A prospective, multicenter, open-label study of the clinical efficacy of tapentadol extended-release in the treatment of cancer-related pain and improvement in the quality of life of opioid-naïve or opioid-resistant patients.

Introduction

Pain is the most common symptom in cancer patients. Up to two-thirds of patients experience pain, and with tumor progression, the pain worsens. More than 40% of cancer patients have moderate to severe pain [ 1 – 3 ], an important factor that influences the quality of life (QoL) of these patients. However, most cancer patients do not receive adequate treatment for pain owing to the difficulty in pain management [ 4 , 5 ]. This is mainly because cancer pain is a mixed type of pain arising from nociceptive and neuropathic pain [ 6 , 7 ]. In a previous study on cancer patients, 60% complained of nociceptive pain, 20% of neuropathic pain, and the remaining 20% complained of a combination of neuropathic and nociceptive pain [ 8 ]. It has been reported that although cancer itself causes neuropathic pain, treatments such as surgery, chemotherapy, and radiation therapy also contribute to neuropathic pain. In particular, some patients do not receive adequate chemotherapy owing to chemotherapy-induced peripheral neuropathy [ 9 – 11 ]. Therefore, pain control is as important as frontline treatment for cancer patients, in particular the control of neuropathic pain [ 12 , 13 ]. The World Health Organization (WHO) recommends aggressive control of cancer pain and suggests a three-step type of pharmacological management called the "analgesic ladder," which includes the administration of weak to strong opioids [ 13 ]. However, according to a recent report, many experts recommend using strong opioid analgesics as soon as possible for moderate to severe pain, together with anti-neuropathic pain drugs, such as pregabalin [ 14 ]. Despite these recommendations, it is difficult to control cancer pain along with neuropathic pain as many studies have failed to show promising results. In addition, a decrease in compliance to a particular drug when other classes of drugs are added is also an important factor for treatment failure [ 15 – 19 ].

Tapentadol extended-release (ER) is a dual-acting mu-opioid receptor agonist and noradrenaline reuptake inhibitor. These two mechanisms of action contribute to the regulation of nociceptive and neuropathic pain. Due to the synergistic effect of these separate mechanisms, this drug has increased ability to control pain, decreased side effects, and shows good patient compliance [ 20 , 21 ]. Several clinical trials have demonstrated the efficacy and safety of tapentadol ER in nonmalignant patients when compared with that of other types of opioid analgesics, such as morphine or oxycodone, and there have also been reports of its use in treating cancer pain [ 22 – 27 ]. However, the majority of these studies were conducted with < 200 patients, and there are only a few large-scale studies on the improvement of the QoL of patients following the improvement of neuropathic pain. Therefore, further research is required to accurately evaluate the efficacy of these drugs and their improvement of QoL.

We conducted a prospective, multicenter, open-label, large-scale study with a total of 650 participants, including 349 cancer patients, and we aimed to analyze the improvement of patients' QoL according to the improvement of nociceptive pain and neuropathic pain. We evaluated this improvement in opioid-naïve or opioid-resistant patients using an objective index: the clinical global impression change (CGI-C) [ 28 – 30 ]. The primary endpoint was pain intensity difference (PID), and the secondary endpoint was the CGI-C and safety.

Patients and methods

This prospective, multicenter, open-label, observational study was conducted at 13 centers in South Korea from October 2017 to May 2020. This study was conducted according to the Declaration of Helsinki, and the study protocol was approved by the respective Institutional Review Board of each center.

Patients

This study enrolled patients ≥ 18 years of age for whom tapentadol ER had been newly prescribed for the treatment of severe chronic pain, including the cancer-related pain (Numeric Rating Scale (NRS) score ≥ 7 or NRS score ≠ 0, even with the use of WHO ladder II or high drugs) based on the locally approved label. Patients with contraindications for tapentadol, such as a history of hypersensitivity to tapentadol or any component of the product; with significant respiratory depression, acute or severe bronchial asthma, or hypercapnia with mu-opioid receptor agonist; with paralytic ileus; with acute intoxication with alcohol, hypnotics, centrally acting analgesics, or psychotropic drugs; who received monoamine oxidase inhibitors or had received them within the last 14 days; and with genetic problems, such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption were excluded from the study. Patients who signed informed consent to the use of personal information in connection with, and were willing to participate in, post-marketing surveillance were included for the analysis.

