Opioid Toxicity

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Opioid Toxicity

• Nathaniel Katz, MD
• Harvard Medical School
• Boston, MA

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Opioid Treatment of Chronic Pain Major Concerns

• Addiction
• Tolerance
• Neuropsychological effects
• Symptoms
• Nausea, vomiting, constipation
• Dizziness, sweating
• Itching, etc.

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Definitions

• Addiction (also dependence, abuse)
• 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

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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.

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Drugs with High Abuse Potential
Mentions
Other
Narcotic
Analgesics
Antidepressants
Benzodiazepines
Marijuana
Heroin
Cocaine
Alcohol-in-combination
Source Drug Abuse Warning Network
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Studies demonstrating rarity of addiction in
patients treated with opioids

• Medina JL, Diamond S. Drug dependency in patients
  with chronic headaches. Headache 1977
  Mar17(1)12-4
• Porter J, Jick H. Addiction rare in patients
  treated with narcotics. N Engl J Med 1980 Jan
  10302(2)123
• Perry S, Heidrich G. Management of pain during
  debridement a survey of U.S. burn units. Pain
  1982 Jul13(3)267-80
• Several retrospective survey studies

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No published study of opioids for chronic pain
has prospectively evaluated the incidence of
addiction, by any definition.
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Which Population?Chronic opioid therapy for
patients with history of substance abuse (n20)

• 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
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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

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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 198212285-94
• Fishbain DA, Cutler RB, Rosomoff HL, et al.
  Validity of self-reported drug use in chronic
  pain patients. Clin J Pain 199915184-91.
• 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

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Tolerance
A.
B.
T.I.
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
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Published, Non-Opioid-Controlled RCTs of Opioids for Chronic Non-Cancer Pain, With at Least One Month Observation Published, Non-Opioid-Controlled RCTs of Opioids for Chronic Non-Cancer Pain, With at Least One Month Observation Published, Non-Opioid-Controlled RCTs of Opioids for Chronic Non-Cancer Pain, With at Least One Month Observation
Arkinstall, 1995 Mixed CP, n46, 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, n61 No info on tolerance.
Jamison, 1998 LBP, RCT, MS-CR vs. oxy vs. naprox 3-mo tx, titration n36 Dose, pain stable after initial escalation.
Watson, 1998 PHN, Oxycontin vs. placebo, 4 wks, n50, OL ext. Dose stable in subgroup.
Caldwell, 1999 OA, RCT, enriched, Oxycontin vs. oxy/APAP vs. placebo, fixed, 4 wks, n167 Diminution of analgesia in all 3 groups worst in placebo.
Peloso, 2000 OA, CR codeine vs. placebo, titration, 4 wks, n66 Dose tripled over 4 wks.
Roth, 2000 OA, n133, 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, n117, tramadol vs. placebo RCT, OL ext. this report Pain scores, dose stable over 6 mo. Only 4/117 DOLE
Caldwell, 2002 OA, n295, Avinza 30qd vs. MSContin 15 bid vs. placebo, 4 wks, OL ext. Pain and dose stable in the completers (48 at 30 weeks)
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Daily Dose Requirements in Long-Term Follow-Up
Study
(N 150)
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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
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The phenomenon of tolerance to opioids in the
treatment of chronic pain has not been
systematically investigated in published medical
literature.
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Neuropsychological Function

• Concerns psychomotor performance, cognitive
  function, affective disturbance

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

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Endocrine Function in Males with Chronic Pain on
Opioid Therapy

• All patients on opioid therapy underwent
  endocrine testing
• Data available on N25 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
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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

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

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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)

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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.