Access to pain management is a fundamental human right for all people, including those who are at the end of life (EOL). In end-stage patients, severe and uncontrolled pain is a common cause of admission to the emergency department (ED), and its treatment is challenging due to its complex, often multifactorial genesis. The aim of this narrative review was to identify the available literature on the management of severe EOL pain in the ED. The MEDLINE, SCOPUS, EMBASE, and CENTRAL databases were searched from inception to 1 April 2023 including randomised controlled trials, observational studies, systemic or narrative reviews, case reports, and guidelines on the management of EOL pain in the ED. A total of 532 articles were identified, and 9 articles were included . Included studies were heterogeneous on the scales used and recommended for pain assessment and the recommended treatments. No study provided evidence for a better approach for EOL patients with pain in the ED. We provide a narrative summary of the findings and a review of the management of EOL pain in clinical practice, including (i) the identification of the EOL patients and unmet palliative care needs, (ii) a multidimensional, patient-centred assessment of the type and severity of pain, (iii) a multidisciplinary approach to the management of end-of-life pain, including an overview of non-pharmacological and pharmacological techniques; and (iv) the management of special situations, including rapid acute deterioration of chronic pain, breakthrough pain, and sedative palliation. Pain is a common symptom at the end of life and can manifest itself in both acute and chronic forms. In particular, severe pain at the end of life is common, with a high prevalence two years before death and a marked increase in the last four months . HagartyRegardless of the clinical setting or cause, the management of severe pain is a highly complex problem. According to the revised 2020 definition of the International Association for the Study of Pain, pain is “an unpleasant sensory and emotional experience associated with or resembling that associated with actual or potential tissue damage” . ChronicEnd-stage patients are often admitted to the emergency department because of severe, uncontrolled pain. Admission to the ED often occurs when symptoms are unbearable and cannot be adequately treated at home to intensify palliative care ,21. NeveThe aim of this manuscript was to (i) identify the available literature on the management of severe EOL pain in the emergency department (ED) and (ii) provide a clinical review on the identification of patients worthy of palliative care and on the multidimensional approach to the identification and management of pain in EOL patients in the ED, taking into account the available literature and the experience of the SedoAnalgesia Group (SAU) of the Società Italiana di Medicina d’Emergenza-Urgenza (SIMEU).This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2021 version and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines  24]. No. No24]. Randomised clinical trials (RCTs), prospective or retrospective observational studies, case reports, surveys, systematic reviews, narrative reviews, guidelines and position papers on pain management  in terminally ill patients over 18 years of age in the emergency department were included. Studies on topics other than pain management in EOL patients in the ED, studies conducted outside the ED, unavailable full-text studies, duplicate studies, studies not in English, and studies on populations other than humans were excluded.A comprehensive review was conducted by 20 March 2023. The databases MEDLINE, SCOPUS, EMBASE and “Cochrane Central Register of Controlled Trials” (CENTRAL) were searched. The search strategy of each database was modelled using the following medical subject headings (MeSH) and Boolean operators: “emergency department” AND  AND . Two independent reviewers (SS and SMD) assessed relevant manuscripts from each database for possible inclusion. Disagreements about eligibility were resolved by a third reviewer (FDI). The full texts were reviewed by two reviewers (MG and AR), and discrepancies were resolved with the help of a third author (AF).The following information has been extracted (if applicable): author, publication year, manuscript type, primary outcome or purpose of the study, population, sample size, age of included patients, pain scale used, analgesics assessed with dosage, and author’s conclusion.Data were presented with an overview of the number, type, and distribution of included studies, which was followed by a narrative synthesis and presentation of results. A corresponding table with a synthesis of the results is provided, and each study is briefly discussed. No quantitative data meta-analysis was conducted.Due to the varying and inconsistent definitions of terms in the literature, this review employs the terms outlined in the 2015 Australian Commission on Safety and Quality in Health Care National Consensus Statement :Actively dying: the hours, days, and sometimes weeks preceding a patient’s death. This is occasionally called the “terminal phase”.End-of-life: The period during which a patient is suffering from a terminal illness, even if the illness’s prognosis is uncertain or unknown. This includes people with (i) advanced, progressive, incurable conditions; (ii) general frailty and concomitant conditions that make death within 12 months likely; (iii) pre-existing conditions that put them at risk of dying from a sudden acute crisis in their condition; and (iv) life-threatening acute conditions caused by sudden catastrophic events. End-of-life care: consists of physical, mental, and psychosocial evaluations, care, and treatment administered by medical professionals and support staff. It also includes support for families and carers as well as care for the deceased patient’s body. Palliative care: a treatment approach that enhances the quality of life for patients and their families facing a life-limiting illness by preventing and alleviating suffering. This includes the early detection, accurate evaluation, and treatment of pain and other  problems. The terminal phase: the hours, days, and sometimes weeks preceding a patient’s death. This is sometimes referred to as the patient’s “actively dying” state.The World Health Organisation defines palliative care as “an essential component of person-centred, integrated health services”. Alleviating severe health-related physical, psychological, social and spiritual suffering is a global ethical responsibility. For patients with cardiovascular disease, cancer, severe organ failure, drug-resistant tuberculosis, severe burns, end-stage chronic disease, acute trauma, extreme prematurity or extreme frailty in old age, palliative care may be required and must be available at all levels of care . Often, The pain terms and definitions adopted in this narrative review are according to the International Association for the Study of Pain, and they are reported in A total of 532 articles were identified , and no article was excluded before screening. After reviewing the titles, abstracts and full texts, 212 articles were excluded because they led to another topic, 310 were excluded because they addressed another topic about EOL in ED, 126 were excluded because they addressed another topic about EOL patients outside ED, 12 were excluded because the full text was not available, 8 were excluded because they were not in English, and no article was excluded because it was not conducted in humans. In total, 19 articles were eligible for inclusion, and after removing duplicates, 9 articles were included , three Four studies recommended the use of the numerical rating scale, the Wong–Baker FACES scale, the verbal rating scale, or the Pain Assessment in Advanced Dementia scale, while four studies made no recommendation. Observational studies reported the following: one retrospective study reported the use of opioids in 70.2% of patients ; two stNone of the included studies reported data on the effectiveness of different pain assessment strategies or on the prevalence of different types of pain; none of the included studies reported a comparison of different treatments in terms of effectiveness and safety. Bell et al.  reportedDealing with terminally ill patients in the emergency department has become increasingly common. As mentioned earlier, such patients have complex needs, and it can be challenging to make a decision that is acceptable to both the patient and the caregivers. However, the 2005 “American College of Emergency Physicians policy statement on end-of-life care in the emergency department” states that emergency physicians should respect the dying patient’s need for care, comfort, and compassion; communicate promptly and appropriately with patients and their families about end-of-life care decisions; inquire about the patient’s goals of care; and respect the dying patient’s wishes, including those expressed in living wills, whenever possible . AccordiPalliative or end-of-life care may be necessary for ED patients in two circumstances: (i) following a likely fatal event  and (ii) in advanced chronic illness with progressive symptom burden and an unmet need for palliative care. In both cases, patients and their families may not be aware that they are dying. Several screening tools have been developed to identify patients in the emergency department who are eligible for palliative care consultation , which iDue to poorly controlled symptoms or conflicts between the patient (who may refuse life-prolonging measures) and carers (who insist on life-prolonging measures), terminal patients are occasionally referred to the emergency department. In addition, referral to ED may indicate that the patient or family is anxious and unable to cope with the distressing symptoms of impending death. According to Reeves , when a Pain assessment is critical to pain management and should include information about the location, quality, intensity, onset, duration, and frequency of pain as well as factors that relieve or exacerbate pain. Cancer-related pain should be classified according to the ICD-11 taxonomy and the intensity and impact of pain on quality of life determined . The disHowever, chronic pain often affects patients at the end of life, so a multidimensional assessment may be more appropriate. The Brief Pain Inventory (BPI)  measures−Setting: creating time, space, and resources for appropriate, uninterrupted communication with patients and their families.