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12 Articles in Volume 12, Issue #1
Ask the Expert: Escalating Opioids
Can Yoga and Stretching Exercises Relieve Chronic Low Back Pain?
Cortisol Screening in Chronic Pain Patients
Editor's Memo: FDA Removes Homeopathic HCG; Helps Legitimate Use In Pain Treatment
Formulation: The Four Perspectives of a Patient in Chronic Pain
Guide to Chronic Pain Assessment Tools
How to Select an In-Office Electromagnetic Field Device
Letters to the Editor: Hormone Therapies
Managing Pain in Active or Well-Controlled Systemic Lupus Erythematosus
PPM Editorial Board Examines Steps to Prevent Accidental Overdoses
Saliva Drug Screening in the Office Setting: Detection of Drug Use and Abuse
Understanding the Toxicology of Diazepam

Cortisol Screening in Chronic Pain Patients

Screening for cortisol serum levels can give treating clinicians an insight into whether patients with chronic pain are at risk for diabetes, hyperlipidemia, and osteoporosis.

Why screen chronic pain patients for cortisol levels? An abnormal serum concentration is an excellent biologic marker for uncontrolled pain.1-8 It can also give you a good idea about whether the patient is in a depressed, catabolic state or if the patient is at high risk for excess corticoid complications, including osteoporosis, dental decay, hypertension, hyperlipidemia, and diabetes.9-26 Most critical, to clinicians, cortisol serum levels should be viewed as an essential biologic marker to guide treatment.1,7,8

Enough information about pain and its effects on the endocrine system has accumulated to provide a basis for specific clinical interpretations and recommendations.27-33 This article provides simple guidelines to begin cortisol screening of your patients with chronic pain.

Good Indicator of Stress
Cortisol is an end product of hypothalamic-pituitary-adrenal (HPA) stimulation (see Table 1). Often called an “axis,” this biologic system is stimulated by any inflammatory, emotional, or physical stress.34,35 There is no greater stress than pain, and chronic pain may be accompanied by neuroinflammation.28,36-42 When pain occurs, the axis is stimulated, causing corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), catecholamines, and serum cortisol to rise.43-47 Interestingly, testosterone may lower during acute pain.1,4,29-33 Cortisol may rise in any acute pain episode, including a breakthrough pain flare in a patient with chronic pain.33,35 When acute pain turns chronic, the stimulation of the HPA axis continues, resulting in elevated serum cortisol levels.1,4,29,30 The natural purpose of elevated cortisol is activation of the body’s immune defenses and healing to eliminate the cause of pain and facilitate tissue recovery.48-53 Uncontrolled and unresolved severe pain may overstimulate and later impair the HPA axis to the point that normal adrenal cortisol secretion does not occur. In this situation, cortisol serum levels drop below normal.1-5

Most endocrine studies, including those on cortisol, have been done in patients with fibromyalgia and rheumatoid arthritis.29-32 Some studies also have examined patients with headache, osteoarthritis, and lumbar spine disease.38,48 Different studies show variability in the hypothalamic-pituitary response to chronic pain, with some showing hypo- or hyperresponsiveness of CRH and ACTH.30,32,37 This difference is best explained by the long time course, usually a lifetime, of chronic pain and the great variations in neuroinflammation and neuroplasticity that are present when chronic pain becomes central in nature. Despite variability in pain causation and varying effects of chronic pain on the hypothalamus and pituitary gland, the effects of chronic pain on the adrenal gland show a rather consistent pattern. In the early phase of severe, chronic pain, adrenal hypersecretion with elevated serum cortisol concentration is present.1-5 Later, low cortisol serum levels occur because of pain’s suppression of CRH and ACTH in the hypothalamus and pituitary gland.2,4,28,29,32,37 Exactly how severe chronic pain suppresses CRH and ACTH in the hypothalamus and pituitary gland is not known, but it clearly occurs.

To the practitioner, the message is clear. Severe, uncontrolled acute or chronic pain initially causes hypersecretion of adrenal cortisol, resulting in an elevated serum level, which is later followed by HPA suppression, resulting in a low cortisol serum concentration. Serum cortisol concentrations that are too high or too low are biologic markers that call for aggressive pain management to bring the cortisol level into normal range (see Table 2).

Who Should Be Screened?
To date, testosterone testing and replacement are the only endocrine measures that have emerged to any extent in pain practice.54-56 Cortisol screening should be a routine measure in any patient with chronic pain who claims his or her pain to be constant or persistent and severe enough to require daily opioid treatment. Patients who experience mild or episodic forms of chronic pain, demonstrate normal immunologic markers such as erythrocyte sedimentation rate, and require only nonopioid medication are likely to maintain normal endocrine function and normal serum cortisol levels and need not be screened.2,8,30-32,40,48

The patients with chronic pain who most likely will have an abnormal (high or low) cortisol serum concentration are those who have central pain. This form of pain recently has been referred to as “maldynia” in that the pain is constant and is not provoked or worsened by any stimulus such as movement, pressure, or stress. Patients will complain of insomnia and periodic episodes of allodynia (pain to light touch) and/or hyperalgesia (extra pain on pressure).

