Pain Sensitivity and Recovery From Mild Chronic Sleep Loss

Abstract

Study Objectives:

To determine whether an extended bedtime in sleepy and otherwise healthy volunteers would increase alertness and thereby also reduce pain sensitivity.

Setting:

Outpatient with sleep laboratory assessments.

Participants and Interventions:

Healthy volunteers (n = 18), defined as having an average daily sleep latency on the Multiple Sleep Latency Test (MSLT) < 8 min, were randomized to 4 nights of extended bedtime (10 hr) (EXT) or 4 nights of their diary-reported habitual bedtimes (HAB). On day 1 and day 4 they received a standard MSLT (10:00, 12:00, 14:00, and 16:00 hr) and finger withdrawal latency pain testing to a radiant heat stimulus (10:30 and 14:30 hr).

Results:

During the four experimental nights the EXT group slept 1.8 hr per night more than the HAB group and average daily sleep latency on the MSLT increased in the EXT group, but not the HAB group. Similarly, finger withdrawal latency was increased (pain sensitivity was reduced) in the EXT group but not the HAB group. The nightly increase in sleep time during the four experimental nights was correlated with the improvement in MSLT, which in turn was correlated with reduced pain sensitivity.

Conclusions:

These are the first data to show that an extended bedtime in mildly sleepy healthy adults, which resulted in increased sleep time and reduced sleepiness, reduces pain sensitivity.

Citation:

Roehrs TA; Harris E; Randall S; Roth T. Pain sensitivity and recovery from mild chronic sleep loss. SLEEP 2012;35(12):1667-1672.

INTRODUCTION

The prevalence in the general population of excessive sleepiness, as defined by the Multiple Sleep Latency Test (MSLT), is estimated to be 13-25%.^1,2 The excessive sleepiness can be caused by primary sleep disorders (such as obstructive sleep apnea and periodic limb movement during sleep) that disrupt the continuity of sleep, by central nervous system (CNS) pathologies (such as narcolepsy or idiopathic hypersomnia), or sedating CNS-acting drugs.² However, for most of the population, excessive sleepiness is due to chronically insufficient time in bed and consequently reduced sleep time. In the 1960s sleep duration was estimated to be approximately 8 hr per 24-hr period, whereas by 2005 it was reported that sleep duration was 7 hr or less.³ A national survey reported that 21% of the population obtains 6 hr or less of sleep per 24-hr period.⁴ These reduced sleep times can be attributed to a variety of causes including 24-hr access to entertainment, social and family responsibilities, time spent commuting, and around-the-clock demand for commercial services that require night and shift work.

The behavioral and physiologic consequences of chronically insufficient sleep are myriad. But, one consequence recently gaining clinical and research attention is the effect of sleep loss on pain. Studies of healthy, pain-free volunteers have consistently shown that total sleep deprivation increases pain sensitivity and reduces pain thresholds to hot and cold experimental pain stimuli.^5–7 Partial deprivation, the reduction of bedtime by 50% for one night, reduced finger withdrawal latency (increased pain sensitivity) to a radiant heat stimulus by 24%.⁷ In a fully alert, healthy person such a 4-hr bedtime reduces the average daily sleep latency on the MSLT to < 8 min.⁸ A study compared finger withdrawal latency to radiant heat in healthy, pain-free volunteers with an average daily sleep latency of < 8 min on the MSLT to those with a latency ≥ 8 min.⁹ Finger withdrawal latency was 31% shorter in the sleepy individuals compared with the nonsleepy individuals. Finally, in sleepy (as defined by MSLT) healthy individuals the analgesic effect of codeine (60 mg) in testing to a radiant heat stimulus was absent compared with nonsleepy individuals in whom codeine increased finger withdrawal latency (by 14%).¹⁰

A critical question is whether increased bedtime and consequently increased sleep time will restore alertness in such sleepy individuals and thereby also reduce pain sensitivity. Several studies have shown that an extended bedtime to 10 hr nightly, for 1 wk in one study and 2 wk in another, reverses the sleepiness of such otherwise healthy individuals.^11,12 In this study we sought to determine whether an extended bedtime would increase alertness and thereby also reduce pain sensitivity in sleepy individuals.

METHODS

Participants

Eighteen healthy, pain-free volunteers age 21-35 yr participated. All were respondents to advertisements for healthy pain-free volunteers. All were in good medical and psychiatric health with no history of alcoholism or drug abuse. All had sleep efficiencies of > 85% on a screening 8-hr nocturnal polysomnogram (NPSG) and no evidence of primary sleep disorders. On a standard MSLT (10:00, 12:00, 14:00, and 16:00 hr) during the day following the NPSG, as a study entry criteria, participants had to show an average daily sleep latency of < 8 min.

