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Management of Neuropathic Pain

Management of Neuropathic Pain. Mellar P Davis MASCC ,June 2009. Pharmacological treatment of neurologic pain relies on evidence from large randomized controlled trials. Attal 2006 Dworkin 2007.

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Management of Neuropathic Pain

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  1. Management of Neuropathic Pain Mellar P Davis MASCC ,June 2009

  2. Pharmacological treatment of neurologic pain relies on evidence from large randomized controlled trials Attal 2006 Dworkin 2007

  3. Despite advances in research and clinical trials, a considerable number of individuals do not get relief NNT- 3-5 for most drugs

  4. Response is defined as a “30-50% reduction in pain severity empiric drug trials – “trial and error” choices based on mechanism gulf between empiricism and mechanistic drug choices Baron 2006 Woolf 1998

  5. It is unclear which laboratory pain responses are most strongly associated with the experience of pain in daily life Edwards 2003

  6. Tools for Neuropathic Pain • Neuropathic pain questionnaire, Leeds assessment of neuropathic signs and symptoms Neuropathic Pain Symptom Inventory • Definite NP, possible NP, unlikely NP • Definite NP had greater pain intensity • Definite NP had greater opioid escalation index Mercadante 2009

  7. Differences Between Peripheral and Central Neuropathic Pain • Less evidence for central pain syndromes • Differences in drug classes (cannabinoids) • Central pain syndromes do not respond to peripheral blocks or ablative procedures • Motor cortex stimulation

  8. Pain Relief • 30-50% pain relief may not correlate with Patient Global Impression of change (PGIC) • Analgesia vs. function • Differential response on the several pain mechanisms found in a single individual • Allodynia • Burning C fiber pain • Spontaneous pain Baron 2006 Farrar 2001

  9. Pain Relief • Not “all or none” but continuous • Balance of pain relief, medication burden, side effects, QOL, function • Artifact to use binomial outcomes

  10. Dosage • Tolerable dose vs therapeutic dose (serum levels vs empiric recommendations) • Combinations may reduce the tolerable dose

  11. Duration • Maximum tolerable dose and duration of time to see maximum benefit • Pharmacodynamic optimal time for response is largely unknown • Maintenance period of 3 weeks, longer if suggested by RCTs • Drug specific • Poorly related to drug half-life • Challenge in neuropathic pain

  12. Treatment Paradigm • Drug classes proven by RCT TCA SNRI Alpha-2-delta ligands Opioids Topical lidocaine Sodium channel blockers • Monotonous (single drug)

  13. Peripheral neuropathic pain yes Postherpetic neuralgia and focal neuropathy no Lidocaine patch TCA contraindication yes no Gabapentin / pregabalin TCA (SNRI) TCA contraindication yes no TCA (SNRI) Gabapentin / pregabalin Tramadol, oxycodone

  14. ‘Numbers Need to Treat’ Calculated for Various Drug Classes in the Treatment of Painful Neuropathy SSRIs 6.7 Gabapentin 3.7 TCAs-NE 3.4 TCAs-5HT/NE 2 TCAs-5HT/NE* 1.4 0 2 4 6 8 *Optimal dose achieved. SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. Study by Sindrup and Jensen (1999)

  15. Pharmacoresistance • Pharmacorotation fails to produce response or produces intolerable side effects • Lowers QOL, increases symptoms • Expensive

  16. Definition of Pharmacoresistance “A neuropathic pain condition is resistant to pharmacotherapy when mono or a rational combination treatment using drugs proved efficacious in RCTs fails in inducing useful pain relief from the patients/physicians point of view after an appropriate duration of treatment with adequate dosage or if intolerable side effects occur” Hansson 2009

  17. Combination Therapy • Rationale-non-overlapping mechanism • Paucity of data • Polypharmacy, side effects • No data for central pain syndromes

  18. Polypharmacy • Gabapentin plus opioids • Gabapentin plus venlafaxine Gilron 2005 Hanna 2008 Simpson 2001

  19. Morphine, Gabapentin, or Their Combination for Neuropathic Pain Ian Gilron, M.D., Joan M. Bailey, R.N., M.Ed.,Dongsheng Tu, PhD., Ronald R. Holden, Ph.D., Donald F. Weaver, M.D., Ph.D., and Robyn L. Houlden, M.D.

