Patients were treated twice weekly, over 3 weeks. Primary outcome was pain intensity, measured 15 min after the last treatment session and at 24-, 48-, 72-h, and 7-days after the last treatment. Secondary outcomes were ROM, patient’ treatment satisfaction, and adverse effects. PBMT-sMF was able to reduce pain intensity in all time points tested compared to placebo (p < 0.05). There was no difference between groups in the secondary outcomes (p > 0.05). Our results suggest that PBMT-sMF is better than placebo to reduce pain in patients with chronic nonspecific neck and/or shoulder pain at short-term.Photobiomodulation therapy (PBMT) has been used to treat patients with chronic neck and/or shoulder pain. However, it is unknown whether the concurrent use of PBMT and static magnetic field (PBMT-sMF) also has positive effects in these patients. The aim of this study was to investigate the effects of PBMT-sMF versus placebo on pain intensity, range of motion (ROM) and treatment satisfaction in patients with chronic nonspecific neck and/or shoulder pain. A randomized controlled trial, with blinded assessors, therapists and patients was carried out. Seventy-two patients with chronic nonspecific neck and/or shoulder pain were randomized to either active PBMT-sMF ( Pain in the neck and/or shoulder is one of the most common and prevalent condition worldwide ,2,3. PatPBMT is a non-thermal light therapy that consists of the application of non-ionizing forms of lights sources such as light amplification by the stimulated emission of radiation (laser) and light-emitting diode (LED) to promote photophysical and photochemical events on biological tissues . These pThere is evidence about the effects of PBMT alone to treat patients with chronic neck and shoulder pain. A systematic review and meta-analysis showed that pain intensity was reduced in these patients after treatment with PBMT alone . This reAlthough there is evidence about the effects of PBMT alone on chronic neck and/or shoulder pain, to date, there are no studies demonstrating the effects of PBMT-sMF on pain intensity of patients with chronic neck and/or shoulder pain. It is unknown whether the concurrent use of PBMT and sMF is able to reduce pain intensity in these patients. Furthermore, it is unknown whether PBMT-sMF can increase the effect size on pain intensity in patients with neck and/or shoulder pain due the synergistic effect between these therapeutic agents. Therefore, the investigation about the effects of PBMT-sMF could be able to establish this therapeutic approach as an alternative to treat patients with chronic nonspecific neck and/or shoulder pain.We hypothesized that PBMT-sMF would have advantage over placebo to reduce pain intensity and increase range of motion (ROM) in patients with chronic nonspecific neck and/or shoulder pain. Therefore, this study aimed to investigate the effects of PBMT-sMF versus placebo on pain intensity, ROM and treatment satisfaction in patients with chronic nonspecific neck and/or shoulder pain.A registered (NCT02940119), parallel randomized, triple-blinded , placebo-controlled trial was performed at Laboratory of Phototherapy and Innovative Technologies in Health (LaPIT), São Paulo, Brazil. This study was approved by the Research Ethics Committee of Nove de Julho University (#1409527). All eligible patients signed written informed consent prior to the study start.The inclusion criteria were: patients with chronic nonspecific neck and/or shoulder pain, defined as pain in the neck and shoulder regions, persisting over at least 3 months and without a specific etiology ; of any The exclusion criteria were: patients presenting nerve root compromise, cervical spinal canal stenosis, and cervical spondylosis/cervical osteoarthritis; neck pain caused by diseases such as rheumatoid arthritis, meningitis or cancer/tumors; use of local corticosteroids/botulin toxin injection within the prior 30 days; fibromyalgia; diabetic neuropathic pain; surgery to the neck and/or shoulder region in the past 12 months; pregnant; and breast feeding.Randomization was generated through the random.org website and performed by a researcher not involved with any phase of the study. It was generated a simple randomization with an allocation ratio of 1:1. The same researcher programmed the device as active PBMT-sMF or placebo PBMT-sMF and coding the treatments according to the prior randomization. This researcher was instructed not to disclose the programmed intervention and codes to the assessors, therapists or any of the patients and other researchers involved in the study until its completion. Concealed allocation was achieved through the use of sequentially numbered, sealed, and opaque envelopes. Prior to initiation of treatment, patients were allocated to their respective intervention groups (active PBMT-sMF or placebo PBMT-sMF).The assessors, therapists, and patients were blinded throughout the study. To ensure complete blinding, the device used had no thermal effects , and emiThe active and placebo PBMT-sMF were performed using the same device and the irradiated sites were the same for both therapies: 9 sites on the neck and shoulder region. The neck and shoulder region were separated in three zones  for the irradiation of PBMT-sMF or placebo PBMT-sMF, in order to sufficiently cover the whole painful area. The SE25 plus LS50 emitters were positioned over the first target area (Zone 1): spinous processes of C3, left elevator scapulae, left trapezius. The SE25 plus LS50 emitters were then positioned over the second target area (Zone 2): spinous processes of C7, right elevator scapulae, right trapezius. The SE25 plus LS50 emitters were then positioned over the third and final target area (Zone 3): spinous process of T4, left rhomboid major, and right rhomboid major . The totIntervention specifications included:® Laser Therapy Systems manufactured by Multi Radiance Medical, Solon, OH, USA, using SE25 and LaserShower (LS50) as emitters. The full description of parameters is provided in ®, Newton, NJ, USA) before the beginning of the study and after the study was completed.(1) Active PBMT-sMF group: Active PBMT-sMF was delivered by the MR4(2) Placebo PBMT-sMF group: The placebo treatment was delivered using the same device that active PBMT-sMF but without any emission of therapeutic dose. In the placebo mode, the only visible diode was the red one. For the placebo mode, the 905 nm laser diodes and the 875 nm LED diodes were turned off. In addition, the power of the 640 nm LED diodes was turned off to 1 mW (for each diode) to keep the visual aspect of the red light. Finally, in the placebo mode, the sMF was also turned off.The primary outcome was pain intensity measured by a visual analog scale (VAS)-100 mm scale. Patients were instructed to report the pain intensity perceived in the neck and shoulder region based on a 0–100 mm-scale, with 0 (zero) being “no pain” and 100 being “the worst possible pain”.The secondary outcomes were active range of motion (ROM)  of cervical and shoulder, measured by a blinded assessor using goniometer. In addition, patient’ satisfaction with the treatment, measured by a Likert scale ranging from “very satisfied”, “somewhat satisfied”, “neither satisfied nor dissatisfied”, “not very satisfied” to “not at all satisfied”. Finally, adverse effects were collected by a report.The study was divided into three separate phases and the outcomes were collected during each of these phases . The phaThe success criterion was predefined as a 30% or greater reduction in the pain intensity from baseline to the final evaluation. The overall efficacy of the PBMT-sMF therapy was considered successful if a minimal difference of 35% is found between the active and placebo group. It was anticipated that about 55% of patients in the active group and about 20% of patients in the placebo group would meet the individual success criteria and intended application of a two-tailed test with an alpha of 0.05 and power of 0.8. A sample size of 33 eligible participants per group was calculated  and a pat-tests for independent samples were performed and the level of statistical significance was set at p < 0.05. The data were presented in absolute values and percentage of change.The statistical analysis was conducted following intention-to-treat principles . The Fisp > 0.05)  were recruited and completed all procedures between November 2016 and Abril 2017 . Proport > 0.05) .n = 36) of patients met the study individual subject success criteria, i.e., 36 patients had 30% or greater reduction in the pain intensity from baseline to the final evaluation. In the placebo PBMT-sMF group 61% (n = 22) of patients met the study individual subject success criteria.In active PBMT-sMF group 100% (p < 0.0001) at 15 min post-intervention  at 24-, 48-, 72-h, and 7 days post-intervention   .p > 0.05) in all time points tested . 83% (n = 30) of patients from the PBMT-sMF group and 83% (n = 30) of patients of the placebo PBMT-sMF group reported being “Satisfied” (Very Satisfied or Somewhat Satisfied) at the end of the treatment. In addition, 86% (n = 31) of patients from PBMT-sMF group and 89% (n = 32) of patients of the placebo PBMT-sMF group reported being “Satisfied” (Very Satisfied or Somewhat Satisfied) in the last follow up assessment.There was no difference between PBMT-sMF and placebo PBMT-sMF groups regarding the outcome patients’ satisfaction with the treatment (p > 0.05). In total, 11% (n = 4) of patients from the PBMT-sMF and 3% (n = 1) of patients from placebo PBMT-sMF group did not use any medication during the Stabilization Phase (phase 1). In total, 22% (n = 8) of patients from the PBMT-sMF group and 17% (n = 6) of patients from placebo PBMT-sMF group did not use any medication during the Treatment Phase (phase 2). Finally, 53% (n = 19) of patients from PBMT-sMF and 31% (n = 11) of patients from the placebo PBMT-sMF group did not use any medication during the Post Treatment Phase (phase 3).There was no difference between PBMT-sMF and placebo PBMT-sMF groups regarding medication usage  compared to placebo in patients with chronic nonspecific neck and/or shoulder pain. PBMT-sMF was able to decrease pain intensity in all time points tested compared to placebo. Moreover, we observed that ROM measurements increased in both groups, however there was no difference between PBMT-sMF and placebo groups. Finally, there was no difference between groups on patients’ satisfaction with the treatment and medication usage.2, 3 min of irradiation over the trigger points, in 10 sessions of treatment) was able to reduce pain intensity at rest and at movement after the end of the treatment and 10 weeks after the end of the treatment [2, 3 min and 16 s of irradiation) associated with stretching was superior to stretching alone in reducing pain intensity after 10 sessions of treatment and 3 weeks after the end of the treatment [It was previously demonstrated that PBMT alone  was no different to placebo in the treatment of patients with chronic neck pain. Although both groups had an improvement in pain intensity, ROM and functional disability, PBMT was not superior to placebo . On the We observed that PBMT-sMF was able to reduce pain in patients with chronic neck and/or shoulder pain when compared to placebo, however it was not enough to have a positive impact on ROM. We believe that in order to increase ROM, PBMT-sMF would need to increase the extensibility of the different tissues in the neck and shoulder area, which is not supported by the current evidence. These aspects can partially explain the results observed in our study. Thus, the results found in this clinical trial support the use of PBMT-sMF only to reduce pain intensity, but not to improve ROM in patients with chronic neck and/or shoulder pain.One of the strengths of this clinical trial was that is had a low risk of bias, since we used true randomization, concealed allocation, intention-to-treat analysis, and assessors, therapists, and patients were blinded. In addition, we used a placebo group to control possible confounding factors. Moreover, we controlled for cointerventions in both groups through an individualized patient diary used during the whole trial. Finally, we had no drop-out or loss to follow-up. On the other hand, we can consider a limitation of this clinical trial was not having measured disability through a disability scale. In addition, we only measured the short-term effects of PBMT-sMF.Further randomized controlled trials are needed to investigate the medium- and long-term effects of PBMT-sMF in patients with chronic nonspecific neck and/or shoulder pain. In addition, it is important to investigate the effects of PBMT-sMF also on the disability of these patients.There is an advantage in the use of PBMT-sMF to reduce pain intensity in patients with chronic nonspecific neck and/or shoulder pain in the short-term. However, there is no advantage in the use of PBMT-sMF to increase ROM and patient treatment satisfaction.