Study design

The primary objective of this study was to evaluate the effect of tapentadol ER in opioid-naïve or opioid-resistant patients in Korea with chronic pain, including cancer pain, which was not sufficiently controlled in clinical practice. The effect of the drug on neuropathic pain as well as nociceptive pain was investigated in detail. The second objective of this study was to evaluate the improvement in patients' QoL due to tapentadol ER; this evaluation was conducted using the CGI-C, which was assessed by the physicians who participated in the study.

After baseline evaluation (visit 1), tapentadol ER was administered to patients. Next, the efficacy, CGI-C, and adverse drug reactions were assessed at 4 (visit 2), 12 (visit 3), and 24 weeks (visit 4), respectively. During the baseline study, previous drug usage was investigated, particularly that of opioid analgesics. In opioid-resistant patients who required conversion to tapentadol ER, all other opioids were discontinued before tapentadol ER was initiated, considering the equivalent dose according to the National Comprehensive Cancer Network guidelines. In opioid-naïve patients, drug administration was initiated with a dose of 50 mg twice daily. After treatment initiation, the dose was individually titrated under the close supervision of the prescribing physician at a level that produced an adequate analgesic effect and minimized the side effects. According to the clinical trial data, the method of increasing the dose by 50 mg every 3 days while maintaining the administration twice daily was observed to be an appropriate titration method. This drug has not been studied in daily doses exceeding 500 mg; hence, this drug is not recommended for such usage [ 31 , 32 ].

All adverse drug reactions and special situations following exposure to a product in the study were systematically recorded, regardless of the seriousness or causality. Adverse drug reactions were recorded at the first use of tapentadol ER within the study period and applied to all adverse events that occurred within 30 days after a patient’s last use of tapentadol ER.

Assessment

The effective outcome measure for this study was average pain intensity over the preceding 24 h. At each visit, the patients were asked to indicate their pain score using the 11-point NRS, where a score of 0 indicated “no pain” and a score of 10 indicated “pain as bad as you can imagine.” Effectiveness was assessed by the percentage of patients achieving various levels of improvement in pain intensity from baseline at various time points. Disease severity was evaluated based on the NRS score. Each visit and the change from baseline to the final assessment of pain intensity (11-point NRS) was summarized using the number, mean, standard deviation (SD), median, minimum (min), and maximum (max) values. For analyzing the proportion of response, the change from baseline to each visit or the final assessment was calculated. The %PID30 and %PID50 (defined as a 30% and 50% reduction in pain intensity from baseline) were also calculated using 95% two-sided confidence intervals (CI). \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\% {\text{ Pain Intensity Difference }} = \frac{{({\text{NRS score }}\left( {\text{Visit 1}} \right) - {\text{NRS score }}\left( {{\text{Visit 2}},{ 3},{\text{ 4 or final assessment}}} \right)}}{{{\text{NRS score }}\left( {\text{Visit 1}} \right)}} \times {1}00$$\end{document} % Pain Intensity Difference = ( NRS score Visit 1 - NRS score Visit 2 , 3 , 4 or final assessment NRS score Visit 1 × 100

Neuropathic pain was evaluated as “yes,” “none,” or “unknown” by the investigator directly interviewing the patient at each visit. Questions about neuropathic pain were asked by the investigator to the patient personally, and there were no special regulations or questions.

The CGI-C was assessed by the clinician who responded to the question “compared with the patient’s condition at baseline, how has it changed?” using 1 of 7 possible responses: very much improved = 1, much improved = 2, minimally improved = 3, no change = 4, minimally worse = 5, much worse = 6, very much worse = 7. Effectiveness was assessed by the percentage of patients achieving “no change = 4” or higher. The CGI-C assessments were summarized descriptively by presenting the number and percentage of participants in each category. In addition, the percentage of participants with “no change” or higher improvement was summarized. All findings from the examinations were medically adjudicated, interpreted, and described. The missing data correction for the effectiveness evaluation at the baseline was not executed. When data was missing from the NRS or CGI-C data on other visits, the last observation carried forward (LOCF) method was used.

