Peripheral neuropathies are common neurological disorders affecting sensory, autonomic, and motor nerves, with an estimated prevalence exceeding 2% in the general population. Typical symptoms include numbness and distal limb muscle weakness, resulting from somatosensory nerve damage. Here, we investigate the genetic architecture of mono- and polyneuropathies and their relationships with comorbid traits using data from FinnGen and the UK Biobank. Our genome-wide association study (GWAS) and meta-analysis identified 48 genome-wide significant (P < 5 × 10-8) independent loci and 66 fine-mapped credible sets. These included associations with genes involved in neurotransmitter signaling (HTR3A), immune function (HLA-DQB1, BCL11A), extracellular matrix remodeling (COL11A1, ADAMTS17, LOXL4), axon guidance and neural development (DCC, ETV1, NEGR1), and carpal tunnel syndrome (DIRC3). Public variant association data across cohorts, genetic correlation, and Mendelian randomization analyses supported shared genetic links of neuropathies with sleep problems, chronic pain, and psychiatric disorders. Together, our results highlight a strong polygenic basis for neuropathies and further confirm their genetic comorbid relationships with sleep, pain, psychiatric, and autoimmune traits.

Background Patient-reported outcome measures (PROMs) are key elements of assessing the efficacy of perioperative pain management. Here, we aimed to capture the association of 10 individually reported aspects of patient's specific impression of change since surgery (PSIC) related to four outcome domains of a previously defined core outcome set, relative to the patient's global impression of change (PGIC). We further evaluated the influence of type of surgery, sex, preoperative baseline characteristics, and satisfaction with pain management on PGIC. Methods This exploratory analysis used the PROMPT NIT-1 study data (2661 patients, 18 sites, four surgery types: total knee arthroplasty, sternotomy, breast cancer surgery, or endometriosis surgery). Male and female adults were included. All PROMs were assessed on postoperative day 3. We used ordinal regression models with PGIC as a dependent variable and PSICs as independent variables. Results The overall model achieved a pseudo-R2 of 0.55 (relative domain contributions: pain intensity 55%, self-efficacy 19%, adverse events 15%, and pain-related interference of physical functioning 10%). Pain-related worrying and depression had no association with the PGIC, whereas anxiety, preoperative pain, opioid intake, low satisfaction with and wish for more treatment, low treatment agency, and overall dissatisfaction were associated with less improvement after surgery. Receiving information about treatment was associated with greater improvement on the PGIC. Conclusions Although all four domains contributed to PGIC after surgery, pain intensity was the most important. These findings highlight the importance of both managing postoperative pain and optimising patient experience by addressing self-efficacy, adverse events, and pain-related interference of physical functioning. Clinical trial registration NCT 03834922

Evidence suggests that neuropathic pain (NP) and comorbid mood disorders are associated with circadian abnormalities. This suggests a role for chronotherapies, such as time-restricted feeding (TRF), to alleviate pain and comorbid anxiety. We investigated the effects of TRF on pain and anxiety-related behaviours in spared nerve injury (SNI) mice with NP and diurnal changes in the hypothalamus transcriptome, an important hub for modulating fear and anxiety. SNI male and female C57BL/6JRj mice received TRF during the dark active phase or ad libitum feeding (ALF) for three weeks post-surgery. Behavioral tests, von Frey, hot plate, light-dark box (LDT), and open field (OFT), were performed at baseline and post-surgery; hypothalamus tissues were dissected in the morning (zeitgeber time (ZT) 2-6) and afternoon (ZT 8-12). Male, but not female, SNI mice under TRF showed significantly reduced anxiety-like behaviors (LDT: p = 0.0259, Cohen's d = 1.245; OFT: p = 0.0054, Cohen's d = 1.643). Differentially expressed gene (DEG) analysis identified 33 DEGs in the hypothalamus in male SNI mice between TRF and ALF in the afternoon, with enriched anxiety-related, mitochondrial, and circadian genes. These findings support TRF as a potential therapeutic approach to alleviate comorbid anxiety in NP.

Circadian disruption increases the risk of neurological disorders, yet its impact on neuropathic pain (NP), a type of pain caused by nerve lesion, remains poorly understood. This study examined how three weeks of repetitive circadian disruption affects mechanical sensory thresholds and the spinal transcriptome in male C57BL/6JRj mice subjected to spared nerve injury (SNI) by using the chronic jet lag (JL) model. We also compared behavioural and transcriptomic outcomes between SNI and sham-operated control mice under either JL or a regular light/dark (LD) schedule. Mechanical hypersensitivity was assessed using von Frey tests at baseline and on post-surgical days 7, 14, and 21. Ipsilateral spinal cord tissues were collected four-hourly for 24 h for RNA sequencing. Differentially expressed genes (DEGs) were identified, and rhythmic transcripts analysed to compare changes in mesor, amplitude, and phase. Repetitive circadian disruption reduced mechanical thresholds in sham controls and in the uninjured paw of SNI mice, indicating increased mechanical hypersensitivity. Under JL, there were 137 upregulated and 25 downregulated spinal DEGs in SNI, enriched for immune-related processes. Rhythmicity analysis revealed 140 rhythmic transcripts in SNI and 801 in sham mice under JL. SNI mice exhibited a marked reduction in rhythmic transcripts under JL (140) relative to LD (680), whereas sham mice maintained similar rhythmic transcript numbers across conditions (801 in JL; 758 in LD). Three DEGs showed significant JL-related changes in rhythmic parameters and were rhythmic only in sham mice. These findings demonstrate that JL-induced circadian disruption exacerbates pain sensitivity and alters spinal transcriptional rhythms.

Abstract The importance of neuroimmune interactions in neuropathic pain (NP) has been established, but antibody-mediated mechanisms remain underexplored. In this explorative case-control study, we analyzed antibody profiles in patients with intercostobrachial nerve injury during breast cancer (BC) surgery. We compared 27 patients who developed chronic NP with 30 who remained NP-free, despite similar nerve injury. Plasma samples were collected before surgery and 4–9 years later. Mimotope variation analysis (MVA), a next generation random peptide phage display method revealed highly individual yet shared antigen profiles. We identified 1882 antibody epitopes differing between the study groups and that were associated with 79 common human pathogens. NP patients showed elevated pre-surgical antibody responses to viral epitopes of CMV (cytomegalovirus), EBV (Epstein-Barr virus), human papilloma virus-16 (HPV-16), human rhinovirus C3 (HRV C3), Herpes Simplex-1 (HSV-1), Herpes Simplex-2 (HSV-2), while antibody levels against Coxsackievirus B3 (CVB3) were lower. These findings persisted over time. The combination of responses to five viral epitopes (CVB3, EBV, CMV, HPV-16, HSV-2) predicted persistent NP (AUC 0.9, 95% CI 0.794–0.963). These findings implicate elevated antiviral immune responses in NP pathogenesis and encourage further clinical and basic research on the molecular mechanisms and novel treatment strategies for managing NP.