Wound pain after surgery for lumbar spine disease may interfere with patients’ recovery. Acupuncture is commonly used for pain management, but its efficacy for postoperative pain control is unclear. This study aimed to evaluate the effectiveness of acupuncture for adjuvant pain control after surgery for degenerative lumbar spine disease.We retrospectively reviewed the records of consecutive patients who received surgery for degenerative lumbar spine disease at our institution from 2013 to 2014. Surgical procedures included open laminectomy, discectomy, and trans-pedicle screw instrumentation with posterior-lateral fusion. Patients were grouped by pain control methods, including routine analgesia, patient-controlled analgesia (PCA), and acupuncture. The routine analgesia group received oral acetaminophen/non-steroidal anti-inflammatory drugs with meperidine as needed for immediate pain control. The PCA group received a basal dose of morphine and subsequent user-demand doses. The acupuncture group received acupuncture every other day after surgery.p = 0.026) on postoperative day 4 than scores of patients treated with acupuncture and traditional analgesia, a difference likely due to PCA being discontinued on postoperative day 3. No major complications were noted in the acupuncture group, but 2 patients dropped out because of fear of needle insertion.Ninety-six patients were included, of whom 37 received acupuncture, 27 received PCA, and 32 received routine analgesics for pain control. Visual analog scale (VAS) pain scores in all 3 groups decreased significantly, and to the same degree, from the first postoperative day to the second day. No significant differences were found in VAS scores over the next 6 postoperative days; however, the scores of patients treated with PCA were slightly but still significantly higher (Acupuncture may be as effective as traditional analgesia and PCA for adjuvant pain control after surgery for degenerative lumbar spine disease. Low back pain caused by degenerative spine disease is a common health issue for which individuals seek medical care. Ravindra et al.  reportedAcetaminophen and non-steroid anti-inflammatory drugs (NSAIDs) are the most frequently used first-line oral analgesics for postoperative pain control. However, side effects, such as liver toxicity with acetaminophen and peptic ulcer disease or cardiovascular events with NSAIDs, are of concern . Opiate Acupuncture is another approach for pain control. In traditional Chinese medicine (TCM), acupuncture helps energy, or “qi,” flow through the body smoothly and helps keep yin and yang balanced . Over thThe surgical approach for spinal disease has evolved significantly in recent years. In our hospital during 2013–2014, our surgical procedure for degenerative lumbar spine disease was standardized into open laminectomy with or without pedicle screws fixation. As a result, potential biases caused by different surgical approaches were able to be minimized. On the other hand, TCM at our hospital began to promote acupuncture for pain control and cooperated with various other departments in our hospital during that period. In this study we evaluated the efficacy of acupuncture as adjuvant therapy for the control of pain after surgery for degenerative lumbar spine disease during this time period.n = 1), incomplete medical records (n = 6), equivocal trauma history (n = 2), or incomplete acupuncture course (n = 3). Surgical procedures included standard open laminectomy, discectomy, and posterior-lateral fusion with trans-pedicle screw instrumentation. All surgical procedures were standardized under the hospital system.In this retrospective study, all medical records data of patients who received traditional open surgery  for degenerative spine disease at our institution from 2013 to 2014 were analyzed. The study protocol was approved by the Institutional Review Board (IRB) of our Foundation (IRB reference number: 202000811B0). During the study, 120 lumbar spine surgeries were performed, and twelve patients with trauma, tumors, or infection were excluded. An additional 12 patients were also excluded for discharge against medical advice (n = 32). (2) The PCA group (n = 27) received a basal dose of morphine (1 mg/h) plus user-demand dosing beginning immediately postoperatively in the recovery room until the morning of postoperative day 3. 3) The acupuncture (AC) group (n = 37), received acupuncture given by our Chinese medical physician every other day after the surgery. The choice for pain control was not randomly assigned. Instead, after thoroughly explaining to the patients about the advantages and disadvantages of different pain control methods, the method was determined by the patients. This was done mainly because PCA and acupuncture were not covered by the Taiwan national health insurance (NHI). Although this study was not a multiple treatment modalities trial, patients could still have additional medications for pain control if they experienced intolerable pain. Fourteen of 32 patients in the NA group and 7 of 37 patients in the AC group received additional analgesia. Acupuncture was administered at 7 acupoints: GB-34 (Yanglingquan), Ki-3 (Taixi), Du-20 (Baihui), Ex-UE7 (Yaotongxue), Bl-60 (Kunlun), St-36 (Zusanli), and SI-3 (Houxi). The acupuncture group was further divided into 2 subgroups for additional analysis: subgroup A (n = 23) received acupuncture prior to surgery on the day of the operation, and then 24 h after surgery and every other day thereafter; subgroup B (n = 14) received acupuncture every other day beginning 24 h after surgery. Twenty-eight patients discontinued acupuncture two days before discharge and nine patients received acupuncture one day before discharge. No patients received acupuncture on the day of discharge.Finally, the data of 96 consecutive patients were included as the analytic sample. All patients received regular acetaminophen 500 mg/ibuprofen 400 mg four times a day postoperatively, categorized according to their adjuvant pain control method. (1) The routine analgesia (NA) group received oral acetaminophen/NSAIDs with meperidine (25 mg intramuscular injection) every 4 h as needed for immediate pain control  with these cut points: 0, no pain; 1–4, mild pain; 5–7, moderate pain; 8–10, severe pain, worst imaginable pain [p < 0.05 was considered to indicate a statistically significant difference.All statistical analyses were carried out using IBM SPSS statistical software version 24 for Windows . Comparisons of pre- and postoperative parametric data of each group were performed using the D’Agostino and Pearson test for normality. Comparison of parametric results between the 3 groups was performed using ANOVA. The non-parametric (Mann–Whitney test) was used for the subgroup who received preoperative acupuncture (Pre AC) and those who did not (No Pre AC). Contingency results, including improvement of the chief complaint, sex, and surgical methods, were compared using Chi-square analysis. All statistical assessments were 2 tailed, and a value of Data of 108 patients were initially retrieved and 97 patients who met the inclusion criteria were identified. Recruited patients were categorized into different pain control groups based on their own preferences. No significant differences were found between the 3 groups in sex, age, spinal segment operated on, surgical method, blood loss, operation time, and preoperative VAS pain score , and it was borderline significantly different on day 5 (p = 0.076). By day 6, the VAS score in the PCA group had declined to that of the NA group, but VAS was significantly lower than those in both the PCA group and the NA group (p = 0.0471). Due to persistent pain, 4 patients requested acupuncture after discontinuation of PCA on postoperative day 3; 3 patients received acupuncture on postoperative day 4, and 1 patient received acupuncture on postoperative day 5.The daily changes in VAS pain scores over the first postoperative week are illustrated in Fig. p = 0.438, postoperative day 2 = 0.695) . When compared individually by using Chi-square test with Fischer exact test, the p value for outcomes was 0.192 between the AC and PCA groups and 0.0082 between the AC and NA groups. These results showed better outcomes in the AC group compared to those in the routine analgesia group. Outcome of “modestly improved” and “worse” were not significantly different between the three groups. Only one patient in the AC group received a single dose of meperidine (25 mg intramuscular) during the treatment course due to intolerable pain before the start of acupuncture. Four patients received AC after stopping PCA because of persistent pain. The characteristics of the three analgesia methods are compared in Table Surgical outcomes were assessed on the day of discharge and are summarized in Table No major complications  occurred in the AC group. However, 2 patients requested another form of analgesia because of fear of needle placement.The present study compared acupuncture, routine analgesic medications , and PCA for adjuvant control of postoperative pain after open surgery for degenerative spine disease. The most important finding was that acupuncture was as effective as the other two methods of pain control. The decline in VAS pain scores between postoperative days 1 and 2 was not significantly different between the three groups. Over the next six postoperative days, pain scores were essentially similar among the three groups, except that pain scores in the PCA group on postoperative day 4 were slightly higher than those of the other two groups. Interestingly, significantly more patients treated with acupuncture reported complete resolution or much improvement of their back pain after surgery than did patients in the other two groups.Variables in the pain control regimens and the surgeries of the three groups in this study complicate the comparison of the results of the different pain control methods . Nonetheless, acupuncture achieved greater pain control than the other two methods, without the disadvantages of side effects of opioids or NSAIDs or the cost of PCA. Acupuncture also was found to be safe, with no recognized adverse effects. Acupuncture has a disadvantage, though, in that a small number of patients are afraid of needle placement. Until rigorous controlled, prospective studies unequivocally establish acupuncture as safe and effective in the management of postoperative pain after surgery for degenerative spine disease, it will remain an attractive option but without proven superiority over conventional methods.Achieving great improvement in postoperative pain relief in patients undergoing spinal surgery is often a challenge. Therefore, complementary approaches, including chiropractic therapy, physiotherapy, massage, exercise, herbal medicine, and acupuncture, in addition to conventional analgesic are usually integrated into the rehabilitation programs. However, the effectiveness of these complementary therapies in improving postoperative pain control is not well defined.Acupuncture has been gaining popularity for the treatment of pain arising from various causes, particularly