−Perception: asking first about illness awareness and severity.−Invitation: ensuring that the patient or family members are ready to discuss palliative or end-of-life care.−Knowledge: ensure that the patient or family members are aware of the disease context in which the pathology manifests.−Emotion: address emotions empathically; use the mnemonic NURSE   to promote well-being or other aspects related to well-being such as stress, fatigue, anxiety, and depression can be beneficial in palliative care  and evenThe three-step WHO pain ladder is a benchmark for the selection of pharmacological agents for pain treatment . This stSee Interventional pain management may be an option for patients with severe, persistent pain who do not respond to other pharmacological treatments. However, it should be integrated into a multidisciplinary approach to pain management and not just considered as a last resort . InterveOpioids are increasingly used to treat chronic pain in terminally ill patients. Patients currently receiving opioids should be assessed for the amount of opioids they were taking daily before the onset of the new pain, and appropriate doses of opioids should be prescribed to treat the baseline pain in combination with short-acting opioids to treat the new severe pain. Equianalgesia refers to the amount of different opioid formulations and/or different routes of administration that achieve the same analgesic effect , while opioid titration refers to the individual adjustment of the drug dose . There aDavies et al.  define bOpioid-induced hyperalgesia is characterised by increased pain sensitivity despite a higher opioid dose, which is often accompanied by a diffuse extension of the pain site and allodynia. It can occur at any dose but is more pronounced at higher parenteral doses of morphine and hydromorphone. The initial treatment consists of reducing or eliminating the current opioid dose or switching to an opioid with less neurotoxic effects, such as fentanyl, and maximising non-opioid adjuvants when indicated. The use of low-dose ketamine for pain relief may have a role in the management of this issue in the ED .Although pain symptoms in EOL patients often respond to pharmacological and/or non-pharmacological interventions, there may be cases where treatment is extremely difficult, impossible, or ineffective. This is the case with so-called refractory symptoms because (i) the treatment does not respond, (ii) the analgesic effect is too long in coming, or (iii) the patient cannot tolerate the side effects ,120,121.For the purposes of this review, all studies were considered that addressed pain management in terminally ill, EOL, palliative or hospice patients admitted to the emergency department. However, some limitations due to the inclusion criteria need to be discussed. First, despite the broad inclusion criteria, only a few observational studies were included, and more rigorous, high-quality studies are needed to investigate the efficacy and safety of actual pain management in this specific category of patients. Second, the included studies were based on data obtained in settings other than the emergency department, so data on effectiveness in this specific setting may vary. Third, the included studies were on adult patients, while no data were available for the paediatric population. Fourth, because of the heterogeneity and small number of studies, it was not possible to conduct a meta-analysis and make a definitive statement about the best method to ensure effective pain management. Fifth, studies, guidelines and recommendations from societies that were not in English were excluded, which could potentially alter the conclusions of this review.Pain management is a fundamental component of patient care at every stage of life, regardless of the causes of pain, concomitant diseases, state of consciousness, and life expectancy. Although pain is a leading cause of admission to the emergency department, oligoanalgesia is a common, deeply inexcusable phenomenon that should be vigorously addressed through research, the education of healthcare professionals, and the establishment of appropriate treatment pathways. Emergency departments are often crowded, chaotic environments with a mismatch between medical staff and patients admitted with unique organisational and therapeutic resources. Despite intensive research in palliative care on the management of end-of-life symptoms, there is limited data on how to better manage palliative care patients and terminally ill patients admitted to the emergency department with severe pain. The identification of patients eligible for palliative and hospice care, the identification of unmet needs for palliative care, patient-centred multidimensional pain assessment, and a multidisciplinary approach are critical steps in the care of patients in the ED. Further research is needed in these areas to provide the best evidence-based supportive therapy. Although strong opioids remain the cornerstone of treatment for severe pain, ‘total pain’ has multiple components, and appropriate treatment should be carefully selected for the specific type of pain, including non-pharmacological and pharmacological pain management and sedative palliation.


Chronic pain alters the experience of owning a body and leads to disturbances in bodily perception. We tested whether women with fibromyalgia (FM) are receptive to bodily illusions of owning a visible and progressively invisible body in immersive virtual reality (VR), and what modulates this experience. Twenty patients participated in two experimental sessions; each session included two conditions in a counterbalanced order. We found that patients with FM could indeed experience virtual embodiment. Sentiment analysis revealed significantly more positive reactions to the progressively invisible body, yet twice as many patients declared they preferred the illusion of a visible virtual body. A linear mixed model revealed that the strength of embodiment was positively associated with body perception disturbances and negatively associated with FM symptoms intensity. No effect of pain during the VR experience nor interoception awareness on embodiment was found. The results indicated that patients with FM are receptive to virtual bodily illusions and that the impact of the embodiment depends on affective reactions, the level of cognitive body distortions, and the intensity of symptoms. Importantly, there is a large variation among patients which should be considered in future VR-based interventions. In fibromyalgia (FM), the most common symptoms are a generalized chronic pain in muscles and fibrous connective tissue (ligaments and tendons) described as ‘pain of everything’, joint stiffness, and chronic fatigue. Patients tend to report multiple soft tissue ‘tender points’ that are especially painful2. While specific pain location might change from 1 day to another, pain and fatigue are felt over the whole body. Patients with FM have enhanced sensitivity to aversive and non-aversive stimuli which is linked to altered interoception3. Cognitive modulation of pain and interoceptive perception can be influenced by various factors including attention, beliefs, conditioning, expectations, mood, and the regulation of the emotional response to sensory events6.Pain is a bodily sensation that connects the neural correlates of pain perception and body representation. It is not only a distinct sensation but also a piece of information about our bodies8. Thus, the intensity of pain can, to a certain degree, be modulated through bodily sensations and their manipulation. For example, in patients with chronic low back pain, visual feedback of one’s low back reduces pain intensity compared with visual hand feedback or controls9. Chronic pain is associated with changes in sensorimotor processing, mostly evident in the form of motor deficits, sensory changes, and body representation distortions11. Brun et al.12 demonstrated a positive correlation between pain intensity and conflict-induced sensorimotor disturbances, with patients with FM and complex regional pain syndrome (CRPS) being more prone to report disturbances than patients with arthritis and healthy participants. Patients with FM often present with an unstable body schema (the representation of a body for action planning and control)13, negative attitudes toward their bodies, and increased vigilance to their bodily signals14. Altogether, the body-pain relationship in patients with FM is complicated and can be described as a paradox:5.