1. Definition of generalized anxiety and sleep disorders

1.1.

Anxiety is a condition characterized by the subjective and physiologic manifestations of fear. In anxiety disorders, individuals experience apprehension, but, in contrast to fear, the source of the danger is unknown. The physiologic manifestations of fear include sweating, shakiness, dizziness, palpitations, mydriasis, tachycardia, tremor, gastrointestinal disturbances, diarrhoea, and urinary urgency and frequency.

1.2.

If anxiety is generalized and persistent over months but not restricted to any particular environmental circumstances, the term generalized anxiety disorder is usually used. The dominant symptoms are variable but include complaints of persistent nervousness, trembling, muscular tensions, sweating, light headedness, palpitations, dizziness, and epigastric discomfort. Fears that the patient or a relative will shortly become ill or have an accident are often expressed.

1.3.

The onset of generalized anxiety is usually before the age of 25 years, and the incidence in men is half that in women. The course is fluctuating, and often quite debilitating. In western countries the 12-month prevalence rate is around 3%. Anxiety symptoms may be associated with psychiatric or medical disorders.

1.4.

Major depression occurs in almost two third of patients with generalized anxiety disorder, panic disorder in a quarter and alcohol abuse in more than one third of patients with generalized anxiety disorder.

1.5.

Insomnia is a disturbance of normal sleep patterns, with adverse daytime consequences. It affects up to 50% of all adults at some point in their life. The prevalence of insomnia seems to be higher in women and in late life. Individuals with insomnia report difficulty to fall asleep or to remain asleep, and usually feel nonrestored from sleep.

1.6.

Generalized anxiety and sleep disorders may be the consequence of medical conditions, psychiatric conditions (mood or anxiety disorders), concomitant medicine treatments or medicine withdrawal, substance abuse (caffeine, nicotine, alcohol), stress and bad habits.

2. Preliminary assessment and initial management strategies

2.1.

In evaluating patients with anxiety and/or sleep disorders health care providers should initially consider possible underlying medical causes, including hyperthyroidism and other endocrine illnesses, cardiac problems and other organ system dysfunctions. Medicine use (caffeine, cocaine) and medicine or substances withdrawal (alcohol, opiates, benzodiazepines) can cause anxiety and insomnia. If medical disorders, medicine use or withdrawal is a plausible reason for anxiety, the underlying cause should be removed or treated.

2.2.

If medical disorders, medicine use or withdrawal is not a plausible reason for anxiety or insomnia, health care providers might investigate whether major depression or other psychiatric disorders are present. If another psychiatric disorder is present, health care providers should treat that disorder first.

2.3.

In individuals with sleep disorders, if no psychiatric comorbidities are present, health care providers may suggest educational interventions, such as going to bed at the same time, reserving bed for sleep, reducing caffeine intake and avoiding strenuous exercise or mental activities near bedtime.

2.4.

In individuals with anxiety disorders, if no psychiatric comorbidities are present, health care providers may explain to the patient that chest pain, indigestion, sweating, and sexual dysfunction are symptoms of anxiety.

3. Short-term treatment with benzodiazepines

3.1.

Health care providers should initially consider non-pharmacological treatment strategies. Empathic listening, reassurance and guidance should always be offered. Additionally, specific psychotherapeutic techniques, such as cognitive-behavioural therapy, are effective measures to reduce anxiety and insomnia, and non specific supportive therapy may initially be offered to patients with uncomplicated generalized anxiety or sleep disorders. Relaxation techniques may additionally be offered.

3.2.

Benzodiazepines are a group of structurally-related compounds that reduce anxiety when given at low doses and induce sleep at higher doses. Clinical guidelines generally recommend to prescribe benzodiazepines to treat anxiety or insomnia that is severe, disabling and causing extreme distress. Health care providers should consider that benzodiazepine use is associated with dependence liability and withdrawal symptoms, and should therefore be used at the lowest effective dose for the shortest period of time (maximum 4 weeks).

3.3.

The use of benzodiazepines is under international control. These agents are internationally regulated by the Convention on Psychotropic Substances, 1971 (United Nations).

