Journal of Clinical Psychopharmacology
&
Volume 34, Number 1, February 2014
13. Young RR, Shahani BT. Asterixis: one type of negative myoclonus. In: Fahn S, Marsden CD, Van Woert MH, eds. Myoclonus. Advances in Neurology, Vol. 43. New York, NY: Raven Press; 986:137Y156. 14. Jime´nez-Jime´nez FJ, Puertas I, de Toledo-Heras M. Drug-induced myoclonus: frequency, mechanisms and management. CNS Drugs. 2004;18:93Y104. 15. Burnet PW, Chen CP, McGowan S, et al. The effects of clozapine and haloperidol on serotonin-1A, -2A and -2C receptor gene expression and serotonin metabolism in the rat forebrain. Neuroscience. 1996;73(2):531Y540. 16. Wong J, Delva N. Clozapine-induced seizures: recognition and treatment. Can J Psychiatry. 2007;52:457Y463. 17. Kontaxakis VP, Ferentinos PP, Havaki-Kontaxaki BJ, et al. Risperidone augmentation of clozapine: a critical review. Eur Arch Psychiatry Clin Neurosci. 2006; 256:350Y355.
The Effect of Naltrexone on Sleep Parameters in Healthy Male Volunteers To the Editors: altrexone is an opiate receptor antagonist typically used in the management of opioid dependence1 and alcohol addiction.2 Naltrexone is associated with a number of adverse events when administered to healthy volunteers including nausea, vomiting, and drowsiness.3 Sleep disturbances after naltrexone administration were reported in patients with opiate dependence and alcohol addiction,4Y6 obese smokers,7 and patients with Crohn disease8 and uremic pruritus.9 In patients with chronic sleep apnea, naltrexone induced significant decreases in total sleep time, slow-wave sleep, and rapid eye movement (REM) sleep while significantly increasing total wake time and the number of awakenings per hour compared to placebo.10 Despite these reports, controlled studies of naltrexone’s effect on sleep parameters are lacking, and naltrexone’s reported effects on sleep are likely complicated by withdrawal and presence of other disease states. The purpose of this pilot study was to assess the effects of naltrexone on sleep parameters in healthy volunteer subjects. Six subjects, aged 18 to 40 years (inclusive) with a body mass index greater than 18 and less than 28 kg/m2, in good health based on screening, medical history, physical examination (including vital signs), routine laboratory tests, and electrocardiogram (ECG), were included in this study. Exclusion criteria included the
N
* 2014 Lippincott Williams & Wilkins
following: subjects with a history or presence of any sleep disorder; symptoms suggesting sleep apnea upon review of the Modified Berlin Questionnaire; abnormal habitual sleep and wake time; greater than 1 awakening for urination per night; night shift work within 1 week of day j1; regular use of centrally acting medications; meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for any psychoactive substance use disorder or psychotic, mood, or organic mental disorder; ingestion of greater than 2 caffeinated beverages or alcoholic drinks per day; positive urine drug screen or alcohol breath test; polysomnography (PSG) demonstrating sleep onset latency greater than 30 minutes or wake time after sleep onset greater than 45 minutes. Subjects were not allowed caffeine or alcohol during the study. Each subject received a single dose of naltrexone and a single dose of placebo. Subjects were randomized in a double-blind manner to receive either 50 mg of naltrexone on day 1 and placebo on day 7 (3 subjects) or the opposite (3 subjects). Subjects who qualified for the study checked into the sleep center on the evening of day j1 and underwent their initial PSG study for acclimation and assessment for significant sleep disorders. Subjects who demonstrated clinically significant sleep anomalies during the acclimation night were not allowed to continue participation. Subjects received either naltrexone, 50 mg, or placebo 1 hour before their habitual sleep time on the evening of day 1.