[T]he intensification of fibromyalgia pain does in fact affect different aspects of body awareness: in particular, experienced body size, weight, and localization, as well as the experience of owning one’s own body. In addition, these disruptions in patient’s body awareness have as a result, a modification of the experience of pain, leading to the apparently paradoxical experience of being in pain while not feeling itThe perception of pain, its multisensory influences, non-aversive sensations arising from within the body, and the sense of body ownership are all closely related15, for example in the well-known rubber hand illusion, in which synchronous visuotactile stimulation leads to an illusion of ownership over a rubber arm16. Immersive VR has opened up further possibilities for inducing and experiencing body illusions17. In immersive VR technology, a computer-generated 3D audiovisual environment is experienced on a head-mounted display (HMD), replacing the user’s sensory inputs from the real world. In VR, a life-sized virtual body can be programmed to substitute the participant’s real body. Hence, when looking down towards themselves they will see a virtual body rather than their real one. Through real-time tracking the virtual body can be programmed to move synchronously and in correspondence with real body movements, and when an object is seen to touch the virtual body this touch can be felt on the real body (e.g. through vibrotactile stimulation). This setup typically gives rise to a sensation of ownership over the virtual body (termed embodiment). Embodiment consists of three subcomponents: the body ownership illusion (This is my body), agency (I control my body), and the sense of self-location (I am where my body is)18. It is still possible to experience an embodiment illusion when some of these conditions are modified, for example, when the user’s point of view is outside the body (e.g. in a third-person perspective)19 or the virtual body does not resemble one’s real body 20. The feeling of ownership over an external dummy or virtual body (or body part) has both physiological and behavioural consequences. For example, the vision of one’s own body can modulate pain perception21. Furthermore, seeing a virtual arm can significantly increase the thermal pain threshold, independently of attentional and stimulus adaptation processes23. When a subject observes the skin colour of their virtual arm dynamically changing, this can modulate pain sensitivity. In particular, a reddened arm significantly decreases the pain threshold compared with normal and bluish skin23.The sensation of ownership of our  body is, under physiological conditions, a stable experience that is critical for sensorimotor interactions with the environment. Despite such stability, it can be easily modified24 demonstrated that viewing one’s semi-transparent body may reduce the ownership over that body. Still, participants that did report stronger body ownership of a semi-transparent body had a lower pain threshold in this condition, an observation that was suggested to be related to the unpredictability of potential harmful stimuli.A key feature of VR is the possibility of inducing manipulations that are otherwise impossible, such as making the body (semi)transparent, what can modulate the threshold to pain. In a study on healthy participants, Martini et al.25. This suggests that body transparency may modulate pain under certain conditions, and such manipulations are increasingly being tested in pain research and treatment28.If owning a semi-transparent virtual body increased pain sensitivity (or decreased pain threshold), this would not seem a good strategy to treat chronic pain. However, the modulation of pain threshold that was observed in healthy subjects is not a good predictor of how such manipulations influence chronic pain. For example, making a virtual arm semi-transparent diminished pain ratings in patients with CRPS, but had no effect in patients with peripheral nerve injurydisembodiment5, as a result of the body in FM being painful and ‘problematic’. Here, our aim was to evaluate whether it is possible for patients with FM to experience being embodied in a virtual body and then disembodied by observing it progressively becoming invisible. In a second step, we investigated this potential dual role of progressive invisibility in lowering pain threshold (as demonstrated in the pain-free population) while decreasing pain intensity (as demonstrated in patients with CRPS). Since the population of patients with FM is characterized by high heterogeneity of both psychological and physiological characteristics29, we applied a mixed methods design which allowed for a deeper understanding of the unique experience.Some fibromyalgia patients report a disruption in their body perception, leading to The study was carried out in compliance with the Declaration of Helsinki  in addition to the Law 14/2007 of July 3 on Biomedical Research. The experimental protocol was approved by the Clinical Research Ethics Committee of the Hospital Clínic of Barcelona (HCB/2021/0501). Written informed consent was obtained from all patients before being included in the study.We carried out a within-group experiment with two conditions, the visible and progressively invisible bodies, presented in a counterbalanced order across two sessions. Repeated measures were used to control for the inference of the novelty effect of VR, the order of conditions, and daily fluctuations of symptoms.N = 15) calculated in g*Power 3.1 for a repeated-measures ANOVA (within factors), assuming effect size d = 0.4 and power 0.80.Twenty-one female patients with FM were recruited for the study. The sample size was established on the basis of the minimal sample size (N = 5) to secondary or high school (N = 8) to a university degree .The inclusion and exclusion criteria can be found in Supplementary Information (p.1). One patient withdrew from the study, due to the physical discomfort experienced in the first session, and thus 20 patients were included in the analyses. The mean age of the group was 43 (SD = 5) years , and the mean number of years lived with the diagnosis of FM was 9 (SD = 12). Two patients claiming that they had symptoms all their life, but the majority (12 patients) were diagnosed within the last 5 years. The group had diverse levels of education, from primary school . Finally, the VR scene was displayed  presented in a pseudo-randomized order .Participants were asked about their pain level (baseline) and responded by selecting a number from 0 to 100 on a visual analogue scale (15 s).The virtual room scene was displayed, and participants could see their virtual body sitting on the chair from the first-person perspective that moved in synchrony with their real body (15 s).Participants were asked to do simple movements (30 s) .Four cubes appeared in front of the participant, who was asked to touch them with their virtual hands. When touched, the object disappeared, the corresponding controller vibrated, and a short sound was played.visible body condition) (100 s);their normal virtual body (invisible body condition) ;how their body gradually becomes transparent  is a questionnaire developed to estimate the current health status of women with FM syndrome in clinical and research settings. The FIQ has been translated and validated into 14 different languages and has been used in hundreds of research articles as an outcome measure. A Spanish version of the latest, revised FIQ was validated in 2013 by Salgueiro et al.31. Individual scores range from 0 to 150.Interoceptive awareness was measured with the Multidimensional Assessment of Interoceptive Awareness (MAIA) scale, a self-report questionnaire evaluating various aspects of interoceptive awareness. There are eight subscales: Noticing, Not Distracting, Not Worrying, Attention Regulation, Emotional Awareness, Self-Regulation, Body Listening and Trusting. We used the 30-item Spanish adaptation of the scale33 in a slightly adapted version, where we replaced the word back with the word body 34:Please indicate the intensity of pain you are feeling right now. A value of 0 means "no pain", and a value of 100 means "the worst pain imaginable". Select the desired value using the joystick on the right controller and confirm by pressing the trigger.Pain was measured on a visual analogue scale ranging from 0 (no pain) to 100 (most intense pain imaginable), after each condition, participants responded out loud to one of the corresponding questions: What did you feel when you had a virtual body? and What did you feel when your body became transparent and disappeared? Answers to the open questions asked during the VR experience were recorded in audio form and then manually transcribed.During the VR experienceI felt that the virtual body I saw when I looked down was my own body (ownership).I felt that the movements of my virtual body were caused by my own movements (agency).To what extent were the sensations of your real body surprising and unexpected? (surprising reactions).Some measures were taken afterwards to shorten the time spent in HMD and reduce the overall difficulty of the experimental procedure. The illusion of virtual body ownership was measured after the virtual reality experience on three Likert scale questions, using a scale from 1 , to 7 (very much):Which of the two scenes did you prefer, which one did you like the most, and why?Open questions were asked to better understand the experience of patients and determine their preferred scenario.The Oculus Quest headset uses an OLED panel with a resolution of 1600 × 1440 per eye display. It has a refresh rate of 72 Hz and weighs 470 g, 6 degrees of freedom, and rotational and positional tracking. To track hand movements, we used the Oculus Quest controllers, which are comfortable and easy to use. Oculus Quest does not need a computer to run the applications and has a comfortable in-ear speaker system, which makes use of the system user-friendly.We used CleanBox CX1 to disinfect the system. It uses ultraviolet C light-emitting diodes to disinfect surfaces from viruses, bacteria, and fungi.35. The model assumptions were tested visually and formally with the Shapiro–Wilk test for normality and the White Lagrange multiplier test for heteroscedasticity.We adapted a mixed methods approach to analyse the answers to the open questions transcribed verbatim by running a sentiment analysis  and clustering the content of the answers into nine main themes related to affective and physiological states. A repeated-measures ANOVA was used to test the differences in sentiment between session and conditions. Differences in symptoms, interoception awareness, body perception disturbances, and embodiment between sessions were verified with the Friedman test. A random intercepts and random slopes mixed linear model was built to estimate the effect of ongoing pain, symptom intensity, interoceptive awareness, and body perception disturbances on embodiment (python statsmodels library)There were no differences between session 1 and 2 in any of the baseline questionnaire scores. Patients evaluated the intensity of their symptoms (FIQ-3) as medium to high  (Table p < 0.05), thus we applied non-parametric tests. In any case non-parametric tests are more conservative than parametric, in the sense that null hypothesis rejected by a parametric test might not be rejected by the equivalent appropriate non-parametric test. In both sessions, patients rated their overall embodiment  scale and the data points were not normally distributed . This group reported a wide range of embodiment scores , with a median of 4.3 (IQR = 3) in session 1 and 5 (IQR = 1.3) in