ORIGINAL RESEARCH
Sleep Profile in Opioid Dependence: A Polysomnographic Case–Control Study Vijay Mehtry,* S. Haque Nizamie,† Nizamuddin Parvez,† and Nityananda Pradhan‡
Purpose: Many opioid receptors are located in the same nuclei that are active in sleep regulation. It has been suggested that opioid peptides are involved in the induction of the sleep state. Prolonged opioid use has been hypothesized to cause disturbed sleep. It also causes excessive daytime sleepiness and fatigue. This study was conducted to compare the polysomnographic sleep profile of patients with opioid dependence with normal matched controls and to see the correlation between various clinical profiles of patients with opioid dependence with their polysomnographic sleep profile. Methods: Fifteen opioid-dependent male patients were selected, and after the detoxification procedure, the patients were assessed using Objective Opioid Withdrawal Scale, Obsessive Compulsive Drug Use Scale, Hamilton Rating Scale for Depression, Hamilton Anxiety Rating Scale, and Global Assessment of Functioning. Fifteen healthy volunteers matched for age, education, and handedness were taken as controls and were assessed using Epworth sleepiness scale and General Health Questionnaire-12. All night polysomnography recording was done on patient and control group, and staging of sleep was done. Results: Patients had significantly decreased total sleep time, sleep efficiency and stage N1 sleep, prolonged sleep latency, and increased limb movement index. No significant correlation was found between sleep profile and various clinical variables. Conclusions: Use of opioids cause sleep disturbance, and these changes occurring in sleep can persist even after substance use has been stopped. Opioids seem to affect non-rapid eye movement stages of sleep. Key Words: Sleep, Polysomnography, Opioid dependence. (J Clin Neurophysiol 2014;31: 517–522)
S
leep provides simple rest and recovery. But the magical world of sleep remains a halo of mystery. For sleep researchers, and even for general scientists, the mystery increases: the brain does not rest, even in the deepest sleep. Sleep is an evolutionarily conserved process that occupies approximately one-third of a human’s life (Lu and Zee, 2010). Sleep is a highly evolved global behavioral state in homeothermic vertebrates (Datta, 2010). Sleep is more than a respite from consciousness or sensory stimulation. It is a complex and dynamic process. Substance dependence is said to be present when an individual continues to use a substance despite experiencing several problems directly stemming from its use. Dependence is manifested by a combination of behavioral, cognitive, and physiologic symptoms
From the *Department of Psychiatry, A.J. Institute of Medical Sciences, Mangalore, Karnataka, India; †Department of Psychiatry, Central Institute of Psychiatry, Ranchi, Jharkhand, India; and ‡Department of Psychopharmacology, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India. Address correspondence and reprint requests to Vijay Mehtry, MD, No. 29, Staff Quarters, A.J. Hospital Campus, A.J. Institute of Medical Sciences, Kuntikana, Mangalore 575004, Karnataka, India; e-mail: [email protected]. Copyright Ó 2014 by the American Clinical Neurophysiology Society
ISSN: 0736-0258/14/3106-0517
and typically leads to compulsive drug-taking behavior, tolerance, and withdrawal. The term “opioid” is a broad term used to refer to any substance, natural or synthetic, that binds to specific opioid receptors in the brain (Julien, 1998). The National Household Survey of Drug use in India revealed that 0.7% of the general population abused opioids in one form or the other. The Drug Abuse Monitoring System revealed that out of the patients in in-patient treatment centers, 26% abused opioids (Ray, 2004). Sleep disturbances occur in several forms, along the various stages of psychoactive substance abuse. Sometimes, sleep complaints are not just a symptom of substance intoxication or withdrawal; the problem can mount to reach a category of “substance-induced sleep disorder” when sleep disturbance is sufficiently severe to warrant independent clinical attention, not attributable to other mental disorder or delirium and causing significant stress or impairment of functioning (American Psychiatric Association, 2000; Nofzinger, 1996). Psychoactive substances differ in the mechanisms by which they affect sleep; moreover, they differ in their acute as well as chronic effects on sleep architecture. Dealing with sleep problems in substance abuse is of utmost importance as they may have their negative impact on treatment success and precipitation of relapse (Brower et al., 2004; Karam-Hage, 2004). Many cases of opioid dependence have experience sleep disturbances for a long period. This occurs in the phenomenon of “protracted abstinence,” which is defined as drug abstinence after an acute withdrawal state (usually 1 week postacute withdrawal) (Koob and Le Moal, 2006). Sleep disturbances especially insomnia are very common symptoms of opioid protracted abstinence, which may persist up to 6 months. These symptoms are considered one of the most common causes of craving and relapse (Ling, 2007). Individuals using opioids on a long-term basis are reported to exhibit a high prevalence of abnormal sleep architecture and breathing difficulties during sleep (Walker et al., 2007).
Effect of Opioids on Sleep in Healthy Adults Even acute administration of opioids to healthy adults affects sleep with increased frequency of shifts to stage 1 sleep, increased delay to onset of the first stage 2 sleep, and decrease in percentage of rapid eye movement (REM) sleep (Lewis et al., 1970). A study by Shaw et al. (2005) showed that acute administration of a single intravenous dose of morphine sulfate in normal individual resulted in reduction in slow wave sleep (SWS) and REM, and increase in non-rapid eye movement (NREM) stage 2 sleep. The overall effect was a shift to lighter stages of sleep with no change in total sleep time (TST). In a double-blind cross-over study, Dimsdale et al. (2007) studied the acute effects of opioids on sleep architecture in healthy volunteers using methadone and morphine and showed that both these opioids increase the percentage of time spent in light sleep (stage 2) and substantially decreased the percentage of time in deep
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sleep (stages 3 and 4). No drug effects were seen on sleep efficiency (SE), TST, or wake after sleep onset. Methadone administration was associated with small but significant reductions in both the arousal index and apnea–hypopnea index, effects not observed with sustained-release morphine sulfate administration.
