Follow-Up Psychophysical Studies in Bortezomib-Related Chemoneuropathy Patients


      Many frontline chemotherapeutic agents produce robust neuropathy as a dose-limiting side effect; however, the persistence of chemotherapy-related sensory disturbances and pain are not well documented. We have previously investigated the qualities of bortezomib-induced pain, and now seek to determine the ongoing nature of this pain. Twenty-six control subjects and 11 patients who had previously been treated with bortezomib and who were experiencing ongoing pain consented to recurring quantitative sensory testing. A pilot immunohistochemistry study of skin innervation was also performed on patient-obtained biopsies. Psychophysical testing in patients revealed persistent changes including decreased skin temperature in the area of pain, diminished touch and sharpness detection, increased pegboard completion times, and decreased sensitivity to skin heating. Additionally, the intensity of pain, as captured by the use of a visual analog scale and pain descriptors, was reported by patients to be unchanged during the retest despite similar morphine equivalent daily doses. The patient skin biopsies displayed a marked decrease in the density of epidermal nerve fibers and Meissner’s corpuscles. These results signify a persistent and severe impairment of Aβ, Aδ, and C fibers in patients with chronic bortezomib-induced chemoneuropathy. Further, this study reports a loss of both epidermal nerve fibers and Meissner’s corpuscles.


      The results of this article indicate a persistent, painful peripheral neuropathy in patients treated with bortezomib. Pilot data indicates a loss of nerve fibers innervating the area of pain. This is the first paper to address the persistence, and potential contributing factors, of bortezomib chemoneuropathy.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Basu S.
        • Sodhi A.
        Increased release of interleukin-1 and tumour necrosis factor by interleukin-2-induced lymphokine-activated killer cells in the presence of cisplatin and FK-565.
        Immunol Cell Biol. 1992; 70: 15-24
        • Benn T.
        • Halfpenny C.
        • Scolding N.
        Glial cells as targets for cytotoxic immune mediators.
        GLIA. 2001; 36: 200-211
        • Boyette-Davis J.
        • Dougherty P.M.
        Protection against oxaliplatin-induced mechanical hyperalgesia and intraepidermal nerve fiber loss by minocycline.
        Exp Neurol. 2011 Mar 5; ([Epub ahead of print])
        • Boyette-Davis J.
        • Xin W.
        • Zhang H.
        • Dougherty P.M.
        Intraepidermal nerve fiber loss corresponds to the development of Taxol-induced hyperalgesia and can be prevented by treatment with minocycline.
        Pain. 2011; 152: 308-313
        • Cata J.P.
        • Weng H.R.
        • Burton A.W.
        • Villareal H.
        • Giralt S.
        • Dougherty P.M.
        Quantitative sensory findings in patients with bortezomib-induced pain.
        J Pain. 2007; 8: 296-306
        • Cata J.P.
        • Weng H.R.
        • Dougherty P.M.
        The effects of thalidomide and minocycline on taxol-induced hyperalgesia in rats.
        Brain Res. 2008; 1229: 100-110
        • Cavaletti G.
        • Bogliun G.
        • Marzorati L.
        • Zincone A.
        • Marzola M.
        • Colombo N.
        • Tredici G.
        Peripheral neurotoxicity of taxol in patients previously treated with cisplatin.
        Cancer. 1995; 75: 1141-1150
        • Cheng H.L.
        • Steinway M.L.
        • Xin X.
        • Feldman E.L.
        Insulin-like growth factor-I and Bcl-X(L) inhibit c-jun N-terminal kinase activation and rescue Schwann cells from apoptosis.
        J Neurochem. 2001; 76: 935-943
        • Conti G.
        • De Pol A.
        • Scarpini E.
        • Vaccina F.
        • De Riz M.
        • Baron P.
        • Tiriticco M.
        • Scarlato G.
        Interleukin-1 beta and interferon-gamma induce proliferation and apoptosis in cultured Schwann cells.
        J Neuroimmunol. 2002; 124: 29-35
        • Contreras P.C.
        • Vaught J.L.
        • Gruner J.A.
        • Brosnan C.
        • Steffler C.
        • Arezzo J.C.
        • Lewis M.E.
        • Kessler J.A.
        • Apfel S.C.
        Insulin-like growth factor-I prevents development of a vincristine neuropathy in mice.
        Brain Res. 1997; 774: 20-26
        • Dougherty P.M.
        • Cata J.P.
        • Burton A.W.
        • Vu K.
        • Weng H.R.
