Highlight
– In a mouse spared nerve injury (SNI) model of neuropathic pain, SNI reduced REM sleep and disrupted locomotor and body temperature circadian rhythms in both sexes; increased wakefulness was prominent in females.
– Continuous pregabalin (11 mg/kg/day) restored REM sleep, improved circadian rhythmicity of locomotion and temperature, reversed spinal circadian gene expression changes, and increased sleep spindle occurrence and 3.5–5.5 Hz REM power.
– Morphine (6 mg/kg/day) failed to restore disrupted sleep architecture or circadian rhythms and had mixed effects on spinal circadian gene expression.
– These preclinical data suggest analgesic selection may influence sleep and circadian homeostasis in neuropathic pain states and warrant clinical evaluation.
Background: Clinical context and unmet needs
Neuropathic pain frequently coexists with disturbances in sleep quality and circadian regulation. Patients commonly report fragmented sleep, difficulty maintaining sleep, and daytime hypersomnolence; these disturbances in turn worsen pain perception and quality of life. Therapeutic decisions in neuropathic pain traditionally focus on analgesia, functional outcomes, and adverse effect profiles, but the differential impact of analgesic agents on sleep architecture and circadian biology is underappreciated. Understanding whether commonly used agents differ in their effects on sleep and circadian homeostasis could inform treatment selection for patients in whom sleep impairment is prominent.
Study design and methods
Dai and colleagues (Anesthesiology, 2025) used a well-characterized mouse model of peripheral neuropathic pain—the spared nerve injury (SNI) model—to evaluate how neuropathic injury and subsequent analgesic therapy affect sleep-wake architecture, circadian rhythmicity, and spinal circadian gene expression. Key experimental features included:
- Subjects: Male and female C57BL/6JRJ mice implanted with wireless telemetry transmitters for continuous electroencephalogram (EEG), electromyogram (EMG), locomotion, and body temperature monitoring.
- Intervention: After baseline recordings, SNI surgery was performed. Mechanical and dynamic allodynia were assessed on post-op days 3, 7, and 14. In male mice, continuous drug administration was delivered via intraperitoneal osmotic minipumps: pregabalin 11 mg/kg/day or morphine 6 mg/kg/day.
- Outcomes: Sleep architecture (REM and non-REM sleep, wakefulness), sleep microstructure (spindle occurrence, spectral power), circadian rhythmicity of locomotion and body temperature, and spinal cord circadian gene expression were assessed at baseline and on post-op days 7 and 14.
Key findings
The study reported several reproducible and mechanistically informative observations. Below are the major results grouped by domain.
Effect of SNI on sleep and circadian measures
– REM sleep: SNI significantly reduced REM sleep duration during the light phase (the habitual sleep phase for nocturnal mice) in both male and female mice.
– Wakefulness: Females showed an SNI-associated increase in wakefulness; non-REM sleep duration was not significantly changed by SNI in either sex.
– Circadian rhythmicity: SNI impaired the circadian rhythmicity of locomotor activity and body temperature, indicating a broader disruption of internal timekeeping beyond sleep staging.
Pregabalin vs morphine: differential restorative effects
– Pregabalin effects: Continuous pregabalin administration largely restored REM sleep duration to presurgical levels. Pregabalin also more effectively re-established circadian rhythmicity of locomotor activity and body temperature compared with morphine. At the molecular level, pregabalin reversed SNI-induced alterations in spinal circadian gene expression.
– Sleep microstructure: Pregabalin increased the occurrence of sleep spindles during sleep stage transitions and enhanced EEG power in the 3.5–5.5 Hz frequency band specifically during REM sleep, suggesting effects on sleep quality and microarchitecture beyond gross time spent in stages.
Morphine effects
– Morphine did not significantly restore REM sleep or improve overall sleep architecture and sleep microstructure in SNI mice.
– At the gene-expression level, morphine showed mixed effects on spinal circadian genes but did not produce the consistent restorative pattern seen with pregabalin.
Sex as a variable
– Both sexes exhibited reduced REM sleep after SNI, but the increase in wakefulness was more pronounced in females. The drug-intervention arms were performed in male mice; therefore, drug effect generalizability to females will require confirmation.
Mechanistic interpretation and biological plausibility
Pregabalin binds the α2δ subunit of voltage-gated calcium channels, reducing calcium influx and decreasing excitatory neurotransmitter release in dorsal horn neurons—actions that dampen aberrant nociceptive signaling thought to underlie neuropathic pain. By reducing sustained nociceptive input to sleep-regulating networks, pregabalin may allow normalization of REM-generating circuits and downstream circadian outputs. Additionally, the reversal of spinal circadian gene expression suggests that pregabalin’s actions extend beyond symptomatic analgesia to modulation of molecular clock components within the spinal cord, which may contribute to restored systemic rhythmicity (e.g., locomotor and thermo-regulatory cycles).
