Pregabalin for the Prevention of Oxaliplatin-Induced Painful Neuropathy: A Randomized, Double-Blind Trial

Daniel Ciampi de Andrade, Manoel Jacobsen Teixeira, Ricardo Galhardoni, Karine S L Ferreira, Paula Braz Mileno, Nathalia Scisci, Alexandra Zandonai, William G J Teixeira, Daniel F Saragiotto, Valquíria Silva, Irina Raicher, Rubens Gisbert Cury, Ricardo Macarenco, Carlos Otto Heise, Mario Wilson Iervolino Brotto, Alberto Andrade de Mello, Marcelo Zini Megale, Luiz Henrique Curti Dourado, Luciana Mendes Bahia, Antonia Lilian Rodrigues, Daniella Parravano, Julia Tizue Fukushima, Jean-Pascal Lefaucheur, Didier Bouhassira, Evandro Sobroza, Rachel P Riechelmann, Paulo M Hoff, PreOx Workgroup, Fernanda Valério da Silva, Thais Chile, Camila S Dale, Daniela Nebuloni, Luiz Senna, Helena Brentani, Rosana L Pagano, Ângela M de Souza, Daniel Ciampi de Andrade, Manoel Jacobsen Teixeira, Ricardo Galhardoni, Karine S L Ferreira, Paula Braz Mileno, Nathalia Scisci, Alexandra Zandonai, William G J Teixeira, Daniel F Saragiotto, Valquíria Silva, Irina Raicher, Rubens Gisbert Cury, Ricardo Macarenco, Carlos Otto Heise, Mario Wilson Iervolino Brotto, Alberto Andrade de Mello, Marcelo Zini Megale, Luiz Henrique Curti Dourado, Luciana Mendes Bahia, Antonia Lilian Rodrigues, Daniella Parravano, Julia Tizue Fukushima, Jean-Pascal Lefaucheur, Didier Bouhassira, Evandro Sobroza, Rachel P Riechelmann, Paulo M Hoff, PreOx Workgroup, Fernanda Valério da Silva, Thais Chile, Camila S Dale, Daniela Nebuloni, Luiz Senna, Helena Brentani, Rosana L Pagano, Ângela M de Souza

Abstract

Lessons learned: Pregabalin is a medication that can decrease neuronal hyperexcitability, relieve neuropathic pain, and reach stable plasma levels after a titration period of only a few days.Its use during oxaliplatin infusions was not able to decrease the incidence of chronic, oxalipaltin-related neuropathic pain, compared with placebo.

Background: Patients with colorectal cancer (CRC) receiving oxaliplatin (OXA) develop acute and chronic painful oxaliplatin-induced peripheral neuropathy (OXAIPN). Acute and chronic OXA-related neuropathies have different pathophysiological bases, but both lead to a common phenomenon: central sensitization (CS) of nociceptive neuronal networks, leading to increased sensitivity (hyperlgesia, allodynia) in the somatosensory system, the common ground of chronic neuropathic pain. Because CS is related to increased risk of painful OXAIPN, we hypothesized that preemptive use of the anti-hyperalgesic drug pregabaline (known to decrease CS) during OXA infusions would decrease the incidence of chronic OXAIPN.

Methods: Pain-free, chemotherapy-naïve CRC patients receiving at least one cycle of modified-FLOX [5-FU(500 mg/m2)+leucovorin(20 mg/m2)/week for] 6 weeks+oxaliplatin(85 mg/m2) at weeks 1-3-5 every 8 weeks] were randomized (1:1) into the study. Patients received either pregabalin or placebo for 3 days before and 3 days after each OXA infusion and were followed for up to 6 months. Clinical assessments were performed at baseline, at the end of chemotherapy, and after the follow-up period. The main outcome was average pain at the last visit assessed by the visual analogic scale (0-10) item of the Brief Pain Inventory (BPI). Secondary endpoints were presence of neuropathic pain according to the Douleur Neuropathique-4 (DN-4), pain dimensions (short- form McGill Pain Questionnaire [MPQ]), Neuropathic Pain Symptom Inventory (NPSI), and changes in nerve conduction studies (NCS) and side effect profile.

Results: One hundred ninety-nine patients (57.0 ± 10.7 years old, 98 female, 101 male) were randomized. Data from 56 patients were not included in the analyses (as they did not receive at least one full cycle of modified FLOX). Data from 78 patients in the pregabalin group and 65 patients in the placebo group were retained for analyses. At the last visit, pain intensity in the pregabalin group was 1.03 (95% confidence interval [CI] = 0.79-1.26), and 0.85 (95% CI = 0.64-1.06) in the placebo group, which did not reach significance. Scores from the BPI, MPQ, DN-4, NPSI, and NCS and side-effect profiles and incidence of death did not differ between groups. Quality of life (QoL) score did not differ between groups (placebo = 76.9 ± 23.1, pregabalin group 79.4 ± 20.6). Mood scores were not significantly different between groups (placebo 9.7 [8.1-11.2]; pregabalin 6.8 [5.6-8.0]).

