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Keywords:

  • rapid eye movement sleep;
  • sleep inertia;
  • thermal pain

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. Acknowledgements
  9. References

Patients with chronic pain often complain of pain when they wake at night, but the accuracy of their perception of the pain after waking at night is unknown. While cognitive functions are reduced for a short time after waking from sleep, a situation known as sleep inertia, it is unclear how sleep inertia may affect the perception of pain. We investigated the effects of sleep inertia on the perception of experimentally induced pain. Fourteen male volunteers were exposed to a randomized thermal heat stimulus of 43.1 °C ‘hot’ and 46.5 °C ‘hurting’ during provoked waking from Stage 2 sleep, slow wave sleep and rapid eye movement (REM) sleep. Subjects rated their pain on awakening on a Visual Analogue Scale at 30 s after awakening and each minute thereafter for 5 min. We found no change in pain perception over the 5-min period irrespective of temperature used or sleep stage. However, perceived pain when awoken abruptly from REM sleep was significantly lower than the awake score for both the hot (= 0.0069) and hurting (= 0.0025) temperatures. Pain perception when woken from Stage 2 sleep or slow wave sleep was not significantly different from perception when awake. Our findings indicate that sleep inertia reduces pain perception when awoken abruptly from REM. This suggests that patients who wake up in pain either perceive accurately the pain they are experiencing, or at worst underestimate the level of pain if woken from REM sleep.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. Acknowledgements
  9. References

Patients with chronic pain often suffer concomitantly from insomnia and list pain as the primary reason for their disrupted sleep and insomnia (Choiniere et al., 2007; Sutton et al., 2001). This sleep disruption may be related to a direct interference of noxious stimuli on sleep or a heightened pain perception on waking during the night, which then prevents easy return to sleep.

Previous research on the interference of noxious stimuli on sleep has shown effects during all sleep stages to a greater or lesser extent depending on the modality of noxious stimulus assessed and the different sleep stages that are used. For example, studies using thermal devices capable of supplying different temperatures from 37 °C to 46 °C have shown that more arousals were observed during Stage 2 than in slow wave sleep (SWS) and rapid eye movement (REM) sleep. This suggests that slow wave and REM sleep are relatively more resistant to noxious stimuli compared with Stage 2 sleep (Bentley et al., 2003; Foo and Mason, 2002; Lavigne et al., 2000, 2004).

It is not known, however, whether these differences in perception of noxious stimuli which are related to different sleep stages persist for a period of time after a subject is woken from sleep. If so, such changes could influence the pain perception felt on awakening by patients in pain. When awoken abruptly from sleep the brain undergoes a transitional state of lowered arousal called sleep inertia, which is known to produce a reduction in various cognitive abilities (Tassi and Muzet, 2000). Most of the work investigating the impact of sleep inertia has focused on performance variables showing a reduction in a broad range of tasks, including simple reaction time, complex reaction time, coordination, complex behaviour simulation tasks, logical reasoning and a number of cognitive tasks such as mental arithmetic (Bruck and Pisani, 1999; Hofer-Tinguely et al., 2005; Jewett et al., 1999).

It has been hypothesized that sleep inertia is a continuation of the altered cognitive state occurring during sleep extending through into the waking period. Electroencephalogram (EEG) recordings of the awakening process indicate that the first 10 min after awakening are characterized by changes in EEG power consistent with increased sleepiness, or of decreased vigilance, when compared with wakefulness before sleep onset (Bruck and Pisani, 1999; Ferrara et al., 2006; Jewett et al., 1999; Salzarulo et al., 2002; Tassi and Muzet, 2000).

