Chronic Pain and Sleep

Sleep disturbances are common in individuals experiencing chronic pain.

Subjective measures of sleep in various chronic pain conditions mostly demonstrate a high number of complaints of disrupted and unrefreshing sleep.

Polysomnographic studies of patients with chronic pain have been less conclusive; many studies have shown that patients with chronic pain have a fragmented slow wave sleep with intrusion of alpha waves, while others report few perceptible changes in the sleep of patients with chronic pain.

Experimental studies in healthy humans have shown that the pain-sleep relationship is bidirectional: pain stimuli provoke changes in sleep architecture and partial or complete sleep deprivation lowers pain thresholds in healthy individuals.

The International Association for the Study of Pain defines pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage (i.e, experience of pain in the absence of tissue damage).

Pain is a defensive response by the organism to prevent further damage from occurring. Sleep, on the other hand, is a basic biological function as essential for survival as food and water.

Animal studies have shown that total sleep deprivation in rats causes death in less than 1 month [1]. Sleep deprivation in humans was not born with industrialization; the first known writings on its effects date from ancient Egypt circa 1300 BC.

Both chronic pain and sleep disturbances are widespread in the general population [2].

As many as one-third of the population suffers from frequent or persistent pain, and an equal number have sleep disturbances. Individuals suffering from painful physical conditions often have concomitant sleep disturbances [3-11].

Pain and sleep problems are especially prevalent among the elderly [3,2].

The direction of cause and effect of this association is not yet fully understood and is still a matter of debate. There is experimental evidence that pain augments arousals during sleep, causing sleep disruption. However, it is unlikely that this association is only unidirectional, as illustrated by partial or complete sleep deprivation studies in humans.

TOLERANCE TO PAIN IN SLEEP DEPRIVATION IN HEALTHY VOLUNTEERS

Study of the relationship between pain and sleep deprivation in healthy individuals is not new, with the oldest article written on this topic in 1898 [12].

Some studies have investigated the effect of a single night of total sleep deprivation on pain tolerance thresholds, while others have examined the outcomes of sleep restriction, or the effects of selective sleep stage deprivation.

Moldofsky et al. assessed the effects of selective non-rapid eye movement sleep (NREM) deprivation over three consecutive nights in six healthy subjects [13]. Selective deprivation of sleep stage 4 was associated with an increased sensitivity to pressure pain and more musculoskeletal pain.

A similar experiment was conducted in seven healthy subjects deprived of REM sleep. REM deprived subjects did not show increased muscle tenderness or more musculoskeletal pain after sleep deprivation [14].

Similar conclusions were obtained in an uncontrolled study involving 12 healthy middle-aged women [15], who were deprived of slow-wave sleep (SWS) for three consecutive nights with minimal alterations of total sleep time, sleep efficiency, and other sleep stages. After the third night, the women showed a 24% decrease in musculoskeletal pain threshold and reported increased discomfort, tiredness, fatigue, and reduced vigor.

Another study investigated the effect of delta wave sleep (sleep stages 3 and 4) interruption in 13 healthy volunteers (six control and seven experimental subjects) for three consecutive nights [16]. Delta wave sleep interruption was not associated with a lowering of pain thresholds compared with the control group in any of the three conditions (baseline, deprivation, and recovery).

A double-blind crossover experiment on pain tolerance thresholds with nine healthy male subjects was conducted over two periods of six consecutive nights (night 1 adaptation, night 2 baseline, night 3 total sleep deprivation, night 4 and night 5 SWS or REM interruption, and night 6 recovery) [17]. Total sleep deprivation, but not REM sleep interruption, was associated with a decreased tolerance to pressure pain. SWS interruption was associated with greater pain tolerance on the recovery day, suggesting an analgesic effect related to SWS recovery.

Kundermann et al. investigated the effects of two nights of total sleep deprivation on thermal pain thresholds in 20 healthy volunteers [18]. Sleep-deprived individuals showed a significant decrease in heat pain and cold pain thresholds, but warmth and cold detection thresholds remained unaffected.

These experimental studies show that partial or complete sleep deprivation produced hyperalgesic changes [13-20]. Deprivation of SWS may also be associated with a decrease in pain tolerance. None of these studies found a significant association between REM deprivation and tolerance to pain.

Therefore, if pain affects the quality of sleep, it appears that the reverse is also true: sleep deprivation can lower pain thresholds, increasing the level of experienced pain.

SLEEP AND PAIN CONDITIONS

The effects of pain on objective and subjective measures of sleep quality and quantity have been documented in both clinical and general populations.

The most commonly studied pain conditions are:

• headaches
• rheumatic pain and arthritis
• back pain and fibromyalgia.

