Pain is one of the most feared symptoms that concern cancer patients and their families. Despite well-established guidelines set forth by the World Health Organization (WHO) on the treatment of cancer pain, nearly half of cancer patients report poorly controlled pain. One of the most serious side effects of systemic oral opioid use is neurotoxicity, which is characterized by altered mental status and systemic neurologic impairments. Treatment strategies are supportive in nature and focused on reducing or changing the offending opioid and correcting any metabolic deficiencies. Herein, we discuss a case of opioid-induced neurotoxicity treated with intrathecal targeted drug delivery (TDD). The timing and implementation of advanced therapies such as intrathecal TDD is not well delineated. More importantly, patients and their oncologic providers are often unaware of this useful tool in treating challenging cancer-associated pain and significantly minimizing systemic opioid side effects. To ensure that patients have comprehensive oncologic care, best-practice guidelines suggest involvement of an interdisciplinary team and coordinated care. Early referral to a pain and palliative specialist may allow for improved patient outcomes and removal of unnecessary barriers to optimal patient care. Pain is one of the most feared symptoms that concern cancer patients given its profound link to impaired quality of life, psychological distress, impaired sleep and relationships, and global functioning. Cancer-associated pain ranges widely, but is a common and prevalent theme for many in the advanced stages . TraditiIntrathecal targeted drug delivery (TDD) is a proven and accepted therapy in cancer patients for the treatment of uncontrolled pain refractory to systemic opioid regimens and intolerable side effects , 4–8. DeA 57-year-old female with widely metastatic high-grade serous adenocarcinoma of the ovary was referred to our tertiary palliative care clinic by her oncologist for management of severe cancer-related pain. Following her original diagnosis, she underwent a number of multimodal disease-directed therapies, including surgical resection and chemotherapy. She had significant ongoing mixed somatic and neuropathic pain in the left lower back as well as her pelvis, both sites of known metastatic disease. The back pain was noted to be a deep sharp pain without radiation to her extremities, located primarily around the region of her nephrostomy tube and into the abdomen. She would also have sharp lancinating neuropathic pain in her pelvis due to tumor burden with prolonged periods of sitting, walking, or activity.Initial treatment consisted of multimodal pharmacologic therapy including short-acting and long-acting opioids with nonopioid and adjuvant neuropathic agents. Despite these therapies, she had progressive pain and was ultimately increased to an opioid combination of morphine sulfate controlled-release (120 mg by mouth every 8 hours) and morphine sulfate immediate-release (30–45 mg by mouth every 3 hours as needed). Early changes yielded acceptable analgesia. Conversations and medication adjustments continued over the phone, given the distance between the patient's home and our institution. However, over several weeks' time, pain progressed despite further opioid increases. Given concern for escalating pain and poor response to several attempts at altering her opioid therapy, it was advised that she present for a consultation in the palliative medicine clinic. Fortunately, focused discussions with the patient and her family around the patient's goals of care were addressed with her palliative medicine team at every meeting. She was very clear that her top priority in her ongoing medical care was to achieve acceptable analgesia. During the interview in the clinic, the patient noted significant pain with generalized discomfort, a sense of restlessness, and new muscle fasciculations. Her husband accompanied her and noted intermittent confusion. Her physical exam featured delirium (Confusion Assessment Method positive) with diffuse myoclonus.Out of concern for opioid-induced neurotoxicity (OIN), the patient was admitted to the hospital for analgesic control and treatment of what was felt to be a toxic encephalopathy. Despite the known shared metabolic pathway (phase II metabolism) between morphine and hydromorphone, the patient's opioids were rotated from oral morphine to parenteral hydromorphone as the clinical picture continued to unfold. Further workup revealed an unremarkable head CT and EEG. Clinical evaluations and laboratory assessments suggested that, in the setting of her declining physical and renal function (creatinine 1.0 mg/dL with prior baseline 0.6 mg/dL and estimated glomerular filtration rate (eGFR) 55 ml/min/BSA with prior baseline >60 ml/min/BSA), the delirium could be the result of an accumulation of active neurotoxic morphine metabolites (morphine-3-glucuronide). In addition, she was dehydrated, constipated, and had not slept in several days. Unfortunately, her delirium persisted despite correction of metabolic derangements, hydration, and an aggressive bowel regimen.Urology was consulted, and a nuclear medicine dimercaptosuccinic acid (DMSA) scan revealed minimal function of the left kidney, despite the presence of a nephrostomy tube. Subsequent vascular radiological investigations revealed tumor-induced thrombosis with surmised infarction of her left kidney. It was concluded that the altered renal function due to infarction likely resulted in an inability to adequately excrete the morphine, and the accumulation of polar morphine metabolites resulted in OIN. As exemplified in this case, even with opioid rotation, centrally active metabolites of hydromorphone (hydromorphone-3-glucuronide) theoretically exist, given that it follows a similar phase II metabolic glucuronidation pathway as morphine, although the relative potency and effect of such hydromorphone metabolites are thought to be significantly less than morphine. The patient continued to have signs of OIN and was eventually transitioned to parenteral fentanyl, given that fentanyl is a unique medication that is largely hepatically metabolized into inactive metabolites. Despite common lore that fentanyl and methadone are agents that do no produce active metabolites and therefore do not elicit OIN, case reports of synthetic opioids eliciting OIN do exist in the literature , 15. UnfGiven the concern for poorly controlled cancer-associated pain, the palliative care and pain medicine teams collaborated from the initial visit with concerning symptoms of OIN. At our institution, the palliative clinic shares space within the pain clinic, and the collaboration required a simple conversation followed by same day pain consultation. Initially, the shared thought was moving directly to intrathecal (IT) TDD therapy, as this had been discussed over numerous palliative care visits as a potential option with her physicians and was in line with her goals to achieve enhanced pain control with limited side effects. However, given the underlying metastatic disease process and concurrent cancer treatments, she had a metabolic coagulopathy due to nutritional and micronutrient deficits that required correction with vitamin k to assist in the reversal of her international normalized ratio (INR), thus allowing for any type of procedural intervention.Ultimately, given the persistent multifactorial delirium and rapidly changing situation, the pain medicine and palliative care teams convened a family conference with the husband, the patients' health-care power of attorney, to again address the current situation and make recommendations that seemed consistent with the patient's predetermined goals. Given the rapid progression of her symptoms despite aggressive attempts to correct potentially remediable factors, the shared medical decision-making discussion included moving forward with TDD, given that this therapy was thought to be the best chance for meeting the patients' goals for comfort and hope to have meaningful interaction with family by reducing the burden of systemic side effects from oral or parenteral opioid therapy. The patient's advanced directive was clear that she appointed her husband to make decisions on her behalf if she was ever in a situation where she was unable to provide consent. Informed consent was obtained through her appointed surrogate decision maker and designated health-care power of attorney.After correction of her metabolic coagulopathy yielding an INR <1.2, she proceeded with placement of an intrathecal TDD system (Medtronic SynchroMed™ II 40 mL pump and Ascenda catheter). The pump reservoir was placed in her right lower abdominal quadrant, and the catheter tip was placed at T10. Her TDD system was efficiently titrated to achieve acceptable levels of analgesia using a combination of opioid (hydromorphone 2 mg/mL) and local anesthetic (bupivacaine 10 mg/mL). The initial postoperative settings were 0.5 mg/day of hydromorphone in a simple continuous mode without bolus dosing (2.5 mg/day of bupivacaine). Within 24 hours of TDD placement, the patient experienced near complete resolution of her toxic encephalopathy and was able to engage in meaningful conversation with her family and health-care teams. There were no signs or symptoms of opioid withdrawal. In the early postoperative phase, she required additional dosing of oral hydromorphone, but was responsive to 2 mg orally every 3 hours as needed for breakthrough postsurgical pain totaling three to four doses per day. Given the robust response to TDD therapy, the patient was able to participate in goals of care discussions with her interdisciplinary palliative care team and elected to discharge closer to home under the provision of hospice services postoperative day (POD) two. Prior to leaving the hospital, the TDD rate was increased to 0.8 mg/day of hydromorphone, and she was provided with a personal therapy manager (PTM) allowing 0.1 mg/dose every six hours totaling four doses per day. The dose remained stable for seven days. As her oncologic disease continued to evolve, her TDD system was adjusted by her hospice provider to accommodate her daily use of oral opioid therapy. The pump was again adjusted on postoperative day nine, yielding a basal rate of 1.4 mg/day of hydromorphone with four PTM boluses of 0.15 mg/dose of hydromorphone every six hours. This dose remained for POD 9–13, and she passed away peacefully with acceptable analgesia at home with her family under the auspices of hospice two weeks after TDD implantation.As colleagues in pain and palliative medicine understand, there is a paucity of data regarding the exact timing of TDD in patients with advanced cancer. Despite well-validated World Health Organization (WHO) guidelines on cancer pain management that serve approximately 80% of the cancer pain population, the remaining 20% may continue to have poorly controlled pain and be at an increased risk for systemic opioid side effects . ManagemFirst, best practices to enhance patient care involve interdisciplinary teams and coordinated care . True inSecondly, building a team-based care model allows each specialist the opportunity to highlight their expertise and discuss the role of potential treatment options early in the care paradigm. Early discussion of all treatment options facilitates an environment of trust and allows the members of the patient's care team the greatest opportunity to offer interventions when most appropriate . Early dLastly, timely intervention allows for proper postimplant coordination, education, and collaboration required for ongoing care with palliative medicine and hospice providers. Effective intrathecal drug therapy management is required after implantation to ensure that the therapy is providing optimal outcomes through confirmation of the program performance, system integrity, and reports on battery longevity  , 23, 24.Several randomized control trials have observed the outcomes of IDDS with comprehensive medical management (CMM) compared to CMM alone , 26. OpiCurrent guidelines suggest pursuing maximal medical therapy prior to considering implantation of a TDD , 23, 27.Originally, one of the most compelling arguments supporting the use of TDD in cancer pain focused on the cost-effectiveness of the intervention with the expectation for the patient to live at least six months. This rationale was based on data that suggested an arbitrary number, for which the intrathecal device would breakeven in terms of cost and outcome , 27, 28.The process of TDD implant entails review of the patient's medical condition and comorbidities, advanced imaging of the neuraxial space , and assessment of current medication regimen , 23. If One of the most important questions implanting physicians face is the conversion of systemic opioid dose to a safe and effective intrathecal opioid dose. The application of an equianalgesic conversion ratio for oral to intrathecal opioid depends on the hydrophilic nature of the opioid medication. The only three FDA approved medicines to be used intrathecally through a TDD device are morphine, baclofen, and ziconotide. For purposes of this conversation, we will only discuss the conversion of morphine. It is well accepted that oral to parenteral morphine is a conversion factor of three, parenteral to epidural morphine is a conversion factor of ten, and epidural to IT morphine is a conversion factor of ten , 30. TheThe vast majority of interventional pain practices follow the updated 2017 Polyanalgesic Consensus Conference (PACC) guidelines when implanting and managing TDD systems for cancer pain. First-line medication selection includes FDA approved medications, including ziconotide and morphine. Additionally, fentanyl and hydromorphone are both considered first line in treating cancer pain particularly when combined with nonopioid adjuvants such as bupivacaine . The addThe goal of cancer-directed pain care should focus on reducing delay and apprehension regarding IT TDD intervention, thus reducing the known morbidity and mortality associated with oral systemic opioid therapies. We strongly encourage collaborative communication in patients that are terminally ill, as the available resources of hospice programs vary greatly and may impact the medical decision-making around the application of TDD therapy near the end of life . In our In summary, cancer-associated pain continues to be a prevalent concern for numerous patients, their families, and their treating providers. The burden of uncontrolled pain symptoms can greatly affect function, daily activities, interpersonal relationships, and quality of life at the end of life. Comprehensive cancer care includes a multidisciplinary team to ensure that clear communication and consultation with collaborating providers guarantees the best possible outcome for each patient. As highlighted in this case, consideration of an intrathecal TDD system is an important therapeutic intervention that may correct a known systemic opioid side effect and allow patients' greater control during an otherwise tumultuous journey. We strongly recommend considering this option sooner rather than later in treatment of cancer pain.


