Implications of Sleep Loss Pain Interaction

Clinical Implications of sleep loss-pain interactions

Poor sleep quality and sleep loss are common for many groups in society whose individual sleep-wake rhythm is fragmented or forced to changes frequently, such as health care workers with on-call duty, military personnel, parents attending to infants and toddlers, night-shift workers, time zone travelers, patients in the intensive care unit and hospital environment, older adults, and those suffering from painful medical conditions and sleep disorders (such as insomnia, apnea, or periodic leg movements). The prevalence of adults reporting insufficient sleep is estimated to be approximately 40% in the general population; 40% obtain 7 hours or less total sleep time, and 15% report sleeping less than 6 hours per night. National Sleep Foundation. 2002 Sleep in America Poll. Washington, DC: National Sleep Foundation, 2002

A recent longitudinal study of 971 participants showed that obtaining less than 6 hours of sleep per night predicted next-day pain report in the general population. – Edwards RR, Almeida DM, Klick B, Haythornthwaite JA, Smith MT. Duration of sleep contributes to next-day pain report in the general population. Pain 2008;137:202-207

Potential influences on sleep loss and pain

Poor quantity or quality of sleep may facilitate nociceptive processing through various mechanisms. In humans, one of the most robust findings in experimental sleep deprivation studies is an increase of various inflammatory markers, in particular proinflammatory cytokines, which are known for their pain-sensitizing effects.

In clinical settings, patients suffering from primary insomnia (that is, difficulties falling asleep and staying asleep, waking up often during the night, and waking up too early) show increased interleukin 6 (IL-6) levels and a diurnal shift of IL-6 levels from nighttime peak to evening peak. These alterations in the secretory pattern have been suggested to explain daytime fatigue and poor concentration in insomnia patients. Vgontzas AN, Zoumakis M, Papanicolaou DA, et al. Chronix insomnia is associated with a shift of interlukin-6 and tumor necrosis factor secretion from nighttime to daytime. Metabolism 2002;51:887-892

Increases in plasma IL-6 levels were connected with tiredness and fatigue in healthy participants undergoing prolonged sleep restrictions. IL-6 has also been found to increase in disorders in which sleep disturbances are common, such as sleep apnea and depression.  Administration of a tumor necrosis factor (TNF-alpha) a receptor blocker; which lowers IL-6 levels, led to a decrease in sleepiness in apnea patients.Vgontzas AN, Zoumakis E, Lin HM, Bixler EO, Trakada G, Chrousos GP. Marked decrease in sleepiness in patients with sleep apnea by etanercept, a tumor necrosis factor alpha antagonist. J Clin Endocrinol Medtab 2004;89:4409-4413

Influence on pain

It is well accepted that both pro-inflammatory cytokines and PGs, and in particular IL-6 and PGE mediators, have pronociceptive (preceding or leading to nociception, the perception of pain) properties. Anti-inflammatory medications given for 1 day or more prior to surgery may preemptively minimized postoperative pain by blocking the establishment of nociceptor sensitization. A recent study demonstrated that pre-surgical administration of cyclooxygenase (COX) inhibitors reduced both peripheral and central PGE and IL-6 levels and decreased postoperative pain. Buvanendran A, Kroin JS, Berger RA, et al Upregulation of prostaglandin E2 and interleukins in the central nervous system and peripheral tissue during and after surgery in humans. Anesthesiology 2006; 104:403-410

It seems inflammatory markers appear to be bona fide mechanistic mediators of the pain-enhancing effect of insufficient sleep. However, the data is largely correlational; causation has yet to be established. Nevertheless, under controlled, in-laboratory conditions, increased IL-6 levels observed in response to sleep restriction to 4 hours per night over a 10-day period were associated with the degree of spontaneous pain experienced by the participants, including headaches, muscle, and joint pain. – Haack M, Sanchez E, Mullington JM. Elevated inflammatory markers in response to prolonged sleep restriction are associated with increased pain experience in healthy volunteers. Sleep 2007;30:1145-1152

In a study of sleep deprivation participants were kept awake for 88 hours under controlled in-laboratory conditions. An increase in urinary PGE2 metabolite levels was associated with the frequency and intensity of spontaneous pain experienced by participants.

