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11 Articles in Volume 12, Issue #10
An Anti-inflammatory Diet For Pain Patients
Focus on the Foot
How to Use Adrenocorticotropin As a Biomarker in Pain Management
Iatrogenic Nerve Injury Following Dry Needling For Foot Pain: Case Challenge
Methamphetamine Urine Toxicology: An In-depth Review
Musculoskeletal Ultrasound: A Primer for Primary Care
November 2012 Letters to the Editor
Off-label Use of Pain Treatment No Longer Covered by Insurance
Proper Disposal of Fentanyl Patches: What Patients Need to Know
The Next Barriers to Care: Your Local Pharmacy
Why Podiatric Medicine Must Embrace Pain Management

How to Use Adrenocorticotropin As a Biomarker in Pain Management

A normal ACTH serum level generally should be interpreted to mean that pain is well managed. In contrast, abnormally high or low ACTH serum levels may indicate a need for aggressive pain control measures, including around-the-clock opioids.

An adrenocorticotropin, or corticotropin, serum level is a valuable biomarker that the pain practitioner can use to help manage patients with severe, chronic pain. Why? It is a direct, objective indicator of whether the brain is being over-stressed and stimulated by pain.1,2 Since pain, per se, can not be measured, an adrenocorticotropin hormone (ACTH) serum level provides some objectivity in assessing pain severity, rather than just relying on the patient’s history. Although many physicians do not routinely order ACTH tests, it is my belief that this is a new approach to monitoring pain. This article summarizes the basic physiology of ACTH, explains how to interpret serum level results, and when to refer to an endocrinologist. Some guidelines for prescribing opioids are recommended based on ACTH serum levels.

Basic Physiology of ACTH
ACTH is a polypeptide hormone, composed of 39 amino acids that is secreted by corticotrophin cells in the anterior pituitary gland. It derives from preproopiomelanocortin, a preprohormone that undergoes several post-translational modifications resulting in the production of many peptide fragments, including ACTH, melanotropin ɣ (ɣ-MSH), lipotropin ɣ (ɣ-LPH), and endorphin.3 ACTH maintains the adrenal gland size, structure, and function, and induces adrenal steroid production and secretion.4

Figure 1. ACTH secretion patterns.Figure 1

ACTH is secreted in two patterns (Figure 1). The circadian pattern starts at 4:00 am, peaks before 7:00 am, and reaches its nadir between 11:00 pm and 3:00 am. The pulsatility pattern is characterized by secretory bursts that occur about 40 times per 24 hours. ACTH secretion is regulated by the hypothalamus through corticotropin-releasing hormone and vasopressin, by some paracrine factors, and by negative feedback of the glucocorticoids (Figure 2). Under stressful conditions, such as pain, the hypothalamic-pituitary-adrenal (HPA) axis is activated to produce glucocorticoid and to counteract the insult.5,6

Figure 2. Relationships in HPA axisFigure 2

Meaning of Normal Serum ACTH Levels
Only severe, chronic pain will stimulate the pituitary-adrenal axis enough to show elevated ACTH and cortisol levels.7,8 A normal serum ACTH level should, therefore, be interpreted to mean that the patient’s pain is not overstimulating the pituitary and that aggressive, additional pain control measures likely are not needed. A normal level also means that the brain-hypothalamic-pituitary system is intact and has not suffered a loss of its normal stress- and immune-protection capabilities.3,4,8,9 It is a most welcome finding because it means the patient has a good pituitary reserve, is managing baseline pain relatively well, and can respond to pain flares and inflammation to protect itself. It also means that the patient does not have significant opioid or glucocorticoid suppression or a disease of the pituitary gland. The majority of patients I see who have a normal (neither high nor low) ACTH serum level do not require around-the-clock opioid administration or invasive pain control measures (Table 1).

Meaning of High Serum ACTH Levels
A high ACTH level may help confirm the claims of a patient who perceives that his/her medical regimen is inadequate in controlling pain. Many causes of severe stress, including trauma, surgery, and depression may cause ACTH levels to elevate, but these elevations tend to be temporary.2,5 Severe, chronic pain, however, causes rather continuous excess secretion of ACTH as a physiologic reaction to severe pain. With adequate pain control, high ACTH levels return to normal, unless the patient has an ACTH-secreting tumor.3 Aggressive opioid administration with around-the-clock dosing may be required to bring a high ACTH level into normal range. Other measures including invasive interventions, sleep medication, and anti-anxiety agents also may be required. When a patient has a high ACTH serum level, monthly screening tests should be repeated until the ACTH serum level falls into the normal laboratory range. Once a normal ACTH serum level is attained, some reduction in medication usually is possible and should be a goal of treatment.

Table 1. Interpretation and Action for ACTH Levels

Meaning of Low Serum ACTH Levels
If a patient is complaining of severe, uncontrolled pain and demonstrates a low serum ACTH level, it is most likely due to a low pituitary reserve caused by excess, chronic overstimulation by the patient’s pain.1,5,9 Besides chronic overstimulation by pain, there are other conditions that may cause a low ACTH serum level. Just as in the case of a high ACTH level, a low level should be followed up with monthly serum levels. If they do not return to normal within 3 months, another cause of a low ACTH level must be sought, and a referral to an endocrinologist is in order. Some autoimmune conditions and head trauma, which often are associated with severe pain, can produce hypopituitarism.10,11 In these cases, other pituitary hormones such as luteinizing hormone (LH), follicle-stimulating hormone (FSH), and thyroid-stimulating hormone will be reduced.

