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Hormone Therapies: Newest Advance in Pain Care

Severe, uncontrolled pain may exhaust the adrenal gland, resulting in low levels of pregnenolone and cortisol. While adequate pain control will usually normalize serum hormone levels, opioid-induced suppression of the system may require additional treatment.
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Included here are hyperglycemia, hyperlipidemia, immune suppression, osteoporosis, and brain atrophy, all of which are commonly observed in patients with severe, chronic pain (see Figure 4). There is no greater treatment need in patients with severe, chronic pain than to control pain flares, because any severe pain will raise cortisol levels. It is highly recommended that all patients with severe, chronic pain be initially screened with an early-morning cortisol level and that patients be periodically monitored with serum cortisol levels, especially if they exhibit poor pain control or develop hypertension, hyperglycemia, hyperlipidemia, osteoporosis, or mental difficulties.

Figure 4. Diagram of the consequences of excess glucocorticoids in the blood.

Here are two illustrative cases:

A 35-year-old woman had severe facial neuropathies sustained in a beating. Her initial cortisol level was 58 mcg/dL (normal is 5 to 20 mcg/dL). Within 10 years, despite medical pain treatment, her thoracic spine collapsed from osteoporosis, and she required multiple surgeries with implanted metal rods.

A 25-year-old woman with severe fibromyalgia presented with a serum cortisol of 28 mcg/dL. Despite medical treatment, she developed mental incapacity and required custodial care within 10 years.

Screening and Monitoring

The easiest way to identify hormone abnormalities and provide hormonal therapy is to routinely screen patients with pain who need around-the-clock, daily opioid medication. I recommend a 3-hormone screen: pregnenolone, cortisol, and testosterone (see Table 3). A simple, early-morning fasting blood specimen is all that is required, and all commercial laboratories can provide the screen. In patients who require daily, around-the-clock opioids, this screen should be repeated every 3 to 6 months so that the need for replacement hormones can be identified.

Table 3. Hormone Screening

Essentially, all health plans will pay for these 3 hormones, as they are relatively inexpensive and easy to assay. More important, these 3 hormones have well-published normal ranges and provide a good picture of pituitary, adrenal, and gonadal function as well as which hormones need to be replaced.

Biological Indicator of Pain

There has been interest in the use of biological tests as an objective indicator that pain is present for a long time. Serum or saliva levels of cortisol and pregnenolone are excellent indicators of uncontrolled pain. High levels of these hormones indicate severe pain and a good adrenal reserve. Low levels indicate severe pain with exhaustion of pituitary or adrenal reserves. If testosterone serum levels are low and the patient is not on opioid drugs, this finding is suggestive of pituitary exhaustion. The author has identified a small number of patients with severe, uncontrolled, intractable pain who demonstrated a number of pituitary deficiencies that resolved with adequate pain treatment. Today, most patients with pain fortunately are able to receive sufficient pain treatment to avoid pituitary exhaustion, so it is unknown how often this occurs.

Opioid Pituitary Suppression

As discussed above, severe pain per se has a profound impact on the body’s hormonal system. Unfortunately, the administration of daily opioids may cause suppression of some pituitary hormones, including follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This suppression likely is related to the presence of opioid receptors in the hypothalamus. Recently, the term “opioid endocrinopathy” has been applied to this condition. The most common hormones suppressed by opioids are pregnenolone and testosterone, which results from low serum LH or FSH. Suppression occurs approximately equally in men and women. Other hormones, including cortisol and thyroid, are rarely suppressed.

Clinical Manifestations of Testosterone Deficiency

Testosterone deficiency is clinically quite apparent in patients with pain maintained on opioids (see Table 4). Patients complain of fatigue, weight gain, depression, and loss of libido, similar to the complaints of patients without pain who have testosterone deficiencies. They also complain of poor pain control and routinely ask for higher opioid dosages. When higher doses of opioids are given, however, pain relief may not be forthcoming, as adequate testosterone levels are required for central opioid receptor binding. These patients therefore may be misdiagnosed as having hyperalgesia. In addition, sleep patterns, which are routinely disturbed in patients with pain, may worsen, as adequate testosterone levels are required for normal sleep.

Table 4. Symptoms of Testosterone Deficiencies in a Patient With Pain

Laboratory Screening for Testosterone

When testosterone deficiency is suspected, a one-time blood specimen is adequate to make the diagnosis in a patient with pain maintained on opioids. Either a low total or free testosterone level should be considered confirmatory. For the treatment of testosterone deficiency, clinicians can prescribe either human chorionic gonadotropin (HCG) or a testosterone formulation. It is poorly appreciated that the labeled indication of HCG is hypogonadism. It is discussed more fully below.

There are multiple testosterone formulations, including topical, injection, sublingual, and patch preparations. All are labeled only for male use. Administration to women is not approved by the FDA, so female patients need to be informed of this. When testosterone is deficient in women with pain, it must be replaced, otherwise they will not obtain adequate pain relief.11 I recommend the starting dose in women to be one fourth to one half of that in men. The initial dosage can be titrated upward as needed based on symptoms.

The major complications observed with testosterone or HCG are acne, facial hair, and/or loss of scalp hair in women. Testosterone dosage must, of course, be reduced if these occur.

The following case illustrates typical laboratory findings in patients with pain with opioid-induced suppression of hormones and need for testosterone and pregnenolone replacement. Note that cortisol level is normal. It is unknown why opioids preferentially suppress the gonadal rather than the adrenal or thyroid hormones.

A 39-year-old former veteran who weighed 292 pounds had severe arthritis of his knees and spine. He required daily methadone, oxycodone, and hydrocodone for pain control. He complained of poor pain relief, impotence, low libido, fatigue, insomnia, and depression. Laboratory screening showed low pregnenolone levels of less than 5 ng/dL (normal is 13-208), low total testosterone of 141 ng/dL (normal is 250-1,000), and normal cortisol of 9.5 mcg/dL. He was prescribed pregnenolone 400 mg per day and topical testosterone. Within 1 month, the patient reported greater pain control, more energy, better sleep, and a return to normal sexual activity.

The following case demonstrates the usual finding in a patient with pain in which the LH and FSH are suppressed by opioids, but the adrenocorticotropic hormone (ACTH) or thyroid-stimulating hormone (TSH) are not.

Last updated on: September 6, 2011
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