- Email: [email protected]
The effect of methylphenidate on the sleep-wake cycle of brain-injured patients undergoing rehabilitation
Sleep Medicine 7 (2006) 287–291 www.elsevier.com/locate/sleep
Brief Communication
The effect of methylphenidate on the sleep-wake cycle of brain-injured patients undergoing rehabilitation Samir Al-Adawi a,*, David T. Burke b, Atsu S.S. Dorvlo c a Department of Behavioral Medicine, College of Medicine and Health Sciences, Sultan Qaboos University, P.O. Box 35, Al-Khoudh 123, Muscat, Sultanate of Oman b Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, USA c Department of Mathematics and Statistics, College of Science, Sultan Qaboos University, Muscat, Oman
Received 27 September 2004; received in revised form 4 November 2005; accepted 5 November 2005
Abstract Background and purpose: A number of neurostimulants are routinely used as part of post-acute care of hospitalized brain-injured patients. To our knowledge, the effect of these stimulants on the sleep–wake cycles of brain-injured patients undergoing rehabilitation has not been addressed. We examined the effect of one of the most commonly used neurostimulants, methylphenidate, on the sleep–wake behavior of brain-injured patients undergoing rehabilitation at a dedicated brain injury clinic. Patients and method: For this study, records of patients admitted between January and December 1999 were scrutinized retrospectively for the data on observationally defined sleep–wake distribution. A total of 30 patients diagnosed with traumatic brain injury were identified as having been observed for a full 24 h a day for at least 10 days. Some of these patients (nZ17) were administered methylphenidate on clinical grounds. They served as the experimental group, while the unmedicated patients (nZ13) served as controls. For the present analysis, the sleep–wake cycles were arbitrarily designated as nighttime and daytime, respectively. A cumulative sleep–wake quantity in a 24-h period was also observed. Result: The average number of hours of sleep during a 24-h period was not significantly different for the two cohorts. Similar trends emerged for the nighttime and daytime observations. On the whole, methylphenidate appears not to have unfavorable effects on sleep–wake cycles, presently defined as nighttime, daytime and 24-h, in the traumatic brain injury population. Conclusion: This study sought to gain better understanding of the effect of methylphenidate on daytime sleepiness and nighttime sleep, and the data suggest that administration of methylphenidate does not appear to have an adverse effect on sleep–wake quantity. q 2005 Elsevier B.V. All rights reserved. Keywords: Brain injury; Sleep pattern; Methylphenidate; Daytime sleep; Nighttime sleep
1. Introduction Each year 1.5 million Americans sustain a brain injury, and 2% of the US population is living with disability secondary to traumatic brain injury (TBI) as a result of vehicular incidents, falls, acts of violence, or sports incidents [1,2]. Globally, TBI can be characterized as a silent epidemic, and it is becoming a major public health problem with considerable morbidity and mortality [3]. The World Health Organization has predicted that TBI will * Corresponding author. Tel./fax: C968 24545203. E-mail address: [email protected] (S. Al-Adawi).
1389-9457/$ - see front matter q 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2005.11.008
surpass traditional ‘enemies’ such as malnutrition and infectious disease as the major cause of death and disability by the year 2020 [4]. TBI affects people of all ages and is the leading cause of long-term disability among young adults [5]. Brain injury, which entails the tearing and shearing of the brain, is likely to compromise various neuronal systems that are critically involved in vegetative functions. Patients who have sustained significant head trauma may be at risk for various sleep disorders, including post-traumatic hypersomnia [6,7], post-traumatic narcolepsy [8,9] and post-traumatic insomnia [10]. These conditions and their variants result in difficulty falling asleep, disturbed sleep, nocturnal awakenings, early morning awakenings, sleeping too much or too little, non-refreshing sleep, daytime fatigue and excessive daytime sleepiness. Individuals with a
288
S. Al-Adawi et al. / Sleep Medicine 7 (2006) 287–291
disrupted sleep–wake cycle, as in the case of excessive daytime sleepiness, may be at risk for poor occupational competency and may be compromised in activities of daily living. This, in turn, has adverse repercussions for the burden of living with disability and the quality of life that may entail [7,11]. A number of neurostimulants such as methylphenidate, adderal, modafinil, Dexedrine, amantadine and bromocriptine are used as part of the post-acute care of the hospitalized brain-injured patient. Among these, methylphenidate is one of the most commonly used. Gualtieri and Evans [12] performed a randomized, controlled trial involving 15 patients with severe TBI and found that patients improved in memory, attention and verbal fluency. Peach [13] performed a randomized control trial involving 12 patients with TBI and found a trend towards improved processing speed. Whyte et al. [14] undertook a blinded crossover study that suggested that the use of this medication was effective for improving the processing speed of patients with brain injury, as well as for improving arousal. Plenger et al. [15] studied 23 patients with complicated mild to severe TBI and documented improved attention and functional outcome at one month with no difference in performance at 90 days. Goldstein [16] suggested an improved long-term functional outcome in animals given methylphenidate soon after a cardiovascular accident. As the net benefits of the use of methylphenidate among patients with brain injury has been related to kick-starting functional improvement and ameliorating cognitive, emotional and sensorimotor deficits [17,18], the effect of these medicines on the already altered sleep–wake cycle has yet to be determined. Studies are therefore needed to gain better understanding of the effect of methylphenidate on sleep–wake cycles with the view that 66–92% of patients who have incurred brain injury have a disturbance in their sleep–wake cycles [19] and disrupted sleep–wake cycles are likely to impede rehabilitative processes [7], which has implications for the treatment provider. Awareness of the correlates of sleep–wake pattern is likely to enhance identification, evaluation, and treatment of brain-injured patients. We therefore examined whether administration of methylphenidate adversely affected the sleep–wake cycle in a TBI population at periods that were operationalized as nighttime, daytime and 24-h periods.
