Research Progress on Anesthetic Drugs Impacting Postoperative Sleep

1 Xuzhou Medical University, School of Anesthesia, Xuzhou 221004; 2 Huai’an First People’s Hospital, Department of Anesthesia, Huai’an 223300

[Review]

Sleep is a high-level physiological activity of humans, and good sleep is essential for the recovery of body functions and the maintenance of normal central nervous system functions. Research has reported that most patients experience sleep-wake disorders (SWD) after surgery, often manifested as changes in sleep structure and subjective sleep quality, or abnormal behaviors during sleep. SWD often increases the occurrence of adverse events such as delirium, hypersensitivity to pain, and episodic hypoxemia, leading to circulatory instability and suppressed immune function, which in turn affects postoperative recovery.

Studies have confirmed that commonly used anesthetic drugs during the perioperative period affect the sleep structure and quality of patients by acting on the sleep-wake cycle, leading to the occurrence of SWD. The use of general anesthetics during the perioperative period may be an independent risk factor for postoperative SWD. Therefore, this article explores the sleep-wake mechanisms and current status of postoperative sleep, reviewing the impact of commonly used perioperative drugs such as anesthetics, sedatives, and analgesics on postoperative sleep and their potential mechanisms, providing preliminary references for the prevention and treatment of postoperative SWD.

1.1 Physiological Sleep Patterns and Sleep-Wake Mechanisms

1.1.1 Physiological Sleep Patterns

Normal physiological sleep consists of non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep alternating cyclically, occurring 4-6 cycles each night. NREM is divided into three stages: N1 light sleep, N2 moderate sleep (characterized by sleep spindle waves or K-complex waves), and N3 deep sleep (also called slow-wave sleep, SWS), which account for 2%-5%, 45%-55%, and 15%-20% of total sleep time, respectively. REM sleep accounts for 20%-25% of total sleep time, often accompanied by rapid eye movements and loss of skeletal muscle tone. NREM sleep promotes physical recovery and the clearance of metabolic waste in the brain, while REM sleep is crucial for learning, memory, and energy restoration.

1.1.2 Sleep-Wake Related Mechanisms

It is currently believed that the regulation of sleep and wakefulness is ultimately achieved through various neurons in the brain containing different chemical substances. In the sleep-wake system, the transition between sleep and wakefulness is a mutually inhibitory pattern similar to a “seesaw”. Activation of the wakefulness system can inhibit sleep-promoting neurons, while removing inhibition on the wakefulness system is conducive to maintaining a stable wakefulness state, and vice versa.

The brain regions and projection systems related to wakefulness mainly include: ① Brainstem reticular formation (most important, glutamate is the main neurotransmitter); ② Locus coeruleus noradrenergic system; ③ Dorsal raphe serotonin system in the lower brainstem; ④ Cholinergic neurons in the pontine tegmentum; ⑤ Dopaminergic system of the substantia nigra; ⑥ Cholinergic system in the basal forebrain; ⑦ Histaminergic neurons in the tuberomammillary nucleus and orexinergic neurons in the lateral hypothalamus. The brain regions primarily associated with sleep include NREM-promoting and REM-promoting areas. The NREM-promoting areas include the ventrolateral preoptic area (VLPO), brainstem sleep-promoting areas (ascending inhibitory system), diencephalic sleep-promoting areas, and basal forebrain sleep-promoting areas. The VLPO is the most important, where a large number of sleep-promoting neurons send nerve fibers projecting to wakefulness-promoting areas, inhibiting wakefulness activity and producing NREM sleep, with γ-aminobutyric acid (GABA) as the main neurotransmitter. Additionally, the VLPO receives circadian rhythm information transmitted by fibers from the suprachiasmatic nucleus to regulate sleep. The REM-promoting areas mainly include cholinergic neurons in the pontine tegmentum (REM-on neurons), locus coeruleus noradrenergic system, and dorsal raphe serotonin system (REM-off neurons). The occurrence and maintenance of REM sleep may be controlled by the interaction between REM-off and REM-on neurons.