Previous or current use of potent glucocorticoids (eg, prednisone, methylprednisolone, dexamethasone) may suppress ACTH production.3,4 Opioids that can preferentially suppress LH, FSH, and testosterone occasionally can suppress ACTH and cortisol.12

When to Refer To an Endocrinologist
Fear of missing a serious organic, non–pain-related diagnosis should not occur if a few simple guidelines are followed. Mainly, repeat abnormal (high or low) ACTH serum levels monthly for 3 consecutive months as you enhance pain treatment. If, after 3 months, abnormal high or low levels of ACTH persist, a referral to an endocrinologist is in order. Send the endocrinologist the patient’s brief history, test results, and information about your efforts to normalize ACTH.

One exception to this general rule is the patient who has an extremely high ACTH level (>200 pg/mL) (Table 2). Ectopic and some pituitary tumors may excrete these astronomic levels.3 Uncontrolled pain seldom raises the ACTH level by more than double the normal upper level.

Laboratory and Testing Guidelines
Fortunately, in the last couple of years, ACTH testing has become commercially available. The best time to test is early morning. The patient should take all of their medications, including any hormones, on their usual schedule.

Case Series of ACTH Testing in Practice
Over the past 6 months, the author obtained early-morning ACTH serum levels on 35 new chronic pain patients referred for pain control (Table 3). All were already on opioids in varying dosages. Twelve patients (34.3%) had high ACTH levels ranging from 20% to 100% above normal; 5 patients (14.3%) had low levels; and the remaining 18 patients (51.4%) had normal ACTH levels. All of the patients with high levels, and 3 of the 5 patients with low levels had their levels return to normal within 90 days after enhanced pain control, which consisted of increasing the patients’ opioid medication, sleeping aids, and/or adding an anti-anxiety agent. The 2 patients with low levels of ACTH who did not normalize proved to have autoimmune pituitary insufficiency (1 patient) or opioid-induced suppression (1 patient).

Table 2. when to Refer to an Endocrinologist

Table 3. Results of Case Series

This small case series found that about 50% of a referred-patient population requiring opioids for pain control had ACTH abnormalities (high or low). In this series, the author did not have to add around-the-clock opioids to the patients’ regimens to achieve good pain control in patients who had normal ACTH serum levels—low to moderate dosages of short-acting opioids and non-opioid measures were satisfactory.9

ACTH Not a supstitute For Patient Claims
It is the author’s clinical experience that a high or low serum ACTH is almost always associated with patient claims of excess baseline and/or flare pain, insomnia, and impairment of some activities of daily living. Despite my experiences, it must be emphasized that a biomarker, including ACTH, cannot be the sole determinant of whether pain is adequately controlled. Only the patient can do this. Serum ACTH levels should be used along with the patient’s history and claims to determine whether the patient has poorly controlled pain and requires enhanced treatment.

Relationship of Serum ACTH and Cortisol Levels
Since ACTH stimulates the adrenals to produce cortisol, a high or low cortisol level usually, but not always, parallels a high or low ACTH level.1,9 One reason for this is that ACTH is secreted from the pituitary in intermittent, pulsatile bursts over every 24-hour period, but the adrenal glands function in a more constant state.3,4 A high or low serum cortisol level in the face of a normal ACTH level should, however, suggest the possibility of poorly controlled pain.7,8 Cortisol serum levels should be assessed anytime an ACTH level also is being determined.

Need to Normalize ACTH Levels
High ACTH levels, even those that are intermittently high, must be lowered into normal range. Why? Elevated ACTH means that glucocorticoids (cortisol, pregnenolone, corticosterone) will be excessively produced and result in the classic complications observed in Cushing’s syndrome. These include hypertension, hyperglycemia, muscle wasting, osteoporosis, and mental deficiencies.3,4 Low ACTH levels result in low serum glucocorticoids and produce the complications of Addison’s syndrome.3,4 They include weakness, apathy, muscle wasting, immune impairment, and depression.

Although pain cannot, per se, be measured, an ACTH serum level is an excellent proxy or biomarker to help the pain practitioner manage severe, chronic pain. ACTH serum levels will become elevated with severe pain and remain elevated as long as severe pain continues. Extended periods of severe pain may reduce pituitary reserve and lower ACTH levels. A normal ACTH serum level in a chronic pain patient is a positive finding, because it means that the pituitary has a reserve and can respond to pain flares and raise glucocorticoid levels to produce an anti-inflammatory and immune response to protect the patient. A normal ACTH serum level means that the patient’s pain is not so severe as to deplete pituitary reserve. Consequently, a normal ACTH serum level should be generally interpreted to mean that pain is not so severe as to require aggressive, around-the-clock opioid treatment or invasive measures. In contrast, abnormally high or low ACTH serum levels may indicate a need for aggressive pain control measures, including around-the-clock opioids.

Last updated on: December 5, 2012
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