Anxiolytic

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An anxiolytic (also antipanic or antianxiety agent)[1] is a medication or other intervention that inhibits anxiety. This effect is in contrast to anxiogenic agents, which increase anxiety. Together these categories of psychoactive compounds or interventions may be referred to as anxiotropic compounds or agents. Some recreational drugs such as ethanol (alcohol) induce anxiolysis initially; however studies, show that many of these drugs are anxiogenic. Anxiolytic medications have been used for the treatment of anxiety and its related psychological and physical symptoms. Anxiolytics have been shown to be useful in the treatment of anxiety disorders. Light therapy and other interventions have also been found to have an anxiolytic effect.[2]

Beta-receptor blockers such as propranolol and oxprenolol, although not anxiolytics, can be used to combat the somatic symptoms of anxiety such as tachycardia and palpitations.[3]

Anxiolytics are also known as minor tranquilizers.[4] The term is less common in modern texts, and was originally derived from a dichotomy with major tranquilizers, also known as neuroleptics or antipsychotics.[citation needed]

There are concerns that some GABAergics, such as benzodiazepenes and barbituates, may have an anxiogenic effect if used over long periods of time.[5]

Medications

Barbiturates

Main article: Barbiturate

Barbiturates exert an anxiolytic effect linked to the sedation they cause. The risk of abuse and addiction is high. Many experts consider these drugs obsolete for treating anxiety but valuable for the short-term treatment of severe insomnia, though only after benzodiazepines or non-benzodiazepines have failed.

Benzodiazepines

Main article: Benzodiazepine

Benzodiazepines are prescribed for short-term or episodic relief of severe and disabling anxiety. Benzodiazepines may also be indicated to cover the latent periods associated with the medications prescribed to treat an underlying anxiety disorder. They are used to treat a wide variety of conditions and symptoms and are usually a first choice when short-term CNS sedation is needed. Longer-term uses include treatment for severe anxiety. If benzodiazepines are discontinued rapidly after being taken daily for two or more weeks there is some risk of benzodiazepine withdrawal and rebound syndrome, which varies by the specific drug.[6] Tolerance and dependence may also occur, but may be clinically acceptable.[7] Cognitive and behavioral adverse effects are possible.[8] Benzodiazepines include:

Benzodiazepines exert their anxiolytic properties at moderate dosage. At higher dosage hypnotic properties occur.[9]

  • Tofisopam (Emandaxin and Grandaxin) is a drug that is a benzodiazepine derivative. Like other benzodiazepines, it possesses anxiolytic properties, but, unlike other benzodiazepines, it does not have anticonvulsant, sedative, skeletal muscle relaxant, motor skill-impairing, or amnestic properties.

Carbamates

Marketed as a safer alternative to barbiturate anxiolytics, meprobamate (Miltown, Equanil) was commonly used to relieve anxiety in the late 1950s and 1960s. Like barbiturates, therapeutic doses produce sedation and significant overdoses may be fatal. In the US, meprobamate has generally been replaced with benzodiazepines while the drug is now withdrawn in many European countries and Canada. The muscle relaxant carisoprodol has anxiolytic effects by metabolizing to meprobamate. Various other carbamates have been found to share these effects, such as tybamate and lorbamate.

Opioids

Opioids are drugs that are usually only prescribed for their painkilling properties, but some research is beginning to find that some varieties are effective at treating depression, obsessive compulsive disorder, and other ailments often associated with or caused by anxiety. They have a very high potential for abuse and have one of the highest addiction rates for all drugs. Many people become addicted to these drugs because they are so effective at blocking emotional pain, including anxiety. Similarly to alcohol, people with anxiety disorders are more likely to become addicted to opioids due to their anxiolytic effect. These drugs range from the commonly prescribed hydrocodone, to the notoriously illegal Diamorphine, and all the way to much more potent varieties like fentanyl often used in trauma or end of life pain management. Most people purchasing these drugs illegally are seeking them out to get a euphoric like high, but many others seek them out because they are so effective at reducing both physical pain and emotional pain.[10]

Because of their high potential for abuse and high overdose rates, prescribing opioids for mental health issues is very uncommon and frowned upon within the medical community. Safer opioids which are less likely to be abused, have less deadly drug interactions, and are less likely to cause overdose are the ones that are being looked into the most for their anxiolytic-type properties. Given that many anxiety sufferers are more prone to alcohol and opioid addiction, the potential danger in prescribing opioids is apparent. Benzodiazapenes are very similar to alcohol in how they impact the user and the brain, and even though anxiety sufferers are more prone to alcohol addiction these drugs are still prescribed. The same logic is being used in the push to get opioids used for anxiety treatment. Opioids and benzodiazapenes are very dangerous to use together, and using them together is one of the most common reasons for accidental mixed drug overdose in the United States, so great caution should be taken if opioid prescriptions for anxiety become more accepted.

