To provide an overview of phantom limb pain (PLP) in China. This includes the prevalence of PLP and possible risk factors.In a retrospective study, telephone interviews were conducted with 391 amputation patients who underwent extremity amputations at a tertiary hospital in China.P = 0.002) and postoperative analgesia  were identified as high-risk factors for PLP. 82.1% of PLP patients experienced pre-amputation pain. The average pain intensity of PLP was 5.1 ± 2.2, with 31.9% having severe intensity. The effects of PLP on the quality of the PLP patients were as follows: 7.8% of the patients had to limit their daily life and 29.0% of the patients had to limit their social activities. 17.3 and 25.7% of patients experienced depression and sleeping disorder respectively, while 18.9% had loss of interest and even 16.1% of PLP patients had attempted suicide. No effective treatments were found in 78.9% of these patients.PLP was found in 29% of the amputees. Pre-amputation pain (OR = 10.4, PLP has markedly affected the lives of patients. Pre-amputation pain and postoperative epidural analgesia might be risk factors for the phantom limb pain after amputation. Prevention of pre-amputation pain and sudden post-amputation deafferentation should be recommended to the amputees. The term ‘phantom limb’ was coined in 1866 by Silas Weir Mitchell, who described phantoms as ghostly replicas of the lost limb, some of which are painful (i.e. phantom limb pain) and others are not (i.e. phantom limb sensations (PLS)) . PhantomAlthough diagnosis is uncomplicated, the etiology of PLP, especially risk factors are elusive, and correspondingly, no consensus has emerged on its prophylaxis and management , 15. MorThis study was conducted at West China Hospital, which is an affiliate of Sichuan University. The IRB of West-China Hospital of Sichuan University approved the study.n = 60) was re-interviewed 7 to 10 days after the initial interview, by an independent interviewer as a reliability check. A total of 10 key questions were repeated.Patients who underwent amputation from January of 2002 to December of 2013 at West China Hospital  were enrolled in this survey. The total number of patients who underwent amputation was 583. Patients were excluded if they had died or they were untraceable, confused, unable to communicate in the telephone interview, or refused to participate. Telephone interviews were conducted with 391 amputation patients, which were conducted by trained and supervised study personnel (research study assistants). Consent prior to the telephone interview was obtained. A random sample of the respondents  basic demographic variables  and cause of the amputation; 2) the presence of PLP and when it started, pain intensity, pain description , the number of attacks a day, and aggravating/relieving factors; 3) the effective pain treatment and its cost; 4) the impact of the PLP on the patients’ daily life, psychosocial abilities such as work and social abilities and the impact on their mental status; 5) the anesthesia technique used for the amputation; the postoperative analgesia, if there was a preemptive analgesia, and whether they accepted radiotherapy or chemotherapy. The information of modules 1 and 5 was confirmed by reviewing the patient’s medical records. All patients were asked about the presence of PLP and when it started. If PLP was present, the other questions were completed. If PLP was not present, questions about the amputation such as if they had pre-amputation pain, postoperative analgesia, and the effect of the amputation on their life were asked instead.The intensity of pain was measured by using the pain intensity numeric rate scale . Respondents were asked to assess a number along the scale to indicate their most serious level of pain after amputation operation (“How intense was your worst pain?”). The NRS scores were collapsed into mild, moderate, and severe categories of intensity by dividing the pain intensity numeric rate scale as:1 to 3 was mild, 4 ~ 6 was moderate, and 7 ~ 10 was severe.The consequences of PLP and amputation were described by assessments of the limitation on activities of daily life, social activities and work abilities, employment, expression, downhearted feelings , sleep disturbance, and suicide ideations. PLP as well as amputation would affect the quality of the patients’ life, the difference of the limitation on activities of daily life, social activities and work abilities, employment, expression, downhearted feelings , sleep disturbance, and suicide ideations between the PLP and PLP free amputee were thought to be the net effect of PLP on the quality of PLP patients.x2 tests. The correlation of PLP with gender, age, employment status, occupation, and educational level, disease before amputation, the pre-amputation pain and the anesthesia of the amputation were conducted by correlation analysis. Logistic regression was used to identify major risk factors of the PLP.On reliability testing, intraclass correlation (ICC) was used for numerical data between the first and second interviews. For categorical data, kappa statistics were presented. Descriptive statistics, primarily percentages and averages, were used to describe the participants and their experiences of phantom sensations and phantom pain. This was mainly descriptive, using SPSS version 19. Percentages of each phenomenon were calculated. The impact on daily life activities, psychosocial abilities such as work and social abilities and the impact on their mental status in PLP and PLP free patients were compared by An independent interviewer who was blind to the responses from the 10 same key item-questions in the first interview performed a reliability check on 60 respondents. This showed that the information from the survey was reliable, with ICC coefficients ranging from 0.85 to 0.99 while the kappa coefficients ranged from 0.75 to 1.Of the 391 patients with amputations recruited for the study, one hundred and thirteen (113) patients (29.0%) reported that they experienced PLP. The majority of the PLP patients  were male. The ages of the PLP patients ranged from 21 to 81 years old (39 ± 14.9 years), most of whom (70%) ranged from 30 to 59 years old. Nearly 78.4% of the PLP patients reported an education of senior school or below. The most common level of amputation was transfemoral , with transtibial  being the next most common. Upper limb amputation (20.8%) was the third most common type of amputation. Trauma including car accident, work injury and earthquake accounted for 60.5% of the amputations, with chronic diseases, including vascular disease accounting for 21.1% and cancer for 18.4% in this sample. In the patients with PLP, the average pain intensity was 5.1 ± 2.2, with 31.9% having severe intensity. 82.1% PLP patients suffered from the pre-amputation pain. Additionally two thirds (66.7%) of those with PLP patients received postoperative analgesia. Routes of analgesic administration for these PLP patients were oral for 35.6% of the patients, intramuscular for 25.7%, intravenous for 33.3% and epidural for 4.4% of the patients. And the dominant medicines used in postoperative analgesia were pethidine, morphine, tramadol and epidural morphine and ropivacaine.P = 0.002) compared with pre-amputation pain free patients. The use of postoperative analgesia was identified as a high-risk factor  of PLP, but no statistically significant difference was found amongst the patients between the different routes of administration of analgesia . However, taking oral analgesia as the baseline (OR = 1), postoperative epidural analgesia had a higher OR value than intravenous and intramuscular analgesia .In a multiple logistic regression model including all general socio-demographic characteristics and associated factors, pre-amputation pain and postoperative analgesia were consistently associated with PLP. Patients with pre-amputation pain had a higher prevalence of PLP  who reported to have PLP, 83.6% of them had to limit their work, 76.1% felt it affected their daily life and 80.6% reported difficulties with social activities. Moreover, 38.8% of the PLP patients experienced dispirited, 46.3% of them had sleeping disorder, and 26.9% of them lost of interest because of the PLP in these 113 interviewed patients. Importantly, 20.9% of the PLP patients attempted suicide. Of the 278 patients who did not have PLP, 58.0% of them had to limit their work, 68.3 and 51.6% of them reported their daily life activities and social activities limited respectively because of the amputation. 44.8% of them reported they lost their jobs due to the amputation. Moreover, 21.5% of them had depression, 20.6% of them had sleeping disorder, and 8% of them had loss of interest. Only 4.8% of them reported they ever had a suicide attempt. After subtracted the influence of amputation in the PLP patients, the effects of PLP on the quality of their lives are as follows: 7.8% of the patients had to limit their daily life and 29.0% of the patients had to limit their social activities and work. 17.3 and 25.7% of patients experienced depression and sleeping disorder respectively, while 18.9% had loss of interest and even 16.1% of PLP patients had attempted suicide  of them reported that they had no effective treatments for PLP and had to endure pain, while only 21.1% of them reported that they got the relieve after treatments. 69.2% PLP patients only spent below 50 Chinese Yuan (CNY) and 23.1% spent 100 to 300 CNY every month on their treatment for PLP. And another 7.7% patients spent over 2000 CNY monthly to manage their pain.The purpose of this study was to examine the possible etiology of PLP, as well as determine any risk factors of PLP and the prevalence in a sample of Chinese population. The main results demonstrated that patients with pre-amputation pain in the affected limb and the postoperative analgesia were at great risk for PLP. Patients with pre-amputation pain and who received postoperative analgesia had almost ten times and five times higher prevalence of PLP respectively, compared with pre-amputation pain and postoperative analgesia free patients.Ten to Fifty percent of patients with postsurgical pain develop chronic pain, which is the primary predictor of patients’ dissatisfaction . The prePLP has been shown to be more frequent in patients with pre-amputation pain , while iThe other purpose of this survey was to investigate the prevalence of PLP in this sample of Chinese population. Phantom limb pain is a common phenomenon in amputees. Most studies report the prevalence of PLP as ranging from 50 to 80% , while tStudies suggest that work and social abilities are limited in PLP patients and that evidence of clinical depression were observed in these patients. Sherman and Arena  found thAlthough this survey shows that PLP really influences the patients’ work and social ability and daily life, indicating that these individuals need of early, intensive pain interventions. This study also shows that the treatment of PLP was poor in these patients. 78.9% of them reported that they were not on effective treatments for the PLP, and most of them (69.2%) only spent less than 50 CNY every month on the PLP. This is partly explained by the mechanism of PLP being unclear thereby calling for more research, and also suggests that PLP has been neglected by the health service of Chinese society.The major limitation of this study is that it was retrospective and the prevalence was assessed by a single phone interview, and relied upon the amputees’ memory. Thus, there might be some recall bias and the prevalence rate of PLP reported in this study might be underestimated. Future research could overcome this problem by the use of a prospective diary. Since phantom sensations and phantom pain do occur in adolescent amputees, this population warrants further investigation, especially in determining how to prevent and treat these phenomena.PLP was found in 29% of the amputees in China, which had markedly affected the lives of patients. We found that pre-amputation pain and the use of postoperative epidural analgesia which aggravates the sudden deafferentation of the amputated extremities were risk factors for the development of phantom limb pain. This finding suggests that prevention of pre-amputation pain and sudden post-amputation deafferentation should be recommended to the amputees.


