To identify patterns of analgesic prescription and to explore patient-reported pain intensity, sleep disturbance, and quality of life among cancer patients with pain in Southeast Asia (SEA).This cross-sectional observational study included 465 adult outpatients prescribed analgesics for cancer pain for 1 month or longer at 22 sites in Indonesia, Malaysia, Philippines, Singapore, Thailand, and Vietnam. Data on analgesic prescription and cancer characteristics were extracted from medical records. Pain intensity, sleep disturbance, and quality of life measures were recorded via questionnaires.Most patients (84.4%) had stage III or IV cancer. A total of 419 patients (90.7%) were prescribed opioids; of these, 42.2% received only weak opioids, whereas 57.8% received at least one strong opioid. The mean worst pain intensity during the past 24 hours was 4.76  on a scale of 0 (no pain) to 10 (worst possible pain); the mean current pain intensity was 4.10 . More than half of patients (54.8%) reported sleep disturbance caused by pain in the past 7 days. The majority of patients reported problems with pain/discomfort (82.3%), usual activities (65.8%), mobility (58.2%), and anxiety/depression (56.3%). The median daily dose prescribed in oral morphine equivalents was 30 mg for both morphine and tramadol.Despite unrelieved pain, sleep disturbance, and issues with quality of life, a notable proportion of patients were prescribed only weak opioids, and opioid doses prescribed were generally low. Efforts focused on encouragement of prescriptions with analgesic strength and/or doses proportional to the pain management needs of patients are vital to improve the status of cancer pain management in the region. Pain can affect the physical and psychological well-being of patients, and it is associated with the perception of low quality of life.11 Recommendations include the use of quantitative pain assessment tools and a step-up prescription of analgesics in the order of nonopioids, weak opioids, and strong opioids until adequate relief from pain is achieved.11 When applied as recommended, analgesic therapy can be effective to relieve cancer pain in most cases. However, despite broad distribution of these pain management guidelines, undertreatment of cancer pain is still widely documented.13Various international guidelines have been published to guide pain management for patients with cancer.13 However, the prevalence of undertreated cancer pain in Asia has remained relatively high: the weighted mean is 45.2% in Asia compared with 20.2%, 29.5%, and 32.0% in Australia, Europe, and North America, respectively.13 Although similar data specific to Southeast Asia (SEA) are not available, the situation is likely to be grim, because the adequacy of opioid analgesic consumption has been reported to be very low or virtually none in many SEA countries .14It is encouraging to note a general trend toward better pain management for patients with cancer in recent years. A systematic review of articles published during the last two decades reported an overall reduction in the prevalence of undertreated cancer pain from 41.5% in 2008 to 31.8% in 2014.To better understand how cancer pain is managed in the SEA region, the analgesic treatment of cancer pain in Southeast Asia (ACE) study aimed to identify analgesic prescription patterns among cancer patients with pain in six SEA countries. This study also sought to explore patient-reported pain intensity, sleep disturbance, quality of life, levels of satisfaction with analgesic treatment, and the potential associations between these factors with the types of analgesics prescribed.This multicenter, multinational, cross-sectional, observational study was conducted between October 2015 and December 2015 at 22 sites in six countries in SEA . Patients who met the eligibility criteria were recruited consecutively into the study. Inclusion criteria were as follows: age 18 years or older; pathologic diagnosis of cancer; outpatient status, with cancer pain caused by cancer itself or its treatment; and treatment with any analgesics for more than 1 month for the management of cancer pain. Exclusion criteria were as follows: had an operation for any reason within the past 3 months; an oncologic emergency; any interventional therapy  related to cancer pain within the past 6 weeks; and current participation in any other interventional clinical trials for cancer treatment or supportive care. All patients provided written informed consent before study enrolment.All study data were collected in a single visit via patient medical records and questionnaires. The primary variables of interest were analgesic prescription patterns, quality of life, pain intensity (current pain intensity and worst pain intensity during the past 24 hours), and satisfaction with pain control. Secondary end points included sleep disturbance because of pain in the past 7 days, Eastern Cooperative Oncology Group (ECOG) grade, and cancer-related information. The study protocol, case report forms, and documents used for informed consent were reviewed and approved by the local ethics committee at each study site. All study procedures were conducted in accordance with the Declaration of Helsinki and in compliance with local regulatory requirements.16), sleep disturbance caused by cancer pain within the last 7 days, quality of life , and patient satisfaction with pain control status . Investigators evaluated patient performance statuses with the ECOG grading scale  and recorded sites of pain for each patient.Patient medical records were reviewed to extract data about demographics, cancer characteristics, treatment histories, and current analgesic prescriptions. Patient questionnaires were administered to assess pain intensity ; 462 patients fulfilled the eligibility criteria and were included in the analyses. Patient demographics, cancer characteristics, treatment histories, ECOG grades, sites of pain, pain intensities, EQ-5D-3L responses, and satisfaction with pain control were summarized with descriptive statistics. Continuous variables were expressed as the mean (standard deviation [SD]), and categoric variables were expressed as the number (percentage).2 test and Fisher’s exact test for categoric variables. All variables with univariable P values of < .10 were included in subsequent multivariable regression models. The associations between variables and analgesic type prescribed were tested with multiple logistic regression or multiple linear regression that controlled for potential confounders. P values < .05 were considered statistically significant. All statistical analyses were performed with R, version 3.1.3 .Patients subsequently were grouped into three groups according to the type of analgesics prescribed: nonopioid only, opioid only, or nonopioid and opioid. Differences between groups in terms of cancer stage, treatment, pain intensity, sleep disturbance, EQ-5D-3L, and satisfaction with pain control were analyzed by using one-way analysis of variance for continuous variables or χA total of 465 patients were enrolled in the study. Of these, three patients did not fulfill the eligibility criteria and were excluded from the analysis; 462 patients remained in the analysis population.Demographics and baseline characteristics of the analysis population are listed in Overall, the majority of patients had an ECOG grade of 2 or less . The most common sites of pain were lower back (23.2%), chest (22.3%), and abdomen (19.5%). More than a quarter of patients (27.1%) had pain at other sites .More than half of the analysis population  received a combination of nonopioid and opioid analgesics for cancer pain . A smallOf the 419 patients (90.7%) who were prescribed opioid analgesics , 42.2% received only weak opioids, whereas 57.8% received at least one strong opioid. Morphine was the most common strong opioid prescribed , and tramadol was the most common weak opioid prescribed  for only nonopioid analgesics prescription, 37.27%  for only opioid analgesics prescription, and 51.40%  for prescription of both nonopioid and opioid analgesics. See the Data Supplement for a summary of the guidelines used for cancer pain management in the participating centers within the six countries.On a numeric rating scale from 0 (no pain) to 10 (worst pain imaginable), the mean current pain intensity was 4.10 , and the mean worst pain intensity during the past 24 hours was 4.76 , usual activities (65.8%), mobility (58.2%), and anxiety/depression 56.3%; . HoweverMore than half of patients indicated satisfaction with their pain control status. A total of 192 (41.6%) were satisfied, and 86 (18.6%) were very satisfied.P = .019), metastasis (P = .016), surgery/radiotherapy/chemotherapy treatment (P = .049), concurrent complementary pain therapy (P < .001), and EQ-5D dimension of pain/discomfort (P = .046) and of anxiety/depression  was significantly associated with cancer stage (P = .028).In multivariable analyses that adjusted for potential confounders, only the EQ-5D-3L dimension of anxiety/depression was associated with type of analgesic prescribed. The odds of reported problems in anxiety/depression in the EQ-5D-3L questionnaire were 2.14-fold  higher for patients prescribed a combination of nonopioid and opioid compared with patients prescribed only nonopioids . The median daily dose of tramadol prescribed was 150.00 mg , which was equivalent to 30.00 mg  of oral morphine (Data Supplement).20 To our knowledge, the ACE study is the first multinational prospective study conducted in SEA to identify analgesic prescription patterns among patients with cancer and the relationship of these patterns with pain outcomes. In this study, the cancer characteristics, treatment histories, and prescribed analgesic types and doses were obtained directly from patient medical records. In addition, established tools were used to assess pain intensity  and quality of life (EQ-5D-3L). More than 80% of patients in this study had stage III or IV cancer. Overall, nine in 10 patients were prescribed opioids for cancer pain; however, a significant proportion of these patients were prescribed only weak opioids. Although the majority of patients indicated satisfaction with respect to pain control, most still reported unrelieved pain, problems with pain/discomfort, quality-of-life issues, and sleep disturbance because of cancer pain. Surprisingly, receipt of opioids was not associated with significantly different pain intensity and odds of quality-of-life problems.Current data available in the literature on cancer pain management and practices in SEA are mostly country specific.24 Almost half of patients in the recent ACHEON (Current Practices of Cancer and Chronic Noncancer Pain Management) survey reported that pain was assessed subjectively without the use of a quantitative pain scale.6 The lack of objective pain assessment practices may stem from inadequate physician training in pain assessment methods25 and/or limited ability of patients to understand or use pain scales effectively. Because pain is a subjective experience, it is important that analgesic therapy for cancer pain management be individualized and guided by patient-reported intensity of pain.26 Comprehensive pain assessment techniques, which take psychological distress and quality-of-life measures into account, may help capture the multidimensional nature of cancer pain27; however, these are usually more complex to administer. More initiatives are needed to standardize pain assessment approaches across SEA and to enhance both patient and physician competency in effective reports and assessments of pain.Despite