FormalPara Key Summary Points

Pain-insomnia-depression syndrome (PIDS) is a group of symptoms characterized by the coexistence of chronic pain, insomnia, and depression in individuals with chronic nonmalignant pain (CNMP).

Pain, insomnia, and depression have an interactive relationship, with each condition contributing to the development or worsening of the other.

The initial treatment strategies for chronic pain, depression, and insomnia include the use of noninvasive treatment methods.

Invasive treatments such as deep brain stimulation (DBS) may only be considered for selected patients who have demonstrated resistance to noninvasive approaches.

Introduction

Pain-insomnia-depression syndrome (PIDS) could be considered a group of symptoms observed in individuals with chronic nonmalignant pain (CNMP) [1]. In the term “PIDS,” “chronic pain” is defined as a feeling of discomfort that persists or recurs beyond the usual recovery period, usually exceeding a time threshold of 3 months [2]. Pain, in all its sensory, cognitive, motivational, and emotional aspects, refers to an unpleasant sensation caused by actual or potential damage to body tissues [3]. It includes not only the perception of the characteristics, location, causes, duration, and intensity of the stimulus, but also the responses and reactions evoked by the stimulus, including involuntary reflexes and autonomic processes [4, 5]. Pain prevalence standardized by age and gender varies significantly across countries, with an estimated overall weighted average of 27.5%. This prevalence ranges from as low as 9.9% to as high as 50.3% in different countries [6]. There is evidence that chronic pain has reached epidemic proportions in the United States and Europe [7]. Insomnia is different from sleep deprivation and is defined by a feeling of dissatisfaction with the amount or quality of sleep. It is characterized by significant stress or dysfunction, as well as daytime symptoms such as fatigue, excessive sleepiness, impaired cognitive performance, and mood disturbances [8]. Approximately 6% of individuals meet strict diagnostic criteria for insomnia, while up to 48% experience insomnia symptoms [9].

Depression is characterized by a pervasive feeling of sadness, anhedonia, difficulty concentrating or making decisions, feelings of worthlessness or excessive guilt, recurrent thoughts of death or self-harm, changes in sleep patterns or appetite, restlessness or slow movements, and a persistent feeling of tiredness or lack of energy [10, 11]. It is one of the most common manifestations of psychiatric pathologies and is closely associated with significant disability, impaired health-related quality of life, and increased mortality [12]. The prevalence of depression varies depending on the population group. Recent estimates suggest that approximately 10.4% of people are affected within 12 months and 20.6% during their lifetime [13].

Given the importance of interrelated symptoms for developing treatment plans, as Williams emphasizes, co-occurring symptoms should be considered when selecting appropriate treatment strategies [14]. With the well-documented coexistence of pain, insomnia, and depression [9, 15,16,17,18,19], and the complex relationships between pain, insomnia, and depression [20,21,22], there is a need to explore the triangular relationships, pathobiological correlations, current treatment modalities, and future prospects associated with these phenomena. The primary objective of this study is not to generate novel knowledge, but rather to present a contextualized compilation of previously relevant materials within the scope of the study topic. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Neurobiological Correlations

The complex relationships between chronic pain, insomnia, and depression are currently being investigated, and ongoing efforts are being made to elucidate their precise relationships. However, existing evidence suggests the presence of common brain structures, neural pathways, and neurobiological processes underlying these disorders [23] (Fig. 1). In the context of chronic pain [24], insomnia [25], and depression [24, 25], the hippocampus, which is an important component of the limbic system, has been observed to exhibit abnormalities. These abnormalities have been documented in academic research and suggest possible underlying mechanisms linking these disorders [24, 26].

