Sleep Disturbances and Chronic Pain in People with HIV: Implications for HIV-Associated Neurocognitive Disorders

Abstract

Purpose of Review:

Antiretroviral therapy has significantly reduced morbidity and mortality in people with HIV. Despite being virally suppressed, sleep disturbances, chronic pain, and neurocognitive impairments persist which can negatively impact quality of life for people with HIV. This article presents relevant literature related to sleep disturbances and chronic pain in people with HIV. The potential impact of these comorbidities on cognition is discussed with implications for managing HIV-associated neurocognitive disorder (HAND).

Recent Findings:

People with HIV and chronic pain report greater insomnia and depressive symptoms compared to those without chronic pain. The neurotoxic effects of HIV itself and sleep and chronic pain induced inflammation can contribute to poorer cognitive outcomes.

Summary:

Sleep disturbances and chronic pain are prevalent conditions in people with HIV that may perpetuate the development and exacerbation of HAND. Sleep and pain interventions may preserve cognitive function and improve quality of life for people aging with HIV.

Introduction

Sleep disturbances in people with HIV (PWH) have been linked to negative psychological, cognitive, and everyday function outcomes even in those who are virally suppressed [1–3]. A meta-analysis of 27 articles reported estimates of sleep disturbances affecting 58% of the HIV population [4]. In 2016, UNAIDS proposed the following 90–90-90 HIV testing and treatment strategy: 90 percent of PWH will know their status; 90 percent of those will be on treatment; and 90 percent of that group will be virally suppressed [5]. As PWH live longer and achieve viral suppression on antiretroviral therapy (ART), some will prematurely develop chronic conditions that occur in older adults. A ‘fourth 90’ was proposed to ensure that 90% of people with viral load suppression have good health-related quality of life [6]. This fourth 90 addresses comorbidities such as poor sleep and chronic pain, both of which can reduce quality of life for PWH. Poor management of HIV and age-related comorbidities can lead to poor ART adherence and inadequate viral suppression which in turn increases the risk of HIV transmission [7].

Sleep Disturbances in PWH

Sleep disturbances consist of a wide range of sleep disorders, including insomnia, sleep-disordered breathing, hypersomnolence, circadian rhythm sleep-wake disorders, and sleep-related movement disorders and parasomnias [8]. There are several factors specifically related to HIV that may explain the increased prevalence of sleep disturbances. First, studies suggest that disease exacerbation (i.e., low CD4 counts) is associated with poor sleep quality [9,10]. However other studies do not support these findings. In a study of South African patients with HIV on ART (N = 139), higher CD4 counts were significantly associated with poorer sleep quality, even after adjusting for depression severity, daytime sleepiness, and pain [11]. Second, medications have been implicated in sleep disturbances among PWH, and the ART medication most consistently associated with insomnia is the non-nucleoside transcriptase inhibitor, efavirenz [12]. In fact, studies have consistently shown improvements in sleep quality among PWH who switched to non-efavirenz-based ART regimens [13,14]. Third, studies suggest that psychosocial factors (e.g., substance use) may precipitate sleep disturbances. Sun-suslow and colleagues evaluated sleep quality in PWH with a lifetime history of marijuana use (N = 84) and found that they had significantly worse sleep quality compared to PWH without a lifetime history of marijuana use (N = 141)[15]. In addition, poorer sleep quality among PWH with a lifetime history of marijuana use was associated with worse functional outcomes and poorer overall quality of life [15]. Finally, sleep disturbances can further complicate physical comorbidities such as cardiovascular disease, diabetes mellitus, chronic pain, and suicide [16].

Evidence has suggested that the prevalence of insomnia in PWH is as high as 70% compared with 10–15% in the U.S general adult population [17,18]. Among 25 adults with HIV and 19 adults without HIV, 56% of those with HIV met diagnostic criteria for insomnia while none of the adults without HIV had symptoms consistent with the diagnosis [19]. Insomnia is characterized by difficulty falling asleep and/or staying asleep despite adequate opportunity and circumstances to sleep [20]. Many PWH with insomnia report not feeling refreshed when waking up, low energy levels or fatigue, lack of enthusiasm to get things done, difficulty staying awake during the daytime, and/or poor concentration [21]. Unfortunately, sleep disturbances in PWH can interfere with daytime function and lead to consequences in other areas such as employment, socialization, and interpersonal relationships, all of which are associated with reduced quality of life [1,18]. In a longitudinal study of 240 PWH, Rogers and colleagues found that poor sleep quality predicted worse health-related quality of life and poorer life satisfaction [22]. More specifically, sleep disturbances were shown to contribute to health-related impairments such as depression, chronic pain, and poor cognitive function [22]. In turn, comorbid symptoms of HIV such as pain and depression can exacerbate sleep disturbances, thus leading to a vicious cycle of adverse outcomes [18,23]. Rather than focus on potential determinants of insomnia, this review article will highlight the consequences of insomnia specifically as they relate to chronic pain and cognitive impairments in PWH.