Sleep in Methadone Maintenance Therapy Patients on methadone maintenance therapy (MMT) for opioid dependence frequently report sleep complaints (Peles et al., 2006). Martin et al. (1973) studied sleep among male prisoners who were on MMT. The study revealed slower electroencephalogram, increased delta burst, vocalization during REMs, and increased daytime sleepiness. During withdrawal, increased REM and delta sleep were noted after 10 weeks. Orr and Stahl (1978) showed that there is decreased percentage of SWS, increased NREM1, decreased REM latency in patients, whereas no changes were reported in REM percentage, NREM2, TST, sleep latency, and awakenings. Teichtahl et al. (2005) studied sleep and respiration in clinically stable opioid-dependent patients receiving MMT. As compared with the normal controls, the patient group had increased wake time, decreased SE, decreased percentage of NREM2, decreased percentage of SWS. In addition, there was decreased REMs (minutes and periods). Sharkey et al. (2011) assessed sleep in opioid-dependent patients who were on methadone maintenance treatment who reported insomnia. Sleep times did not differ significantly among the subjective and objective measures. Objective sleep duration was significantly correlated with age with older participants having shorter polysomnography (PSG) sleep times. Gender, MMT treatment duration, methadone dose, and other drug use were not correlated with any subjective or objective sleep duration measure.
Sleep architecture changes are different various phases of withdrawal. In general, during the induction phase, the use of morphine-like opioids significantly disrupts sleep with reduced REM sleep and SWS and increased wakefulness and arousals from sleep. Total sleep time and SE are usually reduced, whereas percentage stage 2 sleep and REM sleep latency are often increased. During the maintenance phase of mu-opioid use, the decreases in SWS and REM sleep tend to normal as do the increases of wakefulness, arousal, and REM sleep latency. Vocalization during REM sleep, significant delta burst, and increased daytime sleepiness may commonly appear in this phase. Limited evidence is available regarding sleep during acute withdrawal from prolonged opioid use (Howe et al., 1980). Changes in sleep from withdrawal of short-term opioid administration may be different from changes seen in withdrawal from prolonged opioid use (Lewis et al., 1970). Significant insomnia is the major complaint during prolonged opioid withdrawal, accompanied by frequent arousals and decreased REM sleep. During the protracted abstinence phase, TST significantly increases with rebound of SWS and REM sleep. After prolonged methadone use, the rebound of SWS and REM sleep usually occurs between 13 and 22 weeks after withdrawal of the opioid (Kay, 1975b; Martin et al., 1973). Prolonged opioid use is associated with symptoms of fatigue and excessive daytime sleepiness (Moore and Dimsdale, 2002; Wang et al., 2005). The abnormal sleep architecture discussed above can affect daytime functioning in its own right. However, it is difficult to know how much the abnormal sleep architecture noted in these studies impacts on daytime function and excess daytime sleepiness (Wang and Teichtahl, 2007).
MATERIALS AND METHODS Sleep in Patients With Prolonged Opioid Use Prolonged morphine use produces signs of small but persistent sleep changes. Delta sleep was seen to be less stable, and a shift toward later part of night was seen in one study. In addition, there was increase in waking state, decreased REM and increased bursts of delta activity (Kay, 1975b). It was further seen that these patients while on MMT, showed an increase in SWS and a decrease in fast wave activity of their sleep electroencephalogram. After 6 weeks, REM sleep and delta sleep were increased (Kay, 1975a). These data provide evidence that prolonged administration of narcotic analgesics may induce persistent functional changes in the central nervous system. In another study, it was seen that during acute withdrawal phase, there was decreased TST, increased number of awakenings, decreased percentage of REM sleep (Howe et al., 1980). Asaad et al. (2011) studied sleep profile in patients with prolonged opioid use by polysomnographic evaluation. This was a cross-sectional case–control observational study. Sleep latency, efficiency, and arousal index were significantly affected in cases with lengthening of sleep latency, diminution of SE, and increase in arousal index. Non-REM sleep analysis showed significant increase in stages 1 and 2, with reduction in stages 3 and 4 in opioiddependent patients. Analysis of REM parameters showed no significant differences regarding REM percentage of TST, REM density, and REM latency. The same finding was related also to respiratory variables, as well as periodic leg movement, which showed no statistical significant differences between case and control groups. The data revealed that there was a statistically significant increase in sleep latency and arousal index of case in comparison with control group when recorded by polysomnography (PSG). 518
The study was conducted at Central Institute of Psychiatry, Ranchi, India who were admitted to the de-addiction center. In this study, 16 male patients, with ICD-10 DCR diagnosis of Opioid Dependence Syndrome were selected and comprised the patient group. Similarly, 15 age-, sex-, education-, and handednessmatched normal controls were selected. The subjects were recruited for the study by purposive sampling technique. This was a crosssectional case–control study. Informed written consent from all participants was taken, to the effect that all information would be kept confidential. Adequate matching for age, sex, education, and handedness was ensured. Comprehensive socio-demographic details were taken from both patient and control group. To rule out the presence of comorbid depression and anxiety, the patient group was rated on Hamilton Rating Scale for Depression and The Hamilton Anxiety Scale (Hamilton, 1959; Hamilton, 1960). Patients who had syndromal level of depression or anxiety were not involved in the study. Apart from opioids, these patients had not taken any other psychoactive substance in the past 1 year. For the assessment of their clinical status, they were also rated on Objective Opioid Withdrawal Scale (Handelsman et al., 1987), Obsessive Compulsive Drug Use Scale (Franken et al., 2002), and Global Assessment of Functioning Scale (American Psychiatric Association, 2000). The control group was rated on General Health Questionnaire-12 to screen for the presence of any psychiatric morbidity (Goldberg and Williams, 1988). Both the patient and control group were rated on Epworth sleepiness scale (Johns, 1991), which is a subjective scale to assess level of daytime sleepiness and were rated on Sidedness Bias Schedule to assess their handedness (Mandal et al., 1992). Copyright Ó 2014 by the American Clinical Neurophysiology Society
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Sleep Profile in Opioid Dependence
The patients were allowed to undergo the standard detoxification procedure followed in the institute. Patients were involved in sleep analysis only after 1 week after the detoxification procedure. Neither patients had any significant withdrawal features as indicated by Objective Opioid Withdrawal Scale nor any of the patients were on any medications at the time of the study.
having mean years of education of 11.46 (66.79) years. No significant difference was noted in between two groups about age and education. There was no statistically significant difference noted between the patient and control group about marital status, religion, occupation, residence, and type of family, and hence, the study had controls adequately matched with the patient group.
Polysomnography
Clinical Profile of the Cases
Assessment of sleep was done by 40-channel polysomnography using Sandman Elite 8.0 EB Neuro Software. The assessment included 28-channel electroencephalography, electrooculogram, electromyography, electrocardiography, respiratory effort, snoring, oxygen saturation, and limb movements. Sleep assessment was performed when the participants were medication free for at least 1 week to exclude the effect of any medications on sleep. The patients were informed in detail about the procedure involved and were made to sleep during their usual routine of sleep. Subjects were also refrained from having any daytime naps in between the study and were refrained from any beverages like coffee and tea in the evening. Whole night polysomnographic recording was conducted for 2 consecutive nights on both patient and control group. The first night was adaptation night and was not considered for study. Second night’s recording was taken for analysis and staging of sleep.
