The Science and Art of Prescribing for Insomnia
8.3 Drugs Which Increase Function of Sleep-Promoting Neurotransmitters
The majority of brain cells are inhibited by GABA, so increasing its function reduces arousal and produces sleep and eventually anaesthesia. There are many sub- sets of GABA neurons distributed throughout the brain, but a particular cluster in the hypothalamus (ventrolateral preoptic nucleus) can be considered to be the sleep
‘switch’ (Saper et al. 2005). These neurons switch off brain arousal systems at the level of the cell bodies and therefore promote sleep. GABA receptors in the cortex can also promote sedation and sleep by inhibiting the target neurons of the arousal system.
The inhibitory effects of GABA are mediated through the GABA-A receptor, which is a complex of proteins with a binding site for a number of sleep-promoting drugs, in particular the benzodiazepine receptor agonists (which include benzodiaz- epines themselves and the so-called ‘Z’ drugs like zolpidem and zopiclone) which enhance the effects of GABA’s actions at the GABA-A receptor, by an action called positive allosteric modulation. This is why they are known as GABA-PAMs.
Table 8.1 Neurotransmitter effects on sleep and wakefulness Endogenous
transmitter
Increasing function maintains wakefulness
Increasing function promotes sleep
GABA ✓
Melatonin (✓—Brings forward sleep
onset)
Adenosine ✓
Noradrenaline ✓
Dopamine ✓
Serotonin ✓
Histamine ✓
Acetylcholine ✓
Orexin ✓
8.3.1 Benzodiazepine-Receptor Agonists (GABA-A-Positive Allosteric Modulators)
These drugs are licensed for use in insomnia as they have been proven to improve sleep in clinical trials. They all work in the same way but differ in their speed of onset and duration of action. The faster the drug enters the brain, the sooner sleep is induced.
As well as inducing sleep, these drugs are anticonvulsant and antianxiety and produce muscle relaxation, ataxia and memory impairment, while they are in the brain. The latter three are not usually a problem, while people are asleep in bed, but if the effects outlast sleep, then these side effects are undesirable. Therefore, it is important to con- sider both speed of onset and duration of action when choosing a drug.
The ease of waking and the propensity to daytime carry-over (‘hangover’) effects are determined by the duration of action—most typically defined by the elimination half-life of the drugs (see Tables 8.2 and 8.3) and the dose taken. Drugs with half- lives of more than 6h tend to leave sufficient residual drug in the brain to cause hangover in the morning. This was particularly the case with the first benzodiaze- pine agonists such as nitrazepam which was associated with daytime sedation and falls (Trewin et al. 1992). The rationale for developing the Z-drugs was in part to make shorter half-life benzodiazepine agonists with minimal carry-over effects (Nutt 2005). This was largely achieved although there is some hangover seen with zopiclone (Staner et al. 2005). The very short half-life of zaleplon means that it could be taken as little as 5h before the desired time of arising, without the risk of hangover impairment (Walsh et al. 2000). However, at the time of writing, this drug is no longer on the market.
A very short half-life limits a drug’s duration of action on sleep, and zaleplon and, to some extent, zolpidem are not particularly effective at maintaining sleep throughout the night. A controlled release formulation of zolpidem (currently only available in the USA) prolongs its nocturnal actions and enhances sleep continuity, though only by tens of minutes (Greenblatt et al. 2006). Individual factors seem
Table 8.2 Sleep-promoting neurotransmitters Endogenous sleep- promoting
neurotransmitter
Examples of drugs increasing function and promoting sleep
Examples of drugs decreasing function and promoting wakefulness
GABA Benzodiezepine receptor
agonists (positive allosteric modulators) e.g. temazepam, zopidone
None
Melatonin Melatonin M1 and M2 receptor
agonists (e.g. melatonin, ramelteon) (bring sleep onset forward)
None
Adenosine None Adenosine receptor
antagonist (caffeine)
important, and some people are more susceptible to carry-over than others, probably due to individual differences either in the rate of drug clearance, which can vary by as much a twofold between subjects, or sensitivity to drug actions; there are also gender differences with women being more susceptible to the hangover effects, par- ticularly relating to driving (Booth et al. 2016).
8.3.2 Tolerance, Dependence and Withdrawal Considerations with GABA-Acting Drugs
Dose escalation above recommended doses in patients with insomnia alone is uncommon, and tolerance to drug effects is not a frequent problem in clinical expe- rience; many patients use the same dose of sleep medication for months or years and still feel it works.
