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: lina.fine@swedish.org
Phys Med Rehabil Clin N Am 26 (2015) 301308
http://dx.doi.org/10.1016/j.pmr.2015.01.002
1047-9651/15/$ see front matter 2015 Elsevier Inc. All rights reserved.

pmr.theclinics.com

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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 individuals 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.)

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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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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

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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 (68 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 persons
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

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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.
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