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10 Articles in Volume 10, Issue #1
An Overview of CRPS
Balancing Evidence, Efficacy and Stakeholder Values in Practical Pain Care
Biopsychosocial Approach to Management of Total Joint Arthroplasty Patients
Dextrose Prolotherapy Injections for Chronic Ankle Pain
Genetic Influences on Pain Perception and Treatment
Headache in Children and Adolescents
Hormone Replacements and Treatments in Chronic Pain: Update 2010
Opioid Treatment 10-year Longevity Survey Final Report
Therapeutic Laser in the Treatment of Herpes Zoster
Use and Effectiveness of Spinal Cord Stimulation

Hormone Replacements and Treatments in Chronic Pain: Update 2010

When severe pain and stimulation of the pituitary-adrenal-gonadal axis goes unabated for a considerable time period, exhaustion of some adrenal compounds may develop and, left untreated, may pose a combination of a serious, life-threatening condition, a vegetative state with incapacitation, mental disturbance, and a house- or bed-bound state.

In 2005, I published an article in these pages entitled “Hormone Treatment of Chronic and Intractable Pain.” At that time, I suggested that testosterone and perhaps other hormones would join corticosteroids in pain treatment. Since that report, corticosteroids—due to their numerous pain-related functions—continue to be a mainstay in pain treatment for epidural and paraspinal interventions, intralesional injections, and numerous topical and oral applications.1-3 Testosterone replacement in males who require regular opioid dosing has become a standard practice.4-6

The major hormone developments since 2005 are two-fold. First, it is now clear that severe pain, per se, may produce some hormonal deficiencies in the pituitary-adrenal-gonadal axis (here-after “axis”) that may need replacement7,8 (see Figure 1). Opioid administration may also cause various hormonal deficiencies of which testosterone is the most notable. Testosterone replacement is now routine in males and starting to be used in females.9,10 Occasionally, opioid administration may require other hormone replacement.3 The second major development is the use of hormonal compounds and analogues for healing of injured, degenerated or painful tissue sites. Early clinical reports indicate that human chorionic gonadotropin (HCG), human growth hormone (HGH), and some intermediaries of the steroidogenic pathway such as progesterone, androstenedione, and dehydroepiandrosterone (DHEA) may have clinical merit.12-15

It essentially appears that a subspecialty or body of knowledge involving pain endocrinology is emerging. In fact, pain management is beginning to learn aspects about the endocrine system that has not been a necessary area of interest or pursuit in classic endocrinology, gynecology, or urology. This article attempts to give a “point-in-time” endocrine update that is specifically geared to the pain practitioner.

Table 1. Sympathetic Signs Caused By Catecholamine Release
  • Tachycardia (high pulse rate)
  • Hypertension
  • Dilated pupil (mydriasis)
  • Cold extremities
  • Gooseflesh
  • Hyperreflexia
Table 2. Vegetative State Induced by Hormone Disturbances
  • Incapacitated
  • Pain is constant
  • Insomnia
  • Muscle wasting
  • Stares/looks straight ahead
  • Speaks softly and slowly
  • Poor responder to questions and history
  • Walks slowly
  • May appear apathetic, unmotivated, or uncooperative
  • Poor function at home and work
  • House-, bed-, or couch-bound
  • Depressed, lethargic

The Critical Knowledge About Hormones

Every pain practitioner must have a basic understanding of how severe pain, acute and chronic, affects the axis. This knowledge is fundamental to knowing if pain is severe enough to require aggressive medical intervention. It is the disturbance of the axis that fundamentally incapacitates a chronic pain patient and puts them in a vegetative, non-functional, bed- or house-bound state.7

Chronic, severe, uncontrolled pain will initially over-stimulate the axis to cause high serum levels of glucocorticoids (e.g., cortisol, pregnenolone), and catecholamines (e.g., adrenaline, noradrenaline) and this sequence of events is illustrated in Figure 1. If over-stimulation continues, adrenal and gonadal exhaustion will occur resulting in low serum glucocorticoids and catecholamines, and possibly other compounds in the steroidogenic pathway. The steroidogenic pathway8,16 in the adrenal and gonads is illustrated in Figure 2. I recommend these figures be kept in the office for ready reference and education of patients.

