Chronic Neuropathic Pain Modulators

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Chronic Neuropathic Pain Modulators

• Gray Dawson, MD, MBA, FAAFP
• LCDR, MC, USN
• Officer in Charge, Naval Branch Health Clinic,
  St. Mawgan, UK

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Overview

• What is Neuropathic Pain?
• Pain assessment adequate pain relief
• EBM of pain modulators
• TCAs
• SNRIs
• Anticonvulsants
• Opiates
• Topical agents
• Practice based recommendations

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Why Bother?

• Common problem
• Unclear evidence (at least in a 15 min appt)
• Difficult patients
• What they dont say I am having problems with
  my voltage gated sodium channels
• Drug seeking behavior vs. pain seeking behavior
• Physicians are not using the right medications1
• NSAIDs and SSRIs more than TCAs and
  Anticonvulsants
• State Medical Board requires CME on pain
  management

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What is Neuropathic Pain?

• Neuronal maintenance of pain either peripherally
  or in the central nervous system1
• Generally chronic in nature and less associated
  with inflammation
• Goal for relief is affecting the
  neurotransmitters involved (serotonin,
  norepinephrine, glutamate, GABA)

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Acute Pain vs. Chronic Pain

• Acute Pain
• Protective response to injury
• Results from injury or inflammation of somatic
  tissue (nociceptive)
• Treated with anti-inflammatory or analgesic
  medications

• Chronic Pain
• Often maladaptive response
• Nociceptive or neuropathic (neuronal maintenance
  of pain)
• Treated with medications that influence
  neurotransmitters

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Causes of Neuropathic Pain

• Diabetic Peripheral Neuropathy
• Post-herpetic Neuralgia
• Trigeminal Neuralgia
• Central Pain
• Painful Polyneuropathy
• HIV Polyneuropathy
• Phantom Limb Pain
• Post-surgical Neuropathic Pain

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Pain Assessment

• PQRST
• Functional assessment
• Emotional / relational / psychological /
  spiritual assessment
• Visual analog scale / numerical scales
• For pain assessment and relief of pain assessment

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Key Points in Pain Assessment

• Assess pain in your patients
• How bad is your pain today?
• What is the worst your pain has been since your
  last visit?
• How satisfied are you with your pain relief?
• How is your pain affecting your activities and
  relationships?
• Assess side effects
• Are you experiencing any problems from the
  medications you are on?

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Treating Chronic Pain

• Goal 100 relief of pain
• Problem most patients dont get there!

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Clinical Trial Measurements of Success

• Percent of patients with 50 or 70 reduction in
  pain
• Improvement in function
• Decrease in narcotic use
• Overall percent decrease in mean pain scores

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Problems with Studies

• Inconsistent pain rating scales
• Short duration of study
• True significance of results
• What does a mean pain scale difference of 5.6 to
  4.3 mean to the patient who still experiences
  daily pain?
• If a 50 reduction in pain is success, does my
  patient measure that as success?

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TCAs

• No FDA indication for neuropathic pain
• TCAs studied amitriptyline, imipramine,
  desipramine and nortriptyline
• NNT 3.6 (moderate pain relief in peripheral
  neuropathy)
• Amitriptyline is most studied (25-150 mg/d)
• NNT 1.3 (mod. pain relief in diabetic PN)
• NNT 2.7 (mod. pain relief in post-herpetic
  neuralgia)
• NNH 28 (major adverse event leading to withdrawal
  from the study)
• Higher the dose, greater the benefit

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TCAs Adverse Events

• Anticholinergic dry mouth, constipation,
  dizziness, blurred vision, and urinary retention
• Cardiac arrhythmias and sudden cardiac death
• Not recommended in patients over 60 y/o and those
  with CV disease (risk of prolonged QT syndrome)
• Amitriptylines risk
• Relative risk of 2.53 in doses of 300 mg/d
• Relative risk of 0.97 in doses less than 100 mg/d
• Others may be safer, but less well studied

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Serotonin-Norepinephrine Reuptake Inhibitors
(SNRIs)

