Skip to main content
Log in

Combination Therapy for Neuropathic Pain

A Review of Current Evidence

  • Review Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Neuropathic pain is a debilitating chronic condition that remains very difficult to treat. Recently, a number of clinical studies have compared the effectiveness of combination drug therapy with monotherapy for neuropathic pain treatment. In this article, we summarize up-to-date clinical studies of combination therapy for the treatment of both cancer- and non-cancer-related neuropathic pain. Despite a relatively small number of clinical studies on this topic, several positive indications have emerged. First, clinical studies using gabapentin (five positive trials) and pregabalin (five positive trials and one negative trial) in combination with an opioid, cyclo-oxygenase-2 inhibitor or antidepressant have shown positive responses greater than the respective monotherapies for pain related to diabetic neuropathy and post-herpetic neuropathy. Second, high-concentration (8%) topical capsaicin and a 5% lidocaine patch seem to be effective add-on therapies (a modality of combination therapy) for various neuropathic pain conditions. Third, combination therapy for cancer-related neuropathic pain has yielded only limited success based on a number of small-scale clinical studies.

While there are benefits of using combination therapy for neuropathic pain treatment, including better pain relief and reduced adverse effects, more clinical studies are required in order to (i) make head-to-head comparisons between combination and single-drug therapies, (ii) identify symptom-specific combination therapies for distinctive clinical neuropathic pain conditions, (iii) explore combination therapies that include non-drug modalities such as physical therapy, psychological coping and biofeedback to facilitate functional restoration and (iv) develop new and objective evaluation tools for clinical outcome assessment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II

Similar content being viewed by others

References

  1. Treede RD, Jensen TS, Campbell JN, et al. Neuropathic pain: redefinition and a grading system for clinical research purposes. Neurology 2008; 70(18): 1630–5

    Article  PubMed  CAS  Google Scholar 

  2. Willis Jr WD. Central nervous system mechanisms for pain modulation. Appl Neurophysiol 1985; 48(1–6): 153–65

    PubMed  Google Scholar 

  3. Dubner R, Hargreaves KM. The neurobiology of pain and its modulation. Clin J Pain 1989; 5 Suppl. 2: S1–4

    Article  PubMed  Google Scholar 

  4. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000; 288(5472): 1765–9

    Article  PubMed  CAS  Google Scholar 

  5. Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature 2001; 413(6852): 203–10

    Article  PubMed  CAS  Google Scholar 

  6. Woolf CJ, King AE. Dynamic alterations in the cutaneous mechanoreceptive fields of dorsal horn neurons in the rat spinal cord. J Neurosci 1990; 10: 2717–26

    PubMed  CAS  Google Scholar 

  7. Ren K, Hylden JL, Williams GM, et al. The effects of a non-competitive NMDA receptor antagonist, MK-801, on behavioral hyperalgesia and dorsal horn neuronal activity in rats with unilateral inflammation. Pain 1992; 50 Suppl. 3: 331–44

    Article  Google Scholar 

  8. Willis WD Jr. Role of neurotransmitters in sensitization of pain responses. Ann NY Acad Sci 2001; 933: 142–56

    Article  PubMed  CAS  Google Scholar 

  9. Mendell LM, Wall PD. Responses of single dorsal cord cells to peripheral cutaneous unmyelinated fibres. Nature 1965; 206: 97–9

    Article  PubMed  CAS  Google Scholar 

  10. Price DD, Hayes RL, Ruda M, et al. Neural representation of cutaneous aftersensations by spinothalamic tract neurons. Fed Proc 1978; 37 Suppl. 9: 2237–9

    Google Scholar 

  11. Kenshalo DR Jr, Leonard RB, Chung JM, et al. Responses of primate spinothalamic neurons to graded and to repeated noxious heat stimuli. J Neurophysiol 1979; 42: 1370–89

