papr_417 282..

289

REVIEW ARTICLE

Treatment of Chronic Pain by

Long-Acting Opioids and the
Effects on Sleep

Kyriaki Mystakidou, MD, PhD*; A. John Clark, MD, FRCPC†;

Jürgen Fischer, MD, PhD‡; Annette Lam, MHEcon§; Karin Pappert, MD¶;
Ute Richarz, MD¶
*Pain Relief & Palliative Care Unit, University of Athens, School of Medicine, Athens,
Greece; †Pain Management Unit, Capital Health, Halifax, Canada; ‡Lehrstuhl für
Rehabilitationswissenschaft der Universität Witten/Herdecke, Klinik Norderney, Norderney,
Germany; §Johnson & Johnson Pharmaceutical Services, Toronto, Canada;
¶
Janssen-Cilag, Baar, Switzerland

䊏 Abstract: Chronic pain affects a substantial part of the
population, and conveys a huge economic cost to society.
Owing to its prevalence and adverse impact, it is of particular
interest to clinicians, patients, and the pharmaceutical indus-
try. Conversely, the effects of pain on sleep, sleep on pain,
and opioid analgesics on sleep represent a large gap in our
understanding, even though pain and sleep are closely
linked, inter-related conditions. Chronic pain is often treated
by opioid analgesics, which are often thought to promote
restful sleep. Indeed it may be assumed that by relieving
pain, sleep quality will improve concomitantly. In fact, the
reality is much more complicated. The effects of opioids vary
according to their formulation and duration of action, and
Address correspondence and reprint requests to: Kyriaki Mystakidou,
MD, PhD, Pain Relief & Palliative Care Unit, Department of Radiology,
University of Athens, School of Medicine, Areteion Hospital, 27 Korinthias
St., Ampelokipi, 11526 Athens, Greece. E-mail: mistakidou@yahoo.com.
Disclosure: Ute Richarz and Karin Pappert are employed by Janssen-
Cilag, Switzerland. Annette Lam is employed by Janssen-Ortho, Canada.
This study was funded by Janssen-Cilag Medical Affairs EMEA, a division of
Janssen Pharmaceutica NV, Beerse, Belgium.
Submitted: March 3, 2010; Revision accepted: August 1, 2010
DOI. 10.1111/j.1533-2500.2010.00417.x
© 2010 Johnson & Johnson Pharmaceutical Services
Pain Practice © 2010 World Institute of Pain, 1530-7085/11/$15.00
Pain Practice, Volume 11, Issue 3, 2011 282–289
have diverse effects on sleep processes. Despite the preva-
lence of this problem, there is a surprising paucity of data on
the effects of opioids on sleep. This review attempts to sum-
marize the links between pain and sleep, and to look at the
studies with opioid analgesics, particularly those with
extended-release formulations, that have investigated the
effects of opioid analgesics on sleep. 䊏
Key Words: chronic pain, opioid analgesics, long-acting
opioids, sleep
INTRODUCTION
Humans spend approximately one-third of their life
asleep. Although it appears essential for survival,1 its
function remains a mystery. Sleep and pain share a close
relationship as pain can influence and sometimes
severely disturb sleep, and similarly sleep deprivation
can modify pain sensitivity and exacerbate pain symp-
toms.2 Indeed they are so are closely interlinked, their
complicated neuronal circuits have some neuronal and
neurochemical substrates, such as serotonin and
glutamate, in common.2 Sleep disturbance is therefore a
major complaint of patients experiencing both acute
and chronic pain. Acute pain, for the most part, results

