Dependence on opioid pain medication:
a framework for diagnosis and treatment
Jane C Ballantyne, University of Washington...
What is addiction?
Mrs S is a 65 yr old with failed back syndrome on high dose
fentanyl patch. She presents to the Pain Clinic in much
distre...
She returns to the Clinic (early), again in great pain distress. The
story is that she has been vomiting up the methadone ...
Kreek, LaForge & Butelman Nat Rev Drug
Discov 2001;1:710-26
Substance abuse
Maladaptive drug seeking that does not meet criteria for “substance dependence”,
in part because of lack o...
1.Historic notes
2.Neurobiology
3.DSM V
4.Dependence vs. addiction
Historic notes
Before 1950s
• Addiction considered a weakness of character or control, not
a medical illness
• Understanding of addiction...
1950s
• First DSM (1952) grouped alcohol and substance abuse
under Sociopathic Personality Disturbances
• Did not recogniz...
1970s
• Discovery of opioid receptors, although addiction
researchers had surmised the existence of the receptor
types (μ,...
1980s
• DSM-III tolerance and withdrawal included as addiction
criteria together with social and cultural factors
• Term “...
Neurobiology
The brain on opioids
The brain that is exposed to opioids is different from the brain
that is not exposed.
Nestler Neuron ...
Positive reinforcing effects
• mesocorticolimbic dopamine systems
• “reward circuits”
• cause euphoria and reinforcement o...
Negative reinforcing effects
• withdrawal anhedonia (same system) during early
withdrawal
• physical effects of withdrawal...
Stress and contextual clues
• Conditioning, powerful memory input
• Not easy to eradicate, even after drug cessation
• Mor...
Enduring adaptations
• Explain relapse
• Result of complex interactions between drugs themselves and
the circumstances und...
Cami, J. et al. N Engl J Med
2003;349:975-986
Metabotropic
Mechanisms of Action
of Drugs of Abuse
DSMV
What’s new about DSM V?
• No longer using the word “dependence”
• Abandoned the concept of a progression from abuse to
dep...
Ballantyne & LaForge
Pain 2007;129:235-55
Dependence versus addiction
GRAY ZONE
ADDICTED NOT ADDICTED
Meets DSM criteria
for addiction
• No lost prescriptions
• No ER visits
• No early prescri...
DSM V Behavioral criteria for Substance Use Disorder
A maladaptive pattern of substance use leading to clinically signific...
 Physical – regions of control of somatic function - locus
ceruleus (noradrenergic nucleus)
upregulation of cAMP  arous...
Drivers of opioid seeking:
 Memory, including memory of pain, pain relief and euphoria
 Pain, including withdrawal hyper...
• Tolerance is the need to increase dose to
achieve the same effect
• Tolerance may develop for both the euphoric
and anal...
TOLERANCE
DEPENDENCE
WITHDRAWAL
SYMPTOMS
CRAVING
OPIOID SEEKING
NORMAL
EUPHORIA
ANALGESIA
DYSPHORIA
HYPERALGESIA
What we understand about opioid dependence
PAIN
PAIN RELIEF
• Pain and mood are interdependent whether opioid treated or
not
• Pain patients taking opioids continuously develop toler...
Ballantyne et al Arch Int Med 2012;172:1342
Enduring adaptations produced by established behaviors
For the illicit drug user:
• Procurement behaviors
For the pain pat...
The dependent/addicted pain patient
Not generally recognized as addiction
• Periodic requests for dose escalation
• Refusa...
Summary points
• Patients who stay on opioid pain treatment long-term and
continuously will inevitably develop dependence
...
Plenary 1a  ballantyne dependence framework
Plenary 1a  ballantyne dependence framework
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Plenary 1a ballantyne dependence framework

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27th Annual Pain & Suffering Symposium
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Plenary 1a ballantyne dependence framework

  1. 1. Dependence on opioid pain medication: a framework for diagnosis and treatment Jane C Ballantyne, University of Washington, Seattle
  2. 2. What is addiction?
  3. 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. 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.
  5. 5. Kreek, LaForge & Butelman Nat Rev Drug Discov 2001;1:710-26
  6. 6. 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
  7. 7. 1.Historic notes 2.Neurobiology 3.DSM V 4.Dependence vs. addiction
  8. 8. Historic notes
  9. 9. 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
  10. 10. 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”
  11. 11. 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
  12. 12. 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
  13. 13. Neurobiology
  14. 14. 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
  15. 15. Positive reinforcing effects • mesocorticolimbic dopamine systems • “reward circuits” • cause euphoria and reinforcement of drug- seeking behaviors
  16. 16. 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
  17. 17. 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
  18. 18. 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
  19. 19. Cami, J. et al. N Engl J Med 2003;349:975-986 Metabotropic Mechanisms of Action of Drugs of Abuse
  20. 20. DSMV
  21. 21. 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
  22. 22. Ballantyne & LaForge Pain 2007;129:235-55
  23. 23. Dependence versus addiction
  24. 24. 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)
  25. 25. 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
  26. 26.  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
  27. 27. 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
  28. 28. • 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
  29. 29. TOLERANCE DEPENDENCE WITHDRAWAL SYMPTOMS CRAVING OPIOID SEEKING
  30. 30. NORMAL EUPHORIA ANALGESIA DYSPHORIA HYPERALGESIA What we understand about opioid dependence PAIN PAIN RELIEF
  31. 31. • 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
  32. 32. Ballantyne et al Arch Int Med 2012;172:1342
  33. 33. 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
  34. 34. 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
  35. 35. 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

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