Letters to the Editors
Approximately 1 hour after dosing, subjects underwent a second 8-hour PSG study. Treated subjects were released on day 2 after an impairment assessment including administration of the Karolinska Sleepiness Scale, a general impairment questionnaire, and evaluation with the Romberg test, Finger-Nose-Finger, and Tandem Walk tests. After the washout period, the subjects returned to the sleep center on the evening of day 7 to receive the treatment they did not receive on day 1. Approximately 1 hour after dosing, the subjects underwent their third 8-hour PSG study. On day 8, the subjects were released after impairment assessments were completed. An outpatient follow-up visit occurred on day 11 (T 1 day). Polysomnography sleep parameters were analyzed using repeated-measures analysis of variance preformed using a mixed model with fixed effects of treatment, time, and treatment-time interaction. Sleep parameters in patients treated with placebo remained relatively consistent between the acclimation night and the placebo night, ranging between 90% and 110% of acclimation night values. Total sleep time and sleep latency were unchanged in naltrexone-treated subjects compared to placebo; however, the mean time in stage 2 sleep increased significantly by 38% (P = 0.0023), while the subjects spent 47% less mean time (P G 0.0001) in REM sleep, with mean REM latency increased by 331% on naltrexone versus placebo (P = 0.0026).
FIGURE 1. Average percent change of PSG indices in naltrexone-treated subjects compared to placebo. P G 0.05 represents probability that the average percent value of naltrexone is significantly different from that of placebo. www.psychopharmacology.com
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
167
Letters to the Editors
Furthermore, trends were noted (P G 0.10) in naltrexone-treated subjects regarding a decrease in stage 3 sleep and a greater mean wake time after sleep onset compared to placebo (Fig. 1). There was no evidence of impairment on any of the assessments performed at discharge from the sleep center for any subjects, nor were there any adverse events considered related to naltrexone.
DISCUSSION To the best of our knowledge, this preliminary study represents the first well-controlled PSG sleep study of naltrexone in healthy subjects. Naltrexone at tolerable and recommended doses was associated with several significant changes in PSG parameters compared to placebo including increases in stage 2 sleep and REM latency with accompanying decreases in REM sleep. The observed increase in REM latency and decrease in percent of time spent in REM sleep seem to mimic other marketed central nervous system drugs such as benzodiazepines, tricyclic antidepressants, selective serotonin reuptake inhibitors, trazodone, and opioids.11Y17 In addition, opioids, such as morphine, have also been found to increase stage 2 sleep and decrease stage 3 sleep.16,18 This preliminary study suggests the possibility of subclinical sleep disturbance associated with naltrexone use. Based on these results, further investigation with a larger sample size is warranted to examine naltrexone’s potential for inducing clinical sleep disturbances with repeated dosing.
AUTHOR DISCLOSURE INFORMATION This study was funded by Worldwide Clinical Trials, and there were no external sources of funding. James M. Andry, MD, was compensated by Worldwide Clinical Trials for the performance of polysomnography procedures. There are no other sources of conflict of interest declared. John Sramek, PharmD Worldwide Clinical Trials Beverly Hills, CA [email protected]
James M. Andry, MD Sleep Therapy & Research Center San Antonio, TX
Hong Ding, MSc, MA Worldwide Clinical Trials King of Prussia, PA
Henry J. Riordan, PhD Worldwide Clinical Trials King of Prussia, PA
168
www.psychopharmacology.com
Journal of Clinical Psychopharmacology
Mark Leibowitz, MD Worldwide Clinical Trials San Antonio, TX
Neal R. Cutler, MD Worldwide Clinical Trials Beverly Hills, CA