from disease, inflammation, or injury to tissues. The
pain is self-limiting, confined to a given period of time
and severity. In contrast, chronic pain is described by the
International Association for the Study of Pain as “pain
which has persisted beyond normal tissue healing time,”
taken in the absence of other criteria to be 3 months.3
Both chronic pain and sleep restriction impose a wide
range of severe emotional, physical, and social stresses
on the patient, which affect every aspect of life.2,4
Despite the fact that chronic pain is highly prevalent,
and that opioid analgesics are widely prescribed for its
treatment, there are a surprisingly small number of
studies addressing the issue of opioid analgesics on
sleep. Sleep is currently not always an important issue
for physicians, despite clinical evidence suggesting that
this is a significant problem for patients with pain. Con-
cerns have been raised about the effect of opioids on
sleep, but clearly there is still much to be learned in this
complex area.
This review will attempt to explore the close relation-
ship between opioids and sleep, and ask whether new
formulations of extended-release opioids could help in
improving sleep quality.
PREVALENCE AND BURDEN OF CHRONIC PAIN
Chronic nonmalignant pain is a prevalent condition that
is often undertreated. Although attempts have been
made to assess prevalence, estimations vary widely; their
inconsistency owing to the complex nature of chronic
pain and variable definitions used.5 The data are difficult
to compare as studies use different criteria to assess pain
or vary in their design. In addition, some studies have
low response rates, and because the patients or subjects
that do respond may not be representative of the whole
population, this can introduce bias.
One study of all patients who visited eight general
practitioners over a 10-month period estimated the inci-
dence of chronic nonmalignant pain to be less than 1%.6
Other studies report a range from 2% of the population5
up to between 25% and 50% in industrialized
countries.7–9 The prevalence of chronic non-malignant
pain in Canada from a random sample of over 2,000
patients estimated the rate at 29%,10 with a similar
prevalence found in Canada in a follow-up study.11 The
World Health Organization undertook a study of nearly
5,500 patients in primary care settings over five conti-
nents and showed a prevalence of 21.5%.12 Data from a
large survey of chronic pain in 15 European countries
and Israel showed that the prevalence of chronic pain
ranged from 12% to 30%; osteoarthritis and rheuma-
Chronic Pain, Long-Acting Opioids, and Sleep • 283
toid arthritis were the most common causes (42%).13
The prevalence of chronic pain is higher in women and
increases significantly with age.14,15
Chronic nonmalignant pain has huge economic costs
to society. A report from the MBF Foundation (part of
the MBF Insurance Group, Australia) estimated total
costs of chronic nonmalignant pain in 2007 in Australia
to be 34.3 billion Australian dollars. The largest share of
costs (55%) was borne by the patients suffering from
chronic pain, mainly due to costs associated with the
burden of disease.16 Another report estimated that
absenteeism from work due to pain costs European
economies €34 billion every year.17 It is therefore clear
that chronic pain represents a substantial burden on
society.
CHRONIC PAIN AND SLEEP DISTURBANCES
It is well documented that a number of diseases and
syndromes are commonly associated with increased
sleep disorders.18 Pain from known physical disease
usually begins the cycle of pain leading to sleep depri-
vation, which contributes to worsening pain. The
decreased sleep quality and quantity caused by chronic
pain results in chronic sleep deprivation, which, through
a reciprocal process, actually increases the subjective
experience of pain and lowers the pain threshold.19–21
Soon, a cycle of escalating pain and ever-worsening
sleep disruption is established (Figure 1). If untreated,
the conjunction of these two processes can have drastic
consequences; the combination of high pain intensity
and insomnia has been shown to even further increase
the already doubled suicide risk found in patients suf-
fering from chronic pain.22–25
Increased
ongoing pain
More sleep Altered sleep
disruption architecture
Figure 1. The vicious cycle of ongoing pain and sleep disruption.
284 • mystakidou et al.

Table 1.Studies with 24-hour hydromorphone

Reference Study duration Patients Results

Gajria et al. (2008)87 6 weeks
Binsfeld et al. (2010)88 24 weeks with 28 weeks
optional extension period
124 patients with moderate
to severe osteoarthritis
504 patients with chronic
non-malignant pain
Significantly greater improvements in sleep
in the 24-hour hydromorphone group
(P < 0.045). Also a significant difference
between groups for “waking short of
breath” in favor of 24-hour
hydromorphone (P = 0.014)
No significant difference between
treatments apart from somnolence,
which was in favor of 24 hours
hydromorphone (P = 0.020)

