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Canadian Journal of Anesthesia/Journal canadien d'anesthésie
Published in: Canadian Journal of Anesthesia/Journal canadien d'anesthésie 8/2014

01-08-2014 | Review Article/Brief Review

Brief review: Chemotherapy-induced painful peripheral neuropathy (CIPPN): current status and future directions

Authors: Robert L. Massey, PhD, Hee Kee Kim, PhD, Salahadin Abdi, MD, PhD

Published in: Canadian Journal of Anesthesia/Journal canadien d'anesthésie | Issue 8/2014

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Abstract

Purpose

Chemotherapy-induced painful peripheral neuropathy (CIPPN) affects up to 90% of cancer patients treated with chemotherapy agents. Despite the fact that it is relatively common, the underlying pathophysiology is still unclear and its treatment remains generic. Mechanisms of CIPPN are multifactorial, dependent on the specific chemotherapeutic agent used, and include multiple patient-related factors, including genetic factors that may predispose patients to either develop or not develop CIPPN. The purpose of this article is to review mechanisms, clinical signs and symptoms, diagnosis, treatment options, and prognosis for patients who develop CIPPN. We also offer research considerations for this complex and unpredictable phenomenon.

Principal findings

Chemotherapeutic agents can damage the peripheral nervous system, including the nerve terminals, axons, cell body, and myelin sheath of sensory nerves. Herein, we describe some of the anatomical and functional changes that are thought to take place at various levels of the nervous system. On a clinical level, patients with CIPPN report multiple symptoms. It is essential to obtain an accurate history from the patient and to perform a thorough physical examination in order to obtain the patient’s subjective perspective. Additionally, objective measurements may be needed in order to articulate clearly the effects of this complex syndrome and to ensure an accurate diagnosis, treatment, and prognosis.

