Introduction

Chronic pain is one of the most common conditions in the United States, impacting over 50 million adults nationwide [1]. In fact, the economic impact of pain disorders has been shown to surpass that of other prevalent conditions such as heart disease, cancer, and diabetes [2]. Accordingly, there is a great need for finding efficacious treatments for chronic pain. One potential therapeutic target in the management of chronic pain is sleep. Pain and sleep have a complex reciprocal relationship. Disordered sleep impacts 40–80% of patients with chronic pain conditions [3,4,5,6,7], and 25–50% of patients with sleep disorders have chronic pain [8,9,10]. Sleep disturbance is common regardless of the potential underlying pain mechanism (e.g., nociceptive [11], neuropathic [12], or nociplastic [13]), and is present in conditions ranging from cancer pain [14] and low back pain [15] to fibromyalgia [16]. Patients with concomitant sleep and chronic pain disorders are likely to experience significant lifestyle and social limitations and decreased work productivity, leading to significant quality of life and economic impacts [17, 18]. On the other hand, given the intertwined relationship between sleep disorders and chronic pain, effective interventions optimizing sleep thereby have great potential for improving chronic pain management. While many reviews evaluate the relationship between pain and sleep, none focuses on how sleep-targeted interventions specifically can be used as modalities to treat chronic pain. This narrative review focuses on the utilization of sleep as a therapeutic target for chronic pain and aims to evaluate the literature on current and proposed pharmacologic and non-pharmacologic sleep interventions.

The Effect of Sleep Disruption on Pain

It has long been observed that sleep, particularly disturbed sleep, worsens pain. In the 1930s, Copperman et al. found an inverse relationship between sleep deprivation and sensory thresholds to von Frey filaments [19]. Years later in 1976, Moldofky and Scarisbrick showed that non-REM sleep deprivation-induced diffuse musculoskeletal pain in healthy volunteers [20]. Since then, numerous studies have supported the concept that poor sleep increases pain sensitivity and severity. Notably, Haack et al. demonstrated that quantitative accumulation of sleep deprivation over a 12-day period can lead to the spontaneous development of body aches, stomach pain, and back pain [21]. Schuh-Hofer et al. showed that even just one night of sleep deprivation increased hyperalgesia to cold, pinprick, blunt pressure, and heat stimuli in healthy volunteers [22]. More recently, Iacovides et al. showed that healthy female volunteers experienced increased pain sensitivity to both superficial (pinprick) and deep (ischemic) pain after 2 days of fragmented sleep [23]. There has been special attention paid to slow wave sleep disruption with overall findings suggesting it may increase pain sensitivity [24,25,26,27]. Previous reviews by Smith and Haythornthwaite [28] and Finan et al. [29] list a plethora of articles demonstrating that sleep is both a predictor and aggravator of numerous pain disorders, including headache [30,31,32], fibromyalgia [33,34,35], burn injury pain [36], musculoskeletal pain [37], and rheumatoid pain [38, 39]. The effects of sleep deprivation may even apply to the so-called “chronification” of acute pain. In one observational study of 110 patients undergoing total knee replacement surgery, patients who experienced disordered sleep during their post-operative course had a greater risk of developing subsequent chronic pain [40]. Also of clinical interest is the potential for sleep deficiency to reduce the efficacy of opioids, leading to higher opioid requirements and a potentially greater risk of opioid use disorder [41]. Two secondary analyses of randomized controlled trial (RCT) data by Vitiello and colleagues found that improved sleep is associated with improved chronic pain symptoms [42, 43]. Overall, there is a significant volume of literature that associates sleep deprivation with diverse forms of pain and suggests that treating disordered sleep could have a secondary benefit of treating chronic pain conditions as well.

Non-pharmacologic Therapies

The non-pharmacologic sleep-targeted therapies for chronic pain have a favorable safety profile and avoid the side effects associated with pharmacologic sleep therapies (Table 1).

