Optimized treatment efficacy is an imperative need

Management of chronic severe pain

In routine clinical care settings, 50% of patients with chronic pain do not experience adequate pain relief.1

Therapeutic outcome is currently compromised by high rates of tolerability-related treatment discontinuations.2

Currently, pharmacological treatment of severe chronic pain is often ineffective.2

  • Because it is hard to maintain a balance between pain relief (analgesia) and tolerability of the medication.2
(1)
Galvez R. Variable use of opioid pharmacotherapy for chronic non-cancer pain in Europe: causes and consequences. Journal of Pain & Palliative Care Pharmacotherapy, 2009;23(4):346-356.
(2)
Varrassi G et al. Pharmacological treatment of chronic pain the need for CHANGE. Curr Med Res Opin 2010;26(5):1231-1245.

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The Vicious Circle in pharmacological management

The central Vicious Circle

The central Vicious Circle1:

  • Insufficient analgesic efficacy accompanied by acceptable tolerability leads to dosage increases
  • Higher dosages may result in effective analgesia – however, the risk of side effects also increases
  • When tolerability becomes unacceptable, the dose that provided effective analgesia has to be reduced again

The Vicious Circle in pharmacological management highlights the challenges in balancing adequate pain relief and acceptable tolerability.

The result: treatment discontinuation1

  • Chronic pain patients stop their opioid treatment more frequently due to adverse events (AEs) than due to lack of efficacy.
(1)
Varrassi G et al. Pharmacological treatment of chronic pain the need for CHANGE. Curr Med Res Opin, 2010, 26:1231-1245

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The Vicious Circle in pharmacological management

Tolerability limitations of classical opioids

The main reasons for treatment discontinuation with opioids are adverse events, especially gastrointestinal side effects (i.e. nausea, vomitting and consstipation) along with central nervous system (CNS) side effects.1

Therefore, negotiating these adverse effects remains an important clinical challenge. In this context, four different approaches to the management of opioid adverse effects have been reported:
  • Dose reduction of systemic opioid
  • Symptomatic management of the adverse effect
  • Opioid rotation (or switching)
  • Switching route of systemic administration
(1)
Kalso E et al. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain 2004;112(3):372-380

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The Vicious Circle lack of efficacy

Influence of drug-drug interaction on the Vicious Circle

The Vicious Circle and insufficient analgesia1

  • Insufficient analgesic efficacy which is accompanied by an acceptable tolerability leads to dose increase in order to achieve satisfactory pain relief.
  • Insufficient analgesia can also be evoked by e.g. drug-drug interactions or development of analgesic tolerance
  • Result may be treatment discontinuation!

Consequences in chronic pain treatment:

  • Insufficient analgesia (e.g., wrong substance, wrong dose, NP component, other reasons)
    • Dose↑
    • Tolerability↓
  • The Vicious Circle starts rotating
(1)
Varrassi et al. Pharmacological treatment of chronic pain - the need for CHANGE. Curr Med Res Opin 2010, 26(5):1231-1245

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The Vicious Circle side effects

The Vicious Circle and side effects

The Vicious Circle and side effects1:

  • Reasons for increased side effects include low tolerability, interactions or polymedication

An increased rate of side effects during analgesic treatment generally leads to dose reduction which turn reduces analgesic efficacy.

Primarily, side effects are related to the tolerability profile of the substance.

Embedded in the process of entire pain management other factors can increase the side effect rate: insufficient analgesia, drug-drug interaction, analgesic tolerance development.

Consequences in chronic pain treatment:

  • Increased rate of side-effects (e.g. low tolerability, interactions, polymedication, ...)
    • dose↓
    • analgesic efficacy↓
  • The Vicious Circle starts rotating
(1)
Varrassi et al. Pharmacological treatment of chronic pain - the need for CHANGE. Curr Med Res Opin 2010, 26(5):1231-1245

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The Vicious Circle treatment reliability (drug-drug interactions)

Pharmacodynamic drug-drug interactions

Factors limiting long-term treatment reliability include drug-drug interactions which may result in increased side effects or decreased analgesic efficacy

  • Pharmacodynamic drug-drug interactions1 starting the Vicious Circle
    • e.g. two co-administered substances can evoke cumulative effects → reduced tolerability
  • Pharmacokinetic drug-drug interactions1 starting the Vicious Circle:
    • Increase of serum concentration of substances that induce side effects and/or are toxic (red circle)
    • Reduction of serum concentration, leading to insufficient analgesic efficacy (green circles)

Drugs with a high potential for interaction may increase the risk for adverse effects.

(1)
Varrassi et al. Pharmacological treatment of chronic pain - the need for CHANGE. Curr Med Res Opin 2010, 26(5):1231-1245

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The Vicious Circle treatment reliability (analgesic tolerance)

Development of analgesic tolerance

Analgesic tolerance development1 means that a constant dose of a substance loses ist analgesic effect over time.

Besides the option to switch to another opioid (opioid rotation), the therapeutic reaction to this phenomenon is often a dose increase which in turn raises the risk of side effects.

Consequently, the vicious circle starts rotating.

Analgesic tolerance development, related dose instability and reduced treatment reliability may result in low compliance and treatment discontinuation, both indicators for the often occurring inefficiency of chronic pain treatment.

(1)
Varrassi et al. Pharmacological treatment of chronic pain - the need for CHANGE. Curr Med Res Opin 2010, 26(5):1231-1245

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Quick check

Which of the following statements about the Vicious Circle is not correct?
Insufficient analgesic efficacy often leads to dose increase
Dose increase may result in effective analgesia
Concurrently, dose increase is associated with decreased risk of side effects
When tolerability becomes unacceptable the dose often will be reduced again
Which factors trigger the Vicious Circle? I. Insufficient analgesia II. Side effects III. Analgesic tolerance development
All factors can trigger the Vicious Circle
Only the factors I. and II. can trigger the Vicious Circle
Only the factors II. and III. can trigger the Vicious Circle
Only the factors I. and III. can trigger the Vicious Circle
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Congratulations

Thank you for participating in the eighth basic module “Vicious Circle”. We hope you enjoyed it. The PAIN EDUCATION platform provides more eModules concerning pain therapy. If you like to, please continue with these eModules and check your knowledge.
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