    PubMed  Google Scholar 

  12. Woolf CJ. Evidence for a central component of post-injury pain hypersensitivity. Nature 1983; 306 Suppl. 5944: 686–8

    Article  Google Scholar 

  13. Mao J, Mayer DJ, Hayes RL, et al. Spatial patterns of increased spinal cord membrane-bound protein kinase C and their relation to increases in 14C-2-deoxyglucose metabolic activity in rats with painful peripheral mononeuropathy. J Neurophysiol 1993; 70: 470–81

    PubMed  CAS  Google Scholar 

  14. Mao J, Mayer DJ, Price DD. Patterns of increased brain activity indicative of pain in a rat model of peripheral mononeuropathy. J Neurosci 1993; 13: 2689–702

    PubMed  CAS  Google Scholar 

  15. Zhuo M. Glutamate receptors and persistent pain: targeting forebrain NR2B subunits. Drug Discov Today 2002; 7: 259–67

    Article  PubMed  CAS  Google Scholar 

  16. Simone DA, Zhang X, Li J, et al. Comparison of responsesof primate spinothalamic tract neurons to pruritic and algogenic stimuli. J Neurophysiol 2004; 91: 213–22

    Article  PubMed  Google Scholar 

  17. Basbaum AI, Fields HL. Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. Annu Rev Neurosci 1984; 7: 309–38

    Article  PubMed  CAS  Google Scholar 

  18. Porreca F, Lai J, Bian D, et al. A comparison of the potential role of the tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2, in rat models of chronic pain. Proc Natl Acad Sci U S A 1999; 96 Suppl. 14: 7640–4

    Article  Google Scholar 

  19. Gebhart GF. Descending modulation of pain. Neurosci Biobehav Rev 2004; 27: 729–37

    Article  PubMed  CAS  Google Scholar 

  20. Sorkin LS, Westlund KN, Sluka KA, et al. Neural changes in acute arthritis in monkeys: IV. Time-course of amino acid release into the lumbar dorsal horn. Brain Res Brain Res Rev 1992; 17: 39–50

    CAS  Google Scholar 

  21. Porreca F, Ossipov MH, Gebhart GF. Chronic pain and medullary descending facilitation. Trends Neurosci 2002; 25: 319–25

    Article  PubMed  CAS  Google Scholar 

  22. Waxman SG, Dib-Hajj S, Cummins TR, et al. Sodium channels and pain. Proc Natl Acad Sci U S A 1999; 96: 7635–9

    Article  PubMed  CAS  Google Scholar 

  23. Watkins LR, Maier SF. Glia: a novel drug discovery target for clinical pain. Nat Rev Drug Discov 2003; 2 Suppl. 12: 973–85

    Article  Google Scholar 

  24. Sung B, Lim G, Mao J. Altered expression and uptake activity of spinal glutamate transporters after nerve injury contribute to the pathogenesis of neuropathic pain in rats. J Neurosci 2003; 23: 2899–910

    PubMed  CAS  Google Scholar 

  25. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev 2007; (4): CD005454

  26. Malanga G, Reiter RD, Garay E. Update on tizanidine for muscle spasticity and emerging indications. Expert Opin Pharmacother 2008; 9 Suppl. 12: 2209–15

    Article  Google Scholar 

  27. Sinatra R. The fentanyl HCl patient-controlled transdermal system (PCTS): an alternative to intravenous patient-controlled analgesia in the postoperative setting. Clin Pharmacokinet 2005; 44 Suppl. 1: 1–6

    Google Scholar 

  28. Sittl R. Transdermal buprenorphine in the treatment of chronic pain. Expert Rev Neurother 2005; 5 Suppl. 3: 315–23

    Article  Google Scholar 

  29. Kaplan KM, Brose WG. Intrathecal methods. Neurosurg Clin N Am 2004; 15 Suppl. 3: 289–96

    Article  Google Scholar 

  30. Simpson Jr RK. Mechanisms of action of intrathecal medications. Neurosurg Clin N Am 2003; 14 Suppl. 3: 353–64

    Article  Google Scholar 

  31. Bennett G Deer T Du Pen S et al.Future directions in the management of pain by intraspinal drug delivery. J Pain Symptom Manage 2000; 20 Suppl. 2: S44–50

