Sleep Important Considerations in Management of Pain Lina Fine,
MD, MPhil
KEYWORDS Sleep Pain Fragmentation Nociception Mood Circadian rhythm Insomnia KEY POINTS Sleep patterns share common pathways with nociceptive stimuli. Causes for sleep fragmentation include (1) sleep disordered breathing; (2) abnormal leg movements, including restless legs syndrome, occurring while the patient is awake, and periodic limb movements that occur while the patient is asleep; (3) underlying mood disorder, which may be exacerbated by physical symptoms; (4) hormonal changes.
SUMMARY AND OBJECTIVES
1. Sleep patterns share common pathways with nociceptive stimuli. Several important factors are reviewed in considering connections between sleep and pain. 2. Causes for sleep fragmentation include: a. Sleep disordered breathing, which may present with snoring, witnessed apneas, daytime sleepiness, and also with more subtle symptoms like morning headache and anxiety. Home sleep testing or more extensive in-laboratory polysomnography may be used for diagnosis of this condition. Treatment options include use of continuous positive airway pressure (CPAP); oral advancement devices (OAD); weight loss; surgical interventions; and, most recently, US Food and Drug Administration (FDA)–approved upper airway stimulation devices. b. Abnormal leg movements, including restless legs syndrome (RLS), occurring while the patient is awake and periodic limb movements that occur while the patient is asleep. c. Underlying mood disorder, which may be exacerbated by physical symptoms. 3. Identification and management of insomnia includes the definition of the condition, pharmacologic interventions, the role of circadian rhythms and clock adjustments, and the use of cognitive behavior therapy (CBT) for insomnia.
Swedish Sleep Medicine, Swedish Neuroscience Institute, Swedish Medical Center, 500, 17 Ave, Seattle, WA 98122, USA E-mail address: [email protected] Phys Med Rehabil Clin N Am 26 (2015) 301–308 http://dx.doi.org/10.1016/j.pmr.2015.01.002 1047-9651/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
pmr.theclinics.com
302
Fine
Pain and sleep disorders share a reciprocal relationship: pain interferes with sleep quality and, in turn, poor and truncated sleep perpetuates pain symptoms. Furthermore, nociceptive pathways and sleep-wake pathways may share common central serotonergic transmission. A survey of 18,980 individuals from 5 European countries showed that significantly more participants with chronic painful conditions (eg, limb or joint pain, backache, gastrointestinal pain, and headache) than those without pain experienced insomnia. Compared with individuals without chronic pain conditions, those with pain were 3 times more likely to report difficulties with initiating sleep, maintaining sleep, early morning awakenings, and nonrestorative sleep.1 There may be confounding factors, such as underlying mental illness and the onset of menopause. These confounding factors are often important and need to be considered when addressing sleep difficulties in patients with pain. Menopause is an important physiologic change in women that has both physiologic and psychological implications. As Fig. 1shows, sleep difficulties arise during this period that may layer on the nocturnal symptoms associated with pain. Average adults require 7 to 8 hours sleep, with less than 6 and more than 9 hours correlating with adverse health outcomes. Insomnia encompasses the inability to initiate sleep, maintain sleep, or reach a state of restfulness and refreshment on awakening. It may be associated with daytime symptoms of fatigue, memory deficits, social/vocational/academic performance deficits, mood changes, daytime sleepiness, lack of motivation, vulnerability to accidents, somatic symptoms, and a preoccupation with sleep that perpetuates the cycle of insomnia. Thirty percent of the working population in the United States sleeps for less than 6 hours a day. Sleep deprivation may lead to a one-third reduction in glucose metabolism2 and increase in C-reactive protein and interleukin-6 levels.3 Sleep for longer than 9 hours seems to have similar effects. Onen and colleagues4 found that men showed hyperalgesia to mechanical stimuli following 40 hours of total sleep deprivation and a robust analgesic effect after selective slow wave sleep recovery. Sleep deprivation may be dictated by the individual’s lifestyle and habits, but several identifiable sleep conditions may magnify pain symptoms and trigger awakenings. When assessing an individual who has sleep difficulties it is helpful to have a checklist of potential conditions that need to be ruled out or addressed. The first important step in such assessment is to evaluate the patient for sleep disordered breathing. Snoring, awakenings with gasping, palpitations, panic, and dry mouth/sore throat are common symptoms of sleep apnea syndrome. In addition, there are often more subtle symptoms, such as morning headache, anxiety, and poor daytime concentration, that point to potential sleep disordered breathing (Table 1). always or almost always dissatisied with sleep awakening too early in the morning waking up during night and can not sleep dificulty initiating sleep
pre peri post
waking up repeatedly during
Fig. 1. Odds ratios for self-reported sleep problems among premenopausal, perimenopausal, and postmenopausal women (n 5 589). (Data from Young T, Rabago D, Zgierska A, et al. Objective and subjective sleep quality in premenopausal, perimenopausal, and postmenopausal women in the Wisconsin Sleep Cohort Study. Sleep 2003;26(6):670. Available at: http://www.ncbi.nlm.nih.gov/pubmed/14572118.)