session 2. The 25% of the group who chose the scene where their body became progressively invisible reported a high level of embodiment . Some patients did not respond (N = 3) or preferred both or none of the sessions equally  to neutral  to very positive . Looking at the complete answers, we noticed an important role for the meaning or interpretations patients gave to the virtual scenarios. For example, a few patients associated their disappearance with death, which resulted in overall negative affective reactions. Others, who had a more neutral or no interpretation, reacted in a neutral or even positive manner. Many patients had various physical reactions, from dizziness to a weightlessness, from increased pain to no pain. Four patients said they felt nothing and four did not respond at all Table .Table 2CF = 5.21, p = 0.037, eta squared = 0.258), with the invisible body evoking more positive reactions  than the visible one . There were no differences between sessions. However, the most positive sentiment was recorded among patients who indicated that visible body conditions were preferred  to 1 (very positive). The mean sentiment was rather negative . Furthermore, repeated measures ANOVA yielded significant differences between bodily illusions  so that they had M = 0 and SD = 137. Next, we fitted a random intercept and random slope model for session, with observations clustered in individuals and fixed (session) and random  factors. The model formula included the embodiment as a dependent variable, and the mean pain in VR, FBAQ, FIQ, MAIA, and session as factors. (model = "emb_z ~ pain_mz + fbaq_z + fiq_z + maia_z + C(session)", re_formula = "C(session)").To test the influence of measured variables on embodiment, we built a mixed effects model using the mixedlm in python statsmodels library, following Harrison et al.W = 0.952, p = 0.087) and the White’s Lagrange multiplier test for heteroscedasticity  were not significant.Both visual analysis and formal statistical tests confirmed that the assumptions were not violated. In particular, the Shapiro–Wilk test for normality of the residuals , which measures the similarity of the responses within a random effect Table . In our We found significant random effects of fbaq_z and fiq_z, indicating that more body perception disturbances led to higher embodiment levels, while more intensive FM symptoms (reported for the last 7 days) had the opposite effect Fig. . Neither38 and calculated the marginal and conditional R2GLMM, which allows separation of the contributions of fixed and random effects. In our model, the marginal R2GLMM = 18.86% of the variance explained by fixed factors and the conditional R2GLMM = 67.84%, which can be interpreted as the variance explained by the entire model (both fixed and random factors).To obtain the explained variance, we followed the approach proposed by Nakagawa and Schielzeth39, may be involved in modulation of these reactions. Many patients described their state as anxious or strange, while others felt relaxed. A wide range of bodily sensations was also mentioned, including changes in weight, such as a feeling of weightlessness or floating, in contrast to the commonly experienced feeling of heaviness or swelling40. Although the progressively invisible body illusion evoked more positive sentiment, it was not reflected in behaviour, operationalized here as the preference of one of the illusions, as patients more frequently chose the visible body condition.FM is an intriguing and still rather poorly understood chronic pain condition. In this study, we explored the experience of owning a body and observing it become progressively invisible in women with FM. We found that patients with FM can experience embodiment illusions in immersive VR in both visible and invisible conditions, and in spite of their chronic pain. We also observed that these experiences led to diverse reactions on both affective and physiological levels and that cognitions, and perhaps also metacognitions41 distinguished two forms of disturbed body awareness in the context of schizophrenia, namely disembodiment and hyper-embodiment. The first is experienced as a disconnection with one’s body  and the latter refers to the experience of being totally immersed in it, a feeling of the physiological experiences being “too real”, which can be both pleasant and painful, depending on the context. Such hyper-embodiment is a daily experience of patients with FM, as their bodies are often felt to be an unavoidable obstacle, rigid and heavy42. In our study, the progressive invisibility triggered in several participants a feeling of weightlessness and relief. We speculate that in these patients the constant experience of hyper-embodiment was broken or transformed into a pleasant feeling of virtual disembodiment (“no body” ownership). Nonetheless, for other participants the experience was rather unpleasant and attracted their attention towards their symptoms, perhaps due to the multisensory conflict caused by the absence of visual cues (invisible body) during ongoing proprioceptive and painful stimulation.Fuchs and Schlimme5 hypothesized that disruption of implicit knowledge of the topography of patients’ bodies leads to a paradoxical feeling of being in pain while not feeling it. A disturbed body image is a signal of a desynchronization of brain and body, which is one of the main characteristics of FM43. We speculate that body distortions are a form of plasticity in body representation, and thus some patients with FM may be more prone to incorporate virtual bodies, which is also a form of plasticity44. Importantly, FM not only affects interoception, but also exteroception, and reduces the tendency to actively listen to the body for insight45. We suggest that disturbances in body awareness might lead to increased sensitivity to external cues such as strong visual stimulation in VR. However, more studies are required to validate this preliminary result.The most important result was that higher levels of body perception disturbance predicted a higher embodiment. While the cause of this is not known, we can speculate. Valenzuela-Moguillansky27. However, whether very intense or acute pain prevents virtual embodiment, deserves further investigation.Interestingly, while stronger fibromyalgia symptoms (including pain) in the prior week decreased embodiment, the pain ratings reported during the virtual experience had no effect on the embodiment. This suggests that ongoing musculoskeletal pain can be partially overridden by strong synchronous visuomotor and visuotactile stimulation, confirming that chronic pain does not completely prevent embodimentWe observed a large variation between participants and sessions. The patients who reported higher embodiment in the first session rated the strength of the illusion as lower in the second session. We speculate that in the first session, some participants were surprised or baffled with the illusion, but the novelty effect had worn off in the second exposure.An important contribution of this study is a demonstration of usefulness of the mixed methods in chronic pain research, obtained here by combining sentiment analysis with a quantitative and qualitative text analysis and multilevel modelling. The collected data helped us to improve our understanding of the bodily experiences among patients with FM and added context to the large variability of variance observed in the questionnaires.28. For the same reasons, we only measured overall pain, without specifying the location or type of pain. Future studies dedicated to embodiment and pain modulation should apply a standardized scale, such as the one proposed by Gonzalez-Franco & Peck46 and the short form of the Brief Pain Inventory47. We also take note of the weak effects obtained in the mixed linear model. Although the sample was sufficient to obtain a converged model with satisfactory parameters, a larger sample is recommended in future studies.The study had several limitations. We chose to keep the duration of the procedure as short as possible to minimize fatigue and discomfort of the patients48), a greater similarity of the avatar to the subject may be important in the case of chronic pain patients who are less sensitive to virtual embodiment. Thus, future studies should investigate the role of look-alike avatars in embodiment among patients with FM.Four patients reported that they did not feel embodied because the virtual avatar did not look like them. Although the embodiment illusion is normally triggered automatically at a low level if the basic conditions are accomplished (namely a first-person perspective, human-shaped body, congruent visuomotor/visuotactile cues29, it is unclear whether these profiles can explain the differences observed in experiencing virtual embodiment. Another interesting research path which has not received much attention until now is the role of cognition and metacognition in embodiment among both clinical and healthy populations, especially in scenarios which offer limited context and broad space for interpretation. Moreover, in future more attention should be paid to the rich affective reactions patients present during the virtual experience. In general, virtual embodiment is a promising tool for diagnosing and treating some of the least understood symptoms of FM related to the bodily self and its disturbances which have a severe impact on patients’ quality of life.Future studies should also investigate the sources of variability among patients with FM in the context of body perception and embodiment to identify potential subgroups of patients who may be more sensitive to specific types of virtual bodily illusion. Although several subtypes of patients have already been identifiedWomen with fibromyalgia are characterized by a large intra- and interpersonal variety which leads to diverse affective reactions to the same bodily illusion in virtual reality. Fibromyalgia symptoms intensity may negatively affect the proneness to virtual embodiment. Paradoxically, more disturbed body perception may strengthen the embodiment illusion. Moreover, pain reported during the virtual experience as well as interoception awareness did not affect the strength of virtual body illusions.Supplementary Information.