BACKGROUND:Patient-reported outcome measures (PROMs) are essential instruments for assessing postsurgical pain-related outcomes from the patient's perspective. The concept of minimal clinically important difference (MCID) aims to identify the smallest change in PROMs that is meaningful to patients. In this multicenter study, data were used to calculate MCIDs for several PROMs assessing pain intensity and physical function after surgery and to perform a sensitivity analysis. METHODS:Data from 2,661 patients undergoing sternotomy, total knee arthroplasty, breast surgery, or surgery related to endometriosis, recruited from 18 centers in 10 European countries, were included in the analysis. Eight PROMs were collected on days 1 and 3 after surgery, assessing pain intensity (at rest, average, worst, during movement, during physiotherapy) and physical function (in bed, during movement, during physiotherapy). MCIDs were calculated using a combination of distribution-based (30% of SD, standard error of the measurement) and anchor-based (calculating the absolute change between day 1 and day 3 for patients reporting "minimal improvement" or "minimal worsening" on 7-point global and specific impression of change scales) methods. RESULTS:The MCID estimates for pain intensity ranged from 1.2 (at rest) to 1.6 (during activity), while physical function was consistent between 1.5 (in bed) and 1.6 (during physiotherapy) on an 11-point scale. Sensitivity analyses revealed no significant difference in MCID estimates between symptom improvement and worsening for all PROMs. However, baseline pain influenced MCID estimates, with higher baseline pain leading to patients reporting higher changes as meaningful ( e.g. , for pain at rest, MCID mild pain 1.0, MCID severe pain 2.1). CONCLUSIONS:The authors found differences between MCID estimates for eight PROMs related to pain intensity and physical function. Baseline values appear to have a significant impact on what patients consider to be a minimal relevant change, which should be addressed in future studies.

BACKGROUND:Psychosocial aspects underlie and maintain persistent pain. Emotions have emerged as a target for psychological interventions in pain management. Our aim was to better understand the relationship between emotions and bodily sensations, including pain sensitivity, using two new approaches. METHODS:110 patients with confirmed endometriosis and 110 age- and gender-matched pain-free controls completed computer-based Bodily Sensation Maps for six basic emotions and a neutral emotional state, tactile, nociceptive, and hedonic sensitivities, as well as current and persistent pain. All participants also evaluated their current emotional experience of six basic emotions, depression, and anxiety, and answered the Brief Pain Inventory questionnaire; 102 endometriosis patients also answered the Multidimensional Assessment of Interoceptive Awareness questionnaire. RESULTS:Endometriosis patients coloured in significantly larger painful areas on body maps and greater sensitivities to both nociceptive and hedonic sensations than did the pain-free controls. The endometriosis patients reported more current fear than controls but did not differ from controls in the colouring in of basic emotions on the body maps. Emotional awareness was associated with higher pain intensity, and with more colouring for persistent pain. More trusting was associated with less affective interference and with less colouring for current pain. Less worrying and more trusting were associated with more colouring for hedonic sensitivity. CONCLUSIONS:Bodily sensation maps and multidimensional assessment of interoceptive awareness provide important information about the interface of emotions and pain. Our results suggest that a less worrying and a more trusting nature have a protective role in pain interference. SIGNIFICANCE:Bodily emotions and interoceptive awareness associate with sensitivity to pain and should be addressed when targeting emotions in pain management.

BACKGROUND:Pain is the leading cause of disability and reduced quality of life worldwide. Despite the increasing burden for patients and healthcare systems, pain research remains underfunded and under focused. Having stakeholders identify and prioritize areas that need urgent attention in the field will help focus funding topics, reduce 'research waste', improve the effectiveness of pain research and therapy and promote the uptake of research evidence. In this study, the European Pain Federation (EFIC) developed a Pain Research Strategy for Europe. METHODS:The study used multiple methods, including literature searches, multidisciplinary expert debate, a survey and a final consensus meeting. The cross-sectional survey was conducted among 628 European pain researchers, clinicians, educators and industry professionals to obtain the rating and hierarchy of pain research priorities. The final consensus meeting involved a multidisciplinary expert panel including people with lived experience from 23 countries. The survey results guided discussions where top priorities were agreed. RESULTS:Content analysis identified nine survey themes, of which five emerged as top priorities: (i) understand the pathophysiology of pain; (ii) understand and address comorbidities; (iii) critically assess current therapies; (iv) develop new treatments; and (v) explore the biopsychosocial impacts of pain. Physical, psychological and social approaches were prioritized at the same level as pharmacological treatments. The top priorities were endorsed by a multidisciplinary expert panel. The panel emphasized the importance of also clearly communicating the concepts of prediction, prevention self-management and personalized pain management in the final strategy. CONCLUSIONS:The content of the final top research priorities' list reflects a holistic approach to pain management. The equal importance given to physical, psychological and social aspects alongside pharmacological treatments highlights the importance of a comprehensive biopsychosocial-orientated research strategy. The expert panel's endorsement of five top priorities, coupled with an emphasis on communicating the concepts of prediction, prevention, self-management and personalized pain management, provides a clear direction for future basic, translational and clinical research. SIGNIFICANCE:EFIC has developed a Pain Research Strategy for Europe that identifies pain research areas deserving the most focus and financial support. Implementation and wide dissemination of this Strategy is vital to increase the conduct of urgent pain projects, pain research funding and the implementation of research findings into practice, to ultimately decrease the personal, societal and financial burden of pain.

BACKGROUND:Neuropathic pain (NP) resulting from nerve damage shows diurnal fluctuation of intensity in patients, indicating circadian regulation. However, mechanisms linking NP and circadian regulation remain unclear. This study aimed to investigate time-dependent transcriptomic changes during a 24-hour period using a spared nerve injury (SNI) mouse model of NP. METHODS:Pain-related behaviours were assessed at baseline and on days 7, 14, and 21 after SNI and control sham surgeries in C57BL/6JRJ mice. Spinal cord (SC) and periaqueductal gray (PAG) were collected 4-hourly over 24 h upon completion of behavioural testing. RESULTS:RNA sequencing revealed 111 up- and 21 downregulated differentially expressed genes (DEGs) in the SC, and 35 up- and 33 downregulated DEGs in the PAG, across all six time points. The large majority of DEGs, 245 in the SC and 191 in the PAG, are involved in regulation of immunity. Among the top expressed genes, five DEGs in the SC, Atf3, Anxa10, Gpr151, Cxcl10, Sprr1a, and two DEGs in the PAG, Igf2 and Wnt6, were previously reported to regulate pain. Circadian analysis using CircaCompare identified 383 SC transcripts and 261 PAG transcripts with altered rhythmicity. Variability of gene expression during circadian day was increased in the SC and decreased in the PAG from the SNI mice. CONCLUSION:These findings suggest that NP disrupts the circadian expression of rhythmic transcripts in the SC and PAG, potentially revealing new targets for chronotherapy of NP.

BACKGROUND:Paracetamol-codeine combination tablet is widely used in pain management after day surgery. For safety reasons, its use has decreased in recent years. Codeine is a prodrug metabolised in the liver by the cytochrome P450 2D6 (CYP2D6) enzyme to morphine that produces the analgesic effect of codeine. CYP2D6 is highly polymorphic, and based on genotypes, individuals can be divided into four categories: poor-, intermediate-, normal- and ultrarapid metabolisers. Differences in morphine and its metabolite concentrations have been described between different CYP2D6 genotypes following codeine administration. The aim of the study was to investigate the possible effect of CYP2D6 genotype on codeine efficacy and adverse effects in a large cohort of adult patients undergoing ambulatory surgery. METHODS:A total of 987 patients scheduled for ambulatory surgery were included in the analyses. Operation types or anaesthesia methods were not limited in the study protocol. All study patients received a fixed dose of paracetamol (1000 mg) and codeine (60 mg) orally for premedication. A blood sample was drawn to identify the genotype of CYP2D6. At home, the first-line analgesic was paracetamol-codeine combination of 1-2 tablets at 1-3 times per day. Data on the efficacy and side effects of codeine were collected on the day of surgery and the following two postoperative days. RESULTS:Of the studied patients, 37 (3.7%) were poor CYP2D6 metabolisers, 264 (27%) were intermediate, 623 (63%) were normal and 63 (6.4%) were ultrarapid metabolisers. Activity scores ranged from 0 to 4. CYP2D6 genotype was not associated in a statistically significant manner with postoperative pain, opioid consumption or the adverse effects of codeine, except for constipation at home. Poor CYP2D6 metabolisers reported significantly less severe constipation compared with normal metabolisers (p = .009, OR 0.40, 95% Cl 0.20-0.80). CONCLUSION:CYP2D6 genotype appears to be of minor importance for the analgesic efficacy of oral paracetamol-codeine combination therapy after ambulatory surgery in adult patients undergoing similar types of surgery as in the present study but it may affect the risk of constipation.

