The Cycle of Chronic Pain and Addiction

1. The Cycle of Chronic Pain and Addiction Suzette Glasner-Edwards, Ph.D. UCLA Integrated Substance Abuse Programs July 25th, 2012

2. Overview • Pain and addiction basics • Neurobiology of pain • Pain and health • Neurobiology of addiction • Cross-addiction • The chronic pain-addiction cycle

3. Pain • Definition • An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage International Association for the Study of Pain

4. Chronic Noncancer Pain (CNCP) • CNCP Definition: Pain that is: • Unassociated with a terminal medical condition; and • Unlikely to abate as a result of tissue healing, thus requiring long-term management. • Often refers to pain not caused by ongoing tissue pathology (e.g., backache, fibromyalgia). • CNCP is challenging to assess and treat. • It can be managed but not necessarily completely eliminated.

5. Pain and Addiction Basics • CNCP and addiction commonly co-occur. (Savage et al., 2008; Chelminski et al., 2005) • Chronic pain and addiction have many common neurophysiological patterns. • Abnormal neural processing in peripheral and central nervous systems underlie pain. • Likewise, repeated drug use may result in dysfunctional alternations to the brain’s memory, reward, and stress systems.

6. Function of Pain • Pain protects humans by providing warning of biologically harmful processes • Reflexes, regulated at the level of spinal cord, protect us by removing a body part away from danger • Associated emotional arousal, experienced as distress or fear, may also motivate a person to move away from a painful stimulus • Fear of pain can also prevent a person from moving, which in turn promotes healing of the injury resulting in that pain • Pain may elicit an empathic, comforting, and health promoting behavior in people observing a person in pain.

8. Efforts to Improve Pain Treatment Resulted in: • Increasing availability of opioid analgesics • Increased production and distribution • Increased marketing to physicians and public • Increase in the number of prescriptions filled • 150% increase in controlled substance Rx • Increased internet availability • Increase in prescription opioid use, misuse, abuse and addiction • Increase sharing and diversion of opioids

9. As Prescriptions Increase, Emergency Room Reports Have Increased at the Same or Faster rate 24000 80000 . Hydrocodone 70000 prescriptions 18000 emergency 60000 50000 Number of Prescriptions (in 1000s) ED Mentions 12000 40000 Oxycodone 30000 prescriptions 6000 emergency 20000 10000 0 0 1994 1995 1996 1997 1998 1999 2000 2001 Source: IMS Health for Prescriptions and SAMHSA (DAWN) for Emergency Department Mentions

10. Unintentional Drug OverdoseDeath Rates and Total Sale of Opioids Paulozzi, LJ. Congressional Testimony. CDC. 2007.

11. Number of New Non-Medical Users of Therapeutics SOURCE: SAMHSA, NSDUH, 2010 results.

12. Chronic Pain & Opioid Statistics Twenty percent of the general population are significantly affected by chronic non cancer pain (CNCP) Chronic Opioid Therapy (COT) for CNCP Doubled 1980-2000, doubled again 2000-2010 Now 2-3% of the US adult population, 10 million are treated with opioids Verhaak PF, Kerssens JJ, Dekker J, Sorbi MJ, Bensing JM. Prevalence of chronic benign pain disorder among adults: a review of the literature. Pain. 1998 Sep;77(3):231-9. Review. Gureje O, Von Korff M, Simon GE, Gater R. Persistent pain and well-being: a World Health Organization Study in Primary Care. JAMA. 1998 Jul 8;280(2):147-51. Erratum in: JAMA 1998 Oct 7;280(13):1142.

13. Addiction Abuse/Dependence Prescription Drug Misuse Aberrant Medication-Taking Behaviors (AMTBs) A spectrum of patient behaviors that may reflect misuse Total Chronic Pain Population Adapted from Steve Passik. APS Resident Course, 2007 Daniel Alford, MD

14. Pain and Addiction Basics (cont’d) • Commonalities between chronic pain and addiction • Both are neurobiological conditions involving disordered CNS function. • Both are mediated by genetics and environment. • Both may have significant behavioral components. • Both may have serious harmful consequences if untreated or not treated properly. • Both often require comprehensive treatment.

