Hormone treatments for chronic and intractable Pain

Hormone Treatments in Chronic and Intractable Pain

An Emerging Practice

By Forest Tennant, MD, DPH

Page 1 of 5

Once chronic or intractable pain is reasonably well controlled, patient and physician alike want some curative or permanent amelioration, in addition to symptom relief. To date, some physical therapy techniques and possibly some nutritional supplements provide a degree of permanent amelioration of pain, but these measures often fall short of wanted results.
Although early in what is clearly an emerging practice, some hormone treatments appear — albeit based primarily as anecdotal reports — to greatly enhance symtomatic pain control and possibly bestow some curative and ameliorative properties. Basic science research on some hormones distinctly points out sound reasons why some hormones should enhance pain treatment. Summarized here is a compilation of hormone treatments and their rationale for current usage by pain physicians to compliment their standard symptomatic treatments.

Definition Of Hormone

For purposes here, a hormone is defined as a compound which is produced in a body organ and secreted into the blood stream to perform some physiologic function(s). Some hormones, such as gamma amino butyric acid (GABA) and pregnenolone are produced within neurons and secreted into the blood as well as function within neurons as neurotransmitters.^1-4

Why Are Hormone Treatments Needed?

Undertreated severe, chronic, and intractable pain depletes many hormones.^5-8 With good pain control, some low serum hormone concentrations may return to normal.⁹ Some adrenal stress hormones, such as cortisol and adrenalin, may elevate in uncontrolled pain as evidenced by tachycardia and hypertension. Prolonged hypercortisolemia produced in severe, intractable pain may produce manifestations of Cushing’s disease including osteoporosis, dental erosion, obesity, fatigue, and muscle wasting. Adrenal insufficiency, with symptoms of Addison’s disease including cachexia, hypotension, electrolyte depletion and muscle wasting, may occur as the adrenal gland exhausts. While severe, chronic pain produces some hormone deficiencies, opioid administration may also suppress pituitary excretion and worsen some hormone deficiencies, particularly testosterone and possibly thyroid.^10,11 Hormone treatments are basically given to replace those that are depleted or suppressed by severe, chronic, or intractable pain and/or the underlying disease. It may also be that intermittent supraphysiologic serum levels of some hormones such as pregnenolone, adrenal androgens, GABA, human growth hormone, and chorionic gonadotropin may promote healing of nerve and other soft tissues to permanently reduce pain^12-15 (see Table 1).

Hormone	Pain-Related Functions
Pregnenolone	Nerve construction Central neurotransmitter Precursor of adrenal and sex hormones GABA & NMDA receptor binding
Gamma Amino Butyric Acid (GABA)	Inhibitory Neurotransmitter Immune stability Tissue construction Neuron stability Release growth hormone
Cortisol	Immune stability Tissue construction
Testosterone	Tissue construction Libido Anti-fatigue
Androstenedione	Tissue construction
Dihydroepiandrostone (DHEA)	Testosterone production
Thyroid	Energy Tissue construction Metabolism
Human Growth Hormone (HGH)	Tissue construction
Chorionic Gonadotropin (HCG)	Tissue construction Releases thyroid and testosterone

Table 1. Table of hormones currently used in pain patients

Testing For Hormone Deficiencies

Serum testing is available, reliable, and accurate for pregnenolone, androstenedione, DHEA, testosterone, cortisol, and thyroid. However, serologic tests for GABA, growth hormone (HGH), and chorionic gonadotropin (HCG) are best considered research at this time. GABA and HCG have such baseline low levels that deficiency assessment is impractical, and HGH is secreted in pulsatile fashion, making a single blood analysis unreliable.
Serum testing is best done in the early morning when most hormone serum levels are at their peak.^5,9 All clinical laboratories have connections to reference laboratories who perform most of the hormone tests which are used in pain treatment. Almost all insurance and health plans cover the cost of hormone testing. Testing for certain hormone deficiencies is particularly recommended for the severe, intractable pain patient who is going to require long term pharmacologic treatment with opioids and neuropathic agents. Re-testing can be done at any interval such as quarterly or yearly once hormone treatment is initiated or a hormone abnormality is detected.