including low back pain. Xiang et al.  conducteAcupuncture also has economic benefits. The total cost of one PCA treatment course is approximately 300 US dollars, while the total cost of acupuncture is only about 30 US dollars. Such cost-effectiveness of acupuncture is also in accordance with other studies. In a systematic review that included 7 cost-utility analyses and 1 cost-effectiveness analysis concerning acupuncture for chronic pain, the authors showed that the cost per quality-adjusted life-year gained was below the commonly quoted thresholds used by the UK National Institute for Health and Clinical Excellence for “willingness to pay” . In anotIn 2003, the World Health Organization approved acupuncture for postoperative pain control of low back pain . The resThe mechanism by which acupuncture can reduce pain is not fully understood. Acupuncture can relieve muscle pain through increasing the levels of endorphins, which are natural pain killers and stress fighters . AnotherAs results of the present study have shown, PCA is an effective method for pain control. A systematic review of randomized trials found that PCA provided better pain control than did traditional analgesic drugs . AlthougThis study has several limitations. First, it is a retrospective study with the inherent potential biases of that design. Second, it is a single-center study and thus the results may not be generalizable to other centers, populations, or acupuncture practitioners. Third, the use of NSAIDs and meperidine by some AC patients makes assessment of the possible benefit of acupuncture alone difficult in those patients. Fourth, although patients were able to choose their preferred pain control methods, patients still needed to pay an extra amount of approximately 300 US dollars for the PCA in compliance with the health insurance regulations in Taiwan, which may lead to selection bias.The results of this study show that acupuncture is as effective as PCA and routine analgesics for adjuvant pain control after open surgery for degenerative lumbar spine disease. Its efficacy compared with that of traditional analgesia and patient-controlled analgesia is not established because of methodologic problems with this study. Large, multi-center, rigorously controlled trials are needed to conclusively determine if acupuncture has a role in relieving pain in this patient population.


Pain is one of the most frequent health problems, and its evaluation and therapeutic approach largely depend on patient self-report. When it is not possible to obtain a self-report, the therapeutic decision becomes more difficult and limited. This study aims to evaluate whether some membrane platelet proteins could be of value in pain characterization. To achieve this goal, we used 53 blood samples obtained from palliative patients, 44 with non-oncological pain and nine without pain. We observed in patients with pain a decrease in the percentage of platelets expressing CD36, CD49f, and CD61 and in the expression levels of CD49f and CD61 when compared with patients without pain. Besides that, an increase in the percentage of platelets expressing CD62p was observed in patients with pain. These results suggest that the levels of these platelet cluster differentiations (CDs) could have some value as pain biomarkers objectively since they are not dependent on the patient’s participation. Likewise, CD40 seems to have some importance as a biomarker of moderate and/or severe pain. The identification of pain biomarkers such as CD40, CD49f, CD62p and CD61 can lead to an adjustment of the therapeutic strategy, contributing to a faster and more adequate control of pain and reduction in patient-associated suffering.  The International Association for the Study of Pain (IASP) defines pain as an “unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” . Pain isPain characterization is essential for the correct approach for patients with chronic pain, starting with the assessment of pain intensity . The proPreclinical and clinical studies have investigated the hypothesis that biomarkers may also be used to identify and quantify pain. Findings from a preclinical study show that inflammatory pain and neuropathic pain have different biomarkers , but mosPlatelet heterogeneity and subpopulations may suggest distinct biological roles for different platelet subpopulations and may be useful in evaluating inherited or acquired platelet disorders and platelet function in health and disease . BesidesSince discovered by Giulio Bizzozero in 1882 , plateleIdentifying blood and platelet pain biomarkers has been advanced as the next great tool for pain identification and characterization, allowing tailored treatments ,16.Few studies relate pain with platelet activation, as pain inhibition occurs with platelet antiaggregants ,18,19,20Here, we evaluated the levels of membrane proteins, namely receptors related to several recognized functions of platelets, such as recognition, adhesion, aggregation, activation, inflammation, and immune modulation. In this context, the levels of the glycoprotein IV (CD36), the adhesion molecules, integrin α6 (CD49f), integrin β3 (CD61) and p-selectin (CD62p), the complement activation inhibitor protein (CD59) and the TNFα family receptor CD40 were evaluated in palliative patients platelets.The main aim of this study is to evaluate whether some known platelet membrane proteins could be of value in pain characterization and can be used as non-invasive pain biomarkers in patients where we cannot rely on their self-report, particularly patients with advanced dementia.For this study, we collected individual and clinical data and peripheral blood samples from 53 palliative patients with non-oncological diseases, followed by a specialized palliative care team between 1 September and 31 December 2021. This is an observational, analytic, transversal, non-interventional study using medical and nursing records on chronic pain patients.The Ethics Committees of the Faculty of Medicine of the University of Porto and the North Regional Health Administration of Portugal approved the research procedures, and the study was conducted following the Declaration of Helsinki. Before enrollment, participants or their legal representatives provided informed consent for participation. The international ethical guidelines of confidentiality, the anonymity of personal data, and the abandonment option were followed.For the collection of individual and clinical data, we consulted the records in the individual clinical files, after which they were registered in a protected Microsoft Excel sheet. To identify each patient, an alphanumeric code was used, thus keeping the identity confidential since only the researcher knows it. Following the European General Data Protection Regulation (GDPR), these electronic files will be deleted after the end of the study and the publication of the results. Data were collected regarding the following variables: age, sex, type and intensity of pain, opioid and other analgesics, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen, and doses in use. We also noted whether the patient had pain control at the moment of blood sample collection.We also collected information regarding the presence of a diagnosis of dementia and its type. For patients that had severe dementia, we used the Pain Assessment in Advanced Dementia Scale (PAINAD)  to identFor the purpose of analyzing the expression of the platelet biomarkers, we selected the following: glycoprotein IV (CD36), integrin α6 (CD49f), integrin β3 (CD61), and p-selectin (CD62p), the complement activation inhibitor protein (CD59) and TNFα family receptor CD40, that we analyzed in absolute and relative concentration.We proceeded to the ROC curve analysis to evaluate the significance of the area under the curve and if we have a cut-off point for CD40.g for 20 min at room temperature (RT). Then, the platelet-rich plasma was collected into a tube, and the platelets were washed using 2 mL of wash buffer (BD cell wash). Next, 1 × 106 platelets were incubated with the monoclonal antibodies anti-CD36 conjugated with FITC , anti-CD49f conjugated with PE conjugate , anti-CD61 conjugated with PerCP-Cy5.5 , anti-CD62 conjugated with APC , anti-CD59 conjugated with BV421, and anti-CD40 conjugated with BV510  for 15 min at RT in the dark, according to manufacture instructions. Then, cells were washed twice with FACS flow (BD Biosystems) by centrifugation at 300× g for 5 min and immediately analyzed in a FACS Canto II flow cytometer (BD Biosystems). At least 50,000 events were collected using FACS DIVA software (BD Biosystems), and the results were analyzed through Infinicyte software . The results are expressed in the percentage of cells expressing each protein marker and as mean fluorescence intensity (MIF). The platelet phenotyping was performed in freshly prepared platelet suspensions. None of the participants were recently transfused. Briefly, platelets were separated by centrifuging citrated blood specimens at 120× t-test for independent samples, Mann–Whitney U test, and Kruskal–Wallis test. The normality of distribution was analyzed with the Shapiro-Wilk test, and the homogeneity of variances was analyzed with Levene’s test. We analyzed the Chi-squared assumption that there should not be more than 20% of cells with expected frequencies inferior to 5. In those situations where this assumption could not be satisfied, we used the Chi-squared test with the Monte Carlo simulation.Statistical analysis was performed using the SPSS software . For the statistical analysis of data, we used measures of descriptive statistics  and inferential statistics. The significance level for rejecting the null hypothesis was set at (α) ≤ 0.05. We used the Pearson correlation coefficient, Fisher’s test, Chi-squared test of independence, Student’s The following variables were included: age, sex, type of pain, the intensity of pain, opioid and dose used, and other analgesics, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol, and absolute (MIF) and relative concentration levels of CD36, CD49f, CD61, CD62p, CD59, and CD40. We also included the type of dementia (because most of the patients had this condition) and controlled pain time for patients diagnosed with chronic pain, but their pain is controlled at the moment of blood collection. For patients that had severe dementia, we used the Pain Assessment in Advanced Dementia Scale (PAINAD)  to identAll patients under clinical follow-up from a palliative care specialized team from the North region of Portugal with non-oncological diseases. All patients or their legal representatives provided informed consent for participation.We selected 95 patients. However, five patients or their legal representatives refused to participate in this study and 20 of them were in their last days of life, and it was decided not to conduct a blood collection in this clinical condition. We could not collect blood samples from 17 patients, as they were too fragile, with hypovolemia and bad venous accesses. n = 39 (73.6%)]. Forty-four patients suffered from pain, and nine had no pain. We had no patients with known