Third molar extraction is a very common procedure in Dentistry. The aim of this study was to evaluate the quality of life (QoL) and satisfaction of patients undergoing extraction of an upper third molar under local anesthesia. A second objective was to describe the evolution of self-reported pain measured in a visual analogue scale (VAS) in the 7 days after surgery and its relationship with pre- and intraoperative factors.A prospective longitudinal cohort study was made. Fifty-five patients received a questionnaire assessing social and working isolation, eating and speaking ability, diet modifications, sleep impairment, physical appearance, discomfort at suture removal and overall satisfaction. Pain was registered daily on a VAS scale. A descriptive and bivariate analysis of the data was performed.Forty-seven patients were included. Pain decreased lineally across the 7 days, and relief was significant between days 2 and 3. Intraoperative complications were significantly associated with pain. The complication that showed the highest pain score was the tuberosity fracture.Upper third molar removal significantly affects the patient’s quality of life, particularly during the first 2 days after extraction. Key words:Quality of life, upper third molar, extraction, complications. The term quality of life (QoL) describes a multidimensional concept concerning the ability of the patients to carry out their daily activities -3.QOL is a concept difficult to be assessed considering that the result might have differences depending on individual perception. However, the questionnaires to assess QoL are designed to measure the quality, the effectiveness and the efficiency of the treatment methods as well as physical, psychological and social consequences for patients with different health states .Most people require the extraction of the third molar at some time in life mostly due to pain, tooth decay or periodontal disease. Therefore, third molar extraction is still one of the most frequent interventions in oral surgery -4. PericAs in any surgery, the extraction of the upper third molar causes tissue damage and has an impact both at local and systemic level that deteriorates the QoL of the patient ,7. The uThe main objective of this report was to measure the QoL for the first 7 days after the removal of a third upper molar, using a previously validated questionnaire ,2.The secondary objective was to measure by means of a validated questionnaire the degree of satisfaction of outpatients under-going extraction of the third upper molars ,2, to asPatients who had an appointment to extract an upper third molar at the Master of Oral Surgery and Orofacial Implantology of the University of Barcelona were recruited for the study.Inclusion criteria were: patients older than 18 years old requiring an extraction of a single upper third molar. Exclusion criteria were: systemic diseases (ASA III or higher) that contraindicate surgery or impair wound healing, patients with antibiotic premedication or under pharmacological treatment that might interfere with wound healing, patients with contraindications of the extraction under local anesthesia, patients on chronic NSAID therapy, and patients unable to understand the visual analogue scales or the questions related to the QOL. If another tooth had to be extracted in the same appointment, the patient was excluded as well.The study protocol was approved by the Institutional Review Board (Comitè Ètic d’Investigació Clínica) before recruitment of the patients. The guidelines of the Helsinki Declarations were considered and followed through all the study. Patients signed an informed consent for the participation in this study. All extractions were preformed from March 2015 to June 2015 at the Dental Hospital of the University of Barcelona by postgraduate students  of the Master of Oral Surgery and Orofacial Implantology of the University of Barcelona. Data were collected by a single investigator who was not involved in the surgery.The molars were extracted for prophylactic reasons, pericoronitis, or orthodontic reasons. In case it was required, a full-thickness flap was raised and bone removal was performed using a round carbide bur on a straight handpiece. Third molars were extracted using Pott elevators. If a flap was raised, the wound was closed with 3-0 silk sutures.The instruction about postoperative medication was 600mg ibuprofen TID during 3-5 days. Antibiotics were prescribed when bone removal was required (amoxicillin 750 mg TID during 7 days).The variables registered were: age, gender, side of the third molar, eruption status, bone retention, previous symptoms, bone re-moval, tooth sectioning, experience of the surgeon, and intraoperative complications such as mucosal tear or fracture of the tuberosity. For 7 days patients recorded the average pain on a 10 cm visual analogue scale (VAS) and the number of consumed analgesic or NSAID tablets.The same day of the surgery, patients received the first questionnaire  and the Data were processed using IBM SPSS version 22.0 .T-tests were used to compare the duration of the changes (in days) in males and females. The duration of the changes for the eruption status, bone retention, presence of previous symptoms, bone removal, tooth sectioning, experience of the surgeon, and intraoperative complications were assessed with one-way ANOVA tests.The association of pain with gender was measured by Pearson’s χ²-tests. The pain VAS scores were analyzed by analysis of variance (ANOVA) for repeated measures with the Greenhouse-Geisser correction if sphericity did not hold and post-hoc contrasts with the Bonferroni correction.Questionnaires were delivered to 55 patients. Forty-seven were returned . Five patients lost the questionnaire and 3 failed to fill it correctly and were excluded from the study. The mean age was 36 years, with a standard deviation (SD) of 9.3 years. All patients were Caucasian. Questionnaire results are shown on P<0.005), with a lineal pattern . On day 2 and day 3 this decrease in the VAS of pain was statistically significant (day 2 compared with day 3 and 4: P=0.035 and P=0.026 respectively) with a mean reduction of 16.3mm and 12.4mm respectively =3,324; P=0.071). Pain scores were not significantly lower when neither bone removal nor tooth sectioning was performed. . Patients who had total retention of the upper third molar had higher VAS scores than those with partially or totally erupted molars .Pain differences by gender were not significant, and the pattern of decline was similar for men and women . However, patients who had intraoperative complications had significant higher VAS scores than patients without complications . The complication that showed the highest pain score was the tuberosity fracture . From the day 3 there was a 23% reduction of the inake of of analgesics, and from the day 4 a 50 % reduction.A limitation of the present study is that data are subjective, based only on the patient perception. However, this is always an issue in studies of QoL ,12. AnotPain seemed to lineally decrease and practically disappeared on day 4. Other studies about lower third molar extraction showed that pain is more persistent, and disappears around day 6 or 7 . Despiteet al. and Sancho-Puchades et al., . As a result, the quality of life was basically affected by eating difficulties. These figures were considerably higher after removing the 4 third molars in the same appointment (57.1%) .Changes in chewing ability and trismus, were reported by 7% and 33%, respectively. However, after lower third molar removal up to 80% of patients report changes in chewing ability . When 4 Around 3 % of patients noticed changes in their voice and their ability to speak. There is a great difference when the 4 third mo-lars are extracted in the same operation, with 10% noticing voice changes and a 60% experiencing difficulties to be understood by other people.  In the eet al.  . Howeveret al. cohort study confirms that after third molar extraction there is a deterioration in the quality of life in the short term, but better oral health in the long term, especially observed in cases of previous pericoronitis (The McGrath oronitis .Regarding the level of satisfaction, 93 % of patients were satisfied and believed that their problem was solved. Most studies show similar satisfaction rates above 90 % -3,5,9.A variable that we did not take into account is tobacco use after surgery, which could affect postoperative pain levels, especially in extractions that require more aggressive surgical techniques or are more prone to postoperative infection.The analysis of the repercussions of the extraction on patients’ QoL is important for an optimal preoperative assessment and development of appropriate indications after the surgery. Furthermore, it enables the surgeon to give the patient realistic information on the postoperative course, and helps the patient to choose the best moment to undergo the procedure, thus minimizing major interferences with everyday life.In conclusion, most patients were satisfied with the treatment and believed that their problem was solved although there was a small percentage of patients that would not repeat it nor recommended it. Tuberosity fracture significantly increased the postoperative pain. The patients’ major complaints were inflammation and chewing difficulties. Upper third molar extraction had a small negative impact on quality of life, considering that most of patients continued their normal activities.


