**7.9 Antidepressants**

Antidepressants with sedative effect as tryciclic antidepressants (TCA), mirtazapine, and trazodone are often prescribed for insomnia comorbid with pain. Such pharmacological approach showed to relieve both insomnia, depressive, and pain-related symptoms. Often they are effectively used to treat neuropathic pain. Attention should be taken however regarding their differential effects on sleep. Imipramine and desipramine are less sedating and may disrupt sleep, amitriptyline, nortriptyline, trimipramine, and doxepine lead to a reduction in sleep latency, increase of sleep efficiency, and increase in sleep duration [87]. Those properties should be taken into account either on the prescription time or in the evaluation in order to control comorbid conditions.

Doxepin is approved as a hypnotic in doses from 1 to 6 mg and as an antidepressant in doses from 150 to 300 mg. At hypnotic doses, it reduces wakefulness after sleep onset, increases sleep efficiency, and total sleep time without next day impact on diurnal excessive sleepiness [88].

The adverse effects of TCAs are mainly due to anti-adrenergic and anticholinergic effects: orthostatic hypotension, xerostomia and xeropthalmia, constipation, and cardiac electric changes (delays in conduction). The risk of those side effects are age-related and particular care should be taken when prescribing TCAs to patients with comorbid depression and suicidal ideation because they are extremely lethal in overdose [89].

Trazodone, a type 2 serotoninergic, histaminergic and alfa1-adrenergic antagonist acts by inhibition of serotonin reuptake. As other antidepressants, trazodone has a hypnotic function at low doses whereas antidepressant effects occur at higher doses. It improves sleep in elderly, depressed, and anxious patients and patients with post-traumatic stress and has shown clear benefit in several painful conditions. Side effects include sleepiness the next day, rebound insomnia, orthostatic hypotension, xerostomia, and priapism [90].

Mirtazapine, a sedative antidepressant agent, at doses of 15–30 mg, improves sleep onset, total sleep time, sleep efficiency, and wakefulness after sleep onset. Additionally, it has a positive impact on pain (recurrent headache and postherpetic neuralgia), mood, and appetite [91].

## *7.9.1 Selective serotonin (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI)*

This class of drugs is both effective for depression and pain, but it is linked to sleep disruption. So, whenever needed, attention should be paid to avoid its use in the evening hours [92].

### **7.10 Antipsychotics**

Despite the limited evidence, some off-label atypical antipsychotics drugs (olanzapine, quetiapine, and risperidone) are used for managing sleep disruption and insomnia. Self-reported and objectively evaluated outcomes suggest efficacy in increasing sleep duration, slow wave sleep and decreasing sleep latency. However, long-term safety and efficacy studies should be done in order to corroborate these findings. Meanwhile, even in low dose (<150 mg/day) quetiapine was associated to xerostomia and dizziness. Some cases of hepatotoxicity, restless legs, and akathisia were also reported. Risperidone was associated to somnolence and sialorrhea and olanzapine is suggested to be related to a degree of sedation which impacts morning rising time [93].

**101**

*Sleep and Orofacial Pain: Physiological Interactions and Clinical Management*

GABA analogs Gabapentin and pregabalin are two anticonvulsants often used to treat chronic pain with comorbid insomnia and studies suggest positive effects on sleep outcomes as sleep latency and wakefulness after sleep onset as well as in deep slow wave sleep. Both are effective as adjuncts in depression and anxiety. Frequent adverse effects are dizziness, diurnal sedation, gastrointestinal problems, and

Some studies show that melatonin, an hormone for regulating mammalian circadian biology exerts anti-nociception effects in animal models and humans, and a

nociception against many types of pain [95]; thus, suggesting that melatonin directed

The majority of over-the-counter agents used for sleep contain first generation anti-histamines with complementary anticholinergic effects. Those agents are associated to a fast development of tolerance and the lack of long-term studies on these agents requires some caution particularly because of the link to diurnal sedation and

One relevant aspect not sufficiently discussed is the placebo effect, which can be sometimes one of the most important pieces of the treatment. Conceptualization of the placebo phenomenon has significantly changed during the last decades and this armamentarium is now intended as related to the patient's perception of a treatment. Of course, this is directly related to the patient's previous experience and the patient-practitioner relationship and confidence as well as with expectations, emotions, and beliefs. However, all those factors impact on cerebral function and release of endogenous opioids. Moreover, the placebo effect has a psycho-neurobiological base, since brain image studies performed in healthy volunteers show increased cortical activity particularly in the dorsolateral prefrontal cortex and orbitofrontal cortex, possibly associated with expectations of pain relief. On the other hand, the placebo analgesia is related to decrease of the neural activity in structures like thalamus, insula, and the anterior cingulate cortex, which constitute the so-called pain matrix [97]. The endogenous opioid system is probably involved in the placebo analgesia mechanism since opioid antagonists were shown to block the placebo effect [98]. Interestingly, the placebo mechanism was shown also to interfere with insomnia, even when patients did know they were taking a pharmacologically inactive substance [99]. It is of crucial importance for clinicians to be aware of how the placebo components may affect (enhance or reduce) the outcome of active treatment in chronic pain patients in order to separate either the therapeutic effect from

recent metanalysis strongly supports the utilization of melatonin on anti-

to comorbid condition should be effective without any major adverse effects.

*DOI: http://dx.doi.org/10.5772/intechopen.86770*

**7.11 Anticonvulsants**

peripheral edema [94].

**7.13 Anti-histamines**

**7.14 Placebo effect**

impaired cognitive function [96].

the placebo one and to optimize treatment outcome.

**7.12 Melatonin**

*Sleep and Orofacial Pain: Physiological Interactions and Clinical Management DOI: http://dx.doi.org/10.5772/intechopen.86770*
