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Hormone Testing and Treatment Enters Pain Care Forest Tennant MD, DrPH To cite this article: Forest Tennant MD, DrPH (2014) Hormone Testing and Treatment Enters Pain Care, Hospital Practice, 42:5, 7-13 To link to this article: http://dx.doi.org/10.3810/hp.2014.12.1154
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CLINICAL FOCUS: ONCOLOGY
Hormone Testing and Treatment Enters Pain Care
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DOI: 10.3810/hp.2014.12.1154
Forest Tennant, MD, DrPH Veract Intractable Pain Clinic, West Covina, CA
Abstract: A number of factors have recently coalesced to bring hormone testing and treatment to the field of pain care. Uncontrolled, severe pain as well as opioid drugs have a profound impact on the endocrine system. Because pain is a potent stressor, it initially causes pituitary, adrenal, and gonadal hormones to elevate in the serum. If severe pain goes uncontrolled for too long, however, hormone levels deplete in the serum. The finding of abnormal (too high or low) serum hormone levels serve as biomarker of endocrinopathies, which helps inform the clinician that enhanced analgesia as well as hormone replacement may be necessary. Adequate, physiologic levels of some specific hormones are necessary for optimal analgesia, neuroprotection, and neurogenesis. Although not a substitute for opioids, some hormone replacements may minimize their use. We know that the central nervous system produces a group of hormones called neurohormones whose natural function is neuroprotection and neurogenesis. Their clinical use in centralized pain states is new, and early reports indicate that they may have considerable benefit for treatment. Keywords: hormone; endocrine; adrenal; pain
Introduction
A new dimension in pain care is the entry of hormone testing and treatment.1,2 This recent development is underpinned by the urgent need to enhance our current therapies and reexamine the need for opioid drugs. A key factor that has allowed the emergence of hormone testing and treatment in pain care is advances in laboratory technology. Today, panels or profiles of several serum hormone concentrations can be rapidly obtained at relatively modest cost.3 This article reviews the current status of hormone testing and treatment in pain care.
Materials and Methods
A literature search was conducted in September 2014 of PubMed, the Cochrane Central Register of Controlled Trials, the National Library of Medicine, and Bing. The search terms were pain, hormones, endocrine, and adrenal. The applicable articles are discussed here.
Why Hormones are Essential to Pain Care
Correspondence: Forest Tennant, MD, PhD, Veract Intractable Pain Clinic, 338 S Glendora Avenue, West Covina, CA 91790-3043. Tel: 626-919-7476 E-mail: [email protected]
Research during the last 5 decades has progressively shown that pain control is interdependent on adequate hormone body levels or homeostasis of certain hormones.4–14 Immune function, inflammation control, and tissue healing have long been known to be critical physiologic functions of cortisol and other hormones15,16 (Table 1). Above and beyond these basic hormonal functions are some specific central nervous system (CNS) functions that are essential for adequate pain control. Some hormones facilitate,
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Forest Tennant
Table 1. Major Pain Control Mechanisms of Hormones
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• Immune facilitation • Anti-inflammatory action • Tissue regeneration • Glucose control • Central nervous system pain functions • Receptor binding • Nerve conduction • Neuroprotection • Neurogenesis • Maintenance of blood–brain barrier
within the CNS, receptor site binding, nerve conduction, and maintenance of the blood–brain barrier.17–20 For example, opioids may not exert their maximal effect on opioid receptors if there is a hormone deficiency.18 Some hormones are now known to have neuroprotective and neurogenic properties.21–31 For example, they keep nerve cells from disintegrating due to an insult such as severe pain, and they stimulate cell regrowth in the CNS. This is often referred to as neuroplasticity.
Why the Recent Emergence of Testing and Treatment?
