Abstract
A number of agents from diverse pharmacological classes are used to treat neuropathic pain associated with diabetic peripheral neuropathy. Only three of these have regulatory approval for this indication in the U.S. In this focused article, I will discuss selected drugs, newly approved or in development, to treat neuropathic pain in patients with diabetic neuropathy. These will include agonists and antagonists of the transient receptor potential channels, a family of receptor proteins that play a role in the transduction of physical stress; sodium channel isoform specific antagonists; a recently approved dual-action opioid receptor agonist–norepinephrine reuptake inhibitor; gene therapy for neuropathic pain; and anti-nerve growth factor molecules. Mechanisms of action, preclinical supporting data, clinical trial evidence, and adverse effects will be reviewed.
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Daousi C, MacFarlane IA, Woodward A, Nurmikko TJ, Bundred PE, Benbow SJ. Chronic painful peripheral neuropathy in an urban community: a controlled comparison of people with and without diabetes. Diabet Med. 2004;21:976–82.
Davies M, Brophy S, Williams R, Taylor A. The prevalence, severity, and impact of painful diabetic peripheral neuropathy in type 2 diabetes. Diabetes Care. 2006;29:1518–22.
Ziegler D, Rathmann W, Dickhaus T, Meisinger C, Mielck A. Neuropathic pain in diabetes, prediabetes and normal glucose tolerance: the MONICA/KORA Augsburg Surveys S2 and S3. Pain Med. 2009;10:393–400.
Ziegler D, Rathmann W, Dickhaus T, Meisinger C, Mielck A. Prevalence of polyneuropathy in pre-diabetes and diabetes is associated with abdominal obesity and macroangiopathy: the MONICA/KORA Augsburg Surveys S2 and S3. Diabetes Care. 2008;31:464–9.
Freeman R. Pharmacotherapy of neuropathic pain. In: Simpson DM, McArthur JC, Dworkin RH, editors. Neuropathic Pain: Mechanisms, Diagnosis and Treatment. New York: Oxford University Press; 2012. p. 112–31.
Caterina MJ. Vanilloid receptors take a TRP beyond the sensory afferent. Pain. 2003;105:5–9.
Pingle SC, Matta JA, Ahern GP (2007) Capsaicin receptor: TRPV1 a promiscuous TRP channel. HandbExpPharmacol: 155–171
Facer P, Casula MA, Smith GD, et al. Differential expression of the capsaicin receptor TRPV1 and related novel receptors TRPV3, TRPV4 and TRPM8 in normal human tissues and changes in traumatic and diabetic neuropathy. BMCNeurol. 2007;7:11.
Lauria G, Morbin M, Lombardi R, et al. Expression of capsaicin receptor immunoreactivity in human peripheral nervous system and in painful neuropathies. J Peripher Nerv Syst. 2006;11:262–71.
Derry S, Lloyd R, Moore RA, McQuay HJ (2009) Topical capsaicin for chronic neuropathic pain in adults. CochraneDatabaseSystRev: CD007393
Nolano M, Simone DA, Wendelschafer-Crabb G, Johnson T, Hazen E, Kennedy WR. Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation. Pain. 1999;81:135–45.
Simone DA, Nolano M, Johnson T, Wendelschafer-Crabb G, Kennedy WR. Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: correlation with sensory function. J Neurosci. 1998;18:8947–59.
Polydefkis M, Hauer P, Sheth S, Sirdofsky M, Griffin JW, McArthur JC. The time course of epidermal nerve fibre regeneration: studies in normal controls and in people with diabetes, with and without neuropathy. Brain. 2004;127:1606–15.
Gibbons CH, Wang N, Freeman R. Capsaicin induces degeneration of cutaneous autonomic nerve fibers. Ann Neurol. 2010;68:888–98.
Wood JN, Winter J, James IF, Rang HP, Yeats J, Bevan S. Capsaicin-induced ion fluxes in dorsal root ganglion cells in culture. J Neurosci. 1988;8:3208–20.
Sikand P, Premkumar LS. Potentiation of glutamatergic synaptic transmission by protein kinase C-mediated sensitization of TRPV1 at the first sensory synapse. J Physiol. 2007;581:631–47.
Amantini C, Mosca M, Nabissi M, et al. Capsaicin-induced apoptosis of glioma cells is mediated by TRPV1 vanilloid receptor and requires p38 MAPK activation. J Neurochem. 2007;102:977–90.
Mason L, Moore RA, Derry S, Edwards JE, McQuay HJ. Systematic review of topical capsaicin for the treatment of chronic pain. BMJ. 2004;328:991.