Neck pain is a leading cause of individual and societal burden worldwide, affecting an estimated 1 in 5 people aged 70 years and older. The nature and outcomes of chiropractic care for older adults with neck pain, particularly those with co-morbid headaches, remains poorly understood. Therefore, we sought to ascertain: What proportion of Australian chiropractors’ caseload comprises older adults with neck pain (with or without headache); How are these conditions treated; What are the reported outcomes?An online survey examining practitioner and practice characteristics, clinical patient presentations, chiropractic treatment methods and outcomes, and other health service use, was distributed to a random nationally representative sample of 800 Australian chiropractors. Quantitative methods were used to analyze the data.Two hundred eighty-eight chiropractors (response rate = 36%) completed the survey between August and November 2017. Approximately one-third  of the chiropractors’ patients were older adults (i.e. aged ≥65 years), of which 45.5% (SD 20.6) presented with neck pain and 31.3% (SD 20.3) had co-morbid headache. Chiropractors reported to combine a range of physical and manual therapy treatments, exercises and self-management practices in their care of these patients particularly: manipulation of the thoracic spine (82.0%); activator adjustment of the neck (77.3%); and massage of the neck (76.5%). The average number of visits required to resolve headache symptoms was reported to be highest among those with migraine . The majority of chiropractors (57.3%) reported a moderate response to treatment in reported dizziness amongst older adults with neck pain. Approximately 82% of older adult patients were estimated to use at least one other health service concurrently to chiropractic care to manage their neck pain.This is the first known study to investigate chiropractic care of older adults living with neck pain. Chiropractors report using well-established conservative techniques to manage neck pain in older adults. Our findings also indicate that this target group of patients may frequently integrate chiropractic care with other health services in order to manage their neck pain. Further research should provide in-depth investigation of older patients’ experience and other patient-reported outcomes of chiropractic treatment. Neck pain, with or without headache or dizziness, is a leading cause of disability affecting over 350 million people worldwide as of 2015 . FurtherNeck pain in older adults is not extensively studied and this population is generally poorly represented in musculoskeletal research –12. ManyMany older adults in Australia suffering from neck pain and associated conditions seek chiropractic treatment . In factmusculoskeletal interventions were soft tissue therapy, trigger point therapy, massage therapy and/or stretching (66.1%), followed by specific exercise therapy/rehabilitation/injury taping (49.3%) and heat/cryotherapy (16.6%). However, considerable knowledge gaps in the field still remain. For instance, despite being a major clinical concern, clinical management characteristics for neck pain remain largely unexplored. Furthermore, prior investigations of Australian chiropractic care have given little consideration to the older adult patient population. Given the ageing population and the consequent increase in the prevalence of neck pain projected over the coming decades ; b) how neck pain (with or without headache) is treated by chiropractors; and c) the reported outcomes of these treatments.The study was a national, cross-sectional survey of Australian chiropractors and constituted a sub-study of the Australian Chiropractic Research Network (ACORN) Project –26. The Participants for the study were recruited from the ACORN database of practicing Australian chiropractors, which consisted of 1680 chiropractors. The sample was nationally representative of chiropractors in Australia in terms of key indicators such as age, gender and practice location , 26. A sIn addition to demographic information, the survey aimed to collect data on the reported treatment of older adults with neck pain with/out headache by Australian chiropractors, as well as the practicing chiropractors’ perception of the effectiveness of such treatments. The online survey was developed by MFA, drawing from the relevant literature and refined in consultation with the co-authors of this manuscript. The survey was piloted by three practicing Australian chiropractors, the results of which led to minor changes in the wording of some questions. The survey instrument was created and distributed using Qualtrics software. The survey comprised of 28 questions  addressing: chiropractors’ demographic and practice characteristics; estimates of how often the chiropractors treat older adults with neck pain (with and without headaches); the treatment methods employed for this population; estimates of treatment effectiveness; and estimates of usage of other health services among this population. The average completion time of the survey was 5–6 min.SD) for continuous variables. Pearson’s chi-square (χ2) tests were performed to test for associations between categorical variables, and independent samples t-tests and ANOVAs were performed to test for group differences in continuous variables. Where expected frequencies were too small (i.e. < 5), categories were collapsed into broader groupings for χ2 tests. Outliers, defined as values with a standardised residual greater than ±3.29, were winsorized . ObservIn addition to the ACORN ethics approval, the study reported here was reviewed and approved by a College Human Ethics Advisory Network (CHEAN) subcommittee of RMIT University Human Research Ethics Committee (HREC) .Two hundred and eighty-eight chiropractors completed the survey, yielding a response rate of 36%.Two hundred and seven participants were male and 81 were female (Table SD = 14.2) of their patients were older adults. This proportion was slightly higher among practitioners working in rural/regional locations  than those working in urban locations , though this difference just missed statistical significance (t (286) = − 1.95, p = .052). The proportion of older adult patients was not reported to differ according to the practitioner’s gender (t (286) = 0.28, p = .781), age group  = 0.71, p = .587), or number of years in practice  = 0.58, p = .679).On average, chiropractors reported that 28.5% . This was found to differ according to the practitioner’s gender (t(262) = − 2.82, p = .005) and age group  = 3.00, p = .024). Specifically, this estimated proportion of older adult patients with neck pain was significantly higher among male  than female  practitioners and, according to Games-Howell post hoc tests, was significantly higher among practitioners aged 25–34 years  than those aged 65+ years  . However, the estimated proportion of older adult patients with neck pain did not differ according to the number of years the chiropractor had been in practice  = 1.18, p = .319).The respondents also reported, on average, that almost half of their older adult patients had presented with neck pain . Of these patients, 36.5% (SD = 23.1) reportedly had cervicogenic headache, 24.0% (SD = 18.0) had tension-type headache, and 8.5% (SD = 7.6) had migraine headache. Congruently, the majority (79.6%) of chiropractors reported that cervicogenic headache was the most common type of headache experienced by their older adult patients with neck pain  of their older adult patients with neck pain suffered from dizziness, with 24.1% (SD = 21.3) suffering from cervicogenic dizziness. On average, 44.2% (SD = 28.2) of older adult patients with neck pain were reportedly concerned about, or afraid of, falling.Beyond headaches, chiropractors reported, on average, that 28.0% , activator adjustment of the neck (77.3%), and massage of the neck (76.5%)  = 0.73, p = .393). However, chiropractors under 45 years of age were significantly more likely to claim to use more than 3 treatments (93.3%) than those aged 45 years or older (81.8%) (χ2(1) = 6.37, p = .012). Additionally, the number of treatments reported to be used (≤3 vs. > 3) differed according to the chiropractor’s number of years in practice (χ2(2) = 7.14, p = .028) – the 97.9% of chiropractors who each had less than 10 years of chiropractic clinical experience claimed to use more than 3 treatments, compared to 85.2% of those with 11–19 years of clinical experience, and 82.3% of those with 20 or more years of clinical experience.Most (85.9%) chiropractors reported to employ more than three different methods to treat the older adult neck pain patient population. This was the case for both male and female practitioners , followed by those with cervicogenic headache , tension-type headache , and those without headache .Chiropractors reported that the average number of chiropractic visits that older adult patients with neck pain received, before they considered their complaint to be resolved, was highest among those with migraine headache (t(253) = − 0.32, p = .750), tension-type headache (t(253) = − 1.79, p = .075), or no headache (t(253) = − 1.57, p = .118). However, male chiropractors estimated a significantly higher number of visits  than female chiropractors  among their older adult patients with neck pain and concurrent migraine headache (t(253) = − 2.85, p = .005).The number of reported chiropractic visits did not significantly differ by the chiropractor’s gender for patients with cervicogenic headache  = 0.33, p = .855; tension-type headache: F = 1.51, p = .199; migraine headache: F = 0.61, p = .654; cervicogenic headache: F = 1.72, p = .146). Likewise, the number of chiropractic visits for older adult patients with neck