Animal and human research demonstrates that brain receptor function changes in response to chronic treatment with benzodiazepine receptor agonists, and this takes time to return to premedication levels after cessation of medication. There is evi- dence from animal studies that chronic administration of benzodiazepines produces adaptive changes in the receptor which attenuate the effects of the endogenous neu- rotransmitter GABA and so produce symptoms on withdrawal (Bateson 2002).
Considerations of dependence are very much contingent on what happens when treatment is stopped. A psychological dependence is seen in many patients, and some are unwilling to stop treatment. If they do stop, there can be relapse, where the patient’s original symptoms return, or rebound of symptoms, where for one or
Table 8.3 Wake-promoting neurotransmitters Endogenous
wakefulness-promoting neurotransmitter
Examples of drugs increasing function and promoting wakefulness
Examples of drugs decreasing function and promoting sleep and/or daytime sedation Noradrenaline Uptake blocker (e.g. atomoxetine);
uptake blocker and neurotransmitter releaser (e.g. amphetamines)
Alpha-1 receptor antagonists (e.g. prazosin, but also e.g.
chlorpromazine, clozapine) Dopamine Uptake blocker (e.g. modafinil);
uptake blocker and neurotransmitter releaser (e.g. amphetamines)
None
Serotonin Uptake blocker (SRI) but mild effect and often just early in treatment
5HT2 antagonists (e.g.
trazodone). 5HTP Histamine H3 receptor antagonist (e.g.
pitolisant) (H3 is an autoreceptor and therefore antagonizing it increases histamine cell firing)
H1 antagonists (e.g. low-dose doxepin)
Acetylcholine None Muscarinic receptor
antagonist (e.g. amitriptyline, olanzapine)
Orexin None Orexin receptor antagonist
(e.g. suvorexant)
two nights there is a worsening of sleep disturbance, with longer sleep onset latency and increased waking during sleep. This is commonly reported by patients and has been documented in some research studies (Soldatos et al. 1999; Hajak et al. 2009).
It is also seen in healthy volunteers who have been taking zopiclone or zolpidem for 3 weeks and then stop (Voderholzer et al. 2001). More rarely, there is a longer withdrawal syndrome. All of these can be ameliorated by resuming medication.
The withdrawal syndrome is characterized by the emergence of symptoms not pre- viously experienced, such as agitation, headache, dizziness, dysphoria, irritability, fatigue, depersonalization and hypersensitivity to noise and visual stimuli. This syndrome typically resolves within a few weeks, but in some patients it persists, and this may be related to personality traits and cognitive factors (Murphy and Tyrer 1991).
8.3.3 Melatonin
Melatonin is a natural hormone that is produced in the pineal gland and which has an important role in regulating circadian rhythms (Dijk and von Schantz 2005;
Cajochen et al. 2003). The circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus drives melatonin synthesis and secretion from the pineal gland. Once melatonin appears in the plasma, it enters the brain and binds to mela- tonin receptors in the hypothalamus, forming a feedback loop. The SCN contains melatonin 1 and melatonin 2 receptors, and much research is ongoing about their role in sleep-wake regulation and circadian rhythms. Giving melatonin tablets has both phase-shifting effects, thus changing the timing of the biological clock, and direct effects to promote sleep onset. A slow-release formulation of melatonin has been licensed on the basis of improved sleep continuity and daytime well-being in people aged over 55 years with insomnia. Numerous melatonin preparations are available off the shelf in many countries. Ramelteon, a synthetic melatonin agonist, is available in the USA. There are very few side effects of melatonin; in particular there are no effects on movement or memory.
8.3.4 Adenosine
Another sleep-promoting neurotransmitter is adenosine. Brain levels of this rise during the day and are thought to lead to sleepiness, which increases the longer the time since the last sleep. The arousing and sleep-impairing effects of caffeine (Landolt et al. 2004) are thought to be due to antagonism of adenosine-A2 recep- tors, so attenuating this natural process (Porkka-Heiskanen et al. 2002). Caffeine is a useful translational model for insomnia as its effects in rodents are very similar to those in humans and could be used to screen potential new treatments (Paterson et al. 2007). However, there is no adenosine agonist drug available for use in humans, though this may be a target for future drugs.
8.4 Drugs Which Decrease Function of Wakefulness-