Phase One: Overstimulation of the Pituitary-Adrenal-Gonadal Axis

Severe pain is a potent—if not the most potent—stressor to the axis. In severe acute or chronic pain, the axis will be over-stimulated resulting in release of catecholamines (adrenalin and noradrenaline) from the adrenal medulla. Clinically, they give a classic sympathetic picture that includes tachycardia, pupil dilation (mydiacis), and cold extremities (see Table 1). The adrenal cortex is activated by adrenocorticotrophin hormone (ACTH) from the pituitary. Glucocorticoids, particularly cortisol and pregnenolone, are released and can be measured in the serum. Glucocorticoids may contribute to hypertension caused by catecholamine release. A short-term duration of serum glucocorticoid (e.g. cortisol) elevation produces no lasting effects and may positively contribute to the immune and healing response. Long-term high serum cortisol levels, however, produce all the destructive effects caused by classic Cushing’s Disease (Hyperadrenalism).3 The most destructive effects in severe chronic pain patients that have been observed first-hand by the author are osteoporosis, dental erosion, obesity, hyperglycemia, hyperlipidemia and poor pain control. Of particular note has been progressive spine degeneration often involving the entire spine. Excess serum catecholamines produce musculoskeletal pain and are probably the cause of the generic label “myofascial pain syndrome.” For example, you may have damage to the lumbar spine, hip, or foot with severe pain and develop muscular pain in the chest and shoulder muscles. There is an old myth that only acute pain (i.e., post-trauma or surgery) causes overstimulation of the axis with tachycardia and/or hypertension. All severe pain—acute, chronic, persistent, or intractable of any duration—can cause overstimulation of the axis, and the malady does not stop until medication, usually opioids, is administered.

Phase Two: Exhaustion of the Pituitary-Adrenal-Gonadal Axis

If pain is severe and uncontrolled for a long time period, overstimulation of the axis continues unabated. At some point adrenal reserves exhaust or deplete.16 When this occurs, serum pregnenolone and cortisol may drop to dangerously low levels. The drop may be to levels that are usually not compatible with life (e.g., cortisol under 2 ug/dl or pregnenolone under 5ng/dl). It is my belief that adrenal exhaustion is responsible for many, if not most, of the sudden unexplained deaths in chronic pain patients. At this time, it is unclear as to how much pituitary and gonadal exhaustion may occur with severe uncontrolled pain; data is only available for adrenal exhaustion. There is, however, a very high prevalence of pituitary tumors and deficiencies in chronic pain patients and some serum deficiencies of androgens and estrogens may be observed in severe, chronic pain patients.

The severe chronic pain patient who has axis exhaustion and abnormal serum levels of hormones will likely be in a vegetative state. It is highly recommended that pain practitioners recognize the hormone-induced vegetative state (see Table 2). If hormone exhaustion is severe, the patient will likely be bed– or house–bound. They will appear apathetic, depressed, and have difficulty providing a coherent history or performing normal daily tasks of living such as eating, working, or sleeping. They often sit with a straight-ahead stare and may falsely appear unmotivated or uncooperative. In fact, their overall mentation is grossly disturbed. They may move slowly and demonstrate facial creasing and muscle wasting. Adrenal exhaustion in a severe chronic pain patient must be considered a serious, life-threatening condition.

Figure 1. Overstimulation of the pituitary-adrenal axis followed by adrenal exhaustion. Figure 1. The steroidogenic pathway is the major metabolic pathway in the adrenals and gonads; it is incorrect to state some hormones are “male” or “female.” Adapted from Kronenberg M et al. (eds). Williams Textbook of Endocrinology, 11th Edition. Saunders. 2007.

Table 3. Candidates For Hormone Screening
  • Patient with chronic, persistent, or intractable pain who requires daily analgesic medication
  • Patients who require opioids for treatment
  • Patients who demonstrate tachycardia, hypertension, or vegetative symptoms
  • Patients who complain their current pain-control regimen is ineffective
  • Patient with musculoskeletal pain at a distance from the primary pain site
  • Patients who demonstrate marked dental erosion or osteoporosis

Blood Screening for Hormone Deficiencies

Not every pain patient needs to be tested for hormone deficiencies. Only those that have severe chronic, persistent, or intractable pain and require regular analgesic medications are candidates for hormone screening. Table 3 lists candidates for hormonal screening. I recommend a simple, short screening panel: cortisol, pregnenolone and testosterone (summarized in Table 4). This screening panel can be done by any licensed clinical laboratory on an 8:00 am, fasting, whole blood specimen. These three serum hormone levels will give a pain practitioner enough information to know if severe overstimulation or exhaustion is present.

