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CASE REPORT
Year : 2013  |  Volume : 3  |  Issue : 1  |  Page : 73-76

Hypothesis: Are beta-blockers safe for patients with multiple sclerosis?


Department of Internal Medicine, St. Johannes Hospital, Germany

Date of Submission23-Feb-2012
Date of Acceptance15-Mar-2012
Date of Web Publication6-Feb-2013

Correspondence Address:
Auda Fares
Wilhelm-Busch-Straße 9, 53844 Troisdorf
Germany
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2231-0738.107000

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   Abstract 

Beta-adrenergic receptor blockers are an important class of drugs in the management of patients with cardiovascular diseases. Patients with multiple sclerosis have a higher risk of cardiovascular diseases than the general population. Melatonin has been implicated in the pathogenesis and clinical course of MS. When melatonin levels decline, an exacerbation of MS symptoms is seen. Beta-blockers have been shown to reduce the production of melatonin. Various central nervous system side effects associated with using of beta-blockers are linked with reduction of melatonin levels. Exogenous melatonin administration as a supplement in MS patients taking beta-blockers could reduce the central nervous system side effects as well as decrease diseases progression.

Keywords: Beta-blockers, multiple sclerosis, melatonin


How to cite this article:
Fares A. Hypothesis: Are beta-blockers safe for patients with multiple sclerosis?. Int J Nutr Pharmacol Neurol Dis 2013;3:73-6

How to cite this URL:
Fares A. Hypothesis: Are beta-blockers safe for patients with multiple sclerosis?. Int J Nutr Pharmacol Neurol Dis [serial online] 2013 [cited 2020 Jan 26];3:73-6. Available from: http://www.ijnpnd.com/text.asp?2013/3/1/73/107000


   Introduction Top


Beta-blockers are primarily used in the treatment of cardiovascular diseases; it soon became clear that they had much to offer as therapy for other clinical disorders such as migraine and tremor. Patients with multiple sclerosis (MS) have a higher risk of cardiovascular diseases (CVD) than the general population. [1] Moreover, MS patients have been found to be high users of prescribed medicines, having almost twice as many prescriptions from the GP compared to other patients. [2] Over the past several years, evidence has been accumulating that shows beta- blockers can rapidly reduce melatonin secretion via specific inhibition of adrenergic beta 1 -receptors. Depression, emotional liability, and sexual dysfunction have been reported as central nervous system side effects associated with use of beta-blockers. [3] It has been suggested that these central nervous system (CNS) side-effects are related to a reduction of melatonin levels. Melatonin has been implicated in the pathogenesis and clinical course of MS. [4] Exogenous administration of melatonin has been recently addressed in future research to treat central nerves system side effects associated with use of beta-blockers. [5] However, safety of using beta-blocker in MS patients is the main concern of this paper.

Melatonin and multiple sclerosis

Relatively recently, the pineal gland has been implicated in the pathogenesis and clinical course of MS. When melatonin levels decline, an exacerbation of MS symptoms is seen. [5] Remission effects in MS are thought to relate to the stimulatory influence of melatonin on the immune system. In one study, 32 MS patients were randomly selected from patients consecutively admitted to a neurology service in a hospital for exacerbations of their symptoms. Nocturnal levels of melatonin and the activity of the pineal gland were monitored over the course of each patient's illness. The study revealed a progressive decline in melatonin levels over the duration of the illness. Since patients with chronic progressive MS had a lower mean melatonin level compared to those with a relapsing-remitting course of the disease, an analysis of melatonin levels may be crucial for understanding the pathophysiology of MS and, specifically, the course of its progression. [6] In another study, nocturnal melatonin levels were found to be lower than daytime levels in 11 of 25 patients with MS. [7] furthermore, Melatonin deficiency has been reported to occur in association with depression and risk of suicide in MS patients. [8],[9] In contrast, nocturnal administration of melatonin has been shown to improve visual acuity in MS patients. [10]