N-methyl-d-aspartate receptor (NMDAR) results in increased sensitivity of spinal cord and brain pathways that process sensory information, particularly those which relate to pain. The NMDAR shows increased activity in fibromyalgia and hence modulation of the NMDAR is a target for therapeutic intervention. A literature review of interventions impacting on the NMDAR shows a number of drugs to be active on the NMDAR mechanism in fibromyalgia patients, with variable clinical effects. Low-dose intravenous ketamine and oral memantine both show clinically useful benefit in fibromyalgia. However, consideration of side-effects, logistics and cost need to be factored into management decisions regarding use of these drugs in this clinical setting. Overall benefits with current NMDAR antagonists appear modest and there is a need for better strategy trials to clarify optimal dose schedules and to delineate potential longer–term adverse events. Further investigation of the role of the NMDAR in fibromyalgia and the effect of other molecules that modulate this receptor appear important to enhance treatment targets in fibromyalgia. Activation of the  There are multiple pain-related mechanisms that are active in patients with fibromyalgia. The relative contribution of each mechanism appears to vary between patients. This results in different responses to different drugs in different patients suggesting that the symptoms that characterize fibromyalgia need to be targeted through a number of different approaches .One important mechanism in fibromyalgia is enhanced reactivity in a number of sensory systems, particularly the pain-related nervous system ,3. Of imN-methyl-d-aspartate receptor (NMDAR) [Increased sensitivity of spinal cord neurons occurs in fibromyalgia ,4. This  (NMDAR) ,6.This clinical review examines publications that relate to NMDAR modulation in patients with fibromyalgia. We performed a search of PubMed using the following keywords in various combinations: “fibromyalgia, NMDA, ketamine, memantine, mechanisms, glutamate”. We felt that PubMed would provide a comprehensive collection of studies on fibromyalgia. The bibliography of relevant identified papers was surveyed and information from abstracts and on-line sources was included as deemed relevant. We supplemented this information with that contained in the authors’ own databases.Various imaging techniques have shown elevated glutamate levels in the brains of patients with fibromyalgia . For insN-Methyl-d-aspartic acid) [d-serine) to different sites of the NMDAR. Cellular depolarization repels the magnesium and zinc ions from the channel allowing voltage dependent entry of sodium and small amounts of calcium into the cell and egress of potassium out of the cell. This process is primarily gated by ligand binding, but is also voltage dependent [The amino acid glutamate, acting on two different groups of receptors (labeled ionotropic and metabotropic), is primarily involved in excitatory synaptic transmission in the brain and spinal cord. Ionotropic glutamate receptors are ligand-gated ion channels. They are divided into different receptor types based on their pharmacological properties. The key receptor sub-groups are GluA , GluD (δ), GluK (kainate), and the GluN  . The NMDic acid) ,14. In iic acid) . The NMDependent . Thus anependent ,17. NMDAR antagonists that inhibit activation by agonists to the NMDAR fall into four categories. These comprise competitive antagonists, which bind to and block the binding site of either the neurotransmitter glutamate or that of glycine, noncompetitive antagonists, which inhibit NMDARs by binding to allosteric sites, and other antagonists, which block the ion channel by binding to a site within the channel .S (+) stereo-isomer is the most potent NMDAR-antagonist in clinical use, and is 3–4 times that of the R (-) isomer. Ketamine binds to an intrachannel site and decreases channel opening time [Ketamine 2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone) is a non-competitive NMDAR antagonist. The ing time . Ketamining time . Thus thing time . The coming time ,22.While ketamine has been widely used in the management of a number of chronic pain disorders  there arp < 0.05) and 20–80 min after the test period (p < 0.01). There was a decrease in tenderness (p < 0.02) and increased endurance (p < 0.02). The change in pain threshold and pain tolerance at tender points (<0.02 and <0.0001 respectively) and control points (<0.03 and <0.02 respectively) were each significant. Six of the 8 responders had reduction in pain for 2 to 7 days. In addition to the 11 ketamine-infused patients, 9 other patients were treated with morphine and compared to saline (no significant change in the above outcomes) and 11 other patients were treated with lidocaine and compared to saline .The clinical effects of ketamine have been evaluated in a small sample of patients with fibromyalgia. A double-blind study of 11 female patients with fibromyalgia given low-dose ketamine infusions (0.3 mg/kg) or sodium chloride (placebo) at different times over a period of 0 to 10 min in a random cross-over design evaluated a number of relevant outcome measures . Pain inThese studies were extended, using saline, lidocaine, morphine and ketamine, in a total of 18 patients . ThirteeA third study using similar methodology identified 17 of 29 fibromyalgia patients as responders to ketamine . Thus, oA subsequent study assessed the effect of either placebo or ketamine on pain induced by intramuscular infusion of hypertonic saline in patients with fibromyalgia who had previously been defined as ketamine responders. These studies showed significant parallel reduction in pain intensity, temporal summation, allodynia and area of referred pain in those given the NMDAR-antagonist ketamine compared to those given placebo . Taken as a whole, these described studies imply that NMDAR activation significantly contributes to the pathophysiology of the pain of fibromyalgia. However, the short time period of observation in these studies in a chronic pain condition such as fibromyalgia limits the clinical usefulness of this data.S-ketamine to an infusion of 5 mg midazolam, each over 30 min [S-ketamine treated patients and midazolam treated patients at 2.5 h after the infusion or during the 8-week follow-up time period. Psychomimetic side effects were mild to moderate and similar between groups. The S-ketamine provided a dose that was 2.5 times higher than the racemic ketamine used in the studies of Sorenson [A double-blind placebo controlled trial in 24 fibromyalgia patients examined durability of response to ketamine by comparing a single infusion of low dose (0.5 mg/kg) r 30 min . This shSorenson  and GravSorenson  but the Complex regional pain syndrome (CRPS) shares many pathophysiological features with fibromyalgia , includiAnecdotal contemporary use of intravenous ketamine for the pain of fibromyalgia generally involves doses that are higher, of longer duration and of greater frequency than in the initial clinical studies. For instance, the dose may start at 200 mg over 4 h on day 1, 600 mg over 4 h on day 2, and 800 mg over 4 h on day 3, 4 and 5, with a booster of 800 mg over 4 h on each of two days some two weeks later . The dosThere are no randomized controlled studies of this higher dose and longer duration use of ketamine in fibromyalgia.The use of oral ketamine for treatment of fibromyalgia has not been widely studied, however one study reported clinically meaningful responses (>50% pain reduction) in a small number of patients . If effeSpecial issues arise regarding recreational use of this drug and these need to be considered when planning future studies in fibromyalgia and other pain disorders .Dextromethorphan is often present in over-the-counter cough medications and has mild NMDAR non-competitive channel blocking actions .p < 0.001). There was a statistically significant association between the occurrences of side effects in each group. Ketamine side effects included dizziness, confusion, euphoria or a combination of these. Dextromethorphan related side effects included dizziness and sedation.The response to an intravenous low-dose (0.1 mg/kg) ketamine infusion in 34 patients with fibromyalgia predicted the subsequent response to the oral NMDAR-antagonist dextromethorphan (mean dose in responders 160 mg/day), although 56% of patients responded to neither drug . The valIn a study of fibromyalgia patients compared to healthy controls, there was a similar response to the NMDAR antagonist dextromethorphan when assessed using the effects of temporal summation of dorsal horn neuronal responses, which reflects nociception-dependent central sensitization . This suMemantine is a non-competitive blocker of the NMDAR channel that leads to reduction of glutamate and prevents entry of excess calcium . It dissA randomised, double-blind study in 63 patients with fibromyalgia compared memantine (titrated up to 20 mg/day over one month) with placebo over a 6-month period . CompareIn an associated study, it was shown that patients treated with memantine showed significant changes in brain glutamate-related metabolites compared to placebo-treated patients . There wAmantadine is a weak non-competitive NMDAR channel blocker  that hasp < 0.0001), and 70 percent had complete resolution of mechanical allodynia [Methadone is a μ-opioid receptor agonist that also has NMDAR antagonist activity . It is ullodynia . It is nThere is little role for the use of pure opioids in fibromyalgia as intrinsic brain opioid activity is already optimized and this, together with the significant medical issues associated with long-term opioid use, limits consideration of the usual form of this drug for its NMDAR antagonist properties in fibromyalgia . This drGuaifesin, a drug with expectorant properties, may also have NMDAR antagonist actions . HoweverA number of drugs used in the management of fibromyalgia, such as different antidepressants, likely have an indirect effect on NMDAR function through reduction of the NMDAR ligands glutamate and aspartate ,51. GlutDietary modification of foods high in glutamate has been trialed in fibromyalgia. One study showed that 4 weeks of exclusion of monosodium glutamate (MSG), aspartame, and other excitotoxins, resulted in over 30% improvement in fibromyalgia symptoms in 84% of those who completed the diet . When acDrugs that are active against NMDARs are either not mentioned or not recommended in a number of evidence-based guidelines and reviews for management of fibromyalgia ,56,57. SThe NMDAR plays a prominent role in the pathophysiology of fibromyalgia. A number of drugs that target and down-regulate this structure cause a reduction of fibromyalgia-related symptoms. While this review provides evidence for the participation of NMDARs in the mechanism of fibromyalgia, it also highlights limitations in methodology of the identified studies. These are characterized by several short duration studies in a condition that is usually long-standing. Additionally, there are few studies examining different doses of NMDAR antagonists and none assessing combinations with drugs of different classes. Further study of currently available NMDAR antagonist drugs and assessment of new drugs in this class is warranted.


