This finding held for postoperative pain scores at POD #10 as well (staples (1.0 (IQR 0.0–4.0)) and suture (2.0 (IQR 0.0–5.0), adjusted β −0.39 (95% CI −1.35 to 0.58), P=0.432)). A regression analysis was performed to identify secondary factors impacting postoperative pain scores. Higher preoperative pain score (β 0.50 (95% CI 0.09 to 0.92), P=0.019) and female gender (β 1.09 (95% CI 0.15 to 2.02), P=0.023) were predictive of higher incisional pain scores at POD#10. Increasing age was associated with decreased incisional pain scores at POD#10 (β −0.06 (95% CI −0.09 to −0.03), P < 0.001). These findings are of interest to the pain practitioner and may be valuable in preoperative discussions with prospective patients.Spinal cord and dorsal root ganglion stimulation are minimally invasive surgical techniques used to treat an array of chronic pain disorders. There is a paucity of data related to defining best practices in these specific patient populations, and historically, providers have relied on consensus committees to opine on the best techniques for patient safety and experience. The most efficacious mechanism of surgical closure—specifically a running suture closure compared to a surgical staple closure—is debated. A retrospective review of 155 patients implanted with either a spinal cord or dorsal root ganglion stimulator between 2017 and 2019 was undertaken to determine if the type of surgical closure was related to degree of postoperative surgical site discomfort. The primary outcome showed no statistically significant difference on postoperative pain scores between the suture (6.0 (IQR 5.0–8.0)) and staple (7.0 (IQR 5.0–8.0)) cohorts at postoperative day (POD) #1 (adjusted  Spinal cord stimulation (SCS) and dorsal root ganglion stimulation (DRG-S) are minimally invasive surgical approaches that are commonly used for certain refractory pain conditions –4. The eData from other specialties have been published to look for differences in cosmesis, surgical site infection, and patient satisfaction between the two closure methods –15. WhenThe primary aim of this retrospective study is to provide data from the SCS and DRG-S implant population regarding the impact of closure type, specifically skin staples versus running subcuticular Monocryl, on patient-reported postoperative incisional pain. Second, this study will attempt to isolate patient factors that are predictive of higher postoperative pain scores.This study was reviewed and approved by the corresponding author's Institutional Review Board as an exempt study. This was a retrospective comparative cross-sectional study that included 155 patients who were seen in the chronic pain clinic at a tertiary referral center  between January 1, 2017, and December 31, 2019. Patients >18 years old who underwent percutaneous SCS or DRG-S implantation were identified. Patients were only included if they provided either a postoperative day (POD) #1 incisional pain score or a POD#10 incisional pain score. This strategy was selected to maximize our sample size for analysis. The need for consent was waived by the IRB.All patients' records were reviewed retrospectively by a single, unbiased individual (TJN). Data that were abstracted included age, sex, body mass index (BMI), overall preprocedural pain score , POD#1 pain score at incisional site of implant, POD#10 pain score at incisional site of implant, history of fibromyalgia, history of preprocedural opioid use, type of implant , device vendor, and type of suture material used (staples or running subcuticular 4-0 Monocryl suture). The type of closure utilized is dictated by surgeon' preference at the time of surgery. The 11-point numeric rating scale (NRS) was used to rate pain scores, with a score of 0 indicating “no pain” and score of 10 indicating the “worst possible pain.”Variables were summarized by median and interquartile range (25–75 percentile) for continuous outcomes and frequency (%) for categorical outcomes. Mean and standard deviation were not presented for continuous data as they were not normally distributed. Demographic characteristics and other clinical variables were reported separately for patients that provided a preprocedural NRS score and a POD#1 score or a preprocedural NRS score and a POD#10 score.The primary outcome of interest was comparison of POD#1 and POD#10 NRS pain scores between patients who received staples versus patients who received running suture for superficial skin closure. The two cohorts (staples and suture cohort) in our overall sample were not matched on a case-by-case basis, and there was concern for results being impacted by various confounding variables. Therefore, linear regression analysis with adjustment for selected confounding variables was chosen as the preferable analysis method. Both unadjusted and adjusted linear regression models were fitted for the primary outcome. Adjusted linear regression controlled for age, sex, BMI, preprocedural pain score, type of implant, history of opioid use, and history of fibromyalgia. These variables were selected a priori for adjustment in the regression model based on author expertise and experience in potential confounding variables that may impact pain-related outcomes. This was also based on prior literature highlighting potential risk factors that may impact postprocedural pain scores across a variety of pain-related procedures , 17.β-coefficients and 95% confidence interval (CI). A P < 0.05 was considered the threshold for statistical significance for all comparisons. All analyses, including the primary outcome and secondary outcomes, were performed using SPSS .For linear regression models, we reported Secondary outcome analysis included identification of patient risk factors and postoperative pain scores for POD#1 and POD#10. Similar to the primary outcome of interest, this was performed separately for patients that provided a preprocedural NRS score and a POD#1 score and patients that provided a preprocedural NRS score and a POD#10 score. Unadjusted linear regression models were performed to identify associations between selected risk factors  and postoperative pain scores.r) was calculated to determine the correlation between incisional pain and time (POD#1 to POD#10). A subgroup analysis of this trend line was also performed noting changes in postoperative incisional pain scores over time based on suture technique as well as sex. Therefore, this subgroup analysis will present change in incisional pain score for females in the staples cohort, females in the suture cohort, males in the staples cohort, and males in the suture cohort separately over time (POD#1 to POD#10).An additional secondary outcome included change in postoperative incisional pain scores based on suture technique over time (from POD#1 to POD#10). Since this outcome necessitates inclusion of patients who reported pain scores at all time points, only patients who reported preprocedural pain score, POD#1 incisional pain score, and POD#10 incisional pain score were included in this portion of the secondary outcome analysis. Pearson's correlation coefficient  for the overall cohort that reported POD#1 NRS incisional pain scores and 62.0 (IQR 50.5–74.0) for the overall cohort that reported POD#10 NRS incisional pain scores. Females comprised 50.6% of the overall cohort among those that reported POD#1 NRS incisional pain scores and 52.4% among those that reported POD#10 NRS incisional pain scores.Demographic characteristics and other clinical variables based on superficial closure technique are presented in β 0.17 (95% CI −0.61 to 0.95), P=0.670). Similarly, adjusted and unadjusted linear regression models also revealed comparable POD#10 NRS incisional pain scores between the staples cohort (1.0 (IQR 0.0–4.0)) and the suture cohort (2.0 (IQR 0.0–5.0), adjusted β −0.39 (95% CI −1.35 to 0.58), P=0.432) ) versus those who received sutures (6.0 (IQR 5.0–8.0), adjusted P=0.432) .β 0.41 (95% CI 0.08 to 0.73), P=0.014) as well as the suture cohort (β 0.78 (95% CI 0.26 to 1.31), P=0.004). Similarly, severity of preprocedural pain score was associated with greater POD#10 incisional pain scores in the overall cohort (β 0.50 (95% CI 0.09 to 0.92), P=0.019) and the staples cohort (β 0.58 (95% CI 0.06 to 1.10), P=0.030) (β −0.06 (95% CI −0.09 to −0.03), P=0.001) and the staples cohort (β −0.07 (95% CI −0.12 to −0.03), P=0.001). Finally, female sex was associated with greater POD#1 incisional pain scores in the overall cohort (β 1.19 (95% CI 0.47 to 1.91), P=0.001) and the staples cohort (β 1.43 (95% CI 0.50 to 2.36), P=0.003). Similarly, female sex was associated with greater POD#10 incisional pain scores in the overall cohort (β 1.09 (95% CI 0.15 to 2.02), P=0.023).Unadjusted regression analysis was performed for the initial portion of the secondary outcomes to identify risk factors of postoperative incisional pain scores. This analysis identified that severity of preprocedural pain score was associated with greater POD#1 incisional pain scores in the overall cohort (P=0.030) . As age r). When analyzing the correlation of NRS incisional pain scores over time in patients who reported preprocedural scores, POD#1 scores, and POD#10 scores, there was an inverse correlation between NRS incisional pain scores and POD for both the staples cohort  and the suture cohort   . This wa< 0.001)  and simiThe primary aim of this retrospective study was to differentiate whether staples or suture-based skin closure results in different postoperative pain scores for patients undergoing implantation of a neuromodulation device. The results from this retrospective review show that there is not a statistically significant difference at either the POD#1 or POD#10 time points between the two cohorts: skin staples versus running Monocryl skin closure. Secondary outcomes were revealing several important findings. First, patients with higher preoperative chronic pain scores at baseline reported higher postoperative procedural pain. In addition, regardless of skin closure type, there was a dramatic improvement in postoperative surgical pain at the ten-day postoperative follow-up time period. Next, female sex was associated with higher reported postoperative pain scores. Finally, as age increased, postoperative pain scores decreased.Pain is a unique experience that is individualized and can be particularly complex for patients living with chronic pain. Our findings would suggest that when skin closure is performed appropriately, there was not a statistical difference between skin closure type and postoperative incisional pain. This is consistent with other surgical specialty literature. A recent systematic review suggested that the use of sutures slightly reduced the patient's reported postoperative procedural pain; however, significant challenges with heterogeneity were reported and admittedly based on imprecise high confidence interval data . One addInterestingly, some associations between patient characteristics and postoperative incisional pain scores were uncovered. It is important to note that in this dataset, the patients are specifically asked to comment on their procedural/incisional pain as a distinct entity from their chronic pain. This can be a challenging endeavor. The overall cohort showed that patients with a higher preoperative (chronic) pain score had an association of higher postoperative incisional pain scores on POD#1 and POD#10. This is not clinically surprising given the concepts of central sensitization and neurophysiologic pathology of chronic pain, but it is important to recognize this association. It has been well established that chronic pain is a known risk factor for the development of higher acute postoperative pain scores . An impoWhen the data were analyzed for possible contribution of gender, it was discovered that female patients reported higher postoperative pain scores. While the exact explanation is indeterminate for this observation, it is an interesting finding. An additional association was that of advancing age and decreased reported pain scores. These are important patterns to understand as the nature of spinal cord stimulation is completely elective. Patient selection is critical for long-term success of the therapy. Being able to properly educate patients on individual risk factors for immediate postoperative pain may be reassuring for patients and providers.As with all studies, this retrospective review is not without limitations. The primary limitation is attributed to the retrospective nature of the study-causal relationships that cannot be established. Second, the dataset had a small number of patients that did not complete the standard follow-up pathway. Therefore, POD#1 or POD#10 NRS scores were not documented for these patients and were not included in the study sample. Finally, results of a single center experience are not ubiquitous, and there likely are regional differences that factor into a patient's perception of postoperative pain. Ideally, a multicenter randomized controlled trial could be executed to definitively address this question in the SCS and DRG-S populations.This retrospective study indicates that there may not be a significant relationship between choice of surgical skin closure and relationship to postoperative incisional pain following implantation of SCS or DRG-S devices. However, several important associations were discovered: a positive association between preoperative pain severity and postoperative incisional pain severity, an association between female sex and higher reported incisional pain scores, and an inverse correlation between age and reported postoperative pain scores. This information can be useful to inform patients and implanting physicians alike on the expected postoperative course and help to predict which patient may have a more painful postoperative course.