Beta-blocker and melatonin

Beta-adrenergic receptor blockers are an important class of drugs in the management of patients with cardiovascular diseases. Extensive epidemiological evidence and experimental animal studies suggest that melatonin exerts certain effects upon the cardiovascular system. The presence of vascular melatoninergic receptors has been demonstrated; these receptors are functionally associated with either vasoconstrictor or vasodilatory effects of melatonin. [5] Synthesis and release of melatonin are stimulated by norepinephrine via beta 1-adrenoceptors and this process is further potentiated by stimulation of alpha 1-adrenoceptors. [5] Beta blockers have been shown to reduce the production of melatonin via specific inhibition of beta-1adrenergic receptors. The impact of beta-adrenergic receptor blockers on melatonin production was evaluated in 15 healthy volunteers. In that study, there was a significant decline in the nocturnal production of melatonin after receiving single oral doses of selective beta1-blocker. Vivid and bizarre dreams, hallucinations, sleep disturbance and psychosis have all been described following treatment with beta-blockers. [11] It has been suggested that these central nervous system (CNS) side effects are related to a reduction of melatonin levels. Results of two placebo-controlled studies of hypertensive patients, investigating the relationship between beta blocker induced central nervous system (CNS) side effects and the nightly urinary excretion of melatonin, demonstrated that the CNS side effects (sleep disorder, nightmares) during beta blockade are related to a reduction of melatonin levels. [12] Similar findings have been found in a case-control study of six patients with nightmares and hallucinations during treatment with beta-adrenoceptor blocking agents compared to six control patients with similar diagnoses and treatment but without such symptoms of the CNS. Nightly melatonin excretion was lower in all cases with nightly CNS symptoms than in the control patients. [13] The CNS side effects have also been documented in a randomized double-blind crossover study that was performed to compare the incidence of CNS side effects with beta-blockers in hypertensive patients who had reported CNS side effects with lipophilic beta-blockers. Eleven women and six men completed the study, in which a 30-item psychiatric questionnaire was used to detect changes in psychological status and possible CNS side effects. Discontinuation of the original lipophilic beta-blocker produced a significant improvement in quality of sleep, dreams, concentration, memory, energy, and anxiety. [11] Other side effects such as depression, emotional liability, and sexual dysfunction have been also reported as central nervous system side effects associated with use of topical beta-blockers. The incidence of such reported side effects is approximately 10%, with about 5% of patients having to discontinue the medicine. [14]

Multiple sclerosis and cardiovascular diseases

Patients with MS may have an increased risk of cardiovascular diseases (CVD) due to certain risk factors, such as reduced physical activity, smoking, abnormal uric acid levels, and use of glucocorticoids for acute relapses. Furthermore, about 40-45% of patients with MS have been found to have cardiovascular autonomic dysfunction. [15] In another study, moderate cardiovascular disturbances were found in 16.6% of the patients, and 10.7% had severe cardiovascular autonomic abnormalities. [16] Furthermore, cardiovascular diseases have been documented as a one of the most common courses of death among patients with multiple sclerosis. In one study conducted in Denmark it was reported that patients with MS had an approximately 17.6% higher risk of death due to CVD (including cerebrovascular disease) compared with the age-matched general population, [17] while a 6% higher risk of death due to CVD (excluding cerebrovascular disease) was observed in a study from South Wales. [18] In another study conducted in western Norway, cardiovascular diseases accounted for 13.1% among the causes of death associated with multiple sclerosis. [19]

Additionally, exacerbations of MS are usually treated with a high dose of adrenocortical steroids customarily administered intravenously. Various cardiac arrhythmias have been reported during corticosteroid pulse therapy. In a study conducted in Tehran, Sinus tachycardia was the most common change in cardiac rhythms before, during, and after corticosteroid pulse therapy. Up to 41.9% of the patients developed sinus bradycardia after pulse infusion. Sinus arrest and sinus exit blocks were observed in 12 patients. Atrial fibrillation and ventricular tachycardia were observed in three patients and one patient, respectively. [20] Moreover, atrial fibrillation has been reported associated with an acute exacerbation of multiple sclerosis. [21] However, understanding of the cardiovascular diseases risk in MS has important clinical implications for patient management and appreciating the clinical course of the disease.