    Article  PubMed  CAS  Google Scholar 

  32. Yaksh TL. Spinal pharmacology of pain and its modulation. Clin Neurosurg 1983; 31: 291–303

    PubMed  CAS  Google Scholar 

  33. Yaksh TL. New horizons in our understanding of the spinal physiology and pharmacology of pain processing. Semin Oncol 1993; 20(2 Suppl. 1): 6–18

    PubMed  CAS  Google Scholar 

  34. Yaksh TL. Spinal systems and pain processing: development of novel analgesic drugs with mechanistically defined models. Trends Pharmacol Sci 1999; 20 Suppl. 8: 329–37

    Article  Google Scholar 

  35. Coluzzi PH. Sublingual morphine: efficacy reviewed. J Pain Symptom Manage 1998; 16 Suppl. 3: 184–92

    Google Scholar 

  36. 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

    Article  PubMed  CAS  Google Scholar 

  37. Mao J, Gold MS, Backonja MM. Combination drug therapy for chronic pain: a call for more clinical studies. J Pain 2011; 12(2): 157–66

    Article  PubMed  CAS  Google Scholar 

  38. Gilron I, Max MB. Combination pharmacotherapy for neuropathic pain: current evidence and future directions. Expert Rev Neurother 2005; 5: 823–30

    Article  PubMed  CAS  Google Scholar 

  39. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain 2011; 152(3 Suppl. ): S2–15

    Article  PubMed  Google Scholar 

  40. Gilron I, Bailey JM, Tu D, et al. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. Lancet 2009; 374: 1252–61

    Article  PubMed  CAS  Google Scholar 

  41. Simpson DA. Gabapentin and venlafaxine for the treatment of painful diabetic neuropathy. J Clin Neuromuscul Dis 2001; 3(2): 53–62

    Article  PubMed  CAS  Google Scholar 

  42. Hanna M, O’Brien C, Wilson MC. Prolonged-release oxycodone enhances the effects of existing gabapentin therapy in painful diabetic neuropathy patients. Eur J Pain 2008; 12(6): 804–13

    Article  PubMed  CAS  Google Scholar 

  43. Gilron I, Bailey JM, Tu D, et al. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med 2005; 352(13): 1324–34

    Article  PubMed  CAS  Google Scholar 

  44. Rowbotham M, Harden N, Stacey B, et al. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 1998; 280: 1837–42

    Article  PubMed  CAS  Google Scholar 

  45. Gatti A, Sabato AF, Occhioni R, et al. Controlled-release oxycodone and pregabalin in the treatment of neuropathic pain: results of a multicenter Italian study. Eur Neurol 2009; 61(3): 129–37

    Article  PubMed  CAS  Google Scholar 

  46. Romanò CL, Romanò D, Bonora C, et al. Pregabalin, celecoxib, celecoxib, and their combination for treatment of chronic low back pain. J Orthop Traumatol 2009; 10(4): 185–91

    Article  PubMed  Google Scholar 

  47. Dworkin RH, Corbin AE, Young Jr JP, et al. Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology 2003; 60: 1274–83

    Article  PubMed  CAS  Google Scholar 

  48. Sabatowski R, Gálvez R, Cherry DA, et al., 1008-045 Study Group. Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomized, placebo-controlled clinical trial. Pain 2004; 109(1–2): 26–35

    Article  PubMed  CAS  Google Scholar 

  49. Zin CS, Nissen LM, O’Callaghan JP, et al. A randomized, controlled trial of oxycodone versus placebo in patients with postherpetic neuralgia and painful diabetic neuropathy treated with pregabalin. J Pain 2010; 11(5): 462–71