DPYD gene. To date, many known polymorphisms cause DPD deficiency and subsequent increase of 5-FU toxicity. In addition, reduced inactivation of 5-FU could lead to increased 5-FU intracellular concentration and augmented efficacy of this drugs. Therefore DPD expression, particularly intratumoral, has been investigated as predictive and prognostic marker in 5-FU treated patients. There also seems to be a tendency to support the correlation between DPD expression and response/survival in patients treated with fluoropyrimidine even if definitive conclusions cannot be drawn considering that some studies are conflicting. Therefore, the debate on intratumoral DPD expression as a potential predictor and prognostic marker in patients treated with fluoropyrimidines is still open. Four DPD-polymorphisms are the most relevant for their frequency in population and clinical relevance. Many studies demonstrate that treating a carrier of one of these polymorphisms with a full dose of fluoropyrimidine can expose patient to a severe, even life-threatening, toxicity. Severe toxicity is reduced if this kind of patients received a dose-adjustment after being genotyped. CPIC  is an International Consortium creating guidelines for facilitating use of pharmacogenetic tests for patient care and helps clinicians ensuring a safer drug delivery to the patient. Using predictive DPD deficiency tests in patients receiving 5FU-based chemotherapy, in particular for colorectal cancer, has proven to be a cost-effective strategy.Fluoropyrimidines are widely used in the treatment of solid tumors, mainly gastrointestinal, head and neck and breast cancer. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for catabolism of 5-FU and it is encoded by  The most common side effects are represented by emesis, bone marrow suppression, diarrhea, mucositis, fatigue and hand-foot syndrome. Fluoropyrimidines cause severe toxicities in 10% to 40% of patients and deaths in 0.2% to 0.8%.Fluoropyrimidines (FU) are the most prescribed anticancer drugs for the treatment of solid cancers, in particular breast, colorectal, head and neck, pancreas and gastric cancers-7. The metabolic pathway of 5-fluorouracil depends on the activity of many intracellular enzymes including dihydropyrimidine dehydrogenase (DPD).The correct management of fluoropyrimidine toxicity consists in the temporary suspension or interruption of treatment,9.DPD expression varies throughout several tissues and exerts his activity predominantly in liver, peripheral blood mononuclear cells, tumor and inflammatory tissues. Genotype can explain high evident interindividual variability of DPD levels and a circadian rhythm of expression of this enzyme is described-12. Patients who receive 5-FU-based chemotherapy usually eliminate over 80% of this drug by converting it into its inactive metabolite 5,6-dihydro-5-fluorouracil,13,14, owing to levels of DPD within the normal range. In patients showing DPD deficiency, decreased catabolism of 5-FU is observed and thus, increased risk of toxicity.On top of that, differences in DPD activity have been reported among different ethnic groupsIn addition to a major risk of toxicity, reduced inactivation of 5-FU, could theoretically lead to increased 5-FU intracellular concentration and augmented efficacy of this chemotherapeutic agent. Therefore DPD expression, especially intratumoral, assessed by either enzymatic activity or mRNA expression, has been investigated as a predictive and prognostic marker in 5-FU treated patients, especially in those affected by colorectal cancer (CRC) given the prominent role of this chemotherapeutic agents in both metastatic and adjuvant setting.In this review we will discuss the impact of 5-FU pharmacogenomics in the clinical outcome of patients treated with fluorouracil-based chemotherapy and in particular we will analyze the importance of polymorphisms of the enzyme DPD regarding the toxicity and efficacy of chemotherapy 5FU-based. We also want to underline how the prospective analysis of DPD mutations has a good cost-effectiveness ratio.,3,14.5-FU is a cytotoxic agent that belongs to the class of antimetabolites. It is administered intravenously and has a short half-life (10-15 min). 5-FU undergoes a series of bio-transformative reactions that convert it into nucleotide metabolites; one of these metabolites forms a complex with the enzyme thymidylate synthase with inhibition of DNA synthesis through a “thymineless death” mechanism. Capecitabine and tegafur are pro-drugs of 5-FU; they have a bioavailability of approximately 70%-80% after oral administration,13,14.Only a small fraction of 5-FU (1%-5%) is converted into cytotoxic metabolites. More than 80% of the 5-FU undergoes hepatic metabolism by the DPD enzyme whose action consists in the transformation of 5-FU into its inactive product dihydrofluorouracil which is degraded and eliminated through the urine. This causes the DPD to be the rate-limiting step of the inactivation of 5-FU. Other factors such as age, race, comorbidities and concomitant therapies can influence metabolism,16. Approximately 0.1% has a complete DPD deficit; this implies null enzymatic activity,16-18.The activity of the DPD presents numerous inter-individual variations. In about 3%-8% of the population there is a partial lack of DPD expression which determines a reduction of the enzymatic activity of about 50%,19. Retrospective assessment of patients who developed severe toxicity during treatment with 5-FU, showed that 39%-61% had reduced activity of DPD enzyme-23. The DPD is encoded by the DPYD gene located on chromosome 1p22 and composed of 23 exons. DPD deficiency is usually the result of genetic polymorphisms of DPYD. DPYD is a highly polymorphic gene; over 50 polymorphic variants have been described,25. The screening of the DPYD variants is a valuable aid in clinical practice in predicting the occurrence of any toxicity in patients with DPD deficiency,26.In patients that receive 5-FU-based therapy and who have partial DPD deficiency, decreased enzymatic activity results in a reduction in 5-FU inactivation and also in a high risk of severe or fatal toxicityDPYD, that leads to DPD deficiency, can cause severe toxicity in patients treated with a fluoropyrimidine-based chemotherapy. Because of the high doses administered, DPD-deficient patients are likely to experience life-threatening toxicities. This pharmacogenetic “DPD syndrome” manifests typically as severe or fatal diarrhea, mucositis/stomatitis, myelosuppression and even rarer toxicities, such as hepatitis and encephalopathy. It is hypothesized that safety could be improved by prospective evaluation of DPD-deficiency before treatment start and through adequate dose-adjustment.It is confirmed that genetic variation of DPYD gene.Many different methods are used to test DPD deficiency and they can be mainly divided into three groups: tests aimed at assessing DPD enzyme activity, mRNA variants and genetic variants in et al.,30 demonstrated how upfront DPD testing with this ratio and tailored dosing can reduce the incidence of toxicities, while maintaining optimal efficacy in patients treated with 5-FU in a variety of settings.In the routine the best way to identify DPD-deficient patients is measurement of physiological plasma dihydrouracil/uracil (UH2/U) ratio. Analysis of uracil (U) and dihydrouracil (UH2) is performed in frozen plasma using a high-performance liquid chromatography with ultraviolet detection method; DPD deficiency is reflected by plasma UH2/U decrease or plasma uracil increase. Launay Due to the difference in terms of enzymatic activity of each variant they will be treated separately in the following section.DPYD gene are known to change the protein sequence or mRNA splicing process; the consequence is that some of them do not affect DPD activity, instead of other that can cause severe deficiency and related adverse events. Four variants are of primary relevance, because of their frequency in population and their clinical impact .Numerous genetic variants in DPYD*2A genotype  is the first described as being functionally relevant and the most studied polymorphism. This allele frequency varies between 0.1% and 1% in African-American and Caucasian population respectively-36. Its located at the intron of exon 14 and results in skipping of all the exon and in a nonfunctional protein,37.In vitro” studies showed several DPYD variants that were homozygous in mammalian cells; the enzymatic activity of DPD protein was absent when it was assessed in DPYD*2A carriers. So, it can be assumed that heterozygous carriers of this variant have approximately half of enzyme activity.“et al. conducted a prospective clinical trial focused on DPYD*2A-guided dosing of fluoropyrimidines, as to prevent severe toxicity. Patients who would be treated with fluoropyrimidine-based chemotherapy were genotyped for DPYD*2A before treatment start: DPYD*2A variant allele carriers were treated with a starting dose reduction of 50%. Then, if well tolerated, the patients would receive a dose-titration phase. Toxicity data for variant allele patients treated with a reduced dose were compared with controls from literature, i.e., DPYD*2A variant allele carriers receiving standard dose, since of the lack of a proper treatment arm with full-dose fluoropyrimidine-based chemotherapy: in particular, due to the already well-known association between DPYD*2A and increased risk of severe and lethal toxicity it was considered unethical to have such a treatment arm.Deenen DPYD*2A variant allele carriers undergoing genotype-guided dosing than in the historical controls, respectively, 28% and 73% (P < 0.001). Drug-related death was reduced from 10% in historical controls to 0% in this study.The study showed that risk of severe (grade ≥ 3) treatment-related toxicity was significantly lower in . Allele frequency varies from 0.1% in African-Americans to 1.1% in Caucasians,39-41. In vitro data by Offer et al. reveal that patients with homozygous expression of this variant have a 59% activity, compared to WT. These results show that even if enzyme activity is significantly reduced it is also more active if compared to homozygous carriers of DPYD*2A.c.2846A>T variant allele  causes a structural change in DPD enzyme that leads to a deficient function.We can deduce that if homozygous expression of c.2846A>T variant allele causes approximately 50% enzyme activity reduction, heterozygous carriers are likely to have 25% reduction in DPD activity; it is then suggested that they would advantage from a 25% drug dose reductionDPYD*13; I560S; rs55886062) is a rare DPYD polymorphism: its frequency varies from 0.07% to 0.1% in Caucasians,40. In vitro study by Offer et al. demonstrated that homozygous carriers have a reduction of 75% in DPD enzyme activity and suggests that the heterozygous carriers would have around 50% reduction in DPD enzyme activity.c.1679T>G  located deep in intron 10 causes abnormal splicing and maybe it is responsible for the DPD enzyme deficiency,43.c.1236G>A polymorphism  is in exon 11 and it is in complete linkage with all the variants named haplotype B3 (HapB3) -46. DPD activity is not completely absent in homozygous carriers; so it is expected that a 25% dose reduction for heterozygous carriers is convenient,47.The frequency of heterozygous patients in Caucasian populations varies between 2.6% and 6.3%et al. in a systematic review and meta-analysis. They collected data from 7356 patients and demonstrated that c.1679T>G, c.1236G>A, and c.2846A>T are clinically relevant predictors of fluoropyrimidine-associated toxicity, as the DPYD*2A variant.The clinical validity of all these three variants, in particular the toxicity related to fluoropyrimidine-based chemotherapy in patients carriers of these mutations, was studied by Meulendijks DPYD polymorphisms will result in reduction of toxicityOn the base of these findings, it can be expected that initial dose reductions in heterozygous carriers of these three other et