Additive Duloxetine for Cancer-Related Neuropathic Pain Nonresponsive or Intolerant to Opioid-Pregabalin Therapy: A Randomized Controlled Trial (JORTC-PAL08)

Abstract

Context. Although opioids and pregabalin are widely used for cancer-related neuropathic pain (CNP), no clinical trials exist to determine which medications are effective when an opioid-pregabalin combination therapy fails.Objectives. We investigated the efficacy of duloxetine for CNP nonresponsive or intolerant to opioid-pregabalin combination therapy.Methods. A multicenter, randomized, double-blind, placebo-controlled trial was performed at 12 specialized palliative care services in Japan. Patients with CNP average pain scores (Brief Pain Inventory [BPI]eItem 5) $ 4 in the previous 24 hours and nonresponsive or intolerant to opioid-pregabalin combination therapy were eligible. Patients with chemotherapy-induced peripheral neuropathies were excluded. Patients were administered duloxetine 20 mg/day titrated to 40 mg/day or placebo for 10 days. The primary endpoint was BPI-Item 5 on Day 10. Responder analysis measured proportions of patients with 30% and 50% pain decreases.Results. Seventy patients were enrolled. Complete case analysis revealed mean BPI-Item 5 on Day 10 of 4.03 for Group D vs. 4.88 for Group P (P ¼ 0.053). Baseline observation carried forward analysis revealed mean BPI-Item 5 on Day 10 of 4.06 and 4.91 for Groups D and P, respectively (P ¼ 0.048). Clinically meaningful pain improvement ($30%) was reported by 44.1% (n ¼ 15) of patients in Group D vs. 18.2% (n ¼ 6) in Group P (P ¼ 0.02); 32.4% (n ¼ 11) vs. 3.0% (n ¼ 1) of patients in Groups D and P, respectively, reported pain reduction $ 50% (P ¼ 0.002).Conclusion. Adding duloxetine to opioid-pregabalin therapy might have clinical benefit in alleviating refractory CNP. Further studies are needed to conclude the efficacy of adding duloxetine. J Pain Symptom

Frequently asked questions about managing cancer pain: An update

“…[4][5][6] Recent studies suggest that duloxetine, alone or in combination with opioids and gabapentinoids (eg, gabapentin, pregabalin), also offers benefi t in 2 cancer-related pain conditions, chemotherapy-induced peripheral neuropathy and cancer-related neuropathic pain. 7,8 The dosing used in studies ranged from 20 to 60 mg per day. Common adverse effects are nausea, fatigue, and both insomnia and somnolence.…”

Combination Therapy for Neuropathic Pain. A Systematic Review

“…Among the six RCTs which provided data on the primary outcome, three compared the combination of interest to placebo alone [43][44][45], one compared a combination of 2 drugs against monotherapy of each and placebo [38], another one compared CT only against high-dose monotherapy of each, with no placebo control [42], and the last one compared the combination of three painkiller drugs to the combination of only two of these painkiller drugs in cancer patients with NP [32]. It is noteworthy that only three of them had a treatment period of at least 12 weeks, excluding titration period [43][44][45].…”

“…We identified 16 studies which fulfilled the inclusion criteria for this review: RCTs, double-blind, comparing combinations of two or more drugs to placebo and/or at least one other comparator for the treatment of NP [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]. Of them, only six provided data on the primary outcome (proportion of participants reporting ≥ 50% or ≥ 30% pain reduction from baseline), either by direct reporting or by deduction through study figures or graphs (Data from such studies can be seen on Table 1).…”

“…Of them, only six provided data on the primary outcome (proportion of participants reporting ≥ 50% or ≥ 30% pain reduction from baseline), either by direct reporting or by deduction through study figures or graphs (Data from such studies can be seen on Table 1). 1243 participants for the study drugs vs 928 for the control groups: one RCT evaluated the combination of cannabinoids delta-9tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray and the existing treatment regimen for central neuropathic pain (CNP) in patients with multiple sclerosis [43], a different drug combination (opioid plus pregabalin (PGB) plus duloxetine (DXT) was tested in one RCT in NP in cancer patients [32,40], one tested a combination of DXT and PGB against both of them on monotherapy in painful diabetic neuropathy (PDN) [42] and another compared a drug combination of dextromethorphan and quinidine against placebo, again in PDN [45], and capsaicin 8% dermal patch (CP8) in combination with systemic NP medications was evaluated in another RCT in postherpetic neuralgia (PHN) [44]. Likewise, these studies also provided data on the secondary outcomes: i) proportion of participants dropping out of the study due to treatment-emergent adverse effects, and ii) proportion of participants reporting each specific adverse effect (i.e., sedation, dizziness) of ≥ moderate severity.…”

Between-group difference in mean values or changes in pain intensity? Evaluating the distribution of change from baseline in a neuropathic cancer pain clinical trial

“…Our recent studies (2,3) have also yielded different results within a single study, making interpretation difficult. One such study of ours, the DIRECT study, which was a multicenter double-blinded randomized placebo-controlled two-parallel group trial, investigated the efficacy of duloxetine for cancer-related neuropathic pain (CNP) nonresponsive or intolerant to opioidpregabalin combination therapy.…”