Pre-hospital pain management has traditionally been performed with intravenous (IV) morphine, but oligoanalgesia remain a recognized problem. Pain reduction is essential for patient satisfaction and is regarded as a measure of successful treatment. We aim to establish whether non-invasive methods such as inhalation of methoxyflurane is non-inferior to intranasal fentanyl or non-inferior to the well-known IV morphine in the pre-hospital treatment of acute pain.The PreMeFen study is a phase three, three-armed, randomized, controlled, non-inferiority trial to compare three regimens of analgesics: inhalation of methoxyflurane and intranasal (IN) fentanyl versus IV morphine. It is an open-label trial with a 1:1:1 randomization to the three treatment groups. The primary endpoint is the change in pain numeric rating scale (NRS) (0–10) from baseline to 10 min after start of investigational medicinal product administration (IMP). The non-inferiority margin was set to 1.3, and a sample size of 270 patients per protocol (90 in each treatment arm) will detect this difference with 90% power.We chose a study design with comparison of analgesic regimens rather than fixed doses because of the substantial differences in drug characteristics and for the results to be relevant to inform policymakers in the pre-hospital setting. We recognize that easier administration of analgesics will lead to better pain management for many patients if the regimens are as good as the existing, and hence, we chose a non-inferiority design. The primary endpoint, the change in pain (NRS) after 10 min, is set to address the immediate need of pain reduction for patients with acute prehospital pain. On a later stage, more analgesic methods are often available.PreMeFen is a non-inferiority randomized controlled trial comparing three analgesic regimens aiming to establish whether inhalation of methoxyflurane or intranasal fentanyl is as good as IV morphine for fast reduction of acute pain in the prehospital setting.The online version contains supplementary material available at 10.1186/s13063-023-07590-9. Pre-hospital underuse of analgesics  remains a global health problem –4. BetweThe rationale of the PreMeFen-study is to provide evidence for earlier, safe, non-invasive pain management in the pre-hospital setting.Inhaled low-dose methoxyflurane is non-inferior to IN fentanyl orInhaled low-dose methoxyflurane is non-inferior to IV morphine orIN fentanyl is non-inferior to IV morphineWe aim to investigate whether regimens of:in managing a variety of moderate to severe acute pain conditions in adult patients from 18 years of age administered by the EMS.Norway has a governmentally funded healthcare system aiming to provide equal access to healthcare regardless of geographical location and resource availability. The Ministry of Health and Care Services carries supervisory responsibility for all the public hospitals and is the owner of four regional health trusts . The ambWe applied the Norwegian Clinical Research Infrastructure Network (NorCRIN) templates  to desigThe study kit contains all three IMP, patient information letter, information letter to receiving hospital, and a sealed randomization envelope. Computer-generated block randomization with variable block sizes is provided by the department of clinical trial unit (CTU), Oslo University Hospital. All the sealed randomization envelopes were provided in one batch from the CTU, which also kept the code file secret and hidden from the study team. The sealed envelopes were further distributed into the study kits by the study team. Following routine clinical primary survey, the EMS providers screen for eligibility and ask for consent. The study kit remains sealed until the patient is included, and the consent form is signed by the EMS provider. Patients are then randomized 1:1:1 between the three treatment regimes, as shown in Fig. General blinding was considered unfeasible due to the complexity of study context, but the datasets is blinded for the statistician.EMCC does not pre-screen patients, making eligibility evaluation solely to be performed on-scene. Patients considered not eligible are treated according to local analgesic protocols. See Table The intervention is the administration of IMP with three different medication regimens of inhalational methoxyflurane, IN fentanyl, and IV morphine; see Table Administration of each of the 3 IMPs is based on pre-specified treatment regimens, including a flexible dosing of the analgesic and titration to effect, but only using the specific drug in the allocated treatment arm. Each regimen is defined with doses, dose intervals, and maximum doses  despite repeated doses, patients are treated with standard pain relief protocol. All analgesics other than the allocated IMP is referred to as rescue medication. Any need for rescue medication is noted with time and dose.In cases where rescue medication is administered before the primary endpoint assessment at 10 min, the patient will be excluded from the per-protocol analysis.NRS is a scale with integer values from 0 to 10 where 0 indicates no pain and 10 indicates unbearable pain. Patients indicate on a line with numbers ranging from 0 to 10 or verbally, what numbered value the pain correlates to, and the score is documented in the case report form (CRF).Primary endpoint is the change in NRS pain score measured prior to administration of IMP to 10 min after IMP administration; see Table mx is the mean reduction in NRS for treatment x and The primary hypotheses describe the comparisons of the primary endpoints for the three different analgesic regimens:Null hypothesis h01: methoxyflurane regimen is inferior to IN fentanyl regimen.Null hypothesis : methoxyflurane regimen is inferior to IV morphine regimen.Null hypothesis : IN fentanyl regimen is inferior to the IV morphine regimen.Alternative hypothesis : methoxyflurane regimen is non-inferior to IN fentanyl regimen.Alternative hypothesis : methoxyflurane regimen is non-inferior to IV morphine regimen.Alternative hypothesis t-test [n = 88 in each arm. That gives a total number of participants of 264, and the plan is to include 3 × 90 = 270 patients per protocol allowing for two dropouts in each group, in total six dropouts, of the per-protocol population without losing power for the calculations of the primary endpoint.The sample size with d t-test , 21, 22.d t-test , 19, 20.based on . Sample a. The test will be performed in the following order:The hypotheses in Eq.  will be Test : If part of the 95% confidence interval is below non-inferiority margin, we stop testing without any conclusion on efficacy. If the 95% confidence interval is above the non-inferiority margin, then we claim non-inferiority of methoxyflurane vs fentanyl and proceed with testing Test : If part of the 95% confidence interval is below the non-inferiority margin, we stop testing without any further conclusion on efficacy. If the 95% confidence interval is above the non-inferiority margin, then we claim non-inferiority of methoxyflurane vs morphine and proceed with testing Test : If part of the 95% confidence interval is below the non-inferiority margin, we stop testing without any further conclusion on efficacy. If the 95% confidence interval is above the non-inferiority margin, then we claim non-inferiority of fentanyl vs morphine.The statistical chain of testing and decisions will be:t-test on the per protocol population and confirmed, for sensitivity reasons, on the modified intention to treat population.The nominal significance level is set to 5%, and the non-inferiority margin is set to 1.3. Non-inferiority is determined based on a 1-sided equivalence We plan to compare the incidence of serious and non-serious adverse events between the groups using a chi-squared test or a Fisher exact test if necessary (expected frequency less than 5). We will summarize patient satisfaction and medical personnel view on practicality.t-tests (means), Mann–Whitney U (medians), and chi-square (proportions) tests. If there are any significant differences, linear regression will be performed to adjust for significantly different covariates. No interim analysis will be performed.Demographic and baseline information of the three study groups will be compared using Data are collected from ambulance records with study specific CRF, including hospital records and follow-up call to the patients 14 days after inclusion. In addition to IMP, the study kit contains a stopwatch and an EtCO2 nasal cannula. The investigators manually enter data into the electronic data capture software Viedoc . All study-related information will be securely stored at the study site.For non-inferiority calculation of the primary endpoint, missing data will be replaced using imputation. We will perform a linear regression adjustment for baseline pain.Due to the pre-hospital circumstances with patients in pain and a situation of urgency, some missing data are to be accepted. The principal investigator is responsible for deciding whether participants with missing data are evaluable. Missing data are to be recorded and reported to maintain transparency.A data monitoring plan is established and describes regular reviews of the CRFs for accuracy and completeness. According to the data management process, a specific data handling report will be made after the closing of the database.An independent data monitoring committee (DMC) and safety board is established and governed by its charter. The DMC reviews