Sleep and Breathing

https://doi.org/10.1007/s11325-021-02363-7

SLEEP BREATHING PHYSIOLOGY AND DISORDERS • REVIEW

Positive airway pressure therapy for chronic pain in patients

with obstructive sleep apnea—a systematic review
Kristian McCarthy 1 & Aparna Saripella 1 & Janannii Selvanathan 1 & Mahesh Nagappa 2 & Marina Englesakis 3 &
David Wang 4,5 & Philip Peng 1 & Frances Chung 1

Received: 13 December 2020 / Revised: 6 March 2021 / Accepted: 24 March 2021

# The Author(s), under exclusive licence to Springer Nature Switzerland AG 2021

Abstract
Purpose Obstructive sleep apnea (OSA) is prevalent in patients with chronic non-cancer pain. OSA may lead to low sleep quality
and an increase in pain sensitivity. Patients reporting greater sleep impairment tend to experience higher pain intensity and vice
versa. Positive airway pressure (PAP) is the current gold standard treatment for OSA. This review aims to evaluate the efficacy of
PAP therapy in patients with comorbid chronic pain and OSA in influencing pain outcomes like pain intensity, tolerance,
threshold, and sensitivity.
Methods We performed a systematic literature search for studies published after 1990, utilizing the following databases:
Medline, Medline In-Process/ePubs, Embase, Cochrane CENTRAL, and the Cochrane Database of Systematic Reviews.
Search terms included “chronic pain,” “sleep disorders,” and “positive airway pressure.”
Results Of 1982 initial studies, ten studies met the study inclusion criteria. Seven of these studies examined the effect of PAP
therapy on chronic pain, of which five demonstrated improved pain outcomes, specifically, headache pain. The effect of PAP
therapy on chronic non-headache pain was found to be inconclusive. When examining the three studies that did not involve
chronic pain patients, PAP therapy effectively increased pain threshold and tolerance in two studies (p = 0.03 and p = 0.01).
Conclusion An association exists between PAP therapy and decreased chronic headache outcomes in patients with OSA.
Additionally, research shows that PAP therapy may increase pain tolerance and threshold. Future high-quality evidence is
required to further investigate the association between PAP and non-headache chronic pain.

Keywords Chronic pain . Headache . Sleep-disordered breathing . Obstructive sleep apnea . Positive airway pressure

* Frances Chung
frances.chung@uhn.ca
1
Department of Anesthesiology and Pain Management, Toronto
Western Hospital, University Health Network, MCL 2-405, 399
Bathurst St, Toronto M5T 2S8, ON, Canada
2
Department of Anesthesia and Perioperative Medicine, London
Health Sciences Centre and St. Joseph Health Care, Western
University, London, Ontario, Canada
3
Library and Information Services, University Health Network,
Toronto, Canada
4
Centre for Integrated Research and Understanding of Sleep (CIRUS),
Woolcock Institute of Medical Research, Sydney Medical School,
The University of Sydney, Sydney, Australia
5
Department of Respiratory and Sleep Medicine, Royal Prince Alfred
Hospital, The University of Sydney, Sydney, Australia
Introduction
In the USA, approximately 50 million individuals live with
chronic pain [1]. These individuals often have comorbid sleep-
disordered breathing (SDB) as well as general sleep disturbances.
As well, SDB is highly prevalent in patients on opioids for
chronic pain management [2]. SDB is characterized by abnormal
respiratory patterns or insufficient ventilation during sleep. SDB
consists of several different disorders, including obstructive sleep
apnea (OSA), central sleep apnea, and sleep-related
hypoventilation [3]. OSA is a pervasive disorder affecting up to
50% of middle-aged men and 23% of middle-aged women [4].
OSA is characterized by repetitive periods of complete or partial
collapse of pharyngeal soft tissue during sleep, causing apneas or
hypopneas, respectively. OSA ultimately results in respiratory
effort in the absence of airflow, resulting in decreased arterial
oxygen saturation and sleep disturbances [5].