al. published a multicenter prospective study to investigate the effect of dose-individualization chemotherapy, on the basis of four DPYD variants, on fluoropyrimidine drugs toxicity. Patients were genotyped for the four variants of DPYD and received an initial dose reduction of 5-FU following the current guidelines. This study shows that dose-individualization is achievable and can improve patient safety: it reduces risk of severe toxicity for DPYD*2A carriers, it is safe in c.1679T>G variant and decrease the toxicity risk in c.2846A>T, although the risk was still higher than WT. For c.1236G>A carriers, a reduction of 25% is not enough to diminishing toxicity. When compared with patients in historical cohort, the frequency of severe toxicity in DPYD*2A carriers was lower (31% vs. 72%); the only patient with c.1679T>G did not have toxicity after 50% dose reduction (the authors could not make correlation because of it was only one). For c.1236G>A and c.2846A>T reduction of 25% seemed not safe: 39% of the first group and 47% of the second had severe toxicity. The authors proved even that dose adjustment chemotherapy can reduces hospital admission due to severe toxicity and therapy discontinuation of treatment. The authors compared the patients treated with genotyped-dose reduction RR for severe toxicity with the same RR in DPYD variant allele carriers from a historical cohort from a meta-analysis, .Henricks The role of DPD expression as a predictor of effectiveness of 5-FU has been highly investigated in CRC, in comparison to other types of cancer. However, definitive consensus on its reliability as predictive factor has not been reached yet. Below the studies in the metastatic and adjuvant setting are disussed separately given the difference between advanced and localized disease in terms of prognosis and biology.et al. demonstrated a statistically significant correlation between DPD expression and response to 5-FU based chemotherapy. This study enrolled 37 patients with metastatic CRC treated with first-line capecitabine whose intratumoral DPD mRNA levels were assessed using laser capture microdissection and real-time (RT) PCR. Patients that had at least 50% tumor shrinkage at the CT scan were classified as responders to therapy. The results highlighted a significant association between high levels of intratumoral DPD and resistance to capecitabine while patients with lower mRNA expression levels of DPD showed better progression free survival (PFS).Some studies analyzed the level of response of advanced CRC to 5-FU chemotherapy in relation to DPD values. Vallböhmer et al.. By using a pre-established cut-off value , authors confirmed the negative predictive value of high levels of DPD .A correlation between intratumoral gene expression levels of DPD and response to 5-FU was also reported by a study conducted by Salonga ,54.In addition to studies that suggested a potential correlation between DPD expression and 5-FU-based chemotherapy activity, there are a few reports where this assumption was not proven, either in patients with metastatic or unresectable locally advanced colorectal canceret al. (CAIRO) randomized 803 advanced CRC patients between sequential treatment  or combination treatment . Retrospective evaluation of DPD expression by immunohistochemistry (IHC) was performed in formalin-fixed paraffin-embedded samples obtained from 556 patients. A statistically significant positive predictive value for low versus high DPD values was noted in 283 patients treated with capecitabine plus irinotecan, in terms of improved median PFS and overall survival (OS).Other studies have assessed the role of DPD expression values as a prognostic factor in metastatic CRC. A large Phase III study conducted by Koopman et al. also highlighted a positive correlation of low DPD expression and OS in a small number of patients affected metastatic CRC treated with a regimen composed by 5-FU, irinotecan and leucovorin (MIFL). Further studies evidenced a benefit in terms of PFS and time to progression in patients with low DPD expression treated respectively with capecitabine and first-line 5-FU based regimen.Yanagisawa The potential influence of the DPD expression on outcome in patients treated with 5-FU based chemotherapy has been also investigated in adjuvant setting.et al. investigated the prognostic role of DPD values  in 62 patients who underwent surgery and received 5-FU adjuvant treatment. At multivariate analysis, high DPD expression was significantly correlated with worse DFS and OS. Further studies reported a shorter DFS-60 and both worse DFS and OS in patients with high DPD expression. Some studies evidenced that low DPD expression levels were associated with trends for better OS,62 even if not statistically significant. Kornmann et al. examined the prognostic value of thymidylate synthase (TS) and DPD expression in 295 patients who received adjuvant 5-FU based chemotherapy after surgery. Patients who had tumors with low TS and high DPD levels had worse prognosis in contrast with the ones who expressed high TS and low DPD.Ciaparrone -66. These results taken together seem to suggest a correlation between low DPD expression and better prognosis in patients with colorectal cancer treated with 5-FU based chemotherapy in both metastatic et al. realized the only prospective study in which the expression of TS and DPD , led the choice of the first line chemotherapy. They proved that patients who had low TS and low DPD levels have higher response rate to 5-FU/LV compared with patients treated with non 5-FU containing regimen. The most relevant limitation of this study is that the population was divided into two groups with different markers and treated with different chemotherapy; so this does not allow a comparison between the groups and does not confirm the DPD expression predictive role.Nevertheless, some other studies, reported no correlation between DPD expression and prognosis in this settingThe B-CAST study is a multicenter, prospective cohort trial aimed to identify a correlation between tumor biomarkers expression, including DPD expression determined by RT-PCR, and outcome benefit from adjuvant treatment with different 5-FU based regimens in a population with stage III colon cancer: preliminary results of the study are actually unavailable, but we believe that this study might contribute to clarify the role of DPD as a predictive marker in this setting, owing to the large number of patients (2128) enrolled.5-FU based chemotherapy is commonly used for both palliative treatment of metastatic gastric cancer (GC) and adjuvant therapy in patients who underwent surgery. Therefore the role of DPD expression as a predictive biomarker for chemotherapy sensitivity and for outcome in patients treated with 5-FU has been widely investigated in this setting.et al. reported a statistically significant correlation, in vitro, between sensitivity to 5-FU therapy and DPD expression: in particular, cells that exhibited high expression of DPD mRNA were resistant to 5-FU; a weak inverse correlation between DPD level and sensitivity to 5’-deoxy-5-ﬂuorouridine (5’-DFUR) in vitro was also reported by Terashima et al.. Some other studies also showed high DPD expressions levels in 5-FU resistant cell lines,71 while DPD mRNA expression did not correlate with 5-FU sensitivity in a study conducted by Kodera et al.. In vivo studies by Nishina et al. and by Koizumi et al., conducted in a population affected by advanced GC, suggested that patients with high thymidine phosphorylase (TP) and low DPD expression are more sensitive to 5’-DFUR and capecitabine respectively. However a low DPD association has been associated with worst response rate in patients treated with S-1, a chemotherapy containing 5-chloro-2,4-dihydroxypiridine (CDHP) with anti-DPD activity widely used in Japan, and other studies demonstrated not statistically significant results with the same agent.Toriumi Similarly to colon cancer patients, also in GC, the predictive role of DPD was investigated in both metastatic and adjuvant setting.. Opposite results were reached by other two studies, where low intratumoral DPD expression was correlated with worse DFS and OS in patients who received S-1 adjuvant therapy.In adjuvant setting a longer survival was reported in patients treated with 5’-DFUR chemotherapy showing high TP to DPD ratioet al. investigated the role of genetic variations in DPYD in place of looking at DPD expression, analyzing the prognostic value of genetic single nucleotide polymorphisms (SNPs) of intratumoral DPYD and CDA  in patients with GC treated with adjuvant fluoropyrimidine (tegafur). SNP of DPYD1  was associated with better survival while the SNP  of DPYD2 showed a benefit in terms of relapse and survival if associated with the polymorphism of CDA .A study conducted by Grau ,81 and 5-FU, while a study conducted by Nishina et al. highlighted a connection between high TP to DPD ratio and longer OS in patients treated with 5-DFUR chemotherapy. At the same time various studies reported the absence of statistically significant impact of DPD value on survival in patients treated with S-1,76,82 and 5-FU,83.Conflicting results are reported also in the metastatic setting. Some studies have demonstrated that high DPD expression can be a predictor of poor survival in patients treated with S-1et al. performed a meta-analysis aimed to assess the potential impact of intratumoral DPD expression level on chemotherapy sensitivity and long-term survival for GC. The meta-analysis confirmed a correlation between high DPD expression and 5-FU activity, whereas long-term survival was not significantly different.Given the controversial results previously reported, in 2017, Zhang in vitro is established, the degree of intratumoral DPD activity inhibited by this agent in clinical setting is unknown.It should be noted that, while studies that assessed the activity of the chemotherapy regimens were conducted mainly by using 5-FU, studies that contributed in the meta-analysis to survival outcomes were those where S-1 was used more frequently. S-1 is a combined drug consisting of tegafur and CDHP, a chemotherapeutic agent characterized by DPD inhibitor activity; proof of this activity is the absence of hand-foot syndrome due to the lower concentration of 5-FU degradation products in patients treated with S-1 unlike patients treated with 5-FU or capecitabine. Thus, an enhancement of the antitumor effect would be expected in patients with high intratumoral DPD expression in comparison with patients treated with 5-FU, potentially invalidating the prognostic role of DPD expression level. While part of the previously cited studies confirm this hypothesis highlighting no significant prognostic difference between patients with high or low DPD expression or a worse prognosis in case of patients with low DPD levels treated with S-1, other studies provide opposite results. In fact, even if CDHP inhibiting activity Furthermore, the retrospective design of these studies, coupled with the lack of a reproducible assay for DPD expression, represents a severe limitation that could explain the lack of consistent data. Moreover, due to the fact that the majority of the studies included in the meta-analysis were conducted in Japan, due to the aforementioned described ethnic differences in terms of DPD expression, definitive conclusions concerning the association between DPD and sensitivity to chemotherapy can not apply to all populations. or 5-FU,87 after the resection of pancreatic cancer. However, in a study conducted by Murakawa et al., no significant difference in terms of 3-year OS following surgery was reported between DPD-postive and DPD-negative expression groups in patients treated with S-1 chemotherapy. In other studies which enrolled a small number of pancreatic cancer patients adjuvantly treated with 5-FU based chemotherapy, low TP/DPD ratio was significantly correlated with longer survival,90.The role of DPD expression as a prognostic