pain was not claimed to significantly differ by number of years in practice  = 0.76, p = .553; tension-type headache: F = 1.24, p = .293; migraine headache: Welch’s F = 1.01, p = .407; cervicogenic headache: F = 0.96, p = .430).The number of chiropractic visits for older adult patients with neck pain was not reported to significantly differ by the practitioner’s age group, regardless of concurrent headache type (no headache: 2(1) = 0.06, p = .805), age group (χ2(4) = 3.19, p = .527), or years in practice (χ2(4) = 2.21, p = .697).With regard to older adult patients with neck pain who also had dizziness, most chiropractors rated the typical response of dizziness to their treatment as ‘moderate’ (57.3%)  (see Table SD = 26.8) of their older adult patients with neck pain use other health services in addition to chiropractic care. These included (in descending order of frequency): over-the-counter analgesics and/or anti-inflammatories; massage (by a massage therapist); prescription medications (for pain or inflammation); physiotherapy; and acupuncture/dry-needling  compared to male chiropractors  (t(253) = 2.03, p = .044). This also differed according to the chiropractor’s age group  = 3.23, p = .013) and years in practice  = 3.52, p = .008). Tukey’s post hoc tests revealed that chiropractors aged 25–34 years reported a significantly higher rate of other health service use among their older adult patients with neck pain  than those aged 65+ years  (p = .014), and chiropractors with 6–10 years of experience reported a significantly higher rate of other health service use  than those with 20+ years of experience  (p = .012).Female chiropractors reported a significantly higher rate of other health service use among their older adult patients with neck pain , or tension-type (one-quarter) or migraine (less than 9%). This is consistent with the reported prevalence of tension-type headache, cervicogenic headache and migraine among older adults . It is aAustralian chiropractors reported to use diverse manual and physical therapy techniques to manage neck pain in older adults, including manipulation, mobilization, a wide range of exercises and self-management strategies. The most frequently reported treatments , which may be viewed as constituting ‘usual chiropractic care’ for this condition in this population, were thoracic manipulation, massage manipulation and mobilization of the neck (including Activator adjustments), passive stretching and stretching exercises. These treatments reflect best practice in the use of manual therapy for neck pain in adults . HoweverThe finding that younger (< 45 years of age) chiropractors  claimed to use more than three treatment modalities to manage neck pain in older adults is interesting. This may reflect limited clinical expertise, or on the other hand, a greater willingness to experiment with combinations of treatment modalities to achieve better results. Alternatively, it may be indicative of a greater willingness on the part of younger chiropractors to follow current clinical guidelines that recommend multimodal care  and hencAccording to responses from the surveyed chiropractors, older adult patients with neck pain requiring the lowest dose of chiropractic treatment were generally without headache. As expected, the response of headaches to chiropractic treatment in older adults with neck pain was reported to vary according to headache type. Older adult patients with neck pain and tension-type headache, followed by cervicogenic and migraine headache, were reported to need progressively higher doses of treatment before they considered their condition to be resolved. However, many chiropractors justifiably commented that these presenting complaints rarely permanently ‘resolved’ in older adults and they needed long-term management. However, an intriguing finding was that male chiropractors estimated 50% more treatment visits were needed for older adult patients with neck pain and migraine headaches. It is important for future research to identify whether male chiropractors provide more treatment sessions to this subpopulation of older adults and to explore the reason/s for this.Most chiropractors reported moderately positive responses  to chiropractic treatments for dizziness in older adult patients with neck pain. This is a potentially important finding that could have significant ramifications for falls prevention strategies in primary care, as dizziness is an important risk factor for falls in older adults . HoweverInterestingly, Australian chiropractors estimated that one in three older adult patients receiving chiropractic care for their neck pain also accessed other health services in order to manage their neck pain. These included (in descending order of frequency): over-the-counter analgesics and/or anti-inflammatories, massage (by a massage therapist), prescription medications (for pain or inflammation), physiotherapy, and acupuncture or dry-needling Table . The reaOf further interest was that female chiropractors’ estimates of the proportion of older adult patients with neck pain who simultaneously use other health services was significantly higher than their male colleagues. This was also the case for younger chiropractors and those with fewer years of clinical practice experience. Again, a number of possible explanations exist for these observations. It may be that the treatment approaches of female chiropractors are less clinically effective. It also may be that a female chiropractors’ relationship with their patient is more open, hence allowing their patients to more readily disclose the use of other health care services.Given the high burden of illness associated with neck pain in older people, including those with comorbid headaches, and the societal burden worldwide, a better understanding of the nature and outcomes of chiropractic care may help inform improved, intra and multidisciplinary approaches to the management of this condition. This nationally representative study found that Australian chiropractors claim to employ commonly used manual and physical therapy techniques to manage neck pain in older people. Chiropractic care may therefore provide a particularly valuable service for older adults, particularly those unable to tolerate analgesic and anti-inflammatory medications.Despite some variations in the volume and frequency of treatments reported between male and female chiropractors in this study, on average, the reported health-related outcomes for neck pain and associated comorbidities appear favourable for older adults. The findings also indicate that this target group of patients may frequently integrate chiropractic care with other health services in order to effectively manage and co-manage their neck pain. Providing evidence-based and patient-centred treatment options for older people experiencing neck pain and associated comorbidities may help facilitate improved pathways to healthy ageing in this population.This study used a self-reported questionnaire to gather data on the proportion of older Australian patients with neck pain (with or without headache) using chiropractic, the characteristics of chiropractors treating a higher or lower proportion of older people, how neck pain (with or without headache) was managed, and the outcomes of such treatments. Limitations of the study included: practitioner bias in the description of treatments; professional bias ; and recall bias . Notwithstanding, it is difficult to gauge the influence of recall bias in this study as the respondents were not asked to produce estimations of their clinical encounters over a specified period of time. The large number of respondents, the national representativeness of the sample, and the strong patterns observed in the responses to questions represent important strengths of this study.Future studies should aim to validate the findings of this survey, by surveying a large cross-section of older adult patients with neck pain, or by auditing a representative sample of the clinical files of chiropractors treating this condition. Further studies could also focus on exploring the differences between treatment patterns and outcomes between female and male chiropractors, other health-service use and predictors for improved treatment outcomes for neck pain (with or without the various types of headache).This is the first known study to investigate chiropractic care of older adults living with neck pain. The findings suggest that chiropractors use well-established manual and physical therapy techniques to manage neck pain in older adults. The favourable outcomes reported by participants highlight a potential role for using non-pharmacological multimodal therapeutic approaches for the management of neck pain in older adults. The findings also indicate that this target group of patients may frequently integrate chiropractic care with other health services in order to manage their neck pain. Understanding the patient’s motivation for using multiple services may shed light on the health care needs of this population. Further research should also explore how chiropractic treatment of neck pain in older adults impacts patient experience, and other patient-reported outcomes. Given the high prevalence of neck pain in older people, the evidence for the effectiveness of manual and physical treatments for neck pain, the reported demand for chiropractic care in this population, the barriers to pain relief, and concerns among older adults regarding polypharmacy, further studies are needed to provide a more solid evidence-base upon which clinical guidelines for chiropractic management and/or co-management of this condition can be developed. Until then, we recommend that the current clinical guidelines be followed.