Conclusion: The preemptive use of pregabalin during OXA infusions was safe, but did not decrease the incidence of chronic pain related to OXAIPN.

Trial registration: ClinicalTrials.gov NCT01450163.

©AlphaMedPress; the data published online to support this summary is the property of the authors.

Figures

Figure 1.
Figure 1.
Consolidated Standards of Reporting Trials flowchart of screened and included patients.
Figure 2.
Figure 2.
Effects of study medications on pain intensity. (A): Brief Pain Inventory pain intensity scores (0–10). (B): Neuropathic pain symptoms (Douleur Neuropatique‐4). Statistical significance is considered when confidence intervals from both groups do not intersect. *Main outcome. Abbreviations: BPI, brief pain inventory; DN‐4, Douleur Neuropatique‐4.

References

    1. Attal N, Bouhassira D, Gautron M et al. Thermal hyperalgesia as a marker of oxaliplatin neurotoxicity: A prospective quantified sensory assessment study. Pain 2009;144:245–252.
    1. Ventzel L, Jensen AB, Jensen AR et al. Chemotherapy‐induced pain and neuropathy: A prospective study in patients treated with adjuvant oxaliplatin or docetaxel. Pain 2016;157:560–568.
    1. Nikolajsen L, Ilkjaer S, Krøner K et al. The influence of preamputation pain on postamputation stump and phantom pain. Pain 1997;72:393–405.
    1. Zeilig G, Enosh S, Rubin‐Asher D et al. The nature and course of sensory changes following spinal cord injury: Predictive properties and implications on the mechanism of central pain. Brain 2012;135:418–430.
    1. Hansen N, Obermann M, Uçeyler N et al. [Clinical application of pain‐related evoked potentials]. Schmerz 2012;26:8–15.
    1. Mihara Y, Egashira N, Sada H et al. Involvement of spinal NR2B‐containing NMDA receptors in oxaliplatin‐induced mechanical allodynia in rats. Mol Pain 2011;7:8.
    1. Schmidt PC, Ruchelli G, Mackey SC et al. Perioperative gabapentinoids: Choice of agent, dose, timing, and effects on chronic postsurgical pain. Anesthesiology 2013;119:1215–1221.
    1. Buvanendran A, Kroin JS, Kari M et al. Can a single dose of 300 mg of pregabalin reach acute antihyperalgesic levels in the central nervous system? Reg Anesth Pain Med 2010;35:535–538.
    1. Buvanendran A, Kroin JS, Della Valle CJ et al. Perioperative oral pregabalin reduces chronic pain after total knee arthroplasty: A prospective, randomized, controlled trial. Anesth Analg 2010;110:199–207.
    1. Cascinu S, Catalano V, Cordella L et al. Neuroprotective effect of reduced glutathione on oxaliplatin‐based chemotherapy in advanced colorectal cancer: A randomized, double‐blind, placebo‐controlled trial. J Clin Oncol 2002;20:3478–3483.
    1. Gamelin L, Boisdron‐Celle M, Delva R et al. Prevention of oxaliplatin‐related neurotoxicity by calcium and magnesium infusions: A retrospective study of 161 patients receiving oxaliplatin combined with 5‐Fluorouracil and leucovorin for advanced colorectal cancer. Clin Cancer Res 2004;10:4055–4061.
    1. Nagashima M, Ooshiro M, Moriyama A et al. Efficacy and tolerability of controlled‐release oxycodone for oxaliplatin‐induced peripheral neuropathy and the extension of FOLFOX therapy in advanced colorectal cancer patients. Support Care Cancer 2014;22:1579–1584.
    1. Argyriou AA, Chroni E, Polychronopoulos P et al. Efficacy of oxcarbazepine for prophylaxis against cumulative oxaliplatin‐induced neuropathy. Neurology 2006;67:2253–2255.
    1. Kautio AL, Haanpää M, Leminen A et al. Amitriptyline in the prevention of chemotherapy‐induced neuropathic symptoms. Anticancer Res 2009;29:2601–2606.
    1. Grothey A, Nikcevich DA, Sloan JA et al. Intravenous calcium and magnesium for oxaliplatin‐induced sensory neurotoxicity in adjuvant colon cancer: NCCTG N04C7. J Clin Oncol 2011;29:421–427.
    1. Penz M, Kornek GV, Raderer M et al. Subcutaneous administration of amifostine: A promising therapeutic option in patients with oxaliplatin‐related peripheral sensitive neuropathy. Ann Oncol 2001;12:421–422.
