**10. Prazosin**

The American Academy of Sleep Medicine published a position paper on the treatment of nightmare disorder in 2018 [119]. The position paper divided nightmares into those associated with post-traumatic stress disorder (PTSD) and those not associated with PTSD. Nightmares associated with PTSD are more difficult to suppress and thus a wide variety of behavioral and drug combinations have been used, beyond the capability of this chapter. The drugs that may be used in nightmare disorder in the absence of PTSD are benzodiazepines, not including clonazepam, and prazosin.

Prazosin is a quinazoline derivative and peripheral vasodilator [120]. Its vasodilator properties are due to postsynaptic alpha adrenergic receptor blockade. Prazosin is extensively metabolized in the liver producing high first pass elimination and resultant low oral bioavailability after oral dosing. With an oral dose of 1 mg in normal subjects the bioavailability of prazosin ranged from 43.5 to 69.3% [121]. The mean elimination half-life is about 2.5 hours. Prazosin shows initial dose postural hypotension which disappears with continued administration.

On acute administration of prazosin, only very low levels crossed the blood– brain barrier [122]. On chronic administration of high dose prazosin, however, prazosin apparently crossed the blood–brain barrier in adequate concentrations to affect the central alpha adrenergic receptor density in the cerebral cortex [123]. This effect would not have occurred without significant penetration of prazosin into the brain. There were a number of studies showing efficacy of prazosin in veterans with PTSD induced nightmares [119]. In contrast, however, there was a recent large randomized, placebo-controlled study with negative results [124], leading to uncertainty about this treatment.

### **11. The opioids**

Various opioids have been used for intractable restless legs syndrome. These include propoxyphene [125]. tramadol [126], oxycodone [127], hydrocodone [128], and methadone [129]. Most of these have been used as adjunctive therapy, but methadone has been used in monotherapy. The mechanism of action of the opioids in RLS is unclear, however, it appears to work through a central dopaminergic neurotransmission as dopamine receptor antagonists will block the therapeutic effect. The current opioid crisis has lent a stigma to chronic use of methadone that has discouraged its use by many patients suffering with intractable restless legs syndrome. This is unfortunate as opioid therapy with management directed towards restless legs syndrome rather than chronic pain syndromes can be quite helpful [130]. The concern with long-term opioid therapy is the occult development or exacerbation of a sleep related breathing disorder. For this reason, all patients on chronic opioids should be clinically monitored for evidence of sleep apnea [131].

#### **11.1 Methadone**

Methadone is a synthetic opioid that is nearly equipotent with morphine, but with dramatically different pharmacokinetic characteristics [132]. Methadone

is a racemic mixture of R and S-methadone with the R isomer being 8–50 times more potent. Methadone may prevent or attenuate opioid tolerance via its weak antagonist properties on the N-methyl-D-aspartate (NMDA) receptor. Methadone is rapidly absorbed with maximal plasma concentrations 2.5 to 4 hours after oral administration. The bioavailability of methadone is 70–80%, though this can vary depending on the degree of first pass metabolism. Methadone is hepatically metabolized to inactive metabolites by the cytochrome P450 enzymes, CYP3A4 and CYP2B6. The elimination half-life of methadone ranges from 5 to 130 hours with a mean of 20–35 hours. The elimination half-life of the R isomer is approximately 25% longer than the S isomer. Methadone shows apparent autoinduction of its own metabolism. The half-life during chronic therapy is only 40% of the half-life with acute administration. A number of medications can either decrease or increase methadone levels via induction or inhibition of CYP3A4. Quantitative plasma levels may be necessary. Of note, there have been unintentional deaths with methadone. Many of these deaths occurred on the fifth day of regular dosing [133]. Prescribers need to be aware of methadone's peculiar pharmacokinetics.

In practice doses of methadone from 5–40 mg daily have been used. Given the pharmacokinetics starting therapy at a small dose of 2.5–5 mg is appropriate with up-titration of the dose as needed for symptoms. Methadone in patients with intractable RLS can produce remarkable improvement [68, 129].

#### **11.2 Oxycodone-naloxone**

Constipation and bowel dysfunction is the prime adverse effect of long-term opiate therapy. The combination of an opioid with a competitive mu receptor antagonist in a sustained release formulation is a unique answer to opioid adverse effects. The combination is also a tool against abuse of oxycodone since dissolution and injection results in naloxone having a much greater effect blocking mu receptors. A doubleblind, randomized, placebo-controlled trial with this formulation was performed with 276 RLS patients [134]. The study started participants on a dose of oxycodone 5.0 mg and naloxone 2.5 mg twice a day increasing per each study site's investigator to a maximal dose of oxycodone 40 mg and naloxone 20 mg. Adverse effects more than twice as frequent as placebo included fatigue, constipation, somnolence, dry mouth and pruritis. There was clear efficacy of the combination over placebo.

### **12. Conclusions**

This chapter did not attempt to be all inclusive, as a full description of the pharmacological interventions into sleep related movement disorders and parasomnias would fill the entire book. The chapter does attempt to provide pharmacological basis for treatment of the most challenging areas for pharmaceutical intervention, notably the REM sleep parasomnias and restless legs syndrome.

A challenge of REM sleep parasomnia management is the continuing use of clonazepam as first line therapy. This potent drug is effective, but due to its extremely long half-life, is prone to adverse effects in many patients. Unfortunately, the even more potent drug, triazolam, is too short acting and the two drugs (alprazolam and lorazepam) with duration of actions that are reasonable for the goal of suppressing dream enactment are less potent than either triazolam or clonazepam, thus appearing to need higher doses. Unexpectedly, the observational experience of the University of Texas Southwestern Medical Center at Dallas Clinical Center for Sleep and Breathing Disorders has been that the efficacy of alprazolam is half the expected dose that was used in trials in Minneapolis. Retrospective review is in progress.

#### *The Pharmacology of Parasomnias and Movement Disorders of Sleep DOI: http://dx.doi.org/10.5772/intechopen.100472*

The other pharmacological challenge is the management of severe persistent and intractable restless leg syndrome. In recent decades the algorithms for management have become clearer pointing to the early use of gabapentin and pregabalin and the use of opioids in intractable patients, however, there is a lag of that knowledge reaching the medical community that is faced with these patients and their demands for treatment. This is another area where the growth of medical knowledge is exceeding our educational capabilities.
