Alternative Indications for p-Blockers The action and efficacy of

~-blockers

in anxiety

Initial reports regarding the efficacy of propranolol in controlling sinus tachycardia in anxiety and cardiac symptoms in neurosis have led to further investigations into the use of /3-blockers in anxiety states. Interest has been aroused in developing alternative treatments for anxiety without the problems of dependence and withdrawal symptoms associated with benzodiazepine therapy. Several placebo controlled studies have produced clear evidence of the efficacy of propranolol and oxprenolol in anxiety states, mainly in generalised anxiety rather than phobic states, and also in normal subjects under stress. /3-Blockers seem to be less effective overall than benzodiazepines but most studies have included patients previously on benzodiazepines, without an adequate washout period. A combination of propranolol + diazepam may be more effective than either drug alone. No long term studies regarding the efficacy of }3-blocker treatment in anxiety have been carried out so far. It seems likely that the efficacy of /3-blockers in anxiety is due to the blockade of /3-adrenoceptors, as 0propranolol (which has no /3-adrenoceptor blocking activity) is no more effective than placebo in anxiety. However, it should not be ignored that /3-blockers have other pharmacological properties such as the ability to bind to 5-hydroxytryptamine receptors. Peripheral }3-blockade, rather than central blockade, is more likely to be the main mechanism of action, as practolol (which does not enter the brain readily) is effective in anxiety. Also, /3-blockers generally seem to be more effective in somatic rather than psychic anxiety but there may still be some central component to their action. The efficacy of /3-blockers in the treatment of somatic anxiety symptoms is well established, although it may be less than the efficacy of benzodiazepines. Long term efficacy and the possibility of withdrawal symptoms require further investigation. Peet, M. Postgraduate Medical Journal 60. 16-18 (Suppl. 2, 1984) [34 references]

~-Blockers

in the treatment of situational anxiety . ..

Sympathetic activation in fear or situational anxiety produces cardiovascular and biochemical changes as well as affecting performance. Fear and anxiety can produce tachycardia of 110-210 beats/min in stressful situations such as driving in heavy traffic, public speaking, the giving of a musical performance and competition driving. Blood pressure probably increases producing a great strain on the cardiovascular system. The outpouring of catecholamines stimulates the release of free fatty acids which are incorporated into triglycerides, if not immediately utilised to produce energy. These may encourage the development of atheroma and coronary artery disease. Free fatty acid can also produce dysrhythmias as can the hypokalaemia produced by catecholamines. There seems to be a complex relationship between anxiety and performance. Initial apprehension improves performance up to a certain level, then further anxiety produces a deterioration in performance. However, different components of performance behave differently under stress. The effects of }3-blockers in reducing catecholamine-induced effects, such as tachycardia, ST changes and hyperventilation, are well known. Systolic increases in blood pressure are probably decreased and tremor is reduced by drugs with iJ2-adrenoceptor blocking activity while hypokalaemia is blocked by non-cardioselective iJ-blockers. There is also an anti-anxiety effect which is probably peripherally mediated. Several studies have been carried out on the effects of iJ-blockers in situational anxiety, particularly during musical performance. A crossover double-blind study of 24 musicians given 40mg oxprenolol showed marked improvement of anxiety and anxiety-induced disturbances of performance by subjective and objective assessment. A similar study of 40mg propranolol in 29 musicians gave similar results. Increased /3-stimulation produced by oral terbutaline caused an increase in anxiety and marked deterioration of performance. A double-blind study of 5mg pindolol in 30 musicians also showed a decrease in anxiety and subjective improvement in performance. A crossover study comparing 40mg nadolol or 2mg diazepam with placebo showed that nadolol produced a fall in pulse rate and abolished anxiety-induced tachycardia and disturbances of performance although there was no clear effect on anxiety. However, diazepam had no effect on pulse rate or anxiety, and subjects were more lethargic and tended to overvalue their performance, which actually deteriorated. Beneficial effects of /3-blockers have been noted in other situations. Similar results were seen in examinations. Students given 80mg oxprenolol showed a decrease in anxiety without undue confidence but had better results than expected, while those given diazepam showed increased confidence but worse results. Propranolol 40mg and metoprolol 50mg have both been shown to improve anxiety, speech and nonverbal behaviour during public speaking. However, some studies have shown impaired recall (propranolol), decrease in complex tracking scores and concentration (oxprenolol) and complex reaction time (propranolol), although generally these have not been seen in anxiety-provoking situations and more lipid-soluble }3-blockers have been implicated more frequently. For a single important anxiety-provoking event, iJ-blockers are very useful and preferable to benzodiazepines. A trial run is recommended. Cardioselective /3-blockers should be avoided if tremor is prominent. Cold fingers in musicians may be worsened by /3-blockers, lipid-soluble iJ-blockers may cause insomnia and no }3-blockers should be prescribed for asthmatics, In these cases, a placebo may be effective. Recurrent anxiety-provoking events can be a problem and can produce alcohol or benzodiazepinedependence. This may be a self-taught phenomenon, often produced by negative feedback. Here /3-blockers, 0156-2703/84/0901-0015/0$01.00/0 © ADIS Press