autoimmune diseases .So, we collected samples from a total of 53 patients with an average age of 74.8 years old, a minimum of 29 and a maximum of 98 years old; most were female [Among the 44 patients with chronic pain, 38 had severe dementia. We could not evaluate the type of pain and intensity in these patients. Therefore, we used PAINAD to distinguish those who probably have uncontrolled pain , and we separated PAINAD values  because in the clinical evaluation, there was a correlation between these PAINAD values and the possibility of having mild, moderate or severe pain, respectively. Among the 44 patients with pain, 19 were under opioid treatment (15 with dementia and four without dementia).We had six patients with pain and without dementia and nine without pain and without dementia (controls), as shown in p = 0.002)  . While the differences observed in CD36, CD49f and CD61 are age and sex independent, the difference observed in CD62p were more accentuated in men (about three times higher) comparatively with the observed in women . When wep = 0.026) and in the expression levels of CD49f , CD61  and CD59 . As we can observe in p = 0.002)  .The clinical history (other diseases) of the patients does not seem to interfere with platelet biomarkers.p = 0.047), as it is shown in With regard to pain intensity, we observed a significant relationship with the percentage of platelets expressing CD40. In fact, the percentage of platelets expressing CD40 is significantly higher in patients with moderate-severe pain (considering PAINAD ≥5) compared with those with mild pain  analysis to verify if CD40 could be a peripheral biomarker of pain intensity. We proceed to the ROC curve analysis to evaluate the significance of the area under the curve and if we have a cut-off point for this biomarker. The area under the curve is statistically significant, 0.777, with The ideal cut-off point corresponds to 0.025 .In patients with severe dementia, we cannot rely on self-report, and the characterization of the pain is difficult. The identification of biomarkers could be a valuable solution to enable targeted medical treatment. In this study, we find that CD36, CD49f, percentage of CD49f, CD61, percentage of CD61, and CD62p can be considered as platelet biomarkers of pain, CD62p as a platelet biomarker for nociceptive pain and CD40 as a platelet biomarker for moderate-severe pain.The hypothesis that biomarkers may be used to identify and quantify pain was investigated in several preclinical and clinical studies. A preclinical study showed that inflammatory and neuropathic pain have different biomarkers . FurtherPlatelet receptors are important for their normal functioning as they either activate platelets or act as adhesion molecules interacting with the damaged endothelium, other platelets, and leukocytes. Besides the platelet role in hemostasis, they also have a role in inflammation, antimicrobial activity, angiogenesis, tumor growth, and metastasis. In the absence of their receptors, platelets are unable to perform these functions. Some of the well-recognized platelet receptors are integrins, leucine-rich repeats receptors, selectins, tetraspanins, transmembrane receptors, prostaglandin receptors, lipid receptors, immunoglobulin superfamily receptors, tyrosine kinase receptors, and other platelet receptors . The preCD36 or Glycoprotein IV is a member of the class B scavenger receptor family of cell surface proteins, a multiligand pattern recognition receptor that interacts with a large number of structurally dissimilar ligands, including long chain fatty acid (LCFA), advanced glycation end products (AGE), thrombospondin-1, oxidized low-density lipoproteins (oxLDLs), high density lipoprotein (HDL), phosphatidylserine, apoptotic cells, beta-amyloid fibrils (fAβ), collagens I and IV, and Plasmodium falciparum-infected erythrocytes . CD49f is an adhesion molecule, namely α6-integrin 1, associated with inflammation towards the regulation of differentiation, adhesion, and migration of human mesenchymal stem cells . CD61 isPlatelet surface receptors have also been quantified as markers of the activation state of platelets, and platelet activation is increased in dementia . Both plWe already know that there is platelet activation in pain, especially inflammatory pain , but we are still unaware of all the pathophysiology and molecular biology involved [For patients with well-controlled pain, in comparison with those with non-controlled pain, we did not find statistically significant differences regarding laboratory data, including patients with well-controlled pain for seven or more days. These data are relevant because we could expect a reduction in platelet activation with pain control, considering that the half-life of platelets is seven days. However, it may mean that some underlying mechanisms and causes of pain may be equally active, and there is only pain desensitization. In opioid-treated patients presenting a better control of pain, there is less expression of biomarkers such as CD36, CD49f, CD61, and CD59. These data are in agreement with the literature on the effect of opioids on platelets, particularly in reducing their activity ,45,46.The sample was too small to assess more types of pain in addition to nociceptive and mixed pain. However, CD62p has been shown to be a reliable marker of nociceptive pain. Although it has not yet been specifically studied in this regard, the role of p-selectin is already known and has been linked to inflammatory pain ,48.CD40 (TNFα receptor family) was identified as a potential biomarker of moderate or severe pain intensity. The association of a biomarker with pain severity has not yet been established, although there are several references to platelet markers and disease severity ,50,51. IFurther, and besides the involvement of platelets in several diseases the presented markers, such as CD40, in autoimmune diseases such as inflammatory bowel disease, multiple sclerosis, psoriasis, or other autoimmune diseases, we had no patients with these diseases. Other diseases from the known medical history of these patients (such as hypertension) did not influence the platelet markers, according to what we found in the literature ,12,17,26This is one of the largest studies on pain biomarkers that we know of, and it is the only study comparing patients with non-oncological pain with specific platelet biomarkers. However, the sample is small, and further studies are needed considering these markers to confirm their viability as pain markers and CD40 as a marker of moderate-severe pain. In vulnerable and dependent patients, in whom we cannot rely on self-report, the identification of pain biomarkers such as CD40 can lead to an adjustment of the therapeutic strategy, according to the WHO ladder [


Cancer pain is one of the most frequent and relevant symptoms in cancer patients and impacts on patient’s quality of life. International and local standards recommend as an initial strategy the use of an analgesic scheme composed of strong opioids associated with adjuvants such as acetaminophen, based upon the assumption that combining drugs could have a better analgesic effect, could allow lowering opioid dosing, and could prevent the occurrence of adverse effects of opioids. However, there is uncertainty about the impact of acetaminophen as an adjuvant in patients who use strong opioids for moderate to severe pain management in cancer patients. The aim of this study is to assess the efficacy and safety of intravenous acetaminophen associated with strong opioids in hospitalized adult cancer patients who have moderate to severe cancer-related pain.We will perform a randomized double-blinded controlled study comparing intravenous acetaminophen 1 g 4 times a day versus placebo for 48 h as an adjuvant to strong opioids. We will assess pain intensity as a primary outcome, using the verbal numerical rating scale , and we will compare the mean difference in pain intensity between baseline and 48 h among the placebo and intervention groups. We estimate that a decrease of 1 point in the VNRS would be clinically significant. Assuming a standard deviation in pain intensity of 1.7 points, an alpha of 0.025, and a power of 0.8, we estimate a sample size of 112 patients, with 56 patients in each arm. Secondary outcomes include the difference in total opioid use between baseline and at 48 h among the groups, and adverse effects such as drowsiness, constipation, nausea, and vomiting would be evaluated.The randomized, double-blind, placebo-controlled design is the best strategy to assess the efficacy of acetaminophen as an adjuvant in adult cancer patients with moderate to severe pain who are receiving strong opioids. We expect to contribute to national and international guidelines with these results.NCT04779567. Registered on March 3, 2021. Retrospectively registered.Clinicaltrials.gov The online version contains supplementary material available at 10.1186/s13063-022-06442-2. Cancer-related pain is a relevant clinical problem. During the last decades, the incidence of cancer has increased around the world  and painSpecifically, the WHO analgesic strategy proposes that for moderate (step II) to severe (step III) pain, an analgesic scheme based on strong opioids  should be established, associated or not with adjuvants, such as acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs) among others. This adjuvant scheme is justified on the basis of a possible additive or synergistic effect between drugs, since adjuvants have different mechanisms of action than opioids. The benefits of this association could allow an improvement in relieving cancer-related pain and could decrease the total opioid dose used per day. Also, as opioids are associated with relevant adverse effects such as drowsiness, nausea and vomiting, sedation, and constipation, among others, the addition of adjuvants could decrease the frequency and intensity of adverse effects with the consequent improvement of quality of life for this population , 9. In aLooking at the downsides of this medication, the addition of acetaminophen implies the administration of an extra drug every 6 to 8 h either orally or intravenously adding to the burden that these patients experience. Also, despite the relatively low cost of acetaminophen, the wide extent of its use in some clinical contexts could imply an unnecessary increase in patients’ and health systems’ expenses.In the context of cancer, acetaminophen is known to be effective in patients with mild pain . HoweverThese observations motivated our team to establish a single-center, prospective, two-group, placebo-controlled, double-blind, randomized study with the primary objective to assess the analgesic effectiveness of intravenous acetaminophen compared to placebo in cancer inpatients with moderate to severe pain who are receiving strong opioids. The analgesic effectiveness will be assessed by comparing pain intensity before enrolment and at 48 h after the intervention. Secondary objectives include assessment of the effect of acetaminophen in the reduction of opioids and in the frequency of opioid-related side effects.This