It appears that buprenorphine is gaining some acceptability within in the medical community for being used to treat anxiety, OCD, and depression. Buprenorphine is similar to methadone in that it is used in opioid replacement therapy as well as pain management. It is much safer than methadone and lots of other opioids and has a very long half-life leading to less compulsive use among those who attempt to abuse it or become mentally addicted to it. There has been research into more commonly abused opioids being prescribed for anxiety disorder, but given that these drugs produce more euphoria and require more constant dosing when compared to buprenorphine, there is a much higher danger for abuse and overdose.[11]

Antidepressants

Antidepressant medications can reduce anxiety, and several selective serotonin reuptake inhibitors have been USFDA approved to treat various anxiety disorders. Antidepressants are especially beneficial because anxiety and depression often occur together.[6]

Selective serotonin reuptake inhibitors

Selective serotonin reuptake inhibitors or serotonin-specific reuptake inhibitors[12] (SSRIs) are a class of compounds typically used in the treatment of depression, anxiety disorders, OCD and some personality disorders. Primarily classified as antidepressants, most SSRIs have anxiolytic effects, although at higher dosages than used to treat depression. Paradoxically, SSRIs can increase anxiety initially due to negative feedback through the serotonergic autoreceptors. For this reason a concurrent benzodiazepine is sometimes used temporarily until the anxiolytic effect of the SSRI occurs.

Serotonin–norepinephrine reuptake inhibitors

Serotonin–norepinephrine reuptake inhibitor include venlafaxine and duloxetine drugs. Venlafaxine, in extended release form, and duloxetine, are indicated for the treatment of GAD. SSNRIs are as effective as SSRIs in the treatment of anxiety disorders.[13]

Tricyclic antidepressants

Tricyclic antidepressants (TCAs) have anxiolytic effects; however, side effects are often more troubling or severe and overdose is dangerous. Examples include imipramine, amitriptyline, nortriptyline and desipramine.

Tetracyclic antidepressant

Mirtazapine has demonstrated anxiolytic effects with a better side effect profile to all other classes of antidepressants, for example it rarely causes or exacerbates anxiety. However, in many countries (such as USA and Australia), it is not specifically approved for anxiety disorders and is used off label.

Monoamine oxidase inhibitors

Monoamine oxidase inhibitors (MAOIs) are effective for anxiety, but their dietary restrictions, side effects and availability of newer effective drugs, have limited their use.[6] First generation MAO inhibitors include: phenelzine, isocarboxazid and tranylcypromine. Moclobemide, a reversible MAO-A inhibitor, lacks the dietary restrictions associated with classic MAOI's, The drug is used in Canada, the UK and Australia.

Beta blockers

Although not officially approved for this purpose, beta blockers also can have an antianxiety effect.[14][15]

Miscellaneous

Alpha-adrenergic agonist

Alpha 2A receptor agonists clonidine and guanfacine has demonstrated both anxiolytic and anxiogenic effects.

Mebicar

Mebicar (mebicarum) is an anxiolytic produced in Latvia and used in Eastern Europe. Mebicar has an effect on the structure of limbic-reticular activity, particularly on hypothalamus emotional zone, as well as on all 4 basic neuromediator systems – γ aminobutyric acid (GABA), choline, serotonin and adrenergic activity.[16] Mebicar decreases the brain noradrenaline level, exerts no effect on the dopaminergic systems, and increases the brain serotonin level.[17]

Fabomotizole

Fabomotizole[18] (brand name Afobazole) is an anxiolytic drug launched in Russia in the early 2000s. Its mechanism of action remains poorly defined, with GABAergic, NGF and BDNF release promoting, MT1 receptor antagonism, MT3 receptor antagonism, and sigma agonism all thought to have some involvement.[19][20][21][22][23] It has yet to find clinical use outside of Russia.