Studies suggest that sleep disturbances may modify the
sensitivity to nociceptive stimuli, resulting in abnormal pain
sensitivity [6, 7]. Evidence also demonstrates a bidirectional
relationship between sleep disturbance and pain [8].
Individuals with pre-existing chronic pain who report higher
pain intensity levels also experience a greater degree of sleep
impairment and vice versa [8]. Emerging findings suggest that
OSA is associated with the progression of many painful con-
ditions (such as headaches and fibromyalgia), which may fur-
ther deteriorate sleep resulting in a reinforcing cycle [9].
Currently, the standard management of OSA, including
those who suffer from chronic pain, is positive airway pres-
sure (PAP). This treatment modality includes continuous pos-
itive airway pressure therapy (CPAP), automatic positive air-
way pressure therapy (APAP), and bi-level positive airway
pressure therapy (BPAP). Although there is robust evidence
supporting PAP’s use in improving the Apnea-Hypopnea
Index (AHI) of OSA, its use in improving pain outcomes in
chronic pain patients with OSA is mostly unknown. The ob-
jective of this systematic review is to evaluate whether PAP
therapy for OSA in the chronic pain population will reduce
pain by improving sleep. We hypothesize that PAP therapy
will improve pain outcomes in chronic pain patients with
OSA.
Methods
Inclusion and exclusion criteria
The inclusion criteria were as follows: (1) adults (at least 18
years old) with non-cancer pain that persisted for at least 3
months; (2) known comorbid SDB, diagnosed by
polysomnography; (3) PAP therapy used as an intervention;
(4) assessment of pain outcomes (5) randomized controlled
trials, prospective cohort, and retrospective studies; and (6)
published in English. This review focused on the general
chronic pain experience; thus, our review excluded studies
with the following types of pain: (1) cancer/malignant; (2)
spinal cord injuries; (3) palliative conditions.
Search strategy
This systematic review identified studies that addressed the
impact of PAP on chronic non-cancer pain in patients with
comorbid sleep-disordered breathing. This systematic review
protocol was registered in the International Prospective
Register of Systematic Reviews (PROSPERO), registration
number: CRD42020200476. This review was planned and
performed in accordance with the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses (PRISMA) guide-
lines [10]. An information specialist (ME) designed the liter-
ature searches and restricted it to articles published after 1990.
Sleep Breath
The first PAP therapy was invented in 1981 and was not
widely used before 1990. All the following databases were
searched using the OvidSP search interface: Medline,
Medline In-Process/ePubs, Embase, Cochrane CENTRAL,
and the Cochrane Database of Systematic Reviews. Blocks
of search terms included “chronic pain,” “sleep disorders,”
and “positive airway pressure.” A supplementary file presents
the complete search strategy (see Additional file 1). Citation
searches were done to identify additional studies.
Study selection
Deduplication was completed by using Endnote and Rayyan.
Next, two authors (KM, AS) independently used the inclusion
criteria to assess the remaining titles and abstracts in Rayyan.
Disagreements were resolved by consensus or by consulting a
third author (FC, JS). Finally, abstracts that were approved
underwent full-text review, independently, by both authors
(KM, AS).
Data extraction and quality assessment
Independently, two authors (KM, AS) extracted study charac-
teristics from the approved full-text articles. For each included
study, the following data were extracted: study design, year,
demographics, types of pain, SDB/OSA classification/severi-
ty based on reported Apnea-Hypopnea Index (AHI) values,
types of PAP therapy, and pain outcomes. Two authors (KM,
AS) independently rated each article’s quality using the
Newcastle-Ottawa Quality Assessment Scale. Data extraction
and quality assessment were conducted on aspects of the stud-
ies that included individuals with chronic non-cancer pain and
SDB utilizing PAP therapy or individuals used as controls
against this group. We did not complete a meta-analysis due
to the lack of a comparison group in most studies.
Results
Search results
The literature search yielded 1982 results (Fig. 1). We identi-
fied an additional four records through the citations. After we
removed duplicates, 1659 studies remained. After we
screened titles and abstracts, we found 13 articles to be eligible
for full-text review. Of these articles, ten studies met the in-
clusion criteria (Table 1) [11–20].
Study characteristics
Of the ten studies, one was a randomized blinded crossover
study [18], four were retrospective cohort [12, 13, 16, 17], and
five were pre-post cohort studies [11, 14, 15, 19, 20]. Study
 Sleep Breath

