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Opioid Risk:Benefit Issues. U.S. Food and Drug Administration Anesthetic and Life Support Drugs Advisory Committee Bethesda MD September 9. 2003 Arthur G. Lipman, PharmD Professor of Pharmacotherapy, College of Pharmacy Director of Clinical Pharmacology, Pain Management Center

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Opioid Risk:Benefit Issues

U.S. Food and Drug Administration

Anesthetic and Life Support Drugs Advisory Committee

Bethesda MD

September 9. 2003

Arthur G. Lipman, PharmD

Professor of Pharmacotherapy, College of Pharmacy

Director of Clinical Pharmacology, Pain Management Center

Pain Medicine & Palliative Care Advisory Group, Huntsman Cancer Institute

Investigator, Pharmacotherapy Outcomes Research and Pain Research Centers

University of Utah Health Sciences Center

Editor, Journal of Pharmaceutical Care in Pain & Symptom Control

Salt Lake City, Utah


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  • We are appalled by the needless pain

  • that plagues the people of the world -

  • in rich and poor nations alike. By any reasonable code, freedom from pain should be a basic human right limited only by our ability to achieve it.

    • Liebeskind J, Melzack R. Pain 1987;30:1


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U.S. News & World Report

March 17, 1997

Old Thinking

New Science


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AHCPR Clinical Practice Guideline

Full Guideline Available

in searchable format

on the WWW

at

www.ahrq.gov

1992


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AHCPR Clinical Practice Guideline

Full Guideline Available

in searchable

format

on the WWW

at

www.ahrq.gov

1994


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American Pain Society

Clinical Practice

Guideline

Released

March 15, 2002

Available through the

American Pain Society Website

www.ampainsoc.org


Principles of analgesic use in the treatment of acute pain and cancer pain fifth edition 2003 l.jpg
Principles of Analgesic Use in the Treatment of Acute Pain and Cancer PainFifth Edition, 2003

Available from

American Pain Society

4700 West Lake Avenue

Glenview IL 60025-1485

Phone: 847 375-4715

Fax: 847 375-6315

E-mail: [email protected]

Web Site:www.ampainsoc.org


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Physiological and Cancer Pain Effects of Pain

  • increased catabolic demands

    poor wound healing, weakness, muscle breakdown

  • increased risk of thromboembolic event

  • respiratory effects

    shallow breathing, tachypnea (acutely), cough suppression increasing risk of atelectasis and pneumonia

  • increased sodium and water retention (renal)

  • decreased gastrointestinal motility

  • tachycardia and elevated blood pressure

    sympathetic autonomic activation

AHCPR Acute & Cancer Pain Guidelines: www.ahrq.gov


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Psychological Effects of Pain and Cancer Pain

  • negative emotions

    anxiety

    depression

  • sleep deprivation

  • existential suffering

    may cause patients to seek end of life

AHCPR Acute & Cancer Pain Guidelines: www.ahrq.gov


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Immunological Effects of Pain and Cancer Pain

  • impaired immune response

    decreased natural killer (NK)

    cell count

AHCPR Acute & Cancer Pain Guidelines: www.ahrq.gov.

Fakata KL, Lipman AG, Mullin S. APS Annual Meeting Abstracts, 2002.


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Correlation of of Pain Intensity and Impact and Cancer PainActivities Impaired by Increasing Pain on a Pain intensity Scale of 1-10

Relate

Walk Walk

Sleep Sleep Sleep

Active Active Active Active

Mood Mood Mood MoodWork Work Work Work Work

Enjoy Enjoy Enjoy Enjoy Enjoy Enjoy

3 4 5 6 7 8

>>>>> >>>>> >>> Worst Pain Rating >>> >>>>> >>>>>

Cleeland CS, Ryan KM. Ann Acad Med Singapore. 1994;23:129-138.