These results lend support to the premise that inflammatory markers, such as IL-6 and PGE2 , may play a role in mediating the effects of sleep loss on the development of pain.

Pharmacology influenced

A sleep or sleepiness-promoting role of the PG system is also supported by experiments showing that inhibition of PG synthesis through administration of a cyclooxygenase 2 (COX-2) inhibitor reduces spontaneous sleep in rats.  In humans, some studies have implied that acute administration of dual-COX inhibitors, such as ibuprofen or aspirin, disturbs sleep physiology in healthy adults. Aspirin given in a dose of 1,800 mg per day over 4 consecutive days seems to reduce deep slow-wave sleep and increases stage 2 sleep. An increase in nocturnal awakenings has been reported after administration of aspirin (1,950mg per day) or ibuprofen (1,200mg per day) over a single day.

The long-term effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on sleep in clinical pain populations is largely unknown.  Though, at least one study found that NSAIDs has minimal sleep-disrupting effects in patients with chronic widespread pain. Given that NSAIDs are one of the most frequently used over-the-counter medications in the United States, doctors should inform their patients that acute administration may interfere with sleep physiology and thereby may counteract to some extent their pain-relieving properties.

Emotional influence

Sleep loss not only enhances pain, it also modifies emotional well-being, which is an integral part of the pain experience. Being optimistic has been shown to be associated with lower levels of bodily pain as well as with higher pain tolerance in patients suffering from painful medical conditions. When healthy young participants are restricted to 4 hours of sleep per night across 10 days, sociability and optimism markedly decreased compared to those exhibited by control subjects permitted 8 hours of sleep per night. Thus, sleep loss-induced deterioration of emotional well-being may present an additional means by which insufficient sleep contributes to the experience of pain.

Significance of sleep loss and pain

The nociceptive and sleep-wake systems function in a complex and reciprocal interrelationship. The experience of pain can impair the quantity and quality of sleep, and in turn, sleep loss induces and/or intensifies spontaneous pain and hyperalgesia. The prevalence of sleep disturbances in various clinical pain conditions constitutes a major epidemiologic problem.  Approximately 22% to 60% of patients hospitalized for acute care report a sleep disturbances, and approximately 20% of the general population experiences some sort of chronic pain and sleep disturbance. The combination of pain and sleep disturbance has negative consequence from patients’ overall daily functioning  and well-being. Plus, there is a compelling need to investigate the mediators that interlink pain and sleep.

Clarification of these mechanism is vital for development of therapeutic strategies such as novel anti-inflammatory agents have the potential to minimize the impact of sleep disruption and pain on the socioeconomic cost to society and physical function in at-risk populations, nightshift workers, parents with infants and toddlers, sleep-deprived motor vehicle drivers, frequent travelers and students as well as the population of patients with pain in acute hospital settings and in chronic pain management clinics.

Sleep patterns in the postoperative period can be severely disrupted with a suppression of both slow-wave and rapid eye movement (REM) sleep. The quality and quantity of sleep after surgery are influenced by a multitude of factors:

  • including the extent of tissue injury
  • the effectiveness of the analgesics
  • the activation of surgical stress response

Opiates have been demonstrated to disrupt sleep in humans and suppress both slow-wave and REM sleep. This suggest that opioids may contribute to postoperative sleep disturbances. A sleep-disrupting effect also has been suggested for acute treatment with COX enzyme inhibitors such as NSAIDs based on short-term studies in healthy volunteers. Yet, little is known about the effect of clinical use of COX enzyme inhibitors on sleep in subjects with pain.

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