Conclusions

The management of CIPPN remains a clinical challenge for pain practitioners. As more research is being carried out to elucidate its pathophysiology and therapy, the innovative use of several non-traditional categories of drugs seems promising in the management of this complex phenomenon. Studies addressing predictability and possible genetic predisposition are necessary not only for preventive measures but also for targeted treatments.
Literature
1.
Bokhari F, Sawatzky JA. Chronic neuropathic pain in women after breast cancer treatment. Pain Manag Nurs 2009; 10: 197-205.PubMedCrossRef
2.
Polomano RC, Farrar JT. Pain and neuropathy in cancer survivors. Cancer Nurs 2006; 29(2 Suppl): 39-47.PubMedCrossRef
3.
Reyes-Gibby C, Morrow PK, Bennett MI, Jensen MP, Shete S. Neuropathic pain in breast cancer survivors: using the ID pain as a screening tool. J Pain Symptom Manage 2010; 39: 882-9.PubMedCentralPubMedCrossRef
4.
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: 1359-67.PubMedCentralPubMedCrossRef
5.
Golan-Vered Y, Pud D. Chemotherapy-induced neuropathic pain and its relation to cluster symptoms in breast cancer patients treated with paclitaxel. Pain Pract 2013; 13: 46-52.PubMedCrossRef
6.
Boyette-Davis JA, Cata JP, Driver LC, et al. Persistent chemoneuropathy in patients receiving the plant alkaloids paclitaxel and vincristine. Cancer Chemother Pharmacol 2013; 71: 619-26.PubMedCentralPubMedCrossRef
7.
Cooney MA, Culleton-Quinn E, Stokes E. Current knowledge of pain after breast cancer treatment: a systematic review. Pain Manag Nurs 2013; 14: 110-23.PubMedCrossRef
8.
9.
Siau C, Xiao W, Bennett GJ. Paclitaxel- and vincristine-evoked painful peripheral neuropathies: loss of epidermal innervation and activation of Langerhans cells. Exp Neurol 2006; 201: 507-14.PubMedCentralPubMedCrossRef
10.
Boyette-Davis J, Dougherty PM. Protection against oxaliplatin-induced mechanical hyperalgesia and intraepidermal nerve fiber loss by minocycline. Exp Neurol 2011; 229: 353-7.PubMedCentralPubMedCrossRef
11.
Seltzer Z, Devor M. Ephaptic transmission in chronically damaged peripheral nerves. Neurology 1979; 29: 1061-4.PubMedCrossRef
12.
Dougherty PM, Cata JP, Burton AW, Vu K, Weng HR. Dysfunction in multiple primary afferent fiber subtypes revealed by quantitative sensory testing in patients with chronic vincristine-induced pain. J Pain Symptom Manage 2007; 33: 166-79.PubMedCrossRef
13.
Pal PK. Clinical and electrophysiological studies in vincristine induced neuropathy. Electromyogr Clin Neurophysiol 1999; 39: 323-30.PubMed
14.
Carozzi VA, Canta A, Oggioni N, et al. Neurophysiological and neuropathological characterization of new murine models of chemotherapy-induced chronic peripheral neuropathies. Exp Neurol 2010; 226: 301-9.PubMedCrossRef
15.
Adelsberger H, Quasthoff S, Grosskreutz J, Lepier A, Eckel F, Lersch C. The chemotherapeutic oxaliplatin alters voltage-gated Na(+) channel kinetics on rat sensory neurons. Eur J Pharmacol 2000; 406: 25-32.PubMedCrossRef
16.
Grolleau F, Gamelin L, Boisdron-Celle M, Lapied B, Pelhate M, Gamelin E. A possible explanation for a neurotoxic effect of the anticancer agent oxaliplatin on neuronal voltage-gated sodium channels. J Neurophysiol 2001; 85: 2293-7.PubMed
17.
Park SB, Krishnan AV, Lin CS, Goldstein D, Friedlander M, Kiernan MC. Mechanisms underlying chemotherapy-induced neurotoxicity and the potential for neuroprotective strategies. Curr Med Chem 2008; 15: 3081-94.PubMedCrossRef
18.
Meijer C, de Vries EG, Marmiroli P, Tredici G, Frattola L, Cavaletti G. Cisplatin-induced DNA-platination in experimental dorsal root ganglia neuronopathy. Neurotoxicology 1999; 20: 883-7.PubMed
19.
Gregg RW, Molepo JM, Monpetit VJ, et al. Cisplatin neurotoxicity: the relationship between dosage, time, and platinum concentration in neurologic tissues, and morphologic evidence of toxicity. J Clin Oncol 1992; 10: 795-803.PubMed
20.
Argyriou AA, Koltzenburg M, Polychronopoulos P, Papapetropoulos S, Kalofonos HP. Peripheral nerve damage associated with administration of taxanes in patients with cancer. Crit Rev Oncol Hematol 2008; 66: 218-28.PubMedCrossRef
