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B-vitamin Mixture Improves the Analgesic Effect of Diclofenac in Patients with Osteoarthritis: A Double Blind Study

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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 effect and safety of diclofenac and B vitamins against diclofenac alone in patients with severe osteoarthritis. Forty eight patients programmed to total knee arthroplasty with a pain level ≥7 in a 1-10 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 effect 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 effect of diclofenac by B vitamins in patients with osteoarthritis programmed to total knee arthroplasty, as a clinical model of inflammatory pain.
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DRUG DEVELOPMENT RESEARCH 66:36–39 (2006)
Research Article
A B-Vitamin Mixture Reduces the Requirements of
Diclofenac After Tonsillectomy: A Double-Blind Study
Roberto Medina-Santilla
´n,
1
Eusebio Pe
´rez-Flores,
2
Eduardo Mateos-Garcı
´a,
1
Gerardo Reyes-Garcı
´a,
1
Vinicio Granados-Soto,
3
and Francisco Javier Flores-Murrieta
1,2
1
Seccio
´n de Estudios de Posgrado e Investigacio
´n, Escuela Superior de Medicina del Instituto
Polite
´cnico Nacional, Mexico City, Mexico
2
Instituto Nacional de Enfermedades Respiratorias, Secretarı´a de Salud, Mexico City, Mexico
3
Departamento de Farmacobiologı´a, Centro de Investigacio
´n y de Estudios Avanzados del Instituto
Polite
´cnico Nacional, Mexico City, Mexico
Strategy, Management and Health Policy
Enabling
Technology,
Genomics,
Proteomics
Preclinical
Research
Preclinical Development
Toxicology, Formulation
Drug Delivery,
Pharmacokinetics
Clinical Development
Phases I-III
Regulatory, Quality,
Manufacturing
Postmarketing
Phase IV
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.
INTRODUCTION
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
DDR
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
´n XVI,
14080 Me
´xico, D.F, Mexico.
E-mail: fjfloresmurrieta@prodigy.net.mx; fjfloresmurrieta@yahoo.
com.mx
c2006 Wiley-Liss, Inc.
during the surgery since they are able to prolong
the bleeding time by inhibiting the biosynthesis of
thromboxane A
2
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
after tonsillectomy.
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
s
(Astra-Zeneca), fentanyl
hydrochloride 2 mg/kg, Fentanest
s
(Janssen-Cilag)
vacuronium bromide 200 mg/kg, and Norcuron
s
(Orga-
non). Sevoflurane (Sevorane
s
, 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
ends, respectively.
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.
RESULTS
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
a
Diclofenac alone
group (n 520)
Diclofenac1B vitamins
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)
a
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).
DISCUSSION
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
´a
et al. [2002] 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. [1995] 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. [1990]
reported that B-vitamins increased the analgesic
activity of diclofenac and Kuhlwein et al. [1990] 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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TIME (h)
0183654
VISUAL ANALOG SCALE (cm)
0
2
4
6
8
*
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).
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TOTAL DICLOFENAC
ADMINISTERED (mg)
0
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200
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DIC. ALONE DIC. + B VITS.
*
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39B-VITAMIN DICLOFENAC MIXTURE IN TONSILLECTOMY PAIN
Drug Dev. Res. DOI 10.1002/ddr
... Con el fin de optimizar la intervención analgésica en las patologías osteomusculares y evaluar el potencial adyuvante, varios estudios se han centrado en el análisis de las terapias combinadas de las vitaminas B (TPC) con este tipo de medicamentos, para evaluar su potencial como analgésico adyuvante. En el caso de pacientes con osteoartritis severa de rodilla y fractura de miembros inferiores, se han reportado niveles de analgesia más elevados evaluados mediante las escalas VAS y Likert en pacientes que recibían la combinación TPC con diclofenaco en comparación con monoterapia con AINE 36,40,137 . Magaña-Villa et al. realizaron un estudio que tuvo como objetivo caracterizar el efecto analgésico y la seguridad de la monoterapia con diclofenaco y la combinación entre este medicamento y el complejo de vitaminas B (TPC) en pacientes con osteoartritis severa de rodilla. ...
