The Science and Art of Prescribing for Insomnia
8.5 When to Prescribe Drugs for Insomnia
In order to address the issue of when it is appropriate to prescribe a sleep-promoting drug, it is necessary to differentiate between acute prescribing and chronic prescrib- ing. The risks and side effects that may be unacceptable in the long term may be tolerable and manageable if the medication is only used for a short period of time.
Short-term prescribing may be appropriate where there is a clear, time-limited stressor that is driving the insomnia, and therefore the insomnia is likely to resolve when that stressor is removed. Similarly, some patients may benefit from occasional doses when their insomnia is sporadic.
It may also be appropriate to use a short course of sleep medication in chronic insomnia if the patient is awaiting a more definitive intervention such as cognitive behaviour therapy for insomnia. However, the value of short-term prescribing in chronic insomnia is questionable. Sleeping tablets can be effective as long as they are being taken, but there is rarely any sustained improvement once the medication is stopped (Riemann and Perlis 2009). Therefore, the common practice of giving someone with chronic insomnia a ‘two week course of hypnotics to reset their sleep cycle’ seldom works.
What this means is that when prescribing for chronic insomnia, one either needs an exit strategy, such as CBT for insomnia, or one needs to be comfortable with the idea of prescribing the medication in the long term. Many clinicians baulk at the idea of prescribing benzodiazepine agonists for the long term, and in many coun- tries these are not licensed for long-term use. However, when one considers that insomnia is often a chronic and debilitating condition, one should not automatically dismiss the idea of chronic prescribing. Severe insomnia’s impact on quality of life is on a par with major depression (Katz and McHorney 2002), and many patients are willing to accept the risks of chronic medication use if it improves their overall
quality of life. Indeed, clinicians are rarely uncomfortable with chronic prescrip- tions of antidepressants, mood stabilizers and antipsychotics; when insomnia is viewed as a serious psychiatric illness in its own right, the idea of chronic medical treatment seems less troubling.
There is also the question of whether the proactive treatment of insomnia with hypnotics may reduce the risks of other psychiatric symptoms. The evidence that insomnia is a risk factor for other psychiatric conditions is mounting, particularly in relation to depression (Baglioni et al. 2011; Neckelmann et al. 2007). Comorbid insomnia worsens depression outcomes (Pigeon et al. 2008), and treating insomnia comorbid with depression improves the depressive symptoms and prognosis (Manber and Chambers 2009). However, it has not yet been definitively shown that treating insomnia in patients without comorbid psychiatric illnesses is preventa- tive. In practice, however, this should not change one’s management of insomnia.
Given its significant negative impact on quality of life, insomnia should be treated aggressively regardless of whether it leads to other psychiatric (or physical) illnesses.
The other scenario to consider is the use of hypnotics in the acutely unwell psy- chiatric patient. These are often prescribed as short-term or as-needed doses in the acute treatment of patients with severe depression, mania or psychosis. From a patient’s perspective, this can be very helpful; while many psychiatric drugs can take days or weeks before they start to noticeably improve the patient’s symptoms, hypnotics can provide relief from one of their symptoms immediately. However, there are two factors that should be borne in mind. Firstly, acutely unwell patients are likely to be taking a number of medications, and therefore the risk of dangerous interactions is significantly increased, particularly if they are on other sedative drugs such as benzodiazepines. Secondly, hypnotics should only be prescribed if they improve the patient’s symptoms and should not be used as a form of behavioural management or as emergency sedation. Staffing levels on psychiatric wards are gen- erally lower at night, and while it is tempting to give patients hypnotics to help the staff manage the ward at night, this is clearly inappropriate.
There is also the risk of overdose to be considered in suicidal patients, and there- fore only limited supplies of hypnotics should be given to this population. Ideally, these should be monitored and controlled by another person to minimize the risk of stockpiling the medication. There is mounting evidence that insomnia may be an independent risk factor for suicide (Woznica et al. 2015), but there is a lack of data on whether the treatment of insomnia with hypnotics reduces this risk.