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Therapeutic Interventions Must Have Favorable Risk:Benefit Ratios

  • The risk of pain is >> than is generally appreciated

    • More aggressive analgesia often is needed

  • There is inherent risk in all pharmacotherapy

    • Every drug is a poison

  • Opioid risks must be contrasted to:

    • Risks of alternative pharmacotherapy

    • Risks of nonpharmacological therapy


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Treatment Alternatives for Moderate –Severe Pain Ratios

  • Oral NSAIDs

  • Oral Opioids

  • Invasive procedures

    • CNS stimulators

    • Spinal alnalgesia


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NSAIDs Ratios

  • Over 125,000,000 NSAID prescriptions written in U.S. annually in 1998

  • Gastroduodenal and platelet effects problematic

    • Toxicities limit usefulness

    • Effects decrease adherence (compliance)


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FDA NSAID Class Warning Ratios

“Risk of GI ulceration, bleeding, and perforation with NSAID: Serious GI toxicity such as bleeding, ulceration, and perforation can occur at any time, with or without warning symptoms, in patients treated chronically with NSAID…symptomatic upper GI ulcers, gross bleeding, or perforation appear to occur in approximately 1% of patients treated for 3–6 months and in about 2%–4% of patients treated for 1 year…”


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NSAID Gastrointestinal Toxicity RatiosUlcers and Complications of Ulcers

  • 107,000 hospitalizations and 16,500 deaths in U.S. reported in 1998

  • Endoscopically documented lesions

  • Over three-quarters of patients were asymptomatic prior to N+SAID-induced bleeds

  • COX-1 vs. COX-2

Singh G Recent considerations in nonsteroidal anti-inflammatory drug gastropathy.Am J Med. 1998 Jul 27;105(1B):31S-38S. 1998


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Invasive Procedures Ratios

  • Generally not supported by evidence

  • Very expensive

    • highly profitable

    • seldom questioned by insurers

  • Often must be repeated

  • Adverse sequelae


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Opioid Concerns Ratios

  • physical dependence

  • psychological dependence - addiction

  • tolerance

  • cognitive impairment

  • respiratory depression

  • psychomotor impairment

  • legal sanction risks

  • therapeutic efficacy


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Opioid Addiction Ratios

Addiction in the context of pain treatment with opioids is characterized by a consistent pattern of dysfunctional opioid use that may involve:

adverse consequences associated with the use of opioids

  • loss of control over the use of opioids

  • preoccupation with obtaining opioids despite the presence of adequate analgesia

    American Society of Addiction Medicine

    Public Policy Statement, April, 1997


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American Society of Addiction Medicine Public Policy Statement

“...Individuals who have severe, unrelieved pain may become intensely focused on finding relief for their pain. Sometimes, such patients may appear to observers to be preoccupied with obtaining opioids, but the preoccupation is with finding relief of pain, rather than using opioids, per se. This phenomenon has been termed ‘pseudoaddiction’…”

April, 1997


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Distinct Types of Opioid Tolerance Statement

  • Tolerance to Analgesia

    may occur in first days to weeks of therapy; rare after pain relief achieved with consistent dosing without increasing or new pathology.

  • Tolerance to Respiratory Depression, Confusion, Sedation, and Nausea

    predictable after 5-7 days of consistent opioid administration

  • Tolerance to Constipation

    does not occur; scheduled stimulating laxatives are indicated with regularly scheduled opioids

    Lipman AG, Jackson KC. Opioids. In C. Warfield and Z Bajwa, Eds, Principles and Practice of Pain Management, 2nd edition, NY, McGraw Hill, 2003


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Diamorphine Use: 62 YO Man with Lung Cancer Statement

Twycross, RG. Int J Clin Pharmacol 9:184-98


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Myth: Opioids Always Statement Depress Respiration

  • Acutely, opioids can be profound respiratory depressants

    opioid-naïve patients

  • After 5-7 days of continuous opioids, patients predictably become tolerant to respiratory effects

    opioid-tolerant patients

  • pain is a powerful analeptic in awake patients


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Myth: Patients in Pain Don’t Skip Analgesic Doses Statement

