Neuropathic Pain and Sleep: A Review
Neuropathic Pain and Sleep: A Review
Luigi Ferini-Strambi 0 1
0 Compliance with Ethics Guidelines
1 L. Ferini-Strambi (&) Sleep Disorders Center, Department of Neurology, Scientific Institute Ospedale San Raffaele, Vita-Salute University , Milan , Italy
Neuropathic pain is associated with sleep disturbances, and inturn poor sleep quality leads to increased pain sensitivity, so it is essential to assess sleep alongside neuropathic pain. Responses to drugs are inconsistent and identifying the best treatment option that will reduce pain and improve sleep quality remains challenging for clinicians. Anticonvulsants such as pregabalin and gabapentin improve neuropathic pain and have a positive effect on comorbid sleep disturbances. Opioids and antidepressants are effective in reducing pain but can exacerbate sleep disturbances. Funding: Pfizer, Italy.
Anticonvulsants; Antidepressants; Neuropathic pain; Opioids; Sleep disturbances; Sleep quality
Healthy sleep is composed of two repeated
phases with different neocortex firing patterns:
the non-rapid eye movement (NREM) phase,
comprising four stages, and the rapid eye
movement (REM) phase [
]. The first stage of
the NREM phase (decrease of alpha waves)
initiates sleep and is followed by the second stage
(spindles and K complexes) and the third and
fourth stages or deep sleep (slow-wave). The
REM phase consists of desynchronized brain
wave activity, dreaming, and muscle atonia [
The effects of neuropathic pain on sleep
quality have been examined directly . One
study revealed that 68% of patients with
neuropathic pain had ‘‘strongly’’ or ‘‘mostly’’
disturbed sleep . Patients with post-herpetic
trigeminal neuropathy (unilateral head/facial
pain caused by herpes zoster) have reduced
sleep efficiency with shorter REM and NREM
stages 3 and 4 . Trigeminal nerve dysfunction
following trauma (trigeminal neuropathy) is
also characterized by unilateral facial or oral
pain, and patients are four times more likely to
wake up during sleep than subjects without
trigeminal neuropathy . Nearly two-thirds of
patients with trigeminal neuralgia (extreme,
sporadic, sudden burning or shock-like facial
pain) report at least occasional awakenings due
to innocuous stimuli at the trigger points 
whilst 22.6% report pain-related awakening .
Neuropathic pain occurs in about 15–20% of
patients with diabetes and is also associated
with mood and sleep disturbances .
RELATIONSHIP BETWEEN SLEEP
AND NEUROPATHIC PAIN
The relationship between neuropathic pain and
sleep disturbances is bidirectional [1, 9]. Patients
with neuropathic pain are more likely to develop
sleep disorders and in turn pain is exacerbated by
the lack and/or poor quality of sleep . A
positive association between pain sensitivity and the
frequency/severity of insomnia and a synergistic
reduction of pain tolerance in patients with both
chronic pain and insomnia have been reported
]. A clinical evaluation of neuropathic pain
following spinal cord injury should include a
sleep assessment [
Reducing pain improves sleep ; however, it is
difficult for clinicians to prescribe the most
adequate treatment for neuropathic pain as the
response to most drugs remains
]. Treatments for neuropathic pain
include antidepressants, anticonvulsants,
tramadol, opioids and topical analgesics [
Special Interest Group on Neuropathic Pain
(NeuPSIG) of the International Association for
the Study of Pain (IASP) carried out a systematic
review and meta-analysis of double-blind studies
of oral and topical therapies for neuropathic pain
]. Their findings support a revision of the
NeuPSIG recommendations for the
pharmacotherapy of neuropathic pain and include a
strong recommendation for the use of tricyclic
antidepressants, serotonin and noradrenaline
reuptake inhibitors, pregabalin, and gabapentin
as first-line treatments and a weak
recommendation for the use of lidocaine patches, capsaicin
high-concentration patches, and tramadol as
second-line treatments [
Novel anticonvulsants such as pregabalin
and gabapentin represent an attractive
treatment strategy as they are efficient in improving
neuropathic pain and have a positive effect on
comorbid sleep disturbances [
Ameliorations in sleep latency and wakefulness after
sleep onset, increased deep sleep, and
adjunctive effects on depression and anxiety have been
reported by patients with neuropathic pain
treated with gabapentin or pregabalin [
Pregabalin significantly reduces pain score and
pain-related sleep interference score in patients
with neuropathic pain [
], regardless of
previous treatment with gabapentin; it can therefore
be administered to patients intolerant or
refractory to gabapentin [
]. Quality of sleep
was ‘‘mostly’’ or ‘‘strongly’’ improved in 77% of
patients with neuropathic pain treated with
pregabalin as monotherapy or add-on therapy
. Anticonvulsants including oxcarbazepine,
lamotrigine, gabapentin, and pregabalin as well
as baclofen (muscle relaxer and an antispastic
agent) may be used as second-line therapy .
