1. Nathaniel Katz, MD Harvard Medical School Boston, MA
Opioid Toxicity
Nathaniel Katz, MD
Harvard Medical School
Boston, MA

2. Opioid Treatment of Chronic Pain: Major Concerns
Addiction
Tolerance
Neuropsychological effects
Symptoms
Nausea, vomiting, constipation
Dizziness, sweating
Itching, etc.

3. Definitions Addiction (also dependence, abuse) Physical Dependence
Loss of control over drug use
Compulsive drug use
Continued use despite harm
Physical Dependence
Stopping the drug leads to a withdrawal syndrome
Tolerance
Less effect after prolonged use; dose escalation required to maintain effect

4. Historical Perspectives
“It is better to suffer pain than to become dependent upon opium”
Diagoras of Melos, 3rd Cent. B.C.
“Opium should be completely avoided [due to risk of dependence]”
Erasistratus of Chios, 5th Cent. B.C.

5. Drugs with High Abuse Potential
Mentions
Other
Narcotic
Analgesics
Antidepressants
Benzodiazepines
Marijuana
Heroin
Cocaine
Alcohol-in-combination
Source: Drug Abuse Warning Network

6. Studies demonstrating rarity of addiction in patients treated with opioids
Medina JL, Diamond S. Drug dependency in patients with chronic headaches. Headache 1977 Mar;17(1):12-4
Porter J, Jick H. Addiction rare in patients treated with narcotics. N Engl J Med 1980 Jan 10;302(2):123
Perry S, Heidrich G. Management of pain during debridement: a survey of U.S. burn units. Pain 1982 Jul;13(3):267-80
Several retrospective survey studies

7. No published study of opioids for chronic pain has prospectively evaluated the incidence of addiction, by any definition.

8. Which Population? Chronic opioid therapy for patients with history of substance abuse (n=20)
Good Outcome (11)
Primarily alcohol
Good family support
Membership in AA or similar groups
Bad Outcome (9)
Polysubstance
Poor family support
No membership in support groups
Dunbar & Katz, 1996

9. Which Instrument? DSM-IV Substance Use Disorder and the Typical Pain Patient on Opioids
A maladaptive pattern of substance use leading to significant impairment or distress as manifested by 3 or more of the following 9 symptoms:
Need for markedly increased doses to achieve effect
Diminished effect with same dose
Withdrawal syndrome
Taking substance to relieve or avoid withdrawal symptoms
Dose escalation or prolonged use
Persistent desire or unsuccessful efforts to cut down or control substance use
Excessive time spent obtaining, using or recovering from use of the substance
Activities abandoned because of substance use
Use despite harm

10. Self-report-based measures
Self-report-based measures? Four studies demonstrating unreliability of patient self-report
Ready LB, Sarkis E, Turner JA. Self-reported vs. actual use of medications in chronic pain patients. Pain 1982;12:285-94
Fishbain DA, Cutler RB, Rosomoff HL, et al. Validity of self-reported drug use in chronic pain patients. Clin J Pain 1999;15:
Katz NP, et al. Behavioral Monitoring and Urine Toxicology Testing in Patients on Long-Term Opioid Therapy. APS Abstract, 2001
Belgrade M. Non-compliant drug screens during opioid maintenance analgesia for chronic non-malignant pain. APS Abstract, 2001

13. Tolerance A. B. C. D. T.I. = Therapeutic Index Dose Required
Side Effects
Dose Required
Dose Required
T.I.
Analgesia
Time
Time C. D.
T.I.
Dose Required
Dose Required
T.I.
Time
Time
T.I. = Therapeutic Index

