The literature examining the bidirectional relationship between sleep disorders and chronic pain is reviewed by Dr. Jason Attaman.

1. The Pain-Sleep Nexus
Jason G. Attaman, DO
Dr. Attaman, PLLC
Interventional Pain Management
www.jasonattaman.com
206.395.4422

2. Overview
• Sleep disturbance is one of the most prevalent complaints
of patients with chronically painful conditions
• Experimental studies suggest that the relationship
between sleep disturbance and pain might be reciprocal,
such that pain disturbs sleep continuity/quality and poor
sleep further exacerbates pain
• Evaluation and treatment should focus on sleep
disturbances and painful symptoms at the same time

3. Sleep
XPain
6A

4. Why you want to know…
• Incidence of sleep disorders shown to correlate with chronic
pain
• Treatment of one may improve the other
• An extra tool to use with difficult chronic pain patients

5. Outline
• Statistics
• Sleep stages
• Sleep effecting pain:
– Experimental research
– Clinical research
• Pain effecting sleep:
– Experimental research
– Clinical research
• Animal research
• Possible explanations
• Effect of specific painful diseases on sleep
• Treatment options
• Questions

6. Sleep Disorders
• Estimated to cost the US $70 billion per annum
• Increased incidence in later life, and thus can be expected to increase in
prevalence as the population ages
• 30% of the general American population suffers sleep disturbance (Gallup,
1995)
• Average nightly sleep duration has fallen from 9 hours in 1910 to 7 hours in
2002
• 10-15% of the US has severe or chronic insomnia
• Sleep apnea affects 5-10% of the US population
• Restless legs syndrome causes awakenings in 5-10% of the US
• Sleep deprivation has been linked to obesity, DM II, metabolic disease,
heart disease, psychiatric disease and dementia
• 50% of older people report sleep problems. This complaint is evaluated by
physicians only 10% of the time

7. Pain Disorder Statistics
• Estimated to cost the US $70 billion annum
• Has increased incidence in later life, and thus can be expected to
increase in prevalence as the population ages
• Back pain, headaches, and muscles aches, respectively, most frequent
type of pain experience at night by a sample of 2000 US adults (Gallup,
1996)
• Survey of 1765 Australians found pain to be the most significant factor
in determining poor sleep (Moffitt PF, 1991)
• 50-70% of chronic pain patients have sleep disruption (Atkinson, 1988)
(Pilowsky, 1985)
• Estimated 28 million Americans have sleep complaints in the
context of chronic pain
• Pain may be the most common cause of a co-morbid or secondary
cause of sleep D/O. (Moffitt, 1991)

8. Most Frequent Sleep Complaints in Chronic
Pain Patients
1. Initial insomnia (delayed sleep onset)
2. Frequent Awakenings
3. Decreased sleep duration
4. Daytime sleepiness or fatigue
5. Non-restorative sleep

9. Definitions
• Pain: an unpleasant sensory and emotional experience associated
with actual or potential tissue damage or described in terms of
such damage. (International Assoc. for the Study of Pain)
• Sleep: a natural periodic state of rest for the mind and body, in
which the eyes usually close and consciousness is completely or
partially lost, so that there is a decrease in bodily movement and
responsiveness to external stimuli. During sleep the brain in
humans and other mammals undergoes a characteristic cycle of
brain-wave activity that includes intervals of dreaming.
– NREM: non rapid eye movement
– SWS: slow wave sleep
• Fatigue: caused by muscular or mental exertion (i.e., extended
time-on task) and relieved with rest

10. Stages of Sleep
• Stage 1 Sleep: This is experienced as falling to sleep and is a transition stage between
wake and sleep. It usually lasts between 1 and 5 minutes and occupies approximately
2-5 % of a normal night of sleep. This stage is dramatically increased in some
insomnia (restless legs) and disorders that produce frequent arousals such as apnea.
• Stage 2 Sleep: This follows Stage 1 sleep and is the "baseline" of sleep. This stage is
part of the 90 minute cycle and occupies approximately 45-60% of sleep.
• Stage 3 and 4 or Delta sleep: Stage 2 sleep evolves into "Delta" sleep or "slow wave"
sleep in approximately 10-20 minutes and may last 15-30 minutes. It is called "slow
wave" sleep because brain activity slows down dramatically from the "theta" rhythm of
Stage 2 to a much slower rhythm of 1 to 2 cycles per second called "delta" and the
amplitude of the waves increases dramatically. In most adults these two stages are
completed within the first two 90 minute sleep cycles or within the first three hours of
sleep. Contrary to popular belief, it is delta sleep that is the "deepest" stage of sleep
(not REM) and the most restorative.
• Stage 5: REM (Rapid Eye Movement Sleep): This is a very active stage of sleep.
Composes 20-25 % of a normal nights sleep. Breathing, heart rate and brain wave
activity quicken. Vivid Dreams can occur. After REM stage, the body usually returns to
Stage 2 sleep.