active analgesic treatment, many patients with cancer in the ACE study still experienced pain; the mean reported pain level was moderate intensity . One possible reason for this observed undermanagement of pain may be the lack of use of objective pain scales  to assess and monitor pain on a routine basis in Asia.28especially because the majority of patients were diagnosed with late-stage cancer and had metastatic disease. Moreover, greater than 90% of patients had received treatment of their cancer , and adverse effects from these treatments may affect perceived quality of life.28Although greater than 90% of patients in the ACE study were prescribed opioids for cancer pain management, the majority still reported sleep disturbance because of pain and problems with quality of life . Patient-reported quality of life may be confounded by cancer-related anxiety or depression,30 Often, adverse effects can limit the doses of opioids that the patient is able to tolerate. Symptomatic management of these adverse effects is commonly applied in clinical practice; however, many of the agents used have their own adverse effect profiles as well.31 Other recommended strategies include opioid dose reduction, opioid rotation, and changes to the route of systemic administration.32 A careful review of predisposing patient factors, comorbidities, and performance status may aid clinicians in selection of a strategy to manage opioid-induced adverse effects and to maximize the effectiveness of opioids but reduce the impact of the adverse effects on patient quality of life.Notably, even when multivariable analyses were adjusted for potential confounders, opioid prescription was not associated with lower pain scores, lesser sleep disturbance because of pain, better quality of life, or more satisfaction with pain control. When the between-group differences were significant, the group that received opioids had higher odds of problems with quality of life. Although the specific reasons for patient-reported problems with quality of life were not explored in this study, we speculate that undermanaged opioid-related adverse effects may be a plausible source of these quality-of-life issues. Opioid use is known to be accompanied by adverse effects and complications, such as constipation, nausea, and sedation, which can significantly impair quality of life and affect treatment compliance.34 In this study, more than 80% of the patients had either stage III or IV cancer. Patients in advanced cancer stages tend to suffer from greater intensity of pain and, in most instances, require strong opioids for adequate relief of cancer pain.11 However, many of the participating SEA countries have considerable regulatory restrictions on the use of strong opioids, which include (1) limited duration of opioid prescription , (2) burdensome procedures to report opioid prescriptions (Indonesia), (3) complex procedures to obtain a license to prescribe opioids , and (4) excessively restrictive policies that govern the use of opioids (Vietnam and Philippines).24 These regulatory barriers may lead to physician reluctance to prescribe strong opioids or to prescribe an adequate dose proportional to pain intensity of patients. In addition, affordability issues in SEA  may affect both prescription and consumption patterns of opioids and may limit accessibility to strength and/or doses of opioids that meet pain management needs for patients.38 Indeed, although most patients in the ACE study had late-stage cancer and reported unrelieved pain and problems with pain/discomfort, a notable proportion received only weak opioids, and opioid doses prescribed were generally low . Although regulatory restrictions were intended to prevent opioid abuse, their profound effects on prescribing practices, pain management, and patient quality of life should not be overlooked and must be addressed.The majority of cancers in low-income and middle-income Asian countries are diagnosed in advanced cancer stages.As with most patient-reported outcomes, pain score, quality of life, and satisfaction with pain control are subjective and may be affected by sociocultural differences between countries. Furthermore, confounding factors related to cancer and/or its treatment  on patient-reported outcomes were not captured in this cross-sectional study. Importantly, study sites included in the ACE study were large hospitals situated in the major cities of participating SEA countries; thus, interpretation of the study findings may be limited to more developed regions of SEA. Undermanagement of cancer pain is expected to be even more severe in less-developed regions of SEA, where accessibility to pain management specialists and analgesics is limited.v weak opioids) and to the prescription of analgesic doses that provide adequate pain control. Finally, effective assessment and proactive management of adverse effects are needed to support analgesic compliance and to improve patient quality of life.The majority of cancer pain in patients in this study from the participating SEA countries were prescribed opioids (often in combination with nonopioids), although a notable proportion of patients were prescribed only weak opioids. Despite active analgesic treatment, many patients still experienced unrelieved pain, problems with pain/discomfort, quality-of-life issues, and sleep disturbance because of pain. Notably, management with opioids was not associated with better patient outcomes . The ACE study results suggest suboptimal cancer pain management in SEA. To address this issue, pain should first be assessed systematically through application of standardized pain assessment techniques. Next, beyond the prescription of analgesics, particular attention should be paid to the appropriate selection of analgesics (eg, strong


Randomized clinical trial.To investigate the association of the Val158Met polymorphism with pain and function outcomes in women with carpal tunnel syndrome (CTS) who received surgery or manual therapy including desensitization manoeuvres of the central nervous system.A pre-planned secondary analysis of a randomized controlled trial investigating the efficacy of manual therapy including desensitization manoeuvres of the central nervous system vs. surgery in 120 women with CTS was conducted. Women were randomized to receive 3 sessions of manual therapy (n = 60) or decompression of the carpal tunnel (n = 60). The primary outcome was intensity of pain (mean pain and the worst pain), and secondary outcomes included function and symptoms severity subscales of the Boston Carpal Tunnel Questionnaire. Outcomes were assessed at baseline, and 1, 3, 6, and 12 months after the intervention. Rs4680 genotypes were determined after amplifying the Val158Met polymorphism by polymerase chain reactions. We classified subjects according to their Val158Met polymorphism: Val/Val, Val/Met, or Met/Met. The primary aim  was examined with repeated measures ANCOVA with intention-to-treat analysis.At 12 months, 111 (92%) women completed the follow-up. No interaction was observed between the Val158Met genotype and any outcome: mean pain intensity , worst pain intensity , function  or symptom severity .The current clinical trial did not show an association between the Val158Met polymorphism and changes in pain and function outcomes after either surgery or physical therapy in women with CTS. Carpal tunnel syndrome (CTS) is a common entrapment neuropathy of the upper extremity which can cause considerable pain and disability resulting in significantly costs for the society . It has Management of CTS can be conservative or surgical in nature. There is some controversy on the optimal treatment strategies for CTS since both approaches are effective, although surgery has shown to be slightly superior than localized conservative treatment at long term ,4. It isSupporting the complexity of pain perception is the potential influence of genetic factors. The catechol-O-methyltransferase (COMT) gene is a potential genetic determinant associated to nociceptive pain processing ; howeverA recent randomized clinical trial compared a physical therapy intervention consisting of manual therapies including desensitization maneuvers of the central nervous system with surgery on pain and function in women with CTS . The resThis study consisted of a pre-planned secondary analysis of a randomized clinical trial  comparing the effectiveness of surgery and physical therapy in CTS . The stuConsecutive women with clinical and electrophysiological findings of CTS were recruited from a regional Hospital . Patients had to exhibit pain and paresthesia within the median nerve distribution, increasing symptoms during night, positive Tinel and Phalen signs, and electro-diagnostic findings of deficits in sensory/motor median nerve conduction according to American Association of Electrodiagnosis, American Academy of Neurology and American Physical Medicine and Rehabilitation Academy guidelines . InternaParticipants were randomly assigned to receive either physical therapy or surgery. Details on the randomization procedure have been previously published . As descPatients allocated to the surgery group underwent open or endoscopic decompression and release of the carpal tunnel conducted by experienced surgeons with at least 15 years of practice in hand surgery. Since no particular surgical procedure seems to be more effective, surgery was based on surgeon’s and patient’s preference  TGAAGGACAAGGTGTGCATGCCTGA2 tests of independence for categorical data. To determine the effect of the Val158Met polymorphism, 5x2x3 repeated measures ANCOVAs were performed with time  as within-subject factor, group  and polymorphism genotype  as between-subject factors, and adjustment for baseline outcomes. In addition, severity of CTS according to EMG analysis was also included as potential covariable. The hypothesis of interest was the 3-way interaction treatment group*Val158Met*time. Separate ANCOVAs were performed for pain, function and symptom severity. A corrected P value of P<0.017 (Bonferroni correction) for the 3-way interaction was required to be statistically significant.Statistical analysis was performed using SPSS software, version 21.0 . Sample size was based on changes in the intensity of hand pain at 1-year follow-up as described previously in detail . An inteFig 1 provides a flow diagram of subject recruitment and retention. At one-year follow-up, 111 (92%) patients provided follow-up data.Two hundred consecutive patients with CTS were screened for eligibility criteria. One hundred and twenty women , satisfied all criteria, agreed to participate, and were randomly allocated into physical therapy (n = 60) or surgical (n = 60) groups. Of those in the physical therapy group, 14 had a Met/Met genotype (23%) whereas within those in the surgery group 17 had a Met/Met genotype (28%). Table 1). Fifty-six (93%) of the participants allocated to the surgery group received open surgery with minimal incision. The main 3-way group interaction  for the repeated-measures ANCOVA was not statistically significant for the mean level of hand pain , the worst pain experienced in the last week , function  or symptom severity : long-term treatment outcomes were similar in all groups independently of the Val158Met genotype. The inclusion of CTS severity did not influence the results on any outcome . The graphical evolution of pain, function, and symptoms severity by Val158Met genotype can be found in Figs 3.Baseline characteristics among the groups were similar for all variables Click here for additional data file.S2 Text(DOC)Click here for additional data file.


