June M. Fry

Long-term follow-up on restless legs syndrome patients treated with opioids.

The medical records of 493 patients with restless legs syndrome (RLS) from three major centers were studied to determine the number and outcome of patients who had been treated with opioids as a monotherapy. At one time or another 113 patients (51 men, 62 women; age range, 37–88 years) had been on opioid therapy either alone (36 patients) or with opioids added secondarily to other medications used to treat RLS (77 patients). Twenty‐three of the 36 opioid monotherapy patients had failed dopaminergic and other therapeutic agents prior to the initiation of opioid monotherapy. Twenty of the 36 opioid monotherapy patients continue on monotherapy for an average of 5 years 11 months (range, 1–23 years), despite their knowledge of the availability of other therapies. Of the 16 patients who discontinued opioids as a sole therapy, the medication was discontinued in only one case because of problems related to addiction and tolerance. Polysomnography on seven patients performed after an average of 7 years 1 month of opioid monotherapy (range, 1–15 years) showed a tendency toward an improvement in all leg parameters and associated arousals (decrease in PLMS index, PLMS arousal index, and PLM while awake index) as well as all sleep parameters (increase in stages 3 and 4 and REM sleep, total sleep time, sleep efficiency, and decrease in sleep latency). Two of these seven patients developed sleep apnea and a third patient had worsening of preexisting apnea. Opioids seem to have long‐term effectiveness in the treatment of RLS and PLMS, but patients on long‐term opioid therapy should be clinically or polysomnographically monitored periodically for the development of sleep apnea.

Ropinirole in the Treatment of Patients With Restless Legs Syndrome: A US-Based Randomized, Double-Blind, Placebo-Controlled Clinical Trial

OBJECTIVE To assess the efficacy, safety, and tolerability of the dopamine agonist ropinirole in the treatment of patients with moderate to severe primary restless legs syndrome (RLS). PATIENTS AND METHODS This multicenter, 12-week, double-blind, placebo-controlled, flexible-dose study enrolled US patients and was conducted between September 2003 and May 2004. Patients were randomized to ropinirole or placebo, 0.25-4.0 mg as needed and tolerated, once daily, 1 to 3 hours before bedtime. The primary end point was mean change from baseline to week 12 in International Restless Legs Scale (IRLS) total score. Key secondary efficacy measures included the Clinical Global Impression-Improvement scale. RESULTS A total of 381 patients were enrolled; 164 (87.7%) of 187 patients randomized to ropinirole and 167 (86.1%) of 194 randomized to placebo completed the study. Significant treatment differences favoring ropinirole, compared with placebo, were observed for change in IRLS total score at week 12 (adjusted mean treatment difference, -3.7; 95% confidence interval, -5.4 to -2.0; P P =.10). Ropinirole was generally well tolerated, with an adverse-event profile consistent with other dopamine agonists. CONCLUSION This study confirms that ropinirole improves RLS symptoms and subjective measures of sleep, quality of life, and anxiety and that it is generally well tolerated.

Rotigotine Improves Restless Legs Syndrome: A 6-Month Randomized, Double-Blind, Placebo-Controlled Trial in the United States

This randomized, double‐blinded, placebo‐controlled trial (NCT00135993) assessed efficacy and safety of the dopamine agonist rotigotine in the treatment of idiopathic restless legs syndrome (RLS) over a 6‐month maintenance period. A total of 505 eligible participants with moderate to severe RLS (IRLS sum score ≥ 15) were randomly assigned to five groups to receive either placebo or rotigotine (0.5, 1, 2, or 3 mg/24 hr) delivered by once‐daily transdermal patch (fixed‐dose regimen). The two co‐primary efficacy parameters decreased from baseline to end of maintenance in IRLS sum score and in clinical global impressions (CGI‐1) score. On both primary measures, 2 and 3 mg/24 hr rotigotine was superior to placebo (P < 0.001). Adjusted treatment differences to placebo for the IRLS sum score were −4.5 (95% CI: −6.9, −2.2) for 2 mg/24 hr rotigotine, −5.2 (95% CI: −7.5, −2.9) for 3 mg/24 hr rotigotine, and for CGI item 1 −0.65 (95% CI: −1.0, −0.3) and −0.9 (95% CI: −1.3, −0.5) for the 2 and 3 mg/24 hr doses, respectively. Skin reactions (27%) and known dopaminergic side effects such as nausea (18.1%) and headache (11.6%) were mostly mild or moderate in rotigotine subjects. Rotigotine transdermal patches releasing 2 to 3 mg/24 hr significantly reduced the severity of RLS symptoms. Treatment efficacy was maintained throughout the 6‐month double‐blind period.

Problems in the Interpretation of Nocturnal Penile Tumescence Studies: Disruption of Sleep by Occult Sleep Disorders

A review of the sleep of 31 patients 45 years old or older undergoing nocturnal penile tumescence studies showed that 19 had a previously undiagnosed sleep disorder. Of the patients 9 had periodic leg movements in sleep, 9 had sleep apnea and 1 had both disorders. In 10 of these patients the sleep disorders affected nocturnal penile tumescence by disrupting sleep and causing brief periods of detumescence, movement artifacts and delays in the tumescing phase of nocturnal penile tumescence. These disruptions resulted in an apparently abnormal nocturnal penile tumescence that appeared as if the patient had difficulty in achieving or maintaining an erection. The nocturnal penile tumescence disruptions may have reflected only a disruption of the necessary conditions for normal nocturnal penile tumescence to occur, namely adequate sleep and rapid eye movement sleep. The results strongly suggest that failure to measure concurrent sleep parameters and screen for occult sleep disorders could result in the incorrect diagnosis of abnormal nocturnal penile tumescence.