11. Sleep Architecture
1. Sleep is entered through non-
REM sleep
2. Non-REM and REM sleep
alternate approximately every
90 to 120 minutes
3. Slow wave sleep predominates
in the first third of the night
4. REM sleep predominates in the
last half of the night
5. REM sleep occurs in four to six
discrete episodes each night
with episodes generally
lengthening as sleep period
progresses

16. Polysomnography (PSG)
• Polysomnography (PSG) is used to evaluate abnormalities of sleep
and/or wakefulness and other physiologic disorders that have an
impact on or are related to sleep and/or wakefulness.
• By international standards, a PSG must have a minimum of 4
neurophysiologic channels.
– One electroencephalography (EEG) channel (central with an ear
reference provides the best amplitude) to monitor sleep stage
– Two electrooculogram (EOG) channels to monitor both horizontal
and vertical eye movements (electrodes are placed at the right and
left outer canthi, 1 above and 1 below the horizontal eye axis)
– One electromyography (EMG) channel (usually chin or mentalis
and/or submentalis) to record atonia of rapid eye movement (REM)
sleep

17. What is the evidence that sleep disruption
contributes to pain?

18. Effect of Sleep on Pain: Experimental Studies
• Early research: after 60 hrs total
sleep deprivation, reduced
cutaneous thresholds for touch
and pain were observed in
response to von Frey hairs
applied to multiple sites
(Copperman, 1934)
• One evening sleep deprivation in
young, healthy adults reduced
pain threshold to radiant heat
stimuli by 27%!
– This study also found that 4
hours of sleep loss reduced
pain thresholds by 13.5%.
(Roehrs T, 2003)

20. by 24%
(1 night
SW-SD
achieved)

21. Summary of Experimental Investigations on Humans
• Trend indicates sleep deprivation does produce hyperalgesia
• Deprivation or disruption of SWS especially predictive
• Deprivation of REM sleep unclear
• SWS deprivation caused most sensitivity to pressure pain
– Targets both superficial (skin) and deep (muscle) tissue nociceptors
– Heat pain targets superficial (skin) nociceptors
• Muscle (deep) nociception likely influenced to a stronger degree by the
descending pain inhibitory control system (Mense S, 2000)
– Therefore SWS disruption may preferentially alter this pain
modulating pathway
– Explains systemic change in pain sensitivity from Onen and Lentz
• Some argue the extent, irrespective of sleep stage, in sleep time
reduction and the subsequent level of sleepiness produced by the
sleep time reduction may be the critical factor.

22. Human Experimental Problems
• Findings not consistent, low number of studies, not controlled
for co-morbidity
• Sleep disturbance reported by chronic pain patients cannot be
equated temporally with sleep deprivation in these studies
• Not clear whether externally induced reductions in SWS are
qualitatively similar to endogenously induced abnormalities in
pain patients
• Experimental studies have tested only acute pain models;
generalization to chronic pain conditions may be limited
• Experimental studies have largely limited manipulations to
reducing stage 3 or 4 sleep.

23. Animal Experiments

24. (Enkephalinase-inhibitor)
(MAO-B inhibitor)
(MAO-B sub-s)
(a+b potentiated
antinociception of c)

26. Summary of Experimental Investigations on Animals
• More consistent than human studies, more controlled for other
factors
• Focus on REM-SD vs. SWS-SD
• REM-SD increased nociceptive behavior in almost all studies
– Suggests a hyperalgesic action of REM-SD
• REM-SD appeared to prevent the analgesic action of
endogenous and exogenous opiods
• Potentiation of opiods by monoamines was abolished by REM
sleep deprivation