Bernstein JE, Korman NJ, Bickers DR, Dahl MV, Millikan LE. Topical capsaicin treatment of chronic postherpetic neuralgia. J Am Acad Dermatol. 1989;21:265–70.
(1992) Effect of treatment with capsaicin on daily activities of patients with painful diabetic neuropathy. Capsaicin Study Group. Diabetes Care 15: 159–165
Tandan R, Lewis GA, Badger GB, Fries TJ. Topical capsaicin in painful diabetic neuropathy. Effect on sensory function. Diabetes Care. 1992;15:15–8.
Low PA, Opfer-Gehrking TL, Dyck PJ, Litchy WJ, O'Brien PC. Double-blind, placebo-controlled study of the application of capsaicin cream in chronic distal painful polyneuropathy. Pain. 1995;62:163–8.
Watson CP, Tyler KL, Bickers DR, Millikan LE, Smith S, Coleman E. A randomized vehicle-controlled trial of topical capsaicin in the treatment of postherpetic neuralgia. Clin Ther. 1993;15:510–26.
Ellison N, Loprinzi CL, Kugler J, et al. Phase III placebo-controlled trial of capsaicin cream in the management of surgical neuropathic pain in cancer patients. J Clin Oncol. 1997;15:2974–80.
Watson CP, Evans RJ. The postmastectomy pain syndrome and topical capsaicin: a randomized trial. Pain. 1992;51:375–9.
• Backonja M, Wallace MS, Blonsky ER, et al. NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomised, double-blind study. Lancet Neurol. 2008;7:1106–12. The first pivotal trial demonstrating efficacy of a high-concentration capsaicin patch for the treatment of postherpetic neuralgia.
Backonja MM, Malan TP, Vanhove GF, Tobias JK. NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomized, double-blind, controlled study with an open-label extension. Pain Med. 2010;11:600–8.
Irving GA, Backonja MM, Dunteman E, et al. A multicenter, randomized, double-blind, controlled study of NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia. Pain Med. 2011;12:99–109.
Simpson DM, Brown S, Tobias J. Controlled trial of high-concentration capsaicin patch for treatment of painful HIV neuropathy. Neurology. 2008;70:2305–13.
Kennedy WR, Vanhove GF, Lu SP, et al. A randomized, controlled, open-label study of the long-term effects of NGX-4010, a high-concentration capsaicin patch, on epidermal nerve fiber density and sensory function in healthy volunteers. J Pain Off J Am Pain Soc. 2010;11:579–87.
Jancso N, Jancso-Gabor A, Szolcsanyi J. Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin. Br J Pharmacol Chemother. 1967;31:138–51.
Schuller TB, Hermann K, Baron R. Quantitative assessment and correlation of sympathetic, parasympathetic, and afferent small fiber function in peripheral neuropathy. J Neurol. 2000;247:267–72.
Low VA, Sandroni P, Fealey RD, Low PA. Detection of small-fiber neuropathy by sudomotor testing. Muscle Nerve. 2006;34:57–61.
Parkhouse N, Le Quesne PM. Impaired neurogenic vascular response in patients with diabetes and neuropathic foot lesions. N Engl J Med. 1988;318:1306–9.
Berghoff M, Kilo S, Hilz MJ, Freeman R (2006) Differential impairment of the sudomotor and nociceptor axon-reflex in diabetic peripheral neuropathy. Muscle Nerve
Boulton AJ, Kirsner RS, Vileikyte L. Clinical practice. Neuropathic diabetic foot ulcers. N Engl J Med. 2004;351:48–55.
Abbott CA, Carrington AL, Ashe H, et al. The North-West Diabetes Foot Care Study: incidence of, and risk factors for, new diabetic foot ulceration in a community-based patient cohort. Diabet Med. 2002;19:377–84.
Abbott CA, Vileikyte L, Williamson S, Carrington AL, Boulton AJ. Multicenter study of the incidence of and predictive risk factors for diabetic neuropathic foot ulceration. Diabetes Care. 1998;21:1071–5.
Young MJ, Breddy JL, Veves A, Boulton AJ. The prediction of diabetic neuropathic foot ulceration using vibration perception thresholds. A prospective study. Diabetes Care. 1994;17:557–60.
• Brederson JD, Kym PR, Szallasi A (2013) Targeting TRP channels for pain relief. Eur J Pharmacol. Review of current TRP channel therapeutic approaches.
