Emerging Treatments for Chronic Pain

Emerging Treatments for Chronic Pain

Dickenson Anthony , Rahman Wahida
Published: BTG - FUTURE DIRECTIONS IN NEUROLOGY
download article

| More
dots

Pain can be classified as acute (rapid-onset) or chronic (outlasting the original insult by months/years). Chronic pain is different from acute pain in that therapies that provide transient pain relief do not resolve the underlying pathological processes maintaining the pain; therefore, it is not simply the duration of the pain that differentiates between acute and chronic pain, but also the inability of the body to heal itself. Thus, damaged tissues and nerves can provide continued inputs into the central nervous system that drive multiple changes at many levels of the pain-signaling pathways. Since pain is not only a sensory response but also an affective state, the pain produces a series of comorbidities such as fatigue, anxiety, and depression. These interact to produce impaired quality of life in chronic pain patients.

The signal interpreted as pain can be altered at many points along the pain pathway, providing a multitude of strategic targets for rational therapeutic intervention. However, despite the huge increase in our understanding of the cellular and molecular mechanisms that initiate and maintain maladaptive pain processing, chronic pain remains a huge unmet clinical need. The pharmacopeia of available drugs is effective in some chronic pain patients, but not all of the time, due to disease progression, low efficacy, and, more often, intolerable side effects. Thus, efforts need to continue to boost the pharmaceutical profile of available agents by improving efficacy, tolerability, and pharmacokinetics, in addition to developing new chemical entities to manage pain refractory to current drugs. This article will focus on some of the molecular mechanisms and targets that are currently attracting interest in chronic pain research.

Excitatory Mechanisms—Blocking Aberrant Activity

Voltage-gated Sodium Channel Blockers
Sodium channel (NaV) blockers such as local anesthetics, carbamazapine, etc. have been the mainstay of pain medicine for decades, producing anesthesia and analgesia by preventing action potential propagation; however, blocking conduction is not their only role. Three of the nine isoforms of the human sodium channel family, NaV 1.7, 1.8, and 1.9, are expressed selectively in damage-sensing peripheral neurons.1,2 Animal studies have demonstrated a role for these channels in mechanosensation. Accordingly, mechanical hypersensitive behaviors akin to allodynia (painful experience to innocuous stimulation, e.g. touch) and hyperalgesia (heightened pain experience to painful stimuli) seen in chronic pain models are attenuated in tissueselective knock-out mice lacking these selective pain-related channels.3

Aberrant activity in damage-sensing peripheral fibers following inflammation arises from the processes of peripheral sensitization, whereas clustering of these channels at the site of injury and neuroma after nerve injury is thought to be a major drive for the induction of disordered central processing.3 The newly dense distribution along the sensory neurone supports spontaneous firing of action potentials along the neurone in the absence of peripheral stimuli. Additionally, a concomitant upregulation of the embryonic NaV 1.3 occurs, whose biophysical properties and re-expression in adult neurones after nerve injury have been associated with increased neuronal excitability and neuropathic pain.4 However, a recent study has refuted its role in nerve-injury or chronic inflammatory pain,5 although its role in central neuropathic pain could be considered on the basis of its upregulation in thalamic nuclei.6 Pre-clinical data point to a major role for NaV 1.7 in acute and inflammatory pain states.7 Differential mutations in the encoding gene, SCN9A, have been linked to the intense burning pain in erythermelalgia patients, a congenital absence of pain perception, and reduced lidocaine effectiveness in some pain patients.8,9 Understanding the genetic basis for altered nociceptive profiles in chronic pain patients could lead to selective therapy on an individual basis.