2. Methods 2.1. Participants As part of a wider study, patients admitted to a dedicated brain injury unit were observed every hour to see whether they were asleep or awake. For this study, records of patients admitted between January and December 1999 were scrutinized. The inclusion criteria were as follows: (i) single incidence of TBI which is operationalized here as an injury to brain tissues caused by an external mechanical
force as evidenced by a loss of consciousness, posttraumatic cognitive and behavioral changes or an objective neurological finding that can reasonably be attributed to the TBI on a physical or cognitive and behavioral status examination [20], (ii) patients should be observed for a full 24 h a day for at least 10 days, not necessarily consecutively, and (iii) patients should not be on any other medications besides methylphenidate. Following this protracted exercise, 30 patients out of the 43 patients in the wider study were identified. These 30 patients yielded 892 records. The study was approved by institutional review board (IRB) guidelines for the wider study.
2.2. Study design The records for patients selected indicated that staff evaluated sleeping or waking states on an hourly basis for 24 h a day. Patients were characterized as awake and agitated, awake and calm, asleep and restful, or asleep and restless at these hourly checks. A sleep state in our study was defined as (i) closed eyes, (ii) reversibly unconscious state, (iii) characteristic sleeping posture, and (iv) reduced response to external stimulation [21]. The patients’ records showed that information on sleep was recorded throughout the day. As detailed elsewhere [19], staff, including nurses, physical therapists, occupational therapists, and speech language pathologists, collected data once per hour concerning the wakefulness of their patients. Data were collected at the therapy gym or the patient’s hospital room. At each hour, staff recorded whether the patient appeared to be awake or asleep. Patients with eyes closed and regular breathing were considered to be sleeping. Staff designated one of five sleep–wake categories for each patient: peaceful sleep (PS), restless sleep (RS), awake-calm (AC), awakeagitated (AA) and awake-drowsy (AD). For data analysis, all responses of PS and RS were considered sleep and other responses (AC, AA, AD) were considered awake. The time from 8 am to 5 pm was arbitrarily determined as the period appropriate for patients to be awake, and 9 pm to 6 am was designated as the period of time appropriate for patients to be asleep. The data outside of these time periods were used only in the 24-h analysis. The number of hours that the patients were observed to be asleep during the daytime, the number of hours that patients were observed to be asleep during the designated sleep hours, as well as the number of hours that they were observed to be asleep in 24-h periods were calculated for each patient. In addition to the above-mentioned observations, demographic and functional data including the Functional Independence Measure (FIM) scores were obtained from the records for each of the selected patients and scored as described elsewhere [19]. The Rancho Los Amigo Levels of Cognitive Functioning [22] was employed to determine various levels of recovery within cognitive domain. These parameters are reported in Table 1.
S. Al-Adawi et al. / Sleep Medicine 7 (2006) 287–291
289
Table 1 Summary of the FIM scores and cognitive functioning
FIM activity of daily living FIM mobility FIM cognition Total FIM Rancho scale
Drug No drug Drug No Drug Drug No drug Drug No drug Drug No drug
N
MeanGSD
Minimum
Median
Maximum
P-value
17 13 17 13 17 13 17 13 17 13
11.9G5.9 17.0G11.0 6.3G2.2 7.3G3.3 12.2G5.9 10.5G4.5 30.0G11.4 34.9G17.5 5.8G1.9 5.2G2.6
5 8 4 5 5 5 18 18 2 2
8 13 5 6 10 12 27 33 6 5
27 42 12 14 24 17 63 69 8 8
0.118 0.287 0.411 0.400 0.479
FIM, functional independent measures; Rancho Los Scale, Rancho Los Amigo Hospital: scale of cognitive functioning.
Methylphenidate was administered to some of the patients at 8 am and 2 pm. The pharmacology of methylphenidate and recommended dosage, which ranged between 5 and 10 mg for brain-injured patients has been described elsewhere [23,24]. The decision to introduce methylphenidate was made on clinical grounds. In rehabilitation literature, the pharmacology of methylphenidate is viewed as a ‘wakeness-promoting’ drug that increases the state of vigilance as preclinical studies have been shown to heighten the organism’s tendency toward learning and retaining information [25]. The routine clinical usage of methylphenidate is that neurostimulants may improve rehabilitation and recovery in the patients with brain injury, albeit indirectly, by enhancing retention of skills being taught during rehabilitation [25,26]. The other rationale for the wide usage of methylphenidate is its wellknown efficacy of ameliorating compromised emotional and cognitive functioning among brain-injured patients [27]. As the decision to introduce methylphenidate was made on the above-mentioned clinical grounds by the attending physician, this study constitutes a naturalistic observation on descriptions of patient states. 2.3. The statistical analysis The statistical packages SPSS and StatXact were used for the analysis. Summary statistics were computed. Both parametric and non-parametric analyses of variance were used to compare the sleep patterns. The parametric methods were used as a check since the validity of some of the
underlying assumptions for the parametric tests were questionable [28].