Whether or not a hypnotic is effective, one should always assume that it renders the patient incapable of making clear decisions or taking responsibility. Therefore, one should check that the patient will not be responsible for the care of a child or have similar responsibilities during the night. Even if they are rousable on the hyp- notic, they may not be sufficiently compos mentis to be able to look after that child.
Similarly, patients should be told very clearly that they should not drive, cook or do any other potentially dangerous activity after taking the medication until they are absolutely certain that the sedative effects of the medication have worn off.
8.5.1 Does the Patient Need a Hypnotic?
A good guiding principle in prescribing is to avoid polypharmacy wherever possi- ble. Therefore, if one is also selecting an antipsychotic, antidepressant or mood stabilizer in a patient with comorbid insomnia, one should consider whether it may be appropriate to select a psychiatric drug with sedative side effects. While the evi- dence for the use of these drugs in insomnia is somewhat limited, if all else is equal, a sedative drug may be a wise choice. It is the experience of one of the authors (HS) that trazodone and mirtazapine can be effective in many patients for treating both the mood disorder and the sleep disorder in patients with depression and comorbid insomnia. These two drugs have been shown to cause less sleep disturbance than the more activating antidepressants (Manber and Chambers 2009).
Insomnia is a not uncommon side effect of selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs) and noradrena- line reuptake inhibitors (Manber and Chambers 2009). If prescribing one of these drugs, it may be worth considering a short course of sleep-promoting medication during the early stages of treatment when the insomnia tends to be worse.
There is also some evidence that combining benzodiazepine receptor agonists with antidepressants may improve or accelerate the response to the antidepressant in depressed patients. Combining eszopiclone with fluoxetine leads to a more rapid response and a greater magnitude of response to the fluoxetine (Fava et al. 2006).
Similarly, the combination of eszopiclone and fluoxetine leads to a greater improve- ment in generalized anxiety disorder than placebo and fluoxetine (Pollack et al.
2008). The improvements in depression and anxiety were maintained even when the sleep questions were removed from the rating scales. Interestingly, a study looking at the impact of zolpidem controlled release in combination with escitalopram in depression showed improvements in insomnia but not in the depression (Fava et al.
2011) raising the possibility that the effects seen with eszopiclone may be mediated by some other properties of the medication and not its impact on sleep.
8.5.2 Selecting a Medication for Insomnia
The choice of medication is largely dictated by when you want it to work and how important it is to avoid residual sedation the next day. Amongst the commonly used benzodiazepine receptor agonists, there is very little difference in the time taken to reach maximum plasma concentration (Tmax), and therefore the time to onset of action will be much the same. In practice this means that the majority of these drugs will be most effective in the first couple of hours after taking the pill. They are there- fore likely to be equally effective for sleep onset insomnia, and, in those patients with pure sleep onset insomnia, it makes sense to try a short-acting hypnotic first.
However, when looking to treat middle-of-the-night insomnia or early-morning waking, the half-life becomes important, and here there are significant differences between drugs. A longer half-life drug is likely to be more effective for maintaining sleep in the middle and end of the night. However, the trade-off is that the longer
half-life drugs are more likely to lead to daytime sedation the next day. One needs to balance the need for sedation in the latter part of the night with the desirability of avoiding daytime sedation.
It is vital to ask patients about their routines and responsibilities in the mornings.
