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The chemistry and
psychiatry of tapering
JANE C BALLANTYNE
UNIVERSITY OF WASHINGTON, SEAT TLE
Dr Ballantyne has no conflicts of interest or disclosures
Consider the role of endogenous opioid systems
Current theories about the purposes of the
endogenous opioid system suggest two
important categories:
• to provide stress-related pain relief and pain
enhancement (injury-related “physical pain”)
• to facilitate maternal-infant and other attachments
Top down viewpoint
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Disruption of social attachments, particularly
maternal-infant attachments is one of the primary
causes of “social and emotional pain”
The suffering of chronic pain patients encompasses
both physical and emotional pain that has often been
refractory to treatment other than opioids
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Dysphoric social
dimension
Contributes as much as
nociception
Accepts that mechanisms
at the cellular level have
evolved through
evolutionary processes
over millions of years
Opioid adaptations
Neuroadaptations are integrated biological adaptations
that underlie the clinical manifestations of analgesia,
hyperalgesia, tolerance, dependence and addiction
2) way to avoid iatrogenic addiction
• Opioid induced hyperalgesia
• Tolerance, dependence and withdrawal hyperalgesia
• Enduring adaptations – role of memory - irreversible
Opioid induced hyperalgesia
Angst & Clark
Anesthesiology
2006;104:570
Model of neuroadaptive changes underlying expression and recovery of opioidinduced hyperalgesia
Tolerance, dependence and withdrawal hyperalgesia
Tolerance has an important
psychological component
Psychological
Associative (learned) tolerance
•Environmental clues
•Psychological factors
Pharmacological
Nonassociative (adaptive) tolerance
•Cellular process
•Receptor down-regulation
turnover rate
number
•Receptor desensitization
NMDA linked
Pharmacological (but not psychological) tolerance can be partly overcome by
opioid rotation
Rotation to another
opioid overcomes
tolerance to some
degree. Clinically, can
reduce to ½ MED to
achieve same analgesia.
Pasternak Neuroscientist
2001;7:220-31
Confocal microscopy of
MOR-1 and MOR-1C in the
dorsal horn of the spinal cord
Dependence is inevitable with continuous use
Physical – regions of control of somatic function - locus ceruleus
(noradrenergic nucleus)
upregulation of cAMP
arousal, agitation, diarrhea, rhinorrhea, piloerection
Emotional/psychological – reward centers
hedonia and anhedonia
Pain pathways
analgesia and hyperalgesia
Ballantyne & LaForge, Pain 2007;129:235
Ballantyne et al, Arch Int Med 2012;172:1342
Opioid dependence is an adaptation
EUPHORIA
ANALGESIA
PAIN RELIEF
NORMAL
DYSPHORIA
HYPERALGESIA
PAIN
Manifestations of withdrawal
Note: Withdrawal symptoms are not necessarily explosive and
obvious. They may be insidious and even imperceptible.
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Hyperalgesia – whole body aches and pains
Dysphoria and distress
Restlessness
Anxiety
Tearing up
Runny nose
Sweating
Nausea and vomiting
Abdominal pain
Yawning
WITHDRAWAL
SYMPTOMS
TOLERANCE
CRAVING
OPIOID SEEKING
DEPENDENCE
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
Metabotropic Mechanisms of
Action of Drugs of Abuse
Cami, J. et al. N Engl J Med
2003;349:975-986
What is addiction?
Ballantyne & LaForge
Pain 2007;129:235-55
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:
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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
How we think of addiction
How we think of dependence
on pain medication
Are they biologically
any different?
GRAY ZONE
ADDICTED
Meets DSM criteria for
addiction
NOT ADDICTED
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No lost prescriptions
No ER visits
No early prescriptions
No requests for dose
escalation
• No UDT aberrancies
• No doctor shopping (PMP)
Opioid seeking behaviors
Dependence/addiction develops
through pain treatment
• Pestering reluctant doctors
• Using opioid to treat pain
• Predominant symptom of
withdrawal - pain
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Dependence/addiction develops
through recreational drug use
• Need to procure opioid
• Often use paraphernalia
• Predominant symptom of
withdrawal - anhedonia
DSM Criteria
Social Disruption
Loss of control over use
Continued use despite
knowledge of harm
(Craving)
(may not be manifest until off)
Do not accept that
anything is wrong other
than pain
Accept that they are
addicted
What happens when you taper?
• Withdrawal symptoms can be insidious and last for months
• Withdrawal hyperalgesia can trick the mind into believing opioids were
needed
• The difficulty of overcoming withdrawal symptoms often hampers efforts
to taper opioids
• The most difficult to overcome is psychological dependence
• Enduring adaptations may mean risk of relapse after successful tapering
(this applies to prescription opioid dependence as well as opioid use
disorder)