Of the 15 patients, 11 patients (73.3%) used heroin, 3 patients (20%) consumed capsule spasmo proxyvon, and 1 (6.7) patient consumed syrup codeine. The duration of opioid use, age of onset, Obsessive Compulsive Drug Use Scale, and Global Assessment of Functioning Scale score of the patient group are as shown in Table 1.
Sleep Staging Sleep stage scoring was done according to the American Academy of Sleep Medicine manual for the scoring of sleep and associated events, an internationally recognized and recommended scoring manual (Iber et al., 2007). This is the first study till date to use American Academy of Sleep Medicine manual for sleep scoring to study sleep in opioid dependence. All previous studies have made use of Rechtshaffen and Kales (R&K) criteria (Rechtschaffen and Kales, 1968). Initially, computer-assisted scoring was done, which was subsequently validated by manual scoring. According to the American Academy of Sleep Medicine manual used here, sleep is divided into non-REM (N1, N2, and N3) and REM sleep. N3 encompasses NREM3 and NREM4 or R&K criteria.
Statistical Analysis Statistical analysis of the data was conducted by using Statistical Package of Social Science (SPSS) 16.0 version. Description of the sample characteristics was done with descriptive statistics to calculate percentage, mean, and SD. Group differences for the categorical variables of sample characteristics (socio-demographic variables), clinical, and sleep variables were obtained by independent sample t-test. Pearson correlation was computed to find out the association between the clinical variables and the sleep variables. Level of significance was taken as P , 0.05.
Sleep Variables Results of comparison of two groups about polysomnographic sleep variables are shown in Table 2, and the comparison of respiratory events and limb movements are shown in Table 3. Comparison of sleep variables between patient and control group revealed statistically significant difference in certain parameters. Total sleep time (P ¼ 0.042) and SE (P ¼ 0.004) were reduced in the patient group in comparison with normal control group. Sleep onset latency (P ¼ 0.004) and wake after sleep onset (P ¼ 0.028) were increased in the patient group. Stage N1 duration (P ¼ 0.024) was decreased in the patient group, and limb movement index (P ¼ 0.015) was increased in the patient group in comparison with the control group. There were no significant differences between the two groups about other sleep parameters.
Correlation Between Clinical Data and Sleep Variables The results of correlation between clinical data and sleep variables of the patients are shown in Table 4. It was seen that there was significant differences in TST, SE, Sleep Onset Latency, N1 Duration, and Limb Movement Index between the patient and control groups. These parameters were correlated with the clinical variables of the patient group to see for any correlation by using Pearson correlation. There was no significant correlation found between the clinical variables and the sleep parameters of patient group.
DISCUSSION This study revealed a statistically significant increase in sleep onset latency of patients in comparison with control group when recorded by polysomnography. This finding is consistent with previous studies indicating increase of sleep onset latency in opioid-dependent patients (Asaad et al., 2011; Lukas et al., 1996;
TABLE 1.
RESULTS Characteristics of the Participants Fifteen patients and 15 matched controls underwent the full procedure. One patient had to drop out because of lack of adequate artifact-free data. All the participants in patient and control group were right handed. The mean age of patient group was 28.86 (66.73) years having mean years of education of 10.00 (64.56) years. The mean age of control group was 27.86 (62.92) years Copyright Ó 2014 by the American Clinical Neurophysiology Society
Clinical Profile of the Patients
Variable Duration of opioid use (years) Age of onset (years) OCDUS GAF
Mean 6 SD (n ¼ 15)
Range
6 6 6 6
0.25–22 14–31 5–17 50–85
5.05 23.8 10.6 66.67
5.39 4.88 3.92 9.75
GAF, Global assessment of functioning; OCDUS, Obsessive Compulsive Drug Use Scale.
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TABLE 2.
Comparison of Sleep Variables
Sleep Parameter Total recording period (minutes) Total sleep time (minutes) Sleep efficiency (%) Sleep onset latency (minutes) Wake after sleep onset No. of arousals Arousal index (per hour) No. of REM N1 duration (minutes) N 1 (%) N II duration (minutes) N II (%) N III duration (minutes) N III (%) REM duration (minutes) REM (%) REM latency
Patient (n ¼ 15) (Mean 6 SD) 384.18 279.24 66.75 31.94 103.58 33.20 7.08 3.00 54.95 21.44 109.06 38.06 60.63 22.53 54.51 18.72 110.66
6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6
42.40 65.72 13.97 28.66 43.08 39.03 7.75 1.25 32.02 15.31 50.72 14.28 28.73 9.00 27.72 8.34 64.24
Control (n ¼ 15) (Mean 6 SD)
t
P
6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6
20.811 22.130 23.141 3.180 2.311 20.625 20.180 21.702 22.382 20.906 0.105 0.930 20.813 0.237 20.699 20.023 1.414
0.424 0.042* 0.004** 0.004** 0.028* 0.537 0.859 0.100 0.024* 0.373 0.917 0.360 0.423 0.814 0.490 0.982 0.168
394.74 321.85 79.86 7.98 71.88 41.00 7.52 3.80 82.79 25.55 107.53 33.94 69.91 21.71 61.61 18.78 82.00
27.33 41.04 8.11 5.45 31.07 28.56 5.21 1.32 31.97 8.64 25.38 9.51 32.33 10.05 27.83 7.28 45.16
*P , 0.05. REM, rapid eye movement.
not be replicated in this study (Lukas et al., 1996; Staedt et al., 1996; Teichtahl et al., 2001). This study did not find any statistically significant difference in various parameters of REM sleep, which was also reported by others (Asaad et al., 2011; Walker et al., 2007; Wang et al., 2008). Few studies have reported decreased REM percentage and decreased REM latency (Lukas et al., 1996; Wang et al., 2005). Rapid eye movement sleep abnormalities have been previously linked to depression, and none of the patients involved in this study had depression or anxiety as evaluated by Hamilton Depression Rating Scale and Hamilton Anxiety Scale, which explains the lack of REM abnormalities in this study. There was no significant difference noted in respiratory variables on comparison of the two groups unlike others who reported sleep-disordered breathing in prolonged opioid abusers (Teichtahl et al., 2005; Walker et al., 2007; Wang et al., 2005; Webster et al., 2008). A possible explanation for this difference might be attributed to the fact that most of these studies considered patients using opioids at the time of assessment. But in this study, the
Staedt et al., 1996). Some studies have found no difference in sleep onset latency between the two groups (Teichtahl et al., 2001; Wang et al., 2005). The difference could be attributed to the use of methadone treatment as a maintenance which is not the case in this study. The finding of decreased TST resulting in decreased SE in this study is also consistent with previous studies (Sharkey et al., 2009; Wang et al., 2005). The study also revealed that the patient group experienced increased waking as indicated by wake after sleep onset. This finding is consistent with some of the previous studies (Asaad et al., 2011; Kay, 1975a; Kay et al., 1969, 1979, 1981). The study revealed that the duration of stage 1 NREM in patients was significantly reduced in the patient group on comparison with the control group, which is consistent with some of previous studies (Wang et al., 2005). Regarding SWS (N3), there was no statistically significant difference between the two groups. This finding is consistent with some studies (Howe et al., 1980; Lewis et al., 1970). However, some other studies have reported reduction of SWS, a finding which could
TABLE 3.