Chen J, Joshi SK, DiDomenico S, et al. Selective blockade of TRPA1 channel attenuates pathological pain without altering noxious cold sensation or body temperature regulation. Pain. 2011;152:1165–72.
Andrade EL, Meotti FC, Calixto JB. TRPA1 antagonists as potential analgesic drugs. Pharmacol Ther. 2012;133:189–204.
Kremeyer B, Lopera F, Cox JJ, et al. A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome. Neuron. 2010;66:671–80.
Waxman SG, Cummins TR, Dib-Hajj S, Fjell J, Black JA. Sodium channels, excitability of primary sensory neurons, and the molecular basis of pain. Muscle Nerve. 1999;22:1177–87.
Catterall WA, Goldin AL, Waxman SG. International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev. 2005;57:397–409.
Hains BC, Saab CY, Klein JP, Craner MJ, Waxman SG. Altered sodium channel expression in second-order spinal sensory neurons contributes to pain after peripheral nerve injury. J Neurosci. 2004;24:4832–9.
Craner MJ, Klein JP, Renganathan M, Black JA, Waxman SG. Changes of sodium channel expression in experimental painful diabetic neuropathy. Ann Neurol. 2002;52:786–92.
Dib-Hajj SD, Fjell J, Cummins TR, et al. Plasticity of sodium channel expression in DRG neurons in the chronic constriction injury model of neuropathic pain. Pain. 1999;83:591–600.
Black JA, Cummins TR, Plumpton C, et al. Upregulation of a silent sodium channel after peripheral, but not central, nerve injury in DRG neurons. J Neurophys. 1999;82:2776–85.
Devor M, Govrin-Lippmann R, Angelides K. Na + channel immunolocalization in peripheral mammalian axons and changes following nerve injury and neuroma formation. J Neurosci. 1993;13:1976–92.
Devor M, Wall PD, Catalan N. Systemic lidocaine silences ectopic neuroma and DRG discharge without blocking nerve conduction. Pain. 1992;48:261–8.
• Fischer TZ, Waxman SG. Familial pain syndromes from mutations of the NaV1.7 sodium channel. Ann NY Acad Sci. 2010;1184:196–207. Review of the inherited pain syndromes associated with mutations in the NaV1.7 sodium channel.
Dib-Hajj SD, Rush AM, Cummins TR, et al. Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons. Brain. 2005;128:1847–54.
Nilsen KB, Nicholas AK, Woods CG, Mellgren SI, Nebuchennykh M, Aasly J. Two novel SCN9A mutations causing insensitivity to pain. Pain. 2009;143:155–8.
Cox JJ, Reimann F, Nicholas AK, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006;444:894–8.
Cregg R, Momin A, Rugiero F, Wood JN, Zhao J. Pain channelopathies. J Physiol. 2010;588:1897–904.
•• Faber CG, Hoeijmakers JG, Ahn HS, et al. Gain of function Na(V) 1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol. 2012;71:26–39. First report suggestion that gain of functions NaV1.7 mutations may be present in idiopathic small-fiber neuropathies.
Hoeijmakers JG, Faber CG, Lauria G, Merkies IS, Waxman SG. Small-fibre neuropathies-advances in diagnosis, pathophysiology and management. Nat Rev Neurol. 2012;8:369–79.
Chattopadhyay M, Zhou Z, Hao S, Mata M, Fink DJ. Reduction of voltage gated sodium channel protein in DRG by vector mediated miRNA reduces pain in rats with painful diabetic neuropathy. Molecular pain. 2012;8:17.
Chattopadhyay M, Mata M, Fink DJ. Continuous delta-opioid receptor activation reduces neuronal voltage-gated sodium channel (NaV1.7) levels through activation of protein kinase C in painful diabetic neuropathy. J Neurosci Off J Soc Neurosci. 2008;28:6652–8.
Nassar MA, Baker MD, Levato A, et al. Nerve injury induces robust allodynia and ectopic discharges in Nav1.3 null mutant mice. Mol Pain. 2006;2:33.
Nassar MA, Levato A, Stirling LC, Wood JN. Neuropathic pain develops normally in mice lacking both Na(v)1.7 and Na(v)1.8. Mol Pain. 2005;1:24.
Ossipov MH, Lai J, King T, et al. Antinociceptive and nociceptive actions of opioids. J Neurobiol. 2004;61:126–48.
Pasternak GW. Molecular insights into mu opioid pharmacology: From the clinic to the bench. Clin J Pain. 2010;26 Suppl 10:S3–9.