Sleep–Management of Pain
Table 1 Sleep deprivation symptoms
Snoring/apneas Sleepiness
Men
Women
***
*
***
**
*
***
Depressive features
*
**
Apnea frequency
**
*
Hypopnea frequency
*
**
AM
Headaches
* Qualitative index comparing findings in males and females. Adapted from Kapsimalis F, Kryger MH. Gender and obstructive sleep apnea syndrome, part 1: Clinical features. Sleep 2002;25(4):411. Available at: http://www.ncbi.nlm.nih.gov/pubmed/ 12071542.
Using a quick screening tool such as the STOP BANG questionnaire is a helpful way to screen many patients. Snoring (yes/no) Tired (yes/no) Observed apneas (yes/no) Pressure, treatment of blood pressure (yes/no) Body mass index greater than 35 (yes/no) Age more than 50 years (yes/no) Neck circumference greater than 40 cm (yes/no) Gender male (yes/no). Answering “Yes” to more than 3 of these questions suggests a high risk of sleep apnea.5 Patients at risk can then be assessed with a polysomnogram in a sleep laboratory setting or with a home sleep test device, which is especially helpful in severe cases of sleep apnea. If sleep apnea is diagnosed, treatment options include CPAP, oral appliance, weight loss, and surgical intervention. Resultant improvement in sleep continuity and daytime energy level facilitates improved coping with a range of pain symptoms. The next important step is to assess for abnormal leg movements during sleep and for RLS (Fig. 2).
Fig. 2. Prevalence of RLS. (Data from Allen RP, Walters AS, Montplaisir J, et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med 2005;165(11):1289.)
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Fine
Patients may describe grabbing sensations, sensations that feel creepy-crawly or shocklike, sensations that feel like worms moving, or bubbling in the veins. RLS results in disturbed sleep and sleep onset insomnia and is also associated with a higher risk of depression, anxiety, and somatic pain.6 Diagnostic criteria for RLS include: 1. 2. 3. 4.
Urge to move: irresistible, involving both legs and may involve arms and trunk Worsening symptoms at rest (body position should not matter) Relief with movement (no symptoms during movement) Worsening in the evening or at night (circadian fluctuation)
RLS may mimic positional discomfort, cramps, positional ischemia, neuropathy, radiculopathy, or hypnic jerks, and should be carefully distinguished from these conditions.7 RLS is 4 times more likely in first-degree relatives. A polysomnogram is typically unnecessary unless the patient is unable to articulate symptoms. Although RLS is a condition that the patient is able to report to the provider, periodic limb movements of sleep is a condition diagnosed in the sleep laboratory with recorded periodic episodes of repetitive and highly stereotyped limb movements that occur during sleep and lead to impairment in sleep quality or daytime functioning. Periodic limb movement disorder is defined by the presence of periodic limb movements, electrographic arousals on a sleep study that result in broken sleep, and daytime symptoms of fatigue. Pharmacologic treatments of RLS and periodic limb movement disorder are similar. Some patients with RLS develop symptoms when ferritin levels decrease to less than 50 ng/mL, and supplementation with iron may improve the symptoms. Other conditions associated with RLS are pregnancy (more commonly the second half), renal insufficiency/failure, neuropathy (Charcot-Marie-Tooth type II only), lumbosacral radiculopathy, anxiety, Parkinson disease, and multiple sclerosis. Dopamine agonists, such as ropinirole and pramipexole, and gamma-aminobutyric acid (GABBA)–ergic (GABA normalizing and increasing) medications are the first approach to the management of restless legs as well periodic limb movements. Long-term use of carbidopa/ levodopa may have limited efficacy because of augmentation, which is the process of diminishing efficacy despite dose escalation as frequency of movements, number of duration, body parts affected, and intensity of restlessness worsen with increasing doses. These patients should be cautious in their use of selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, antihistamines, alcohol, and caffeine because these agents may exacerbate restless legs. The next step is to assess underlying psychological factors, including pain and mood, which can affect sleep. Patients with pain and/or mood disorders may have excess central autonomic activity triggered by pain as well as peripheral autonomic hyperactivity, including tachycardia, hypertension, mydriasis, vasoconstriction in extremities, and hyperreflexia. Such states of hyperarousal can interfere with the normal process of relaxation that precedes sleep.8,9 Because of the difficulty of assessing the direction of cause and effect between insomnia and mood, it is often most effective to manage these conditions by using both pharmacologic and nonpharmacologic approaches. Pharmacologic approaches to the treatment of insomnia can be split into hypnotic and psychotropic medications that can be used to induce or maintain sleep. Hypnotics and benzodiazepines carry the risk of dependence and respiratory suppression at high doses, especially if combined with opioid agents. For this reason, careful medication selection is especially critical in patients with pain (because of frequent coadministration of opioids, antiepileptic agents, neuropathic agents, and
