Cardiovascular drugs in human mechanical
nociception: digoxin, amlodipine,
propranolol, pindolol and atenolol.
Alfredo Del Giaccio1 and Antonio Eblen-Zajjur2.
1Servicio de Medicina Interna, Hospital Universitario “Dr. Angel Larralde”,
Instituto Venezolano de los Seguros Sociales y
2Departamento de Ciencias Fisiológicas, Facultad de Ciencias de la Salud,
Universidad de Carabobo, Valencia, Venezuela.
Calcium channel blockers, b adrenergic receptor blockers and
Na/K ATPase inhibitors are widely used drugs, mainly for cardiovascular dis-eases. Their pharmacological targets are not restricted to the cardivasculartissue, nociceptive system structures also express similar targets, whichstrongly suggests a direct effect on pain sensation. To evaluate the pain inten-sity changes in outpatient groups, who receive these drugs as a therapy, across-sectional sampled, randomized patient groups receiving the calciumchannel blocker amlodipine for blood hypertension (n=45), b adrenergic re-ceptor blockers (propranolol, atenolol or pindolol; n=40) for blood hyperten-sion, or digoxin (n=40) for heart failure, were compared to an aparentlyhealthy volunteers control group (n=60). A calibrated noxious pressure of890 g/mm2 was applied for 5 seconds on the patient’s sternum. Subjectivepain intensity was reported by the visual analog scale (VAS, 0 to 10). Painmodulation system was evaluated by the application of a second stimulus witha 5 minutes delay. The analgesic effect of the b blockers group (propanolol,atenolol, pindolol) was dosage-dependant (–36.8%; P=0.0000003), withoutdifferences among them. The calcium channel blocker amlodipine showedlower
(P=0.0000003). Digoxin presented the highest pain scores (+56.5%;P=0.0000003). All pain scores for the second stimulus were lower than thefirst stimulus and were differentially affected by b-blockers (atenolol, pindololand propanolol) and calcium channel blocker (amlodipine), but not bydigoxin. These results suggest the influence of widely clinically used cardio-vascular drugs on nociception.
Corresponding author: Antonio Eblen-Zajjur. Facultad de Ciencias de la Salud, Universidad de Carabobo, P.O.
Box 3798, El Trigal. Valencia, Venezuela. E-mail: [email protected]
Medicamentos cardiovasculares en la nocicepción mecánica
humana: digoxina, amlodipina, propranolol, pindolol y atenolol.
Invest Clin 2010; 51(1): 77 - 86
Nocicepción mecánica, modulación del dolor, atenolol, pindolol,
Los bloqueadores de los canales de calcio, los bloqueadores de
los receptores b adrenérgicos y los inhibidores de la ATPasa Na/K son medica-mentos ampliamente usados en enfermedades cardiovasculares. Sus blancosfarmacológicos no se restringen al tejido cardiovascular, el sistema nerviosonociceptivo expresa blancos similares, lo que sugiere fuertemente un efectodirecto en la sensación del dolor. El objetivo del presente estudio fue evaluarlos cambios en la intensidad del dolor en grupos de pacientes ambulatoriosque reciban estos medicamentos como terapia. Grupos aleatorios de pacien-tes que reciben el bloqueador de canales de calcio amlodipina contra la hiper-tensión arterial (n=45), bloqueadores de receptores b adrenérgicos (propra-nolol, atenolol or pindolol; n=40) contra la hipertensión arterial o digoxina(n=40) por insuficiencia cardíaca fueron comparados con un grupo controlde voluntarios aparentemente sanos (n=60). A todos los grupos se les aplicóuna presión nociva calibrada de 890 g/mm2 durante 5 segundos sobre el es-ternón. El paciente reportó la intensidad subjetiva del dolor mediante la esca-la visual análoga (VAS). El sistema de modulación descendente del dolor fueevaluado mediante la aplicación del mismo estímulo 5 minutos después delprimero. Se determinó un efecto analgésico en el grupo de b bloqueantes(propanolol, atenolol, pindolol) dosis dependiente (–36,8%; P=0,0000003)sin mostrar diferencias entre ellos. El bloqueador de canales de calcio amlodi-pina mostró un efecto analgésico (–50,6%; P=0,0000003) que fue mayor queel de los b bloqueantes (P=0,0000003). El grupo con digoxina expresó unefecto hiperalgésico (+56,5%; P=0,0000003). Todos los valores de dolor parael segundo estímulo fueron menores que para el primero y fueron diferencial-mente afectados por los b bloqueantes (atenolol, pindolol and propanolol) ypor la amlodipina pero no por la digoxina. Estos resultados claramente sugie-ren la intensa influencia en la nocicepción de los ampliamente usados medica-mentos cardiovasculares.
