Treating anxiety with either beta blockers or antiemetic antimuscarinic drugs: a review

Mental Health in Family Medicine 2015; 11:89-99 2015 Mental Health and Family Medicine Ltd Treating Anxiety with either Beta Blockers or Antiemetic Antimuscarinic Drugs: A Review Thomas P. Dooley, Ph.D.
TPD LLC, 7100 Cabin Lane, Pinson, Alabama 35126, USA; Tel: 205-222-6145; E-mail: Beta adrenergic receptor antagonists and antiemetic scopolamine) or over-the-counter (e.g., meclizine) for the muscarinic receptor antagonists are useful for mental health treatment of non-cardiovascular symptoms that manifest in in primary care and family medicine settings, as they provide anxiety disorders. Antiemetic agents inhibit nausea, vomiting, favorable risk/benefit profiles, and especially so relative to sweating, and in some instances other psychic (CNS) symptoms. benzodiazepines. Beta blockers (e.g., propranolol) prescribed The symptoms affected by antimuscarinic agents represent the off-label have been known for decades to provide some, "inverse" of the symptoms of acute anxiety affected by beta albeit limited, anxiolytic benefit for patients affected by blockers. Thus, anxiety disorders can be treated by alternative social anxiety disorder (social phobia), including performance biochemical pathways, as well as by affecting alternative anxiety. Blockage of adrenaline's binding to cardiovascular symptoms thereof. The results of human clinical studies are beta adrenergic receptors inhibits tachycardia, reduces blood summarized for both classes of anxiolytic agents that display pressure, and thus diminishes palpitations in acute anxiety complementary pharmacologic approaches to a diverse array and panic. However, beta blockers are not effective against of symptoms.
the psychic (CNS) symptoms, such as anxiousness, fear, and avoidance. Another approach involves antiemetic muscarinic MeSH Headings/Keywords: Anxiety, Panic, Anxiolytic,
receptor antagonists that are available by prescription (e.g., Beta Adrenergic, Muscarinic, Cholinergic, Antagonist, The biochemical pathways of the beta adrenergic receptor and muscarinic receptor gene families are appropriate anxiolytic The pharmaceutical marketplace in the Western World targets for treating the symptoms of social anxiety disorder provides numerous medical treatments for anxiety disorders. (social phobia) including performance anxiety (e.g., stage fright), Two classes of medications that have demonstrated some as well as panic attack (PA), panic disorder (PD), agoraphobia, effectiveness and desirable risk/benefit profiles in the clinical generalized anxiety disorder, and post-traumatic stress disorder literature are beta blockers and antiemetic antimuscarinic drugs. (PTSD). These various anxiety Disorders are delineated within These agents have been widely used as monotherapies for a the Diagnostic and Statistical Manual of Mental Disorders least half of a century around the globe. (e.g., DSM-V). These molecular targets can be components They are appealing in large part due to historic safety profiles of the central nervous system (CNS), the peripheral nervous and because they do not exhibit the potential for chemical system, and/or of target somatic tissues (e.g., cardiovascular dependence or substance abuse. Therefore, these two classes and gastrointestinal tissues). The multiplicity of symptoms of of agents are not subject to the US Food & Drug Administration anxiety disorders are under the complex regulation of different (FDA) and Drug Enforcement Agency (DEA) as Controlled neurologic, neuroendocrine, and endocrine pathways.
Substances (i.e., "Scheduled" drugs). Furthermore, many Let us consider the multiplicity of symptoms that occur antimuscarinic drug products are sold without prescriptions, in an acute anxiety episode, of which a panic attack serves as such as over-the-counter (OTC) or in some foreign settings the foremost and severe example. Perception of a "trigger" behind-the-counter with pharmacists' assistance.
circumstance results in the autonomic release of epinephrine Beta blockers and antiemetic antimuscarinic (adrenaline), as well as cortisol and norepinephrine. This in (anticholinergic) active pharmaceutical ingredients (APIs) are turn causes multiple effects consistent with a "fight-or-flight" of particular interest for primary care physicians (PCPs), such response. Symptoms include tachycardia, palpitations (self as family practitioners, internists, and osteopaths, as well as perception of an elevated heart rate and/or of a strong heart beat), physician assistants, nurse practitioners, and dentists. There hypertension, hyperventilation with reduced blood CO and is a need to provide drugs to their affected patients with some altered pH, dyspnea, nausea, vomiting, sweating, anxiousness, anxiolytic efficacy, yet without incurring unnecessary safety fear, avoidance, trembling (tremors), headache, among others. risks. In contrast, this is problematic with the alternative, Many of the somatic and/or psychic (CNS) symptoms of panic more potent, and risk-laden options, such as benzodiazepines. attack are shared in common with other acute anxiety episodes. The more potent drugs are more likely to be prescribed by Therefore, it follows that a treatment for an array of the psychiatrists or hospitalists. Many prescribers in primary care symptoms of panic per se can also be effective against a broader settings are reluctant to prescribe the more potent drugs (e.g., list of anxiety disorders.
benzodiazepines) or are restricted from doing so. Thus, beta Some patients anticipate future episodes of panic or acute blockers and antimuscarinic agents help address this need, anxiety based upon his/her history of prior encounters with a wherein safety is the paramount decision factor.
known "trigger" circumstance. A trigger circumstance might Thomas P. Dooley
be public speaking or music performance, flying or driving, stated regarding benzodiazepines as a class of anxiolytic drugs, a crowd, decision making, an unfamiliar setting, among "Only lorazepam is currently available in a form suitable for others. Treatments may be tailored to be either prophylactic sublingual administration, which was developed in the hope or therapeutic in nature. Given the patients' anticipation of a that, by bypassing the gut, a more rapid onset could be achieved trigger leading toward likely future symptoms, p.r.n. "as needed" similar to that with intramuscular administration. However drug treatments can begin either during or immediately prior Greenblatt et al., [11] found that the sublingual formulation was to the time when symptoms would be expected to commence. absorbed at a rate that did not differ significantly from that of Alternatively prophylatics could be administered continuously regular oral administration of the standard tablets or even from over weeks or years, or within hours of the anticipated triggers.
that of sublingual administration of the standard oral tablets." In aggregate anxiety disorders are extremely common, Thus, benzodiazepines are not suitable APIs for rapid treatment affecting nearly 40 million in the US. With regard to the subset of symptoms of panic attacks or acute anxiety episodes, even experiencing the most severe episodes, the lifetime prevalence when delivered sublingually (mucosally). When "time is of the of PA is 28.3% of the adult US population [1]. The 12-month essence" for therapy, benzodiazepines are inadequate, regardless prevalence of panic disorder (PD) is estimated to be 2.7% of the of the oral or sublingual routes of administration. Perhaps the adult US population [2], with 1.2% considered as "severe" [3]. perception of benzodiazepines' fast-action is due to comparison More than half of affected adults (59.1% or 3.8 million) are with SSRIs, which require a very slow dose-escalation approach receiving treatment(s) [4]. Patients affected by PAs are often over weeks of time to produce a beneficial effect. In that context also affected by the co-morbid conditions of depression [5] as benzodiazepines are faster than SSRIs. But, in spite of FDA well as migraines and other forms of headaches [6,7].
approvals for p.r.n. use of certain benzodiazepines and their broad availability, there still remains a need for fast-acting p.r.n. The current standards-of-care for panic disorder are oral anxiolytics. In fact, an academic psychiatrist characterized this psychiatric prophylactic pharmaceuticals, including: (a) Selective need to the author as "…the Holy Grail of modern psychiatry." serotonin reuptake inhibitors (SSRIs), which are considered as the first choice medicines for PD. Examples include paroxetine Benzodiazepine and SSRI drugs can produce disabling (Paxil®), sertraline (Zoloft®), and fluoxetine (Prozac®); (b) psychic and somatic side effects, such as sedation, lethargy, Benzodiazepines, such as alprazolam (Xanax®), clonazepam chemical dependence, tolerance, impaired cognition, and sexual (Klonopin®), lorazepam (Ativan®), and diazepam (Valium®); dysfunction. As a result of these negative side effects and some and (c) Serotonin-norepinephrine reuptake inhibitors (SNRIs), potential for abuse, benzodiazepines are classified by the FDA such as duloxetine (Cymbalta®) and venlafaxine (Effexor®). as Schedule 4 (IV) Controlled Substances. Many physicians These oral therapies are taken daily for the prevention of and other prescribers are reluctant to prescribe or are restricted panic attacks. Some of these drugs are FDA approved for the from prescribing benzodiazepines. Therefore, beta blockers or prophylaxis of PD, such as paroxetine, sertraline, alprazolam, antiemetic agents that are generally perceived as historically and clonazepam. Other anxiety disorders are also treated in the safe or safer than benzodiazepines are often preferable. This same or a similar manner. For instance, social anxiety disorder, is especially true in the primary care and family practice generalized anxiety disorder, agoraphobia, and PTSD are also disciplines. Sedation and lethargy are often problems for many treated using the same or similar oral daily pharmaceutical of the oral daily anxiolytic therapies, such as benzodiazepines. regimens [8].