    Article  PubMed  CAS  Google Scholar 

  50. Baron R, Mayoral V, Leijon G, et al. Efficacy and safety of combination therapy with 5% lidocaine medicated plaster and pregabalin in post-herpetic neuralgia and diabetic polyneuropathy. Curr Med Res Opin 2009; 25(7): 1677–87

    Article  PubMed  CAS  Google Scholar 

  51. Backonja M, Wallace MS, Blonsky ER, et al., NGX-4010 C116 Study Group. NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomised, double-blind study. Lancet Neurol 2008; 7: 1106–12

    Article  PubMed  CAS  Google Scholar 

  52. Simpson DM, Brown S, Tobias J. Controlled trial of high-concentration capsaicin patch for treatment of painful HIV neuropathy. Neurology 2008; 70(24): 2305–13

    Article  PubMed  CAS  Google Scholar 

  53. McCleane G. Topical application of doxepin hydrochloride, capsaicin and a combination of both produces analgesia in chronic human neuropathic pain: a randomized, double-blind, placebo-controlled study. Br J Clin Pharmacol 2000; 49: 574–9

    Article  PubMed  CAS  Google Scholar 

  54. Gustin SM, Schwarz A, Birbaumer N, et al. NMDA-receptor antagonist and morphine decrease CRPS-pain and cerebral pain representation. Pain 2010; 151(1): 69–76

    Article  PubMed  CAS  Google Scholar 

  55. Siddall PJ, Molloy AR, Walker S, et al. The efficacy of intrathecal morphine and clonidine in the treatment of pain after spinal cord injury. Anesth Analg 2000; 91: 1493–8

    Article  PubMed  CAS  Google Scholar 

  56. Agrawal RP, Goswami J, Jain S, et al. Management of diabetic neuropathy by sodium valproate and glyceryl trinitrate spray:a prospective double-blind randomized placebo-controlled study. Diabetes Res Clin Pract 2009; 83(3): 371–8

    Article  PubMed  CAS  Google Scholar 

  57. Khoromi S, Cui L, Nackers L, et al. Morphine, nortriptyline and their combination vs. placebo in patients with chronic lumbar root pain. Pain 2007; 130(1–2): 66–75

    Article  PubMed  CAS  Google Scholar 

  58. Silver M, Blum D, Grainger J, et al. Double-blind, placebo-controlled trial of lamotrigine in combination with other medications for neuropathic pain. J Pain Symptom Manage 2007; 34(4): 446–54

    Article  PubMed  CAS  Google Scholar 

  59. Eichenberger U, Neff F, Sveticic G, et al. Chronic phantom limb pain: the effects of calcitonin, ketamine, and their combination on pain and sensory thresholds. Anesth Analg 2008; 106: 1265–73

    Article  PubMed  CAS  Google Scholar 

  60. Lynch ME, Clark AJ, Sawynok J, et al. Topical 2% amitriptyline and 1% ketamine in neuropathic pain syndromes: a randomized, double-blind, placebo-controlled trial. Anesthesiology 2005; 103: 140–6

    Article  PubMed  CAS  Google Scholar 

  61. Baron R. Neuropathic pain: a clinical perspective. Handb Exp Pharmacol 2009; (194): 3-30

  62. Zin CS, Nissen LM, Smith MT, et al. An update on the pharmacological management of post-herpetic neuralgia and painful diabetic neuropathy. CNS Drugs 2008; 22(5): 417–42

    Article  PubMed  CAS  Google Scholar 

  63. World Health Organization. Cancer pain relief with a guide to opioid availability. 2nd ed. Geneva: World Health Organization, 1996

    Google Scholar 

  64. Lussier D, Portenoy RK. Adjuvant analgesics in pain management. In: Doyle D, Hanks G, Cherny NI, et al. Oxford textbook of palliative medicine. 3rd ed. New York (NY): Oxford University Press, 2003: 349–78