    1. Durand JP, Deplanque G, Montheil V et al. Efficacy of venlafaxine for the prevention and relief of oxaliplatin‐induced acute neurotoxicity: Results of EFFOX, a randomized, double‐blind, placebo‐controlled phase III trial. Ann Oncol 2012;23:200–205.
    1. Paatero P, Tapper U. Positive matrix factorization: A non‐negative factor model with optimal utilization of error estimates of data values. Environmetrics 1994;5:111–126.
    1. Loprinzi CL, Qin R, Dakhil SR et al. 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.
    1. Rao RD, Michalak JC, Sloan JA et al. Efficacy of gabapentin in the management of chemotherapy‐induced peripheral neuropathy: A phase 3 randomized, double‐blind, placebo‐controlled, crossover trial (N00C3). Cancer 2007;110:2110–2118.
    1. Smith EM, Pang H, Cirrincione C et al. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy‐induced painful peripheral neuropathy: A randomized clinical trial. JAMA 2013;309:1359–1367.
    1. Kono T, Hata T, Morita S et al. Goshajinkigan oxaliplatin neurotoxicity evaluation (GONE): A phase 2, multicenter, randomized, double‐blind, placebo‐controlled trial of goshajinkigan to prevent oxaliplatin‐induced neuropathy. Cancer Chemother Pharmacol 2013;72:1283–1290.
    1. Afonseca SO, Cruz FM, Cubero Dde I et al. Vitamin E for prevention of oxaliplatin‐induced peripheral neuropathy: A pilot randomized clinical trial. Sao Paulo Med J 2013;131:35–38.
    1. Hershman DL, Lacchetti C, Dworkin RH et al. Prevention and management of chemotherapy‐induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2014;32:1941–1967.
    1. Guo X, Gao G, Wang X et al. Effects of bilateral deep brain stimulation of the subthalamic nucleus on olfactory function in Parkinson's disease patients. Stereotact Funct Neurosurg 2008;86:237–244.
    1. Kus T, Aktas G, Alpak G et al. Efficacy of venlafaxine for the relief of taxane and oxaliplatin‐induced acute neurotoxicity: A single‐center retrospective case‐control study. Support Care Cancer 2016;24:2085–2091.
    1. Treede RD, Jensen TS, Campbell JN et al. Neuropathic pain: Redefinition and a grading system for clinical and research purposes. Neurology 2008;70:1630–1635.
    1. Cleeland CS, Ryan KM. Pain assessment: Global use of the Brief Pain Inventory. Ann Acad Med Singapore 1994;23:129–138.
    1. Melzack R. The McGill Pain Questionnaire: Major properties and scoring methods. Pain 1975;1:277–299.
    1. Ferreira KA, de Andrade DC, Teixeira MJ. Development and validation of a Brazilian version of the short‐form McGill pain questionnaire (SF‐MPQ). Pain Manag Nurs 2013;14:210–219.
    1. Santos JG, Brito JO, de Andrade DC et al. Translation to Portuguese and validation of the Douleur Neuropathique 4 questionnaire. J Pain 2010;11:484–490.
    1. de Andrade DC, Ferreira KA, Nishimura CM et al. Psychometric validation of the Portuguese version of the Neuropathic Pain Symptoms Inventory. Health Qual Life Outcomes. 2011;9:107.
    1. Bouhassira D, Attal N, Fermanian J et al. Development and validation of the Neuropathic Pain Symptom Inventory. Pain 2004;108:248–257.
    1. Cavaletti G, Frigeni B, Lanzani F et al. The Total Neuropathy Score as an assessment tool for grading the course of chemotherapy‐induced peripheral neurotoxicity: Comparison with the National Cancer Institute‐Common Toxicity Scale. J Peripher Nerv Syst 2007;12:210–215.
    1. National Cancer Institute : Common Terminology Criteria for Adverse Events, 2003. Available at . Accessed June 9, 2017.
    1. Cavaletti G, Bogliun G, Marzorati L et al. Grading of chemotherapy‐induced peripheral neurotoxicity using the Total Neuropathy Scale. Neurology 2003;61:1297–1300.
    1. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983;67:361–370.
    1. Kuhn M, Johnson K. Applied predictive modeling. Berlin, Germany: Springer, 2013.
    1. Reshef DN, Reshef YA, Finucane HK et al. Detecting novel associations in large data sets. Science 2011;334:1518–1524.
    1. Prantner B, Visualization of imputed values using the R‐package VIM, 2011. Available at . Accessed June 9, 2017.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe