Propranolol, clonidine, urapidil and trazodone infusion in essential tremor: a double-blind crossover trial

Accelerometric tremorgrams were recorded from 25 subjects affected by essential tremor and analysed by a Berg-Fourier frequency analyser before and during venous infusion of the following drugs: propranolol (beta-blocker), clonidine (alpha-presynaptic adrenergic agonist), urapidil (alpha-postsynaptic blocker), trazodone (adrenolytic agent) and placebo. The washout interval between infusions was 3 days. Recordings and data analyses were performed in a double-blind crossover trial. Tremor was classified as: at rest; postural (arms hyperextended); and intention (finger-nose test). Analysis of the results showed that propranolol and clonidine reduced significantly (P = 0.01 and P = 0.009, respectively) the power spectrum of postural tremor, but left at rest and intention tremors unchanged. No significant effects on the tremor power spectrum were observed after placebo, urapidil or trazodone administration. None of the drugs had any effect on tremor frequency.     

Clonidine in prophylaxis of migraine

Various drugs have been used in migraine to bring down the frequency of attacks. Recently clonidine hydrochloride, an antihypertensive agent, has been reported to be effective. The mechanism of action of this drug is not clear, but it is thought to act through its effect on tyramine metabolism. A double-blind cross-over trial using clonidine and identical-looking placebo tablets was carried out in 20 patients of migraine. There was no statistically significant difference between clonidine and the placebo in reducing the frequency of attacks, as evaluated by the non-parameteric test of Wilcoxon. No side effects of clonidine were observed.     

Transiently overexpressed alpha2-adrenoceptors and their control of DNA synthesis in the developing brain

During brain development, neurotransmitters act as trophic factors controlling the patterns of cell replication and differentiation. Alpha2-adrenoceptors (alpha2ARs) are transiently overexpressed in zones with high mitotic activity and we evaluated whether these receptors are linked to DNA synthesis in the perinatal rat brain. Acute administration of clonidine (2 mg/kg), an alpha2AR agonist, elicited dramatic decreases in DNA synthesis in the forebrain, brainstem, and cerebellum whether given on gestational day (GD) 21, or on postnatal days (PN) 1 or 8. However, alpha2AR blockade elicited by yohimbine (2.5 mg/kg) also resulted in decreased DNA synthesis on GD21 and PN8, albeit to a smaller extent than with clonidine. Yohimbine was able to blunt the effects of clonidine, verifying that both drugs are acting through the same receptor population. Because betaARs are also known to regulate DNA synthesis, we used propranolol (10 mg/kg) blockade of betaARs to evaluate whether the alpha2AR effects were mediated by presynaptic autoreceptors that regulate the release of norepinephrine and consequent betaAR responses; the effects of yohimbine were still discernible in the presence of propranolol. Accordingly, transiently overexpressed alpha2ARs in the developing brain participate in the control of DNA synthesis in a biphasic manner, with promotional actions at low, endogenous levels of stimulation, but inhibitory effects when stimulation is high. Effects on alpha2ARs are likely to contribute to long-term consequences of adrenergic agents used in obstetrics or neurotoxicants that affect adrenergic activity.     

The alpha(2C)-adrenergic receptor mediates hyperactivity of coloboma mice, a model of attention deficit hyperactivity disorder

Drugs that modify noradrenergic transmission such as atomoxetine and clonidine are increasingly prescribed for the treatment of attention deficit hyperactivity disorder (ADHD). However, the therapeutic targets of these compounds are unknown. Norepinephrine is also implicated in the hyperactivity exhibited by coloboma mice. To identify the receptor subtypes that regulate the hyperactivity, coloboma mice were systematically challenged with adrenergic drugs. The beta-adrenergic receptor antagonist propranolol and the alpha(1)-adrenergic receptor antagonist prazosin each had little effect on the hyperactivity. Conversely, the alpha(2)-adrenergic receptor antagonist yohimbine reduced the activity of coloboma mice but not control mice. Subtype-selective blockade of alpha(2C)-, but not alpha(2A)- or alpha(2B)-adrenergic receptors, ameliorated hyperactivity of coloboma mice without affecting activity of control mice, suggesting that alpha(2C)-adrenergic receptors mediate the hyperactivity. Localized in the basal ganglia, alpha(2C)-adrenergic receptors are in a prime position to impact locomotor activity and are, therefore, potential targets of pharmacotherapy for ADHD.     

Functional neuroteratology of drugs acting on adrenergic receptors.

Noradrenaline neurotransmission becomes functional early in the development of the brain. Therefore, interference with this transmission by receptor agonists or antagonists, which are used clinically in various conditions in pregnancy, may alter brain development. Long-term biochemical, morphological, behavioural and electrophysiological effects have been reported after pre- or postnatal exposure of rats to adrenergic drugs, the alpha 2-agonist clonidine and the beta-antagonist propranolol in particular, and are summarized here.     