Dosage

Hormone treatments are generally started at a low, daily dosage and titrated upward over time to either normalize a low serum concentration or achieve a therapeutic response. Table 2 lists the author’s recommended starting dosages. Human growth hormone, chorionic gonadotropin, and testosterone products have recommended, labeled dosages. Total daily thyroid replacement is about 3 to 4 grains and cortisone is about 20 mg. Lesser dosages than total replacement usually suffice in pain patients who initially demonstrate serum deficiencies.

Hormone Treatments in Chronic and Intractable Pain

An Emerging Practice

By Forest Tennant, MD, DPH

Page 2 of 5

Hormone	Starting Dosage
Pregnenolone	50 to 100mg a day
Gamma amino butyric acid (GABA)	1500 to 3000mg a day
Androstenedione	25 to 50mg a day
Dehydroepiandrosterone (DHEA)	25 to 50mg a day
Thyroid	1 to 3 grains a day
Cortisone	10 to 15mg a day
Human Growth Hormone (HGH)	5mg a day
Chorionic Gonadotropin (HCG)	1000 USP units (1cc), 1 to 3 times a week
Testosterone	Males— 5 grams of 1% gel each day, Females— 2.5 grams of 1% gel every other day
* Dose is titrated upward, over time, to achieve a clinical response.

Table 2. Recommended starting dosages.
Daily dosages of GABA, pregnenolone, androstenedione, and DHEA, have no labeled dosage levels and there are few reported, serious side-effects. Consequently, these hormones have been labeled as food supplements and are available without a doctor’s prescription.

Endocrinology Consultation

Physicians who are inexperienced or uncomfortable with hormone treatments should obtain consultation with an endocrinologist. The management of a patient who requires a hormone treatment with known side-effects — such as cortisone or growth hormone — may require co-management.

Pregnenolone

Basic science research shows that pregnenolone has many positive properties which suggest it should be almost a routine treatment in chronic and intractable pain.^1-3,15-18 It is produced in the adrenal gland and central nervous system, and it is frequently referred to as a neurosteroid. It modulates GABA and NMDA receptors.^2,17-18 Pregnenolone enhances cognitive and memory functions of the CNS.^16,18,19 In the adrenals, ovary, and testicle, it is the precursor of all other hormones including cortisol, testosterone, and estrogen. Serum cholesterol is the substrate for pregnenolone (see Figure 1).
Figure 1. Adrenal Gland Hormone Synthesis. Note: the hormone synthesis above is similar in the ovary and testicle except that cortisol and aldosterone are not synthesized
This hormone might best be described as the “mystery hormone,” because it appears to have multiple, major physiologic roles in the body that are poorly understood. Amazingly, it is the most ubiquitous compound in the central nervous system. Some practitioners call it a “brain food” which may prevent dementia.^13,16 Of particular relevance to pain treatment is that pregnenolone appears to have nerve construction properties, and it has shown ability to help heal spinal cord and sciatic nerve injuries in animals.^13,14 Uncontrolled, intractable pain consistently suppresses pregnenolone production and produces low serum concentrations.
Once pain is controlled with opioids, serum pregnenolone normalizes. Pregnenolone supplements are inexpensive and appear very safe. There are no reported serious side-effects even with daily dosages of several hundred milligrams. The author uses a daily supplemental dose of 50 to 200mg per day in most intractable pain patients.
Patients usually report an enhanced feeling of well-being, increased energy, less depression, and better pain control. It is unknown, however, if pregnenolone may cause permanent healing of nerve tissue and permanent reduction in pan intensity, but research in animals suggests that this is a strong possibility.^13,14

Adrenal Anabolic Androgens

The term anabolic means to construct tissue from basic elements. A steroid is a chemical structure related to cholesterol, which is the precursor of all adrenal and sex hormones. Healing and tissue construction requires adequate serum concentrations of the body’s natural anabolic, adrenal hormones, dehydroepiandrosterone (DHEA) and androstenedione. Treatment with anabolic adrenal steroids in pain states is not to be confused with their use in sports, which requires non-physiologic serum concentrations and excessive tissue growth.^20,21 DHEA has several properties which should benefit pain patients. It is known, in many instances, to reduce abdominal fat, lower insulin resistance, relieve depression, and raise testosterone levels.^22-26 It has been recommended, along with glucocorticoids, as a replacement in adrenal insufficiency which is common in intractable pan.²² Many poorly controlled, severe intractable pain cases demonstrate serum deficiencies of DHEA and androstenedione, and these deficiencies should be treated.
Androstenedione converts to testosterone, and serum testosterone levels rise within 30 minutes after androstenedione is ingested.^27,28 Although androstenedione may have direct affects on muscle or other organs, it likely exerts its major affects in pain treatment as a precursor to testosterone.
There are few side-effects at daily dosages under 100mg. The most common is acne, which is a helpful indicator of excess dosage in pain patients.