Selank

Selank is an anxiolytic peptide based drug developed by the Institute of Molecular Genetics of the Russian academy of sciences. Selank is a heptapeptide with the sequence Thr-Lys-Pro-Arg-Pro-Gly-Pro. It is a synthetic analog of a human tetrapeptide tuftsin. As such, it mimics many of its effects. It has been shown to modulate the expression of interleukin-6 (IL-6) and affect the balance of T helper cell cytokines. There is evidence that it may also modulate the expression of brain-derived neurotropic factor in rats.

Bromantane

Bromantane is a stimulant drug with anxiolytic properties developed in Russia during the late 1980s, which acts mainly by inhibiting the reuptake of both dopamine and serotonin in the brain, although it also has anticholinergic effects at very high doses. Study results suggest that the combination of psychostimulant and anxiolytic actions in the spectrum of psychotropic activity of bromantane is effective in treating asthenic disorders compared to placebo.

Emoxypine

Emoxypine is an antioxidant that is also an anxiolytic. Its chemical structure resembles that of pyridoxine, a form of vitamin B6.

Azapirones

Azapirones are a class of 5-HT1A receptor agonists. Currently approved azapirones include buspirone (Buspar) and tandospirone (Sediel).

Hydroxyzine

Hydroxyzine (Atarax) is an antihistamine originally approved for clinical use by the FDA in 1956. In addition to its antihistamine properties hydroxyzine possesses anxiolytic properties and is approved for the treatment of anxiety and tension. Its sedative properties are useful as a premedication before anesthesia or to induce sedation after anesthesia.[24] Hydroxyzine has been shown to be as effective as benzodiazepines in the treatment of generalized anxiety disorder, while producing fewer side-effects.[25]

Pregabalin

Pregabalin's anxiolytic effect appears after one week of use and is similar in effectiveness to lorazepam, alprazolam, and venlafaxine, but has demonstrated more consistent therapeutic effects for psychic and somatic anxiety symptoms. Long-term trials have shown continued effectiveness without the development of tolerance, and unlike benzodiazepines, it does not disrupt sleep architecture and produces less severe cognitive and psychomotor impairment. Pregabalin also exhibits a lower potential for abuse and dependence than benzodiazepines.[26][27]

Menthyl isovalerate

Menthyl isovalerate is a flavoring food additive which is marketed as a sedative and anxiolytic drug in Russia under the name Validol. Sublingual administration of Validol produces a sedative effect, and has moderate reflex and vascular dilative action caused by stimulation of sensory nerve receptors of the oral mucosa followed by the release of endorphins. Validol is typically administered as needed for symptom relief.[28][29][30]

Cannabidiol

Cannabidiol (CBD) is a cannabinoid produced by Cannabis sativa and Cannabis indica, and in marginal quantities by Cannabis ruderalis. It is available in the United States in states where cannabis has been legalized for medical and general use. No lethal dose (or LD50) has been established from cannabidiol [citation needed]. In feral strains of cannabis, cannabidiol is produced in large quantities alongside the psychoactive cannabinoid tetrahydrocannabinol. Special strains of cannabis have been bred to yield high amounts of cannabidiol with significantly lowered synthesis of THC. Specific formulations for anxiety with a CBD to THC ratio of 18:1 are available in the US markets [citation needed].

Tetrahydrocannabinol

Tetrahydrocannabinol appears to be capable of both, having anxiolytic effect(s) and having anxiogenic effect(s).

Propofol

Propofol produces anxiolytic effect, beneficial during medical procedures requiring sedation.[31][32]

Racetams

Some racetam based drugs such as aniracetam can have an antianxiety effect.[33]

Herbal treatments

Certain natural substances are reputed to have anxiolytic properties, including the following:

Supplements and over-the-counter pharmaceutical drugs

Picamilon is a prodrug formed by combining niacin with GABA that is able to cross the blood–brain barrier and is then hydrolyzed into GABA and niacin. It is theorized that the GABA released in this process activates GABA receptors, with potential to produce an anxiolytic response.[39][40] Picamilon is sold in the United States as a dietary supplement, while in Russia it is sold as a prescription drug.

