The Foundation for Medical Excellence 27th Annual Pain & Suffering Symposium http://tfme.org

1. Dependence on opioid pain medication:
a framework for diagnosis and treatment
Jane C Ballantyne, University of Washington, Seattle

2. What is addiction?

3. Mrs S is a 65 yr old with failed back syndrome on high dose
fentanyl patch. She presents to the Pain Clinic in much
distress. Her husband is with her and is also distressed. She
is leaning over the exam table throughout the consultation,
and grimacing throughout. She can hardly speak she is in so
much pain, so her husband fills in.
We decide to convert her to methadone on the basis that
she may have developed tolerance to fentanyl. Initially she
does well on methadone, pain is greatly improved and they
are both happier.

4. She returns to the Clinic (early), again in great pain distress. The
story is that she has been vomiting up the methadone and is not
getting any pain relief. She has run out of methadone 2 weeks
early. Her husband is in tears stating it is all his fault because he
gave her too much, and he can’t bear to see her suffering. After
controlling her pain with IV ketorolac, we discuss options (at
length) and eventually agree to try methadone suppositories. The
clinic pharmacist arranges for a compounding pharmacy near their
home to make up the suppositories. However, they leave in a
hurry stating that they need help immediately and will go to the
emergency room.

6. Kreek, LaForge & Butelman Nat Rev Drug
Discov 2001;1:710-26

7. Substance abuse
Maladaptive drug seeking that does not meet criteria for “substance dependence”,
in part because of lack of tolerance and physical dependence
Substance dependence (“drug addiction”)
Maladaptive drug seeking together with tolerance and dependence
Concept of layers of substance use disorder now abandoned
Use of the word “dependence” to mean addiction now abandoned
DSM III and IV

9. 1.Historic notes
2.Neurobiology
3.DSM V
4.Dependence vs. addiction

10. Historic notes

11. Before 1950s
• Addiction considered a weakness of character or control, not
a medical illness
• Understanding of addiction neurobiology was rudimentary
• Existence of endogenous opioid system only imagined

12. 1950s
• First DSM (1952) grouped alcohol and substance abuse
under Sociopathic Personality Disturbances
• Did not recognize the key role of tolerance and withdrawal
in drug addiction
• “Reward” center in the brain first recognized
• Addiction began to be understood as essentially a
compulsive and pathological pursuance of natural
“rewards”

13. 1970s
• Discovery of opioid receptors, although addiction
researchers had surmised the existence of the receptor
types (μ, κ, δ and σ) earlier, and on the basis of
pharmacological studies
• Discovery of endogenous opioids
Pert and Snyder Science 1973;179:1011-4
Hughes et al Nature 1975;258:577-80

14. 1980s
• DSM-III tolerance and withdrawal included as addiction
criteria together with social and cultural factors
• Term “dependence” first used to denote drug addiction
• “Dependence” is distinguished from “abuse” which is
considered a precursor to dependence or addiction

15. Neurobiology

16. The brain on opioids
The brain that is exposed to opioids is different from the brain
that is not exposed.
Nestler Neuron 1996;16:897
Nestler Neuropharmac 2004:47 Suppl 1:24
Cami & Farre NEJM 2003;349:975

17. Positive reinforcing effects
• mesocorticolimbic dopamine systems
• “reward circuits”
• cause euphoria and reinforcement of drug-
seeking behaviors

18. Negative reinforcing effects
• withdrawal anhedonia (same system) during early
withdrawal
• physical effects of withdrawal arising from physical
dependence (upregulation of cAMP in locus ceruleus
and other locations)
NOTE: Both are significant driving force in drug-seeking behavior, but must be
distinguished from long-term drug craving which persists long after
recovery from withdrawal

19. Stress and contextual clues
• Conditioning, powerful memory input
• Not easy to eradicate, even after drug cessation
• More incessant stimulation less easy to eradicate
• Structures involved are those involved in memory,
conditioning and learning: amygdala, hippocampus,
prefrontal cortex and thalamus

20. Enduring adaptations
• Explain relapse
• Result of complex interactions between drugs themselves and
the circumstances under which they are taken
• Neuroadaptation occurs through gene regulation, remodeling
of circuits, changes in intrinsic excitability, increased in
synaptic strength, actual morphological changes
• These adaptations may also alter analgesia and tolerance