    Google Scholar 

  65. Zech DFJ, Grond S, Lynch J, et al. Validation of World Health Organization guidelines for cancer pain relief: a 10-year prospective study. Pain 1995; 63: 65–76

    Article  PubMed  CAS  Google Scholar 

  66. Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: characteristics and impact in patients with cancer pain. Pain 1999; 81: 129–34

    Article  PubMed  CAS  Google Scholar 

  67. Twycross R, Wilcock A. Symptom management in advanced cancer. 3rd ed. Abingdon: Radcliffe Medical Press, 2001

    Google Scholar 

  68. Wall PD, Melzack R. Textbook of pain. 5th ed. Philadelphia (PA): Churchill Livingstone, 2005

    Google Scholar 

  69. Mercadante S, Arcuri E, Tirelli W, et al. Amitriptyline in neuropathic cancer pain in patients on morphine therapy: a randomized placebo-controlled, double-blind crossover study. Tumori 2002; 88(3): 239–42

    PubMed  CAS  Google Scholar 

  70. Goodchild CS, Nelson J, Cooke I, et al. Combination therapy with flupirtine and opioid: open-label case series in the treatment of neuropathic pain associated with cancer. Pain Med 2008; 9(7): 939–49

    Article  PubMed  Google Scholar 

  71. Kannan TR, Saxena A, Bhatnagar S, et al. Oral ketamine as an adjuvant to oral morphine for neuropathic pain in cancer patients. J Pain Symptom Manage 2002 Jan; 23(1): 60–5

    Article  PubMed  CAS  Google Scholar 

  72. Yomiya K, Matsuo N, Tomiyasu S, et al. Baclofen as an adjuvant analgesic for cancer pain. Am J Hosp Palliat Care 2009; 26(2): 112–8

    Article  PubMed  Google Scholar 

  73. Keskinbora K, Pekel AF, Aydinli I. Gabapentin and an opioid combination versus opioid alone for the management of neuropathic cancer pain: a randomized open trial. J Pain Symptom Manage 2007 Aug; 34(2): 183–9

    Article  PubMed  CAS  Google Scholar 

  74. Takahashi H, Shimoyama N. A prospective open-label trial of gabapentin as an adjuvant analgesic with opioids for Japanese patients with neuropathic cancer pain. Int J Clin Oncol 2010 Feb; 15(1): 46–51

    Article  PubMed  CAS  Google Scholar 

  75. Arai YC, Matsubara T, Shimo K, et al. Low-dose gabapentin as useful adjuvant to opioids for neuropathic cancer pain when combined with low-dose imipramine. J Anesth 2010 Jun; 24(3): 407–10

    Article  PubMed  Google Scholar 

  76. Kornhuber J, Bleich S, Wiltfang J, et al. Flupirtine shows functional NMDA receptor antagonism by enhancing Mg2+ block via activation of voltage independent potassium channels. J Neural Transm 1999; 106(9–10): 857–67

    Article  PubMed  CAS  Google Scholar 

  77. Virani A, Mailis A, Shapiro LE, et al. Drug interactions in human neuropathic pain pharmacotherapy. Pain 1997; 73(1): 3–13

    Article  PubMed  CAS  Google Scholar 

  78. Haanpää ML, Gourlay GK, Kent JL, et al. Treatment considerations for patients with neuropathic pain and other medical comorbidities. Mayo Clin Proc 2010; 85(3 Suppl. ): S15–25

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by National Institutes of Health (NIH) grants R01DE18214, R01DE18538 and P20DA26002 (to Dr Mao). Dr Vorobeychik has been a speaker bureau member for Eli Lilly and Forest Pharmaceuticals. The remaining authors have no conflicts of interest that are directly relevant to the content of this review.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lucy Chen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vorobeychik, Y., Gordin, V., Mao, J. et al. Combination Therapy for Neuropathic Pain. CNS Drugs 25, 1023–1034 (2011). https://doi.org/10.2165/11596280-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11596280-000000000-00000

Keywords

Navigation