Chlorpheniramine (Chlor-Trimeton)[41] and diphenhydramine (Benadryl) have hypnotic and sedative effects with mild anxiolytic-like properties (off-label use). These drugs are approved by the FDA for allergies, rhinitis, and urticaria.

Melatonin has anxiolytic properties, likely through interactions between GABAA and melatonin2 (MTNR1B) receptors activating the GABAergic system.[42][43] It has been used experimentally as an effective premedication for general anesthesia in surgical procedures, replacing the benzodiazepine midazolam.[43][44]

Inositol:[45] In a double-blind, controlled trial, myo-inositol (18 grams daily) was superior to fluvoxamine for decreasing the number of panic attacks and had fewer side-effects.[46]

Future drugs

Due to deficits with existing anxiolytics (either in terms of efficacy or side-effect profile), research into novel anxiolytics is active. Possible candidates for future drugs include:

Common drugs

Prescription-free drugs are often poor anxiolytics and often worsen the symptoms over time[citation needed]. However, they are often used for self-medication because of their wide availability (e.g. alcoholic beverages).

Alcohol

See also: Short-term effects of alcohol

Ethanol is used as an anxiolytic, sometimes by self-medication. fMRI can measure the anxiolytic effects of alcohol in the human brain.[47] The British National Formulary states, "Alcohol is a poor hypnotic because its diuretic action interferes with sleep during the latter part of the night." Alcohol is also known to induce alcohol-related sleep disorders.[48]

Inhalants

See also: Inhalant abuse § Patterns of non-medical usage, and Street children in Latin America § Drugs

The anxiolytic effects of solvents act as positive modulators of GABAA receptors (Bowen and colleagues 2006).[49]

Alternatives to medication

Psychotherapeutic treatment can be an effective alternative to medication.[50] Exposure therapy is the recommended treatment for phobic anxiety disorders. Cognitive behavioral therapy (CBT) has been found to be effective treatment for panic disorder, social anxiety disorder, generalized anxiety disorder, and obsessive-compulsive disorder. Healthcare providers can also help by educating sufferers about anxiety disorders and referring individuals to self-help resources.[51] CBT has been shown to be effective in the treatment of generalized anxiety disorder, and possibly more effective than pharmacological treatments in the long term.[52] Sometimes medication is combined with psychotherapy, but research has not found a benefit of combined pharmacotherapy and psychotherapy versus monotherapy.[53]

However, even with CBT being a viable treatment option, it can still be ineffective for many individuals. Both the Canadian and American medical associations then suggest the use of a strong but long lasting benzodiazepine such as clonazepam and alprazolam and an antidepressant, usually Prozac for its effectiveness.[54][unreliable source][original research?]

Note that adolescent anxiety once the patient becomes pubescent can often turn into depression, at which time other treatments may be required.[citation needed]

Transcendental Meditation technique shows marked efficacy in treating anxiety disorders says a meta-analysis of randomized controlled trials, "TM practice is more effective than treatment as usual and most alternative treatments, with greatest effects observed in individuals with high anxiety"[55] And a meta-analysis says: "Differential effects of relaxation techniques on trait anxiety: a meta-analysis. Effect sizes for the different treatments (e.g., Progressive Relaxation, EMG Biofeedback, various forms of meditation, etc.) were calculated. Most of the treatments produced similar effect sizes except that Transcendental Meditation had significantly larger effect size (p less than .005)"[56]

Regular practice of Transcendental Meditation enables some active duty service members battling post-traumatic stress disorder to reduce or even eliminate their psychotropic medication and get better control of their often-debilitating symptoms, researchers report in the journal Military Medicine.[57]

See also

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  54. ^ CMA & AMA Home medical guides 2012 & 2014, along with personal experiences and WebMD reviews
  55. ^ David W. Orme-Johnson; Vernon A. Barnes (2014). "Effects of the Transcendental Meditation Technique on Trait Anxiety: A Meta-Analysis of Randomized Controlled Trials". THE JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE. 20 (5): 330–341. doi:10.1089/acm.2013.0204. {{cite journal}}: Cite has empty unknown parameter: |month= (help)
  56. ^ Eppley K, et al. (1989). "Differential effects of relaxation techniques on trait anxiety: a meta-analysis". Journal of Clinical Psychology (45): 957–974.
  57. ^ PTSD Symptoms May Be Reduced With Transcendental Meditation - Neuroscience News January 11, 2016
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