Comparison of Limb Movements and Respiratory Events
Parameter Limb movement without arousal Limb movement with arousal Limb movement index Limb movement sleep apnea index Obstructive apnea Mixed apnea Central apnea Hypopnea Apnea 1 hypopnea Apnea index (per hour) Hypopnea index (per hour) Apnea hypopnea index (per hour)
Patient (n ¼ 15) (Mean 6 SD) 93.40 4.44 20.04 0.89 0.46
1.40 1.86 0.10 0.27 0.38
6 6 6 6 6 0 0 6 6 6 6 6
Control (n ¼ 15) (Mean 6 SD)
t
P
6 6 6 6 6 0 0 6 6 6 6 6
50.92 2.93 7.17 0.56 0.59
1.884 1.180 2.595 1.164 0.710
0.070 0.248 0.015* 0.254 0.484
1.14 1.45 0.11 0.23 0.29
0.260 0.445 0.861 0.283 0.590
0.797 0.660 0.397 0.779 0.560
75.22 6.73 17.69 1.54 0.91
49.20 2.20 7.24 0.40 0.26
2.74 3.15 0.20 0.49 0.58
1.20 1.46 0.05 0.23 0.28
*P , 0.05.
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TABLE 4.
Sleep Profile in Opioid Dependence
Correlation Between Clinical Variables and Sleep Variables of Patient Group
Variable Duration of opioid use Age of onset of opioid use OCDUS GAF
Total Sleep Time
Sleep Efficiency
Sleep Onset Latency
N I Duration
Limb Movement Index
20.063 20.318 20.096 0.364
0.082 20.36 20.118 0.343
20.081 0.387 0.326 20.109
0.502 20.129 0.412 20.41
0.179 0.47 0.002 20.047
GAF, Global Assessment of Functioning; OCDUS, Obsessive Compulsive Drug Use Scale.
patients were opioid free and had undergone detoxification procedure and were free of any withdrawal features. This is supported by one study, which found that sleep-disordered breathing would completely resolve in patients who stopped methadone after prolonged use (Martin et al., 2007). It was seen that limb movement index was increased in the patient group, which is similar to an analysis by Scherbaum et al. (2003). Patients describe transient restless leg syndrome emerging during opiate detoxification treatment. Transient restless leg syndrome during opiate detoxification merits further interest to improve the treatment of sleep disturbances during detoxification and as a model of interaction of the dopaminergic and endorphine system in motor activity (Scherbaum et al., 2003). In long-term opioid use, there are subcellular changes on chronic opioid exposure, which causes induction of adenylyl cyclase and protein kinase A which in turn causes electrical excitability and increased activity of tyrosine hydroxylase (a rate limiting enzyme for dopamine synthesis) and a decrease in endogenous opiates. So in opioid withdrawal state, there is a sharp decline in the level of aforementioned substrates, causing a dopamine and opioid depleted state in brain especially in the basal ganglia/spinal cord region, implicated in restless leg syndrome (Allen et al., 2003). The study did not find any significant correlation between the various clinical variables (age, age of onset of opiate use, duration of opiate use, Obsessive Compulsive Drug Use Scale score, and Global Assessment of Functioning Scale score) and the polysomnographic findings. Some previous studies have found similar results (Asaad et al., 2011; Burke et al., 2008). However, some studies could find significant correlation with duration of opioid use with subjective sleep quality. Opioids are involved in sleep–wake regulation by means of direct central opioid input to the ventrolateral preoptic nucleus of the anterior hypothalamus. The ventrolateral preoptic consists of m and k receptors, which are likely involved in mediating the hypnotic response to high level of opioid analgesics (Greco et al., 2008). Ventrolateral preoptic also plays a crucial role in initiating and maintaining NREM sleep to such an extent that it is considered to be the main switch of NREM sleep (Kryger et al., 2005). Opioid dependence causes severe disturbance in the endogenous opioid system. Therefore, it is expected that opioid-dependent patients will have disruption in the sleep architecture. Use of opioids cause sleep disturbance, and these changes occurring in sleep can persist even after substance use has been stopped. Opioids seem to affect NREM stages of sleep thereby resulting in decreased SE. This study was limited by presence of only male participants, rather small study size, absence of baseline polysomnographic evaluation before detoxification and absence of concurrent neuroimaging. Various neuroimaging techniques can be incorporated along with polysomnography in the future and more than one adaptation night can be considered. Copyright Ó 2014 by the American Clinical Neurophysiology Society
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Rechtschaffen A, Kales A. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Los Angeles: Brain Information Service/Brain Research Institute, 1968:1–12. Scherbaum N, Stüper B, Bonnet U, Gastpar M. Transient restless legs-like syndrome as a complication of opiate withrawal. Pharmacopsychiatry 2003:36:70–72. Sharkey KM, Kurth ME, Corso RP. Home polysomnography in methadone maintenance patients with subjective sleep complaints. Am J Drug Alcohol Abuse 2009;35:178–182. Sharkey KM, Kurth ME, Anderson BJ, et al. Assessing sleep in opioid dependence: a comparison of subjective ratings, sleep diaries, and home polysomnography in methadone maintenance patients. Drug Alcohol Depend 2011;113:245–248. Shaw IR, Lavigne G, Mayer P. Acute intravenous administration of morphine perturbs sleep architecture in healthy pain-free young adults: a preliminary study. Sleep 2005;28:677–682. Staedt J, Wassmuth F, Stoppe G. Effects of chronic treatment with methadone and naltrexone on sleep in addicts. Eur Arch Psychiatry Clin Neurosci 1996;246:305–309. Teichtahl H, Prodromidis A, Miller B, et al. Sleep-disordered breathing in stable methadone programme patients: a pilot study. Addiction 2001;96:395–403. Teichtahl H, Wang D, Cunnington D. Ventilatory response to hypoxia and hypercapnia in stable methadone maintenance treatment patients. Chest 2005;128;1339–1347. Walker JM, Farney RJ, Rhondeau SM. Chronic opioid use is a risk factor for the development of central sleep apnea and ataxic breathing. J Clin Sleep Med 2007;15:455–461. Wang D, Teichtahl H. Opioids, sleep architecture and sleep-disordered breathing. Sleep Med Rev 2007;11:35–46. Wang D, Teichtahl H, Drummer OH, et al. Central sleep apnea in stable methadone maintenance treatment patients. Chest 2005;128:1348–1356. Wang D, Teichtahl H, Goodman C. Subjective daytime sleepiness and daytime function in patients on stable methadone maintenance treatment: possible mechanisms. J Clin Sleep Med 2008;4:557–562. Webster LR, Choi Y, Desai H, et al. Sleep-disordered breathing and chronic opioid therapy. Pain Med 2008;9:425–432.