Hormone testing and treatment have recently come to the forefront due to a number of reasons. The use of contemporary pharmaceuticals including opioids may entail hormone replacement to achieve endocrine homeostasis.30–35 Numerous studies dating back 5 decades show that severe pain, acute and chronic, has a profound effect on the endocrine system.8,36–48 The seminal study was done in 1964 when Shenkin, 36 a Philadelphia neurologist, found that 87% of hospitalized patients with pain compared with 16% of those without pain demonstrated elevated cortisol levels. Similarly, Lascelles et al49 in 1974 found that psychiatric patients with chronic pain had elevated cortisol levels. Several studies since then have shown that only patients with severe pain compared to those with mild or moderate pain demonstrate abnormal hormone levels.45,50–54 Another factor that has driven the interest in hormone testing and treatment is that opioids may commonly suppress some hormones, particularly testosterone and estrogen.55–59 Pain patients who are being treated with opioids and who alter their hormone levels may develop comorbidities including low libido, impaired sexual performance, depression, amenorrhea, lethargy, hyperalgesia, and hypoalgesia.58,59 A recent development that has boosted hormone testing and treatment in pain care is laboratory technology. Hormone panels of profiles consisting of 6 to 10 hormones can now 8
be obtained rapidly.3 This rapid access makes it possible not only to screen patients, but also to assess treatment effectiveness over time. The author’s experience, to date, indicates that third-party payer approval is usually granted when the payer is informed that test results frequently result in a change in pain treatment that may be more effective clinically and possibly less expensive.
The 2-Phase Physiologic Effects of Pain
Severe, chronic pain is a major stressor that has a profound effect on the endocrine system.1,3 Initially, pain causes the hypothalamus and pituitary to secrete hormones into the serum including thyroid-stimulating hormone, adrenocorticotropin, and follicle-stimulating hormone, and to induce the pineal gland to secrete melatonin.36,37,48–57 Pain produces an increase of serum hormones including cortisol, pregnenolone, and testosterone, among others. The elevation of serum hormones is phase 1. If severe pain goes uncontrolled and disabling for a considerable period of time, the hypothalamicpituitary-adrenal-gonadal system cannot keep up, and serum hormones may drop below their normal range.48,53,60,61 The depletion of serum hormones is phase 2 (Figure 1). Because severe chronic pain may produce either serum hormone concentrations that are too high or too low, a finding of a hormone level outside the normal physiologic range should prompt an assessment about whether enhanced analgesia is advisable.
Hormones Most Critical in Pain Care
It has long been known that cortisol is essential for the control of inflammation, healing, and immunosuppression.15,16 Hydrocortisone and its various analogues have been a mainstay in pain treatment for decades, as the corticosteroids have been and continue to be used topically, systemically, intralesionally, and for epidural injection. Numerous studies have found, however, that a number of other hormones are critical for pain care,2,7,11–13 such as thyroid-stimulating hormone, pregnenolone, progesterone, estrogen, dehydroepiandrosterone (DHEA), and testosterone. Vitamin D, whose chemical structure closely resembles that of progesterone and pregnenolone, is considered a hormone by many observers.62 It has been the realization that multiple hormones contribute to pain control that has driven the need for pain practitioners to obtain panels or profiles of multiple hormones. Some hormones that are not listed here may contribute to pain control, but limited knowledge about them, the lack of laboratory
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Hormone Testing and Treatment Enters Pain Care Figure 1. Uncontrolled pain initially elevates but may later cause serum levels to drop.1 36–38 44–50
oxytocin and human chorionic gonadotropin are currently being tested in clinical trials of chronic pain patients who have likely centralized their pain65–69 (which is often called central sensitization). Early trials and anecdotal reports suggest that neurohormones may reduce certain aspects of chronic pain such as intensity, length, or severity of flares as well as prevent opioid hyperalgesia and allodynia.23,27 Also, they appear to help maintain opioid effectiveness.11,18,30,31
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Hormone Suppression by Opioids
testing availability, or clinical nonavailability make them currently impractical to test and administer in pain care.63,64
Neurohormones
One of the more amazing discoveries of the past decade is that the CNS is an endocrine organ2,11,12 (Table 2). It produces $ 6 hormones that are active within the CNS for neuroprotection and neurogenesis. They are pregnenolone, progesterone, DHEA, estrogen, oxytocin, and human chorionic gonadotropin. These hormones are produced independently of hypothalamic-pituitary control.3,7,13 At this time little is known or understood about production levels, reserve storage, or diurnal variation. Also, it is unknown how much they contribute to serum levels. Two things are, however, clear and important for pain control: (1) a deficient serum level of 1 of these hormones probably represents low production by the CNS as well as in adrenals and gonads, and (2) the CNS requires these hormones for neurogenesis and neuroplasticity. Given the critical importance of neurohormones in neuroprotection and neurogenesis, consideration should be given to replacement when any neurohormone is found to be deficient on serum testing. All the neurohormones including Table 2. Neurohormones Produced in the Central Nervous Systema • Pregnenolone • Progesterone • DHEA • Estrogen • Human chorionic gonadotropin • Oxytocin a The hormones listed here have neuroprotective and neuroregenerative properties.2 4–7 12 13 20–29 Abbreviation: DHEA, dehydroepiandrosterone.