27. Problems With Animal Studies
• Exclusive focus on REM-SD
• Animals!

28. What Is The Evidence That Pain Disturbs
Sleep?

29. Effect of Acute Pain on Sleep
• Cumulatively, about 100 postoperative patients have been studied with
PSG from 1 to 6 postoperative nights
– Total sleep time was reduced for 1 or 2 nights duration and sleep
was fragmented with frequent arousals and awakenings.
– Duration of slow wave sleep was reduced for up to 4 nights
– REM sleep was absent on the first 2 post-op nights with
“rebound” shown over subsequent nights
• Possible factors causing this disturbance (Rosenberg, 1996)
– Noise, temperature, light
– Stress response of the surgical insult
– Medications
– Difficult to attribute sleep disturbance solely to pain
• No definitive answers

30. Cross–sectional Studies: Chronic Pain
• Have consistently found that sleep disturbance is positively associated
with pain severity
• Some studies have shown complaints of poor sleep to be more robustly
linked to cognitive-behavioral factors such as mood disturbance and
inactivity than pain severity
– A nearly equal number of studies have found pain to be a more
important predictor of sleep disorders
• PSG study of 26 chronic pain patients compared to 12 patients with
insomnia and psychiatric disorder, and 16 insomniacs without other
diagnoses (Wittig RM, 1982)
– Chronic pain patients had disturbed sleep efficiency, and increased
wake time in bed
– Eight chronic pain patients showed alpha-delta patterns
• No definitive consensus

31. Longitudinal Clinical Studies: Chronic Pain
• Among burn unit patients followed for 5 days, a history of sleep
disturbance prior to injury correlated with greater pain during the
night, pain in the morning, and pain during debridement (Raymond,
2001)
– Possibility that prior sleep disturbance might alter pain modulation
mechanisms
– In the same study, ratings of poor sleep quality and increased
nocturnal awakenings each predicted next morning pain and pain
during burn care procedures
• In a 30 day pain diary study of women with FM, a poor night’s sleep
predicted next day pain and that day’s pain predicted that night’s
sleep (Affleck, 1996)
• In a study of 35 rheumatoid arthritis patients followed over 1 week,
cross-sectional analysis indicated that sleep quality ratings, but not
estimates of total sleep time were negatively correlated with both
fatigue and pain (Stone AA, 1997)

32. Longitudinal Clinical Studies: Chronic Pain
• 35 RA patients monitored with home PSG at baseline and then
6 months later. Authors used a complex graphical chain
statistical model to develop a probabilistic causal model
(Drewes AM, 2000)
– When increased pain, disease severity, and morning
stiffness were simulated, increased wakefulness(insomnia),
increased SWS and decreased stage two sleep resulted.
– Supports a bi-directional model, though results surprising,
because other studies suggest pain is associated with
decreased SWS in this population

33. Clinical Studies: Chronic Pain
• In burn unit patients, nighttime pain predicted same night sleep.
However, daytime pain did not predict same night sleep
disturbance (Raymond I, 2001)
• However, in FM patients, daytime pain did predict a poor night’s
sleep (Affleck, 1996)
• Differences might be due to chronic vs. acute pain

34. Clinical Studies: Chronic Pain
• Does pain predict sleep disturbance symptoms on long-term
follow up (>6mos)? Very possible.
• Pain severity and reported sleep problems at baseline were
independent predictors of sleep disturbance two years later in
RA patients (Nicassio PM, 1992)
• In chronic orofacial pain patients, initial sleep quality, depression
severity, and pain severity predicted 39% of the variance in
sleep quality at 8 month follow-up (Riley JL, 2002)

35. Summary
1) The impact of sleep disturbance on pain is more evident when
sleep is experimentally manipulated or ratings of sleep
disturbance are linked to next day pain;
2) There is consistent evidence to suggest that pain negatively
impacts sleep both proximally and long-term;
3) There is some evidence to suggest that the relationship
between pain and sleep may be reciprocal.
4) Heterogeneous “chronic pain” sample population

37. Sleep in Specific Clinical Pain Conditions

38. SCI
• 192 SCI patients reported subjective pain, mood, and sleep data
(Budh, 2005)
– Group with continuous (as opposed to intermittent) pain
reported the poorest sleep and highest ratings of anxiety and
depression
– Anxiety, along with pain and depression, were the major
predictors of sleep quality