It is estimated that 50% to 90% of patients with
chronic pain report “unrefreshing” sleep or poor sleep
quality.20,26,27 A strong correlation between quality of
sleep and pain in patients with cancer has also been
reported.28 This may also be true for patients with acute
pain, as common complaints for acutely ill hospitalized
patients include difficulty falling asleep, frequent awak-
enings, somnolence, and poor sleep quality.29,30
Epidemiological studies have shown a high prevalence
of pain is the strongest predictor of a sleep problem. A
Swedish study of the elderly (n = 10,216) reported that
patients with neck, back, or hip pain were twice as likely
to report daytime drowsiness than those with no pain.31
A Canadian cross-sectional study (n = 11,924) reported
that severe pain was the second strongest predictor (after
stress) among various sociodemographic, lifestyle, stress-
related, and health-related factors significantly associ-
ated with difficulties in initiating or maintaining sleep.32
This was judged by the size of the odds ratio. It is not clear
from these studies whether the pain was currently being
treated with opioids.
There are study limitations to consider with these
large epidemiological studies. First, all the results are
based on self-report, which are subject to bias. Second,
criteria and definitions are not standardized. Finally,
none of the studies took into account the presence of
pre-existing primary sleep disorders that are known to
influence sleep.33 Pain severity does not predict sleep
quality.34 Indeed in one study, sleep variables were
more associated with measures of emotional distress,
such as measures of depression and anxiety, more than
pain severity.35 This finding has also been shown in
adolescents.36
It appears that chronic pain can affect sleep architec-
ture as well as the increasing sleep disruption. These
findings have been primarily made in patients with
fibromyalgia, and have identified abnormalities in rapid
eye movement (REM) sleep architecture in chronic pain
(Table 1). These changes include decreased slow-wave
sleep (SWS)37,38 and increased alpha sleep.39,40 There is
some discussion whether sleep quality can dictate pain
levels the following day. A very recent study used a
representative national sample of adults in the U.S.A.
(n = 971) and analyzed data from a daily assessment of
hours slept and frequency of pain symptoms. The
number of hours of reported sleep the previous night
was a highly significant predictor of pain the next day.
Furthermore, the propensity of pain symptoms pre-
dicted sleep duration.41 Although some data from these
studies should be interpreted with caution because, in
general, no control group was used,42 they show that
sleep deprivation produces hyperalgesia in healthy
subjects.42 In addition, studies indicate that influences
of concomitant variables such as age, anxiety, or
other medical conditions need to be assessed on an
individual basis.43
OPIOIDS AND ALTERATION OF SLEEP QUALITY
Sleep disruption (where sleep is disturbed) and depriva-
tion (a sleep disorder of having too little sleep) is a major
complaint of patients experiencing pain, and it is
reported that sleep deprivation lowers the pain thresh-
old.19,44 Opioids have a variety of effects on sleep and
can cause sleep disturbance even in the absence of
pain.45 The sedative effects of opioids are relatively well
established, and these are thought to be mediated by the
anticholinergic properties of opioids.46 Although dose
initiation and rapid dose escalation may result in seda-
tion and consequently lead to noncompliance and/or
reduced quality of life, tolerance to these side effects
often develops. Sedation is usually treated with opioid
dose reduction, opioid rotation, and use of psychoso-
matic stimulants. At the time of writing, methylpheni-
date was the most common medication investigated to
treat opioid-induced sedation.46

