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Diagnosis and Management of Centralized Pain Forest Tennant, MD, DrPH


Nothing to Disclose

Learning Objectives Differentiate a patient with centralized pain from one with peripheral pain Describe treatment plans for centralized pain Evaluate impairment and functional ability of a patient with centralized pain Review replacement, neurogenic, and neuroprotective hormones for centralized pain

Definition Pain that arises in the periphery or in the central nervous system (CNS) and imprints itself in the permanent memory of the CNS

Henry DE, Chiodo AE, Yang W. Central nervous system reorganization in a variety of chronic pain states: a review. PMR 2011;3(12):1116-25.

Centralized vs. Central pain Central pain is the classic term that follows or accompanies a recognized CNS disease such as multiple sclerosis or a stroke

Jay GW. Classic central pain syndrome: review of neurologic causes of pain. Pract Pain Manag 2012;12:48-63.

Conceptually The most important discovery of the past generation

WHY? Management and outcomes are quite different from peripheral pain Watkins LR, Hutchinson MR, Ledeboer A, et al. Normal Cousins lecture. Glia as the bad guys: implications for improving clinical pain control and the clinical utility of opioids. Brain Behav Immun 2007;21(2):131-146.

Terminology PAST


 Severe Chronic

 Centralized Chronic

 Intractable

 Centralized Intractable

 Persistent

 Centralized Persistent

Tracey I, Bushnell MC. How neuroimaging studies have challenged us to rethink: is chronic pain a disease? J Pain 2009;10(11):1113-1120.

Time For Centralization To Occur Post Injury Can Be Immediate With Sudden Injury Usual – About 6 To 8 Weeks Post-surgery Can Be Delayed After Injury And Suddenly Occur Patient Example: “It Took Me Over”

Perkins FM, Kehlet H. Chronic pain as an outcome of surgery: a review of predictive factors. Anesthesiology 2000;93(4):1123-1133.

Why Make A Diagnosis Of Centralized Pain? Outcome Treatment Education Impairment/Disability Different from peripheral pain Tennant FS. The critical necessity to diagnose pain that is centralized. Prac Pain Manag 2012;12:55-58.


Centralized Pain Mild Moderate Severe

CNS Cellular Characteristics Progressive Inflammatory Tissue Destructive Must be considered a severe chronic disease with a tragic outcome Apkarian AV, Sosa Y, Sonty S, et al. Chronic back pain is associated with decreased prefrontal and thalamic gray matter density. J Neurosci 2004;24(46):10410-10415.

How Centralized Pain Develops  Injured peripheral nerves  Retrograde chemical and/or electronic signals enter CNS  Microglial cell activation  Neuroinflammation

How Centralized Pain Develops (cont’d)  Release of excess glutamate/neurotoxins  Cell death, apoptosis, reformation*  Imprinting of pain sensation *may also be called neuroplasticity or reorganization Teutsch S, Herken W, Bingel U, Schoell E, May A. Changes in brain gray matter due to repetitive painful stimulation. Neuroimage 2008;42(2):845-849.

Glial Activation Normal


Courtesy of Practical Pain Management

Diagnosis Of Centralized Pain Made by history and physical examination Laboratory tests are supportive – NOT confirmatory

Tennant F. The critical necessity to diagnose pain that is centralized. Prac Pain Manag 2012;12:55-58.

Hallmarks Of Clinical Diagnosis Pain Is Constant Poor Or Zero Response To Peripheral Treatments Insomnia Excess Sympathetic Discharge

Specific Clinical And Diagnostic Characteristics  Constant pain-never leaves  Poor or no response to peripheral treatments such as corticoid injections, acupuncture, topical anesthetics, and electromagnetic measures  Peripheral site shows no swelling, redness, edema, or pain on pressure  Periodic episodes of allodynia, burning, and hyperalgesia Strittamatter M, Bianchi O, Ostertag D, et al. Altered function of the hypothalamic-pituitary-adrenal axis in patients with acute, chronic and episodic pain. Schmerz (Berlin Germany) 2005;19(2):109-116.

