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PAIN AND THE ENDOCRINE SYSTEM Forest Tennant MD, DrPH.


Disclosure  Nothing to Disclose


Learning Objectives  Recite how hormones control pain  Identify which chronic pain patients should be tested for hormone serum levels  Interpret the significance of hormone serum levels  Review replacement, neurogenic, and neuroprotective hormones


HORMONES FOR REPLACEMENT, NEUROGENESIS AND NEUROPROTECTION


HOW HORMONES CONTROL PAIN  REDUCTION OF INFLAMMATION  CONTROL NERVE CONDUCTION  MEDIATE RECEPTOR BINDING  TISSUE GROWTH

1. Bateman A, Singh A, Kral T, et a1. The immune-hypothalamic-pituitary adrenal axis. Endocr Rev 1989;10:92-112. 2. McEwen BS, deKloet ER, Rostene WH. Adrenal steroid receptors and actions in the nervous system. Physiol Rev 1986;66:1121-1188.


BASIC HORMONE RESPONSE IN A PAIN FLARE Stimulation of Hypothalamic-Pituitary-Adrenal System

Serum Levels Go Up Corticotropin (ACTH) Pregnenolone Cortisol Testosterone


BASIC HORMONE RESPONSE IN CHRONIC SEVERE PAIN Suppression of Hypothalamic-Pituitary-Adrenal System

Serum Levels Go Down Corticotropin (ACTH) Pregnenolone Cortisol Testosterone


WHY HORMONE TEST?  Determine if replacement of one or more hormones is necessary to achieve pain control  Determine if a severe stress state is present and more aggressive pain management is needed  Separate legitimate pain patients from drug seekers  Identify a hormone abnormality such as hyper or hypocortisolemia that has long-term complications


WHO SHOULD BE TESTED ď śChronic pain patients with constant pain ď śChronic pain patients who complain of poor pain control, insomnia, and failure of standard opioid dosages to relieve pain


HORMONE METABOLIC PATHWAY IN ADRENALS AND GONADS


ADRENAL AND GONADAL METABOLISM Corticotropin (ACTH) – Pituitary hormone that activates adrenal metabolism PRECURSORS Pregnenolone Progesterone Dehydroepiandrosterone (DHEA)

 Cortisol  Estrogen  Testosterone  Aldosterone

END PRODUCTS


WHAT HORMONES SHOULD BE TESTED? A four panel test is recommended:

Cortisol Pregnenolone Testosterone Corticotropin (ACTH) Other hormones are optional.


OPTIONAL HORMONES THAT CAN BE TESTED Corticotropin Releasing Hormone (CRH) Dehydroepiandrosterone (DHEA) Progesterone Estrogen


WHEN TO TEST

6:00 TO 10:00 AM NON-FASTING


FOLLOW-UP TESTING 1 TO 3 MONTHS

IF ABNORMALITY DETECTED


Cortisol

REPLACEMENT GUIDELINE 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 Pregnenolone*

200 mg a day titrating up to 800 1. 2. 3.

mg a day

Hughe J. Adrenocorticol insufficiency in Conn’s Current Therapy 2011, Bolec, Keller, Rakes, Elseveir/Sander, Philadelphia, 2011;p651-653. 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) ďƒ˜Testosterone a. Males: use a commercial testosterone preparation per manufacturer’s instructions

1. 2.

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.