Sleep–Management of Pain
muscle relaxants). In patients at low risk for addiction, these medications may be a helpful for managing acute insomnia (symptoms lasting less than 30 days). Overthe-counter antihistamines may also be of modest efficacy. Benzodiazepine receptor agonists are among the most common prescription sleeping aids and include eszopiclone and zaleplon. These agents are highly selective for the alpha-1 subunits of the GABA-a receptors, which facilitates a specific sedative effect. However, adequate time (6–8 hours, depending on the agent) must be allowed to pass between dose administration and the next morning awakening. When blood levels of eszopiclone were checked 8.5 hours after administration, driving impairment equivalent to that of an individual with blood alcohol concentration of 0.5% was observed.10 Other concerning side effects include daytime sedation, risk of falls (especially in the elderly), confusion, exacerbation of underlying breathing difficulties (most concerning in patients who are also on opioid medications), and short-term memory issues. Sleep walking and sleep eating have been reported with zolpidem specifically but are possible with other hypnotics in the same class. Benzodiazepines specifically targeting sleep include temazepam, triazolam, and estazolam. Concern remains regarding the effect of benzodiazepines and hypnotics on cognition. A recent case-control study by Billioti de Gage and colleagues11 found that benzodiazepine use may be associated with higher risk of developing Alzheimer disease (the study tracked individuals more than 66 years of age over 5 years after starting benzodiazepines). Other medications to consider in the treatment of sleep problems: Antidepressant medications with sedative properties include tricyclic antidepressants (doxepin, nortriptyline, amitriptyline), the tetracyclic antidepressant mirtazapine, and the selective serotonin reuptake inhibitor trazodone. In 2014 the FDA approved a novel sleeping aid called suvorexant. It blocks orexin receptors in lateral hypothalamus. Orexin is required for alertness and blocking this pathway may help with sleep induction (the sleep initiation effect is dose related). Another agent with a unique mechanism of action is ramelteon, which is a melatonin receptor (MT-1 and MT-2) agonist that can be used for sleep initiation difficulties. MT-1 binding inhibits circadian-mediated wake-promoting activity, thereby allowing the brain to turn off. MT-2 receptors are involved in the timing of sleep. Melatonin (discussed further later) has an important role in sleep initiation because it advances individual circadian clocks by inducing drowsiness earlier in the night, thus allowing earlier sleep onset when used to advance a person’s biological clock. Sleep-wake cycles are intricately linked to multiple environmental and internal stimuli. These circadian rhythms dictate when an individual may become drowsy or wake up. Melatonin is a biogenic amine that is found in humans, animals, and plants. In mammals, melatonin is produced by the pineal gland. Secretion of melatonin increases in darkness and decreases with exposure to light (Fig. 3). Melatonin production begins gradually after sunset, peaks in the earlier part of the night, and drastically diminishes by early morning. Hence, if a melatonin supplement is used to address insomnia, it is advisable to take a low dose several hours before bedtime. Because its concentration increases with dimming of light, it is advisable to keep lights dim following a dose of melatonin. This supplement should be used cautiously in patients who have nightmares because it may cause vivid, although not necessarily disturbing, dreams. Some individuals, often known as night owls,
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Fig. 3. Regulation of melatonin production and receptor function. Melatonin is synthesized in the pineal gland and in the retina. In the pineal gland, melatonin (MLT) synthesis follows a rhythm driven by the suprachiasmatic nucleus, the master biological clock. Neural signals from the SCN follow a multisynaptic pathway to the superior cervical ganglia. Norepinephrine released from postganglionic fibers activates a1- and b1-adrenoceptors in the pinealocyte, leading to increases in second messengers (i.e., cAMP and inositol trisphosphate) and the activity of AA-NAT, the rate-limiting step in melatonin synthesis. The system is dramatically inhibited by light, the external cue that allows entrainment to the environmental light/dark cycle. The photic signal received by the retina is