Chronic Pain in PWH

Like insomnia, chronic pain is a growing concern for PWH with prevalence estimates varying from 25% to 90% [24,25]. A systematic review of the literature indicated that over half of all PWH are likely to experience recurring pain symptoms throughout their lifetimes, with increasing prevalence as these individuals age [26]. Chronic pain in PWH is multifactorial and characterized as neuropathic or non-neuropathic. Neuropathic pain, which typically affects hands and feet, has been associated with the use of neurotoxic ART and complications of HIV and other viral infections [27]. In a longitudinal multi-national study of people with and without HIV, peripheral neuropathy was more common in PWH and decreased neuropathic symptoms were reported in those who achieved HIV viral load suppression over time [28]. Despite the development of less toxic ART, residual neuropathic pain persists even in PWH who are virally suppressed [28].

In addition, PWH have disproportionately high rates of non-neuropathic pain which can present as chronic low back pain, osteoarthritis, and/or multi-site pain [24,29]. In a sample of 140 PWH with and without chronic pain, the most common site of pain was low back (86%) and PWH with chronic pain had higher levels of inflammatory markers compared to those without chronic pain [24]. Other studies demonstrate that elevated inflammatory cytokines are associated with increasing age and with worsening measures of chronic pain [29]. In a study of 80 older adults with HIV, increasing age was associated with elevated levels of circulating proinflammatory cytokines, and these elevated levels correlated with enhanced temporal summation of mechanical pain [29]. Thus, study findings suggest that elevated levels of circulating proinflammatory cytokines as well as increased pain sensitivity may contribute to the chronic pain experienced by older adults with HIV.

Studies suggest that neuropathic pain may be due to peripheral sensitization which is caused by an inflammatory condition (e.g., fibromyalgia or physical trauma) in which the pain remains even after the inflammation is no longer present [30]. Additionally, studies hypothesize that chronic pain in PWH is related to alterations in endogenous pain modulatory processes that promote exaggerated pain responses and central nervous system (CNS) sensitization. In a study of PWH with chronic pain (N = 59) and without chronic pain (N = 51) and 50 controls without HIV or chronic pain, pressure and heat pain thresholds were significantly lower among PWH with chronic pain compared to the other groups [31]. Also, lower pressure pain thresholds were significantly associated with greater average clinical pain severity for PWH with chronic pain [31]. These study findings suggest that alterations in endogenous pain modulatory processes may be an important contributor to the development and/or experience of chronic pain for PWH.

Current research suggests that HIV itself stimulates cytotoxic immune processes which influences sensitivity to pain [27,32]. Research in animals and humans have shown that persistent immune activation of HIV envelope glycoproteins, such as GP120, promote hyperalgesia [32]. However, dysregulation of immune activity may be due to other HIV-related health outcomes including cardiovascular disease, co-infections, cancer, Type II diabetes and frailty, all of which can exacerbate chronic pain symptoms [27,32]