Long-term use of opioid analgesics (OA) for chronic pain may result in opioid use disorder (OUD). This is associated with adverse outcomes for individuals, families and society. Treatment needs of people with OUD related to chronic pain are different compared to dependence related to use, and also injection, of illicit opioids. In Nordic countries, day-to-day practical advice to assist clinical decision-making is insufficient.To develop principles based on expert clinical insights for treatment of OUD related to the long-term use of OA in the context of chronic pain.Current status including an assessment of barriers to effective treatment in Finland, Denmark, Iceland, Norway, Sweden was defined using a patient pathway model. Evidence to describe best practice was identified from published literature, clinical guidelines and expert recommendations from practice experience.Availability of national treatment guidelines for OUD related to chronic pain is limited across the Nordics. Important barriers to effective care identified: patients unlikely to present for help, healthcare system set up limits success, diagnosis tools not used, referral pathways unclear and treatment choices not elucidated. Principles include the development of a specific treatment pathway, awareness/ education programs for teams in primary care, guidance on use of diagnostic tools and a flexible treatment plan to encourage best practice in referral, treatment assessment, choice and ongoing management via an integrated care pathway. Healthcare systems and registries in Nordic countries offer an opportunity to further research and identify population risks and solutions.There is an opportunity to improve outcomes for patients with OUD related to chronic pain by developing and introducing care pathways tailored to specific needs of the population. The long-term use of opioid analgesics (OA) in the context of chronic pain syndromes may result in opioid use disorder (OUD) . This isWithout intervention, OUD commonly results in serious psychosocial issues, medical problems and a significant risk from overdose . PharmacIt is recognised that the characteristics , behavioCountries have published guidelines for the use of OA in relation to chronic pain  were identified from professional societies or bodies responsible at national level for care, in Norway , FinlandEngagementPatients or users of OA often do not engage with healthcare services to seek help for OUD related to chronic pain. This is due to a lack of awareness of the potential problems of long-term opioid therapy aiming to reduce symptoms associated with chronic pain from both patients and prescribing doctors, limited knowledge on the benefits of treatment, and limited engagement with the addiction services, which provide care mainly for patients with problems related to injection of illicit opioids and/ or psychoactive drugs, due to fear or stigma.Advocacy from healthcare professionals (HCP) in primary care (PC) and other settings may be insufficient in many cases, reducing the chance of patients agreeing to further steps towards diagnosis, referral and treatment. This lack of advocacy is often related to a low level of knowledge in PC of OUD in general and options for care specifically related to OUD and chronic pain.Diagnosis in PC and addiction specialist settings is not optimal.Physicians, nurses and other HCP often have little training in the recognition and treatment of OUD. A lack of familiarity with appropriate diagnostic tools limits ability to effectively define patient problems and progress to appropriate care. Diagnosis may be difficult; for some patients it may be a challenge to accept that OUD is present, especially because the source of the dependence – OA pain medication – was prescribed and provided from within the medical system and is taken to reduce symptoms. Some pain relief is recognised upon taking the medication by the patient but less is recognised of side-effects such as the risk in escalating doses, developing dependence, cognitive impairment, gastrointestinal symptoms or other symptoms caused by opioids. Patients may avoid diagnosis despite evident problems due to a fear of attracting stigma when entering the conventional OUD treatment pathway.Referral pathways are poorly defined or are inadequate.This limits the potential for progress with effective management. Care services developed for the management of addiction, related commonly to illicit opioid or drug use, often do not meet the needs of this specific population. The stigma associated with using existing, conventional treatment services limits participation of many patients after referral. HCP may be unaware of the risk of progression from OA use related to chronic pain to other forms of opioids and the risk of harm associated – limiting the urgency of referral.Treatment assessment must be based on a full clinical picture and understanding of the needs of the patient.The goal of early intervention is important to prevent the gradual worsening of OUD and associated comorbidities over time. The difficulty in establishing a detailed clinical picture for each individual patient, including OUD, pain, psychiatric comorbidity (anxiety disorders and depression), and also in building relationships with patients due to limited engagement and inappropriate treatment service set-up often complicate adequate assessment. Success in treatment is limited due to lack of an integrated and holistic approach to care. Across the range of stakeholders who provide the necessary parts of care, a lack or insufficient awareness of the specific and different nature of treatment for OUD related to chronic pain make it hard to deliver an integrated program required for success.Treatment success is limited if the approach is not specific to the needs of patients with OUD related to chronic pain.Treatment must be based on a holistic approach and individual needs. The chronic pain patients seek relief from is difficult to treat in terms of reduced pain independent of given treatment. When tapering of opioids HCP should consider the potential of opioids to induce hyperalgesia and the possible outcome of, in a part of the population, worsening pain and function in daily life. Many stakeholders are required for effective care and outcomes are not optimal if clinical services are not integrated and aligned. Inappropriate treatment choices regarding medication, duration and therapy may result from inexperience or uninformed decisions. Guidelines do not provide information to assist clinicians in the practicalities of building and delivering a treatment plan by means of an integrated team specialized in this particular setting. Functions including medical treatment, psychological and social therapy must be aligned for success – a lack of awareness and experience in treating patients in this population makes this more difficult to achieve. Disjointed management across different healthcare functions may lead to inadequate service delivery and poor outcomes.Structured assessment of the limits to successful care:Overall the lack of understanding of the size and nature of the epidemiology of OUD related to chronic pain limits the development and provision of care services. In policy, at national and regional level, there is often a lack of clarity on the commitment to provide appropriate resources to ensure the identification and treatment of OUD related to chronic pain.There is potential to improve the approach for the management of OUD related to chronic pain. Current policy and practice does not reflect the specific needs of patients and available guidance does not provide sufficient direction on the practicalities of care overall. Guidance for clinical practice in pain management and/or OUD care may not be sufficiently useful beyond providing general information; it is recommended that such policy and guidance is developed further to meet the needs of the patients considering the comorbidity and challenges of treatment of this group. In relation to this, principles for best practice care of people with OUD related to chronic pain are described according to a patient journey model Fig. .Fig. 2SuIn PC and with specialists in addiction medicine, provide educational programs aimed at increasing advocacy by building awareness of the problem, knowledge of referral pathways and successful interventions , 36.Consider prescription data reviews to identify patients at risk, with a potential need for help, as in other locations including: Europe , UK 12]12], DenmDevelop simple decision-support tools to help prescribers of OA, pharmacists and others to target, plan and hold discussions with patients about dependence problems, referral and treatment options , 39.Set up and support the use of digital and other easy-to-access, publicly available tools  to provide support and trusted resources for patients, carers, and family members , 40.Presentation and engagement with care – the starting point for treatment – can be made easier and more accessible. Awareness, advocacy and risk-based reviews of treatment are needed in services that are perceived as attractive, relevant and are specifically designed for the patient population .In PC anProvide specific training for HCP in PC to improve skills and knowledge of diagnosis and referral pathways. Addiction and pain management specialists and national authorities should collaborate in providing educational pathways for HCP and psychiatrists. This includes drug screening and detection of relevant behavioural changes such as using opioids for reasons other than pain, to “get high” or “manage stress” , rapidlyProvide resources to set up and encourage the development of clinical practice aiming to achieve diagnosis in a joint effort between pain management specialists, addiction specialists and PC . The modProvide tools to assist HCP in working with patients to agree a “contract” defining goals of treatment and prescription renewal. If this contract cannot be maintained, this may be a point of acceptance of the need for help. Experience with a trial of tapering of prescribed opioids, performed in cooperation with the patient, is an important step in diagnosis; a lack of progress in dose tapering may indicate OUD.The gap in diagnosis and referral limits uptake of successful interventions and is based on limited awareness of proven tools and successful pathways to treatment.Ensure at policy and clinical practice level that there is a referral pathway appropriate to the needs of patients with an option, when practical, to offer initial specialist consultation in PC to reduce stigma . PatientReferrals to specialist care are limited because of unclear or inappropriate pathways.A specific clinical assessment is recommended for patients with OUD related to chronic pain , 46, 52.A joint individualised , 57 treaManagement of existing OA medications for chronic pain and planning to reduce or taper medications over time in agreement with the patient . TaperinTreatment choices start with a managed reduction/ tapering of current OA, which can be tried either as a slow tapering in an outpatient setting, or faster in an inpatient setting. If these options are not successful, treatment with opioid agonist therapy (OAT) as part of an integrated psychosocial care program may be required , 46, 52.Treatment with OAT may be recommended if dose reduction/ tapering does not lead to improvement and OUD is considered to be moderate to severe. Based on the patient inventory including full listing of prescription and other drugs in use by the patient, a single dose of one opioid agonist can be prescribed. Commonly prescribed options include buprenorphine/ naloxone , methadone or buprenorphine . The decBuprenorphine/ naloxone is a common initial recommendation if OAT medication is considered, in alignment with guidance . BuprenoIntensive treatment monitoring is needed as standard , especiaAdjustments of dose and choice of programs for psychosocial support may be necessary; decisions are guided by clinical progress including factors such as use of other opioids or addictive substances, craving and potentially other psychiatric symptoms such as anxiety or depression.Cessation of OAT is guided by clinical response; many patients are expected to complete therapy and cease using any opioids. Duration of therapy may extend beyond 1 year . TherapyAccess to appropriate specialist support groups specific to OUD and chronic pain problems for patients and their families should be available and actively referred to, for example behavioural therapy . TherapyNon-optimal treatment assessment and choices of treatment may result from inexperience of HCP.This analysis focuses on the steps of care specific to OUD related to chronic pain; it is important to also act to prevent problems emerging. It is important that all patients with chronic pain receive appropriate care. Where treatment with OA is considered, screening for risk of substance use disorder (SUD) in general is important in the evaluation of medication treatment of pain. Prescribing OA needs special attention for people at risk for SUD and special precautions are needed if OA are necessary. OA prescription practice should be well-founded to ensure appropriate pain care is provided for chronic pain patients – this in turn will limit initiation of large scale harmful opioid use. Early intervention is needed to avoid treatment with OA for pain developing into chronic OUD. An integrated and multidisciplinary service should be provided for all patients who develop OUD in relation to chronic pain. It is important to set up an environment in which there is an ongoing recognition of the specific needs of populations with OUD related to chronic pain, to design care services to meet the needs of these groups and to support HCP and other services in providing integrated and individualised care. It is important to define the ideal care set up at community and specialist levels, with goals of initial, short and longer-term treatment. In the longer-term perspective education to reduce the impact of stigma and related barriers to treatment may be valuable: starting with practical treatment steps can also be a part of changing this.This work is based on an assessment of current approaches to OUD care in chronic pain setting with insights from specialists each with at least 10 years’ experience in OUD (10) and pain management (1); there can be benefit in including other pain specialists and organisations. This work is based on review of evidence from Nordic countries; this may limit wider applicability but the challenges and principles for managing OUD related to chronic pain identified here likely do however apply more widely. The existence of health registries and the similar approaches to OUD management and healthcare in general in Nordic countries present an opportunity to collect evidence to define the magnitude of the problem in greater detail, for example by assessing OA prescription data, and to develop further evidence-based approaches to clinical practice.The population with OUD related to chronic pain may be underserved for healthcare and find it hard to access therapy matched to their specific needs; there is an opportunity to improve the outcomes of treatment in these populations with specific care pathways. Principles for managing this complex problem are recommended here based on a consensus of clinical experience. Clinical practice experience highlights the need for policy change and specific practice development to make it possible to address the needs of this population; this includes the development of specific tailored care pathways. There is a need also to plan for research based on the opportunity in the region, provided by integrated health registries and common approaches to care, to define with increased resolution population needs and to confirm evidence supporting specific interventions. This is a call to action for health services and research organisations to act to improve outcomes for many with chronic pain and OUD.