Additional endocrine testing can be done if this screen shows an abnormality. Also, pain practitioners may wish to obtain an endocrine consult. I recommend a total serum testosterone rather than any free or sub-total test. Testosterone is critical for pain control, libido, and proper mental function.17,18 Although some of testosterone’s functions (e.g., libido) may rely on the non-protein bound serum fraction, testosterone has other functions critical to pain management that may require the protein-bound component.17,18

Management of Serum Cortisol Levels

Some severe chronic pain patients may demonstrate serum cortisol levels that range 2 to 3 times above the upper normal level (about 20-25 ug/dl).8 If the patient is in the exhaustion phase, serum cortisol levels will be under 5ug/dl. The key to normalizing high or low serum cortisol levels is aggressive opioid management. Opioid dosage should be raised from any current daily dosage or initiated if the patient is not taking opioids. Normalization of serum cortisol will almost always take place within 4 to 6 weeks.8

Cortisol replacement is rarely necessary. I recommend plain hydrocortisone or prednisone administration for 1 to 2 weeks if the serum cortisol is below 2 ug/dl. This is a precautionary measure done as a potential life-saving procedure as serum cortisol levels this low pose grave danger to the patient.

Management of Serum Pregnenolone Levels

Few physicians are even aware of pregnenolone and its biologic roles. First, pregnenolone is the primary precursor in the steroidogenic pathway (see Figure 2). A low serum pregnenolone represents a potential, problematic situation in that there may not be enough substrate for the major metabolic pathway in the adrenals and gonads.

Pregnenolone is, itself, a critical hormone.19-21 It is probably the most plentiful hormone in the human brain. Normal levels are necessary for gamma amino butyric acid (GABA) neurotransmission and helps stabilize the NMDA receptor.22,23 If serum concentrations are below 20ng/dl, I recommend a daily supplement dosage of 100 to 200mg a day. At this time, pregnenolone, due to its high safety and non-abuse profile, is available without prescription in health food stores.

Serum pregnenolone may drop to subnormal levels when patients are maintained on opioids. In these cases, patients complain that their medication is “no longer working.” Opioids may suppress pregnenolone production and require replacement as is the case with testosterone.

Table 4. Recommended Basic Screening Hormone Panel
  • Cortisol
  • Pregnenolone
  • Testosterone-total
Done at 8:00 am and with a fasting blood specimen.
Table 5. Some Symptoms Of Testosterone Deficiency
  • Lack of energy
  • Loss of libido
  • Depression
  • Poor healing
  • Diminished opioid affects
  • Loss of motivation
  • Apathy
Table 6. Hormonal Compounds Which Are Clinically Used And Indicate Potential Promise
  • Human chorionic gonadotropin (HCG)
  • Human growth hormone (HGH)
  • Progesterone
  • Androstenedione
  • Dihydroepiandrostenedione (DHEA)
  • Oxandrolone
The hormonal compounds listed in this table are being clinically used by practitioners throughout the Country. Reports are anecdotal but promising. All are anabolic compounds which promote tissue development. Some are being used topically over pain sites.

Management of Low Serum Testosterone

Commercial laboratories now report normal levels for males and females making it easy for the practitioner to make a diagnosis of “low serum testosterone.” Patients with low serum testosterone usually present with a number of symptoms that are outlined in Table 5.

If the serum testosterone is low, several testosterone products are available including injectable, patch, buccal tablet, and gel formulations. I recommend a female starting dose of about 20 to 25% of the male dose.10 In addition to plain testosterone, the use of human chorionic gonadotropin (HCG), androstenedione, or dehydroepiandrosterone (DHEA) may assist or enhance testosterone activity.24-26

The Problem of Opioid Supression of Hormones

When pain is severe enough to require regular treatment with opioids, the practitioner must be aware that opioids may suppress one or more hormones of the axis.3,6,11,27 The understanding of opioid suppression is poorly understood at this time, but it is clear that hormone suppression is a major opioid complication.

First, opioid suppression may apparently occur at one of these sites: (1) pituitary; (2) adrenals; (3) ovary or testicle. There is no convincing evidence at this time that opioids cause suppression of any biologic pathways in the thyroid, pancreas, parathyroid, or pineal glands. Although somewhat uncertain, opioids are probably more likely to suppress some hormones if the opioid is constantly in the blood of a patient for several continuous days. It is unknown if some opioids produce more hormone suppression than others, and it is unknown if short-acting opioids are more or less likely than long-acting opioids to produce suppression.