factor has been mainly investigated in CRC and GC as previously described, however the widely use of 5-FU based chemotherapy has encouraged researchers to examine its value as a predictive and prognostic factor in other tumor types. Some studies showed a survival benefit in patients with low DPD expression treated with adjuvant S-1 and neoadjuvant setting. In contrast, in a recent study conducted by Hasegawa et al., higher DPD expression was predictive of better response to induction chemotherapy with 5-FU/cisplatin.In regard to head and neck cancer, intratumoral overexpression of DPD has been correlated with resistance to 5-FU-based chemotherapy in metastatic and for DFS in adjuvant setting, other ones did not found a significant difference between high and low DPD groups in terms of DFS in adjuvantly treated patients,97 and OS in metastatic ones. A recent study conducted by Qin et al. was the first aimed to investigate the prognostic role of DPYD polymorphisms in breast cancer. They demonstrated that DPYD c.1627A>G AG/GG polymorphism, detected from tumor tissue, was associated with poor OS and PFS in non-luminal patients treated with fluoropyrimidine-based chemotherapy.Few studies has been carried out in breast cancer patients treated with FU-based treatment. While some studies assessed a role of low DPD expression as a predictive factor for chemosensitivity or not significantly associated with prognosis.Conflicting data are also reported in lung cancer patients, with DPD expression pointed out as either relatedIn addition to the described limitations of the studies regarding the potential predictive and prognostic role of DPD expression in CRC and GC, the relative small number of investigations focused on different tumor types makes a hypothetical consensus unreachable at the moment.®) is an International Consortium establishing guidelines interested in facilitating use of pharmacogenetic tests for patient care; it helps clinicians interpreting genetic test results and ensuring a safer drug delivery to the patient.Clinical Pharmacogenetics Implementation Consortium , followed by c.1905+1G>A (1.6%) and c.2846A>T (0.7%). Adding all the four variants 7% of Europeans carry one decreased function DPYD genotype, assessed only for few variants, because the functional impact of rarer polymorphism has been only evaluated in vitro. The DPD phenotype is assigned using a gene activity-score (DPYD-AS): carriers of two no functional alleles are classified as DPYD poor metabolizers (DPYD-AS:0); carriers of one no function or decreased function are DPYD intermediate metabolizers (DPYD-AS:1 or 1.5) and those with normal function alleles are DPYD normal metabolizers (DPYD-AS:2).In DPYD activity score (DPYD-AS).DPYD decreased/no function variants should receive reduced starting dose because of partial enzyme activity. In particular heterozygous carriers of DPYD*2A treated with 50% dose reduction showed a rate of severe toxicity comparable to non carriers (DPYD-AS:1). In patients with c. 2846A>T heterozygous polymorphism a retrospective study established that the capecitabine starting dose was reduced by 25% compared to non carriers, just like the carriers of c.1236G>A. So the finally deduction is that patients carriers of DYD-AS:1.5 can tolerate higher doses than patients carriers of no function variants (DPYD-AS:1). In patients with decreasing function other circumstance should be considered to determine the initial dose-reduction, 50% starting dose followed by dose titration or only a 25% dose reduction.Patients heterozygous for If the first two cycles are well tolerated, to maintain effectiveness dose could be increased in subsequent cycles, given that some patients, even if carriers of no function or less function variants, tolerate normal dose of 5-FU. Similarly, if no tolerated, dose should be decreased.DPYD poor metabolizers (DPYD-AS: 0.5 or 0) it is strongly recommended to avoid 5-FU based chemotherapy. However, if there are no other options, 5-FU regimen at a heavily reduced dose in association with early drug monitoring may be considered for DPYD-AS:0.5. It should be noted that no reports of successful administration of a low dose of 5-FU in DPD poor metabolizers are available. It is estimated that a dose-reduction of 75% would be required. The CPIC defines as poor metabolizer only patients with two no-functional alleles; this score could be considered poor sensitive and high specific. We speculate that this approach aims to avoid false positive results in order not to deprive patients of 5-FU, given its primary role in solid tumors treatment.In DPYD mutations tests are not routinely performed because of the initial costing concerns of the tests and the absence of clear dose reduction guidelines in patients who have a deficit of DPD in prospective tests. Considering the ever-increasing number of patients that will require fluoropyrimidine-based chemotherapy, concerns regarding also the usefulness and costs of prospective testing have arisen.DPYD mutations is that, careful monitoring and gradual dose escalation, may allow patients with DPD deficiency to receive fluoropyrimidine chemotherapy safely,105.Furthermore, the absence of a mutation does not guarantee the absence of serious toxicity. Conversely, the potential benefit of prospective identification of et al. have shown that the cost of managing patients with severe toxicity to chemotherapy and with DPYD reactive test is higher than the cost of the prospective test on each new patient who initiates fluoropyrimidine chemotherapy. These results therefore showed that tests for the detection of DPYD mutations in the study population would be associated with significant cost savings. Another not-randomized study showed that prospective tests for DPD deficiency in patients receiving 5FU-based chemotherapy for CRC could be a cost-effective strategy.Murphy DPYD mutation, associated with a dose reduction from the start of therapy, can avoid chemotherapy-related toxicity and improve quality of life. In clinical practice, it is therefore reasonable to reduce the doses appropriately for the best characterized polymorphisms, avoiding testing polymorphisms with a still undefined meaning. In patients with these polymorphisms, greater vigilance may be suggested without dose reductions from the start of therapy. Routine prospective tests are therefore economically viable even if further research and clear dose reduction recommendations are needed. The DPYD test has the potential to prevent premature cessation of potentially curative therapy for patients with deficiencies,107.Prospective identification of patients with a DPYD*2A, c.1679T>G, c.2846A>T and c.1236G>A. These polymorphisms differ in the degree of toxicity and therefore each patient should receive dosage of these drugs that is based on the activity of this enzyme.Fluoropyrimidines still remain a class of pivotal drugs in the treatment of solid tumors. In this context the DPD enzyme plays an essential role as responsible for the inactivation of 5-FU. To date, many polymorphisms of the gene coding for this enzyme are known, determining various degrees of toxicity in patients who are treated with these drugs. The studies focused on 4 of these genotypes, those with the highest reported frequency in the population and those with a greater clinical impact: Furthermore, the expression of DPD should have profound impact in terms of prognosis and as predictor of effectiveness of these drugs. Speaking from a prognostic point of view, the presence of high intratumoral DPD expression should be associated with chemoresistance and worst outcome. The validation of this assumption would guide clinicians in everyday practice, encouraging, for instance, the use of 5-FU-based adjuvant therapy in patients at intermediate risk of recurrence after surgical resection or, moreover, the use of fluoropyrimidine-including treatment in metastatic setting, in presence of low DPD expression. On other hand, from a predictive point of view, due to the paramount importance of 5-FU-based chemotherapy in CRC, low DPD expression should be associated to better response/outcome in patients treated with fluoropyrimidine. This matter has been assessed in a series of studies in the setting of CRC. However, these studies are affected by various limitations: most of these studies are retrospective analyses and the majority of them is characterized by small sample size. We must mention also the lack of a standardized method of measurement of DPD, as it has been carried out in various papers through different ways , and the absence of a defined cut-off which could differentiate high from low DPD expression. Furthermore, there was no standardization even for chemotherapy regimens, given the use of different types and doses of fluoropyrimidine and the combinations with different chemotherapeutic agents such as cisplatin and oxaliplatin, which could have highly influenced reported results. Therefore, even if there seems to be a trend supporting the correlation between DPD expression and response/survival in patients treated with fluoropyrimidine, no definitive conclusions can be pointed out, considering also that some studies showed not statistically significant or even opposite results. The same statements could be referred to GC setting, which is also affected by limitations of ethnicity  and possible results distorsions due to the wide use of S-1 (in Japanese population), whose DPD inhibiting activity may invalidate possible statement concerning the role of DPD expression as a predictive factor., standardized for DPD expression assessment method and chemoterapeutic regimen used. Moreover, given the complexity of 5-FU pharmacokinetic, it would be useful to integrate future prospective studies with the evaluation of the other enzymes involved in 5-FU metabolic pathway.Thus the debate on the intratumoral DPD expression as a potential predictive and prognostic marker in fluoropyrimidine treated patients, is still open and it is crucial to analyze its role through prospective studies


Chronic neck pain is a leading cause of disability worldwide, affecting the lives of millions of people. Research investigating functional brain alterations in relation to somatosensory function is necessary to better understand mechanisms underlying pain development and maintenance in individuals with chronic neck pain, yet remains scarce. This case-control study aimed to examine resting-state functional connectivity alterations and associations with pain outcomes, self-reported central sensitization-related symptoms and quantitative sensory testing (QST) measures in patients with chronic non-traumatic (idiopathic/CINP) neck pain and chronic traumatic (whiplash associated/CWAD) neck pain compared to pain-free controls.Resting-state functional magnetic resonance images were acquired in 107 female participants . After data pre-processing, seed-to-seed analyses were conducted focusing on resting-state functional connectivity involving pre-defined regions of interest that have previously been observed to be structurally or functionally altered and/or associated with pain-related measures in this patient population.Findings demonstrate enhanced left amygdala functional coupling during rest with the left frontal operculum in women with CINP and CWAD compared to controls. This increased resting-state functional connectivity was associated with more self-reported symptoms related to central sensitization and decreased efficacy of conditioned pain modulation. Furthermore, enhanced connectivity between the left amygdala and left frontal orbital cortex, and between the left pallidum and the left frontal operculum was observed only in patients with CWAD compared to healthy controls. In patients, additional associations between local hyperalgesia and enhanced connectivity between the left superior parietal cortex and the left and right precentral gyrus were found.In line with our hypotheses, patients with CWAD showed the most pronounced