Beta-blockers and exercise tolerance

For patients with multiple sclerosis (MS), fatigue, motor weakness, spasticity, poor balance, heat sensitivity, and mental depression are the most commonly reported symptoms. A vast number of studies have now demonstrated beneficial effects of physical exercise therapy in MS without stating any important deleterious outcome. [22] However, beta-blockers have been noted to decrease exercise tolerance in normal individuals. Many patients complain of lack of energy, fatigue, and aching muscles while taking ß-adrenoceptor blocking drugs. [23] Antagonizing of the effects of catecholamines and decrease in the norepinephrine release have been postulated to the underlying mechanism of the exercise intolerance after taking beta-blockers. In addition, the availability of nonesterified fatty acids for energy production is decreased, due to inhibition of beta-adrenoceptor-mediated adipose tissue lipolysis, and possibly also to the intramuscular triglyceride breakdown. In normally fed subjects plasma glucose concentration is maintained at a normal level during submaximal endurance exercise after beta-blocker administration, although lower glucose concentrations are found in fasting subjects and during high-intensity exercise after beta-blocker administration. Plasma lactate concentrations tend to be somewhat lower after beta-blocker administration while plasma potassium concentration during exercise is increased. Beta-blocker administration may also interfere with thermoregulation during prolonged exercise. [24] However, the possible effects of beta-blockers on exercise capacity should be considered when prescribing beta-blockers to MS patients.


   Conclusion Top


A closer look at the available evidence has cast serious doubts on safety of beta-blockers for patients with MS. Beta-blockers can lead to an exacerbation of MS symptoms. Various CNS side effects associated with use of beta-blockers are linked with reduction of melatonin levels. Exogenous melatonin administration as a supplement in MS patients taking beta-blockers could reduce the central nervous system side effects as well as decrease diseases progression. However, concern about side-effects may deter clinicians from prescribing these life-saving drugs. In reality, absolute contraindications of beta-blocker in MS patients are not documented. Further research regarding the safety of beta-blockers in MS patients is required.

 
   References Top

1.Christiansen CF , Christensen S , Farkas DK , Miret M , Sørensen HT , Pedersen L . Risk of arterial cardiovascular diseases in patients with multiple sclerosis: A population-based cohort study. Neuroepidemiology 2010; 35:267-74.   Back to cited text no. 1
    
2. Tremlett HL, Luscombe DK, Wiles CM. Prescribing for multiple sclerosis patients in general practice: A case-control study. J Clin Pharm Ther 2001; 26:437-44.  Back to cited text no. 2
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3.Stewart WC, Castelli WP. Systemic side effects of topical beta-adrenergic blockers. Clin Cardiol 1996; 19:691-7.  Back to cited text no. 3
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4.Sandyk R. The pineal gland and the clinical course of multiple sclerosis. Int J Neurosci 1992;62:65-74.  Back to cited text no. 4
    
5.Fares A. Night-time exogenous melatonin administration may be a beneficial treatment for sleeping disorders in beta blocker patients. J Cardiovasc Dis Res 2011; 2:153-5.  Back to cited text no. 5
[PUBMED]  Medknow Journal  
6.Sandyk R, Awerbuch GI. Relationship of nocturnal melatonin levels to duration and course of multiple sclerosis. Int J Neurosci 1994; 75:229-37.  Back to cited text no. 6
    
7.Sandyk R, Awerbuch GI. Nocturnal plasma melatonin and alpha-melanocyte stimulating hormone levels during exacerbation of multiple sclerosis. Int J Neurosci 1992; 67:173-86.  Back to cited text no. 7
    
8.Akpinar Z , Tokgöz S , Gökbel H , Okudan N , Uðuz F, Yilmaz G . The association of nocturnal serum melatonin levels with major depression in patients with acute multiple sclerosis. Psychiatry Res 2008; 161:253- 7.   Back to cited text no. 8
    