transmitted to the SCN via the retinohypothalamic tract, which originates in a subset of retinal ganglion cells. Pineal melatonin thus serves as the internal signal that relays day length, allowing regulation of neuronal activity (MT1) and circadian rhythms (MT1, MT2) in the SCN (Dubocovich, 2007), of neurochemical function in brain through the MT1 and MT2 receptors (Dubocovich, 2006), of vascular tone through activation of MT1 (constriction) and MT2 receptors (dilation) in arterial beds (Masana et al., 2002), and seasonal changes in reproductive physiology and behavior through activation of MT1 receptors in the pars tuberalis (Duncan, 2007). The pars tuberalis of the pituitary gland interprets this rhythmic melatonin signal and generates a precise cycle of expression of circadian genes through activation of MT1 receptors. Melatonin synthesis in the photoreceptors of the retina follows a similar circadian rhythm generated by local oscillators (Tosini et al., 2007). Activation of MT1 and MT2 melatonin receptors regulate retina function and hence transmission of photic information to the brain (Dubocovich et al., 1997). (Adapted from Dubocovich ML, Masana M. Melatonin receptor signaling. In: Henry H, Norman A, editors. Encyclopedia of hormones and related cell regulators. San Diego: Academic Press; 2003; with permission.)
experience a delay in their melatonin production (and other physiologic processes, including nocturnal temperature regulation). Specific genetic mutations have been isolated in so-called clock genes (including Per2, Per 3, and aralkylamine N-acetyltransferase [AANAT]) that may explain the predilection for different sleep-wake schedules.12 When faced with distracting external stimuli, as well as the burden of physical ailments, such patients are prone to develop sleep initiation insomnia (ie, their
Sleep–Management of Pain
sleep-wake phases become delayed, resulting in later bedtimes and further difficulty awakening in the morning). In addition to using melatonin in these patients, keeping lights dim in the evening can help to advance the sleep schedule, thereby allowing sensations of drowsiness to occur earlier in the evening. With evening sleep phase delay (later bedtime) may also come later awakening times. These individuals must maintain regular wake up times with morning light exposure to help regulate this cycle and enhance morning alertness. Sunlight or light boxes (10,000 lx) are the most effective methods. Circadian shifting ideally should be combined with CBT to address disrupted sleep. When applied independently and in coadministration with hypnotic zolpidem to address insomnia, CBT alone was the most effective long-term treatment at 6-month follow up. Note that a hypnotic was helpful when used briefly during the first stages of insomnia.13 The cognitive component of CBT includes addressing dysfunctional beliefs about sleep and catastrophizing thoughts about next-day performance. Behavioral components focus on healthy sleep habits, including avoidance of caffeine in the later part of the day, avoidance of television in bed, and avoidance of excessive time in bed without sleep. There is evidence to suggest that both components are important for the management of insomnia.14 Just as it is important to use a broad range of tools to address individual pain symptoms, it is essential to adopt a nuanced approach to diagnosis and management of insomnia. Such an approach, which reflects the common physiologic pathways and unique psychological forces that dictate patterns of sleep, is best suited to interrupting dysfunctional pain/sleep cycles. REFERENCES
1. Ohayon MM. Relationship between chronic painful physical condition and insomnia. J Psychiatr Res 2005;39(2):151–9. 2. Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet 1999;354(9188):1435–9. 3. Patel SR, Zhu X, Storfer-Isser A, et al. Sleep duration and biomarkers of inflammation. Sleep 2009;32(2):200–4. Available at: http://www.pubmedcentral.nih. gov/articlerender.fcgi?artid52635584&tool5pmcentrez&rendertype5abstract. 4. Onen SH, Alloui A, Gross A, et al. The effects of total sleep deprivation, selective sleep interruption and sleep recovery on pain tolerance thresholds in healthy subjects. J Sleep Res 2001;10(1):35–42. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/11285053. 5. Chung F, Yegneswaran B, Liao P, et al. STOP questionnaire: a tool to screen patients for obstructive sleep apnea. Anesthesiology 2008;108(5):812–21. 6. Allen RP, Picchietti D, Hening WA, et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med 2003;4(2):101–19. Available at: http://www.ncbi.nlm.nih. gov/pubmed/14592341. 7. Hening WA, Allen RP, Washburn M, et al. The four diagnostic criteria for restless legs syndrome are unable to exclude confounding conditions (“mimics”). Sleep Med 2009;10(9):976–81. 8. Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain 2009;10(9):895–926. 9. May A. Chronic pain may change the structure of the brain. Pain 2008;137 (1):7–15.