Patients usually will complain of poor pain control and report that they receive little or no help from a variety of therapeutic modalities, such as nonopioid medications and physical therapy. When in doubt, cortisol screening is highly recommended as an adjunctive evaluation tool to a standard history and physical examination.

Patients on opioids who complain of poor pain control also should be screened, because adrenal corticoids are necessary for opioid receptor binding and maintenance of the blood–brain barrier.52,53 In rare cases, the drop in serum cortisol even can be life threatening. Severe hypocortisolemia lower than 1.0 mg/dL will result in a clinical picture that may include hypotension, slow movement and mentation, and muscle wasting (see Table 3). The patient usually sits in a rather fixed position, stares straight ahead, and speaks very softly. Emergency opioid administration to relieve pain is a necessity and temporary cortisol replacement may be essential.

When Should Patients Be Screened?
Screening should occur as soon as you determine that a patient with chronic pain has constant pain and doesn’t respond well, if at all, to some standard pain treatments. Any delay puts the patient at risk for hyper- and hypocortisolemia.

Recommended Screen
A single, early-morning cortisol test is the easiest and most practical screen for most practitioners. All communities in the United States, big and small, have a lab or blood-drawing station that can perform or acquire a cortisol screen. If a practitioner desires, he or she may concomitantly order other endocrine tests, such as serum testosterone, pregnenolone, or ACTH, which will give a more complete picture of the pain patient’s HPA axis. Saliva testing and performing multiple screens, such as in the early morning and late afternoon, are also perfectly acceptable. When done by a sophisticated practitioner, a subtle change in diurnal secretion, such as high serum cortisol in the afternoon, may be a tip-off that pain control should be improved. Table 2 shows results of 40 consecutive patients screened for cortisol levels. These patients described their pain as constant and disabling and were on low dosages of opioids or none at all.

Very Low Cortisol Level—Danger Sign
A patient with a very low cortisol level, less than 1.0 mg/dL, may present in a vegetative, catabolic state. This state can be life threatening if immediate pain control and temporary corticoid support are not administered. Unfortunately, severe hypocortisolemia may present very subtly and not be suspected. In fact, these patients may initially give the impression that they are uncooperative, unmotivated, depressed, psychotic, or drug seeking. For example, very low cortical levels interfere with mentation, so the patient may not respond rapidly or even sensibly to a practitioner’s questions.57-61 The patient may sit very still, stare straight ahead, and speak in almost inaudible tones. Physical exam may show hypotension, tachycardia, and muscle wasting. Recent weight loss may have occurred.

An adequate cortisol serum concentration is required for opioid effectiveness, as this hormone helps maintain the blood–brain barrier and enhance receptor binding.52,53 The patient may perceive this neurodeficiency as a need for more opioids.

Set up a system in your practice to review cortisol laboratory reports as soon as possible. Regard a serum cortisol concentration below 1.0 mg/dL as an emergency. On more than one occasion, I have missed the subtle signs and symptoms of hypocortisolemia during the history and physical, and not until the laboratory report crossed my desk did I realize I had a serious problem on my hands. The following case is illustrative and somewhat humiliating.

Case Example
A 29-year-old, unemployed female registered nurse was referred for poor pain control due to fibromyalgia. At the time of initial evaluation, she gave very vague answers to questions. Her blood pressure was 105/70 mm Hg, and she had a pulse rate of 110 beats per minute. My initial impression was that she was a depressed patient simply looking for more opioids. Not until the early morning cortisol screen came back at “less than 1.0 mg/dL” did I realize how far off my initial impression had been. The patient was called back to the clinic and given methylprednisolone 80 mg intramuscular and started on prednisone 5 mg four times a day for 2 weeks. Her opioid dosage was progressively raised over 60 days to the point that her depression lifted, her pain was controlled, and she returned to work. Within 60 days, her serum cortisol concentrations were normal and ranged from 10 to 15 mg/dL.