Table 1 Study characteristics

Study Study design Total Patients with OSA severity Age (years) Sex (%M)
populationa OSA+PAP (n) n (%)b

Chronic pain
Poceta, 1995, USA [11] Pre-post cohort 19 14 Mild, moderate, severe OSA: 3 (21), CPAP responders: 59 ± 10 Responders: 57
5 (36), 6 (43) CPAP non-responder: 57 ± 19 Non-responders: 57
Loh, 1999, USA [12] Retrospective pre-post cohort 80 25 Mild, moderate, severe OSA: 50c NR
4 (16), 4 (16), 17 (68)
Goksan, 2009, Turkey [13] Retrospective pre-post cohort 462 76 OSA: 76 (100) 51 ± 11 NR
Kallweit, 2011, Switzerland [14] Pre-post cohort 107 11 Mild, moderate, severe OSA: 47 ± 8 73
3 (27), 5 (45), 3 (27)
Cruz, 2012, Portugal [15] Pre-post cohort 98 97 Mild, moderate, severe OSA: 0 (0.0), 55 ± 11 100
16 (16.3), 82 (83.7)
Johnson, 2013, USA [16] Retrospective pre-post cohort 82 CPAP adherent: 27 Mild, moderate, severe OSA: 15 (45.4), 50 ± 11 18
CPAP non-adherent: 6 10 (30.3), 8 (24.2)
Jaoude, 2016, USA [17] Retrospective cohort 113 CPAP adherent: 35 CPAP adherent: mild, moderate, severe CPAP adherent: 57 ± 10 CPAP adherent: 91
CPAP non-adherent: 58 OSA: 6 (17), 10 (29), 18 (54) CPAP non-adherent: 59 ± 9 CPAP non-adherent:
CPAP non-adherent: mild, moderate, 95
severe OSA: 16 (28), 21 (36), 21 (36)
Pain tolerance or threshold
Onen, 2010, France [18] Randomized blinded crossover 11 11 OSA: 11 (100) 78 ± 5 82
Khalid, 2011, USA [19] Pre-post cohort 12 12 OSA: 12 (100) 50 ± 13 58
Jitsuparat, 2018, Thailand [20] Pre-post cohort 15 15 OSA: 15 (100) 39 ± 12 40

Age is in mean ± SD unless otherwise stated

a
Total population denotes the number of individuals the study recruited for all their analyses, regardless of PAP use
b
Mild OSA: AHI/RDI 5–15 events/h; moderate: 15–30 events/h; severe: >30 events/h (if not stated, distribution of OSA severity not reported)
c
Standard deviation not reported (NR)