Neurotransmitters or neuromodulators related to wakefulness mainly include catecholamines, acetylcholine, orexin, glutamate, and histamine. In contrast, neurotransmitters or neuromodulators associated with slow-wave sleep mainly include serotonin, adenosine, GABA, inflammatory cytokines, and prostaglandin D2.

1.2 Current Status of Postoperative Sleep

SWD may affect postoperative recovery. A study on patients undergoing total knee arthroplasty found that the occurrence of SWD was related to limited knee function three months postoperatively. Furthermore, previous studies have confirmed that postoperative SWD increases the incidence of episodic hypoxemia and postoperative cardiovascular events, alters patients’ mental states, and even affects cognition. Therefore, improving postoperative sleep for patients has profound implications for their recovery.

Patients commonly complain of decreased total sleep time, increased awakenings, decreased sleep quality, and frequent nightmares after surgery. This is usually reflected in polysomnography as severe sleep deprivation, sleep fragmentation, and reduced or lost SWS and REM sleep at night. About 1/4 of patients report insufficient sleep 15 days postoperatively, with 24% requiring pharmacological treatment to improve sleep. Survey results indicate that currently, 62.5% of patients with concurrent surgical diseases in China experience SWD during hospitalization, with 23% experiencing sleep problems for 4 days continuously. Elderly patients, as well as gynecological, thoracic, and orthopedic surgery patients, have a significantly higher incidence of postoperative SWD compared to other ages and surgical types. Previous studies have shown that over 70% of lung cancer surgery patients experience sleep problems during the perioperative period. A clinical study reported that the incidence of SWD in patients undergoing laparoscopic gynecological surgery could be as high as 95%.

2.1 Anesthetic Drugs

2.1.1 Intravenous Anesthetic – Propofol

Studies have shown that in the thalamocortical system, the hyperpolarization associated with slow waves and spindles is closely linked to GABA receptors (including GABAA and GABAB receptors). The transmission of γ-GABA first inhibits the wakefulness system, then induces, regulates, and stabilizes spindle and slow-wave activity based on thalamocortical burst discharges, thus participating in the basic induction and maintenance of slow-wave sleep. As a GABAA receptor agonist, propofol primarily alters sleep structure by increasing SWS and inhibiting REM sleep. A study involving anesthetizing monkeys also reported that propofol could cause loss of consciousness in monkeys during NREM sleep. Another study indicated that flumazenil could block the sleep induced by propofol infusion in the medial preoptic area of rats, suggesting that there may be an interaction between propofol and the GABA-benzodiazepine receptor complex.

Clinical doses of propofol can mildly inhibit excitatory transmission mediated by the central excitatory glutamate receptor – N-methyl-D-aspartate receptor (NMDAR) in the olfactory cortex and spinal cord multisynaptic pathways, with the process of propofol activating sleep-promoting neurons and leading to loss of consciousness also involving non-sleep-promoting neurons in the VLPO cluster. Additionally, propofol interferes with the secretion of orexin and melatonin during the perioperative period, exacerbating the disorder of the sleep-wake cycle postoperatively.

In a study on painless gastrointestinal endoscopy, patients with good sleep preoperatively reported decreased sleep quality one week postoperatively after receiving intravenous anesthesia with propofol, and it took about a month postoperatively for them to fully recover. Gardner et al. found that in flies deprived of sleep for 10 hours, continuous infusion of propofol or placebo for 6 hours resulted in a significant delay in sleep recovery in the propofol group compared to the control group. However, some studies reported that propofol could alleviate sleep debt in insomnia patients and improve insomnia symptoms to some extent.

Most current studies believe that propofol disrupts sleep structure, but there is still controversy regarding its effects on the sleep of patients with preoperative SWD, and whether different effects arise from acute versus chronic sleep deprivation also needs to be confirmed in future research.