21.
Peters CM, Jimenez-Andrade JM, Jonas BM, et al. Intravenous paclitaxel administration in the rat induces a peripheral sensory neuropathy characterized by macrophage infiltration and injury to sensory neurons and their supporting cells. Exp Neurol 2007; 203: 42-54.PubMedCrossRef
22.
Flatters SJ, Bennett GJ. Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction. Pain 2006; 122: 245-57.PubMedCentralPubMedCrossRef
23.
Melli G, Taiana M, Camozzi F, et al. Alpha-lipoic acid prevents mitochondrial damage and neurotoxicity in experimental chemotherapy neuropathy. Exp Neurol 2008; 214: 276-84.PubMedCrossRef
24.
Broyl A, Corthals SL, Jongen JL, et al. Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol 2010; 11: 1057-65.PubMedCrossRef
25.
Sun X, Windebank AJ. Calcium in suramin-induced rat sensory neuron toxicity in vitro. Brain Res 1996; 742: 149-56.PubMedCrossRef
26.
Siau C, Bennett GJ. Dysregulation of cellular calcium homeostasis in chemotherapy-evoked painful peripheral neuropathy. Anesth Analg 2006; 102: 1485-90.PubMedCentralPubMedCrossRef
27.
Xiao W, Boroujerdi A, Bennett GJ, Luo ZD. Chemotherapy-evoked painful peripheral neuropathy: analgesic effects of gabapentin and effects on expression of the alpha-2-delta type-1 calcium channel subunit. Neuroscience 2007; 144: 714-20.PubMedCentralPubMedCrossRef
28.
Matsumoto G, Ichikawa M, Tasaki A, Murofushi H, Sakai H. Axonal microtubules necessary for generation of sodium current in squid giant axons: I. Pharmacological study on sodium current and restoration of sodium current by microtubule proteins and 260 K protein. J Membr Biol 1984; 77: 77-91.PubMedCrossRef
29.
Nieto FR, Entrena JM, Cendan CM, Pozo ED, Vela JM, Baeyens JM. Tetrodotoxin inhibits the development and expression of neuropathic pain induced by paclitaxel in mice. Pain 2008; 137: 520-31.PubMedCrossRef
30.
Ghelardini C, Desaphy JF, Muraglia M, et al. Effects of a new potent analog of tocainide on hNav1.7 sodium channels and in vivo neuropathic pain models. Neuroscience 2010; 169: 863-73.PubMedCrossRef
31.
Descoeur J, Pereira V, Pizzoccaro A, et al. Oxaliplatin-induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors. EMBO Mol Med 2011; 3: 266-78.PubMedCentralPubMedCrossRef
32.
Alessandri-Haber N, Dina OA, Joseph EK, Reichling DB, Levine JD. Interaction of transient receptor potential vanilloid 4, integrin, and SRC tyrosine kinase in mechanical hyperalgesia. J Neurosci 2008; 28: 1046-57.PubMedCrossRef
33.
Ta LE, Bieber AJ, Carlton SM, Loprinzi CL, Low PA, Windebank AJ. Transient receptor potential vanilloid 1 is essential for cisplatin-induced heat hyperalgesia in mice. Mol Pain 2010; 6: 15.PubMedCentralPubMedCrossRef
34.
35.
Joseph EK, Chen X, Bogen O, Levine JD. Oxaliplatin acts on IB4-positive nociceptors to induce an oxidative stress-dependent acute painful peripheral neuropathy. J Pain 2008; 9: 463-72.PubMedCrossRef
36.
Kim HK, Zhang YP, Gwak YS, Abdi S. Phenyl N-tert-butylnitrone, a free radical scavenger, reduces mechanical allodynia in chemotherapy-induced neuropathic pain in rats. Anesthesiology 2010; 112: 432-9.PubMedCrossRef
37.
Muthuraman A, Jaggi AS, Singh N, Singh D. Ameliorative effects of amiloride and pralidoxime in chronic constriction injury and vincristine induced painful neuropathy in rats. Eur J Pharmacol 2008; 587: 104-11.PubMedCrossRef
38.
Joseph EK, Levine JD. Caspase signalling in neuropathic and inflammatory pain in the rat. Eur J Neurosci 2004; 20: 2896-902.PubMedCrossRef
39.
Boehmerle W, Zhang K, Sivula M, et al. Chronic exposure to paclitaxel diminishes phosphoinositide signaling by calpain-mediated neuronal calcium sensor-1 degradation. Proc Natl Acad Sci U S A 2007; 104: 11103-8.PubMedCentralPubMedCrossRef
40.
Horvath P, Szilvassy J, Nemeth J, Peitl B, Szilasi M, Szilvassy Z. Decreased sensory neuropeptide release in isolated bronchi of rats with cisplatin-induced neuropathy. Eur J Pharmacol 2005; 507: 247-52.PubMedCrossRef
41.