alterations in resting-state functional connectivity, encompassing subcortical limbic  and basal ganglia , and ventral frontal regions  when compared to CINP and controls. Findings are generally in line with the idea of a continuum, in absence of significant group differences across CINP and CWAD. Enhanced amygdala-frontal operculum functional connectivity was the most robust and only connectivity pair in the cluster that was associated with QST , and that was observed in both patient groups. In addition, independent of group differences, enhanced resting-state functional connectivity between superior parietal cortex (involved in attention) and primary motor cortex was associated with static QST . Taken together, our findings show a key role for enhanced amygdala-ventral frontal circuitry in chronic neck pain, and its association with diminished endogenous pain inhibition further emphasizes the link between cognitive-affective and sensory modulations of pain in women with chronic non-traumatic and traumatic neck pain. AlthougIn line with increased pain sensitivity as assessed with QST, Magnetic Resonance Imaging (MRI) research has shown structural and functional brain changes in patients with chronic pain in regions associated with pain modulation  . Such brThe first aim is therefore to examine seed-to-seed rsFC alterations using predefined seeds in patients with CINP and CWAD compared to pain-free individuals and to investigate post hoc associations between rsFC group differences and self-reported pain-related and CS-related symptoms, and QST measures. The second aim is to investigate associations between seed-to-seed rsFC across all selected regions and self-reported CS-related symptoms, and QST measures. Brain regions in which we previously identified structural brain alterations or altered network properties based on resting-state fMRI graph theoretical analyses in this chronic neck pain sample were selected as seeds , in addi22.1This cross-sectional case-control study took place at the Department of Rehabilitation Sciences and Physiotherapy of Ghent University in cooperation with the Ghent Institute for Functional and Metabolic Imaging (GIfMI). Inclusion of participants took place from February 2014 until September 2015 and was carried out in accordance with the principles of the Declaration of Helsinki. The local Ethics Committee of the Ghent University Hospital (EC/2013/1053) approved the research protocol. All participants were thoroughly informed about the study procedures and signed an informed consent prior to study enrolment.First, all participants completed a survey to acquire information on demographics, and filled out a series of questionnaires to obtain information on disability, pain intensity, and CS-related symptoms. Subsequently, QST assessments were performed. On a separate test day (10 ± 7 days apart), high-resolution T1-weighted magnetic resonance (MR) images, axial T2*-weighted images, diffusion-weighted images and resting-state functional MR images of the brain were acquired. Two researchers  acquired the MRI scans and 1 researcher (IC) carried out the QST. Part of this dataset has already been described, with regard to alterations in grey matter morphology , white m2.2107 female participants −38 patients with CINP, 37 patients with CWAD and 32 healthy pain-free controls– were enrolled in this study. In order to exclude the confounding factor of sex, only women were included, as research has demonstrated significant differences between men and women regarding functional brain alterations in chronic pain , and paiInclusion criteria for patients with CINP and CWAD were persistent neck pain lasting more than 3 months , with a Healthy pain-free women could participate if they were pain-free on each test day VAS < 2/10)01, had nGeneral exclusion criteria for all study groups were the presence of major depression, anxiety, psychiatric, neurologic, metabolic, cardiovascular and inflammatory disorders, fibromyalgia, chronic fatigue syndrome, and a history of neck or shoulder girdle surgery. Furthermore, all participants completed the MRI safety checklist and women who presented contraindications for MRI such as metal implants, a cardiac pacemaker, or pregnancy were excluded.2.32.3.1On each test day, participants scored current neck pain intensity on the 11-point verbal numeric rating scale (VNRS-11). Scores range from 0 to 10, with 0 reflecting ‘no pain at all’ and 10 reflecting ‘the worst pain imaginable’. The validity of the VNRS-11 has been demonstrated . In addi2.3.2The Dutch NDI was used to investigate self-reported pain-related disability levels (0–50) . Higher 2.3.3All participants completed the Dutch version of the Central Sensitization Inventory (CSI). The CSI is a self-reported screening instrument to measure symptoms related to CS in chronic pain populations . The CSI2.4QST is able to measure pain processing changes with a psychophysical testing approach where the stimulus is quantified and used to measure perception and pain thresholds (static QST measures), and descending pain modulation (dynamic QST measures) .2.4.12 tip  at a symptomatic local region  to assess local (primary) pressure hyperalgesia  equipped with a 32-channel matrix head coil, located at GIfMI, Ghent University Hospital, Ghent, Belgium. High-resolution whole-brain T1-weighted MR images of the brain were acquired using a three-dimensional magnetization prepared rapid acquisition gradient echo sequence (MP-RAGE) with the following parameters, repetition time (TR) = 2250 ms, echo time (TE) = 4.18 ms, voxel size = 1 × 1 × 1 mm, FoV-matrix = 256 × 256 mm, flip angle = 9°, 176 coronal slices, acquisition time (TA) = 5′14′′;. All T1-weighted anatomical scans were checked to assure that no brain lesions were present. Axial T2*-weighted brain images were acquired using a T2*-weighted acquisition gradient echo with TR = 893 ms, TE = 18.6 ms, voxel size = 1 × 0.7 × 3 mm, FoV read = 230 × 230 mm, flip angle = 20°, 33 slices, and an acquisition time of 3′ 48′′. All T2*-weighted images were visually inspected by 2 expert neuroradiologists  to evaluate possible microhemorrhages or hemorrhagic shearing lesions related to trauma or diffuse axonal injury. No hemorrhagic shearing lesions or microhemorrhages related to trauma or axonal injury were detected.Resting-state fMRI was acquired using a T2*-weighted EPI sequence with the following parameters: TR = 2000 ms, TE = 29 ms, flip angle = 90°, number of slices = 40, FoV read = 192 mm × 192 mm, voxel size = 3 × 3 × 3 mm, 300 volumes, and acquisition time = 10′12′′. Participants were asked to close their eyes but to remain awake and not fall asleep. In addition, they were asked not to think about anything in particular. None of the participants reported falling asleep during the resting-state fMRI scanning procedure.2.62.6.1U test. All statistical analyses of the behavioral data were performed with IBM SPSS Statistics version 26 at a significance level of α = 0.05. Bonferroni correction was applied where necessary to correct for the number of post-hoc comparisons.Normality of variables was examined with the Shapiro-Wilk test and by visual evaluation of histograms and quantile–quantile plots. The Levene’s test was used to assess the equality of variance. If the assumptions of normality and equal between-group variances were met, data were analyzed with parametric tests. Otherwise, nonparametric tests were applied. Group differences in demographics, self-reported pain-related and CS-related outcomes and QST variables were investigated with a one-way ANOVA with post-hoc pairwise comparisons or with the Kruskal-Wallis test with post-hoc pairwise comparisons using the Mann-Whitney In addition to the CPM effect being analyzed as a continuous variable, CPM was also considered as a categorical variable to calculate the percentage of participants in each group showing an inhibitory  versus facilitatory  CPM effect. A Chi-Square test was performed to analyze group differences.2.6.2MRI data were analyzed using CONN . For res2.6.3Motion parameters were inspected. Participants were excluded if any of the six absolute motion parameters exceeded 2 mm/degrees and/or if the mean framewise displacement exceeded 0.2 mm . Based oF2,97 = 1.37, p = .26), maximum absolute motion , mean framewise displacement , maximum framewise displacement , number of outliers volumes , mean global BOLD signal changes , and maximum global BOLD signal changes  , and mean and maximum global BOLD signal changes were compared between the groups. There were no significant group differences in mean absolute motion (.79) see .2.6.4For denoising purposes, the six absolute motion parameters and their first derivatives were added as regressors of no interest, as well as noise signals from the cerebral spinal fluid and white matter . Denoising also included scrubbing of excessive motion by means of ART outlier detection  threshold was applied, which is a standard and appropriate choice for thresholding ROI-to-ROI parametric maps while appropriately controlling the family-wise error rate (2) across models was inspected, as well as the interaction term.ROI-to-ROI  rsFC analyses were conducted in the CONN toolbox v20b using the recommended settings for cluster-based inferences: parametric multivariate statistics . Potentiror rate . Bivariap < .05 cluster-level threshold with a post-hoc uncorrected p < .05 connection-level threshold). For significant associations, bivariate correlations were extracted, transformed using Fisher’s z and visually plotted. Again, we inspected whether there were any differences in correlations across groups by assessing a potential interaction effect.In addition, within the patient group (taking both groups together), associations were explored in CONN between rsFC across all selected seeds and self-reported symptoms related to CS , and static  and dynamic (CPM) QST measures  are presented in H2 = 68.79, p < .001), pain-related disability , and CSI scores . Patients with CWAD reported higher neck pain intensity on the day of MRI testing (p < .001. Cohen's d = 1.37) and more severe neck pain-related disability  compared to the CINP group. Patients with CWAD and CINP reported significantly more symptoms associated with CS than healthy women , and women with CWAD reported significantly more CS-related symptoms compared to CINP . Also, a significant main effect of group was found for local hyperalgesia , distant hyperalgesia , and CPM effect . Both patient groups showed significantly decreased pressure pain thresholds at the trapezius muscle  compared to healthy controls, while the patient groups did not differ . Furthermore, patients with CWAD showed significantly decreased pressure pain thresholds at the quadriceps muscle  compared to healthy controls , while there were no significant differences between CINP patients and healthy controls (p = .38) and CWAD patients (p = .15). In addition, efficacy of CPM was significantly lower in people with CWAD compared to CINP patients  and healthy controls . In contrast, individuals with CINP and healthy controls demonstrated no significant differences in CPM effect (p > .99). Also when looking at percentages of individuals showing normal versus abnormal CPM responses, it was observed that less patients with CWAD  showed an inhibitory CPM effect compared to healthy controls   but no significant differences were found between patients with CINP  and healthy controls or CWAD . During the CPM test, 5 patients with CINP and 5 patients with CWAD removed their hand out of the cold water before the end of the 2 min because the test was too painful.3.2F6,186 = 4.62, p-FDR = 0.01), comprising three rsFC pairs across the amygdala, pallidum, frontal operculum and frontal orbital cortex . As presented in p < .001, Cohen's d = 1.15; CINP: p = .02, Cohen's d = 0.67). No rsFC group differences were observed between patients with CWAD and CINP (p = .19). In addition, a main effect of group in rsFC between left amygdala