        Dysfunction in multiple primary afferent subtypes revealed by quantitative sensory testing in patients with vincrsitine induced pain.
        J Pain Symptom Manag. 2006; 33: 166-179
        • Dougherty P.M.
        • Cata J.P.
        • Cordella J.V.
        • Burton A.
        • Weng H.R.
        Taxol-induced sensory disturbance is characterized by preferential impairment of myelinated fiber function in cancer patients.
        Pain. 2004; 109: 132-142
        • Forsyth P.A.
        • Balmaceda C.
        • Peterson K.
        • Seidman A.D.
        • Brasher P.
        • DeAngelis L.M.
        Prospective study of paclitaxel-induced peripheral neuropathy with quantitative sensory testing.
        J Neuro-oncol. 1997; 35: 47-53
        • Fuchs P.N.
        • Campbell J.N.
        • Meyer R.A.
        Secondary hyperalgesia persists in capsaicin desensitized skin.
        Pain. 2000; 84: 141-149
        • Gan X.H.
        • Jewett A.
        • Bonavida B.
        Activation of human peripheral-blood-derived monocytes by cis-diamminedichloroplatinum: Enhanced tumoricidal activity and secretion of tumor necrosis factor-alpha.
        Nat Immun. 1992; 11: 144-155
        • Gao W.-Q.
        • Dybal N.
        • Shinsky N.
        • Murnane A.
        • Schmelzer C.
        • Siegel M.
        • Keller G.
        • Hefti F.
        • Phillips H.S.
        • Winslow J.W.
        Neurotrophin-3 reverses experimental cisplatin-induced peripheral sensory neuropathy.
        Ann Neurol. 1995; 38: 30-37
        • Glasmacher A.
        • von Lilienfeld-Toal M.
        The current status of thalidomide in the management of multiple myeloma.
        Acta Haematol. 2005; 114: 3-7
        • Hayakawa K.
        • Itoh T.
        • Niwa H.
        • Mutoh T.
        • Sobue G.
        NGF prevention of neurotoxicity induced by cisplatin, vincristine and taxol depends on toxicity of each drug and NGF treatment schedule: In vitro study of adult rat sympathetic ganglion explants.
        Brain Res. 1998; 794: 313-319
        • Kennedy W.R.
        • Wendelschafer-Crabb G.
        • Johnson T.
        Quantitation of epidermal nerves in diabetic neuropathy.
        Neurology. 1996; 47: 1042-1048
        • Krady J.K.
        • Basu A.
        • Allen C.M.
        • Xu Y.
        • LaNoue K.F.
        • Gardner T.W.
        • Levison S.W.
        Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy.
        Diabetes. 2005; 54: 1559-1565
        • Lauria G.
        • Lombardi R.
        • Borgna M.
        • Penza P.
        • Bianchi R.
        • Savino C.
        • Canta A.
        • Nicolini G.
        • Marmiroli P.
        • Cavaletti G.
        Intraepidermal nerve fiber density in rat foot pad: Neuropathologic-neurophysiologic correlation.
        J Peripher Nerv Syst. 2005; 10: 202-208
        • Ledeboer A.
        • Sloane E.M.
        • Milligan E.D.
        • Frank M.G.
        • Mahony J.H.
        • Maier S.F.
        • Watkins L.R.
        Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation.
        Pain. 2005; 115: 71-83
        • Lisak R.P.
        • Bealmear B.
        • Benjamins J.
        • Skoff A.
        Inflammatory cytokines inhibit upregulation of glycolipid expression by Schwann cells in vitro.
        Neurology. 1998; 51: 1661-1665
        • Magri F.
        • Buonocore M.
        • Oliviero A.
        • Rotondi M.
        • Gatti A.
        • Accornero S.
        • Camera A.
        • Chiovato L.
        Intraepidermal nerve fiber density reduction as a marker of preclinical asymptomatic small-fiber sensory neuropathy in hypothyroid patients.
        Eur J Endocrinol. 2010; 163: 279-284
        • Oaklander A.L.
        The density of remaining nerve endings in human skin with and without postherpetic neuralgia after shingles.
        Pain. 2001; 92: 139-145
        • O’Brien Jr., J.M.
        • Wewers M.D.
        • Moore S.A.
        • Allen J.N.
        Taxol and colchicine increase LPS-induced pro-IL-1 beta production, but do not increase IL-1 beta secretion. A role for microtubules in the regulation of IL-1 beta production.
        J Immunol. 1995; 154: 4113-4122
        • Otten U.
        • März P.
        • Heese K.
        • Hock C.
        • Kunz D.
        • Rose-John S.
