Mechanisms of sleep loss-pain interactions
The involvement of clinical pain can cause sleep disturbances. – Meneffee LA, Cohen MJM, Anderson WE, Doghramji K, Frank ED, Lee H. Sleep Disturbance and nonmalignant chronic pain: A comprehensive review of the literature. Pain Med 2000;1:156-172
Strong experimental evidence has amassed over the last 30 years supporting the notion that sleep loss itself can neuroplastically alter function of the nociceptive system (eg, in a reversible manner). Sleep loss has been shown to cause hyperalgesia, that is, an increased sensitivity to painful stimulation, and the development of spontaneous pain complaints, such as muscle pain, headache, stomach pain, or generalized body pain, arising in the absence of any peripheral input. – Lautenbacher S, Kundermann B, Krieg JC. Sleep depravation and pain perception. Sleep Med Rev 2006;10:357-369.
This association has been demonstrated in numerous studies using various experimental sleep models and pain measurement approaches.
Clinically, the bidirectional relationship between pain and sleep loss may serve to perpetuate and amplify sleep loss and chronic pain via a vicious cycle. A bad night’s sleep enhances pain. Pain, in turn, disrupts sleep. Poor sleep quantity and quality further worsen pain, and so on. This complex inverse relationship between sleep and pain may be influenced by various biologic and psychologic factors. – Lavigne GJ, McMillan D, Zucconi M. Pain and sleep. In:Kryger MH, Roth T, Dement WC. Principles and Practice of Sleep Medicine, ed 4. Philadelphia: Saunders, 2005:1246-1255
Despite the well-established bidirectional linkages between pain and sleep loss, there is surprisingly very little direct scientific knowledge of the basic neurochemical mechanisms that explain the reciprocal association. This information is essential to formulate interventions that would unlock the sleep-pain interaction to safely and effectively improve patients’ emotional and physical well-being.
Potential Mechanisms of Interaction
Pain can be caused by multiple neurobiologic mechanisms, involving neuronal as well as non-neuronal components of the monoaminergic system, opioid system, immune system, hypothalamus-pituitary-adrenal (HPA) system, and melatonin system, among others. Some of the components involved in the pathophysiology of pain are also affected by sleep loss. Therefore, these components might establish potential candidates in mediating the sleep loss-induced development of spontaneous pain and hyperalgesia. Potential mechanisms that have been hypothesized to mediate the effects of sleep loss on pain are:
Monoaminergic system
The monoaminergic (norepinephrine and serotonin) and opioidergic systems are closely related and can interact to regulate several behavioral functions, including nociception (the sensory nervous system’s response to certain harmful or potentially harmful stimuli). An intact serotonergic system, along with noradrenergic neurons, appears to be necessary for mu-opioid antinociception (the action or process of blocking the detection of a painful or injurious stimulus by sensory neurons) functioning involved in endogenous pain inhibition. – Milan MJ. Descending control of Pain. Prog Neurobiol 2002;66:355-474
The association of serotonin receptors in the modulation of pain is further suggested by effectiveness of serotonin reuptake inhibitor analgesics for management of various clinical conditions, such as fibromyalgia.
The serotonergic system is also suspected in sleep-wake regulation and has long been thought to play a key role based on animal studies. Scientists have induced sever insomnia by blocking serotonin synthesis. – Jouvet M. Role of monoamines and acetylcholine-containing neurons in regulation of sleep-waking cycle. Ergeb Physiol 1972;64:166-307
Then again, sleep deprivation in animals leads to impairment of the serotonergic system, including a reduction in extracellular serotonin levels in various brain areas and desensitization of the serotonin IA receptor. – Penalva RG, Lancel M, Flachskamm C, Reul JMHM, Holsboer F, Linthorst ACE. Effect of sleep and sleep deprivation on serotonergic neurotransmission in the hippocampus: A combined in vivo microdialysis/EEG study in rats. Eur J Neurosci 2003;17:1896-1906
Given that the serotonergic system is involved in pain and sleep-wake regulation (eg, serotonin type 1 and 2 receptor), an alteration in this system may present a potential mechanistic factor mediating the hyperalgesic effects of sleep loss that deserves further investigation.