2.1.2 Inhalational Anesthetics

Inhalational anesthetics primarily act on multiple targets in the central nervous system to produce effects, including activating GABAA receptors, inhibiting NMDAR, blocking hyperpolarized cyclic nucleotide-gated channels, and thalamic two-pore potassium channels. In addition to the aforementioned GABAA mediating the hyperpolarization of spindles and slow waves, specific glutamate receptors are activated during SWS, participating in burst discharges, and this burst discharge is similar to that of pyramidal neurons during SWS. This may partly explain the phenomenon in animal experiments where the use of isoflurane alone without surgery leads to a migration of NREM sleep from deep (stage III and IV) to light (stage I and II). Researchers have also found that the use of isoflurane alone does not affect REM sleep, but if surgery is performed, REM sleep may exhibit early suppression followed by rebound.

Studies have found that inflammatory factors such as IL-1, IL-6, and TNF-α can excite sleep-active neurons in the preoptic area, promoting NREM while inhibiting REM. In a meta-analysis of 72 studies by Irwin et al., acute elevations of IL-6 and C-reactive protein mediated the formation of sleep disorders, indicating that the inflammatory response caused by surgery itself also participates in the occurrence of postoperative SWD. Additionally, Zhang Hao’s research found that sleep disorders mediated by inhalational anesthetics are related to the involvement of the brain G protein signaling regulator/G protein α2 subunit/cyclic adenosine monophosphate pathway. Inhalational anesthetics can also alter the rhythm of sleep-wake cycles by changing the expression of circadian clock genes (such as PER2 and CRY1) and activating hypothalamic orexinergic neurons’ activity at night.

In a study observing infants, both propofol and sevoflurane led to SWD within two weeks postoperatively, but compared to propofol, sevoflurane had a smaller impact on their sleep. A study on elderly patients also reported that sevoflurane could extend total sleep time early postoperatively and improve sleep quality. However, conversely, in studies targeting non-elderly adult patients, patients who received sevoflurane anesthesia showed significantly decreased sleep continuity and sleep efficiency compared to those receiving propofol. For adult patients undergoing laparoscopic surgery, sevoflurane had a more pronounced effect on REM sleep, with patients reporting significantly increased dreaming postoperatively. The aforementioned studies suggest that sevoflurane has different impacts on postoperative sleep across different age groups, potentially exacerbating postoperative SWD in non-elderly adult patients while improving postoperative sleep in children and elderly patients. This difference may be related to changes in the development and functional state of neurons in the brain across different age groups, and the specific mechanisms still require further research.

2.1.3 Intravenous Anesthetic – Ketamine

Ketamine is a high-affinity, non-competitive NMDAR antagonist closely related to sleep regulation mechanisms. Ketamine first blocks the abnormal excitatory effect of NMDAR on γ-GABAergic interneurons, leading to disinhibition of pyramidal neurons, accompanied by glutamate release and bursts, increasing excitatory transmission and brain-derived neurotrophic factor release, ultimately activating cellular signaling cascades, increasing SWS activity and amplitude (it is currently believed that cortical brain-derived neurotrophic factor infusion increases synaptic strength, which helps produce SWS).

Reports indicate that although ketamine increases high-frequency synchrony in the frontal cortex and basal ganglia, similar to REM neural activity, it does not induce the occurrence of slow and rapid eye movements. In animal experiments, sub-anesthetic doses of ketamine can inhibit REM sleep and increase γ high-frequency oscillations, altering the dynamics of γ phase amplitude coupling. This may also explain findings in clinical studies: children with burns who received ketamine anesthesia showed significantly reduced REM sleep compared to those who did not receive ketamine anesthesia. However, while some studies indicate that even sub-anesthetic doses of ketamine disrupt sleep structure, a clinical study on patients undergoing abdominal surgery found that ketamine combined with low-dose fentanyl effectively alleviated postoperative pain while improving sleep quality. This may be because, for surgical patients, the analgesic effect of ketamine in improving postoperative sleep may far outweigh its own disruptive effects on sleep. Additionally, in patients with depression, ketamine may improve sleep. Reports indicate that ketamine increased total sleep time, SWS, and REM sleep in patients with treatment-resistant depression. More research is needed to further explore the effects of ketamine on postoperative sleep.