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10. Gustavsen I, Hjelmeland K, Bernard JP, et al. Individual psychomotor impairment in relation to zopiclone and ethanol concentrations in blood–a randomized controlled double-blinded trial. Addiction 2012;107(5):925–32. 11. Billioti de Gage S, Moride Y, Ducruet T, et al. Benzodiazepine use and risk of Alzheimer’s disease: case-control study. BMJ 2014;349:g5205. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid54159609&tool5 pmcentrez&rendertype5abstract. 12. Lamont EW, James FO, Boivin DB, et al. From circadian clock gene expression to pathologies. Sleep Med 2007;8(6):547–56. 13. Morin CM, Vallie`res A, Guay B, et al. Cognitive behavioral therapy, singly and combined with medication, for persistent insomnia: a randomized controlled trial. JAMA 2009;301(19):2005–15. 14. Harvey AG, Be´langer L, Talbot L, et al. Comparative efficacy of behavior therapy, cognitive therapy, and cognitive behavior therapy for chronic insomnia: a randomized controlled trial. J Consult Clin Psychol 2014;82(4):670–83.
MD, MPhil
KEYWORDS Sleep Pain Fragmentation Nociception Mood Circadian rhythm Insomnia KEY POINTS Sleep patterns share common pathways with nociceptive stimuli. Causes for sleep fragmentation include (1) sleep disordered breathing; (2) abnormal leg movements, including restless legs syndrome, occurring while the patient is awake, and periodic limb movements that occur while the patient is asleep; (3) underlying mood disorder, which may be exacerbated by physical symptoms; (4) hormonal changes.
SUMMARY AND OBJECTIVES
1. Sleep patterns share common pathways with nociceptive stimuli. Several important factors are reviewed in considering connections between sleep and pain. 2. Causes for sleep fragmentation include: a. Sleep disordered breathing, which may present with snoring, witnessed apneas, daytime sleepiness, and also with more subtle symptoms like morning headache and anxiety. Home sleep testing or more extensive in-laboratory polysomnography may be used for diagnosis of this condition. Treatment options include use of continuous positive airway pressure (CPAP); oral advancement devices (OAD); weight loss; surgical interventions; and, most recently, US Food and Drug Administration (FDA)–approved upper airway stimulation devices. b. Abnormal leg movements, including restless legs syndrome (RLS), occurring while the patient is awake and periodic limb movements that occur while the patient is asleep. c. Underlying mood disorder, which may be exacerbated by physical symptoms. 3. Identification and management of insomnia includes the definition of the condition, pharmacologic interventions, the role of circadian rhythms and clock adjustments, and the use of cognitive behavior therapy (CBT) for insomnia.
Swedish Sleep Medicine, Swedish Neuroscience Institute, Swedish Medical Center, 500, 17 Ave, Seattle, WA 98122, USA E-mail address: [email protected] Phys Med Rehabil Clin N Am 26 (2015) 301–308 http://dx.doi.org/10.1016/j.pmr.2015.01.002 1047-9651/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
pmr.theclinics.com
302
Fine
Pain and sleep disorders share a reciprocal relationship: pain interferes with sleep quality and, in turn, poor and truncated sleep perpetuates pain symptoms. Furthermore, nociceptive pathways and sleep-wake pathways may share common central serotonergic transmission. A survey of 18,980 individuals from 5 European countries showed that significantly more participants with chronic painful conditions (eg, limb or joint pain, backache, gastrointestinal pain, and headache) than those without pain experienced insomnia. Compared with individuals without chronic pain conditions, those with pain were 3 times more likely to report difficulties with initiating sleep, maintaining sleep, early morning awakenings, and nonrestorative sleep.1 There may be confounding factors, such as underlying mental illness and the onset of menopause. These confounding factors are often important and need to be considered when addressing sleep difficulties in patients with pain. Menopause is an important physiologic change in women that has both physiologic and psychological implications. As Fig. 1shows, sleep difficulties arise during this period that may layer on the nocturnal symptoms