It is not uncommon to note a "zombie-like" state in patients taking benzodiazepines. By contrast, beta blockers are non- The pharmaceutical standards-of-care in routine psychiatric addicting and non-sedating. And, the antimuscarinic agents care of panic and anxiety disorders involve two key aspects: are non-addicting, and are non-sedating or minimally sedating (A) prophylaxis, rather than treatment of the symptoms per at appropriate antiemetic doses. However, high doses of some se; and (B) the medications are routinely given as daily oral antiemetics can produce sedation.
"maintenance" medications for persistent use (i.e., chronic prophylaxis), rather than as occasional administration p.r.n. Beta Blockers: Beta adrenergic receptor antagonists are
"as needed" at the time of episodes of symptoms (i.e., acute prescribed "off label" (i.e., without FDA approval) for anxiety disorders, and most notably for performance anxiety and social phobia. Beta adrenergic receptor antagonist agents may be Although oral benzodiazepines have been used as selected from a large group of APIs consisting of propranolol, persistent daily medications for the prophylaxis of panic and atenolol, alprenolol, acebutolol, betaxolol, bisoprolol, acute anxiety, they are not reasonable candidates for a "fast- bucindolol, celiprolol, nadolol, sotalol, esmolol, carteolol, acting" p.r.n. therapy approach. Benzodiazepines are often carvedilol, mepindolol, nebivolol, oxprenolol, penbutolol, mistakenly considered to be "fast-acting", although multiple pindolol, landiolol, metoprolol, timolol, labetolol, among clinical reports indicate otherwise. Zamorski and Albucher others. For convenient recall by prescribers the nomenclature stated, "Benzodiazepines should not be used on an as-needed for all beta blockers contains an "LOL" suffix (and not to be basis for panic disorder. None of the oral benzodiazepines confused with the abbreviation for "laughing out loud").
works quickly enough to affect any but the most prolonged panic attacks [9]." Altamura, et al. stated recently, "…it would Propranolol is the most thoroughly studied and reported in be desirable for the development of new anxiolytic drug(s) the literature of the beta blockers, having been discovered by that are more selective, fast acting and free from the unwanted Sir James Black in 1958. It serves as the prototype for this effects associated with the traditional benzodiazepines as class of drugs, having also been the most prescribed medicine tolerance or dependence [10]." Altamura and coworkers also in the world at one juncture. Propranol is a beta adrenergic Treating Anxiety with either Beta Blockers or Antiemetic Antimuscarinic Drugs: A Review 91 receptor antagonist that affects the autonomic nervous system and reduces cardiovascular symptoms (e.g., tachycardia and Table 1: Clinical Evidence for Beta Blockers as Anxiolytics.
hypertension) resulting from epinephrine in the circulation. Beta blockers interfere with receptor binding by catecholamines, epinephrine and norepinephrine, of which epinephrine is the principal catecholamine affecting the cardiovascular symptoms. Performance anxiety Propranolol is a lipophilic beta blocker that readily crosses the Test-taking anxiety blood-brain barrier. Therefore, it can affect both somatic and Cognitive flexibility CNS target tissues.
Propranolol is routinely delivered orally. Propranolol in Inderal® is available in oral doses ranging from 10 to 80 mg per dose for the treatment of hypertension. Multiple doses per day Cocaine withdrawal may be permitted. This drug can also be absorbed mucosally, as TSST-induced anxiety demonstrated by sublingual delivery [12], and its bioavailability CO -induced panic is higher when absorbed by this route rather than orally [13,14]. Performance anxiety Propranolol has been delivered sublingually at 10 and 40 mg Alcohol withdrawal per dose [12,13], although this can produce mouth paresthesia, Performance anxiety an undesirable effect. Also, propranolol has been delivered by Alcohol withdrawal rectal administration in mammals [15]. It does not demonstrate Alcohol withdrawal chemical dependence or sedation that are common side effects of many psychiatric medications.
Performance anxiety Propranolol is prescribed for the treatment of various cardiovascular indications with FDA approval, most notably hypertension, arrhythmia, angina, as well as prophylaxis of Performance anxiety migraines. However, there is evidence that it can have some benefit with regard to a subset of the symptoms of panic and a single dose of 40 mg of oxprenolol prior to speaking to an anxiety disorders. The drug's anxiolytic potential was recognized audience suppressed tachycardia in performance anxiety [21]. as early as 1966, "Emotions are expressed through the autonomic In contrast, in another clinical study daily oral propranolol was nervous system, and anxiety states are associated with increased not effective at treating panic disorder and agoraphobia with secretion of catecholamines. Propranolol may therefore have a panic attacks [22].
place in the treatment of anxiety, especially when the symptoms There is some evidence suggesting that propranolol might be are related to the cardiovascular system [16]." This prescient beneficial in academic test-taking among normal and anxiety- comment five decades ago was subsequently validated by prone students. Examination performance might be increased clinical studies with regard to both aspects: (a) propranolol and by pretreatment with this beta blocker [23, 24].
other beta blockers have been used "off label" in the USA for the near-term prophylaxis of performance anxiety; and (b) the To assess the clinical efficacy of an anxiolytic drug, trials pharmacologic benefits of propranolol and other beta blockers can be performed either "in life" or in a laboratory setting are restricted to the cardiovascular system's effects per se. The intended to induce anxiety. One established clinical trial design evidence is provided below. The beneficial anxiolytic effects are to provoke anxiety is the Trier Social Stress Test (TSST). This limited to blocking the pharmacologic effects of catecholamines method is used in a clinic and involves subjecting an individual upon the cardiovascular system without addressing the psychic to public speaking and mathematics questions as stressors.