What is known is that the major hormone suppressed by opioids is testosterone in males and females. Most of the suppression is due to suppression of follicle stimulation hormone (FSH) in the posterior pituitary. For example, intrathecal opioids don’t enter the general blood circulation to reach the adrenals or gonads, but they suppress testosterone production via the pituitary route.27

It is known that opioids may, in a few select patients, suppress ACTH or directly impact the adrenals.3,11 In these cases, it may be necessary to replace preg-nenolone, cortisol, and possibly other compounds. Other than testosterone, however, there is little data published on opioid hormone suppression. One common suppression may be aldosterone in the adrenal.3 This is apparently the cause of opioid edema. It can usually be relieved by a corticoid injection that probably converts to aldosterone (see Figure 2), which is the adrenal compound involved in fluid retention

Treatment With Hormonal Compounds

Replacement and restoration of hormonal homeostasis must become a cornerstone of modern day pain management. Pain practitioners routinely observe patient in treatment who progressively deteriorate. Common deterioration conditions include severe dental erosion, spine degeneration, decrease in mental function, and joint degeneration. Hormonal homeostasis with natural hormone replacement or synthetic analogues may hopefully prevent the progressive deterioration observed in chronic pain patients. Indeed, there is nothing more new and exciting in pain management than treatment with hor-monal compounds. While some of the current hormonal compounds may not prove to have long-term staying power in practical pain management, some hormones or their analogues are now being used by pain practitioners and are summarized in Table 6.

Human growth hormone (HGH) and human chorionic gonadotropin (HCG) are birthing a number of very positive reports. Both of these compounds are produced in the pituitary of males and females.28,29 Both are anabolic and grow tissue. HCG activates a number of adrenal-gonadal compounds such as estrogen, progesterone, and testosterone, and so it helps prevent opioid suppression of hormones in the adrenal and gonads.12 Besides activating hormones, HCG causes tissue growth by increasing blood flow and activating cyclic adenosinemonophosphate (CAMP). HGH is well known to cause tissue growth and has recently had great success in treating fibromyalgia.13-15 Its only drawback is cost that is too expensive for practical clinical use in all but a few settings. In contrast, the cost of HCG is a fraction of HGH, and so it is within reach for most patients. Some intermediaries in the steroidogenesic pathway (see Figure 2) may have great merit. Included here are progesterone, androstenedione, and dehydroepiandrosterone (DHEA).24-26

The author has received several positive reports on the use of progesterone used topically over pain sites. In some cases, it is being used under ultrasound or infrared light to achieve deep penetration into pain sites. Other hormones may also be beneficial when used topically over pain sites. Oxandrolone is an oral anabolic steroid classified under the Uniform Controlled Substances as a Schedule III Drug. Its package insert lists its indication for osteoporosis, which is a most common complication in severe, chronic pain patients who have hormonal disturbances.

To date, I have found good use for all the hormonal compounds listed in Table 6. I highly encourage practitioners to try these compounds and share the results. Chronic pain patients eagerly like to try hormone treatments because they are aware that this approach likely offers them their best hope for a permanent reduction in pain and possibly even cure.

Summary

Severe pain, acute and chronic, is a potent stressor that stimulates the pituitary-adrenal-gonadal axis to release and raise serum levels of catecholamines (adrenalin) and glucocorticoids (cortisol, preg-nenolone). If severe pain and stimulation of the axis goes unabated for a considerable time period, exhaustion of some adrenal compounds may develop which results in low serum levels of cortisol and pregnenolone. Very low cortisol levels below 2ug/dl may pose a serious, life-threatening condition. Chronic hormonal disturbances may cause a vegetative state with incapacitation, mental disturbance and a house– or bed–bound state. Severe chronic pain patients who require daily analgesic medication and demonstrate poor function should be screened with a baseline, early morning, fasting cortisol, pregnenolone and testosterone. Not only will this screen provide a diagnosis of adrenal overstimulation or exhaustion, the testosterone level can serve as a baseline or diagnosis of gonadal suppression and an indication for testosterone replacement. Pain patients on opioids maintenance will have to be periodically screened for testosterone deficiency. At present, there is a great deal of clinical investigation into replacement and treatment using a variety of hormones or their analogues. Some topical hormones applied over pain sites appear promising. In summary, hormone replacement and treatment is taking pain management to an exciting, new level of care.

 

Last updated on: February 25, 2011
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