• Duloxetine has FDA approval for peripheral
  neuropathy (venlafaxine does not)
• Antidepressants SNRIs studied duloxetine and
  venlafaxine
• Duloxetine 60 mg/d
• NNT 5.2 (mild-mod pain relief in diabetic PN)
• NNH 58
• Venlafaxine 150-225 mg/d
• NNT 4.6 (mild-mod pain relief in diabetic PN)
• NNH 16.2

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SNRIs Risk vs. Benefit

• Safer in elderly (65 y/o) than TCAs
• Significant bothersome side effects
• Duloxetine nausea, sweating, sleepiness, loss of
  appetite, constipation
• Venlafaxine nausea, sweating, sleepiness,
  dyspepsia, insomnia, impotence (5 men)
• No major life-threatening risks at recommended
  doses

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Gabapentin Pregabalin

• a2d-ligand anticonvulsants
• FDA Approved Uses
• Pregabalin for diabetic peripheral neuropathy and
  post-herpetic neuralgia
• Gabapentin for post-herpetic neuralgia
• Both are taken three times daily (compliance
  issues)
• Pregabalin 300 mg/d and 600 mg/d
• 100 mg TID or 200 mg TID
• Gabapentin 900 mg/d to 3600 mg/d
• 300 mg TID up to 1200 mg TID

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Pregabalin

• NNT of 3 to 7 depending on the study to get 50
  pain relief (approx 50 will get 50 regardless
  of dosage) for DPN or PHN
• No drug-drug interactions
• Relief in 1-4 weeks
• No significant difference between 300mg and 600
  mg/d until looking at NNT to get 70 pain relief
  (NNT difference is 9 patients at 600 mg/d)
• Significant side effects dizziness (27-39),
  sleepiness (24-27), edema (7-13), infections
  (15) but few quit because of them
• Greater side effects at the 600mg/d dose

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Gabapentin

• NNT of 3.7 to 4.1 for significant reduction in
  pain (peripheral neuropathy of PHN and diabetes)
• Side effects of dizziness and somnolence (10-15)
• Compared head to head, an average 1500mg/d
  gabapentin with 60mg/d amitriptyline, showed no
  difference in outcomes
• Very few discontinuations relative to placebo
• NNH is 20-40
• NNH withdrawal from the study due to side effect

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Carbemazepine and Oxcarbazepine

• Primarily beneficial in trigeminal neuralgia
• NNT of 1.8 (for moderate pain reduction in
  trigeminal neuralgia)
• No significant differences between the two meds
• Improved pain in diabetic PN, but overall weak
  efficacy
• Carbemazepine 200mg daily, increase by 200mg
  weekly to 400mg TID (1200mg/d)
• SEs dizziness, nausea, diploplia
• Rare aplastic anemia

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Lamotrigine

• Anti-seizure / bipolar med effective in diabetic
  and HIV peripheral neuropathy
• Effective dose is 200mg to 400mg
• Titration requires slow increases at 50mg every
  two weeks to avoid serious life-threatening skin
  reactions
• Actual threat is low (0.1 in post-marketing
  analysis)
• Slow titration delays effective pain control

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Opioids and Tramadol

• Side effects nausea 33 vs. 9, constipation 33
  vs. 10, drowsiness 29 vs. 12
• NNT 2 (opioids), 4 (tramadol) for neuropathic
  pain
• NNH (withdrawal from study) 16 (opioids)
• Issues of addiction / dependence
• Can be added to other therapies

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Topical Agents

• Capsaicin
• Minimally effective
• Relatively cheap and low risk
• Most useful in post-herpetic neuralgia
• Topical Lidocaine
• NNT of 4-6 (mild benefit), NNH 40
• Expensive, but low risk of side effects
• Most useful in post-herpetic neuralgia

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Others worth mentioning

• Topiramate
• Slight benefit over placebo to 50 vs. 34
  achieved a 30 reduction in pain (NNT 6.2)
• SEs diarrhea, somnolence, loss of appetite
• NNT 6 for reducing diabetic PN pain by at least
  30, but small studies and other studies suggest
  no significant benefit
• SSRIs very limited to no benefit
• Some studies suggest NNT 6-8, but usually
  inclusive of all antidepressants, not just SSRIs
• Valproate very limited to no benefit except
  possibly as secondary in PHN
• Benzodiazepines very limited to no benefit

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Caution or Avoid Use!