Background: Leydig cells secrete the steroid hormone, testosterone, which is essential for male fertility and reproductive health. Stress increases the secretion of glucocorticoid  that decreases circulating testosterone levels in part through a direct action on its receptors in Leydig cells. Intratesticular CORT level is dependent on oxidative inactivation of CORT by 11β-hydroxysteroid dehydrogenase 1 (HSD11B1) in rat Leydig cells. Pain may cause the stress, thus affecting testosterone production in Leydig cells.Methods: Adult male Sprague–Dawley rats orally received vehicle control or 5 or 10 mg/kg dehydroepiandrosterone (DHEA) 0.5 h before being subjected to pain stimulation for 1, 3, and 6 h. In the present study, we investigated the time-course changes of steroidogenic gene expression levels after acute pain-induced stress in rats and the possible mechanism of DHEA that prevented it. Plasma CORT, luteinizing hormone (LH), and testosterone (T) levels were measured, and Leydig cell gene expression levels were determined. The direct regulation of HSD11B1 catalytic direction by DHEA was detected in purified rat Leydig, liver, and rat Hsd11b1-transfected COS1 cells.Results: Plasma CORT levels were significantly increased at hour 1, 3, and 6 during the pain stimulation, while plasma T levels were significantly decreased starting at hour 3 and 6. Pain-induced stress also decreased Star, Hsd3b1, and Cyp17a1 expression levels at hour 3. When 5 and 10 mg/kg DHEA were orally administered to rats 0.5 h before starting pain stimulation, DHEA prevented pain-mediated decrease in plasma T levels and the expression of Star, Hsd3b1, and Cyp17a1 without affecting plasma CORT levels. DHEA was found to modulate HSD11B1 activities by increasing its oxidative activity and decreasing its reductive activity, thus decreasing the intracellular CORT levels in Leydig cells.Conclusion: Stress induced by acute pain can inhibit Leydig cell T production by upregulation of corticosterone. DHEA can prevent the negative effects of excessive corticosterone by modulating HSD11B1 activity. Many stressors, such as noise, pain, diseases, and pollution, are present in our daily life . Pain isStar), and T biosynthetic enzymes, including cholesterol side-chain cleavage enzyme , 3β-hydroxysteroid dehydrogenase 1 , 17α-hydroxylase/20-lyase , and 17β-hydroxysteroid dehydrogenase 3  (Nr3c1) binding exclusively, since other factors such as testicular opioids (Nos2) (Stress induced the elevation of circulating glucocorticoid (GC) level . IncreasHsd17b3) . It is i opioids  or nitris (Nos2) , might aScarb1), into Leydig cells, where cholesterol was released for storage as cholesterol esters or use in steroidogenesis. In Leydig cells, after stimulation by pituitary-secreted luteinizing hormone (LH), cholesterol was mobilized to the inner mitochondrial membrane via STAR , the rate-limiting subunit. LH binds to the LH receptor  on the surface of the Leydig cell to activate adenylyl cyclase, leading to a cascade to stimulate T production. In the pituitary, LH secretion was positively regulated by gonadotropin-releasing hormone (GnRH), which bound to its receptor , and negatively regulated by estradiol, which bound to its receptor α   .Hsd11b1). This enzyme acted as a primary oxidase and inactivated biologically active CORT into inert 11-dehydrocorticosterone (DHC), thus controlling the level of active CORT in Leydig cells  can prevent pain-induced hypogonadism via targeting HSD11B1.3H-CORT, 3H-hydroxycholesterol, 3H-pregnenolone, 3H-progesterone, 3H-androstenedione, and 3H-T were purchased from DuPont-New England Nuclear . 3H-DHC was prepared as previously described . RU486 was from Roussel . DHEA, 2-hydroxypropyl-cyclodextrin, etiocholan-3β-ol-17-one, M-199, DMEM, and Ham’s F-12 medium were purchased from Sigma .Rat LH standard NIDDK-r-LH-I9 was obtained through the National Hormone and Pituitary Program (United States). escribed . The CORAdult male Sprague–Dawley rats (90-day-old) were purchased from Shanghai Animal Center , and housed under controlled environmental conditions . All animals were handled to become adapted for at least 3 weeks prior to the beginning of the experiment. All animal procedures were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals according to protocols approved by the Animal Care and Use Committee of Wenzhou Medical University.n = 6 per time point). Control animals orally received vehicle control and then were left undisturbed in their cages for the duration of the experiment and sampled at the same time point. At the end of each stress period, animal were euthanized by CO2, trunk blood was collected in tubes containing heparin and centrifuged at 500 × g, and the plasma were stored at -20°C until assay. Testes and pituitaries were removed and stored at -80°C. Testes were used for analysis of Leydig-cell-specific gene and protein expression levels. The pituitaries were used for analysis of pituitary-specific gene expression.Experiment 1 (acute pain stimulation): Thirty-six 90-day-old male Sprague–Dawley rats were randomly divided into two groups: the unstressed control and the stress. Rats in the stress group orally received 0.5 ml vehicle control (a solvent for DHEA) and 0.5 h later they were subjected to pain simulation. DHEA was first dissolved in ethanol and subsequently diluted with the vehicle, 45% aqueous 2-hydroxypropyl-cyclodextrin, to attain the needed concentrations. The thermal pain stimulation was performed using a radiant heat. Rats were placed in clear plastic cages on an elevated glass plate. A radiant thermal stimulator was focused onto the plantar surface of the hind paw through the glass plate. The heat stimulation was performed for 2 min every 5 min for six times at hour 1, 3, and 6. Then, rats were placed back in the original cage. The pain stimulation began at 9 AM and the treatment durations were 1, 3, and 6 h (Experiment 2 (DHEA treatment): Eighteen rats were randomly divided into three groups: the stress control (0 mg/kg DEHA), 5 mg/kg DHEA, and 10 mg/kg DHEA. Rats were gavaged 0, 5, or 10 mg/kg DEHA and then 0.5 h later they were subjected to a 3-h period of pain stimulation as above.in vivo via intratesticular injection 0.5 h prior to the pain stimulation session. We selected the RU486 dose as 16 μg based on our previous observation (n = 6 per group) were divided into four groups: (1) control no-pain group (injected with vehicle); (2) no-pain group with injection of RU486; (3) pain group (injected with vehicle); and (4) pain group with injection of RU486. Rats of pain groups were subjected to pain stimulation as above during the course of a 6-h period. At the end of the session, animals were euthanized by CO2, testes were taken, and interstitial fluids were prepared according to the previously described method (Experiment 3 (NR3C1 antagonist study): To investigate whether NR3C1 acted in pain-induced T decline during the course of pain, the specific blocker of NR3C1, RU486, was administered ervation . RU486 wervation . Twenty-d method .g for 10 min to collect the interstitial fluid.Testes were taken after treatment and interstitial fluids were prepared according to the previously described method . Brieflyn = 6 per group) were subjected to no pain or pain stimulation for 3 h as above, since at the end of this time point, plasma T levels were significantly decreased. At the end of the pain stimulation session, animals were euthanized by CO2, and trunk blood was collected for hormonal assays. Leydig cells were harvested for direct measurement of T production and steroidogenic enzyme activities ex vivo as follows:Experiment 4 (Leydig cell stimulation study): To investigate whether Leydig cell steroidogenesis was affected after pain stimulation, animals . Leydig cells were recovered starting at a density of 1.07 mg/ml. Leydig cells were washed using M-199 and were pelleted at 800 × g for 10 min at 4°C. The Leydig cell purity was >95% (n = 6), as determined by histochemical staining for HSD3B1 using 0.4 mM etiocholan-3β-ol-17-one as the enzyme substrate and NAD+ as cofactor according to a previously described method . Incubations of quadruple samples were conducted in medium alone  or in medium plus a maximally stimulating concentration of ovine LH (100 ng/ml), 20 μM 22-R-hydroxysteroid cholesterol (22OHC). LH was used to examine the Leydig cell functionality after it bound to LHCGR. 22OHC was used to examine the steroidogenic enzyme activity of CYP11A1 or beyond. At the end of 3 h, the samples were centrifuged at 500 × g. Supernatants were used to measure T levels by RIA.The steroidogenesis of isolated adult Leydig cells was conducted escribed . Leydig in situ with a calcium-free buffer, then dispersed by a solution containing 0.05% collagenase, and parenchymal cells were purified by density gradient centrifugation in Percoll. The purity of parenchymal cells in the final suspension was assessed by judging the uniformity of cell size in hematocytometer counts and was typically over 95%.Liver parenchymal cells were isolated according to the previously described method . Livers 3H-CORT. CORT standards (10–2000 pg/100 μl) were assayed in parallel. Bound steroid was separated from free steroid by mixing with dextran-coated activated charcoal followed by centrifugation. The bound supernatant was put into a bottle with a scintillation cocktail and the relative amount of radioactivity was determined by a liquid scintillation counter . Assay sensitivity was 10 pg of CORT per assay tube. The interassay coefficient of variability was calculated and it was 7% (n = 4).Plasma CORT level was measured according to a previously described method . Briefly125I rat LH and immunoglobulin-G (IgG) antiserum. LH reference standards (NIDDK-rLF-RP-3) were used. The lower limit of detection for this assay is 0.12 ng/ml and LH values are expressed in relation to the RP-3 standards. The intraassay and interassay coefficients of variation were 5 and 10%, respectively (Plasma LH level was measured by RIA according to a previously described method . Brieflyectively .3H-T RIA according to a previously described method (3H-T at 4°C. T standards (10–2000 pg/100 μl) were assayed in parallel. Bound steroid was separated from free steroid by mixing with dextran-coated activated charcoal followed by centrifugation. The bound supernatant was put into a bottle with scintillation cocktail and the relative amount of radioactivity determined as above. The interassay coefficient of variability was calculated and it was 7.5% (n = 4).Plasma, testicular fluid, and medium T levels were measured