Fig. 1
figure 1

Common neurobiological correlations between chronic pain, insomnia, and depression

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In all three diseases, atrophy of the hippocampus [27] and increased activation of the limbic area are observed, with abnormal patterns in similar brain regions. Patients with depression and insomnia experience decreased activity in the prefrontal cortex (PFC), which leads to increased limbic activity through disinhibition. This increased activation may be a common mechanism contributing to the symptoms of all three disorders, with depression increasing emotional responses and chronic pain leading to increased emotional symptoms, insomnia, and sleep disturbances [28]. Furthermore, reduced hippocampal volume, also affected by chronic pain and depression, has been linked to reduced neurogenesis and neuroplasticity in both human patients and rodent models. This could potentially indicate a neuropathological mechanism underlying comorbid chronic pain and depression [29].

Furthermore, inflammation is recognized as an important regulator of hippocampal neurogenesis. Pain [30], insomnia [31], and depression are thought to be related to inflammatory responses in the hippocampus and may influence hippocampal neurogenesis [30]. Pain, insomnia, and depression are all associated with increased sensitization of the central nervous system, manifested by increased responsiveness to pain signals, sleep disturbances, and altered emotional processing [32]. In addition, chronic pain, insomnia, and depression are closely related to changes in neurotransmitter levels in the central nervous system, including serotonin (5-HT) [33], dopamine (DA), and norepinephrine (NE), which are critical for pain signaling, sleep regulation, and mood control [34,35,36,37,38]. Imbalances in these neurotransmitters can lead to the development of chronic pain, insomnia, and depression [34, 37, 38].

Chronic pain and depression are influenced by various molecular mechanisms, including monoamine neurotransmitters, inflammatory factors, and glutamate receptor subtypes. The dopaminergic system in the midbrain influences neuroplastic changes, with persistent pain negatively affecting DA activity. Decreased monoamine neurotransmitters in the central nervous system increase susceptibility to depression. Inflammatory factors cross the blood–brain barrier and alter neurotransmitter metabolism and neuroendocrine function. Glutamate, a primary excitatory neurotransmitter, is also linked to their development. Therapeutic medications can be developed to target specific areas common to both diseases, allowing for more precise treatment strategies. Epigenetic modifications alter chromatin structure and influence the accessibility of transcription factors to DNA promoter regions. MicroRNAs target histone deacetylase (HDAC) factors in both neuronal and non-neuronal cells and play a crucial role in gene regulation. The role of adult neurogenesis in chronic pain-related depression is not fully understood, but ongoing research suggests its possible importance [39].

Proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), nerve growth factor (NGF), interleukin-1 (IL-6), leukemia inhibitory factor (LIF), bradykinin, and prostanoids are neurobiological factors that are associated with chronic pain, insomnia, and depression. These cytokines act on nociceptive terminals in inflamed tissues, contribute to axonal damage, and modulate spontaneous nociceptor activity [28]. Nadeau et al. found that the preoperative level of mechanical pain hypersensitivity was almost indistinguishable in IL-1/TNF receptor knockout mice and wild-type littermates before partial sciatic nerve ligation [40]. However, both groups showed a significant reduction in the paw withdrawal threshold when exposed to a mechanical touch stimulus. The absence of interleukin-1 receptor (IL-1R1) and TNFR1 is necessary for pain relief, highlighting the critical role of proinflammatory cytokines in mediating neuropathic pain effects. Depression is associated with increased levels of proinflammatory cytokines that activate the hypothalamic–pituitary–adrenal axis (HPA or HTPA axis) and affect serotonergic, noradrenergic, and dopaminergic neurotransmission. The proinflammatory cytokines IL-1 and TNF-α are essential for the regulation of sleep patterns, particularly non-rapid eye movement sleep (NREMS), even in the absence of immune stress. A study by Moldofsky et al. showed a significant increase in IL-1 activity during sleep, accompanied by changes in immune function and the initiation of slow-wave sleep (SWS). IL-1β and TNF-α are substances that regulate sleep, and their introduction can mimic symptoms associated with poor sleep, such as depression, sleepiness, and fatigue. The exact mechanism by which these cytokines influence sleep regulation is not yet fully understood. However, they directly affect neurons in specific brain regions, such as the hypothalamic preoptic nucleus and basal forebrain [28].