Chronic Pain Related Factors and Sleep Disturbances in PWH

Chronic pain in PWH has been associated with poor health outcomes and quality of life that worsens with aging. In a study of 89 breast cancer survivors and 73 PWH with neuropathic pain, PWH reported significantly higher anxiety, depressive symptoms, pain interference, poorer sleep, and lower quality of life [33]. Similarly, a recent study found significantly greater insomnia severity and depressive symptoms among PWH with chronic pain (N= 85) compared to those PWH without chronic pain (N=36) [34]. Insomnia severity was greater among 49 PWH with chronic pain who reported opioid use compared to 36 who denied opioid use, even after controlling for pain severity and number of comorbidities [34]. Additional analysis indicated that greater pain severity was significantly associated with greater insomnia severity and depressive symptoms among PWH with chronic pain who reported opioid use [34]. Another adverse effect of chronic opioid use is respiratory depression and sleep-disordered breathing disorders such as sleep apnea, particularly central sleep apnea [35]. These study findings suggest that opioid use is a chronic pain related factor that can potentiate sleep disturbances in PWH. Despite national efforts to address the opioid epidemic crisis and clinical practice guidelines calling for more conservative opioid prescribing [36], PWH have a higher prevalence of opioid use disorder and undertreated pain compared to the general population [37]. In addition, chronic high risk opioid prescriptions are still prevalent in PWH, especially those with chronic pain [37]. Whether PWH are self-medicating with “street opioids” or taking prescribed opioids for chronic pain, the potential benefits and consequences of opioid use on sleep quality and chronic pain warrants additional research to better inform pain management and opioid prescribing practices in PWH. In older PWH, chronic pain and insomnia have been associated with poorer quality of life and are predictive of substance abuse. In a sample of 55 older adults with HIV, greater pain severity predicted heavier alcohol use, and heavier alcohol use and poorer sleep quality predicted greater pain [38]. Like opioid use, chronic alcohol use seems to make pain and sleep quality worse which necessitates strategies for achieving safe and effective pain management in the aging HIV population [39]. Also, acute alcohol ingestion can be analgesic and promote sleep which can lead to greater misuse of alcohol and an increase in sleep disturbances over time [40].

Similar to substance use, stigma is another chronic pain related factor that can affect sleep quality in PWH [27]. Recent literature focuses on the consequences of self-stigma, which occurs when someone internalizes and applies the stigmatizing beliefs of others to themselves, on chronic pain severity and insomnia symptoms [3,41]. Stigma is a form of social pain and activates many areas of the brain (e.g., limbic system) that are activated with physical pain [42]. Hobson and colleagues examined the intersectionality of HIV and chronic pain stigma with depression, sleep quality, and chronic pain symptoms in 82 PWH [3]. Individuals in the high intersectional HIV and chronic pain stigma group reported significantly greater depressive, pain severity, and insomnia symptoms compared to the moderate and low groups [3]. These findings are aligned with previous studies demonstrating that HIV and chronic pain stigma is associated with greater sleep disturbances [43,44]. However, additional studies are needed to examine whether insomnia contributes to the impact of internalized HIV and chronic pain stigma on pain outcomes in PWH.

Sleep Disturbances, Chronic Pain, and Cognitive Function in PWH

While the prevalence of severe neurocognitive impairments has drastically reduced since the introduction of ART, asymptomatic and moderate forms of neurocognitive impairments persist and can contribute to everyday function impairments and poor quality of life for PWH [45]. According to the Frascati criteria, HIV-associated neurocognitive disorder (HAND) is classified into three categories: asymptomatic neurocognitive impairment (cognitive impairment with no impairments in everyday functioning), mild neurocognitive impairment (cognitive impairment with some impairments in everyday functioning), and severe neurocognitive impairment (cognitive impairment with marked impairments in everyday functioning) [45,46]. Several studies suggest that sleep disturbances relate to cognitive function in PWH [2,47]. In a study of 562 PWH and 562 HIV-negative controls, poor daytime sleep behaviors such as frequent daytime sleeping was associated with poor overall cognitive performance [48]. Compared to the HIV-negative controls, PWH reporting poor sleep behaviors had significantly poorer cognitive performance [48][1]. Similarly, in a study of 116 adults (66 with HIV and 50 without HIV), PWH with poorer sleep quality had poorer scores in domains of learning and memory compared to those with better sleep quality [2]. These studies demonstrate that sleep disturbances can negatively impact cognitive function in healthy subjects with and without HIV [2,48]. The impact of sleep disturbances on cognitive function and quality of life may be more profound for PWH with cognitive impairments, especially those with HAND. A recent study suggests the use of sleep-based electroencephalography (EEG) markers to identify cognitive impairment in PWH [47]. In this study of 18 PWH with and without cognitive impairment, polysomnography features among sleep stages indicated different patterns of sleep quality among cognitively-impaired PWH and those not impaired [47]. For example, slow-wave and theta activity during sleep reflected important aspects of memory processing [47]. This study demonstrates that polysomnography features during certain sleep stages may be predictive of cognitive impairments in PWH with poor sleep. This information can be useful in guiding sleep interventions in PWH, which may also prevent further decline in cognitive function.