Copyright Ó 2014 by the American Clinical Neurophysiology Society
Sleep Profile in Opioid Dependence: A Polysomnographic Case–Control Study Vijay Mehtry,* S. Haque Nizamie,† Nizamuddin Parvez,† and Nityananda Pradhan‡
Purpose: Many opioid receptors are located in the same nuclei that are active in sleep regulation. It has been suggested that opioid peptides are involved in the induction of the sleep state. Prolonged opioid use has been hypothesized to cause disturbed sleep. It also causes excessive daytime sleepiness and fatigue. This study was conducted to compare the polysomnographic sleep profile of patients with opioid dependence with normal matched controls and to see the correlation between various clinical profiles of patients with opioid dependence with their polysomnographic sleep profile. Methods: Fifteen opioid-dependent male patients were selected, and after the detoxification procedure, the patients were assessed using Objective Opioid Withdrawal Scale, Obsessive Compulsive Drug Use Scale, Hamilton Rating Scale for Depression, Hamilton Anxiety Rating Scale, and Global Assessment of Functioning. Fifteen healthy volunteers matched for age, education, and handedness were taken as controls and were assessed using Epworth sleepiness scale and General Health Questionnaire-12. All night polysomnography recording was done on patient and control group, and staging of sleep was done. Results: Patients had significantly decreased total sleep time, sleep efficiency and stage N1 sleep, prolonged sleep latency, and increased limb movement index. No significant correlation was found between sleep profile and various clinical variables. Conclusions: Use of opioids cause sleep disturbance, and these changes occurring in sleep can persist even after substance use has been stopped. Opioids seem to affect non-rapid eye movement stages of sleep. Key Words: Sleep, Polysomnography, Opioid dependence. (J Clin Neurophysiol 2014;31: 517–522)
S
leep provides simple rest and recovery. But the magical world of sleep remains a halo of mystery. For sleep researchers, and even for general scientists, the mystery increases: the brain does not rest, even in the deepest sleep. Sleep is an evolutionarily conserved process that occupies approximately one-third of a human’s life (Lu and Zee, 2010). Sleep is a highly evolved global behavioral state in homeothermic vertebrates (Datta, 2010). Sleep is more than a respite from consciousness or sensory stimulation. It is a complex and dynamic process. Substance dependence is said to be present when an individual continues to use a substance despite experiencing several problems directly stemming from its use. Dependence is manifested by a combination of behavioral, cognitive, and physiologic symptoms
From the *Department of Psychiatry, A.J. Institute of Medical Sciences, Mangalore, Karnataka, India; †Department of Psychiatry, Central Institute of Psychiatry, Ranchi, Jharkhand, India; and ‡Department of Psychopharmacology, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India. Address correspondence and reprint requests to Vijay Mehtry, MD, No. 29, Staff Quarters, A.J. Hospital Campus, A.J. Institute of Medical Sciences, Kuntikana, Mangalore 575004, Karnataka, India; e-mail: [email protected]. Copyright Ó 2014 by the American Clinical Neurophysiology Society
ISSN: 0736-0258/14/3106-0517
and typically leads to compulsive drug-taking behavior, tolerance, and withdrawal. The term “opioid” is a broad term used to refer to any substance, natural or synthetic, that binds to specific opioid receptors in the brain (Julien, 1998). The National Household Survey of Drug use in India revealed that 0.7% of the general population abused opioids in one form or the other. The Drug Abuse Monitoring System revealed that out of the patients in in-patient treatment centers, 26% abused opioids (Ray, 2004). Sleep disturbances occur in several forms, along the various stages of psychoactive substance abuse. Sometimes, sleep complaints are not just a symptom of substance intoxication or withdrawal; the problem can mount to reach a category of “substance-induced sleep disorder” when sleep disturbance is sufficiently severe to warrant independent clinical attention, not attributable to other mental disorder or delirium and causing significant stress or impairment of functioning (American Psychiatric Association, 2000; Nofzinger, 1996). Psychoactive substances differ in the mechanisms by which they affect sleep; moreover, they differ in their acute as well as chronic effects on sleep architecture. Dealing with sleep problems in substance abuse is of utmost importance as they may have their negative impact on treatment success and precipitation of relapse (Brower et al., 2004; Karam-Hage, 2004). Many cases of opioid dependence have experience sleep disturbances for a long period. This occurs in the phenomenon of “protracted abstinence,” which is defined as drug abstinence after an acute withdrawal state (usually 1 week postacute withdrawal) (Koob and Le Moal, 2006). Sleep disturbances especially insomnia are very common symptoms of opioid protracted abstinence, which may persist up to 6 months. These symptoms are considered one of the most common causes of craving and relapse (Ling, 2007). Individuals using opioids on a long-term basis are reported to exhibit a high prevalence of abnormal sleep architecture and breathing difficulties during sleep (Walker et al., 2007).
Effect of Opioids on Sleep in Healthy Adults Even acute administration of opioids to healthy adults affects sleep with increased frequency of shifts to stage 1 sleep, increased delay to onset of the first stage 2 sleep, and decrease in percentage of rapid eye movement (REM) sleep (Lewis et al., 1970). A study by Shaw et al. (2005) showed that acute administration of a single intravenous dose of morphine sulfate in normal individual resulted in reduction in slow wave sleep (SWS) and REM, and increase in non-rapid eye movement (NREM) stage 2 sleep. The overall effect was a shift to lighter stages of sleep with no change in total sleep time (TST). In a double-blind cross-over study, Dimsdale et al. (2007) studied the acute effects of opioids on sleep architecture in healthy volunteers using methadone and morphine and showed that both these opioids increase the percentage of time spent in light sleep (stage 2) and substantially decreased the percentage of time in deep
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sleep (stages 3 and 4). No drug effects were seen on sleep efficiency (SE), TST, or wake after sleep onset. Methadone administration was associated with small but significant reductions in both the arousal index and apnea–hypopnea index, effects not observed with sustained-release morphine sulfate administration.