3.4.

Health care providers should consider that, in addition to international control, benzodiazepine use may be under national control. Health care providers must therefore comply with national, regional and local regulations.

3.5.

Benzodiazepines can be grouped, according to their elimination half-life, into short/intermediate and long half-life agents. Short/intermediate half-life agents include alprazolam (intermediate), lorazepam (short), oxazepam (short), temazepam (intermediate) and triazolam (ultra-short); long half-life agents include diazepam, chlordiazepoxide, flurazepam and nitrazepam. Benzodiazepines with short elimination half-life are preferred to minimise daytime sedation, but they can cause rebound symptomatology more often than agents with longer elimination half-life.

3.6.

Ultra-short benzodiazepines are generally not recommended due to the possibility of rebound symptomatology.

3.7.

Benzodiazepines hasten sleep onset, decrease nocturnal awakenings, increase total sleeping time, and reduce pathological anxiety, agitation and tension.

3.8.

According to the WHO EML, essential medicine for anxiety and sleep disorders is diazepam. Diazepam is indicated as an example of the class for which there is the best evidence for effectiveness and safety. Thus diazepam represents benzodiazepines.

3.9.

In individuals with insomnia, if short-acting agents such as lorazepam are available, these are generally used when residual sedation is undesirable, if falling asleep is a problem, or, when necessary, in elderly patients. Longer-acting benzodiazepines such as diazepam are indicated when early waking is a problem and possibly when an anxiolytic effect is needed during the day or when some impairment of psychomotor function is acceptable.

3.10.

Health care providers should consider that in recent years non-benzodiazepine hypnotics such as zopiclone and zolpidem have progressively become widely used in individuals with insomnia. However, these agents may be as likely as the benzodiazepines to cause rebound symptoms, dependence and other adverse reactions.

3.11.

In individuals with generalized anxiety disorder health care providers may consider using a benzodiazepine only for a limited course of time. The main objective may be to reduce symptoms enough to allow the patient to engage in treatments based on cognitive-behavioural techniques. A short course (maximum 4 weeks) started at the lowest possible dose for a pre-defined duration of treatment may be used for initial management. Diazepam may be indicated when an anxiolytic effect is needed during the day and an hypnotic effect is required at night.

3.12.

Considering that major depression often complicates anxiety symptoms, health care providers should consider using antidepressants. Some tricyclic antidepressants (imipramine, clomipramine) and selective serotonin reuptake inhibitors have been shown to be effective for treating patients with generalized anxiety alone or in association with depression. Antidepressants may be prescribed at low doses initially, and then treatment may be up-titrated into the normal antidepressant dosage. Treatment response should be assessed after six weeks.

4. Long-term treatment with benzodiazepines

4.1.

Benzodiazepines should not be continued beyond 4 weeks, as chronic use may induce dependence and withdrawal symptoms. Length of therapy should be discussed with patients, and a follow-up visit should be defined in advance (by office visit if possible, or by telephone or by other means) to re-evaluate anxiety and the sleep patterns.

4.2.

Health care providers should taper benzodiazepines gradually. If anxiety symptoms are still present, a trial with an antidepressant may be considered. Antidepressants usually take weeks to relieve symptoms and, after remission is achieved, treatment should be prolonged for up to 6-8 months to prevent relapse.

5. Administration of benzodiazepines

5.1.

Benzodiazepines should be given at the lowest effective dose for as short a period as possible. Diazepam may be given in oral doses of 2 mg one to three times daily, up to oral doses of 5-10 mg twice a day. Lower doses are generally advised in children and adolescents.

5.2.

Patients should be advised not to drive or operate machinery while taking benzodiazepines.

5.3.

Health care providers should not prescribe two or more benzodiazepines concurrently.

5.4.

Health care providers should avoid benzodiazepines in addiction-prone individuals.

5.5.

Health care providers should not prescribe benzodiazepines in patients with respiratory failure.

6. Adverse reactions of benzodiazepines

6.1.