Recibido: 13-01-2009. Aceptado: 22-10-2009.
system structures express similar receptors(1), channels (2-5) and ionic pumps (6-8),
gic receptors blockers, and Na/K ATPase in-
hibitors are widely administered for hyper-
tension, arrhythmia or heart failure, respec-
tively. Neuronal membranes of nociceptive
voltage sensitive calcium channels (2, 4, 9).
Cardiovascular drugs in mechanical nociception
Calcium channels blockers show anti-noci-
ceptive effects in both, experimental (4, 5)and clinical studies (3), but can also abol-
ish opioid-induced hypersensitivity (10).
lization action on the cellular membranes
(11). Propranolol shows a local anesthetic
the Social Security Hospital “Dr. Angel
effect similar to lidocaine by decreasing so-
Larralde”. Informed consent was obtained
dium (12) and calcium influxes (13).
tive neurons increase ATPase activity as a
countermeasure to sodium influx (14).
ple consisted of patients from the outpa-
tient Internal Medicine Service and by, ap-
parently, healthy volunteers, workers of the
(FRAP) in the ipsilateral spinal dorsal horn,
to restore the Na+ and K+ gradients associ-
grouped according to their drug therapy as
follows: b receptors blockers group: with
b-blockers treatment, distributed in three
lease (6). These two factors are strongly as-
(7). Digoxin, a Na/K ATPase inhibitor, in-
creases the intracellular concentration of
group: with digoxin. Due to the nature of
sodium and calcium (16) inducing neuronal
the study, internal controls (pain scores be-
depolarization (16), which antagonizes the
antinociceptive effect of morphine in mice
cluded with apparently healthy, asymptom-
atic, volunteers without any pharmacologi-
stimulus can activate various antinocicep-
cal treatment. An interview was performed
tive mechanisms, such as diffuse nocicep-
(20); however, the action of calcium chan-
blocker (amlodipine) or cardiac glycoside
(digoxin), for more than 6 months and clin-
nisms has not been extensively analysed.
ically stable. Those patients who had re-
ceived analgesic drugs 72 hours previous to
mechanisms of action of these drugs vide
less attention has been paid to ac-
bacco two hours before the test, or those
patients taking calcium channels blockers,
their sensitive, cognitive, or discriminative
b adrenergic blockers or ATPase inhibitors
capabilities, or those that received pharma-
therapeutically for cardiovascular diseases
cological polytherapy, or those clinically un-
compensated, were excluded from the study.
Treatment and measurements
Wilcoxon test. Linear regression analysis
was performed. Significance level was set at
history, physical examination, recording of
drug dose and values of the Visual Analogi-cal Scale VAS to a calibrated noxious me-
chanical test. Drugs were administrated indaily oral doses as follows: amlodipine
2.5-10 mg, propranolol 20-600mg, atenolol
ple of 185 subjects (Table I). Sixty asymp-
tomatic, apparently healthy subjects were
age was 48.29 ± 17.86 years (range 21-86
years), 51.35% of the subjects were male.
generated by a 2 mm2 flat tip spring device
Arterial hypertension (AH) was present as
was applied for 5 seconds on the sternum’s
the sole illness in 85 (68%) patients, which
showed blood pressure of 85.2 ± 3.2 mmHg
body location for the stimulus was selected
to avoid individual asymmetries in pain sen-
systolic values respectively, not statistically
sation (14). The noxious pressure did not
different to those from the control group
induce lesions in the skin. The patient used
(P>0.1). Heart failure (HF) was present in
a vertical Visual Analog Scale VAS1, a self
40 (32%) patients which received digoxin as
reported subjective pain intensity scale. Af-
treatment. The primary cause of HF of this
group was arterial hypertension. No age or
stimuli was applied again to evaluate the
sex distribution differences were found be-
pain modulation systems, this interval of
lasting antinociceptive effects of the first
(conditioning) noxious stimulus (18).