with a tritium-based d method . BrieflyRps16 . The RNA was reversely transcribed using a random hexamers and MMLV reverse transcriptase  according to the manufacturer’s instruction. Real-time PCR (qPCR) was carried out in a 25-μl volume with SYBR Green kit  according to the manufacturer’s instruction. Reactions were carried out and fluorescence was detected on a Bio-Rad qPCR system . The Ct values were recorded and the standard curve was generated and the gene expression levels were calculated according to the standard curve as previously described  according to the manufacturer’s instruction. Twelve genes in the testes and four genes in the pituitary were analyzed and their primers were listed in Supplementary Table escribed .STAR and LHCGR levels in the testes were measured using Western blotting analysis as previously described . In brieHsd11b1 cDNA in pcDNA I expression vector from its original rat Hsd11b1 vector (p11DH-I)  according to the manufacturer’s protocol. Cells were allowed to grow for 24 h in media containing 10% fetal bovine serum. Then, the media were removed, and cells were harvested for HSD11B1 assay.Rat HSD11B1 expression plasmids were constructed to express rat HSD11B1 using p11DH-I) . The Escex vivo were measured according to the previously described method , HSD3B1 , CYP17A1 , and HSD17B3  were added. Reactions were initiated by adding to the reaction medium an aliquot of 0.1 × 106 Leydig cells. The reaction mixtures, conducted in triplicate, were maintained at 34°C in a shaking water bath (75 rpm) for 10 min. The radioactive products were produced. Reactions were terminated by adding ice-cold ether, and steroids were rapidly extracted. The ether layer was dried up under a nitrogen gas. The radioactivity was measured by System 200/AC3000 radioactive scanned . The activity of HSD3B1 was determined by measuring the conversion of pregnenolone into progesterone. The activity of CYP17A1 was determined by measuring conversion of progesterone into 17α-hydroxyprogesterone and androstenedione. The activity of HSD17B3 was determined by measuring the conversion of androstenedione into T. The steroids were separated on thin layer chromatographic plates in chloroform-methanol  for HSD3B1 and HSD17B3 assays, chloroform-ether  for CYP17A1 assay. The activity of CYP11A1 was determined by measuring the conversion of side-chain labeled 3H-hydroxycholesterol to radioactive 4-hydroxyl-4-methyl-pentanoic acid. The mixture was extracted twice with 2 ml chloroform and mixed with neutral alumna to remove non-metabolized substrate, and an aliquot was removed for measurement by liquid scintillation counting at a scintillation counter .CYP11A1, HSD3B1, CYP17A1, and HSD17B3 activities in intact Leydig cells d method . In brieg for 30 min. The supernatants were transferred and centrifuged at 10,000 × g for an additional 30 min to get rid of mitochondria. The remaining supernatants were further centrifuged at 105,000 × g for 1 h twice. Microsomal pellets were resuspended by adding 1 ml ice-cold PBS and homogenized by a glass homogenizer. Protein concentrations in the microsomal fractions were measured by Bio-Rad Protein Assay Kit  according to manufacturer’s protocol. Microsomal fractions were used for the measurement of HSD11B1.Leydig cell microsomal fraction was prepared from rat testis as described previously , because3H-CORT into 0.1 × 106 Leydig, liver, and COS1-Hsd11b1 cells using the endogenous NADP+. HSD11B1 reductive activity was measured by adding 25 nM 3H-DHC into 0.1 × 106 Leydig, liver, and COS1-Hsd11b1 cells using the endogenous NADPH. For HSD11B1 reductive activity in the microsomes, the enzyme assay tube contained 25 nM DHC spiked with 60,000 dpm of 3H-DHC, 0.2 mM NADPH, and 10 μg rat microsomal fractions in 0.25 ml PBS. The reaction was initiated by adding microsomal fractions. For testing the potential of DHEA to affect HSD11B1 activity, DHEA was dissolved in ethanol, with a final ethanol concentration of 0.4%, and this concentration did not affect rat HSD11B1 activity. The reaction was started by incubating the reaction mixture at 34°C in the 75 rpm shaking water bath. The reactions were stopped by adding 2 ml ice-cold ether. The reaction mixtures were mixed with ether thoroughly by vortexing, and the steroids were extracted. The ether layer was transferred into a new glass tube and was dried up under nitrogen gas. The steroids were plotted onto a thin layer chromatographic plate and separated chromatographically in chloroform and methanol . The plate was dried up, and the radioactivity on the plate was measured using Bioscan scanning radiometer  according to the manufacturer’s instructions. The percentage conversion of 11DHC to CORT or cortisone to cortisol was calculated by dividing the radioactive counts identified by the total counts.HSD11B1 activity was assayed according to the previously described method . HSD11B150 value was determined by adding either 25 nM CORT or DHC with 0.2 mM cofactor and various concentrations of DHEA in 250 μl reaction buffer (0.1 mM PBS) containing rat enzyme in Leydig cell microsomes as previously described , 39.66 ± 5.49, and 36.81 ± 6.78 ng/ml at hour 1, 3, and 6 during the course of pain stimulation, respectively, and there were no differences between these groups . This level of plasma CORT conformed to the unstressed level of rats as previously reported , indicating that these rats were under stress condition starting at hour 1. Plasma LH levels in pain-stimulated rats did not significantly alter during the course of pain in all groups , indicating that pituitary LH secretion was not affected by pain. Since there was a circadian nature of plasma T, the concentrations of T during the course of pain were compared to the respective control time-point. Plasma T concentrations were significantly reduced when compared to the control group starting at hour 3 , suggesting that the lower T levels followed the increase of plasma CORT levels 2 h later and the primary cause of the reduced T levels was not a result of the change of plasma LH levels.The concentrations of plasma CORT in the control group were 36.96 ± 4.70 , but significantly suppressed LH-stimulated  and 22OHC-mediated  T production of Leydig cells , indicating that the lower plasma levels of T were caused by the defects of Leydig cell steroidogenesis after LH binding as well as the androgen biosynthetic enzymes.We further purified Leydig cells from the control rats and the pain-stimulated rats at hour 3. Leydig cells were treated without  or with 100 ng/ml LH   or 20 μMLhb that was the rate-limiting step for LH . Pituitary Lhb expression was not affected during the course of pain , conforming to plasma LH levels. The regulatory genes, including Gnrhr, Esr1, and Nr3c1, were not affected by pain . The expression levels of Lhcgr, Scarb1, Star, Cyp11a1, Hsd3b1, Hsd17b3, and Hsd11b1 were significantly lower at hour 3 and 6, while Cyp17a1 and Nos2 levels were lower at hour 6 during the course of pain . Interestingly, Nr5a1, Nr3c1, and Sgk1 were all lower at hour 3 and recovered at hour 6 . These indicated that the steroidogenesis-related genes in the testis of the pain-stimulated group were downregulated in a different pattern.Pituitary LH production depends on the expression level of p for LH  and its Figure 3, both STAR and LHCGR levels were significantly lower at hour 3 and 6 during the course of pain, conforming to the change of their mRNA levels. The steroidogenic enzyme activities for CYP11A1, HSD3B1, CYP17A1, and HSD17B3 were listed in Figure 3. CYP11A1, HSD3B1, and HSD17B3 activities were significantly lower at hour 3 after pain stimulation and CYP17A1 was also lower at hour 6 after pain stimulation.The STAR protein was the rate-limiting step for Leydig cell steroidogenesis. LHCGR is the signaling transducer for LH binding and their levels were analyzed by Western blot. As shown in Figure 4, RU486 significantly reversed the pain-mediated inhibition of T level at hour 3, indicating that pain caused suppression of T production via increase of plasma CORT, which in turn bound to NR3C1 to act.Since the elevated CORT levels were followed by the lower T levels in the serum 2 h later during the course of pain, we investigated whether CORT suppressed T production via NR3C1. We injected rats with RU486, an antagonist of NR3C1, and then the rats were subjected to pain stimulation immediately. As shown in Hsd11b1 cells. As shown in Figure 5, DEHA concentration-dependently increased HSD11B1 oxidase activity in intact Leydig cells with EC50 value of 896 ± 2 nM  without affecting HSD11B1 oxidase activity in intact liver cells  and intact COS1-Hsd11b1 cells . DHEA concentration dependently inhibited HSD11B1 reductase activity in intact Leydig , liver , and COS1-Hsd11b1 cells with IC50 values of 829 ± 1, 766 ± 1, and 767 ± 4 nM, respectively. This indicated that the effects of DHEA on HSD11B1 in the liver and Leydig cells were different.We asked whether DHEA can directly regulate HSD11B1 direction, because this enzyme is a bidirectional enzyme . We studHsd11b1 microsomes. We found that it competitively inhibited HSD11B1 reductase activity when the substrate DHC was added . We further used the docking software to analyze the binding site of DHEA on human HSD11B1, and the crystal structure of the enzyme was obtained from the Protein Data Bank , and that DHEA bound to the steroid-binding site of human HSD11B1. According to the literature . However, the treatment of DHEA did not affect the total plasma CORT levels . DHEA treatment did not alter plasma LH levels either . However, pain stimulation reduced plasma T levels and 5 and 10 mg/kg DHEA treatment significantly reversed pain-induced reduction of plasma T levels  . This indicated that DHEA can act locally to reverse pain-induced reduction of testosterone production. We further examined the testis and pituitary gene expression without or with DHEA for the acute stress model. Again, DHEA did not alter pituitary Lhb, Gnrhr, Esr1, and Nr3c1 levels , suggesting that the acute treatment of DHEA did not alter pituitary function. DHEA reversed the expression levels of Lhcgr, Scarb1, Star, Cyp11a1, Hsd3b1, Hsd17b3, and Hsd11b1 in the testis at hour 3 after pain .We checked whether DHEA could prevent the pain-induced T reduction. We treated rats with DHEA (5 or 10 mg/kg) and 0.5 h later, these rats were subjected to pain stimulation. Indeed, compared to the normal control, pain stimulation increased plasma CORT levels significantly (Lhcgr), cholesterol transporter (Scarb1 and Star), and steroidogenic enzyme  expression. DHEA