Complex regional pain syndrome (CRPS) is a multifactorial disorder with complex aetiology and pathogenesis. At the outpatient pain clinic of Magdeburg University Hospital, all patients, without exception, are subject to permanent psychiatric care delivered by a consultation-liaison psychiatrist. In CRPS, psychological stabilization and treatment of the neuropathic aspects are equally important. The aim of this single-center retrospective study was to determine mental/psychiatric defects impairing pain processing at the time of investigation and show the effects of treating mental disorders and neuropathic pain with the same psychotropic drugs.  On admission, the consultation-liaison psychiatrist examined the mental state of every patient in a semistructured interview according to AMDP (working group for methods and documentation in psychiatry). Due to the model of the Department of Anaesthesiology, we are able to compare the group of CRPS patients with all other outpatients treated for pain.  The medical treatment of psychiatric dysfunction leads to an analgesic effect. Only every second CRPS patient had an additional psychiatric diagnosis, and 15.6% were diagnosed with depressive mood disorders and show a higher prevalence of depressive symptoms than the general population and exceed the mean for all patients treated in our pain clinic.  In neuropathies, treatment of the neuropathic pain has a modulating effect on mental disorders. As CRPS patients are frequently affected by depressions, and owing to the connection between depression and suicidal tendencies, patients should be seen by a consultation-liaison psychiatrist, and nonpsychiatrists should pay special attention to this patient group. CRPS I, formerly known as reflex sympathetic dystrophy (RSD)—here, no nerve lesions can be identified.CRPS II . The symptoms of this syndrome include evidence of a nerve lesion .The complex regional pain syndrome (CRPS) can be divided into two groups:As CRPS belongs to the neuropathic diseases, the patients were subject to drug therapy, with special attention paid to the administration of anticonvulsant and antidepressant drugs. Wertli et al.  performeThe care by a consultation-liaison (CL) psychiatrist is a permanent feature of the Department of Anaesthesiology, where the CL psychiatrist is employed full time since 2001. All patients, without exception, undergo psychological evaluation. In this way, it is possible to obtain an overview of the group of CRPS patients and relate them to the entire group of outpatients treated for pain.This retrospective study describes the neuropathic and psychiatric aspects of CRPS patients and their treatment.For this retrospective study, we collected data from CRPS patients examined at the Department of Anaesthesiology  between January 1, 2001, and June 30, 2014. Data were analysed after consultation with the Ethics Committee of Otto-von-Guericke University and in strict compliance with data protection by pseudonymization. The correctness of the referral diagnosis of CRPS for outpatient treatment was checked and confirmed at our clinic according to the clinical data and criteria published by Stanton-Hicks et al.  and, aftOne of the central issues of the patients' medical history is pain quality and pain severity. The Visual Analogue Scale (VAS) is a 10 cm scale that measures the severity of pain. The scale has different descriptors at each end on a horizontal line . In addition to the current pain level (current VAS), the patients are interviewed for their maximum (maximum VAS), minimum (minimum VAS), and target VAS (“Which pain level would you accept if we say that we cannot reach VAS 0?”).To complete the medical history, the CL psychiatrist questioned the patients in a semistructured interview according to AMDP to get an overview of their psychic state. To evaluate and classify the findings, a comparison was made with the entire group of pain outpatients with corresponding somatic and psychiatric diagnoses for the period 2001–June 2014.The AMDP System is a Manual for the Assessment and Documentation of Psychopathology. The AMDP is an addition to a small number of instruments that have been created and tested in an international setting .The SCL-90-R assesses psychological distress in terms of nine primary symptom dimensions and three summary scores termed global scores. SCL-90-R test was applied to all patients involved in this study. Somatization (SOM), Obsessive-Compulsive (O-C), Anxiety (ANX), Hostility (HOS), Phobic Anxiety (PHOB), Paranoid Ideation (PAR), and Psychoticism (PSY) subscales of SCL-90-R test were performed, and general assessment of SCL-90-R test was performed by the means of Global Severity Index (GSI). Its score is found by the average of the ratings of all items (range 0–4). GSI results indicate general assessment of SCL-90-R questionnaire.Statistical analysis was conducted with IBM SPSS version 24 .At first, descriptive analyses were carried out. The associations between qualitative variables were investigated by contingency table analyses using Pearson's chi-square test. The Mann–Whitney test was applied for comparison between quantitative variables (VAS). Wilcoxon's paired test was used to ascertain differences in quantitative data (VAS) between the time of the last consultation and the time of admission. This was done separately for the different groups to be investigated .α of 0.05 was assumed .In all statistical tests, an error probability of Since the consequent registration of patients with somatic and psychiatric diagnoses at the Department of Anaesthesiology of Magdeburg Medical Faculty began in 2001, 64 CRPS patients  have been treated . From the time of admission onwards, patients' age ranged from 19 to 89 years, with a mean (±standard deviation) of 49.6 ± 13.1 years. It must be pointed out that 47 patients developed CRPS after surgery. The demographic data are presented in n=59)Medical treatment (n=48), lymphatic drainage (n=12), occupational therapy (n=8), manual treatment (n=7), electrotherapy (n=8), and transcutaneous electrical nerve stimulation (n=13)Physical therapy with remedial gymnastics (n=8) and autogenic training (n=6)Psychotherapy (n=14), local anaesthesia (n=3), stellate ganglion block (n=2), spinal cord stimulation (n=2), and intravenous therapy with NMDA receptor antagonist (n=1)Invasive treatments with intra-articular injection of corticosteroids (n=7)Alternative medicine with acupuncture  were mentioned by 60 of the 64 patients.Altogether, the GSI data of 47 patients (73.4%) were compared. For 17 patients, no data were available. GSI had a mean value of 53.8 ± 8.4 . Thirty-seven patients (78.3%) had GSI scores ≤ 60 , whereas 10 patients (21.3%) had GSI scores > 60. These patients showed increased values  for anxiety  and depression .Twenty-eight of 64 CRPS patients received a psychiatric diagnosis. For 36 patients (56.3%), the psychiatric findings were unremarkable. Seven of 28 patients with psychiatric diagnosis received a double diagnosis (25.0%), one patient a triple diagnosis (3.6%), and one patient a quadruple diagnosis (3.6%). The diagnoses are presented in n=2439) gave the following picture:The psychological findings of 805 patients (33%) were unremarkable.1634 patients (67%) had at least one psychiatric diagnosis.866 (35.5%) of the patients had two, 173 (7.1%) had three, 10 (0.4%) had four, and two patients (0.1%) had five psychiatric diagnoses at the same time.n=378).Depression (F3) was diagnosed in 15.5% (207 (8.5%) of the patients abused pain killers or other substances.636 patients (26.1%) were affected by a neurotic spectrum disorder .The psychiatric examinations of all the patients treated at the Department of Anaesthesiology (p < 0.001). These differences especially apply to female patients (p=0.005).The CRPS patients and all the other pain outpatients of our department were compared for the frequency of psychiatric diagnoses. This comparison revealed that CRPS patients were less frequently affected by organic defects including symptomatic psychiatric disorders (F0), as well as by neurotic stress and somatoform disorders. No anxiety disorders were noted. They also more frequently suffered from personality and behavioral disorders (F6) without any psychopathological findings (Psychiatric findings classified as F3 and F4 (mood and adjustment disorders) of patients with somatic pain diagnoses  in our CRPS patients had the lowest proportion of psychiatric disorders and come after the group of patients with tumour pain. However, as far as the F3 depressions are concerned, their proportion is higher than the mean of the entire group of pain patients.p=0.037). At the end of the medication switch, CRPS patients with nerve lesions reached a VAS pain level of 4.25 ± 2.2 and those without nerve lesions reached a VAS level of 3.39 ± 2.2   VAS current: 5.63/3.97 (p=0.015)  VAS minimum: 4.0/2.63 (p=0.008)  VAS target: 3.08/2.03 (There were significant differences in patients with psychiatric diagnosis on admission. The VAS data at presentation were as follows (psychiatric diagnosis yes/no):p=0.658) and VAS end .Here, the CRPS patients with psychiatric diagnosis showed significantly higher VAS values. No differences were found for VAS maximum  when compared to the baseline values . In 1998, Monti et al.  comparedIn their most recent systematically performed psychiatric investigation performed in 2001, Rommel et al.  concentrIn our study, we registered a depression rate of 15.6%, which is similar to the percentage reported by Rommel et al. When compared to the entire group, anxiety disorders were not diagnosed.In our department, both an anaesthesiologist and a permanently present CL psychiatrist take care of all the pain patients. This means that psychological findings are available for all patients (100%). Compared to the entire patient cohort of the Department of Anaesthesiology, the proportion of psychiatric disorders in CRPS patients is lower. A specific comparison with back pain and muscle-joint pain revealed that the proportion was considerably lower.According to Feliu and Edwards , specifia higher prevalence (15.6%) for depression. The TACOS study in Germany (Transitions in Alcohol Consumption and Smoking) interviewed 4075 persons by telephone and found that 11.5% of the questioned participants were affected by major depression ,a higher prevalence for depression compared to the majority of somatic patients of the entire group,that concerning depression, our data are similar to those of Rommel et al. .However, compared to the common population, the CRPS patients of our study showRommel et al. concluded that depressive mood disorders constitute a factor that promotes disease and intensifies pain. In our study, pain was more intense in patients with psychiatric disorders. Other studies also confirm that psychiatric disorders intensify pain in CRPS patients .In general, patients with neuropathic pain have a lower incidence of depression than patients with other forms of physical pain. In our study population, 7.2% had a F3 diagnosis, while 15.9% of CRPS patients showed a F3 diagnosis . Smith eIn a publication from our study group, we could show that neuropathic pain has an incidence of 8.2% for F3 depression as opposed to lower back pain (14.0%) and muscle-joint pain (15.0%) in a population of 485 outpatients assessed over a consecutive 6-month period .Maier et al. found in a general population a prevalence of 4.5% for F3 depression , whereasDifferent therapies have been recommended for the treatment of CRPS. A large number of studies have investigated the analgesic effects of different therapy forms . HoweverDue to the association between depression and suicidal tendencies among pain patients –37, survThis study only compared the psychiatric diagnoses of CRPS patients with those of other chronic pain patients in an outpatient clinic of a university hospital. It was not the aim of this study to perform an expansive psychological assessment or to systematically determine radical and stressing life events and their timely assignment to the disease process.Also, the diagnostic criteria of CRPS were revised and adopted by the IASP in 2010. The Budapest Criteria have a sensitivity nearly identical to that for the IASP criteria, but with substantially improved specificity, and furthermore lead to improved diagnostic consistency between clinicians .CRPS is a syndrome that offers an extremely variable picture. Emphasis is placed on two psychiatric factors (anxiety and depression). Some authors assign a repeatedly noted anxiety to a type of personality, whereas others regard this as a clue to anxiety disorders and their differential diagnoses . In our The depressions were assigned to affective disorders F3) in two publications based on SCID for DSM-III  and, res in two pHowever, as the number of cases is very small, this conclusion should be regarded with caution. But those data are confirmed by current investigations and by comparison with all disease courses evaluated by the Department of Anaesthesiology to date. As depressions may lead to a higher rate of suicidality in CRPS patients , 37, psy