Sleep in Methadone Maintenance Therapy Patients on methadone maintenance therapy (MMT) for opioid dependence frequently report sleep complaints (Peles et al., 2006). Martin et al. (1973) studied sleep among male prisoners who were on MMT. The study revealed slower electroencephalogram, increased delta burst, vocalization during REMs, and increased daytime sleepiness. During withdrawal, increased REM and delta sleep were noted after 10 weeks. Orr and Stahl (1978) showed that there is decreased percentage of SWS, increased NREM1, decreased REM latency in patients, whereas no changes were reported in REM percentage, NREM2, TST, sleep latency, and awakenings. Teichtahl et al. (2005) studied sleep and respiration in clinically stable opioid-dependent patients receiving MMT. As compared with the normal controls, the patient group had increased wake time, decreased SE, decreased percentage of NREM2, decreased percentage of SWS. In addition, there was decreased REMs (minutes and periods). Sharkey et al. (2011) assessed sleep in opioid-dependent patients who were on methadone maintenance treatment who reported insomnia. Sleep times did not differ significantly among the subjective and objective measures. Objective sleep duration was significantly correlated with age with older participants having shorter polysomnography (PSG) sleep times. Gender, MMT treatment duration, methadone dose, and other drug use were not correlated with any subjective or objective sleep duration measure.
Sleep architecture changes are different various phases of withdrawal. In general, during the induction phase, the use of morphine-like opioids significantly disrupts sleep with reduced REM sleep and SWS and increased wakefulness and arousals from sleep. Total sleep time and SE are usually reduced, whereas percentage stage 2 sleep and REM sleep latency are often increased. During the maintenance phase of mu-opioid use, the decreases in SWS and REM sleep tend to normal as do the increases of wakefulness, arousal, and REM sleep latency. Vocalization during REM sleep, significant delta burst, and increased daytime sleepiness may commonly appear in this phase. Limited evidence is available regarding sleep during acute withdrawal from prolonged opioid use (Howe et al., 1980). Changes in sleep from withdrawal of short-term opioid administration may be different from changes seen in withdrawal from prolonged opioid use (Lewis et al., 1970). Significant insomnia is the major complaint during prolonged opioid withdrawal, accompanied by frequent arousals and decreased REM sleep. During the protracted abstinence phase, TST significantly increases with rebound of SWS and REM sleep. After prolonged methadone use, the rebound of SWS and REM sleep usually occurs between 13 and 22 weeks after withdrawal of the opioid (Kay, 1975b; Martin et al., 1973). Prolonged opioid use is associated with symptoms of fatigue and excessive daytime sleepiness (Moore and Dimsdale, 2002; Wang et al., 2005). The abnormal sleep architecture discussed above can affect daytime functioning in its own right. However, it is difficult to know how much the abnormal sleep architecture noted in these studies impacts on daytime function and excess daytime sleepiness (Wang and Teichtahl, 2007).
MATERIALS AND METHODS Sleep in Patients With Prolonged Opioid Use Prolonged morphine use produces signs of small but persistent sleep changes. Delta sleep was seen to be less stable, and a shift toward later part of night was seen in one study. In addition, there was increase in waking state, decreased REM and increased bursts of delta activity (Kay, 1975b). It was further seen that these patients while on MMT, showed an increase in SWS and a decrease in fast wave activity of their sleep electroencephalogram. After 6 weeks, REM sleep and delta sleep were increased (Kay, 1975a). These data provide evidence that prolonged administration of narcotic analgesics may induce persistent functional changes in the central nervous system. In another study, it was seen that during acute withdrawal phase, there was decreased TST, increased number of awakenings, decreased percentage of REM sleep (Howe et al., 1980). Asaad et al. (2011) studied sleep profile in patients with prolonged opioid use by polysomnographic evaluation. This was a cross-sectional case–control observational study. Sleep latency, efficiency, and arousal index were significantly affected in cases with lengthening of sleep latency, diminution of SE, and increase in arousal index. Non-REM sleep analysis showed significant increase in stages 1 and 2, with reduction in stages 3 and 4 in opioiddependent patients. Analysis of REM parameters showed no significant differences regarding REM percentage of TST, REM density, and REM latency. The same finding was related also to respiratory variables, as well as periodic leg movement, which showed no statistical significant differences between case and control groups. The data revealed that there was a statistically significant increase in sleep latency and arousal index of case in comparison with control group when recorded by polysomnography (PSG). 518
The study was conducted at Central Institute of Psychiatry, Ranchi, India who were admitted to the de-addiction center. In this study, 16 male patients, with ICD-10 DCR diagnosis of Opioid Dependence Syndrome were selected and comprised the patient group. Similarly, 15 age-, sex-, education-, and handednessmatched normal controls were selected. The subjects were recruited for the study by purposive sampling technique. This was a crosssectional case–control study. Informed written consent from all participants was taken, to the effect that all information would be kept confidential. Adequate matching for age, sex, education, and handedness was ensured. Comprehensive socio-demographic details were taken from both patient and control group. To rule out the presence of comorbid depression and anxiety, the patient group was rated on Hamilton Rating Scale for Depression and The Hamilton Anxiety Scale (Hamilton, 1959; Hamilton, 1960). Patients who had syndromal level of depression or anxiety were not involved in the study. Apart from opioids, these patients had not taken any other psychoactive substance in the past 1 year. For the assessment of their clinical status, they were also rated on Objective Opioid Withdrawal Scale (Handelsman et al., 1987), Obsessive Compulsive Drug Use Scale (Franken et al., 2002), and Global Assessment of Functioning Scale (American Psychiatric Association, 2000). The control group was rated on General Health Questionnaire-12 to screen for the presence of any psychiatric morbidity (Goldberg and Williams, 1988). Both the patient and control group were rated on Epworth sleepiness scale (Johns, 1991), which is a subjective scale to assess level of daytime sleepiness and were rated on Sidedness Bias Schedule to assess their handedness (Mandal et al., 1992). Copyright Ó 2014 by the American Clinical Neurophysiology Society
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Sleep Profile in Opioid Dependence
The patients were allowed to undergo the standard detoxification procedure followed in the institute. Patients were involved in sleep analysis only after 1 week after the detoxification procedure. Neither patients had any significant withdrawal features as indicated by Objective Opioid Withdrawal Scale nor any of the patients were on any medications at the time of the study.
having mean years of education of 11.46 (66.79) years. No significant difference was noted in between two groups about age and education. There was no statistically significant difference noted between the patient and control group about marital status, religion, occupation, residence, and type of family, and hence, the study had controls adequately matched with the patient group.