Opioid system
The opioid system is well known to modulate nociceptive processing, and painful events are associated with the release of endogenous opioid peptides in various brain areas in animals and humans. It was hypothesized that deprivation of rapid eye movement (REM) sleep may increase pain sensitivity in rat through alterations in the opioid system. In rats, Scientists showed that the experimentally activated analgesic properties of endogenous and exogenous opioids, through stress, intracerebroventricular administration of an enkephalinase inhibitor, or the mu-opioid agonist morphine, are reversed by REM sleep deprivation. This suggests that the hyperalgesic effects of REM sleep deprivation are mediated through an opioid antinociception mechanism. – Ukponmwan OE, Rupreht J, Dzoljic MR, REM-sleep deprivation decreases the antinociceptive property of enkephalinase-inhibition, morphine and cold-water-swim. Gen Pharmcaol 1984;15:255-258
In humans, the role of the opioid system in sleep-wake regulation and in mediating the hyperalgesic effects of sleep loss has not been directly addressed, but Scientists have shown that sleep loss vis multiple forced awakenings impairs “natural” descending pain inhibition, which is in part mediated by the endogenous opioid and monoaminergic systems. – Smith MT, Edwards RR, McCann UD, Haythornthwaite JA. The effects of sleep deprivation on pain inhibition and spontaneous pain in women. Sleep 2007;30:494-505
Immune system
Mobilization of the inflammatory system is a key feature in various types of painful conditions and experimental sleep loss. Inflammatory markers are elevated during sleep deprivation and various painful conditions. The role of the prostaglandin (PG) system and the proinflammatory cytokine system are important in pain and sleep-wake modulation.
Inflammatory markers and pain
PGs mediate some of the basic features of inflammation. – Griffiths RJ. Prostaglandins and inflammation. In: Gallin J, Synderman R (eds). Inflammation: Basic Principles and Clinical Correlates. Philadelphia:Lippincott Williams & Wilkins, 1999:349-360
They belong to a class of lipid mediators called eicosanoids that are derived from unsaturated fatty acids, such as arachidonic acid, the major lipid component of the cell membrane. Free arachidonic acids are converted to PGs through activation of cyclooxygenase I (COX-I) and cyclooxygenase 2 (COX-2) catalysts by cytokines, growth factors, and other inflammatory processes at the site of the injury and in the central nervous system. There are several endogenously produced PGs in the human body (PGD2, PGE2, PGF2a, PGI2, and thromboxane A2).
PGE2 appears to have a major role in mediating pain and pain hypersensitivity. However, other PGs have been shown to have proalgesic properties. PGs generate pain hypersensitivity through sensitization of primary sensory neurons and reduce the nociceptor response threshold to a number of stimuli within the nociceptive peripheral terminals. – Burian M, Geisslinger G. COX-dependent mechanisms involved in the antinociceptive action of NSAIDS at central and peripheral sites. Pharmacol Ther 2005;107:139-154.
PGs have been found to be amplified in various experimental models of inflammation and in clinical disorders, including increased PGs in the synovial fluid of patients with temporomandibular disorders, rheumatoid arthritis, and elevated levels in gingival tissue of patients suffering from periodontal disease. – Alstergren P, Kopp S. Prostaglandin E-2 in temporomandibular jointsynovial fluid and its relation to pain and inflammatory disorders. J OrmalMaxillofac Surg 2000;58:180-186
– Prete PE, Gurakar-Osborne A. The contribution of synovial fluid lipoproteins to the chronic synovitis of rheumatoid arthritis. Prostoglandin 1997;54:689-698.
– Howell TH, Williams RC. Nonsteroidal anti-inflammatory drugs as inhibitors of periodontal-disease progression. Crit Rev Oral Biol Med 1993;4:177-196
Furthermore, evidence of PG involvement in the development of the marked analgesic therapeutic affect of nonsteroidal anti-inflammatory drugs, which primarily act by preventing the synthesis of PGs through inhibition of COX-I and/or COX-2 enzymes.