Statistical analyses

The Wilcoxon signed-rank test was applied to test the statistical significance of the difference of NRS scores between the baseline (visit 1) and subsequent visits (visit 2, visit 3, and visit 4). To test the statistical significance of the CGI-C at each subsequent visit, which is the difference value itself, the range of CGI-C was modified to {-3, 3} from {1, 7} by modifying “very much worse” to be − 3 instead of 7, “no change” to be 0 instead of 4, and “very much improved” to be 3 instead of 1. This modification was done by calculating (4 − [CGI-C]). The Wilcoxon signed-rank test was applied to the modified CGI-C value to test the statistical significance of the CGI-C at subsequent visits (visit 2, visit 3, and visit 4). Testing was done both with and without using the LOCF method. All analyses were defined as significant when the two-sided p -value was < 0.05. Data collection, trimming, and statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, North Carolina, USA).

Results

Study populations

This study included 752 patients who had uncontrolled chronic pain including cancer pain with or without the use of other analgesics. From this group, 64 patients were excluded from safety evaluation, leaving 688 patients, of whom 367 were cancer patients (Fig. 1 ). The initial course of this study recruited patients with other chronic pain; however, in this study, we analyzed only the 367 patients with cancer pain. Of these, 18 were excluded from the efficacy evaluation owing to the lack of efficacy data; finally, 349 cancer patients completed the assessment. Table 1 lists the baseline demographics and clinical characteristics of these patients ( n = 367). The median age was 65 years (range, 20–90 years), and approximately 70% were aged > 60 (68.7%). At the baseline evaluation (visit 1), the mean NRS score ± SD was 7 ± 0.84. There were 53 patients (15.2%) with neuropathic pain, 270 (77.6%) had no neuropathic pain, and 25 (7.2%) were not investigated. There were 265 (72.2%) opioid-naïve patients with no history of analgesics, and 102 patients (27.8%) who were previously taking the analgesics discontinued them immediately before the treatment. Of these 102 patients, 96 (98%) used opioid analgesics, among whom 71 (74.0%) were reported to have switched the treatment because of the ineffectiveness of the prior analgesics (Table 2 ). The most common primary cancer type was lung cancer (14.7%), followed by gastric cancer (12.8%), hepatobiliary cancer (12.3%), pancreatic cancer (10.6%), colorectal cancer (10.4%), and breast cancer (9%). Hematologic malignancies such as multiple myeloma, lymphoma, and leukemia were also included (8.7%). Fig. 1 Flow diagram of the patients who were enrolled in the study Table 1 Baseline demographic and clinical characteristics of the cancer patients Characteristic No. of patients ( n = 367) N (%) Age, years Mean ± SD 64.63 ± 11.39 Median 65 Sex Male 225 (61.3) Female 142 (38.7) Pregnancy Pregnant 0 (0) Not pregnant 142 (38.7) N/A 225 (61.3) Breastfeeding Yes 0 (0) No 142 (38.7) N/A 225 (61.3) Type of care Outpatient 294 (80.1) Inpatient 73 (19.9) NRS at baseline Number 349 Mean ± SD 7 ± 0.84 Median 7 Neuropathic pain at baseline Yes 53 (15.2) None 270 (77.6) Unknown 25 (7.2) Hepatic impairment Absent 329 (89.7) Present 38 (10.4) Renal impairment Absent 355 (96.7) Present 12 (3.3) Concomitant medication Absent 14 (3.8) Present 353 (96.2) Analgesic discontinued immediately before study treatment Absent 265 (72.2) Present 102 (27.8) Malignant neoplasms 367 (100.0) Lung cancer 54 (14.7) Gastric cancer 47 (12.8) Hepatobiliary cancer 45 (12.3) Pancreatic cancer 39 (10.6) Colorectal cancer 38 (10.4) Breast cancer 33 (9.0) Hematologic malignancy 32 (8.7) Head and neck cancer 12 (3.3) Soft tissue sarcoma 9 (2.5) Esophageal cancer 6 (1.6) Others 67 (18.2) SD , standard deviation; NRS , Numeric Rating Scale; N/A , not applicable Table 2 Prior opioid analgesic treatment and discontinuation reason No. of patients used opioid analgesics ( n = 96) N (%) Prior opioid analgesics 1) Morphine 1 (1.0) Oxycodone 16 (16.7) Naloxone + oxycodone 33 (34.4) Fentanyl 13 (13.5) Buprenorphine 1 (1.0) Hydromorphone 4 (4.2) Codein 4 (4.2) Codein + ibuprofen + paracetamol 17 (17.7) Pethidine 1 (1.0) Tramadol 3 (3.1) Tramadol + paracetamol 14 (14.6) Reason for discontinuation of prior analgesics 1) Ineffectiveness of the prior analgesics 71 (74.0) Investigator’s judgment 17 (17.7) Patient requirement 6 (6.3) Others 2) 3 (3.1) 1) Duplicate response, 2) other specify; for convenience of prescription (2), adverse event (1)