2.2 Sedatives

2.2.1 Midazolam

Midazolam has the shortest half-life among all traditional benzodiazepines (BDZ), exhibiting retrograde amnesia, sedation, hypnosis, and anticonvulsant effects. The γ-GABA-BDZ receptor complex is highly concentrated in the preoptic area and is recognized as the molecular target for BDZ drugs. It is currently believed that BDZ mainly induces sleep by acting on common neuroanatomical sites in the hypothalamic preoptic area through γ-GABAergic inhibitory neurons. Studies have shown that traditional BDZ mainly improves insomnia by shortening sleep latency, reducing awakenings, and increasing total sleep duration. Compared to barbiturates, BDZ mildly inhibits REM sleep and strongly inhibits SWS. In a polysomnographic study, BDZ increased the proportion of N1 sleep in elderly insomnia patients but reduced SWS and REM sleep. However, there have been no clinical studies reported on the effects of midazolam on postoperative sleep after intravenous use of flumazenil as an antagonist.

2.2.2 Dexmedetomidine (Dex)

Dex, as an α2 adrenergic receptor agonist, primarily induces sedation and hypnosis by stimulating α2 receptors in the brainstem locus coeruleus, inhibiting the release of norepinephrine, and promoting the release of γ-GABA and glycine from VLPO, thereby maintaining natural sleep during NREM stage 3.

Some studies have reported that intraoperative infusion of low-dose Dex (0.2-0.4 μg·kg−1·h−1) can increase N2 sleep, reduce N1 sleep, and improve sleep continuity and efficiency, providing a “preconditioning” effect to enhance postoperative sleep quality and reduce the occurrence of severe postoperative sleep disorders. In the ICU, whether in mechanically ventilated or non-mechanically ventilated patients, nighttime injection of sedative doses of Dex can improve subjective sleep quality by enhancing sleep efficiency and N2 sleep state. However, Chamadia et al. found that Dex increased NREM N2 sleep but also reduced REM sleep, and the restorative sleep that followed the structural changes induced by Dex often remained at relatively low levels. In the study by Garrity et al., Dex also showed negative effects on sleep structure. Currently, it is believed that Dex has a short-term improvement effect on subjective sleep quality after surgery, but its long-term effects on sleep are still debated.

2.3 Analgesics

2.3.1 Opioids

Opioids are widely used analgesics during the perioperative period, and the initiation and maintenance of sleep are closely related to the participation of endogenous opioid peptides. Endogenous opioid peptides are spatially distributed not only in brain regions involved in regulating NREM sleep (nucleus tractus solitarius, preoptic area, etc.) but are also directly linked to neurotransmitters (such as norepinephrine) that regulate sleep. Studies have found that opioid peptides bind to vasopressin to participate in the regulation of circadian rhythms in the suprachiasmatic nucleus, thus participating in the initiation and maintenance of sleep. The receptors related to sleep mainly include μ, δ, and κ receptors, with the μ and δ receptors involved in the changes of slow-wave sleep induced by opioids. Garzón et al. found that microinjection of κ receptor agonists into the locus coeruleus of cats did not significantly affect the total amount of slow-wave sleep but extended the duration of single episodes of slow-wave sleep. This indicates that in the central system, the increase in SWS induced by opioids is primarily regulated by μ receptors, while κ receptors play a supplementary role in regulating sleep. Furthermore, the effects of μ receptor agonists may vary depending on their site of action: direct action on certain brain areas may increase SWS, while intravenous or intraperitoneal injection may decrease SWS.

