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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.
Key words: Mechanical
Abstract. 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:
Medicamentos cardiovasculares en la nocicepción mecánica
humana: digoxina, amlodipina, propranolol, pindolol y atenolol.
Invest Clin 2010; 51(1): 77 - 86
Palabras clave: Nocicepción mecánica, modulación del dolor, atenolol, pindolol,
Resumen. 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. INTRODUCTION
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 Patients
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 supra, 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.
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 DISCUSSION
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 r = –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 = –0.43; 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 = 0.24), amlodipine (r = 0.042; p = 0.80) as well as plained by b1 selectivity, blood-brain barrier for the digoxin group (r = 0.22; P = 0.17).
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- vide supra. 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 ACKNOWLEDGEMENTS
(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- REFERENCES
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