        Cytokines and neurotrophins interact in normal and diseased states.
        Ann N Y Acad Sci. 2000; 917: 322-330
        • Pai K.
        • Sodhi A.
        Effect of cisplatin, rIFN-Y, LPS and MDP on release of H2O2, O2- and lysozyme from human monocytes in vitro.
        Indian J Exp Biol. 1991; 29: 910-915
        • Petersen K.L.
        • Rice F.L.
        • Farhadi M.
        • Reda H.
        • Rowbotham M.C.
        Natural history of cutaneous innervation following herpes zoster.
        Pain. 2010; 150: 75-82
        • Postma T.J.
        • Benard B.A.
        • Huijgens P.C.
        • Ossenkoppele G.J.
        • Heimans J.J.
        Long term effects of vincristine on the peripheral nervous system.
        J Neurooncol. 1993; 15: 23-27
        • Richardson P.G.
        • Xie W.L.
        • Mitsiades C.
        • Chanan-Khan A.A.
        • Lonial S.
        • Hassoun H.
        • Avigan D.E.
        • Oaklander A.L.
        • Kuter D.J.
        • Wen P.Y.
        • Kesari S.
        • Briemberg H.R.
        • Schlossman R.L.
        • Munshi N.C.
        • Heffner L.T.
        • Doss D.
        • Esseltine D.L.
        • Weller E.
        • Anderson K.C.
        • Amato A.A.
        Single-agent bortezomib in previously untreated multiple myeloma: Efficacy, characterization of peripheral neuropathy, and molecular correlations with response and neuropathy.
        J Clin Oncol. 2009; 27: 3518-3525
        • Rowbotham M.C.
        • Yosipovitch G.
        • Connoly M.K.
        • Finlay D.
        • Forde G.
        • Fields H.L.
        Cutaneoous innervation density in the allodynic form of postherpetic neuralgia.
        Neurobiol Dis. 1996; 3: 204-214
        • Rowinsky E.K.
        • Chaudhry V.
        • Forastiere A.A.
        • Sartorius S.E.
        • Ettinger D.S.
        • Grochow L.B.
        • Lubejko B.G.
        • Cornblath D.R.
        • Donehower R.C.
        Phase I and pharmacologic study of paclitaxel and cisplatin with granulocyte colony-stimulating fator: Neuromuscular toxicity is dose-limiting.
        J Clin Oncol. 1993; 11: 2010-2020
        • Ruff R.M.
        • Parker S.B.
        Gender and age-specific changes in motor speed and eye-hand coordination in adults: Normative values for finger tapping and grooved pegboard tests.
        Percept Motor Skills. 1993; 76: 1219-1230
        • Shubayev V.I.
        • Myers R.R.
        Endoneurial remodeling by TNFα- and TNFα-releasing proteases. A spatial and temporal co-localization study in painful neuropathy.
        J Peripher Nerv Syst. 2002; 7: 28-36
        • Shun C.T.
        • Chang Y.C.
        • Wu H.P.
        • Hsieh S.C.
        • Lin W.M.
        • Lin Y.H.
        • Tai T.Y.
        • Hsieh S.T.
        Skin denervation in type 2 diabetes: Correlations with diabetic duration and functional impairments.
        Brain. 2004; 127: 1593-1605
        • Siau C.
        • Xiao W.
        • Bennett G.J.
        Paclitaxel- and vincristine-evoked painful peripheral neuropathies: Loss of epidermal innervation and activation of Langerhans cells.
        Exp Neurol. 2006; 201: 507-514
        • Sorensen L.
        • Molyneaux L.
        • Yue D.K.
        The relationship among pain, sensory loss, and small nerve fibers in diabetes.
        Diabetes Care. 2006; 29: 883-887
        • Teare K.A.
        • Pearson R.G.
        • Shakesheff K.M.
        • Haycock J.W.
        α-MSH inhibits inflammatory signalling in Schwann cells.
        Neuroreport. 2004; 15: 493-498
        • Walk D.
        • Wendelschafer-Crabb G.
        • Davey C.
        • Kennedy W.R.
        Concordance between epidermal nerve fiber density and sensory examination in patients with symptoms of idiopathic small fiber neuropathy.
        J Neurol Sci. 2007; 255: 23-26
        • Zaks-Zilberman M.
        • Zaks T.Z.
        • Vogel S.N.
        Induction of proinflammatory and chemokine genes by lipopolysaccharide and paclitaxel (Taxol) in murine and human breast cancer cell lines.
        Cytokine. 2001; 15: 156-165