Neurobiology of pain and addiction:
Implications for patients with chronic pain
and addictive disorders
Peggy Compton, RN, PhD, FAAN
Professor and Associate Dean
School of Nursing and Health Studies
Georgetown University
“For pain is perhaps but a violent pleasure?
Who could determine the point where pleasure
becomes pain, where pain is still a pleasure?
–Honoré De Balzac (1799–1850)
“Pleasure and pain, though directly opposite, are
yet so contrived by nature as to be constant
companions; and it is a fact that the same
motions and muscles of the face are employed
both laughing and crying.
Pierre Charron (1541 - 1603)
Pain
Pleasure
A Continuum of Sensation
Neuro-anatomical overlap of pain and reward
Becerra L. et al. Neuron. 2001;32(5):927-946.
Opioid systems in underlie both
Pain and Reward responses
Ballantyne and LaForge, 2007
•Effects can be blocked with naloxone
•Binding induces second-messenger induced changes
Opioid Responses by Murine
Strain
BALB/c
CXBH
C57
CXBK
(common (recombinant (common (recombinant
inbred)
inbred)
inbred)
inbred)
1
1
1
1
2,3,4,6
2,3,5
2,4,5,6,7
2,3,5,8,9
Reinforcement/
Reward Responses
2,4
2
2,4,10
2
Opioid Receptor
Binding
2
2,9
+/-2
2,9,12
Pain Tolerance
Analgesic
Response
1Elmer,
et al. 1998. 2Elmer, et al. 1995. 3Oliverio, et al. 1997. 4Semenova, et al. 1995. 5Elmer, et al. 1993. 6Olivero &
Castellano. 1974. 7Brase, et al. 1977. 8 Gwynn & Domino. 1984. 9Mogil, et al. 1996. 10Belknap, et al. 1995. 11Berrettini, et
al. 1994. 12Mogil, et al. 1995. 13Petruzzi, et al. 1997, 14Gelernter, et al. 1998.
Pain Tolerance in
Opioid and Cocaine abusers
180
150
120
opioid abusers
90
cocaine abusers
ex-opioid abusers
60
ex-cocaine abusers
30
0
cold-pressor pain tolerance (seconds)
(Compton, 1994)
Length of cold-pressor immersion (min)
Pain tolerance by
-opioid agonist activity
120
100
80
60
*
40
20
0
methadone
(n = 18/group)
buprenorphine
control
Compton, P et al., Drug Alcohol Depend 2001; 63:139-146.
Not a new observation
“At such times I have certainly felt it a great
responsibility to say that pain, which I know is an
evil, is less injurious than morphia, which may be
an evil. Here experience is needed. Does morphia
tend to encourage the very pain it pretends to
relieve?”
“On the abuse of hypodermic injections of morphia,”
Clifford Albutt, Practitioner 1870; 3:327-330.
“He is also affected by a hypersensitiveness to
pain, or a morbid intolerance of any kind of distress
…. He suffers. His suffering is actually great. To his
astigmatic inner eye it seems even greater than it
is.”
“What is the morphine disease?”
Charles W. Carter Journal of Inebriety 1908;30:28-33.
Opioid-induced Hyperalgesia
 Increased sensitivity to pain resulting from opiate
administration
 Pain-free murine models made tolerant
to morphine have significantly
decreased tolerance of pain
• Opioids, in addition to providing analgesia, set in
motion anti-analgesic or hyperalgesic processes
 Opioid-withdrawal hyperalgesia as an
“unmasking” of underlying opioid-induced
hyperalgesic state
OIH in animal models
•
•
•
•
•
•
Detectable during opioid analgesia
Dose-dependent
Increases with repeated withdrawal episodes
Intensifies with antagonist precipitated withdrawal
Gender differences
Can be detected within hours of opioid administration
Li X, et al., Brain Res Mol Brain Res 2001;86:56-62.
Opioid Responses by
Murine Strain
C57BL/6J common inbred
- Poor baseline pain tolerance
- Poor analgesia response
- High opioid reinforcement
Liang DY, et al., Pharmacogenet Genomics. 2006;16(11):825-35.
