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9 Articles in Volume 14, Issue #6
Migraine Treatment From A to Z
Alternative Medicine in Chronic Migraine 2014: What Clinicians Need to Know
Hormone Abnormalities in Uncontrolled Chronic Pain Patients: Use of Hormone Profiles
Interpreting Negative Urine Drug Test Results
Case Challenge: Chronic Opioid Use Causing Adrenal Insufficiency
Editor's Memo: Toxic Insurance Plans
Guest Editor's Memo: The Forgotten Patients: Those Who Benefit From Opioid Treatment
Ask the Expert: Multiple Benzo Prescriptions
Ask the Expert: Burning Foot Syndrome

Hormone Abnormalities in Uncontrolled Chronic Pain Patients: Use of Hormone Profiles

Hormone profile testing is readily available and may be recommended for any chronic pain patient who is not achieving good pain control with their current medical regimen.

The emergence of hormone testing and treatment in pain management, to a great extent, has been caused by a rapid access to hormone panels or profiles. Compared to the recent past, a panel of 6 to 10 hormones now can be determined rapidly from a single tube of blood, giving the practitioner a broad-based hormone profile to improve management of pain patients. Due to this technological advance, some specialty laboratories that offer body fluid toxicology and pharmacogenetic testing to pain practitioners are beginning to add hormone panel testing to their portfolio of services. 

One of the best uses of hormone profiles is for the chronic pain patient who has not responded to a standard treatment regimen and continues to have uncontrolled pain. Keep in mind that today’s standard pain control regimens are extremely effective in the vast majority of chronic pain patients, so non-responders are somewhat uncommon. A hormone profile can measure multiple hormones simultaneously. This usually will give the practitioner some clues as to why the treatment regimen is not effective and provide enough information so the clinician can take measures to help the patient adjust, or modify, their regimen to attain better pain control. 

To illustrate the value of hormone profiles, I report here a case series of hormone abnormalities in a group of 61 consecutive, chronic pain patients who were referred to my clinic because they were not responding well to a standard pain control regimen, which included opioids and a variety of non-opioid pharmaceuticals. This group was tested with a 6-hormone panel and demonstrated an array of hormone abnormalities, which would be typical of what a pain practitioner might find when testing poorly controlled, chronic pain patients. A few of the abnormalities were of a most serious nature. Guidelines for interpretation and actions to take after a hormone profile is done and abnormalities are detected are included.


Benefits of Hormone Testing

There are 4 major benefits or attributes of hormone profiles (Table 1). When hormone panel testing is performed on a chronic pain patient who has poor pain control, the practitioner primarily is interested in knowing if the patient requires additional analgesia, including opioids, and/or requires hormone replacement.1-6 Low levels of any one of several different hormones may cause poor pain control.

Sequential hormone testing over time may be an excellent indicator of treatment success or failure in a given patient. High or low levels of cortisol, thyroid, or testosterone levels should cause the practitioner to look for clinical complications such as osteoporosis, gynecomastia, or hypertension.7,8

Contents of Hormone Profile

Modern day laboratory technology makes it possible to have a large number of hormones assayed in a single blood test, and pain practitioners can design their own profiles. Table 2 outlines the basic profile I use routinely and which was used in the case series described here.

The 6 hormones included in the basic profile provide a good picture of hypothalamic, pituitary, adrenal, and gonadal functions (HPAG axis). Pregnenolone, dehydroepiandrosterone (DHEA), and progesterone are produced not only in the adrenal and gonads but also in the brain. This class of hormones is referred to as neurosteroids.9-11 Their natural brain functions are neuroprotection and neurogenesis.11 Low serum levels of pregnenolone, DHEA, and progesterone likely reflect suppression of adrenal, gonadal, and brain production. All the hormones in the panel can be replaced easily with the exception of adrenocorticotropic hormone (ACTH), which, like human growth hormone, is cost prohibitive. All the hormones in the panel can be elevated or depressed and serve as biomarkers of uncontrolled pain.

There are options that can be added to the basic panel that I routinely use. These include thyroid, estradiol, and vitamin D. Note that many pain practitioners consider vitamin D to be a hormone because it has receptors throughout the body and its chemical structure is similar to pregnenolone and progesterone.12

Physiologic Effects of Pain

The analysis and interpretation of hormone serum levels primarily is based on the effect of pain on the endocrine system.1 Uncontrolled pain is a stressor that stimulates the hypothalamus and pituitary glands to secrete trophic hormones that cause release of adrenal, thyroid, and gonadal hormones (Figure 1).13-17 For example, a chronic pain patient who is not getting enough pain relief may show elevated serum levels of ACTH from the pituitary, cortisol and pregnenolone from the adrenal, and testosterone from the gonad glands. If pain goes unabated for an extended period of time, various hormones may become depleted.1,15-17 In this case, serum levels of ACTH from the pituitary, pregnenolone from the adrenals, and progesterone from the gonads may be lowered. These 2 phases—stimulation and depletion—provide an excellent set of biomarkers to diagnose uncontrolled pain. The normalization of serum hormones, as determined by sequential profile testing, provides an excellent determinant of pain treatment success.