9. Sandyk R, Awerbuch GI. Nocturnal melatonin secretion in suicidal patients with multiple sclerosis. Int J Neurosci 1993; 71:173-82.  Back to cited text no. 9
    
10.Sandyk R. Diurnal variations in vision and relations to circadian melatonin secretion in multiple sclerosis . Int J Neurosci 1995; 83:1-6.  Back to cited text no. 10
    
11.Cove-Smith JR, Kirk CA. CNS-related side-effects with metoprolol and atenolol. Eur J Clin Pharmacol 1985;28: 69-72.  Back to cited text no. 11
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12.Brismar K, Hylander B, Eliasson K, Rössner S, Wetterberg L. Melatonin secretion related to side-effects of beta-blockers from the central nervous system. Acta Med Scand 1988;223:525-30.  Back to cited text no. 12
    
13.Brismar K, Mogensen L, Wetterberg L. Depressed melatonin secretion in patients with nightmares due to beta-adrenoceptor blocking drugs. Acta Med Scand 1987;221:155-8.  Back to cited text no. 13
[PUBMED]    
14.Stewart WC, Castelli WP. Systemic side effects of topical beta-adrenergic blockers. Clin Cardiol 1996;19:691-7.  Back to cited text no. 14
[PUBMED]    
15.Christiansen CF, Christensen S, Farkas DK, Miret M, Sørensen HT, Pedersen L. isk of arterial cardiovascular diseases in patients with multiple sclerosis: A population-based cohort study. Neuroepidemiology 2010;35:267-74.  Back to cited text no. 15
    
16.Merkelbach S, Dillmann U, Kölmel C, Holz I, Muller M. Cardiovascular autonomic dysregulation and fatigue in multiple sclerosis. Mult Scler 2001;7:320-6.  Back to cited text no. 16
    
17.Koch-Henriksen N, Brønnum-Hansen H, Stenager E. Underlying cause of death in Danish patients with multiple sclerosis: Results from the Danish Multiple Sclerosis Registry. J Neurol Neurosurg Psychiatry 1998;65:56-9.  Back to cited text no. 17
    
18.Hirst C, Swingler R, Compston DA, Ben-Shlomo Y, Robertson NP. Survival and cause of death in multiple sclerosis: A prospective population-based study. J Neurol Neurosurg Psychiatry 2008;79:1016- 21.  Back to cited text no. 18
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19.Grytten Torkildsen N, Lie SA, Aarseth JH, Nyland H, Myhr KM. Survival and cause of death in multiple sclerosis: Results from a 50- year follow-up in Western Norway. Mult Scler 2008;14:1191-8.  Back to cited text no. 19
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20.Vasheghani-Farahani A, Sahraian MA, Darabi L, Aghsaie A, Minagar A. Incidence of various cardiac arrhythmias and conduction disturbances due to high dose intravenous methylprednisolone in patients with multiple sclerosis. J Neurol Sci 2011;309:75-8.  Back to cited text no. 20
    
21.Schroth WS, Tenner SM, Rappaport BA, Mani R. Multiple sclerosis as a cause of atrial fibrillation and electrocardiographic changes. Arch Neurol 1992;49:422-4.  Back to cited text no. 21
    
22.Dalgas U, Stenager E, Ingemann-Hansen T. Multiple sclerosis and physical exercise: Recommendations for the application of resistance-, endurance- and combined training. Mult Scler 2008;14:35-53.  Back to cited text no. 22
    
23.Pearson SB, Banks DC, Patrick JM.The effect of beta-adrenoceptor blockade on factors affecting exercise tolerance in normal man. Br J Clin Pharmacol1979; 8:143-8.  Back to cited text no. 23
    
24.Van Baak MA. Beta-adrenoceptor blockade and exercise. An update. Sports Med 1988;5:209-25.  Back to cited text no. 24
    




 

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