In particular, one should enquire about driving. Clearly the impact of a sleep medi- cation on driving performance will depend on the nature of the drug, the dose, the half-life and the time between taking the drug and driving (Roth et al. 2014). The benzodiazepines, as a rule, impair next-morning driving, particularly if they have half-lives greater than 6h. Zopiclone 7.5 mg has been consistently shown to impair driving performance the morning after taking a dose, and this impairment lasts for 11h after taking the medication (Leufkens and Vermeeren 2014), though driving in the afternoon appears to carry less risk than in the morning (Verster and van de Loo 2017). Interestingly, this impairment in driving can occur even if subjects report that they did not feel any drowsier than usual, and so subjective reports of daytime effects need to be treated with caution (Leufkens and Vermeeren 2014). The situa- tion with zolpidem is more complicated as the US Food and Drug Administration has cautioned that it may affect driving in the morning, but objective studies of driv- ing the day after taking zolpidem have not found this, as long as the drug is taken at bedtime. If it is taken in the middle of the night, driving is adversely affected (Verster and van de Loo 2017). Therefore, a good rule of thumb is that driving should always be avoided if a sleeping tablet is taken in the middle of the night. The melatonin agonist, ramelteon, also affects driving in the morning (Verster and van de Loo 2017).
Hence, it is important to warn patients of the potential for sleep medications to affect driving performance. We should always advise our patients never to drive if sleepy, but as mentioned above, their driving may be affected even if they do not feel sleepy. Therefore, if they are taking a hypnotic, they need to exercise extra caution even in the absence of subjective sleepiness.
8.5.3 Hypnotics and Sleep Apnoea
Any comorbid sleep disorder will add a layer of complexity to the prescribing pro- cess, but obstructive sleep apnoea (OSA) deserves particular attention. In OSA, patients will choke in their sleep which will lead to an arousal where they reopen their airway. Some patients will have their arousal before they experience an oxygen desaturation, while others may experience quite profound desaturations before an arousal is triggered. Hypnotics are liable to increase the arousal threshold, and therefore they may prolong the duration of the desaturations. Furthermore, benzodi- azepines have muscle-relaxing properties, and this can exacerbate the sleep apnoea;
this has been shown in some, though not all, studies. It is thought that zolpidem, which is more specific to the α-1 subunit, causes less muscle relaxation and may therefore be safer in untreated sleep apnoea. Hence, it is essential to screen patients for potential sleep apnoea if one is considering using hypnotics. However, once the patient is established on an effective treatment for their sleep apnoea, such as
continuous positive airway pressure (CPAP), the use of these drugs does not appear to worsen the sleep apnoea; indeed there is some evidence that using them in the early stages of CPAP treatment may increase long-term compliance with the CPAP (Luyster et al. 2010).
8.5.4 How to Initiate, Titrate and Monitor Hypnotics
Unless the situation is urgent, it is sensible to start with the lowest dose of any medi- cation. However, it is important to explain to the patient that if the medication does not work at the lower dose, it may yet become effective at the higher end of the dose range. If it doesn’t work when they first start the medication, they may develop anxi- ety that all medication is ineffective for them which will negate much of the effect of the medication even when given at an adequate dose.
If the patient is living in the community, and they do not need to start the medica- tion immediately, it is sensible to suggest that they start the medication on a night when they have few responsibilities the next day and in particular when they don’t have to drive the next day. This will allow them to gauge how the medication affects their daytime function.
Ideally one should review the patient within a few days of starting the medication to screen for side effects and check that it is effective. This involves not only asking about the medication’s impact on sleep but also its effect on daytime symptoms. In suicidal patients a limited supply of medication should be issued at any one time, and having an early review is essential.
There is rarely a case to be made for exceeding the licensed dose of a hypnotic and if a patient develops tolerance to a drug, it is probably better to switch to a dif- ferent class of drug than to escalate the dose beyond the recommended maximum (Wilson et al. 2010). It is also advisable for the patient to take occasional drug holi- days if there is concern about dependence developing, though the patient should be warned about the possibility of rebound insomnia (see below) during these periods.
8.5.5 When and How to Discontinue Hypnotics
Before stopping the medication, it is essential to be certain that one is stopping for the right reasons. Appropriate triggers for stopping medication include:
• Unacceptable side effects
• Signs of dependence
• Loss of efficacy
• Resolution of the insomnia (difficult to ascertain if hypnotics are taken nightly)
• Initiation of alternative therapy, e.g. cognitive behaviour therapy for insomnia and sedative antidepressant
• Patient’s request
Therefore, the medication should be stopped if the risks or side effects outweigh the benefits, if the insomnia resolves or if an alternative effective treatment is put in place.
