Treating Chronic Pain with NMDA- Receptor Blockers

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Treating Chronic Pain with NMDA- Receptor Blockers

• Palliative Care Institute of Southeast Louisiana
• Hospice of St. Tammany

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Acute Pain

• Pathway for acute pain perception is conventional
• Duration is short
• Endorphins and enkephalins are released by CNS to
  block pain perception
• Opioids are effective for acute pain

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Changing from Acute to Chronic Pain

• Acute pain causes release of the neurotransmitter
  glutamate
• Glutamate binds to AMPA receptors in cells of the
  dorsal horn, which triggers pain signals to the
  CNS
• When AMPA receptors are over whelmed or burned
  out by repeated activation, changes occur in
  neural membranes which activate NMDA receptors.
• Activation of NMDA receptors marks the transition
  to chronic pain

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Consequences of NMDA receptor Activation

• Windup
• Neural Remodeling
• Activation of NK-1 Receptors
• Afferent becomes Efferent
• Neurogenic Inflammation

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Chronic Pain is a potentially fatal medical
disease. The general lack of understanding of how
persistent pain becomes magnified and ingrained
prevents many patients from receiving the level
of care that they need to regain control of their
lives and resume natural activities.
Brookoff, David,2000,U. Tenn
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Prescribing Opioids for Chronic Pain- General
Principles

• Use WHO pain ladder to select analgesic
• Around-the-clock, q. 3-4 hr.
• Assess frequently, adjust dose
• Add up total opioid taken q. 24hr.
• Select long-acting opioid q. 12 hr.
• Use short-acting opioid for breakthrough pain
  prn.
• Use one short- and one long-acting
• Reassess to titrate dose

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Drugs that block NMDA receptors

• Opioids
• Methadone
• Levorphanol
• Non-opioids
• Dextromethorphan
• Ketamine
• Amantadine
• Memantine

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Methadone

• Methadone, a synthetic opioid developed in 1940
  has been used worldwide for pain relief.
• The development of sustained-action morphine,
  oxycodone, and fentanyl in the 80s, promoted and
  marketed by commercial interests in the U.S,
  relegated methadone to use mainly in
  substance-abuse until recently.

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Advantages of Methadone

1. Long duration of action
2. Short initial distribution half-life
3. No active metabolites
4. No ceiling dose
5. NMDA receptor-blocker action in spinal cord
   (important in neuropathic and chronic pain)
6. Cost approx. 20-25/month( vs. 200-500/mo. for
   hydromorphone,sust.act. morphine,oxycodone,fentany
   l patch.

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Advantages (contd)

• Potency at least equal to morphine
• Oral, rectal absorption excellent
• Low incidence of side-effects
• Less constipating
• Lower incidence of tolerance
• Available for iv infusion use
• Most important,methadone is both a mu opioid
  agonist and an NMDA receptor antagonist as it
  relates to pain relief

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Disadvantages

• Stigma and association with substance-abuse
• Accumulation due to long and variable elimination
  half-life in some persons
• Said to be hard to convert to and from other
  opioids
• Fear of regulators
• Lack of education and experience

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Rationale for using Methadone in Chronic Pain

• Knowing the difference between acute and chronic
  pain
• Understanding the importance of NMDA receptor
  activation in chronic pain
• Efficacy of Methadone (and Levorphanol) as NMDA
  receptor blockers and mu opioid agents
• Conventional opioids ineffective for neuropathic
  pain
• Methadone is now the drug of choice for
  neuropathic pain
• Can rotate to methadone when tolerance to
  conventional opioids developes

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Uses of Methadone

• Complex chronic non-malignant pain, often
  low-dose (failed back, fibromyalgia,polyarthralgia
  s)
• Chronic neuropathic pain (post-herpetic,
  diabetic, phantom limb, causalgia)
• Cancer, either as first-line or when tolerance to
  other opioids developes

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Prescribing Methadone

• Methadone can be prescribed by any licensed
  physician. Be sure that the label directions
  state for chronic pain.
• Any pharmacist can dispense Methadone for chronic
  pain.
• Available as oral 5, 10, 40mg tabs.,and can be
  compounded as rectal suppos., oral concentrate
  sol. 20mg/ml, and for iv use.
• Document clinical picture thoroughly- in LA,
  stable patient to be seen at least q. 12
  wks.(this applies to all opioids)

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Changing to Methadone

• Pain control by other major opioid is
  unsatisfactory (poor relief or side-effects)
• Modalities used for neuropathic pain
  (anticonvulsants, tricyclics, conventional
  opioids) are ineffective
• Cost is a factor

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Low-dose Methadone Dosing Method

• R. Donlop (St. Christophers) begin with 2.5mg
  orally q. 30 min. prn until pain relief.
• Patients establish an effective dose and an
  effective dosing interval.
• Less likelihood of overdose or side-effects.
  Safe way to begin.