• SNRIs and TCAs together (incr. risk serotonin
  syndrome)
• Caution with tramadol and SNRIs or TCAs
• Meperidine mixed agonist-antagonist
• TCAs with cardiac disease, suicidality, glaucoma,
  or risk for falling
• Pregabalin and depression or falls risk
• If weight gain is an issue dont use TCA or
  pregabalin
• NSAIDs target for inflammatory conditions, not
  neuropathic pain

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Evidence Based Recommendations

• Diabetic and Poly-neuropathies
• First line TCA, gabapentin, and pregabalin
• Secondary lamotrigine, opioids, SNRI, tramadol
• Post-herpetic Neuralgia
• First line TCA, gabapentin, pregabalin, and
  topical lidocaine
• Secondary capsaicin, opioids, tramadol, valproate

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More Evidence Based Recommendations

• Trigeminal Neuralgia
• First line carbemazepine and oxcarbazepine
• Secondary surgery
• HIV Peripheral Neuropathy
• First line lamotrigine (though small studies and
  limited results, poor results with any other
  medication)

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References

• Argoff CE, et al. Consensus Guidelines Treatment
  planning and options. Mayo Clin Proc
  200681S12-S25.
• Attal N, et al. EFNS Task Force. EFNS
  guidelines on pharmacological treatment of
  neuropathic pain. Eur J Neurol
  2006131153-1169.
• Berger A, Dukes EM, Oster G. Clinical
  characteristics and economic costs of patients
  with painful neuropathic disorders. Journal of
  Pain. 20045143-149.
• Cruccu G, et al. EFNS guidelines on neuropathic
  pain assessment. Eur J Neurol 200411153-62.
• Eisenberg E, McNicol E, Carr DB. Opiods for
  neuropathic pain. Cochrane Database of
  Systematic Reviews 20063. Retrieved from
  http//www.cochrane.org/reviews/en/ab006146.html
  on 11Dec07
• Hadj Tahar, A. Pregabalin for peripheral
  neuropathic pain. Issues in Emerging Health
  Technologies 2005671-4.
• Hollingshead J, Dühmke RM, Cornblath DR. Tramadol
  for neuropathic pain. Cochrane Database of
  Systematic Reviews 20063.
• Institute for Clinical Systems Improvement
  (ICSI). Assessment and management of chronic
  pain. Bloomington (MN) Institute for Clinical
  Systems Improvement (ICSI) 2007. Retrieved from
  http//www.guideline.gov/summary/summary.aspx?doc_
  id10724nbr005586 on 11Dec07
• Khaliq W, Alam S, Puri N. Topical lidocaine for
  the treatment of postherpetic neuralgia. Cochrane
  Database of Systematic Reviews 20072.

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More References

• Maizels M, McCarberg B. Antidepressants and
  antiepileptic drugs for chronic non-cancer pain.
  Am Fam Phys 200571483-90.
• Mason L, et al. Systematic review of topical
  capsaicin for the treatment of chronic pain. BMJ
  2004328991-4.
• Moulin DE, et al. Pharmacologic management of
  chronic neuropathic pain. Consensus statement
  and guidelines from the Canadian Pain Society.
  Pain Research and Management 20071213-21.
• Saarto T, Wiffen PJ. Antidepressants for
  neuropathic pain. Cochrane Database of
  Systematic Reviews 20053. Retrieved from
  http//www.cochrane.org/reviews/en/ab005454.html
  on 11Dec07
• Wiffen PJ, McQuay HJ, Moore RA. Carbemazepine
  for acute and chronic pain. Cochrane Database
  Syst Rev 20053. Retrieved from
  http//www.cochrane.org/reviews/en/ab005451.html
  on 11Dec07
• Wiffen P, Collins S, McQuay H, Carroll D, Jadad
  A, Moore A. Anticonvulsant drugs for acute and
  chronic pain. Cochrane Database of Systematic
  Reviews 20053.
• Wiffen PJ, McQuay HJ, Edwards JE, Moore RA.
  Gabapentin for acute and chronic pain. Cochrane
  Database of Systematic Reviews 20053.
• Wiffen PJ, Rees J. Lamotrigine for acute and
  chronic pain. Cochrane Database of Systematic
  Reviews 20072.