39. Rheumatoid Arthritis
• Arthritic pain 2nd most significant factor in predicting sleep disturbance
in >1000 Australian residents (Moffit PF, 1991)
• 242 RA patients, 60% reported arthritis pain interfered with sleep to
some degree. 14% reported very severe ratings (Nicassio PM, 1992)
• 100 RA patients; 34% with insomnia, 52% with middle of night
awakenings (Hart FD, 1970)
• Actigraphic sleep quality of RA patients more disturbed than healthy
controls and patients with LBP (Lavie P, 1991)
• PSG study of 16 RA patients showed sleep fragmentation (Mahowald
MW, 1989)
• 13 RA patients; NSAID tenoxicam made significant RA symptom
improvements, but sleep NOT improved. However, primary sleep
disorders found in 8/13 patients (Lavie P, 1991)

40. Osteoarthritis
• PSG study of 14 OA vs. 16 controls; more stage 1 and less
stage 2 sleep in OA group (Leigh TJ, 1988)

41. Sjogren’s Syndrome
• 75% of patients experienced moderate to severe sleep
disturbance (Tishler M, 1997)
– Higher than individuals from 3 rheumatologic comparison
groups

42. Ankylosing Spondylitis
• Patients had worse pain after a subjective “good nights
sleep” (Jamieson, 1995)
– More lumbar stiffness
– Possibly result of decreased nocturnal movement
– Might benefit from middle of sleep stretching exercises?

43. Rheumatic Studies: Limitations
• None of the studies used standardized self-report measures of
sleep disturbance
• PSG studies found primary sleep disorders in some participants
• Participants mostly men, in whom primary sleep disorders are
most common

44. Headache
• Most common pain syndrome in the general population
• PSG frequently shows low sleep efficiency, frequent
awakenings, and reduced SWS
• Morning headache a frequent symptom of obstructive sleep
apnea
• 20 of 25 patients with cluster headache had sleep apnea
syndrome! (Chervin RD, 2000)
• 10% of patients with headache had a primary sleep disorder
such as OSA or restless legs (Paiva T, 1997)
– Treatment reduced symptoms

45. Migraine and Cluster Headache
• PSG of Migraine patients showed excessive percentage of
stage 3, 4, and REM sleep (Dexter JD, 1975)
• PSG evidence that nocturnal cluster headaches occur during
REM sleep (Sahota PK, 1990)
• Depriving cluster headache patients of REM sleep prevented
headaches for 24 hours in 14/27 patients and reduced
headache frequency for the entire group during the next four
days (Bono G, 1985)

46. Fibromyalgia
• Reduced SWS, REM sleep, and total sleep time compared to age-
matched normals
• Number of transient arousals and full awakenings are increased
• Up to 76% of FM patients report sleep disturbances compared to
10-30% for healthy controls (Wolfe F, 1990)
• Presence of high frequency α wave intrusions into SWS, referred to as
α-delta sleep, is reported to be a prominent characteristic of sleep in
FM patients (Hauri P, 1973)
– Has been experimentally induced in normals; produces FM
symptoms!
– Shows frequently in those with RA and Chronic Fatigue (Moldofsky
H, 1988)
– Appears in depressed patients as well
• However, a study of 1076 patients with PSG showed fewer than 40% of
patients exhibiting α-delta sleep had chronic pain (Schaefer KM, 1995)

47. α-Delta Sleep
• The central EEG channels (C4-
A1 and C3-A2) demonstrate
low-frequency (< 2 cycles per
second), high-amplitude (> 75
μV) delta waves with
superimposed 7 to 11 cycle per
second α waves characteristic
of alpha-delta sleep
• α-Delta causes arousals
(fragmented sleep)
• Percent of alpha-delta intrusion
during non-REM sleep is
positively correlated with pain,
hostility, and decreased mood
(Moldofsky HM, 1989)

48. Chronic Fatigue Syndrome
• Reductions in sleep efficiency and REM sleep have been
reported (Buchwald, 1994)
– Sleep may be disturbed by co-morbid depression, not by
CFS

49. Neuropathic Pain
• The only PSG study assessed patients with diabetic and
postherpetic neuropathy (Mundel T, 2003)
– The 19 neuropathic pain patients had lower sleep
efficiencies and fragmented sleep as reflected in reduced
amounts of stage 3 and 4 and REM sleep, with elevated
stage 1 sleep