15. Pain and Addiction Basics (cont’d) • Effects on Health and Well-Being • Insomnia • Depression • Impaired functioning across various domains • Chronic pain and addiction are not static conditions • Tx for one can interfere with tx for the other • Medications suited for one may not be appropriate for the other • Integrated treatment addressing both pain and addiction conditions simultaneously is the gold standard (Traston et al., 2004)

16. The Experience of Pain • Pain is both a sensory and an emotional experience. • Factors that affect pain perception include: • Culture • Temperament • Psychological state • Memory • Cognition • Beliefs and expectations • Co-occurring health conditions • Gender • Age

17. Neurobiology of Pain • Pain signals stimulate brain activity via the spinal cord • Signals continue to travel from spinal cord  brain • Along the way, several regions/pathways are involved: • Somatosensory cortex • Limbic system • Autonomic centers controlling breathing, respiration, HR • Nerve pathways where the pain is localized (inflammatory response - protective) • Antinociceptive response involves various chemicals: • Oxytocin • Endorphins • Enkephalins • Serotonin

18. Nociceptors free nerve endings in skin respond to noxious stimuli

19. Nociceptors • Nociceptors are special receptors that respond only to noxious stimuli and generate nerve impulses which the brain interprets as "pain".

21. Neurobiology of Pain (cont’d) • Antinociceptive response involves various chemicals: • Endorphins • Enkephalins • Serotonin • GABA • Norepinephrine • Relaxin • These chemicals, involved in “inhibitory” signaling, serve to dampen pain sensation and provide pain relief. (Brookoff, 2005)

23. Types of Pain • Acute : Ex, Postoperative pain • Acute intermittent: Ex, Migraine headache • Chronic: persistent, may be of unknown etiology • Categories of pain are not mutually exclusive • Ex: Acute pain may shift to become chronic • One type of pain may be superimposed on another type

24. Chronic Pain • Can be nociceptive, neuropathic, or a mixture of both • Pains not involving a noxious stimulus or a neurological lesion are thought to result from CNS dysfunction (e.g., migraine headache, fibromyalgia). • Often the result of a process of sensitization following injury or illness, which involves: • Lowered pain thresholds • Hyperalgesia (def: amplified pain responses) • Allodynia (def: things that were not previously painful can produce a pain response) • Increased signalling in the absence of pain stimuli can progress to produce a continuous experience of pain even in the absence of ongoing tissue damage.

25. Hyperalgesia: The skin, joints, or muscles that have already been damaged are unusually sensitive. A light touch to a damaged area may elicit excruciating pain; Primary hyperalgesia occurs within the area of damaged tissue; Secondary hyperalgesia occurs within the tissues surrounding a damaged area.

26. Allodynia • It occurs when normally innocuous stimuli begin to produce pain. • Following intense, repeated, or prolonged stimulation, or if inflammation is present, • the threshold for primary afferent nociceptors is lowered and • the frequency of firing is higher for all stimuli. • Example: after a sunburn, light breeze may elicit pain Lundy-Ekman, 2002, Chapter 7: Somatosensation

27. Chronic Pain (Cont’d) • Tissue damage can trigger release of chemicals that sensitize nerve fibers and alter gene expression. • Altered gene expression causes changes in signaling. • Some of these signaling changes enable non-pain-conducting fibers to trigger pain in the Central Nervous System. • Chronic pain can also result from injured nerve fibers that regenerate in a neuroma • Neuroma  pain signals with little or no stimulation.

28. Fast and Slow Pain • Most pain sensation is a combination of the two types of messages. • If you prick your finger you first feel a sharp pain which is conducted by the A fibres, • and this is followed by a dull pain conveyed along C fibres.