Fig. 1 PRISMA study flow Records identified through
diagram of the study selection database searching
process (n = 1,982)
Full-text articles assessed for eligibility
locations included the USA (n = 5) [11, 12, 16, 17, 19],
Turkey (n = 1) [13], Switzerland (n = 1) [14], Portugal (n =
1) [15], France (n = 1) [18], and Thailand (n = 1) [20]
(Table 1). In total, these studies included 323 patients with
comorbid chronic pain and OSA that underwent PAP therapy.
These studies included 64 control individuals with comorbid
chronic pain and OSA who were not adherent to PAP therapy.
Apart from one study, which used auto-titrating positive air-
way pressure (APAP) [15], all studies utilized continuous
positive airway pressure (CPAP) therapy. The average age
was 52 ± 12 years, and 80% were male. Six studies investi-
gated headaches as a chronic pain presentation [11–16], one
study investigated non-malignant non-headache pain [17],
and three studies focused on patients’ perception of pain tol-
erance or threshold [18–20]. Since patients enrolled in the
studies investigating pain tolerance or threshold were not di-
agnosed with chronic pain, their measurements acted as an
indirect surrogate marker of pain outcome.
Study outcomes
Chronic pain
Six studies examined the effect of PAP therapy on chronic
headache pain. Two studies examined only awakening head-
aches [13, 15], and one study examined only migraine head-
aches [14]. The remaining three studies investigated a combi-
nation of different headache types (Table 2) [11, 12, 16].
Notably, Loh et al. investigated both awakening headaches
and migraines [12]. Three of these six studies were of a retro-
spective cohort design [12, 13, 16], and three were pre-post
cohort studies [11, 14, 15]. In total, these six studies included
250 patients with comorbid chronic headaches and OSA who
underwent PAP therapy. Additionally, these six studies also
Sleep Breath
Additional records identified by
citation
(n = 4)
Records after duplicates removed
(n = 1,659)
Titles and Abstracts screened Records excluded
(n = 1,659) (n = 1,646)
Reasons for exclusion
Case reports (n = 2)
(n = 13) Inadequate data (n = 1)
Studies included in final review
(n = 10)
consisted of six control individuals: participants with
comorbid chronic headaches and OSA who were not
adherent to PAP therapy and whose pain outcomes were
directly compared against the individuals mentioned
above [16]. The average age was 53 ± 11 years, and
83% were male.
Overall, of the six studies, five demonstrated an im-
provement in pain outcomes, including headache fre-
quency, duration, or intensity (Table 2) [11–14, 16].
Four out of these five studies reported positive re-
sponses ranging from 50 to 92% at the time of the last
follow-up, ranging from 1 day to 42 months [11–13,
16]. Additionally, Loh et al. found “minimal” improve-
ment at follow-up with non-awakening tension, mi-
graine, and cervicogenic headaches [12]. For migraine
headaches, Kallweit et al. found that treatment with
CPAP significantly improved headache frequency (p <
0.05), duration (p < 0.05), and intensity (p < 0.001)
[14]. Cruz et al. reported that 70% of patients achieved
improved pain outcomes but did not achieve statistical
significance (10/97 to 3/97 pre- and post-APAP, p =
0.065) [15]. There was insufficient data to conclude
the relationship between OSA severity and pain out-
comes in response to PAP therapy in these studies.
One study examined the effect of PAP therapy on chronic,
non-headache, non-malignant pain [17]. The study population
was opioid-treated veterans [17]. This was a retrospective co-
hort study with 35 patients with comorbid chronic pain and
OSA who underwent PAP therapy. These individuals
were compared against 58 controls: individuals with
the same comorbidities who were not adherent to the
PAP therapy [17]. They found that CPAP adherence
did not significantly decrease pain intensity at follow-
up after 12 months (p > 0.05) [17].
Sleep Breath
Pain tolerance or threshold
In three studies measuring pain tolerance or threshold as sur-
rogate markers of pain outcome, two studies demonstrated
improvements after PAP treatment (Table 2) [18, 19]. One
of the studies showed negative results [20]. One of the three
studies was a randomized blinded crossover design [18], and
two were pre-post cohort studies [19]. These three studies
included 38 patients with comorbid chronic pain and OSA
that underwent PAP therapy. The average age was 53 ± 19
years, and 56% were male.
In a randomized blinded crossover trial of elderly patients
with OSA, CPAP therapy significantly increased pain toler-
ance from baseline (p = 0.03) [18]. They found significant
improvement when providing 5 to 10 cmH2O APAP; howev-