(n=45; Table II) were distributed according
means ± standard deviations. Distribution
of difference of VAS values between groups
SAMPLE SIZE, AGE, RANGE AND STATISTICAL COMPARISON AMONG DIFFERENT PATIENT
Cardiovascular drugs in mechanical nociception
(Table III) but, patients with heart failure
or VAS values distribution, thus, they were
the control group. HF in patients with AH
tween the different groups in the b-blockers
statistical differences (P=0.13) in age, sex
PATIENT DISTRIBUTION IN THE b-BLOCKERS GROUP ACCORDING
TO THE DRUG AND COMPARISON BETWEEN THEIR VAS VALUES
VAS values are X±SD; P is the best value of all pair tests from the three groups.
DISTRIBUTION AND VAS VALUES OF CONTROL SUBJECTS, PATIENTS WITH ARTERIAL
HYPERTENSION OR ARTERIAL HYPERTENSION INDUCED HEART FAILURE
**P<0.0000001. Last row of % is the differences between AH+HF group and AH group.
VAS VALUES, ANALGESIC INDEX, PERCENTAGE OF CHANGE AND T-TEST FOR THE STUDIED
VAS values are X±SD. All reported P values are control group comparison. Dgroup (%) are differences betweenthat particular VAS group value against the control group (100%), negative values means analgesia and positivevalues means hyperalgesia. For DVAS1-2, VAS1 was considered 100%.
showed and increment up to +56.5%(P=0.0000001) when comparing the VAS
values with the control group. The group ofpatients who received amlodipine showed
the strongest reduction of pain intensity
uated the effect of the therapy of cardiovas-
values for the mechanical noxious stimula-
cular diseases, such as arterial hypertension
tion with –50.6% and –57.8%; P<0.0000001
and/or heart failure with b-blockers, cal-
for VAS1 and VAS2 respectively (Table IV),
cium channel blocker or cardiac glycoside
less than the control group. The highest dif-
on mechanical nociception in 125 patients,
ferences in pain scores respect to control
compared to 60 healthy volunteers without
is associated to hypoalgesia in animals (22,
higher than the values reported for the con-
23) and humans (24). In the present study,
therapy, according to the inclusion criteria,
tered dosage of b-blockers and VAS values
were clinically stable with diastolic and sys-
revealed dose-dependent effects for atenolol
= –0.61; P=0.0013), but not for
evidence that blood pressure correlates pos-
propranolol (n=13; VAS1 r
= –0.46; P =
itively with pain thresholds and negatively
0.12; VAS2 r
= –0.31; p = 0.30). No regres-
with pain ratings (23) thus, the lower pain
sion analysis was made for pindolol due to
scores respect to control values observed in
the use of only 5 mg dose schedule. The ad-
patients with b-blockers therapy, could not
ministered dosage of amlodipine was associ-
be explained only by the arterial hyperten-
ated inversely to VAS1 (n = 40; r
P=0.005) and VAS2 values (n = 40; r
were not different than those of the control
–0.42; P=0.0074). No regression analysis
group. The results suggest that the three
was made for digoxin due to the use of only
b-blockers tested play a direct effect for
0.25 mg dose schedule. The duration of the
lowering pain scores. The dose-effect corre-
treatment was not related to VAS values for
lation observed in the atenolol, but not in
the b-blockers (r
= 0.18; P =
= 0.042; p =
0.80) as well as
plained by b1 selectivity, blood-brain barrier
for the digoxin group (r
= 0.22; P =
impermeability and less membrane stabiliz-
ing effect for atenolol. The current study
confirms previous findings about the role of
who received digoxin. The ranking of pain
b-adrenergic receptors in nociception (12,
13), based on decrease of the adenylcyclase
was Control < b-blockers (propranolol,
activity (25), reduction of intracellular
AMPc and inhibition of voltage sensitive cal-
(amlodipine) with –6.13%; –16.28% and
cium and sodium channels activity (12, 13,
–23.78% respectively (Table IV). Addition-
26), which lead to a decrease of neuronal
Cardiovascular drugs in mechanical nociception
release and to inhibit the phospholipase A
fect of ouabain is not completely clear. Spi-
(29), all these actions are strongly linked to
nal intrathecally administered ouabain has
b-blockers therapy, neither systolic nor dia-
mission in the spinal nociceptive processing
amlodipine therapy was different to those
application of ouabain antagonizes opioid
from the control group. Thus, the possible
contribution of blood pressure values to re-
The analgesic effect observed in
interleukins IL-6 and TNFa rise in patients
patients receiving amlodipine agrees with
with heart failure showing a direct correla-