and left frontal orbital cortex , and between left pallidum and left frontal operculum  was observed. The pairwise group comparisons demonstrated enhanced rsFC in patients with CWAD compared to healthy controls between the left amygdala and left frontal orbital cortex , and between the left pallidum and the left frontal operculum . No significant rsFC differences for these connections were revealed between patients with CINP and healthy controls, or between both patient groups (p > .05).One significant cluster was detected in the rsFC analysis in CONN  and decreased efficacy of CPM  , and hence correlations are presented separately per group, emphasizing that this effect is driven by the CINP group .Zooming into these group differences by performing post-hoc associations, we observed that across all patients (taking CINP and CWAD together), enhanced rsFC between left amygdala and left frontal operculum was associated with more self-reported CS-related symptoms (p = .02) B. Follow3.3F3, 60 = 8.07, p-FDR = 0.009) comprising of left superior parietal cortex and bilateral precentral gyrus  and left precentral gyrus   were associated with enhanced rsFC in a cluster  . Neither = 0.02) B. No oth4In this study, seed-to-seed rsFC alterations were examined in women with CINP and CWAD compared to pain-free women, as well as associations between rsFC and self-reported pain-related and CS-related symptoms and QST measures within the patient group. The main findings . The most robust group difference was enhanced rsFC between amygdala and a region in the ventrolateral frontal cortex , which was observed both in women with CINP and CWAD, as compared to pain-free controls. Across the entire patient group, we observed that enhanced amygdala-frontal operculum coupling was moderately associated with decreased endogenous pain inhibition, and in CINP it was furthermore related to more self-reported CS-related symptoms. This rsFC pair was not related to pain intensity, disability, and hyperalgesia.. A role of the frontal operculum and adjacent dorsal insula in the early sensory-discriminative dimensions of pain processing has been suggested  processing and regulation  and contuggested , althouguggested . Additioted fear . This isted fear , our finThese finding are in line with previous studies. For instance, Ihara et al. recently also revealed aberrant prefrontal rsFC in patients with chronic neck pain compared to healthy controls, albeit in coupling of the dorsolateral prefrontal cortex . Also inThe other rsFC pairs  were only significantly enhanced in patients with CWAD compared to controls , and were not associated with any of the self-reported or QST measures. The amygdala is a core threat center and part of the limbic system and the pallidum is a critical node in the mesolimbic network  and partIn chronic low back pain, previous research showed perturbed connectivity of the amygdala with the default mode network, including also the medial prefrontal cortex . We prevTaken together, our rsFC results of enhanced coupling in circuitry comprising ventromedial fronto-limbic and ventrolateral frontal-pallidum rsFC suggest alterations that are potentially related to movement, reward, emotional processing and/or decision-making, in particular in patients with CWAD, going beyond pain sensitivity. Further research is warranted to examine whether these circuit alterations may be related to cognitive deficits, motor impairment, and stress that have been observed in patients with CWAD.4.3r = −0.35 to r = −0.39) were identified between local hyperalgesia at the trapezius muscle  and enhanced rsFC between the left superior parietal cortex and bilateral primary motor cortex  in patients with chronic neck pain. Noteworthy, these regions were not involved in the observed rsFC group differences. No additional associations with endogenous pain inhibition  or self-reported CS-related symptoms were observed. M1 is part of the sensorimotor network and has an essential role in motor execution . Thus, although our approach encompassed all regions that were relevant based on previous findings in patients with chronic neck pain, yet it did not include all possible combinations of brain regions, and hence was a mixture of explorative and driven by previous literature. The present results therewith add evidence to our previously published findings in this study sample of brain network changes during rest , changesOur results emphasize the role of functional brain alterations in rest and their association with decreased endogenous pain inhibition, and associations between enhanced rsFC in sensorimotor circuitry and local hyperalgesia in women with CWAD and CINP. Accordingly, it can be recommended that therapy approaches for individuals with CWAD and CINP should take into account neuroplasticity of the central nervous system (being most pronounced in CWAD) and be mindful of the involvement of cognitive/affective neural circuitry in relation to pain sensitivity. Multi-modal treatment approaches, combining cognitive behavioral and physical therapy  processing and regulation - and its association with diminished endogenous pain inhibition emphasizes the link between cognitive-affective and sensory modulations of pain in patients with chronic neck pain. In addition, independent of group differences, increased rsFC of the superior parietal cortex with bilateral precentral gyrus showed associations with more local hyperalgesia, pointing towards an important role for this sensorimotor circuitry in pain hypersensitivity in patients with chronic neck pain – which may even extend beyond neck pain.Iris Coppieters: Conceptualization, Methodology, Software, Formal analysis, Investigation, Data curation, Writing - original draft, Writing - review & editing, Visualization, Funding acquisition. Barbara Cagnie: Conceptualization, Writing - review & editing, Supervision, Project administration, Funding acquisition. Robby De Pauw: Conceptualization, Investigation, Data curation, Writing - review & editing. Mira Meeus: Conceptualization, Writing - review & editing, Supervision, Project administration, Funding acquisition. Inge Timmers: Conceptualization, Methodology, Software, Formal analysis, Writing - review & editing, Visualization, Supervision.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


The aim of this study was to longitudinally assess the characteristics of background pain and breakthrough pain (BTcP), analgesic treatment, and satisfaction with treatment four weeks after the first assessment. Methods: Adult cancer patients with a diagnosis of BTcP were included. At T0, age, gender, visit setting, cancer diagnosis, the extent of the disease, ongoing anticancer treatments, and Karnofsky level were recorded. The background pain intensity in the last 24 h , opioids used for background pain, and their doses, expressed as oral morphine equivalents (OME), as well as other analgesic drugs, were recorded. The number of BTcP episodes, their intensity, predictability and precipitating factors, onset duration of untreated episodes, and interference with daily activities were collected. Analgesics and doses used for BTcP, and the mean time to meaningful pain relief after taking medication, were assessed. The level of satisfaction with BTcP medication was also assessed. Adverse effects to be attributed to these medications were also recorded. At T4, the same data were evaluated. Results: After one-month follow-up, patients had a lower number of BTcP episodes and peak intensity, possibly due to the optimization of background analgesia. The principal characteristics of BTcP did not change significantly. Conclusion: A careful and continuous assessment should be guaranteed to all patients to limit the burden induced by BTcP, other than treating BTcP episodes with short-onset opioids. Pain is frequently reported by cancer patients, and the prevalence is reported to be variable according to the stage of disease, ranging from 20–30% during the initial stages and up to 75% in advanced disease. This symptom strongly affects the patients’ quality of life (HRQoL) and their daily activities . RelieviCancer pain management can be particularly critical when patients face peaks of pain intensity, even though the background pain is adequately controlled by opioids given around the clock for most hours of the day. This phenomenon is commonly known as breakthrough cancer pain (BTcP) . BTcP isIn a study of BTcP with a sample of more than 4000 patients diagnosed with BTcP, a large percentage of patients 86%) experienced marked interference with their daily activities due to BTcP [% experieIndeed, BTcP is a chameleonic phenomenon that may change in individuals according to different clinical features, stages of disease, and treatments . For exaThe aim of this study was to longitudinally assess the characteristics of background pain and BTcP, analgesic treatment, and satisfaction with treatment four weeks after the first assessment.This paper is based on data from the IOPS-MS study, a prospective multicenter study conducted in 32 centers in Italy . An exteAdult cancer patients were included in the IOPS-MS study . PatientAt T0, age, gender, visit setting, cancer diagnosis, the extent of the disease , ongoing anticancer treatments, and Karnofsky level were recorded.The background pain intensity in the last 24 h , opioids used for background pain, and their doses, expressed as oral morphine equivalents (OME), as well as other analgesic drugs, were recorded.The number of BTcP episodes, their intensity , predictability and precipitating factors, onset (≤10 min or >10 min), duration of untreated episodes, and interference with daily activities , were collected. Analgesics and doses used for BTcP, and the mean time to meaningful pain relief after taking medication, were assessed. The level of satisfaction  with BTcP medication was also assessed. Adverse effects to be attributed to these medications were also recorded.At T4, the same data were evaluated. During this interval, patients were visited or contacted by phone to eventually modify the analgesic regimen, according to their clinical needs.All patients provided written informed consent, and the committees for medical research ethics in each center approved the study before initiation.p-values <0.05 were considered statistically significant. The correlation of the change in background pain intensity between T0 and T4 with the change in intensity and number of BTcP episodes was evaluated using Spearman’s correlation coefficient.Patient, BTcP, background pain, and BTcP management characteristics at T0 and T4 were described using mean ) or frequency (and percentage) as appropriate. For drug doses, the 95% CI was calculated only when at least five patients were receiving that drug. When necessary, 95% confidence intervals were censored at 0, and the upper limit was adjusted to ensure 95% coverage. Changes in BTcP, background pain, and BTcP management characteristics between T0 and T4 were assessed using McNemar’s chi-squared test or the paired two-sample t-test, as appropriate. The partially overlapping samples t-test [Of the original 4016 patients, 145 patients had a follow-up visit four weeks after the first evaluation. The characteristics of patients are described in n = 93, 64.1%), nociceptive , and neuropathic . The mean background pain intensity was 3.06 (CI 1.88–3.23) and 2.37 (CI 2.18–2.57) at T0 and T4, respectively. The difference was significant (<0.001). The mean daily OME was 98.3 mg (77.1- 119.4) and 102.8 mg (83.1-122.5) at T0 and T4, respectively. The difference was not significant (p = 0.73). Drugs and doses used for background pain are listed in The pain mechanisms were mixed (p < 0.001). BTcP intensity was 7.37 (CI 7.17–7.57) and 7.02 (CI 6.79–7.25) at T0 and T4, respectively. The difference was significant (p = 0.001).The mean number of BTcP episodes/day was 2.5 (CI 2.3–2.7) and 2.1 (CI 1.9–2.3) at T0 and T4, respectively. The difference was significant .There