3. Results There were 23 males and 7 females in the group of selected patients. The ages of the patients ranged from 18 to 88 years, with the mean age at 51 years. There were 17 patients that were administered methylphenidate, and 13 were not administered the drug. Functionally, the patients on methylphenidate averaged a total FIM score of 30.0. The total FIM score for patients not on methylphenidate was slightly higher at 34.9 (Table 1). There were no significant differences in activity of daily living, mobility and cognition scores on admission between the two groups. The smallest P-value was 0.118. The average number of hours of sleep during a 24-h period for the entire cohort was 8.6 h. The average hours of sleep in 24 h was not significantly different (P-valueZ 0.096) for the patients on methylphenidate (8.3 h) and the patients not on the drug (9.0 h), even though those not on the drug slept a little longer (Table 2). The patients on methylphenidate averaged 6.4 h of nighttime sleep with a 95% confidence interval of (5.8, 7.0) h, while they slept for only 0.8 h during the day. The patients not on methylphenidate slept a little longer at night (6.9 h); however, this was not significantly different from those who were on the drug. This suggests that
Table 2 Summary of the number of hours of sleep per day in those on methylphenidate and those who were not
Hours of sleep in 24 h Hours of sleep in day time Hours of sleep at night time
Drug
N
MeanGSD
LB
UB
Minimum
Maximum
P-value
Drug No drug Drug No drug Drug No drug
17 13 17 13 17 13
8.3G1.2 9.0G1.2 0.8G0.7 1.0G0.7 6.4G1.1 6.9G0.9
7.7 7 0.5 0.5 5.8 6.3
11 12 1.1 1.4 7.0 7.4
6 7 0 0 4 5
11 12 2 3 8 8
0.096
LB, lower bound of 95% confidence interval; UB, upper bound of 95% confidence interval.
0.526 0.214
290
S. Al-Adawi et al. / Sleep Medicine 7 (2006) 287–291
methylphenidate was not significantly involved in dysregulation of the sleep–wake cycle.
4. Discussion This study demonstrates that methylphenidate does not appear to have a detrimental effect on sleep–wake cycle when such medication is used in commonly accepted dosages, which ranged between 5 and 10 mg as described elsewhere [24]. According to our measurements, the study found no evidence that the use of methylphenidate detrimentally affected sleep–wake quantity or distribution. In the operationalized nighttime period (defined as from 9 pm to 6 am), no significant changes in nighttime sleep were noted in the patient group taking methylphenidate compared to the control group. Cumulative sleep time and the amount of time that patients slept during the day or night did not differ between groups. The lack of statistical significance between treatment and control groups strongly argues for a lack of drug effect on sleep quantity and sleep distribution throughout the day and night in patients with brain injury. It is worthwhile to note that methylphenidate was administered at 8 am and 2 pm, so that the last of the doses would not interfere with night sleep. Methylphenidate is readily absorbed and has a half-life ranging from 2 to 4 h, a time to peak rate of 1.9 h (0.3–4.4 h), and duration of action of 3–6 h [24]. Because of the half-life of methylphenidate, no direct influence of the medication on the sleep– wake cycle was expected. This is one of few studies that employs staff to observe and document sleep–wake patterns of hospitalized brain injury patients [19]. This study, being preliminary, may appear to lack the sophistication and reliability of using quantification such as actigraphy. In addition, it could be criticized that none of the well-validated subjective questionnaires were utilized to document sleep–wake cycles. Notwithstanding, it appears that asking staff to document sleep–wake behavior is adequate to examine the effect of neurostimulants in the TBI population. In contrast to subjective questionnaires, staff observation of sleep–wake patterns can circumvent of the patient’s inability to personally describe their sleep–wake states because of sensory and motor deficit due to TBI. There is evidence to suggest that a significant number of the TBI population is marked with inability to perceive their subjective state. This renders them unable to complete self-reporting questionnaires [29]. Although a comparison between subjective opinions of the patient with the subjective assessment of the staff would have been helpful, a confounding factor here is the uncertainty of how one would be able to inquire about the state of arousal without concurrently meddling with the arousal itself. Theoretically, such teleological discourse is further hampered by what is known as Heisenberg’s Uncertainty Principle. According to this principle, observed events
may be influenced by the act of observation, thus implying that measurement itself may change the events [30]. This further implies, metaphorically, that scientific studies of protean concepts without central features, such as sleep–wake behavior, in the words of William Butler Yeats may not separate the dance from the dancer [31]. In addition, recall bias as well as memory and cognitive impairment secondary to brain injury made retrospective questioning of the patient an option that is less than ideal. Though the importance of subjective measurement should not be underestimated, observationally defined sleep is essential as much clinical decision-making is based on clinical observation. Studies have shown that even sleep architecture quantified with electroencephalography is fraught with uncertainty about its efficacy [32], while subjective measures are marred with the question of reliability [33,34]. Observationally defined sleep, although done on an hourly basis, in addition to overriding unreliable retrospective recall, is conceptually related to ecological momentary assessment that is increasingly being recognized as a promising alternative to paperand-pencil self-monitoring. Nevertheless, a natural extension of this study would be an actigraphic study to provide more objective measures of wakefulness and sleep. This study has several potential limitations. First, it is limited by a small data set. Future studies with an increased number of subjects would improve statistical power. Second, descriptions of patient states by nurses were limited by the fact that observation was not continuous but instead on an hourly basis. Although this brings the implication of recorded data into question, bias was equally distributed between all the subjects. Finally, there was no randomization in assigning patients to methylphenidate; the assignment was based on the judgment of the attending physician. Despite the above-mentioned caveats, the slightly less sophisticated descriptors used in this study seemed clinically adequate to address the pharmacologic effects of methylphenidate in our population. On the whole, the present study suggests that methylphenidate appears not to have unfavorable effects on sleep–wake cycles, presently defined as nighttime, daytime and 24-h, in the TBI population. Future studies with a larger number of subjects and better design are warranted in order to continue to explore the consequences of these and other pharmacologic interventions in brain-injured populations.
Acknowledgements We would like to thank anonymous reviewers for their constructive comments and suggestions. We also thank the staff and patients involved for their time and help in cooperating so fully with this study.