BACKGROUND:Neuropathic pain is commonly associated with disturbances in sleep architecture and circadian rhythms, leading to fragmented sleep, body temperature fluctuations, and altered locomotion. While pregabalin and morphine are frequently prescribed for neuropathic pain management, their effects on sleep and circadian regulation are poorly understood. METHODS:To identify the effects of spared nerve injury (SNI) on sleep architecture and circadian rhythms, male and female C57BL/6JRJ mice were implanted with wireless transmitters for continuous monitoring of electroencephalogram, electromyogram, locomotion, and body temperature. After baseline recordings, SNI was performed, and mechanical and dynamic allodynia was assessed on days 3, 7, and 14 after the surgeries. Pregabalin (11 mg/kg each day) or morphine (6 mg/kg each day) was administered continuously to male mice via intraperitoneal osmotic minipumps. Recordings were repeated on postoperative days 7 and 14. RESULTS:SNI significantly disrupted the sleep-wake cycle by reducing rapid eye movement (REM) sleep duration during the light phase (the habitual sleeping phase for mice) in both sexes and increasing wakefulness in females, without significantly affecting non-REM sleep. Additionally, SNI significantly impaired the circadian rhythmicity of locomotion and body temperature. Pregabalin, but not morphine, significantly restored REM sleep to presurgical levels and restored locomotor activity and body temperature rhythmicity more effectively than morphine. At the molecular level, SNI altered spinal cord circadian gene expression, which pregabalin significantly reversed, whereas morphine showed mixed effects. Furthermore, pregabalin increased sleep spindle occurrence during sleep stage transitions and enhanced the power spectra within the 3.5- to 5.5-Hz range during REM sleep. Morphine did not significantly alter either sleep architecture or microstructure in SNI mice. CONCLUSIONS:Pregabalin, unlike morphine, restores SNI-disrupted sleep architecture, circadian rhythms, and spinal circadian gene expression.

BACKGROUND:Measures of physical activity and pain-related patient-reported outcomes are important components of patient recovery after surgery. However, little is known about their association in the early post-operative period. This study aims to increase this knowledge. Our primary objective was to determine the association between average pain intensity and activity (in steps) 1 week after surgery. Secondary objectives were the association of activity with other patient-reported outcomes, age, sex, comorbidities and body mass index. METHODS:Data were obtained from the PROMPT sub-project of IMI-PainCare. Patients after breast and endometriosis-related surgery, sternotomy and total knee arthroplasty completed pain-related outcomes questionnaires and wore an ActiGraph activity-tracking device. We correlated steps with average pain intensity on post-operative days 6 and 7. Secondary analyses were done using correlations and t-tests. RESULTS:In 284 cases, there was no statistically significant correlation between steps and average pain intensity. In addition, none of the 28 secondary analyses showed a statistically significant result. CONCLUSIONS:Pain-related patient-reported outcome measures and physical activity are separate entities. Both should be measured after surgery to assess patient recovery and to identify treatment deficiencies. SIGNIFICANCE STATEMENT:Measuring recovery is a multi-dimensional challenge. After surgery, clinicians need to be aware that neither pain intensity nor activity levels tell the whole story. Each can hint to problems and treatment requirements.

BACKGROUND AND OBJECTIVE:A multidisciplinary approach is the gold standard in the management of persistent pain and is current practice in tertiary pain clinics. However, such approaches seem to be a rarity in primary care, although pain is the most common reason for visiting a primary care physician. A comprehensive systematic review was conducted to explore whether studies on multidisciplinary management programs for persistent pain exist in primary care. DATABASES AND DATA TREATMENT:PubMed, Ovid MEDLINE, Scopus, CINAHL, and PsychINFO were searched from inception to October 2022, and supplementary research was conducted in June 2023. Screening, data extraction, and quality assessment were independently carried out by two researchers. The inclusion criteria were (1) adult patients (age >18 years); (2) non-cancer pain, persisting over 3 months; (3) multidisciplinary intervention (treatment included ≥3 heathcare professionals); (4) intervention conducted in a primary care setting; and (5) reports published in English. RESULTS:Of the 1250 initially identified studies, 17 were selected for final analysis. Only studies reporting empirical data were included (cohort, case-control, randomized controlled trial, and observational). The study settings and intervention characteristics showed great heterogeneity. The primary care practices also varied across different countries and cultures. Overall, the quality of the studies was rather low and sample sizes were relatively small. CONCLUSIONS:The review revealed that studies about such treatment interventions for persistent pain patients are scarce. The existing studies were heterogeneous in terms of intervention characteristics, population, outcome variables, and study methodology. Future studies are urgently needed. SIGNIFICANCE:Persistent pain is a growing challenge to the health care system, and most patients are treated in primary care. The biopsychosocial concept is the basis for the multidisciplinary management of pain. The review revealed that studies about treatment interventions for persistent pain patients are scarce. Existing studies were heterogeneous in terms of intervention characteristics, population, outcome variables, and study methodology. There is an urgent need for further studies on systematic multidisciplinary treatment protocols for managing persistent pain in primary care.

OBJECTIVES:Pain catastrophizing is a core psychological factor determining pain experience. We addressed the question of whether patients with different pain syndromes group into different pain catastrophizing phenotypes. METHODS:A total of 727 patients with chronic pain associated with four primary syndromes: Breast cancer (BC) survivors (n = 400), fibromyalgia (FM, n = 52), complex regional pain syndrome (CRPS, n = 155), and HIV (n = 120) were first studied for differences in levels of pain catastrophizing (Pain Catastrophizing Scale, PCS) and pain intensity by analysis of variance. Subsequently, individual scores of the PCS subscales "rumination", "magnification," and "helplessness" from the pooled cohorts were submitted to multivariate k-means clustering to explore subgroups. RESULTS:Three clusters defined by the level of catastrophizing were identified. The "low catastrophizing" cluster (n = 377) included most of the BC patients (71.0%) and the "moderate catastrophizing" cluster (n = 256) most of the FM patients (61.5%). HIV (31.9%) and CRPS (44.7%) patients were over-represented in the "high catastrophizing" cluster (n = 94) with the highest catastrophizing tendencies in all dimensions. These patients reported more helplessness than the patients in the two other clusters. CONCLUSIONS:The primary syndrome causing the pain has an impact on self-reported pain-related catastrophizing. Helplessness is a predominant feature in HIV and CRPS patients and therefore an important target in pain rehabilitation.