(CNS) symptoms or other somatic symptoms of acute anxiety The TSST method has been used to study the effects of oral and panic, with the possible exception of tremors.
propranolol in volunteer subjects [25-28]. The assessments (Table 1) summarizes the relevant evidence from clinical of psychic anxiety can be assessed by the State-Trait Anxiety investigations in the literature regarding beta blockers used Inventory (STAI) or other similar tools [29,30]. The somatic to treat anxiety conditions. Daily oral propranolol has been and psychic effects of oral propranolol were tested using the demonstrated in one prophylactic study to suppress panic attacks TSST method in healthy adult volunteers. Propranolol (40 mg) in subjects diagnosed with panic disorder and agoraphobia one hour prior to TSST significantly reduced heart rate, reduced [17]. Tyrer and Lader demonstrated some effectiveness of systolic blood pressure, and enhanced cognitive flexibility oral propranolol in treating somatic anxiety symptoms, but during stress. In another study propranolol (80 mg) one hour not psychic (mental) anxiety [18,19]. Another daily oral prior to TSST significantly reduced heart rate, but paradoxically prophylactic study compared propranolol (3 x 80 mg/day) to increased salivary cortisol, and did not significantly affect BP oxprenolol (3 x 80 mg/day) and revealed that both beta blockers or subjective stress [25]. But, in another TSST study daily oral reduced symptoms of anxiety at one or two weeks duration [20]. propranolol (80 mg) did not affect the salivary cortisol response Both treatments reduced heart rate; propranolol by 21 - 32 bpm and oxprenolol by 16 - 23 bpm. However, propranolol An alternative clinical trial design involves the intentional was more effective at reducing palpitations when assessed on chemical provocation of a panic attack in a clinic. Several day 7 compared to oxprenolol. Another study demonstrated that methods of provocation of PA have been reported, wherein Thomas P. Dooley
atenolol has been delivered by a mucosal route in mammals Table 2: Clinical Evidence for Antimuscarinic Agents as
Another beta blocker is nadolol, which is non-selective and with a preference for beta-1 receptors. It does not pass through the blood-brain barrier. In a clinical trial with musicians, nadolol reduced pulse rate and improved one aspect of performance related to tremor [48]. A similar result was obtained for nadolol in students' singing performance [49]. In spite of being non- selective, nadolol might ironically benefit the pulmonary function in asthma patients based upon the appropriate dosage, an anti-intuitive result [50].
An alternative beta blocker is pindolol, a non-selective agent, a physician intentionally stimulates a physiologic response which can enhance the effects of co-administered antidepressants by CO inhalation [31], sodium lactate infusion [32,33], or and has some 5-HT antagonist property. Pindolol reduced cholecystokinin tetrapeptide (CCK-4) injection [32,34]. These symptoms of performance anxiety in musicians [51].
chemical exposures are used as potent tools to design controlled studies with predictable levels of PA episodes. In a study with Another example is betaxolol that can also cross the blood- healthy volunteer subjects using carbon dioxide inhalation to brain barrier. Daily oral betaxalol was delivered at 5 - 40 mg provoke panic and anxiety, propranolol significantly decreased per day in the treatment of generalized anxiety disorder and heart rate, a cardiovascular somatic symptom, but did not other anxiety-related conditions. Anxiety and panic attacks provide psychic anxiolytic benefit [35].
were reduced within several days [52]. This anxiolytic benefit is prophylactic, as the effects are observed in days, rather than Propranolol has also been investigated in patients suffering from severe posttraumatic stress disorder (PTSD). Two clinical studies of this beta blocker have shown possible benefits in the In view of the clinical studies and off-label use of various early-stage interventional prevention and subsequent therapy beta blockers, psychiatrists are aware that beta blockers can of PTSD [36,37]. Subsequent reports have also echoed that provide some symptomatic relief with regard to performance propranolol might be effective for this condition [38-40], anxiety [53]. However, beta blockers alone do not sufficiently although other reports dispute this conclusion [41,42].
address the aggregate symptoms of panic and acute anxiety episodes, and especially the psychic symptoms thereof (e.g., When considered in aggregate these clinical studies of fear, avoidance, and anxiousness).
propranolol, as the well known prototypical beta blocker, provide convincing evidence that the drug can exert somatic (i.e., Beta blockers also exhibit some benefit with regard to peripheral) effects on the cardiovascular system in the context of alcohol and drug abuse. The abuse of alcohol, prescription panic and anxiety disorders. With regard to affecting the psychic drugs, and illegal drugs (e.g., opioids, opiates, and cocaine) (CNS) symptoms, the results have been negative, inconsistent, are major mental health care concerns. The repetitive abuse of or inconclusive. That being said, there is some limited evidence these chemicals can produce physiologic dependence, tolerance, that propranolol can exert some psychic (CNS) benefits in addiction, and neurologic damage. The symptoms of sudden clinical stress trials. In a pair of clinical studies, propranolol withdrawal depend upon the abused substance, the impairment (a central and peripheral beta-blocker) significantly enhanced of neurological and neuroendocrine pathways, as well as problem solving during stress, whereas nadolol (peripheral only somatic organ impairment. The withdrawal from addictive beta-blocker) and lorezapam (benzodiazepine) did not [43, 44].
substances produces an array of symptoms, many of which Thus, propranolol enhanced cognitive flexibility ("creativity") overlap with the symptoms of panic and acute anxiety episodes. during stress. It remains unclear whether propranolol alone can Delirium tremens (DTs) occur in some alcoholics upon abrupt appreciably reduce psychic effects. In aggregate the clinical cessation of drinking. The symptoms of alcohol-related DTs are evidence does not support a benefit regarding psychic (CNS) very similar to those of panic attacks, and are in part related to anxiety symptoms.
beta adrenergic effects. The DTs can have serious and even life- threatening consequences. The standards-of-care for DTs are Numerous alternative beta blockers are available in lieu oral benzodiazepines. Withdrawal from opioid and/or opiate of propranolol. Notable among these is the common drug, addiction is physiologically distinct from alcohol withdrawal.
atenolol, that is available in oral solid dose forms ranging from 25 to 100 mg for the treatment of hypertension. Multiple doses With regard to beta blockers in substance abuse, atenolol per day may be permitted. It has been used to suppress stage has been shown in placebo-controlled trials to be beneficial fright in performers when administered orally in advance [45]. in alcohol withdrawal [54-56]. Pindolol has been used to treat Atenolol is a beta-1 selective peripheral-acting agent without alcohol withdrawal [57]. Timolol had a minimal effect on a CNS effects, which should reduce the risk for asthmatic subjects subset of symptoms of patients experiencing alcohol withdrawal [46]. Thus, atenolol might be preferred over the nonselective [58].With regard to cocaine abuse, propranolol has been used to beta blockers for patients affected by asthma or COPD [47]. treat withdrawal and overdoses [59, 60]. Note that propranolol Oral atenolol at 50 - 200 mg doses suppressed heart rate by 23 has also been shown to suppress tremors [61], consistent with - 24 beats per minute (bpm) vs. 10 bpm on placebo [46]. Also, one of the perceived benefits of beta blockers in performance anxiety in musicians (above).
Treating Anxiety with either Beta Blockers or Antiemetic Antimuscarinic Drugs: A Review 93 Migraine is a co-morbid condition in approximately two- mg, and a maximum daily dose of 1.2 mg [78]. Scopolamine thirds of patients suffering from panic disorder [6,62]. The can also be absorbed mucosally, as demonstrated by sublingual prevalence of migraine in the USA according to the American delivery [79,80]. It has been delivered sublingually at 0.15 mg/ Migraine Prevalence and Prevention (AMPP) study is 11.7% dose [79], intranasally at 0.4 mg [81,82], orally at 0.4 - 1.0 mg/ and probable migraine is 4.5%, for a combined total of 16.2% dose [80,83], and transdermally (Transderm Scop®) at 1.5 mg/ [63]. The rate is higher in females than in males. According dose over 3 days as antiemetic treatments or prophylactics. Oral to Smitherman and coworkers, "The first-line migraine delivery, unlike mucosal or transdermal delivery, involves first- prophylactics are not indicated for PD, and the selective pass hepatic metabolism of scopolamine, thus restricting its serotonin re-uptake inhibitors used to treat PD are not efficacious for migraine; thus, separate agents are often required to address each condition [6]." Furthermore, according to Marazziti and Antiemetic muscarinic receptor antagonist agents can be coworkers, "…the comorbidity of headache with panic disorder selected from a large group beyond scopolamine, examples of renders this condition more severe and possibly responsive to which include diphenhydramine, meclizine, buclizine, cyclizine, different treatments compared to panic disorder alone [64]." hydroxyzine, pirenzepine, benztropine (benzatropine), atropine, hyoscyamine, butylscopolamine, methylscopolamine, It is feasible that a beta blocker alone may provide therapeutic doxylamine, promethazine, trihexyphenidyl, orphenadrine and benefit for both conditions, panic and migraine. Beta-adrenergic its metabolite tofenacine. Depending on the choice of country, receptor antagonists are considered to be effective prophylactics OTC or "behind-the-counter" antiemetic antimuscarinic for chronic or episodic migraine [65-70]. Although one study agents include diphenhydramine, orphenadrine, doxylamine, reported no benefit from propranolol for treatment of acute meclizine, buclizine, cyclizine, and scopolamine. This further symptoms [71], there is some, albeit limited, evidence that underscores the perception by regulatory agencies of the safety beta adrenergic receptor antagonists, especially when delivered of antimuscarinic agents. Dryness of the mouth is a common mucosally, can also have benefit in the therapy of acute migraine side effect of antiemetic agents.