... Magaña-Villa et al. realizaron un estudio que tuvo como objetivo caracterizar el efecto analgésico y la seguridad de la monoterapia con diclofenaco y la combinación entre este medicamento y el complejo de vitaminas B (TPC) en pacientes con osteoartritis severa de rodilla. En este estudio aleatorizado doble ciego, se evaluaron 48 pacientes con un dolor mayor o igual a 7 en la escala VAS, cuyo resultado determinó que la terapia combinada mostró mejores resultados analgésicos tras 12 horas de la administración parenteral 137 . Un efecto similar se evidencia en un estudio prospectivo, aleatorizado y doble ciego realizado por Ponce-Monter et al. en el 2012, en el que se evaluó la eficacia del diclofenaco como monoterapia y en combinación con TPC intramuscular en 122 pacientes quirúrgicos y con dolor agudo producto de fractura de miembros inferiores. ...
Article
Full-text available
Resumen El dolor lumbar, así como otras alteraciones musculoesqueléticas (cervicalgia, artrosis, etc.), son causa muy frecuente de consulta tanto en atención primaria como en otras especialidades hospitalarias y suelen asociarse con una alta discapacidad funcional y laboral. La lumbalgia aguda puede presentar diferentes componentes nociceptivos, neuropáticos y nociplásticos, lo que lleva a considerarlo como un dolor de tipo mixto. La importancia del concepto de dolor mixto obedece a que el alivio sintomático de dichas patologías requiere un enfoque terapéutico multimodal a diversas dianas farmacológicas. Desde hace varias décadas se reconoce el papel antinociceptivo del complejo de vitaminas B, específicamente de la combinación de tiamina, piridoxina y cianocobalamina (TPC). Asimismo, hay evidencia acumulada que indica una acción analgésica adyuvante en el dolor lumbar. El objetivo de la presente revisión es presentar la evidencia existente y los últimos hallazgos sobre los efectos terapéuticos de la combinación TPC en el dolor lumbar. Asimismo, se analizan algunos de los mecanismos de acción más relevantes implicados que pueden explicar dichos efectos. La evidencia revisada indica que el uso combinado de TPC tiene un efecto adyuvante analgésico en el dolor mixto, específicamente en el dolor lumbar y otras alteraciones musculoesqueléticas con componentes nociceptivos y neuropáticos. Dicho efecto puede ser explicado por una acción antiinflamatoria, antinociceptiva, neuroprotectora y neuromoduladora de la combinación TPC sobre el sistema descendente del dolor.
... Los estudios con vitaminas B (tiamina, piridoxina y cianocobalamina [B 1 , B 6 y B 12 respectivamente]) surgieron como alternativa de tratamiento analgésico-antin amatorio, debido a su e cacia clínica en diversas enfermedades como osteoartritis, lumbalgias, dolor neuropático, etc. La mayoría de estudios clínicos con vitaminas B las han asociado con AINE (diclofenaco) o anticonvulsivantes (carbamazepina o gabapentina) 13 . Sin embargo, hace algunos años se empezaron a realizar estudios preclínicos experimentales de la asociación de un corticoide (dexametasona) con vitaminas B, y se encontraron efectos sinérgicos analgésicos, antin amatorios y antialodínicos, sin incrementar la incidencia de efectos adversos. ...
... Asimismo, coincide con lo reportado por Magaña-Villa y cols. 13 , quienes demostraron el efecto analgésico superior de la asociación de diclofenaco con vitaminas B (B 1 , B 6 y B 12 ) en pacientes con osteoartritis severa. Se ha sugerido que el efecto analgésico temprano de la asociación de dexametasona con vitaminas B se debe a que durante las primeras horas se estimula la vía del óxido nítrico-GMPc y se inhiben los canales de sodio dependientes de voltaje en la neurona aferente primaria, inhibiendo así la respuesta dolorosa [14][15][16]18,20,22 . ...