1. Introduction Sleep is essential for health. It has an important bidirectional relationship with pain: Pain disrupts sleep, while poor sleep augments pain intensity and enhances spread to multiple sites.2,79 Anxiety, fear, and worry are often associated with sleep problems and chronic pain. Sleep problems are reported by two-thirds of pain clinic patients.72 The different stages of sleep serve various functions that aim to preserve the homeostasis of both body and mind. Insufficient sleep has negative effects on immune, metabolic, cardiovascular, and cognitive functions, as well as on emotional regulation. Increased understanding of the importance of sleep has inspired pain researchers to focus on sleep as a target for therapeutic interventions in patients with pain.46 In this context, it is important to be aware of the effects that commonly used analgesics have on sleep. In this review, we provide a short summary of the physiology of sleep and how it is affected by pain. We focus on the effects of analgesics on sleep in patients with persistent pain and in healthy volunteers to address the purely pharmacological effects of analgesics on sleep. We also provide insight from preclinical animal studies. We have restricted the review to common analgesic drugs such as paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, tricyclic and dual-action antidepressants, and gabapentinoids. Finally, we provide some thoughts about where future research in this field might go. 2. Sleep 2.1. Sleep structure and physiology Sleep is a dynamic process consisting of alternations between rapid eye movement (REM) sleep and non-REM (NREM) sleep. NREM sleep is further divided into 3 stages, N1, N2, and N3, which can be differentiated by their increasing threshold to arousal and characteristic electroencephalogram (EEG) oscillatory features. The sleep structure, stages, and their characteristics are presented in more detail in Figure 1A.Figure 1.: (A) Sleep stages and their characteristics. One sleep cycle includes different stages of non-rapid eye movement (NREM) sleep followed by REM sleep, and in humans, its average length is about 90 minutes.19 The transition from wakefulness to sleep happens through the N1 sleep stage, during which the occipital alpha (8-11 Hz) rhythm indicating the wake stage in humans starts to disappear in the EEG and slower theta waves (4-7.5 Hz) appear.1,34 The appearance of specific sleep microarchitectural features, K-complexes and sleep spindles, indicates transition to the N2 sleep stage. N2 is the predominant sleep stage and comprises about 50% of the total sleep time. Transitions to the N3 sleep and to REM sleep happen through N2 sleep. The deepest sleep stage with the highest arousal threshold is N3 sleep, characterized by slow waves, during which large populations of cortical neurons activate and deactivate in synchrony.1 During the night, the amount of deep N3 sleep is highest in the first sleep cycles and in the following cycles, its amount dissipates, whereas the amount of REM sleep increases toward the morning. In the EEG, REM sleep differs remarkably from NREM sleep resembling more the wake state; therefore, it is also called paradoxical sleep.57 Rapid eye movements and vivid dreaming occur during REM sleep, and muscle tone in skeletal muscles completely disappears. (B) NREM and REM sleep have different neurochemical environments in the brain. During REM sleep, noradrenergic, serotonergic, and histaminergic signaling are absent, while acetylcholine levels are simultaneously elevated. In NREM sleep, the levels of acetylcholine, histamine, norepinephrine, and serotonin are low, but noradrenergic and serotonergic neurons can show rhythmic, fluctuating activity.6,27,58,61,69,81 Despite the different levels during NREM and REM sleep, norepinephrine, serotonin, histamine, and acetylcholine are present at the highest levels during wakefulness and are able to promote cortical activation.69 (B) Created with BioRender.com.The timing of sleep is controlled by a circadian and the duration by a homeostatic process.12 The master oscillator in the suprachiasmatic nucleus (SCN) creates an endogenous circadian rhythm of about 24 hours.82 Most physiological functions, including sleep, are connected to this rhythmicity, either by directly adhering to the endogenous oscillator or indirectly as diurnal rhythms. Failure to conform to this rhythmicity will create physiological dysfunction and is one of the most important factors leading to sleep problems. Homeostatic control of sleep entails an extended period of wakefulness followed by a prolonged, intensified sleep period, often manifested by increase in N3 sleep.12 The key concept of sleep homeostasis is the sleep pressure that accumulates during waking and initiates sleep. Several mediators of sleep pressure have been proposed, for example, adenosine, increased number or size of synapses in the brain, and accumulation of metabolites associated with wakefulness.86 The glymphatic system, a brain-wide perivascular pathway that is most active during deep sleep, seems to play an important role in facilitating the clearance of metabolic products accumulated in the brain during wakefulness.53,109 Sleep and the immune system are bidirectionally connected. Some proinflammatory cytokines such as TNF-α and interleukin-1, as well as prostaglandin D2 can have sleep promoting effects.80,101 The increased sleep observed in response to infection can be beneficial by augmenting immune system function, whereas sleep loss per se can induce an inflammatory state and impair immune response.10,80 In the brain, sleep has an essential role in plasticity, memory consolidation, and cognition. Sleep spindles, the characteristic oscillations during N2 sleep, as well as N3 sleep slow waves and REM sleep have been associated with memory consolidation and learning.15,32,100 Sleep, in particular REM sleep, also seems to be important for emotional regulation.42 For instance, uninterrupted REM sleep episodes can afford protection from amygdala overactivation associated with anxiety.106 During sleep, notable physiological changes occur. In NREM sleep, body temperature, heart rate, blood pressure, and breathing rate decrease, whereas in REM sleep, their control is more irregular.86 Changes in the brain neurochemical environment between wake, NREM, and REM sleep can explain some of the physiological and functional differences observed in these distinct brain states (Fig. 1B). 2.2. Sleep disturbances and pain The effects of sleep disturbances on pain sensitivity are well conserved across species, but sex differences exist as female patients develop more hypersensitivity than male patients.63 Disturbed sleep can mediate pain hypersensitivity at both sensory and emotional levels of the pain system. Sleep loss promotes a proinflammatory effect that can aggravate pain complaints.43,76 Elevated levels of proinflammatory cytokines can amplify nociceptive signaling, for example, by increasing the sensitivity of nociceptors or by affecting the mesolimbic system.51,54,107 The mesolimbic system has an important role in determining the salience of the painful stimulus and modulating the reward system.112 Consequently, sleep loss-induced dysregulation of this system can change the salience of the pain experience or its expectation.95,103 The core brain regions of the mesolimbic system, ventral tegmental area and nucleus accumbens, are also involved in the regulation of sleep-wake behaviours.22,29,77,113,114 It is challenging to discriminate the function of different sleep stages on pain sensitivity, but evidence highlights the importance of N3 slow wave sleep. Restoring the amount of N3 sleep after sleep deprivation elevates pain threshold, whereas experimental disruption of slow wave sleep decreases pain threshold and increases musculoskeletal discomfort in healthy volunteers.68,73,78 In addition, decrease in N3 sleep has been observed in patients with neuropathic pain.11,31 Neuropathic pain involves a neuroinflammatory element defined by pathological glial activation and release of neuroinflammatory cytokines to the extracellular space.56 Because the glymphatic system is most active during deep sleep, one important question is whether pain-induced sleep reduction disturbs glymphatic flow and affects pain chronification by inhibiting clearance of cytokines. Indeed, a preclinical study has shown that acute nociceptive stimulation hinders tracer clearance from deep brain structures.97 Shorter duration of N2 sleep has been linked to higher pain intensity in patients with fibromyalgia.16 The occurrence and characteristics of sleep spindles, typical of N2 sleep, show individual variability. A reduced amount of spindles has been observed in patients with fibromyalgia and in rats with inflammatory pain.17,66 The role of disturbed REM sleep and pain is complex because it would most likely involve the mesolimbic processes associated with emotion and cognition. It has been suggested that loss of REM sleep could induce hyperalgesia the following day. However, on the whole, it seems that the main driver for pain hypersensitivity is the significant total sleep loss over time, rather than specific loss of REM sleep.63,87 3. The effects of analgesics on sleep A simple search of PubMed was conducted using the terms "polysomnography", "EEG", and "sleep" combined with the analgesic or analgesic group names. After screening, studies where sleep parameters were reported using polysomnography (PSG) were included for consideration. Studies where sleep was only assessed using questionnaires or other subjective measures were excluded. The selected studies evaluated drug effects on sleep in patients with pain but also in healthy adult volunteers, to avoid the confounding effects of pain. The patient groups included those with fibromyalgia, dysmenorrhea, low back pain, osteoarthritis, and painful diabetic polyneuropathy. The small number of subjects in most studies and the heterogeneity of study designs precluded meta-analysis. Detailed information about the studies can be found in Table 1. Table 1 - Effects of analgesics on sleep structure—detailed information of the studies. Treatment Subjects and study design Sleep parameters PAIN Drug and dose reference Treatment duration Subjects Design N1drug X̅ ± SDplacebo X̅ ± SD N2drug X̅ ± SDplacebo X̅ ± SD N3drug X̅ ± SDplacebo X̅ ± SD REMdrug X̅ ± SDplacebo X̅ ± SD WAKEdrug X̅ ± SDplacebo X̅ ± SD TSTdrug X̅ ± SDplacebo X̅ ± SD Sleep efficiencydrug X̅ ± SDplacebo X̅ ± SD WASOdrug X̅ ± SDplacebo X̅ ± SD NSAIDs and paracetamol, healthy volunteers Paracetamol 650 mg74 1 d, drug given at night 9 drug, 10 placebo, F/M RCT, placebo-controlled ns ns ns ns ns ns ns ASA 650 mg74 1 d, drug given at night 9 drug, 10 placebo, F/M RCT, placebo-controlled ns ns ns ns ↑ P < 0.059.0 ± 2.4%8.0 ± 0.6% ↓ P < 0.0591.0 ± 2.4%96.2 ± 0.6% ASA 600 mg x350 4 d 8 drug, 8 placebo, F RCT, placebo-controlled ↑ P ≤ 0.01197 ± 22.6 min170 ± 20.5 min ↓ P ≤ 0.0188 ± 22.5 min109 ± 20.0 min ns ns ns Ibuprofen 400 mg74 1 d, drug given at night 9 drug, 10 placebo, F/M RCT, placebo-controlled ns ns ns ns ↑ P < 0.0512.5 ± 2.1%3.8 ± 0.6% ↓ P < 0.0587.5 ± 2.1%96.2 ± 0.6% Ibuprofen 400 mg x340 1 d, (drug given 3 pm, 7 pm, 11 pm) 15 drug, 15 placebo RCT, placebo-controlled ns ns ns ns ns ns ns NSAIDs and paracetamol, patients Paracetamol 1300 mg x38 1 d (5 hours before sleep, lights off, morning) 16 healthy or dysmenorrhea, F RCT, placebo-controlled, crossover ns ns ns ns ns ns Not assessed Diclofenac 50 mg x352 1 d (last 30 minutes before bedtime) 15 patients with dysmenorrhea pain, F RCT, placebo-controlled, crossover ↓ P < 0.054 ± 1%6 ± 3% ns ns ↑ P < 0.0126 ± 3%22 ± 5% ns ns ↑ P < 0.0597 ± 1%95 ± 3% ns 100 mm VAS ↓ P < 0.05 Drug Duration Subjects Design N1 N2 N3 REM WAKE TST SE WASO PAIN Opioids and tramadol, healthy volunteers Morphine sulphate 15 mg (sustained release), p.o25 1 d 42 RCT, placebo-controlled, crossover ns ↑ P < 0.0561.3 ± 1.1%58.5 ± 1.4% ↓ (N3 + N4) P < 0.057.5%11.6% ns ns ns ns Morphine sulphate 0.1 mg/kg, i.v96 1d (30-60 minutes bef. lights off and 3-4 am) 7, F/M RCT, placebo-controlled, crossover ns ↑ P = 0.00170.3 ± 3.9%55.1 ± 3.8% (SEM) ↓ P = 0.00275.5 ± 2.9%16.8 ± 2.0% (SEM) ↓ P = 0.04615.6 ± 2.5%21.8 ± 2.4% (SEM) ns ns ns Tramadol 50 mg104 1 d (evening) 8, F/M RCT, placebo-controlled, crossover ns ↑ P = 0.03 Stage 4 ↓ P = 0.04 ns Tramadol 100 mg104 1 d (evening) 8, F/M RCT, placebo-controlled, crossover ns ↑ P = 0.02 Stage 4 ↓ P = 0.02 ↓ P = 0.005 Methadone 5 mg, p.o25 1 d 42 RCT, placebo-controlled, crossover ns ↑ P < 0.0563.8 ± 1.3%58.5 ± 1.4% ↓ (N3 + N4) P < 0.057.1%11.6% ns ns ns ns Opioids and tramadol, patients Different opioids23 Patients with fibromyalgia with insomnia, 65 opioid users, 128 nonusers, F: 94% Opioid vs nonopioid users ns ↑ P =0.04B = 1.39 ± 0.71% (SE) ↓ P = 0.002B = −4.90 ± 1.53% (SE) ns ns ns ns Scale0-100 Morphine sulphate 30 mg (extended release)89 14 d (morning) 10 sleep disturbances + osteoarthritis F/M Single-blind, placebo-lead-in ↑ P ≤ 0.05296.7 min260.5 min ns ns ↑ P ≤ 0.05422.9 min385.6 min ns ns BPI ↓ P < 0.05 Morphine sulphate 60 mg (extended release)89 14 d (morning) 12 osteoarthritis + sleep disturbances, F/M Single-blind, placebo-lead-in ns ns ns ns ns ns BPI ↓ P < 0.05 Drug Duration Subjects Design N1 N2 N3 REM WAKE TST SE WASO PAIN Tricyclic and SNRI antidepressant drugs, healthy volunteers Amitriptyline 50 mg108 4 d (PSG at night 3) 19 drug, 20 placebo, F/M RCT, placebo-controlled ns ↑ P < 0.00154.2 ± 5.8%45.7 ± 5.4% ns ↓ P < 0.00112.9 ± 3.4%22.6 ± 4.8% ns ns ns ns Amitriptyline 75 mg26 1 d 14, M RCT, placebo-controlled, crossover ns ↑ P < 0.00164.3 ± 6.9%53.2 ± 4.1% ns ↓ P < 0.0018.6 ± 4.7%21.4 ± 3.4% ns ns Ns ↓ P = 0.04526.3 ± 18.8 min 31.2 ± 13.6 min Amitriptyline 50 mg45 28 d (20 minutes before bedtime) 14, M Placebo-controlled, crossover ns ↑ P < 0.0141.6 min compared with placebo* ns ↓ P < 0.00160 min compared with placebo* ns Amitriptyline 75 mg41 1 d (25 mg 9:30 pm + 50 mg 1:30 am) 13 drug, 15 placebo, M RCT, placebo-controlled ns ↑ P = 0.00161.4 ± 10.1%46.5 ± 8.1% ns ↓ P < 0.0014.1 ± 3.5%16.9 ± 6.1% ↑ P = 0.02438.5 ± 32.8 min 410.1 ± 38.2 min ↑ P = 0.0491.9 ± 6.9% 86.1 ± 8.1% ↓ P = 0.024.3% ± 1.69.5% ± 7.0 Imipramine 40 mg111 1 d total 40 mg: 9 pm (−1), 8 am, 12 pm, 6 pm, 9 pm 8, M RCT, single-blind, placebo-controlled, crossover ↑ +N1 P < 0.00278.7 ± 5.2%63.6 ± 7.7% ns ↓ P = 0.000712.3 ± 3.3%22.3 ± 7.3% ns ns Desipramine 50 mg x220 7 d 12, M RCT, placebo-controlled, crossover ns ns ns ↓ P < 0.000143.5 ± 22.6 min 103.6 ± 17.7 min ↓ P = 0.005349.9 ± 82.0 min 411.7 ± 37.1 min ns ns Duloxetine 80 mg (morning)20 7 d (PSG day 6) 6, M RCT, placebo-controlled, crossover ns ↑ P = 0.004271 ± 34.6 min 209.3 ± 32.8 min ns ↓ P < 0.000144.3 ± 21.7 min103.6 ± 17.7 min ns ns ns Duloxetine 60 mg x220 7 d (PSG day 6) 6, M RCT, placebo-controlled, crossover ns ↑ P = 0.001281.4 ± 47.3 min209.3 ± 32.8 min Stage 4 ↓ P = 0.01327.1 ± 24.7 min54.2 ± 21.2 min ↓ P < 0.000126.6 ± 10.4 min103.6 ± 17.7 min ns ns ns Venlafaxine 75 mg 2 d + 150 mg 2 d92 4 d (evening, 1 hour after sleep recording started) 8, F/M Compared with baseline ↑ P < 0.0001148.6 ± 40.4 min26.3 ± 9.2 min ↓ P < 0.007121.1 ± 57.3 min212.0 ± 26.9 min ↓ P < 0.00910.9 ± 10.6 min35.2 ± 9.9 min (stage 4 ns) ↓ P < 0.000010.0 ± 0.0 min31.0 ± 9.1 min ↑ P < 0.0007161.8 ± 65.3 min29.4 ± 18.4 min Tricyclic and SNRI antidepressant drugs, patients Amitriptyline 25 mg x2 for 14d and 25 mg + 50 mg for 14d14 28 d (opioids, NSAIDs, paracetamol allowed) 23 painful diabetic polyneuropathy, F/M RCT, placebo-run-in NREM ↑ P < 0.0001343.6 ± 9.3 min291.6 ± 7.4 (SE) ↓ P < 0.000150.2 ± 5.4 min77.0 ± 5.2 min (SE) ns ns ↓ P < 0.0566.6 ± 10.8 min91.0 ± 9.4 min (SE) BPI ns Amitriptyline 25 mg18 8 wk (bef. bedtime) on/off + 8 wks off/on 22, fibromyalgia, F: 95.5% RCT, placebo-controlledCrossover ↓ P ≤ 0.058.14 ± 4.2%5.55 ± 2.8% ns ns ns ns 10 cm VAS ↓ P < 0.05 Duloxetine 60 mg x1 for 14 d and 60 mg x2 for 14 d14 28 d (opioids, NSAIDs, paracetamol allowed) 23, painful diabetic polyneuropathy F/M RCT, placebo-run-in NREM ↑ P < 0.05326.7 ± 12.6 min298.0 ± 9.6 min (SE) ↓ P < 0.000129.9 ± 5.7 min83.4 ± 7.5 min (SE) ↓ P < 0.05356.6 ± 13.8 min381.4 ± 9.4 min (SE) ↓ P < 0.0574.2 ± 2.9%79.4 ± 2.0% (SE) ns BPI ns Drug Duration Subjects Design N1 N2 N3 REM WAKE TST SE WASO PAIN Gabapentinoids, healthy volunteers Gabapentin 600 mg x335 Titration to 1800 mg for 6d, PSG 7-10 later 10 drug, 9 control, F/M Compared with baseline ns ns ↑ P = 0.00713.0 ± 0.07%8.0 ± 0.03% ns ns ns ns Gabapentin 300 mg85 1 d 8 community-dwelling older men RCT, placebo-controlled, crossover ns ns ns ns ns ns ns Pregabalin 150 mg x347 3d 24, M RCT, placebo-controlledCrossover ↓ P < 0.001Last day3.1 ± 2.1%5.3 ± 2.5% ↓ P < 0.05Last day39.0 ± 7.2%39.8 ± 8.0% ↑ N4: P < 0.001Last day N3 + N436.4%25.3% ns ↑ P < 0.001Last day:458 ± 10.3 min432.7 ± 22.4 min ↑ P < 0.001Last day:95.3 ± 2.1%90.1 ± 4.7% Gabapentin 250 mg88 1 d 127 placebo, 125 drug, sleep phase advance 5 hours, M/F RCT, placebo-controlled ↓ P ≤ 0.00111.8 ± 0.7%15.1 ± 1.0% (SE) ns ↑ P ≤ 0.0515.4 ± 1.0%12.6 ± 0.9% (SE) ns ↑ P ≤ 0.001356.5 ± 7.3 min311.4 ± 8.4 min (SE) ↓ P ≤ 0.001100.7 ± 5.8 min135.7 ± 7.0 min (SE) Gabapentin 500 mg88 1 d 127 placebo, 125 drug, sleep phase advance 5 hours, M/F RCT, placebo-controlled ↓ P ≤ 0.00110.8 ± 0.7%15.1 ± 1.0% (SE) ns ↑ P ≤ 0.00117.0 ± 1.1%, 12.6 ± 0.9% (SE) ns ↑ P ≤ 0.001378.7 ± 7.3 min311.4 ± 8.4 min (SE) ↓ P ≤ 0.00173.2 ± 5.8 min135.7 ± 7.0 min (SE) Gabapentin 250 mg37 28 d 115 placebo, 122 drug, acute sleep phase advance 5 hours, F/M RCT, placebo-controlled ns ns ns ↑ P ≤ 0.0515.6 ± 0.5%13.6 ± 0.6% (SE) ↑ P ≤ 0.001335.3 ± 8.2 min289.1 ± 10.2 min (SE) ↓ P ≤ 0.001113.6 ± 8.1 min152.3 ± 9.3 min (SE) Gabapentinoids, patients Pregabalin 150 mg x2 for 14d and 300 mg x2 for 14 d14 28 d (opioids, NSAIDs, paracetamol allowed) 19 painful diabetic polyneuropathy, F/M RCT, placebo-lead-in NREM ↑ P < 0.0001348.3 ± 10.1 min291.5 ± 10.6 min (SE) ↓ P < 0.0162.0 ± 6.9 min80.1 ± 6.0 min (SE) ↑ P < 0.01410.3 ± 10.2 min371.6 ± 11.8 min (SE) ↑ P < 0.0185.4 ± 2.1%77.3 ± 2.5% (SE) ↓ P < 0.0157.2 ± 10.3 min90.9 ± 11.8 min (SE) BPI ns Pregabalin 300-450 mg90 4 wks, including titration max 14 d 115 patients with fibromyalgia, F:87% RCT, placebo-controlled, crossover ↑ P = 0.002417.2 ± 1.0%15.0 ± 1.0% ↑ P < 0.0001396.2 ± 4.7 min370.6 ± 4.7 min ↑ P < 0.000182.6 ± 1.0%77.2 ± 1.0% ↓ P < 0.000151.5 ± 3.8 min70.7 ± 3.8 min Scale0-10 ↓ P = 0.0084 ↑, increase; ↓, decrease; ASA, acetyl salicylic acid; BPI, brief pain inventory; F, female; i.v., intravenous; M, male; NSAID, nonsteroidal anti-inflammatory drug; p.o., per os (oral administration); PSG, polysomnography; RCT, randomized controlled trial; SD, standard deviation; SE, standard error; SEM, standard error of mean; TST, total sleep time; VAS, visual analogue scale; WASO, wake after sleep onset; ns, not significant, X̅, mean. 3.1. The effects of analgesics on sleep stages 3.1.1. Nonsteroidal anti-inflammatory drugs and paracetamol Nonsteroidal anti-inflammatory drugs convey their analgesic effect by inhibiting the cyclo-oxygenase (COX) enzymes COX-1 or COX-2, depending on their selectivity. Cyclo-oxygenase-2 converts omega-6 arachidonic fatty acid to prostaglandins that sensitize both peripheral and central neurons.84 The mechanism by which paracetamol alleviates pain has not yet been determined, but central COX inhibition and modulation of the endocannabinoid system have been suggested to be involved.7 Ibuprofen and paracetamol did not induce notable alterations in sleep architecture after acute (1 day) treatment in healthy volunteers but ibuprofen impaired sleep efficiency by increasing the amount of wakefulness.40,74 Acetylsalicylic acid (ASA) increased N2 sleep and decreased N3 sleep in healthy volunteers during 4 days of administration; however, these effects were not observed in a study where only one dose of ASA was administered before bedtime.50,74 In patients with dysmenorrhea, diclofenac increased REM sleep compared with placebo, whereas paracetamol did not significantly affect sleep.8,52 3.1.2. Opioids The endogenous opioid peptides control or modify several physiological functions, including pain and vigilance. Opioids convey most of their effects by activating the opioid receptors MOP, DOP, KOP, and NOP (ORL1).60 The analgesic effects are mediated by the MOP receptors and the sedative effects by the MOP and KOP receptors.55 Long-term opioid administration can significantly weaken the endogenous opioid system and thereby also its effects on sleep regulation. Opioid use can lead to sleep-disordered breathing, central apnea, upper airway obstruction, and hypoxemia.36 Unlike other analgesics, opioids consistently decreased deep N3 sleep in healthy volunteers.25,96,104 The amount of N2 sleep, on the contrary, was increased. In some studies, also the amount of REM sleep was reduced.96,104 The amount of wake after sleep onset (WASO) was not affected by acute opioid treatment in healthy volunteers or by chronic opioid treatment in patients. The sleep effects of long-term opioid treatment in patients with fibromyalgia and patients with osteoarthritis resemble those observed in healthy volunteers. However, in patients with pre-existing sleep disturbances, the amount of N3 sleep was not further reduced.23,89 The response to opioids might differ depending on the dose and treatment duration. Especially in animal studies, opioids can cause agitation or wakefulness rather than sleep.5,24,28,39,105 3.1.3. Tricyclic and dual-action antidepressant drugs Tricyclic antidepressants are efficacious in the treatment of neuropathic pain at lower doses than those needed to treat depression.33,70 Amitriptyline and its metabolite nortriptyline have serotonergic, noradrenergic, anticholinergic, and antihistaminergic effects. The dual-action antidepressants duloxetine and venlafaxine inhibit the reuptake of both serotonin and norepinephrine (SNRI), the latter effect being essential for their efficacy in neuropathic pain. Antidepressant drugs increase descending inhibition to the spinal cord, which is considered their main analgesic mechanism.71 Serotonin and norepinephrine antidepressants also have anxiolytic properties which can indirectly reduce the pain experience.13,91 The most remarkable effect of tricyclic and SNRI antidepressant drugs on sleep is reduction of REM sleep, demonstrated by all the compounds that belong to the class of antidepressant drugs in the examined studies.14,20,26,41,62,67,92,108,111 The REM-suppressing effect of antidepressant drugs has also consistently been found in preclinical studies.59,75,93,94 Total sleep time and N1 or N3 sleep stages were not invariably affected. Rather, the REM sleep reduction seemed to be compensated by an increased amount of N2 sleep. Particularly, treatment with tricyclic antidepressants seemed to maintain the amount of N3 sleep. These compensatory increases in NREM sleep preserve the total sleep time, which is more important for pain sensitivity than a reduction in REM sleep.63 The tricyclic antidepressant used in most studies was amitriptyline. It has antihistaminergic properties and has sedative effects already at the low doses commonly used in chronic pain and is administered in the early evening hours. In healthy volunteers, administration of the SNRI antidepressant venlafaxine in the evening for 4 days reduced the amount of N2 and N3 sleep.92 However, the comparison was made with baseline measurements and not with placebo. After 6 days of treatment, another SNRI antidepressant duloxetine did not alter N3 sleep when administered in a dose of 80 mg in the morning. However, when duloxetine 60 mg was administered twice daily, the amount of deep sleep was reduced after 6 days of treatment.20 These results could indicate that SNRI antidepressants negatively affect deep sleep, especially when administered close to bedtime. 3.1.4. Gabapentinoids Gabapentin and pregabalin bind to the α2δ1-subunit of the voltage-gated calcium channels and reduce the release of pronociceptive neurotransmitters including glutamate.21 In addition to being efficacious in neuropathic pain, both drugs have anxiolytic effects which may also enhance analgesia.49 Pregabalin has been shown to improve sleep in patients with generalized anxiety disorder.48 When administered to healthy volunteers and patients with fibromyalgia, gabapentinoids increased N3 sleep and total sleep time, while reducing light N1 sleep and WASO.47,88,90 When pregabalin was administered long-term to patients with painful diabetic polyneuropathy, NREM sleep was increased.14 Unfortunately, the NREM stage-specific effects were not described. In some studies, gabapentinoids seemed to reduce N2 sleep or increase REM sleep, but these effects were not as consistent as the N3-increasing effect.9,14,47,88 Only 1 study, conducted on community-dwelling older men receiving a single dose of gabapentin, did not detect any effects on sleep structure.85 Supporting the clinical findings, gabapentinoids have increased NREM sleep amount and duration in animal studies, as well as restored NREM sleep in a mouse model of neuropathic pain.30,64,99 3.2. Interactions between circadian rhythms and analgesics Circadian rhythms influence the efficacy of analgesics by affecting both pharmacokinetics (absorption, distribution, metabolism, excretion) and pharmacodynamics (intracellular signaling, target molecules, gene transcription), suggesting that time-targeted analgesic administration could optimize drug efficacy and safety.82 This is particularly evident for NSAIDs, opioids, antidepressants, and gabapentinoids that have downstream targets or receptors showing circadian rhythmicity.65,98,110 Analgesics can also directly interfere with circadian rhythmicity by altering the expression of core circadian genes.3,38,102 4. Conclusions and future directions Disturbed sleep is increasingly recognized as a key factor in the development and maintenance of chronic pain and is considered an important target for treatment.46 Sleep problems and pain share a number of comorbidities such as anxiety, stress, and depression, resulting in a vicious circle where independent factors may reinforce each other. To break this circle, the contributing factors in the individual patient need to be identified to optimize the treatment, including pharmacological interventions. Polysomnography is the preferred research tool, but only few studies have used it to assess the effects of analgesics on sleep in patients with pain. There is generally a paucity of information concerning the effects of analgesics on sleep, especially regarding long-term use. This is the case for even the most commonly used analgesics such as NSAIDs. Opioids seem to have the most deleterious effects on sleep because they reduce deep N3 sleep. Opioids can also cause sleep-disordered breathing and respiratory depression, providing further argumentation for limiting their use in chronic noncancer pain. Tricyclic antidepressants or gabapentinoids seem to have beneficial effects on both sleep and pain. How much the improved sleep contributes to the analgesic effect of these drugs is not known. Gabapentinoids and SNRI antidepressants also have anxiolytic effects which may indirectly contribute to improved sleep and pain. The effects of disturbed glymphatic clearance on pain chronification is an important topic for future research. Preclinical studies suggest that glymphatic clearance is under circadian control and is enhanced during slow wave sleep or anaesthesia, during which noradrenergic tone is low.44,53,109 The sedative α2-adrenergic agonist dexmedetomidine reduces central norepinephrine levels and induces cortical slow waves and has been shown to promote glymphatic flow.83 How other drugs that target the noradrenergic system, such as SNRI antidepressants, affect glymphatic clearance needs to be elucidated. An interesting question is also whether promoting sleep with other pharmacological agents, such as melatonin, could alleviate pain. A recent systematic review concluded that only low-quality evidence is available on this topic.4 Conflict of interest statement Eija Kalso has received lecture fees from GSK and Haleon and financial compensation for advisory board work from Pfizer and Orion Pharma, unrelated to this work. Other authors report no conflicts of interest.