Structurally-related derivatives of scopolamine are Beta blockers may be effective as a treatment for aggression. alternative antimuscarinic APIs, such as butylscopolamine, Systemic adrenaline can produce excited, anxious, and methylscopolamine, atropine, hyoscyamine (the levo aggressive behavior in some individuals. Propranolol has been isomer of atropine), and benztropine (benzatropine). For shown to have a therapeutic effect with regard to aggressive instance, peripherally-acting butylscopolamine (scopolamine behavior [74,75].
butylbromide) is used for the treatment of abdominal spasms. Although psychiatrists (and some other physicians) are aware The butylbromide modification prevents the API from crossing of off-label use of beta blockers as prophylactics for performance the blood-brain barrier. However, direct pharmacologic action anxiety (e.g., stage fright during musical performances), the by the antimuscarinic agent upon the CNS might be preferable, current pharmaceutical standard-of-care for anxiety disorders if not necessary, for mediating psychic benefits in anxiety.
does not routinely include the use of beta blockers. But, beta In addition to the scopolamine "family" of APIs, adrenergic receptor antagonists can provide limited benefit, such there are other closely-related families of APIs exhibiting as the suppression of cardiovascular symptoms - tachycardia, antimuscarinic activities. In some cases the APIs also exhibit palpitations, and increased blood pressure, which are symptoms antihistamine properties. Examples of other "families" of of acute anxiety episodes and panic. That being stated, Zamorski antiemetic antimuscarinic agents include: (a) Ethanolamines: and Albucher concluded, "Beta blockers, once widely touted diphenhydramine (Benadryl®), doxylamine (Unisom® or as effective antipanic medications, have proven disappointing Nyquil®), orphenadrine (an OTC in Canada) and its metabolite as monotherapy in subsequent placebo-controlled trials." The tofenacine; and (b) Piperazines: meclizine (Dramamine® multiplicity, severity, and short duration of symptoms in a panic Less Drowsy Formulation or Bonine®), buclizine, cyclizine, attack make it a difficult disorder to treat by p.r.n. therapies.
hydroxyzine (Atarax® or Vistaril®), and pirenzepine. Muscarinic Receptor Antagonists: Scopolamine is the Furthermore, other types of antiemetic antimuscarinic agents
prototypical antiemetic antimuscarinic agent. It is a plant-derived are available, such as promethazine (Phenergan®) and natural product derived from the Solanaceae "nightshade" trihexyphenidyl.
family of plants (e.g., jimson weed), and is commonly used for (Table 2) summarizes the relevant evidence from clinical the treatment of motion sickness, nausea, and vomiting. It is investigations in the literature regarding antimuscarinic agents a potent nonselective muscarinic receptor antagonist that can used to treat anxiety conditions. Hydroxyzine is an FDA- inhibit all five human receptor subtypes with 0.34 - 5.3 nM Ki approved prescription medicine for the treatment of anxiety [84]. values [76]. It is lipophilic and crosses the blood-brain barrier The package insert for Atarax® (Roerig) states it is indicated to exert psychic parasympathetic (CNS) pharmacologic effects.
"for symptomatic relief of anxiety and tension associated Scopolamine is sold by prescription in the USA as a with psychoneurosis and as an adjunct in organic disease transdermal patch (Transderm Scop®) [77]. However, states in which anxiety is manifested." As a first-generation scopolamine is available without a prescription in many foreign antihistamine this drug entered the healthcare marketplace in markets, where it can be purchased OTC or behind-the-counter the mid-1950's. It displays broad receptor binding, affecting with pharmacist's assistance. For instance, in Australia it is an histamine, muscarinic, and 5-HT receptors. Placebo-controlled oral OTC product with a recommended adult dose of 0.3 or 0.6 studies with a total daily dose of 50 mg have revealed anxiolytic benefit following weeks or months of treatment in generalized Thomas P. Dooley
anxiety disorder [84-86]. This "old" drug is no longer among of pharmacologic effects can precede the zenith of plasma the frontline choices for anxiety, having been superceded levels, except for rapid intravenous administration wherein by benzodiazepines and subsequently SSRIs and SNRIs. pharmacologic effects might be concurrent or delayed slightly.
However, it has at least two beneficial properties -- an effect can be perceived faster than many other oral anxiolytics, and like The antidepressant dose via the i.v. route (4 ug/Kg) is likely other antimuscarinic agents it has a desirable risk/benefit profile to be above the blood levels attained during routine antiemetic (i.e., doesn't produce dependency). In addition to treating dosing (e.g. transdermal patches or oral dose forms), wherein generalized anxiety disorder, a few case reports suggests it sedation would be considered a significant and undesirable might be beneficial in treating panic disorder [87,88].
side effect. For comparison, sedation is generally considered in the literature to occur at 1.2 mg or higher by the oral route. Promethazine is another antimuscarinic agent with Scopolamine has been used as a safe pre-sedative, for instance antihistamine and CNS activities. Oral promethazine at 25 mg/ in pregnant women prior to delivery.
dose reaches a peak serum level (C ) in 2-3 hours, which is relatively slow for an oral drug, and can result in drowsiness In addition to scopolamine, two other muscarinic receptor within a similar time window [89]. As a premedication prior to antagonists, orphenadrine and its major metabolite, tofenacine, surgery, it produced an anxiolytic effect that was substantially have also been reported to exhibit an antidepressant effect [99- greater than placebo [90].
101]. Orphenadrine is beneficial in treating multiple symptoms of Parkinsonism. Orphenadrine administered orally (300 mg/ Although depression per se is not the focus of this review, day) for three weeks in patients afflicted by Parkinsonism was selected antimuscarinic agents can display psychic (CNS) very effective at blocking depression relative to placebo [100]. pharmacologic effects on mood, such as depression (e.g., Tofenacine at 120 – 240 mg/day for six weeks was effective major depressive disorder). Scopolamine can exhibit an in treating neurotic depression, endogenous depression, mixed antidepressant effect when administered intramuscularly [91], depression, and phobic anxiety diagnoses and within two weeks intravenously [92-94], or orally [83]. With regard to patients of initiation of therapy [101].
treated with i.v. infusions of 4 ug/Kg (e.g., 0.28 mg/70 Kg), "Significant clinical responses were observed in the evaluation Although not common knowledge among physicians at after the first scopolamine administration, 3 to 4 days after present, there is some historic evidence that scopolamine can the first treatment." And, "…those patients who observed an exert anxiolytic effect(s). Scopolamine was described a century improvement in their depression severity generally reported ago to have a "calming effect" when injected hypodermically into relief from their depressive symptoms on the first morning after patients afflicted by various psychiatric disorders (e.g., manias) scopolamine infusion (i.e., within 24 hours of drug exposure). at doses of 0.2 - 1.0 mg [102]. Coincidentally, these doses are In contrast, no improvement in mood was evident within 150 still relevant in clinical use to this day. This 1906 publication minutes of scopolamine infusion based upon the POMS" (i.e., mentioned, "…the calming effect of the medicament…The Profile of Mood States) [95]. Although i.v. administration at action of scopolamine shows itself rapid in maniacal excitement 4ug/Kg can affect depression, many patients receiving this and in acute hallucinatory delirium. The patients become calm treatment regime also experienced sedation. In addition, they gradually, and fall asleep if the dose is somewhat larger." experienced dry mouth, blurred vision, and/or lightheadedness.
