Opioid Induced Hyperalgesia

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Opioid Induced Hyperalgesia

• Jill Mosby, MD
• June 18th 2008

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History OIH

• 1880 Rossbach When dependence on opioids
  finally becomes an illness of itself, opposite
  effects like restlessness, sleep disturbance,
  hyperesthesia, neuralgia, and irritability become
  manifest 2

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History OIH

• Six decades later Himmelsbach described opioid
  abstinence syndrome aching in bones, joints,
  muscles is probably the most common withdrawal
  symptom 2

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Definitions

• Analgesia
• absence of sense of pain
• Nociceptive
• Causing pain
• Agonist
• a chemical substance capable of activating a
  receptor to induce a full or partial
  pharmacological response
• Antagonist
• a drug that counteracts the effects of another
  drug

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More definitions

• TOLERANCE
• Exposure to a drug induces changes that cause
  decreased response to drugs effects over time
• Can develop quickly or slowly
• Cross tolerance can occur (ie with opioids)
• SENSITIZATION
• A form of nonassociative learning characterized
  by an increase in responsiveness upon repeated
  exposure to a stimulus

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Standard Risks of Opioid

• Physical dependence
• Tolerance
• Addiction
• Overdose
• Typical side effects
• ? Opioid Induced Hyperalgesia

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Opioid Induced Hyperalgesia

• Enhanced pain response to a noxious stimulus
• Evidence for changes/ source in spinal cord and
  brain
• AKA Opioid Neurotoxicity

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Types of OIH

• Maintenance therapy and withdrawal (MW)
• Very high dose, or escalating dose (HD)
• Ultra-low dose (LD)

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Early evidence OIH MW Rodent Studies Summery

• Rodents mice, rats, guinea pigs
• gt 75 studies since 1970s
• Multiple opioids (Morphine, Fentanyl, Heroin,
  experimental)
• Multiple routes (IT/SQ/IV/PO/IP)
• Time frame of OIH hours, days, or longer
• Pain threshold measured Mechanical, Electrical
  or Thermal stimuli

This must not be one of the experimental
ratsits too happy!
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Rat studies during opioid exposure
Vanderah et al, J Neurosc 2001 Angst (chart)
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Rats Persistent hyperalgesia
Celerier et al, J Neurosc 2001 Angst (chart)
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Rats Persistent hyperalgesia
Celerier et al, J Neurosc 2001 Angst (chart)
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Celerier et al, J Neurosc 2001
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Acute hyperalgesia after isolated exposure
Celerier et al, Anes 2000 Angst (charts)
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Mechanisms studied OIH-MW

• Opioid receptors Mu receptor ?
• NMDA antagonist (ketamine, MK-801) ?
• NMDA activation ?
• PKC inhibition ?
• IT glutamate/ substance P ?
• Spinal EAA (increase in chronic opioid use) ?
• IT Cyclooxygenase inhibitors (NSAID) ?
• Spinal dynophin ?
• Spinal cytokines ?
• IT GM1 ganglioside ?
• Dorsal horn Fos-C ?
• Hemoxygenase nitric oxide synthase inhibitors ?
  

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Evidence for MW in humans

• Human studies former opioid addicts
• Maintained on methadone vs. no maintenance
• Show increased sensitivity to some types of pain

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OIH MW

• Surgery pts, volunteer
• High vs. low/no opioid dose intraop
• Increased postop pain, opioid use in pts received
  high dose

Angst Anesth 2006
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Chronic Pain Patients

• 6 Pts chronic back pain gt6 months
• Started on LA morphine
• ? Tolerance Threshold of CPP
• Pain scores ? 30
• Secondary outcomes not changed

Angst J Pain 2006
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OIH MW

• Human volunteers
• Capsaicin-heat for mechanical pain
• Pain ? remifentanil
• Pain allodynia ? after infusion

Wood, Anesth Analg
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Clinical significance of MW

• Argues acute chronic opioid use may have new
  risk OIH (MW)
• Opioids may worsen initial pain ? sensitivity
  to other sources of pain
• Query NMDA antagonists future role help prevent
  OIH

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OIH LD Animal Studies

• Animal studies opioid 1000x lower normal dose
  OIH to mechanical thermal
• Locally injected LD?hyperalgesia Normal
  dose?antinociceptic
• Both reversed with antagonist
• Theory LD opioid trigger excitatory signaling
  cascade