A close collaboration between surgeons and non-surgical spine experts is crucial for optimal care of low back pain (LBP) patients. The affiliation of a chiropractic teaching clinic to a university hospital with a large spine division in Zurich, Switzerland, enables such collaboration. The aim of this study was to describe the trajectories and outcomes of patients with chronic LBP referred from the spine surgery division to the chiropractic teaching clinic.The patients filled in an 11-point numeric rating scale (NRS) for pain intensity and the Bournemouth Questionnaire (BQ)  at baseline and after 1 week, 1, 3, 6 and 12 months. Additionally, the Patient’s Global Impression of Change (PGIC) scale was recorded at all time points apart from baseline. The courses of NRS and BQ were analyzed using linear mixed model analysis and repeated measures ANOVA. The proportion of patients reporting clinically relevant overall improvement (PGIC) was calculated and the underlying factors were determined using logistic regression analyses.p = 0.011] to 4.05 (SD 2.88) after 12 months. A significant reduction was not observed before 6 months after treatment start (p = 0.04). BQ significantly diminished  to 29.00 (SD 17.96) after 12 months and showed a significant reduction within the first month (p < 0.01). The proportion of patients reporting overall improvement significantly increased from 23% after 1 week to 47% after 1 month (p = 0.004), when it stabilized . Reduction in bio-psycho-social impairment (BQ) was of higher importance for overall improvement than pain reduction.Between June 2014 and October 2016, 67 participants  were recruited, of whom 46 had suffered from LBP for > 1 year, the rest for > 3 months, but < 1 year. At baseline, mean NRS was 5.43 (SD 2.37) and mean BQ was 39.80 (SD 15.16) points. NRS significantly decreased [F = 3.15, Chiropractic treatment is a valuable conservative treatment modality associated with clinically relevant improvement in approximately half of patients with chronic LBP. These findings provide an example of the importance of interdisciplinary collaboration in the treatment of chronic back pain patients. Low back pain (LBP) is globally the leading cause for years lived with disability . The poiIn some countries where chiropractic belongs to complementary and alternative medicine –9, some The aim of this analysis was to study the trajectories and outcomes of patients with chronic low back pain (LBP) referred from the spine division to the chiropractic teaching clinic over the course of 12 months after start of chiropractic treatment.Patients referred from the spine surgery division to the chiropractic teaching clinic filled in a numeric rating scale (NRS) for present pain intensity and the Bournemouth Questionnaire (BQ), a bio-psycho-social outcome measure (maximum score = 70 points), at baseline (before the first chiropractic treatment) and after 1 week, 1, 3, 6 and 12 months. The BQ is a valid and reliable questionnaire that covers the multidimensionality of musculoskeletal pain in seven items . AdditioN = 7/10.4% (NRS at 6 months) and N = 13/19.4% (PGIC at 12 months)] were handled in two ways to get a comprehensive picture . With regard to previous treatments in the last year, 4 patients had received infiltrations, 38 patients had undergone physiotherapy (3 of them in combination with training therapy), 4 had received massage therapy, 2 complementary medical treatments, and 6 patients had received multi-disciplinary therapy . Of 13 patients, it was unknown whether they had received other treatments. With regard to other therapies in parallel to the chiropractic treatment, 13 patients reported to receive other therapies at the time of chiropractic treatment , 13 reported to have stopped other therapies, and no information about current therapy status was available of the remaining patients.Between June 2014 and October 2016, 67 patients with chronic (> 3 months) LBP  were referred from the spine surgeons to the chiropractic teaching clinic. The majority of the patients  after 12 months, with significant pairwise-comparison between baseline and 6 months after treatment start (p = 0.04)  = 4.77, p = 0.002. Post hoc tests showed a significant reduction in present pain intensity 6 months after treatment start. This finding was consistent in all imputations with the exception of one model, which showed significant pain reduction after the first month.At baseline, mean NRS for present pain was 5.43 (SD 2.37) and mean BQ was 39.80 SD 15.16) points (Table 5.16 poinp < 0.001] to 29.00 (SD 17.96) after 12 months, with significant reduction after 1 month (p < 0.01)  = 17.57, p < 0.001. Consistent in all imputations, significant reduction in the BQ total score was observed 1 month after start of the chiropractic treatment, while four of five models showed significant reduction in BQ total score after 1 week.The total score of the BQ significantly diminished  significantly decreased over time: ‘average pain over the last week’ , ‘interference of pain with daily activities over the last week’ , ‘feeling anxious’ , ‘feeling depressed’ , ‘impact of work on back pain’  and ‘own ability to control back pain’ . LMM revealed significant reduction in all items within the first month of treatment  apart from ‘depression’ that did not decrease before 3 months after treatment start  significantly decreased within the first month after treatment start with the exception ‘interference with recreational, social, and family activities’ that did not decrease before 6 months (p < 0.05).All single BQ items except the item ‘interference of back pain with ability to take part in recreational, social and family activities’ [LMM: F5,101.64) = 1.55, 01.64 = 1p = 0.004): 56% of the patients  reported overall improvement after 3 and 6 months, and 44%  after 12 months. Overall improvement was not associated with reduction in pain (NRS), but with bio-psycho-social impairment (BQ) from 1 month onward after start of chiropractic treatment  after 1 week to 47%  after 1 month, when it stabilized (2 = 0.20–0.39) of variance after 1 month, 46–62% after 3 months, 50–59% after 6 months and 41–54% after 12 months. The only significant single item was the item ‘fear avoidance beliefs’ that was significant after 6 months (p = 0.023).Model 2 , explained 20–39%  and 32% (‘own ability to control back pain’). The observed overall improvement (PGIC ‘better’ or ‘much better‘) from 1 month onwards, reported by approximately half of the patients, was associated with a significant reduction in bio-psycho-social impairment  at each point in time, but not with pain reduction (NRS), and could, apart from the item ‘fear avoidance beliefs’ at 6 months, not be related to single BQ-items.For the patients in this study, the reduction in pain intensity seemed of minor importance for their rating of overall improvement, which is in accordance with previous literature . In contIn contrast to acute patients, where present pain intensity substantially diminishes within the first week of treatment , presentAverage pain over the last week and present pain decreased by 29 and 25%, respectively within the first 12 months after the start of chiropractic treatment. This is close to 30%, which is considered a clinically meaningful change for chronic musculoskeletal pain , 29. ThuThe proportion of patients who indicated overall improvement was slightly lower than in a similar study that recruited chronic LBP patients from multiple chiropractic practices throughout Switzerland, which reported 69% improved patients 3 months after start of chiropractic treatment . Again, Nevertheless, it is important to note that these results do not inform about the efficacy of chiropractic treatment for several reasons: Many patients had other therapies besides chiropractic treatment, foremost physiotherapy. Furthermore, this study did not include a natural history control group and did not track patients who returned to orthopedic care. Another limitation is that the study reports associations between outcome measures and no conclusions about causation can be drawn.These results illustrate that chronic LBP patients with long-lasting pain, reduced general health and high bio-psycho-social impairment, referred from spine surgery to a chiropractic teaching clinic, benefit from being co-managed by surgeons and chiropractors. These findings emphasize the advantages and importance of close collaboration between the two disciplines in order to provide optimal care for chronic back pain patients. The consequence might be an even closer collaboration between the disciplines with focus on spine medicine. In Switzerland, this has now been established at the joint University Spine Center Zurich, where multiple disciplines  are closely working together for optimal patient care.


Anorectal pain is a symptom which may have both structural and functional causes, and can, sometimes, develop into a chronic pain syndrome. Functional causes in particular are challenging to treat when conservative treatment measures fail. Botulinum toxin A (BTX-A) can be applied to relax the anal sphincter and/or levator ani muscle to break the vicious circle of pain and contraction. In our tertiary referral proctology clinic, we evaluated the outcome of patients treated with BTX-A for chronic functional anorectal pain.Our electronic database was searched for patients who had BTX-A treatment for chronic functional anorectal pain from 2011 to 2016. All medical data concerning history, treatments, and clinical outcome were retrieved. The clinical outcome (resolution of pain) was scored as good, temporary, or poor.A total of 113 patients  with chronic functional anorectal pain were included. The outcome of BTX-A treatment was good in 53 (47%), temporary in 23 (20%), and poor in 37 (33%). To achieve this outcome, 29 (45%) patients needed a single treatment, 11 (44%) a second treatment, and 13 (54%) ≥ 3 treatments.Chronic functional anorectal pain can be treated successfully with BTX-A in 47% of patients who fail conservative management. Repeated injections may be needed to ensure complete cure in a subgroup of patients. Anorectal pain is a symptom with a negative impact on the quality of life, and can sometimes develop into a chronic pain syndrome . The etiFunctional disorders associated with chronic anorectal pain as defined by the Rome IV criteria  are LAS,Pelvic floor dyssynergia can be a primary disorder that leads to anorectal pain, but it can also develop secondary to disorders causing anorectal pain. The vicious circle of pain and increased tension of the external anal sphincter and levator ani muscle can lead to even more pain. Patients with PFD are first treated with lifestyle modification, pharmacological, behavioural, and pelvic floor physical therapy including biofeedback. When these treatments are unsuccessful, BTX-A may be offered, although its success has been shown to be limited , 5.Clostridium botulinum [BTX-A is the product of the anaerobic bacterium otulinum . There aotulinum . Repeateotulinum , 9. BTX-Injection of BTX-A has provided the best results in treating anal fissure, and has been widely accepted with success rates up to 96% . HoweverThe aim of this study was to evaluate the use of BTX-A treatment in patients suffering from chronic functional anorectal pain.The electronic database at the Proctos Clinic  was searched for patients who had treatment with BTX-A for chronic anorectal pain between 2011 and 2016. Chronic anorectal pain was defined as pain > 3 months in the anus or pelvic floor according to the Rome IV criteria. All patients with a concomitant structural disorder at the time of BTX-A treatment such as an anal fissure or fistula were excluded. Patients who had had the previous anorectal surgery, including rubber band ligation for hemorrhoids, were also excluded.At the first visit, a full medical history and physical examination, including a routine digital rectal examination of the anal sphincters and the levator ani muscle, were performed. The combined results of electromyography and digital rectal examination provided a diagnosis of hypertonia of the anal sphincter and/or levator ani muscle. The pain was classified as LAS when the levator ani muscle was painful during palpation. A classification of unspecified anorectal pain was given in the absence of a painful palpation of the levator ani muscle.Before BTX-A was considered, all patients followed standard conservative treatment, consisting of regulation of bowel movements , pain medication , and psychosomatical counselling if required. All eligible patients had been treated with one or more of these conservative measures for at least 3 months. In addition, patients were seen by a pelvic floor physiotherapist to receive biofeedback. Electromyography of the anal sphincter and levator ani was performed using the MAPle® probe. This probe is able to distinguish muscle tone of individual pelvic floor muscles . PhysiotPatients with hypertonia of the anal sphincter muscle received 2 injections of 30 units of BTX-A, and patients with hypertonia of the levator ani muscle 2 injections of 40 units each. If patients suffered from hypertonia in both muscles, they received both treatments . All injections were given under local anesthesia with the patient in the left lateral position or under general anesthesia with the patient in lithotomy position. The skin around the anus was disinfected. Injections into both the anal sphincter and levator ani muscle were given under digital guidance of one finger which was positioned in the anus. The needle for injection in the anal sphincter muscle was placed laterally to the anus in the inter-sphincteric space and inserted up to 2 cm proximally to inject the BTX-A, depending on the length of the anal canal. The procedure was repeated contralaterally (3 and 9 o’clock). The needle for injection into the levator ani muscle was placed in the skin at 3–4 cm laterally to the anus  and inserted proximally with a slight deviation to the middle of the rectum. The levator ani muscle was hooked up with the tip of the finger in the anus and retracted downwards. The needle was then inserted into the muscle until the tip of the needle could be identified with palpation of the finger inside the rectum near to the rectal mucosa without perforating it. The needle was retracted slightly and BTX-A was injected. The procedure was repeated at the opposite site (4 and 8 o’clock). A total of 4 different surgeons were involved in the care of the patients.Patients were reviewed at 3 months after BTX-A treatment. Those with complete resolution of their functional anorectal pain were discharged from further follow-up. Patients with an initial good response to BTX-A treatment but a relapse of their symptoms, or those who had no response or worsening of their symptoms were offered a repeat treatment with BTX-A. Patients with no response to BTX-A were offered up to 3 treatment cycles, and patients with an initial response to treatment up to 8 treatment cycles.For analysis, patients were further divided into groups based on sex, number of treatments, duration of complaints, hypertonia of the anal sphincter, levator muscle, or both. Informed consent was obtained from all the individual patients in this study. The VU University Medical Centre Ethics Committee approved this study.The outcome of treatment was scored as good, temporary, or poor. Good was defined as complete resolution of pain and no further treatment or follow-up needed for chronic functional anorectal pain following BTX-A treatment. Temporary was defined as the initial good response but relapse within 3 months. Poor was defined as no improvement, or even worsening of symptoms and anal pain, necessitating treatment with transcutaneous electrical nerve stimulation (TENS), or were referral to a pain specialist. Patients whose outcome was temporary were offered the same options after a relapse of their symptoms and cessation of BTX-A therapy. Up to 8 subsequent treatments with BTX-A were offered.All statistical analyses were performed using SPSS . Continuous data were described as mean or median depending on the distribution, with standard deviation or range, respectively. To detect differences in outcome between groups, the Chi-square test was performed. If additional testing between subgroups was performed, a Bonferroni correction for the p value was applied. A difference was considered significant if p < 0.05.A total of 118 of eligible patients were identified, but 5 were lost to follow-up. Thus, 113 patients were evaluated. There were 47 males (42%) and the mean age was 51 years (range 18–88 years). The mean duration of complaints before the first visit to our clinic was 6 years (range 3 months – 40 years). The mean defecation frequency was twice daily. 15 patients (13%) reported obstructed defecation concomitant with their anorectal pain.Eleven patients (10%) were diagnosed with LAS, while the other 102 (90%) were found to have unspecified anorectal pain. All patients had a form of hypertonia . Eighteen (16%) patients were active smokers. The median number of BTX-A treatments was 2 with a range of 1–8 treatments.p = 0.06). The number of treatments did not influence the overall outcome of treatment (p = 0.051), while a relatively large percentage of patients (39%) had a poor outcome following single treatment with BTX-A. The duration of patients’ complaints did not seem to influence the overall outcome (p = 0.18), although the proportion of good outcomes among patients with longstanding complaints (≥ 5 years) was substantially lower than among patients with a more recent onset of anorectal pain (28% vs 52% and 48%). There was no difference in overall outcome between patients diagnosed with unspecified anorectal pain or LAS (p = 0.72). The results are shown in Table Overall, the outcome was good in 53 (47%) patients, temporary in 23(20%) patients, and poor in 37 (33%) patients. Sex, age, smoking, or duration of complaints did not significantly influence the outcome. Patients with isolated hypertonia of the levator ani (38%) seemed to perform worse when compared to patients with isolated hypertonia of the anal sphincter (20%) or a combination of hypertonia (42%), although these results were not statistically significant . The anorectal pain in patients suffering from hypertonia in both muscles might have been caused only by the hypertonic state of the anal sphincter, which could possibly respond better to treatment with BTX-A.In this study, treatment with BTX-A provided a sustained cure in 47% of patients suffering from chronic functional anorectal pain. An additional 20% had an initial response to treatment, but relapsed within 3 months. Factors like sex, age smoking, and psychiatric history did not influence outcome. However, these subgroups were small, so no firm conclusions could be drawn. Patients with the isolated hypertonia of the levator ani seem to perform worse than those with solely hypertonia of the anal sphincter or a combination of both, but these results were not statistically significant . This may in part be due to the development of behavioural changes and sensitisation [Patients whose symptoms initially improved but who had a recurrence of their anorectal pain, or showed no improvement, were offered repeated injections after 3 months. Repeated treatment seems to be effective in some patients, which suggests that, sometimes, injections need to be repeated to achieve a better outcome. Patients with longstanding anorectal pain had remarkably less sustained response (28%), although this was not statistically significant in overall outcome p = 0.8. This mtisation . Early aIn this study, a standard dose of 60, 80, or 140 units of BTX-A was given to each patient based on hypertonia of the anal sphincter and/or levator ani muscle. A recent meta-analysis suggests that a low dose of BTX-A is just as effective as a higher dose when treating an anal fissure, but is associated with fewer complications and side effects . In contThe strengths of this study are the large patient population, and the experienced team in a specialized referral centre for proctology. Furthermore, our results show that continuation of physiotherapy may have led to success, because it gave the patient increased awareness of pelvic floor physiology. Limitations are the retrospective nature of the study and the lack of an explicit patient-related outcome measurement (PROM) or visual analogue scale (VAS). There are very few studies reporting on the treatment of chronic functional anorectal pain and outcome is generally scored as clinical response. We believe more prospective studies evaluating the effect of BTX-A treatment in chronic functional anorectal pain are warranted to investigate whether BTX-A treatment should be implemented in the protocol for the treatment of patients with this condition. Furthermore, a validated patient-related outcome score should be developed to validate and interpret results found in future studies.Treatment with BTX-A is a safe and reasonably effective treatment for chronic functional anorectal pain. It can provide a sustained resolution of anorectal pain in 47% of patients who are refractory to conservative measures. Repeated treatments with BTX-A after initial treatment failure can still provide a sustained cure in up to 50% of patients. Patients with longstanding duration of anorectal pain might respond less to BTX-A treatment. Patients with anorectal pain should be offered BTX-A treatment after 3–6 months to prevent the development of chronic pain by behavioural changes, sensitisation, and to minimise the impact on daily activities. Patients need to be made aware that anal pain leads to paradoxical contraction of the levator ani muscle and that this might be the onset of the development of chronic anal pain. Continuing pelvic floor therapy after BTX-A may be of added value.


