# Presentation: 588322

## Opioid Toxicity

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

## Opioid Treatment of Chronic Pain: Major Concerns

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

## 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

## 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.

## Drugs with High Abuse Potential

**Cocaine**

**Heroin**

**Marijuana**

**Benzodiazepines**

**Antidepressants**

**Narcotic**

**Alcohol-in-combination**

**Other**

**Analgesics**

- Source:  Drug Abuse Warning Network

- Mentions

## 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

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

## 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

## Which Instrument?DSM-IV Substance Use Disorder and the Typical Pain Patient on Opioids

- 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

- A _maladaptive_ pattern of substance use leading to significant _impairment or distress_ as manifested by 3 or more of the following 9 symptoms:

## 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;15:184-91.
- 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

## Slide 11

## Slide 12

## Tolerance

- Dose Required

- Time

- Side Effects

- Analgesia

- T.I.

**A.**

- Dose Required

- Time

- T.I.

**B.**

- Dose Required

- Time

- T.I.

**C.**

- Dose Required

- Time

- T.I.

**D.**

- T.I. = Therapeutic Index

## Slide 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) |

## Daily Dose Requirements in Long-Term  Follow-Up Study

- (N = 150)

## Mean Daily Dose of Study Medication: Change From Baseline to Week 4

**Mean Daily Opioid Dose**

**P = 0.025**
**Comparison of Change From Baseline to Week 4**

**Change 16 mg**

**Change 1.6 mg**

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

## Neuropsychological Function

- Concerns: psychomotor performance, cognitive function, affective disturbance

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

## 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

## 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

## 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

## Symptom Distress Checklist in Opioid Analgesia

| Symptom | None | Mild | Moderate | Severe |
| --- | --- | --- | --- | --- |
| Nausea |  |  |  |  |
| Vomiting |  |  |  |  |
| Dizziness |  |  |  |  |
| Drowsiness |  |  |  |  |

- Jamison, Katz, 1998

## 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)

## 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)

## 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.