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 pcompton@georgetown.edu

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