recruitment, safety, protocol deviation, and adverse events with a session when half of the patients are included.In case of overdosage of IN fentanyl or IV morphine, standard treatment procedure will be initiated, including IN or intramuscular (IM) naloxone, physical stimulation to keep patient awake, and respiratory support as indicated. Because the participant administers the methoxyflurane themselves, overdose symptoms such as drowsiness will self-limit when the administration whistle is not actively held in the mouth and sealed with the lips. Nevertheless, an overdose of methoxyflurane will be treated according to protocols for patients with drug overdose.We established a study telephone number to use for patients who want to withdraw from study and for EMS providers to report serious adverse events (SAE). Study kit management with control and return of IMP is administrated by the study group.A mandatory 8-h training program is required to qualify as certified study personnel. The training consists of three parts: a practical simulation, a theory part, and a workshop with the study group.EMS provider will continuously describe any adverse events (AE) in the CRF. The monitoring of vital signs will detect clinical adverse events in addition to general questions and physical examination usual to the pre-hospital treatment situation. AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) system by investigator. For each participant, the standard time for collecting and recording AE and serious adverse event (SAE) will be from first IMP dose until end of intervention. EMS providers must report SAE to the principal investigator (PI) within 24 h. If the SAE is considered to be a suspected unexpected serious adverse reaction (SUSAR), a report will be sent to the Norwegian Medicines Agency within a maximum of 7 days for fatal or life-threatening SUSARS and within maximum 15 days for other SUSARS from first knowledge of sponsor. The EMS provider can use a dedicated telephone number to contact a member of the study working group if they have any questions or concern about an AE or possible SAE.The study rationale is to provide evidence for early, safe, and effective pain management in EMS with non-invasive and fast-acting analgesics.Cmax, and Tmax are different for all three IMPs. Furthermore, clinical needs and pain characteristics are heterogenous with individual needs for titration and redosing that cannot be foreseen and hence should be tailored with redosing within the allocated regimen. Finally, comparison of regimens will address the clinical setting where the interesting objective is to find whether the regimens of non-invasive methods are non-inferior to the existing IV morphine procedure. This will make the results relevant for decision-makers when implementing new procedures in pre-hospital pain management.We aim to compare regimens rather than a fixed dose of the medicaments. With regimen we mean a flexible dosing of the allocated analgesic by titrating to effect, but only administer the allocated IMP. There are several reasons for comparing regimens rather than a fixed dose. Firstly, the route of administration differs to a large extent, with the inhalation of methoxyflurane being continuous depending on the patient needs, versus bolus dosing of the others. In addition, pharmacokinetics with bioavailability, Our choice of a non-inferiority trial design is based on the expectation that IN fentanyl and inhalation of low-dose methoxyflurane are as good as (non-inferior to) IV morphine and that the first two will contribute to an earlier and more practical administration of the analgesics in the pre-hospital setting. Furthermore, it is of great interest to establish whether the self-administrated inhalation of methoxyflurane is as good as IN fentanyl, because it would ease the pain management in many acute pre-hospital settings.Guideline on the clinical development of medical products intended for the treatment of pain state that pain self-assessment is the most valid measure of pain assessment [The rationale for selecting the primary endpoint is based on valid outcome measures gained from previous research , 24–26. sessment . Studiessessment , 30. TheThe non-blinding aspect is a limitation of the study and carries a risk that administration method can influence the patients or EMS providers preferences. Methoxyflurane has a distinct odor, and the routes of administration are entirely different in the three arms and impossible to blind without dummies. The only way to double-blind the study would be to provide a triple-dummy procedure, which is considered too complex and not feasible in this study context. On the contrary, the administration method can itself be considered part of the treatment; for example, the self-administering of methoxyflurane can give the patient a feeling of control with a positive impact on the pain treatment. Our open-label design without dummies will include these aspects in the results and can represent real life to a more significant extent.In spite that self-assessment of pain is considered as the most valid pain-assessment for this kind of studies, NRS is a one-dimensional scale and does not describe the whole perspective of pain , 31.To avoid inflating the significant level for the overall test, we chose a statistical plan to test the hypotheses by using fixed-sequence procedures. If the study fails to prove a non-inferiority in the first test (methoxyflurane to fentanyl), this will terminate the subsequent tests comparing methoxyflurane to morphine and fentanyl to morphine. The subsequent tests could in that case only be performed as exploratory tests with less impact.PreMeFen is a non-inferiority randomized controlled study comparing three analgesic regimens aiming to establish whether inhalation of methoxyflurane or IN fentanyl is as good as IV morphine for fast reduction of pain in the prehospital setting.This article is based on protocol 3.0, dated 2 September 2021. The Study is ongoing, and patient recruitment started on 12 November 2021. We estimate an 18-month recruitment period; the estimated date for completed recruitment is April 2023.The results of the study will be published in per-reviewed medical journals.Additional file 1. SPIRIT Checklist.


In our article ?Methadone switching for refractory cancer pain’  we explore the efficacy, safety and economics of methadone in treatment of patients with refractory cancer pain in China. Professor Mercadante provided a better interpretation of data regarding the opioid switching to methadone in the Matters Arising. In this article, we answered the questions in Mercadante et al.’s comments one by one. We have read with interest the “Matters Arising” text of Professor Mercadante, in which he comments on some parts of our recent paper entitle “Methadone switching for refractory cancer pain” . As he iFirst, Professor Mercadante wondered if patients were uncontrolled pain given the fact that the median pain score was 4/10. It is well known that the frequency of breakthrough pain (BTP) requiring supplemental doses is as important as pain score in pain evaluation . “poor pSecond, as Professor Mercadante interprets, it is difficult to understand why some patients were assigned to 3-day switch (3DS) or stop and go (SAG) attributed to the design of retrospective study. And the modality of switching to methadone in our study reflects the practice of the local institution. We accept the limitation in incomprehensibile choice of SAG or 3DS in our study. However, it is imperative to conduct practice or exploration and report the results on methadone treatment in Chinese patients with cancer pain. Subjected to law and drug production restrictions, the exploration of methadone in treatment of patients with refractory cancer pain have just begun in China in recent years.We started to use methadone to treat refractory cancer pain in 2016. In the course of exploration, we have tried both SAG and 3DS strategy. The SAG strategy has gained popularity for the obvious pharmacokinetic advantages . Our cliFinally, Mercadante S. suggested that the design and results of the randomized controlled study quoted in our study have some limitations , 12. TheThere is currently no consensus on recommendation for the most effective and safest method for switching to methadone from other opioids. McLean S. et al. reviewed the available evidence regarding methods of rotation to methadone . Twenty-We agree that there is no reason to maintain a drug in patients with high doses of opioid experiencing poor pain control. However, the treatment level varies greatly between countries or regions. Many cancer pain patients were prescribed high dose opioids (above 300 mg OME/day) and the doses might even be increased to > 1000 mg OME/day in China. Switching to methadone may be an effective strategy for these patients with uncontrolled pain. 3DS is based on the concerns about safety of switching to methadone. It showed better tolerance especially in patients prescribed with high doses of other opioids.In our center, SAG was also adopted for patients with high dose of OME. However, according to the NCCN guideline for cancer pain , the recAccording to the published literature and our local practice, we still can not conclude which switching method for methadone is more superior. Therefore, a rigorously designed randomized controlled study may be helpful in determining the optimal rotation method for specific patients and guiding future clinical practice.