Pain, insomnia, and depression may be related to brain-derived neurotrophic factor (BDNF), which increases the excitability of spinal neurons and mimics the effects of peripheral nerve injury. In vitro studies show increased BDNF levels in animal models of acute and chronic spinal cord pain. However, gene expression of BDNF and its receptor (neurokinin-1) was decreased in the hippocampus but increased in the spinal cord, suggesting an increase in BDNF in the spinal cord and a possible decrease in the hippocampus. Research shows that BDNF is crucial in the neurobiology of depression, with stressors such as forced swimming and chronic immobilization leading to declines in BDNF messenger RNA (mRNA) levels and reductions in BDNF stores in the hippocampus. However, this downregulation can be reversed by antidepressants that increase BDNF synthesis, neurogenesis, and signaling. BDNF also plays an important role in sleep regulation, with release increasing during both the NREMS and REMS phases in rabbits. Sleep deprivation can cause disruptions in BDNF levels, resulting in increases in BDNF protein and mRNA levels in the hippocampus but not the cerebellum or brainstem [28].

The orexin system is also involved in various physiological functions, including pain regulation [41], insomnia [42], and depression [43]. There are two types of orexin, namely orexin-A and orexin-B [44]. Both regulate their different influences through the binding and activation of two G protein-coupled receptors (GPCRs), orexin receptor type 1 (OX1R) and orexin receptor type 2 (OX2R) [45]. Orexin-producing cell bodies are located in particular in the lateral and perifornical regions of the hypothalamus. These cells send out fibers that extend throughout the central nervous system, forming a wide network. Orexin receptors are distributed throughout the brain and spinal cord. They are abundantly expressed in various regions, including the cerebral cortex, basal ganglia, ventral tegmental area (VTA), nucleus accumbens (NC), hippocampus, hypothalamic and thalamic nuclei, dorsal and median raphe, locus coeruleus (LC), des preoptic area, and the periaqueductal gray (PAG) and reticular formation. The different functions of the orexin receptors in many areas are due to the coexpression of OX1R and OX2R receptors, while in some areas only one of the two orexin receptors is predominantly expressed [41]. Numerous studies have provided evidence that injection of exogenous orexin at specific sites in the spinal cord and supraspinal sites associated with the descending pain regulatory circuits can result in significant reductions in nociceptive pain in various animal models of formalin-induced inflammatory pain responses [46]. Both OX1R and OX2R play a crucial role in the initiation and maintenance of sleep [47].

Preclinical models have shown reciprocal interactions between OX1R and OX2R [48]. It is worth noting that OX2R is particularly involved in the inhibition of NREM, while both receptors [48] contribute equally to the suppression of REM [49]. In addition, there is evidence that partial, prolonged, or total sleep deprivation is associated with increased orexin levels in the cerebrospinal fluid (CSF) [50]. Additionally, numerous animal studies have shown that both total sleep deprivation and selective REM deprivation result in increased orexin tone. This is supported by increased firing and projections of orexinergic neurons [51,52,53]. This evidence demonstrates the potential of exploiting antagonism at orexin receptors to regulate the orexin system and restore sleep in individuals suffering from insomnia [54,55,56]. Several experimental studies suggest a close connection between orexin and depression [57,58,59]. Consequently, continuous inhibition of orexin signaling could potentially lead to a state of lack of motivation or depression. It is worth noting that the function of the orexin system is impaired in both rats and individuals showing depression-like symptoms [60]. In the clinic, patients suffering from major depressive disorder and suicidal ideation show a decrease in orexin levels in their cerebrospinal fluid [57]. In contrast, it is worth noting that orexin has a direct stimulatory effect on GABAergic ventral pallidum (VP) neurons, thereby inhibiting depressive behavior in rats [61].

