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Opioid Tolerance and Opioid-Induced Hyperalgesia. David J. Clark. Loss of Effect Advancing disease Analgesic tolerance Hyperalgesia. Creation of Problems Side Effects CNS Gastrointestinal Sweating Physical Dependence Abuse, Addiction. Chronic Opioid Use: Long-Term Difficulties.

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Presentation Transcript
chronic opioid use long term difficulties
Loss of Effect

Advancing disease

Analgesic tolerance


Creation of Problems

Side Effects




Physical Dependence

Abuse, Addiction

Chronic Opioid Use: Long-Term Difficulties
opioid tolerance does it matter
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

analgesic tolerance
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
human opioid tolerance direct studies acute
Human Opioid Tolerance(Direct Studies, Acute)

Model: Cold Pressor

Vinik et al. 1998

human opioid tolerance direct studies acute9
Human Opioid Tolerance(Direct Studies, Acute)

Gustorff et al., Anesth Analg 2002

human opioid tolerance indirect studies
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


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
human opioid tolerance indirect studies11
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

human opioid tolerance indirect studies12

Crawford et al. 2006

Remifentanil vs. Morphine

Guignard et al. 2000


Chia et al. 1999


Cooper et al. 1997

Intrathecal fentanyl


Cortinez et al. 2001


Hansen et al. 2005


Higher 2 hr pain scores

Human Opioid Tolerance(Indirect Studies)

Intraoperative opioid administration versus postoperative opioid consumption

human opioid tolerance indirect studies13
Human Opioid Tolerance(Indirect Studies)

Intrathecal morphine dose escalation in patients with FBSS

Rainov et al., 2001

human opioid tolerance indirect studies14
Human Opioid Tolerance(Indirect Studies)

Fentanyl dose escalation in patients with chronic non-malignant pain

Milligan et al., 2001

opioid dose escalation and tolerance factors involved
Increasing Doses

Advancing disease



Limiting Doses

Better controlled pain

Side effects

Lack of efficacy

Fear of addiction



Opioid Dose Escalation and Tolerance(Factors Involved)
opioid induced hyperalgesia historical perspective
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

opioid related hyperalgesia direct studies acute
Opioid-Related Hyperalgesia(Direct Studies, Acute)

Remi (30min)

Remi (30min)

Model: Electrical Pain/Hyperalgesia

Koppert et al. 2003

opioid related hyperalgesia direct studies acute21
Opioid-Related Hyperalgesia(Direct Studies, Acute)

Model: Heat/Capsaicin

Hood et al. 2003

tolerance and opioid induced hyperalgesia what should we do in clinic
Tolerance and Opioid-Induced Hyperalgesia:What 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
perioperative management of opioid consuming patients
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
tolerance and opioid related hyperalgesia perioperative management
Tolerance and Opioid Related Hyperalgesia:Perioperative 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.