Neurobiology of pain and addiction: Implications for patients with chronic pain and addictive disorders
Peggy Compton, RN, PhD, FAAN
Professor and Associate DeanSchool 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
Becerra L. et al. Neuron. 2001;32(5):927-946.
Neuro-anatomical overlap of pain and reward
•Effects can be blocked with naloxone•Binding induces second-messenger induced changes
Opioid systems in underlie both Pain and Reward responses
Ballantyne and LaForge, 2007
BALB/c (common inbred)
CXBH
(recombinant inbred)
C57
(common inbred)
CXBK
(recombinant inbred)
Pain Tolerance
1
1
1
1
Analgesic Response
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
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.
Opioid Responses by Murine Strain
Pain Tolerance in Opioid and Cocaine abusers
0
30
60
90
120
150
180
cold-pressor pain tolerance (seconds)
opioid abusers
cocaine abusers
ex-opioid abusers
ex-cocaine abusers
(Compton, 1994)
Pain tolerance by -opioid agonist activity
0
20
40
60
80
100
120
methadone buprenorphine control
*
(n = 18/group)
Length
of
cold
-pre
ssor
imm
ers
ion
(min
)
Compton, P et al., Drug Alcohol Depend 2001; 63:139-146.
“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.
Not a new observation
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 administrationLi X, et al., Brain Res Mol Brain Res 2001;86:56-62.
Opioid Responses by Murine Strain
Liang DY, et al., Pharmacogenet Genomics. 2006;16(11):825-35.
C57BL/6J common inbred
- Poor baseline pain tolerance- Poor analgesia response- High opioid reinforcement
Pain tolerance
Opioid-induced analgesia
Opioid-induced hyperalgesia
Adapted from: Solomon R, American Psychologist 1980; 35(8):691-712; Koob GF, et al, Neuroscience & Biobehavioral Reviews 1989;13:135-140.
Opioid-induced hyperalgesia as an Opponent Process
Opioid administration
*P = 0.013**P = 0.004
***
-300
-250
-200
-150
-100
-50
0
50
100
5 Minutes 15 Minutes
Secon
ds
IM morphine IV morphine IV hydromorphone Placebo
Change in Cold-Pressor Pain Tolerance by Condition at 5 and 15 Minutes
Compton P, et al. J Pain. 2003;4(9):511-519.
↑ cytokine, chemokine
+
Peripheral neuron
Central neuronMaier D, et al. , 2004 ; DeLeo JA, et al., 2004
GluGluGluGlu
GluGlu
GluGlu
NMDA-RNMDA-R
PKC
+
mu opioid-R
+ morphine
Glial cell
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
0
10
20
30
40
50
baseline 1 month*p < 0.01
tim
e (
s)
*
Cold-pressor pain tolerance before and after one month of opioid therapy (75mg MS) in chronic pain patients (n = 6)
Chu, Clark & Angst, 2006
OIH in chronic pain patients
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
VA
S p
ain
in
tensi
ty
Dose in morphine equivalents Duration on opioid therapy
Chronic Pain Opioid Therapy
Improved functioning Unimproved functioning
Addictive disease
+
opioid non-responsive pain
Adapted from: Weaver & Schnoll The Clinical Journal of Pain 2002 18:S61-S69 Mitra Journal of Opioid Management 2008 4:123-130.
Psychiatric Illness
Opioid-induced hyperalgesia
Opioid-responsive pain
Absence of addiction
Differential Dx Nature of pain Onset
Response to opioid
administration
Type ofprevious 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
Pseudo-addiction
Localized to pain site
Ongoing Pain improves either
Addictive disease
Diffuse, hyperalgesia
Ongoing Pain worsens Short acting
Pain Characteristics and Opioid Analgesia responses
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
• No overall GPN effect on pain responses by group
*p=0.02, **p =0.01
***
*
*p=0.03
•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
THANK YOU!
Presenter Contact Details:
Peggy Compton RN, PhD, FAANAssociate Dean and ProfessorSchool of Nursing and Health StudiesGeorgetown University [email protected]
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