Tapentadol ER treatment

During this study, the mean duration of exposure to tapentadol ER was 73.8 days, and the daily dose was 126.7 ± 53.88 mg/day (mean ± SD). The majority of patients (71.4%) started tapentadol ER with a dose of 50 mg twice daily, 20.2% of patients were treated with a dose of 100 mg twice daily, and 3.8% were treated with 150 mg twice daily. At visits 2 and 3, 349 and 218 patients were assessed, respectively, and 90 patients completed the extended visit 4.

Efficacy

From the baseline evaluation, the NRS results for the four visits were 7 ± 0.84, 4.9 ± 2.06, 4.4 ± 2.18, and 4.1 ± 2.02, respectively. The mean pain intensity at each visit was significantly decreased compared to the baseline (Fig. 2A ). In addition, it was observed that even if the missing values were corrected using the LOCF method at each visit, there was a significant reduction (Fig. 2B ). Among the 326 patients at visit 2, the PID in 132 (40.5%) improved by > 30%, and in 73 (22.4%), it improved by > 50%. Of the 204 patients at visit 3, the PID in 110 (53.9%) improved by > 30%, and in 64 (31.4%), it improved by > 50%. At baseline evaluation (visit 1), there were 53 patients with neuropathic pain, among whom 48 patients answered that they still had neuropathic pain at visit 2. In fact, only 5 patients (9.4%) showed improvement in neuropathic pain; however, the mean pain intensity was significantly decreased in those 48 patients (Fig. 3 ). Fig. 2 Changes in mean pain intensity in the NRS score at each visit compared to baseline for cancer patients. Data are represented as the mean of pain intensity in the NRS, which was collected at baseline and during each visit. Patients were enrolled at baseline ( n = 349). A There were 328, 204, and 87 patients at visit 2, visit 3, visit 4, respectively, and the NRS score was evaluated at each visit. p -values are based on the Wilcoxon signed-rank test. B For the LOCF group, the LOCF method was performed with each patient’s NRS value at visit 2 or later visits. NRS, Numeric Rating Scale; LOCF, last observation carried forward; ** p < 0.0001 Fig. 3 Changes in mean pain intensity in the NRS score at each visit compared to baseline for cancer patients who had neuropathic pain at visit 1 and no change in subsequent visits. Patients were enrolled at baseline ( n = 48). A There were 45, 31, and 14 patients at visit 2, visit 3, visit 4, respectively, and the NRS score was evaluated at each visit. p -values are based on the Wilcoxon signed-rank test. B For the LOCF group, the LOCF method was performed with each patient’s NRS value at visit 2 or later visit. NRS, Numeric Rating Scale; LOCF, last observation carried forward; ** p < 0.0001

Of the patients examined at each visit after baseline, 91.9%, 88.5%, and 97.8% of the patients, respectively, showed improvement in pain management (no change or greater, 0 to 4) based on the CGI-C assessment. The effectiveness in each case also showed statistically significant results ( p < 0.0001, p < 0.0001, and p < 0.0001, respectively; Fig. 4 ). These results indicated that tapentadol ER improved the QoL of cancer patients, and the CGI-C was reflective of the patients’ QoL. Fig. 4 The CGI-C of cancer patients ( n = 349) at each visit compared to baseline. Data are represented as the mean of the CGI-C, which was collected at each visit. The CGI-C ranges from 1 = “very much improved” to 7 = “very much worse.” Patients were enrolled at baseline ( n = 349). A There were 349, 218, and 90 patients at visit 2, visit 3, and visit 4, respectively, and the CGI-C was evaluated at each visit. p -values are based on the Wilcoxon signed-rank test. The Wilcoxon signed-rank test was performed on the recalculated CGI-C values that ranged from − 3 = “very much worse” to 3 = “very much improved,” to make “no change” to be 0. B For the LOCF group, the LOCF method was performed with each patient’s CGI-C value at visit 2 or later visits. CGI-C, clinical global impression change; LOCF, last observation carried forward; ** p < 0.0001