Clinical And Diagnostic Characteristics  Severe insomnia  Neuroinflammation as evidenced by elevated erythrocyte sedimentation rate (ESR)or C-reactive protein (CRP)  Overstimulation of the pituitary as evidenced by high serum levels of corticotropin (ACTH), pregnenolone, and cortisol  Pituitary-adrenal suppression in late stage with low serum levels of corticotropin (ACTH), pregnenolone, and cortisol  Excess sympathetic discharge as evidenced by tachycardia, hypertension, mydriasis, hyperthyroidism, hyperreflexia, and vasoconstriction (cold hands and feet)

Patient with centralized pain who is cold in Southern California

Centralized pain patient with pale, cold, muscle-wasted hands (“spindling�)

Laboratory And Written Diagnostic Measures  Inflammatory Markers – Crp – Esr  Hormones – Corticotropin (Acth) – Pregnenolone – Testosterone – Cortisol  Cytochrome P450 Metabolic Enzymes – 2d6 – 2c9 – 2c19  Depression Scales (Beck Or Other)  Mental Ability Scales (Mini-mental Or Other)

Benefits Of Clinically Diagnosing Centralized Pain  Determine whether the patient needs testing for inflammatory markers and serum hormone levels  Eliminate useless peripheral treatment measures  Avoids mislabeling patients as drug seekers, pseudo-addicts, or mentally ill  Justifies aggressive pharmacologic treatments  Provides a definitive diagnosis to help settle disability and worker’s compensation claims  Establishes a solid reason to prescribe opioids and helps satisfy regulators  Educate all concerned parties about central pain, including, family, pharmacists, regulators, the legal community, and third-party payers

Aggressive Medical Treatment May Be Required  Opioids including topical  Neuropathic agents  Antidepressants  Bedtime sedatives  Anti-inflammatory agents  Hormone replacement  Stimulants

Stimulants In Centralized Pain  Usually needed in severe cases  Seems counterintuitive since excess sympathetic-efferent discharge  Administration usually stops sympathetic discharge, allodynia, and hyperalgesia  Reason? Decreased dopamine and norepinephrine?  Agents: Dextroamphetamine, methylphenidate, phentermine Miksic S, Shearman GT, Lal H: Differential enhancement of narcotic discrimination and analgesia by amphetamine and haloperidol: an evidence for distinct mechanisms underlying analgesia and euphoria. Subst Alcohol Actions Misuse 1980; 1(3):281-5. Drago F, Caccamo G, Continella G, et al. Amphetamine-induced analgesiadoes not involve brain opioids. Eur J Pharmacol 1984; 101(3-4):267-9.

Topical Opioids  Seem to work well with centralized pain  Opioids have been known to suppress electrical charges since Dr. Galvani’s work in the 1700s  Appears to calm efferent, sympathetic discharges

Vera-Portocarrero LP, Zhang ET, Ossipov MG, et al. Descending facilitation from the rostral ventromedial medulla maintains nerve injury-induced central sensitization. Neurosci. 2006;14(4):1311-1320. Coyle DE. Partial peripheral nerve injury leads to activation of astroglia and microglia which parallel the development of allodynic behavior. Glia.1998;23:75-83.

Opium prevents death of frog shocked with a Leyden jar

Treatment Measures DIET




B12 Vitamin-Mineral Preparation GABA or Precursors (Taurine, Glutamine)

Any increase in blood flow. (Walking, Massage, etc.)

Psycho-Social-Family Support  Family must be involved  Counseling directed at: 1. Life-time, impairment 2. Compliance with a comprehensive therapy program 3. Prevention of mental deterioration 4. Socialization 5. Hope 6. Activity 7. “Spirituality” and “Happiness”

Hormone Replacement Testosterone Cortisol Pregnenolone Estrogen

Prevention Of Complications Osteoporosis Hyperlipidemia/diabetes Mental deterioration

40 year old nurse with neck injury, centralized pain, and pituitary overstimulation note: asymmetry

note: asymmetry

note: asymmetry

note: asymmetry

14 years later

Low Testosterone + High Cortisol = Osteoporosis And Sudden Spinal Collapse

Ancillary Agents From Animal Studies Drug –minocycline –pentoxyfille –acetazolamide

Possible Actions –anti-inflammatory –blood flow antiinflammatory –central edema antiinflammatory

Hormone Treatment In Centralized Pain

Replacement Neurogenesis Neuroprotection

Testing For Replacement Corticotropin (Acth) Cortisol Pregnenolone Testosterone

Replacement Guideline  Cortisol choice of: a. Hydrocortisone 20 to 40 mg a day b. Methylprednisolone 16 to 48 mg a day c. Prednisone 20 to 30 mg a day Hughe J. Adrenocorticol insufficiency in Conn’s Current Therapy 2011, Bolec, Keller, Rakes, Elseveir/Sander, Philadelphia, 2011;p651-653.

Replacement Guideline (cont’d)  Pregnenolone 200 mg a day titrating up to 800 mg a day

Tennant FS. Low pregnenolone serum levels are associated with poor pain control. Amer Acad Pain Med, Washington DC, 2011. McGavack TH, Chevalley J, Weissberg J. The use of delta 5 pregnenolone in various clinical disorders. J Clin Endocrinol 1951;11:559-577.