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In a more recent study of propranolol 80-160 mg/day In c4t) patIents Wltn mIgraIne, ("LlO responaea to propranolol. In a double-blind crossover study, 11 of 24 patients responded to propranolol 160 mgjday compared with 3 of 24 who responded to femoxitine, a 5-hydroxytryptamine uptake inhibitor, given in a dose of 400mg/day. A retrospective study of 1036 patients treated for migraine showed that 84% of patients treated with propranolol (up to 320 mg/day) for 1 year or more were improved compared with 32% of patients given other treatments. Another study showed no significant difference between timolol 20 mg/day and propranolol 160 mg/day, but results-from only 18 patients were available. A study of nadolol, another pure f3adrenoceptor antagonist, showed that 160-240mg nadolol was more effective than 80mg nadolol or placebo in reducing migraine attacks in a group of 80 patients. Atenolol, which has cardioselective properties, was significantly better, in doses of 100 mg/day, than placebo in reducing incidence of headaches in a doubleblind crossover study of 24 patients. Thus f3-adrenoceptor drugs which do not have partial agonist properties seem to be more effective than partial agonist drugs in prophylaxis of migraine regardless of cardioselective properties. They are generally well-tolerated, although there may be problems in asthmatics or ischaemic changes especially in association with ergotamine. It is not yet known whether migraine is caused primarily by vascular changes or whether these are secondary to another primary disorder. Not all migraine patients respond to f3-blocking treatment. This may be because of heterogenicity in the disease process or in the drug action. The fact that drugs without partial agonist activity are more effective in migraine may suggest that partial agonist activity prevents the therapeutic effect. As their action is prophylactic, they may affect the disease process at an early stage. f3-Adrenoceptor blockade is unlikely to be the mechanism of action as f3-blockers with partial agonist activity are not effective in migraine. Antagonism of 5-hydroxytryptamine is also unlikely to be important as f3blockers are not effective in acute migraine attacks. Drugs which have partial agonist activity and are 5hydroxytryptamine antagonists are not effective in migraine. Atenolol is relatively inactive in 5hydroxytryptamine antagonism. There seems to be no good evidence of increased central sympathetic discharge in migraine in man. Atenolol is only poorly lipid soluble and enters the brain with difficulty but is effective in migraine. D-propranolol, DL-propranolol, timolol and metoprolol all inhibit thromboxane synthesis by platelets and platelet aggregation. If migraine is caused by an abnormality in platelet behaviour, the basic mechanism could be a membrane effect. D-propranolol has little f3-blocking activity but a marked membranestabilising effect. This effect could be mediated by interference with calcium mobilisation through the membrane. Calcium antagonists (verapamil) have been shown to be active in migraine. However atenolol has virtually no membrane stabilising effect. Pure antagonists such as propranolol increase the number of f3receptors and their responsiveness during prolonged treatment. However, no generalised f3-adrenoceptor defect has been shown in migraine patients and, as previously noted, not all f3-blockers are effective in migraine. f3-Blockers may also increase responsiveness to other agonists such as prostacyclin [epoprostenol]. Pure antagonists are more likely to produce this effect than partial agonists which would explain the difference in their effect in migraine. However, 1 study has found no evidence of prostacyclin receptor defect in migraine. Although some f3-blocking drugs are useful prophylactically in some patients, the mechanism of their action is still not known. Turner, p . Postgraduate Medical Journal 60: 51-55 (Suppl. 2, 1984) [39 references]