Previous outcome studies for extracorporeal shock wave therapy (ESWT) have included clinically diagnosed greater trochanteric pain syndrome (GTPS). The purpose of this study is to investigate outcome of ESWT on GTPS with gluteal tendinopathy documented by magnetic resonance imaging (MRI).Medical records of 38 consecutive patients were retrospectively reviewed, who underwent ESWT for GTPS with MRI-documented gluteal tendinopathy (> 6 months). ESWT was conducted (1/week) when the Roles-Maudsley score (RMS) showed “Poor” or “Fair” grade after conservative treatment until RMS had reached “Good” or “Excellent” grade (treatment success) or until 12 treatments had been applied. Numeric rating scale (NRS) and RMS were evaluated before, 1 week after (immediate follow-up) and mean 27 months after ESWT program (long-term follow-up). Success rate was calculated at each follow-up point.p< 0.01) and long-term follow-up , respectively. Success rates were 83.3% (immediate) and 55.6% (long-term), respectively. There was no correlation among age, symptom duration and NRS.Initial NRS (5.9 ± 1.6) significantly decreased at immediate (2.5 ± 1.5, Low-energy ESWT can be an effective treatment for pain relief in chronic GTPS with MRI-documented gluteal tendinopathy. However, its long-term effect appears to decrease with time. Greater trochanteric pain syndrome (GTPS) refers to a clinical condition with pain and tenderness at or around greater trochanter, which can radiate to the lateral aspect of the hip or thigh ,2. ClassPrimary management of GTPS is conventional conservative management including rest, non-steroid anti-inflammatory drug, physiotherapy, and corticosteroid injection. In refractory cases, operative treatment such as lengthening of iliotibial band and fascia lata may be considered ,2,5. SevTo our knowledge, no study has investigated the outcome of ESWT on clinically diagnosed GTPS with MRI-documented gluteal tendinopathy. The aim of our study was to investigate the effect of ESWT for chronic refractory GTPS with gluteal tendinopathy documented by MRI.We retrospectively reviewed the medical records of 38 consecutive patients who underwent ESWT with clinical diagnosis of chronic GTPS and MRI-confirmed gluteal tendinopathy. Chronic GTPS was diagnosed if patients had pain in the lateral aspect of hip or thigh impairing their daily activities for more than 6 months, tenderness over the greater trochanter and at least one positive finding on the clinical tests including lateral hip pain with a FABER test, resisted external derotation test, or single leg stance test. MRI-documented gluteal tendinopathy was determined when MRI showed abnormal findings in and around gluteal tendon as follow: tendinosis; peritendinitis; partial tear or calcific tendinitis . ExclusiOutcome measures consisted of the numerical rating scale (NRS), the Roles and Maudsley score (RMS) and treatment success rate. The NRS is an 11-point pain intensity rating scale, where 10 points indicated worst possible pain and 0 point no pain. The RMS is a subjective 4-point patient assessment of pain and limitations of activity . NRS and2; 600 shocks per session) was conducted when patient’s symptom did not improved after previous conventional conservative treatment and still showed “Poor” or “Fair” grade in the Roles-Maudsley score (RMS) , the electrohydraulic type. While patient lied with lateral decubitus position, shockwave was applied to the area with maximal tenderness at or around greater trochanter. The probe with 25–45 mm of penetration depth was used. The frequency of shockwave was 1 Hz. Local anesthetics was not used.ESWT (0.10 mJ/mmre (RMS) . PatientMRI examinations were performed using 1.5T MRI scanner  using a dedicated hip coil . MR images were evaluated by two radiologists in consensus on high-resolution monitors of a PACS.P values <0.05 were considered statistically significant.We used repeated measures ANOVA to analyze the immediate and long-term effect of ESWT on the subjective pain. Correlations between the following variables: age; symptom duration; and NRS (baseline and at each follow-up) were assessed by Pearson’s correlation coefficient. All analyses were performed with the Statistical Package for the Social Sciences software, Version 18.0 . Eighteen patients who met our eligibility criteria were included. The basic characteristics of the subjects were shown in The results of our study demonstrated that subjective pain started to decrease significantly at immediate follow-up (1 week after ESWT program). NRS did not show significant difference between immediate and long-term follow-up (mean 27 months after) while it showed tendency of increase with time . These r2; 2,000 shocks per session; total 360 mJ/mm2 per session) and Rompe et al. [2, 2,000 shocks per session; total 240 mJ/mm2 per session). These two studies applied different total energy which is usually defined by EFD multiplied by total number of shocks applied. It has been reported that over-delivered shockwave energy is likely to be associated with greater pain and tissue damage, which may result in treatment failure [2; 600 shocks per session; total 60 mJ/mm2 per session) until treatment success [2) than Furia (360 mJ/mm2) and Rompe (240 mJ/mm2). In addition, the number of treatment session was inevitably flexible ranging from 1 to 11 sessions according to patient’s response, which makes it difficult to compare with former studies.Standard protocol of ESWT for GTPS is not yet established. Two reported well designed studies in the literature used different treatment protocol although both studies applied a standardized number of treatment sessions. Furia et al.  performee et al.  conducte failure ,12. In o failure . Therefo success . ConsequThe present study is unique and differs from former reports because we first addressed the outcome of low-energy ESWT in chronic refractory GTPS with MRI-documented gluteal tendinopathy while previous studies included subjects with clinically diagnosed GTPS –9. GTPS Previous studies demonstrated MRI appearances of gluteal tendinopathy as follows: soft tissue edema surrounding intact tendon (peritendinitis); thickening or increased intrasubstance T2 hyperintensity (tendinosis); focal absence of intact tendon fibers ; or tendon discontinuity (complete tear). ,6,20 In Although ultrasonography is most commonly selected option for investigation of GTPS due to its easy accessibility and cost-effectiveness, sensitivity for the detection of low-grade tears is relatively low (61%). ,25 In adThere are several limitations in this study that should be discussed. Firstly, small number of subjects with the exclusion of nearly 60% of the intended cohort is a source of bias that may reduce statistical power and alter the outcomes. Secondly, the lack of blinding as well as selection bias is likely associated with artificially inflated clinical outcomes. Thirdly, there was no control group. Thus, the effect of natural progression of the condition cannot be ruled out. Lastly, this study was conducted by retrospective chart review for immediate outcome and cross-sectional data gathering using telephone interview for long-term outcome. Therefore, there is no standardized outcome measure time point for long-term follow-up because all the telephone interviews on each subject were made at one point in time. Further studies are needed to supplement these limitations.When the diagnosis is established through meticulous physical examination and MRI, low-energy ESWT seems to be an effective treatment option for pain relief in chronic refractory GTPS. However, its long-term effect appears to decrease with time.S1 Dataset(SAV)Click here for additional data file.


Idiopathic scoliosis is the most common type of spinal deformity. Scoliosis is defined as a lateral curvature of the spine greater than 10° accompanied by rotation of the vertebrae. The treatment available for adolescent idiopathic scoliosis is observation, orthosis, and surgery. The surgical options include open anterior release and instrumentation, posterior instrumentation, and thoracoscopic approaches. The Scoliosis Research Society Questionnaire (SRS-30) is a specific instrument to measure health-related quality of life in patients with scoliosis, who had or had not undergone surgery. The purpose was to assess the post-operative functional outcome using SRS-30 in children who underwent anterior release, instrumentation, and fusion using autogenous rib graft for adolescent idiopathic scoliosis (AIS).In a retrospective cohort study, 25 patients between the ages of 11 and 17 years, who underwent anterior release, instrumentation, and fusion using autogenous rib graft for adolescent idiopathic scoliosis (AIS) between 2008 and 2014, were included in the study.The total average score was 4.26 with a SD of 0.014 and had maximum average score 4.5 (for pain) and minimum average score 3.8 (for self-image).Anterior release, instrumentation, and fusion using autogenous rib graft is having good functional outcome in all domains. Idiopathic scoliosis is the most common type of spinal deformity attended by orthopedic surgeons . ScoliosIn structural scoliosis, the vertebral body is rotated towards the convex side of the curve, so the spinous process is rotated towards the concave side of the curve. The asymmetric deformities seen within the vertebral bodies of scoliosis differ significantly from its normal counterpart. The compressive and the distractive force acting on the growing spine produces wedging of the vertebrae. The rotation of the vertebrae produces a hypokyphotic or lordotic curvature of the spine in the sagittal plane. This three-dimensional deformity is better termed as the torsion of the spine and is maximum at the apex of the curve –9. The aThere is no definite definition regarding curve progression in the literature but an increase of more than 5–6° over 6 months is considered to be an indicator of progression by most of the studies. Factors such as family history of scoliosis, patient’s height to weight ratio, thoracic kyphosis, lumbosacral transition anomaly, spinal balance, and lumbar lordosis are having high predictive value for curve progression in skeletally immature patients –13.Curves less than 40° at maturity may progress to an average of 9° during adulthood and curves more than 40° progress to an average of 20° . AdolescThere are different systems to classify scoliosis like Ponseti and Fredman classification, King Classification, and Lenke classification. Lenke is the most recent and commonly used classification system. There are three steps involved in this classification system: identification of the primary curve, assignment of the lumbar modifier, and assignment of the thoracic sagittal modifier –19.The treatment options available for adolescent idiopathic scoliosis are observation, non-surgical intervention, and surgical intervention. In general, no treatment is needed for curves less than 25° regardless of the patient maturity, but follow-up examinations are necessary at regular intervals. Bracing is recommended for skeletally immature patients having curves between 25° and 45° , 21. NumIn skeletally immature patients in whom the curve reaches 40° to 50°, or skeletally mature patients with curves greater than 50°, surgery is a reasonable option . The priThe correction and stabilization for scoliosis through anterior approach is introduced by Dwyer in 1964 . Later swww.srs.org , we conducted a retrospective cohort study in a consecutive series of children with adolescent idiopathic scoliosis who underwent anterior release, instrumentation, and fusion using autogenous rib graft in the orthopedic department of our institution. The primary indication for surgery was cosmetic correction of the deformity. There were no cases with back pain. All patients included in the study were concerned about the physical appearance of the back and that was the main indication for surgery. They were included after obtaining the written informed consent from the parents. There were 30 patients who underwent surgical treatment during the period from August 2008 to December 2014. Out of the 30 patients, one patient expired due to unrelated problem and we lost follow-up of four patients. The remaining 25 patients included in the study were having either type I or type V curve after obtaining informed consent from their parents. No children with thoracic insufficiency syndrome was included in our study, and those who underwent posterior procedure were excluded.All surgery were done under general anesthesia, and preoperative prophylactic antibiotics were given. The patients were positioned laterally with convex side up and thoracotomy/thoracolumbar approach was used. Exposure was completed by removing the rib of one level above the most proximal instrumented vertebrae. After exposing the vertebrae, the anterior release was done by removing disc material and endplate. Correction was done by derotating the apical vertebrae and fixation using pedicle screw and rod instrumentation. Fusion was aided with the help of autogenous rib graft. The whole procedure was done under motor-evoked potential surveillance. Suture removal was done on the 14th day, and patients were discharged with thoracolumbosacral orthosis, which they wore till complete fusion, that was achieved in 9 months.The age of patients at the time of final evaluation was between 11 and 17 years. SRS-30 was used to measure the patient outcome at the time of the final follow-up. It was divided into five domains according to question type—pain, function /activity, self-image/appearance, mental health, and satisfaction with management. All questions had scores from 1 to 5. The mean score of each domain was used for analysis. The best score is 5 and the worst score is 1.Our study included 17 girls and 8 boys Fig. . The totIn this study, we retrospectively analyzed functional outcome of 25 patients with adolescent idiopathic scoliosis, who underwent anterior release, instrumentation, and fusion using autogenous rib graft. All the surgeries were done by a single surgeon. We got grade 1 fusion in 84% of the cases, grade 2 in 12% of the cases, and grade 3 in 4% of the cases, using Newton et al. grading system for spinal fusion . No caseThe results of our study cannot be compared with other similar studies conducted to find out HRQL of children with adolescent idiopathic scoliosis treated by using braces and corrective surgeries through anterior or posterior approach because of sociocultural difference among different population. The sociocultural differences will affect the domain of SRS. We have no such similar studies from our population for comparison. This is the first ever attempt to find out HRQL of adolescent idiopathic scoliosis children post-operatively from an Indian subcontinent.Our study has several limitations. We have conducted this study in a small number of patients. The follow-up of patients varied from 1 to 7 years. We did not have a preoperative patient-based questionnaire, so longitudinal analysis of this measure was not possible.From our study, using the SRS-30 scoring system in Lenke I and V, we found that anterior release, instrumentation, and fusion using autogenous rib graft is having good functional outcome in all domains: function, pain, self-image, mental health, and satisfaction with management.