Article
Objetivo: Evaluar el efecto antinflamatorio de la administración preoperatoria de la asociación de dexametasona con vitaminas B en cirugías de tercer molar mandibular. Materiales y métodos: Estudio experimental conformado por 54 pacientes de 18-25 años, que se asignaron en dos grupos: al grupo control se le administró 4 mg de dexametasona y al grupo experimental la asociación de 4 mg de dexametasona con vitaminas B1, B6 y B12; ambos por vía intramuscular antes de la cirugía. El efecto antinflamatorio se determinó por la evaluación del dolor y la tumefacción. El dolor se evaluó mediante la escala visual análoga, el tiempo para analgesia de rescate y el consumo total de analgésicos. La tumefacción se evaluó mediante mediciones del contorno facial. Resultados: Se demostró que la intensidad máxima de dolor apareció a las 24 horas, siendo este significativamente menor en el grupo experimental (4,0 vs. 5,8 cm), p < 0,05; luego los valores fueron disminuyendo progresivamente a las 48 horas, siendo significativamente menor el valor en el grupo experimental (3,3 vs. 5,4 cm), p < 0,05. El grupo experimental demostró un mayor tiempo para analgesia de rescate (2,48 vs. 2,08 h), p > 0,05; y menor consumo de analgésicos (8,5 vs. 9,4 tab), p < 0,05. La tumefacción facial se incrementó progresivamente hasta el tercer día, sin diferencia significativa entre los grupos (45,4 vs. 46 cm), p > 0,05. Conclusiones: Se evidenció una significativa mayor actividad analgésica y un significativo menor consumo total de analgésicos en el grupo experimental en comparación con el grupo control. No se evidenció diferencia significativa en la tumefacción.
... Los estudios con vitaminas B (tiamina, piridoxina y cianocobalamina [B 1 , B 6 y B 12 respectivamente]) surgieron como alternativa de tratamiento analgésico-antinflamatorio, debido a su eficacia clínica en diversas enfermedades como osteoartritis, lumbalgias, dolor neuropático, etc. La mayoría de estudios clínicos con vitaminas B las han asociado con AINE (diclofenaco) o anticonvulsivantes (carbamazepina o gabapentina) 13 . Sin embargo, hace algunos años se empezaron a realizar estudios preclínicos experimentales de la asociación de un corticoide (dexametasona) con vitaminas B, y se encontraron efectos sinérgicos analgésicos, antinflamatorios y antialodínicos, sin incrementar la incidencia de efectos adversos. ...
... Asimismo, coincide con lo reportado por Magaña-Villa y cols. 13 , quienes demostraron el efecto analgésico superior de la asociación de diclofenaco con vitaminas B (B 1 , B 6 y B 12 ) en pacientes con osteoartritis severa. Se ha sugerido que el efecto analgésico temprano de la asociación de dexametasona con vitaminas B se debe a que durante las primeras horas se estimula la vía del óxido nítrico-GMPc y se inhiben los canales de sodio dependientes de voltaje en la neurona aferente primaria, inhibiendo así la respuesta dolorosa [14][15][16]18,20,22 . ...
... Several experimental animals and in vitro models have shown that B vitamins (including thiamine, pyridoxine, riboflavin and cobalamin) produce antinociceptive, anti-hyperalgesic, and anti-inflammatory effects and reduce mechanic allodynia [12,[27][28][29][30][31]. Similarly, it has been described that B vitamins can enhance the therapeutic effects of analgesics [32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48]. Considering that the mechanisms involved in the pathophysiology of pain are diverse, the combined use of different agents, each with own mechanisms of action, can be more effective in reducing pain in a synergistic way with lower doses and with fewer adverse effects. ...