associated with pain. Average adults require 7 to 8 hours sleep, with less than 6 and more than 9 hours correlating with adverse health outcomes. Insomnia encompasses the inability to initiate sleep, maintain sleep, or reach a state of restfulness and refreshment on awakening. It may be associated with daytime symptoms of fatigue, memory deficits, social/vocational/academic performance deficits, mood changes, daytime sleepiness, lack of motivation, vulnerability to accidents, somatic symptoms, and a preoccupation with sleep that perpetuates the cycle of insomnia. Thirty percent of the working population in the United States sleeps for less than 6 hours a day. Sleep deprivation may lead to a one-third reduction in glucose metabolism2 and increase in C-reactive protein and interleukin-6 levels.3 Sleep for longer than 9 hours seems to have similar effects. Onen and colleagues4 found that men showed hyperalgesia to mechanical stimuli following 40 hours of total sleep deprivation and a robust analgesic effect after selective slow wave sleep recovery. Sleep deprivation may be dictated by the individual’s lifestyle and habits, but several identifiable sleep conditions may magnify pain symptoms and trigger awakenings. When assessing an individual who has sleep difficulties it is helpful to have a checklist of potential conditions that need to be ruled out or addressed. The first important step in such assessment is to evaluate the patient for sleep disordered breathing. Snoring, awakenings with gasping, palpitations, panic, and dry mouth/sore throat are common symptoms of sleep apnea syndrome. In addition, there are often more subtle symptoms, such as morning headache, anxiety, and poor daytime concentration, that point to potential sleep disordered breathing (Table 1). always or almost always dissatisied with sleep awakening too early in the morning waking up during night and can not sleep dificulty initiating sleep
pre peri post
waking up repeatedly during
Fig. 1. Odds ratios for self-reported sleep problems among premenopausal, perimenopausal, and postmenopausal women (n 5 589). (Data from Young T, Rabago D, Zgierska A, et al. Objective and subjective sleep quality in premenopausal, perimenopausal, and postmenopausal women in the Wisconsin Sleep Cohort Study. Sleep 2003;26(6):670. Available at: http://www.ncbi.nlm.nih.gov/pubmed/14572118.)
Sleep–Management of Pain
Table 1 Sleep deprivation symptoms
Snoring/apneas Sleepiness
Men
Women
***
*
***
**
*
***
Depressive features
*
**
Apnea frequency
**
*
Hypopnea frequency
*
**
AM
Headaches
* Qualitative index comparing findings in males and females. Adapted from Kapsimalis F, Kryger MH. Gender and obstructive sleep apnea syndrome, part 1: Clinical features. Sleep 2002;25(4):411. Available at: http://www.ncbi.nlm.nih.gov/pubmed/ 12071542.
Using a quick screening tool such as the STOP BANG questionnaire is a helpful way to screen many patients. Snoring (yes/no) Tired (yes/no) Observed apneas (yes/no) Pressure, treatment of blood pressure (yes/no) Body mass index greater than 35 (yes/no) Age more than 50 years (yes/no) Neck circumference greater than 40 cm (yes/no) Gender male (yes/no). Answering “Yes” to more than 3 of these questions suggests a high risk of sleep apnea.5 Patients at risk can then be assessed with a polysomnogram in a sleep laboratory setting or with a home sleep test device, which is especially helpful in severe cases of sleep apnea. If sleep apnea is diagnosed, treatment options include CPAP, oral appliance, weight loss, and surgical intervention. Resultant improvement in sleep continuity and daytime energy level facilitates improved coping with a range of pain symptoms. The next important step is to assess for abnormal leg movements during sleep and for RLS (Fig. 2).
Fig. 2. Prevalence of RLS. (Data from Allen RP, Walters AS, Montplaisir J, et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med 2005;165(11):1289.)
303
304
Fine
Patients may describe grabbing sensations, sensations that feel creepy-crawly or shocklike, sensations that feel like worms moving, or bubbling in the veins. RLS results in disturbed sleep and sleep onset insomnia and is also associated with a higher risk of depression, anxiety, and somatic pain.6 Diagnostic criteria for RLS include: 1. 2. 3. 4.