was found to regulate HSD11B1 direction by inhibiting HSD11B1 reductase activity, thus lowering the intracellular CORT levels in Leydig cells to reverse CORT mediated reduction of T.In the present study, we demonstrated that acute pain stimulation to male adult rats caused the elevated plasma CORT level as early as 1 h under pain stimulation. The plasma T levels were significantly lowered after 3 h of being subjected to pain stimulation. The decrease of T levels followed downregulation of LH signaling . The decrease of plasma T levels may be due to the reduction of production of T in Leydig cells, as plasma LH levels were not altered. Therefore, CORT appears to directly suppress Leydig cell steroidogenesis. We observed the downregulation of cholesterol transportation system (Scarb1 and Star) and steroidogenic enzyme  at hour 3 and later. The downregulation of many steroidogenesis-related genes including the Star at hour 3 after pain stimulation might explain the reduction of T biosynthesis. After 3-6 h during the course of pain, Lhcgr level was significantly downregulated, conforming to the lower T production of Leydig cells after LH stimulation .The plasma T levels of the stressed rats were decreased significantly by 3-6 h during the course of pain (Nos2) . Instead, Nos2 expression was downregulated at hour 6 . Acute stress-induced suppression of T production in the Leydig cells could be mediated by NR3C1. Indeed, the intratesticular injection of NR3C1 antagonist RU486 completely prevented the interstitial fluid T level suppression in the stressed rats , suggesting that CORT acted via the NR3C1 in Leydig cells. This antagonist was also observed in rats and mice under immobilization stress , suggesting a compensatory mechanism to minimize CORT action at hour 3 .In the present study, pain stimulation caused significant elevation of CORT, indicating a stress condition during the course of pain. Several other factors that induce stress may also affect the suppression of T biosynthesis. These factors included testicular opioids  and NOS n stress . We alsot hour 3 . HoweverHsd11b1 . This difference could be due to the cell-specific effects of DHEA. However, in the present study, we demonstrated that DHEA potently inhibited HSD11B1 reductase activity in Leydig, liver, and COS1-Hsd11b1 cells  without affecting HSD11B1 oxidase activity in liver and COS1-Hsd11b1 cells, thus inhibiting the reactivation of inert GCs into active GCs. This inhibition that DHEA exerted was competitive against the steroid substrate . The docking study suggested that DHEA had a higher binding affinity with the steroid-binding site of human HSD11B1  . Interestingly, DHEA significantly increased HSD11B oxidase activity in rat Leydig cells . This action was not the same for HSD11B oxidase in liver and COS1-Hsd11b1 cells. One explanation is the presence of minor HSD11B2 in rat Leydig cells, although its expression level in Leydig cells was only 0.1% that of Hsd11b1  that utilize NADPH to yield more NADP+. Thus, under these conditions, HSD11B1 operates in the oxidative mode, inactivating GCs generating NADPH that couples with androgen biosynthetic reactions and promoting testosterone synthesis. Provided there is enough substrate for HSD11B1 like CORT, that will operate in a cyclic manner coupled with androgen biosynthetic pathway.DHEA and its sulfate ester DHEA-S are the most abundant steroids in the human circulation . Previou Hsd11b1 . Indeed,ncreased , indicatt enzyme . Whether+-dependent HSD3B. Androstenedione being a substrate of HSD17B3, it is converted to testosterone. There are at least three enzymes involved in the metabolism of T utilizing three NADPH and generating three NADP+. Abundance of NADP+ cofactor stimulates HSD11B1 in oxidase direction. So, DHEA accelerated oxidase activity in Leydig cells, but not in the liver or transfected COS cells because there is no such enzymatic machinery to utilize NADPH. In liver or COS cells, NADPH is generated by glucose-6-phosphate dehydrogenase and with the redox potential being reversed , cholesterol transport genes (Scarb1 and Star), and steroidogenic enzyme  gene expression. Inhibition of the reductase of HSD11B1 by DHEA makes the minor HSD11B2 as the dominant isoform which is capable of eliminating local GCs by its oxidase activity.In summary, acute pain stimulation led to the elevated CORT levels as early as 1 h which is followed by the reduced T levels 3 h after acute pain stimulation. High CORT level may bind to NR3C1, which blocked LH signaling (QZ, XL, FG, MY, and R-SG designed the study. QZ, XL, FG, H-SD, MX, TB, JL, YW, and YS performed the experiments. R-SG analyzed the data. XL and R-SG wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


INTensive care (PAINT) study aimed to evaluate the frequency and type of physician pain assessments with respect to published guidelines. This observational service evaluation considered all pain and analgesia‐related entries in patients’ records over a 24‐h period, in 45 adult intensive care units (ICUs) in London and the South‐East of England. Data were collected from 750 patients, reflecting the practice of 362 physicians. Nearly two‐thirds of patients  received no physician‐documented pain assessment during the 24‐h study period. Just under one‐third  received no nursing‐documented pain assessment, and over one‐fifth % received neither a doctor nor a nursing pain assessment. Two of the 45 ICUs used validated behavioural pain assessment tools. The likelihood of receiving a physician pain assessment was affected by the following factors: the number of nursing assessments performed; whether the patient was admitted as a surgical patient; the presence of tracheal tube or tracheostomy; and the length of stay in ICU. Physician‐documented pain assessments in the majority of participating ICUs were infrequent and did not utilise recommended behavioural pain assessment tools. Further research to identify factors influencing physician pain assessment behaviour in ICU, such as human factors or cultural attitudes, is urgently needed.Pain is a common and distressing symptom experienced by intensive care patients. Assessing pain in this environment is challenging, and published guidelines have been inconsistently implemented. The Pain Assessment in  Pain is common among patients admitted to intensive care units (ICUs), with a prevalence of 40–77% Evidence suggests that over half of critically unwell patients do not receive regular pain monitoring in the ICU Pain assessment in ICU is challenging, as the subjective experience of pain requires reliable communication to alert staff to its presence. Communication is, however, often impaired in ICU as a result of sedation, delirium, and disease or due to the presence of iatrogenic airway devices. Consequently, the use of ‘gold‐standard’ self‐assessment tools are not always appropriate. Under these circumstances, staff rely on either subjective, often inaccurate assessments We aimed firstly to evaluate the frequency and type of pain assessment conducted by physicians in ICUs in London and South‐East of England; and secondly to identify whether pain assessment was documented less frequently than other physiological parameters, and to describe any patient or unit‐specific factors that influenced pain assessment. Finally, we also evaluated nursing assessment and documentation of pain, to identify whether ICUs were meeting recognised standards, and to provide information about the culture of pain assessment for individual ICUs.www.uk-plan.net) and the South‐East Anaesthetic Research Chain . We audited practice against standards described by the American College of Critical Care Medicine http://www.hscic.gov.uk). Figure http://www.hra-decisiontools.org.uk/research/)). The protocol was registered, and appropriate approval granted from audit departments at each individual Trust. Between January and March 2015, individual ICUs identified one weekday 24‐h study period (Monday to Friday), to collect data.The Pain Assessment in INTensive Care (PAINT) study was a retrospective observational service evaluation conducted by two anaesthetic trainee networks, the Pan‐London Peri‐operative Audit and Research Network ; bed occupancy; and format (paper or computerised) for recording observations, prescribing analgesia and recording medical notes.The number of nursing pain assessments and tools utilised, along with assessment scores, were collected from observation charts and nursing notes. No patient outcome data were collected. Anonymised patient data were collected on paper case report forms before submission to the secure central server via the nhs.net email system.We analysed the data using IBM SPSS v22.0 and Stata v13.0  in collaboration with the statistics service at Imperial College, London. Data were tested for normality (Shapiro–Wilk test). The p values underwent Bonferroni correction to account for multiple comparisons. We performed univariate analysis of variables that influenced the frequency of pain assessments using Mann–Whitney U‐test comparisons for grouped non‐continuous data. Spearman's correlation was used for correlation of continuous measures, and chi‐square testing for categorical group comparisons such as physician grade. Variables identified as important in determining the frequency of physician pain assessments were then tested using hierarchical regression modelling. Because the data had a nested structure (patients were nested within units), the use of hierarchical models was required, since this took into account the variability between units, as well as the correlation between patients within the same unit. The two‐level model identified unit and patient‐specific predictors of the frequency of documented physician pain assessments. Each hospital was coded, and investigators were blinded to patient location. The largest proportion of missing data related to the type of pain assessment used by physicians, representing 22 (5.3%) patient assessments. In 13 (1.7%) patients, the presence or absence of a physician‐documented pain assessment was incomplete, being partially recorded. Therefore, to calculate incidence, we used n = 737 as the denominator. For all other analyses (other than incidences) in these 13 individuals, we imputed that if the data collector had not recorded whether an assessment had taken place on the data extraction form, no assessment had been documented in the medical notes.All 45 recruited ICUs submitted patient and hospital data. Data were collected from 755 patients; five were under the age of 18 years and were not studied, leaving