To interpret a hormone panel, the pain practitioner must know that opioids can suppress one or more components of the endocrine system.18-20 For reasons that are unclear, when opioids are given to male and female pain patients, they primarily and preferentially suppress gonadal-releasing hormone (GRH) in the hypothalamus.18-20 This, in turn, suppresses trophic hormones in the pituitary, resulting in gonadal suppression of testosterone and estrogen.21 Opioid therapy sometimes will cause suppression of other hormones, including DHEA, progesterone, pregnenolone, and cortisol.18,22-25 Since uncontrolled pain and opioid therapy both can suppress hormones, a low hormone serum level of testosterone and cortisol, for example, may be a combination of both pain and opioid use.

Who Should Have a Hormone Profile?

Not every chronic pain patient should go through the time and expense of obtaining a hormone profile. Only patients who have severe chronic pain will stimulate the HPAG axis enough to secrete hormones to raise serum levels. The average patient with arthritis or neuropathic pain will not have increased serum levels of hormones.4,26 However, chronic pain patients who demonstrate hormone abnormalities tend to be those who have severe, chronic painful conditions with multiple contributing factors.27,28 Pain that is constant, as seen with centralized pain, is a major factor in causing hormone abnormalities. If the pain remits or subsides on an intermittent basis, the endocrine system seems to recover.

The second group of patients who benefit from hormone profiling are those whose pain is severe enough to require daily opioid therapy because regular opioid administration, particularly long-acting opioids, notoriously suppresses hormone production.18-20 Ideally any patient who is not responding to non-opioid measures should have a hormone profile before starting a opioid, since hormone replacements may obviate the need for opioids.

A chronic pain patient who is not responding well to their treatment regimen (whether opioids or non-opioids) is a top candidate for hormone profile testing. In today’s pain practice, chronic pain patients who are not well-controlled usually will have consulted multiple practitioners and be on a regimen of multiple pharmacologic agents, which may include antidepressants, anti-inflammatories, neuropathic agents, and opioids. These patients characteristically complain of disabling pain unrelieved by their current regimen. Other common complaints include insomnia, reclusiveness, hopelessness, and anorexia. These patient may seek early refilling of their medications, and family members may be quite distraught that their loved one can’t get pain relief (Table 3).


Case Series

Hormone Profile Testing In Uncontrolled Pain Patients

The study includes 61 chronic pain patients, who were referred to the author between January 2013 and June 2014 because they were not responding to a standard chronic pain management regimen. The treatment regimens all included opioids, as well as a wide variety of antidepressants, antiinflammatory agents, and neuropathic drugs. All the patients were adults who had undergone physical therapy and had been treated with sedatives, nutritional agents, and a variety of surgeries and interventions. All of the patients complained of constant pain, insomnia, and episodic flares of pain for a duration of a year or longer. All demonstrated one or more signs of excess sympathetic discharge: hypertension, tachycardia, mydriasis, hyperhidrosis, and/or hyperreflexia. Based on their histories and physical examinations, all the patients were presumed to have centralized pain.

At the time of referral, and before any therapeutic measures were taken, all patients had a basic 6-panel hormone profile performed through the patient’s local laboratory. The results of the screens are shown in Tables 4-7. The vast majority of patients (80.3%) had one or more serum hormone abnormalities, defined as levels that were too high or too low. Low- and high-serum levels were found for all 6 hormones; 20.8% of patients had progesterone abnormalities and 37.2% of patients had DHEA and testosterone abnormalities.


Therapeutic Measures

The therapeutic measures taken in patients who demonstrated hormone abnormalities included increase in dosage or change of analgesic medications; hormone replacement of deficient hormones; and a combination of both. If a patient had a normal hormone profile, no hormones were administered and other therapeutic avenues were sought to treat the patient. Over a 3- to 6- month period, all patients with serum hormone abnormalities were retested with the 6-panel hormone profile. Adjustments in analgesic medications and hormone replacements were performed over a 3- to 6-month period until their hormone serum profile normalized and patients and family reported a significant improvement in pain control, and in both physical and intellectual functions.

Profile Interpretations and Recommended Actions

Hormone levels fall into 3 classes: normal; elevated, and depressed or low. A normal hormone profile means that pain is not severe enough to stimulate the HPAG axis and alter serum hormone levels. In addition, a normal profile indicates that the patient has adequate hormone reserves to support pharmacologic therapy and other measures. An elevated hormone profiles means the HPAG axis is over-stimulated by uncontrolled pain, and enhanced pain control is needed. A low or depressed serum hormone profile in a patient who has never achieved good pain control should be interpreted to mean that pain has been so severe that hormone production can’t keep up with the stress that severe pain elicits. This patient will need immediate analgesic enhancement as well as hormone replacement.

