Opioid Risk:Benefit IssuesU.S. Food and Drug Administration

Anesthetic and Life Support Drugs Advisory CommitteeBethesda MD

September 9. 2003

Arthur G. Lipman, PharmDProfessor of Pharmacotherapy, College of Pharmacy

Director of Clinical Pharmacology, Pain Management CenterPain Medicine & Palliative Care Advisory Group, Huntsman Cancer Institute

Investigator, Pharmacotherapy Outcomes Research and Pain Research Centers

University of Utah Health Sciences CenterEditor, Journal of Pharmaceutical Care in Pain & Symptom Control

Salt Lake City, Utah

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

U.S. News & World ReportMarch 17, 1997

Old Thinking

New Science

AHCPR Clinical Practice Guideline

Full Guideline Available

in searchable format

on the WWW at

www.ahrq.gov

1992

AHCPR Clinical Practice Guideline

Full Guideline Available

in searchable format

on the WWWat

www.ahrq.gov

1994

Released March 15, 2002

American Pain SocietyClinical Practice

Guideline

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

Available from

American Pain Society4700 West Lake AvenueGlenview IL 60025-1485

Phone: 847 375-4715Fax: 847 375-6315E-mail: info@ampainsoc.orgWeb Site:www.ampainsoc.org

Physiological 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

Psychological Effects of Pain

negative emotionsanxiety

depression sleep deprivation existential suffering

may cause patients to seek end of life

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

Immunological Effects of Pain

impaired immune responsedecreased natural killer (NK)

cell count

AHCPR Acute & Cancer Pain Guidelines: www.ahrq.gov.Fakata KL, Lipman AG, Mullin S. APS Annual Meeting Abstracts, 2002.

Correlation of of Pain Intensity and Impact Activities 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 Mood

Work 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.

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

Treatment Alternatives for Moderate –Severe Pain

Oral NSAIDs Oral Opioids Invasive procedures

– CNS stimulators– Spinal alnalgesia

NSAIDs

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)

FDA NSAID Class Warning

“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…”

NSAID Gastrointestinal ToxicityUlcers 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

Invasive Procedures

Generally not supported by evidence Very expensive

– highly profitable – seldom questioned by insurers

Often must be repeated Adverse sequelae

Opioid Concerns

physical dependence psychological dependence - addiction tolerance cognitive impairment respiratory depression psychomotor impairment legal sanction risks therapeutic efficacy

Opioid Addiction

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 analgesiaAmerican Society of Addiction MedicinePublic Policy Statement, April, 1997

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

Distinct Types of Opioid Tolerance

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

Diamorphine Use: 62 YO Man with Lung Cancer

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

Myth: Opioids Always 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

Myth: Patients in Pain Don’t Skip Analgesic Doses

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

Physiological Responses to Repetitive Nociceptive Input

Winduphighly 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.

Oral Long Acting Opioid Dosage Forms

Pharmacologically Long Acting

methadone levorphanol

Pharmaceutically

Long Acting morphine

– Oramorph SR, MS Contin, Kadian, Avinza Morphine ER

oxycodone – OxyContin

Methadone

Biphasic elimination– alpha (analgesic) T1/2 8-12 hours

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

Risk of accumulation toxicity

Methadone Biphasic Elimination

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

Therapeutic windowTherapeutic window

Analgesic onset ~ 1 hAnalgesic offset ~ 8 h

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

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

Myth: Patients Taking Opioids Cannot Drive Safely

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

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

Myth: Opioids Cause End Organ Toxicity

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

Myth: Opioids Cause End Organ Toxicity

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

Some Pain Management Guidelines 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

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