REFERENCES 1. Cugurra F. Naltrexone, opiate antagonist, in the therapy of drug dependence. Clin Ter. 1988;127(3):173Y180. 2. Latt NC, Jurd S, Houseman J, et al. Naltrexone in alcohol dependence: a randomised controlled trial of effectiveness in a standard clinical setting. Med J Aust. 2002;176(11):530Y534. 3. Riordan H, Newberry B, Sramek J, et al. Use of Naltrexone to Block Opioid Side Effects in Healthy Volunteers: Effects of Dose and Food. American Pain Society Conference; 2009; San Diego, CA. Poster Presentation. 4. Hoque MM, Hossain KJ, Kamal MM, et al. Naltrexone in drug addiction: significance in the prevention of relapse. Mymensingh Med J. 2009;18(suppl 1):S56YS65. 5. Mangado EO, Horcajadas FA, Hernandez MAT. Alcohol dependence treatment with naltrexone: safety assessment. Observation study group of alcoholic dependence. Actas Esp Psiquiatr. 2000;28(3):161Y168. 6. Staedt J, Wassmuth F, Stoppe G, et al. Effects of chronic treatment with methadone and naltrexone on sleep in addicts. Eur Arch Psychiatry Clin Neurosci. 1996;246(6):305Y309. 7. Wilcox CS, Oskooilar N, Erickson JS, et al. An open-label study of naltrexone and bupropion combination therapy for smoking cessation in overweight and obese subjects. Addict Behav. 2010;35(3):229Y234. 8. Smith JP, Stock H, Bingaman S, et al. Low-dose naltrexone therapy improves active Crohn’s disease. Am J Gastroenterol. 2007;102(4):820Y828. 9. Legroux-Crespel E, Cledes J, Misery L. A comparative study on the effects of naltrexone and loratadine on uremic pruritus. Dermatology. 2004;208(4):326Y330. 10. Ferber C, Duclaux R, Mouret J. Naltrexone improves blood gas patterns in obstructive sleep apnoea syndrome through its influence on sleep. J Sleep Res. 1993;2(3):149Y155. 11. Obermeyer WH, Benca RM. Effects of drugs on sleep. Neurol Clin. 1996;14(4):827Y840. 12. Gursky JT, Krahn LE. The effects of antidepressants on sleep: a review. Harv Rev Psychiatry. 2000;8(6):298Y306. 13. Foldvary-Schaefer N, De Leon Sanchez I, Karafa M, et al. Gabapentin increases slow-wave sleep in normal adults. Epilepsia. 2002;43(12):1493Y1497.
&
Volume 34, Number 1, February 2014
14. Cronin A, Keifer JC, Baghdoyan HA, et al. Opioid inhibition of rapid eye movement sleep by a specific mu receptor agonist. Br J Anaesth. 1995;74(2):188Y192. 15. Kay DC, Eisenstein RB, Jasinski DR. Morphine effects on human REM state, waking state and NREM sleep. Psychopharmacologia. 1969;14(5):404Y416. 16. Shaw IR, Lavigne G, Mayer P, et al. Acute intravenous administration of morphine perturbs sleep architecture in healthy pain-free young adults: a preliminary study. Sleep. 2005;28(6):677Y682. 17. Barbanoj MJ, Clos S, Romero S, et al. Sleep laboratory study on single and repeated dose effects of paroxetine, alprazolam and their combination in healthy young volunteers. Neuropsychobiology. 2005;51(3):134Y147. 18. Dimsdale JE, Norman D, DeJardin D, et al. The effect of opioids on sleep architecture. J Clin Sleep Med. 2007;3(1):33Y36.
Effects of Switching to Once-Daily Modified-Release Methylphenidate From Previous Treatment With Other Psychostimulants in Children and Adolescents With ADHD An Observational Study With Clinician, Parent, and Teacher Evaluations To the Editors: sychostimulant medication has been a mainstay in the multimodal treatment of attention-deficit/hyperactivity disorder (ADHD), and methylphenidate (MPH) is the substance most frequently used with robust clinical effects of immediate (IR) and modified release (MR) preparations being well documented in several metaanalyses.1Y4 Actually, different MPH-MR formulations exist with different release profiles and duration of clinical effects: (1) Concerta, with an ultralong clinical effect profile of 10 to 12 hours, containing 22% MPH-IR and 78% MPH-MR; (2) Equasym XL, with clinical effects of 8 hours, containing 30% MPHYIR and 70% MPHYMR; (3) Medikinet XL and Ritalin LA, with clinical effects of 8 hours, containing equal portions of MPHYIR and MPHYMR but differing from each other in different release properties; and (4) Focalin XR, the D-threo-enantiomer of Methylphenidat, with clinical effects of
P
* 2014 Lippincott Williams & Wilkins
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
&
Volume 34, Number 1, February 2014
13. Young RR, Shahani BT. Asterixis: one type of negative myoclonus. In: Fahn S, Marsden CD, Van Woert MH, eds. Myoclonus. Advances in Neurology, Vol. 43. New York, NY: Raven Press; 986:137Y156. 14. Jime´nez-Jime´nez FJ, Puertas I, de Toledo-Heras M. Drug-induced myoclonus: frequency, mechanisms and management. CNS Drugs. 2004;18:93Y104. 15. Burnet PW, Chen CP, McGowan S, et al. The effects of clozapine and haloperidol on serotonin-1A, -2A and -2C receptor gene expression and serotonin metabolism in the rat forebrain. Neuroscience. 1996;73(2):531Y540. 16. Wong J, Delva N. Clozapine-induced seizures: recognition and treatment. Can J Psychiatry. 2007;52:457Y463. 17. Kontaxakis VP, Ferentinos PP, Havaki-Kontaxaki BJ, et al. Risperidone augmentation of clozapine: a critical review. Eur Arch Psychiatry Clin Neurosci. 2006; 256:350Y355.