References 1. McDonald RK, Evans ET, Weise VI, et aI. Effect of morphine and nalorphine on plasma hydrocortisone levels in man. J Pharrn Exper Ther 1959; 125: 241247 2. Shenkin HA. Effect of pain on diurnal pattern of plasma corticoid levels. NeuroI1964;14: 1112-1115. 3. Glynn CJ, Lloyd JW. Biochemical changes associated with intractable pain. Br Med J 1978; 1 :280-281. 4. Moore RA, Evans PI, Smith RF, et al. Increased cortisol excretion in chronic pain. Anesthesia 1983; 38: 788- 791 5. Holaday JW, Law PY, Loh HR, et al. Adrenal steroids indirectly modulate morphine and B- endorphin effects. J Pharm Exper Ther 1979; 208 (2): 176-183. 6. HLong JB, Holaday JW, Blood -brain barrier: Endogenous modulation by adrenal-cortical function. Science 1985227: 1580-1583. 7. Russell U. Neurohormonal aspects of fibromyalgia syndrome. Rheum Dis Clin North Am 1989;15: 149-168. 8. Akil H, Shiomi H, Mathews J. Induction of the intermediate pituitary by stress: Synthesis and release of a non-opioid form of B-endorphin. Science 1985; 227: 424-428. 9. Buckingham Je. Secretion of corticotrophin and its hypothalamic releasing factor in response to morphine and opioid peptides, Neuroendocrinology 1982; 35: 111~116. 10. Tennant F. Intractable pain is a severe stress state associated with hypercortisoiemia and reduced adrenal reserve. Drug Alcoh Dep 2000;60(suppl):220221. 11. Mechlin B, Morrow AL, Maixner W, et al. The relationship of allopregnanolone immunoreactivity and HPA-axis measures to experimental pain sensitivity: evidence for ethnic differences. Pain 2007;131(1-2):142-152. 12. Goodchild CS, Robinson A, Nadeson R. Antinociceptive properties of neurosteroids IV: Pilot study demonstrating the analgesic effects of Îądolone administered orally to humans. Br J Anaesth 2001;86(4):528-534. 13. Mensah-Nyagan AG, Meyer L, Schaeffer V, et al. Evidence for a key role of steroids in the modulation of pain. Psychoneuroendocrinology 34 Suppl 2009;1:5169-5177. 14. Mensah-Nyagan AG, Kibaly C, Schaeffer V, et al. Endogenous steroid production in the spinal cord and potential involvement in neuropathic pain modulation. J Steroid Biochem Mol Bio 2008;109:286-293. 15. Pettus EH, Wright DW, Stiein DG, et al. Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury. Brain Res 2005;1049:112-119.


References (cont.) 16. Cutolo M, Foppiani L, Prete C, et aI. Hypothalamic-pituitary-adrenalcortical axis function in premenopausal women with rheumatoid arthritis not treated with glucocorticoids. I RheumatoI1999;26:282-288. 17. Tennant F, Hermann L. Normalization of serum cortisol concentration with opioid treatment of severe chronic pain. Pain Med 2002;3: 132-134. 18. Khorami S, Muniyappa R, Nackers L, et aI. Effect of chronic osteoarthritis pain on neuroendocrine function in men. Clin Endo Metab 2006;11:4313-4318. 19. Griep EN, Boersma JW, Lenties E, et al. Function of the hypothalamic-pituitary-adrenal axis in patients with fibromyalgia and low back pain .. Rheumatol 1998;25: 1374-8. 20. Chikanza JC, Petrou P, Kingsley G, et aI. Defective hypothalamic response to immune and inflammatory stimuli in patients with rheumatoid arthritis. Arthritis Rheum 1992;35: 1281-8. 21. Moore RA, Evans PI, Smith RF, et aI. Increased cortisol excretion in chronic pain. Anesthesia 1983;38:788-791. 22. Strittamatter M, Bianchi 0, 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): 109-16 . 23. Chikanza JC, Petrou P, Kingsley G, et al .. Defective hypothalamic response to immune and inflammatory stimuli in patients with rheumatoid arthritis . Arthritis' Rheum 1992;35: 1281-1288. 324. McEwen BS, Biron CA, Brunson KW, et aI .. The role of adrenocorticoids as modulators of immune function in health and disease: neural endocrine and immune interactions. Brain Res Rev 1997;23:79- 133. 25. Sapolsky RM, Krey LC, McEwen BS. Prolonged glucocorticoids exposure reduces hippocampal neuron number: implications for aging. J N eruosci 1985;5: 1222-1227. 26. Tennant F, Shannon JA, Nork JG, et al. Abnormal adrenal gland metabolism in opioid addicts: implications for clinical treatment. J Psycho Drugs 1991;23:135-149. 27. Tennant F, Hermann L. Using biologic markers to identify the legitimate chronic pain. Amer Clin Lab 2002;(June) 8-17. 28. Daniell HW. DHEA's deficiency during consumption of sustained-action prescribed opioids: evidence for opioid-induced inhibition of adrenal androgen production. J of Pain 006;7:901-907. 29. Vuong C, Van Urim SHM, O'Dell, et al. The effects of opioids and opioid analogs in animal and human endocrine systems. Endocrin Rev 2010;31 :98-132. 30. Rhodin A, Stridaberg M, Gordh T. Opioid endocrinopathy: a clinical problem in patients with chronic pain and long-term oral opioid treatment. Clin J Pain2010;26:374-380. 31. Arlt W, Callies F, Van Vligmen JC, et al. Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med 1999;341:1013-1020.