Table 1 Recent clinical studies on the effect of non-pharmacologic therapy for insomnia on pain symptoms
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Cognitive Behavioral Therapy

Cognitive behavioral therapy for insomnia (CBT-I) involves multiple components including cognitive interventions, behavioral interventions, and psychoeducational interventions to improve sleep. Several systematic reviews and meta-analyses [44,45,46] and RCTs [47,48,49,50] have demonstrated that CBT-I improves both sleep quality and pain symptoms. Two of these RCTs specifically showed that reductions in sleep disturbance could predict subsequent pain reduction [49, 50]. CBT-I, which specifically addresses insomnia, may yield a longer duration of pain reduction compared to cognitive behavioral therapy for pain alone (CBT-P) [51, 52], and a combination of CBT-I and CBT-P techniques may be even more advantageous [53, 54]. An open-label study assessing changes on functional magnetic resonance imaging found that CBT-I was superior to CBT-P in decreasing neural activation in response to painful stimuli, suggesting improved sleep could be the underlying mechanism [55]. CBT-I has been shown to have superior outcomes for sleep quality, pain intensity, and emotional distress compared to sleep hygiene alone in fibromyalgia [56]. CBT-I has the additional advantage of being available via remote methods (e.g., internet or telephone), potentially facilitating improved patient access [57, 58]. There is some limited and conflicting evidence that suggests CBT-I only improves sleep quality and not pain symptoms, namely one RCT of 54 patients [59], one systematic review [60] in which only two RCTs were ultimately assessable, and one meta-analysis that was underpowered [61]. However, CBT-I overall appears to be a compelling sleep-targeted therapy for pain management given the breadth of evidence supporting its efficacy and its lack of reported adverse effects.

Sensory-Based Interventions

Other sleep-targeted pain therapies focus on the senses. One murine study found that exposure to pink noise could increase sleep spindle density with a correlated reduction in chronic pain [62]. Like pink noise, audio-visual stimulation (AVS) is another sensory-based intervention targeting sleep. Using pre-programmed light and sound patterns, AVS can promote sleep quality, as it has been shown to potentiate delta brain waves on electroencephalography [63]. A pilot study by Tang et al. showed that AVS may be efficacious in improving both insomnia and pain [64]. However, a third, albeit small scale, follow-up study failed to find significant differences between AVS and placebo, as patients in both groups reported an improvement in pain and sleep [65]. Bright light therapy, which targets sleep via the Circadian rhythm, has also been used. Bright light therapy has been shown to be effective in treating sleep problems such as circadian rhythm disorders and insomnia [66]. Two pilot studies [67, 68] and two prospective trials [69, 70] suggest it can also improve pain sensitivity across multiple chronic pain disorders. Considering their ease, accessibility, and lack of reported side effects, sensory-based interventions are an enticing target for future research into the utilization of sleep therapy in the treatment of pathologic pain, but larger-scale, placebo-controlled trials are needed.

Pharmacologic Therapies

Many pharmacologic modalities for sleep may benefit pain (Table 2). However, it is important to remember that these agents may come with several adverse effects. Sleep medications have been linked to decreased physical quality of life [71] and increased mortality [72]. Drugs such as diphenhydramine may result in daytime sleepiness [73]. Notably, benzodiazepines are associated with a high risk for addiction [74]. However, according to the American Academy of Sleep Medicine, pharmacologic sleep aids may be indicated for people with short-term sleep disruptions caused by emotional upset, jet lag, and shift workers, and for those in whom behavioral therapies fail [75].

Table 2 Recent clinical studies on the effect of pharmacologic therapy for insomnia on pain symptoms
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Melatonin

Melatonin is an endogenous hormone which is thought to be involved in sleep and pain pathways. Melatonin is long known to play an essential role in the regulation of circadian rhythms [76]. Many studies suggest that melatonin can also reduce chronic pain symptoms, including four RCTs [77,78,79,80], a pilot study [81], two systematic reviews [82, 83], and two meta-analyses [84, 85]. However, it is not clear whether melatonin directly provides analgesia, or whether it simply promotes sleep with analgesia as an indirect consequence of improved rest. Four RCTs found that melatonin’s analgesic properties were independent of its improvements on sleep quality [77,78,79, 81]. Perhaps, as one animal study suggests, sleep deprivation induces hyperalgesia by decreasing serum melatonin levels, and melatonin supplements can attenuate this effect [86]. Overall, whether and how melatonin directly provides analgesia remains unclear, with GABA receptors, opioid receptors, endorphins, and other neurotransmitters potentially involved [87].

Z-drugs

Non-benzodiazepine sedative hypnotics, commonly referred to as “Z-drugs” (e.g., zolpidem and zopiclone), act as GABAA receptor agonists. We did not identify any studies evaluating the utility of Z-drugs for chronic pain. However, there is evidence that zolpidem may have benefits for acute perioperative pain which includes four RCTs [88,89,90,91], a systematic review [92], and a meta-analysis [93]. Only one RCT, which involved 20 patients who underwent fast-track total hip or knee arthroplasty, found no benefit for perioperative pain despite an improvement in sleep quality [94]. Conversely, an RCT by Gong et al. assessing 148 patients undergoing total knee arthroplasty found that improved sleep quality from zolpidem was correlated with increased post-operative activity and lower reported pain scores [91]. Although these findings may suggest that Z-drugs could be a promising sleep-targeted therapy in the treatment of pain disorders, their use must be carefully weighed against their potentially serious side-effect profile, which can include sedation, driving impairment, mechanical falls and fractures, and misuse [95, 96].

