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
Mentions
900,000
Other
800,000
Analgesics Narcotic
700,000
Antidepressants
600,000 Benzodiazepines

500,000 Marijuana

400,000 Heroin

300,000 Cocaine

200,000

100,000 Alcohol-in-combination

0
1994 1995 1996 1997 1998 1999 2000
Source: Drug Abuse Warning Network
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) Bad Outcome (9)
Primarily alcohol Polysubstance
Good family support Poor family support
Membership in AA or No membership in
similar groups support groups

Dunbar & Katz, 1996

 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
 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
T h e R o le o f U r in e T o x ic o lo g y M o n ito r in g
in P a tie n ts o n O p io id s fo r C h r o n ic P a in

BE H A V IO R IS S U E S
YE S NO TOTAL
U R IN E T O X P O S IT IV E 1 0 (8 % ) 2 6 (2 1 % ) 3 6 (2 9 % )
N E G A T IV E 1 7 (1 4 % ) 6 9 (5 7 % ) 8 6 (7 1 % )
TOTAL 27 (2 2 % ) 9 5 (7 8 % ) 122

5 3 /1 2 2 (4 3 % ) o f p a tie n ts h a d c o m p lia n c e p r o b le m s
(p o s itiv e u r in e s c r e e n o r b e h a v io r a l is s u e s )

K a tz & F a n c iu llo , 2 0 0 1
 Prescription M onitoring Program Data
Epidemiology of O pioid Use: M assachusetts, 2000

T o ta l o p io id p re s c rip tio n s (C II) 1 ,0 9 3 ,1 0 0

M e a n d a ys su p p ly 1 1 .6
M e a n p ill c o u n t 4 9 .9
(0 -4 0 0 )
U n iq u e in d iv id u a ls re c e iv in g o p io id s c . 5 4 0 ,0 0 0
M e a n p re s c rip tio n s/p e rs o n 2 .0

P re s c rip tio n s w ith > 9 0 p ills 1 9 4 ,0 7 7

(1 7 .8 % )
P re s c rip tio n s w ith m a x . d a ys s u p p ly 2 2 0 ,1 1 7 (2 0 % )
(3 0 )
P e rc e n t o f M a s s a c h u se tts p o p u la tio n A p p ro x . 9 %
re c e iv in g > 1 p re s c rip tio n in 2 0 0 0
 Tolerance
A. B.

Side Effects T.I.

Dose Dose
T.I.
Required Required
Analgesia

Time Time
C. D.

T.I.

Dose Dose T.I.

Required Required

Time Time
T.I. = Therapeutic Index
Published, Non-Opioid-Controlled RCTs of Opioids for Chronic
Non-Cancer Pain, With at Least One Month Observation
*Arkinstall, Mixed CP, n=46, CR codeine vs. placebo, Pain at 19 wks stable.
1995 1 wk, 28 in OL ext.
Moulin, 1996 Mixed CP, MS-CR vs. active placebo, No info on tolerance.
9wks, x-over, n=61
*Jamison, LBP, RCT, MS-CR vs. oxy vs. naprox; 3- Dose, pain stable after initial
1998 mo tx, titration; n=36 escalation.
*Watson, 1998 PHN, Oxycontin vs. placebo, 4 wks, Dose stable in subgroup.
n=50, OL ext.
*Caldwell, OA, RCT, enriched, Oxycontin vs. Diminution of analgesia in all 3
1999 oxy/APAP vs. placebo, fixed, 4 wks, groups; worst in placebo.
n=167
*Peloso, 2000 OA, CR codeine vs. placebo, titration, 4 Dose tripled over 4 wks.
wks, n=66
*Roth, 2000 OA, n=133, Oxycontin 10 vs 20 bid vs. Pain relief, dose stable in 58/106
placebo; fixed, 2wks, OL (6 mo), 15/106 (18 mo)
*Harati, 2000 Diabetic neuropathy, n=117, tramadol Pain scores, dose stable over 6
vs. placebo RCT, OL ext. this report mo. Only 4/117 DOLE
*Caldwell, OA, n=295, Avinza 30qd vs. MSContin Pain and dose stable in the
2002 15 bid vs. placebo, 4 wks, OL ext. completers (48% at 30 weeks)
Daily Dose Requirements in Long-
Term Follow-Up Study
(N = 150)
180
160
Median Daily Dose (mg)

140
120
100
80
60
40
20
0
1 2 3 4 5 6 7
Month
Mean Daily Dose of Study Medication:
Change From Baseline to Week 4
P = 0.025
Comparison of Change From Baseline to Week 4
225
Baseline
Mean Daily Opioid Dose

Change 16 mg Week 4

215

205
Change 1.6
mg
195

185
MS MS/DM
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.