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Pain is a complex sensory and emotional experience with nociceptive, nociplastic, and neuropathic components. An involvement of neurotropic B vitamins (B1 - thiamine, B6 - pyridoxine, and B12 - cyanocobalamin) as modulators of inflammation and pain has been long discussed. New evidence suggests their therapeutic potential in different pain conditions. In this review, we discuss the main role of neurotropic B vitamins on different nociceptive pathways in the nervous system and to describe their analgesic action mechanisms. The performed literature review showed that, through different mechanisms, these vitamins regulate several inflammatory and neural mediators in nociceptive and neuropathic pain. Some of these processes include aiming the activation of the descending pain modulatory system and in specific intracellular pathways, anti-inflammatory, antioxidative and nerve regenerative effects. Moreover, recent data shows the antinociceptive, antiallodynic, and anti-hyperalgesic effects of the combination of these vitamins, as well as their synergistic effects with known analgesics. Understanding how vitamins B1, B6, and B12 affect several nociceptive mechanisms can therefore be of significance in the treatment of various pain conditions.
... An intramuscular injection of diclofenac + B vitamin mixture showed a superior analgesic effect compared with the injection of diclofenac alone (Magaña- Villa et al., 2013). A human experiment of patients with knee OA indicated stronger analgesic property of vitamin B than vitamin E and diclofenac; the study highlighted the potential effects of vitamin B on TMD (Dehghan, 2015). ...
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Temporomandibular joint disorders (TMD) are a common health condition caused by the structural or functional disorders of masticatory muscles and the temporomandibular joint (TMJ). Abnormal mandibular movement in TMD patients may cause pain, chronic inflammation, and other discomfort, which could be relieved by a variety of drugs through various delivery systems. In this study, we summarized commonly used therapeutic agents in the management of TMD as well as novel bioactive molecules in preclinical stage and clinical trials. The emerging therapy strategies such as novel intra-TMJ delivery systems and implants based on tissue engineering are also discussed. This comprehensive review will strengthen our understanding of pharmacological approaches for TMD therapy.
... Examples of such drugs are diclofenac (Bartoszyk & Wild, 1989;Magana-Villa et al., 2013;Mibielli et al., 2009;Ponce-Monter et al., 2012), ketorolac (Beltran-Montoya et al., 2012), metamizole (Jurna, 1998) and morphine (Deng et al., 2017). However, there are no reports, to our knowledge, on the antinociceptive effect of a combination of statins and BVs. ...
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Evidence suggests that the antinociceptive activity of various drugs can be increased when administered in combination with B vitamins (BVs). The aim of this study was to examine the potential interaction between statins and BVs to counter nociception, the latter measured by the formalin test. Rats were orally administered atorvastatin (1, 3, 10 and 30 mg/kg), pravastatin (1, 3, 10 and 30 mg/kg), rosuvastatin (1, 3, 10 and 30 mg/kg), BVs (31, 56, 100 and 180 mg/kg) or calculated combinations of BVs with each drug. The effective dose 30 (ED30) was calculated for each statin and BVs and subjected to isobolographic analysis, thus finding the ED30 of the combinations. The antinociceptive experimental ED30 values for BVs administered with atorvastatin, pravastatin or rosuvastatin were 1.53 ± 0.38, 6.74 ± 0.04 and 4.26 ± 0.39, respectively, being lower (p < .05) than the corresponding theoretical ED30: 28.02 ± 2.20, 28.17 ± 2.20 and 29.86 ± 2.21. Since BVs likely boost the antinociceptive effect of statins, these combinations could possibly be advantageous in pain management.