Opioid analgesics are the cornerstone of moderate to severe cancer pain management, and do not have ceiling doses unless unmanageable adverse effects occur. Oral, short-acting pure μ agonists such as morphine are most frequently used, but other agents and administration formulations allow finding the right opioid and dose for most patients. In addition, clinicians must understand the metabolism, pharmacokinetics, and elimination of particular drugs to individualize opioid selection, select initial doses, and appropriately escalate doses to satisfactory pain relief or uncontrollable toxicity. Anticipation and proactive management of possible adverse effects, particularly constipation, confusion or delirium, opioid-specific adverse effects, and opioid abuse, are also integral to primary and secondary prophylaxis and management. Opioids—mu (μ) agonists and buprenorphine—are essential for managing moderate to severe cancer pain. They have no analgesic ceiling, and doses can usually be escalated to pain relief without unmanageable side effects. Key strategies are to individualize opioid doses and schedules, weigh benefits and burdens, and anticipate possible adverse effects with an eye toward prophylaxis and effective, timely management. JADPRO, or on advancedpractitioner.comThe first part of this series on cancer pain management addressed nonopioid analgesics. It can be found in the July/August 2017 issue of Opioids activate the endogenous pain-modulating system of opioid peptides  and spinal cord and brain receptors  to alter pain perception . The μ aMetabolism biotransforms some drugs to intermediate metabolites, which are potentially more potent than a parent drug, or to inactive (and possibly toxic) metabolites, which all must be detoxified and excreted . Some unAll CYP genes are highly polymorphic, but CYP2D6 is of particular interest because polymorphisms directly or indirectly affect the pharmacokinetics of half of all drugs . More thThe clinical significance for PMs and UMs depends on whether the parent drug or metabolite is analgesic . CodeineSome clinicians start opioid-naive patients with moderate pain on a "weak" oral (po) opioid: codeine, hydrocodone, or tramadol with or without acetaminophen (APAP). Others prescribe a small dose of a "strong" opioid: po morphine at 5 to 15 mg or the equivalent every 4 hours, eliminating the need to switch opioids if the pain worsens . FormulaCodeine (po [IR])Codeine, a weak μ and δ agonist, may be less effective than a nonsteroidal anti-inflammatory drug (NSAID), and combinations with APAP are slightly better than APAP alone . CYP3A4 Tramadol Tramadol is a weak μ agonist and a serotonin and norepinephrine reuptake inhibitor SNRI; . TramadoCYP2D6 poor metabolizers and those with deficient serotonin (5-HT) uptake who take tramadol may be at risk for serotonin syndrome (SS), which begins within 24 hours of starting or increasing a 5-HT reuptake or CYP2D6 inhibitor . Table 2Seizures after tramadol ingestion have been reported, usually after intentional or accidental overdose or abuse. Most reports originate in Europe or the Middle East, where tramadol abuse is more common. For instance, tramadol was implicated in 4.8% of seizures reported to a Swiss poison center . Tapentadol Tapentadol is a high-affinity μ, δ, and κ receptor agonist as well as a strong SNRI. It undergoes phase 2 glucuronidation and minor phase 1 CYP2D6 metabolism to inactive metabolites excreted in urine . TapentaHydrocodone Hydrocodone, classified as a "weak" opioid, is similarly effective (mg per mg) to morphine . HydrocoMorphine Morphine is a μ agonist with minor κ and δ agonist effects at high doses . Most moLiver impairment does not impact dosing, but there is an inverse relationship between renal function and excretion. Morphine must be titrated cautiously when creatinine clearance is < 30 mL/minute to avoid M3G-related neurotoxic effects, which are more common with morphine than oxycodone to TD fentanyl or buprenorphine . Oxycodone Oxycodone has lower binding affinity for μ receptors than does morphine . Phase 1Hydromorphone Hydromorphone, a μ and δ agonist, is structurally similar to morphine but more lipid soluble . It is mOxymorphone Oxymorphone is a complex, potent, highly selective μ receptor agonist. Immediate-release po doses are more useful for acute, moderate pain, whereas SR doses are preferable for severe, persistent cancer pain , but it Levorphanol (po)Levorphanol, a μ, κ, and δ receptor agonist, is also an SNRI and N-methyl-D-aspartate (NMDA) antagonist . N-methyMethadone (po)Methadone is a low-cost potent, lipophilic μ agonist, SNRI, and NMDA antagonist that has high oral and rectal absorption, long duration of action, and no neurotoxic metabolites . Highly Fentanyl Fentanyl is a rapid-onset, lipophilic μ agonist 50 to 100 times more potent than morphine . ContinuBuprenorphine Buprenorphine is a lipophilic μ receptor agonist opioid with no analgesic ceiling, a partial agonist (ceiling) for respiratory depression, and a κ receptor antagonist . It is 2An effective opioid and dose for one patient may cause dose-limiting adverse effects for another patient. This highlights the importance of patient teaching, follow-up assessment, and proactive management  is a rare, potentially serious adverse effect of methadone and other drugs that can block human ether-a-go-go gene (hERG)-related potassium ion channels and alter cardiac repolarization . The norThe incidence of long QTc is undefined. One prospective study identified it in 4.6% of 173 individuals receiving maintenance methadone ≥ 120 mg/day (and none taking buprenorphine); mortality was merely 0.06 per 100 patient-years . ConsensDrug-induced long QTc is twice as common in blacks as in whites or Hispanics . Other sVandael and colleagues  found noConstipationOpioid-induced constipation (OIC) occurs because of binding to gastrointestinal (GI) tract opioid receptors and slows motility with fewer, harder bowel movements BMs; . ExacerbDrowsiness or Sedationmay be beneficial if it allows restful sleep, but safety is a concern until tolerance develops, usually in 3 to 7 days with short-acting opioids. Psychostimulants may counteract persistent sedation and cognitive impairment and enhance analgesia, but evidence is limited  is most common in patients starting tramadol or morphine, but it occurs with other opioids . About 1routinely ask patients about feeling confused or having vivid dreams, nightmares, or visual hallucinations  is a brief, free to use, sensitive clinical tool to aid rapid identification . Alternainations . Switchiinations . Other cinations .Nausea and VomitingNausea (N) or vomiting (V) can occur with new opioids secondary to decreased GI motility, chemoreceptor trigger zone stimulation, or vestibular apparatus activation and often resolves in 1 or 2 weeks . A dopamHypogonadismUp to 90% of those taking opioids for chronic pain develop dose-related hypogonadism. Opioids bind to receptors in the hypothalamus, pituitary, and testes, leading to downstream decreases in sex hormones, adrenal androgen, cortisol, and testosterone . Net effOpioids also bind to osteoclast receptors, accelerating bone loss and reducing bone formation. Although more common in women, almost half of all men with chronic opioid intake develop osteoporosis , so boneRespiratory DepressionDahan, Aarts, and Smith  reviewedextreme caution because of the risks for dangerous and life-threating adverse effects, especially in hypovolemic or hypotensive patients —poorly defined pain spreading beyond the initial site—occurs rarely in patients taking high opioid doses, especially with rapid dose escalation . Opioid-Prescription Opioid AbuseStrategies to decrease opioid abuse include opioid safety contracts and prescription drug monitoring programs (PDMPs). An opioid safety contract might articulate how and when the patient will take opioid analgesic(s), mention keeping opioids in a lockbox, include an agreement to get prescriptions from one provider, and perhaps list recreational substances  that will or will not be allowed . RelatedA vital resource for prescribers is their state’s PDMPs, which are fully or partially operational in the District of Columbia and in all states except Missouri. Prescription drug monitoring programs are online databases of controlled substances and other drugs with misuse or abuse potential . Within max), and duration of analgesia (max) occur approximately 45 to 80 minutes after po or pr, 20 to 40 minutes after SC, and 6 to 20 minutes after IV opioid doses  absorb slowly across the GI mucosa, cell membranes, and the blood-brain barrier, whereas lipophilic drugs  diffuse more rapidly. The route of administration also influences onset, peak level . Intravenous dosing is advantageous for patients who require rapid dose escalation, have GI obstruction or unrelenting nausea, or when large po doses are impractical . The bioBaseline scheduled plus prn doses per 24 hours, current pain intensity, and any adverse effects are considered in dose increases (or decreases). Sustained release and TD opioids, which are best for patients with satisfactory analgesia, decrease serum opioid fluctuations, extend analgesia, draw patients’ attention away from pain and pill-taking, allow greater focus on "normal" aspects of life, and may enhance adherence . ConversTransdermal OpioidsTransdermal fentanyl (TDF) or transdermal buprenorphine (TDB) may be an option for opioid-tolerant patients with no po intake, to minimize pill-taking behaviors or to enhance adherence. Transdermal patches are formulated as a drug-containing reservoir (fentanyl) with a rate-controlling drug delivery membrane or as an adhesive polymer layer with a drug-incorporated matrix (fentanyl or buprenorphine) in which the drug amount controls delivery. Impaired skin integrity or heat (fever or a heating pad over a patch) can increase drug delivery with either TD system . MagnetiAfter first-patch application, a TD opioid slowly diffuses through skin layers, forming a "skin depot," and then absorbs into capillaries. Serum levels are measurable in 8 to 12 hours; TDF levels off at 24 to 36 hours, and TDB levels off at 36 to 48 hours . As-needWays to switch to TD opioids, illustrated in p < .001).In one study, 42 patients with chronic or cancer pain had poor analgesia or intolerable side effects with po opioids  were switched to TDB ≥ 52.5 mg/hour . The proA larger prospective multicenter study of 520 cancer patients with moderate to severe pain were randomly assigned to morphine SR, oxycodone SR, TDF, or TDB and followed for 28 days . Pain deFine and Portenoy  addresseTransmucosal FentanylTransitory, breakthrough cancer pain (BTCP) episodes usually peak within a few minutes and last for about 30 to 35 minutes . Oral moOne prospective study compared po morphine and sublingual TMF for BTCP in cancer patients . TransmuClinicians must review TMF products to determine which might be best for their patients. Several oral  and intranasal TMF products (aqueous or pectin sprays) are similar but not exactly the same. For instance, sublingual TMF absorbs more rapidly than buccal because of differences in mucosal thickness, and 50% to 70% of some oral TMF products dissolve in saliva and are swallowed. The bioavailability of TMF products varies from as low as 30% to 89% with aqueous intranasal fentanyl spray because of high nasal mucosal vascularity and permeability . Time toManufacturers incorporate bioavailability data into their formulated doses, and different products are not directly interchangeable. No matter the baseline dose, experts recommend using the lowest TDF dose (any selected product) when starting TMF for breakthrough pain . A firstPossible reasons for switching a patient from one opioid to a different opioid include inadequate analgesia despite aggressive dose titration, dose-limiting adverse effects, clinical status change, serious drug-drug interactions, financial or drug-availability issues, or hyperalgesia . CliniciAn ad hoc pain expert panel formulated guidelines for calculating doses of new opioids . Step onThe second recommended step is to consider any patient or drug characteristics that support further equianalgesic dose adjustment . For exaOpioid analgesics are one cornerstone of cancer pain management, the others being nonopioid analgesics, thorough baseline and timely reassessments, and interprofessional, patient-centered collaborative management that includes nondrug measures and interventions. Collaborative management, particularly calling upon the expertise of oncology pharmacists and the rich clinical experiences of other colleagues in fields such as palliative or supportive care, pain centers, physical therapy, and complemental therapies can enhance patient safety and quality of life, even for those with moderate to severe pain at any point along the cancer trajectory. In terms of opioids, this is especially relevant when using more unfamiliar drugs or prescribing higher doses than most patients require. Continuing education, clinical and didactic, will also help advanced practitioners make substantial and meaningful contributions to optimal pain management for individuals with cancer.