Post-herpetic neuralgia may be first treated
with tricyclic antidepressants, gabapentin,
pregabalin, and topical lidocaine (local anesthetic);
second- and third-line treatment may include
opioids, topical capsaicin (analgesic), and
tramadol (narcotic-like pain reliever) . Two
meta-analyses found that patients with
post-herpetic neuralgia treated with daily
gabapentin reported a significant improvement
in sleep rating scores compared with patients
who had received placebo; however, treatment
was associated with somnolence, dizziness,
peripheral edema, ataxia, or gait disturbance
and diarrhea [
]. A drug evaluation review
reported significant improvements in pain relief
and pain-related sleep interference in patients
treated with pregabalin compared with those
who had received placebo .
Carbamazepine (anticonvulsant) is
recommended as first-line therapy for trigeminal
]. Pregabalin, gabapentin,
venlafaxine, duloxetine, tricyclic antidepressants,
and opioids are the drugs with the best
evidence to support their use for painful diabetic
]. The opioid tapentadol
has also received FDA approval for painful
diabetic neuropathy. Benzodiazepines have
been approved for insomnia by the US FDA
and their short-term use also relieves
neuropathic pain .
Opioids must be administered with caution
to relieve pain but cannot be used to treat
insomnia. Moreover, chronic opioid use has
been associated with the development of
sleep-disordered breathing, such as central sleep
apnea (CSA). Studies indicate that the overall
prevalence of CSA in patients taking chronic
opioids is about 24% [
]. Older age, lower BMI,
male gender, higher pain levels, higher
benzodiazepine doses, and higher opioid doses were
all predictors for CSA [
In another situation, opioid receptor
agonists provide symptomatic relief from
dysesthesias and pain in patients with severe restless
legs syndrome (RLS), a condition that may have
prolonged sleep induction or sleep
]. Antidepressants can reduce
pain-related sleep disturbances and reduce chronic
pain in both depressed and non-depressed
]. However, many antidepressants,
including tricyclic antidepressants, serotonin
and norepinephrine reuptake inhibitors, and
serotonin-specific reuptake inhibitors, may
exacerbate RLS [
A polysomnography study in subjects with
insomnia and epilepsy reported a significant
relative increase in slow-wave sleep and a
decrease of stage 1 sleep in patients treated
with pregabalin versus placebo [
systematic review on the effects of epilepsy
treatments on sleep architecture concluded that
epilepsy drugs including gabapentin and
pregabalin reduce sleep latency and/or improve
sleep efficiency [
]. Although their
pain-relieving efficacy is comparable, antidepressant
drugs and opioids tend to worsen sleep quality
whilst the anticonvulsants pregabalin and
gabapentin improve it.
Both antidepressants and cannabis have
been shown to improve sleep in patients with
]. However, amitriptyline can favor
RLS and periodic legs movements (PLM);
duloxetine can promote bruxism .
Additionally, antidepressants have a suppressant
effect on REM sleep [
] and for this effect
experts in sleep medicine are reluctant to
prescribe them. The use of cannabis for sleep
disorders has been extensively reviewed recently
by Babson and colleagues [
]. While cannabis
has been shown to improve sleep in subjects
with pain, the authors do note that ‘‘research on
cannabis and sleep is in its infancy and has
yielded mixed results’’. They suggest that
further controlled and longitudinal research
should be conducted to ‘‘advance our
understanding’’ about the clinical implications of
using cannabis to improve sleep [
Insomnia may be treated with relaxation, sleep
restriction, cognitive, and cognitive behavioral
therapies . Although cognitive behavioral
therapies for pain and for insomnia are well
developed, efficacious, and cost-effective, most
clinicians are not trained to use them effectively
and access remains limited .