50. Comorbid Primary Sleep Disorders
• Found by several researchers in the chronic pain population
• Lack of research focused on this subset of the chronic pain
population

51. Obstructive Sleep Apnea
• 8/13 female RA patients found to have OSA on PSG (Lavie P,
1991)
• 3/11 OSA patient met criteria for FM (Molony RR, 1986)
– Some FM patients might actually have OSA as primary
etiology?
– Distinguishing is important, as some FM meds are CNS
depressants which are contra-indicated for OSA
• 3/18 headache patients diagnosed with OSA. Nocturnal
headaches positively correlated with nighttime O2 sats (Paiva T,
1997)

52. Periodic Limb Movements/Restless Legs
• 13/13 RA patients met criteria for PLM (Mahowald MW, 1989)
• PSG study of 7 patients with chronic LBP found majority of
people met PLM criteria (Atkinson JH, 1988)

53. Depression
• Very common in chronic pain
• Depressed patients have frequent awakenings, longer sleep
latencies, and REM abnormalities (Gillin JC, 1979)
• Fibromyalgia patients report higher frequency of depression and
anxiety than controls (Celiker R, 1997)
• 7 year treatment outcome study of 538 patients with FM. Found
depression, anxiety, and sleep disturbance unchanged over the
study period (Wolfe F, 1997)
– Specific treatments not clarified
• Persistent pain increases risk of affective disturbance (Smith
RG, 1992)
– It is likely that insomnia develops as a secondary symptom
of depression in some patients.

54. Anxiety
• Few quality studies

55. Which Comes First? Sleep or Pain
• Few studies have looked specifically at sleep, pain, mood
interactions
• Longitudinal study; pain at baseline period was predictive of
sleep disturbance and that, over time, both pain and sleep
disturbance were predictive of depression (Nicassio PM, 1992)
• Pain frequency and intensity were stronger predictors of sleep
disturbance than mood or personality (Goodrich SM, 1998)

56. Causal Relation of Pain and Sleep Loss
• Difficult to determine
• Most researchers have not carefully distinguished fatigue from
daytime sleepiness
• Most studies have only used investigators’ qualitative, not
quantitative, assessments of sleep fragmentation and α
intrusion
• Many of these musculoskeletal conditions are heterogeneous,
and only recently have diagnostic criteria been applied
• Many of these patients also have depression and anxiety
disorders which themselves disturb sleep
• Many also have primary sleep disorders (discussed earlier)

57. Summary of Sleep Disorders in Pain
• Decreased sleep efficiency (decreased sleep time in bed)
– Delayed sleep onset (insomnia)
– Frequent awakenings
– Daytime sleepiness
– Undiagnosed sleep D/O’s (OSA, RLS)
• Alpha-Delta NREM intrusions (31% of chronic pain patients)
– Emphasized in FM
– Documented in RA
– Seen in heterogeneous pain D/Os
• Pain measures inversely correlated to sleep disturbance
• Anxiety and Depression inversely correlated to sleep disturbance

58. Potential Interactions of Sleep and Pain
Systems

59. Overview
• Extremely complex interaction which has not been well
described nor understood
• Few current neurobiological hypothesis explain the complex
relationship between chronic pain and sleep

60. α-Delta Sleep
• Six healthy individuals subjected to auditory stimulus during NREM
sleep caused α-Delta EEG pattern (Moldofsky HM, 1975)
– Induced msk pain and mood disturbance similar to FM patients!
• Follow up study showed symptoms disappeared with two nights
undisturbed sleep following α-Delta intrusion! (Moldofsky H, 1976)
• FM patients average 60% duration of α-Delta intrusion during NREM
sleep, compared to 25% of insomniacs (Gupta MA, 1986)
• Chlorpromazine given to FM patients increased SWS and decreased
pain and psychological distress (Moldofsky H, 1980)
• Presence of α-Delta in healthy normals prevents conclusions
• Moldofsky’s the man!