12345next ›last »
References:
  1. Akopian AN, Sivilotti L,Wood JN, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons, Nature, 1996;379:257–62.
  2. Djouhri L, Newton R, Levinson SR, et al., Sensory and electrophysiological properties of guinea-pig sensory neurones expressing Nav 1.7 (PN1) Na+ channel alpha subunit protein, J Physiol, 2003;546:565–76.
  3. Wood JN, Ion channels in analgesia research, Handb Exp Pharmacol, 2007;329–58.
  4. Hains BC, Klein JP, Saab CY, et al., Upregulation of sodium channel Nav1.3 and functional involvement in neuronal hyperexcitability associated with central neuropathic pain after spinal cord injury, J Neurosci, 2003;23:8881–92.
  5. 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.
  6. Hains BC,Waxman SG, Sodium channel expression and the molecular pathophysiology of pain after SCI, Prog Brain Res, 2007;161:195–203.
  7. Nassar MA, Stirling LC, Forlani G, et al., Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain, Proc Natl Acad Sci U S A, 2004;101:12706–11.
  8. Drenth JP,Waxman SG, Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders, J Clin Invest, 2007;117:3603–9.
  9. Sheets PL, Jackson JO 2nd,Waxman SG, et al., A Nav1.7 channel mutation associated with hereditary erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity, J Physiol, 2007;581:1019–31.
  10. Jarvis MF, Honore P, Shieh CC, et al., A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat, Proc Natl Acad Sci U S A, 2007;104:8520–25.
  11. McGaraughty S, Chu KL, Scanio MJ, et al., A selective Nav1.8 sodium channel blocker, A-803467 [5-(4-chlorophenyl-N-(3,5- dimethoxyphenyl)furan-2-carboxamide], attenuates spinal neuronal activity in neuropathic rats, J Pharmacol Exp Ther, 2008;324:1204–11.
  12. Rauck RL, Shaibani A, Biton V, et al., Lacosamide in painful diabetic peripheral neuropathy: a phase 2 double-blind placebo-controlled study, Clin J Pain, 2007;23:150–58.
  13. Shaibani A, Biton V, Rauck R, et al., Long-term oral lacosamide in painful diabetic neuropathy: A two-year open-label extension trial, Eur J Pain, 2008.
  14. Beyreuther BK, Freitag J, Heers C, et al., Lacosamide: a review of preclinical properties, CNS Drug Rev, 2007;13:21–42.
  15. Thienel U, Neto W, Schwabe SK, Vijapurkar U, Topiramate in painful diabetic polyneuropathy: findings from three doubleblind placebo-controlled trials, Acta Neurol Scand, 2004;110:221–31.
  16. Vinik AI, Tuchman M, Safirstein B, et al., Lamotrigine for treatment of pain associated with diabetic neuropathy: results of two randomized, double-blind, placebo-controlled studies, Pain, 2007;128:169–79.
  17. Zhang SH, Blech-Hermoni Y, Faravelli L, Seltzer Z, Ralfinamide administered orally before hindpaw neurectomy or postoperatively provided long-lasting suppression of spontaneous neuropathic pain-related behavior in the rat, Pain, 2008.
  18. Matthews EA, Dickenson AH, Effects of spinally delivered Nand P-type voltage-dependent calcium channel antagonists on dorsal horn neuronal responses in a rat model of neuropathy, Pain, 2001;92:235–46.
  19. Saegusa H, Matsuda Y, Tanabe T, Effects of ablation of N- and R-type Ca(2+) channels on pain transmission, Neurosci Res, 2002;43:1–7.
  20. Williams JA, Day M, Heavner JE, Ziconotide: an update and review, Expert Opin Pharmacother, 2008;9:1575–83.
  21. Lu Y,Westlund KN, Gabapentin attenuates nociceptive behaviors in an acute arthritis model in rats, J Pharmacol Exp Ther, 1999;290:214–19.
  22. Donovan-Rodriguez T, Dickenson AH, Urch CE, Gabapentin normalizes spinal neuronal responses that correlate with behavior in a rat model of cancer-induced bone pain, Anesthesiology, 2005;102:132–40.
  23. Dooley DJ, Taylor CP, Donevan S, Feltner D, Ca2+ channel alpha2delta ligands: novel modulators of neurotransmission, Trends Pharmacol Sci, 2007;28:75–82.
  24. Xiao W, Boroujerdi A, Bennett GJ, Luo ZD, Chemotherapyevoked 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.
  25. Brown SM, Dubin AE, Chaplan SR, The role of pacemaker currents in neuropathic pain, Pain Pract, 2004;4:182–93.
  26. Chaplan SR, Guo HQ, Lee DH, et al., Neuronal hyperpolarization-activated pacemaker channels drive neuropathic pain, J Neurosci, 2003;23:1169–78.