Efficacy and Tolerability of 14-Day Administration of Zaleplon 5mg and 10mg for the Treatment of Primary Insomnia

AbstractObjective: The efficacy and tolerability of zaleplon 5mg and 10mg, a selective benzodiazepine subtype A receptor agonist, was evaluated during 14-day administration in a double-blind, placebo-controlled design, with triazolam included as an active comparator. Patients and Methods: Polysomnographic data, subjective reports, performance measures, and clinical assessments were made for 132 primary insomniacs, aged 18 to 60 years, during three baseline, 14 drug, and two discontinuation nights. Results: Polysomnographic data indicated that both doses of zaleplon shortened latency to persistent sleep relative to placebo, during early drug administration. By the end of the administration period the difference was no longer statistically significant, principally due to improvement in the placebo group. No effect on total sleep time or measures of awakenings was seen with either zaleplon dose. Triazolam increased total sleep time and reduced latency to persistent sleep compared with placebo on early drug nights, but not at the end of the 2-week administration. In general, subjective data were consistent with polysomnography findings. Clinical evaluations indicated that zaleplon was well tolerated and without residual effects or discontinuation effects. Adverse effects were infrequent, mild and no more common with zaleplon than with placebo. Conclusion: At the doses evaluated, zaleplon appeared to have hypnotic properties consistent with its pharmacokinetic profile, and a low likelihood of undesired effects.

Short-Term Efficacy of Zaleplon in Older Patients with Chronic Insomnia

AbstractObjective: To assess the short-term efficacy of zaleplon in older patients with insomnia. Design and Setting: Randomised, double-blind, placebo-controlled, Latin-square design conducted in six sleep research centres. Patients: 48 chronic insomnia patients, aged 60 to 80 years, without significant psychiatric or medical illness. Interventions: Placebo and zaleplon 2, 5 and 10mg. Main Outcome Measures: Polysomnographic (PSG) and subjective sleep latency and total sleep time. Results: PSG studies showed that latency to persistent sleep was shortened significantly (p < 0.015 or better) with all three zaleplon doses, as compared with placebo. Subjective sleep latency was reduced significantly with zaleplon 5 or 10mg (p < 0.017 or better). Additionally, total sleep time was significantly increased (p < 0.03 or better) compared with placebo at the 5 and 10mg doses based on PSG measures, but subjective assessments indicated that only the 10mg dose (p < 0.011) was superior to placebo on this variable. Psychomotor tests conducted the morning after each polysomnogram showed no deficits with any dose of zaleplon as compared with placebo. Conclusions: This study demonstrates short-term efficacy of zaleplon, particularly at the 5 and 10mg doses, in older patients with insomnia.

Avoiding false positive findings in measuring nocturnal penile tumescence

The measurement and interpretation of nocturnal penile tumescence (NPT) studies depend on appropriate measurement techniques, knowledge of the conditions during which NPT was recorded, and a lack of preconceived notions about the relationship of penile circumference to penile rigidity. This case report illustrates several of the most common problems in the measurement and interpretation of NPT that could result in a false positive finding.

Effects of Low-Dose Naloxone on Subjective Alertness and Pupil Diameter in Normal and Narcoleptic Subjects

Recent evidence suggests that endogenous opiates may be involved in the pathophysiology of narcolepsy. To test this theory, the effect of 0.8 mg naloxone hydrochloride on pupil size and subjective alertness was measured in normal and narcoleptic subjects. Naloxone resulted in significant pupillary constriction in the normal but not in the narcoleptic subjects. The extent of contraction of the pupil light reflex was reduced significantly in the narcoleptic but not in the normal subjects. There was no effect on subjective ratings of alertness on the Stanford Sleepiness Scale or the visual analogue scale in either group. The naloxone-related miosis in the normal group confirms that naloxone is not a pure opiate antagonist. The lack of naloxone-related miosis in the narcoleptics suggests that narcoleptic individuals do not respond to naloxone as do normal individuals. However, this difference can not be definitely attributed to the antagonism of endogenous opiates. The reduction of the extent of contraction of the light reflex suggests that naloxone caused an increase in supranuclear inhibition of parasympathetic pupil reflex activity. However, this finding may have resulted from mechanical limitations of a small pupil or technical limitations of the recording equipment. This study does not support previous reports that naloxone causes an increase in subjective alertness in narcoleptics.

Rem Sleep Abnormality In Patients With Sleep Apnea

Some patients with obstructive sleep apnea have REM sleep during a multiple sleep latency test (MSLT). The MSLT REM sleep r esolves after adequate nasal CPAP treatment in patients with 1 or 2 REM naps during the diagnostic MSLT. These patients also have a significant increase in the MSLT mean sleep latency after treatment. Patients with 3 REM naps during the diagnostic MSLT tend to have less severe obstructive sleep apnea, do not have resolution of MSLT REM naps and have no significant increase in the MSLT mean sleep latency after nasal CPAP treatment. These patients may be more likely to have an additional s leep disorder.