This severity of the decreased vigilance caused by sleep inertia may be a function of the sleep stage immediately preceding the wakening. Abrupt awakening during SWS produces more sleep inertia on cognitive tasks than awakening from lighter stages, such as Stages 1 or 2 sleep, or REM sleep (Feltin and Broughton, 1968; Stones, 1977). However, while many studies have investigated the effects of sleep inertia on cognitive aspects the impact on other biological processes occurring in sleep such as pain sensitivity have been ignored. The aim of this study, therefore, was to investigate the impact of sleep inertia on the perception of thermal pain, and whether any sleep inertia which may be present was influenced by pain intensity or stage of sleep prior to awakening.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. Acknowledgements
  9. References

Subjects

Fourteen male volunteers between the ages of 19 and 25 years participated in this study. Only male subjects were considered for the study due to concerns with possible menstrual cycle-related changes in pain and sleep in women. Subjects were distributed equally between those of African and Indian descent. All subjects were considered healthy and pain-free based on the completion of a general health questionnaire before participating in the study. During the study, subjects followed their normal daytime schedules but were asked to refrain from alcohol for the duration of the study as well as tea and coffee on the days of the study. None of the subjects were taking any medication or any recreational drugs. Each subject also completed a Pittsburgh Sleep Quality Index questionnaire (Buysse et al., 1989) to eliminate sleep disorders. Each subject gave written consent and the study was approved by the Human Research Ethics Committee of the University of the Witwatersrand (protocol number: M070451).

Experimental protocol

Subjects came to the Wits Dial.a.Bed sleep laboratory on three non-consecutive nights, with at least one night sleeping at home between each visit. The first night was used for adaptation to sleeping under the conditions present in the sleep laboratory and to assess wake responses to the thermal stimuli. Nights 2 and 3 were experimental nights.

Thermal stimuli

The noxious thermal stimuli were produced by a thermode (World Precision Instruments Inc., Sarasota, FL, USA) comprised of a round metal thermal plate (diameter = 4 cm) attached to a thermode control panel. We attached a second plastic insulating disk around the thermodes to allow for stability when attached to the skin. The controller has an operating range of −20 °C to 60 °C, a resolution of 0.1 °C and an accuracy of 0.1 ± 0.1 °C. A wire thermal couple connected to a Bailey thermometer (Sensortek, Clifton, NJ, USA) was attached to the thermal plate to measure the temperature accurately at the centre of the thermal plate. The Bailey was calibrated against a quartz thermometer (Quat 100; Heraeus, Hanau, Germany) in an insulated water bath, to an accuracy of 0.01 °C. All temperature readings were taken from the Bailey thermometer as the validated temperature of the thermal plate.

Night 1: adaptation night

After subjects arrived at the sleep laboratory the thermode was attached to the lateral aspect of the subject’s thigh with a light bandage while the subject was positioned in a supine position on a bed. The temperature of the thermode was increased from 32 °C at a constant rate of 0.1 °C s−1. Subjects were asked to state when the thermal sensation corresponded to one of six words: ‘warm’, ‘hot’, ‘pricking’, ‘hurting’, ‘burning’ and ‘pain tolerance’, established previously as valid for this range of thermal stimuli (Bentley et al., 2003). The corresponding temperature for each word was recorded and plotted to create an evening thermal–pain perception curve. The thermode was turned off when pain tolerance was reached and removed from the leg if the pain persisted for longer than 10 s, and re-attached once the thermode had cooled sufficiently. Subjects were blinded to all the temperatures on both thermode control panel and the Bailey thermometer during all tests while awake.

Standard sleep recording electrodes were attached to measure EEG (using standard C3, C4, O1 and O2 positions), electro-oculogram and electromyogram activity. Subjects then slept undisturbed for the remainder of the night with all the equipment attached.

The following morning all equipment was removed and the subject prepared for the day’s activities. Just prior to leaving the sleep laboratory, the thermode was reattached to the same thigh, and a morning thermal–pain perception curve was created following the same procedure as the previous night. These two curves were used to determine the temperature which corresponded to each subject’s individual ‘hot’ and ‘hurting’ sensations. These were the temperatures used as the stimulus temperatures on nights 2 and 3. Selection of these two sensations and their corresponding temperatures was based on the statistical difference in pain perception between the two words, as reported in a previous study (Bentley et al., 2003).