The use of opioids during the perioperative period, even for short-term use, can affect sleep, primarily manifested as prolonged REM latency, significantly reduced total sleep time, increased awakenings, and decreased overall sleep time and efficiency. A clinical study reported that remifentanil, although it does not inhibit the secretion of melatonin at night, still significantly suppresses REM sleep in subjects, validating this viewpoint. In previous studies, the disruption of sleep structure by opioids was shown to be dose-dependent, with single low doses of opioids only reducing SWS, while high doses reduced both SWS and REM sleep. However, for patients experiencing pain, the analgesic effects of opioids may reduce the number of awakenings during sleep and improve sleep efficiency. Reasonable use of opioids in surgical patients not only alleviates postoperative pain but also improves subjective sleep quality. In rats subjected to REM sleep deprivation, the orexin system was found to be attenuated, delaying the development of morphine tolerance. This indicates that the effects of opioids on sleep are multi-pathway, but the specific mechanisms are not yet fully understood.

2.3.2 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

NSAIDs exert moderate analgesic effects by inhibiting the synthesis of prostaglandins in the central and peripheral systems, suppressing lymphocyte activity, activating T cell differentiation, and directly acting on nociceptors to inhibit the formation and release of pain-inducing substances. NSAIDs primarily affect sleep by reducing the synthesis of prostaglandin D2, inhibiting the normal nighttime peak synthesis of melatonin, and decreasing normal nighttime body temperature reduction. Acute oral administration of aspirin and ibuprofen has shown decreased sleep efficiency and increased wakefulness in healthy subjects. Reports of NSAIDs improving postoperative sleep quality may be attributed to the reduction of subjective pain. Currently, there are no good polysomnographic control studies on individuals with pain experiences or surgical traumatic stimuli.

2.4 Other Drugs

2.4.1 Glucocorticoids

Glucocorticoids are believed to act on the suprachiasmatic nucleus, causing changes in the expression levels of mRNA in the main circadian rhythm pacemaker cells in the suprachiasmatic nucleus, thereby affecting sleep. Healthy subjects using corticosteroids have shown reduced REM sleep in polysomnography. The use of hydrocortisone, dexamethasone, and prednisone increases nighttime awakenings, but the interference of corticosteroids on sleep may also be influenced by differences in dosage and receptor affinity. For patients experiencing nerve root injury symptoms during epidural anesthesia puncture, administering 5 mg of dexamethasone intraoperatively and postoperatively significantly reduces inflammatory responses and improves postoperative sleep quality. This also indicates that the use of glucocorticoids during the perioperative period may improve postoperative sleep quality through anti-inflammatory effects, reducing intraoperative opioid use, alleviating postoperative pain, and preventing postoperative nausea and vomiting. However, more research is needed to explore the direct effects of glucocorticoids on postoperative sleep.

2.4.2 Pentetrazol Hydrochloride

Pentetrazol hydrochloride has strong anticholinergic effects both centrally and peripherally, and due to its minimal impact on heart rate, it is commonly used as a preoperative medication for general anesthesia. Previous studies have reported that in elderly patients undergoing total hip replacement surgery, preoperative use of pentetrazol hydrochloride can interfere with early postoperative sleep by prolonging sleep latency, reducing sleep efficiency, and promoting sleep disorders, thereby lowering sleep quality. This may be related to its strong central anticholinergic effects, but more research is needed to confirm this, and whether different doses have varying impacts on postoperative sleep also requires exploration.

Current research has found that anesthetic drugs have a certain degree of impact on postoperative sleep. Most anesthetic drugs disrupt sleep structure, but some drugs (analgesics, Dex, etc.) have shown improvement effects on patients’ sleep in the short term postoperatively, while their long-term effects on postoperative sleep remain unclear. The impact of different anesthetic drugs on sleep under the multifactorial composite effects during the perioperative period still requires further exploration.

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