er, treatment fixed to 4 cmH2O APAP did not yield a signif-
icantly positive effect (p = 0.44). In a pre-post cohort study,
Finger Withdrawal Latency Testing was used to determine
participants’ pain threshold [19]. The duration until the indi-
vidual perceived pain and consequently withdrew their finger
from a heat source was used as the outcome measure. Two
nights of treatment with CPAP therapy resulted in a signifi-
cantly increased pain threshold than baseline (p = 0.01) [19].
The pain threshold remained elevated with continued CPAP
use for 6 to 8 weeks [19]. Conversely, one study found that the
use of CPAP therapy for 1 month resulted in a decreased pain
threshold in a population of individuals newly diagnosed with
OSA [20].
Quality assessment
Table 3 provides the quality scores of the studies. Nine studies
were of good quality [11–19], and one study was of fair qual-
ity [20]. The studies’ main concerns were the lack of random-
ization [11–17, 19, 20] and the lack of control groups [11–15,
18–20]. These two concerns were the major limitations of our
study results.
Discussion
Since PAP therapy is a validated tool to treat obstructive sleep
apnea in the chronic pain patient population, we aimed to
evaluate the effect of PAP therapy on patients with comorbid
conditions of chronic pain and obstructive sleep apnea. Our
results suggest that PAP therapy for OSA in the chronic pain
population improves headache frequency, duration, and inten-
sity [11–14, 16]. Out of six studies that analyzed headaches,
five displayed improved pain outcomes due to PAP therapy
[11–14, 16]. These results support the use of PAP therapy,
both for chronic awakening headaches and non-awakening
chronic headaches. In one study that showed negative results,
the sample size studied was small [15]—only ten individuals
experiencing headache symptoms before using PAP [15].
Regarding non-headache chronic pain, the effect of PAP
therapy is not apparent. One study in a specific pain popula-
tion (war veterans on chronic opioid therapy) did not display
positive pain intensity results [17]. Additionally, out of three
studies, two demonstrated increased pain tolerance or pain
threshold due to PAP therapy. However, these three studies
were not conducted on individuals with chronic pain; thus,
their results can only be seen as an indirect surrogate marker
of pain outcome [18, 19]. Overall, there are very few well-
designed studies with large sample sizes investigating the ef-
fect of PAP therapy in the non-headache chronic pain popu-
lation. Future randomized controlled studies should be con-
ducted to demonstrate whether PAP therapy affects general
chronic pain.
Chronic pain
Chronic headache is a common condition in patients with
OSA and may occur daily [21]. After awakening, the head-
ache frequently lasts for several hours, and its regularity is
typically correlated with the severity of OSA [12, 13, 21].
The exact cause of the headache is not well established, and
the mechanism may be multifactorial. Hypercapnia, as well as
hypoxia, at least transiently, are present in OSA patients [11].
Subsequent cerebral vasodilation due to these states has been
found to induce headaches [11]. The close relationship be-
tween the degree of oxygen desaturation and morning head-
aches’ severity lends credence to this hypothesis [12]. Thus,
one may suspect that OSA may be a contributing factor to
their headaches in individuals who are susceptible to vascular
headaches. Another proposed mechanism is that a hypoxic
state may release inflammatory neuropeptides, which play a
role in headache pathophysiology [22]. Furthermore, untreat-
ed OSA is recognized as a risk factor for systemic hyperten-
sion, resulting in headaches [22, 23]. Lastly, the frequent
arousals, sleep fragmentation, and sleep disruption typical in
OSA may increase daytime fatigue, resulting in an awakening
headache due to sleep deprivation or disturbance [24].
In our systematic review, we found that the treatment of
OSA with PAP was beneficial for many patients in terms of
headache frequency, duration, and intensity [11–16]. The lev-
el of success attained by Kallweit et al. even compared favor-
ably to the pharmacologic treatment of chronic headache [14].
Additionally, our results suggest that PAP therapy provides
benefits for both chronic awakening headaches [12, 13] (a
common presenting symptom of OSA) as well as non-
awakening chronic headaches [11, 12, 14, 16]. Conversely,
Jaoude et al. found that CPAP therapy was ineffective for non-
headache chronic pain [17]. They found a lack of improve-
ment in pain intensity following 12 months of CPAP treat-
ment [17]. However, this study lacks generalizability, as the
Table 2 Study outcomes