S. Al-Adawi et al. / Sleep Medicine 7 (2006) 287–291
References [1] Thurman DJ, Alverson C, Dunn KA, et al. Traumatic brain injury in the United States: a public health perspective. J Head Trauma Rehabil 1999;14:602–15. [2] Schootman M, Fuortes LJ. Ambulatory care for traumatic brain injuries in the US, 1995–1997. Brain Inj 2000;14:373–81. [3] Zitnay GA. Lessons from national and international TBI societies and funds like NBIRTT. Acta Neurochir Suppl 2005;93:131–3. [4] Holm L, Cassidy JD, Carroll LJ, Borg J. Neurotrauma task force on mild traumatic brain injury of the who collaborating centre. Summary of the WHO collaborating centre for neurotrauma task force on mild traumatic brain injury. J Rehabil Med 2005;37:137–41. [5] Guluma K, Zink B. Traumatic brain injury. Semin Respir Crit Care Med 2002;23:37–45. [6] Dauvilliers Y, Baumann CB, Carlander B, et al. CSF hypocretin-1 levels in narcolepsy, Kleine-Levin syndrome, and other hypersomnias and neurological conditions. J Neurol Neurosurg Psychiatry 2003;74: 1667–73. [7] Castriotta RJ, Lai JM. Sleep disorders associated with traumatic brain injury. Arch Phys Med Rehabil 2001;82:1403–6. [8] Bruck D, Broughton RJ. Diagnostic ambiguities in a case of posttraumatic narcolepsy with cataplexy. Brain Inj 2004;18:321–6. [9] Francisco GE, Ivanhoe CB. Successful treatment of post-traumatic narcolepsy with methylphenidate—a case report. Am J Phys Med Rehabil 1996;75:63–5. [10] Webb M, Kirker JG. Severe post-traumatic insomnia treated with l-5hydroxytryptophan. Lancet 1981;1365–6. [11] Guilleminault C, Yuen KM, Gulevich MG, et al. Hypersomnia after head-neck trauma: a medicolegal dilemma. Neurology 2000;54: 653–9. [12] Gualtieri CT, Evans RW. Stimulant treatment for the neurobehavioral sequelae of traumatic brain injury. Brain Inj 1988;2:273–90. [13] Peach RK. Factors underlying neuropsychological test performance in chronic severe traumatic brain injury. J Speech Hear Res 1992;35: 810–8. [14] Whyte J, Hart T, Schuster K, et al. Effects of methylphenidate on attentional function after traumatic brain injury. A randomized, placebo-controlled trial. Am J Phys Med Rehabil 1997;76:440–50. [15] Plenger PM, Dixon CE, Castillo RM, et al. Subacute methylphenidate treatment for moderate to moderately severe traumatic brain injury: a preliminary double-blind placebo-controlled study. Arch Phys Med Rehabil 1996;77:536–40. [16] Goldstein LB. Amphetamines and related drugs in motor recovery after stroke. Phys Med Rehabil Clin N Am 2003;14:S125–S34. [17] Ilic TV, Korchounov A, Ziemann U. Methylphenidate facilitates and disinhibits the motor cortex in intact humans. Neuroreport 2003;14:773–6.
291
[18] Deb S, Crownshaw T. The role of pharmacotherapy in the management of behaviour disorders in traumatic brain injury patients. Brain Inj 2004;18:1–31. [19] Burke DT, Shah MK, Schneider JC, et al. Sleep–wake patterns in brain injury patients in an acute inpatient rehabilitation hospital setting. J Appl Res 2004;4:239–44. [20] Sommer JL, Witkiewicz PM. The therapeutic challenges of dual diagnosis: TBI/SCI. Brain Inj 2004;18:1297–308. [21] Chokroverty S. An overview of sleep. In: Chokroverty S, editor. Sleep disorder medicine: basic science, technical considerations, and clinical aspects, Boston, MA; 1999. p. 7–16. [22] Shah MK, Al-Adawi S, Dorvlo ASS, Burke DT. Functional outcomes following anoxic brain injury: a comparison with traumatic brain injury. Brain Inj 2004;18:111–7. [23] Alban JP, Hopson MM, Ly V, Whyte J. Effect of methylphenidate on vital signs and adverse effects in adults with traumatic brain injury. Am J Phys Med Rehabil 2004;83:131–7. [24] Burke DT, Glenn MB, Vesali F, et al. Effects of methylphenidate on heart rate and blood pressure among inpatients with acquired brain injury. Am J Phys Med Rehabil 2003;82:493–7. [25] Al-Adawi S, Calvanio R, Dorvlo ASS, et al. The effect of methylphenidate on attention in acquired brain injury as recorded by useful field of view. J Appl Res 2005;5:61–72. [26] Powell J, Al-Adawi S, Morgan J, Greenwood RJ. Motivational deficits after brain injury: effects of bromocriptine in 11 patients. J Neurol Neurosurg Psychiatry 1996;60:416–21. [27] Napolitano E, Elovic EP, Qureshi AI. Pharmacological stimulant treatment of neurocognitive and functional deficits after traumatic and non-traumatic brain injury. Med Sci Monit 2005;11:RA212–RA220. [28] Sprent P, Smeeton NC. Applied nonparametric statistical methods. 3rd ed. London: Chapman & Hall; 2001. [29] Masel BE, Scheibel RS, Kimbark T, Kuna ST. Excessive daytime sleepiness in adults with brain injuries. Arch Phys Med Rehabil 2001; 82:1526–32. [30] Ozawa M. Uncertainty relations for noise and disturbance in generalized quantum measurements. Ann Phys 2004;311:350–416. [31] Rosenthal ML, editor. Selected poems and four plays of William Butler yeats. Scribner. 4th ed. New York: Scribner; 1996. [32] Durka PJ, Klekowicz H, Blinowska KJ, et al. A simple system for detection of EEG artifacts in polysomnographic recordings. IEEE Trans Biomed Eng 2003;50:526–8. [33] Means MK, Edinger JD, Glenn M, Fins AI. Accuracy of sleep perceptions among insomnia sufferers and normal sleepers. Sleep Med 2002;4:285–96. [34] Tworoger SS, Davis S, Vitiello MV, et al. Factors associated with objective (actigraphic) and subjective sleep quality in young adult women. J Psychosom Res 2005;59:11–19.