Orexin Antagonists

Orexin antagonists (e.g., suvorexant, filorexant, daridorexant, and lemborexant) are a class of sleep-aiding medications that inhibits orexins. Orexins are neuropeptides produced by the hypothalamus and are thought to maintain the awake state [97]. Since orexin antagonists are relatively new to the market, studies assessing these drugs and their impact on chronic pain conditions are scarce. One double-blind crossover study in 2020 found that suvorexant improved sleep time and reduced next-day pain sensitivity for patients with fibromyalgia [98]. However, an RCT of 182 patients evaluating filorexant for painful diabetic neuropathy (PDN) found no analgesic benefit [99]. Orexin antagonists represent a new direction and opportunity for research into the pain-sleep interface, but more information will be needed to determine whether they are a promising treatment modality for patients with chronic pain and comorbid sleep disturbance.

Gabapentinoids

Gabapentinoids (e.g., gabapentin and pregabalin) are anticonvulsants commonly used to treat neuropathic pain. Gabapentinoids have well-established analgesic effects [100] and they have been shown to significantly improve sleep quality with treatment durations of 6 weeks or longer [101]. In one RCT assessing patients with PDN, pregabalin provided analgesia equal to that of duloxetine and amitriptyline, but superior improvement in sleep continuity [102]. A pooled analysis of 500 patients with postherpetic neuralgia from two phase 3 RCTs and one open-label phase 4 study found that gabapentin decreased pain and sleep interference, and improvements in sleep and pain control were correlated to each other [103]. Kantor et al. showed that sleep interference scores during the treatment of postherpetic neuralgia with gabapentin were the strongest predictor for pain quality and pain scores [104]. In addition to these, two pooled analyses [105, 106], two meta-analyses [107,108,109], and two RCTs [110, 111] demonstrate the simultaneous analgesic and sleep-promoting effects of gabapentinoids. Of note, gabapentinoids are often prescribed “off-label” for insomnia even in the absence of concomitant chronic pain [112]. However, gabapentinoids are associated with potentially serious adverse effects, such as sedation, mechanical falls, respiratory depression, and abuse [113]. Additionally, dosages must account for potentially vulnerable patient populations (e.g., older adults) and comorbid conditions (e.g., chronic kidney disease) [114].

Multimodal Therapy

Just as a multimodal approach has gained popularity in the management of acute [115] and chronic pain [116], a multimodal approach to sleep may also be effective. In one RCT, Cheah et al. showed improved analgesia, reduced opioid use, and increased sleep duration and quality in a population of post-operative shoulder arthroplasty patients treated with a multimodal approach of sleep hygiene combined with low dose zolpidem and melatonin [117]. A pilot RCT by Saxena et al. showed that cognitive behavioral therapy as an adjunct to pregabalin had significant benefits for pain intensity in patients with postherpetic neuralgia [118]. There is a paucity of literature describing the combination of non-pharmacologic with pharmacologic sleep-focused interventions for the purpose of treating pain. However, it appears feasible that this could be a powerful new strategy in the simultaneous treatment of chronic pain and comorbid sleep disorders.

Conclusions

Given the widespread impact of chronic pain disorders and their frequent comorbidity with sleep disorders, therapies which benefit both pain and sleep are doubly beneficial. Disrupted sleep has negative implications for the management and prognosis of pain, supporting the idea that addressing sleep quality could be essential for optimizing pain care. From among the non-pharmacologic therapies, cognitive behavioral therapy has the strongest evidence for improving sleep disorders and pain symptoms. From among the pharmacologic therapies, melatonin has the most literature demonstrating benefits for both sleep and analgesia. However, it is unclear whether melatonin improves pain as a secondary effect of improving sleep, or whether it has independent analgesic mechanisms. Other potential therapies which require additional investigation include pink noise therapy to improve sleep spindle density, AVS, morning bright light therapy, and the novel orexin antagonists. “Z-drugs” and gabapentinoids may have a role in improving sleep quality and pain in selected patients, but these medications are susceptible to potential misuse and abuse, and their potentially serious adverse effects (e.g., sedation and mechanical falls in older patient populations) must be considered. The sleep-pain interface plays a significant role in chronic pain conditions, and additional studies assessing sleep as a therapeutic target are necessary.