Eighteen (60%) patients in SILFD vs. 9 (28%) in the BRD group fulfilled responder criteria (p = 0.001). Global IBS symptom severity significantly improved and the number of high-FODMAP items consumed was significantly decreased after SILFD compared to BRD. Post-prandial hydrogen (H2) breath production after SILFD was significantly lower than was seen after BRD (p < 0.001). SILFD was more effective than BRD. This advice method significantly reduced FODMAP intake, improved IBS symptoms, and lowered intestinal H2 production.A low fermentable oligosaccharide, disaccharide, monosaccharide, and polyol (FODMAP) diet has been recommended for irritable bowel syndrome (IBS) patients. This study compared the efficacy of two types of dietary advice: (1) brief advice on a commonly recommended diet (BRD), and (2) structural individual low-FODMAP dietary advice (SILFD). Patients with moderate-to-severe IBS were randomized to BRD or SILFD groups. Gastrointestinal symptoms, 7-day food diaries, and post-prandial breath samples were evaluated. The SILFD included (1) identifying high-FODMAP items from the diary, (2) replacing high-FODMAP items with low-FODMAP ones by choosing from the provided menu. The BRD included reducing traditionally recognized foods that cause bloating/abdominal pain and avoidance of large meals. Responders were defined as those experiencing a ≥30% decrease in the average of daily worst abdominal pain/discomfort after 4 weeks. Sixty-two patients , BRD ( Irritable bowel syndrome (IBS) is a common functional gastrointestinal (GI) disorder that affects 10%–20% of the adult population worldwide . The mec2) and methane (CH4) gas production in Thai IBS patients.The aim of this study was to compare the efficacy of two low-FODMAP dietary advice methods in an out-patient setting administered by gastroenterologist—(1) brief advice on a commonly recommended diet (BRD), and (2) structural individual low-FODMAP dietary advice (SILFD)—on IBS symptoms and postprandial hydrogen (HAdult patients (18–70 years of age) who were diagnosed as IBS by Rome III criteria with moderate-to-severe GI symptoms  were enrolled from the gastroenterology outpatient clinic in King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Exclusion criteria were previous surgery of the GI tract except for appendectomy and hemorrhoidectomy; inflammatory bowel disease; celiac disease; GI malignancy; and severe heart, liver, lung, neurological, or psychiatric diseases. The patients who excessively restricted FODMAPs in their diet (<7 items per week) before study enrollment were also excluded. The use of antibiotics, prebiotics, probiotics, or symbiotics or other supplements were not allowed 4 weeks before or during the study period. All participants needed to have a stable medical treatment at least 4 weeks before the study enrollment.At the first visit (week −1), all eligible participants were asked to complete a food diary to capture their habitual diet for 7 days before the randomization.At the second visit (week 0), food diaries were reviewed to exclude patients who excessively restricted FODMAPs in their diet (frequency less than seven items per week) before the study. Subjects were asked to complete a GI symptoms questionnaire and the Hospital Anxiety and Depression scale . BaselinPatients received 5 min of dietary advice from an investigator, which included reducing certain foods that have been traditionally recognized as triggers for gas, bloating, or abdominal pain, including fruits, vegetables, nuts, beans, and garlic, and avoidance of large meals. The term FODMAP was not used during the advice.High-FODMAP items that might aggravate the patient’s symptoms were identified from an individual 7-day food diary. Then, the investigator discussed with the patients to avoid high-FODMAP items and modify recipe/menu with the commonly available low-FODMAP items. The items low in FODMAPs in our country with an example food menu using these low-FODMAP items were listed in the pamphlets provided to the patients. The typical SILFD session was not more than 30 min in this study.On the third visit (week 4), subjects were asked to complete a GI symptoms questionnaire and the Hospital Anxiety and Depression scale for symptoms assessment during the last 7 days of the study period. They were also asked to have their own breakfast and lunch on this day. Then, end-of-study postprandial hydrogen and methane breath samples were collected every 15 min for 4 h immediately after lunch.The study was conducted in accordance with the Declaration of Helsinki and the protocol was approved by the Institutional Review Board, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.The severity of upper and lower gastrointestinal symptoms including abdominal pain, abdominal discomfort, belching, bloating, and stool urgency was assessed using a 0–10 cm visual analog scale (VAS) at baseline and at the end of the study. The primary endpoint was % responders, defined as the proportion of subjects who had at least a 30% decrease in the average daily worst abdominal pain or abdominal discomfort during the fourth week compared to the baseline. The secondary endpoints were the effect of the dietary advice on postprandial hydrogen and methane gas production, global IBS symptoms, and each GI symptom as well as stool frequency and stool consistency (BSFS type 1–7). Adherence to the dietary advice was also analyzed using a food diary comparing the number of high-FODMAP containing food items between baseline and during the last week of the study period.α = 0.05. This indicated at least 31 subjects in each group. The data were analyzed using SPSS software for Windows . Each categorical parameter was analyzed using Chi-square test or Fisher exact test, and Student’s t-test or Mann–Whitney U test were used for continuous parameters. A per-protocol analysis was used. Data are expressed as the mean ± SD or as median with interquartile range. A p-value < 0.05 was considered statistically significant.The sample size was calculated based on the previous study comparing the symptom response between low-FODMAP dietary advice and standard dietary advice for patients with irritable bowel syndrome  with 90%n = 33) or BRD (n = 33) and followed up for 4 weeks. Three patients in the SILFD group and one patient in the BRD group were lost to follow up. Therefore, sixty-two patients  were analyzed, 30 patients in the SILFD group and 32 in the BRD group (Seventy patients with moderate-to-severe IBS were eligible for this study. Four patients were excluded due to pregnancy (1) and previous GI surgery (3). Then, sixty-six patients were randomized to receive SILFD . After the intervention, the global IBS symptom severity score (VAS 0–100) in the SILFD group was significantly lower in than the BRD group  (p < 0.001), but did not significantly change after BRD (baseline vs. end of the study (VAS 0−100), 56.3 ± 17.8 vs. 53.5 ± 19.2, respectively, p > 0.05) (p > 0.05). Belching and stool urgency after SILFD and BRD did not significantly change compared to baseline.Eighteen of thirty patients (60%) fulfilled the responder criteria after SILFD compared to 9 of 32 patients (28%) who were responders after BRD ( < 0.01) . The glo > 0.05) . Abdomin2 and CH4 concentrations over the 4 h post-prandial period were not significantly different between SILFD and BRD groups  vs. 1230 (443–2138) ppm-min, p > 0.05 and CH4: 705 (927–1305) vs. 255 (0–938) ppm-min, p > 0.05; peak H2, SILFD vs. BRD: 17.0 (7.0–30.0) vs.12.0 (6.5–20.0) ppm, p > 0.05 and CH4: 6.0 (2.3–8.0) vs. 4.0 (0–7.5) ppm, p > 0.05). After intervention, breath H2 concentration over the 4 h post-prandial at 4 weeks was significantly lower in the SILFD group compared to the BRD group, whereas breath CH4 concentrations over the 4 h post-prandial period at 4 weeks after SILFD tended to be lower than those after BRD but did not reach statistical significance  vs. 2520 (885–3810) ppm-min, p < 0.001 and CH4: 465 (128–1110) vs. 1005 (105–1590) ppm-min, p > 0.05; peak H2, SILFD vs. BRD: 7.0 (3.0–14.0) vs. 19.0 (10.0–32.0) ppm, p < 0.001 and CH4: 5.0 (2.0–8.0) vs. 6.0 (3.0–9.0) ppm, p > 0.05)  .p < 0.05). Global IBS symptoms, abdominal pain, and abdominal discomfort severity scores after SILFD were significantly lower than those in the BRD group  35.1 ± 19.6 vs. 53.0 ± 21.7, p < 0.05; abdominal pain, SILFD vs. BRD: (VAS 0–10) 1.2 (0–3) vs. 4.1 (0–5.7), p < 0.05; abdominal discomfort, SILFD vs. BRD: 2.5 (0.8–4.8) vs. 5 (2.6–6.7), p < 0.05). Bloating and belching after interventions were not significantly different between SILFD and BRD groups (p > 0.05). The stool frequency during the last (fourth) week after interventions was not significantly different between SILFD and BRD groups (p > 0.05).Baseline characteristics including global IBS symptom severity, abdominal pain, abdominal discomfort, bloating, belching, stool frequency, and number of high-FODMAP food items consumed per week were similar between SILFD and BRD groups in both IBS—constipation and IBS—non-constipation patients. Among 33 patients who had IBS—constipation, fifteen patients were randomized to SILFD and eighteen patients were randomized to BRD. Eleven of 15 patients (73%) fulfilled the responder criteria after SILFD compared to 5 of 18 patients (28%) who were responders after BRD (p < 0.05). There was no significant difference in post-intervention global IBS symptom severity, abdominal pain, abdominal discomfort, bloating, belching, stool urgency, or stool frequency between SILFD and BRD groups (p > 0.05).On the other hand, among the 29 patients who had IBS—non-constipation, fifteen were randomized to the SILFD group and fourteen were randomized to the BRD group. Seven of fifteen patients (47%) fulfilled the responder criteria after SILFD compared to 4 of 14 patients (29%) who were responders after BRD (p < 0.001). After SILFD, there was a significant reduction in the number of high-FODMAP food items per week from baseline  whereas there was no significant change in the number of high-FODMAP food items per week after BRD compared to baseline  (Food diaries for 7 days during the fourth week after intervention showed that the number of high-FODMAP items per week was significantly lower in the SIFLD compared to the BRD group ( > 0.05) .Studies demonstrated that low-FODMAP diet intake was effective in 50%–80% of patients with IBS compared to regular diet or a commonly recommended diet ,13,14,15This study revealed that 60% of patients with moderate-to-severe IBS had at least a 30% decrease in the average daily worst abdominal pain or abdominal discomfort during the last (fourth) week compared to the baseline after SILFD was given compared to 28% of patients who met this criterion after BRD. The definition of a responder is a part of FDA endpoints for the IBS clinical trials, and 30% pain reduction was considered as the minimally clinically important difference . The resEastern and Western dietary patters are completely different. Although rice, which has a low fiber content and nearly complete absorption in the small intestine, is the main carbohydrate source in the Asian diet , vegetabStudies regarding the amount and frequency of consuming a FODMAP-containing diet in each country or dietary style are essential for giving dietary recommendations to patients with IBS but are lacking in Asia. Complex food dishes or recipes are common in Asia, such as pad Thai (stir-fried noodle) from Thailand, bibimbap (mixed rice dish) from Korea, and ramen (Japanese noodle soup). Each recipe contains 5–7 ingredients considered as high-FODMAP items. Thus, a typical Thai dinner that usually has 3–5 shared dishes will contain 15–35 food items/ingredients. This complex food character may make avoiding high-FODMAP diets in Asian countries more difficult if the patients are not aware of the ingredients of their food. Thus, the application of a low-FODMAP diet in the Asian population is challenging. The SILFD protocol in this study was designed to overcome the problems related to the complex food menus in Asia by (1) assigning all patients to perform a one-week food diary, (2) identifying high-FODMAP items/menus in the diary, and (3) conducting individual discussions with patients to modify the high-FODMAP items/menus with patients’ preferred low-FODMAP items/menus or avoid particular high-FODMAP ingredients. This study showed that Thai patients with moderate-to-severe IBS had been consuming about 16 high-FODMAP items per week. Reducing the number of high-FODMAP items effectively by the SILFD protocol led to symptom improvement. The SILFD protocol described in this study provides an effective concept of low-FODMAP dietary intervention in Thai IBS patients, and should be evaluated in other Asian countries. The BRD protocol was used as a control dietary intervention in this study because the BRD is the routine dietary advice that is commonly given at the out-patient clinic in our center. The failure of BRD was associated with failure to replace the high-FODMAP food items with low-FODMAP items, although they were advised to reduce fruits, vegetables, nuts, beans, and garlic, which have been traditionally recognized as triggers for gas, bloating, and abdominal pain. The avoidance of fat and spicy ingredients was not included in either dietary protocol because we aimed to focus on the gas-related or FODMAP-containing foods.2 and CH4 concentrations in breath samples and GI symptoms after lunch but not after breakfast [We performed breath test studies only after lunch because a previous study in our laboratory found that increased intestinal gas production by a high-FODMAP food item (wheat) had significant effects on Hreakfast . The limreakfast ,15,21, eStructural individual low-FODMAP dietary advice (SILFD) was more effective than brief advice on a commonly recommended diet for moderate-to-severe IBS patients, as it improved IBS symptoms and lowered hydrogen gas production. Patients were able to follow this dietary advice for up to a month with a reduction in the intake of FODMAP-containing items. This study provides a concept of low-FODMAP diet implementation in Asia, and should be evaluated further in other Asian countries.