The Effect of Naltrexone on Sleep Parameters in Healthy Male Volunteers To the Editors: altrexone is an opiate receptor antagonist typically used in the management of opioid dependence1 and alcohol addiction.2 Naltrexone is associated with a number of adverse events when administered to healthy volunteers including nausea, vomiting, and drowsiness.3 Sleep disturbances after naltrexone administration were reported in patients with opiate dependence and alcohol addiction,4Y6 obese smokers,7 and patients with Crohn disease8 and uremic pruritus.9 In patients with chronic sleep apnea, naltrexone induced significant decreases in total sleep time, slow-wave sleep, and rapid eye movement (REM) sleep while significantly increasing total wake time and the number of awakenings per hour compared to placebo.10 Despite these reports, controlled studies of naltrexone’s effect on sleep parameters are lacking, and naltrexone’s reported effects on sleep are likely complicated by withdrawal and presence of other disease states. The purpose of this pilot study was to assess the effects of naltrexone on sleep parameters in healthy volunteer subjects. Six subjects, aged 18 to 40 years (inclusive) with a body mass index greater than 18 and less than 28 kg/m2, in good health based on screening, medical history, physical examination (including vital signs), routine laboratory tests, and electrocardiogram (ECG), were included in this study. Exclusion criteria included the
N
* 2014 Lippincott Williams & Wilkins
following: subjects with a history or presence of any sleep disorder; symptoms suggesting sleep apnea upon review of the Modified Berlin Questionnaire; abnormal habitual sleep and wake time; greater than 1 awakening for urination per night; night shift work within 1 week of day j1; regular use of centrally acting medications; meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for any psychoactive substance use disorder or psychotic, mood, or organic mental disorder; ingestion of greater than 2 caffeinated beverages or alcoholic drinks per day; positive urine drug screen or alcohol breath test; polysomnography (PSG) demonstrating sleep onset latency greater than 30 minutes or wake time after sleep onset greater than 45 minutes. Subjects were not allowed caffeine or alcohol during the study. Each subject received a single dose of naltrexone and a single dose of placebo. Subjects were randomized in a double-blind manner to receive either 50 mg of naltrexone on day 1 and placebo on day 7 (3 subjects) or the opposite (3 subjects). Subjects who qualified for the study checked into the sleep center on the evening of day j1 and underwent their initial PSG study for acclimation and assessment for significant sleep disorders. Subjects who demonstrated clinically significant sleep anomalies during the acclimation night were not allowed to continue participation. Subjects received either naltrexone, 50 mg, or placebo 1 hour before their habitual sleep time on the evening of day 1.