... FPI biomarkers represent and evaluate cytokine-mediated chronic inflammation (kynurenine pathway metabolites), oxidative stress (pyroglutamic acid, ethylmalonate, and hydroxymethylglutarate), micronutrient deficiencies (methylmalonic acid, xanthurenic acid, homocysteine), and neurotransmitter turnover (5-hydroxyindoleacetic acid and vanilmandelic acid), all of which have direct links to the development, worsening, or heightened perception of pain. In addition, many of the non-opioid, biomarkermodulating compounds that would be directly indicated by the FPI test have exhibited significant pain-relieving effects in numerous randomized controlled clinical trials [28,[56][57][58][59][60][61][62]. FPI testing will facilitate and simplify patient selection for these important compounds by affording providers the ability to objectively identify patients who exhibit abnormalities and hence require metabolic correction therapies. ...
Article
IntroductionChronic pain assessment and post-treatment evaluation continues to be challenging due to a lack of validated, objective tools to measure patient outcomes. Validation of mechanistic pain biomarkers would allow clinicians to objectively identify abnormal biochemistry contributing to painful symptoms.Methods We describe the clinical validation of a multi-biomarker assay with algorithmic analysis known as the Foundation Pain Index (FPI) in diverse cohorts of chronic pain patients in a prospective, cross-sectional, observational validation study. Levels of 11 urinary pain biomarkers were measured and tabulated using a proprietary algorithm to generate FPI scores for chronic pain subjects (N = 153) and age- and sex-matched pain-free controls (N = 334).ResultsFPI scores were significantly correlated with the 36-Item Short Form Health Survey (SF-36) scores among chronic pain subjects (P value < 0.015) and specific components of SF-36, including emotional well-being, limitations due to emotional problems, and general health (P value < 0.05). Area under ROC analysis (AUROC) revealed FPI to accurately distinguish biomarker profiles between pain-free and chronic pain cohorts (AUROC: 0.7490, P value < 0.0001) as well as the SF-36 scores between chronic pain subjects with low vs. high FPI scores (AUROC: 0.7715, P value < 0.01).Conclusions Our findings establish the validity and discriminatory power of a novel multi-biomarker test that evaluates the role of biochemistry in chronic pain and correlates with clinical assessments of patients. This test provides novel, reproducible, objective data which may pave the way for non-opioid therapeutic strategies to treat chronic pain.
Article
Objective Multiple disease phenotypes have been identified in knee osteoarthritis (OA) patients based on anthropometric, sociodemographic and clinical factors; however, differential systemic metabolite-based signatures in OA patients are not well understood. We sought to identify differential plasma metabolome signatures in a cross-sectional sample of late-stage knee OA patients. Methods Plasma from 214 (56.5% female; mean age = 67.58 years) non-diabetic, non-obese (BMI <30 kg/m², mean = 26.25 kg/m²), radiographic KL 3/4 primary knee OA patients was analyzed by metabolomics. Patients with post-traumatic OA and rheumatoid arthritis were excluded. Hierarchical clustering was used to identify patient clusters based on metabolite levels. A refined metabolite signature differentiating patient clusters was determined based on ≥ 10% difference, significance by FDR-adjusted t-test (q-value < 0.05), and random forests importance score ≥1, and analyzed by AUROC. Bioinformatics analysis was used to identify genes linked to ≥2 annotated metabolites. Associated enriched pathways (q < 0 0.05) were determined. Results Two patient clusters were determined based on the levels of 151 metabolites identified. Metabolite signature refinement found 24 metabolites could accurately predict cluster classification within the sample (AUC = 0.921). Fifty-six genes were linked to at least 2 KEGG annotated metabolites. Pathway analysis found 26/56 genes were linked to enriched pathways including tRNA acylation and B-vitamin metabolism. Conclusion This study demonstrates systemic metabolites can classify a cross-sectional cohort of OA patients into distinct clusters. Links between metabolites, genes and pathways can help determine biological differences between OA patients, potentially improving precision medicine and decision-making.