The study protocol was approved by the Institutional Review Board of the Henry Ford Health System and participants were compensated monetarily for their participation. All the participants signed an informed consent and had the opportunity to withdraw after experiencing the pain testing procedures during the training session. No participant withdrew due to the pain testing.

Experimental Design

The study was conducted as a mixed design experiment with a between-group comparison in which healthy, sleepy volunteers (MSLT < 8 min) were randomly assigned to four nights of an extended bedtime (10 hr nightly) (EXT group) or four nights on which they maintained their diary-reported habitual sleep times (HAB group). The within-subject comparisons were the daytime assessments of sleepiness and pain conducted on day one and four of the experimental bedtime time manipulation, HAB versus EXT bedtime. For the bedtime of the EXT group, the midpoint of their bedtime reported on a 1-wk sleep diary was determined and 5 hr were added to each side of the diary midpoint.

Procedures

General Medical and Psychiatric Screen

Participants underwent a thorough medical and drug use screening including a brief physical examination. A blood and urine laboratory panel was also used in screening for general health. The panel also included testing for medications and illegal drugs including but not limited to opiates, benzodiazepines, and stimulants, which was the screen for current drug use. Participants with a history of substance use (drug or alcohol) disorders or current use of CNS-acting medications at screening were excluded. Participants reporting any use of illegal drugs within the past 2 yr also were excluded. Participants who reported consuming > 14 standard (1 oz) alcoholic drinks per week, caffeine consumption > 300 mg/day, and smoking during the night (23:00-07:00 hr) were excluded. Participants who reported chronic pain, or any acute, current pain were excluded. Participants also completed a Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4^th Edition, Text Revision, to screen for Axis I psychiatric disorders, which was an exclusion.

Sleep Disorders Screen

Each participant underwent a sleep-wake history, sleep disorders evaluation, and nocturnal NPSG. As part of the sleep-wake history, all participants completed a 1-wk sleep diary, which was used to determine their habitual bedtime (if assigned to the HAB group) and the screening NPSG bedtime. For the screening NPSG bedtime, the midpoint of their bedtime reported on the 1-wk sleep diary was determined and 4 hr were added to each side of the diary midpoint.

Nocturnal Polysomnography

After the screening physical and laboratory tests, the participants underwent the screening 8-hr NPSG. All participants were required to show sleep efficiencies of ' 85% (total sleep time/time in bed) and no other primary sleep disorders. Exclusionary entry criteria were respiratory disturbances (apnea-hypopnea index > 10) or leg movements (periodic limb movement arousal index > 10).¹³ No participant showed respiratory disturbances or periodic limb movement during sleep.

The standard Rechtschaffen and Kales methods for the electrophysiologic recording of sleep were used.¹⁴ The recordings obtained from each participant included standard central (C3-A2) and occipital (Oz-A2) electroencephalograms (EEGs), bilateral horizontal electrooculograms (EOGs), submental electromyogram (EMG), and electrocardiogram (ECG) recorded with a V5 lead. In addition, on the screening night airflow was monitored with oral and nasal thermistors and leg movements were monitored with electrodes placed over the left tibialis muscles; respiration and tibialis EMG recordings were scored for apnea and leg movement events and none were observed.¹³ After the screening night, all subsequent recordings excluded the airflow and leg monitoring. All recordings were scored in 30-sec epochs for sleep stages according to the standards of Rechtschaffen and Kales.¹⁴ Scorers maintained 90% interrater reliability.

Multiple Sleep Latency Test

The MSLT was performed according to the standard protocol on the day after the 8-hr time in bed and was conducted at 2-hr intervals starting at 10:00, 12:00, 14:00, and 16:00 hr.¹⁵ On each test (which lasted approximately 30 min), participants lay down on a bed in a quiet, dark room and were instructed to try to fall asleep. During the screening MSLT the recording continued for 15 min after the first epoch of sleep whereas, on experimental days (day one and day four) the MSLT recording was terminated after three consecutive epochs of stage 1 sleep, an epoch of another sleep stage, or after 20 min of continuous wakefulness. Any participant showing sleep-onset rapid eye movement sleep during the screening MSLT was excluded from the study; none did. Sleep onset latency was defined as the number of min to the first epoch of sleep and the mean latency of the 4 tests was the primary dependent measure. MSLT was tested on experimental day one and four at 10:00, 12:00, 14:00, and 16:00 hr.