NEUROGENESIS


NEUROGENESIS GROWTH OF NERVES


NEUROPROTECTIVE KEEPS NERVES FROM DEGENERATING (I.E. NEURODEGENERATION)


References 1. Mechlin B, Morrow AL, Maixner W, et al. The relationship of allopregnanolone immunoreactivity and HPA-axis measures to experimental pain sensitivity: evidence for ethnic differences. Pain 2007;131(1-2):142-152. 2. Goodchild CS, Robinson A, Nadeson R. Antinociceptive properties of neurosteroids IV: Pilot study demonstrating the analgesic effects of Îądolone administered orally to humans. Br J Anaesth 2001;86(4):528-534. 3. Mensah-Nyagan AG, Meyer L, Schaeffer V, et al. Evidence for a key role of steroids in the modulation of pain. Psychoneuroendocrinology 34 Suppl 2009;1:5169-5177. 4. Mensah-Nyagan AG, Kibaly C, Schaeffer V, et al. Endogenous steroid production in the spinal cord and potential involvement in neuropathic pain modulation. J Steroid Biochem Mol Bio 2008;109:286-293. 5. Pettus EH, Wright DW, Stiein DG, et al. Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury. Brain Res 2005;1049:112-119. 6. Pluchino N, Luisi M, Lenzi E, et al. Progesterone and progestins: Effects on brain, allopregnanolone and beta-endorphin. J Steroid Biochem Mol Biol 2006;102:205-213. 7. Ren K, Dubne R, Murphy A, et al. Progesterone attenuates persistent inflammatory hyperalgesia in females rats: involvement of spinal NMDA receptor mechanism. Brain Res 2000;865:272-277. 8. 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. 9. Schumacher M, Sitruk-Ware R, De Nicola AF. Progesterone and progestins: neuroprotection and myelin repair. Curr Opin Pharmacol 2008;8:740-746. 10. Thomas AJ, Nockels RP, Pan HQ, et al. Progesterone is Neuroprotective after experimental acute spinal cord trauma in rats. Spine 1999;24:2134-2138. 11. Hirono M, Igarashi M, Matsumoto S. The direct effect of HCG upon pituitary gonadotrophin secretion. Encocrin 1972;90:1214-1219. 12. Rao, CV. Nongonadal actions of LH and hCG in reproductive biology and medicine. Sem in Repro Med (Guest editor) 2001;19:1-119. 13. Lei ZM, Rao CV. Neuroal actions of luteinizing hormone and human chorionic gonadotropin. Sem in Repro Med (Guest editor) 2001;19:103-109. 14. 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. 15. Pincus G, Hoagland H. Effects of administered pregnenolone on fatiguing psychomotor performance. Aviation Med 1944;April:98-115. 16. 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. 17. Wu FS, Gibbs TT, Farb DH. Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-asparate receptor. Mol Pharmacol 1991;40(3):3330336. 18. Roglio I, Bianchi R, Gotti S, et al. Neuroprotective effects f dihydroprogesterone and progesterone in an experimental model of nerve crush injury. Neurosci 2008 Aug 26;155(3):673-685. 19. Mayo W, Lemaire V, Malaterre J, et al. Pregnenolone sulfate enhances neurogenesis and PSA-NCAM in young and aged hippocampus. Neurobiol Aging 2005 Jan 26(1):103-114.