Polysomnography
Clinical Profile of the Cases
Assessment of sleep was done by 40-channel polysomnography using Sandman Elite 8.0 EB Neuro Software. The assessment included 28-channel electroencephalography, electrooculogram, electromyography, electrocardiography, respiratory effort, snoring, oxygen saturation, and limb movements. Sleep assessment was performed when the participants were medication free for at least 1 week to exclude the effect of any medications on sleep. The patients were informed in detail about the procedure involved and were made to sleep during their usual routine of sleep. Subjects were also refrained from having any daytime naps in between the study and were refrained from any beverages like coffee and tea in the evening. Whole night polysomnographic recording was conducted for 2 consecutive nights on both patient and control group. The first night was adaptation night and was not considered for study. Second night’s recording was taken for analysis and staging of sleep.
Of the 15 patients, 11 patients (73.3%) used heroin, 3 patients (20%) consumed capsule spasmo proxyvon, and 1 (6.7) patient consumed syrup codeine. The duration of opioid use, age of onset, Obsessive Compulsive Drug Use Scale, and Global Assessment of Functioning Scale score of the patient group are as shown in Table 1.
Sleep Staging Sleep stage scoring was done according to the American Academy of Sleep Medicine manual for the scoring of sleep and associated events, an internationally recognized and recommended scoring manual (Iber et al., 2007). This is the first study till date to use American Academy of Sleep Medicine manual for sleep scoring to study sleep in opioid dependence. All previous studies have made use of Rechtshaffen and Kales (R&K) criteria (Rechtschaffen and Kales, 1968). Initially, computer-assisted scoring was done, which was subsequently validated by manual scoring. According to the American Academy of Sleep Medicine manual used here, sleep is divided into non-REM (N1, N2, and N3) and REM sleep. N3 encompasses NREM3 and NREM4 or R&K criteria.
Statistical Analysis Statistical analysis of the data was conducted by using Statistical Package of Social Science (SPSS) 16.0 version. Description of the sample characteristics was done with descriptive statistics to calculate percentage, mean, and SD. Group differences for the categorical variables of sample characteristics (socio-demographic variables), clinical, and sleep variables were obtained by independent sample t-test. Pearson correlation was computed to find out the association between the clinical variables and the sleep variables. Level of significance was taken as P , 0.05.
Sleep Variables Results of comparison of two groups about polysomnographic sleep variables are shown in Table 2, and the comparison of respiratory events and limb movements are shown in Table 3. Comparison of sleep variables between patient and control group revealed statistically significant difference in certain parameters. Total sleep time (P ¼ 0.042) and SE (P ¼ 0.004) were reduced in the patient group in comparison with normal control group. Sleep onset latency (P ¼ 0.004) and wake after sleep onset (P ¼ 0.028) were increased in the patient group. Stage N1 duration (P ¼ 0.024) was decreased in the patient group, and limb movement index (P ¼ 0.015) was increased in the patient group in comparison with the control group. There were no significant differences between the two groups about other sleep parameters.
Correlation Between Clinical Data and Sleep Variables The results of correlation between clinical data and sleep variables of the patients are shown in Table 4. It was seen that there was significant differences in TST, SE, Sleep Onset Latency, N1 Duration, and Limb Movement Index between the patient and control groups. These parameters were correlated with the clinical variables of the patient group to see for any correlation by using Pearson correlation. There was no significant correlation found between the clinical variables and the sleep parameters of patient group.
DISCUSSION This study revealed a statistically significant increase in sleep onset latency of patients in comparison with control group when recorded by polysomnography. This finding is consistent with previous studies indicating increase of sleep onset latency in opioid-dependent patients (Asaad et al., 2011; Lukas et al., 1996;
TABLE 1.
RESULTS Characteristics of the Participants Fifteen patients and 15 matched controls underwent the full procedure. One patient had to drop out because of lack of adequate artifact-free data. All the participants in patient and control group were right handed. The mean age of patient group was 28.86 (66.73) years having mean years of education of 10.00 (64.56) years. The mean age of control group was 27.86 (62.92) years Copyright Ó 2014 by the American Clinical Neurophysiology Society
Clinical Profile of the Patients
Variable Duration of opioid use (years) Age of onset (years) OCDUS GAF
Mean 6 SD (n ¼ 15)
Range
6 6 6 6
0.25–22 14–31 5–17 50–85
5.05 23.8 10.6 66.67
5.39 4.88 3.92 9.75
GAF, Global assessment of functioning; OCDUS, Obsessive Compulsive Drug Use Scale.
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TABLE 2.
Comparison of Sleep Variables
Sleep Parameter Total recording period (minutes) Total sleep time (minutes) Sleep efficiency (%) Sleep onset latency (minutes) Wake after sleep onset No. of arousals Arousal index (per hour) No. of REM N1 duration (minutes) N 1 (%) N II duration (minutes) N II (%) N III duration (minutes) N III (%) REM duration (minutes) REM (%) REM latency
Patient (n ¼ 15) (Mean 6 SD) 384.18 279.24 66.75 31.94 103.58 33.20 7.08 3.00 54.95 21.44 109.06 38.06 60.63 22.53 54.51 18.72 110.66
6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6
42.40 65.72 13.97 28.66 43.08 39.03 7.75 1.25 32.02 15.31 50.72 14.28 28.73 9.00 27.72 8.34 64.24
Control (n ¼ 15) (Mean 6 SD)
t
P
6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6
20.811 22.130 23.141 3.180 2.311 20.625 20.180 21.702 22.382 20.906 0.105 0.930 20.813 0.237 20.699 20.023 1.414
0.424 0.042* 0.004** 0.004** 0.028* 0.537 0.859 0.100 0.024* 0.373 0.917 0.360 0.423 0.814 0.490 0.982 0.168
394.74 321.85 79.86 7.98 71.88 41.00 7.52 3.80 82.79 25.55 107.53 33.94 69.91 21.71 61.61 18.78 82.00
27.33 41.04 8.11 5.45 31.07 28.56 5.21 1.32 31.97 8.64 25.38 9.51 32.33 10.05 27.83 7.28 45.16
*P , 0.05. REM, rapid eye movement.