Jamieson SM, Liu JJ, Connor B, Dragunow M, McKeage MJ. Nucleolar enlargement, nuclear eccentricity and altered cell body immunostaining characteristics of large-sized sensory neurons following treatment of rats with paclitaxel. Neurotoxicology 2007; 28: 1092-8.PubMedCrossRef
42.
Thibault K, Van Steenwinckel J, Brisorgueil MJ, et al. Serotonin 5-HT2A receptor involvement and Fos expression at the spinal level in vincristine-induced neuropathy in the rat. Pain 2008; 140: 305-22.PubMedCrossRef
43.
Hansen N, Uceyler N, Palm F, et al. Serotonin transporter deficiency protects mice from mechanical allodynia and heat hyperalgesia in vincristine neuropathy. Neurosci Lett 2011; 495: 93-7.PubMedCrossRef
44.
Cata JP, Weng HR, Chen JH, Dougherty PM. Altered discharges of spinal wide dynamic range neurons and down-regulation of glutamate transporter expression in rats with paclitaxel-induced hyperalgesia. Neuroscience 2006; 138: 329-38.PubMedCrossRef
45.
Kassem LA, Gamal El-Din MM, Yassin NA. Mechanisms of vincristine-induced neurotoxicity: possible reversal by erythropoietin. Drug Discov Ther 2011; 5: 136-43.
46.
Norcini M, Vivoli E, Galeotti N, Bianchi E, Bartolini A, Ghelardini C. Supraspinal role of protein kinase C in oxaliplatin-induced neuropathy in rat. Pain 2009; 146: 141-7.PubMedCrossRef
47.
Galeotti N, Vivoli E, Bilia AR, Vincieri FF, Ghelardini C. St. John’s Wort reduces neuropathic pain through a hypericin-mediated inhibition of the protein kinase Cgamma and epsilon activity. Biochem Pharmacol 2010; 79: 1327-36.PubMedCrossRef
48.
Ledeboer A, Jekich BM, Sloane EM, et al. Intrathecal interleukin-10 gene therapy attenuates paclitaxel-induced mechanical allodynia and proinflammatory cytokine expression in dorsal root ganglia in rats. Brain Behav Immun 2007; 21: 686-98.PubMedCentralPubMedCrossRef
49.
Kaur G, Athar M, Alam MS. Dietary supplementation of silymarin protects against chemically induced nephrotoxicity, inflammation and renal tumor promotion response. Invest New Drugs 2010; 28: 703-13.PubMedCrossRef
50.
Mangiacavalli S, Corso A, De Amici M, et al. Emergent T-helper 2 profile with high interleukin-6 levels correlates with the appearance of bortezomib-induced neuropathic pain. Br J J Haematol 2010; 149: 916-8.CrossRef
51.
52.
Farquhar-Smith P. Chemotherapy-induced neuropathic pain. Curr Opin Support Palliat Care 2011; 5: 1-7.PubMedCrossRef
53.
Windebank AJ, Grisold W. Chemotherapy-induced neuropathy. J Peripher Nerve Syst 2008; 13: 27-46.CrossRef
54.
Grisold W, Cavaletti G, Windebank AJ. Peripheral neuropathies from chemotherapeutics and targeted agents: diagnosis, treatment, and prevention. Neuro Oncol 2012; 14 Suppl 4: iv45-54.
55.
Ocean AJ, Vahdat LT. Chemotherapy-induced peripheral neuropathy: pathogenesis and emerging therapies. Support Care Cancer 2004; 12: 619-25.PubMed
56.
Lavoie Smith EM, Barton DL, Qin R, Steen PD, Aaronson NK, Loprinzi CL. Assessing patient-reported peripheral neuropathy: the reliability and validity of the European Organization for Research and Treatment of Cancer QLQ-CIPN20 Questionnaire. Qual Life Res 2013; 22: 2787-99.PubMedCrossRef
57.
58.
Polomano RC, Bennett GJ. Chemotherapy-evoked painful peripheral neuropathy. Pain Med 2001; 2: 8-14.PubMedCrossRef
59.
Xiao WH, Bennett GJ. Chemotherapy-evoked neuropathic pain: abnormal spontaneous discharge in A-fiber and C-fiber primary afferent neurons and its suppression by acetyl-L-carnitine. Pain 2008; 135: 262-70.PubMedCentralPubMedCrossRef
60.
Burton AW, Fine PG, Passik SD. Transformation of acute cancer pain to chronic cancer pain syndromes. J Support Oncol 2012; 10: 89-95.PubMedCrossRef
61.
Caraceni A, Brunelli C, Martini C, Zecca E, De Conno F. Cancer pain assessment in clinical trials. A review of the literature (1999-2002). J Pain Sympt Manage 2005; 29: 507-19.CrossRef
62.
De Conno F, Caraceni A, Gamba A, et al. Pain measurement in cancer patients: a comparison of six methods. Pain 1994; 57: 161-6.PubMedCrossRef
63.
Wong DL, Baker CM. Pain in children: comparison of assessment scales. Pediatr Nurs 1988; 14: 9-17.PubMed
64.
Melzack R. The McGill Pain Questionnaire: major properties and scoring methods. Pain 1975; 1: 277-99.PubMedCrossRef
65.