Recurrent High Cortisol Levels
In the last century, Harvey Cushing, MD, described the serious medical complications of pituitary basophilic adenomas and hypercortisolemia. The chronic exposure of excess serum cortisol in chronic pain patients is no different from Cushing’s syndrome and constitutes one of the most serious health risks of poorly treated pain. Such patients may develop any of the classic complications of Cushing’s syndrome, including hyperlipidemia, diabetes, osteopenia/osteoporosis, dental decay, weight gain, and mental deterioration (see Table 4).59-67

It is essential to know that hypercortisolemia can be intermittent and still cause complications. It does not have to be continuous. Frequent acute flares or episodes of breakthrough pain may elevate cortisol levels.33,35 Unfortunately, the various complications that high serum cortisol may induce have other causes. For example, weight gain and diabetes may be due to diet and inability to move. For these reasons, serum cortisol screening may differentiate causation and should be done periodically. One condition to which I wish to call attention is one I have tragically observed on too many occasions in patients with severe chronic pain. With continued exposure to hypercortisolemia, these patients may develop osteoporosis with vertebral collapse.

Case Example
In 2001, a 50-year-old woman with facial neuropathies secondary to trauma had an early-morning serum cortisol of 28 mg/dL. A repeat screen within 6 months revealed a normal cortisol serum concentration. Consequently, little attention was paid to the original screen. The patient resisted most pain medications, preferring to “tough out” her flares. A repeat cortisol screen about 3 years after the first screen was also elevated (25 mg/dL). Without warning, her spine collapsed about 5 years after her first cortisol screen. She now has required multiple spine surgeries, including fusion and rod placement. Osteoporosis was quite obvious by bone scan. She is now on an osteoporosis preventive regimen and a vigorous medical regimen to control her baseline and pain flares. Cortisol screening is routine, and her levels are in normal range.

How Often Should Cortisol Screening Be Done?
I recommend every 90 to 120 days if the patient has ever had an abnormal (high or low) screen. Otherwise, it should be done every 6 to 12 months.

Opioid Suppression of Cortisol
Opioids usually, but not always, spare cortisol in chronic pain patients.68,69 For unknown reasons, opioids most commonly suppress testosterone serum levels in patients with chronic pain.54,56 If a patient on opioids happens to have a low cortisol level, it is usually because the opioid dosage is too low and not due to opioid suppression. If the patient reports good pain control at the time the serum cortisol is low, however, cortisol may have to be replaced. I have successfully replaced cortisol with bioavailable cortisone, prednisone, and fluorinated corticoids. Pregnenolone supplements are also recommended, as pregnenolone is the precursor of cortisol.

Depression and Cortisol
Cortisol serum levels may be high in depressed pain and non-pain patients.70,71 The relationship between pain, depression, and high serum cortisol levels is unclear and complicated, as patients with severe chronic pain invariably report depression until their pain is controlled. If patients state that their pain is poorly controlled at the time they demonstrate high cortisol levels, the first clinical endeavor should be to prescribe more analgesia. If patients report good pain control when they demonstrate high cortisol levels, assume depression and start an antidepressant. Also, the simultaneous administration of an opioid and antidepressant is often an optimal and recommended approach.

Should Other Hormones Be Tested?
Once you are comfortable with cortisol screening, I recommend that other hormones be simultaneously tested. Because abnormal (high or low) cortisol levels are fraught with so many complications and dangers to the patient, I recommend starting with cortisol. Other than cortisol, these endocrine tests may give you additional information as to whether chronic pain is over- or understimulating the hypothalamic-pituitary-adrenal-gonadal system: CRH, ACTH, pregnenolone, follicle-stimulating hormone (FSH), testosterone, and estradiol. To date, I don’t have enough information to make hard recommendations. In pain practice, our goal is somewhat different from that of the endocrinologist in that we are primarily seeking to control pain in the hope that the endocrine system will subsequently normalize. Other than cortisol, I find serum pregnenolone and testosterone screening to be particularly useful.

Pregnenolone, the precursor of cortisol, may be an even better biologic marker for pain control. Testosterone serum screening is important, as low levels lead to poor pain control, loss of tissue growth, depression, and loss of libido.72,73

Patients who complain of severe chronic pain—particularly when it is constant, disabling, and requires opioids for control—should be screened with a single, early-morning serum cortisol concentration. Uncontrolled pain (acute and chronic) initially shows a high serum cortisol concentration. If the pain has been severe and constant for a prolonged period, HPA suppression may occur, resulting in a low serum cortisol concentration. Low serum cortisol concentrations below 1.0 mg/dL should be considered an emergency and corticoid administration, in conjunction with vigorous pain relief, is in order. Prolonged high cortisol concentration may cause all of the serious complications of Cushing’s syndrome, including hypertension, hyperlipidemia, diabetes, osteoporosis, mental decline, and vertebral collapse. Vigorous medical management of pain often is required to keep abnormal (high or low) cortisol serum concentrations in a normal range and minimize the complications of hypercortisolemia and hypocortisolemia. Serum cortisol should be viewed as an essential biologic marker for adequate pain control.

Last updated on: June 5, 2017
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