Letters to the Editors
Approximately 1 hour after dosing, subjects underwent a second 8-hour PSG study. Treated subjects were released on day 2 after an impairment assessment including administration of the Karolinska Sleepiness Scale, a general impairment questionnaire, and evaluation with the Romberg test, Finger-Nose-Finger, and Tandem Walk tests. After the washout period, the subjects returned to the sleep center on the evening of day 7 to receive the treatment they did not receive on day 1. Approximately 1 hour after dosing, the subjects underwent their third 8-hour PSG study. On day 8, the subjects were released after impairment assessments were completed. An outpatient follow-up visit occurred on day 11 (T 1 day). Polysomnography sleep parameters were analyzed using repeated-measures analysis of variance preformed using a mixed model with fixed effects of treatment, time, and treatment-time interaction. Sleep parameters in patients treated with placebo remained relatively consistent between the acclimation night and the placebo night, ranging between 90% and 110% of acclimation night values. Total sleep time and sleep latency were unchanged in naltrexone-treated subjects compared to placebo; however, the mean time in stage 2 sleep increased significantly by 38% (P = 0.0023), while the subjects spent 47% less mean time (P G 0.0001) in REM sleep, with mean REM latency increased by 331% on naltrexone versus placebo (P = 0.0026).
FIGURE 1. Average percent change of PSG indices in naltrexone-treated subjects compared to placebo. P G 0.05 represents probability that the average percent value of naltrexone is significantly different from that of placebo. www.psychopharmacology.com
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
167
Letters to the Editors
Furthermore, trends were noted (P G 0.10) in naltrexone-treated subjects regarding a decrease in stage 3 sleep and a greater mean wake time after sleep onset compared to placebo (Fig. 1). There was no evidence of impairment on any of the assessments performed at discharge from the sleep center for any subjects, nor were there any adverse events considered related to naltrexone.
DISCUSSION To the best of our knowledge, this preliminary study represents the first well-controlled PSG sleep study of naltrexone in healthy subjects. Naltrexone at tolerable and recommended doses was associated with several significant changes in PSG parameters compared to placebo including increases in stage 2 sleep and REM latency with accompanying decreases in REM sleep. The observed increase in REM latency and decrease in percent of time spent in REM sleep seem to mimic other marketed central nervous system drugs such as benzodiazepines, tricyclic antidepressants, selective serotonin reuptake inhibitors, trazodone, and opioids.11Y17 In addition, opioids, such as morphine, have also been found to increase stage 2 sleep and decrease stage 3 sleep.16,18 This preliminary study suggests the possibility of subclinical sleep disturbance associated with naltrexone use. Based on these results, further investigation with a larger sample size is warranted to examine naltrexone’s potential for inducing clinical sleep disturbances with repeated dosing.
AUTHOR DISCLOSURE INFORMATION This study was funded by Worldwide Clinical Trials, and there were no external sources of funding. James M. Andry, MD, was compensated by Worldwide Clinical Trials for the performance of polysomnography procedures. There are no other sources of conflict of interest declared. John Sramek, PharmD Worldwide Clinical Trials Beverly Hills, CA [email protected]
James M. Andry, MD Sleep Therapy & Research Center San Antonio, TX
Hong Ding, MSc, MA Worldwide Clinical Trials King of Prussia, PA
Henry J. Riordan, PhD Worldwide Clinical Trials King of Prussia, PA
168
www.psychopharmacology.com
Journal of Clinical Psychopharmacology
Mark Leibowitz, MD Worldwide Clinical Trials San Antonio, TX
Neal R. Cutler, MD Worldwide Clinical Trials Beverly Hills, CA