was a significant correlation between the change in background pain intensity (from T0 and T4) and the changes in BTcP intensity and the number of BTcP episodes (from T0 to T4) .At T0, BTcP was predictable and unpredictable in 89 (61.4%) and 56 (38.6%) patients, respectively. After four weeks (T4) data were stackable  and swallowing . Other triggers were cough , procedures , defecation , and others . Drugs and doses used for BTcP are listed in BTcP onset was ≤10 min and >10 min in 130 (89.7%) and 15 patients (10.3%), respectively. The principal triggers for predictable BTcP were movement (p = 0.49). Adverse effects attributable to BTcP medications were minimal (see The mean meaningful pain relief after BTcP medication was 12.8 (CI 10.4–15.3) and 12.7 (CI 10.3–15.1) minutes, at T0 and T4, respectively. The difference was not significant (imal see . At T4, imal see .The main finding of this explorative study performed in patients who had a follow-up four weeks after the first assessment was that, after an initial assessment, the improvement of background pain was able to reduce the number of BTcP episodes and their intensity. Although the increase in opioid doses was not significant, comprehensive management of pain and BTcP was likely to benefit the patients. Thus, better basal analgesia may allow us to prevent the gravity of BTcP episodes. Optimization of opioid therapy has largely been considered fundamental in reducing the development of BTcP. Studies have shown that the higher the pain intensity, the higher the prevalence of BTcP ,10, and In general, no substantial changes regarding the characteristics of BTcP were found, at least in a one-month period. This observation was reported in a concomitant study . Of inteThe second point is that the type of BTcP medications did not notably change, unless for FPNS and FBT. Opioid doses were slightly increased, as it occurred with opioids used for background pain. Of interest, the level of satisfaction with BTcP medication did not change and was considered acceptable in even more patients after one month. This observation confirms that BTcP medications maintain their effectiveness in time. Of interest, the initiation of fentanyl products as BTcP medication was associated with a reduced time for meaningful pain relief just after a week and maintained for one month, although doses of opioids for both background pain and BTcP were unavailable . Few lonLongitudinal analyses with repeated measures, as performed in the present study, increase the analytical strength of observations because of the individual changes in background pain, BTcP, and opioid drugs used. The sample size for a longitudinal study of palliative cancer patients is relatively acceptable. Thus, the results from this study allow clinicians to have more information to treat patients suffering from BTcP.The study has some limitations. Only some of the patients recruited in the original study approved or were able to have a follow-up visit four weeks after the first evaluation. Thus, data should be considered explorative. This inevitable problem, often encountered in palliative care patients, could have biased the results. Second, patients were included in the study at different time points in their disease trajectory. For example, patients could be still receiving anticancer therapy in an oncologic setting or were receiving only palliative supportive care, being considered off-therapy. On the other hand, this reflects the real world in which most patients are followed. There is no standardized starting point for pain development, and this remains a challenge in cancer pain studies . Third, The strong point of this study is that information was gathered from the real world, as this reflects the spontaneous clinical activity of experienced people working with cancer pain in different settings.After an initial assessment, cancer patients with a diagnosis of BTcP had a lower number of BTcP episodes and peak intensity, possibly due to better comprehensive management, while the principal characteristics of BTcP did not seem to change significantly, at least in a one-month period. This suggests that careful and continuous assessment should be guaranteed to all patients to limit the burden induced by BTcP. There is a need for a longitudinal assessment of a phenomenon that is invariably dependent on the stage of disease, patient characteristics, and therapeutic interventions. Further longitudinal studies on a large scale should be performed to confirm this preliminary information.


Background: One in five Canadians experience chronic pain, and interdisciplinary pain programs are well established as the gold standard of treatment. However, not all patients are ready to engage in interdisciplinary treatment for chronic pain.Aims: The aims of this study were to (1) first demonstrate changes in patient-related outcomes after attending a publicly funded 8-week interdisciplinary pain program and (2) evaluate pain-related predictors of readiness for change.Methods: The institution’s research ethics board approved this study. One hundred twenty-nine patients completed questionnaires on the first and last day of attending the program. Paired sample t-tests were utilized to evaluate the changes in patient-related outcomes after attending the program, and linear regressions were utilized to evaluate pain-related predictors of the stages of change.Results: Postprogram, there were significant decreases in pain-related interference, fear of pain/re-injury, pain catastrophizing, and symptoms of stress, depression, and anxiety and a significant increase in wellness-focused coping and self-efficacy. Postprogram, patients also demonstrated lower scores in precontemplation and contemplation and higher scores in action and maintenance stages of readiness for change. In predicting precontemplation, fear of pain/re-injury was the sole predictor, and self-efficacy was the sole predictor of the contemplation, action, and maintenance stages.Conclusion: These results demonstrate the short-term benefits of an 8-week interdisciplinary pain program. It is suggested that preprogram interventions targeting kinesophobia for individuals who are precontemplative and self-efficacy for others may be important to facilitate patient engagement. The biopsychosocial approach takes into account the complex interaction between physiological, psychological, and social factors that influence one’s experience of chronic pain.4 Furthermore, group interdisciplinary treatments for chronic pain  have been well established for their efficacy, cost-effectiveness, and longitudinal effects.7One in five Canadians experience chronic pain, which imposes a significant burden on patients, caregivers, and the health care system and has a large personal, social, and economic impacts. Chronic pain is challenging to treat and unfortunately is frequently undertreated and undermanaged within Canada.4 Interdisciplinary pain programs may also utilize additional therapeutic modalities, such as acceptance and commitment therapy and mindfulness-based interventions, which are associated with improvements in physical and mental health in patients with chronic pain.8In 2015, the Ministry of Health and Long Term Care in Ontario, Canada, provided funding for a number of pain clinics to develop interdisciplinary treatment programs for chronic pain. Such treatment programs aim to assist individuals in adopting a self-management approach to cope with their pain, emphasizing modifying unrealistic and negative thinking and increasing activity and productive functioning. Cognitive–behavioral therapy–focused programs are effective in reducing symptoms of pain; pain-related interference; and symptoms of depression, anxiety, and stress and improving functioning and active coping.9 The issue of high levels of attrition can be problematic, especially in publicly funded chronic pain management programs. Evaluating factors that are associated with understanding which patients engage and benefit from the programming while others do not is warranted due to both limited resources within a publicly funded system as well as burden on the patient in terms of time and effort. Evaluating the stage of change that an individual is in at the present time is one way of assessing for how ready he or she might be to engage in this approach to treatment.Though interdisciplinary treatment programs are effective in the treatment of chronic pain, not all individuals are successful in engaging with and participating in such programs.10 Readiness for change is divided into four stages, including precontemplation, contemplation, action, and maintenance. In the precontemplation stage of change, individuals express little interest in changing specific behaviors, and in the contemplation stage individuals report thinking about the possibility of making specific behavioral changes but are unlikely to make those changes soon. In the action stage, individuals actively take steps to change their behavior. Lastly, in the maintenance stage, individuals work to maintain health-related changes that they have made.10 Kerns et al. adapted these stages to individuals with chronic pain in the development of the Pain Stages of Change Questionnaire (PSOCQ).9 They further added to the stages in which individuals in the precontemplative stage of change continue to seek a medical cure for their pain and demonstrate reliance on passive coping strategies. Additionally, individuals in the maintenance stage are thought to have more self-control and accommodation of their pain and use more active coping strategies.The transtheoretical model of behavioral change suggests that individuals are in different stages of preparedness to make active behavioral changes.11 Kerns and colleagues suggest that cognitive therapy strategies, such as cognitive restructuring, might be more appropriate for individuals in the precontemplative and contemplative stages of change, whereas behavioral strategies requiring more active coping might be more appropriate for individuals in the action and maintenance stages of change.9 Evaluating pain-related predictors of patients who are in various stages of change has the potential to increase efficiency of programs with limited resources and to provide potential targets for pre-intervention depending on which stage a patient is in. For example, a patient who is in the precontemplation stage of change and is enrolled in an interdisciplinary pain program may not be ready for such an approach, which might lead to suboptimal outcomes such as poor attendance, not engaging in the components of the program, or being disruptive to other patients and/or resistant during the program. As such, a targeted pretreatment intervention might help prepare the patient to better engage in the programming.Research has demonstrated that measuring a patient’s stage of readiness for change may be useful in making treatment more efficient.13 Moreover, patients with higher precontemplation scores are less likely to complete treatment.14 Kerns and colleagues attempted to identify patients with chronic pain based on profiles of subscale scores on the PSOCQ and, as predicted, these patients did not differ in terms of measures of pain, disability, or demographics.15 For the purposes of clinical utility, this study was interested in evaluating pain-related variables that could be subject to modification with brief treatment in an interdisciplinary setting. Research has demonstrated that variables such as pain catastrophizing, kinesiophobia, and pain-related self-efficacy are modifiable with brief intervention.19Literature evaluating patient-related factors that are associated with the stages of change is limited. Research has demonstrated that the stage of precontemplation is associated with a low intention to self-manage pain, higher pain-related interference, depression and pain-related anxiety, and beliefs that others/chance control their pain.20 and (2) evaluate pain-related predictors