Head (39.0%) accounted for the highest proportion of overall pain locations in subjects with OSA, with 28.8% of OSA patients experiencing headaches. Pain in OSA was associated with impaired HRQoL and psychological problems. Patients with very severe OSA had an increased risk for pain problems . Associated factors for pain intensity in OSA included age, ESS ≥ 9.0, and lowest pulse oximetry (LSpO2) < 80.0%. Pain intensity in OSA decreased significantly after CPAP treatment (p < 0.001). Pain was prevalent among patients with moderate-to-severe OSA and was associated with depression, anxiety, and a lower HRQoL. Patients with very severe OSA had an increased risk for pain problems. The intensity of pain in OSA can be predicted by age, ESS ≥ 9.0, and LSpO2 < 80.0%, and it can be alleviated through CPAP treatment.Pain problems are common in patients with obstructive sleep apnea (OSA), but few studies have thoroughly evaluated pain in these patients. The objective of this study was to examine the prevalence and characteristics of pain in moderate-to-severe OSA patients and the effect of continuous positive airway pressure (CPAP) treatment. Moderate-to-severe OSA patients and healthy controls (HC) completed the Short Form McGill Pain Questionnaire (SF-MPQ) and a portion of the Brief Pain Inventory (BPI) Short Form to assess pain characteristics. The Epworth Sleepiness Scale (ESS), the Short Form-36 (SF-36), and the Hospital Anxiety and Depression Scale (HADS) were used to measure daytime sleepiness, health-related quality of life (HRQoL), and psychological status, respectively. The OSA patients with pain were divided into a CPAP-treated group and a CPAP-untreated group based on their adherence to CPAP. The subjects' pain intensity was reassessed after 3 months. The prevalence of pain was 57.5% in OSA versus 27.1% in HC ( Moreover, OSA has been associated with various health complications, such as diabetes, hypertension, and cardiovascular disorders2.Obstructive sleep apnea (OSA) is a prevalent condition characterized by complete or partial upper airway obstruction during sleep, leading to fragmented sleep patterns and recurrent nocturnal hypoxia. Individuals with OSA commonly experience psychological difficulties, increased daytime sleepiness and fatigue, impaired concentration and memory, as well as other symptoms3. Numerous painful conditions such as headaches, temporomandibular disorders, and fibromyalgia are influenced by OSA and prone to development and exacerbation4. A recent study revealed that a significant number of patients with high-impact chronic pain, who were referred for specialized pain management also presented with OSA5. The influence of sleep deprivation and intermittent hypoxia has been combined to be the effects of OSA on pain, according to a theory6. Furthermore, OSA patients have also been reported to have greater odds of comorbid moderate and severe pain7. However, the prevalence and characteristics of pain in individuals with obstructive sleep apnea (OSA) remain inadequately understood, with limited studies comparing the experience of pain between OSA patients and healthy individuals. Furthermore, the association between significant clinical features of OSA, such as disrupted sleep structure, hypoxemia, microarousals, daytime drowsiness, and pain, has not been extensively investigated. Therefore, it is imperative to conduct a more detailed examination of the relationship between OSA and pain outcomes.OSA and pain exhibit a strong association8. Research has found that individuals with OSA frequently encounter psychological symptoms such as despair and anxiety in addition to the typical excessive daytime sleepiness9. Moreover, the literature has already reported on the effects of OSA on health-related quality of life (HRQoL)10. A recent study has highlighted the pervasive nature of pain among primary care patients, significantly impacting their overall quality of life8. However, it remains unknown how pain affects the health-related quality of life (HRQoL) and psychological well-being of individuals with obstructive sleep apnea (OSA). To date, no studies have investigated this aspect.Due to the intricate nature of pain, involving both psychological and physical elements, it is often associated with heightened emotional distress and a reduced quality of life11. Therefore, our study aimed to investigate the prevalence, intensity, and location of pain in patients with moderate-to-severe OSA, explore the physiological functioning, psychological symptoms, and quality of life in OSA patients experiencing pain, examine significant clinical features associated with worse pain outcomes in OSA patients, and evaluate the effects of CPAP treatment on pain outcomes among individuals with moderate-to-severe OSA.Continuous positive airway pressure (CPAP) treatment is a well-established therapeutic approach for obstructive sleep apnea (OSA), yet limited research has been conducted on its impact on pain relief11. The exclusion criteria were: (1) AHI (apnoea hypopnea index) < 15 (events/hour); (2) diagnosis of complication except for hypertension, hyperlipemia, hyperuricaemia, and hypercapnia; (3) severe chronic debilitating conditions or pregnancy; (4) concurrent use of painkillers; and (5) inability to complete questionnaires.Consecutive patients referred for suspected OSA at the Sleep Disorders Center of the Second Xiangya Hospital of Central South University were screened from September 2021 to September 2022. The OSA diagnosis was based on the International Classification of Sleep Disorders, third editionHealthy, age-matched control participants were recruited from the Health Management Center of the Second Xiangya Hospital of Central South University. Except for possible obesity, all control subjects had a normal physical examination and laboratory tests. Control subjects were excluded from the study if they (1) were diagnosed with any kind of sleep-disordered breathing through polysomnography; (2) had concurrent use of painkillers; or (3) were unable to complete questionnaires.11.All participants received diagnostic PSG . The monitoring was conducted at a specialized sleep center. Non-OSA, mild OSA, moderate OSA, and severe OSA were defined based on the Apnea–Hypopnea Index (AHI) as < 5, 5–15, 15–30, and ≥ 30 events per hour, respectively. Additionally, within the severe OSA category, a subgroup known as very severe OSA was defined with an AHI ≥ 60 events per hour12. The Short Form McGill Pain Questionnaire (SF-MPQ) was used to evaluate the pain intensity of subjects, which was divided into three parts: the Pain Rating Index (PRI), the Present Pain Intensity (PPI) index and the visual analogue scale (VAS). Based on pain intensity, the PPI is categorized into six levels: 0—no pain, 1—mild, 2—discomforting, 3—distressing, 4—horrible, and 5—unbearable. The three pain scores are derived from the sum of the intensity rank values of the words chosen for sensory, affective, and total descriptors, with a higher score indicating greater pain intensity14. The Brief Pain Inventory (BPI) was used by the subjects to locate the pain on the body chart15.Data on baseline medical history, anthropometric, polysomnographic parameters and common questionnaires were collected. For all of the participants, demographic details  were recorded. All participants completed the Epworth Sleepiness Scale (ESS) questionnaire, and excessive daytime sleepiness was defined as an ESS score ≥ 916. The Short Form-36 (SF-36) was used to evaluate HRQoL. The scores of the SF-36 test are separated into 8 categories , with lower scores indicating worse HRQoL17.The subjects with OSA also completed the following questionnaires: The Hospital Anxiety and Depression Scale (HADS) was used to measure the severity of anxiety and depression, with a higher score indicating greater anxiety or depressionThe OSA patients with pain were divided into a CPAP-treated group and a CPAP-untreated group based on their adherence to CPAP. Patients undergoing CPAP therapy were telephonically followed up on a weekly basis. The follow-up encompassed assessing patients’ adherence and tolerance to treatment, comfort levels while wearing the ventilator, discomfort experienced, and treatment efficacy in promptly addressing any issues encountered during the course of treatment. Participants adherent to CPAP were defined as those who received CPAP therapy for a minimum of 4 h per night on more than 70% of nights. CPAP compliance data, including device usage and hours of use per night at the prescribed pressure, were automatically recorded by the CPAP device and extracted using the appropriate software. Subsequently, after 3 months, the pain intensity of these participants was reassessed using the Short Form McGill Pain Questionnaire (SF-MPQ).p < 0.05 was considered significant.The statistical analysis was conducted using SPSS software . Descriptive data were presented as percentages. Normally distributed continuous variables were reported as mean values with standard deviations (SD), while non-normally distributed continuous variables were described as medians with interquartile ranges (IQR). Group comparisons for continuous measurements were performed using independent t-tests, Mann–Whitney U tests, paired t-tests or Wilcoxon rank-sum tests. Categorical data were analyzed using the Chi-Square test. A multivariate logistic regression analysis was carried out to identify risk factors for pain by including significant variables from the univariate analysis. The correlations analyses of pain intensity were examined using Spearman’s correlation. Multiple linear regression was employed to assess potential independent factors predicting the most significant factor influencing pain intensity in OSA patients. This study was approved by the Ethics Committee of the Second Xiangya Hospital of Central South University (2019-215). All methods were performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from all subjects.p < 0.001). The ESS scores, AHI (apnea hypopnea index), REM-AHI (apnea hypopnea index during rapid eye movement stage), NREM-AHI (apnea hypopnea index during non-rapid eye movement stage), LSpO2 (lowest pulse oximetry), MSpO2 (mean pulse oximetry), ODI (oxygen desaturation index), N3 period, sleep efficiency, and arousal index exhibited significant differences between the OSA group and HC group   (Table p < 0.001). The median pain rank index (PRI) score was 4.0 (2.0–5.8) in the OSA group versus 2.0 (1.0–2.0) in the HC group (p < 0.001). The median visual analogue scale (VAS) score was 4.0 (4.0–6.0) in the OSA group versus 2.0 (2.0–4.0) in the HC group (p = 0.011), while the present pain intensity (PPI) score and PPI rank did not show an obvious difference between the two groups  in the OSA group compared to 19 27.1%) in the healthy control group  in the OSA patients with