While the literature suggests adverse effects of persistent pain-induced inflammation on neurotoxicity [27,32], the relationship between chronic pain and cognitive function remains unclear. Chronic pain and cognitive impairments are independently related to insomnia, and these comorbidities are consequences of some HIV and age-related conditions [2,34]. In turn, chronic pain, insomnia, and cognitive impairments may exacerbate or lead to the development of other chronic conditions. In a recent meta-analysis of eighteen studies with samples sizes ranging from 205 to 1555, the estimated prevalence of HAND was 44.9% [45]. There are several physical and psychological risk factors for HAND. Research studies demonstrate that sleep disorders such as insomnia are associated with heightened systemic inflammation in several populations [49–51]. For example, in a study of 144 schizophrenia patients and 134 non-psychiatric comparison patients, the schizophrenia group had longer sleep duration, worse sleep quality, and increased levels of proinflammatory cytokines [51]. Compared to the non-psychiatric control group, worse sleep quality and global cognitive functioning were associated with higher high sensitivity C-Reactive Protein and Interleukin-6 levels in the schizophrenia group [51]. Some PWH and insomnia may be more susceptible to increased systemic inflammation which can lead to neurotoxicity and cognitive decline. The cognitive reserve framework may explain why some PWH may or may not experience neurocognitive effects of chronic pain and/or insomnia-induced inflammation.

Cognitive Reserve Framework

The cognitive reserve framework has been used to explain individual differences in brain function after an injury or disease. Cognitive reserve refers to the brain’s adaptability and resilience to maintain its function despite the presence of injury [52]. Cognitive reserve can fluctuate across the lifespan, and one’s ability to cope with brain damage is influenced by genetics and relevant lifetime exposures (e.g., education) [52]. Within the context of HIV, the virus itself infects glial cells and macrophages that release inflammatory proteins [53]. The neuroinflammation contributes to neuronal cell death, neurotoxicity, and poorer cognitive reserve, which often manifest as neurocognitive impairments and even HAND [53]. One study linked sleep disturbance to cognitive reserve in older adults [54]. Among subjects with fewer than 11 years of education (a measure of cognitive reserve), greater sleep disturbance was associated with poor cognitive performance on measures of executive function (e.g., set-shifting and working memory) [54]. Additionally, studies have shown that poor sleep quality correlates with depressive symptoms in PWH [34,55], which can negatively impact cognitive reserve. These studies and the cognitive reserve framework support our current hypothesis that lifestyle factors such as sleep quality impacts cognitive reserve in PWH [34,55].

While the relationship between chronic pain and cognitive function is complex, several studies show cortical neural activity is involves in the perception, localization, and modulation of painful stimuli [56,57]. Interpretation of pain sensory input and pain threshold or intensity requires use of cognitive processes such as attention, memory, learning, psychomotor, and executive function [57]. In a study of 54 PWH with cognitive impairment and 73 with chronic pain, the cognitive impairment group had a significantly higher prevalence of chronic pain and reported more neuropathic symptoms [56]. Those with chronic pain performed worse on emotional recognition and verbal learning tasks [56]. These findings and those of other studies provide evidence of the close association between neural systems of cognition and pain which suggest a bi-directional modulatory role.

In non-HIV populations, studies have shown high levels of inflammation promote heightened sensitivity to painful stimuli [58]. In PWH, HIV itself can cause inflammation which may be related to alterations in endogenous pain modulatory processes that promote exaggerated pain responses, known as hyperalgesia, and CNS sensitization [27,31]. Imaging studies in non-HIV subjects have demonstrated that chronic pain is linked to structural changes in the brain (e.g., thinner cortical areas and smaller amygdala volume) that vary by race [59,60]. Adaptation to structural and functional changes in the brain, or cognitive reserve, may explain variations in pain response within PWH. Given chronic pain commonly occurs with sleep disturbances in PWH and both negatively impact mood [3], it is critical to investigate additive effects of these comorbidities on cognitive reserve and quality of life in people with HAND. We hypothesize that, inflammation as a result of insomnia, chronic pain, and pain-related factors (e.g., stigma, depression, substance use, etc) can reduce cognitive reserve over time in PWH. Unfortunately, the decrease in cognitive reserve may be more drastic in PWH with HAND comorbidities and chronic pain. The cognitive reserve framework guides future implementation of sleep and pain interventions that may improve and preserve cognitive function in PWH.