Cleeland CS, Gonin R, Hatfield AK, et al. Pain and its treatment in outpatients with metastatic cancer. N Engl J Med 1994; 330: 592-6.PubMedCrossRef
66.
Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore 1994; 23: 129-38.PubMed
67.
Lauria G, Hsieh ST, Johansson O, et al; European Federation of Neurological Societies; Peripheral Nerve Society. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol 2010; 17(903-12): e44-9.
68.
Dworkin RH, Backonja M, Rowbotham MC, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 2003; 60: 1524-34.PubMedCrossRef
69.
Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 2007; 132: 237-51.PubMedCrossRef
70.
Dworkin RH, O’Connor AB, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc 2010; 85(3 Suppl): S3-14.PubMedCentralPubMedCrossRef
71.
Tsavaris N, Kopterides P, Kosmas C, et al. Gabapentin monotherapy for the treatment of chemotherapy-induced neuropathic pain: a pilot study. Pain Med 2008; 9: 1209-16.PubMedCrossRef
72.
Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain 2010; 150: 573-81.PubMedCrossRef
73.
Corbett CF. Practical management of patients with painful diabetic neuropathy. Diabetes Educ 2005; 31: 523-4.PubMedCrossRef
74.
Wallace M, Pappagallo M. Qutenza®: a capsaicin 8% patch for the management of postherpetic neuralgia. Expert Rev Neurother 2011; 11: 15-27.PubMedCrossRef
75.
Galluzzi KE. Management of neuropathic pain. J Am Osteopath Assoc 2005; 105(9 Suppl 4): S12-9.PubMed
76.
Cassileth BR, Keefe FJ. Integrative and behavioral approaches to the treatment of cancer-related neuropathic pain. Oncologist 2010; 15(Suppl 2): 19-23.PubMedCrossRef
77.
Jung BF, Herrmann D, Griggs J, Oaklander AL, Dworkin RH. Neuropathic pain associated with non-surgical treatment of breast cancer. Pain 2005; 118: 10-4.PubMedCrossRef
78.
Argyriou AA, Polychronopoulos P, Koutras A, et al. Peripheral neuropathy induced by administration of cisplatin- and paclitaxel-based chemotherapy. Could it be predicted? Support Care Cancer 2005; 13: 647-51.PubMedCrossRef
79.
Albers JW, Chaudhry V, Cavaletti G, Donehower RC. Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database Syst Rev 2011; (2): CD005228.
80.
Argyriou AA, Chroni E, Koutras A, et al. Vitamin E for prophylaxis against chemotherapy-induced neuropathy: a randomized controlled trial. Neurology 2005; 64: 26-31.PubMedCrossRef
81.
Kemp G, Rose P, Lurain J, et al. Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin-induced toxicities: results of a randomized control trial in patients with advanced ovarian cancer. J Clin Oncol 1996; 14: 2101-12.PubMed
82.
Smyth JF, Bowman A, Perren T, et al. Glutathione reduces the toxicity and improves quality of life of women diagnosed with ovarian cancer treated with cisplatin: results of a double-blind, randomised trial. Ann Oncol 1997; 8: 569-73.PubMedCrossRef
83.
Gamelin L, Boisdron-Celle M, Morel A, et al. Oxaliplatin-related neurotoxicity: interest of calcium-magnesium infusion and no impact on its efficacy. J Clin Oncol 2008; 26: 1188-9; author reply 1189-90.
84.
Wang WS, Lin JK, Lin TC, et al. Oral glutamine is effective for preventing oxaliplatin-induced neuropathy in colorectal cancer patients. Oncologist 2007; 12: 312-9.PubMedCrossRef
85.
Kottschade LA, Sloan JA, Mazurczak MA, et al. The use of vitamin E for the prevention of chemotherapy-induced peripheral neuropathy: results of a randomized phase III clinical trial. Support Care Cancer 2011; 19: 1769-77.PubMedCentralPubMedCrossRef
86.
Bianchi G, Vitali G, Caraceni A, et al. Symptomatic and neurophysiological responses of paclitaxel- or cisplatin-induced neuropathy to oral acetyl-L-carnitine. Eur J Cancer 2005; 41: 1746-50.PubMedCrossRef
Metadata
Title
Brief review: Chemotherapy-induced painful peripheral neuropathy (CIPPN): current status and future directions
Authors
Robert L. Massey, PhD
Hee Kee Kim, PhD
Salahadin Abdi, MD, PhD
Publication date
01-08-2014
Publisher
Springer US
Published in
Canadian Journal of Anesthesia/Journal canadien d'anesthésie / Issue 8/2014
Print ISSN: 0832-610X
Electronic ISSN: 1496-8975
DOI
https://doi.org/10.1007/s12630-014-0171-4

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