Pain Sensitivity Assessments

A radiant heat method was used to assess pain sensitivity.^16,17 Each participant was seated in a comfortable chair at a desk across from the research assistant who administered the pain stimulation and monitored responses. The participant's hand rested on top of a metal box that housed the heat source. The pad of the index finger (fingerprint whorl) was centered over a 3-mm hole through which the heat radiated.

The heat source used was a 100-watt projection bulb, located at a fixed distance (4 mm) from the participant's finger. A potentiometer was used to control the amount of current delivered to the light bulb, thereby varying heat intensity. Prior to each trial the research assistant set the potentiometer and pressed a switch to trigger the heat source, both of which were hidden from the participant's view.

On each trial, participants were instructed to place the index finger on the hole through which the heat source radiates and to withdraw the index finger when pain was first felt. Once finger withdrawal occurred, a photocell (mounted on a post located above the finger) detected the light (from the bulb underneath) and stopped a digital timer that was connected to the circuit. Both index fingers were tested and the heat intensities were adjusted on each trial such that five different heat intensities (ranging from 83.4 to 101.6°F, measured at steady state after 10-sec duration) were presented in a randomized order. The finger withdrawal latencies from the left and right index fingers were averaged to produce a more stable estimate.

The research assistant confirmed that the participant's finger temperature was between 88 and 92°F before initiating a trial. This was measured by a thermistor attached to the middle finger of one hand. If the temperature criterion was not met, then the fingers were heated or cooled as necessary. The primary dependent measure for this test was mean finger withdrawal latency (to a resolution of 0.01 sec) for each of the five heat intensities.

Participants initially underwent a training session to familiarize them with the pain testing equipment and procedures. It also helped to establish the threshold at which a finger withdrawal response was elicited for each participant. The threshold radiant heat intensity was defined as that stimulus intensity that produced a finger withdrawal response of < 21 sec. The threshold intensity and four higher intensities were maintained for a given participant throughout the experiment. Given previously reported time-of-day differences in stimulant drug effects and in pain sensitivity, finger withdrawal latency was tested twice (10:30 and 14:30 hr) for each participant on experimental day one and four.

Data Analyses

Average daily sleep latency on the MSLT and finger withdrawal latency on the Pain Sensitivity Assessments were the primary dependent measures and they were submitted to multivariate analyses of variance with groups (HAB vs. EXT) as a between-subject factor and experimental days (day one vs four) as a within-subject factor. For both dependent variables we hypothesized a group-by-day interaction with a day four improvement in the EXT group only. Pearson product correlations compared the change in nightly sleep time during the four experimental nights with the change in MSLT and likewise the change in MSLT with the change in finger withdrawal latency.

RESULTS

The demographic information for the HAB and EXT groups is presented in Table 1. The groups did not differ in sex distribution or mean age. Although the participants were similar in their diary-reported bedtimes and on average did not have unusually short bedtimes, the range in their bedtimes was greater than 2 hr, suggesting periodic compensatory oversleeping. Their screening sleep efficiencies were on average above 93% and their MSLTs were on average below 5 min. See Table 2 for the screening sleep data of the two groups. The groups did not differ in screening sleep efficiency and MSLT.

Table 1.

Demographics of study groups

Table 2.

Screening nocturnal polysomnographic measures in the study groups

The average daily MSLT sleep latency on day one and four for the two groups is presented in Figure 1. Sleep latency was increased significantly in the EXT group, but not the HAB group (F = 6.52, P < 0.02; group-by-day interaction). There were no main effects of group or day. Over the four experimental nights the EXT group slept 8.90 ± 0.12 hr nightly and the HAB group 7.14 ± 0.18 hr (t = 6.89, P < 0.001). Not all individuals in the EXT group improved on the MSLT (n = 3), defined as an increase of > 2.5 min, whereas some in the HAB group did (n = 3). Regardless of group assignment, those who improved on the MSLT (n = 12) slept more, 8.58 ± 0.25 hr, than those not improving (n = 6), 7.46 ± 0.27 hr (t = 8.74, P < 0.001). The correlation in improvement on the MSLT and the nightly sleep duration was r = 0.55, P < 0.01.

Figure 1.

Average daily sleep latency on the Multiple Sleep Latency Test (MLST) in the habitual (HAB) and sleep extension (EXT) groups conducted on experimental day 1 and day 4. Sleep latency increased over the 4 days in the EXT, but not the HAB group.