not be replicated in this study (Lukas et al., 1996; Staedt et al., 1996; Teichtahl et al., 2001). This study did not find any statistically significant difference in various parameters of REM sleep, which was also reported by others (Asaad et al., 2011; Walker et al., 2007; Wang et al., 2008). Few studies have reported decreased REM percentage and decreased REM latency (Lukas et al., 1996; Wang et al., 2005). Rapid eye movement sleep abnormalities have been previously linked to depression, and none of the patients involved in this study had depression or anxiety as evaluated by Hamilton Depression Rating Scale and Hamilton Anxiety Scale, which explains the lack of REM abnormalities in this study. There was no significant difference noted in respiratory variables on comparison of the two groups unlike others who reported sleep-disordered breathing in prolonged opioid abusers (Teichtahl et al., 2005; Walker et al., 2007; Wang et al., 2005; Webster et al., 2008). A possible explanation for this difference might be attributed to the fact that most of these studies considered patients using opioids at the time of assessment. But in this study, the
Staedt et al., 1996). Some studies have found no difference in sleep onset latency between the two groups (Teichtahl et al., 2001; Wang et al., 2005). The difference could be attributed to the use of methadone treatment as a maintenance which is not the case in this study. The finding of decreased TST resulting in decreased SE in this study is also consistent with previous studies (Sharkey et al., 2009; Wang et al., 2005). The study also revealed that the patient group experienced increased waking as indicated by wake after sleep onset. This finding is consistent with some of the previous studies (Asaad et al., 2011; Kay, 1975a; Kay et al., 1969, 1979, 1981). The study revealed that the duration of stage 1 NREM in patients was significantly reduced in the patient group on comparison with the control group, which is consistent with some of previous studies (Wang et al., 2005). Regarding SWS (N3), there was no statistically significant difference between the two groups. This finding is consistent with some studies (Howe et al., 1980; Lewis et al., 1970). However, some other studies have reported reduction of SWS, a finding which could
TABLE 3.
Comparison of Limb Movements and Respiratory Events
Parameter Limb movement without arousal Limb movement with arousal Limb movement index Limb movement sleep apnea index Obstructive apnea Mixed apnea Central apnea Hypopnea Apnea 1 hypopnea Apnea index (per hour) Hypopnea index (per hour) Apnea hypopnea index (per hour)
Patient (n ¼ 15) (Mean 6 SD) 93.40 4.44 20.04 0.89 0.46
1.40 1.86 0.10 0.27 0.38
6 6 6 6 6 0 0 6 6 6 6 6
Control (n ¼ 15) (Mean 6 SD)
t
P
6 6 6 6 6 0 0 6 6 6 6 6
50.92 2.93 7.17 0.56 0.59
1.884 1.180 2.595 1.164 0.710
0.070 0.248 0.015* 0.254 0.484
1.14 1.45 0.11 0.23 0.29
0.260 0.445 0.861 0.283 0.590
0.797 0.660 0.397 0.779 0.560
75.22 6.73 17.69 1.54 0.91
49.20 2.20 7.24 0.40 0.26
2.74 3.15 0.20 0.49 0.58
1.20 1.46 0.05 0.23 0.28
*P , 0.05.
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TABLE 4.
Sleep Profile in Opioid Dependence
Correlation Between Clinical Variables and Sleep Variables of Patient Group
Variable Duration of opioid use Age of onset of opioid use OCDUS GAF
Total Sleep Time
Sleep Efficiency
Sleep Onset Latency
N I Duration
Limb Movement Index
20.063 20.318 20.096 0.364
0.082 20.36 20.118 0.343
20.081 0.387 0.326 20.109
0.502 20.129 0.412 20.41
0.179 0.47 0.002 20.047
GAF, Global Assessment of Functioning; OCDUS, Obsessive Compulsive Drug Use Scale.
patients were opioid free and had undergone detoxification procedure and were free of any withdrawal features. This is supported by one study, which found that sleep-disordered breathing would completely resolve in patients who stopped methadone after prolonged use (Martin et al., 2007). It was seen that limb movement index was increased in the patient group, which is similar to an analysis by Scherbaum et al. (2003). Patients describe transient restless leg syndrome emerging during opiate detoxification treatment. Transient restless leg syndrome during opiate detoxification merits further interest to improve the treatment of sleep disturbances during detoxification and as a model of interaction of the dopaminergic and endorphine system in motor activity (Scherbaum et al., 2003). In long-term opioid use, there are subcellular changes on chronic opioid exposure, which causes induction of adenylyl cyclase and protein kinase A which in turn causes electrical excitability and increased activity of tyrosine hydroxylase (a rate limiting enzyme for dopamine synthesis) and a decrease in endogenous opiates. So in opioid withdrawal state, there is a sharp decline in the level of aforementioned substrates, causing a dopamine and opioid depleted state in brain especially in the basal ganglia/spinal cord region, implicated in restless leg syndrome (Allen et al., 2003). The study did not find any significant correlation between the various clinical variables (age, age of onset of opiate use, duration of opiate use, Obsessive Compulsive Drug Use Scale score, and Global Assessment of Functioning Scale score) and the polysomnographic findings. Some previous studies have found similar results (Asaad et al., 2011; Burke et al., 2008). However, some studies could find significant correlation with duration of opioid use with subjective sleep quality. Opioids are involved in sleep–wake regulation by means of direct central opioid input to the ventrolateral preoptic nucleus of the anterior hypothalamus. The ventrolateral preoptic consists of m and k receptors, which are likely involved in mediating the hypnotic response to high level of opioid analgesics (Greco et al., 2008). Ventrolateral preoptic also plays a crucial role in initiating and maintaining NREM sleep to such an extent that it is considered to be the main switch of NREM sleep (Kryger et al., 2005). Opioid dependence causes severe disturbance in the endogenous opioid system. Therefore, it is expected that opioid-dependent patients will have disruption in the sleep architecture. Use of opioids cause sleep disturbance, and these changes occurring in sleep can persist even after substance use has been stopped. Opioids seem to affect NREM stages of sleep thereby resulting in decreased SE. This study was limited by presence of only male participants, rather small study size, absence of baseline polysomnographic evaluation before detoxification and absence of concurrent neuroimaging. Various neuroimaging techniques can be incorporated along with polysomnography in the future and more than one adaptation night can be considered. Copyright Ó 2014 by the American Clinical Neurophysiology Society
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