The major complication of opioids is hormone suppression, which is sometimes called “opioid-endocrinopathy.”34,59 Opioids suppress releasing hormones in the hypothalamus. For unknown reasons they preferentially suppress gonadotropin-releasing hormone but may sometimes suppress corticotropin-releasing hormone.35,39 The usual result is lowering the serum levels of testosterone, DHEA, and estrogen, which may occur following a brief period of elevation.35 Low levels of serum testosterone and DHEA, in both males and females, result in typical symptomatology including depression, lethargy, immobility, loss of libido, poor analgesic response, and elevated pain, as well as erectile dysfunction in males.32,34 The suppression of estrogen in females may result in amenorrhea or oligomenorrhea.59 Males may develop gynecomastia. Fortunately, opioids do not often lower cortisol or pregnenolone to dangerous levels, but there are reported cases of pituitary-adrenal failure with opioids.70–74 Long-acting and intrathecal opioids suppress hormones more than short-acting opioids.32,58,59,75 The apparent, but unproven, rationale for this observation is that long-acting and intrathecal opioids continuously suppress the releasing hormone centers in the hypothalamus, whereas short-acting opioids may allow periods of nonsuppression. Rubenstein and Carpenter76 of the Kaiser Permanente Group recently surveyed 1585 men for androgen deficiency as it related to the intake of 7 opioids: codeine, hydrocodone, hydromorphone, fentanyl, methadone, morphine, and oxycodone. They found, as have others, that the long-acting opioids were more suppressive of testosterone than were the short-acting opioids. Interestingly, higher dosages of the short-acting opioids but not the longacting opioids were more suppressive. The opioids fentanyl, methadone, and oxycodone were more suppressive than were hydrocodone or morphine. Although 60% to 85% of opioidtreated pain patients may initially develop some hormone suppression, some patients apparently develop a tolerance to hormone suppression as serum levels of hormones may normalize after a few months of opioid administration.77
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Forest Tennant
Due to the high incidence and prevalence of hormone suppression in opioid-maintained pain patients, some practitioners recommend that these patients be periodically screened for hormone deficiencies. Under select circumstances, such as the presence of impotence and depression, hormone screening may be an alternative to explore replacement therapy.
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Hormone Abnormalities as Biomarkers
Pain, per se, may not be objectively measurable, but its effect on the endocrine system may reflect pain as an indicator. Hormonal serum abnormalities indicate to the physician that a patient’s pain is severe and that more aggressive analgesia may be needed. Although the patient’s verbal complaint of pain and need for analgesia must always be paramount in pain care, a finding of abnormal adrenocorticotropin, cortisol, or pregnenolone, for example, is a biomarker of pain severity. Foremost, however, it is an indicator that more analgesia, including neuropathic (antiseizure and antidepressant) agents or opioids is needed (Table 3).
Who Should be Tested?
Not every chronic pain patient needs to be tested. For example, patients who have mild to moderate painful conditions such as osteoarthritis, fibromyalgia, headaches, and carpal tunnel syndrome usually have normal hormone levels.50,51,78 The chronic pain patients who complain of severe pain on most days may be a candidate for hormone testing in defined circumstances.3 Those patients who claim their pain is constant and require a sleep aid are most likely to have serum hormone abnormalities. Those pain patients whose pain is severe enough to require daily opioids are candidates for hormone testing. It is highly recommended that patients who currently take opioids and complain that their pain is still not controlled be tested for hormonal deficiencies, which may be the reason that their treatment regimen is unsatisfactory.