BACKGROUND:Chronic postsurgical pain (CPSP) is a clinical problem, and large prospective studies are needed to determine its incidence, characteristics, and risk factors. OBJECTIVE:To find predictive factors for CPSP in an international survey. DESIGN:Observational study. SETTING:Multicentre European prospective observational trial. PATIENTS:Patients undergoing breast cancer surgery, sternotomy, endometriosis surgery, or total knee arthroplasty (TKA). METHOD:Standardised questionnaires were completed by the patients at 1, 3, and 7 days, and at 1, 3, and 6 months after surgery, with follow-up via E-mail, telephone, or interview. MAIN OUTCOME MEASURE:The primary goal of NIT-1 was to propose a scoring system to predict those patient likely to have CPSP at 6 months after surgery. RESULTS:A total of 3297 patients were included from 18 hospitals across Europe and 2494 patients were followed-up for 6 months. The mean incidence of CPSP at 6 months was 10.5%, with variations depending on the type of surgery: sternotomy 6.9%, breast surgery 7.4%, TKA 12.9%, endometriosis 16.2%. At 6 months, neuropathic characteristics were frequent for all types of surgery: sternotomy 33.3%, breast surgery 67.6%, TKA 42.4%, endometriosis 41.4%. One-third of patients experienced CPSP at both 3 and 6 months. Pre-operative pain was frequent for TKA (leg pain) and endometriosis (abdomen) and its frequency and intensity were reduced after surgery. Severe CPSP and a neuropathic pain component decreased psychological and functional wellbeing as well as quality of life. No overarching CPSP risk factors were identified. CONCLUSION:Unfortunately, our findings do not offer a new CPSP predictive score. However, we present reliable new data on the incidence, characteristics, and consequences of CPSP from a large European survey. Interesting new data on the time course of CPSP, its neuropathic pain component, and CPSP after endometriosis surgery generate new hypotheses but need to be confirmed by further research. TRIAL REGISTRATION:clinicaltrials.gov ID: NCT03834922.