21. Cami, J. et al. N Engl J Med
2003;349:975-986
Metabotropic
Mechanisms of Action
of Drugs of Abuse

22. DSMV

23. What’s new about DSM V?
• No longer using the word “dependence”
• Abandoned the concept of a progression from abuse to
dependence
• Because tolerance and dependence do not count as criteria for
drug addiction when an addictive drug is being used medically,
two (instead of one) behavioral criteria are needed
• It will therefore be more difficult to make a diagnosis of addiction
in a patient receiving medical treatment

24. Ballantyne & LaForge
Pain 2007;129:235-55

25. Dependence versus addiction

26. GRAY ZONE
ADDICTED NOT ADDICTED
Meets DSM criteria
for addiction
• No lost prescriptions
• No ER visits
• No early prescriptions
• No requests for dose
escalation
• No UDT aberrancies
• No doctor shopping
(PMP)

27. DSM V Behavioral criteria for Substance Use Disorder
A maladaptive pattern of substance use leading to clinically significant impairment
or distress as manifested by 2 or more of the following:
• Failure to fulfill major role obligations at work, school or home
• Continue in situations in which it is physically hazardous (eg driving)
• Persistent or recurrent social or interpersonal problems
• Substance taken in larger amounts or longer than was intended
• Persistent desire or unsuccessful efforts to cut down
• Great deal of time spent in activities necessary to obtain substance, use substance or
recover from substance use
• Important social, occupations or recreational activities given up or reduced
• Continued use despite knowledge of harm
• Craving

28.  Physical – regions of control of somatic function - locus
ceruleus (noradrenergic nucleus)
upregulation of cAMP  arousal, agitation, diarrhea, rhinorrhea,
piloerection
 Emotional/psychological – reward centers
hedonia  anhedonia
 Pain pathways
analgesia  hyperalgesia
Ballantyne & LaForge, Pain 2007;129:235
Ballantyne et al, Arch Int Med 2012;172:1342
Dependence is inevitable with continuous use

29. Drivers of opioid seeking:
 Memory, including memory of pain, pain relief and euphoria
 Pain, including withdrawal hyperalgesia, which may be subtle
 Withdrawal anhedonia
 Physical symptoms of withdrawal which may be subtle
 Addiction (craving, compulsive use)
Koob et al, Trends Neurosci 1992;15:186
Nestler & Aghajanian, Science 1997;278:58
Hyman et al, Ann Rev Neurosci 2006;29:565
Dependence drives opioid seeking but is not necessarily addiction

30. • Tolerance is the need to increase dose to
achieve the same effect
• Tolerance may develop for both the euphoric
and analgesic effects of opioids
• Tolerance can be produced by both
psychological (associative) and pharmacological
(non-associative) factors
Ballantyne & LaForge Pain 2007;129:235

31. TOLERANCE
DEPENDENCE
WITHDRAWAL
SYMPTOMS
CRAVING
OPIOID SEEKING

32. NORMAL
EUPHORIA
ANALGESIA
DYSPHORIA
HYPERALGESIA
What we understand about opioid dependence
PAIN
PAIN RELIEF

33. • Pain and mood are interdependent whether opioid treated or
not
• Pain patients taking opioids continuously develop tolerance and
dependence
• For them, psychosocial stressors not only increase pain, as in
non-treated patients, but also increase tolerance
• Doses are increased to avoid withdrawal and worsening pain
• Ultimately leads to the patient for whom no dose is enough

34. Ballantyne et al Arch Int Med 2012;172:1342

35. Enduring adaptations produced by established behaviors
For the illicit drug user:
• Procurement behaviors
For the pain patient – much more complex:
• Continuous opioid therapy may prevent opioid seeking
• Memory of pain, pain relief and possibly also euphoria
• Even if the opioid seeking appears as seeking pain relief, it
becomes an adaptation that is difficult to reverse
• It is hard to distinguish between drug seeking and relief
seeking

36. The dependent/addicted pain patient
Not generally recognized as addiction
• Periodic requests for dose escalation
• Refusal to try other treatments, claim of allergies
• High pain score despite opioid
• Not working/on disability
• Anger
Generally recognized as addiction
• Doctor shopping (PMP)
• Aberrant UDT
• Frequent lost prescriptions

37. Summary points
• Patients who stay on opioid pain treatment long-term and
continuously will inevitably develop dependence
• Dependence is not simply physical, nor is it easily reversed
• Distinguishing dependence from addiction is not easy in the
setting of pain treatment with opioids
• Addiction is still not fully understood
• Since the treatment is similar, it may be better to avoid labels, or
create a new label for dependency on prescription analgesics