Future Directions

Future research should examine potential mechanisms linking chronic pain and poor sleep quality. Additionally, recent studies suggest that poor sleep quality negatively impacts cognitive function in middle-to-older aged PWH. Li and colleagues examined 562 PWH and 562 people without HIV and found that, among PWH, there was a significant decrease in cognitive performance among those who reported daytime sleepiness burden [61]. These findings warrant additional pain studies to explore poor sleep quality as a potential driver of chronic pain and cognitive function in PWH. Studies are needed to address sleep disorders and chronic pain given their prevalence among older adults and their potential additive effects on cognitive function in PWH, especially those with HAND. Bowen and colleagues have already began studying sleep as a predictor of pain perception in older adults with mild cognitive impairment [62]. In a sample of 15 older adults with mild cognitive impairment, poor sleep increased pain intensity, pain interference, and pain behavior [62]. Sleep interventions may improve sleep quality as well as pain in aging populations more broadly, but especially in cognitively vulnerable aging populations such as PWH. Given the prevalence of HAND and risk of other neurodegenerative disease (e.g., Alzheimer’s disease), interventions that target sleep disorders and chronic pain may help preserve cognitive function among adults aging with HIV.

The role of sleep disorders, specifically obstructive sleep apnea, in the development and exacerbation of other HIV-related comorbidities (e.g., cardiovascular disease and diabetes) is trending throughout the sleep literature [63]. Studies suggest that few PWH with obstructive sleep apnea are diagnosed or treated due to several factors including lack of provider expertise, typical risk factors such as obesity that are not always present in PWH, and symptoms such as fatigue that are ascribed to HIV itself [63]. Older ART medications were associated with lipodystrophy, a disorder of unequal fat distribution which causes narrowing of the airway [63]. The persistently higher prevalence of obstructive sleep apnea in PWH who are virally suppressed suggest other underlying mechanisms. Untreated obstructive sleep apnea is associated with increased inflammation, especially in PWH not taking ART [64]. A recent study of 159 PWH found that higher pain severity was associated with airflow obstruction, dyspnea, and sleep disturbance [65]. Future studies should examine the pathophysiology of obstructive sleep apnea in PWH and potential mechanisms (e.g., inflammation) linking this comorbidity to other comorbidities such as chronic pain and cognitive impairments.

Conclusion

Older adults are the fastest growing HIV population with over half of PWH aged 50 and older in the United States [66]. The development of ART prolonged life for many PWH, however it did not eliminate HIV and age-related comorbidities. In fact, some HIV-related comorbidities are a consequence of long-term ART use which can be detrimental to quality of life among PWH who are virally suppressed. Poor sleep quality, chronic pain, and cognitive impairments are commonly reported in PWH, and greater incidence of these comorbidities is predicted with the increasing aging population. Potential mechanisms linking these comorbidities are understudied. Sleep interventions may be beneficial to improving sleep quality and chronic pain in PWH. In addition, sleep and pain interventions may protect cognitive reserve which may in turn slow cognitive decline in PWH, especially those with HAND.

Key References.

• Madden VJ, Parker R, Goodin BR. Chronic pain in people with HIV: a common comorbidity and threat to quality of life. Pain Manag; 2020;10:253–60. https://doi.org/10.2217/pmt-2020-0004

  This review article highlights biological, psychological, and social risk factors that may explain the higher prevalence of chronic pain in people with HIV compared to the general population.

• Cody SL, Hobson JM, Gilstrap SR, Gloston GF, Riggs KR, Justin Thomas S, et al. Insomnia severity and depressive symptoms in people living with HIV and chronic pain: associations with opioid use. AIDS Care - Psychological and Socio-Medical Aspects of AIDS/HIV. Routledge; 2021. https://doi/abs/10.1080/09540121.2021.1889953

  Findings from this study suggest that people with HIV with chronic pain are likely to experience poor sleep and depressed mood. People with HIV with chronic pain who reported opioid use experienced poorer sleep and greater pain severity compared to those who denied opioid use.

• Azimi H, Gunnarsdottir KM, Sarma S v., Gamaldo AA, Salas RME, Gamaldo CE. Identifying sleep biomarkers to evaluate cognition in HIV. Annu Int Conf IEEE Eng Med Biol Soc;2020:2332. https://doi.org/1109EMBC44109.2020.9176592

  This study demonstrates significant differences in sleep patterns in people with HIV who are cognitively impaired. Study findings suggest that polysomnography (PSG) recordings may serve as a biomarker for early detection of cognitive decline in people with HIV.