Neuropathic pain is associated with sleep
disturbances in a reciprocal manner, and it is
essential for clinicians to consider both aspects
of treatment. Anticonvulsants such as
pregabalin and gabapentin and antidepressants are
good candidates for pain relief, and the effects
of anticonvulsants on sleep are preferable to
those of antidepressants.
This supplement has been sponsored by Pfizer,
Italy. The article processing charges for this
publication were also funded by Pfizer, Italy.
Luigi Ferini-Strambi thanks Dr Ce´cile
Duchesnes, PhD, of Springer Healthcare
Communications who drafted the outline and first draft of
this manuscript. This medical writing assistance
was funded by Pfizer, Italy. The named author
meets the International Committee of Medical
Journal Editors (ICMJE) criteria for authorship
for this manuscript, takes responsibility for the
integrity of the work as a whole, and has given
final approval for the version to be published.
Disclosures. Luigi Ferini-Strambi has received
honorarium from Pfizer, and payment for lectures
and/or participation in advisory board from
Resmed, Philips Respironics, UCB-Pharma,
Valeas, Mundipharma, Italfarmaco, and
Compliance with Ethics Guidelines. This
article is based on previously conducted studies
and does not involve any new studies of human
or animal subjects performed by the author.
Data Availability. Data sharing is not
applicable to this article as no datasets were
generated or analyzed during the current study.
Open Access. This article is distributed
under the terms of the Creative Commons
Attribution-NonCommercial 4.0 International
by-nc/4.0/), which permits any
noncommercial use, distribution, and reproduction in any
medium, provided you give appropriate credit
to the original author(s) and the source, provide
a link to the Creative Commons license, and
indicate if changes were made.
Cheatle MD , Foster S , Pinkett A , Lesneski M , Qu D , Dhingra L . Assessing and managing sleep disturbance in patients with chronic pain . Anesthesiol Clin . 2016 ; 34 ( 2 ): 379 - 93 .
2. Institute of Medicine (US) Committee on Sleep Medicine and Research. Sleep physiology . In: Colten HR , Altevogt BM , editors. Sleep disorders and sleep deprivation: an unmet public health problem . Washington, DC: The National Academies Press; 2006 .
Lampl C , Schweiger C , Haider B , Lechner A . Pregabalin as mono- or add-on therapy for patients with refractory chronic neuropathic pain: a post-marketing prescription-event monitoring study . J Neurol . 2010 ; 257 ( 8 ): 1265 - 73 .
Roth T , van Seventer R , Murphy TK . The effect of pregabalin on pain-related sleep interference in diabetic peripheral neuropathy or postherpetic neuralgia: a review of nine clinical trials . Curr Med Res Opin . 2010 ; 26 ( 10 ): 2411 - 9 .
Benoliel R , Eliav E , Sharav Y . Self-reports of pain-related awakenings in persistent orofacial pain patients . J Orofac Pain . 2009 ; 23 ( 4 ): 330 - 8 .
Vinik A. The approach to the management of the patient with neuropathic pain . J Clin Endocrinol Metab . 2010 ; 95 ( 11 ): 4802 - 11 .
10. Sivertsen B , Lallukka T , Petrie KJ , Steingrimsdottir OA , Stubhaug A , Nielsen CS . Sleep and pain sensitivity in adults . Pain . 2015 ; 156 ( 8 ): 1433 - 9 .
11. D'Angelo R , Morreale A , Donadio V , et al. Neuropathic pain following spinal cord injury: what we know about mechanisms, assessment and management . Eur Rev Med Pharmacol Sci . 2013 ; 17 ( 23 ): 3257 - 61 .
12. Attal N , Cruccu G , Baron R , et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision . Eur J Neurol . 2010 ; 17 ( 9 ): 1113 - e88 .
13. Finnerup NB , Attal N , Haroutounian S , et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis . Lancet Neurol . 2015 ; 14 ( 2 ): 162 - 73 .
14. Argoff CE . The coexistence of neuropathic pain, sleep, and psychiatric disorders: a novel treatment approach . Clin J Pain . 2007 ; 23 ( 1 ): 15 - 22 .
15. Backonja M , Beydoun A , Edwards KR , et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial . JAMA . 1998 ; 280 ( 21 ): 1831 - 6 .
16. Sabatowski R , Galvez R , Cherry DA , et al. Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial . Pain . 2004 ; 109 ( 1-2 ): 26 - 35 .