Nights 2 and 3: experimental

Wake–thermal test

Sleep recording electrodes and the thermode were attached as on the adaptation night. Once the subject was lying in bed and ready to sleep, the thermode was turned on and allowed to reach the temperature corresponding to either the individual subject’s previously established ‘hot’ or ‘hurting’ sensations. Once the appropriate temperature was reached the thermode was turned off and the subjects were asked to record the pain intensity on a continuous 100-mm Visual Analogue Scale (VAS) anchored at ‘no pain’ to ‘the worst pain he had ever felt’. The chosen temperature was maintained for up to 20 s after the thermode was switched off. They were also asked to state to which of the six words the temperature correlated. Once the thermode had cooled to 32 °C, the procedure was repeated for the second temperature. The two temperatures were randomized for order on each experimental night.

The subjects then went to sleep. All subjects went to sleep between 22:00 and 23:00 hours and slept for approximately 9 h. Sleep stages were monitored on a computerized EEG (Cadwell Easy EEG-II; Cadwell Laboratories, Kennewick, Washington, WA, USA). Sleep stage identification was performed according to Rechtschaffen and Kales (1968) criteria.

Sleep–thermal test

Once the subject had spent 2–3 min in either of Stage 2, REM or SWS, the thermode was switched on. During the rise in temperature the sleep stage was monitored to ensure that the sleep was stable and that the subject remained in the selected sleep stage. If any sleep stage shift occurred during this phase the thermode was switched off until a stable sleep phase had been obtained. Once the selected temperature, corresponding either to the ‘hot’ or ‘hurting’ temperature was reached, the thermode was switched off and the subject was woken immediately and deliberately. The subject was asked to notice the pain intensity on waking, and was then asked to record this intensity 30 s later using both the VAS and the six-word scale. The subject was then asked to recall the pain intensity on waking every minute for the next 5 min, providing a total of six measurements for each awakening. After 5 min the subject was allowed to return to sleep. The period of wakefulness was limited to allow rapid return to sleep and as little interference with overnight sleep architecture and sleep length as possible. None of the subjects had difficulty falling back to sleep and all subjects showed Stage 2 sleep within 15 min of being allowed to return to sleep. Selection of the first temperature used was randomized for each night and each subsequent intervention throughout the night alternated between the two temperatures. The process was repeated a maximum of nine times on each night using both temperatures and all three sleep stages. Due to the deliberate disruption of sleep the polysomnograms were not analysed for sleep architecture nor were subjects asked about sleep quality, or whether or not they remembered the awakenings. The following morning, approximately 1 h after awakening, the wake–thermal test was repeated for both the ‘hot’ and ‘hurting’ temperatures.

Data analysis

The temperatures selected for the ‘hot’ and ‘hurting’ sensations were determined using the means of the night-time and morning temperatures for each subject. All VAS results were arcsine-transformed to perform parametric analyses of the data and were back-transformed for graphic representation. All data were analysed using GraphPad Prism 4 statistical package (GraphPad Sofware, San Diego, CA, USA) and Statistica (Statsoft, Tulsa, OK, USA). A paired t-test was used to compare the evening and morning temperatures for both thermal intensities to identify any circadian effect which might have been present. A one-way anova with a Tukey post hoc test for multiple comparisons was used to test for differences in temperature selected for each of the six words.

A repeated-measures anova with a Tukey post hoc test was used to test for changes in pain perception as recorded on the VAS scales during the 5 min after awakening from each stage of sleep. The mean VAS score for each subject over the 5 min and for each sleep stage was calculated and compared with the VAS obtained from the mean wake–thermal test. A one-way anova with a Tukey post hoc test was used to test for differences between the mean VAS from the wake–thermal test and the mean VAS for each of the three sleep stages. A two-tailed probability of P < 0.05 was considered statistically significant.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. Acknowledgements
  9. References

Pain perception during wake

There were no circadian differences in thermal pain perception, as indicated by no significant differences (paired t-test; = 0.1750) between the median temperatures and ranges, for each of the pain words between the evening and the following morning of the adaptation night for all 14 subjects (Fig. 1). All subjects were able to distinguish each of the six sensations. The ‘warm’ sensation was perceived at a median temperature of 37.9 °C and pain tolerance occurred at a median temperature of 48.1 °C. The mean (±SD) pain intensity, as measured by the VAS scale, for the ‘hot’ temperature was 23 (±6) mm and the same measurement for the ‘hurting’ temperature was 58 (±3) mm. There was no significant difference in pain perception as measured by the VAS scales between the evening and morning wake–thermal test for either the ‘hot’ (= 0.4449) or ‘hurting’ (= 0.5172) temperatures.