BACKGROUND Chronic postsurgical pain (CPSP) is a clinical problem, and large prospective studies are needed to determine its incidence, characteristics, and risk factors. OBJECTIVE To find predictive factors for CPSP in an international survey DESIGN Observational study SETTING Multicentre European prospective observational trial PATIENTS Patients undergoing breast cancer surgery, sternotomy, endometriosis surgery, or total knee arthroplasty (TKA). METHOD Standardised questionnaires were completed by the patients at 1, 3, and 7 days, and at 1, 3, and 6 months after surgery, with follow-up via E-mail, telephone, or interview. MAIN OUTCOME MEASURE The primary goal of NIT-1 was to propose a scoring system to predict those patient likely to have CPSP at 6 months after surgery. RESULTS A total of 3297 patients were included from 18 hospitals across Europe and 2494 patients were followed-up for 6 months. The mean incidence of CPSP at 6 months was 10.5%, with variations depending on the type of surgery: sternotomy 6.9%, breast surgery 7.4%, TKA 12.9%, endometriosis 16.2%. At 6 months, neuropathic characteristics were frequent for all types of surgery: sternotomy 33.3%, breast surgery 67.6%, TKA 42.4%, endometriosis 41.4%. One-third of patients experienced CPSP at both 3 and 6 months. Pre-operative pain was frequent for TKA (leg pain) and endometriosis (abdomen) and its frequency and intensity were reduced after surgery. Severe CPSP and a neuropathic pain component decreased psychological and functional wellbeing as well as quality of life. No overarching CPSP risk factors were identified. CONCLUSION Unfortunately, our findings do not offer a new CPSP predictive score. However, we present reliable new data on the incidence, characteristics, and consequences of CPSP from a large European survey. Interesting new data on the time course of CPSP, its neuropathic pain component, and CPSP after endometriosis surgery generate new hypotheses but need to be confirmed by further research. TRIAL REGISTRATION clinicaltrials.gov ID: NCT03834922

