Opioid Tolerance and OpioidInduced Hyperalgesia

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Opioid Tolerance and Opioid-Induced Hyperalgesia

• David J. Clark

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Chronic Opioid Use Long-Term Difficulties

• Loss of Effect
• Advancing disease
• Analgesic tolerance
• Hyperalgesia

• Creation of Problems
• Side Effects
• CNS
• Gastrointestinal
• Sweating
• Physical Dependence
• Abuse, Addiction

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Opioid Tolerance(Does it matter?)

• Tolerance is relevant?
• Clinicians
• Bhamb et al. 2006, 61 of primary care physicians
  concerned about tolerance occurring when managing
  chronic pain
• Researchers, Clinical and Basic (5500
  publications, key words opioid tolerance)
• Drug manufacturers, Black Box warnings
• Tolerance is irrelevant?
• Pharmacological tolerance is not a significant
  determinant of opioid dosing requirements. South
  and Smith, 2001
• In terms of analgesic efficacy, clinically
  significant tolerance does not seem to be an
  issue for acute or cancer pain or in most
  patients with chronic pain. Auret and Schug,
  2005

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Analgesic Tolerance vs. Opioid-Induced
Hyperalgesia
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Analgesic Tolerance

• Pharmacokinetic etiologies
• Quantities and ratios of morphine and major
  metabolites (M6G, M3G)
• Pharmacodynamic etiologies
• Receptor density, efficiency
• Second messenger system alterations
• Target effector molecule alterations
• Diminished activity of antinociceptive circuits
• Enhanced activity of pronociceptive circuits

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Human Opioid Tolerance(Direct Studies, Chronic)
Athanasos et al. 2006
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Human Opioid Tolerance(Direct Studies, Chronic)
Chu et al., 2006
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Human Opioid Tolerance(Direct Studies, Acute)
Model Cold Pressor
Vinik et al. 1998
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Human Opioid Tolerance(Direct Studies, Acute)
Gustorff et al., Anesth Analg 2002
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Human Opioid Tolerance(Indirect Studies)

• Rapp et al. 1995
• 180 Control/180 CPOC patients having surgery
• Average CPOC pre-op daily parenteral morphine
  equivalent use 12.7mg
• Average Daily PCA Morphine
• Control CPOC
• 42.8mg 135.8mg
• CPOC pain scores were worse despite larger
  morphine use.
• Greater side effects including sedation (50) in
  CPOC group
• On-service approximately 3 times as long

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Human Opioid Tolerance(Indirect Studies)

• de Leon-Casasola et al., 1993
• 99 Control, 17 CPOC patients having major surgery
• Average pre-op opioid use 183mg
• Epidural bupivacaine/morphine post-op management
• Total epidural MSO4 137 vs. 44mg (CPOC vs.
  Control)
• Total IV breakthrough 48 vs. 10mg
• Length of therapy 218 vs. 76 hrs

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Human Opioid Tolerance(Indirect Studies)
Intraoperative opioid administration versus
postoperative opioid consumption

• Supporting
• Crawford et al. 2006
• Remifentanil vs. Morphine
• Guignard et al. 2000
• Remifentanil
• Chia et al. 1999
• Fentanyl
• Cooper et al. 1997
• Intrathecal fentanyl

• Refuting
• Cortinez et al. 2001
• Remifentanil
• Hansen et al. 2005
• Remifentanil/Epidural
• Higher 2 hr pain scores

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Human Opioid Tolerance(Indirect Studies)
Intrathecal morphine dose escalation in patients
with FBSS
Rainov et al., 2001
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Human Opioid Tolerance(Indirect Studies)
Fentanyl dose escalation in patients with chronic
non-malignant pain
Milligan et al., 2001
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Opioid Dose Escalation and Tolerance(Factors
Involved)

• Increasing Doses
• Advancing disease
• Tolerance
• Hyperalgesia

• Limiting Doses
• Better controlled pain
• Side effects
• Lack of efficacy
• Fear of addiction
• Cost
• Stigmatization

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Tolerance vs. Hyperalgesia
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Opioid-Induced Hyperalgesia(Historical
perspective)
when dependence on opioids finally becomes an
illness of itself, opposite effects like
restlessness, sleep disturbance, hyperasthesia,
neuralgia and irritability become manifest
Rossbach, Pflugers Archieve 1880
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Opioid-Related Hyperalgesia(Direct Studies,
Chronic)
Doverty et al., 2001
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Opioid-Related Hyperalgesia(Direct Studies,
Chronic)
Chu, Clark and Angst J Pain 2006
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Opioid-Related Hyperalgesia(Direct Studies,
Acute)
Remi (30min)
Remi (30min)
Model Electrical Pain/Hyperalgesia
Koppert et al. 2003
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Opioid-Related Hyperalgesia(Direct Studies,
Acute)
Model Heat/Capsaicin
Hood et al. 2003
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Opioid-Related Hyperalgesia(Direct Studies,
Acute)
Compton, Journal of Pain 2003
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Opioid-Related Hyperalgesia(Direct Studies,
Acute)
Angst et al., Pain 2003
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Opioid-Related Hyperalgesia(Direct Studies,
Chronic)
Galer et al., 2005
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Opioid-Related Hyperalgesia(Direct Studies,
Acute)
Koppert et al., 2006
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Tolerance and Opioid-Induced HyperalgesiaWhat
should we do in clinic?

• Inform
• Tolerance and hyperalgesia may reduce the
  efficacy of therapy.
• More pain might be experienced during or after
  surgical procedures.
• Follow
• Pain control, dose escalation
• Distribution of pain
• Consider
• Detoxification in certain circumstances

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Perioperative Management of Opioid Consuming
Patients

• Preoperative
• Identify, quantify, stabilize, collaborate
• Intraoperative
• Opioids doses, short versus long acting
• Adjuvants NSAIDS, ketamine, alpha-2, etc.
• Regional anesthesia
• Postoperative
• Opioids, adjuvants, regional analgesia
• Transition planning

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Tolerance and Opioid Related HyperalgesiaPeriope
rative Management

• Carroll, I.R., M.S. Angst, and J.D. Clark,
  Management of perioperative pain in patients
  chronically consuming opioids. Reg Anesth Pain
  Med, 2004. 29(6) p. 576-91.
• de Leon-Casasola, O.A., Cellular mechanisms of
  opioid tolerance and the clinical approach to the
  opioid tolerant patient in the post-operative
  period. Best Pract Res Clin Anaesthesiol, 2002.
  16(4) p. 521-5.
• 3. Mitra, S. and R.S. Sinatra, Perioperative
  management of acute pain in the opioid-dependent
  patient. Anesthesiology, 2004. 101(1) p. 212-27.

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Thank You