Drowsiness, sedation and muscle weakness are the most frequent adverse effects of benzodiazepine use. Less frequent effects include vertigo, headache, confusion, depression, dysarthria, changes in libido, tremor, visual disturbances, urinary retention or incontinence, gastrointestinal disturbances, changes in salivation, and amnesia. If patients develop drowsiness, sedation and muscle weakness health care providers may decrease the dosage by one third; patients do not necessarily need to come back to your office to make this dose decrease.

6.2.

Health care providers should consider that risk factors for dependence include high dosage, continuous use, use of short half-life benzodiazepines, use in addiction-prone individuals or in those with a history of medicine or alcohol dependence.

6.3.

Abrupt benzodiazepine withdrawal can cause a syndrome characterized by anxiety, depression, impaired concentration, insomnia, headache, dizziness, tinnitus, loss of appetite, tremor, perspiration, irritability, perceptual disturbances such as hypersensitivity to physical, visual, and auditory stimuli and abnormal taste, nausea, vomiting, abdominal cramps, palpitations, mild systolic hypertension, tachycardia, and orthostatic hypotension.

6.4.

Benzodiazepine withdrawal symptoms usually begin within a few hours after withdrawal of a short-acting benzodiazepine, but may not develop for up to 3 weeks after stopping a longer-acting benzodiazepine. Resolution of symptoms may take several days or months. The dependence induced by short- and long-acting benzodiazepines appears to be qualitatively similar although withdrawal symptoms may be more severe with short-acting benzodiazepines. Rebound effects are also more likely with short-acting benzodiazepines.

7. Overdosage of benzodiazepines

7.1.

The outcome of benzodiazepine overdoses is generally favourable unless other medicines, such as alcohol, antipsychotics and antidepressants, have been ingested.

7.2.

Benzodiazepine poisoning is associated with rapid impairment of consciousness. A sleep-like state from which the patient can be temporarily roused by appropriate stimuli is generally induced. There is usually little or no respiratory depression, and cardiac rate and rhythm remain normal in the absence of anoxia or severe hypotension.

7.3.

If benzodiazepine overdosage is suspected, referral to acute medical facility is recommended.

8. Special patient populations

8.1.

Health care providers should use benzodiazepines with care in elderly or debilitated patients who may be more prone to adverse effects. Individuals with impaired liver or kidney function may require reduced doses. Benzodiazepine use should be avoided in severe hepatic impairment. Long-term use may exacerbate underlying dementia in elderly patients.

8.2.

Benzodiazepines should be avoided during pregnancy. Health care providers should advise child-bearing women to discontinue benzodiazepines if they intend to become, or suspect that they are, pregnant. Use during the first trimester has been associated with congenital malformations in the infant. Use in the third trimester may be associated with neonatal withdrawal symptoms (floppy infant syndrome). Benzodiazepines should not be given to lactating mothers.

9. Potentially relevant interactions

Alcohol and benzodiazepines. Sedation is enhanced by 20-30%.

Clozapine and benzodiazepines. Sedation and hypotension are enhanced.

Levodopa and benzodiazepines. The effect of levodopa is reduced.

10. Essential medicines for generalized anxiety and sleep disorders

Diazepam

• Starting dose: 2-10 mg/day orally.
• Therapeutic dose: 10-20 mg/day orally.
• For prompt control of severe symptoms: 2-10 mg intramuscular or intravenous injection, may be repeated after 3-4 hours if needed.
• Common adverse effects: drowsiness, sedation, muscle weakness. Diazepam can adversely affect parameters of driving performance in healthy subjects.
• Serious adverse effects: vertigo, headache, confusion, depression, dysarthria, changes in libido, tremor, visual disturbances, urinary retention or incontinence, gastrointestinal disturbances, changes in salivation, and amnesia. Some patients may experience a paradoxical excitation which may lead to hostility, aggression, and disinhibition. Jaundice, blood disorders, and hypersensitivity reactions have been reported rarely. Respiratory depression and hypotension occasionally occur with high dosage and parenteral administration.
• WHO Model List: tablet 2 mg; tablet 5 mg.