CLONIDINE (CATAPRESAN)-DOUBLE-BLIND STUDY AFTER LONG-TERM TREATMENT WITH the DRUG IN MIGRAINE

A double-blind, cross-over study with clonidine (Catapresan) and placebo was carried out in 29 patients with migraine, who had received clonidine during a 4 to 32 months pre-test period (mean 10 months) and who appeared to have benefited from the treatment. Clonidine and placebo were given for 7 weeks each, but only the last 5 weeks in each period were used for the statistical evaluation. In the entire material, clonidine was significantly superior to placebo. In nine of the patients, however, various other factors might have influenced the attack frequency and severity. If these nine patients were excluded, no statistically significant difference between clonidine and placebo was found.     

Pharmacotherapy for posttraumatic stress disorder: A status report

Pharmacotherapy for posttraumatic stress disorder (PTSD) appears to be a promising approach because many neurobiological systems appear to be altered in PTSD patients. This review encompasses the current published literature on clinical trials with antiadrenergic agents (propranolol, clonidine, guanfacine), selective serotonin reuptake inhibitors (SSRI), other serotonergic agents, monoamine oxidase inhibitors (MAOI), tricyclic antidepressants (TCA), benzodiazepines, anticonvulsants, narcotic antagonists and antipsychotic agents. It is suggested that although more randomized clinical trials are needed with the drugs cited in the present review, that an important future direction would be with drugs that directly modify the complex psychobiology of the human stress response, in general, and PTSD-related abnormalities, in particular.     

Differential involvement of sympathetic nervous system and immune system in the modulation of TNF-alpha production by alpha2- and beta-adrenoceptors in mice

In the present study, the regulation of tumor necrosis factor-alpha (TNF-alpha) production by alpha2- and beta-adrenoceptors located on noradrenergic nerve terminals and on macrophages was studied in endotoxaemic mice. We found that reduction of the sympathetic outflow by reserpine dramatically increased the lipopolysaccharide (LPS)-induced TNF-alpha production, demonstrating that the release of endogenous noradrenaline (NA), controlled by presynaptic alpha2-adrenoceptors, was a determinant factor in this model. By using alpha2- and beta-adrenergic drugs (clonidine, CH-38083, isoproterenol, propranolol) we provided the first in vivo evidence that, beside the dominance of neuronal alpha2- and macrophage beta-adrenoceptors, the alpha2-adrenoceptors on macrophages were also involved in the modulation of LPS-induced TNF-alpha production. Since adrenergic drugs are widely used in the clinical practice, our findings may have therapeutical implications.     

A comparison of primidone, propranolol, and placebo in essential tremor, using quantitative analysis.

The effects of placebo, propranolol and primidone were compared in 14 patients with essential tremor in a double blind, randomised, crossover study. Objective measures of tremor were obtained using an accelerometer with subsequent spectral analysis. Both propranolol (p less than 0.01) and primidone (p less than 0.01) gave significant improvement in tremor, but there was no significant difference in improvement between these drugs. Patients with higher dominant frequencies of tremor tended to respond to both drugs, while those with lower frequencies improved on one or other. There was no differential effect between the drugs with the frequency of tremor.     

Case report of propranolol (Inderal) pharmacotherapy for neuroleptic-induced akathisia and tremor

This case report describes a schizophrenic patient who developed akathisia and tremor following neuroleptic pharmacotherapy with fluphenazine decanoate. The patient also suffered from familial (benign essential) tremor. The patient's neuroleptic-induced extrapyramidal side effects were not relieved by anticholinergic antiparkinson drugs or by phenobarbital. The patient was started on propranolol 10 mg b.i.d. She was also started on diazepam 5 mg t.i.d. for anxiety. The diazepam dose was held constant and propranolol was gradually increased to 40 mg q.i.d. The patient's extrapyramidal symptomatology gradually resolved over the course of one month, during which time the propranolol dose was being steadily increased. Propranolol also effectively controlled her familial tremor. After nine months as an outpatient, during which time the patient was neuroleptic-free, she developed psychotic decompensation for which she was treated with thiothixene. Akathisia or tremor did not develop, possibly because the patient was taking propranolol simultaneously. Propranolol may be useful for treating neuroleptic-induced akathisia. This requires systematic investigation with open and controlled trials.     