or without pain. The patients with OSA and pain had higher Hospital Anxiety and Depression Scale (HADS) scores than the patients with OSA but without pain. The median HADS anxiety score was 6.0 (4.0–7.0) in OSA patients with pain versus 4.0 (2.3–4.8) in OSA patients without pain (p < 0.001), and the HADS depression score was 5.0 ± 2.4 in OSA patients with pain versus 3.4 ± 2.3 in OSA patients without pain (p = 0.017). From the different dimensions of HRQoL measured by the SF-36, HRQoL was significantly impaired in patients with OSA and pain, which was reflected in the SF total score (106.7 (95.6–124.2) in OSA patients with pain, 129.1 (124.5–133.8) in OSA patients without pain, p < 0.001) and performed in physical functioning (p = 0.014), bodily pain (p < 0.001), general health (p < 0.001), vitality (p = 0.01), social functioning (p = 0.01), role emotional (p = 0.008), mental health (p = 0.002), and health transition (p = 0.015).In the OSA group Table , the aveThe clinical characteristics of patients with obstructive sleep apnea (OSA) were analyzed, comparing those with and without headache. However, no significant variables, including demographics, hypercapnia, comorbidities, and sleep parameters, were found between OSA patients with and without headache Table .Table 3C18, BMI (divided line as 28.0 kg/m2), AHI (divided line as 60 events/hour), LSpO2 (divided line as 80%), arousal index (divided line as 30.0 events/hour), N3 period (divided line as 12.0%), REM period (divided line as 20.0%) and sleep efficiency (divided line as 80.0%)11. After adjusting for ESS and LSpO2, the results of logistic regression analysis revealed that an AHI ≥ 60 events/hour was a risk factor for pain in OSA patients .A multivariate logistic regression analysis was carried out to identify risk factors for pain by including significant variables from univariate analysis, which is presented in Table r = 0.511, p < 0.001), and a negative correlation with LSpO2 levels . Furthermore, the VAS score showed a positive correlation with ESS scores . Additionally, the PPI score demonstrated a negative correlation with LSpO2 levels  , while LSpO2 negatively predicted the PRI score in OSA patients . Regarding the VAS score, ESS positively predicted the VAS score . Therefore, age, ESS, and LSpO2 may be the predictors of the pain intensity in OSA.As is shown in Table p < 0.001), which remained statistically significant only among adherent patients receiving CPAP therapy.All OSA patients experiencing pain were followed up after three months, and the pain intensity in these patients was reassessed. Out of the total, 26 (56.5%) patients demonstrated adherence to CPAP treatment and were categorized as the CPAP-treated group, while 20 (43.5%) patients exhibited non-compliance with CPAP treatment and were classified as the CPAP-untreated group. Table 4. The comprehensive assessment of pain issues in patients with OSA and healthy controls is conducted for the first time in this study.Patients with obstructive sleep apnea (OSA) frequently experience pain-related issues. However, limited research has been conducted in this area. Recent studies have demonstrated that OSA can contribute to the development and exacerbation of various unpleasant conditions, such as headaches, temporomandibular disorders, and fibromyalgia19. The findings of our study demonstrate that pain manifested as a prevalent impairment among individuals with OSA, surpassing its occurrence in healthy controls. According to multivariate logistic regression analysis, we found that very severe OSA had an increased risk for pain problems. Very severe OSA is defined as an Apnea–Hypopnea Index (AHI) ≥ 60 events per hour, which typically exhibits more pronounced nocturnal hypoxemia and symptom burden. According to a research study, individuals with severe OSA reported significantly higher rates of drowsy driving and accidents caused by falling asleep20. Therefore, clinicians should prioritize the management of pain in individuals with very severe OSA.In a recent research, the prevalence of obstructive sleep apnea (OSA) was found to be 13.8% in a retrospective analysis conducted among patients attending a pain management clinic21, and treating OSA resulted in clinically significant improvements in over 30% of patients with undifferentiated headache22. In our study, the head was found to be the most prevalent location for pain in subjects with OSA, accounting for 39% of overall pain locations. Additionally, a significant proportion (28.8%) of patients diagnosed with OSA reported experiencing headaches, suggesting a high prevalence of headache among individuals with OSA. However, upon comparing the clinical characteristics of OSA patients with and without headache, we did not identify any specific factors associated with headache in OSA patients. As reported in the literature, the impact of OSA severity on the prevalence of sleep apnea headache is minimal. The underlying mechanisms behind sleep apnea headache remain elusive, as there are no significant differences in average oxygen desaturation and lowest oxygen saturation between OSA patients with or without headache23.According to earlier research, patients with OSA had considerably more morning headache than patients without OSA10. The findings of a comparative mixed-methods study indicate that individuals experiencing pain exhibit lower health-related quality of life (HRQoL) compared to both the general population and patients with other chronic conditions, owing to the multifaceted adverse effects associated with pain24. We observed that patients with obstructive sleep apnea (OSA) and pain exhibited significantly poorer health-related quality of life (HRQoL) and psychological well-being compared to those without pain. The SF-36 questionnaire revealed substantial impairments in mental health, bodily pain, vitality, and role emotional domains among these patients, which were further supported by the results obtained from the SF-MPQ and HADS assessments. These findings underscore the detrimental impact of pain on HRQoL in individuals with OSA, emphasizing the need for clinicians to prioritize this comorbidity and consider screening for OSA in patients experiencing pain.The term “health-related quality of life” (HRQoL) refers to how one's health, encompassing physical, psychological, and social functions, affects their level of life satisfaction and pleasure6 put forth, OSA’s overall impact on pain is a culmination of the effects of sleep deprivation, inflammatory mediators, and hypoxia markers. These effects increase pain sensitivity, that contributes to neuronal pain sensitivity, and increase spontaneous pain26. The mechanisms in OSA result in sleep fragmentation and nocturnal hypoxemia. These two changes in OSA patients may be involved in the development of a number of OSA comorbidities  and molecular changes 27. We further found that the associated factors for pain intensity in OSA included age, ESS ≥ 9.0 and lowest pulse oximetry (LSpO2) < 80.0%. Many patients with OSA experience excessive daytime sleepiness (EDS), which can negatively affect daily functioning, cognition, mood, and other aspects of well-being. The Epworth Sleepiness Scale (ESS) is an eight-item self-report measure used to assess trait excessive daytime sleepiness (EDS), where patients rate their propensity for dozing off or falling asleep in various scenarios such as reading, watching television, or riding in a car; an ESS score of ≥ 9.0 indicates the presence of excessive daytime sleepiness28. Hypoxemia in OSA has been proven to have a significant impact on increased expression of proinflammatory cytokines influencing the hyperalgesic priming of nociceptors. Moreover, hypoxia markers by themselves are hypothesized to modulate intracellular signal transduction in neurons and have an impact on nociceptive sensitization6. We found that the pain intensity of OSA patients was also related to worse pulse oximetry and severe nocturnal hypoxemia may be one of the predictors of pain intensity in OSA. These results indicated that the degree of daytime sleepiness and nocturnal hypoxia, may play an important role in the development of pain in OSA.It is unclear exactly how OSA and pain are related. According to a theory29. CPAP treatment prevents hypoxia and oxygenation injury and inhibits the cascade of deleterious OSA-induced consequences30. Patients with severe OSA and metabolic syndrome who exhibit good compliance with CPAP treatment may exhibit improved insulin sensitivity and reduced systemic inflammation, and global cardiovascular disease risk31. Previous studies have demonstrated that severe OSA patients are hyperalgesic, their pain sensitivity improves with CPAP treatment, and the improvement disappears immediately with discontinuation of CPAP therapy32. In patients with moderate-severe OSA at high risk of cardiovascular events and without severe sleepiness, CPAP improved daytime sleepiness and multiple domains of HRQoL over 6–12 months of follow-up, with the largest improvement observed in bodily pain33. The results of this study show that in patients with moderate-to-severe OSA and pain, good compliance with CPAP treatment can improve pain intensity. Therefore, OSA patients should be evaluated for pain and receive timely intervention, and there should be a focus on education for OSA patients with pain to increase compliance with CPAP treatment.The use of continuous positive airway pressure (CPAP) is an effective treatment for OSA because CPAP normalizes sleep architecture, reduces subjective excessive daytime sleepiness and reverses other OSA symptomsTo the best of our knowledge, this study represents the first attempt to investigate the prevalence, distribution, intensity, nature, and associated factors of pain and its severity in patients with OSA. However, it is important to acknowledge certain limitations in our study. Firstly, the study was conducted at a single center with a limited sample size, predominantly consisting of male patients, which may limit the generalizability to the overall OSA population. Secondly, it is important to consider that comorbidities such as hypertension, hyperuricemia, and hypercapnia, which have the potential to influence pain assessment in OSA patients, were not specifically excluded from this study. Lastly, it is worth mentioning that participants' verbal comprehension and subjective experiences might have influenced their responses on the questionnaire ratings, particularly regarding the visual analog scale (VAS) score.Pain was prevalent among patients with moderate-to-severe OSA and was associated with depression, anxiety, and a lower HRQoL. Patients with very severe OSA had an increased risk for pain problems. The intensity of pain in OSA can be predicted by age, ESS ≥ 9.0, and LSpO2 < 80.0%, and it can be alleviated through CPAP treatment.