Study Pain classification PAP therapy duration Outcome measure Conclusion Effect of PAP

Chronic pain
Poceta, 1995 [11] Headache-type: CPAP: range, 4–36 months Morning headache questionnaire: CPAP: 50% overall showed headache improvement Positive
• Cluster: 1 Frequency of waking up with a headache: “never,” • Cluster: 1/1
• Migraine: 5 “rarely,” “weekly,” or “nightly.” “Weekly” or • Migraine: 3/5
• Tension: 3 “nightly” considered symptomatic • Tension: 0/3
• Mixed: 5 • Mixed: 3/5
Loh, 1999 [12]a Headache-type: CPAP: duration NRb Telephone interview: Headache AM or cluster: CPAP: average of 80% Positive
• Headache AM: 23 Numerical rating scale of headache intensity headache improvement
• Tension: 12 improvement: 0–100% (in increments Tension, migraine, or cervicogenic: CPAP:
• Migraine: 6 of 10%), lowest to highest minimal improvement
• Cervicogenic: 5
• Cluster: 1
• Other: 12
Goksan, 2009 [13] Headache AM: 76 CPAP: follow-up, 1 day, Morning headache questionnaire: One-day, 1-week, 1-month headache improvement: Positive
1 week, and 1 month Presence of morning headache (yes/no) 72.4%, 84.2%, 92.1% showed headache improvement
Kallweit, 2011 [14] Migraine: 11 CPAP: 12 months Migraine disability assessment scale Attack frequency post-CPAP vs. baseline: 0.1 ± 0.3 vs. Positive
5.8 ± 7.8 attacks per month (p < 0.05)
Attack duration post-CPAP vs. baseline: 0.5 ± 0.7 vs.
6.4 ± 11.9 h (p < 0.05)
Intensity of attacks (VAS) post-CPAP vs. baseline:
2.1 ± 3.2 vs. 7.4 ± 1.7 (p < 0.001)
Workdays lost post-CPAP vs. baseline: 0.2 ± 0.3 vs.
1.8 ± 2.2 days/month (p < 0.05)
Acute antimigraine medication post-CPAP vs. baseline:
0 vs. 6.5 ± 8.0 units/month (p < 0.05)
Cruz, 2012 [15] Headache AM: 10 APAP: 6 months Sleep Disorder Questionnaire: Post-APAP vs. baseline: 3.0% vs. 10.0% considered Negative
Presence of morning headache: 5-point Likert symptomatic (p = 0.065)
scale, “4” or “5” considered symptomatic
Johnson, 2013 [16]c Headache-type: CPAP: range, 18–42 months Telephone interview: CPAP adherent vs. CPAP non-adherent or no CPAP: Positive
• Migraine Headache improvement definition: ≥50% 78% vs. 33% or 42% showed headache
• Tension reduction in headache severity and frequency improvement (p = 0.045)
• Post-traumatic
• Medication overuse
• Total: 27
Jaoude, 2016 [17] Non-malignant pain CPAP: 12 months Numerical Categorical Scale: CPAP adherent at 12 months vs. baseline: 1.9 ± 1.5 vs. Negative
Pain intensity scored from 0 to 10, lowest-highest 2.1 ± 1.4 (p > 0.05)
CPAP non-adherent at 12 months vs baseline: 2.6 ±
1.5 vs. 2.7 ± 1.4 (p > 0.05)
Pain tolerance or threshold
Onen, 2010 [18]d Pain tolerance CPAP: 3 dayse Pain Matcher: Mean tolerance post-high CPAP Rx vs baseline: Positive
Pain tolerance scored from 0 to 99, lowest-highest 28.4 ± 16.0 vs. 21.2 ± 10.9 (p = 0.03)
Mean tolerance post-low CPAP Rx vs. baseline:
23.8 ± 12.4 vs. 21.2 ± 10.9 (p = 0.44)
Sleep Breath
Sleep Breath