Brief Communication
The effect of methylphenidate on the sleep-wake cycle of brain-injured patients undergoing rehabilitation Samir Al-Adawi a,*, David T. Burke b, Atsu S.S. Dorvlo c a Department of Behavioral Medicine, College of Medicine and Health Sciences, Sultan Qaboos University, P.O. Box 35, Al-Khoudh 123, Muscat, Sultanate of Oman b Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, USA c Department of Mathematics and Statistics, College of Science, Sultan Qaboos University, Muscat, Oman
Received 27 September 2004; received in revised form 4 November 2005; accepted 5 November 2005
Abstract Background and purpose: A number of neurostimulants are routinely used as part of post-acute care of hospitalized brain-injured patients. To our knowledge, the effect of these stimulants on the sleep–wake cycles of brain-injured patients undergoing rehabilitation has not been addressed. We examined the effect of one of the most commonly used neurostimulants, methylphenidate, on the sleep–wake behavior of brain-injured patients undergoing rehabilitation at a dedicated brain injury clinic. Patients and method: For this study, records of patients admitted between January and December 1999 were scrutinized retrospectively for the data on observationally defined sleep–wake distribution. A total of 30 patients diagnosed with traumatic brain injury were identified as having been observed for a full 24 h a day for at least 10 days. Some of these patients (nZ17) were administered methylphenidate on clinical grounds. They served as the experimental group, while the unmedicated patients (nZ13) served as controls. For the present analysis, the sleep–wake cycles were arbitrarily designated as nighttime and daytime, respectively. A cumulative sleep–wake quantity in a 24-h period was also observed. Result: The average number of hours of sleep during a 24-h period was not significantly different for the two cohorts. Similar trends emerged for the nighttime and daytime observations. On the whole, methylphenidate appears not to have unfavorable effects on sleep–wake cycles, presently defined as nighttime, daytime and 24-h, in the traumatic brain injury population. Conclusion: This study sought to gain better understanding of the effect of methylphenidate on daytime sleepiness and nighttime sleep, and the data suggest that administration of methylphenidate does not appear to have an adverse effect on sleep–wake quantity. q 2005 Elsevier B.V. All rights reserved. Keywords: Brain injury; Sleep pattern; Methylphenidate; Daytime sleep; Nighttime sleep
1. Introduction Each year 1.5 million Americans sustain a brain injury, and 2% of the US population is living with disability secondary to traumatic brain injury (TBI) as a result of vehicular incidents, falls, acts of violence, or sports incidents [1,2]. Globally, TBI can be characterized as a silent epidemic, and it is becoming a major public health problem with considerable morbidity and mortality [3]. The World Health Organization has predicted that TBI will * Corresponding author. Tel./fax: C968 24545203. E-mail address: [email protected] (S. Al-Adawi).
1389-9457/$ - see front matter q 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2005.11.008
surpass traditional ‘enemies’ such as malnutrition and infectious disease as the major cause of death and disability by the year 2020 [4]. TBI affects people of all ages and is the leading cause of long-term disability among young adults [5]. Brain injury, which entails the tearing and shearing of the brain, is likely to compromise various neuronal systems that are critically involved in vegetative functions. Patients who have sustained significant head trauma may be at risk for various sleep disorders, including post-traumatic hypersomnia [6,7], post-traumatic narcolepsy [8,9] and post-traumatic insomnia [10]. These conditions and their variants result in difficulty falling asleep, disturbed sleep, nocturnal awakenings, early morning awakenings, sleeping too much or too little, non-refreshing sleep, daytime fatigue and excessive daytime sleepiness. Individuals with a
288
S. Al-Adawi et al. / Sleep Medicine 7 (2006) 287–291
disrupted sleep–wake cycle, as in the case of excessive daytime sleepiness, may be at risk for poor occupational competency and may be compromised in activities of daily living. This, in turn, has adverse repercussions for the burden of living with disability and the quality of life that may entail [7,11]. A number of neurostimulants such as methylphenidate, adderal, modafinil, Dexedrine, amantadine and bromocriptine are used as part of the post-acute care of the hospitalized brain-injured patient. Among these, methylphenidate is one of the most commonly used. Gualtieri and Evans [12] performed a randomized, controlled trial involving 15 patients with severe TBI and found that patients improved in memory, attention and verbal fluency. Peach [13] performed a randomized control trial involving 12 patients with TBI and found a trend towards improved processing speed. Whyte et al. [14] undertook a blinded crossover study that suggested that the use of this medication was effective for improving the processing speed of patients with brain injury, as well as for improving arousal. Plenger et al. [15] studied 23 patients with complicated mild to severe TBI and documented improved attention and functional outcome at one month with no difference in performance at 90 days. Goldstein [16] suggested an improved long-term functional outcome in animals given methylphenidate soon after a cardiovascular accident. As the net benefits of the use of methylphenidate among patients with brain injury has been related to kick-starting functional improvement and ameliorating cognitive, emotional and sensorimotor deficits [17,18], the effect of these medicines on the already altered sleep–wake cycle has yet to be determined. Studies are therefore needed to gain better understanding of the effect of methylphenidate on sleep–wake cycles with the view that 66–92% of patients who have incurred brain injury have a disturbance in their sleep–wake cycles [19] and disrupted sleep–wake cycles are likely to impede rehabilitative processes [7], which has implications for the treatment provider. Awareness of the correlates of sleep–wake pattern is likely to enhance identification, evaluation, and treatment of brain-injured patients. We therefore examined whether administration of methylphenidate adversely affected the sleep–wake cycle in a TBI population at periods that were operationalized as nighttime, daytime and 24-h periods.