IntroductionPeripheral nerve blockade (PNB) can be a useful component of a multimodal analgesia approach in managing pain after knee arthroscopy. However, the impact of PNB and short-term recovery in pediatric patients, particularly adolescents, who underwent knee arthroscopy for anterior cruciate ligament (ACL) reconstruction and/or meniscus surgery (repair or resection) has not been well characterized. This prospective study presents observational data on short-term patient outcomes and side effects for 72 hours following discharging home of pediatric patients who underwent arthroscopic ACL and/or meniscus procedures with PNB.MethodsThis is a single-center, single-surgeon prospective observational study conducted over a three-year period. We characterized 72-hour postoperative outcomes including pain scores, return of sensation to the affected limb, analgesic use [nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids], readmission rate, and activities of daily living (ADL) via telephone survey. In addition, retrospective chart review was conducted to obtain perioperative and anesthesia details. Results for surgery groups were analyzed using descriptive and Pearson correlations using the SPSS version 24 .ResultsWe collected data on 47 patients undergoing ACL reconstruction with or without meniscus surgery  or meniscus surgery only . At 72 hours postsurgery, there were no readmissions or complications related to pain. Median-reported pain scores were 2.5 and 5.0 for the ACL and meniscus groups, respectively. A majority of patients continued to require opioids  and NSAIDs  at 72 hours postsurgery, but the number of daily opioid doses taken decreased with each day postoperatively. Over 93% of the patients could ambulate and shower at 72 hours postsurgery.ConclusionsRegional nerve block appears to be an effective and safe analgesic strategy for pediatric arthroscopic ACL and meniscus procedures, with no short-term complications or readmissions related to pain in our cohort. Future prospective investigation is needed to characterize long-term pain outcomes in this surgical population. Effective pain control following a surgery is critical, and it is increasingly clear that employing a multimodal approach for acute pain management can improve patient outcomes -2. MultiIn orthopedic surgery, peripheral nerve blockade (PNB) is a particularly attractive technique because it is relatively easy to perform and it allows for low-risk, site-specific analgesia to the affected extremity . MultiplIncreasingly, PNB is being employed as a component of the multimodal analgesic approach in pediatric orthopedic surgery. Prior to the development of ultrasound-guided techniques, PNB in pediatric patients using landmarks or nerve-stimulation methods was commonly considered infeasible due to concerns about the procedural risk, the need for deep sedation or general anesthesia during the procedure, which prevents active patient feedback during blockade, and the need to limit total local anesthetic volume to avoid toxicity, which could increase the risk of block failure -11. IncrThis was a single-center, single-surgeon prospective observational study conducted over a three-year period. After obtaining the Institutional Review Board approval, we approached and enrolled patients after obtaining written informed consent and assent from them. The inclusion criteria included: (1) age between 0 and 18 years old; (2) scheduled for arthroscopic knee surgery (ACL reconstruction and/or meniscus surgery); (3) scheduled for same day surgery; (4) case performed at ambulatory surgical center (ASC); and (5) anesthetic management including the use of single-shot PNB, femoral nerve blockade (FNB), and sciatic nerve blockade (SNB). All eligible patients were included. Anesthetic managementAll patients and parents were consented for general anesthesia and PNB prior to induction of general anesthesia. Following induction of general anesthesia and airway management , the managing anesthesiologist performed a single-shot FNB and SNB  for postoperative analgesia. Single-shot FNB alone was utilized if SNB could not be placed easily, and the use of local anesthetic, block additives (clonidine), and ultrasound for PNB were at the discretion of the managing anesthesiologist. The patients were maintained under general anesthesia until the surgery concluded. Supplemental analgesics were given intraoperatively as per the anesthesiologist's discretion. Postoperatively, the patients recovered in the PACU with standard institutional protocols and all patients were discharged home on the day of surgery.Surgical managementn = 18). In Group A, 11/18 (61.1%) patients underwent concomitant meniscus procedures, which included partial meniscectomy in 5/11 (45.5%), meniscus repair in 3/11 (27.3%), and combined meniscus repair and partial meniscectomy in 3/11 (27.3%). The primary procedure for patients in Group B was an arthroscopic meniscus procedure (n = 29), of which 15/29 (51.7%) underwent partial meniscectomy, 10/29 (34.5%) underwent meniscus repair, 3/29 (10.3%) underwent meniscectomy, and 1/29 (3.4%) underwent combined meniscus repair and partial meniscectomy.The primary procedure for patients in Group A was arthroscopic ACL repair (Data collectionData were collected using a telephone survey and chart review. Telephone surveys were conducted at 72 hours postoperatively. Patients or caregivers (depending on family preference) were asked to provide information on patient pain scores on postoperative day 3, day of sensation return to surgical extremity, frequency of opioid or NSAID use, and ability to complete activities of daily living (ADL) including ambulation, sleeping, and showering. Pain levels were assessed via the Numeric Rating Scale, a reliable, validated, and reproducible 11-point assessment where 0 refers to no pain and 10 refers to the worst possible pain, and respondents were asked to provide an integer value representing their pain . RespondThe chart review was performed to obtain perioperative data, which included demographic information, anesthesia and operative times, regional nerve block details, and occurrence of perioperative complications. Details on medications administered in the preoperative, intra-operative, and PACU were collected and reported. Results were analyzed using descriptive statistics as well as Pearson correlations via the SPSS version 24 software . A total of 49 patients were enrolled but two were excluded because they could not be contacted at 72 hours to complete the postoperative survey. Thus, 47 patients were included for analysis . Arthroscopic ACL reconstruction (Group A) was performed in 18 patients with 11/18 (61.1%) requiring concomitant meniscal surgery while arthroscopy with meniscus-only surgery (Group B) was performed in 29 patients. Demographic data  for each procedure group and surgical times are summarized in Table Perioperative analgesic management, including peripheral nerve block (PNB) details are shown in Table Perioperative analgesic medication administration is summarized and shown in Table r = 0.418, p = 0.084), we did observe a positive correlation for Group B  that was statistically significant. To investigate whether the patients complaining of higher pain scores in the PACU had higher pain scores at 72 hours, we performed Pearson correlations. While we did not observe a statistically significant correlation in maximum pain scores and 72 hours pain scores for Group A  on postoperative day one.These are important findings given a previous study that suggests that pain in children may not be well controlled due to parental concerns about side effects . In a 20Many other studies have reported similar findings of inadequate postdischarge analgesia in pediatric patients undergoing ambulatory orthopedic surgery -19, althWhile the femoral PNB has been shown to improve postoperative analgesia in adult arthroscopic ACL repair -25, someOur patients also demonstrated a clinically minor level of average postoperative pain, as shown by studies where ratings between 1 and 4 are considered mild , 28. In Daily opioid and NSAID analgesic doses required by patients in the first 72 hours postoperatively are summarized and shown in Table Most patients’ sensation to the affected limb returned on postoperative day one, consistent with the literature which suggests that PNBs have 12-24 hours duration of action [As far as limitations and future directions of this work, our study is most significantly limited by the sample size. Furthermore, future studies would benefit from a direct comparison to a control group that did not receive PNB, which is lacking in this study although it was designed as an observational study. Timepoints in addition to 72 hours could be included to generate normative data on pain levels throughout the postoperative period. Other limitations include a lack of standardized anesthesiologist and a lack of long-term follow-up; however, low PACU pain scores suggest all patients had functioning blocks. The latter point is particularly important as recent research has suggested that pediatric and adolescent patients who underwent ACL reconstruction with PNB had decreased quadriceps strength at six months postoperatively compared to patients who did not receive PNB . In thisRegional nerve block appears to be an effective and safe analgesic strategy for pediatric arthroscopic ACL and meniscus procedures, with no short-term complications or readmissions related to pain in our cohort. Future prospective investigation is needed to characterize long-term pain outcomes in this surgical population, and our study is limited by the sample size and the lack of a randomized control group. However, our study uniquely offers a snapshot of the postoperative pain levels, analgesic needs, and ADL of pediatric patients for 72 hours after discharge from ambulatory knee arthroscopy and affirms the efficacy and safety of PNBs with no readmissions or complications and overall low levels of postoperative pain, which increase after PNB effects dissipate.