Opioid-induced hyperalgesia as
an Opponent Process
Opioid
administration
Opioid-induced hyperalgesia
Pain
tolerance
Opioid-induced analgesia
Adapted from: Solomon R, American Psychologist 1980; 35(8):691-712; Koob GF, et al,
Neuroscience & Biobehavioral Reviews 1989;13:135-140.
Change in Cold-Pressor Pain Tolerance
by Condition at 5 and 15 Minutes
*P = 0.013
**P = 0.004
100
50
0
Seconds
-50
-100
-150
*
-200
**
-250
-300
5 Minutes
IM morphine
IV morphine
15 Minutes
IV hydromorphone
Placebo
Compton P, et al. J Pain. 2003;4(9):511-519.
Glu
Peripheral
neuron
Glu
NMDA-R
Glu
Glu
+
PK
C
+
+
↑ cytokine, chemokine
morphine
mu opioid-R
Central neuron
Glial cell
Maier D, et al. , 2004 ; DeLeo JA, et al., 2004
Chronic Pain and
opioid-induced hyperalgesia
• Across a number of case studies, the emergence
of hyperalgesia and allodynia has been reported
in patients with malignant and non-malignant
pain
• Occurs large or rapidly escalating doses of
morphine or fentanyl
• symptoms resolved with:
• dramatically decreasing or discontinuation
of opioid
• switching to a weaker opioid
• ketamine (NMDA-antagonist) administration
Opioid-induced Hyperalgesia in
Chronic Pain
Cold-pressor pain tolerance before and after one month of
opioid therapy (75mg MS) in chronic pain patients (n = 6)
50
*
time (s)
40
30
20
10
0
baseline
1 month
*p < 0.01
Chu, Clark & Angst, 2006
VAS pain intensity
OIH in chronic pain patients
Dose in morphine equivalents
Duration on opioid therapy
Pain associated with standard lidocaine injection is
correlated with opioid dose and duration of opioid
treatment
Cohen S, et al., Reg Anesth Pain Med 2008; 33: 199-206
Chronic Pain
Improved functioning
+
Opioid Therapy
Unimproved functioning
opioid nonresponsive pain
Opioid-responsive pain
Absence of addiction
Opioid-induced
hyperalgesia
Psychiatric Illness
Addictive disease
Adapted from: Weaver & Schnoll The Clinical Journal of Pain 2002 18:S61-S69
Mitra Journal of Opioid Management 2008 4:123-130.
Pain Characteristics and
Opioid Analgesia responses
Differential Dx
Nature
of pain
Onset
Response to
opioid
administration
Type of
previous opioid
used
Increased pain
pathology
Localized to
pain site
Variable
Pain improves
Neither
Opioid
tolerance
Localized to
pain site
Gradual
Pain improves
Long acting
Opioid
withdrawal
Diffuse,
hyperalgesia
Abrupt
Pain improves
Short acting
Opioid-induced
hyperalgesia
Diffuse,
hyperalgesia
Abrupt or
Gradual
Pain worsens
Short acting
Pseudoaddiction
Localized to
pain site
Ongoing
Pain improves
either
Addictive
disease
Diffuse,
hyperalgesia
Ongoing
Pain worsens
Short acting
Guidelines for
clinical management of OIH
• Opioid sparing strategies
• Avoid short-acting formulations
• Avoid emergence of withdrawal
• Opioid rotation
• Use of adjuvant medications
• NMDA antagonists
• GABA agonists
• Anti-inflammatory analgesics
• Low dose opioid antagonists
Gaba-agonist effects on OIH
**
*
*
*p=0.02, **p =0.01
*p=0.03
• No overall GPN effect on pain responses by group
• However, for abstinent subjects, significant
improvements in cold-pressor pain responses noted.
(Compton et al., 2010)
Does pain protect patient from
addiction responses?
Under acute pain conditions:
• Significantly less morphine analgesic
tolerance in pain assays
• Significantly less morphine physical
withdrawal symptoms (Brown et al., 2002, Vaccarino et al.,
1993)
• Significantly less opioid reward or euphoria
(Zacny et al., 1996)
Antagonist effect of pain on IL1-ra
Compton et al, 2012
Presenter Contact Details:
Peggy Compton RN, PhD, FAAN
Associate Dean and Professor
School of Nursing and Health Studies
Georgetown University
pcompton@georgetown.edu
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