Article
This review is aimed to summarize the pain relieving effect of non-drug substances, mostly prescribed as integrators in treatment of pain including, especially in chronic postoperative pain (CPSP) and in chronic back pain after acute episodes. Their use reflects the fact that the current treatments for these syndromes continue to pose problems of unsatisfactory responses in a significant portion of patients and/or of an excess of side effects like those noted in the present opioid crisis. As integrators are frequently introduced into the market without adequate clinical testing this review is aimed to collect the present scientific evidence either preclinical or clinical for their effectiveness. In particular, we reviewed the data on the use of: B vitamins; vitamin C; vitamin D; Alpha Lipoic Acid (ALA); N-acetylcysteine (NAC); Acetyl L-Carnitine (ALC); Curcumin; Boswellia serrata; Magnesium; Coenzyme Q10 and Palmitoylethanolamide (PEA). The combination of preclinical findings and clinical observations strongly indicate that these compounds deserve a more careful attention, some of them having interesting clinical potentials also in preventing chronic pain after acute episode. In particular examining their putative mechanisms of action it emerges that combinations of few of them may exert an extraordinary spectrum of activities on a large variety of pain-associated pathways and may be eventually used in combination with more traditional pain killers in order to extend the duration of the effect and to lower the doses. Convincing examples of effective combinations against pain are vitamin B complex plus gabapentin for CPSP, including neuropathic pain; vitamin B complex plus diclofenac against low back pain and also in association with gabapentin, ALA, for burning mouth syndrome. These as well as other examples need, however, careful controlled independent clinical studies confirming their role in therapy.
Article
Disease-modifying osteoarthritis (OA) therapy is not yet available. Several adjuvant therapies have demonstrated promising results in the treatment of OA. The present study aimed to investigate the therapeutic effects and underlying mechanisms of a combination of Lactobacillus acidophilus, vitamin B, and curcumin in the treatment of OA. Monosodium iodoacetate (MIA)-induced arthritis of the knee joint in rat was used as an animal model of human OA. The combination of L. acidophilus LA-1, vitamin B, and curcumin or a saline solution was given orally. Pain was measured according to the paw withdrawal latency, and paw withdrawal threshold. Cartilage destruction was analyzed using histomorphological techniques and the Mankin scoring system. Protein expression in the joint was examined using immunohistochemistry. The effects of the combination of L. acidophilus LA-1, vitamin B, and curcumin on mRNA levels in chondrocytes stimulated with interleukin (IL)-1β were analyzed using real-time polymerase chain reaction. The combination of L. acidophilus, vitamin B, and curcumin effectively downregulated Th17 cells and the related cytokine IL-17, thereby maintained the Treg population, and increased the expression of the Treg-related cytokine IL-10 in human peripheral blood mononuclear cells. The OA animal model exhibited reduced pain and preservation of cartilage in response to the combination treatment. The expression levels of pro-inflammatory cytokines and the catabolic, matrix metalloproteinase-13 (MMP-13), were decreased, whereas the expression of the anabolic tissue inhibitors of metalloproteinases (TIMPs) were upregulated in response to the drug combination. The combination of L. acidophilus, vitamin B, and curcumin was beneficial in OA treatment, controlling the inflammatory response via regulation of the Th17/Treg population and reducing the expression of pro-inflammatory cytokines in human peripheral blood mononuclear cells. The combination treatment also preserved cartilage, suppressed osteoclastogenesis, and regulated the anabolic/catabolic imbalance. These findings indicate the therapeutic potential of combination use of L. acidophilus, vitamin B, and curcumin in patients with OA.
Article
B vitamins have been used as analgesic drugs to treat pain disorders associated with their deficiency. However, more recently it has been claimed that, at pharmacological doses, B vitamins are useful to relieve different pain states as carpal tunnel, migraine and premenstrual tension. Experiments in animals have shown that vitamins B1 (thiamine), B6 (pyridoxine) and B12 (cyanocobalamin) and their combination have antinociceptive activity against chemical- and heat-induced pain. An anti-inflammatory effect has also been reported using the carrageenin-induced edema test. Moreover, the individual administration of thiamine and pyridoxine produce antinociception in acetic acid-induced pain or pain induced by supramaximal electrical stimulation of afferent C fibers. However, the most important effect of B vitamins is related with its use in patients with neuropathic pain. B vitamins have been useful in some painful disorders such as polyneuropathy, neuralgia, radiculopathy, neuritis associated with pain paresthesias, and diabetic peripheral neuropathy. This use has been supported recently by preclinical studies showing the efficacy of these vitamins in well established models of neuropathic pain in rats. The neurophysiological mechanisms induced by B vitamins are still unknown. However, in the last years it has been postulated that B vitamins-induced antinociception could result from activation of opioid receptors or nitric oxide release.