A genetic study of the human M2 muscarinic receptor gene The efficacy and side effects of a drug are dependent upon (CHRM2) has revealed an association between specific genetic the dose delivered and the route of administration. It should be polymorphisms and the risk of depression in major depressive noted that the pharmacokinetic magnitude of effect and the time syndrome [103]. Consistent with these pharmacologic and to reach an effect of a "typical" API is very likely to exhibit a genetic findings in humans are laboratory studies with rodent range from intravenous > intramuscular or mucosal > oral >> models for antidepressant activity. Both pharmacologic and gene transdermal. This pattern is in fact the case for scopolamine knock-out approaches in mice revealed that the antidepressant- in humans. As an example thereof, intramuscular injection like effects of scopolamine are mediated via the M1 and/or M2 of 0.5 mg of scopolamine displayed only 57% of the absolute receptors, but not the M3, M4, and M5 receptors [76]. Thus, bioavailability relative to i.v. infusion of the same dose, and is the human M2 (and/or M1) receptor-linked second messenger subject to some delay [96]. Thus, an i.v. antidepressant dose signaling pathways in the CNS are likely to affect mood and of 0.28 mg/70 Kg of scopolamine is very likely to have an mood disorders (e.g., depression).
immediate and more profound physiologic effect relative to Alcohol dependence is comorbid with depression, and the same dose via other routes of delivery, because there are no has been genetically linked to the same human CHRM2 gene membrane and tissue barriers to entry into the circulation when encoding the M2 muscarinic receptor. Scopolamine has an injected intravenously. By contrast intranasal (mucosal) dosing M1 receptor preference over M2, but it can also bind the M2 of 0.4 mg results in a C (i.e., the peak level in the blood) after receptor [76,103]. Thus, there is a convergence between the 22 minutes [82]. Oral dosage forms of 0.6 mg displayed a peak genetic and the pharmacologic studies in both humans and plasma level at 50 minutes [97]. And, the 1.5 mg transdermal laboratory mice, thereby providing a suggested rationale for patch produces a C of 8 hours [98]. Thus, the timing to the use of scopolamine in treating alcohol addiction and/or reach peak blood levels of scopolamine by various routes of withdrawal. These findings might also apply to other antiemetic administration is or should approximate this progression: i.v. antimuscarinic agents beyond scopolamine.
at 0 min. > intranasal (mucosal) at 22+ min. > oral at 50 Scopolamine has also been shown to reduce aggressive min. >> transdermal at 8 hours. In general, the perception behavior in nonhuman primates under certain environmental Treating Anxiety with either Beta Blockers or Antiemetic Antimuscarinic Drugs: A Review 95 circumstances [104]. It is not yet clear whether this is also true antimuscarinic agent in healthy volunteers when exposed in humans. But, it can be argued that an anxiolytic calming to heat within a sauna [105]. The beta blocker was selected effect might similarly reduce aggression in some humans, which because heat induces cardiovascular stress, especially elevated is perhaps suggested by its historic effect in treating "maniacal heart rate. Scopolamine was selected as it is known to reduce excitement" [102]. sweating. The cardiovascular effects of oral atenolol (50 mg), The Future – Beyond Monotherapy: The monotherapies
oral scopolamine (0.3 mg), and coincident administration of mentioned above provide some, albeit limited, pharmacologic both drugs were monitored before, during, and after heat stress. efficacy for anxiety disorders, yet while being historically safe The coincident administration of both drugs revealed essentially approaches to therapy and/or prophylaxis in mental health. the same cardiovascular effects as atenolol alone (i.e., reduced Reaching beyond current monotherapies, another approach is heart rate and blood pressure), and either at baseline prior to combination therapies with two or more APIs. Combination heat exposure or during it. The relevant antiemetic oral dose drugs can be sold legally to patients, albeit subject to various of scopolamine alone or as an adjunct to atenolol displayed alternative regulatory oversight processes.
essentially no effect with regard to the cardiovascular symptoms, although a slight tachycardia occurred with scopolamine relative Within the USA combination drug products may be FDA to placebo. Overall, the cardiovascular effects (i.e., reduced heart approved for specific medical indications through the FDA's rate and systolic BP) were due to atenolol. Thus, scopolamine drug approval processes that can result in either approved co-adminstration did not abrogate the cardiovascular effects prescription (Rx) drugs or approved OTC drugs. Alternatively, of the beta blocker. The potential for any psychiatric and/or compounding pharmacies may formulate multiple APIs into psychic (CNS) effects of scopolamine and/or atenolol were not a compounded pharmaceutical product via either the 503A or envisioned or addressed by this study.
503B regulatory pathways. But, key parameters must be met for compounded products. For instance, several of the restrictions In view of these results [105] and given that episodes of include: (a) Each of the APIs must have been included in at least acute anxiety and panic are driven physiologically in part by one FDA-approved medication; (b) The compounded product increased epinephrine's effects on the cardiovascular system, must not be a copy of an FDA-approved combination drug; and it is appropriate to include within a combination therapy a (c) The compounded products are subject to USP 795 or USP 797 beta blocker to address the cardiovascular symptoms per se of standards and procedures during compounding or "outsource" anxiety disorders. Based upon the literature an antimuscarinic facility manufacturing, respectively. These compounded agent alone would not be anticipated to be of benefit for the products are sold by prescription only as "unapproved" cardiovascular symptoms of these psychiatric conditions. products, although subject to state boards of pharmacy and FDA Coincidentally, the antimuscarinic agent atropine is known to produce tachycardia, and scopolamine to a lesser extent. Tachycardia is antithetical to the desired outcome.
In view of the historic scientific and clinical literature mentioned above on beta blockers or antiemetic drugs as It should be emphasized that palpitations (resulting from monotherapies for anxiety disorders, the author recognized both elevated heart rate and/or blood pressure) are considered to be a need in the pharmaceutical marketplace and an opportunity to the predominant symptom that patients are aware of during panic augment the limited cardiovascular benefits of a beta blocker attacks and acute anxiety episodes. The beta blocker, within a dual with another type of API to produce a superior anxiolytic drug product, should address this primary (major) symptom of therapy for p.r.n. administration. It would be advantageous for panic and acute anxiety episodes.
the augmenting second agent: (a) to address other symptoms; Recently the author has developed novel pharmaceutical (b) to exert some psychic (CNS) pharmacologic benefits; (c) to formulations to address the augmentation of a beta blocker's effects have a rapid effect; and (d) to not be a Controlled Substance. on the cardiovascular symptoms with an antiemetic antimuscarinic Thus, the augmenting second API could not be an opiate, opioid, agent's effects on non-cardiovascular symptoms (unpublished benzodiazepine, SSRI, or cannabinoid. This led the author to an results). This new dual drug approach holds substantial promise innovative conclusion; a combination of a beta blocker plus an to address p.r.n. all or most of the symptoms of acute anxiety antiemetic antimuscarinic agent should be of substantial clinical episodes or panic, neither of which is addressed by a beta blocker benefit and reaching beyond the pharmacologic benefits of alone or an antiemetic antimuscarinic agent alone. The dual drug either class of drugs acting alone as monotherapies.
compositions provide a complementary broad coverage of the Searches of the literature did not reveal any precedents for this symptoms of acute anxiety: the beta blocker provides benefits dual drug combination therapy approach using these two classes with regard to cardiovascular symptoms (e.g., palpitations, heart of agents (i.e., beta blocker plus antimuscarinic agent) in any rate, and BP); and, the antimuscarinic agent provides benefits with medical indication in mental health or psychiatry. Secondarily, regard to non-cardiovascular symptoms (e.g., nausea, vomiting, searches did not reveal any record of both classes of APIs being sweating, anxiousness, avoidance, fear, etc.).
formulated together into a single drug formulation. Thus, this It should be noted that augmentation of a beta blocker with an dual drug approach was novel with regard to both aspects, even antimuscarinic agent, wherein the latter only affects a subset of though both classes of drugs have been in commercial use for the common symptoms of acute anxiety (i.e., nausea, vomiting, over five decades.
sweating, and/or motion sickness) per se would provide anxiolytic That being said, one relevant article addressed the superiority over a beta blocker alone or an antiemetic agent coincidental co-administration of a beta blocker with an alone. In other words, even without affecting psychic symptoms (e.g., anxiousness, fear, avoidance, etc.), the dual drug approach Thomas P. Dooley
has substantial merits for treatments of the symptoms of anxiety 6. Smitherman TA, Kolivas ED, Bailey JR. Panic disorder and migraine: comorbidity, mechanisms, and clinical implications. Headache 2013; 53: 23-45.