2. Methods 2.1. Participants As part of a wider study, patients admitted to a dedicated brain injury unit were observed every hour to see whether they were asleep or awake. For this study, records of patients admitted between January and December 1999 were scrutinized. The inclusion criteria were as follows: (i) single incidence of TBI which is operationalized here as an injury to brain tissues caused by an external mechanical
force as evidenced by a loss of consciousness, posttraumatic cognitive and behavioral changes or an objective neurological finding that can reasonably be attributed to the TBI on a physical or cognitive and behavioral status examination [20], (ii) patients should be observed for a full 24 h a day for at least 10 days, not necessarily consecutively, and (iii) patients should not be on any other medications besides methylphenidate. Following this protracted exercise, 30 patients out of the 43 patients in the wider study were identified. These 30 patients yielded 892 records. The study was approved by institutional review board (IRB) guidelines for the wider study.
2.2. Study design The records for patients selected indicated that staff evaluated sleeping or waking states on an hourly basis for 24 h a day. Patients were characterized as awake and agitated, awake and calm, asleep and restful, or asleep and restless at these hourly checks. A sleep state in our study was defined as (i) closed eyes, (ii) reversibly unconscious state, (iii) characteristic sleeping posture, and (iv) reduced response to external stimulation [21]. The patients’ records showed that information on sleep was recorded throughout the day. As detailed elsewhere [19], staff, including nurses, physical therapists, occupational therapists, and speech language pathologists, collected data once per hour concerning the wakefulness of their patients. Data were collected at the therapy gym or the patient’s hospital room. At each hour, staff recorded whether the patient appeared to be awake or asleep. Patients with eyes closed and regular breathing were considered to be sleeping. Staff designated one of five sleep–wake categories for each patient: peaceful sleep (PS), restless sleep (RS), awake-calm (AC), awakeagitated (AA) and awake-drowsy (AD). For data analysis, all responses of PS and RS were considered sleep and other responses (AC, AA, AD) were considered awake. The time from 8 am to 5 pm was arbitrarily determined as the period appropriate for patients to be awake, and 9 pm to 6 am was designated as the period of time appropriate for patients to be asleep. The data outside of these time periods were used only in the 24-h analysis. The number of hours that the patients were observed to be asleep during the daytime, the number of hours that patients were observed to be asleep during the designated sleep hours, as well as the number of hours that they were observed to be asleep in 24-h periods were calculated for each patient. In addition to the above-mentioned observations, demographic and functional data including the Functional Independence Measure (FIM) scores were obtained from the records for each of the selected patients and scored as described elsewhere [19]. The Rancho Los Amigo Levels of Cognitive Functioning [22] was employed to determine various levels of recovery within cognitive domain. These parameters are reported in Table 1.
S. Al-Adawi et al. / Sleep Medicine 7 (2006) 287–291
289
Table 1 Summary of the FIM scores and cognitive functioning
FIM activity of daily living FIM mobility FIM cognition Total FIM Rancho scale
Drug No drug Drug No Drug Drug No drug Drug No drug Drug No drug
N
MeanGSD
Minimum
Median
Maximum
P-value
17 13 17 13 17 13 17 13 17 13
11.9G5.9 17.0G11.0 6.3G2.2 7.3G3.3 12.2G5.9 10.5G4.5 30.0G11.4 34.9G17.5 5.8G1.9 5.2G2.6
5 8 4 5 5 5 18 18 2 2
8 13 5 6 10 12 27 33 6 5
27 42 12 14 24 17 63 69 8 8
0.118 0.287 0.411 0.400 0.479
FIM, functional independent measures; Rancho Los Scale, Rancho Los Amigo Hospital: scale of cognitive functioning.
Methylphenidate was administered to some of the patients at 8 am and 2 pm. The pharmacology of methylphenidate and recommended dosage, which ranged between 5 and 10 mg for brain-injured patients has been described elsewhere [23,24]. The decision to introduce methylphenidate was made on clinical grounds. In rehabilitation literature, the pharmacology of methylphenidate is viewed as a ‘wakeness-promoting’ drug that increases the state of vigilance as preclinical studies have been shown to heighten the organism’s tendency toward learning and retaining information [25]. The routine clinical usage of methylphenidate is that neurostimulants may improve rehabilitation and recovery in the patients with brain injury, albeit indirectly, by enhancing retention of skills being taught during rehabilitation [25,26]. The other rationale for the wide usage of methylphenidate is its wellknown efficacy of ameliorating compromised emotional and cognitive functioning among brain-injured patients [27]. As the decision to introduce methylphenidate was made on the above-mentioned clinical grounds by the attending physician, this study constitutes a naturalistic observation on descriptions of patient states. 2.3. The statistical analysis The statistical packages SPSS and StatXact were used for the analysis. Summary statistics were computed. Both parametric and non-parametric analyses of variance were used to compare the sleep patterns. The parametric methods were used as a check since the validity of some of the
underlying assumptions for the parametric tests were questionable [28].
3. Results There were 23 males and 7 females in the group of selected patients. The ages of the patients ranged from 18 to 88 years, with the mean age at 51 years. There were 17 patients that were administered methylphenidate, and 13 were not administered the drug. Functionally, the patients on methylphenidate averaged a total FIM score of 30.0. The total FIM score for patients not on methylphenidate was slightly higher at 34.9 (Table 1). There were no significant differences in activity of daily living, mobility and cognition scores on admission between the two groups. The smallest P-value was 0.118. The average number of hours of sleep during a 24-h period for the entire cohort was 8.6 h. The average hours of sleep in 24 h was not significantly different (P-valueZ 0.096) for the patients on methylphenidate (8.3 h) and the patients not on the drug (9.0 h), even though those not on the drug slept a little longer (Table 2). The patients on methylphenidate averaged 6.4 h of nighttime sleep with a 95% confidence interval of (5.8, 7.0) h, while they slept for only 0.8 h during the day. The patients not on methylphenidate slept a little longer at night (6.9 h); however, this was not significantly different from those who were on the drug. This suggests that
Table 2 Summary of the number of hours of sleep per day in those on methylphenidate and those who were not
Hours of sleep in 24 h Hours of sleep in day time Hours of sleep at night time
Drug
N
MeanGSD
LB
UB
Minimum
Maximum
P-value
Drug No drug Drug No drug Drug No drug
17 13 17 13 17 13
8.3G1.2 9.0G1.2 0.8G0.7 1.0G0.7 6.4G1.1 6.9G0.9
7.7 7 0.5 0.5 5.8 6.3
11 12 1.1 1.4 7.0 7.4
6 7 0 0 4 5
11 12 2 3 8 8
0.096
LB, lower bound of 95% confidence interval; UB, upper bound of 95% confidence interval.