previous reports, that support the notion
tion between their blood concentration and
the heart failure grade (35). These prod-
blockers decrease neuronal excitability, by
means of reducing calcium influx by a dose-
proalgesic effects (36) which could contrib-
response effect (30). Neurons with a wide
ute to the increased subjective pain inten-
variety of calcium channels in their cellular
sity rates of the digoxin/heart failure pa-
tient group; however, this group, were all
tive pathways and centers (31), playing an
clinically stable, condition associated to low
increases of blood concentrations of IL-6
their neuronal network (8, 9). The clinical
lated increase of these cytocines was re-
results of the present study confirms previ-
ported particularly in patients over 85 years
ous findings about the relevant role of volt-
of age (39). The age of the digoxin patient
group evaluated in the present study was 15
years younger, but the role of age related
increase of cytocines cannot be ruled out,
therapy shows the higher values of subjec-
tive intensity to mechanical noxious stimu-
duced by digoxin to explain the increased
lus. The digoxin-induced inhibition of the
subjetive pain intensity reported by the pa-
tient group. However, since cytokines levels
also in neurons, leads to an increase of the
intracellular sodium concentrations, which
the influence of cytokines in the digoxin/
depolarizes the neuron, increases their ex-
citability (6, 14, 16) and opens voltage sen-
sitive calcium and sodium channels with a
and digoxin-like immunoreactivity factors
ronal depolarization and release of excit-
with heart failure (40, 41), but once again,
the clinically stable status for the digoxin/
heart failure patient group, strongly sug-
ATPase activity; on the other hand, the opi-
hyperalgesia is made by digoxin. However, it
ate antagonist, naloxone, decreased the ac-
cannot completely ruled out that patients
tivity of Na/K ATPase (33). However, the ef-
receiving digoxin were age and co-morbidity
different to the control group. The cross-
sectional design of the study raises some
limitations about homogeneity between the
widely used drugs in these cardiovascular
diseases, showing that calcium channel and
b-adrenergic receptors blockers, could de-
showed a higher analgesic effect than the
crease and digoxin could increase pain sen-
b-blockers therapy group, i.e., propranolol,
sation. The clinical possibility to use both
greater effect of the calcium ion and its
voltage sensitive channels over the stabiliz-
tested, based on the advantage of current
b-adrenergic receptor blockers for mechani-
receptors blockers, but careful analysis of
VAS1 values ranged between –7% to –21%observed at least 5 minutes after the first
(conditioning) noxious stimulation whichagrees with pain modulation system activa-
The authors thank Vivas-O´Connor V.
tion (42, 43), was differentially affected by
and Tucci M. for helpful comments. Support-
ed by Grant from the Consejo de Desarrollo
blocker amlodipine, b-adrenergic receptor
Científico y Humanístico, CDCH-UC, Uni-
blockers, i.e., propranolol, atenolol and
pindolol, but not by the ATPase inhibitordigoxin, these different pharmacological re-
sponses confirms that in pain modulationsystems, which includes spinal and su-
CNS-related side-effects of
pra-spinal mechanisms, both calcium chan-
play a fundamental role with a major effect
of the calcium channels as shown intra and
Miljanich GP, Ramchandran J.
nists of neuronal calcium channels: struc-ture, function and implications. Annu Rev
study, with no influence of the treatment
Brose WG, Gutlove DP, Luther RR,
Bowersox SS, McGuire D
. Use of intra-
with previous basic and clinical findings,
the cross sectional experimental design and
age-sensitive, calcium blocker, in the man-
the use of healthy volunteers as a control
avulsion. Clin J Pain 1997; 13:256-257.
study, also generate difficulties in the inter-
Díaz A, Dickenson AH.
Blockade of spinal
pretation of the results because it is no pos-
channels excitability of rat dorsal hornneurones produced by subcutaneous in-
changes in nociception are due to the treat-
flammation ity of rat dorsal horn neurones
ment or to the underlying pathology of the
produced by subcutaneous inflammation.
Martín MI, del Val VL, Colado MI,
are common morbility that affects at least
Goicoechea C, Alfaro MJ.
Cardiovascular drugs in mechanical nociception
in the failing human heart. Cardiovasc Res
Masocha W, Horvath G, Agil A, Ocana M,
Li S, Stys PK.