This novel dual drug approach may also be of value as a supportive p.r.n. therapy during cognitive behavioral therapy 7. Breslau N, Schultz LR, Stewart WF. Headache types and (CBT) or other forms of counseling for anxiety and panic. The panic disorder: directionality and specificity. Neurology pharmaceutical compositions may provide anxiolytic benefit 2001; 56: 350-354.
without cognitive impairment while learning or reinforcing 8. Schneier FR. Clinical practice. Social anxiety disorder. The desirable behaviors. The dual drug therapies may also be used New England journal of medicine 2006; 355: 1029-1036.
when the patients experience acute anxiety episodes or panic between sessions of CBT or other forms of counselling. The 9. Zamorski MA, Albucher RC. What to do when SSRIs fail: calming effect may improve voluntary and involuntary motor eight strategies for optimizing treatment of panic disorder. control, task performance, cognition, memory, and may reduce American family physician 2002; 66: 1477-1484.
fear, avoidance, and anxiousness in patients. Furthermore, 10. Altamura AC, Moliterno D, Paletta S. Understanding the having a convenient fast-acting p.r.n. dual drug medication in pharmacokinetics of anxiolytic drugs. Expert opinion on one's pocket or purse might coincidentally serve as a palliative drug metabolism & toxicology 2013; 9: 423-440.
"security blanket" to enable greater functionality, regardless of whether the patient self-administers the medication for 11. Greenblatt DJ, Divoll M, Harmatz JS. Pharmacokinetic symptoms of acute anxiety or panic [88]. comparison of sublingual lorazepam with intravenous, intramuscular, and oral lorazepam. Journal of pharmaceutical At this juncture, the novel dual drug approach appears sciences 1982; 71: 248-252.
promising for rapid p.r.n. treatment of acute anxiety episodes and panic. This therapeutic option may be especially appealing 12. Wang Y, Wang Z, Zuo Z. Clinical pharmacokinetics in primary care settings, such as family medicine, wherein a of buffered propranolol sublingual tablet (Promptol)- favorable risk/benefit ratio is highly significant in a prescriber's application of a new "physiologically based" model to decision-making process when considering therapeutic options.
assess absorption and disposition. The AAPS journal 2013; 15: 787-796.
13. Mansur AP, Avakian SD, Paula RS. Pharmacokinetics and The author is grateful to Charles Nemeroff MD and Richard pharmacodynamics of propranolol in hypertensive patients Shelton MD for advice on anxiolytic therapies, and to TPS LLC after sublingual administration: systemic availability. and Doug Nesbitt for assistance with compounding pharmacy.
Brazilian journal of medical and biological research 1998; 31: 691-696.
14. Duchateau GS, Zuidema J, Merkus FW. Bioavailability The beta blocker plus antimuscarinic drug combination of propranolol after oral, sublingual, and intranasal therapy approach is patent pending in the USA and internationally administration. Pharmaceutical research 1986; 3: 108-111.
and may be subject to the US Trademark PanX™. All rights are reserved by the author.
15. Morimoto K, Fukanoki S, Morisaka K. Design of polyvinyl alcohol hydrogel as a controlled-release vehicle for rectal administration of dl-propranolol-HCl and atenolol. Chemical 1. Kessler RC, Chiu WT, Jin R. The epidemiology of panic & pharmaceutical bulletin 1989; 37: 2491-2495.
attacks, panic disorder, and agoraphobia in the National 16. Propranolol. British medical journal. 1966; 2: 1311-1312.
Comorbidity Survey Replication. Archives of general psychiatry 2006; 63: 415-424.
17. Ravaris CL, Friedman MJ, Hauri PJ. A controlled study of alprazolam and propranolol in panic-disordered 2. Kessler RC, Chiu WT, Demler O. Prevalence, severity, and and agoraphobic outpatients. Journal of clinical comorbidity of 12-month DSM-IV disorders in the National psychopharmacology 1991; 11: 344-350.
Comorbidity Survey Replication. Archives of general psychiatry 2005; 62: 617-627.
18. Tyrer PJ, Lader MH. Physiological response to propranolol and diazepam in chronic anxiety. British journal of clinical 3. Kessler RC, Berglund P, Demler O. Lifetime prevalence pharmacology 1974; 1: 387-390.
and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Archives of 19. Tyrer PJ, Lader MH. Response to propranolol and diazepam general psychiatry 2005; 62: 593-602.
in somatic and psychic anxiety. British medical journal 1974; 2: 14-16.
4. Wang PS, Lane M, Olfson M. Twelve-month use of mental health services in the United States: results from the National 20. Becker AL. Oxprenolol and propranolol in anxiety states. Comorbidity Survey Replication. Archives of general A double-blind comparative study. South African medical psychiatry 2005; 62: 629-640.
journal 1976; 50: 627-629.
5. Andrade L, Eaton WW, Chilcoat H. Lifetime comorbidity 21. Taggart P, Carruthers M, Somerville W. Electrocardiogram, of panic attacks and major depression in a population-based plasma catecholamines and lipids, and their modification study. Symptom profiles. The British journal of psychiatry : by oxyprenolol when speaking before an audience. Lancet 1994; 165: 363-369.
1973; 2: 341-346.
Treating Anxiety with either Beta Blockers or Antiemetic Antimuscarinic Drugs: A Review 97 22. Munjack DJ, Crocker B, Cabe D. Alprazolam, propranolol, 37. Vaiva G, Ducrocq F, Jezequel K. Immediate treatment with and placebo in the treatment of panic disorder and agoraphobia propranolol decreases posttraumatic stress disorder two with panic attacks. Journal of clinical psychopharmacology months after trauma. Biological psychiatry 2003; 54: 947- 1989; 9: 22-27.
23. Drew PJ, Barnes JN, Evans SJ. The effect of acute beta- 38. Hoge EA, Worthington JJ, Nagurney JT. Effect of acute adrenoceptor blockade on examination performance. British posttrauma propranolol on PTSD outcome and physiological journal of clinical pharmacology 1985; 19: 783-786.
responses during script-driven imagery. CNS neuroscience 24. Faigel HC. The effect of beta blockade on stress-induced & therapeutics 2012; 18: 21-27.
cognitive dysfunction in adolescents. Clinical pediatrics 39. Bell J. Propranolol, post-traumatic stress disorder and 1991; 30: 441-445.
narrative identity. Journal of medical ethics 2008; 34: e23.
25. Andrews J, Pruessner JC. The combined propranolol/TSST paradigm--a new method for psychoneuroendocrinology. 40. Cahill SP, Pontoski K, D'Olio CM. Posttraumatic Stress PloS one 2013; 8: e57567.
Disorder and Acute Stress Disorder II: Considerations for Treatment and Prevention. Psychiatry 2005; 2: 34-46.
26. Alexander JK, Hillier A, Smith RM. Beta-adrenergic modulation of cognitive flexibility during stress. Journal of 41. Stein MB, Kerridge C, Dimsdale JE. Pharmacotherapy to cognitive neuroscience 2007; 19: 468-478.
prevent PTSD: Results from a randomized controlled proof- of-concept trial in physically injured patients. Journal of 27. Kudielka BM, Fischer JE, Metzenthin P. No effect of 5-day traumatic stress 2007; 20: 923-932.
treatment with acetylsalicylic acid (aspirin) or the beta- blocker propranolol (Inderal) on free cortisol responses 42. McGhee LL, Maani CV, Garza TH. The effect of propranolol to acute psychosocial stress: a randomized double-blind, on posttraumatic stress disorder in burned service members. placebo-controlled study. Neuropsychobiology 2007; 56: Journal of burn care & research : 2009; 30: 92-97.