If the patient is using the medication on an as-needed basis, then they will have very little difficulty coming off the medication. In patients who have been using the medication on a nightly basis, the situation is more complex due to the risk of rebound insomnia. This is a temporary worsening of the insomnia with symptoms more severe than one would expect based on the patient’s underlying insomnia. Not all patients will experience rebound insomnia, and it has not been described in all drugs; however, it is wise to warn patients about the potential for rebound insomnia.
When patients understand that this exacerbation of symptoms is temporary (typi- cally lasting no more than a few days), they are generally able to tolerate it and persist with the plan.
There are relatively few studies comparing discontinuation methods, and, to a large extent, one needs to be guided by the patient. Some patients are motivated and able to stop medication immediately, but many prefer a gradual reduction. A 25%
reduction in dose, or frequency of use, every 1–2 weeks is a sensible guideline, but some patients may need to reduce more slowly than this. In order to do a gradual reduction, one should prescribe the medication in the smallest possible denomina- tion. For example, if reducing zopiclone 7.5 mg, it is difficult to do a 25% reduction if one has to cut one 7.5 mg tablet into quarters. Therefore, one should prescribe two 3.75 mg tablets which would allow the patient to reduce the dose by taking one and a half tablets, then one tablet and then a half tablet.
During the reduction, one should monitor the patient’s sleep and mental state closely. If sleep deteriorates significantly, the pace of the reduction should be decreased to minimize distress to the patient. This is particularly important in patients with comorbid psychiatric disorders as there may be a risk of adversely affecting their mental state if their insomnia is not well managed. A practice that one of the authors (HS) uses is to reduce the dose of medication by 25% when, and only when, the sleep efficiency as measured by a sleep diary reaches 90%. This means the medication is only reduced when the patient’s sleep is relatively solid and there- fore able to tolerate a reduction in medication. It also makes it very clear when one should reduce. One of the difficulties patients experience is indecision about whether it is the right or wrong time to reduce medication, and they will often get very anxious about this. Having a clear numerical trigger for dose reduction relieves them of the burden of having to make this decision. An alternative approach is to set target dates for each reduction at the start of the treatment. However, the clinician should be prepared to adjust these targets based on the patient’s response and life circumstances.
Hypnotics are quite unusual drugs in that patients often report that they work even when they don’t take them! Just having a supply of them in the cupboard gives them the reassurance that, if they are really struggling, they are available; this safety net then allows them to sleep well. There may therefore be a case for having a sup- ply of tablets for emergencies once the patient has stopped regular use. However, it does mean there is still an element of psychological dependence on the medication
and if the patient is keen to overcome this, they will need to discard the medication at some point. They will therefore need to learn to be comfortable with the idea that they will not sleep perfectly every single night and acceptance of this is an impor- tant part of the psychological treatment of insomnia. Patients need to learn that nobody sleeps well every night and that they can cope with the occasional bad night.
Once they appreciate this, they will be less tempted to use medication on the nights when they are sleeping badly.
There is some evidence to suggest that melatonin can be a useful ‘step-down’
drug when reducing benzodiazepine receptor agonist hypnotics, particularly in the elderly using hypnotic doses of these drugs (Cardinali et al. 2002), but not all stud- ies have confirmed this (Wright et al. 2015). In a placebo-controlled, randomized and blinded trial of melatonin in schizophrenic and bipolar patients with long-term benzodiazepine use, melatonin did not increase the rate of benzodiazepine discon- tinuation (Baandrup et al. 2015).
The concomitant use of cognitive behaviour therapy for insomnia may increase the likelihood of successful hypnotic discontinuation (Belanger 2009; Morgan et al.
2003). This may be due to the frequent contact between the patient and the therapist or the fact that patients are simply less likely to need the medication if their insom- nia is effectively treated. However, the generalizability of these studies to patients with comorbid psychiatric conditions is yet to be adequately studied.