is a randomized, controlled, double-blind, parallel-group, single-center clinical trial. This study received ethical approval from the Ethics Committee of the Pontificia Universidad Católica de Chile ID #180328004). The study protocol was designed using the recommendations of the Consolidated Standards of Reporting Trials (CONSORT) statement  and acco80328004.The setting of this study is the General Internal Medicine Ward of a tertiary-level university hospital  where patients will be recruited. The academic institution supporting is the Department of Internal Medicine - School of Medicine at Pontificia Universidad Católica de Chile. The statistical support was provided by an academic from the Department of Public Health at the same institution. This work is supported by a grant awarded by the National Commission for Scientific and Technological Research (CONICYT) from the Ministry of Education in Chile, through the National Grant for Research and Development Projects in Health (FONIS) during 2019 (ID number: SA18I0039).Inclusion criteria were patients 18 years old or older, diagnosed with cancer and admitted to UC Christus Clinical Hospital with moderate to severe pain , with any type of pain , who were using opioids or not before enrolment. Exclusion criteria included refusing to participate in the study; being unable to communicate in Spanish; having altered mental status; patients with acute liver failure or Child C cirrhosis, history of allergies, or hypersensitivity to acetaminophen; and patients imminently dying or with a survival prognosis of less than 72 h. Dropout criteria include patients who presented altered mental status or clinical decline during follow-up, patients who died during follow-up, or patients who withdrew consent during the study. The details of the inclusion, exclusion, and dropout criteria are described in Table Before starting the study, a standardized pain management protocol for cancer patients with moderate to severe pain will be implemented across the institution Fig. . In thisIntravenous acetaminophen is usually delivered in a 100cc solution that is prepared in a transparent glass bottle. As the placebo cannot be prepared in the same type of bottle, the content of the acetaminophen preparation will be transferred to a standard 100cc plastic flask for IV infusions, which will be labeled with the name and ID number of the patient, with the drug to be administered labeled acetaminophen/placebo (including both names) and with the allocation number for the randomization. The preparation of the acetaminophen plastic flask will be indistinguishable from the placebo plastic flask. As the intervention will last 48 h, 8 plastic flasks with the drug will be sent directly to the clinical nurse in charge of the administration of the drug in the general ward.The placebo will be prepared using the same plastic flask as used in the acetaminophen group. In the placebo group, it will be filled with 100cc of saline and will have the same label as the acetaminophen group; therefore, they will be indistinguishable from each other. In the case of the placebo group, 8 plastic flasks with the placebo will be sent directly to the clinical nurse in charge of the administration of the drug in the general ward.As the research group wants to assess the impact of this intervention in the real clinical setting, treating clinicians will be allowed to be added according to clinical judgement. Non-steroidal anti-inflammatory drugs (NSAIDS), steroids, anticonvulsants, or other adjuvants could be added.Any adverse effects of opioids and acetaminophen will be monitored regularly at baseline and every 24 h for 48 h. In case of adverse effects, an independent investigator will assess on a case-by-case basis whether it will be appropriate to disclose patient allocation. In general, acetaminophen has a safe profile; however, opioids do present adverse effects more frequently.All cancer patients admitted to the General Internal Medicine ward at UC Christus Clinical Hospital with moderate to severe pain who are using strong opioids will be eligible to participate. Screening will be performed by a trained nurse or health care professional who will actively seek for patients every morning among all admitted cancer patients with moderate to severe pain. Treating clinicians will be approached to ensure patient eligibility. The research nurse will approach the patient and will perform a screening instrument confirming inclusion and exclusion criteria. All patients meeting inclusion criteria and who are willing to participate in the study will sign an informed consent form that will be obtained by the research nurse.After informed consent, eligible patients will be randomly assigned to either control (placebo) or experimental (acetaminophen) group with a 1:1 allocation Fig. . The ranOnce the pharmacist has identified the allocated arm of the enrolled patient, a total of 8 identical plastic flasks will be prepared in the pharmacy service, with a total amount of 100ml of volume each and each one labeled as previously described. For arm A, IV acetaminophen will be prepared; for arm B, IV saline will be prepared. The eight plastic flasks will be delivered to the general ward and the clinical nurses will be in charge of administering the infusions during the 48-h study period. Precautions will be taken to ensure that treating physicians, clinical nurses, data collectors, data adjudicators, patients, and researchers will be blind to patient allocation, including the inability to access the allocation registry, and the similarity of the flasks and drug presentation. During the administration of the placebo/acetaminophen, clinicians will titrate pain medications following the recommendations of the standard analgesic protocol. As previously mentioned, clinicians will be able to make modifications of the standard analgesic protocol according to clinical judgement.Patients will be asked to complete a baseline assessment questionnaire and then two other questionnaires at 24 and 48 h after enrolment. The questionnaires were selected seeking to assess the primary and secondary outcomes and variables that could impact patients’ pain experience. The study plan including the eligibility, the interventions and the assessments are described in Table Outcomes will be adjudicated by data collectors. In case any additional evaluation is required to adjudicate the outcome, precautions will be taken so that whoever does so also remains blinded.T = 0) and 48 h (T = 2) using the Verbal Numerical Rating Scale (VNRS) reported by the patient to assess the effects of the intervention in pain intensity. We will compare the difference in pain intensity between the groups. The VNRS is a tool in which the patient is asked to score the mean intensity of pain during the last 24 h in a scale from 0 to 10 with 0 meaning no pain at all and 10 meaning the worst possible pain. According to the score, pain is classified into no pain (score = 0), mild pain (score = 1 a 3), moderate pain (score = 4 to 6), and severe pain (score = 7 to 10). A patient is considered to have pain requiring therapeutic management if the patient reports a pain intensity of ≥ 4. Of note, this instrument has been recommended by WHO to assess pain in different settings [The primary outcome of this study will be the difference in pain intensity between baseline  which will be used as a secondary outcome. The VAS uses a right triangle drawn on a paper, with a base of 10 cm wide and a height of 1cm on the right, in which its ends are delimited by a mark that expresses “without pain” on the left side and “worst pain I have ever felt” on the right side. The patient is asked to mark a vertical line crossing the horizontal line indicating the intensity of the pain. On the reverse, there is a superimposed line, with a graduation of 1 cm wide, which allows the data collector to identify the position in which the line marked by the patient is located. This indicates patients’ pain intensity score assigned by the patient on a scale from 0 to 10. We will also estimate the difference in pain intensity between baseline and 48 h using the VAS and compare the magnitude of the difference between the arms.T=0) and 48 h (T=2). The MEDD represents the total dose of opioids used over the course of 24 h converted to an equivalent dose of parenteral morphine, following the standard equianalgesic conversion tables [Another secondary outcome that we will use is the total morphine equivalent daily dose (MEDD) during the prior 24 h before the assessment comparing baseline  to assess physical and psychological symptoms and financial and spiritual distress, the HADS to assess psychological distress, the EORTC QLQ-C15-PAL scale to assess the quality of life, and patient perception of pain improvement with a single question scale to assess the minimally clinical important difference .The follow-up for efficacy outcomes will conclude after 48 h.To estimate the sample size, we decided to use the strategy of identifying the minimum clinically important difference (MCID) in pain according to the ESAS scale, which evaluates pain on a scale from 0 to 10, similar to the VNRS, which we will use as our main outcome. The MCID is defined as “the smallest change in a measurement that signifies an important difference in a patient’s symptoms” . In a stIn an unpublished sample of 100 advanced cancer patients assessed in our PC unit, we found that the mean intensity of pain using the VNRS among patients with moderate to severe pain was 5.8 points with a standard deviation (SD) of 1.7 points.Because a difference of 1 point is considered to be what is clinically defined as significant, so we should try to detect a difference greater than that.Because we reported an SD of 1.7 in the initial pain scale in a sample of cancer patients in our unit.From the data obtained from prior publications, considering an alpha of 0.025, with a power of 0.8, we estimated that a sample size of 112 patients would be required, with 56 patients in each group to detect a difference of 1 point in pain intensity between the groups, with a standard deviation (SD) of 1.7. These assumptions are supported by the following reasons:T-test or ANOVA will be used for continuous variables given that our sample size is large enough to assume normal distribution of the averages by Central Limit Theorem. We will use Wilcoxon’s rank sum test to compare non-normally distributed data. Finally, multivariate mixed models will be adjusted for interest scores such as VNRS, VAS, and MEDDs at 48 h. As fixed effects in the model, we will consider de intervention (placebo or acetaminophen) and other factors (as tobacco) and the patient as the random effect. Subgroup analysis will be performed in this population, comparing differences in change of pain intensity according to the severity of pain and according to prior use of opioids. An intent-to-treat analysis will be performed for all relevant outcomes. A significance of 0.05 will be considered. The analyses will be performed using the statistical package STATA 14.0.For numerical variables, baseline characteristic data will be