Article
A randomised, double-blind, parallel-group study was conducted to evaluate, by endoscopic examination, the effects of nonsteroidal anti-inflammatory drug treatment on gastric and duodenal mucosa. Men and women, aged 55 years or older, with chronic osteoarthritis or rheumatoid arthritis, requiring anti-inflammatory therapy for at least 3 months prior to the study, were enrolled. Patients were randomised to receive either diclofenac sodium 150 mg/day or naproxen 1000 mg/day. Patients were permitted to take paracetamol as a rescue analgesic and antacid tablets. Endoscopy revealed an increase in gastrointestinal findings after treatment (compared with baseline) in 29% of the diclofenac sodium group versus 65% of the naproxen group (p These findings demonstrate a significantly greater incidence of gastric and duodenal ulcers in patients treated with naproxen, as well as a greater incidence of endoscopic evidence of mucosal irritation/damage of the upper gastrointestinal mucosa, than in patients treated with diclofenac sodium.
Article
Additive analgesic effects of long-term application of a combination of the vitamins B1 B6B12 (thiamine diphosphate 100 mg, pyridoxsine-HCl 200 mg, cyanocobalamin 20 µg, p.o.) on a single dose of the nonsteroidal anti-inflammatory drug (NSAID) diclofenac (diclofenac-Na, 50 mg, p.o.) were investigated with a noninflammatory experimental pain model in 38 healthy volunteers. B-vitamins were given with 3 dosages/day for 1 week. Then experimental sessions of 3 h followed to test the analgesic efficacy of the NSAID. In these sessions, phasic pain was induced by intracutaneously applied brief electrical pulses (20 ms). Measured were the pain ratings, the cerebral potentials and the EEG δ power in responses to the stimuli as target variables for the analgesic test. Unspecifïc effects upon the vigilance system were evaluated by spontaneous EEG, auditory-evoked potentials and reaction times. The investigation was performed as a placebo-controlled, double-blind cross-over study. Blood samples were taken to monitor the plasma concentrations of the active agents. Whereas in the first block of stimuli (40–60 min after diclofenac medication) no analgesic effects of diclofenac could be observed, either given alone or after pretreatment with the B-vitamins, in the second stimulus block (100–120 min after medication) significant effects appeared in all target variables describing analgesia. Pain ratings were decreased by about 5%, late cerebral potentials by about 9% and stimulus-induced δ power of the EEG by about 14%. These effects were significant (p 6 by 700%, for vitamin B1by 70% and for vitamin B12 by 50%. All B-vitamin concentrations were independent of each other.
Article
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. © 2006 Wiley-Liss, Inc.