Effect of PAP
subjects differed considerably in their phenotype compared to

Negative
the other nine studies in our review and the general chronic

Positive
pain population. Specifically, participants were war veterans
who demonstrated psychiatric comorbidities and comorbid
chronic neuropathic pain.
The success of PAP therapy is important in chronic head-
Post-CPAP (two nights) vs. baseline: 13.7 ± 5.1

ache as it imposes a substantial economic burden [25]. In the

discontinuation: 21.1 ± 16.2 vs. 11.5 ± 5.9 s

Post-CPAP therapy vs. baseline: 1.51 vs. 2.02 USA, the total direct annual costs of chronic headache—
pharmaceutical treatments, primary care visits, diagnostic
Post-CPAP (six-eight weeks) vs. CPAP

tests, blood tests, specialist visits, emergency department

visits, and hospitalizations—were estimated at 9.2 million dol-
lars [25]. As well, indirect costs—work loss and reduced
vs. 9.8 ± 1.3 s (p = 0.01)

productivity—have greatly exceeded direct costs.

Clinically, our findings suggest that patients who present
with chronic headaches should have a sleep history and
(p = 0.027)f

screening with the STOP-Bang Questionnaire [2]. Clinicians

(p = 0.03)
Conclusion

should consider referring patients for evaluation and treatment

if sleep apnea is suspected. Unfortunately, due to the lack of
literature regarding non-headache chronic pain, we cannot
generalize our results to the broader chronic pain population.
Time until participant withdrew finger from

Digital Electronic Algometer (in kg/m2)

Pain tolerance and threshold

Finger Withdrawal Latency Testing:

Studies have demonstrated a hyperalgesic effect related to

Subjects randomized to 2 consecutive 3-day sequences, either beginning with low CPAP or high CPAP

sleep restriction and that restoring sleep architecture may pro-

a heat source, in seconds

duce an analgesic effect. Khalid et al. found that individuals

with OSA had significantly increased pain threshold values
Outcome measure

following PAP use [19]. Furthermore, Onen et al. demonstrat-

ed that following high CPAP therapy, the pain tolerance of
individuals with OSA significantly increased compared to
All ten muscles analyzed displayed similar significant decreases in pain threshold

baseline [18]. Different theories have been advanced to ex-

plain the relationship between sleep and pain.
Low CPAP: 4 cm H2O; High CPAP: 5 to 10 cm H2O auto-adjusted-CPAP

Current hypotheses postulate that several mechanisms to-

nights, and 6–8 weeks

gether mediate the effects of sleep deficiency on pain. OSA

CPAP: follow-up, two
PAP therapy duration

and subsequent arousals during sleep may alter the opioid,

monoaminergic, orexinergic, immune, melatonin, and
CPAP: 1 month

endocannabinoid systems; hypothalamus-pituitary-adrenal

axis; and adenosine and nitric oxide signaling [26]. Overall,
these modifications together result in alterations in pain per-
ception. For example, the sleep deprivation caused by persis-
Headache-types were not mutually exclusive

tent arousals has been proposed to enhance excitatory amino-

Distribution of headache-types not stated
Pain classification

acid concentrations and subsequently enhance nociceptive

Pain threshold

Jitsuparat, 2018 [20] Pain threshold

transmission [26]. Also, sleep disruption may dysregulate

the endogenous opioid system. Experimental studies show
that endogenous opioid peptides are released in the brain dur-
ing sustained pain and reduce pain intensity [26]. However,
Table 2 (continued)

sleep disruption has been found to decrease the analgesic ef-

Khalid, 2011 [19]

fects of opioid agonists and impair the pain inhibition system

Not reported

[26]. Therefore, fragmented sleep may be a modifiable risk

factor underlying increased hyperalgesia in patients with
OSA. Future studies are necessary to determine the exact
Study

mechanism of the analgesic effect of PAP therapy.

b

d
a

f
 Sleep Breath

Table 3 Quality assessment: Newcastle-Ottawa Scale

Criteria Poceta, Loh, Goksan, Kallweit, Cruz, Johnson, Jaoude, Onen, Khalid, Jitsuparat,
1995 1999 2009 [13] 2011 [14] 2012 2013 [16] 2016 2010 2011 2018 [20]
[11] [12] [15] [17] [18] [19]