analyzed and represented with mean ± SD, or median with interquartile range (IQR), according to data type and distribution. Categorical variables will be described with frequencies and percentages. For bivariate analysis, Student In this study, the research team established that a Data Monitoring Committee (DMC) will not be required, given that no interim analysis is planned, patients included are in non-critical indications and will be treated for a relatively short time, and the drug under investigation is well characterized and known for not harming patients. Also, due to the short duration of the intervention and the small sample size established, no interim analysis will be performed and no external audits will be scheduled.clinicaltrials.gov registry. Given that in this case the intervention is of low risk, this project does not include compensation for participants.All protocol modifications will be reported to the Ethics Committee at Pontificia Universidad Católica de Chile and will be reported also in the Today, there is uncertainty whether or not acetaminophen is an effective analgesic in cancer patients with moderate to severe pain who are on strong opioids. The available evidence regarding this issue is scant and inconclusive. Answering this question is relevant to improve the quality of the care of this vulnerable population around the globe. We believe that this study will contribute with high-quality data to help elucidate the real role of acetaminophen as an adjunct to opioids in moderate to severe cancer pain. We expect that our findings will better support the analgesic interventions implemented for cancer patients so that national and international guidelines could be updated based on our results. To achieve this aim, we will use a randomized blind controlled study design, including cancer patients with moderate to severe pain in a way that makes it as inclusive as possible.In this study, we decided to use intravenous acetaminophen, because it is possible to achieve greater control of the bioavailability of the drug given that it can be used in a wider variety of patients, even in patients with no oral intake. This will also facilitate the production of a placebo with similar external characteristics, thus achieving the blind. On the other hand, if the hypothesis that intravenous acetaminophen is not effective as an adjunct to strong opioids in moderate to severe cancer pain, it would be possible to homologate these results with oral acetaminophen. The results of this project will be shared with the community and local health authorities to make recommendations on acetaminophen in cancer patients with moderate to severe pain receiving strong opioids.One strength of our proposal is that it will be carried out in a real clinical setting, allowing the use of other analgesic medications, which are often used in patient care. This will widen the applicability of the results. The study will be carried out in a single, highly complex academic inpatient center with an organized PC team that will ensure that patients will have access to the means and therapeutic alternatives to achieve good pain control. This may not include the reality of all health centers, affecting the generalizability of our results. It is important to highlight that the decision to make the study in the inpatient context will ensure that patients receive the medication as planned and will also contribute to early identify side effects or complications.The main goal of this report is to provide a structured and detailed protocol in such a way as to avoid bias when analyzing the data and to be able to generate good quality evidence for decision-making in health.Actively recruitingProtocol version: III version, 09/28/2020Date recruitment began: 06/10/2019Date recruitment will be completed: 06/14/2021Additional file 1. SPIRIT checklist.


Postoperative axial pain (PAP), characterized by pain and/or stiffness around the posterior neck, periscapular areas and/or shoulder region, is a vexing complication affecting 5–60% of patients undergoing posterior cervical decompression. Given its relatively high frequency and negative impact on patients’ physical and mental status, efforts preoperatively to confirm patients at risk of developing PAP to offer more efficient pain management to minimize this complication have a high priority. The aim of this study is to investigate the role of preoperative dynamic quantitative sensory testing (QST) in predicting the PAP after posterior cervical decompression.This longitudinal observational study included 122 patients with degenerative cervical myelopathy undergoing laminoplasty or laminectomy. Preoperatively, all patients underwent the assessment of pressure pain thresholds (PPTs) at local and remote pain-free areas and both temporal summation (TS) and conditioned pain modulation (CPM) at remote pain free-areas. These patients underwent further pain-related, psychosocial and clinical function assessments before and/or after operation.P < 0.05). Logistic regression further revealed that the presence of preoperative axial pain, TS value  and CPM value  were significant predictors of CPAP (P < 0.05).In the present study, 21 patients  developed PAP, and the 6-month postoperative follow-up demonstrated that 8 of these 21 patients developed chronic PAP (CPAP). All preoperative covariates with significant differences between the PAP and non-PAP groups were subjected to multivariate logistic regression, and the presence of preoperative axial pain, surgical plan including C2 decompression, total international physical activity questionnaire score  and TS value  were independently associated with PAP (The findings of this study support the hypothesis that preoperative endogenous pain modulation efficiency may be associated with axial pain after posterior cervical decompression. Clinically, preoperative estimation of both TS and CPM in remote pain-free areas may provide additional useful information for identifying patients who may be at risk of developing both PAP and CPAP, which may be beneficial in enabling stratification in the perioperative period of patients based on individual vulnerabilities to avoid/reduce this complication.The online version contains supplementary material available at 10.1186/s12891-022-05366-x. Posterior cervical decompression has been widely used to treat degenerative cervical myelopathy (DCM). However, serious complications can occur –6. AmongIncreasing studies has indicated that the preoperative pain response to noxious stimulation is associated with acute/chronic pain after many different kinds of surgeries –12. FurtHence, the aim of the present study was to investigate these dynamic QST measurements in patients with DCM before posterior cervical decompression, and the role of these dynamic QST techniques in predicting PAP after posterior cervical spinal surgeries was also analyzed.All methods used in this longitudinal observational study were carried out in accordance with ‘Declaration of Helsinki’, and the study protocol was approved by Human Ethics Committees . All subjects gave informed consent through written.This study included the patients with cervical spondylotic myelopathy (CSM) or ossification of the posterior longitudinal ligament (OPLL) who underwent posterior cervical decompression .The inclusion criteria included a confirmed diagnosis of multilevel cervical pathologies including CSM or OPLL identified by clinical symptoms, magnetic resonance imaging (MRI), electrophysiological detection, and operative findings. The exclusion criteria included previous spinal surgery, cervical structural pathologies , coexisting conditions that could increase procedural risk or worsen/change the pain .Total intravenous anesthesia (TIVA) was used in all patients in this study because of intraoperative monitoring. Anesthesia was induced with a propofol infusion combined with a single bolus of non-depolarizing short-acting muscle relaxant (vecuronium or atracurium). Anesthesia was maintained with a propofol infusion (6–10 mg/kg/h) and remifentanil (0.15–0.35 μg/kg/min).All patients underwent unilateral open-door laminoplasty or total laminectomy with fusion Fig. , and thePreoperatively, the patients usually did not take analgesic drugs, and only 6 patients with preoperative pain in this study were treated with acetaminophen every 12 hours, and all of these 6 patients stopped the analgesic drugs 1 day before operation. Postoperatively, local infiltration around the incision using 20 ml 0.75% ropivacaine was performed. Furthermore, a flurbiprofen axetil injection (50 mg) was given during the first 24 hours postoperatively. Afterwards, patients were instructed to take acetaminophen (450 mg) every 12 hours during the first 5 days postoperatively. If the patient had moderate or severe pain, supplemented  and/or prolonged use  of pain medication was allowed. In addition, patients were usually discharged from the hospital 5–10 days after operation, and the cervical spine was immobilized with a neck-collar for approximately 3 weeks.Both TS and CPM, as well as pressure pain threshold (PPT), were performed in all patients 1–3 days before operation using a pressure algometer . The procedures of QST were as follows: (1) All patients were asked to refrain from using analgesics for treating pain and consuming caffeine, alcohol, or nicotine 1 day before the assessment; (2) Before the QST assessments, the procedures were introduced to all subjects in detail until they were familiar with these methods; (3) First, PPTs were recorded from both local and remote pain-free areas; (4) After PPT recordings, TS were recorded from the remote pain-free area; (5) At last, CPM were recorded from the remote pain-free area.2, the test was stopped, and this value was recorded as PPT.During the PPT assessments, the measurements were recorded from two different regions in each subject Fig. : (1) uppDuring the TS assessments, 10 sequential mechanical pressure stimulations with the algometer at the pain threshold level  were performed in the remote pain-free area Fig.  18, 19], 1918, 1During the CPM assessments, conditioning stimulus was performed by applying intense pressure to the right upper arm with an 11-cm wide tourniquet to temporarily induce ischemic pain Fig.  20, 21], 2120, 2All patients were asked to rate the axial pain intensity at rest before operation using the NRS, and the average neck pain intensity 1–5 days after operation was also recorded. Furthermore, all patients were routinely followed-up at 1 month, 6 months and 12 months after operation by telephone or in the clinic, and pain intensity was evaluated in these patients with PAP. In this study, PAP was defined as newly developed or worsening pain  around the neck and shoulder persisting for at least 1 month , 23, andPreoperatively, all patients further accepted multiple questionnaires, including the Pain Catastrophizing Scale (PCS), Beck Anxiety Inventory (BAI), Beck Depression Index (BDI) and International Physical Activity Questionnaire (IPAQ), and all of these questionnaires have been validated in the Chinese environment in the previous