AETIOLOGY, CLASSIFICATION AND EPIDEMIOLOGY

Periods of sleep disturbance due to acute stress or environmental change are common human experiences. The diagnostic DSM-IV classification of chronic primary insomnia is differentiated from an acute occurrence of insomnia, requiring the disorder to be a major health complaint, presenting with over 1 month of persistent problems in initiating or maintaining sleep, or having non-restorative sleep.¹ Furthermore, for this diagnosis to be met the sleep disturbance must cause significant distress or impairment in social, occupational functioning, be exclusive of other disorders (such as other sleep or psychiatric disorders), and not due to medications, drugs, alcoholism or a general medical condition. Insomnia may be secondary (caused by) another medical condition, from medicines, recreational drugs or alcohol consumption, or be from environmental factors such as altitude, jet lag, poor bedding, excess light or noise. Because of this a thorough assessment is required to establish the particulars of the cause. It is estimated that 25% of chronic insomnia can be classified as ‘primary’, with approximately 75% due to the aforementioned causes.² Interestingly, people who experience ‘transient’ insomnia (< 1 month), usually from an environmental change, acute social stressors or the loss of a loved one, usually experience daytime sleepiness during this period; a person with chronic insomnia usually does not feel sleepy, and instead may feel ‘hyperstimulated’ even after 4–6 hours’ sleep.²

Parameters measuring sleep outcomes involve evaluating total sleep time, sleep latency (how long it takes to get to sleep) and wake time after sleep onset.³ Little regard in present research is given to next-day functioning or improved outcomes in comorbid psychiatric or medical disorders. These remain areas of significance in enhancing outcomes in sleep disorders.

The prevalence of general sleep disturbance experienced by people over a year is estimated at approximately 85%, while the estimate of diagnosed chronic insomnia is estimated at around 10%.² As in the case of other psychiatric disorders, women have a slightly higher incidence of primary insomnia.

The pathophysiology behind sleep disorders appears to involve:^4–7

Prolonged poor ‘sleep hygiene’ may cause behavioural conditioning towards ‘expecting’ to have bad sleep.⁸ This is reflected in the fact that population surveys indicate that of the 50% of people who have sleep difficulties, between 20% and 36% report the duration is greater than 1 year.⁹ ‘Sleep hygiene’ is a term used to describe lifestyle interventions that assist with preparation for sleep. Aspects of good sleep hygiene focus on replacing stimulating activities with restful and quiescent activities (or non-activities) to establish a regulated circadian rhythm (this is discussed further below). Beyond the socioeconomic cost, the subjective effect of chronic sleep disturbance often involves the person experiencing a low mood or anxiety (this may not meet diagnostic threshold), fatigue or daytime somnolence, poor concentration or memory, tension headaches and digestive disturbances.¹⁰

RISK FACTORS AND ECONOMIC IMPACT

The elderly, female gender, shift workers, chronic-pain sufferers and people with co-occurring medical conditions or psychiatric disorders (especially depression and anxiety) are at greater risk of developing chronic insomnia (see the box below).⁴ A sedentary life and reduced exposure to sunlight may also contribute to sleep disorders. Elderly populations frequently report that they perceive a poorer quality of sleep, commonly that they have interrupted sleep, wake early or feel inadequately rested.¹¹ Interestingly, studies show that, statistically, the elderly sleep similar hours to younger counterparts, and that the reduction of qualitative sleep experience is actually due to comorbid health issues or medications, not to do with ‘being old’.¹¹ Chronic experience of pain increases the risk of insomnia, with a study revealing that 44% of people with chronic pain had co-existing insomnia.¹¹ Furthermore, the more severe the level of pain was, the greater the percentage who experienced insomnia.