Safety

During the study period, 96 patients (26.2%) had an adverse drug reaction, of which the most common was constipation ( n = 14; 3.8%), followed by decreased appetite ( n = 9; 2.5%) and esophageal pain ( n = 7; 1.9%) (Table 3 ). Over the entire course of the study, 18 patients (4.9%) discontinued tapentadol ER owing to adverse drug reactions. Of those, three patients (0.8%) had serious adverse events, which were abdominal distension, asthenia, and pneumonia, respectively. In general, the majority of patients tolerated treatment with tapentadol ER. Table 3 List of adverse drug reactions Adverse drug reactions No. of patients ( n = 367) N (%) Constipation 14 (3.8) Decreased appetite 9 (2.5) Esophageal pain 7 (1.9) Dyspepsia 6 (1.6) Nausea 6 (1.6) Dizziness 4 (1.1) Pyrexia 4 (1.1) Productive cough 4 (1.1) Neutropenia 3 (0.8) Cough 3 (0.8) Diarrhea 3 (0.8) Upper respiratory tract infection 3 (0.8) Insomnia 3 (0.8) Pruritus 3 (0.8) Peripheral sensory neuropathy 3 (0.8) Neuropathy peripheral 2 (0.5) Vomiting 2 (0.5) Sleep disorder 2 (0.5) Anxiety 2 (0.5) Cystitis noninfective 2 (0.5) Pneumonia 2 (0.5) Others* 23 (6.3) * Urethritis, stoma site infection, herpes zoster, hyperkalaemia, biliary tract infection, colostomy, glucose tolerance impaired, pulmonary oedema, erythema, pneumothorax, pneumonitis, asthenia, chest discomfort, dyspnoea, pleural effusion, peripheral circulatory failure, oropharyngeal pain, oral candidiasis, cancer pain, peripheral ischaemia, oedema,bronchitis, neutrophil count decreased, alanine aminotransferase increased, dysuria, cholecystitis infective, deep vein thrombosis, febrile neutropenia, bronchial obstruction, lung neoplasm malignant, headache, ileus, hypomagnesaemia, urinary tract infection, abdominal distension, agitation, anemia, blood alkaline phosphatase increased, hypocalcaemia, hypertension

Discussion

This study showed that tapentadol ER significantly alleviated pain in opioid-naïve or opioid-resistant patients, and it also significantly improved their QoL. Of these patients, 40.5% showed a pain relief effect of > 30% and 22.4% showed a pain relief effect of > 50% at visit 2. Furthermore, 53.9% of the patients showed a pain relief effect of > 30%, and 31.4% of the patients showed a pain relief effect of > 50% at visit 3 (Fig. 2 ). As mentioned above, evaluation at visits 2, 3, and 4 after baseline showed that 91.9%, 88.5%, and 97.8% of patients, respectively, had improved QoL as evaluated by the CGI-C, indicating significant improvement (Fig. 4 ). However, we do not know clearly whether or not neuropathic pain was reduced, because the investigation on neuropathic pain was not quantified in this study. Among the 53 patients who answered that they had neuropathic pain at baseline, 48 answered that they had neuropathic pain at visit 2; nevertheless, the pain relief observed in these 48 patients was statistically significant (Fig. 3 ). These results suggest that neuropathic pain improved even in patients who answered that they still had neuropathic pain. To clarify this, a survey should to be conducted to quantify the neuropathic pain.

There are other limitations to this study. As in many studies of pain in cancer patients, many patients were lost to follow-up, and others discontinued treatment for various other reasons related to cancer. To overcome this limitation and obtain more accurate results, this study used the LOCF method to correct for missing values in statistical analysis. In addition, more accurate evaluation and corresponding results could be obtained if the patients’ QoL was evaluated using subjective indicators, such as the Hospital Anxiety and Depression Scale, Marburger questionnaire on habitual health findings (Marburger Fragebogen zum habituellen Wohlbefinden), and 12-Item Short Form Survey as well as the CGI-C [ 33 – 36 ].