Table 3 presents the finger withdrawal latency on day one for each of the five stimulus intensities on the 10:30- and 14:30-hr tests. Finger withdrawal latency decreased as a function of increase in stimulus intensity (F = 54.96, P < 0.001; main effect of intensity). Finger withdrawal latency also was shorter on the afternoon test compared with the morning test (F = 5.65, P < 0.03; main effect of time of day). There were no significant interactions.

Table 3.

Finger withdrawal latency (sec) as a function of stimulus intensity and time of day

The average finger withdrawal latency over the five intensities and two tests for the EXT and HAB groups on experimental day one and four is presented in Figure 2. Finger withdrawal latency increased in the EXT group, but not the HAB group (F = 5.68, P < 0.03; group-by-day interaction). There were no main effects of groups or days. Five individuals failed to show increases in finger withdrawal latency from day one to day four (four in the HAB group). The nightly sleep duration of those that improved (n = 13) was 8.1 ± 1.0 hr compared with 7.5+1.2 hr in those who did not improve (n = 5) (t = 3.57, P < 0.001). Finally, the correlation of change in mean finger withdrawal latency to change in MSLT was r = 0.51, P < 0.05).

Figure 2.

Average finger withdrawal latency to a radiant heat stimulus tested at 10:30 and 14:30 hr and conducted on experimental day 1 and 4 for the habitual (HAB) and sleep extension (EXT) groups. Finger withdrawal latency increased over the four days in the EXT, but not the HAB group.

Given the day one time-of-day differences in finger withdrawal latency, separate analyses of the morning test and the afternoon test results were conducted. On the morning test, there was a borderline increase in finger withdrawal latency in the EXT group, but not the HAB group (F = 3.92, P < 0.06; group-by-day interaction). On the afternoon test finger withdrawal latency increased in the EXT group, but not the HAB group (F = 6.89, P < 0.02; group-by-day interaction). There were no main effects of groups or days in either of these analyses.

DISCUSSION

These are the first data to have shown that extended bedtime, which resulted in increased sleep time and reduced sleepiness, in sleepy, healthy adults reduces pain sensitivity. The nightly increase in sleep time during the four experimental nights was correlated with the improvement in MSLT, which in turn was correlated with reduced pain sensitivity. More sleep was associated with more alertness, which was associated with less pain sensitivity. In a previous study we reported increased pain sensitivity in otherwise healthy, pain-free, but sleepy individuals compared with their nonsleepy counterparts.⁹ The current results suggest that the increased pain sensitivity of the sleepy individuals is the result of their underlying sleepiness, which the results of this study show is a state and not a trait phenomenon. The participants in the current study were screened and selected in a manner similar to that of the previous study. Their habitual bedtimes were quite similar, as was their screening night sleep efficiency and the next day average daily sleep latency on the MSLT.

The results of the current study indicate that a relatively short bedtime extension, four nights, is sufficient to provide benefit for alertness and pain sensitivity for individuals with this level of excessive sleepiness. The MSLT increased from 4.5 min to 9.6 min by day four, which did not reach the population mean (11.4 min) found in an epidemiologic study.² Our previous studies used a 1-wk bedtime extension; in a second study, a 2-wk bedtime extension was used.^12,13 In the 1-wk study the MSLT increased to approximately 10 min and in the 2-wk study to approximately 13 min.

In all three extension studies not all participants improved. In approximately 30% of the participants of each study the MSLT did not increase with the extended bedtime. In the current study three of the nine participants failed to show a > 2.5 min increase in MSLT. In all three studies those who did not improve failed to benefit from the extra bedtime; their nightly sleep time did not increase. In the current study there was a 1-hr difference on average in nightly sleep time between the improvers and nonimprovers. The reason for the failure to improve is not clear. Sleep efficiency across the 10 hr was relatively and uniformly low, suggesting that a circadian rhythm mismatch is not a likely explanation for the failure to improve. That is, wake time over the 10-hr bedtime was not differentially distributed to the beginning or the end of the 10-hr bedtime.

In the current study and our previous sleepy versus nonsleepy study the habitual bedtimes as reported on their sleep diaries do not appear to be unusually short, 7.4 to 7.8 hr nightly. However, the participants were excessively sleepy with MSLT scores in the pathologic range and their screening sleep efficiency was unusually high, 94%. In our original report identifying the chronic insufficient sleep syndrome¹⁸ these are two of the characteristics of chronic insufficient sleep. The third identified characteristic was oversleeping on days off by at least 2 hr. The participants in this study averaged more than 2 hr in their shortest to longest bedtimes, suggesting compensatory oversleeping. Subjectively these individuals do not experience sleepiness. Only three of the eighteen participants reported Epworth Sleepiness Scale scores greater than 10 (two in the HAB and one in EXT group).