image

Figure 1.  The temperatures corresponding to the six words associated with the thermal–pain perception curves. Data represented as median temperatures with upper and lower extent of ranges for each word descriptor in the morning (bsl00001 with upper limit of range = 14) and evening (♦ with lower limit of range n = 14). *Significant difference (F6,7 = 337.6, < 0.0001) between the ‘hot’ and ‘hurting’ temperature stimuli.

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Perceived pain over 5 min after arousal from sleep

None of the subjects awoke as a direct result of either thermal stimulus during either of the two nights of experimentation. There was no significant difference in pain perception across the 5 min for either temperature or stage of sleep from which subjects were woken. Subjects felt the lowest pain when awoken from REM sleep for both the ‘hot’ and ‘hurting’ temperatures.

Changes in pain perception when woken from sleep compared to wake

As no significant change was noted for the VAS scores over 5 min, a single mean VAS score for each subject and for each sleep stage was calculated and used for comparison against the VAS score obtained from the wake–thermal test for each subject (Fig. 2a and b).

image

Figure 2.  Mean pain intensity measured by visual analogue scale (VAS) after arousal from three different sleep stages and during wakefulness for the ‘hot’ (a) and the ‘hurting (b) temperature stimulus. Data presented as means with standard deviations for each sleep stage. In (a) [Stage 2; n = 14, slow wave sleep (SWS) = 10, rapid eye movement (REM) n = 11] and (b) (Stage 2; = 12, SWS n = 11, REM n = 10), n = number of subjects for whom data were obtained for each sleep stage. (a) *Significant difference between wake and REM (P = 0.001); #significant difference between SWS and REM (P = 0.02). (b) *Significant difference between wake and REM (P = 0.0024); #significant difference between Stage 2 and REM (P = 0.0094).

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The perceived pain for the ‘hot’ stimulus was significantly lower (F3,45 = 6.0, P = 0.0015) after being awoken from REM sleep compared with awake and after arousal from SWS. There was no significant difference between the perceived pain when aroused from Stage 2 sleep (= 0.19) or SWS (= 0.91) compared with awake. There was also no difference in perceived pain after arousals between Stage 2 and SWS (= 0.64) or between Stage 2 and REM sleep (= 0.16).

Pain perception for the ‘hurting’ stimulus was significantly lower (F3,43 = 6.0 P = 0.0016) after being awoken from REM sleep compared with the perception when awake and after arousal from Stage 2 sleep. There was no significant difference between the perceived pain when aroused from Stage 2 sleep (= 0.98) or SWS (P = 0.12) compared with awake. There was also no difference in perceived pain between awakenings from Stage 2 sleep and SWS (P = 0.27) or between SWS and REM sleep (P = 0.44). On waking finally in the morning subjects were aware of having been woken during the night, but underestimated the number of times they were woken and for how long they were awake.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. Acknowledgements
  9. References

This was the first study to report on the effects of sleep inertia on pain perception. We first confirmed that thermal pain perception was not affected by circadian rhythms, as well as confirming that repeated thermal stimuli during the night did not cause any residual hyperalgesia the following morning. Once the subjects had identified the pain intensity after waking from any of the three sleep stages for either stimulus, there was no change in their perception of the pain over the following 5 min. For both mild (‘hot’: 43.2 °C) and moderate (‘hurting’: 46.6 °C) thermal stimuli the pain perceived when woken from REM sleep was significantly less than the intensity perceived when awake. Pain perception after waking from REM sleep was also significantly less than waking from SWS for the ‘hot’ stimulus, and lower than waking from Stage 2 sleep for the ‘hurting’ stimulus.