studies –27. CervP-value < 0.05 was considered significant.All data were analyzed using SPSS version 20.0 , and the Kolmogorov-Smirnov test was used to confirm a normal distribution. Pearson or Spearman correlation analysis was used to evaluate the relationship between the PAP/CPAP intensity and perioperative measurements. The measurements for the non-PAP and PAP/CPAP patient groups were compared using independent t-tests or Mann-Whitney tests, and the frequencies of the different measurements between the patients without PAP and those with PAP/CPAP were compared by Fisher’s exact test or chi-square test. Statistically significant preoperative covariates based on univariate analyses were subjected to multivariate logistic regression analysis, and the cutoff values (CV) and area under the curve (AUC) of the results of the multivariate logistic regression were identified by a receiver operating characteristic (ROC) curve. A This study included 122 patient subjects , and the medical characteristics of these patients were listed in Table n = 7), Codeine (n = 1), Tramadol (n = 1), Ibuprofen (n = 2) and Celecoxib (n = 5).In the present study, 21 patients  presented with PAP after posterior cervical surgeries, and the postoperative 1-month follow-up NRS score in these patients was 3.8 ± 0.9. In these patients, 16  patients used analgetic medication, including Acetaminophen  developed CPAP (NRS: 3.9 ± 0.8), and 6 of these 8 patients still had axial pain at the last follow-up (NRS: 3.5 ± 0.5).r = − 0.54, P < 0.05), PCS , TS  and average pain intensity 1–5 days postoperatively . In the CPAP patient group, there was a significant correlation between CPAP intensity and average pain intensity 1–5 days postoperatively  and CPM .In the patients with PAP, PAP intensity was correlated with moderate IPAQ  between the PAP and non-PAP groups, including the presence of preoperative axial pain, surgical plan including C2 decompression, IPAQ, PCS, local-area PPT, CPM and TS, were subjected to multivariate logistic regression. The results showed that the cases with preoperative axial pain, surgical plan including C2 decompression, total IPAQ score, and TS were independently associated with PAP (Table All preoperative covariates with significant differences (AP Table . ROC curAP Table .Table 4MP < 0.05) between the CPAP and non-PAP groups were subjected to multivariate logistic regression analysis, and the results revealed that the presence of preoperative axial pain, TS and CPM were significant predictors of CPAP. Furthermore, ROC curve analysis revealed the CV of CPM (CV: 0.65) and TS (CV: 2.5) for predicting CPAP  related to PAP. According to the Table The findings of this study demonstrated that preoperative endogenous pain modulation efficiency may be involved in the pathophysiological process of axial pain after posterior cervical decompression. Preoperative estimation of dynamic QST, including both TS and CPM, in remote pain-free areas may provide additional useful information for identifying patients who may be at risk of developing both PAP and CPAP after posterior cervical spinal surgeries, which may be beneficial in enabling stratification in the perioperative period of patients based on individual vulnerabilities to avoid/reduce this complication.Additional file 1.


Temporomandibular joint dysfunction (TMD) is not a single diagnosis, but a term covering a group of conditions that involve pain and dysfunction of the masticatory muscles within the temporomandibular joint (TMJ) and associated structures. It is a set of disease entities comprising various ailments and clinical symptoms. One of the most distressing symptoms for TMD patients is pain. Pain is subjective and always unpleasant. The VAS  was used in this research. The aim of this study was to assess the influence of physical stimuli, namely extremely low frequency magnetic field (ELF-MF) and LED light, on the experience of pain caused by increased tension in the masticatory muscles in adults. Out of 150 people examined, 104 were enrolled in the study after meeting the eligibility criteria. The study group was divided into 4 subgroups. Each subgroup received physical therapy treatment using a different physical stimulus. The effects of four therapeutic modalities were compared. In terms of VAS scores, pain attenuation was observed in all subgroups. The study confirmed the analgesic effect of the selected physical therapy methods. The authors focused on the analysis of the results obtained for each subgroup, comparing the effects of individual modalities on pain intensity (according to VAS scores). After the treatment, pain relief was observed in each of the studied subgroups. Treatment using ELF-MF and ELF-MF in combination with LED light in the course of TMD brings about a significant improvement in the subjective pain experience expressed in VAS pain scores. The use of selected physical stimuli and their beneficial effect on pain symptoms during mandibular movements has important implications for patients' daily life and work. Incorporation of therapeutic methods can help enhance patient satisfaction and comfort during manual TMJ therapy and lengthy dental procedures. Temporomandibular joint dysfunction (TMD) is not a single diagnosis, but rather an umbrella term covering a group of conditions that involve pain and dysfunction of the masticatory muscles within the temporomandibular joint (TMJ) and associated structures. It is a set of disease entities comprising various ailments and, by the same token, clinical symptoms . Fast-paμT [Extremely low frequency magnetic field (ELF-MF) therapy is based on the application of a weak, slow-alternating electromagnetic field. The frequency of the basic waveform ranges from a few to 3000 Hz. Magnetic flux density is 1 pT–15 μT . The altμT ,11. TheiμT ,13. StimμT –17.Due to the extensive scope of its biological action, the low-frequency electromagnetic field is widely used in clinical practice, including complications in bone healing, bone mineralisation disorders, degenerative joint disease, reduced muscle tone, nerve regeneration, pain syndromes of various origins, and soft tissue regeneration .In dentistry, the use of the alternating magnetic field to restore functional balance has been reported in the treatment of inflammation of the pulp and periapical region, as well as in post-traumatic conditions of oral soft and hard tissues. Beneficial effects have also been observed in postoperative conditions, in cases of difficult eruption of third molars and complications following tooth extraction , as well as in the treatment of electrochemical metallosis in the oral cavity. Moreover, this method has been used in the treatment of neuralgia and damage or paralysis of nerves  ,20.β-endorphin group. This action can be attributed to the modulation of neuronal activity, as well as the secretion of melatonin by the pineal gland [The alternating electromagnetic field exerts an analgesic effect on the human body, by increasing the secretion of endogenous opiates from the al gland . Apart fal gland ,22. In aμT. Electromagnetic radiation is emitted by LEDs in the wavelength range corresponding to red (R-red), infrared (IR-infrared), and mixed (RIR) light. The energy of optical radiation in the visible and infrared range produced by LEDs brings about tissue regeneration, anti-inflammatory, and analgesic effects.Magnetic field with LED therapy makes use of the synergistic effect of an alternating electromagnetic field and optical radiation, combining the curative and stimulating effects of magnetic field therapy and LED light therapy. In the literature, it is referred to as extremely low frequency magnetic field (ELF-MF) and LED (Light Emitting Diode) therapy. Magnetic field LED therapy (ELF-MF + LED) harnesses light energy from high-energy LEDs in combination with a magnetic field with a frequency of 180 to 195 Hz and magnetic flux density up to 15 Simultaneous use of both types of electromagnetic radiation provides a synergistic effect, extremely beneficial in analgesic treatment, extensive skin inflammation, burns, as well as trauma . The synThe electromagnetic field is capable of penetrating any body structure, and its action can be deep and uniform. Light of an appropriate length, used simultaneously, can be introduced deeper if used on its own. This effect of treatment is possible only with a combined influence of magnetic field and light, because other physical factors reach only a given depth of the tissue undergoing treatment. The objective of the procedure with the use of the electromagnetic field depends on its parameters . Red ligAs mentioned earlier, one of the most distressing symptoms for TMD patients is pain. Pain is subjective and always unpleasant. In daily clinical practice, dentists do not have the tools or tests to objectively assess the severity of pain. On the other hand, researchers have developed many scales and questionnaires based on the patient's self-assessment to determine the severity of pain. Scales and questionnaires are auxiliary tools that, apart from the assessment of pain intensity at any point in time, can also be used to monitor treatment efficacy, as well as to determine impact on the physical and psychosocial functioning of the patient. Pain assessment instruments can be divided into one-dimensional and multi-dimensional scales. The use of several assessment methods allows for both qualitative and quantitative clinical evaluation, and enables the patient to provide comprehensive information on how they experience pain. On the other hand, the most appropriate methods are those that are clear, quick, understandable, and effective. That is why the visual analogue scale (VAS) was used in our study.The aim of this study was to assess the influence of physical stimuli, namely extremely low frequency magnetic field (ELF-MF) and LED light therapy (Light Emitting Diode), on the experience of pain caused by increased masticatory muscle tension in adults.The research was conducted at the Department of Propaedeutics, Physical Diagnostics, and Dental Physiotherapy of the Pomeranian Medical University in Szczecin from 2016 to 2019. Out of 150 people examined, 104 were enrolled in the study after meeting the eligibility criteria. Accordingly, the study group consisted of 104 patients with diagnosed TMD in the form of increased masticatory muscle tone confirmed in clinical examination.muscle tension and pain in the TMJ region ,patients who were diagnosed with myofascial disorders (Ia/Ib) as per RDC-TMDimpaired mobility of the mandible,tenderness on palpation in the TMJ region,bruxism (centric or eccentric),acoustic symptoms in TMJTo be eligible, respondents had to meet at least one of the following criteria:smoking (chewing) tobacco,use of removable dental prostheses,absence of articular and muscular disorders in the masticatory organ,active neoplastic processes or history of neoplastic disease,pregnancy and breastfeeding,use of/having implanted electronic medical devices such as a heart pacemaker, cochlear implant,intellectual disability,systemic diseases.The following exclusion criteria were adopted:All participants