Chorionic Gonadotropin (HCG)

Chronic gonadotropin is known to most practitioners only as the compound which elevates in pregnancy to construct and maintain the placenta. It is essential to realize that this understanding is far too narrow.
For example, body builders have long used this compound to develop the “cut muscle” appearance and to grow visible blood vessels. Weight control clinics have found it useful for many years. It is currently marketed for prepubertal cryptorchidism not due to obstruction and hypogonadotropic hypogonadism in males.

Hormone Treatments in Chronic and Intractable Pain

An Emerging Practice

By Forest Tennant, MD, DPH

Page 3 of 5

Based on the clinical experience of the author, HCG may have a definite place in treating some intractable pain patients whose pain is due to a variety of causes including fibromyalgia, neuropathies, and immune disorders. HCG is relatively inexpensive and has no known side-effects at recommended clinical dosages.
Knowledge of its physiology other than placental maintenance is incomplete. HCG is produced in the pituitary and its molecular structure is very similar to lutenizing hormone (LH), follicle stimulating hormone (FSH), and thyroid stimulating hormone (TSH). In fact, it is so similar that it will release testosterone and thyroid and raise serum levels of these and other hormones.²⁹ HCG is found in a wide variety of normal tissues including testes, endometrium, kidney, liver, colon, gastric tissue, lung, spleen, heart, fibroblasts, and brain, but its precise physiologic impact on these tissues is not clear.
HCG is available as an intramuscular injection. To determine if it may be of clinical usefulness in pain patients, a therapeutic trial of 1cc or 1000 units should be given. HCG is found in serum at such low levels that testing for deficiencies is difficult and impractical at this time. HCG has a very long half life of about 24 hours. Consequently, the patient is able to report a positive, negative, or neutral clinical response following an injection. To date, responding patients report less pain, enhanced energy, improved strength, well-being, and sleep.

Human Growth Hormone (HGH)

Human growth hormone achieved great notoriety a few years ago when frail, elderly men benefited from its administration. It is now marketed and labeled for cachexia in AIDS. So effective is growth hormone in stimulating tissue growth in adults that it is highly sought after by athletes. Be advised that internet sales and non-prescription products which claim to be growth hormone are probably, in most cases, frauds or releasing agents. A number of compounds including dopamine, clonidine, arginine, and GABA will release growth hormone from the pituitary. Some astute physicians are now administering dopamine agonists to fibromyalgia and other pain patients to release growth hormone. They report a positive clinical response. Growth hormone is released from the pituitary in pulsatile fashion, so a test for deficiencies requires a 24 hour collection or challenge with a releasing measure such as insulin-induced hypoglycemia.^29,30 Although some severe, intractable pain patients have started HGH treatment, there is, as yet, no data to show effectiveness in reducing pain or ameliorating the underlying causative condition.
HGH is extremely expensive, but its allure is compelling. So much so that patients hear about it and request it. Their rationale is, of course, that HGH may regrow their damaged nerves and other tissues. To date there is no evidence to support this perception, and systematic studies will be needed to determine if this hope can be realized.