Growth hormone (GH) response to clonidine and growth hormone releasing factor (GRF) in normal controls

To investigate the relationship between the plasma growth hormone (GH) response to provocative challenge with the hypothalamic peptide growth hormone-releasing factor (GRF) and the alpha 2-adrenergic agonist clonidine, we administered GRF (1 microgram/kg), clonidine (2 micrograms/kg), and placebo to 21 healthy normal controls (13 men and eight women). Both clonidine and GRF caused significant increases in plasma GH levels over baseline. The peak GH-responses to GRF and clonidine were similar (GRF = 8.7 +/- 6.7 ng/ml; clonidine = 6.5 +/- 5.9 ng/ml; Wilcoxon test: s = 361, z = -1.31, p = NS). The GH responses to GRF and clonidine were significantly correlated (rs = 0.62, n = 20, p = 0.004). Unexpectedly, we found that five of the 21 (26%) normal controls had no GH secretory response to either GRF or clonidine. There was a modest gender effect with clonidine (men greater than women; p less than 0.06) and a negative correlation between GH secretion and age with both GRF and clonidine. Neither GRF nor clonidine had an effect on cortisol levels (DRUG x TIME interaction: F(8,152) = 0.60, p = NS). These findings are consistent with animal studies suggesting that the GH response to clonidine is mediated by GRF. The age and gender effects underscore the importance of careful matching for these factors in studies measuring the GH secretory response.     

Tolfenamic acid versus propranolol in the prophylactic treatment of migraine

The prophylactic effect of tolfenamic acid and propranolol was studied in a randomized double-blind cross-over trial of 76 patients with migraine with or without aura. After a 4-week run-in period patients were randomly allocated to treatment with either tolfenamic acid 100 mg three times daily or propranolol 40 mg three times daily for 12 weeks. After a placebo wash-out period of 4 weeks the patients got the alternative drug for 12 weeks; 56 patients completed the study. Both drugs significantly reduced migraine attacks as judged from the reduction in the efficacy parameters (migraine hours, migraine days, and migraine intensity) in the treatment periods compared with the run-in period. No statistical significant difference in any efficacy parameter was found between the two drugs (level 2α= 0.05, α= 0.10). The adverse effects showed no statistical difference in frequency between the 2 treatments. Twenty patients discontinued the study: 12 patients on propranolol and 8 patients on tolfenamic acid. Side effects were the cause of premature discontinuation of study medicine in 9 patients during propranolol treatment (dizziness, fatigue, and fall hi blood pressure) and in 5 patients during tolfenamic acid treatment (gastrointestinal symptoms).     

Opposite role of alpha2- and beta-adrenoceptors in the modulation of interleukin-10 production in endotoxaemic mice

Our aim was to investigate the role of adrenoceptors in the modulation of in vivo interleukin-10 (IL-10) production in lipopolysaccharide (LPS)-treated mice. The effect of different adrenergic drugs on plasma concentration of IL-10 was measured by ELISA 90 min after LPS injection. Our results confirmed the involvement of beta-adrenoceptors since the beta-agonist isoproterenol significantly increased the IL-10 production in response to LPS stimulation, whereas the beta-antagonists propranolol decreased it. In contrast, the alpha2-agonists UK-14304, clonidine and xylazine significantly decreased the IL-10 plasma level, whereas the alpha2-antagonists CH-38083, prazosine and WB-4101 increased it. Our results provide the first in vivo evidence that, in addition to beta-adrenoceptors; alpha-adrenoceptors play also a very important role in the regulation of IL-10 production under endotoxaemic conditions.     

TREATMENT OF FAMILIAL PERIODIC HYPOKALAEMIA WITH PROPRANOLOL (INDERAL ®)

Four patients suffering from familial periodic paralysis with hypokalaemia (FPP) were subjected untreated to standardized induction of paralysis. The induction was repeated after pre-treatment with the beta receptor blocker propranolol (Inderal ®). In three of the patients propranolol had no or even a negative effect upon the development of paralysis or upon the fall in serum potassium. In one patient a slight prophylactic gain was achieved. It was not possible to demonstrate any difference in the serum level of glucose or insulin during the induction of paralysis according to whether the patients were untreated or treated with propranolol. Short-lasting out-patient treatment of the patient who had apparently had some slight prophylactic benefit from propranolol had to be discontinued after 11 days because of an unusually severe and long-lasting attack. It is concluded that propranolol has no major effect in the treatment of FPP—unlike its favourable effect in thyrotoxic familial periodic paralysis (TFPP).     

Atenolol vs. propranolol in essential tremor A controlled, quantitative study

The beta-1 selective, hydrophilic adrenoceptor blocking drug atenolol (100 mg daily) was compared to the non-selective, lipid-soluble beta-blocker propranolol (240 mg daily), and to placebo, in a double-blind cross-over study in 24 patients with essential tremor. Atenolol and propranolol caused a similar decrease in heart rate. Both beta-blockers also suppressed the tremor intensity; there was no significant difference between them, but both were significantly better than placebo. These drugs did not affect tremor frequency. Twelve of the patients preferred propranolol subjectively, one preferred atenolol and none preferred placebo. No marked side-effects were observed. It was concluded that atenolol and other cardio-selective blockers offer an alternative for patients unable to tolerate the non-selective drugs. The site of action and receptor sub-type involved have still to be determined.     

