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, Sheila Piva, Nicla La Verde, Ilaria Spagnoletti, Vittorio Iorno, Claudia Carbone, Antonio Febbraro, Anna Bianchi, Annalisa Bramati, Anna Moretti, Monica Ganzinelli, Mirko Marabese, Marta Gentili, Valter Torri, Gabriella Farina, Marina Chiara Garassino, Sheila Piva, Nicla La Verde, Ilaria Spagnoletti, Vittorio Iorno, Claudia Carbone, Antonio Febbraro, Anna Bianchi, Annalisa Bramati, Anna Moretti, Monica Ganzinelli, Mirko Marabese, Marta Gentili, Valter Torri, Gabriella Farina

Abstract

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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Study design.
Figure 1. Study design.
Figure 2. Patient CONSORT Diagram.
Figure 2. Patient CONSORT Diagram.

References

    1. Irving GA (2005) Contemporary assessment and management of neuropathic pain. Neurology 64(12 Suppl 3)S21–7.
    1. Eisenberg E, McNicol ED, Carr DB (2005) Efficacy and safety of opioid agonists in the treatment of neuropathic pain of nonmalignant origin: systematic review and meta-analysis of randomized controlled trials. JAMA 293(24): 3043–52.
    1. Bruera E, Belzile M, Pituskin E, Fainsinger R, Darke A, et al. (1998) Randomized, double-blind, cross-over trial comparing safety and efficacy of oral controlled-release oxycodone with controlled-release morphine in patients with cancer pain. J Clin Oncol 16(10): 3222–9.
    1. Portenoy R (1998) Ajuvant analgesics in pain management. In: Doyle D HG (MacDonald N editor) Oxford Textbook of Palliative Medicine, ed. Oxford, Oxford University Press p. 361–390.
    1. Furlan AD, Sandoval JA, Mailis-Gagnon A, Tunks E (2006) Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects. CMAJ 174(11): 1589–94.
    1. Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH (2005) Algorithm for neuropathic pain treatment: an evidence based proposal. Pain 118(3): 289–305.
    1. Caraceni A, Zecca E, Bonezzi C, Arcuri E, Yaya Tur R, et al. (2004) Gabapentin for neuropathic cancer pain: a randomized controlled trial from the Gabapentin Cancer Pain Study Group. J Clin Oncol 22(14): 2909–17.
    1. Gordon J, Lister S, Prettyjohns M, McEwan P, Tetlow A, et al. (2011) A cost-utility study of the use of pregabalin in treatment-refractory neuropathic pain. J Med Econ. 2012 15(2): 207–18.
    1. Gatti A, Sabato AF, Occhioni R, Colini Baldeschi G, Reale C (2009) Controlled-release oxycodone and pregabalin in the treatment of neuropathic pain: results of a multicenter Italian study. Eur Neurol 61(3): 129–37.
    1. Gatti A, Longo G, Sabato E, Sabato AF (2011) Long-term controlled-release oxycodone and pregabalin in the treatment of non-cancer pain: an observational study. Eur Neurol 65(6): 317–22.
    1. Campa D, Gioia A, Tomei A, Poli P, Barale R (2008) Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin Pharmacol Ther 83(4): 559–66.
    1. Klepstad P, Rakvag TT, Kaasa S, Holthe M, Dale O, et al. (2004) The 118 A>G polymorphism in the human mu-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease. Acta Anaesthesiol Scand 48(10): 1232–9.
    1. Stamer UM, Stuber F (2007) Genetic factors in pain and its treatment. Curr Opin Anaesthesiol 20(5): 478–84.
    1. Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K (2002) A comprehensive review of genetic association studies. Genet Med 4(2): 45–61.
    1. Fukuda K, Hayashida M, Ide S, Saita N, Kokita Y, et al. (2009) Association between OPRM1 gene polymorphisms and fentanyl sensitivity in patients undergoing painful cosmetic surgery. Pain 147(1–3): 194–201.
    1. Fukuda K, Hayashida M, Ikeda K, Koukita Y, Ichinohe T, et al. (2010) Diversity of opioid requirements for postoperative pain control following oral surgery–is it affected by polymorphism of the mu-opioid receptor? Anesth Prog 57(4): 145–9.
    1. Caraceni A, Cherny N, Fainsinger R, Kaasa S, Poulain P, et al. (2002) Pain measurement tools and methods in clinical research in palliative care: recommendations of an expert working group of the European association of palliative care. J Pain Symptom Manage 23: 239–25.
    1. Negri E, Bettaglio R, Demartini L, Allegri M, Barbieri M, et al. (2002) Validation of the Italian version of the “Neuropathic Pain Scale” and its clinical applications. Minerva Anestesiol 68(3): 95–104.
    1. Bruera E, Kuehn N, Miller MJ, Selmser P, Macmillan K (1991) The Edmonton Symptom Assessment System (ESAS): a simple method for the assessment of palliative care patients. J Palliat Care 7(2): 6–9.
    1. National Cancer Institute: Common Terminology Criteria for Adverse Events v4.0. . Accessed 2013 March 11.
    1. Simon R, Wittes RE, Ellenberg SS (1985) Randomized phase II clinical trials. Cancer Treat Rep 69(12): 1375–81.
    1. Blommel ML, Blommel AL (2007) Pregabalin: an antiepileptic agent useful for neuropathic pain. Am J Health Syst Pharm 64(14): 1475–82.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