Better tools are required for the earlier identification and management of orofacial pain with different aetiologies. The painDETECT questionnaire is a patient-completed screening tool with utility for identification of neuropathic pain in a range of contexts. 254 patients, referred from primary care for management of orofacial pain and attending a secondary care centre, were prospectively recruited, and completed the painDETECT prior to consultation. The aim of this study was to determine the accuracy of the painDETECT to detect neuropathic components of orofacial pain, when compared to a reference standard of clinical diagnosis by experienced physicians, in a cohort of hospital-based patients.p = 0.001). Patients with orofacial pain diagnoses associated with neuropathic components had higher painDETECT scores than those with non-neuropathic components. However, the painDETECT was weaker at distinguishing patients with mixed pain types, and multiple diagnoses were associated with poor accuracy of the painDETECT.For the 251 patients included in the analysis, the painDETECT had a modest ability to detect neuropathic components of orofacial pain  contains supplementary material, which is available to authorized users. Accurate diagnosis of orofacial pain (OFP) is essential for appropriate patient management in primary and secondary care. Acquisition of a detailed pain history and examination directs diagnoses and treatment . HoweverPatient-completed screening questionnaires may supplement the recognition and clinical diagnosis of OFP in a variety of settings. These are paper-based or electronic tools that are easily administered to patients. In differentiating between common dental conditions and unknown OFP diagnoses , screeniOne such tool developed in 2006, the painDETECT screening questionnaire (PD-Q), uses a scoring method between − 1 and 38 to estimate the likelihood of a neuropathic pain component in patients. The PD-Q was originally designed to identify neuropathic components in back pain . Since iGiven its diagnostic nature, this prospective, single-centre cohort study was conducted in concordance with the latest version of the STARD checklist for reporting studies of diagnostic accuracy . EthicalRecruitment was conducted by three specialty dentists between 2010 and 2015, each completing their postgraduate studies. During the project phase of the dentists’ postgraduate studies, all patients referred from primary care, and attending OFP clinics and one oral surgery clinic, were consecutively recruited. Participants were excluded from the study if they: were below 18 years of age at consultation, had declined participation, were unable to complete the questionnaire without assistance. Participants with acute pain and those with more than one OFP diagnosis were recruited. From each participant, the following characteristics were planned, prior to PD-Q completion or consultation, and collected for each participant: age in years, gender, any secondary clinical diagnoses and the presence of anxiety or depression based on Hospital Anxiety and Depression Scale scores .Participants completed a paper-based copy of the PD-Q prior to their consultation with the clinician. The questionnaires were collected by the specialty dentists, and not shown to the assessing clinicians. Uncompleted questionnaires were returned to the patient before consultation to encourage completion, but questionnaires remaining incomplete were excluded from analyses. The clinical diagnosis of each patient, serving as the reference standard of diagnosis, was obtained after a full assessment by an expert in pain medicine by means of a consultation, with a detailed pain history and clinical examination. Secondary diagnoses, classified as either orofacial pain or an alternative pre-existing non-orofacial diagnosis, were assigned to patient if necessary, but the primary diagnosis was classified as the predominant pain experienced. An independent clinician reviewed the initial diagnoses and confirmed these after initiation of a management plan. Clinical diagnosis was selected as a reference test, as it is presently the gold standard for diagnosis; based on the requirement of a detailed pain history and examination for differential diagnosis of OFP . ClinicaThe completed questionnaires were scored according to the methodology described in the original reports of the PD-Q . Cut-offp values between individual diagnoses. The secondary outcome of the study related to factors influencing correct diagnosis of the PD-Q. This included determining Pearson’s correlation co-efficient (r) between PD-Q scores and each patient characteristic, and a stepwise multivariate logistic regression to independently determine the adjusted effect  of each patient characteristic and PD-Q scores.As a previous study found the PD-Q to have an AUC of approximately 0.8 to distinguish BMS from nociceptive pain , it was p values less than or equal to 0.05 were considered statistically significant. 95% CIs were applied to all continuous outcomes, and percentages were calculated for categorical outcomes. All data were managed, analysed and graphed using IBM SPSS Statistics for Macintosh, Version 25.0  and Prism for Macintosh, Version 7 .All continuous variables, where parametric, are presented as means with standard deviations (SD), and where non-parametric, are presented as medians with interquartile range (IQR). Categorical variables are presented numerically and as a percentage of the sample. 254 participants attended the facial pain clinic during recruitment periods between 2010 and 2015, and were given the PD-Q to complete prior to their appointment with the clinician . Our statistical model derived sensitivities and specificities corresponding to the PD-Q scores, and predictive values were calculated from these, given the prevalence of neuropathic or non-neuropathic pain within the patient cohort. At a cut-off of 11.5, given a prevalence of 54.6% patients without neuropathic pain components in the cohort, the PD-Q had a sensitivity of 59.6%, specificity of 56.9%, PPV of 62.4% and NPV of 53.5%. At a cut-off of 19.5, given a prevalence of 45.4% patients with some neuropathic pain components in the cohort, the PD-Q had a sensitivity of 28.9%, specificity of 83.2%, PPV of 58.9% and NPV of 58.5%.ROC curve analysis was performed to determine the accuracy of the PD-Q in detection of neuropathic pain components. The AUC was calculated and compared to an identity line, with an area of 0.50, and sensitivities and specificities were derived for each cut-off of the PD-Q Fig. . The AUC. Overall, there was a significant difference (p < 0.001) between median PD-Q scores of patients with neuropathic pain , non-neuropathic pain  or mixed pain  aetiologies of OFP. Pairwise comparisons revealed statistically significant differences in median PD-Q score between neuropathic and non-neuropathic pain (p < 0.001) and between neuropathic and mixed pain (p = 0.008), but not between non-neuropathic and mixed pain (p > 0.5). The median PD-Q scores for the 12 most common clinical diagnoses, containing five or more patients per group and accounting for 212/251 (84.5%) of the cohort, are shown in Table 3.PD-Q scores were compared between the five most common OFP diagnoses within the cohort, using a Kruskal-Wallis test Fig. . Overallr = − 0.20; p = 0.001) and also anxiety or depression . However, when adjusted in the regression model, only a secondary diagnosis contributed significantly to the PD-Q score  when adjusted for patient age, gender and presence of anxiety or depression. Anxiety or depression, when adjusted for other patient characteristics, did not reach significance .We performed a multivariate linear regression to determine whether any of the patient characteristics including: age, gender, secondary diagnosis or presence of anxiety or depression had an influence on the PD-Q score independently. There was a significant correlation between the PD-Q score and a secondary diagnosis


Background: The present study assessed whether early palliative care (EPC) targeting pain and depression and automated symptom monitoring could improve symptoms in patients with advanced pancreatobiliary cancer. Methods: Patients diagnosed with pathologically confirmed locally advanced or metastatic pancreatic or biliary tract cancer who had cancer-related pain (brief pain inventory (BPI) worst pain score >3) and/or depression  >16) were randomized within 8 weeks after diagnosis to receive EPC or on-demand palliative care (n = 144 each). EPC included (1) nursing assessment of pain and depression, (2) pain control based on National Comprehensive Cancer Network guidelines, (3) depression control by psychoeducation and/or consultation with a psychiatric specialist, and (4) patient education. The primary end points were ≥50% reductions from baseline to week 4 in pain and depression scores. Results: The proportion of patients in the EPC and usual care groups with ≥50% reductions in pain  and depression  scores from baseline to week 4 did not differ significantly. The proportion of patients with BPI worst pain score ≤3 was significantly higher  and the reduction in pain intensity score significantly greater  in the EPC than in the usual care group. At 4 weeks, patients in the EPC group reported significant increases in global health status, role of functioning, nausea and vomiting, and pain scores on the European Organization for Research and Treatment of Cancer Core Quality of Life questionnaire (EORTC QLQ-C30) general questionnaire. Conclusions: Although the primary outcome was not met, this trial indicates that EPC may improve early pain relief in patients with advanced pancreatobiliary cancers. Pancreatic cancer (PC) and biliary tract cancer (BTC) are frequently diagnosed at a late stage, preventing resection. Moreover, tumors may progress despite anticancer treatment. Appropriate treatment plans that improve survival while maintaining subjective quality of life (QoL) are essential. Because the pancreas is anatomically located in the central abdomen at the root of the mesentery and because BTC metastasizes primarily to lymph nodes in the hepatoduodenal ligament and to para-aortic nodes, most patients with PC and BTC have a significant symptom burden and require frequent medical