0.526 0.214
290
S. Al-Adawi et al. / Sleep Medicine 7 (2006) 287–291
methylphenidate was not significantly involved in dysregulation of the sleep–wake cycle.
4. Discussion This study demonstrates that methylphenidate does not appear to have a detrimental effect on sleep–wake cycle when such medication is used in commonly accepted dosages, which ranged between 5 and 10 mg as described elsewhere [24]. According to our measurements, the study found no evidence that the use of methylphenidate detrimentally affected sleep–wake quantity or distribution. In the operationalized nighttime period (defined as from 9 pm to 6 am), no significant changes in nighttime sleep were noted in the patient group taking methylphenidate compared to the control group. Cumulative sleep time and the amount of time that patients slept during the day or night did not differ between groups. The lack of statistical significance between treatment and control groups strongly argues for a lack of drug effect on sleep quantity and sleep distribution throughout the day and night in patients with brain injury. It is worthwhile to note that methylphenidate was administered at 8 am and 2 pm, so that the last of the doses would not interfere with night sleep. Methylphenidate is readily absorbed and has a half-life ranging from 2 to 4 h, a time to peak rate of 1.9 h (0.3–4.4 h), and duration of action of 3–6 h [24]. Because of the half-life of methylphenidate, no direct influence of the medication on the sleep– wake cycle was expected. This is one of few studies that employs staff to observe and document sleep–wake patterns of hospitalized brain injury patients [19]. This study, being preliminary, may appear to lack the sophistication and reliability of using quantification such as actigraphy. In addition, it could be criticized that none of the well-validated subjective questionnaires were utilized to document sleep–wake cycles. Notwithstanding, it appears that asking staff to document sleep–wake behavior is adequate to examine the effect of neurostimulants in the TBI population. In contrast to subjective questionnaires, staff observation of sleep–wake patterns can circumvent of the patient’s inability to personally describe their sleep–wake states because of sensory and motor deficit due to TBI. There is evidence to suggest that a significant number of the TBI population is marked with inability to perceive their subjective state. This renders them unable to complete self-reporting questionnaires [29]. Although a comparison between subjective opinions of the patient with the subjective assessment of the staff would have been helpful, a confounding factor here is the uncertainty of how one would be able to inquire about the state of arousal without concurrently meddling with the arousal itself. Theoretically, such teleological discourse is further hampered by what is known as Heisenberg’s Uncertainty Principle. According to this principle, observed events
may be influenced by the act of observation, thus implying that measurement itself may change the events [30]. This further implies, metaphorically, that scientific studies of protean concepts without central features, such as sleep–wake behavior, in the words of William Butler Yeats may not separate the dance from the dancer [31]. In addition, recall bias as well as memory and cognitive impairment secondary to brain injury made retrospective questioning of the patient an option that is less than ideal. Though the importance of subjective measurement should not be underestimated, observationally defined sleep is essential as much clinical decision-making is based on clinical observation. Studies have shown that even sleep architecture quantified with electroencephalography is fraught with uncertainty about its efficacy [32], while subjective measures are marred with the question of reliability [33,34]. Observationally defined sleep, although done on an hourly basis, in addition to overriding unreliable retrospective recall, is conceptually related to ecological momentary assessment that is increasingly being recognized as a promising alternative to paperand-pencil self-monitoring. Nevertheless, a natural extension of this study would be an actigraphic study to provide more objective measures of wakefulness and sleep. This study has several potential limitations. First, it is limited by a small data set. Future studies with an increased number of subjects would improve statistical power. Second, descriptions of patient states by nurses were limited by the fact that observation was not continuous but instead on an hourly basis. Although this brings the implication of recorded data into question, bias was equally distributed between all the subjects. Finally, there was no randomization in assigning patients to methylphenidate; the assignment was based on the judgment of the attending physician. Despite the above-mentioned caveats, the slightly less sophisticated descriptors used in this study seemed clinically adequate to address the pharmacologic effects of methylphenidate in our population. On the whole, the present study suggests that methylphenidate appears not to have unfavorable effects on sleep–wake cycles, presently defined as nighttime, daytime and 24-h, in the TBI population. Future studies with a larger number of subjects and better design are warranted in order to continue to explore the consequences of these and other pharmacologic interventions in brain-injured populations.
Acknowledgements We would like to thank anonymous reviewers for their constructive comments and suggestions. We also thank the staff and patients involved for their time and help in cooperating so fully with this study.