Prostaglandins are the classic pain-sensitizing substances. However cytokines, such as interleukin I(IL-I), interleukin 6 (IL-6), and tumor necrosis factor a(TNF-a), have been recognized as potent pain-inducing and pain-facilitating factors capable of sensitizing the primary sensory neurons, leading to hyperalgesia in an animal model. IL-6, for example, is a small protein that is produced mainly by monocytes and macrophages but also by cells. IL-6 has pleiotropic effects. It plays a critical role in the acute-phase inflammatory response. It is one of the major cytokines that can activate the hypothalamic–pituitary–adrenal axis system, and it increases the basal lipolysis. It is upregulated in peripheral nerves of animals under conditions of experimental pain, and peripheral injection of IL-6 induces pain.
Inflammatory markers and sleep
Sleep and the immune system are reciprocally linked. Strong evidence in animal studies show that challenging the immune system with infectious agents such as bacterial, viral, or fungal organisms causes disruption in sleep-wake behavior. This was demonstrated in most studies as an increase in plasma cytokine levels, has been shown to increase the amount and intensity of non-REM sleep. – Mullington J, Korth C, Hermann DM et al. Dose-dependent effects of endotoxin on human sleep. Am J Physiol 2000;278:R947-R955
Hypothalamus-pituitary-adrenal system
The Hypothalamus-pituitary-adrenal (HPA) system mediates the response to psychologic and physical stress. The release of corticotropin-releasing hormone from the hypothalamus stimulates the secretion of adrenocorticotropin hormone from the pituitary, which stimulated the secretion of glucocorticoids from the adrenal cortex. Cortisol, the principal stress hormone, affects various immunologic functions and has mostly anti-inflammatory effects.
Activation of the HPA system during inflammatory responses and ensuing inhibition or upregulation of proinflammatory and anti-inflammatory cytokine production appear to be key mechanisms through which stress affects disease susceptibility. In patients with chronic pain conditions, such as rheumatoid arthritis, fibromyalgia or headaches, adrenocortiacal hyporesponsiveness has been reported. This could cause weak immunoregulation and increase the risk of inflammation.
HPA system activity reveals a robust circadian rhythm, with the lowest concentrations of cortisol observed early in the night and peak valued at the end of the sleep phase. Mild increases in cortisol secretion have been found in several human sleep deprivation or fragmentation experiments. When sleep is chronically disrupted, the effects on the HPA axis may accrue and lead to adverse health consequences. – Meerlo P, Sgoifo A, Suchechki D. Restricted and disrupted sleep: Effects on autonomic function, neuroendocrine stress systems and stress responsivity. Sleep Med Rev 2008;12:197-210.
Cortisol and synthetic glucocorticoids (prednisolone and dexamethasone) may modulate the nociceptive system indirectly, through changes in the secretion of prostaglandin E2 biosynthesis, as well as release of opioids or changes in serotonergic functions. – Stein C Mechanisms of disease- The control of pain in peripheral tissue by opioids. N Engl J Med 1995;332:1685-1690.
Melatonin system
Synthesis of melatonin, the main hormone secreted by the pineal gland, is stimulated by darkness and suppressed by light. In humans, maximal plasma levels occur during the night, between 3 and 4 am. Melatonin has many actions and properties, including anti-inflammatory, analgesic, and sleep-promoting effects. For instance, melatonin is able to inhibit PGE2 synthesis and reduce upregulation of proinflammatory cytokines, both markers known for their pain-sensitizing actions. Mechanisms of melatonin’s analgesic properties are not entirely clear but may also involve Beta-endorphin, which is increased in cell cultures after melatonin administration, or potentiating gama-aminobutyric acid transmission, which is involved in endogenous pain-inhibitory actions. Patients suffering from primary insomnia have been found to have lower serum melatonin concentrations than healthy controls, and potentiating the melatonin signal by exogenous melatonin administration has been shown to have a modest sleep-promoting effect. – Brzezinski A, Bangel MG, Wurtman Rj, et al. Effects of exogenous melatonin on sleep: A meta-analysis. Sleep Med Rev 2005;9:41-50
Changes in the melatonin signal appear to be of particular importance in the pathophysiology of headache disorders. –Peres MFP. Melatonin, the pineal gland and the implications for headache disorders. Cephalalgia 2005;25:403-411
Headache and sleep complaints often coexist, and based on patients’ reports, insufficient sleep may trigger or worsen headaches that is alleviated by adequate sleep. Thus, the melatonin system may present another potential candidate through which insufficient sleep may facilitate pain, and this may be of particular importance in those vulnerable to headaches.