attention and hospitalization for symptom management ,2. The mEarly referral of lung cancer patients to palliative care in addition to standard oncology care was found to improve survival and QoL compared with standard oncology care alone . HoweverSymptoms frequently observed in patients with PC or BTC include pain, depression and anxiety, anorexia, cachexia, weight loss, pancreatic exocrine insufficiency, jaundice, and gastric outlet obstruction. However, despite the availability of effective analgesics and new technologies for drug administration, pain management remains suboptimal . Pain afMany palliative care specialists question the feasibility, practicability, and efficiency of this approach. Specialist palliative care has shown minimal effects on QoL , with thn = 144 each). Patients were stratified based on tumor type (PC or BTC) and symptom type .Patients diagnosed with pathologically confirmed locally advanced or metastatic PC or BTC at the National Cancer Center, Korea, between April 2012 and May 2016 and who had cancer-related pain (brief pain inventory (BPI) worst pain score >3) and/or depression  >16) were randomized 1:1 within 8 weeks after diagnosis to receive either EPC or usual oncology care  scores, and overall survival. All the participants continued to receive routine oncologic care throughout the study period. The protocol was approved by the institutional review board of National Cancer Center, Korea . All participants provided written informed consent.Patients who presented to the outpatient cancer clinic were invited by their physicians to enroll in the study; all the physicians in the clinic agreed to approach, recruit, and obtain consent from their patients. Physicians were encouraged, but not required, to offer participation to all eligible patients; no additional screening or recruitment measures were used. Patients were eligible to participate if they had pathologically confirmed locally advanced or metastatic PC or BTC diagnosed within the previous 8 weeks, a Karnofsky performance rating scale ≥50% and cancer-related pain (BPI worst pain score >3) and/or depression (CES-D >16).EPC included: (1) Nursing assessment of pain and depression, (2) pain control based on National Comprehensive Cancer Network (NCCN) guidelines, (3) depression control by psychoeducation and/or consultation with a psychiatric specialist, and (4) patient education. Nursing assessment of pain included a brief evaluation of each patient’s mood state with the CES-D. Patients were managed by three research nurses, led by Meeyoung Lee, trained in assessing symptom response and medication adherence; in providing specific education about pain and depression; and in making treatment adjustments according to NCCN guidelines. Patients with CED-S scores >25 were referred to psychiatric specialists. We delivered the interventions by telephone or during regularly scheduled outpatient care. Follow-up intervention visits or telephone coaching were scheduled daily until BPI worst pain score was ≤3. Participants were contacted at baseline and at 1, 3, 6, 9, and 12 months. In addition, telephone calls were triggered when patients reported inadequate symptom improvement, nonadherence to medication, adverse effects, or suicidal ideation, or when patients requested to be contacted.Patients randomized to the usual-care group received no formal intervention but were informed of their depressive and pain symptoms; moreover, their screening results were provided to their physician. Usual oncology care (UOC), provided to all patients, was directed by an attending physician and consisted of anticancer and symptom control treatments and consultation with psychiatric and pain care specialists. The latter were provided whenever requested, regardless of group assignment.Health-related QoL was measured using the European Organization for Research and Treatment of Cancer Core Quality of Life questionnaire (EORTC QLQ-C30) general questionnaire, Korean version, which assesses multiple dimensions of QoL  during the previous week. Patients were also assessed using the Insomnia Severity Index (ISI), a 7-item self-reported questionnaire assessing the nature, severity, and impact of insomnia . Each itSatisfaction with pain management was measured on a 5-point scale  . The 5-pMood was assessed by caregivers using the CES-D, a 20-item questionnaire that rates the frequency during the previous week of symptoms associated with depression, including restless sleep, poor appetite, and feeling lonely. Each item was rated on a scale from 0 to 3, with total scores ranging from 0 to 60. Higher scores indicated greater depressive symptoms, with scores ≥16 indicating individuals at risk for clinical depression, with good sensitivity and specificity and high internal consistency .The co-primary endpoints were defined as 50% reductions from baseline in BPI pain score and CES-D score after 4 weeks. The target sample size, calculated for a power of 80% and a corrected two-sided alpha of 0.025 and allowing a drop-out rate of 18–20%, was 144 per group. Analyses were based on intention to-treat (ITT) in all randomized participants. To assess sensitivity, the primary endpoints were also analyzed for a modified ITT set, which excluded subjects who did not meet the critical inclusion criteria in the ITT set. The missing value was imputed to the negative results because it was considered that the cause of the missing value was not effective for treatment. All other analyses for secondary purposes excluded missing data.p < 0.05, except for the primary endpoint. All analyses were performed using Statistical Analysis System  and R software .Continuous variables were expressed as median and range and categorical variables as frequency (%). Between-group differences in continuous variables were compared using Mann–Whitney U-tests, and between-group differences in categorical variables were compared using the Chi-square or Fisher’s exact test, as appropriate. Variables at baseline and after four weeks within each group were compared using Wilcoxon signed-rank tests. Survival rates were assessed by the Kaplan–Meier method and compared using a log-rank test. All statistical analyses were two-sided, and statistical significance was defined as p = 0.8035) and depressive symptoms (p = 0.2089).Baseline characteristics were balanced in the two groups . Of the p = 0.4194) and depression  scores from baseline to week 4 , EORTC QLQ-C30 physical (p = 0.0115) and cognitive (p = 0.0078) functioning, 1st line chemotherapy regimen (p = 0.0036), and response to chemotherapy (p = 0.0348). There was no significant difference in the proportion of patients in the EPC and usual care groups with ≥50% reductions in pain  (p < 0.0001), there was no statistically significant difference between the two groups (p = 0.2157). Mean depression scores did not differ significantly in the two groups (p = 0.7792) or between time points (p = 0.1488)  A. Althou 0.1488) B. Howevep = 0.0318, Patients in both study groups reported improvements in assessment of pain intensity by week 4. Mean decrease in score was significantly greater in the EPC than in the usual care group  and the proportions that consulted a psychiatrist (12% vs. 12%) were similar in the two groups. By April 2017, 243 (84.4%) patients had died. There was no difference in overall survival between the two groups .p = 0.0404). In this study of 288 patients with advanced pancreatobiliary cancer, EPC did not significantly increase the proportion of patients with ≥50% reductions in pain and depression scores from baseline to week 4. However, the proportion of patients with BPI worst pain score ≤3, which may be a surrogate for a clinically meaningful endpoint, was significantly higher in the EPC group than in the usual care group  patients at baseline were between 4 and 6 . Our resSpecialist palliative care and early palliative care may have slight effects on QoL in cancer patients, including those with pancreatic cancer ,14,21. AThe percentage of patients with a depressed mood was higher in patients with advanced PC and BTC  than in other cancers , with maOur EPC intervention involved two physician experts in PC and BTC rather than palliative care specialists. These two physicians were involved in both oncologic care and endoscopic interventions, providing advantages in the management of biliary and duodenal obstructions. Early application of advanced endoscopic procedures, such as endoscopic retrograde cholangiopancreatography (ERCP), endoscopic ultrasound (EUS), and enteral stenting, can have a significant impact on oncologic care through the rapid improvement of biliary and duodenal obstruction .In a recent study , all patEarly referral for CPN has been reported to reduce pain and may reduce opioid consumption, resulting in fewer opiate-related complications, such as constipation in patients with painful, advanced PC ,29. HoweThe effect of EPC may depend on the primary tumor . CompareAlthough assessment rates were similar in both groups and uniformly high, only around 10% of patients could be assessed at 12 months, mainly because of their high mortality rates. The EPC team consisted of nurses and attending physicians. Some patients in the control group also received palliative care, but this was limited to advice on the telephone. Lack of blinding is always an issue in clinical research regarding early palliative care for patients with advanced cancer. This bias could not be avoided due to the lack of patient blinding in this prospective, randomized controlled trial. Other limitations of this trial include the accessibility of a well-functioning EPC. The exposure of control subjects to the intervention was unavoidable because the same attending physicians and nursing staff were involved in the care of both groups. This may have led to an underestimation of the true effects of the active intervention.Although the primary outcome was not met, this trial showed promising findings that EPC may improve early pain relief for patients with advanced pancreatobiliary cancers, compared to usual oncologic care. An ongoing randomized controlled trial is testing the hypothesis that EPC may benefit patients with metastatic upper gastrointestinal cancers, including PC and BTC, treated with first-line chemotherapy . Further