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OIH LD in Humans

• 1940s study biphasic response to morphine in
  7/57 former addicts. Mild hyperalgesia to heat
  at low dose, analgesia at high dose.
• 1979 study showed LD opioid antagonist had
  improved post op pain, but was not confirmed
  repeat studies
• No controlled studies in humans

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OIH HD in Animal studies

• IT morphine 10x normal scratching/ biting/
  aversion to touch, not resolved with naloxone
• IT strychnine allodynic/ hyperalgesic
• Spinal cord EP studies HD opioids act similar to
  IT Strychnine
• IT injected Glycine attenuates allodynia

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OIH HD in Animal Studies

• 33 opioid related structures studied,
  characteristic of chemicals produce allodynia/
  hyperalgesia
• Phenantrene structure
• Hydrogen at position 14
• Ether bond
• One or no methyl group on nitrogen
• Free 3-OH position ro glucuronide/sulfate
  conjugate

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OIH HD in humans

• Nine case reports pts with allodynia
• 22 pts, 8 had myoclonus
• Most patients morphine
• Routes PO, IV, IT
• Reducing dose opioid or rotation resolved/
  reduced sx in 21/22 pts
• This is the OIH that is seen clinically in
  palliative care, ? Rad-Onc

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OIH HD Clinical Picture

• Severe allodynia
• Intractable, escalating pain on HD/ED opioid
• lt 50 myoclonus (?), more at rest
• Delirium, mental status changes
• Increased doses caused ? pain
• Can lead to sz, coma, death
• Reducing dose or rotating opioid reversed sx in
  almost all patients

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Culprit Medications

• Morphine is most common
• most used opioid
• Dilaudid
• Oxycodone
• Less often fentanyl or methadone
• I have seen clinically this year

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Mechanism HD

• Phenantrene structure linked
• NMDA linked, with effects on excitatory signals
  in CNS
• ? Metabolites of opioid (Morphine-3-glucuronide),
  this is less discussed in literature

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Phenantrene ring
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Barriers to Treatment

• Clinicians often do not know about, recognize, or
  understand OIH
• Family/ patients understanding How can my
  Morphine do harm?
• Both groups need education

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Management of HD

• Pain controlled/ mild ? opioid dose
• Uncontrolled pain ? dose adjuvant OR rotate to
  non-phenantrene opioid
• Benzodiazapines
• Fluids
• Educate

Davis M, Walsh D
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Bottom Line

• Future of pain control will be greatly influenced
  by this area of research
• Peripheral nerves, spinal cord CNS all involved
  in OIH
• Chronic pain could be worsened by acute and
  ongoing opioid therapy

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Bottom Line (contd)

• For Patients with resistant/ escalating pain,
  hyperalgesia should be considered
• OIH (HD) treat with decreased opioid dose or
  rotation to another opioid
• I hope this has given some insight into some of
  the challenges in treating pain
• I hope this helps you recognize OIH (HD)

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Questions to ponder

• Opioid tolerance hyperalgesia linked?
• Worsening chronic non-malignant pain?
• Are there genetic differences that cause OIH MW
  HD?
• What is on horizon to help HD OIH? Ketamine like
  medication?

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Bibliography

• Angst MA, Clark JD Opioid induced hyperalgesia.
  Anesth 2006 104 570-87
• Mercandante S, Ferrera P, et al Hyperalgesia an
  emerging Iatrogenic Syndrome. J Pain and Sympt
  Management 2003 2 769-775
• Davis MP, Shaiova LA, Angst MS When opioids
  cause pain. 2007 25 4497-4498
• Chang G, Chen L, Mao J Opioid tolerance and
  hyperalgesia. 2007 91 199-211

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Bibliography

• Ballantyne JC, et all Opioid Induced
  Hyperalgesia. Pain Clinical Updates 2008 16
  1-4
• Celerier E, Rivat C, et al Long-lasting
  Hyperalgesia Induced by Fentanyl in Rats. Anesth
  2001 92 465-72
• Celerier E, Laulin JP, et al Progressive
  Enhancement of Delayed Hyperalgesia Induced by
  Repeated Heroin Administration a Sensitization
  Process. J Neurosc 2001 21 4074-80
• Chu LF, Clark DJ, et al Opioid Tolerance and
  Hyperalgesia in Chronic Pain Patients after one
  month of oral morphine therapy a preliminary
  prospective study. J Pain 2006 743-48
• Hood DD, Curry R, Eisenach JC Intravenous
  remifentanyl produces withdrawal hyperalgesia in
  volunteers with capsaicin-induced hyperalgesia.
  Anesth Analg 2003 97 810-5