Tridirectional Associations

PIDS are comorbidities with complex relationships [9, 15,16,17,18,19]. These symptoms influence each other [62], increase the risk that other symptoms will appear or worsen [9], and produce synergistic effects on health outcomes according to the unpleasant symptom theory [62]. Although a comprehensive understanding of the precise mechanisms underlying these relationships has not yet been achieved, studies have proposed three different approaches to elucidate these relationships. While studies have suggested that pain intensity may be influenced by insomnia associated with depression [63] (Fig. 2A), other studies suggest that chronic pain disrupts sleep and may be influenced by mood disorders such as depression [64]. Undoubtedly, mood disorders have been suggested as a potential mediator in the interaction between sleep and pain [65] (Fig. 2B). In addition, there is evidence suggesting that chronic pain affects sleep quality [66], which in turn may contribute partially [67] or fully to the development or exacerbation of depression [13, 23, 66, 68, 69], either partially [67] or completely [70], whichever frequency is higher (Fig. 2C). Chronic pain leads to poorer sleep quality and ultimately more severe depression symptoms [23]. This mechanism has attracted increased attention. Studies have provided evidence of the connection between pain intensity, sleep quality, and depression. In particular, the association between pain disorders and depression appears to be influenced by the individual's sleep quality. In particular, improved sleep quality has been found to attenuate the negative effects of pain disorders on depressive symptoms, while poorer sleep quality increases these effects [71]. Likewise, sleep quality was shown to reduce the influence of pain intensity on negative mood (similar to depression) in individuals with rheumatoid arthritis and fibromyalgia [72]. Likewise, experiencing insomnia is associated with being twice as likely to suffer from depression and anxiety compared to people who report no symptoms of insomnia [73]. This finding is strongly supported by a community-based prospective study indicating that the occurrence of sleep disturbances in individuals with chronic musculoskeletal pain is associated with a threefold increased risk of developing depression [74]. These results confirm previous research highlighting pain as an indicator of depression, as well as several studies demonstrating an association between poor sleep quality and the occurrence of depressive symptoms [75, 76]. Experimental research has also uncovered several mechanisms through which sleep may influence depression, such as an increased negative reaction to stressful stimuli, an improvement in depressive symptoms, reduced frustration tolerance, and reduced emotional intelligence [77,78,79,80]. As a result, taking into account the cumulative results of theoretical reviews, epidemiological studies, cross-sectional analyses, and prospective studies, a comprehensive understanding is emerging that confirms the complex interplay between pain, insomnia, and depression [9, 15,16,17,18,19].

Fig. 2
figure 2

Potential relationship between chronic pain-insomnia-depression (CPID). A Intensity of chronic pain may be influenced by insomnia accompanied by depression; B chronic pain impacts sleep quality by influencing mood factors like depression; C chronic pain has a detrimental impact on sleep quality, which in turn may contribute to the development or exacerbation of depression

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Contemporary Treatment Approaches

Treating pain, insomnia, and depression typically requires a comprehensive treatment approach. A multidisciplinary approach is typically used in the treatment of chronic pain [65], including both pharmacological [81] and noninvasive non-pharmacological therapies (NINPT). Noninvasive, non-pharmacological therapies include various modalities such as physical interventions, psychological interventions, complementary and alternative therapies [82], education, and occupational therapy. In addition, complementary and alternative medicine (CAM) techniques, including practices such as meditation, acupuncture, or music therapy, may be considered, although the level of evidence for their effectiveness is often limited [83]. Treatment of insomnia usually involves a combination of pharmacological and non-pharmacological interventions. The choice of treatment depends on factors such as the specific symptoms and severity of insomnia, the presence of coexisting disorders, the expected duration of treatment, the patient's preference for cognitive therapies, and the individual's susceptibility to medication side effects. Non-pharmacological approaches primarily focus on cognitive behavioral therapy for insomnia (CBTI), which is preferred due to its low side effects. However, there are limitations to the accessibility and availability of qualified CBTI facilitators. Pharmacologic treatment requires careful selection of popular drug categories such as benzodiazepines, non-benzodiazepines, antidepressants, and antihistamines for short-term use. These medications carry a higher risk of side effects, addiction, and abuse [84]. The currently accepted treatment approaches for depression include electroconvulsive therapy, cognitive behavioral therapy, interpersonal psychotherapy, and pharmacological interventions that modulate neurotransmission dependent on biogenic amines. The monoamine hypothesis, which proposes imbalances in the monoamine brain system as a factor contributing to depression, has been a major research focus in this area [85]. Despite all of these, pain management specialists should regularly assess patients with nonmalignant chronic pain for pain, insomnia, and depression [1].