Gamma Amino Butyric Acid (GABA)

GABA is the main inhibitory transmitter within the central nervous system.^31,32 It is clear that ample intraneuronal stores of GABA are essential for pain control, particularly neuropathic pain. A number of agents commonly used to treat neuropathic pain or provide muscle relaxation — including baclofen, gabapentin, tiagabine, and the benzodiazepines — provide their pharmacologic effects by enhancing GABA activity by a variety of mechanisms.
GABA in the cerebral spinal fluid is reduced in a number of neurologic disorders including Huntington’s disease, dementia, cerebellar cortical atrophy, multiple sclerosis, epilepsy, and Parkinson’s Disease.¹⁵ While GABA deficiency is not yet well documented in severe pain states, the close clinical resemblance of these neurologic conditions and severe, intractable pain makes deficiency a reasonable conclusion. GABA causes dopamine and growth hormone release.⁴
Pure GABA can be ingested orally to act as an adjunct to other treatment agents. While oral GABA may not consistently cross the blood-brain barrier in large quantities, it freely enters the spinal cord and exerts significant effects on peripheral nerves and spine.^32,33
GABA appears to be primarily produced in the central nervous system and secreted into the blood.³³ Serum concentrations are quite constant between sexes and at all times of day. GABA clearly has peripheral activity and functions as a hormone.^32,33 For example, there are GABA receptors in the ovary.³³ Orally-ingested GABA may produce a temporary niacin-like flush, but is has no other known side-effects or complications. Daily dosage ranges from 1500 to 4500mg a day. Many chronic or intractable pain patients report enhanced pain control with GABA. GABA treatment of brain neurons in elderly monkeys prevents dementia.³⁴ It may well be that GABA administration in humans may prevent central, spinal, or peripheral nerve degeneration, but this remains to be proven.

Hormone Treatments in Chronic and Intractable Pain

An Emerging Practice

By Forest Tennant, MD, DPH

Page 4 of 5

Testosterone

In many pain practices testosterone replacement is becoming routine in male and female chronic and intractable pain patients. These patients have low serum testosterone levels and report decreased libido, energy, wasting, and a poor feeling of well-being.^35,36 It appears that intractable pain may suppress adrenal testosterone production, and any use of opioids by oral, dermal, or intrathecal routes may further suppress total testosterone levels.^10,11,36,37 Opioids appear to suppress pituitary follicle stimulating hormone (FSH) which reduces testicular and ovarian production of sex hormones.^10,11 It is easy to screen for testosterone deficiency in pain patients. Table 3 shows a simple screening test for low testosterone. Once suspected, a single blood sample can be used to confirm hypotestosteronemia. While high dosages of testosterone may have many serious side-effects including hyperlipidemia, hepatitis, cardiac hypertrophy, and possibly cancer, the dosages of testosterone recommended on the labels of all testosterone replacement products is quite low and safe. If an excess of testosterone is given, patients will usually develop acne at which time the dose can be lowered or temporarily discontinued. Testosterone replacement and maintenance of a normal serum concentration appears critical in male and female pain patients. Pain control, depression control, energy, libido, and muscle construction are all dependent upon testosterone.^35,38 Consequently, testosterone testing and treatment of deficiencies should become routine in pain treatment. Also, the positive clinical effects noted with DHEA, androstenedione, and HCG are, at least in part, related to their ability to raise serum testosterone levels.

Testosterone Screening Test

	YES	NO
1. Do you have a decrease in sex drive?	q	q
2. Do you have a lack of energy?	q	q
3. Has your strength or endurance decreased?	q	q
4. Have you lost weight?	q	q
5. Are you enjoying life less?	q	q
6. Are you sad or grumpy?	q	q
7. Are your erections or orgasms less strong?	q	q
8. Have you noticed a recent deterioration in your ability to
play sports?	q	q
9. Do you fall asleep after dinner?	q	q
10. Has your work performance decreased lately?	q	q
If you answer yes to question 1 or 7 or at least three of the other questions, you might have low testosterone levels.

Table 3. Testosterone Screening Test (Reprinted with permission of Solvay Pharmaceuticals)

Cortisol

The relationship of cortisol to pain control is critical, and the monitoring of serum cortisol should be routine in management of intractable pain patients. It has been understood for over 30 years that severe, intractable pain alters corticoid serum levels.^5-9
Recent research by the author and others shows that intractable pain that is constant is a severe stressor on the hypothalamic-pituitary-adrenal axis.^5-9 For some indeterminate time, this profound stress causes elevated serum cortisol concentrations. Unfortunately, the pituitary and adrenal glands cannot keep pace with the stress of intractable pain, and the adrenal gland finally exhausts.^6,9 Exhaustion is manifested by low serum cortisol concentrations.
To determine the point in the stress-exhaust cycle of a new intractable pain patient, a serum cortisol and pregnenolone concentration should be routinely determined in every new patient. Table 4 gives the interpretation of the results. If a patient demonstrates high or low serum cortisol concentration, vigorous pain control with opioids will likely normalize cortisol serum levels.⁹ Total cortisol replacement is rarely required.