29. Fast and Slow Pain (cont’d) • Fast pain (acute) • occurs rapidly after stimuli (.1 second) • sharp pain like needle puncture or cut • not felt in deeper tissues • larger A nerve fibers • Slow pain (chronic) • begins more slowly & increases in intensity • in both superficial and deeper tissues • smaller C nerve fibers

30. spinothalamic pathway to reticular formation Aδ nerve C nerve nociceptor nociceptor Impulses transmitted to spinal cord by • Myelinated Aδ nerves: fast pain (80 m/s) • Unmyelinated C nerves: slow pain (0.4 m/s)

31. somato- sensory cortex thalamus spinothalamic pathway reticular formation Impulses ascend to somatosensory cortex via: • Spinothalamic pathway (fast pain) • Reticular formation (slow pain)

32. Referred pain • Pain originating from organs perceived as coming from skin • Site of pain may be distant from organ

33. Convergence theory: This type of referred pain occurs because both visceral and somatic afferents often converge on the same interneurons in the pain pathways. Excitation of the somatic afferent fibers is the more usual source of afferent discharge, so we “refer” the location of visceral receptor activation to the somatic source even though in the case of visceral pain. The perception is incorrect. Referred pain The convergence of nociceptor input from the viscera and the skin.

34. Pain’s Effect on Health • Persistent pain can have profound effects on health. • When pain stimuli produce repeated physiological stress responses, the experience of stress can be prolonged and can lead to exhaustion. • Continued pain may trigger emotional responses including depression, anxiety, and insomnia, which in turn, produce more pain. • Physical inactivity and overuse of sedating medications may exacerbate anxiety and depression and is associated with suicidal ideation. • Outcomes of pain treatment are worse in the presence of depression.

35. Pain and Health

36. What is Addiction?Addiction is A Brain Disease • Characterized by: • Compulsive Behavior • Continued abuse of drugs despite negative consequences • Persistent changes in the brain’s structure and function

37. Advances in science have revolutionized our fundamental views of drug abuse and addiction.

38. Decreased Brain Metabolism inDrug Abuser High Low Healthy Heart Diseased Brain/ Cocaine Abuser • Addiction is Like Other Diseases… • It is preventable • It is treatable • It changes biology • If untreated, it can last a lifetime Decreased Heart Metabolism in Heart Disease Patient Healthy Brain Diseased Heart

39. Addiction Involves Multiple Factors

40. Dopamine Movement Motivation Reward& well-being Addiction

41. Why Do People Take Drugs in The First Place? To Feel Better To lessen: pain anxiety worries fears depression hopelessness To Feel Good To have novel: feelings sensations experiences AND to share them

42. Why Do People Abuse Drugs? Drugs of Abuse Engage Motivationand Pleasure Pathways of the Brain

43. Drugs can be “Imposters” of Brain Messages

44. The Neuron: How the Brain’s Messaging System Works Dendrites Cell body (the cell’s life support center) Axon Terminal branches of axon Neuronal Impulse Myelin sheath Donald Bliss, MAPB, Medical Illustration

46. dopamine transporters

47. Natural Rewards Elevate Dopamine Levels 1 2 3 4 5 6 7 8 Sex Food 200 200 NAc shell 150 150 DA Concentration (% Baseline) % of Basal DA Output 100 100 Empty 50 Box Feeding Female Present 0 Sample Number 0 60 120 180 Time (min) Di Chiara et al., Neuroscience, 1999.,Fiorino and Phillips, J. Neuroscience, 1997.

49. Effects of Drugs on Dopamine Release Accumbens Accumbens 400 1100 1000 900 DA 300 DOPAC 800 DA HVA 700 DOPAC HVA 600 % of Basal Release 200 % of Basal Release 500 400 300 100 200 100 0 0 0 1 2 3 4 5 hr 0 1 2 3 4 5 hr 250 Accumbens 250 Dose 200 Accumbens mg/kg 0.5 Caudate 200 mg/kg 1.0 150 mg/kg 2.5 mg/kg 10 150 100 % of Basal Release % of Basal Release 0 1 2 3 hr 100 0 0 0 1 2 3 4 5 hr Time After Drug Amphetamine Cocaine Morphine Nicotine Time After Drug Di Chiara and Imperato, PNAS, 1988

50. But Dopamine is only Part of the Story Scientific research has shown that other neurotransmitter systems are also affected: Serotonin Regulates mood, sleep, etc. Glutamate Regulates learning and memory, etc.