P eggy Compton, RN, PhD, FAAN Professor and Associate Dean School of Nursing and Health Studies

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

4. 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

5. Opioid Responses by Murine Strain 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.

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

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

8. 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.

9. Opioid-induced Hyperalgesia • Increased sensitivity to pain resulting from opiate administration • Pain-free murine models made tolerant to morphine have significantly decreasedtolerance 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 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.

12. 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.

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

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

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 VAS pain intensity Dose in morphine equivalents Duration on opioid therapy Cohen S, et al., RegAnesth Pain Med 2008; 33: 199-206

18. Chronic Pain + OpioidTherapy Improved functioning Unimprovedfunctioning opioid non-responsive pain Opioid-responsive pain Absence of addiction Opioid-induced hyperalgesia Psychiatric Illness Addictive disease Adapted from: Weaver & SchnollThe Clinical Journal of Pain 2002 18:S61-S69 MitraJournal of Opioid Management 2008 4:123-130.

19. 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 ** * * *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)

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