S. Al-Adawi et al. / Sleep Medicine 7 (2006) 287–291
References [1] Thurman DJ, Alverson C, Dunn KA, et al. Traumatic brain injury in the United States: a public health perspective. J Head Trauma Rehabil 1999;14:602–15. [2] Schootman M, Fuortes LJ. Ambulatory care for traumatic brain injuries in the US, 1995–1997. Brain Inj 2000;14:373–81. [3] Zitnay GA. Lessons from national and international TBI societies and funds like NBIRTT. Acta Neurochir Suppl 2005;93:131–3. [4] Holm L, Cassidy JD, Carroll LJ, Borg J. Neurotrauma task force on mild traumatic brain injury of the who collaborating centre. Summary of the WHO collaborating centre for neurotrauma task force on mild traumatic brain injury. J Rehabil Med 2005;37:137–41. [5] Guluma K, Zink B. Traumatic brain injury. Semin Respir Crit Care Med 2002;23:37–45. [6] Dauvilliers Y, Baumann CB, Carlander B, et al. CSF hypocretin-1 levels in narcolepsy, Kleine-Levin syndrome, and other hypersomnias and neurological conditions. J Neurol Neurosurg Psychiatry 2003;74: 1667–73. [7] Castriotta RJ, Lai JM. Sleep disorders associated with traumatic brain injury. Arch Phys Med Rehabil 2001;82:1403–6. [8] Bruck D, Broughton RJ. Diagnostic ambiguities in a case of posttraumatic narcolepsy with cataplexy. Brain Inj 2004;18:321–6. [9] Francisco GE, Ivanhoe CB. Successful treatment of post-traumatic narcolepsy with methylphenidate—a case report. Am J Phys Med Rehabil 1996;75:63–5. [10] Webb M, Kirker JG. Severe post-traumatic insomnia treated with l-5hydroxytryptophan. Lancet 1981;1365–6. [11] Guilleminault C, Yuen KM, Gulevich MG, et al. Hypersomnia after head-neck trauma: a medicolegal dilemma. Neurology 2000;54: 653–9. [12] Gualtieri CT, Evans RW. Stimulant treatment for the neurobehavioral sequelae of traumatic brain injury. Brain Inj 1988;2:273–90. [13] Peach RK. Factors underlying neuropsychological test performance in chronic severe traumatic brain injury. J Speech Hear Res 1992;35: 810–8. [14] Whyte J, Hart T, Schuster K, et al. Effects of methylphenidate on attentional function after traumatic brain injury. A randomized, placebo-controlled trial. Am J Phys Med Rehabil 1997;76:440–50. [15] Plenger PM, Dixon CE, Castillo RM, et al. Subacute methylphenidate treatment for moderate to moderately severe traumatic brain injury: a preliminary double-blind placebo-controlled study. Arch Phys Med Rehabil 1996;77:536–40. [16] Goldstein LB. Amphetamines and related drugs in motor recovery after stroke. Phys Med Rehabil Clin N Am 2003;14:S125–S34. [17] Ilic TV, Korchounov A, Ziemann U. Methylphenidate facilitates and disinhibits the motor cortex in intact humans. Neuroreport 2003;14:773–6.
291
[18] Deb S, Crownshaw T. The role of pharmacotherapy in the management of behaviour disorders in traumatic brain injury patients. Brain Inj 2004;18:1–31. [19] Burke DT, Shah MK, Schneider JC, et al. Sleep–wake patterns in brain injury patients in an acute inpatient rehabilitation hospital setting. J Appl Res 2004;4:239–44. [20] Sommer JL, Witkiewicz PM. The therapeutic challenges of dual diagnosis: TBI/SCI. Brain Inj 2004;18:1297–308. [21] Chokroverty S. An overview of sleep. In: Chokroverty S, editor. Sleep disorder medicine: basic science, technical considerations, and clinical aspects, Boston, MA; 1999. p. 7–16. [22] Shah MK, Al-Adawi S, Dorvlo ASS, Burke DT. Functional outcomes following anoxic brain injury: a comparison with traumatic brain injury. Brain Inj 2004;18:111–7. [23] Alban JP, Hopson MM, Ly V, Whyte J. Effect of methylphenidate on vital signs and adverse effects in adults with traumatic brain injury. Am J Phys Med Rehabil 2004;83:131–7. [24] Burke DT, Glenn MB, Vesali F, et al. Effects of methylphenidate on heart rate and blood pressure among inpatients with acquired brain injury. Am J Phys Med Rehabil 2003;82:493–7. [25] Al-Adawi S, Calvanio R, Dorvlo ASS, et al. The effect of methylphenidate on attention in acquired brain injury as recorded by useful field of view. J Appl Res 2005;5:61–72. [26] Powell J, Al-Adawi S, Morgan J, Greenwood RJ. Motivational deficits after brain injury: effects of bromocriptine in 11 patients. J Neurol Neurosurg Psychiatry 1996;60:416–21. [27] Napolitano E, Elovic EP, Qureshi AI. Pharmacological stimulant treatment of neurocognitive and functional deficits after traumatic and non-traumatic brain injury. Med Sci Monit 2005;11:RA212–RA220. [28] Sprent P, Smeeton NC. Applied nonparametric statistical methods. 3rd ed. London: Chapman & Hall; 2001. [29] Masel BE, Scheibel RS, Kimbark T, Kuna ST. Excessive daytime sleepiness in adults with brain injuries. Arch Phys Med Rehabil 2001; 82:1526–32. [30] Ozawa M. Uncertainty relations for noise and disturbance in generalized quantum measurements. Ann Phys 2004;311:350–416. [31] Rosenthal ML, editor. Selected poems and four plays of William Butler yeats. Scribner. 4th ed. New York: Scribner; 1996. [32] Durka PJ, Klekowicz H, Blinowska KJ, et al. A simple system for detection of EEG artifacts in polysomnographic recordings. IEEE Trans Biomed Eng 2003;50:526–8. [33] Means MK, Edinger JD, Glenn M, Fins AI. Accuracy of sleep perceptions among insomnia sufferers and normal sleepers. Sleep Med 2002;4:285–96. [34] Tworoger SS, Davis S, Vitiello MV, et al. Factors associated with objective (actigraphic) and subjective sleep quality in young adult women. J Psychosom Res 2005;59:11–19.