Background: Propofol is a widely used intravenous hypnotic. Dosing is based mostly on weight, with great interindividual variation in consumption. Suggested factors affecting propofol requirements include age, sex, ethnicity, anxiety, alcohol consumption, smoking, and concomitant valproate use. Genetic factors have not been widely explored. Methods: This study considered 1,000 women undergoing breast cancer surgery under propofol and remifentanil anesthesia. Depth of anesthesia was monitored with State Entropy (GE Healthcare, Finland). Propofol requirements during surgery were recorded. DNA from blood was genotyped with a genome-wide array. A multivariable linear regression model was used to assess the relevance of clinical variables and select those to be used as covariates in a genome-wide association study. Imputed genotype data were used to explore selected loci further. In silico functional annotation was used to explore possible consequences of the discovered genetic variants. Additionally, previously reported genetic associations from candidate gene studies were tested. Results: Body mass index, smoking status, alcohol use, remifentanil dose (ln[mg kg(-1) min(-1)]), and average State Entropy during surgery remained statistically significant in the multivariable model. Two loci reached genome-wide significance (P < 5 x 10(-8)). The most significant associations were for single-nucleotide polymorphisms rs997989 (30 kb from ROBO3), likely affecting expression of another nearby gene, FEZ1, and rs9518419, close to NALCN (sodium leak channel); rs10512538 near KCNJ2 encoding the K(ir)2.1 potassium channel showed suggestive association (P = 4.7 x 10(-7)). None of these single-nucleotide polymorphisms are coding variants but possibly affect the regulation of nearby genes. None of the single-nucleotide polymorphisms previously reported as affecting propofol pharmacokinetics or pharmacodynamics showed association in the data. Conclusions: In this first genome-wide association study exploring propofol requirements, This study discovered novel genetic associations suggesting new biologically relevant pathways for propofol and general anesthesia. The roles of the gene products of ROBO3/FEZ1, NALCN, and KCNJ2 in propofol anesthesia warrant further studies.