Article
1Otolaryngological Hospital, University of Helsinki. Helsinki, and Department of Biomedical Sciences, University of Tampere, Tampere. Finland. The pain-relieving effects of pethidine (1 mg/kg i.m.), tilidine (2.5 mg/kg i.m.) and indomethacin (100 mg rectally) were investigated in 87 voluntary adult patients after tonsillectomy in a double-blind study. All the drugs relieved pain equally. The maximal emerr appeared 60–75 min after drugadministration, and lasted until the end of the 120-min observation period. Bleeding from the operative site w'as the most common side effect. It appeared in 28, 24 and 3% of the patients treated with indomethacin, tilidine and pethidine, respectively. Two patients in the indomethacin group and one patient in the tilidine group needed a suture for stopping the bleeding, whereas the bleeding in the pethidine group stopped without any special treatment. Further side effects were headache, dizziness, nausea and vomiting. Their incidence ranged from 0 to 17% in various groups. On the evening of the operative day, the indomethacin patients received another dose of indomethacin, whereas the other patients received a plarebo suppository. On the following morning, the pain score was lowest and the speech least impaired in the indomethacin patients. After indomethacin, the axillary temperature remained below 37oC, whereas it was slightly elevated in the other groups. In all groups the blood leucocyte count was significantly increased. The control values for the excretion of prostaglandin F., in sputum ranged from 2.9 to 3.9 ng/8 min. The values were increased by 233, 183 and 29% in pethidine, tilidine and indomethacin group, respectively. The control values for prostaglandin E ranged from 1.5 to I.9 ng/8 min. There was an increase of 205, 111, and 80% in the pethidine, tilidine and indomethacin group, respectively. The results suggest that. of the drugs studied, pethidine is most convenient for treatment of throat pain immediately after tonsillectomy in adults. During the later postoperative period, indornethacin may be used for alleviation of pain and inflammatory responses.
Article
Pain syndromes of the lumbar spine are one of the main problems in orthopedic practice. The therapeutic effect of NSAIDs is not subject to doubt in this connection. But considering that the application of NSAIDs is frequently associated with side effects, a reduction of dosage would be to the patient's benefit. Clinical studies have shown that concomitant treatment with vitamins B1, B6, B12 and diclofenac leads to a more efficient pain relief than treatment using diclofenac alone and thus provides the possibility of saving NSAIDs. This clinical trial was carried out in order to determine whether these results can also be achieved when a reduced dosage of diclofenac (75 mg daily) is used. 123 patients with acute pain syndromes of the lumbar spine were treated with either B-vitamins and diclofenac or diclofenac alone for a maximum of 7 days. There was the option to terminate therapy in the trial after 3–4 days in the case of total pain relief. 45 patients could stop the treatment due to remission of symptoms. 30 patients belonged to the combination therapy group, the other 15 took diclofenac alone; this difference is statistically significant (p< 0.05). All parameters concerning pain relief and movement of the vertebral column showed statistically significant differences in favour of the B-vitamin-diclofenac-combination, too. The results document the positive influence of B-vitamins on painful vertebral syndromes and indicate that B-vitamins contribute to saving of NSAIDs by shortening the treatment time and reducing daily NSAID-dosage.
Article
In this study, the anti-nociceptive and anti-inflammatory effects of cyanocobalamin (Vit B12) against acute and chronic pain and inflammation were evaluated in mice. Vit B12 (0.87, 1 and 1.77 mg/kg) were injected intraperitoneally. The anti-nociceptive effects against acute pain were examined using hot-plate and writhing tests. The chronic pain was examined 14 days after sciatic nerve ligation using the hot-plate test. Morphine (10 mg/kg) was used as a positive control. Anti-inflammatory effects of Vit B12 against acute and chronic inflammation were assessed using xylene-induced edema in ears and granuloma caused by compressed cotton implantation, respectively. In these tests, sodium diclofenac (15 mg/kg) was used as a positive control. Vit B12 showed a dose related effect in acute anti-nociceptive test and increased the anti-nociceptive effect of morphine in chronic treatment. Vit B12 demonstrated an anti-nociceptive effect in chronic studies as single or continues daily treatment and increased significantly the anti-nociceptive effect of morphine. All doses of Vit B12 significantly decreased xylene-induced ear edema. Maximum anti-inflammatory effect (37.5%) was obtained at dose of 1 mg/kg. In chronic inflammation, Vit B12 significantly decreased granuloma formation in mice. In conclusion our work presents some experimental evidence supporting the administration of cyanocobalamin in controlling acute and chronic neuropathic pain. Cyanocobalamin may have anti-inflammatory effect. It may reduce tolerance to anti-nociceptive effect of morphine as well.