Tapentadol ER was well-tolerated in opioid-naïve or opioid-resistant patients. Only 4.9% of patients discontinued treatment owing to adverse drug reactions during the entire study, and only 0.8% of them had serious adverse drug reactions. The safety profile of tapentadol ER indicated that it could be used flexibly for the treatment of cancer pain, and significant improvements can be obtained with few side effects.

Previous reports have shown that many cancer patients receive treatment to manage their pain; however, that treatment is often inadequate, meaning the patients endure anti-cancer treatment without adequate pain control. The first reason for this inadequacy is that oncologists may lack awareness regarding the patient’s pain owing to their focus solely on the treatment of cancer, and the second reason is that cancer pain is a mixed type of pain, composed of nociceptive and neuropathic pain. Even though there are many previous studies, there are no reports on any specific opioid being superiorly effective [ 7 , 37 , 38 ]. Therefore, pain must be controlled by separate mechanisms, which inevitably increase the usage of multiple drugs, further leading to decreased patient adherence to the regimen [ 39 ]. However, tapentadol ER regulates pain by two mechanisms: as a mu-opioid receptor agonist and as noradrenaline reuptake inhibitor [ 40 ]. Hence, its pain control effect is superior to that of other strong opioids, such as morphine, as demonstrated in several clinical trials. In addition, the adverse effects of tapentadol ER have been reported to be fewer than those of other strong opioids [ 23 , 24 ]. Therefore, tapentadol ER will continue to be one of the most preferred drugs in the future. However, to date, data from only small-scale clinical trials are available; therefore, large-scale studies are required. This study is meaningful in that it is an extensive, real-world, large-scale study involving 349 patients with cancer who were treated with tapentadol ER regardless of prior opioid use. Our results showed that the pain of the patients treated with tapentadol was significantly reduced, the drug-related adverse reactions were very few, and the drug was well tolerated during the entire 6-month period of the study.

In conclusion, this study demonstrated that tapentadol ER can be readily substituted for other strong opioids for pain control in cancer patients. It has good compliance and can be a promising analgesic in the future for cancer patients with neuropathic pain.

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Acknowledgements

We show our deep appreciation to the physicians of the medical institution who participated in this study and MinJung Koh of Janssen Korea Ltd. who advised on the entire study and manuscript preparation. We would like to thank Editage ( www.editage.co.kr ) for English language editing.

Author contribution

Conceptualization: JYJ, KHL, SEY; methodology: SEY, SYC; formal analysis and investigation: SYC, HJC, YJC; writing — original draft preparation: JYJ, SEY; writing — review and editing: HJC, YJC, KHL; funding acquisition: SEY; supervision: KHL.

Funding

This study was supported by Janssen Korea Ltd, Protocol no. R331333PAI4010.

Data availability

Due to the nature of this research, participants of this study did not agree for their data to be shared publicly, so supporting data is not available.

Code availability

Not applicable.

Declarations

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki, and the study protocol was approved by the respective Institutional Review Board of each center.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Consent for publication

The included patients signed an informed consent form for the use of personal information in connection with post-marketing surveillance.

Conflict of interest

Ji Yoon Jung, Young Jin Choi, Kyung Hee Lee have no conflicts of interest to declare. Hong Jae Chon has received honoraria from Eisai, Roche, Bayer, ONO, MSD, BMS, Celgene, Sanofi, Servier, AstraZeneca, Sillajen, Menarini, GreenCross Cell, Boryung Pharmaceuticals, and Dong-A ST, and has received research grants from Roche, Dong-A ST, Boryung Pharmaceuticals. Sang Eun Yeon and SeokYoung Choi are employees of Janssen Korea Ltd.