  27. Luo L, Chang L, Brown SM, et al., Role of peripheral hyperpolarization-activated cyclic nucleotide-modulated channel pacemaker channels in acute and chronic pain models in the rat, Neuroscience, 2007;144:1477–85.
  28. Caterina MJ, Schumacher MA, Tominaga M, et al., The capsaicin receptor: a heat-activated ion channel in the pain pathway, Nature, 1997;389:816–24.
  29. Tominaga M, Caterina MJ, Malmberg AB, et al., The cloned capsaicin receptor integrates multiple pain-producing stimuli, Neuron, 1998;21:531–43.
  30. Westaway SM, The potential of transient receptor potential vanilloid type 1 channel modulators for the treatment of pain, J Med Chem, 2007;50:2589–96.
  31. Knotkova H, Pappagallo M, Szallasi A, Capsaicin (TRPV1 Agonist) therapy for pain relief: farewell or revival?, Clin J Pain, 2008;24: 142–54.
  32. Binshtok AM, Bean BP,Woolf CJ, Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers, Nature, 2007;449:607–10.
  33. Cortright DN, Krause JE, Broom DC, TRP channels and pain, Biochim Biophys Acta, 2007;1772:978–88.
  34. Frederick J, Buck ME, Matson DJ, Cortright DN, Increased TRPA1, TRPM8, and TRPV2 expression in dorsal root ganglia by nerve injury, Biochem Biophys Res Commun, 2007;358:1058–64.
  35. Fleetwood-Walker SM, Proudfoot CW, Garry EM, et al., Cold comfort pharm, Trends Pharmacol Sci, 2007;28:621–8.
  36. Childers WE Jr, Baudy RB, N-methyl-D-aspartate antagonists and neuropathic pain: the search for relief, J Med Chem, 2007;50: 2557–62.
  37. Brown DG, Krupp JJ, N-methyl-D-aspartate receptor (NMDA) antagonists as potential pain therapeutics, Curr Top Med Chem, 2006;6:749–70.
  38. Campbell-Fleming JM, Williams A, The use of ketamine as adjuvant therapy to control severe pain, Clin J Oncol Nurs, 2008;12:102–7.
  39. Gogas KR, Glutamate-based therapeutic approaches: NR2B receptor antagonists, Curr Opin Pharmacol, 2006;6:68–74.
  40. Imai A, Hizue M, Toide K, Synergy between a NR2B receptor antagonist DHQ and 3-methyl-gabapentin in mice with neuropathic pain, Eur J Pharmacol, 2008;588:244–7.
  41. Ossipov MH, Lai J, Malan TP Jr, Porreca F, Spinal and supraspinal mechanisms of neuropathic pain, Ann N Y Acad Sci, 2000;909: 12–24.
  42. Ossipov M, Lai J, Malan Jr T, et al., Tonic descending facilitation as a mechanism of neuropathic pain. In: Hansson P, Fields H, Hill R, Marchettini P (eds), Neuropathic Pain: Pathophysiology and Treatment. Progress in Pain Research and Management, Seattle: IASP Press, 2001;107–124.
  43. Vera-Portocarrero LP, Xie JY, Kowal J, et al., Descending facilitation from the rostral ventromedial medulla maintains visceral pain in rats with experimental pancreatitis, Gastroenterology, 2006;130: 2155–64.
  44. Suzuki R, Rahman W, Rygh LJ, et al., Spinal-supraspinal serotonergic circuits regulating neuropathic pain and its treatment with gabapentin, Pain, 2005;117:292–303.
  45. Rahman W, Suzuki R,Webber M, et al., Depletion of endogenous spinal 5-HT attenuates the behavioural hypersensitivity to mechanical and cooling stimuli induced by spinal nerve ligation, Pain, 2006;123:264–74.
  46. Suzuki R, Morcuende S,Webber M, et al., Superficial NK1- expressing neurons control spinal excitability through activation of descending pathways, Nat Neurosci, 2002;5:1319–26.
  47. Millan MJ, Descending control of pain, Prog Neurobiol, 2002;66: 355–474.
  48. Oatway MA, Chen Y,Weaver LC, The 5-HT3 receptor facilitates at-level mechanical allodynia following spinal cord injury, Pain, 2004;110:259–68.
  49. Suzuki R, Rahman W, Hunt SP, Dickenson AH, Descending facilitatory control of mechanically evoked responses is enhanced in deep dorsal horn neurones following peripheral nerve injury, Brain Res, 2004;1019:68–76.
  50. Donovan-Rodriguez T, Urch CE, Dickenson AH, Evidence of a role for descending serotonergic facilitation in a rat model of cancer-induced bone pain, Neurosci Lett, 2006;393:237–42.
  51. McCleane GJ, Suzuki R, Dickenson AH, Does a single intravenous injection of the 5HT3 receptor antagonist ondansetron have an analgesic effect in neuropathic pain? A double-blinded, placebo-controlled cross-over study, Anesth Analg, 2003;97:1474–8.