REPLACEMENT GUIDELINE (cont’d)  Testosterone a. Males: use a commercial testosterone preparation per manufacturer’s instructions b. Depo-injectable 200 mg every 2 to 4 weeks c. Females: one fourth the male dosage Tennant F, Lichota L. Testosterone replacement in chronic pain patients. Pract Pain Manag 2012;10:12-15. Male hypogonadism in The Merck Manual of Diagnosis and Therapy. Merck Research Labs Whitehouse Station, NJ. 18th, 2006,pp1944-1947.

Neurogenesis GROWTH OF NERVES NEUROPROTECTIVE Keeps nerves from degenerating (ie, Neurodegeneration)

Neurogenic And Neuroprotective Hormones Those hormones that have anabolic effects and promote growth and repair of nerves –Human Chorionic Gonadotropin –Progesterone –Pregnenolone –Oxytocin

To Date With Neurogenic And Neuroprotective Hormones Severe centralized pain patients who are on opioids and have normal hormone serum levels NEW EXPERIENCE –Chronic pain patients on low dose short-acting opioids (eg, hydrocodone, oxycodone to prevent use of longacting opioids or high dose opioid therapy

HCG Sublingual 125 units a day 1st week and 250 units the second week

Max dosage 750 units a day. Injectable 500 to 1000 units subcutaneous 2 to 3 times a week Lei ZM, Rao CV. Neural actions of luteinizing hormone and human chorionic gonadotropin. Seminars Reprod Med 2001;19:103-109.

Tennant F. Human chorionic gonadotropin (HCG) for intractable central pain. Amer Acad Med, Palm Springs, 2012. Male hypogonadism in The Merck Manual of Diagnosis and Therapy. Merck Research Labs Whitehouse Station, NJ. 18th, 2006,pp1944-1947.

Medroxyprogesterone Topical –30 mg per ounce of base (eg, cold cream or other) applied TiD to QiD

Oral –start at 10 mg BiD –max dosage 50 mg a day Kilts, et al. Neurosteroids and self-reported pain in veterans who served in the Military after September 11, 2001. Pain Med 2010;10:1469-1476. Tennant F. Clinical trial of progesterone for intractable pain. Amer Acad Pain Med, Palm Springs, CA 2012. uluns E, Adashi EY. Postmenopausal hormone replacement in Williams Textbook of Endocrinology 11th Ed, Saunders/Elesevier, Philadelphia, 2008,pp599-604.

Pregnenolone  Start: 200 mg a day  Titrate upward to Max dosage of 800 mg a day  Must chew tablets  Side effects are – headaches – dizziness – dysphoria – acne

Guth L, Zhang Z, Roberts E. Key role for pregnenolone in combination therapy that promotes recovery after spinal cord injury. Proc Natl Acad Sci 1994;91:12308-12312. Tennant FS. Low pregnenolone serum levels are associated with poor pain control. Amer Acad Pain Med, Washington DC, 2011. McGavack TH, Chevalley J, Weissberg J. The use of delta 5 pregnenolone in various clinical disorders. J Clin Endocrinol 1951;11:559-577.

Titration Goals Of Clinical Trails  Move dose upward over 4 to 6 weeks  Endpoint is when patient perceives – more energy – mental abilities – sleep – pain stability

 Stop trial if no effect after 60 to 90 days NOTE: Opioid dosage reduction occurs in the majority of patients

Case Report 1 A 63 year old female with severe lumbar spine degeneration was referred taking celecoxib, carisoprodol and acetaminophen/hydrocodone. Had failed epidurals and IDET procedure. Hormone screening, CRP, and ESR were normal. Rather than increase opioids she is managed on HCG and medroxyprogesterone cream. Took only one opioid dose last month

Case Report 2 A 61 year old male with 3 hip replacement surgeries was referred taking 12 acetaminophen/hydrocodone a day. Rather than continue acetaminophen/hydrocodone or start a long-acting opioid he is managed with buprenorphine/naloxone 3 mg, pregnenolone 200 mg, and HCG 250 units a day

Case Report 3 A 59 year old female was referred with the diagnosis of â&#x20AC;&#x153;RSDâ&#x20AC;? of abdomen and was taking acetaminophen/ hydrocodone, pregabalin, venlafaxine, Topamax, and trazodone. Her corticotropin was below normal, <5 pg/ml. Rather than start additional or high dose opioids, she is maintained on medroxyprogesterone, HCG, and pregnenolone

Case Report 4 A 41 year old school teacher of Asia-Pacific descent was diagnosed with a undifferentiated immune disorder. She has widespread muscular and arthritic pain. At the time of referral she was taking acetaminophen/hydrocodone, ketamine, Tramadol, rizatriptan, morphine, carisoprodol, and tapentadol. She claimed she was getting no relief and genetic testing revealed 2-CYP450 defects (CYP2D6 and CYP2C19). She stopped all opioids and is now treated with only medroxyprogesterone cream and HCG