References

1. Portenoy RK Treatment of cancer pain Lancet 2011 377 2236 2247 10.1016/S0140-6736(11)60236-5 21704873

2. Te Boveldt N Vernooij-Dassen M Burger N Ijsseldijk M Vissers K Engels Y Pain and its interference with daily activities in medical oncology outpatients Pain Physician 2013 16 379 389 10.36076/ppj.2013/16/379 23877454

3. van den Beuken-van Everdingen MH Hochstenbach LM Joosten EA Tjan-Heijnen VC Janssen DJ Update on prevalence of pain in patients with cancer: systematic review and meta-analysis J Pain Symptom Manage 2016 51 1070 1090 e9 10.1016/j.jpainsymman.2015.12.340 27112310

4. Deandrea S Montanari M Moja L Apolone G Prevalence of undertreatment in cancer pain. A review of published literature Ann Oncol 2008 19 1985 1991 10.1093/annonc/mdn419 18632721 PMC2733110

5. Breivik H Cherny N Collett B Cancer-related pain: a pan-European survey of prevalence, treatment, and patient attitudes Ann Oncol 2009 20 1420 1433 10.1093/annonc/mdp001 19244085

6. van den Beuken-van Everdingen MH de Rijke JM Kessels AG Schouten HC van Kleef M Patijn J Prevalence of pain in patients with cancer: a systematic review of the past 40 years Ann Oncol 2007 18 1437 1449 10.1093/annonc/mdm056 17355955

7. Caraceni A Shkodra M Cancer pain assessment and classification Cancers (Basel) 2019 11 510 10.3390/cancers11040510 PMC6521068 30974857

8. Bennett MI Rayment C Hjermstad M Aass N Caraceni A Kaasa S Prevalence and aetiology of neuropathic pain in cancer patients: a systematic review Pain 2012 153 359 365 10.1016/j.pain.2011.10.028 22115921

9. Cavaletti G Zanna C Current status and future prospects for the treatment of chemotherapy-induced peripheral neurotoxicity Eur J Cancer 2002 38 1832 1837 10.1016/S0959-8049(02)00229-0 12204664

10. Windebank AJ Grisold W Chemotherapy-induced neuropathy J Peripher Nerv Syst 2008 13 27 46 10.1111/j.1529-8027.2008.00156.x 18346229

11. Piano V Verhagen S Schalkwijk A Diagnosing neuropathic pain in patients with cancer: comparative analysis of recommendations in national guidelines from European countries Pain Pract 2013 13 433 439 10.1111/papr.12018 23279302

12. Caraceni A Hanks G Kaasa S Use of opioid analgesics in the treatment of cancer pain: evidence-based recommendations from the EAPC Lancet Oncol 2012 13 e58 68 10.1016/S1470-2045(12)70040-2 22300860

13. Rayment C Hjermstad MJ Aass N Neuropathic cancer pain: prevalence, severity, analgesics and impact from the European Palliative Care Research Collaborative-Computerised Symptom Assessment study Palliat Med 2013 27 714 721 10.1177/0269216312464408 23175513

14 Fallon M Giusti R Aielli F Management of cancer pain in adult patients: ESMO Clinical Practice Guidelines Ann Oncol 2018 29 iv166 iv191 10.1093/annonc/mdy152 30052758

15. Attal N Cruccu G Baron R EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision Eur J Neurol 2010 17 1113 e88 10.1111/j.1468-1331.2010.02999.x 20402746

16. Dworkin RH O'Connor AB Audette J Recommendations for the pharmacological management of neuropathic pain: an overview and literature update Mayo Clin Proc 2010 85 S3 14 10.4065/mcp.2009.0649 PMC2844007 20194146

17. Park HJ Moon DE Pharmacologic management of chronic pain Korean J Pain 2010 23 99 108 10.3344/kjp.2010.23.2.99 20556211 PMC2886242

18. Beijers AJ Jongen JL Vreugdenhil G Chemotherapy-induced neurotoxicity: the value of neuroprotective strategies Neth J Med 2012 70 18 25 22271810

19. Loprinzi CL Qin R Dakhil SR Phase III randomized, placebo-controlled, double-blind study of intravenous calcium and magnesium to prevent oxaliplatin-induced sensory neurotoxicity (N08CB/Alliance) J Clin Oncol 2014 32 997 1005 10.1200/JCO.2013.52.0536 24297951 PMC3965262

20. Tzschentke TM Christoph T Kogel B (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties J Pharmacol Exp Ther 2007 323 265 276 10.1124/jpet.107.126052 17656655

21. Kress HG Tapentadol and its two mechanisms of action: is there a new pharmacological class of centrally-acting analgesics on the horizon? Eur J Pain 2010 14 781 783 10.1016/j.ejpain.2010.06.017 20659810