Test Result	Interpretation
High Cortisol & Pregnenolone Concentration	Severe, uncontrolled, constant pain
Either Cortisol or Pregnenolone Concentration is elevated	Moderate pain or some pain control
Normal Cortisol and Pregnenolone	Mild pain or good control of pain
Low Serum Cortisol or Pregnenolone	Severe constant pain which is uncontrolled with adrenal exhaustion

Table 4. Serum Adrenal Screening of an Intractable Pain Patient
There are two clinical situations where exogenous, systemic (not local corticoid injection) corticoids may be helpful. One is autoimmune diseases such as systemic lupus erythematosis which requires exogenous corticoids for control of underlying disease and not pain, per se. The second is the exacerbation or destabilization of an intractable pain patient who has been in treatment for an extended period. In this case the patient complains of return of severe pain, suffering, disability, insomnia, and usually, a house or bedbound state. When a relapse or destabilization occurs, a serum cortisol concentration should be obtained. If high, the pain control regimen is inadequate. If low, short-term systemic corticoid administration is indicated.

Hormone Treatments in Chronic and Intractable Pain

An Emerging Practice

By Forest Tennant, MD, DPH

Page 5 of 5

In addition to cortisol testing, the pain treating physician can also do a therapeutic test by giving an injection or one-time oral dose of a corticoid to see if a clinical response is obtained. For example, if a case of acute flare or destabilization of arachnoiditis, fibromyalgia, headache, or radiscolopathy is due to inflammation, a loading dose of oral prednisone (10 to 20mg) or injectable corticoid will provide a positive response within 12 hours if there is adrenal insufficiency and low serum cortisol levels.
Long-term maintenance with corticoid preparations is seldom necessary in chronic or intractable pain patients, but short-term administration for flares and destabilization is probably under-utilized. If long-term cortisone replacement is necessary, an endocrine consultation may be helpful.

Thyroid

Severe intractable pain may alter thyroid function and produce a variety of abnormal thyroid tests.^7,38 In this situation intractable pain appears to be like other severe illnesses that may suppress a variety of pituitary hormones including thyroid stimulating hormone (TSH). One report suggests that low serum thyroid is a way to differentiate bonafide severe pain from malingering.³⁸ The condition in which there is suppressed thyroid output in severe illness is sometimes called “euthyroid sick syndrome,” “non-thyroid illness,” or “low T3 syndrome.”³⁹
Although no controlled or systematic studies have been reported, the author believes that reasonably well-controlled pain allows adequate pituitary release of TSH resulting in normal serologic tests for T3 and T4. A trial of thyroid replacement can be attempted with considerable safety if the patient demonstrates low T3 or T4. Plain desiccated thyroid in a dose of one to three grains is recommended. Although severe pain, like other severe illnesses, commonly demonstrate low T3 or T4 in serum, exogenous administration has not been reported to be of significant benefit except in post myocardial infarction patients. No side-effects of treating, however, have been reported, so a clinical trial with low dosages of thyroid for three to six weeks can be attempted.

Summary

Severe chronic or intractable pain are profound stressors which deplete many hormones. Additionally, the underlying cause of pain — particularly autoimmune and inflammatory diseases — may produce chronic illness which additionally depresses or exhausts certain hormones. To compound problems, many therapeutic pain control agents including opioids and neuropathic agents may deplete hormones. Laboratory testing easily detects deficiencies of pregnenolone, DHEA, androstenedione, thyroid, cortisol, and testosterone. While aggressive and effective pain control will normalize most hormone deficiencies, replacement of some may be necessary. Some hormones, particularly pregnenolone, GABA, testosterone, chorionic gonadotropin, and human growth hormone may be able to provide some permanent healing of nerves, muscle or other tissue and provide permanent pain reduction. Hormone testing and treatment is an emerging practice which should progressively become an integral component of pain treatment.