Polysomnography (PSG) studies have shown that patients with pain have:

• longer sleep latency
• shorter sleep duration
• a fragmented SWS with intrusion of alpha waves [25-31]

Sleep disturbances may be as a consequence of pain, but there is also experimental evidence revealing that widespread pain can precipitate sleep deprivation [15,16].

Human studies show that disruption of sleep physiology influences daytime musculoskeletal pain and fatigue [13, 32-34], and alpha anomalies in the sleep of patients with chronic pain have been reported on numerous occasions.

RHEUMATIC PAIN AND ARTHRITIS

Sleep disturbances are a common complaint in subjects with rheumatic pain.

Along with back pain, rheumatic pain was the greatest predictor of disrupted sleep and non-restorative sleep in a sample of 18 980 individuals representative of the general population of five European countries [2].

The Canadian Community Health Survey examined the association between arthritis and insomnia symptoms in 118 336 adults. As in the Ohayon study, they found that insomnia and non-restorative sleep were twice as common in individuals with arthritis as in those without [35].

In outpatient and pain clinic studies, 54-70% of patients with rheumatoid arthritis (RA) complained of sleep disturbances. A 24-month longitudinal study found that 60% of the 254 RA patients reported a mild or moderate interference of sleep from pain, with 14% reporting severe interference [36]. Leigh et al. found no difference in the report of sleep problems between 439 hospitalized rheumatic and non-rheumatic patients, with the exception of pain during sleep [37].

A number of PSG studies have been conducted in patients with RA. One study found that RA patients had increased alpha sleep on EEG and an increased number of periodic movements of the legs, compared with healthy subjects [27]. The study also reported that morning stiffness, pain, and joint tenderness related to awakenings from sleep (wake after sleep onset), SWS, and REM sleep.Another study involving 19 patients with RA reported that normal sleep architecture was preserved but a severe sleep fragmentation was seen compared with age- and gender-matched healthy control subjects [38]. A study of children and adolescents with polyarticular juvenile RA (JRA) reported higher indexes of periodic leg movements (number of movements/h), isolated leg movements, and greater sleep fragmentation than in matched healthy controls [39].

Zamir et al. found that in addition to greater sleep fragmentation, JRA children had higher scores on the multiple sleep latency test (MSLT), indicating a tendency for daytime sleepiness and increased length of afternoon naps [40]. A PSG study in 14 patients with osteoarthritis reported a greater percentage of stage 1 sleep and a significantly smaller percentage of stage 2 sleep compared with 16 matched healthy controls [41]. Motility during sleep was also assessed. Patients suffering from osteoarthritis moved more during sleep than controls; however, this difference was non-significant [42].

Of three studies using the MSLT to measure daytime sleepiness in RA patients, two studies found that the majority of RA patients had MSLT results indicating excessive daytime sleepiness [29,43], while the third study found no evidence of sleepiness [38].

CHRONIC BACK PAIN

Second only to headaches, back pain is the most common neurological complaint in the US. Back pain persisting for >3 months is considered chronic.

Chronic back pain affects 14-35% of the general population, depending on the country studied, [44-47] and nearly half of all subjects with chronic back pain complain of sleep disturbances [2]. A 28-year longitudinal study involving a cohort of 902 metal industry workers has shown that sleep disturbances (insomnia and/or nightmares) predicted a 2.1-fold increased risk of back-related hospitalizations in workers with only one sleep disturbance, and a 2.4-fold risk in workers with both sleep disturbances [48].

Only two PSG studies of chronic back pain have been undertaken:

• One study reported that patients with chronic lower back pain had less restful sleep and more alpha EEG sleep compared with controls [49].
• The second study compared four depressed subjects suffering chronic lower back pain with six non-depressed subjects with chronic lower back pain, and 11 controls [50]. The three groups had comparable sleep architecture; however, EEG power spectral analyses revealed that the two groups with chronic lower back pain had lower sigma power than the controls, which could contribute to poor sleep quality.

Studies have also used actigraphy measures to assess the relationship between chronic lower back pain and sleep. Lavie et al., reported that patients with chronic lower back pain did not have significantly different actigraph measures from patients with RA or from controls [28].

Cesta et al., found that workers who had lower back pain reported more disturbed and unrefreshing sleep, and had longer awakenings (as measured by the actigraph) than controls [51]. In another study, 18 patients with chronic lower back pain who wore an Actiwatch for 6 days and 5 nights recorded pain levels every 90 min during the daytime [52]. No association was found between pain levels and sleep the following night, or between sleep and pain levels the next day.

HEADACHE

Headache is the most common neurological complaint. In studies conducted in the general population, headaches and/or migraines have been associated with nightmares [53,54], snoring [53,10,55], sleep excess [55,56], insomnia [56-58], and sleep deprivation [59].