There have been few studies examining the effect of
opioid analgesics on sleep in the presence of pain.47 It
has been shown that increased opioid medication
during the day was a significant predictor of poor sleep
during the following night and a night of poor sleep
was followed by higher levels of opioid intake the fol-
lowing day.48 This was a small, prospective study on
patients with burns (n = 16) that used the actigraphy
technique to measure sleep over 24 hours. Sleep mea-
sures included duration of sleep, number of awaken-
ings, and duration of awakenings. Patients received
morphine infusion or extended-release morphine for
ongoing pain. Although most patients managed to sleep
for 8 hours during a 24-hour period, this sleep was
highly fragmented and unsatisfying.
Fatigue caused by poor sleep quality is a symptom
usually associated with impairments in performing daily
activities, difficulty in concentrating, and reduction in
social activities.49,50 It is the most commonly encoun-
tered symptom in cancer patients,51 and disturbingly, it
can sometimes even reach levels where cancer patients
want to die.52 It is distinct from mere sleepiness as other
factors may contribute to fatigue such as physical exer-
cise or illness rather than just sleep deprivation. Con-
sidering the prevalence of cancer and the amount of
opioids prescribed for pain, there is surprisingly little
known about the effects of opioid medications on cir-
cadian rhythms or next-day fatigue.53 Findings to date
are reviewed by Moore and Dimsdale.53
Ongoing pain significantly alters sleep architecture
and those alterations can increase ongoing pain inten-
sity. There have been relatively few studies investigating
the effect of opioid medication on sleep architecture in
humans, and most involved limited numbers of opiate-
addicted, nondependent subjects.47 A crossover study by
Kay et al.54 used doses of 10 or 20 mg/70 kg morphine
or 3, 6, or 12 mg/70 kg heroin, or placebo, with the
opioids administered just before lights out. These sub-
jects had not taken opioids for 6 to 64 months prior to
the study. Studies have shown that acute administration
of morphine, methadone, and heroin resulted in dose-
related suppression of REM sleep and SWS.45,53–55 This
was mirrored in studies with healthy, pain-free, nonad-
dicted individuals. One study used with morphine at
0.1 mg/kg given intravenously at 30 to 60 minutes
before lights out and again between 3 am and 4 am.56
Treatment with morphine elicited a decrease from
19.8% SWS at baseline to 5.5%, and a decrease from
20.9% to 15.6% in REM sleep. In contrast, non-REM
(NREM) sleep increased from 53.6% to 70.3%.
Chronic Pain, Long-Acting Opioids, and Sleep • 285
Another study used oral, extended-release tramadol at
50 or 100 mg administered just before lights out at 10
pm.57 There was no effect of tramadol on sleep–wake
balance or number of sleep cycles. However, tramadol
did increase NREM sleep and decrease REM sleep.
OPIOIDS AND RESPIRATION
Opioids cause respiration to slow and become irregu-
lar,58,59 leading to hypercapnia and hypoxia. This can
often be reversed with the opioid antagonist naloxone60,61
Opioid usage has also been linked to irregular or ataxic
breathing, also known as Biot’s breathing. A morphine
dose equivalent to 200 mg was found to be associated
with the presence of ataxic breathing in patients with
sleep-disordered patients.62 In two large reviews of more
than 14,000 and 11,000 patients receiving opioids extra-
durally, mostly morphine for the treatment of postopera-
tive, traumatic, and cancer pain, the incidence of severe
respiratory depression was 0.09% and 0.2%, respec-
tively.63,64 These data are reviewed in Walker and Farney,
in 200965 and Dahan et al. in 2010.61 Until this has been
researched in more detail, it would seem sensible that
clinicians carefully monitor patients on chronic opioid
therapy for this potential hazard.
The effects of opioids are associated in some cases
with both central and obstructive sleep apnea and dif-
ficulties with breathing, a problem that has become
more palpable with the large increase in recent years in
opioid prescriptions.65,66 Central sleep apnea is the
absence of airflow for more than 10 seconds with an
absence of ventilatory effort. Obstructive sleep apnea is
associated with continued ventilatory effort. Opioid
receptors are distributed throughout the central and
peripheral nervous system, and the most commonly pre-
scribed opioids are m-receptor agonists, which are
expressed on neurons that process nociception and res-
piration.62 Indeed, there are no commercially available
opioids that do not have respiratory side effects. It also
signifies that this increasingly pressing problem is
extremely complex because of these overlapping path-
ways. However at present, data are scarce. Studies have
been done in patients in methadone maintenance treat-
ment programs for substance abuse, which show a weak
but significant correlation between methadone blood
concentrations and central sleep apneas.67–69 There are
also studies describing a high prevalence of both central
and obstructive sleep apnea in patients undergoing
chronic opioid treatment for nonmalignant pain,62,70,71
with up to 41% of patients in the severe apnea category.
The link between opioid use and sleep apnea was most
286 • mystakidou et al.
clear in patients treated with methadone, and it would
appear there is a link between chronic opioid treatment
and central sleep apnea.62 Indeed, a recent study has