  52. Papadopoulos IA, Georgiou PE, Katsimbri PP, Drosos AA, Treatment of fibromyalgia with tropisetron, a 5HT3 serotonin antagonist: a pilot study, Clin Rheumatol, 2000;19:6–8. 53. Stratz T, Farber L, Varga B, et al., Fibromyalgia treatment with intravenous tropisetron administration, Drugs Exp Clin Res, 2001;27:112–18.
  53. Passmore GM, Selyanko AA, Mistry M, Aet al., KCNQ/M currents in sensory neurons: significance for pain therapy, J Neurosci, 2003;23:7227–36.
  54. Dost R, Rostock A, Rundfeldt C, The anti-hyperalgesic activity of retigabine is mediated by KCNQ potassium channel activation, Naunyn Schmiedebergs Arch Pharmacol, 2004;369:382–90.
  55. Munro G, Dalby-Brown W, Kv7 (KCNQ) channel modulators and neuropathic pain, J Med Chem, 2007;50:2576–82.
  56. Bautista DM, Sigal YM, Milstein AD, et al., Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels, Nat Neurosci, 2008;11:772–9/
  57. Alloui A, Zimmermann K, Mamet J, et al., TREK-1, a K+ channel involved in polymodal pain perception, Embo J, 2006;25:2368–76.
  58. Patel AJ, Honore E, Lesage F, et al., Inhalational anesthetics activate two-pore-domain background K+ channels, Nat Neurosci, 1999;2:422–6.
  59. Dickenson AH, Ghandehari J, Anti-convulsants and antidepressants, Handb Exp Pharmacol, 2007:145–77.
  60. Sindrup SH, Otto M, Finnerup NB, Jensen TS, Antidepressants in the treatment of neuropathic pain, Basic Clin Pharmacol Toxicol, 2005;96:399–409.
  61. Thacker MA, Clark AK, Marchand F, McMahon SB, Pathophysiology of peripheral neuropathic pain: immune cells and molecules, Anesth Analg, 2007;105:838–47.
  62. Tsuda M, Inoue K, Salter MW, Neuropathic pain and spinal microglia: a big problem from molecules in “small” glia, Trends Neurosci, 2005;28:101–7.
  63. Ledeboer A, Sloane EM, Milligan ED, et al., Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation, Pain, 2005;115:71–83.
  64. Mika J, Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness, Pharmacol Rep, 2008;60:297–307.
  65. Thacker MA, Clark AK, Bishop T, et al., CCL2 is a key mediator of microglia activation in neuropathic pain states, Eur J Pain, 2008.
  66. Abbadie C, Lindia JA, Cumiskey AM, et al., Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2, Proc Natl Acad Sci U S A, 2003;100:7947–52.
  67. Zhang J, Shi XQ, Echeverry S, et al., Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain, J Neurosci, 2007;27:12396–406.
  68. 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.
  69. Milligan ED, Sloane EM,Watkins LR, Glia in pathological pain: A role for fractalkine, J Neuroimmunol, 2008;198:113–20.
  70. Milligan ED, Soderquist RG, Malone SM, et al., Intrathecal polymer-based interleukin-10 gene delivery for neuropathic pain, Neuron Glia Biol, 2006;2:293–308.
  71. Sloane EM, Langer SJ, Jekich B, et al., Immunological priming potentiates non-viral anti-inflammatory gene therapy treatment of neuropathic pain, J Immunology, 2008; in press.
  72. Gardell LR,Wang R, Ehrenfels C, et al., Multiple actions of systemic artemin in experimental neuropathy, Nat Med, 2003;9: 1383–9.
  73. Wang R, King T, Ossipov MH, et al., Persistent restoration of sensory function by immediate or delayed systemic artemin after dorsal root injury, Nat Neurosci, 2008;11:488–96.
  74. Mendell LM, Albers KM, Davis BM, Neurotrophins, nociceptors, and pain, Microsc Res Tech, 1999;45:252–61.
  75. Halliday DA, Zettler C, Rush RA, et al., Elevated nerve growth factor levels in the synovial fluid of patients with inflammatory joint disease, Neurochem Res, 1998;23:919–22.
  76. neuropathy: what went wrong, what went right, and what does the future hold?, Int Rev Neurobiol, 2002;50:393–413.
  77. Sarchielli P, Alberti A, Floridi A, Gallai V, Levels of nerve growth factor in cerebrospinal fluid of chronic daily headache patients, Neurology, 2001;57:132–4.
  78. Sarchielli P, Mancini ML, Floridi A, et al., Increased levels of neurotrophins are not specific for chronic migraine: evidence from primary fibromyalgia syndrome, J Pain, 2007;8:737–45.
  79. Wild KD, Bian D, Zhu D, et al., Antibodies to nerve growth factor reverse established tactile allodynia in rodent models of neuropathic pain without tolerance, J Pharmacol Exp Ther, 2007;322:282–7.

Copyright® 2012 Touch Group PLC. All rights reserved.
Touch Neurology is for informational purposes and should not be considered medical advice, diagnosis or treatment recommendations.