Del Pozo E, Szikszay M, Baeyens JM.
lease via reverse Na+-dependent transport
in spinal cord white matter. Neuroscience
Diffuse Noxious Inhibitory
The induction of pain: an inte-
Control (DNIC) as a tool for exploring dys-
WiIlis WD, Coggeshall RE
. Sensory Mech-
Sandkühler J, Stelzer B, Fu QG.
anisms of the Spinal Cord. First Edn. New
teristics of propriospinal modulation of no-
Chaplan SR, Pogrel JW, Yaksh TL.
of voltage-dependent calcium channel sub-
Bee LA, Dickenson AH.
Dorul A, Bilsky EJ, Ossipov MH, Lai J,
Spinal L-Type Calcium Channel
sory Hypersensitivity and Antinociceptive
Lugo M, Isturiz G, Lara C, García N,
Sensory lateralization in
pain subjective perception for noxious heat
The membrane stabilizing
and beta 1-adrenoceptor blocking activity
of +- and -propranolol on the rat left atria.
Zamir N, Segal M.
analgesia: changes in pain sensitivity in ex-
perimental hypertensive rats. Brain Res.
propranolol and a number of its analogues
Akaike N, Ito H, Nishi K, Oyama Y
propranolol and local anaesthetics on the
quences. Hypertension 1996; 28:494-504.
Rosa C, Vignocchi G, Panattoni E, Rossi
B, Ghione S.
Relationship between in-
Czaplinski M, Abad C, Eblen-Zajjur A
additional evidence for the existence of an
abnormality of pain perception in arterial
tivity in spinal dorsal horn of the rat.
Glykys J, Guadama M, Ochoa E, Marcano
L, Eblen-Zajjur A.
Brown AM, Birnbaumer L.
Direct G pro-
tein gating of ion channels. Am J Physiol
Schwinger RH, Bundgaard H, Muller-
Ehmsen J, Kjeldsen K.
The Na, K-ATPase
Rudolph K, Kluger MJ
Cunha FQ, Ferreira SH.
algesic cytokines. Adv Exp Med Biol 2003;
Hogye M, Mándi Y, Csanády M, Sepp R,
Bloksma N, Hofhuis F, Benaissa-Trouw B,
Comparison of circulating levels
Endotoxin-induced release of tu-
mour necrosis factor and interferon in vivo
is inhibited by prior adrenoceptor block-
and in idiopathic dilated cardiomyopathy.
Wykretowicz A, Furmaniuk J, Smielecki
Trotz M, Jellison EJ, Hostetler KY.
J, Deskur-Smielecka E, Szczepanik A,
Banaszak A, Wysocki H.
The oxygen stress
phospholipase A of rat heart mitochondria,
index and levels of circulating interleukin-
Biochem Pharmacol 1987; 36:4251-4256.
chronic heart failure. Int J Cardiol 2004;
Blockade of calcium channels
can prevent the onset of secondary hyper-
Mariani E, Cattini L, Neri S, Malavolta M,
Mocchegiani E, Ravaglia G, Facchini A.
dermal injection of capsaicin in rats. Pain
chemokine and cytokine profiles in elderly
subjects by multiplex technology: relation-
Contribution of central neuro-
plasticity to pathological pain: review of
Bagrov AY, Fedorova OV, Maslova MN,
Roukoyatkina NI, Ukhanova MV, Zhabko
Rosen AS, Morris ME.
Endogenous plasma Na,K-ATPase in-
of anoxia on pyramidal cells of rat neocor-
hibitory activity and digoxin like immuno-
tex. Neurosci Lett 1991; 124:169-173.
reactivity after acute myocardial infarc-
Hajek I, Teisinger J, Sykova E.
tion. Cardiovasc Res 1991; 25:371-377.
Balzan S, Neglia D, Ghione S, D’Urso G,
Baldacchino MC, Montali U, Lábbate A.
Increased circulating levels of ouabain-like
factor in patients with asymptomatic left
Zeng W, Dohi S, Shimonaka H, Asano T.
ventricular dysfunction. Eur J Heart Fail
pump inhibitor ouabain and its interaction
Eblen-Zajjur A, Salas R, Vanegas H.
with morphine and lidocaine in rats. Anes-
neuronal responses to receptive field stim-
Gwechenberger M, Hulsmann M, Berger
ulation and to heterotopic noxious stimu-
R, Graf S, Springer C, Stanek B, Pacher
Interleukin-6 and B-type natriuretic
Willer JC, Roby A, Le Bars D.
worsening of heart failure in patients with
proaches to the pain-relieving effects of
Heart Lung Transplant 2004; 23:839-844.
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