Gimbel JS, Richards P, Portenoy RK. Controlled-release oxycodone for pain in diabetic neuropathy: A randomized controlled trial. Neurology. 2003;60:927–34.
Watson CP, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology. 1998;50:1837–41.
Watson CP, Moulin D, Watt-Watson J, Gordon A, Eisenhoffer J. Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy. Pain. 2003;105:71–8.
Raja SN, Haythornthwaite JA, Pappagallo M, et al. Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology. 2002;59:1015–21.
Rowbotham MC, Twilling L, Davies PS, Reisner L, Taylor K, Mohr D. Oral opioid therapy for chronic peripheral and central neuropathic pain. N Engl J Med. 2003;348:1223–32.
Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med. 2005;352:1324–34.
Gassner M, Ruscheweyh R, Sandkuhler J. Direct excitation of spinal GABAergic interneurons by noradrenaline. Pain. 2009;145:204–10.
Tzschentke TM, Christoph T, Kogel B, et al. (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties. J Pharmacol Exp Ther. 2007;323:265–76.
Bee LA, Bannister K, Rahman W, Dickenson AH. Mu-opioid and noradrenergic alpha(2)-adrenoceptor contributions to the effects of tapentadol on spinal electrophysiological measures of nociception in nerve-injured rats. Pain. 2011;152:131–9.
Christoph T, De Vry J, Tzschentke TM. Tapentadol, but not morphine, selectively inhibits disease-related thermal hyperalgesia in a mouse model of diabetic neuropathic pain. Neurosci Lett. 2010;470:91–4.
Schroder W, Vry JD, Tzschentke TM, Jahnel U, Christoph T. Differential contribution of opioid and noradrenergic mechanisms of tapentadol in rat models of nociceptive and neuropathic pain. Eur J Pain (London, England). 2010;14:814–21.
Daniels SE, Upmalis D, Okamoto A, Lange C, Haeussler J. A randomized, double-blind, phase III study comparing multiple doses of tapentadol IR, oxycodone IR, and placebo for postoperative (bunionectomy) pain. Curr Med Res Opin. 2009;25:765–76.
Hoy SM. Tapentadol extended release: in adults with chronic pain. Drugs. 2012;72:375–93.
Hartrick CT, Rozek RJ. Tapentadol in pain management: a mu-opioid receptor agonist and noradrenaline reuptake inhibitor. CNS drugs. 2011;25:359–70.
•• Schwartz S, Etropolski M, Shapiro DY, et al. Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo-controlled trial. Curr Med Res Opin. 2011;27:151–62. One of two pivotal randomized-withdrawal design trials demonstrating the efficacy of tapentadol ER in the treatment of painful diabetic peripheral neuropathy.
Katz NP, Adams EH, Benneyan JC, et al. Foundations of opioid risk management. Clin J Pain. 2007;23:103–18.
Martell BA, O'Connor PG, Kerns RD, et al. Systematic review: opioid treatment for chronic back pain: prevalence, efficacy, and association with addiction. Ann Intern Med. 2007;146:116–27.
Fink DJ, Wolfe D. Gene Therapy for Pain: A Perspective. Pain Manag. 2011;1:379–81.
•• Simonato M, Bennett J, Boulis NM, et al. (2013) Progress in gene therapy for neurological disorders. Nature reviews Neurology Overview of current issues and strategies in gene therapy for neurological disorders.
Wolfe D, Mata M, Fink DJ. Targeted drug delivery to the peripheral nervous system using gene therapy. Neurosci Lett. 2012;527:85–9.
Goins WF, Cohen JB, Glorioso JC. Gene therapy for the treatment of chronic peripheral nervous system pain. Neurobiol Dis. 2012;48:255–70.
Glorioso JC, Fink DJ. Herpes vector-mediated gene transfer in the treatment of chronic pain. Mol Ther Clin J Am Society Gene Ther. 2009;17:13–8.
• Fink DJ, Wechuck J, Mata M, et al. Gene therapy for pain: results of a phase I clinical trial. Ann Neurol. 2011;70:207–12. First gene therapy trial for neuropathic pain.
Matsumoto K, Nakamura T. Emerging multipotent aspects of hepatocyte growth factor. J Biochem. 1996;119:591–600.
Yang XM, Toma JG, Bamji SX, et al. Autocrine hepatocyte growth factor provides a local mechanism for promoting axonal growth. J Neurosci Off J Soc Neurosci. 1998;18:8369–81.