61. Ascending Arousal System
• Unlike acute pain, chronic pain is associated with functional
changes in the raphe magnus (RM) cells, which modulate both
pain and arousal (Foo H, 2003)
• RM pain-facilitated cell discharge is associated with heightened
states of alertness (Coutinho SV, 1998)
– Possible explanation for sleep disturbances
• Peripheral damage to the sciatic nerve in rats was associated
with persistent regional cerebral blood flow anomalies in the
somatosensory cortex and thalamus (Paulson PE, 2002)
• These data suggest that chronic pain alters the ascending
arousal system, which may lead to frank sleep disturbance

62. Opioid Sensitivity Impairment
• The descending pain inhibitory system contains opioidergic links
• Analgesic action of endogenous and exogenous opioids is
dependent on undisturbed sleep architecture/continuity because
selective REM sleep deprivation prevents opioid analgesia
(Ukponmwan OE, 1984)
• Sleep disruption may cause an inhibition of opioid protein
synthesis (Shapiro C, 1981)
• Sleep disruption may cause a reduced affinity of mu- and delta
opioid receptors (Fadda P, 1991)
• Potentiation of opioidergic analgesic effects seen with MAO
inhibitors can be nullified by REM sleep deprivation
(Ukponmwan OE, 1984)

63. Serotonergic Impairment
• The descending pain inhibitory system contains serotonergic
links
• Tryptophan depletion in humans leads to a loss of potency of
morphine in producing analgesia (Abbott FV, 1992)
• Decreased levels of 5-HT in different brain areas were found in
rats after REM sleep deprivation for 96hrs (Farooqui SM, 1996)
• REM sleep deprivation may render the serotonin system
functionally unable to support pain inhibition produced by
opioidergic activation.

64. Acetylcholine
• Role in antinociception and sleep
• Animal studies show that cholinomimetics have an
antinocieptive effect (Abram SE, 1995)
• Clinical studies have used cholinergics for pain control (spinally
administered neostigmine) (Collins JG, 1995)
• Acetylcholene has a prominent role in the generation of REM
sleep (Sitaram N, 1979)

65. Neuroimmune
• Infection/inflammation may affect sleep through excitatory
cytokines such at interleukin-1 and Tumor Necrosis Factor
• Cytokines affect REM and non REM sleep (Krueger J, 1995)

66. Excitatory Amino Acids (EAA)
• Neurotransmitters like glutamate
• Effectors of peripheral and central sensitization with nerve injury
• EAAs play a role in light transmission to suprachiasmatic nuclei
(Dijk D, 1995)
– The SCN plays a critical role in circadian rhythms such as
sleep and body temp

67. Implications
• Giving dextromethophan to augment opioid analgesia or
gabapentin to reduce neuropathic pain, both decreases EAA
activity
– May therefore improve sleep through EAA effects
• Treatment of infection or inflammation will decrease cytokines
and therefore may improve sleep
• Serotonergic antidepressants may help with sleep through
modulation of 5-HT

68. Treating sleep disturbance in patients with
chronic pain

69. Sleep Disturbance in Patients with Chronic Pain
• Has seldom been systematically explored
• Difficult to study: are reductions in sleep disturbance following a
successful trial of amitriptyline attributed to reductions in the
interference of pain on sleep processes or the sedating effects
of the medication itself?

70. Treatment Principles
1. Evaluation and treatment of the pain problem
2. Recognition and treatment of psychiatric co-morbidity
3. Identification and characterization of sleep disturbances
4. Treatment of sleep disturbances

72. Non-pharmacologic Treatment
• Behavior modification, relaxation, cognitive-behavioral interventions,
exercise, phototherapy
• Behavior modifications:
– Sleep Hygiene: tracking and changing behaviors that cause
insomnia, such as alcohol, tobacco, and caffeine, limit exercise
after 3 pm
– Stimulus Control: limiting bed activities to sleep and sex
– Sleep restriction: finding the optimum sleep duration
• Meta-analysis of 2,102 patients; psychological intervention averaging 5
hours of therapy time improved sleep. Stimulus control and sleep
restriction found to be most effective.
• Exercise: physically fit people have more SWS (Griffin SJ, 1978)
• Aerobic exercise: FM who did aerobics for 20 weeks experienced
reduced pain compared to flexibility training (McCain GA, 1986)
– Endogenous opioid release -> increased SWS

73. Primary Sleep Disorders
• Obstructive Sleep Apnea: common disorder, PSG study needed
for diagnosis, CPAP/BiPAP very successful treatment
– Should avoid hypnotic agents and opioids in the untreated
OSA population
• Restless Legs Syndrome (RLS): clonidine has been shown to
relieve subjective leg symptoms and morning drowsiness.
Increased Stage 3 and 4 sleep (Wagner ML, 1996)