  20. Mean Daily Pain 7 6 5 4 Score for Pain Intensity 3 2 1 0 Baseline Placebo Gabapentin Morphine Combination

  21. Maximal Tolerated Dose 2500 60 50 2000 40 1500 Dose (mg) 30 1000 20 500 10 0 0 Single agent combination Single agent combination Gabapentin Morphine

  22. The Involvement of Endogenous Opioid Mechanisms in the Antinociceptive Effects Induced by Antidepressant Drugs, Desipramine and Trimipramine Yusuf Özturk, Süleyman Aydin, Rana Beis, Tuba Herekman-Demir

  23. 20 16 10 Reaction Time (s) 8 4 0 Control 7.5 15 7.5 15 Desipramine Rats pretreated with Naltrindole (1mg/kg) Desipramine doses (mg/kg)

  24. More Efficacious Drugs • Lower side effect profiles • New classes (CB2 receptor agonists, anti-glia agents) • More trials of combination therapy • Rigorous studies of non-pharmacological measures Hansson 2009

  25. Non-TCA, SNRI Antidepressant: Mirtazapine • Therapeutic with initial dose • Pain control • Sleep, anxiety and appetite improvement • Fewer drug interactions • No QTc effects, hypertension • Anti-emetic • Tolerance to sedation • ? Tolerable in very advanced cancer • Combined with SNRI Sahin 2008 Evsoy 2008 Kim 2008 Hannan 2007

  26. 20 Withdrawal duration (s) 10 0 Vehicle Amitriptylline 3 mgkg Vehicle Mirtazapine 3 mgkg 12 Amitriptylline 10 mgkg Amitriptylline 30 mgkg Mirtazapine 10 mgkg Mirtazapine 30 mgkg Withdrawal latency (s) 6 0 Base 1 Base 2 30 60 90 120 180 Base 1 Base 2 30 60 90 120 180 Time (min) Time (min)

  27. Combinations • NSAIDs plus alpha-2-delta ligand • Opioid plus minocycline (anti-glia) • CB2 agonist plus opioid (anti-glia) • (+) opioid antagonists (anti-glia) • etodolac

  28. Glia and Opioids: Minocycline • Attenuates morphine induced respiratory depression • Reduces conditioned place preference • Potentiate morphine analgesia • Blocks morphine induced upregulation of Cox-1 Hutchinson 2008

  29. Etodolac Attenuates Mechanical Allodynia in a Mouse Model of Neuropathic Pain Naoki Inoue, Sunao Ito, Koyuki Tajima, Masaki Nogawa Yosuke Takahashi, Takahiro Sasagawa, Akio Nakamura, and Takashi Kyoi

  30. Effect on Mechanical Allodynia in PSNL Mice 0.8 Control Etodolac 10 mg/kg Indomethacin 1 mg/kg Celecoxib 30 mg/kg 0.6 0.4 PWT (g) ** ** ** ** 0.2 * ** ** 0.0 Day 0 Pre 1h 4h Pre 1h 4h Pre 1h 4h Day 7 Day 14 Day 21 Time after administration Each symbol represents the mean PWT for 10 mice. Drugs were administered orally once a day for two weeks from seven days after PSNL. *P<0.05, **P<0.01 (vs. control, Steel test).

  31. Opioid Induced Hyperalgesia • Quantitative sensory testing • Reduced heat pain thresholds • Exacerbated temporal summation of a second pain • Dose effect • Opioid tolerance • Narrow therapeutic window Chen 2009

  32. Altered Quantitative Sensory Testing Outcome in Subjects with Opioid Therapy Lucy Chen, Charlene Malarick, Lindsey Seefeld, Shuxing Wang, Mary Houghton,Jianren Mao

  33. Exacerbated Temporal Summation of the Second Pain in Group 3 Subjects 500 * Group 1 Group 2 Group 3 400 * 300 * Increase in VAS (%) 200 100 0 S1/BL S2/BL S3/BL *P<0.05, as compared with group 1 and group 2 subjects. S1/BK, S2/BL, S3/BL: the percent increase in VAS (visual analogue scale) score in response to the second, third, and fourth stimulation over that of the first stimulation in a train of four noxious heat (47°C) stimuli.