Gascon E, Gaillard S, Malapert P, et al. Hepatocyte growth factor-Met signaling is required for Runx1 extinction and peptidergic differentiation in primary nociceptive neurons. J Neurosci Off J Soc Neurosci. 2010;30:12414–23.
Ajroud-Driss S, Christiansen M, Allen JA, Kessler JA (2013) Phase 1/2 Open-label Dose-escalation Study of Plasmid DNA Expressing Two Isoforms of Hepatocyte Growth Factor in Patients With Painful Diabetic Peripheral Neuropathy. Molecular therapy : the journal of the American Society of Gene Therapy
Mantyh PW, Koltzenburg M, Mendell LM, Tive L, Shelton DL. Antagonism of nerve growth factor-TrkA signaling and the relief of pain. Anesthesiology. 2011;115:189–204.
Rotthier A, Baets J, Timmerman V, Janssens K. Mechanisms of disease in hereditary sensory and autonomic neuropathies. Nat Rev Neurol. 2012;8:73–85.
Capsoni S, Covaceuszach S, Marinelli S, et al. Taking pain out of NGF: a "painless" NGF mutant, linked to hereditary sensory autonomic neuropathy type V, with full neurotrophic activity. PLoSOne. 2011;6:e17321.
Obata K, Katsura H, Sakurai J, et al. Suppression of the p75 neurotrophin receptor in uninjured sensory neurons reduces neuropathic pain after nerve injury. J Neurosci Off J Soc Neurosci. 2006;26:11974–86.
Smeyne RJ, Klein R, Schnapp A, et al. Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene. Nature. 1994;368:246–9.
Crowley C, Spencer SD, Nishimura MC, et al. Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons. Cell. 1994;76:1001–11.
Indo Y. Genetics of congenital insensitivity to pain with anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV. Clinical, biological and molecular aspects of mutations in TRKA(NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor. Clin Auton Res. 2002;12 Suppl 1:I20–32.
Indo Y, Tsuruta M, Hayashida Y, et al. Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nat Genet. 1996;13:485–8.
Houlden H, King RH, Hashemi-Nejad A, et al. A novel TRK A (NTRK1) mutation associated with hereditary sensory and autonomic neuropathy type V. Ann Neurol. 2001;49:521–5.
McMahon SB, Bennett DL, Priestley JV, Shelton DL. The biological effects of endogenous nerve growth factor on adult sensory neurons revealed by a trkA-IgG fusion molecule. Nat Med. 1995;1:774–80.
McMahon SB. NGF as a mediator of inflammatory pain. Philos Trans R Soc B-Biol Sci. 1996;351:431–40.
Woolf CJ, Safieh-Garabedian B, Ma QP, Crilly P, Winter J. Nerve growth factor contributes to the generation of inflammatory sensory hypersensitivity. Neuroscience. 1994;62:327–31.
Gerber RK, Nie H, Arendt-Nielsen L, Curatolo M, Graven-Nielsen T. Local pain and spreading hyperalgesia induced by intramuscular injection of nerve growth factor are not reduced by local anesthesia of the muscle. Clin J Pain. 2011;27:240–7.
•• Lane NE, Schnitzer TJ, Birbara CA, et al. Tanezumab for the treatment of pain from osteoarthritis of the knee. N Engl J Med. 2010;363:1521–31. Proof-of-concept trial using antibody to NGF to treat pain due to osteoarthritis.
Ackermann PW (2012) Katz et al., efficacy and safety of tanezumab in the treatment of chronic low back pain [Pain 2011;152:2248–2258] and Hill, blocking the effects of NGF as a route to safe and effective pain relief - fact or fancy? [Pain 2011;152:2200–2201]. Pain 153: 1128–1129; author reply 1129–1131
Evans RJ, Moldwin RM, Cossons N, Darekar A, Mills IW, Scholfield D. Proof of concept trial of tanezumab for the treatment of symptoms associated with interstitial cystitis. J Urol. 2011;185:1716–21.
Acknowledgment
Roy Freeman has received grant support from the NIH.
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Roy Freeman has been a consultant for Pfizer, Eli Lilly, Abbott, Bristol-Myers-Squibb, Chelsea, GlaxoSmithKline, Sanofi-Aventis, Depomed, and Johnson & Johnson.
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This article does not contain any studies with human or animal subjects performed by any of the authors.
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Freeman, R. New and Developing Drugs for the Treatment of Neuropathic Pain in Diabetes. Curr Diab Rep 13, 500–508 (2013). https://doi.org/10.1007/s11892-013-0396-6
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DOI: https://doi.org/10.1007/s11892-013-0396-6