74. Analgesics
• Placebo controlled study of the NSAID tanoxicam in patients
with RA found the drug improved the clinical condition of the
patients but had no effect on the PSG (Lavie P, 1991)
• Placebo-controlled study of opioid levorphanol in patients with
neuropathic pain of various etiologies reported a small
improvement in self reported sleep (Rowbotham MC, 2003)

75. TCAs
• Meta-analytic review of TCA treatment in FM patients showed improved
subjective sleep was greater than the improvement in measures of
morning stiffness and tenderness (Menefee LA, 2000)
• Another review of TCAs with neuropathic pain of various etiologies
noted improvement of sleep in both depressed and nondepressed
patients (Menefee LA, 2000)
• The antinociceptive effect of TCAs may be due to their capacity to
release adenosine in the periphery and their central inhibition of the
neuronal reuptake of adenosine (Ribeiro JA, 2002)
– Adenosine thought by some to be the major sleep-wake homeostat
chemical
• 75mg doses of Amitriptyline may be superior to 25mg and 50mg doses
based on some studies

76. SSRIs
• Trazodone appears to avoid sleep disturbances seen in other
SSRIs
• Fluoxetine and major depression; 16% developed insomnia
when treatment started (Romano, 1999)

77. Sedative-Hypnotics
• Used by up to 15% of the insomnia population
• Interfere with Stage 1, 3, 4 and REM
• Triazolam compared with placebo in RA found improvement in PSG
sleep; morning stiffness and daytime sleepiness also improved (Walsh
JK, 1996)
• Arthritics given sedative-hypnotics reported higher levels of pain and
greater disability (Hardo PG, 1992)
• BZDPs did not improve sleep for chronic pain patients when compared
to chronic pain patients not on these meds (King SA, 1990)
• Double-blind, placebo controlled study of 71 surgery patients; BZDP
antagonist flumazenil was found to enhance morphine effects (Gear
RW, 1997)
• Double-blind, placebo controlled study of 16 FM patients; zolpidem
increased total sleep time, fewer awakenings, increased energy. No
effect on pain or mood (Moldofsky H, 1996)

78. Antieleptic Agents
• Gabapentin, an analogue of GABA, has inhibitory activity on the
excitatory neurotransmitter systems
• 184 subjects with diabetic neuropathy treated with gabapentin.
(Rowbotham, 1998)
– Significant improvement in subjective sleep scores
– Significant improvement in mood symptoms and quality of life
• SCI patients with neuropathic pain were treated with Gabapentin for 5
weeks. After a one week period, self rated pain and sleep interruption
scores were improved. (Backonja M, 1998)
• Improvement relative to placebo in postherpetic neuropathy patients
treated with gabapentin in measures of pain and sleep interference
(Rice AS, 2001)
• Unknown: the degree to which gabapentin directly impacts sleep and
pain, as well as the degree to which improvement in sleep relates to
improvement in pain

79. Gabapentin Focus
• Sleep improvements as significant as pain improvements
• Sleep improvement occurred at a higher level of significance
than mood and quality of life measurements
• Good stuff?!

80. Pharmacotherapy Principles
• Appropriate anti-neuropathic and anti-nociceptive analgesia
• Treatment of anxiety, depression
• Discontinue potentially sleep-disrupting meds:
– Traditional BZDPs, some SSRIs, etc.
– Opioids in untreated OSA patients
• Sleep friendly antidepressants (serzone, trazodone,
mirtazapine, TCAs)
• Short acting BZDP receptor agonists (zolpidem, zalpelon)
• Anticonvulsants (gabapentin)
• Psychostimulants for fatigue (provigil)

81. Summary
• Pain is associated with disturbed sleep
• Specific nature of the sleep disturbance, causal mechanisms, and
effective treatment have not been thoroughly explored
• Part of the problem relates to the complexity and heterogeneity of
chronic pain conditions and the comorbidity with depression and
anxiety
• Experimental models have shown that the relation is bidirectional
• Sleep loss has a hyperalgesic effect
• Do not overlook primary sleep disorders: A PSG sleep study is easy to
order/referral to sleep specialist easy as well
• No concensus on treating disturbed sleep in acute or chronic pain has
arisen
• Bottom Line: Don’t ignore sleep anymore