Effectiveness of duloxetine in treatment of painful chemotherapy-induced peripheral neuropathy: a systematic review
Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect that can be dose limiting and affect patient quality of life. To date, the therapeutic options for CIPN are limited. We performed a systematic literature search of the PubMed and Scopus databases to assess the effectiveness of duloxetine in the treatment of pain in patients with CIPN. The search included randomized controlled trials, nonrandomized controlled trials, retrospective studies, and single-arm studies of duloxetine in treatment of CIPN. A descriptive analysis of the studies was performed. The PubMed database online search identified 41 publications, and a second database search through Scopus identified 29 publications. A total of 10 full-text articles were assessed for eligibility, with 5 articles excluded. Altogether, the included studies reported 431 patients with painful CIPN. An improvement in pain scores was the primary and/or secondary endpoint in the included studies. Pain was assessed by 6 different scores. Comparator drugs were used in 4 studies in our review. The comparator drug was placebo in 1 study only, and the remaining 3 studies used other antineurotoxicity therapy. The chemotherapeutic agents used in the studies were the following: paclitaxel (52.9%), oxaliplatin (39.7%), R-CHOP (rituximab, doxorubicin, vincristine, and cyclophosphamide; 3.30%), combined bortezomib-dexamethasone (1.89%), FOLFOX (folinic acid, fluorouracil, and oxaliplatin; 1.18%), and other taxanes (0.94%). From the descriptive analyses, and from the available data of relatively small sample sized studies, it can be concluded that despite the above limitations, duloxetine remains a useful therapeutic option for pain in CIPN patients, regardless of the type of chemotherapeutic agent used.
Accepted for publication November 20, 2018
Correspondence Wael Ibrahim, MD; dr.wael_ezzat@hotmail.com
Disclosures The authors report no disclosures/conflicts of interest.
©2018 Frontline Medical Communications
doi https://doi.org/10.12788/jcso.0436
Discussion
To our knowledge, this is the first systematic review to discuss the effectiveness of duloxetine specifically in treatment of pain in CIPN. The administration of chemotherapeutic agents such as paclitaxel, cisplatin, oxaliplatin, and vincristine was accompanied by CIPN. The currently available treatment options for CIPN are limited. To date, no drug has been approved specifically for treatment of pain in CIPN.12
In our review, we included cancer patients with CIPN and associated pain. Several previous studies8,27,28 discussed tingling and numbness as a common adverse effect in CIPN, and usually about 20% to 42% of patients develop chronic pain.
Six different pain assessment scores were reported in the total 5 studies in our review, with VAS and NCI-CTCAE scores reported in more than 1 study. This reflects the major challenges facing the assessment of CIPN, as various scales and tools are available for pain assessment but without a standardized approach for CIPN that can be precisely implemented.8 Several other challenges regarding pain scores were observed, with Smith and colleagues as the only authors to report both pretreatment pain score and grade, while the rest of the studies failed to report either pain score or grade, or even both.
,Another difficulty observed in our review was the variability in study participants in both population size and type of cancer treated. The population size in largest study included in our review was 231 patients and the smallest was 25 patients; collectively, there were only 431 patients in the included studies. Although the type of primary cancer varied in between studies, gynecologic malignancies comprised most cases (215 patients), followed by gastrointestinal tumors, and few cases of hematologic and genitourinary malignancies were reported. Similar results were observed by Geber and colleagues in their large study screening pain in cancer patients, in which gynecologic malignancies were diagnosed in 28 patients out of 61 with CIPN, representing the highest percentage (45.9%) of malignancy type in that study.26
In the study by Otake and colleagues12 examining duloxetine for CIPN in patients with gynecologic cancer, the authors concluded that duloxetine dosage either 20 mg/day or 40 mg/day was not associated with the effectiveness of duloxetine treatment by either univariate or multivariate analysis. Previous authors have provided an explanation for the difference in duloxetine response among CIPN patients and attributed those differences to the underlying pain mechanisms.14,29 In other words, pain in those patients is both peripheral nociceptive and central neuropathic, and it is likely to be caused by mixed mechanisms.
Another variation observed among CIPN patients in our review was the chemotherapeutic agents used. That was noted by Smith and colleagues,26 who reported that patients with cancer who received platinum therapies (oxaliplatin) experienced more benefit from duloxetine in terms of pain improvement than those who received taxanes (P = .13). We found no other published studies on the response to duloxetine among different chemotherapeutic agents used. However, 2 studies of duloxetine response in patients with other pain-related disorders (painful diabetic peripheral neuropathy and fibromyalgia) showed significant improvement in pain symptoms compared with placebo. In a study of pain in chemotherapy-induced neuropathy (CIN) by Geber and colleagues,29 the preexisting pain medication was not reported, but the authors concluded that treatment for CIN-related neuropathic pain differs from that for nonneuropathic (ie, musculoskeletal) pain, with the former being treated mainly with pharmacotherapy and the latter with physiotherapy and behavioral exercises. They asserted that different pain patterns could help flag neuropathic or musculoskeletal pain so that the selected treatments would be more specific. Differences in pain improvement related to duloxetine may be attributed to the underlying pain mechanism, and whether it is mixed or centrally or peripherally related was also discussed by Geber and colleagues.29
In the study by
Findings from studies on the effect of duloxetine in treatment of pain in diabetic peripheral neuropathy have shown that duloxetine at a dose of 60 mg/day effectively improves pain in 43% to 68% of patients.15,16,30 Similarly, in our review, the study by Yang and colleagues25 showed a 63% subjective reduction in pain severity by VAS score in CIPN patients but lower improvement of 47.4% by NCI-CTCAE v3.0; this can be attributed to the simplistic 4-grade rating scale of the latter.
During our analysis of studies, we noticed that no diagnostic criteria were implemented for diagnosis or inclusion of CIPN patients in any of the included studies, and this represents a major challenge in any analysis of studies with neuropathic pain patients. In 2016, Finnerup and colleagues updated the previous 2008 grading system for diagnosis of neuropathic pain, which is intended to determine the level of certainty with which the pain in question is neuropathic.31 The system defines the diagnostic certainty into 3 levels: Possible, Probable, and Definite. Although the number of studies used the grading system during the inclusion of neuropathic pain patients increased from 5% in 2009 to 30% in 2014, still more than two-thirds of studies do not use a standardized system for diagnosis and/or inclusion of neuropathic pain in patients.
