Event 1: Opioids for the Treatment of Pain - Global and Local Perspectives

Pain is a Global Problem

  •  Cancer is a major cause of pain globally
  •  HIV is a major cause of pain globally
  •  OA (knee especially) is a major chronic pain source
  • Access to pain medications is severely limited in developing countries*
  • Morphine is a WHO essential medicine, policies represent a major barrier to availability of even miniscule quantities
  • U.S. Pharmacies in areas of socioeconomic disadvantage stock fewer opioids, limiting access to medications that control cancer pain.

Cancer and Pain

  • Pain effects 70% of cancer patients
  • Patient fear dying in pain
  • Diagnostic tools are available in the developed world to: identify causes of pain and plan effective treatments
  • Cancer pain arises from:
  • Bone, nerve, viscera
  • Effects of treatment: surgery, radiation and chemotherapy
  • Therapies are available in the developed world but under-utilized, essential therapies are very limited for much of the developing world population.
  • Opioids are a mainstay of therapy

Access to Opioids Varies by Location

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Access to opioids is varied
Varied access to opioids

Opioid Delivery Methods

Oral Administration Preferred (‘By the Mouth’)

  • I.V.: requires access, pump, trained personnel
  • Intramuscular: short-term relief, painful
  • Rectal: short-term relief, socially stigmatized
  • Subcutaneous: single injections or pump
  • Transbuccal: rapid onset, rapid offset
  • Transdermal: limited to highly lipid soluble agents, slow to titrate, sudden release when heated
  • Intrathecal/epidural: requires catheter, pump, personnel,

Approach to the Cancer Patient with Pain

  • Determine the cause (etiology) of the pain, some causes require specific treatments
  • Increase dose of short-acting opioids in order to
  • Ascertain if pain is responsive to opioids
  • Determine the approximate dose of long-acting opioids
  • Use opioid conversion tables (or widget) to estimate sustained release dosing
  • Prescribe short-acting opioids for breakthrough pain and for further titration of therapy

Barriers to Analgesia in Pain Patients

  • Patient barriers
    • Expectation that cancer is painful
    • Not wanting to disappoint physican/family/staff
    • Wanting to do well, appear strong
    • Worries about about addiction, dependence, side effects
  • Physician barriers
    • Lack of training in pain evaluation and management
    • Beliefs that pain is subjective or pain control is unimportant
    • Worries about regulatory oversight, licensing
  • Societal barriers
    • Biases against opioids, pain relieving medicines generally
    • Costs, Access to care, Prejudice and Stigma

Morphine

Prototypical opioid analgetic, reference standard.

  •  Strong m receptor agonist
  •  Strong analgesia
  •  Other opioids converted to morphine equivalents 
  •  NNT (dose titration protocol) = 1.1
  •  Toxicity
    •  Respiratory suppression
    •  Severe constipation
    •  Reinforcement/addiction
  •  Other side effects: nausea, pruritis, sedation
  •  May be delivered: PO, IV, PR, IM, SL, IT

Oxycodone

  •  Strong m receptor agonist, also k and d agonist
  •  Strong analgesia
  •  2 x more potent than morphine
  •  May be formulated alone or in combination
  •  Sustained release and short-acting formulations
  •  Toxicity: Respiratory suppression, Severe constipation, Reinforcement/addiction
  •  Other side effects: nausea, pruritis, sedation
  •  May be delivered: PO
  •  Active metabolites

Reference

MD Anderson Manual of Medical Oncology

Methadone

  •  Strong m receptor agonist, synthetic opioid

Deaths have occurred with this agent, in part due to long half-life. Methadone should only be used for pain relief by a experienced provider who is expert in pain management or palliative care. It has no application for short-term or acute pain relief.

  •  10 – 15 x more potent than morphine
  •  Very long plasma half-life (up to 190 h)
  •  Toxicity: Respiratory suppression
  •  May be delivered: PO

Fentanyl

  •  Strong m receptor agonist, semi-synthetic opioid
  •  Strong analgesia
  •  Potency relative to morphine is high
  •  Transbuccal may provide rapid relief of cancer pain but is strongly reinforcing and not appropriate for all populations
  •  Transdermal patch is replaced every 72 hours
  •   Toxicity: Respiratory suppression, Severe constipation, Reinforcement/addiction
  •  Other side effects: nausea, pruritis, sedation
  •  May be delivered: IV, IM, SL, IT, TD

Codeine

  •  Prodrug – requires conversion to morphine
  •  Moderate analgesia
  •  15% of population lacks enzyme to convert and may not experience analgesia
  •  Rare ultra-fast metabolizers can experience toxicity 
  •  Toxicity: Respiratory suppression, Severe constipation, Reinforcement/addiction
  •  Other side effects: nausea, pruritis, sedation
  •  May be delivered: PO, IV, PR, IM, SL, IT

Hydrocodone

  •  Strong m receptor agonist
  •  Strong analgesia, also cough suppression
  •  Potency is about 1.5 x morphine
  •  Often combined with APAP, which may lead to liver toxicity
  •  Toxicity
    •  Respiratory suppression, Severe constipation, Reinforcement/addiction
  •  Other side effects: nausea, pruritis, sedation
  •  Originally FDA approved in 1943
  •  May be delivered: PO

Tramadol

  •  Synthetic, centrally acting analgesic 
  • Weak m receptor agonist with active metabolite
  •  Also inhibits NE re-uptake (SNRI) 
  •  NMDA antagonist, chemically similar to venlafaxine
  •  NNT (100 mg) = 4.6
    •  Toxicity
    •  GI: nausea, vomiting
  • Other side effects: sweating, pruritis
  •  May be delivered: PO, others

Buprenorphine

  •  Partial m receptor agonist, k antagonist
  •  Antagonizes strong m receptor agonists
  •  Can provide analgesia, but only approved for the treatment of opioid dependence in the U.S.
  •  Also reduces craving for alcohol
  •  Requires special certification to prescribe
  •  Delivered PO

Reference

AccessMedicine

Naloxone

  •  Strong m receptor antagonist 
  •  Moderate k antagonist
  •  Weak d antagonist
  •  Rapidly antagonizes opioid effects
  •  Management of opioid overdose
  •  Half-life of 1-2 h, may require re-dosing
  •  May induce abstinence syndrome
  •  Delivered IV

Reference

AccessMedicine

Opioids: Potent Analgesia, Serious Risks

“…respiratory depression represents the primary cause of morbidity secondary to opiate therapy.”

Reference

Goodman and Gilman

Opioid receptors are densely distributed in the enteric plexus and opioids induce constipation in as many as 95%, even with acute dosing.

Oxycontin sales topped $3,500,000,000 in 2010 (#5). 

Hydrocodone/APAP was the most commonly prescribed generic in 2010.

Summary

  • Opioids remain essential for the management of moderate to severe acute pain, cancer pain and chronic non-cancer pain that is resistant to other treatments.
  • Access to opioids is severely restricted in much of the developing world meaning that many patients with pain do not have access to meaningful pain relief. Other barriers limit access to pain relief in the developed world.
  • Opioids are clinically utilized in several forms, actions, side effect profiles and delivery mechanisms vary.
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