In contrast, opioids such as morphine exert complex effects on sleep: acute opioid administration can suppress REM and slow-wave sleep, and chronic opioid exposure is associated with disrupted sleep architecture and altered circadian rhythms in both preclinical and clinical studies. In this study, morphine failed to restore SNI-disrupted REM or circadian rhythms, consistent with the notion that opioids may not remediate the sleep-disrupting effects of neuropathic pain and in some contexts may further blunt restorative sleep processes.
Clinical and translational implications
This study raises clinically relevant points for management of neuropathic pain in patients who also suffer sleep disturbances:
- Analgesic selection may have important downstream effects on sleep architecture and circadian biology. Agents that both reduce pain and restore sleep/circadian rhythms (as pregabalin did in this model) could offer dual benefits for patient-centered outcomes.
- Opioids may not be the optimal choice when the restoration of normal sleep and circadian patterns is a therapeutic priority, given their failure to normalize REM and rhythm measures in this preclinical model.
- Sleep microstructure changes (e.g., spindle frequency, spectral power) may be important biomarkers of restored sleep quality beyond stage duration and could be evaluated in clinical trials as secondary endpoints.
Limitations and considerations
Several limitations affect interpretation and translation:
- Species and model: Mouse SNI models capture many aspects of neuropathic pain physiology, but direct extrapolation to human patients is limited by species differences in sleep architecture, drug pharmacokinetics, and circadian organization.
- Drug administration: Continuous intraperitoneal minipump delivery provides steady systemic exposure that differs from intermittent dosing regimens used in clinical practice. Dose equivalence between mouse and human requires careful pharmacokinetic scaling.
- Sex representation: Drug-effect arms were performed in male mice; because females showed distinct wakefulness changes after SNI, confirming drug effects in females is important.
- Molecular endpoints: Spinal circadian gene expression changes are intriguing mechanistic leads but need confirmation of causality and assessment of how spinal clock changes translate to central clock (e.g., suprachiasmatic nucleus) and peripheral outputs in humans.
Expert commentary and context
Current neuropathic pain treatment guidelines emphasize first-line agents such as certain antidepressants, gabapentinoids (including pregabalin), and some anticonvulsants, with opioids generally considered later-line options because of variable efficacy and safety concerns. The findings by Dai et al. dovetail with clinical observations that gabapentinoids can improve subjective sleep outcomes in neuropathic pain and fibromyalgia. They underline the value of assessing sleep and circadian outcomes in analgesic trials and considering them in shared decision-making when comorbid sleep disturbance is present.
Conclusions and future directions
The reported data show that pregabalin, but not morphine, restored REM sleep, improved circadian rhythmicity of locomotion and temperature, and reversed SNI-associated spinal circadian gene changes in mice with neuropathic pain. These findings support the hypothesis that analgesics differ in their capacity to normalize pain-related disruptions of sleep and circadian systems. Clinical trials that incorporate objective sleep measures (polysomnography, actigraphy), circadian biomarkers, and patient-reported sleep outcomes are warranted to determine whether these preclinical observations translate to human patients and whether such effects yield clinically meaningful improvements in pain, function, and quality of life.
Funding and clinicaltrials.gov
See the original publication for study funding statements and trial registration details: Dai W, Kilpeläinen T, Wen M, Roy C, Lundén A, Koskinen MK, Pertovaara A, Talvio AM, Wigren HK, Kalso E, Palada V. Differential Effects of Pregabalin and Morphine on the Sleep-Wake Cycle and Circadian Rhythms in Mice with Neuropathic Pain. Anesthesiology. 2025 Nov 1;143(5):1313-1339. doi: 10.1097/ALN.0000000000005715. PMID: 40802988; PMCID: PMC12513049.
References
1) Dai W, Kilpeläinen T, Wen M, Roy C, Lundén A, Koskinen MK, Pertovaara A, Talvio AM, Wigren HK, Kalso E, Palada V. Differential Effects of Pregabalin and Morphine on the Sleep-Wake Cycle and Circadian Rhythms in Mice with Neuropathic Pain. Anesthesiology. 2025 Nov 1;143(5):1313-1339. doi: 10.1097/ALN.0000000000005715. PMID: 40802988; PMCID: PMC12513049.
2) Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurology. 2015;14(2):162-173. doi:10.1016/S1474-4422(14)70251-0.
(Additional clinical translation and mechanistic discussion in this article draws on established pharmacology of pregabalin and opioids; readers are referred to contemporary reviews for exhaustive citation.)