Serious Hormone Abnormalities

Of the 61 patients in the case series, 2 patients (4.5%) had significant pituitary insufficiency, defined as low ACTH, and 2 or more deficiencies of adrenal and/or gonadal hormones. These 2 patients had a history of head and neck injury. Pituitary insufficiency is well-known to occur following traumatic brain injury, and pain practitioners should be prepared to encounter this issue when they start ordering hormone profiles.28-30 The recommended treatment strategy for pain-induced pituitary insufficiency is simultaneous, aggressive analgesic therapy and hormone replacement. Referral to an endocrinologist should be considered.

Three patients (4.9%) had serum cortisol levels below 1.0 mcg/dL and 6 patient (9.8%) had testosterone levels below 3.0 ng/ml. There were no data on the precise, minimum serum levels needed to sustain life, but these patients were considered to be “possibly near death,” and hormone replacement and enhanced pain control was pursued aggressively to bring their levels up within 2 to 4 weeks.

Low Serum Testosterone: Opioids, Pain, or Both?

The testosterone-suppression effect of opioids has received so much attention that practitioners may be tempted to believe that a low serum testosterone level in a patient on opioids is caused solely by the opioid.18-25 This is simply incorrect—severe, chronic pain, per se, and other systemic diseases may lower adrenal and gonadal hormones.1,27,28 In general, opioid-related hormone suppression occurs primarily among chronic pain patients in whom opioids have lost their effectiveness over time.Opioids may cease to be effective when hormone production decreases.3,5,6 In patients who have never achieved good pain control with opioids, low serum hormone levels usually should be viewed as the result of prolonged pain and over-stimulation of the endocrine system. A diagnosis of opioid endocrinopathy only should be considered if a man complains of impotence and a woman has amenorrhea or oligomenorrhea (Table 8).

Unfortunately, it may not always be possible to determine if opioids or severe, uncontrolled chronic pain is the cause of low serum hormones, including gonadal hormones. The proper actions to take, regardless of the cause, is to immediately and simultaneously replace all deficient hormones and enhance analgesia. I personally try, in these diagnostic dilemma cases, to avoid significant increases in opioid dosage because hormone replacement itself often will provide an increase in pain relief. Sometimes it is possible to avoid additional opioid administration if hormone replacement is accompanied by non-opioid medication such as a stimulant or neuropathic agent. In summary, an out of control, chronic pain patient with low serum gonadal hormones must have hormone replacement plus additional analgesic measures. Sequential follow-up hormone profiles will guide judgments on hormone and analgesic adjustments.

Follow Up Testing

Besides uncontrolled pain and opioid treatment, other factors may contribute to hormone abnormalities.27-31 Chronic pain patients who have hormone abnormalities tend to have centralized pain and comorbidities, such as depression. They also may have underlying pathologic conditions such as systemic lupus, diabetes, genetic disease, or an autoimmune disorder among others.27 Rather than attempt to precisely identify the cause of a hormone deficiency, the prudent and practical approach is to replace hormones and enhance analgesia according to the patient’s complaints of uncontrolled pain. As hormones and analgesia are administered over several weeks, repeat hormone profiles can be done to determine if your treatment approach is on target.


Hormone testing technology recently has advanced to the point that hormone profiles of 6 to 10 hormones can be accessed easily through local or specialty laboratories. One of the best uses of hormone profiles is the chronic pain patient who is not responding well to his/her treatment regimen. The interpretation of a hormone profile is based on pain’s biphasic effect on the endocrine system. In phase 1, pain stimulates the HPAG to hyper secrete hormones and raise serum levels. Phase 2 is the result of continued, uncontrolled pain and the failure of the hormonal system to keep up with demands of unremitting pain. In this phase, hormone serum levels drop. While elevated hormone levels are a clear indication for increased analgesic relief, low serum levels call for hormone replacement and additional analgesic relief. Patients with uncontrolled pain who take opioids may have both factors involved in lowering serum hormone levels.

Treatment of the chronic pain is quite effective; it is the unusual or rare chronic pain patient who doesn’t respond well to therapy. Those that do not respond should be considered to have severe chronic pain that is centralized and likely to have hormone abnormalities. Furthermore, these abnormalities may have to be corrected before some modicum of pain control can be achieved. When these patients are tested with a hormone profile, practitioners need to be prepared to find severe hormonal abnormalities. Some may have dangerously low serum levels of cortisol and testosterone. Others may demonstrate significant hypopituitarism and require the replacement of multiple hormones. Hypopituitarism should especially be suspected in patients with a history of head and neck trauma.

In summary, the 2 major clinical actions that are taken when abnormal serum hormone levels are found are increased analgesia and hormone replacement. Both measures may be necessary to assist a chronic pain patient in achieving better pain relief. Hormone profile testing is readily available and is recommended in any chronic pain patient who is not achieving good pain control with their current medical regimen.

Last updated on: May 19, 2015
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