Although bone marrow aspiration (BMA) is still considered a painful procedure, pain level remains poorly documented. We therefore conducted a prospective study intended to evaluate pain level in adult patients undergoing BMA at the sternal or iliac crest site to identify factors associated with pain. We enrolled a total of 448 patients who underwent 461 BMA and asked those patients to score their pain intensity after BMA using numerical pain rating scale (NPRS). The following factors: level of anxiety, quality of the information given to the patient, operator’s experience, and bone texture were recorded using a standardized questionnaire. The median NPRS score was 3.5  the sternal site (n = 405) was associated with an increased median NPRS score  compared to the iliac crest . For those patients who underwent sternal BMA, the median NPRS score was significantly lower when using lidocaine infiltration (p = 0.0159) as compared with no anesthetic use. Additionally there was no significant effect of anesthetic cream found. After multivariate analysis, the model of NPRS score at the sternal site included patient anxiety (p<0.0001) and the use of lidocaine infiltration (0.0378). This study underlines the usefulness of a comprehensive management including pain relief and efforts to reduce anxiety including appropriate information given to the patient during BMA. Bone marrow aspiration (BMA) allowing quantitative and qualitative assessment of hematopoiesis is essential to the diagnosis, staging, prognosis, follow-up and response to treatment of numerous hematologic and some non-hematologic diseases . In adulIn order to optimize the management of patients undergoing BMA, a prospective study was conducted, aiming at i/ assessing pain level during BMA using numerical pain rating scale (NPRS), and ii/ identifying factors associated with lower pain using a standardized questionnaire completed at the end of the BMA procedure. Finally, a model predicting NPRS score in patients with BMA from the sternal site was created.The study was prospectively conducted in patients undergoing BMA at the university Hôpital Européen Georges Pompidou  between August 2010 and December 2015. HEGP comprises various intensive and acute care units, with no dedicated clinical hematology department. Patients were eligible if they were ≥18 years old and gave their oral consent for participating in the study, and if BMA (without associated BM biopsy) was carried out in the presence of two operators from the hospital Hematology Laboratory, including a senior experienced hematologist. The operator performing the BMA and the assistant could alternatively be either a senior hematologist with an experience of at least 15 years or a junior hematologist (resident). Patients with severe cognitive disorders, deep sedation or language barrier were excluded from the analysis. Within the few minutes following the BMA, a standardized questionnaire was systematically filled out by the assistant . The folThe primary objective of the study was to evaluate pain level using NPRS in adult patients undergoing BMA at the sternal or iliac crest. The second objectives were to identify factors associated with pain during BMA and to build a model predicting NPRS score in these patients.The choice of the topical anesthesia procedure was left to the operator’s discretion. Different anesthesia procedures were proposed: 2.5% lidocaine/2.5% prilocaine cream application (referred below as “anesthetic cream”) at the site of needle insertion (the time of application was recorded); local 20 mg/mL lidocaine infiltration ; 50% nitrous oxide/oxygen gas premix inhalation. A combination of these procedures could be used. Premedication with an anxiolytic or an analgesic were also recorded.The BMA was performed according to a local standard written procedure according to the recommendations of the French Society of Hematology . In Franp values less than 0.15 were entered into a multiple linear regression model and the covariates with a non-null coefficient, according to the 95% bootstrapped confidence interval (CI), were retained in the final model.Computations were performed using the R software . Results were expressed as medians (interquartile range–IQR). All analyses were performed with a linear mixed effect model, using the operator as a random effect, to take into account the potential differences between operators. Tests were done using asymptotic likelihood ratio tests. Since pain score data are not Gaussian, confidence intervals on the model coefficients were obtained using bootstrap to avoid this hypothesis. Covariates were added one by one ; anesthetic procedure as well as other covariates with Of the 1253 patients who had undergone BMA at HEGP between August 2010 and December 2015, 464 patients were eligible in the study with a BMA being performed in the presence of two operators including one among the five senior experienced hematologists . The staOverall, 405 BMA (87.9%) were performed from the sternal site and 56 (12.1%) from the iliac crest site, reflecting the French guidelines of BMA procedure . None ofOf the 461 BMA, 335 (72.7%) were performed by a senior hematologist and 111 (24.1%) by a junior, with missing data for 15 BMA (3.3%). The patients reported to be very anxious for 99 BMA (21.5%), anxious for 147 (31.9%) and non-anxious for 211 . Interestingly, a good agreement was observed when the anxiety level was assessed by the operator with 77.4% of perfect agreement, and only 3 cases of strongly discordant evaluation. After 425 of the 461 BMA (92.2%), patients considered that they had been well informed about the procedure. In 17.1% of BMA, bone texture was evaluated as hard by the operator.For all BMA (n = 461), the median NPRS score was 3.5 IQR . During the study period, the vast majority of patients experienced BMA for the first time with only 12 (2.7%) patients having experienced several BMAs (11 with two BMA and one with three). One third of these repeated BMA experienced lower pain level, one-third equal pain and one-third a higher pain level.For subsequent univariate analyses, all BMA were used. The sternal site was significantly associated with an increased pain when compared to iliac crest, with median NPRS scores of 3.5  and 2.5 , respectively , identity of the operator, none were found significantly associated with NPRS in univariate analyses.Among individual factors potentially influencing NPRS, we found that BMA was significantly more painful in women than in men (p = 0.0352) . In addiWe sought to build a model of the NPRS score for sternal BMA, representing 87.9% of BMA performed in the present cohort. This model included variables potentially influencing NPRS as shown in Noteworthy, the patient’s sex, the quality of information and the bone texture were not retained in the final model; in these cases, p values were comprised between 0.05 and 0.08.i.e. during the infiltration of soft tissue and bone with lidocaine, the needle insertion itself and lastly during BM aspiration [To our knowledge, the present study is the first one assessing pain using NPRS during BMA performed alone by identifying factors influencing pain and their respective impact on the NPRS. Which lead us to the building of a model for evaluating pain at the sternal site. Overall, we found a median NPRS score of 3.5 in the entire cohort (n = 461 BMA). In some studies, pain experienced from the BMA was recorded at different steps, piration . Here, wpiration , reflectpiration . In contAnxiety was also found to be a main predictor of pain during the procedure confirming that the perception of pain may be influenced by the psychological state of the patient. In our cohort, more than half of the patients were anxious or very anxious before BMA. Therefore, prevention and management of pain may require the association of pharmacological and non-pharmacological interventions to reduce pain related to aspiration and that related to anticipatory anxiety in agreement with previous studies –5. It haBeside the use of lidocaine and anxiety as factors significantly influencing pain, we identified other factors that could have an impact on NPRS, although not retained in the final model regarding pain at the sternal site. Women had a trended to have a higher NPRS score. In the literature, inconsistent results have been shown regarding the influence of age and sex on pain level during BMA ,16–17; aet al found that an appropriate explanation of the procedure in a comprehensive and didactic way allowed a trust bond to be formed between the physician and the patient: it was essential to ensure patient confidence and was associated with less pain during iliac BMA [We also found that the quality of the information during the procedure could decrease pain. Similarly, Degen liac BMA –5. In thliac BMA .One strength of our study is the prospective study design with the use of a standardized questionnaire fulfilled in the presence of a senior experienced hematologist during the procedure, therefore limiting biases. Noteworthy, the questionnaire was fulfilled by the assistant, and not by the operator who performed the BMA, to obtain an answer from the patient in a more objective way was moved down just before our limitations of the study.i.e. in 38% of the patients undergoing BMA during the study period. This was chosen to minimize biases due the potential operator dependent variability conducting the study. Secondly, this work was a mono-centric study and evaluating mostly BMA from the sternal site raises the question of whether our findings could be generalizable to other centers. We know that in many countries, the choice of the sternal site is thought to be more hazardous than iliac crest. However, most fatal adverse events that occurred during BMA from sternal site were performed by physicians with lack of experience or performing BMA at an incorrect aspiration site [Our study has some limitations. Firstly, our study was only conducted in patients undergoing BMA in the presence of an experienced senior hematologist, ion site . RemarkaOur study suggests that for BMA from any site, the patient needs to be reassured and well informed regarding the procedure in an attempt at the lowering pain level experienced. For BMA from the sternal site, we recommend the use of lidocaine infiltration. Additional procedures like hypnosis or music therapy could improve the psychological management of the procedure and remain to be investigated .S1 Table(XLSX)Click here for additional data file.


