Randomised Phase II Trial (NCT00637975) Evaluating Activity and Toxicity of Two Different Escalating Strategies for Pregabalin and Oxycodone Combination Therapy for Neuropathic Pain in Cancer Patients

et al. (2013) Randomised Phase II Trial (NCT00637975) Evaluating Activity and Toxicity of Two Different Escalating Strategies for Pregabalin and Oxycodone Combination Therapy for Neuropathic Pain in Cancer Patients. PLoS ONE 8(4): e59981. doi:10.1371/ journal.pone.0059981 Randomised Phase II Trial (NCT00637975) Evaluating Activity and Toxicity of Two Different Escalating Strategies for Pregabalin and Oxycodone Combination Therapy for Neuropathic Pain in Cancer Patients Marina Chiara Garassino 0 Sheila Piva 0 Nicla La Verde 0 Ilaria Spagnoletti 0 Vittorio Iorno 0 Claudia Carbone 0 Antonio Febbraro 0 Anna Bianchi 0 Annalisa Bramati 0 Anna Moretti 0 Monica Ganzinelli 0 Mirko Marabese 0 Marta Gentili 0 Valter Torri 0 Gabriella Farina 0 Sam Eldabe, The James Cook University Hospital, United Kingdom 0 1 Medical Oncology Unit 1, Fondazione IRCCS Istituto Nazionale dei Tumori , Milan , Italy , 2 Department of Oncology, A.O. Fatebenefratelli & Oftalmico , 23, Milan , Italy , 3 A.O. Sacro Cuore di Gesu` , Fatebenefratelli, Benevento, Italy, 4 Policlinico Maggiore, Milan , Italy , 5 Department of Oncology Ospedale Serbelloni , Gorgonzola , Italy , 6 Department of Neurology A.O. Sant'Antonio Abate , Gallarate , Italy , 7 Department of Oncology ''Mario Negri'' Institute , Milan , Italy Purpose: Neuropathic pain is commonly associated with cancer. Current treatments include combination opioid and adjuvant therapies, but no guidelines are available for dose escalation strategies. This phase II study compared the efficacy and tolerability of two dose escalation strategies for oxycodone and pregabalin combination therapy. Methods: Patients (N = 75) with oncological neuropathic pain, previously untreated with pregabalin, were recruited in 5 Italian institutions between 2007 and 2010. Patients were randomised to two different dose escalation strategies (arm A; N = 38) oxycodone at a fixed dose with increasing pregabalin doses; (arm B; N = 37) pregabalin at a fixed dose with increasing oxycodone doses. Patients were evaluated from daily diaries and follow-ups at 3, 7, 10, and 14 days after beginning treatment with a numerical rating scale (NRS), neuropathic pain scale (SDN), and well-being scale (ESAS). The primary endpoint was a $1/3 reduction in pain (NRS); secondary endpoints included the time to analgesia and adverse effects. The study had a 90% probability of detecting the best strategy for a true difference of at least 15%. Results: More patients in arm A (76%) than arm B (64%) achieved $1/3 overall pain reduction even after controlling for baseline factors (gender, baseline pain). Group A reported fewer side effects than group B; constipation 52.8% vs. 66.7%; nausea: 27.8% vs. 44.4%; drowsiness: 44.4% vs. 55.6%; confusion: 16.7% vs. 27.8%; itching: 8.3% vs. 19.4%. Conclusions: Both strategies effectively controlled neuropathic pain, but according to the adopted selection design arm A is preferable to arm B for pain control. Trial Registration: ClinicalTrials.gov NCT00637975. - Neuropathic pain is a common symptom in patients with cancer. Among patients with oncological pain, at least 1/3 is diagnosed with neuropathic pain [1]. In this setting, pain can be caused by a tumour compressing a nerve or it may be a side effect of chemotherapy and radiotherapy. The mainstay of treatment is opioid administration; however, a monotherapy is often insufficient to control neuropathic pain. It is widely recognised that some cancer pain syndromes are only partially responsive to opioids. This has led to the search for new strategies of treatment [2,3]. Currently, adjuvant drugs, like antidepressants or anticonvulsants, are often employed in combination with the primary therapy [4]. Previously, a meta-analysis on the role of opioids in treating benign neuropathic pain showed that some opioids, particularly oxycodone, are more effective than other agents [2,5]. In a metaanalysis by Finnerup et al. [6], anticonvulsants, particularly gabapentin, showed a favourable trade-off between harm and benefit; thus, these were considered the best candidates for combining with opioid treatments. Moreover, previous studies on the use of combination therapies in patients with cancer and neuropathic pain showed that gabapentin enhanced analgesia [7]. Pregabalin, a new anticonvulsant, appeared to be effective for relieving neuropathic pain, and it acted synergistically with oxycodone, with no additional toxicity [3]. Furthermore, pregabalin was active in patients with a resistance to gabapentin. A recent pharmaeconomics analysis demonstrated that pregabalin was cost-effective for patients with refractory neuropathic pain [8]. Gatti et al. demonstrated the effectiveness and tolerability of pregabalin combined with oxycodone in treating non-cancer pain in a large cohort of patients [9]. This combination seemed to be effective, particularly in an escalating dose strategy [10]. However, the strategy for increasing the dose of opioids or anticonvulsants is entirely empirical; currently, there are no data available to advocate any particular strategy. Previous studies have demonstrated that genetic variations in pain-related receptors, transporters, and metabolising enzymes were related to opioid efficacy. The most interesting genes discovered were the mu and kappa opioid receptors [1113]. Those studies generated intense interest in whether genetic analyses can be used to guide the choice of opioid treatment. However, as reviewed by Hirschhorn et al. [14], most studies that found candidate single nucleotide polymorphisms (SNPs) associated with outcomes could not be replicated [15,16]. To our knowledge, no previous studies have investigated different dose escalation strategies in a combination therapy for neuropathic pain. In current clinical practice, this decision is typically made empirically by individual physicians, based on personal experience. The present prospective study aimed to evaluate two different dose escalation strategies for combining pregabalin with oxycodone in treating patients with neuropathic pain caused by neoplasms. We also examined genetic SNPs as a potential basis for differences in drug responses. The protocol for this trial and supporting CONSORT checklist are available as supporting information; see Protocol S1 and Checklist S1. This research has been approved by the Ethics Committee of Fatebenefratelli and Oftalmico Hospital in Milan and has been conducted according to the Declaration of Helsinki Principles. Five Italian institutions participated in the trial from September 2007 to December 2010. The protocol was approved by the ethics committees of each participating centre and written informed consent was obtained from all participants. The study is registered at Clinicaltrial.gov (NCT00637975, Supplementary File Neuropain Protocol). Patient Characteristics Patients with cancer pain were enrolled when they had a clinical diagnosis of cancer and pain with a neuropathic compone (...truncated)