in the study were generally healthy , meaning that none of them took medication on a permanent basis, which could have had a potential adverse effect on the results of the pain analysis. Moreover, we excluded patients who self-reported smoking (or chewing) tobacco or had an active infection . The tests were performed in the morning, i.e. no later than midday, to minimise the impact of fatigue, stress, and other external factors on the perception of pain.Prior to enrolment in the study, all patients were informed about research objectives and procedure, as well as about medical recommendations during the course of therapy, and gave informed written consent to participate. The study was approved by the Bioethics Committee of the Pomeranian Medical University (Resolution No. KB-0012/149/15 of 14/12/2015). Participation in the study was voluntary, and patient anonymity was maintained in accordance with the Polish Personal Data Protection Act.The 104 patients included in the study were consecutively allotted into each subgroup. Patients in each subgroup received physical therapy treatment using a different physical stimulus. The division into subgroups, as described below, was introduced to conduct therapy with the use of four different physical therapy modalities, and to compare their efficacy in the respective subgroups of patients qualified for participation through history and physical examination. The four therapy modalities to be compared employed the following physical stimuli: extremely low frequency magnetic field (ELF-MF) therapy and combination therapy wherein the action of the magnetic field was synchronised with LED light of a specific wavelength range .The above physical stimuli were compared for efficacy in terms of the analgesic effect. Before commencing a series of treatments and after its completion, the patients underwent a clinical examination with the use of an examination chart designed specifically for the purpose of the study and their level of perceived pain/discomfort was quantified in VAS scores.Subgroup one included patients who underwent extremely low frequency magnetic field (ELF-MF) treatments. The subgroup consisted of 21 people (12 women and 9 men).Subgroup two received treatments combining magnetic field therapy with infrared light (ELF-MF + IR). The subgroup consisted of 22 people (18 women and 4 men).In subgroup three, magnetic field therapy was combined with red light (ELF-MF + R). In this subgroup, there were 24 women and 7 men.Subroup four was exposed to physical stimuli in the form of magnetic field and mixed light: red/infrared (ELF-MF + RIR). This subgroup included 29 people (22 women and 7 men).The population of 104 patients included in the study was randomly divided into four study subgroups:The therapy was continued for 3 weeks, with daily treatments excluding the weekends, totalling 15 physical therapy treatments per person.Patient history was taken so as to adequately identify the patients who were eligible for participation in the study, eliminating the influence of possible systemic conditions or injuries on the development of TMD. Medical history was taken from all patients in each subgroup. As a result, it was possible to determine the presence of abnormalities and the associated subjective complaints, as well as the potential causes leading to the development of dysfunctions. The signs and symptoms were then verified in a clinical examination, performed according to the international RDC/TMD questionnaire, which is the most widely used diagnostic tool for patients with TMD. The protocol makes it possible to classify the patient's symptoms according to predefined algorithms and to compare results between different clinical and research centres. The next step in the diagnostic process was a manual examination of the structures of the masticatory motor system based on the RDC/TMD questionnaire. Patients who were diagnosed in this way with myofascial disorders (Ia/Ib) were qualified to participate in the study.ELF-MF and LED light therapy was administered with the use of a single device—Viofor JPS (Med & Life) . The devM1, programme P3, intensity 6, which ensures a constant application of the selected intensity and uses the highest values of ion cyclotron resonance created in the cells. This means that the frequency of the basic wave was in the range of 180–195 Hz, the frequency of the wave packets was in the range of 12.5–29 Hz, and the packet group was in the range of 2.8–7.6 Hz, and that of series 0.08–0.3 Hz  combined with the action of the electromagnetic field. Penetration depth—several centimetres .R) combined with the action of the electromagnetic field. Penetration depth—several millimetres (R magnetic-light applicator—emits pulsed LED radiation—630 nm red light (limetres .R) and 855 nm infrared radiation (IR) combined with the action of the electromagnetic field  and standard deviations (SD) of all baseline measurements in four subgroups before receiving different treatments.Analysis of differences in VAS scores between the subgroups before the application of a specific physical stimulus is presented in The differences between the subgroups were tested for significance using the nonparametric Kruskal-Wallis test. Pain intensity according to VAS scores was found to be the highest in subgroups 1 and 3, and the lowest in subgroup 4. Detailed results are presented in Following the diagnostics performed after the application of physical therapy using ELF-MF, a significant decrease was observed in pain intensity self-reported by the respondents using the VAS—the pain intensity experienced by patients decreased by an average of 26.9%. Results are presented in Following the diagnostics performed after the application of physical therapy using ELF-MF + LED (using infrared light), a significant decrease was observed in pain intensity self-reported by the respondents using the VAS—the pain intensity experienced by patients decreased by an average of 41.18%. The results are presented in Following the diagnostics performed after the application of physical therapy using ELF-MF + LED (with the use of red light), a significant decrease was observed in pain intensity self-reported by the respondents using the VAS—the pain intensity experienced by patients decreased by an average of 29.15%. The results are presented in Following the diagnostics performed after the application of physical therapy using ELF-MF + LED (with the use of mixed red and infrared light), a significant decrease was observed in pain intensity self-reported by the respondents using the VAS—the pain intensity experienced by patients decreased by an average of 39.67%. The results are presented in Comparison of changes in tested parameters across all subgroups following the completion of physical therapy.Pain is difficult to measure because it is a subjective experience influenced by the current situation and health of the person, cultural norms, and several psychological factors ,31. DisoThis study confirmed the analgesic effect of the applied methods of physical therapy. The authors focused on the analysis of the results obtained for each subgroup, comparing the influence of individual modalities on pain intensity . After treatment, significant pain relief was observed in each of the treatment subgroups, but in the overall comparison, ELF-MF + IR was statistically significantly better than the other methods.p=0.06) [p < 0.001 [There are many publications on the anti-inflammatory and analgesic effects of ELF MF. In research, Thomas used this therapeutic approach to treat chronic musculoskeletal pain, achieving relief for patients. The results obtained in the group of these patients were close to statistical significance (p=0.06) . On the p=0.06) . The abop=0.06) . There ip=0.06) . From thp=0.06) . Iannittp=0.06) . These s < 0.001 . The ana < 0.001 .The present study in the subgroup of patients undergoing local treatment with ELF-MF and LED light demonstrated an analgesic effect, even though, in the author's comparison, ELF-MF + LED yielded better results than ELF-MF alone. This may be due to a deeper local effect and the simultaneous application of both stimuli in a single treatment. The light with a fixed wavelength applied together with electromagnetic field penetrates deeper than if used on its own. Such a synergy of the two treatment modalities is therefore more beneficial from a therapeutic point of view.The studies cited above are consistent with the present findings. Moreover, in terms of pain intensity, a statistically significant decrease was observed as a result of treatment. Similar results were obtained by other authors in research of a similar scope.Więckiewicz et al. emphasized a very important issue, discussing the pain in the masticatory muscles and the mental state of the patients. The authors found a relationship between the pain in the masticatory muscles and changes in mental state . This isIt should be emphasized that the treatment of patients with TMD should include appropriately selected physiotherapy. Positive therapeutic effects are achieved through the use of various factors  . Hals etVaca-González et al. focused attention to a very important point—magnetic stimulation is a promising noninvasive therapy that can be used to treat different kind of musculoskeletal pathologies. However, there are some limitations to highlight. The stimulation scheme, different ranges of frequencies, and application of various time stimulation mean that there is no standardized protocol in which ways of stimulation are the most appropriate to be able to treat a specific pathology. Even though studies described in this review showed positive results in treatment of musculoskeletal diseases, there is a need to carry out a standardization of the magnetic stimulation parameters application so that they are implemented in a regulated way at the clinical level .The use of ELF-MF and ELF-MF in combination with LED light brings a significant improvement in subjective pain perception—this action can be successfully used in the management of pain in the course of TMD. The physical factors reduced the intensity of experienced pain during the examination.The use of selected physical stimuli and their beneficial effect on the reduction of pain is of significant importance for patients in everyday life or work. The use of the abovementioned therapeutic methods may help to increase the patient's comfort and improve the results of manual TMJ therapy or the effects of dental procedures.Each patient has a different pain sensitivity threshold, determining the level of its severity, it is subjective, and thus there is no possibility to objectify the results of the research. The duration of the physical treatments lasted 3 weeks—from the initial observations, the reduction of pain in patients allowed for manual TMJ therapy.At the moment, authors do not have sufficient data on the follow up after the cycle of application of physical factors and enabling the determination of the duration of the reduction in the pain level in individual subgroups. However, research is being carried out on the abovementioned issues.