Urge to move: irresistible, involving both legs and may involve arms and trunk Worsening symptoms at rest (body position should not matter) Relief with movement (no symptoms during movement) Worsening in the evening or at night (circadian fluctuation)
RLS may mimic positional discomfort, cramps, positional ischemia, neuropathy, radiculopathy, or hypnic jerks, and should be carefully distinguished from these conditions.7 RLS is 4 times more likely in first-degree relatives. A polysomnogram is typically unnecessary unless the patient is unable to articulate symptoms. Although RLS is a condition that the patient is able to report to the provider, periodic limb movements of sleep is a condition diagnosed in the sleep laboratory with recorded periodic episodes of repetitive and highly stereotyped limb movements that occur during sleep and lead to impairment in sleep quality or daytime functioning. Periodic limb movement disorder is defined by the presence of periodic limb movements, electrographic arousals on a sleep study that result in broken sleep, and daytime symptoms of fatigue. Pharmacologic treatments of RLS and periodic limb movement disorder are similar. Some patients with RLS develop symptoms when ferritin levels decrease to less than 50 ng/mL, and supplementation with iron may improve the symptoms. Other conditions associated with RLS are pregnancy (more commonly the second half), renal insufficiency/failure, neuropathy (Charcot-Marie-Tooth type II only), lumbosacral radiculopathy, anxiety, Parkinson disease, and multiple sclerosis. Dopamine agonists, such as ropinirole and pramipexole, and gamma-aminobutyric acid (GABBA)–ergic (GABA normalizing and increasing) medications are the first approach to the management of restless legs as well periodic limb movements. Long-term use of carbidopa/ levodopa may have limited efficacy because of augmentation, which is the process of diminishing efficacy despite dose escalation as frequency of movements, number of duration, body parts affected, and intensity of restlessness worsen with increasing doses. These patients should be cautious in their use of selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, antihistamines, alcohol, and caffeine because these agents may exacerbate restless legs. The next step is to assess underlying psychological factors, including pain and mood, which can affect sleep. Patients with pain and/or mood disorders may have excess central autonomic activity triggered by pain as well as peripheral autonomic hyperactivity, including tachycardia, hypertension, mydriasis, vasoconstriction in extremities, and hyperreflexia. Such states of hyperarousal can interfere with the normal process of relaxation that precedes sleep.8,9 Because of the difficulty of assessing the direction of cause and effect between insomnia and mood, it is often most effective to manage these conditions by using both pharmacologic and nonpharmacologic approaches. Pharmacologic approaches to the treatment of insomnia can be split into hypnotic and psychotropic medications that can be used to induce or maintain sleep. Hypnotics and benzodiazepines carry the risk of dependence and respiratory suppression at high doses, especially if combined with opioid agents. For this reason, careful medication selection is especially critical in patients with pain (because of frequent coadministration of opioids, antiepileptic agents, neuropathic agents, and
Sleep–Management of Pain
muscle relaxants). In patients at low risk for addiction, these medications may be a helpful for managing acute insomnia (symptoms lasting less than 30 days). Overthe-counter antihistamines may also be of modest efficacy. Benzodiazepine receptor agonists are among the most common prescription sleeping aids and include eszopiclone and zaleplon. These agents are highly selective for the alpha-1 subunits of the GABA-a receptors, which facilitates a specific sedative effect. However, adequate time (6–8 hours, depending on the agent) must be allowed to pass between dose administration and the next morning awakening. When blood levels of eszopiclone were checked 8.5 hours after administration, driving impairment equivalent to that of an individual with blood alcohol concentration of 0.5% was observed.10 Other concerning side effects include daytime sedation, risk of falls (especially in the elderly), confusion, exacerbation of underlying breathing difficulties (most concerning in patients who are also on opioid medications), and short-term memory issues. Sleep walking and sleep eating have been reported with zolpidem specifically but are possible with other hypnotics in the same class. Benzodiazepines specifically targeting sleep include temazepam, triazolam, and estazolam. Concern remains regarding the effect of benzodiazepines and hypnotics on cognition. A recent case-control study by Billioti de Gage and colleagues11 found that benzodiazepine use may be associated with higher risk of developing Alzheimer disease (the study tracked individuals more than 66 years of age over 5 years after starting benzodiazepines). Other medications to consider in the treatment of sleep problems: Antidepressant medications with sedative properties include tricyclic antidepressants (doxepin, nortriptyline, amitriptyline), the tetracyclic antidepressant mirtazapine, and the selective serotonin reuptake inhibitor trazodone. In 2014 the FDA approved a novel sleeping aid called suvorexant. It blocks orexin receptors in lateral hypothalamus. Orexin is required for alertness and blocking this pathway may help with sleep induction (the sleep initiation effect is dose related). Another agent with a unique mechanism of action is ramelteon, which is a melatonin receptor (MT-1 and MT-2) agonist that can be used for sleep initiation difficulties. MT-1 binding inhibits circadian-mediated wake-promoting