43. Beversdorf DQ, White DM, Chever DC. Central beta- 28. von Kanel R, Kudielka BM, Metzenthin P. Aspirin, but not adrenergic modulation of cognitive flexibility. propranolol, attenuates the acute stress-induced increase in Neuroreport 2002; 13: 2505-2507.
circulating levels of interleukin-6: a randomized, double- blind, placebo-controlled study. Brain, behavior, and 44. Silver JA, Hughes JD, Bornstein RA. Effect of anxiolytics immunity 2008; 22: 150-157.
on cognitive flexibility in problem solving. Cognitive and behavioral neurology : 2004; 17: 93-97.
29. Gros DF, Antony MM, Simms LJ. Psychometric properties of the State-Trait Inventory for Cognitive and Somatic Anxiety 45. Neftel KA, Adler RH, Kappeli L. Stage fright in (STICSA): comparison to the State-Trait Anxiety Inventory musicians: a model illustrating the effect of beta blockers. (STAI). Psychological assessment 2007; 19: 369-381.
Psychosomatic medicine 1982; 44: 461-469.
30. Marteau TM, Bekker H. The development of a six-item 46. Ellis ME, Sahay JN, Chatterjee SS. Cardioselectivity of short-form of the state scale of the Spielberger State-Trait atenolol in asthmatic patients. European journal of clinical Anxiety Inventory (STAI). The British journal of clinical pharmacology 1981; 21: 173-176.
psychology 1992; 31: 301-306.
47. Navas EV, Taylor DO. Q: Can patients with COPD or asthma 31. MacKinnon DF, Craighead B, Hoehn-Saric R. Carbon dioxide take a beta-blocker? Cleveland Clinic journal of medicine provocation of anxiety and respiratory response in bipolar disorder. Journal of affective disorders 2007; 99: 45-49.
2010; 77: 498-499.
32. Kellner M. Experimental panic provocation in healthy 48. James I, Savage I. Beneficial effect of nadolol on anxiety- man-a translational role in anti-panic drug development? induced disturbances of performance in musicians: a Dialogues in clinical neuroscience 2011; 13: 485-493.
comparison with diazepam and placebo. American heart journal 1984; 108: 1150-1155.
33. Strohle A, Kellner M, Yassouridis A. Effect of flumazenil in lactate-sensitive patients with panic disorder. The American 49. Gates GA, Saegert J, Wilson N. Effect of beta blockade on journal of psychiatry 1998; 155: 610-612.
singing performance. The Annals of otology, rhinology, and 34. Kronenberg G, Schredl M, Fiedler K. In healthy volunteers laryngology 1985; 94: 570-574.
responses to challenge with cholecystokinin tetrapeptide 50. Hanania NA, Singh S, El-Wali R. The safety and effects differ between administration during REM and delta sleep. of the beta-blocker, nadolol, in mild asthma: an open-label Depression and anxiety 2001; 14: 141-144.
pilot study. Pulmonary pharmacology & therapeutics 2008; 35. Papadopoulos A, Rich A, Nutt DJ. The effects of single 21: 134-141.
dose anxiolytic medication on the CO2 models of anxiety: 51. James IM, Burgoyne W, Savage IT. Effect of pindolol differentiation of subjective and objective measures. Journal of psychopharmacology 2010; 24: 649-656.
on stress-related disturbances of musical performance: preliminary communication. Journal of the Royal Society of 36. Pitman RK, Sanders KM, Zusman RM. Pilot study of Medicine 1983; 76: 194-196.
secondary prevention of posttraumatic stress disorder with propranolol. Biological psychiatry 2002; 51: 189-192.
52. Swartz CM. Betaxolol in anxiety disorders. Annals of clinical psychiatry : 1998; 10: 9-14.
Thomas P. Dooley
53. Brantigan CO, Brantigan TA, Joseph N. Effect of beta 67. Schellenberg R, Lichtenthal A, Wohling H. Nebivolol and blockade and beta stimulation on stage fright. The American metoprolol for treating migraine: an advance on beta-blocker journal of medicine 1982; 72: 88-94.
treatment? Headache 2008; 48: 118-125.
54. Kraus ML, Gottlieb LD, Horwitz RI. Randomized clinical 68. Holroyd KA, Cottrell CK, O'Donnell FJ. Effect of preventive trial of atenolol in patients with alcohol withdrawal. The (beta blocker) treatment, behavioural migraine management, New England journal of medicine 1985; 313: 905-909.
or their combination on outcomes of optimised acute 55. Horwitz RI, Gottlieb LD, Kraus ML. The efficacy of atenolol treatment in frequent migraine: randomised controlled trial. in the outpatient management of the alcohol withdrawal Bmj 2010; 341: c4871.
syndrome. Results of a randomized clinical trial. Archives of 69. Diamond S. Strategies for migraine management. Cleveland internal medicine 1989; 149: 1089-1093.
Clinic journal of medicine 1991; 58: 257-261.
56. Gottlieb LD, Horwitz RI, Kraus ML. Randomized controlled 70. Edvardsson B. Atenolol in the prophylaxis of chronic trial in alcohol relapse prevention: role of atenolol, alcohol migraine: a 3-month open-label study. SpringerPlus 2013; craving, and treatment adherence. Journal of substance abuse treatment 1994; 11: 253-258.
71. Banerjee M, Findley L. Propranolol in the treatment of acute 57. Digranes O. [Beta blocker treatment in alcohol withdrawal. migraine attacks. Cephalalgia : 1991; 11: 193-196.
A double-blind test with pindolol (Visken)/placebo]. Tidsskrift for den Norske laegeforening : tidsskrift for 72. Migliazzo CV, Hagan JC, 3rd. Beta blocker eye drops for praktisk medicin, ny raekke 1976; 96: 226-228.
treatment of acute migraine. Missouri medicine 2014; 111: 58. Potter JF, Bannan LT, Beevers DG. The effect of a non- selective lipophilic beta-blocker on the blood pressure and 73. Chiam PJ. Topical beta-blocker treatment for migraine. noradrenaline, vasopressin, cortisol and renin release during International ophthalmology 2012; 32: 85-88.
alcohol withdrawal. Clinical and experimental hypertension 74. Silver JM, Yudofsky SC, Slater JA. Propranolol treatment of Part A, Theory and practice 1984; 6: 1147-1160.
chronically hospitalized aggressive patients. The Journal of 59. Kampman KM, Volpicelli JR, Mulvaney F. Effectiveness neuropsychiatry and clinical neurosciences 1999; 11: 328-335.
of propranolol for cocaine dependence treatment may 75. Lader M. Beta-adrenoceptor antagonists in neuropsychiatry: an depend on cocaine withdrawal symptom severity. Drug update. The Journal of clinical psychiatry 1988; 49: 213-223.
and alcohol dependence 2001; 63: 69-78.
76. Witkin JM, Overshiner C, Li X. M1 and m2 muscarinic 60. Kampman KM, Dackis C, Lynch KG. A double-blind, receptor subtypes regulate antidepressant-like effects of the placebo-controlled trial of amantadine, propranolol, and rapidly acting antidepressant scopolamine. The Journal of their combination for the treatment of cocaine dependence pharmacology and experimental therapeutics 2014; 351: in patients with severe cocaine withdrawal symptoms. Drug and alcohol dependence 2006; 85: 129-137.