With respect to major depressive disorder, a study¹² showed that patients with chronic insomnia had an increased risk of a major depressive disorder of 1.6 times higher than subjects with good sleep; if the insomnia was maintained for a year the risk was 40 times as high! Sleep disturbance is a frequent symptom of depression, and a strong causal link exists between insomnia and depression.¹¹ It is likely that this is bimodal; that is, insomnia can cause depression and vice versa. Furthermore, epidemiological data have shown that approximately 40% of chronic insomniacs suffer from another comorbid psychiatric disorder.^10,13 The cost that sleep disorders cause is immense, with an estimate of direct cost of insomnia in the United States of America approximating US$13.93 billion in 1999.¹⁴ Interestingly, most of this cost was service-based (especially for nursing home costs) and only a fraction was from

prescriptive costs. While prescriptive drug use is prevalent in insomniacs for the treatment of the disorder, medications for other conditions may also cause insomnia (see the box above).^11,15

It should be noted that while the previously mentioned risk factors may cause sleep disorders chronic sleep disturbances may also in turn cause a variety of physical and mental conditions.^9,17 The most concerning link with chronic insomnia is that evidence indicates that people with poor sleep or < 6 hours per night have a significantly greater risk of: ³

CONVENTIONAL TREATMENT

Sage advice when treating transient insomnia should be to establish the underlying causes, initiate good sleep hygiene changes, commence (or refer) an appropriate psychological intervention and offer lifestyle and prescriptive advice.¹⁵ The medical ‘quick fix’ is usually the use of pharmaceutical hypnotics as the primary first-line pharmacotherapy to treat chronic insomnia.²⁰ The use of benzodiazepines such as diazepam (or its metabolites) or non-benzodiazepine hypnotics such as zolpidem or zopiclone are preferred currently over older barbiturates which can cause death in cases of overdose.²⁰ Although benzodiazepines are relatively safe medications, concerns exist over dependency, and currently most guidelines endorse only short-term use.²¹

Sedating antidepressants, for example mirtazepine or fluvoxamine, may also be prescribed, especially in cases of comorbid depression.²⁰ In some cases the use of sedating antipsychotic or tricyclic medication may also be employed. Opiates also have soporific effects, and may be indicated in cases of chronic pain with insomnia. Melatonin (an endogenous hormone secreted by the pineal gland) is also prescribed in some countries, especially to treat sleep disturbance, especially if caused by jet lag.²² A novel

melatoninergic agent called agomelatine, a melatonin 1,2 receptor agonist and serotonin 5HT2c receptor agonist (at stage IV clinical trials), may in the future be used as a non-addictive hypnotic with anxiolytic properties.²⁵ Referral for psychological interventions such as cognitive modification or behavioural adjustments may also be recommended in primary care.²⁶

KEY TREATMENT PROTOCOLS

Circadian rhythm modulation

The primary circadian ‘clock’ in humans is located in the suprachiasmatic nuclei in the hypothalmus; these cells govern the daily biological rhythm over a cycle lasting approximately 24 hours and 11 minutes.⁵ The wake/sleep cycle is influenced externally by light and dark, with exposure to light increasing the secretion of serotonin, while darkness increases the secretion of melatonin. The circadian rhythm governs internal temperature changes, sleep and eating patterns. Human clock genes have been identified as being involved with various sleep disorders.⁵ Future gene therapy may target the expression of these clock genes to effectively reset the circadian rhythm. In the meantime, the use of interventions that modulate the circadian rhythm and the use of sleep hygiene techniques such as ‘sleep restriction’ and ‘light therapy’ may assist in readjusting the circadian rhythm.

NATUROPATHIC TREATMENT AIMS

• Assess the causes of the sleep disorder.

• Educate on good sleep hygiene practices.

• Regulate circadian rhythm, HPA function and GABAergic activity.

• Regulate and support the nervous system.

• Encourage beneficial lifestyle changes.

• Appropriately address external stressors, e.g. relationship or job factors.

Another neurological factor involved in sleep is the endogenous compound adenosine. This inhibitory compound and the adenosine receptor binding sites are a homeostatic sleep factor responsible for mediating the REM cycle (see Figures 14.1 and 14.2).²⁷ Adenosine can potently inhibit cholinergic neurons that are involved with cortical arousal, and during periods of prolonged wakefulness adenosine accumulates in certain parts of the brain and promotes the transition from a wake state to a sleep state.⁷ This is considered to be one of the factors involved in the theory of ‘sleep debt’, in which sleep deprivation over days accrues a chronological sleep debt (a build-up of adenosine), which then prompts a period of increased sleep to make up for loss. Caffeine antagonises adenosine receptors, thereby increasing wakefulness (see the lifestyle advice section below).²⁸ The compound adenosine would appear to be a potential hypnotic substance; as discussed above, endogenous adenosine is responsible for modulating the wake-sleep cycle via binding to adenosine (A1) and (A2) receptors. A literature search reviewing clinical evidence of this product revealed no clinical evidence, however; this remains an area of potential exploration.