Practical experience of the .use of ~-blockers in migraine Definition of migraine as a disease is difficult, the main common feature being its episodic nature with periods of relative freedom in between. Critical assessment of clinical trials of treatments may be a problem and uncontrolled observations and personal experiences are often reported. Propranolol is frequently used at the Princess Margaret Migraine Clinic in Britain. Further, the author's experience suggests that propranolol which is a non-selective, membrane-stablising, non-agonistic and CNS-penetrating f3-blocker, is the present drug of choice in migraine prophylaxis. when usual contraindications are followed, side effects are few, fatigue, sleep disturbance and coldness of extremities being the most usual. Initial dosage should be 40-80 mg/day and may be increased rapidly to 320 mgjday. Dosage can then be reduced to maintenance levels if response is adequate. If there is no response 480 mgjday can be given or additional small doses of amitryptiline, Maximal response may not be obtained within a few weeks. One study showed that 84% of patients had improvement after 1 year of propranolol treatment compared with 50% after 3 months treatment However, such long term treatment may have problems, especially in compliance, and long acting preparations may be an advantage, Clinical trials have demonstrated the efficacy of propranolol in migraine prophylaxis. Nine double-blind studies of propranolol 80-240mg in 251 patients have shown propranolol to be better than placebo. Only 1 study could show no significant difference. Other studies have shown propranolol to be at least as effective as methysergide or clonidine. The only other f3-blockers which seem to be effective in migraine are atenolol, metoprolol and nadolol. Acebutolol, alprenolol, oxprenoloLand pindolol are ineffective. Thus, it seems likely that factors other than f3blockade are responsible for the effects of these {3-blockers in migraine. The dextro-isomer of propranolol which has little f3-blocking activity may be effective in migraine. All the f3-blockers effective in migraine, (with

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in combination with relaxation techniques and encouragement of a more positive approach, are extremely effective and can result in a permanent behavioural change. James. I.M. Postgraduate Medical Journal 60..' 19-25 (Suppl. 2. 1984) [27 references]

... morbid anxiety Anxiety may be normal, experimental, or morbid. Further, it may be predominantly psychic (worrying, phobias, fear, insecurity), somatic (tight chest, palpitations, gastro-intestinal symptoms) or psychosomatic (hyperventilation syndrome, neurocirculatory asthenia, Da Costas' syndrome). The action of {J-blockers in anxiety seems to involve blocking of peripheral {J-adrenoceptors. Many stUdies have confirmed the efficacy of {J-blockers in the treatment of anxiety, particularly somatic symptoms involving the peripheral system, e.g. cardiovascular and autonomic nervous· system effects, although they seem to be less effective than benzodiazepines. They seem to be more effective in morbid than in experimental anxiety and may be particularly effective in panic attacks where there is a surge of adrenaline, palpitations and intense fear, and in the analogous 'stage fright' which occurs in more appropriate situations. Propranolol + diazepam seem to be more effective than either drug alone in the treatment of somatic anxiety. Although {J-blockers are less effective than benzodiazepines in anxiety, there is concern about overprescription, dependence, tolerance and side effects with the latter. Thus, benzodiazepines are generally contraindicated for chronic treatment. An alternative might be a 1-week trial of a {J-blocker before benzodiazepine or other drug treatment is initiated, as it is difficult to identify those patients with mainly somatic symptoms who would benefit from {J-blocker treatment. An initial dosage of 40-S0mg propranolol tid can be increased by 40 mg/day until resting pulse rate begins to fall. Dosage increases are stopped when pulse rate falls below 70 beats/min and medication discontinued if pulse falls below 60 beats/min. Self monitoring, symptom control and an understanding of symptoms form the basis of this treatment for anxiety. Hallstrom.