Remission of Tardive Dystonia with ECT

A 30-year-old patient with tardive dystonia, who had failed to respond to cessation of neuroleptics, placebo, diazepam, biperiden, propranolol, and clonidine, had an impressive response to courses of electroconvulsive therapy (ECT) on three successive trials.     

Prophylactic treatment of migraine with tolfenamic acid, propranolol and placebo

In 31 patients with at least 3 migraine attacks per month the prophylactic effect of tolfenamic acid 300 mg/day, propranolol 120 mg/day, and placebo was compared in a randomized double-blind cross-over study. The patients were treated for 12 weeks with each drug, but only the last 11 weeks were used for evaluation. Both tolfenamic acid and propranolol significantly reduced the number of attacks, the total duration of attacks and additional drugs taken when compared with placebo. Tolfenamic acid, but not propranolol, significantly reduced the median intensity of pain and the number of attacks confining the patients to their beds when compared with placebo. Only mild adverse reactions occurred with no significant difference between the drugs. It was concluded that the prophylactic effect of tolfenamic acid 300 mg/day in migraine was at least as good as propranolol 120 mg/day.     

Influence of alpha stimulants and beta blockers on yohimbine toxicity

1. Potentiation of yohimbine-induced sublethality has been largely used to predict antidepressant action. 2. Several products were tested in order to understand the mechanism of this toxicity better: an alpha-1 central stimulant (adrafinil); an alpha-2 central stimulant (clonidine); and 4 beta-blockers (propranolol, atenolol, penbutolol and metoprolol). 3. It was found that atenolol and adrafinil could not antagonize toxicity, whereas clonidine and the other 3 beta-blockers could. 4. It is suggested that a central beta-origin toxicity exists since only beta-blockers which cross the blood-brain barrier are capable of antagonizing this activity. 5. The fact that clonidine also antagonized this toxicity may be explained by the beta-antagonist action of this substance at the high doses used.     

Effectiveness of Clonidine in Child and Adolescent Sleep Disorders

Objective We aimed to investigate the improvement in sleep quantity and quality when clonidine was used in children and adolescents with insomnia. We also examined how sociodemographic characteristics such as age, sex, underlying psychological problems, and levels of depression and anxiety affected the effect of clonidine. Methods We retrospectively reviewed outpatients aged 6 to 24 who took clonidine due to insomnia from September 2019 to September 2021 at the Department of Psychiatry at Eunpyeong St. Mary’s Hospital of Catholic University. We used the Pittsburgh Sleep Quality Index (PSQI), Children’s Depression Inventory (CDI), and State-Trait Anxiety Inventory (STAI) for our study. Results A total of 62 participants were included in our study (34 females, mean age 13.94±4.94 years). After using clonidine, there was a significant decrease in PSQI components 1, 2, and 5, especially PSQI component 2. There was a greater decrease in sleep latency when clonidine was used in females, those aged between 13 and 24, those with mood/anxiety disorder or attention-deficit/hyperactivity disorder, those whose sleep latency exceeded 60 minutes at baseline, and those who used clonidine for more than 14 days. Those with higher STAI-Trait scores and CDI scores at baseline showed less improvement in total PSQI scores. Conclusion Considering that there are currently no Food and Drug Administration-approved sleep drugs for children and adolescents and no apparent difference in efficacy and safety among sleep drugs, we demonstrated that treatment with clonidine might be a good approach to improve sleep quality and quantity for children and adolescents.     

The autonomic nervous system in Gilles de la Tourette's syndrome

Twenty-three patients with Gilles de la Tourette's syndrome (GTS) underwent noninvasive investigation of autonomic nervous system (ANS) function, as did 23 age-matched controls. ANS function in GTS patients was no different from that of controls, and patients receiving neuroleptic drugs had the same ANS function as untreated patients. All 23 patients later received clonidine and were retested. The ANS values before administration of clonidine were compared with those while patients were taking clonidine. The only significant change (p less than 0.01) with clonidine was a reduced resting pulse rate. The combination of clonidine and neuroleptic drugs did not induce significant autonomic changes compared with neuroleptic therapy alone. These results indicate that the ANS in GTS patients is normal and that the drugs used to abate tics do not produce clinically significant changes in ANS when chronically given. The findings suggest that the pathophysiology and treatment of GTS do not directly involve the nuclei or tracts of autonomic regulation.