14. Published, Non-Opioid-Controlled RCTs of Opioids for Chronic Non-Cancer Pain, With at Least One Month Observation
*Arkinstall, 1995
Mixed CP, n=46, CR codeine vs. placebo, 1 wk, 28 in OL ext.
Pain at 19 wks stable.
Moulin, 1996
Mixed CP, MS-CR vs. active placebo, 9wks, x-over, n=61
No info on tolerance.
*Jamison, 1998
LBP, RCT, MS-CR vs. oxy vs. naprox; 3-mo tx, titration; n=36
Dose, pain stable after initial escalation.
*Watson, 1998
PHN, Oxycontin vs. placebo, 4 wks, n=50, OL ext.
Dose stable in subgroup.
*Caldwell, 1999
OA, RCT, enriched, Oxycontin vs. oxy/APAP vs. placebo, fixed, 4 wks, n=167
Diminution of analgesia in all 3 groups; worst in placebo.
*Peloso, 2000
OA, CR codeine vs. placebo, titration, 4 wks, n=66
Dose tripled over 4 wks.
*Roth, 2000
OA, n=133, Oxycontin 10 vs 20 bid vs. placebo; fixed, 2wks, OL
Pain relief, dose stable in 58/106 (6 mo), 15/106 (18 mo)
*Harati, 2000
Diabetic neuropathy, n=117, tramadol vs. placebo RCT, OL ext. this report
Pain scores, dose stable over 6 mo. Only 4/117 DOLE
*Caldwell, 2002
OA, n=295, Avinza 30qd vs. MSContin 15 bid vs. placebo, 4 wks, OL ext.
Pain and dose stable in the completers (48% at 30 weeks)

15. Daily Dose Requirements in Long-Term Follow-Up Study

16. Mean Daily Dose of Study Medication: Change From Baseline to Week 4
P = 0.025
Comparison of Change From Baseline to Week 4
Change 16 mg
Mean Daily Opioid Dose
Change 1.6 mg

17. The phenomenon of tolerance to opioids in the treatment of chronic pain has not been systematically investigated in published medical literature.

18. Neuropsychological Function
Concerns: psychomotor performance, cognitive function, affective disturbance

19. No published prospective controlled trial on opioids for chronic non-cancer pain has evaluated neuropsychological function.

20. Opioids and Endocrine Function
Opioids lower testosterone levels in animals, heroin addicts, methadone maintenance pts, and intrathecal opioid pts.
Opioids anecdotally produce loss of libido and impotence in men; amenorrhea and infertility in women.
Low testosterone: fatigue, loss of muscle mass, mood disturbances, osteoporosis

21. Endocrine Function in Males with Chronic Pain on Opioid Therapy
All patients on opioid therapy underwent endocrine testing
Data available on N=25 males
Free testosterone below reference range in 63% of patients aged 25-49
Free testosterone below reference range in 88% of patients aged 50-75
Mean LH, FSH values below normal
Katz N et al, submitted for publication

22. Opioid-Related Symptoms
Nausea, vomiting, dizziness, itching, sweating, dysphoria, constipation
Passive side effects capture inadequate
Dropouts due to symptomatic side effects substantial in acute and chronic pain trials of opioids (10-50% in chronic pain)
Active “symptom distress” assessment, especially for dropouts, necessary for risk-benefit and quality of life assessment

23. Symptom Distress Checklist in Opioid Analgesia
None
Mild
Moderate
Severe
Nausea
Vomiting
Dizziness
Drowsiness
Jamison, Katz, 1998

24. Opioid Sparing as Outcome Measure
Decreased opioid requirements in patients on study drug may be due to:
Study drug has analgesic activity in the model (NSAID)
Study drug enhances opioid analgesia (?NMDA antagonists)
Study drug enhances opioid side effects, patients use less (e.g. a drug that causes nausea)

25. Is Opioid Sparing Meaningful?
Yes, if the scientific question is whether the drug has analgesic activity in the model (given pain & side effects no worse)
No, if the scientific question is whether the treatment helps the patients (need to show clinical benefit, e.g. decreased pain, side effects)

26. Conclusions Opioids are generally safe medications.
Treatment response appears durable in a subgroup; however, tolerance has not been systematically investigated.
Symptom distress or toxicity scales (esp. in dropouts) must be used to assess overall treatment effect.
Addiction, the major concern in chronic treatment, has not been investigated using legitimate methods.
Endocrinopathies may be a major organ toxicity of opioids.