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Converting from Morphine to Methadone- Method of
Ripamonti

• Day 1 Give 2/3 of MS dose begin Methadone q.
  8hr (41 if MS30-90mg/day 61 if
  MS90-300mg/d. 81 if MSgt300mg/d.
• Day 2 Give 1/3 of MS dose continue Meth.
  increase dose if pain moderate or severe. Use
  short-acting opioid for breakthrough
• Day 3 No MS maintain Meth. Use 10 of Meth.
  daily dose as breakthrough. Titrate Meth. daily.

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Converting from Morphine to Methadone Method of
MorleyMakin

• Day 1 Stop Morphine commence fixed dose of
  Methadone q 3hr prn. Meth. Dose 1/10 of daily MS
  (maximum 30mg dose)
• Day 6 calculate avg. daily Meth. dose for days 4
  and 5. Give as b.I.d. dosing with breakthrough
  dose q 3hr prn. Increase dose as needed q 4-6
  days by 30-50.

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Levorphanol

• NMDA-receptor blocker and mu-opioid agonist
• 2 mg tablet equal to 8-15 mg morphine p.o
• Long half-life (6 hr)
• Recent published evidence combination with
  gabapentin effective in chronic neuropathic pain

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Non- Opioid NMDA-Receptor Blockers

• Ketamine- anesthetic used in sub-anesthetic iv or
  sq infusion for intractable neuropathic pain-
  also being tried locally in cream applied to skin
• Dextromethorphan- new SR oral capsule q 12 hr-
  may reduce need for big opioid dose

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Nonopioid NMDA-Receptor Blockers

• Amantadine developed for Parkinsonism,and
  effective blocking Influenza A, has potential in
  blocking pain transmission
• Memantine NMDA-blocker used in Europe for
  Alzheimers is being tried off-label for chronic
  pain

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From the literature

• 108 outpatients with cancer pain on opioids
• 103 successfully switched to methadone- oral q 8
  hrs.
• Significant reduction of pain
• Bruera,E et al, Proceedings of the 9th World
  Congress on Pain,2000,
• p. 957

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From the literature

• 52 prospective, consecutive patients with either
  uncontrolled cancer pain on opioids or
  intolerable side-effects switched to methadone.
• All had significant reduction of pain with less
  nausea, vomiting, constipation and drowsiness.
• Mercandante s et al, J of Clinical Oncology,
  2001 192898-2904

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Personal experience Prescribing Methadone
2001-2003

• Palliative Care Consults(total) 140
• Methadone for Chronic pain 88
• Significant pain relief 68 of 88
• Excellent relief( pain reduced from 7-10 to
  0-3) 50
• Fair relief (pain reduced to 4-6)
  18
• No benefit or side-effects 20
• ( Nausea 6, Sedation 12, Depression 2)

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Number of Analgesic Prescriptions United States
est. 2002 (millions)
Step 3
WHO Stepladder
Total 13.03 Morphine 3.67 Fentanyl
4.35 Meperedine 1.78 Hydromorphone
.77 Methadone 1.66 All others .08
Step 2
Total 173.32 Propoxyphene
28.94 Hydrocodone 91.83 Oxycodone
28.95 Codeine 22.61 Dihydrocodeine
0.32 Pentazocine 0.67
Step 1
Total 135.30 COX-2 52.94 Other
NSAIDs 65.98 Tramadol 16.38
Includes Fiorinal with codeine
combinations Source IMS Healths National
Prescription Audit (NPA) Retail Phcy., LTC M.O.
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Cost Comparison of Opioids ( 30 day supply)

• Duragesic Patch 25mcg/hr 140
• Duragesic Patch 100 mcg/hr 430
• Oxycontin 40 mg q 12 hr 250
• MS contin 60 mg q 12 hr 210
• Dilaudid 4 mg q 4 hr ATC 118
• Percocet 5 mg q 4 hr ATC 210
• Levorphanol 2 mg q 6 hr 120
• Methadone 10 mg q 8 hr 20

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Summary

• Exciting advances in better pain Rx
• Methadone and Levorphanol more effective in
  complex chronic pain and in neuropathic pain
• Less expensive, especially Methadone
• Difficulty in their use appears exaggerated
• Research ongoing for non-opioids