Prospective Directions

Although chronic pain affects a significant number of people and is estimated to affect over 100 million people in the United States alone, study-level treatment failure rates are already significant. They are likely to be even more pronounced in the clinical setting. Evidence of treatment failure is usually derived from controlled trials, such as those evaluating gabapentin in neuropathic pain, where treatment can provide up to 50% relief compared to placebo [86]. The American Academy of Sleep Medicine and the European guidelines for the diagnosis and treatment of insomnia do not provide a clear definition of individuals who continue to experience insomnia despite appropriate therapy. In clinical trials, various terms such as treatment-resistant insomnia, refractory insomnia, residual insomnia, or persistent insomnia are used interchangeably to describe these patients [87]. Treatment-resistant depression (TRD) is characterized by a lack of response to two appropriate antidepressant treatment trials. TRD is often associated with prolonged and costly inpatient treatment. Despite various proposed definitions and criteria for identifying true TRD, no consensus has been reached. Consequently, the management of TRD presents challenges in terms of formulating therapeutic strategies and discovering effective treatments [88]. Given the significant burden of pain experienced by the population and the limited treatment options available, there is growing interest in exploring more radical approaches, including deep brain stimulation (DBS), or transcranial brain stimulation, as well as ketamine infusions, which are offered to patients with pain described as treatment-resistant [86].

Examining the associations between PIDS and individuals with chronic pain is a key area of ​​ research. Future research directions in PIDS will focus on improving the understanding of this complicated syndrome and providing a basis for groundbreaking interventions that reduce the burden of chronic pain, insomnia, and depression on those affected. Currently, brain stimulation (BS) methods such as DBS have attracted widespread attention and cover a wide range of applications, ranging from basic scientific investigations to the practical implementation of therapeutic interventions. DBS is a neurosurgical technique that involves inserting electrodes into specific regions of the brain and delivering continuous or intermittent electrical pulses from an implanted battery source [89].

From a clinical perspective, it offers several advantages over alternative surgical methods of neuromodulation. These advantages include the nonlesional nature of DBS, the ability to adjust stimulation parameters to optimize efficacy and minimize side effects, and the ability to directly interact with the circuit pathology responsible for apparent symptoms. From a scientific perspective, DBS serves as a valuable tool for studying the underlying physiological mechanisms of brain dysfunction. This allows for the identification and correction of pathological neuronal patterns, promotes technological advancement, and improves safety and clinical outcomes [90]. In addition, DBS has proven to be a highly targeted intervention, focusing on specific anatomical areas, often in the millimeter range. In this way, it has provided valuable insights into circuit theories of brain dysfunction. This research has shown that localized dysfunction and subsequent interventions can have significant effects on the broader networks in the brain [91]. The dual nature of DBS, acting as both a probe and modulator of brain circuits, has led to further investigation into its therapeutic potential for a variety of disorders. These include disorders that affect motor skills, emotional regulation, memory, and cognitive function [89]. DBS has been extensively studied as a potential therapeutic approach for the treatment of chronic pain [92]. While the specific mechanism of DBS for pain management is still unknown, several plausible theories have been proposed based on recent studies. DBS is believed to be able to modulate electrical activity and neurochemical transmission in the brain. Abnormal pain signals can be interrupted by electrical pulses via the electrodes, restoring normal brain activity. In addition, DBS can alter the abnormal oscillatory activity in the brain that is associated with chronic pain. DBS can reduce pain perception by altering neuronal oscillation patterns. Additionally, studies have shown that DBS can cause synaptic plasticity, the ability of synapses to strengthen or weaken over time [93,94,95].