shown that withdrawal of opioid treatment resolved
sleep-disordered breathing in one case study of a
30-year-old woman.72 However, as there have been no
prospective studies before and after chronic opioid
treatment, no definitive conclusions can be drawn.
EXTENDED RELEASE OPIOID FORMULATIONS
Most opioids have short half-lives and associated short
durations of action. The fluctuating plasma levels with
these treatments can result in pain recurrence, with asso-
ciated anxiety for the patient.73 The aim of extended-
release formulations of opioid medications is to provide
constant analgesia to patients with chronic pain. As these
formulations allow plasma levels of the analgesic to be
maintained at a more constant level, it is possible, though
not conclusively proved, that these medications may
improve sleep owing to no analgesic gaps and less waking
because of breakthrough pain. From a study of morphine
in patients with advanced cancer, it would appear to be
unimportant whether 24 hours extended-release formu-
lations are taken in the morning or evening, despite
reported diurnal variations in pain perception.74
A double-blind, placebo-controlled study in patients
with moderate-to-severe osteoarthritis pain, who were
treated with two extended-release formulations of mor-
phine, showed that both formulations significantly
improved several sleep measures compared with pla-
cebo.75 Extended-release morphine has also been shown
to be more beneficial than an equivalent dose of mor-
phine sulfate solution for the treatment of severe pain in
a randomized double-blind crossover study.76 Patients in
this study also reported better sleep quality with the
extended-release morphine compared with the mor-
phine sulfate solution. Another study investigated the
effects of extended-release morphine and methadone on
sleep architecture in healthy volunteers. The results
showed that both drugs significantly reduced deep sleep
(stages 3 and 4). However, neither had an effect on sleep
efficiency, total sleep time, or wake time after sleep
onset.77 A study of extended-release morphine sulfate in
patients with moderate-to-severe nonmalignant pain
showed improvements across all sleep measures, includ-
ing total sleep time and REM sleep latency.78
A study showed that extended-release morphine and
transdermal fentanyl both significantly improved insom-
nia in patients with terminal cancer pain.79 Transdermal
fentanyl has also been shown to increase hours of night-
time sleep by 25% in ambulatory patients with cancer
pain.80
There have been several studies investigating
extended-release formulations of tramadol. An open
prospective study has shown extended-release tramadol
is effective for the treatment of neuropathic pain, and
that sleep quality was also improved.81 Its efficacy in
treating osteoarthritis-related pain has been demon-
strated in three randomized double-blind studies, which
also reported improvements in sleep quality as a second-
ary outcome.82–84
An extended-release formulation of oxycodone
(OxyContin®, Purdue Pharma LP, Stamford, CT, U.S.A.)
has been developed that requires twice-daily dosing. It
has been shown to be effective in the treatment of
patients with persistent osteoarthritis-related pain in a
randomized placebo-controlled trial.85 It was also
shown to improve sleep quality.
A new extended-release formulation of hydromor-
phone (OROS® hydromorphone, Jurnista®, Janssen-
Cilag, Beerse, Belgium) delivers its analgesic effect in a
consistent manner over 24 hours.86 In a study in patients
with chronic low back pain, treatment significantly
improved sleep quantity, reduced sleep disturbance, and
improved sleep adequacy compared with baseline.73
Two randomized open-label studies have been con-
ducted with 24 hours hydromorphone comparing effi-
cacy and safety with extended-release oxycodone.87,88
Both studies showed some encouraging results, with
improvements in sleep quality.
However, as with all of the studies in this section,
improvements in sleep were not the primary outcome.
This means that conclusions should be drawn with
caution. However, it does appear that extended-release
opioid formulations warrant further investigation as an
analgesic that promotes better sleep quality.
CONCLUSION
There is some evidence for a circular relationship
between poor sleep and pain, and both can exacerbate
the other. Considering the high prevalence of chronic
pain in the population, and the concomitant widespread
opioid prescriptions, there is a deficiency in the literature
evaluating the effect opioids have on sleep in patients
with chronic pain. Opioids can have both negative and
positive effects on sleep, but more research is needed to
understand the mechanisms that underpin this. It has
been postulated that extended-release opioids may be an
alternative to immediate-release opioids because of less

negative effects on sleep. However until studies focus on
the effects of opioids on sleep as a primary outcome
measure, no conclusions can be drawn.
Reducing pain by “state of the art” analgesic therapy
and thus improving sleep quantity and quality in
patients with painful disorders may break the vicious
circle of poor sleep increasing pain perception and may
lead to improvements in quality of life.
ACKNOWLEDGEMENTS
The authors would like to thank Alice Walmesley of
Dianthus Medical Limited for preparing the manuscript
in accordance with European Medical Writers Associa-
tion guidelines.
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