Selection
Representativeness of exposed * * * * * * * * * *
cohort?
Selection of the non-exposed cohort? - - - - - * * * - -
Ascertainment of exposure? * * * * * * * * * -
Demonstration that outcome of * * * * * * * * * *
interest was not present at start of
study?
Comparability
Study controls for age/sex? * * * * - * * * * -
Study controls for at least three * - * * * * * * * *
additional risk factors?
Outcome
Assessment of outcome? * * - - - * - * * *
Was follow-up long enough for out- * * * * * * * * * *
come to occur?
Adequacy of follow-up of cohorts? * * * * * * * * * *
Overall quality score (maximum = 9) 8 7 7 7 6 9 8 9 8 6

Conversely, Jitsuparat et al. found that CPAP therapy for 1 Conclusion

month resulted in decreased pressure pain thresholds in ten
neck or shoulder muscles in patients newly diagnosed with
OSA [20]. Perhaps, unfamiliarity with CPAP therapy may
have caused muscle tension leading to lower pressure pain
thresholds. Further studies are needed to evaluate the pressure
pain threshold with a longer CPAP therapy duration to evalu-
ate this hypothesis.
Limitations
The present systematic review has some limitations. We
included only English language articles, which may not
have identified all relevant literature. Unfortunately, due
to the studies’ heterogeneity and outcome definitions,
and the lack of a comparison group in most studies,
we could not perform a meta-analysis. Additionally, all
ten included studies had small sample sizes, with under
100 individuals with OSA and chronic pain that
underwent PAP therapy. Lastly, all studies were obser-
vational except for one article [18]. These limitations
and the lack of high-quality randomized controlled stud-
ies illuminate a critical gap in this field’s current liter-
ature and highlight an opportunity for further research.
Despite these limitations, this systematic review is
meaningful. It demonstrates that a growing body of ev-
idence consistently supports the beneficial effect of PAP
therapy in patients with comorbid chronic headache and
OSA.
There is a growing interest in the relationship between the treat-
ment of OSA and pain outcomes. However, very few studies
have investigated PAP’s role in modulating patients’ pain out-
comes with chronic non-cancer pain and comorbid OSA. In
chronic pain patients with OSA, we found that PAP therapy
decreased chronic headaches. As well, our results support the
idea that PAP therapy may increase pain threshold. However, a
gap in the literature exists regarding PAP’s effectiveness in im-
proving non-headache chronic pain outcomes. Thus, further in-
vestigation is required before broad clinical suggestions can be
made. The advancement of this understanding would help in-
form the promotion of OSA screening among patients with
chronic pain, pain management among those diagnosed with
OSA, and PAP’s potential use as an adjunct/alternative therapy
to current analgesic medications, such as opioids.
Abbreviations AHI, Apnea-Hypopnea Index; APAP, automatic posi-
tive airway pressure therapy; BPAP, bi-level positive airway pressure
therapy; CPAP, continuous positive airway pressure therapy; EPAP, ex-
piratory positive airway pressure therapy; OSA, obstructive sleep apnea;
PAP, positive airway pressure therapy; SDB, sleep-disordered breathing
Supplementary Information The online version contains supplementary
material available at https://doi.org/10.1007/s11325-021-02363-7.
Availability of data and materials All included references in the present
review article are available on the internet.
Sleep Breath
Code availability Not applicable.
Author contribution KM devised the protocol, performed title/abstract
and full-text screening, extracted outcomes, created tables and figures,
and primarily wrote and edited the manuscript. AP devised the protocol,
performed title/abstract and full-text screening, extracted outcomes, and
wrote and edited the manuscript. JS wrote and edited the manuscript. MN
wrote and edited the manuscript. ME conducted the literature search and
edited the manuscript. DW edited the manuscript. PP edited the manu-
script. FC devised the protocol, and wrote and edited the manuscript.
Declarations
Ethics approval and consent to participate Not applicable.
Consent for publication Not applicable.
Competing interests FC reports research support from the Ontario
Ministry of Health and Long-Term Care, University Health Network
Foundation, and UpToDate royalties. Consultant to Takeda Pharma and
Masimo Inc. STOP-Bang questionnaire: proprietary to University Health
Network.
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