Despite the novelty of this study there are some limitations, particularly in our use of only one modality of pain. Previous studies have shown differences between sleep stages in response to different modalities of noxious stimuli, thus the results cannot be extrapolated to other modalities of acute pain or even to chronic pain patients (Bentley, 2007). Our protocol was also limited to assessing the memory of pain when woken from sleep, as we were unable to maintain the painful stimulus after waking. Also, as we used only male subjects, the results could not be extrapolated to female subjects due to gender differences in pain perception, as well as the variations induced in both the fields of pain and sleep research by changes in the menstrual cycle. Our data can be used only in the context of acute noxious stimuli and do not imply that in a situation of chronic pain the perception of that type of pain would not change with time after waking.

Most previous studies on sleep inertia have focused upon complex decision-making or reaction times. These studies have shown a significant impairment, particularly in the first 3 min (Bruck and Pisani, 1999; Tassi and Muzet, 2000). These changes are sleep stage-specific, with less inertia found on waking from Stage 2 sleep and maximal inertia after waking from SWS (Stones, 1977; Webb and Agnew, 1964). Our study confirms the data for changes in degree of sleep inertia after waking from different sleep stages. However, we could not confirm that awakening from SWS produces the maximal inertia effect. It appears as though degree of sleep inertia seen with thermal pain is intensity-specific, particularly with regard to waking from Stage 2 and SWS. A repeat study using a larger sample size may confirm this trend, which may have important implications for management of patients in pain.

The major finding in our study was the significant reduction in pain perception after waking from REM sleep for both stimuli. The effect was large, with a 90% reduction in pain intensity for the ‘hot’ stimulus and a 80% reduction in pain intensity for the ‘hurting’ stimulus. These data imply that the reduced perception of noxious stimuli during REM sleep, seen in previous studies (Bentley et al., 2003; Drewes et al., 1997; Lavigne et al., 2000) may continue after waking and produce a sensory inertia. The cause of the reduced response to noxious stimuli found during REM sleep was believed to be tonic suppression of ascending tracts during REM sleep by an as-yet unknown mechanism, although presynaptic inhibition at the spinal cord level has been suggested (Jones, 1993; Soja, 2007). It is possible that the active suppression of pain pathways during REM sleep may also continue for a short while after waking, thus creating a form of biological inertia.

Our data are limited to pain perception immediately on waking. Even so, the initial perception of pain intensity, whether correct or incorrect, is remembered accurately over the first 5 min after provoked waking. Thus, the memory of the pain perception was not subject to sleep inertia, at least over the first 5 min. This was also useful information for future pain and sleep research, as it meant that measuring intensity of pain within the first 5 min after waking was accurate enough to know how severe the pain perception was, on waking. One can also be reassured that, if any misperception of pain intensity is present, patients are most likely to underestimate the sensation of pain on waking.

There is difficulty in extrapolating this work to the situation of the chronic pain patient who is being woken during the night by pain. In chronic pain patients the level of pain is unlikely to be the same as presleep levels, so the effect of sleep inertia in these patients is more difficult to assess. Apart from sleep inertia, any change in pain severity may be due to drop in analgesic dose, sleep stage, circadian rhythms or simply change in pain severity due to the disease process itself. No studies have tried to quantify the severity of pain and link it to sleep inertia or even to stage of sleep for the above methodological reasons. Any biological factors would have to be considered in the context of possible psychological factors, of which there are many affecting pain perception in the chronic pain patient.

In conclusion, our data indicate that on waking from any stage of sleep in pain, a subject is likely to either be correct in their assessment of pain intensity or, at worst, underestimate the intensity of pain if waking from REM sleep. Thus, when reporting pain during the night patients in acute pain are not likely to exaggerate the pain intensity from a biological viewpoint. Future studies need to examine other pain modalities and pain perception in patients with underlying chronic pain to confirm these results for the clinical setting.

Disclosure

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. Acknowledgements
  9. References

Neither author has any conflict of interest. A. Bentley has received honoraria for speaking engagements from Boehringer-Ingelheim and Sanofi Aventis.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. Acknowledgements
  9. References

The study was funded by Dial.a.Bed South Africa and the Medical Faculty Endowment fund of the University of the Witwatersrand.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. Acknowledgements
  9. References
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