activity, thereby allowing the brain to turn off. MT-2 receptors are involved in the timing of sleep. Melatonin (discussed further later) has an important role in sleep initiation because it advances individual circadian clocks by inducing drowsiness earlier in the night, thus allowing earlier sleep onset when used to advance a person’s biological clock. Sleep-wake cycles are intricately linked to multiple environmental and internal stimuli. These circadian rhythms dictate when an individual may become drowsy or wake up. Melatonin is a biogenic amine that is found in humans, animals, and plants. In mammals, melatonin is produced by the pineal gland. Secretion of melatonin increases in darkness and decreases with exposure to light (Fig. 3). Melatonin production begins gradually after sunset, peaks in the earlier part of the night, and drastically diminishes by early morning. Hence, if a melatonin supplement is used to address insomnia, it is advisable to take a low dose several hours before bedtime. Because its concentration increases with dimming of light, it is advisable to keep lights dim following a dose of melatonin. This supplement should be used cautiously in patients who have nightmares because it may cause vivid, although not necessarily disturbing, dreams. Some individuals, often known as night owls,
305
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Fig. 3. Regulation of melatonin production and receptor function. Melatonin is synthesized in the pineal gland and in the retina. In the pineal gland, melatonin (MLT) synthesis follows a rhythm driven by the suprachiasmatic nucleus, the master biological clock. Neural signals from the SCN follow a multisynaptic pathway to the superior cervical ganglia. Norepinephrine released from postganglionic fibers activates a1- and b1-adrenoceptors in the pinealocyte, leading to increases in second messengers (i.e., cAMP and inositol trisphosphate) and the activity of AA-NAT, the rate-limiting step in melatonin synthesis. The system is dramatically inhibited by light, the external cue that allows entrainment to the environmental light/dark cycle. The photic signal received by the retina is transmitted to the SCN via the retinohypothalamic tract, which originates in a subset of retinal ganglion cells. Pineal melatonin thus serves as the internal signal that relays day length, allowing regulation of neuronal activity (MT1) and circadian rhythms (MT1, MT2) in the SCN (Dubocovich, 2007), of neurochemical function in brain through the MT1 and MT2 receptors (Dubocovich, 2006), of vascular tone through activation of MT1 (constriction) and MT2 receptors (dilation) in arterial beds (Masana et al., 2002), and seasonal changes in reproductive physiology and behavior through activation of MT1 receptors in the pars tuberalis (Duncan, 2007). The pars tuberalis of the pituitary gland interprets this rhythmic melatonin signal and generates a precise cycle of expression of circadian genes through activation of MT1 receptors. Melatonin synthesis in the photoreceptors of the retina follows a similar circadian rhythm generated by local oscillators (Tosini et al., 2007). Activation of MT1 and MT2 melatonin receptors regulate retina function and hence transmission of photic information to the brain (Dubocovich et al., 1997). (Adapted from Dubocovich ML, Masana M. Melatonin receptor signaling. In: Henry H, Norman A, editors. Encyclopedia of hormones and related cell regulators. San Diego: Academic Press; 2003; with permission.)
experience a delay in their melatonin production (and other physiologic processes, including nocturnal temperature regulation). Specific genetic mutations have been isolated in so-called clock genes (including Per2, Per 3, and aralkylamine N-acetyltransferase [AANAT]) that may explain the predilection for different sleep-wake schedules.12 When faced with distracting external stimuli, as well as the burden of physical ailments, such patients are prone to develop sleep initiation insomnia (ie, their
Sleep–Management of Pain
sleep-wake phases become delayed, resulting in later bedtimes and further difficulty awakening in the morning). In addition to using melatonin in these patients, keeping lights dim in the evening can help to advance the sleep schedule, thereby allowing sensations of drowsiness to occur earlier in the evening. With evening sleep phase delay (later bedtime) may also come later awakening times. These individuals must maintain regular wake up times with morning light exposure to help regulate this cycle and enhance morning alertness. Sunlight or light boxes (10,000 lx) are the most effective methods. Circadian shifting ideally should be combined with CBT to address disrupted sleep. When applied independently and in coadministration with hypnotic zolpidem to address insomnia, CBT alone was the most effective long-term treatment at 6-month follow up. Note that a hypnotic was helpful when used briefly during the first stages of insomnia.13 The cognitive component of CBT includes addressing dysfunctional beliefs about sleep and catastrophizing thoughts about next-day performance. Behavioral components focus on healthy sleep habits, including avoidance of caffeine in the later part of the day, avoidance of television in bed, and avoidance of excessive time in bed without sleep. There is evidence to suggest that both components are important for the management of insomnia.14 Just as it is important to use a broad range of tools to address individual pain symptoms, it is essential to adopt a nuanced approach to diagnosis and management of insomnia. Such an approach, which reflects the common physiologic pathways and unique psychological forces that dictate patterns of sleep, is best suited to interrupting dysfunctional pain/sleep cycles. REFERENCES
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