# Presentation: 324908

## 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

## 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 Report

**U.S. News & World Report**
**March 17, 1997**

**        ****Old                                          Thinking**

**New Science**

## AHCPR Clinical Practice  Guideline

**AHCPR Clinical Practice  Guideline**

**Full Guideline Available **
**in searchable format **
**on the WWW **
**at**
- _[www.ahrq.gov](http://www.ahrq.gov/)_
**1992**

## AHCPR Clinical Practice Guideline

**AHCPR Clinical Practice Guideline**

**Full Guideline Available**
** ****in searchable **
**format **
**on the WWW**
**at**
- _[www.ahrq.gov](http://www.ahrq.gov/)_
**1994**

## www.ampainsoc.org

**Released **
**March 15, 2002**

**American Pain Society**
**Clinical 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 Society**
- 4700 West Lake Avenue
- Glenview IL 60025-1485
- Phone:    847 375-4715
- Fax:        847 375-6315
- E-mail: info@ampainsoc.org
- Web 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 emotions
- 	anxiety
- 	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 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.**

## 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...”

**Notes:**
The US Food and Drug Administration advises that long-term NSAID use causes symptomatic GI bleeding in some patients. GI bleeding can occur without warning, and patients should be informed of the potential for serious GI side effects and the signs of their occurrence.

## NSAID Gastrointestinal ToxicityUlcers 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**

**Notes:**
GASTROINTESTINAL COMPLICATIONS

·	In the U.S. 107,000 hospitalizations and 16,500 deaths are attributed to NSAID-induced gastrointestinal compliations each year1.  Potential gastrointestinal complications include upper gastrointestinal bleeds, gastroduodenal ulcers and perforations and obstructions.  

·	Endoscopic lesions can be seen with acute NSAID therapy and in up to 80% of patients on chronic therapy.  10-20% of patients will experience gastrointestinal symptoms such as dyspepsia.  There is a poor correlation between symptoms and ulceration demonstrated by endoscopy.

·	When NSAIDs inhibit COX-1 in the gastrointestinal tract, fewer prostaglandins are synthesized.  This results in increased acid production, decreased  platelet adhesiveness, and decreased esophageal sphincter tone, coupled with decreased production of gastric mucosa.

·	The COX-2 enzyme is protective in the stomach, but it is essentially undetectable.  Stimulation of the COX-2 enzyme also produces prostaglandins, which are involved in inflammation and wound healing.  Although inhibition of COX-2 will interfere with wound healing, it appears less damaging than non-specific inhibition.

1.	Singh, G.  Recent Considerations in Nonsteroidal Anti-Inflammatory Drug Gastropathy.  Am J Med.  1998;105(1B):31S-38S.

## 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 analgesia
**	****	****	****American Society of Addiction Medicine**
**	****	****	****Public 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 

**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

## Slide 25

## Physiological Responses to 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.**

## 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 window**

**Therapeutic window**

**Analgesic onset ~  1 h**
**Analgesic 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 opioids
**Vainio 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.

**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