First-line pharmacotherapy for peripheral neuropathic pain (NP) of diverse pathophysiology consists of antidepressants and gabapentinoids, but only a minority achieve sufficient analgesia with these drugs. Opioids are considered third-line analgesics in NP due to potential severe and unpredictable adverse effects in long-term use. Also, opioid tolerance and NP may have shared mechanisms, raising further concerns about opioid use in NP. We set out to further elucidate possible shared and separate mechanisms after chronic morphine treatment and oxaliplatin-induced and diabetic polyneuropathies, and to identify potential diagnostic markers and therapeutic targets. We analysed thermal nociceptive behaviour, the transcriptome of dorsal root ganglia (DRG) and the metabolome of cerebrospinal fluid (CSF) in these three conditions, in rats. Several genes were differentially expressed, most following oxaliplatin and least after chronic morphine treatment, compared with saline-treated rats. A few genes were differentially expressed in the DRGs in all three models (e.g. Csf3r and Fkbp5). Some, e.g. Alox15 and Slc12a5, were differentially expressed in both diabetic and oxaliplatin models. Other differentially expressed genes were associated with nociception, inflammation, and glial cells. The CSF metabolome was most significantly affected in the diabetic rats. Interestingly, we saw changes in nicotinamide metabolism, which has been associated with opioid addiction and withdrawal, in the CSF of morphine-tolerant rats. Our results offer new hypotheses for the pathophysiology and treatment of NP and opioid tolerance. In particular, the role of nicotinamide metabolism in opioid addiction deserves further study.