on the PSOCQ to examine key factors that might lead to improving treatment and its efficacy. Addressing pain interference pre-intervention factors that predict a patient’s stage of change can assist in determining who will benefit from programming and be able to make improvements.This article had two objectives: to (1) first demonstrate the changes in patient-related outcomes after attending the 8-week interdisciplinary pain program The institution’s research ethics board approved this study. Data were collected from patients who attended an 8-week interdisciplinary pain program at the Michael G. DeGroote Pain Clinic in Hamilton, Ontario, between March 2017 and July 2018 and consented to being a part of the study. Patients attending the clinic have a variety of chronic pain conditions. Patients can access the program through a referral from their family physician or from a physician at the Michael G. DeGroote Pain Clinic. All patients referred must attend an orientation session about the programPatients initially attend an orientation session about the program and, if interested, are scheduled for an allied health and fitness assessment. If assessed to be appropriate for the program , patients attend the program once a week for 8 weeks for approximately 3 h each day. Each day consists of three components, including fitness/activation, a psychoeducation class, and relaxation. The psychoeducational classes include topics such as the science of chronic pain, dealing with flare-ups, pacing, activity education, sleep, nutrition, self-talk, and communication. Interdisciplinary team members include nurse practitioners, occupational therapists, pharmacists, physiotherapists, psychologists, psychometrists, and social workers who lead the classes. After consent was obtained, patients completed questionnaires on the first and last days of the program. Questionnaires were administered on the first day to collect baseline measurements before patients attended the programming and on the last day to be able to evaluate whether the programming was associated with any changes from baseline.n = 102) completed at least five classes, 66.95% (n = 86) completed at least six classes, 49.15% (n = 63) completed at least seven classes, and 19.49 (n = 25) completed all eight classes. Briefly, patients were a mean of 49.88 ± 13.55 years old, had experienced pain for 12.88 ± 13.35 years, and were off work for 7.35 ± 6.47 years. Moreover, the majority of the patients were female (73.6%) and Caucasian (62.0%). Sample demographics are displayed in This sample consisted of 129 adult patients who completed the 8-week interdisciplinary pain program, could read and write in English, consented to be a part of this study, and completed both admission and discharge questionnaire packages. Of those people, 80%  to 10 (unbearable pain).21 This scale is a valid measure of assessing for pain intensity and highly reliable in relation to visual and verbal measures, with high responsiveness to change.23Pain intensity was assessed using a visual analog scale measuring patients’ “usual” and “least” amount of pain experienced in the past 2 weeks on a scale from 0  to 3  in the past week. The DASS-21 is a valid measure of depression, anxiety, and stress in both nonclinical samples and clinical samples such as those with chronic pain.25The Depression Anxiety and Stress Scales (DASS-21)26 The PCS asked patients to rate 13 statements describing different thoughts and feelings that may be associated with pain. Each item is scored on a Likert scale ranging from 0  to 4 , with higher scores indicating higher levels of pain catastrophizing. The PCS is a well-established measure that is valid and reliable.27Catastrophizing was assessed using the Pain Catastrophizing Scale (PCS).28 Patients were asked to rate 11 items about how they feel about their pain on a scale from 1 (strongly disagree) to 4 (strongly agree). The TSK is a brief, reliable, and valid measure of fear of movement/re-injury for patients with chronic pain.29Fear of pain/re-injury was assessed using the Tampa Scale of Kinesiophobia (TSK).30 which is a seven-item measure that assesses a patient’s degree of interference within seven life domains . Patients indicated their level of pain-related interference from 0 (no disability) to 10 . The PDI has good internal consistency and validity within chronic pain populations.31Pain-related interference was assessed using the Pain Disability Index (PDI),32 The B-CPCI consisted of 16 items, which asked patients to rate the frequency of use of behavioral and cognitive coping strategies. The items were grouped into the following eight subscales: Guarding, Resting, Asking for Assistance, Relaxation, Task Persistence, Exercising/Stretching, Seeking Social Support, and Coping Self-Statements. The frequency of these coping strategies was measured by the total number of days during which the strategy was used in the past week (0–7 days). Previous studies have demonstrated that the B-CPCI has good internal consistency, test–retest reliability, and significant correlations in the expected direction with measures of patient functioning.33 The illness-focused Coping subscale was calculated by averaging the items for Guarding, Resting, and Asking for Assistance, and the wellness-focused Coping subscale was calculated by averaging the items for Relaxation, Task Persistence, Exercising/Stretching, Seeking Social Support, and Coping Self-Statements.34The Brief–Chronic Pain Coping Inventory (B-CPCI) was used to measure behavioral coping.9 Patients rated 30 statements on a scale from 1 (strongly disagree) to 5 (strongly agree), and the items were used to calculate four stages of change, including precontemplation, contemplation, action, and maintenance. The PSOCQ is a valid and reliable measure in patients with chronic pain.9The PSOCQ was utilized to assess patients’ readiness for change.not at all confident) to 10 (completely confident).35 The PSEQ has strong psychometric properties, including high validity, reliability, consistency, and stability over time.36The Pain Self-Efficacy Questionnaire (PSEQ) was utilized to assess patients’ confidence in being able to perform a behavior/task despite experiencing pain and consisted of ten items rated on a scale from 0 , and data from questionnaires that were at least 85% complete were imputed using simple mean imputation. All other data were considered missing and the cases were deleted from the data set.Data were analyzed using the statistical program SPSS version 25. Paired sample t-tests demonstrate significant improvements in patient-related outcomes postprogram  are more likely to have an increased fear of pain and re-injury, potentially leading to decreased engagement in the program and less readiness for change. Moreover, patients who are more ready to make changes  and manage their pain in accordance with a biopsychosocial framework are more likely to experience higher pain coping self-efficacy.18These results may have some implications for potential preprogram interventions to better engage patients for improved participation. For example, if patients are primarily in the precontemplative stage of change, they might benefit from a preprogram intervention to decrease their fear of pain/re-injury. Patients in the precontemplative stage enrolled in an interdisciplinary pain management program that requires individuals to be active in learning, applying, and integrating coping skills and strategies are likely to be disengaged and might not benefit from the program at that point in time. This is burdensome to patients in terms of their time and efforts, as well as to the program with limited resources in a publicly funded system. There are a number of interventions to decrease kinesiophobia, such as psychoeducation and graded exposure, that might be of benefit as preprogram interventions to help move patients in the precontemplative stage further along the readiness for change continuum.37 Interventions to increase self-efficacy are effective in other clinical populations, such as people with addiction, and can range from verbal persuasion to experiential activities in formats such as group activities or computer-generated letters.38 In samples of patients with chronic pain, recent research has investigated whether the effects of a self-efficacy intervention can improve the outcomes in a sample of patients with chronic low back pain.39 Interventions aimed at increasing self-efficacy in patients with chronic pain can be provided as a brief booster on each day of program attendance or upon completion of the program as a strategy for relapse prevention.Patients who are further along the continuum of readiness for change  might benefit from additional support to increase their pain coping self-efficacy to enhance their ability to engage in learning and utilizing the skills and strategies to better cope with their pain. A 2016 systematic review posited that pain self-efficacy has the most empirical support for increasing treatment adherence in patients with chronic pain in interdisciplinary pain programs in comparison to other pain-related variables.41 this is an important area for future research, especially in relation to publicly funded programs. Additionally, although the regression models suggest that pain-related outcomes predict the stages of change, this is simply an association and not an assumption of direction or causation. Furthermore, multiple tests to demonstrate postprogram outcomes were run in this study, which may result in incorrectly rejecting the null hypothesis. Moreover, the data linking the number of sessions that patients attended could not be connected to patient questionnaires to be able to associate this variable to the pain stages of change, which would be a valuable area for future research. Though the results from this study can provide valuable insights, future research would be helpful to evaluate these relationships longitudinally to determine whether pre-interventions do in fact help to shift patients along the readiness for change continuum and enhance engagement and to ascertain whether the changes found in the program are durable over time. Lastly, results from this study are based on one sample, and future research is needed in order to confirm these results in other samples and potentially within more specific patient populations.There are a number of limitations of this study. First, patients who chose to attend the groups, consented to participate in this study, and completed questionnaires likely are a fairly motivated and engaged sample, which represents a potential sampling bias. However, due to the nature of this study, it was not possible to collect data on patients who did not consent to participating in the research. Future research could collect a larger sample of clinical data to determine the patient characteristics of individuals who are not interested in engaging with or participating in interdisciplinary pain programs. Moreover, the sample of this study was primarily female and Caucasian, which might lead to issues with generalizability and highlight potential issues of program accessibility and barriers to participation. Though the demographics of this sample were comparable to those of similar studies in the region,This study demonstrated that the 8-week interdisciplinary pain program is associated with improvements in patient-related outcomes. It also demonstrated that fear of pain/re-injury was predictive of being in the precontemplative stage of change, whereas pain self-efficacy was predictive of being in the contemplative, action, or maintenance stage of change. These results show the efficacy of a publicly funded interdisciplinary pain management program. They also suggest the importance of potential preprogram targeted interventions to decrease fear of pain/re-injury in some patients and to enhance coping self-efficacy in others for better patient engagement and efficiency of publicly funded programming.