c.. Postgraduate Medical Journal 60.: 26-28 (Suppl.2,

1984) [20. references]

... and withdrawal states Certain symptoms (e.g. tremor, palpitations, nausea, retching and anxiety) are common to alcohol, opiate and benzodiazepine withdrawal states and many are mediated through a- or {J-receptors. Nausea and tremor may also be seen during barbiturate withdrawal. Propranolol was first used for withdrawal symptoms because of evidence that fI-blockers relieve somatically orientated anxiety. There seem to be various mechanisms producing a wide variety of withdrawal symptoms of-different-stages~ Various transmitter systems may be involved and receptor hypersensitivity can produce rebound phenomena. Symptoms produced by {J-adrenergic stimulation (tremor, palpitations, awareness of fast heart beat, flushing and faintness) are likely to be improved most by {J-blocker treatment. Improvement of anxiety and tension may be produced by a central action or by negative feedback from reduction of peripheral symptoms. Propranolol is the {J-blocker used in most studies of treatment of withdrawal states, although other fIblockers may be equally effective with the possible exception, theoretically, of those with partial agonist activity. A controlled trial showed propranolol to be more effective than placebo in reducing tension and depression during alcohol withdrawal. But another study found no significant difference between propranolol and placebo in levels of anxiety and tension in chronic alcoholics. An, uncontrolled study found propranolol 40SO mgjday improved tremor and, in 2 patients, anxiety also. Parenteral propranolol has also been shown to be effective in reducing tremor and heart rate during alcohol withdrawal. Another study showed that propranolol 160 mgjday was more effective than propranolol 40 mgjday or chlordiazepoxide or chlordiazepoxide + propranolol 40 mg/day or placebo in reducing tremor, heart rate and adrenergic overactivity (raised blood pressure, increased urinary catecholamines) during alcohol withdrawal, although subjective evidence suggested propranolol 40 mgjday + chlordiazepoxide was most effective. Only 1 study has supported claims that propranolol reduces craving during opiate withdrawal, but it also seemed to increase the severity of withdrawal symptoms. Another study suggested that propranolol reduces autonomic symptoms of opiate withdrawal, but has no effect on craving. A study of propranolol 60-120 mgjday during benzodiazepine (diazepam or lorazepam) withdrawal showed a significantly lower withdrawal symptom score compared with placebo in 40 patients over a 2-week period. Although {J-adrenoceptor-mediated symptoms account for only a small proporation of benzodiazepine withdrawal symptoms, a second study of 36 patients showed that these did form an important component of this syndrome and could explain propranolol's efficacy. In conclusion, propranolol should be used as an adjuvant to other treatments in alcohol withdrawal, except when there is marked tremor or tachycardia. It can be used in combination with benzodiazepines in more severe cases or for anxiety. In opiate withdrawal, there are no clear indications for use of {J-blockers except possibly where there is marked somatic anxiety. In benzodiazepine withdrawal, propranolol seems promiSing but, further studies are required to clarify its usefulness. Seivewright, N. and Tyrer. P.J: Postgraduate Medical Journal 60.' 47-50. (Suppl. 2, 1984) [22 references]

The efficacy and action of ~-blockers in migraine One recent review concluded that only 3 {J-blocking drugs, propranolol, timolol and atenolol have been shown to be effective in the prophylaxis of migraine. The partial agonists, oxprenolol, pindolol, acebutolol and . alprenolol are ineffective.

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the possible exception of practolol) seem to lack partial agonist activity. There does not seem to be any relationship between membrane-stabilising properties, cardioselectivity or eNS penetration and effect in migraine. Further studies of post-{3-blockade hypersensitivity and effects of selective {3-blockers on platelet function may reveal more about the mechanism of action of [3-blockers in prophylaxis of migraine. Steiner, T.J and Joseph , R.: Postgraduate Medical Journal 60: 56-60 (Suppl. 2, 1984) [37 references]

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