22. Mercadante S Porzio G Ferrera P Tapentadol in cancer pain management: a prospective open-label study Curr Med Res Opin 2012 28 1775 1779 10.1185/03007995.2012.739151 23057488

23. Imanaka K Tominaga Y Etropolski M Efficacy and safety of oral tapentadol extended-release in Japanese and Korean patients with moderate to severe, chronic malignant tumor-related pain Curr Med Res Opin 2013 29 1399 1409 10.1185/03007995.2013.831816 23937387

24. Kress HG Koch ED Kosturski H Tapentadol prolonged release for managing moderate to severe, chronic malignant tumor-related pain Pain Physician 2014 17 329 343 10.36076/ppj.2014/17/329 25054392

25. Mercadante S Porzio G Adile C Tapentadol at medium to high doses in patients previously receiving strong opioids for the management of cancer pain Curr Med Res Opin 2014 30 2063 2068 10.1185/03007995.2014.934793 24926734

26. Stollenwerk A Sohns M Heisig F Elling C von Zabern D Review of post-marketing safety data on tapentadol, a centrally acting analgesic Adv Ther 2018 35 12 30 10.1007/s12325-017-0654-0 29270779 PMC5778188

27. Ferri CM Natoli S Sanz-Ayan P Quality of life and functional outcomes with tapentadol prolonged release in chronic musculoskeletal pain: post hoc analysis Pain Manag 2021 11 173 187 10.2217/pmt-2020-0084 33241725

28. Guy W (ed) (1976) ECDEU assessment manual for psychopharmacology. US Department of Heath, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and Mental Health Administration. https://archive.org/details/ecdeuassessmentm1933guyw/page/218/mode/2up?view=theater . Accessed 21 Oct 2021

29. Ferguson L Scheman J Patient global impression of change scores within the context of a chronic pain rehabilitation program J Pain 2009 10 S73 10.1016/j.jpain.2009.01.258

30. Perrot S Lanteri-Minet M Patients’ global impression of change in the management of peripheral neuropathic pain: clinical relevance and correlations in daily practice Eur J Pain 2019 23 1117 1128 10.1002/ejp.1378 30793414

31. U.S. Food and Drug Administration (2019) Full prescribing information of tapentadol extended-release tablets for oral use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/200533s020lbl.pdf . Accessed 21 Oct 2021

32. Korea Ministry of Food and Drug Safety (2021) Full prescribing information of tapentadol extended-release tablets for oral use. https://nedrug.mfds.go.kr/pbp/CCBBB01/getItemDetail?itemSeq=201603372 Accessed 21 Oct 2021

33. Zigmond AS Snaith RP The hospital anxiety and depression scale Acta Psychiatr Scand 1983 67 361 370 10.1111/j.1600-0447.1983.tb09716.x 6880820

34. Ware J Jr Kosinski M Keller SD A 12-item short-form health survey: construction of scales and preliminary tests of reliability and validity Med Care 1996 34 220 233 10.1097/00005650-199603000-00003 8628042

35. Basler HD The Marburg questionnaire on habitual health findings–a study on patients with chronic pain Schmerz 1999 13 385 391 10.1007/s004820050216 12799914

36. Schikowski A Krings D Schwenke K Tapentadol prolonged release for severe chronic cancer-related pain: effectiveness, tolerability, and influence on quality of life of the patients J Pain Res 2015 8 1 8 25565884 10.2147/JPR.S72150 PMC4278778

37. Benyamin R Trescot AM Datta S Opioid complications and side effects Pain Physician 2008 11 S105 120 10.36076/ppj.2008/11/S105 18443635

38. Bennett MI Graham J Schmidt-Hansen M Prettyjohns M Arnold S Guideline Development Group Prescribing strong opioids for pain in adult palliative care: summary of NICE guidance BMJ 2012 344 e2806 10.1136/bmj.e2806 22623631

39. Jimmy B Jose J Patient medication adherence: measures in daily practice Oman Med J 2011 26 155 159 10.5001/omj.2011.38 22043406 PMC3191684

40. Galie E Villani V Terrenato I Pace A Tapentadol in neuropathic pain cancer patients: a prospective open-label study Neurol Sci 2017 38 1747 1752 10.1007/s10072-017-3035-1 28699105