Chronic pain-related disability , depression  and somatization levels  were evaluated through the Research Diagnostic Criteria for TMD (RDC/TMD) Axis II psychosocial assessment; TMD diagnoses were based on the Axis I criteria.the majority of patients presented a low disability or no disability at all, with only a small portion of individuals showing a severely limiting, high disability pain-related impairment (4.3%). On the other hand, abnormal scores of depression and somatization were high, with almost half of the individuals having moderate-to-severe levels of depression and three-fourths presenting moderate-to-severe levels of somatization. The prevalence of high pain-related disability (GCPS grades III or IV), severe/moderate depression and somatization was 14.3%, 44% and 74.1% respectively. Gender differences in scores of SCL-DEP (p=0.031) and SCL-SOM (p=0.001) scales were signficant, with females presenting the highest percentage of abnormal values.patients with TMD frequently present an emotional profile with low disability, high intensity pain-related impairment, and high to moderate levels of somatization and depression. Therefore, given the importance of psychosocial issues at the prognostic level, it is recommended that clinical trials on TMD treatment include an evaluation of patients’ psychosocial profiles. Therefore, the aim of this study was to describe the frequency of psychosocial diagnoses in a large sample of patients attending a tertiary TMD clinic to provide an epidemiological basis for future comparisons.A total of 691 patients  who sought treatment at the TMD Clinic, Department of Maxillofacial Surgery, University of Padova, Italy, from 2011 to 2015 for pain-related TMD were selected. Exclusion criteria were age less than 18, diagnosis of other orofacial pain disorders, and presence of polyarthritis and/or other rheumatic disease.Complete examination was carried out according to the Italian version of the RDC/TMD protocol (RDC/TMD Consortium Network). Psychosocial status was assessed by the Axis II questionnaire, which contains specific items for the appraisal of chronic pain severity and of subjective signs and symptoms for levels of depression and somatization.The Graded Chronic Pain Scale (GCPS)The frequencies of the different scores for the GCPS, SCL-DEP, and SCL-SOM in the study population were reported by descriptive analysis. Analysis of variance (ANOVA) test was used for age differences between patients with different Axis II ratings, and chi-squared test was used for gender comparisons.All patients gave their written informed consent to the clinical diagnostic procedures undertaken during the investigation, and the study protocol was approved by the University of Padova's Institutional Review Board.GCPS scores showed that most patients were rated as grade I or II, with 42.0% having low disability but high intensity pain-related impairment. Conversely, only 7.9% of patients reported no disability at all (grade 0), and 4.3% showed severely limiting, high disability (grade IV) .Approximately 74.1% of patients showed abnormal values on the SCL-SOM scale, indicating severe (50.9%) or moderate (23.2%) somatization levels. As for the SCL-DEP scale, the percentage of patients with abnormal values was lower  .Age differences between patients with different Axis II scores were not significant . Gender differences in scores of SCL-DEP (p=0.031) and SCL-SOM (p=0.001) scales were signficant, with females presenting the highest percentage of abnormal values. Females had the highest frequency of high pain-related impairment (15.2%) in the GCPS scores, even though most female individuals presented low disability, high intensity pain-related impairment (42.7%) . Likewis,,The importance of assessing psychosocial factors in TMD patients has been recognized in the literature, which showed an association between TMD pain and psychological symptoms including depression, somatization, and anxiety.,,In this investigation, based on GCPS scores, the frequencies of the most severe degrees of pain-related impairment were 10% for grade III and 4.3% for grade IV. Available data on the different GCPS categories reported prevalence of 3.1% and 6.3% of high intensity, severely and moderately limiting pain respectively,,,The importance of assessing the levels of pain intensity and pain-related disability evaluated by the GCPS lies in its influence on the clinical decision-making process, i.e. knowing or not such profile is emerging as a factor that affects the prognosis of TMD symptoms. In short, it can be suggested that patients with severe impairment are the worst treatment responders, while those with low impairment seem to have benefit even from “simple” cognitive-behavioral therapy regimen and may take advantage of the positive natural variation of symptoms.-As for the SCL-90R scores, moderate to severe levels of depression and somatization were detected in 44% and 74.1% of patients, respectively. These findings are similar to available data in which the prevalence of depression and somatization was 49% and 69% respectively;,In TMD patients, somatization severity has been useful to distinguish the perception of the physical intensity of pain, and to evaluate its cognitive and emotional meaning. In addition, several studies have found a relationship between measures for somatization and clinical pain in populations with chronic pain, including chronic TMD patients. In particular, somatization is related to a more widespread pain,Similarly, depression in chronic TMD populations has been associated with several reported pain conditions,,,Selecting behavioral treatments based on psychosocial profiles was shown to be successful in TMD patients,This study also assessed the gender distribution of TMD diagnoses regarding Axis II findings. Gender-stratified distribution showed that females presented the highest scores in all three Axis II scales for abnormal values. This result is similar to that reported in a sample of Asian TMD patients,,This investigation has some shortcomings that could be addressed in future studies. The main limitation is the absence of information on the Axis I diagnosis, which might have given a more complete clinical picture. On the other hand, the absence of correlation with the psychosocial findings has already been shown,Thus, to our knowledge, this investigation presented the largest Axis II data collection in a TMD population for future comparison. Methodological issues concerning the size and representativeness  of the study population should be considered for refinement and comparison with future investigations.Based on our findings, it can be concluded that patients with TMD frequently present an emotional profile with low disability, high intensity pain-related impairment and with high to moderate levels of somatization and depression. Given the importance of psychosocial issues at the prognostic level, it is recommended that these data are taken as reference standpoint for future comparisons and that clinical trials on TMD treatment include an evaluation of patients’ psychosocial profiles in order to identify pain phenotypes related to the TMD manifestation.


Postoperative visceral pain is common after surgery and previous studies have demonstrated that oxycodone is an effective treatment. In this study, we compared the effects of preemptive oxycodone to equal dose of sufentanil on postoperative pain and serum level of inflammatory factors  after laparoscopic cholecystectomy.Forty patients undergoing laparoscopic cholecystectomy were randomized into preemptive oxycodone group or preemptive sufentanil group.n = 20) or sufentanil 0.1 μg/kg  for preemptive analgesia. We evaluated pain/sedation scores at 0 h, 0.5 h, 2 h, 4 h, 6 h, 8 h and 24 h after surgery and measured serum concentrations of TNF-α, IL-6 and IL-10 before surgery and at 0 h, 6 h and 24 h after surgery.Patients were given either oxycodone 0.1 mg/kg  and moving  vs 3, P = 0.015) and 4 h when moving  vs 3, P = 0.043) after surgery were significantly lower than the sufentanil group. Serum concentrations of TNF-α at 6 h  and 24 h  in the oxycodone group were lower than the sufentanil group.Twenty patients were recruited in each group. Numerical rating scale (NRS) of visceral pain in the oxycodone group at 2 h when resting  vs 3, Preemptive oxycodone 0.1 mg/kg administration could effectively suppress visceral pain at 2 h and 4 h after surgery and had lower inflammatory marker, serum TNF-α, level when compared to equal dose of sufentanil.http://www.chictr.org.cn/showproj.aspx?proj=17346. Date of registration: 6th December 2017.Clinical trials registration number: ChiCTR-IOR-17013738 Laparoscopic cholecystectomy (LC) carries short operation time, mild surgical trauma and minimal blood loss, which could greatly enhance recovery after surgery (ERAS) , 2. HoweDegree of analgesia intraoperatively is another factor impacting postoperative pain. The nociceptive stimulation during operation will increase pro-inflammatory cytokines such as TNF-α, IL-6 and decrease anti-inflammatory cytokines such as IL-10  and causOpioids are the most common medication used by anesthesiologists to treat pain. There are three opioids receptors, μ receptor, κ receptor and δ receptor. Sufentanil is high selective μ receptor agonist with fast onset and strong analgesic effect , 10. HowBesides drug types, the timing of drug delivery also impacts perioperative pain. Preemptive analgesia starts administration of analgesic interventions before nociceptive stimulation and is intended to suppress the progress of stress state and central sensitization before they start , 14. PreWe hypothesized that preemptive oxycodone can reduce the degree of postoperative visceral pain and decrease the incidence of postoperative remedial analgesia and PONV. The primary outcome was to evaluate whether preemptive oxycodone administration is superior to equal dose of sufentail on visceral pain after LC in postoperative time points. Secondary outcomes included the serum level of TNF-α, IL-6 and IL-10, the dose of opioid used intraoperative, the postoperative sedation level and the degree of postoperative nausea and vomiting (PONV) and complications after surgery.This double-blinded prospective randomized controlled trial was conducted from March 2018 to September 2018 at the Xuanwu Hospital, Beijing, China, after approval from Xuanwu Hospital Ethics Committee in March 2018. The trial was registered with China Clinical Trial Registry . Forty patients scheduled for LC were included and the written informed consents were obtained from all patients before participation. This manuscript adheres to the applicable CONSORT guidelines.2 2 /(P1-P2)n = 10), emergency surgery (n = 6), long term psychotropic drugs use (n = 4) and refusing to participation (n = 6). After surgery, 5 patients were excluded for converting to open surgery and failing to follow up as planned. Finally, 40 patients were included in present analysis  , P = 0.015) and 4 h  vs 3, P = 0.043) postoperatively.For visceral pain, we found that oxycodone group has lower pain than sufentanil group at 2 h postoperatively  vs 3, One suffered postoperative respiratory depression and two suffered vertigo in the oxycodone group while one patient had recurrence of atrial fibrillation in the sufentanil group. Two patients suffered chest tightness in both groups respectively and were relieved after oxygen inhalation.P<0.001) and 24 h  after surgery. For IL-6 and IL-10, no statistical significance could be found between the groups.Serum TNF-α concentration in both groups gradually rose from preoperation to 24 h after surgery . The results demonstrated that preemptive administration of oxycodone 0.1 mg/kg in LC could effectively suppress the release of TNF-α. According to the role of TNF-α in inflammatory reaction and pain management, we can infer that the systematic inflammatory syndrome in the oxycodone group is less than the sufentanil group. These findings are consistent with our observations of more reduction of visceral pain with preemptive oxycodone.Whether analgesia is adequate could be reflected by the level of inflammatory factors during and after surgery. Previous studies suggested that TNF-α was the initial factor in systematic inflammatory reaction. It acts early and motivates the creation of other cytokines . In addiThere are limitations in our study. First, some of the participants failed to follow-up at 24 h postoperatively because they have already been discharged and a serum specimen was not obtained. Second, the current study is not designed to evaluate hyperalgesia and incidence of chronic pain , 35. FinFor patients undergoing LC, preemptive oxycodone 0.1 mg/kg administration could effectively suppress visceral pain at 2 h and 4 h after surgery and inhibit the rising of serum TNF-α level at 6 h and 24 h after surgery without increasing postoperative complications. Preemptive oxycodone appears to be an effective strategy in dealing with visceral pain after LC.