DBS has been shown to be effective in the treatment of various pain syndromes, including post-stroke pain, phantom limb pain, brachial plexus injuries, failed back surgery syndrome, and pain associated with Parkinson’s disease (PD). The results suggest that applying DBS to different brain nuclei associated with chronic pain produces different results. In particular, the ventral posterolateral nucleus (VPL), anterior cingulate cortex (ACC), periventricular gray (PVG), and PAG were found to be the most effective targets and showed significant or moderate treatment effects. These identified targets are involved in both the sensory-discriminatory and affective aspects of pain perception. DBS can modulate the activity of neural circuits involved in pain processing and perception. The exact mechanism underlying the pain-relieving effects of DBS is not fully understood, but several factors are thought to be involved. These factors include changing the balance between inhibitory and excitatory neurotransmitters within pain pathways, reducing the activity of neurons that transmit nociceptive signals, improving the function of endogenous opioid systems responsible for pain relief, and changing emotional and cognitive aspects of pain such as anxiety and depression and catastrophic. The effectiveness of DBS in relieving chronic pain may vary depending on the brain target stimulated. Among the most common targets is the sensory thalamus (particularly the ventral-posterior-lateral and ventral-posterior-medial nuclei), which primarily contributes to the sensory-discriminatory aspects of pain, such as location, intensity, and quality. The PAG and periventricular gray matter are also targeted because of their role in descending pain modulation and the release of endogenous opioids. In addition, the ACC, which is involved in the emotional and motivational aspects of pain such as discomfort, suffering, and coping, is another commonly targeted area [96].

DBS therapy is effective in treating sleep–wake disorders in PD, including sleep fragmentation, rapid eye movement (REM) behavior disorder, excessive daytime sleepiness, periodic limb movements, and restless legs syndrome [97]. The exact mechanisms behind this improvement are not fully understood, but several possible causes include alteration of neural circuits involved in sleep regulation, control of abnormal oscillatory activity in the brain, and impairment of the production and activity of neurotransmitters such as dopamine, serotonin, and GABA. DBS can also help control sleep–wake cycles and promote better sleep by altering the balance of these neurotransmitters. Additionally, DBS can reduce hyperarousal and increase activity in certain brain regions, such as the PFC and limbic system, which are often associated with insomnia, resulting in less hyperarousal and better sleep initiation and maintenance. Overall, DBS therapy has the potential to significantly improve sleep quality and sleep management in PD [98].

DBS is effective in treating severe, treatment-resistant depression [99]. The exact mechanism of action is still unclear, but it has been suggested that it may modulate dysfunctional neural circuits associated with depression. This can be achieved by electrically stimulating specific brain regions, altering the activity and connectivity of these circuits, and improving depressive symptoms. DBS also affects the release and activity of neurotransmitters involved in mood regulation, such as 5-HT, DA, and norepinephrine. This stimulation can increase the release of these neurotransmitters or modulate their receptors, resulting in an antidepressant effect. DBS has also been found to induce neuroplastic changes in the brain, promoting the growth of new neurons and strengthening existing connections. It targets specific brain regions involved in mood regulation, such as the subcallosal cingulate region, NC, ventral capsule/striatum, medial forebrain bundle, inferior thalamic peduncle, and lateral habenula, to restore neuronal activity and relieve depressive symptoms. Additionally, DBS may have anti-inflammatory effects on the brain, which could contribute to its antidepressant effects [100,101,102].

Conclusion

PIDS exhibits intricate triangular relationships, with pain, insomnia, and depression influencing and exacerbating each other. The pathobiological correlations underlying PIDS involve complex mechanisms including neurophysiology, endocrine regulation, and psychological factors. Current treatment modalities for PIDS encompass a multidisciplinary approach, including both pharmacological and NINPT, which is considered first-line treatment. Invasive treatments such as DBS may only be considered for selected patients in cases where unresponsive patients have shown resistance to noninvasive methods. Overall, advancing our knowledge of the triangular relationships, pathobiological correlations, and current treatment modalities for PIDS is crucial for providing effective and comprehensive care to individuals affected by this syndrome. Continued research and collaboration among various disciplines are key to paving the way for future advancements in the field and ultimately improving the lives of those suffering from PIDS.