surgery Characteristics
group (n 520)
mixture group (n 520)
Sex (male/female) 8/12 12/8
Age (years) 35.44 (9.95) 38.28 (11.40)
Height (cm) 163.33 (4.58) 162.95 (7.28)
Weight (kg) 73.22 (14.27) 71.15 (10.20)
Duration of surgery (min) 90.88 (25.69) 107.50 (18.01)
Data are expressed as mean (SD). There were no signiﬁcant
differences between studied groups.
37B-VITAMIN DICLOFENAC MIXTURE IN TONSILLECTOMY PAIN
Drug Dev. Res. DOI 10.1002/ddr
premedicated with the B-vitamin mixture compared to
that treated with vehicle. However, after post-surgery
diclofenac administration, VAS values were similar in
both groups (Fig. 1).
Both treatments were effective and well toler-
ated, since no rescue medication was required and
no side effects were observed. An interesting result
obtained is that, although similar analgesia was
obtained after 6 h of tonsillectomy, the diclofenac
required by the patients for adequate pain control
was signiﬁcantly lower in the group that was comedi-
cated with the B-vitamin mixture, 29772.8 versus
197.5710.6 mg, indicating that the B-vitamin mixture
can spare analgesic drug usage (Fig. 2).
In this study, a comparison of the analgesic effect
of diclofenac alone or combined with the B-vitamin
mixture after tonsillectomy was evaluated. Both treat-
ments were well tolerated, with no side effects reported
and were effective, as both treatments exhibited a
similar efﬁcacy. Importantly, none of the subjects
needed the use of rescue medication. It has been
established that a B-vitamin mixture is able to produce
analgesic activity, mainly when they are given in
combination [Jurna, 1998] and several mechanisms
have been proposed to explain their analgesic activity.
Among these are: the B-vitamin mixture increases the
availability and/or effectiveness of norepinephrine and
5-HT acting as inhibitory transmitters in the nocicep-
tive system [Zimmermann et al., 1990]; Reyes-Garcı
et al.  have shown that the B-vitamin effect
could be inhibited by administration of naloxone and
L-NAME, indicating that an opioid mechanism as well
as nitric oxide release are involved in the antinocicep-
tive effect of the B-vitamin mixture. There is some
controversy regarding the analgesic effects of infused
B-vitamins. Bromm et al.  reported that B-
vitamins are unable to either produce an analgesic
activity by themselves or increase the analgesic activity
of diclofenac. However, Bruggemann et al. 
reported that B-vitamins increased the analgesic
activity of diclofenac and Kuhlwein et al.  noted
that B-vitamins reduced the consumption of diclofenac
in the treatment of acute pain of the lumbar vertebrae.
In order to establish if diclofenac plus a B-vitamin
mixture is adequate in the management of post-
operative pain, this combination was evaluated in the
treatment of pain after tonsillectomy, a surgery that
frequently is associated with severe pain. The results
indicate that this combination is effective in the
treatment of this kind of pain, reducing the use of
diclofenac. Consequently, the risk of gastrointestinal
side effects may also be reduced as these side effects
are dose-dependent [Moote, 1992].
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VISUAL ANALOG SCALE (cm)
Fig. 1. Visual analogue scale (VAS) obtained after tonsillectomy in
the patients that received diclofenac alone (open circles) or those that
received the combination of diclofenac1B vitamins (closed circles).
Data are expressed as mean7s.e.m. of 20 patients per group.
Po0.05 by Tukey’s test.
DIC. ALONE DIC. + B VITS.
Fig. 2. Diclofenac administered to the patients during the 54 h
following the tonsillectomy in the groups treated with diclofenac alone
or combined with B vitamins. Data are expressed as mean7s.e.m.
Po0.001 by Student’s t-test.
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39B-VITAMIN DICLOFENAC MIXTURE IN TONSILLECTOMY PAIN
Drug Dev. Res. DOI 10.1002/ddr