The relationship between headaches and sleep is complex. Many patients who received a consultation for headaches suffer from sleep disturbances and have an identifiable sleep disorder [6,7, 60] and treatment of the sleep disorder often alleviates or reduces the headache. However, headaches are not specific to any sleep disorder [7,8]. Several clinical studies have shown that the treatment of obstructive sleep apnea syndrome considerably improves symptoms of morning headache [11,61-63]. However, the relationship between obstructive sleep apnea syndrome, headaches, and morning headaches is more complex and other factors may influence this association. A clinical study of 312 patients who consulted a sleep center for snoring revealed that headaches and morning headaches were not correlated with sleep apnea index and architectural sleep parameters, nor with excessive daytime sleepiness, but were strongly correlated with mood disorders [62]. Similarly, anxiety and depressive disorders were identified as the strongest predictors of morning headaches in a general-population based study [53].

FIBROMYALGIA

Fibromyalgia is characterized by:

• widespread pain lasting >3 months in joints, muscles, tendons, and other soft tissues
• non-restorative sleep [64,65]
• chronic fatigue
• morning stiffness

The cause of this disorder is unknown and its prevalence in the general population is estimated at 1-3% [66-69].

Objective and subjective sleep disturbances are present in nearly 75% of patients with fibromyalgia [70].

Several PSG studies have investigated patients with fibromyalgia. An early study by Moldofsky et al. described NREM anomalies in these patients [13], characterized by alpha intrusion on delta waves, which were likely to be related to unrefreshing sleep, diffuse pain, and mood symptoms. Another study comparing 10 fibromyalgia patients with 14 healthy controls found alpha-delta patterns were present in almost all the patients who had fragmented sleep, reduced REM, and SWS [71].

Delta decay across sleep cycles was different in patients with fibromyalgia compared with healthy controls. Alpha activity was greater and declined more when compared to controls. Alpha-delta ratio increased through progressive sleep cycles, a finding not observed in controls. Alpha intrusion has also been observed in RA [29,30].

A study by Horne and Schackell enrolled 11 subjects with fibromyalgia and 15 symptom-free controls who all claimed to be good sleepers [72]. Mean percentage alpha-like activity in sleep stages 2, 3, 4 and NREM sleep were greatest for the fibromyalgia group, but not significantly different from those of the controls. The overlap in the distribution of NREM alpha-like activity in sleep between the two groups suggested that alpha activity was unrelated to musculoskeletal symptoms.

SLEEP AND PAIN MEDICATION

Medication effects can also influence the restorative quality of sleep.

Some studies in healthy subjects have demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs) cause some disruptions in sleep architecture. Namely, an increase in sleep latency, greater WASO, increased in stage 2 and SWS and reduced sleep efficiency were observed with aspirin and ibuprofen [73,74]. On the other hand, in patients with pain, the use of NSAIDs did not modify the sleep architecture but improve the subjective perception of sleep quality [75].

Opioids are known to induce sedative side effects. In healthy volunteers, opioids increased the duration of stage 2 sleep and decreased the duration of SWS [75]. Opioid therapy may also worsen or induce sleep-disordered breathing through an action at mu receptors [77,78].

Tricyclic antidepressants are also used in the management of pain. In healthy volunteers, Tricyclic antidepressants increased total sleep time, stage 2 sleep and reduced arousals. They also increased REM latency and decreased the total REM sleep duration [79-81]. Patients with fibromyalgia or with neuropathic pain who were treated with tricyclic antidepressants reported improvement in the subjective assessment of sleep quality [82,83].

Benzodiazepine and nonbenzodiazepine hypnotics are frequently prescribed in patients with chronic pain: up to 70% of them took regularly hypnotics [84-86]. Benzodiazepines are known to reduce sleep latency, to increase stage 1 and 2 sleep and to increase total sleep time but they also reduce SWS and REM sleep. On the other hand, nonbenzodiazepines are less likely to alter sleep stages but are as effective to improve sleep quality.

The rare polysomnographic studies that examine the effects of hypnotics on pain and sleep in patients with chronic pain found there was no change in sleep parameters during the hypnotic treatment as compared to before initiating the treatment. Changes were in the subjective assessment of sleep quality, which was improved under treatment [87,88].

CONCLUSIONS

It can be tempting to rely only on objective measures to evaluate the importance of sleep disorders in patients with chronic pain. However, lack of PSG evidence does not necessarily indicate there is no sleep disturbance. Changes in the EEG can be very subtle and detected only with more sophisticated measures such as EEG power spectral analyses.

The presence of primary sleep disorders, such obstructive sleep apnea syndrome and periodic limb movement disorder, and the presence of psychiatric disorders may add to the complexity of the relationship between chronic pain and sleep. PSG studies have mainly been conducted in small numbers of patients, and have rarely controlled for the presence of primary sleep disorders or psychiatric disorders.

After 30 years of research on this topic, the specific nature of the relationship between chronic pain and sleep remains largely uncertain.

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