The major new finding of this study is that reversal of mild chronic sleep loss improves pain sensitivity. In the EXT group of the current study finger withdrawal latency was increased by 25%, which reflects a reduction in pain sensitivity. The magnitude of this increase in finger withdrawal latency can be compared with that in a previous study in which 60 mg codeine versus placebo was administered twice a day and finger withdrawal latency was tested in the morning and afternoon as in the current study.¹⁰ In nonsleepy healthy individuals, codeine increased finger withdrawal latency by 14%; it had no effect in sleepy individuals.

The fact that sleepiness is correlated with pain sensitivity is supported by data from patients with obstructive sleep apnea. A truly excessively sleepy patient population is apnea patients. Their sleepiness is due to fragmentation of sleep by the brief arousals that conclude each apnea event. Unlike the chronic insufficient sleepers of this study, increased bedtime does not improve their sleepiness. In a recent study we assessed finger withdrawal latency on a single morning test after the diagnostic night, after the second night of continuous positive airway pressure (CPAP) treatment, and after two nights without CPAP.¹⁹ CPAP treatment reduced the number of apneas from 50 events per hr on average to 2 events. Finger withdrawal latency was increased by 28%. After two nights without CPAP treatment, apnea returned to 32 events per hr and finger withdrawal latency decreased by 17% (pain sensitivity was increased).

The question that remains is the mechanism(s) by which pain sensitivity is reduced as a result of reducing sleepiness. Any number of mechanisms can be hypothesized, but one for which there is accumulating evidence is cytokine activity. Pain is a hallmark of inflammation and studies have shown that sleep disruption and sleep restriction activate the proinflammatory cytokines interleukin-6 and tumor necrosis factor-α.^20,21 Is the converse true? Does reversal of sleepiness activate the anti-inflammatory cytokines? The cytokines act peripherally and there may also be important central mechanisms including the various neurochemicals that are known to be involved in nociception (endogenous opiods, cannabinoids, serotonin, and adenosine) that are involved in the sleep-pain nexus.

Limitations of this study need to be noted. This was a highly controlled laboratory study with a small sample size. How these results generalize to other sleepy populations experiencing acute or chronic pain is unclear. We are in the process of extending these findings to clinical populations as in the CPAP paper described in the previous paragraphs.¹⁹ This study also did not include self-ratings of the pain experienced with each stimulus, such as the standard 100-mm pain ratings used in clinical settings. Finally, the pain testing device used is not commercially available.

In summary, these are the first data to show that extended sleep in mildly, chronically sleep deprived volunteers reduces their pain sensitivity.

DISCLOSURE STATEMENT

This was not an industry supported study. Dr. Roth has served as a consultant for Abbott, Accadia, Acogolix, Acorda, Actelion, Addrenex, Alchemers, Alza, Ancel, Arena, AstraZeneca, Aventis, AVER, Bayer, BMS, BTG, Cephalon, Cypress, Dove, Eisai, Elan, Eli Lilly, Evotec, Forest, Glaxo Smith Kline, Hypnion, Impax, Intec, Intra-Cellular, Jazz, Johnson and Johnson, King, Lundbeck, McNeil, MediciNova, Merck, Neurim, Neurocrine, Neurogen, Novadel, Novartis, Ocera, Orexo, Organon, Otsuka, Prestwick, Proctor and Gamble, Pfizer, Purdue, Resteva, Roche, Sanofi, Schering-Plough, Sepracor, Servier, Shire, Somaxon, Somnus, Steady Sleep Rx, Syrex, Takeda, Transcept, Vanda, Ventus, Vivometrics, Wyeth, Yamanuchi, and Xenoport. He has served on speakers bureau for Cephalon, Sanofi, and Sepracor. He has received research support from Aventis, Cephalon, Glaxo Smith Kline, Merck, Neurocrine, Pfizer, Sanofi, Schering-Plough, Sepracor, Somaxon, Somnus, Syrex, Takeda, TransOral, Ventus, Wyeth, and Xenoport. Dr. Shahly is an employee of the Department of Health Care Policy at Harvard Medical School. That program has received research funding from Pfizer, Sanofi Aventis, Shire Development, Inc., and Janssen Pharmceutica, N.V. Dr. Roehrs has served as a consultant for Sanofi-Aventis and Evotec has received a research grant from Takeda. The other authors have indicated no financial conflicts of interest.