  34. Different Profiles of Buprenorphine Induced Analgesia and Antihyperalgesia in a Human Pain Model Wolfgang Koppert, Harald Ihmsen, Nicole Körber, Andreas Wehrfritz, Reinhard Sittl, Martin Schmelz, Jürgen Schüttler

  35. Antihyperalgesia Analgesia Ratio Buprenorphine i.v. 2.6 (0.8-3.8) Buprenorphine s.i. 1.9 (-0.1-8.1) Fentanyl i.v. 0.6 (-0.3-2.2) Alfentanil i.v. 0.3 (-0.3-0.5) S-ketamine i.v. 5.5 (3.1-6.1) 100 75 50 25 0 25 50 Effect (%)

  36. Chronic Morphine Administration Enhances Nociceptive Sensitivity and Local Cytokine Production After Incision DeYong Liang, Xiaoyou Shi, Yanli Qiao, Martin S Angst, David C. Yeomans, and J David Clark

  37. Saline Chronic Morphine Saline / Incision Chronic Morphine / Incision 1200 IL-1 900 pg/mg Protein 600 300 0 600 TNF 450 pg/mg Protein 300 150 0 2h 24h 72h Time after Incision

  38. 2.0 Saline prior to incision MSO4 prior to incision Paw Withdrawal Threshold (g) 1.0 0.0 Baseline - + - + PTX

  39. Alternative Medications • Melatonin • S-adenosyl methionine • L-carnitine • Vitamin D

  40. Neuropathic Pain: Seed or Soil • Individuals differ widely in their ability to moderate pain • Range from substantial inhibition to substantial facilatation • Diffuse noxious inhibitory controls (DNIC)

  41. Diffuse Noxious Inhibitory Control • Ability to modulate phasic pain when experiencing chronic pain • Supraspinal generated inhibition of spinal wide dynamic range neuron • Reduced in fibromyalgia, temporomandibular disorder, irritable bowel syndrome

  42. Diffuse Noxious Inhibitory Control • Reduced with age • Influenced by certain domains of quality of life • ? premorbid background to neuropathic pain syndrome • ? Improved by non-pharmacologic approaches to pain • ? Altering pain catastrophizing Edwards 2003 Goodin 2009

  43. Individual Differences in Diffuse Noxious Inhibitory Control (DNIC): Association with Clinical Variables Robert R. Edwards, Timothy J Ness, Douglas A Weigent, Roger B Fillingim

  44. Scores on SF-36 Subscales (mean ± SD) SF-36 subscales Younger (n = 37) Older (n = 37) General health (0-100) 79.1 ± 13.8 77.6 ± 18.2 Physical functioning (0-100) 93.2 ± 19.2* 84.6 ± 15.4 Physical role (0-100) 95.3 ± 15.4* 81.1 ± 31.7 Bodily pain (0-100) 76.2 ± 16.5 73.7 ± 16.1 Age groups differ at *P<0.05. Higher SF-36 subscale score represents better functioning (e.g. less pain, better health).

  45. Younger Adults Older Adults DNIC + (n=24) DNIC - (n=13) DNIC + (n=11) DNIC - (n=26) 100 90 80 70 60 50 Younger Older Younger Older Younger Older Younger Older BP* PF* PR GH

  46. Catastrophizing • Interferes with the endogenous opioid system • Distraction which mobilizes the endogenous opioid system is less effective in high catastrophizing individuals • Catastrophizing produces a pro-inflammatory response • Interact with pain genotype (COMT) as a predictor for high pain sensitivity Campbell 2009 Weissman-Fogel 2008 George 2008

  47. Associations Between Catastrophizing and Endogenous Pain Inhibitory Processes: Sex Differences Burel R Goodin, Lynanne Mcguire, Mark Allshouse, Laura Stapleton, Jennifer A Haythornthwaite, Noel Burns, Lacy A Mayes, and Robert R Edwards

  48. DNIC a B* In vivo catastrophizing SF-MPQ pain ratings c’

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