REFERENCES 1. Cugurra F. Naltrexone, opiate antagonist, in the therapy of drug dependence. Clin Ter. 1988;127(3):173Y180. 2. Latt NC, Jurd S, Houseman J, et al. Naltrexone in alcohol dependence: a randomised controlled trial of effectiveness in a standard clinical setting. Med J Aust. 2002;176(11):530Y534. 3. Riordan H, Newberry B, Sramek J, et al. Use of Naltrexone to Block Opioid Side Effects in Healthy Volunteers: Effects of Dose and Food. American Pain Society Conference; 2009; San Diego, CA. Poster Presentation. 4. Hoque MM, Hossain KJ, Kamal MM, et al. Naltrexone in drug addiction: significance in the prevention of relapse. Mymensingh Med J. 2009;18(suppl 1):S56YS65. 5. Mangado EO, Horcajadas FA, Hernandez MAT. Alcohol dependence treatment with naltrexone: safety assessment. Observation study group of alcoholic dependence. Actas Esp Psiquiatr. 2000;28(3):161Y168. 6. Staedt J, Wassmuth F, Stoppe G, et al. Effects of chronic treatment with methadone and naltrexone on sleep in addicts. Eur Arch Psychiatry Clin Neurosci. 1996;246(6):305Y309. 7. Wilcox CS, Oskooilar N, Erickson JS, et al. An open-label study of naltrexone and bupropion combination therapy for smoking cessation in overweight and obese subjects. Addict Behav. 2010;35(3):229Y234. 8. Smith JP, Stock H, Bingaman S, et al. Low-dose naltrexone therapy improves active Crohn’s disease. Am J Gastroenterol. 2007;102(4):820Y828. 9. Legroux-Crespel E, Cledes J, Misery L. A comparative study on the effects of naltrexone and loratadine on uremic pruritus. Dermatology. 2004;208(4):326Y330. 10. Ferber C, Duclaux R, Mouret J. Naltrexone improves blood gas patterns in obstructive sleep apnoea syndrome through its influence on sleep. J Sleep Res. 1993;2(3):149Y155. 11. Obermeyer WH, Benca RM. Effects of drugs on sleep. Neurol Clin. 1996;14(4):827Y840. 12. Gursky JT, Krahn LE. The effects of antidepressants on sleep: a review. Harv Rev Psychiatry. 2000;8(6):298Y306. 13. Foldvary-Schaefer N, De Leon Sanchez I, Karafa M, et al. Gabapentin increases slow-wave sleep in normal adults. Epilepsia. 2002;43(12):1493Y1497.
&
Volume 34, Number 1, February 2014
14. Cronin A, Keifer JC, Baghdoyan HA, et al. Opioid inhibition of rapid eye movement sleep by a specific mu receptor agonist. Br J Anaesth. 1995;74(2):188Y192. 15. Kay DC, Eisenstein RB, Jasinski DR. Morphine effects on human REM state, waking state and NREM sleep. Psychopharmacologia. 1969;14(5):404Y416. 16. Shaw IR, Lavigne G, Mayer P, et al. Acute intravenous administration of morphine perturbs sleep architecture in healthy pain-free young adults: a preliminary study. Sleep. 2005;28(6):677Y682. 17. Barbanoj MJ, Clos S, Romero S, et al. Sleep laboratory study on single and repeated dose effects of paroxetine, alprazolam and their combination in healthy young volunteers. Neuropsychobiology. 2005;51(3):134Y147. 18. Dimsdale JE, Norman D, DeJardin D, et al. The effect of opioids on sleep architecture. J Clin Sleep Med. 2007;3(1):33Y36.
Effects of Switching to Once-Daily Modified-Release Methylphenidate From Previous Treatment With Other Psychostimulants in Children and Adolescents With ADHD An Observational Study With Clinician, Parent, and Teacher Evaluations To the Editors: sychostimulant medication has been a mainstay in the multimodal treatment of attention-deficit/hyperactivity disorder (ADHD), and methylphenidate (MPH) is the substance most frequently used with robust clinical effects of immediate (IR) and modified release (MR) preparations being well documented in several metaanalyses.1Y4 Actually, different MPH-MR formulations exist with different release profiles and duration of clinical effects: (1) Concerta, with an ultralong clinical effect profile of 10 to 12 hours, containing 22% MPH-IR and 78% MPH-MR; (2) Equasym XL, with clinical effects of 8 hours, containing 30% MPHYIR and 70% MPHYMR; (3) Medikinet XL and Ritalin LA, with clinical effects of 8 hours, containing equal portions of MPHYIR and MPHYMR but differing from each other in different release properties; and (4) Focalin XR, the D-threo-enantiomer of Methylphenidat, with clinical effects of
P
* 2014 Lippincott Williams & Wilkins
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
![[The effect of Kaqun-water on the immune parameters of healthy volunteers].](/assets/img/hold.png)