Case Report 5 A 61 year old male developed gum and dental infections 30 years ago and required multiple surgical procedures of the face. He was referred taking codeine and hydrocodone compounds. He has ceased codeine use and maintains on 4 to 6 acetaminophen/ hydrocodone and chewable pregnenolone 500 to 600 mg a day

References From Animal Studies 1. Asiedu M, Ossipov MHO, Kaila K, et al. Acetazolamide and midazolam act synergistically to inhibit neuropathic pain. Pain 2010; 148(2):302-308. 2. He Y, Appel S, Le W. Minocycline inhibits microglial activation and protects nigral cells after 6-hydroxydopamine injection into mouse striatum. Brain Res 2001;909:187-193. 3. Redeboer A, Sloane EM, Milligan ED, et al. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain 2005;115:71-83. 4. Mika J, Osikowicz M, Makuch W, et al. Minocycline and pentoxifylline attenuate allodynia and hyperalgesia and potentiate the effects of morphine n rat and mouse models of neuropathic pain. Eur J Pharmacol 2007;560:142-149. 5. Vale ML, Benevides VM, Sachs D, et al. Antihyperalgesic effect of pentoxifylline on experimental inflammatory pain. Br JPharmacol 2004;143:833-844. 6. Kloppenburg M, Mattie H, Douwes N, et al. Minocycline in the treatment of rheumatoid arthritis: relationship of serum concentrations to efficacy. J Rheumatol 1995;22:611-616. 7. Lin CS, Tsaur ML, Chen CC, et al. Chronic intrathecal infusion of minocycline prevents the development of spinal-nerve ligation-induced pan in rats. Reg Anesth Pain Med 2007;32:209-216. 8. Liu J, Feng X, Yu M, et al. Pentoxifylline attenuates the development of hyperalgesia in a rat model of neuropathic pain Neurosci Lett 2007;412:268-272. 9. Stirling DP, Khodarahmi K, Liu J, et al. Minocycline treatment reduces delayed oligodendrocyte death, attenuates axonal dieback, and improves functional outcome after spinal cord injury. J Neurosci 2004;24:2182-2190. 10. 32.Wordiczek J, Szczepanik AM, Banack M, et al. The effect of pentoxifylline on post-injury hyperalgesia in rats and post-operative pain in patients. Life Sci 2000;66:1155-1164. 11. Yrjanheikki J, Tikka T, Keinanen R, et al. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci USA 1999;96:13496-13500. 12.Tikka, TM, and Koistinabo JE. Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia. J Immunol 2001;166:7527-7533. 13. Yrjanheikki J, Tikka T, Keinaned R. et al. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci USA 1999;96:13496-13500. 14. Radhakrishnan R, Sluka KA. Acetazolamide, a carbonic anhydrase inhibitor, reverses inflammation-induced thermal hyperalgesia in rats. J Pharmacol Exp Ther 2005;313:921-927.

References From Animal Studies 15. Hirono M, Igarashi M, Matsumoto S. The direct effect of HCG upon pituitary gonadotrophin secretion. Encocrin 1972;90:1214-1219. 16. Roglio I, Bianchi R, Gotti S, et al. Neuroprotective effects of dihydroprogesterone and progesterone in an experimental model of nerve crush injury. Neurosci 2008;155:673-685. 17. Schumacher M, Sitruk-Ware R, De Nicola AF. Progesterone and progestins: neuroprotection and myelin repair. Curr Opin Pharmacol 2008;8:740-746. 18. Thomas AJ, Nockels RP, Pan HQ, et al. Progesterone is Neuroprotective after experimental acute spinal cord trauma in rats. Spine 1999;24:21342138. 19. Pollack AEk, Wooten GF. Differential regulation of striatal preproenkephalin mRNA by D, and D2 dopamine receptors. Mol Brain Res 1992;12:111119. 20. Rao, CV. Nongonadal actions of LH and hCG in reproductive biology and medicine. Sem in Repro Med (Guest editor) 2001;19:1-119. 21. Lei ZM, Rao CV. Neuroal actions of luteinizing hormone and human chorionic gonadotropin. Sem in Repro Med (Guest editor) 2001;19:103-109. 22. Lukacs H, Hiatt ES, Lei ZM, et al. Peripheral and intracerebroventricular administration of human chorionic gonadotropin alters several hippocampus associated behaviors in cycling female rats. Hor and Behav 1995;29:42-58. 23. Guth L, Zhang Z, Roberts E. Key role for pregnenolone in combination therapy that promotes recovery after spinal cord injury. Proc Natl Acad Sci 1994;91:12308-12312.

Diagnosis and Management of Centralized Pain