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 (e.g. hydrocodone, oxycodone to prevent use of long-acting 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 1.

Lei ZM, Rao CV. Neural actions of luteinizing hormone and human chorionic gonadotropin. Seminars Reprod Med 2001;19:103-109.

3.

Male hypogonadism in The Merck Manual of Diagnosis and Therapy. Merck Research Labs Whitehouse Station, NJ. 18th, 2006,pp1944-1947.

2.

Tennant F. Human chorionic gonadotropin (HCG) for intractable central pain. Amer Acad Med, Palm Springs, 2012.


MEDROXYPROGESTERONE

TOPICAL 30 mg per ounce of base (e.g. cold cream or other) applied TiD to QiD ORAL Start at 10 mg BiD

Max dosage 50 mg a day. 1. 2. 3.

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. 2. Tennant F. Clinical trial of progesterone for intractable pain. Amer Acad Pain Med, Palm Springs, CA 2012. 3. Buluns 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, and acne. 1. 2. 3.

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, and 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.


CLINICAL RECOGNITION AND PREVENTION OF HORMONE COMPLICATIONS


TESTOSTERONE Lack Energy Depression Insomnia Weakness Lack Motivation Poor Pain Control Lack Libido


MOST CRITICAL RECOGNITION OF HYPER AND HYPO CORTISOLEMIA


COMPLICATIONS OF HIGH CORTISOL SERUM LEVELS IN CHRONIC PAIN PATIENTS Cushing’s Syndrome OBESITY DIABETES HYPERTENSION PLETHORA DECREASED LIBIDO ATROPHIC SKIN DEPRESSION EMOTIONAL LABILITY CERVICAL FAT PAD (Buffalo Hump) OSTEOPOROSIS HEADACHES DENTAL DECAY MUSCLE WASTING IMMUNE DEFICIENCIES-FREQUENT INFECTIONS MENSTRUAL IRREGULARITIES


From Clinical Endocrinology 2nd Ed. 1994, London. CLASSIC CUSHING’S SYNDROME


Hypercortisolemia, moon face, lipid inclusion at lateral side of eye.


ALWAYS LOOK FOR Cervical Fat Pad (Buffalo Hump) Hyercortisolemia (Cushing’s Syndrome) and/or Cervical-thoracic spine contraction


Moon face and cervical fat pad.


Cervical fat pad.


SYMPTOMS AND SIGNS OF LOW CORTISOL IN A CHRONIC PAIN PATIENT Addisonâ&#x20AC;&#x2122;s Syndrome

Dull, Apathetic Demeanor Moves and Talks Slowly Inaudible Voice Stares-looks straight ahead Weight Loss Nausea, Vomiting Muscle Wasting-Spindly Fingers Anorexia Hypotension Salt Craving Tachycardia Insomnia Weakness Vitiligo Pigmentation


VITILIGO-HYPOCORTISOLEMIA From Clinical Endocrinology 2nd Ed. 1994, London.


ALWAYS LOOK FOR Thin, spindly fingers Hypocortisolemia (Addison’s Syndrome)


HYPOCORTISOLEMIA From Clinical Endocrinology 2nd Ed. 1994, London.


Patient with centralized pain who is cold in Southern California.


Centralized pain patient with pale, cold, muscle-wasted hands (â&#x20AC;&#x153;spindlingâ&#x20AC;?) and hypocortisolemia.


A HORMONAL DISASTER IN A PAIN PATIENT


40 year old nurse with neck injury, centralized pain, and pituitary overstimulation. Note: Asymmetry


Note: Asymmetry


14 years later


LOW TESTOSTERONE HIGH CORTISOL RESULT OSTEOPOROSIS AND SUDDEN SPINAL COLLAPSE


Pain and the Endocrine System