17. Freynhagen R , Grond S , Schupfer G , et al. Efficacy and safety of pregabalin in treatment refractory patients with various neuropathic pain entities in clinical routine . Int J Clin Pract . 2007 ; 61 ( 12 ): 1989 - 96 .
18. Markman JD , Jensen TS , Semel D , et al. Effects of pregabalin in patients with neuropathic pain previously treated with gabapentin: a pooled analysis of parallel-group, randomized, placebo-controlled clinical trials . Pain Pract . 2017 ; 17 ( 6 ): 718 - 28 .
19. Fan H , Yu W , Zhang Q , et al. Efficacy and safety of gabapentin 1800 mg treatment for post-herpetic neuralgia: a meta-analysis of randomized controlled trials . J Clin Pharm Ther . 2014 ; 39 ( 4 ): 334 - 42 .
20. Meng FY , Zhang LC , Liu Y , et al. Efficacy and safety of gabapentin for treatment of postherpetic neuralgia: a meta-analysis of randomized controlled trials . Minerva Anestesiol . 2014 ; 80 ( 5 ): 556 - 67 .
21. McKeage K , Keam SJ . Pregabalin: in the treatment of postherpetic neuralgia . Drugs Aging . 2009 ; 26 ( 10 ): 883 - 92 .
22. Al-Quliti KW . Update on neuropathic pain treatment for trigeminal neuralgia. The pharmacological and surgical options . Neurosciences (Riyadh) . 2015 ; 20 ( 2 ): 107 - 14 .
23. Deli G , Bosnyak E , Pusch G , Komoly S , Feher G . Diabetic neuropathies: diagnosis and management . Neuroendocrinology . 2013 ; 98 ( 4 ): 267 - 80 .
24. Bril V , England J , Franklin GM , et al. Evidence-based guideline: treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation . Neurology. 2011 ; 76 ( 20 ): 1758 - 65 .
25. Russell JW , Zilliox LA . Diabetic neuropathies . Continuum (Minneap Minn) . 2014 ; 20 ( 5 ): 1226 - 40 .
26. Correa D , Farney RJ , Chung F , Prasad A , Lam D , Wong J . Chronic opioid use and central sleep apnea: a review of the prevalence, mechanisms, and perioperative considerations . Anesth Analg . 2015 ; 120 ( 6 ): 1273 - 85 .
27. Hassamal S , Miotto K , Wang T , Saxon AJ . A narrative review: the effects of opioids on sleep disordered breathing in chronic pain patients and methadone maintained patients . Am J Addict . 2016 ; 25 ( 6 ): 452 - 65 .
28. Trenkwalder C , Zieglga¨nsberger W, Ahmedzai SH , Ho¨gl B. Pain, opioids, and sleep: implications for restless legs syndrome treatment . Sleep Med . 2017 ; 31 : 78 - 85 .
29. Gilron I , Baron R , Jensen T. Neuropathic pain: principles of diagnosis and treatment . Mayo Clin Proc . 2015 ; 90 ( 4 ): 532 - 45 .
30. Bliwise DL , Zhang RH , Kutner NG . Medications associated with restless legs syndrome: a case-control study in the US Renal Data System (USRDS) . Sleep Med . 2014 ; 15 ( 10 ): 1241 - 5 .
31. Bazil CW , Dave J , Cole J , Stalvey J , Drake E . Pregabalin increases slow-wave sleep and may improve attention in patients with partial epilepsy and insomnia . Epilepsy Behav . 2012 ; 23 ( 4 ): 422 - 5 .
32. Jain SV , Glauser TA . Effects of epilepsy treatments on sleep architecture and daytime sleepiness: an evidence-based review of objective sleep metrics . Epilepsia . 2014 ; 55 ( 1 ): 26 - 37 .
33. Babson KA , Sottile J , Morabito D. Cannabis , cannabinoids, and sleep: a review of the literature . Curr Psychiatry Rep . 2017 ; 19 ( 4 ): 23 .
34. Wichniak A , Wierzbicka A , Jernajczyk W. Sleep and antidepressant treatment . Curr Pharm Des . 2012 ; 18 ( 36 ): 5802 - 17 .
35. Kolla BP , Mansukhani MP , Bostwick JM . The influence of antidepressants on restless legs syndrome and periodic limb movements: a systematic review . Sleep Med Rev . 2017 . https://dx.doi.org/10.1016/j. smrv. 2017 . 06 .002.