a sample of 750 patients.Baseline characteristics are described in Table Data were submitted from 45 ICUs and represented a total of 763 available critical care beds (level 2 and level 3). The ICUs were located in either teaching hospitals  or district general hospitals . Of the 750 patients, 355 (37.3%) were treated in teaching hospitals, and 395 (52.7%) in district general hospitals. Medical and nursing observations were recorded using electronic systems in 16 ICUs (35.6%), whereas 17 ICUs (37.8%) used electronic drug charts. Specific physician daily ward round proformas were used in 37 ICUs (82.2%), of which six ICUs (13.3%) included a section to record pain assessments.Data reflect the practice of 362 physicians . A total of 1734 separate patient assessments were documented during the 24‐h study period.Of the 737 complete patient records, 475 patients  had no documentation of pain assessment by a physician. This was higher for patients with either a tracheal tube or a tracheostomy in situ, than for patients with an absence of these airway devices 211,  vs. 264, ; p < 0.001. Two hundred and sixty‐two patients  had at least one documented pain assessment, as compared with 718  patients who received at least one documented cardiovascular assessment.Of the 227 patients receiving continuous opioid infusions, 85 (37.4%) had a physician‐documented pain assessment. One hundred and twenty‐five (16.7%) patients had a change in analgesic prescription recorded on the drug chart, and 54 (43.2%) of these patients had no reference to pain assessment in their medical notes.2 = 5.00, p = 0.28). Overall, 413 (23.8%) documentation episodes included a pain assessment (146 (22.5%) of consultant, 142 (25.2%) of Specialist Trainee, 81 (27.9%) of Core Trainee, 35 (24.5%) of Foundation Year, and 27 (33.3%) of ‘other doctor’ entries).Physician experience, as identified by grade of training, did not significantly influence frequency of physician‐documented pain assessments  had no documented nursing pain assessment. The median (IQR [range]) number of nursing pain assessments per patient was 2.0 (0.0–5.0 [0.0–24.0]). Three‐hundred and sixteen patients  received fewer than two documented pain assessments during the 24‐h study period. This equates to less than one documented pain assessment every 12‐h nursing shift. Of the 227 patients prescribed strong opioids, 78  did not receive a documented nursing pain assessment. Two of the 45 ICUs used behavioural assessment tools for nursing pain assessment, with the commonest assessment tool being a 0–3 scale ; and the number of documented nursing reviews. Unit‐specific characteristics tested were ICU type  and hospital type . These results are shown in the Table Length of stay had a significant effect on pain assessment, but the effect depended on whether the ICU was general or specialised. For specialised ICUs, as the length of stay increased, so did the number of pain assessments. For a unit increase in number of days in a specialised ICU, the number of pain assessments performed by physicians increased by a factor of 1.003 (p = 0.026). This was in contrast to general ICUs, where the number of pain assessments performed by physicians was reduced by a factor of 0.988 (p = 0.038).Surgical patients without a tracheostomy or tracheal tube had a higher number of physician pain assessments performed when compared with medical patients without a tracheostomy or tracheal tube (p < 0.001). However, for those patients with an airway device present, this difference was not significant. In the final model, patient age did not have an effect on pain assessment.The number of documented nursing assessments significantly influenced the number of documented physician assessments (p < 0.001). An increase by one of the number of nursing assessments was associated with an expected increase in physician assessments by a factor of 1.061.The only unit‐specific factor that showed a significant effect on physician‐documented pain assessment was whether the unit was a general or specialised ICU. However, as described previously, this effect interacted with patient length of stay. The hospital type , had no effect on pain assessment. Although unit and patient‐specific variables helped to explain inter‐unit variability, there was a proportion of unexplained variability, with an estimated effect of 0.771 (0.433–1.371).Nearly two‐thirds of the patients included in this study did not have pain assessments documented by physicians. The absence of documentation does not equate necessarily with the absence of an assessment. However, the failure to record examination findings at best reflected the fact that pain documentation was afforded a low priority, and at worst, that no assessment of pain was undertaken by the medical staff. Documentation of the effects of analgesic medication, and the reasons for changes in pain prescriptions are integral to continuity of patient care. Over three‐fifths of patients receiving opioid infusions, and over two‐fifths of patients who received changes in analgesic medication lacked a physician documentation of pain assessment. Consequently, drug effects and the rationales behind pain medication changes were not transparently communicated in the medical notes. It was notable that over four‐fifths of ward round reviews failed to record pain assessments, again implying that communication of this aspect of patient care was lacking.This was in stark contrast to the frequency of documentation of other physiological systems, such as cardiovascular observations, that were routinely recorded in the majority of physician entries in the medical notes. Therefore, it is unlikely that an absence of documentation of pain assessment reflected poor medical documentation in general. The routine presence of cardiovascular observations in medical notes may have been due to a higher confidence by physicians in parameters recorded using medical devices, which provided recognisable quantitative data. In contrast, the more subjective data produced from an observational pain assessment could have been less familiar to treating physicians, and something in which they had less faith. The consistency with which cardiovascular and respiratory observations were documented when compared with those of pain, could highlight the low priority given to pain as a problem requiring physician attention, or that more patient‐centred variables are seldom documented by physicians.There is a need for these factors to be explored and modified, to identify whether a culture of improved pain assessment by all healthcare professionals also improves patient outcome.Reasons as to why physicians do not record observations about pain in medical records are unclear, although it is likely that human factors play a role. The UK Health and Safety Executive has classified influences on healthcare performance into job or task factors, and as either individual and organisational factors Finally, organisational factors might have included a lack of clarity as to whose role it was to perform pain assessments. Physicians may have assumed that pain assessment was a nurse‐led role (yet there was a positive relationship between nursing and physician assessment); poor communication between nursing staff and physicians, and a culture where pain assessment was routinely ignored may have further influenced performance.It is difficult to fully explain why length of stay influenced physician pain documentation positively in specialist units, but had the opposite effect in general units. This could reflect the fact that in specialist units discharge from ICU might be delayed due to recognition of an issue with pain management, whereas this may not occur in a general unit. Conversely, in general hospitals, it is more likely that step‐down care and discharge from ICU may be delayed due to a shortage of normal ward beds. Therefore, patients who do not require a high level of care remain in the ICU where it is perceived that, because they are less unwell, they require less frequent pain assessment. However, patients in general wards should also be regularly assessed for pain Our findings demonstrate that medical patients without tracheal tubes or tracheostomies received fewer pain assessments than surgical patients. This is despite evidence indicating that medical ICU patients report higher pain scores when compared with surgical patients Internationally, widespread failure of the adoption of frequent validated pain assessments by nurses has been reported Possible reasons for the gap between recommendation and implementation include a lack of knowledge, and staff scepticism regarding the benefits of such behavioural tools Interestingly, an increase in the frequency of nursing pain assessments was associated with an increase in the frequency by physicians. Certainly, some units stood out for prioritising pain assessment, and further qualitative or ethnographic work is required to identify why these units assessed pain more frequently and robustly than others.Limitations of our study include the use of a short observation period, rather than a longitudinal approach. We also used an independent review of documentation as a proxy for bedside review of pain by a physician. A further limitation is that retrospective data collection may fail to capture real‐time changes. However, much of the published literature on pain in ICU has relied on the recall of practice by healthcare professionals using surveys, and so our method adds to the evidence base in a robust way. We recruited ICUs within a specific geographical region, many of which engage in regular audit and research. It is, therefore, unclear how generalisable these results are to practice elsewhere; however, evidence from nursing literature shows that pain is managed poorly in ICUs in many countries This study shows that pain assessment is not being delivered in a reliable manner across ICUs in the UK, mirroring similar problems with ICU pain assessment worldwide. Although ICUs in the UK are well funded, and have good clinical outcomes in terms of survival, for example after sepsis This study adds to evidence that pain assessments conducted in intensive care are inconsistent in both frequency and method of delivery. We have demonstrated that both medical and nursing staff fail to document pain assessments, despite an association with improved patient outcomes. There is an urgent need for ethnographic research exploring pain assessment in intensive care, and qualitative studies to identify reasons for the lack of prioritisation of pain and adoption of guidelines.