  • Once pain is controlled for a few days, patients often skip doses, especially with short acting opioids that must be taken several times a day

    • fear of adverse drug effects

    • family and friends who fear drug effects

  • Long term compliance is aided by less frequent dosing


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Physiological Responses to Statement Repetitive Nociceptive Input

  • Windup

    highly augmented response to repetitive afferent (C-fiber) input

  • Neuronal plasticity

    changes in the CNS in response to repetitive afferent nociceptive input

Herrero JF et al. Wind-up of spinal cord neurons and pain sensation: much ado about something? Prog Neurobiol. 2000;61:1690203.

Mao J, Mayer DJ. Spinal cord neuroplasticity following repeated opioid exposure and its relation to pathological pain. Ann N Y Acad Sci. 2001;933:175-84.


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Pharmacologically StatementLong Acting

methadone

levorphanol

Pharmaceutically

Long Acting

morphine

Oramorph SR, MS Contin, Kadian, Avinza Morphine ER

oxycodone

OxyContin

Oral Long Acting Opioid Dosage Forms


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Methadone Statement

  • Biphasic elimination

    • alpha (analgesic) T1/2 8-12 hours

    • beta T1/2 24-36 hours - protects against withdrawal

  • Risk of accumulation toxicity


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Methadone Biphasic Elimination Statement

Therapeutic window

Therapeutic window

Analgesic onset ~ 1 h

Analgesic offset ~ 8 h

Lipman AG. Oncology. 1999;13:(9):1275-82


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Plot of Methadone Accumulation Statement(dosed q 8 h over 6 days)

Lipman AG. Oncology. 1999;13:(9):1275-82


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Myth: Patients Taking Opioids Cannot Drive Safely Statement

  • Opioids impair cognition and psychomotor coordination initially

    • patients should not drive for 5-7 days after starting opioids or a dose increase

  • After 5-7 days of continuous opioids, tolerance to these effects develops predictably

    • studies show no increase in MVA in patients taking chronic opioids

      Vainio A et al. Lancet 1995;346:667-70

      Fishbain D et al. J Pain Palliative Care Pharmacotherap 2002;16(1):9-28.


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Myth: Opioids Cause End Organ Toxicity Statement

  • Respiratory and CNS toxicity do occur with

    high opioid doses in opioid-naïve patients

  • Long term opioid therapy does not produce reported end-organ toxicity in patients who are titrated to response and monitored correctly

    • Long term NSAIDs may cause GI and renal toxicity

    • High acetaminophen doses can cause hepatotoxicity


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Myth: Opioids Cause End Organ Toxicity Statement

  • Respiratory and CNS toxicity have occurred with high opioid doses in opioid-naïve patients

  • Long term opioid therapy does not produce reported end-organ toxicity in patients who are titrated to response and monitored correctly

    • Long term NSAIDs may cause GI and renal toxicity

    • High acetaminophen doses can cause hepatotoxicity


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Some Pain Management StatementGuidelines and Statements that Advocate Opioids for Safe and Effective Analgesia

  • AHCPR Acute Pain Guideline 1992

  • AHCPR Cancer Pain Guideline 1994

  • ASA Cancer Pain Guidelines 1996

  • AAPM-APS Opioids in Chronic Pain 1997

  • ASAM Public Policy Statement 1997

  • APS Sickle Cell Pain Guidelines 1999

  • APS OA and RA Pain Guideline 2001

  • AGS Persistent Pain in Elderly Guidelines 2002

  • APS Acute and Cancer Principles, 5th ed 2003


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All this needless pain and suffering impoverishes the quality of life of those afflicted and their families; it may even shorten life by impairing recovery from surgery or disease. People suffering severe or unrelenting pain become depressed. They may lose their will to live and fail to take normal health preserving measures; some commit suicide.

Liebeskind J, Melzack R. Pain 1987;30:1


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