Can we use the dynamic and complex interplay between pain and sleep to quantify neuromodulation responsiveness for chronic pain?

KEYWORDS:

• sleep disorders
• pain
• objective outcome measurement
• neuroinflammation
• neurostimulation therapies

1. Introduction

1.1. Current literature addressing the relationship between chronic pain and sleep architecture

The prevalence of chronic pain with varying origins, and pain without identified diagnosis or etiology, in adults and children has been a matter of ongoing debate. Most recently published systematic reviews (meta-analyses) have demonstrated a broad prevalence range depending on the pain’s origin [1]. For instance, King et al. have reported the following ranges: headache, 8–83%; abdominal pain, 4–53%; back pain, 14–24%; musculoskeletal pain, 4–40%; and unspecified pain, 5–88%. In line with previously published literature, the pain prevalence has been found to be higher in older individuals (thus showing age dependency) and to be associated with lower functional capacity, decreased quality of life, impaired cognition, and lower physical activity and socioeconomic status, particularly for headache. Moreover, nearly 70–80% of patients with chronic pain also have a disrupted sleep architecture. Notably, most studies included in the aforementioned systematic review did not apply high quality sleep measures, such as polysomnography, actinography, EEG or EMG [1]. Another meta-analysis has specifically included studies with an objective sleep measure approach in patients with chronic pain and has found perturbed sleep onset latency/efficiency, prolonged time awake after sleep time, impaired NREM sleep, and increased respiratory-related events and limbic movements, thus indicating that patients with chronic pain significantly display pathological sleep patterns. Further characteristics include difficulties in falling asleep, maintenance of sleep, daytime sleepiness and sleep-associated anxiety [2]. Hence, combined diagnostic and therapeutic approaches targeting both sleep and pain have been recommended [3]. Although a limited number of longitudinal studies have addressed the interaction between sleep and pain, sleep disorders are currently believed to promote the development of new-onset pain, the worsening of pain and pain-related disability. Some shared pathways (dopaminergic and opioidergic) have been described in experimental settings, thus linking pain (central descending inhibition pathways), sleep (hypothalamic nuclei preoptic and suprachiasmatic nucleus of the hypothalamus) and associated mood disturbance (anxiety and depression). However, the complex spatial and temporal features of pain, sleep and mood disorders remain poorly understood [4,5].

Notably, sleep and pain regulate each other bidirectionally in a time-dependent manner through circadian brain systems. Acute sleep deprivation decreases pain thresholds, inhibits pain-suppressing descending brain networks and increases pain sensitivity. Most of the relevant literature has been based on experimental studies; therefore more human trials are needed [6]. At the molecular level, neurotransmitters such as melatonin (pineal gland), cortisol, noradrenaline and dopamine are involved in the control of the circadian clock, as well as in the regulation of nociception and pain. In addition, circadian clock rhythmicity promotes and/or suppresses the expression of ion channels (voltage-gated calcium channels, NMDA glutamate receptors and μ-opioid receptors) in neuroanatomical structures involved in pain neural transmission (dorsal root ganglion, dorsal horn of the spinal cord, periaqueductal gray and brainstem) [6].

Depending on the underlying pain disorders (neuropathic pain, inflammatory pain, migraine or headache), the occurrence of the most severe pain thresholds may vary depending on the circadian clock [6].

1.2. State of sleep assessment in chronic pain patients treated with neurostimulation therapies

To date, robustly designed (randomized-controlled) human studies are increasingly evaluating noninvasive and invasive neurostimulation therapies (e.g. deep brain stimulation, motor cortex stimulation, transcranial magnetic stimulation, transcranial direct current stimulation, transcranial alternating stimulation, cervical noninvasive vagus nerve stimulation, different spinal cord stimulation waveforms and dorsal root ganglion stimulation) for refractory chronic pain disorders, such as primary headache disorders, lower back pain, neuropathic leg pain and complex regional pain syndrome [7–13]. These studies have underscored the usefulness of neurostimulation as an adjunctive treatment strategy for use with pharmacological-behavioral therapies. However, none of these studies have incorporated objective sleep measures, such as polysomnography, actinography, electromyography or electroencephalography [7–13].

Although a small number of mostly uncontrolled human neurostimulation-pain trials have assessed possible associations between circulating mediators of neuroinflammation and neurostimulation responsiveness, neuroinflammatory phenotyping may become a useful and easily accessible tool to reveal the molecular mechanisms of pain, sleep and mood alterations [14,15]. For example, cervical noninvasive vagus nerve stimulation has been found to significantly decrease the levels of pro-inflammatory IL-1β in refractory migraines in a randomized sham-controlled human trial. Whether such concentration changes are responsible for the observed vagus nerve stimulation effects and/or might reflect disease state progression warrants further reexamination [14]. In a large systematic review, Irwin et al. have analyzed 72 studies examining the possible associations between inflammation and sleep alterations in more than 50,000 participants [15]. Circulating C-reactive protein and pro-inflammatory interleukin 6 were found to be associated with sleep disturbance, whereas sleep duration changes (either short or long sleep subtype) were associated with only a C-reactive protein increase, thus indicating an effect of neuroinflammation in the pathophysiology of sleep architecture. For instance, pro-inflammatory IL-1β evokes distinct chronic pain and mood disorders [16,17]. Under such circumstances, molecular phenotyping may be biased by a considerable number of confounders such as age, race, sex, medication, lifestyle and environmental factors [14,15].

Beyond the electrophysiological assessment of sleep, molecular inflammatory phenotyping is increasingly gaining scientific recognition in the characterization of sleep, pain and mood disorders by objectively determining changes in the concentrations of circulating neuroinflammatory mediators involved in the development and maintenance of pain, sleep disorders and mood alterations (anxiety and depression) [16–18].

1.3. Conclusion and proposal for future clinical research

The directionality of sleep, pain and mood must be addressed in further experimental and longitudinal human studies. To close this knowledge gap, additional diagnostic methods such as brain imaging, electrophysiological assessment and molecular inflammatory assays will help to extend the currently limited knowledge. Given the extensive data generated in such studies, artificial pattern recognition may become useful to counterbalance intra- and inter-individual variability in both disorders (chronic pain and sleep disorders) and to accurately define subsets or clusters of common pathways [19].

Conclusively, objective sleep measurements are not ready to be used to determine neurostimulation therapy outcomes for chronic pain disorders. In a first step, more longitudinal human studies applying multiple diagnostic tools are warranted to clarify the complex bidirectional nature of sleep disturbance and pain perception. Age, sex and race, among other confounders, have been reported to be relevant co-factors for both chronic pain and sleep disturbance. Nevertheless, neurostimulation pain trials implementing high quality sleep quantification may be worthy of study as a potential objective outcome measure.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One of the reviewers on this paper is a consultant for Abbott, Boston Scientific, and Nevro. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.