Figure 14.1 REM cycle

Figure 14.2 Brain waves

Humulus lupulus is used in Europe extensively in sleep formulations to promote sleep. The bitter herb is regarded by the eclectics as a useful remedy for imparting sedative and hypnotic actions.²⁹ While animal and in vitro models do not currently support sedative or anxiolytic activity, hypnotic effects involving melatoninergic and GABAergic modulation have been documented.³⁰ Humulus lupulus combines well with Valeriana spp. root, demonstrated by a fixed valerian–hop combination (Ze 91019) found to reduce sleep latency and waking time compared to placebo in 30 subjects after 2 weeks of treatment.³¹ Another randomised controlled trial (RCT) comparing the combination to placebo and diphenhydramine revealed less conclusive results.³² The 4-week study involving 184 adults with mild insomnia showed none or only minor improvements of subjective sleep parameters compared to placebo, with most outcomes being similar between all three groups. It is possible that the inclusion of ‘mild’ insomniacs diluted the response from the herbal combination. In vitro studies indicate that hops–valerian preparations invoke hypnotic activity via agonising adenosine, melatonin and serotonin receptors.^33–35

Valeriana officinalis has a rich folkloric tradition of use in conditions of restlessness, hysteria, nervous headache and mental depression,^29,36 with Pliny regarding the powder of the root as effective in cases of spasms causing pain.³⁷ Energetically Valeriana spp. root was regarded by Dioscorides as possessing warming properties;³⁷ this is reflected in the pungent aroma of the essential oils (valerenal, iso/valerianic acid) and terpenes (valerenic acid).³⁸ The use of Valeriana spp. in prescriptions needs to be monitored due to this ‘heating ’ effect, which can evoke stimulation and restlessness (the eclectics classified valerian as a ‘cerebral stimulant’).^29,39 A systematic review and meta-analysis included 16 eligible RCTs involved a total of 1093 patients.³⁸ The results revealed that on six studies with a dichotomous outcome of sleep quality (‘improved’ or ‘not improved’) a statistically significant benefit occurred. Nine out of 16 studies did not, however, have positive outcomes in regard to improvement of sleep quality. It should be noted that many studies included in the review involved combinations of valerian with other herbal medicines (for example Piper methysticum or H. lupulus), differing outcome scales, dosages and participant populations, and eight trials had small sample sizes. Because of this, currently the evidence does not firmly support the use of valerian as a stand-alone hypnotic.

A 2001 clinical trial demonstrated that V. edulis improved sleep architecture over V. officinalis by diminishing waking episodes and improving delta sleep.⁴⁰ This is an important difference with respect to addressing ‘maintenance insomnia’. Valeriana spp. have demonstrated some clinical evidence in enhancing sleep parameters when used for periods of >2 weeks, and acute administration appears to have only minor effect.^31,41,42 The mechanism of action regarding Valeriana spp. hypnotic effect is posited as involving an increase in REM stage and delta sleep,^40,41 mediated by GABA-A receptor (β3 subunit) agonism,⁴³ and adenosine 1, benzodiazepine and serotonin 5-HT (1A) receptor agonism.^33,35,44 Commission E and the World Health Organization support the use of valerian for restlessness and sleep disorders,⁴⁵ but more robust clinical trials are required to provide firm endorsement.

Vitex agnus-castus, although used commonly for hormonal and menstrual irregularities,⁴⁶ may exert a novel melatoninergic activity. While to date no human clinical trials exist testing V. agnus-castus in insomnia, a study of 20 healthy human males demonstrated a significant dose-dependent increase of melatonin secretion using 120 mg, 240 mg, 480 mg of the extract per day compared to placebo for 14 days.⁴⁷

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