77. Nachum Z, Shupak A, Gordon CR. Transdermal 61. Koller WC, Biary N. Effect of alcohol on tremors: scopolamine for prevention of motion sickness : clinical comparison with propranolol. Neurology 1984; 34: 221-222.
pharmacokinetics and therapeutic applications. Clinical 62. Yamada K, Moriwaki K, Oiso H. High prevalence of pharmacokinetics 2006; 45: 543-566.
comorbidity of migraine in outpatients with panic disorder and effectiveness of psychopharmacotherapy for both 78. Corallo CE, Whitfield A, Wu A. Anticholinergic syndrome disorders: a retrospective open label study. Psychiatry following an unintentional overdose of scopolamine. research 2011; 185: 145-148.
Therapeutics and clinical risk management 2009; 5: 719-723.
63. Smitherman TA, Burch R, Sheikh H. The prevalence, 79. Imai K, Ikenaga M, Kodama T. Sublingually administered impact, and treatment of migraine and severe headaches scopolamine for nausea in terminally ill cancer patients. in the United States: a review of statistics from national Supportive care in cancer : 2013; 21: 2777-2781.
surveillance studies. Headache 2013; 53: 427-436.
80. Gray MY. The use of anticholinergics for the management 64. Marazziti D, Toni C, Pedri S. Prevalence of headache of terminal secretions. Evidence Matters 2007; 1: 1-6.
syndromes in panic disorder. International clinical 81. Weerts AP, Pattyn N, Putcha L. Restricted sedation and absence psychopharmacology 1999; 14: 247-251.
of cognitive impairments after administration of intranasal 65. Loder E, Burch R, Rizzoli P. The 2012 AHS/AAN scopolamine. Journal of psychopharmacology 2015.
guidelines for prevention of episodic migraine: a summary and comparison with other recent clinical 82. Putcha L, Tietze KJ, Bourne DW. Bioavailability of practice guidelines. Headache 2012; 52: 930-945.
intranasal scopolamine in normal subjects. Journal of pharmaceutical sciences 1996; 85: 899-902.
66. Shamliyan TA, Kane RL, Ramakrishnan R. Episodic migraines in children: limited evidence on preventive 83. Khajavi D, Farokhnia M, Modabbernia A. Oral scopolamine pharmacological treatments. Journal of child neurology augmentation in moderate to severe major depressive disorder: 2013; 28: 1320-1341.
a randomized, double-blind, placebo-controlled study. The Journal of clinical psychiatry 2012; 73: 1428-1433.
Treating Anxiety with either Beta Blockers or Antiemetic Antimuscarinic Drugs: A Review 99 84. Guaiana G, Barbui C, Cipriani A. Hydroxyzine for 95. Drevets WC, Zarate CA, Jr, Furey ML. Antidepressant generalised anxiety disorder. The Cochrane database of effects of the muscarinic cholinergic receptor antagonist systematic reviews 2010: CD006815.
scopolamine: a review. Biological psychiatry 2013; 73: 85. Llorca PM, Spadone C, Sol O. Efficacy and safety of hydroxyzine in the treatment of generalized anxiety 96. Ebert U, Grossmann M, Oertel R. Pharmacokinetic- disorder: a 3-month double-blind study. The Journal of pharmacodynamic modeling of the electroencephalogram clinical psychiatry 2002; 63: 1020-1027.
effects of scopolamine in healthy volunteers. Journal of 86. Lader M, Scotto JC. A multicentre double-blind comparison clinical pharmacology 2001; 41: 51-60.
of hydroxyzine, buspirone and placebo in patients with 97. Golding JF, Gosden E, Gerrell J. Scopolamine blood levels generalized anxiety disorder. Psychopharmacology 1998; following buccal versus ingested tablets. Aviation, space, 139: 402-406.
and environmental medicine 1991; 62: 521-526.
87. Iskandar JW, Griffeth B, Rubio-Cespedes C. Successful 98. Nachum Z, Shahal B, Shupak A. Scopolamine bioavailability treatment with hydroxyzine of acute exacerbation of panic in combined oral and transdermal delivery. The Journal of disorder in a healthy man: a case report. The primary care pharmacology and experimental therapeutics 2001; 296: companion for CNS disorders 2011; 13.
88. Dowben JS, Grant JS, Froelich KD, et al. Biological 99. Capstick N, Pudney H. A comparative trial of orphenadrine and perspectives: hydroxyzine for anxiety: another look at an tofenacin in the control of depression and extrapyramidal side- old drug. Perspectives in psychiatric care 2013; 49: 75-77.
effects associated with fluphenazine decanoate therapy. The 89. Naicker P, Anoopkumar-Dukie S, Grant GD. The effects of Journal of international medical research 1976; 4: 435-440.
antihistamines with varying anticholinergic properties on 100. Onuaguluchi G. Assessment of drug therapy in Parkinsonism. voluntary and involuntary movement. Clin Neurophysiol British medical journal. 1963; 1: 443-448.
2013; 124: 1840-1845.
101. Bram G, Shanmuganathan N. An evaluation of tofenacine 90. Jalbout N, Karam AN, Karam E. Premedication with (elamol), a new drug for the treatment of depression. Current Midazolam (Dormicum) compared with Promethazine, therapeutic research, clinical and experimental 1971; 13: 625- Droperidol and placebo in relieving anxiety using Beck's anxiety inventory. J Med Liban 1994; 42: 69-73.
102. Houde A. Scopolamine: A Physiological and Clinical Study. 91. Gillin JC, Sutton L, Ruiz C. The effects of scopolamine The American journal of clinical medicine 1906; 13: 365-367.
on sleep and mood in depressed patients with a history of alcoholism and a normal comparison group. Biological 103. Wang JC, Hinrichs AL, Stock H. Evidence of common psychiatry 1991; 30: 157-169.
and specific genetic effects: association of the muscarinic acetylcholine receptor M2 (CHRM2) gene with alcohol 92. Drevets WC, Furey ML. Replication of scopolamine's dependence and major depressive syndrome. Human antidepressant efficacy in major depressive disorder: a molecular genetics 2004; 13: 1903-1911.
randomized, placebo-controlled clinical trial. Biological psychiatry 2010; 67: 432-438.
104. Plotnik R, Mollenauer S, Gore W. Comparing the effects of scopolamine on operant and aggressive responses in squirrel 93. Furey ML, Khanna A, Hoffman EM. Scopolamine produces monkeys. Pharmacology, biochemistry, and behavior 1975; 3: larger antidepressant and antianxiety effects in women than in men. Neuropsychopharmacology : 2010; 35: 2479-2488.
105. Kukkonen-Harjula K, Oja P, Vuori I. Cardiovascular effects of 94. Furey ML, Drevets WC. Antidepressant efficacy of the Atenolol, scopolamine and their combination on healthy men antimuscarinic drug scopolamine: a randomized, placebo- in Finnish sauna baths. European journal of applied physiology controlled clinical trial. Archives of general psychiatry and occupational physiology 1994; 69: 10-15.
2006; 63: 1121-1129.
Address for correspondence
Thomas P. Dooley, Ph.D. TPD LLC, 7100 Cabin Lane,
Pinson, Alabama 35126, USA; Tel: 205-222-6145; E-mail: tom@tomdooley.orgSubmitted Oct 26, 2015Accepted Nov 23, 2015



Série des traités européens - n° 135 CONVENTION CONTRE LE DOPAGE Strasbourg, 16.XI.1989 STE 135 – Convention contre le dopage, 16.XI.1989 Les Etats membres du Conseil de l'Europe, les autres Etats parties à la Convention culturelle européenne, ainsi que les autres Etats, signataires de la présente Convention, Considérant que le but du Conseil de l'Europe est de réaliser une union plus étroite entre ses membres afin de sauvegarder et de promouvoir les idéaux et les principes qui sont leur patrimoine commun et de favoriser leur progrès économique et social;

Con il Patrocinio di: DEGLI STUDI DI TORINO IX CONGRESSO NAZIONALE S.I.T.O.D. ONDE D'URTO EXTRACORPOREE: PRESENTE E FUTURO Dalla ricerca di base alle nuove prospettive terapeutiche 23 - 24 ottobre 2008 .it Centro Congressi Torino Incontra Via Nino Costa, 10123 Torino oo2 Presidente Onorario