1. 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

2. “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

3. Becerra L. et al. Neuron. 2001;32(5):927-946. Neuro-anatomical overlap of pain and reward

4. 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

5. 1 Elmer, et al. 1998. 2 Elmer, et al. 1995. 3 Oliverio, et al. 1997. 4 Semenova, et al. 1995. 5 Elmer, et al. 1993. 6 Olivero & Castellano. 1974. 7 Brase, et al. 1977. 8 Gwynn & Domino. 1984. 9 Mogil, et al. 1996. 10 Belknap, et al. 1995. 11 Berrettini, et al. 1994. 12 Mogil, et al. 1995. 13 Petruzzi, et al. 1997, 14 Gelernter, et al. 1998. Opioid Responses by Murine Strain

6. Pain Tolerance in Opioid and Cocaine abusers (Compton, 1994)

7. Pain tolerance by  -opioid agonist activity (n = 18/group) Length of cold-pressor immersion (min) Compton, P et al., Drug Alcohol Depend 2001; 63:139-146.

8. “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

9. 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

10. 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.

11. 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

12. 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

13. *P = 0.013 **P = 0.004 * ** -300 -250 -200 -150 -100 -50 0 50 100 5 Minutes 15 Minutes Seconds IM morphineIV morphineIV hydromorphonePlacebo Change in Cold-Pressor Pain Tolerance by Condition at 5 and 15 Minutes Compton P, et al. J Pain. 2003;4(9):511-519.

14. ↑ cytokine, chemokine + Peripheral neuron Central neuron Maier D, et al., 2004 ; DeLeo JA, et al., 2004 Glu NMDA-R PK C + mu opioid-R + morphine Glial cell

15. 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

16. 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) Chu, Clark & Angst, 2006

17. 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 VAS pain intensity Dose in morphine equivalentsDuration on opioid therapy

18. 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 Opioid-responsive pain Absence of addiction

19. Differential Dx Nature of painOnset Response to opioid administration Type of previous opioid used Increased pain pathology Localized to pain site VariablePain improvesNeither Opioid tolerance Localized to pain site GradualPain improvesLong acting Opioid withdrawal Diffuse, hyperalgesia AbruptPain improvesShort acting Opioid-induced hyperalgesia Diffuse, hyperalgesia Abrupt or Gradual Pain worsensShort acting Pseudo- addiction Localized to pain site OngoingPain improveseither Addictive disease Diffuse, hyperalgesia OngoingPain worsensShort acting Pain Characteristics and Opioid Analgesia responses

20. 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

21. 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)

22. 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)

23. Antagonist effect of pain on IL1-ra Compton et al, 2012

24. THANK YOU! Presenter Contact Details: Peggy Compton RN, PhD, FAAN Associate Dean and Professor School of Nursing and Health Studies Georgetown University pcompton@georgetown.edu 24