Minimization of Opioids
The administration of hormones ideally may minimize the use of opioids (Table 4). For example, if a chronic pain patient is not responding well to nonopioid measures, a hormone profile that shows deficiencies signals that a clinical trial of hormone replacement is preferable rather than simply turning to opioids (situation 1 on Table 4). If a patient is on short-acting opioids such as tramadol or hydrocodone, a hormone profile that shows deficiencies may lead to a hormone replacement trial that, it is hoped, may obviate the 10
Table 3. Benefits of Serum Hormone Testing • Biomarker of uncontrolled pain • Need to replace hormones • Monitor treatment success • Suspect complications of hormone deficiency or excess
need for additional opioid therapy (situation 2 on Table 4). Patients who are taking opioids on a daily basis frequently show hormonal deficiencies, although the precise dosages required to produce them are unknown.75,76 It is hoped that if hormones are replaced, the patient may be able to reduce the opioids or at least stop an escalation of the daily dosage. Although hormone replacement may minimize or reduce the need for opioids, there are currently only anecdotal reports that this may be possible.
Replacement of Hormones
The majority of chronic pain patients have normal, nondiseased glands, including pituitary, thyroid, adrenals, and gonads. Their deficiencies with severe chronic pain are physiologic, and they usually resolve with increased analgesia or sub-replacement of deficient hormones. Seldom does a pain patient require a full replacement dosage of cortisol, pregnenolone, or other hormone. The exception is a pain patient with autoimmune disease or traumatic brain injury with pituitary insufficiency.79–82 It is recommended that hormones be administered only to pain patients who demonstrate deficient serum levels. At this time it is unknown if bioidentical or synthetic analogues will be the most beneficial. The starting dosages should be low and titrated upward. The author recommends that a patient’s serum level should be monitored every 3 to 4 months to ensure that the hormone levels stay in the physiologic range. If, after a few weeks, better analgesia is attained, hormone replacement may no longer be necessary. By these simple measures, any risk of negative feedback on the glands or the induction of cancer or prostatic hypertrophy is extremely low. Table 4. Case Illustrations of Minimizing Opioids Situation 1: Avoid starting an opioid A 34-year-old woman with fibromyalgia; on duloxetine (Cymbalta) and celecoxib (Celebrex); had low pregnenolone and DHEA; replacement avoided opioids Situation 2: Avoid a long-acting opioid A 44-year-old man with lumbar spine degeneration; on hydrocodone/ acetaminophen (Vicodin) and gabapentin (Neurontin); had low testosterone and pregnenolone; replacement avoided a long-acting opioid
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Hormone Testing and Treatment Enters Pain Care
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Hormones are administered to ambulatory patients by oral, topical, sublingual, or intramuscular routes. Practitioners and their compounding pharmacists are currently developing novel and innovative ways to administer hormones to patients. The recommendation here is that each practitioner tailor the hormones to the individual patient, based on the resources available and the patient’s and practitioner’s personal preferences. Some hormones, including testosterone, have poor oral bioavailability, and are therefore usually given by intramuscular or topical routes. At this time there is not sufficient data on bioavailability with most hormones to recommend a specific route of administration over the others.
Major Hormone Complications
Severe pain that is uncontrolled and goes on for a long period of time may cause 2 serious complications: (1) pituitary-adrenal insufficiency, and (2) osteoporosis. In the former, cortisol serum levels may drop to , 1.0 µg/dL.70–74 This level should be considered an urgency in pain patients, and replacement with hydrocortisone or cortisol should be immediately started. Patients who are symptomatic with great weakness, fatigue, and immobility and have cortisol levels , 1.0 µg/dL may need an immediate injection or infusion of methylprednisolone or other potent corticosteroid as well as aggressive analgesia.74
Conclusion
A number of factors have recently coalesced to bring hormone testing and treatment into the field of pain care. A major factor is the availability of hormone panels or profiles that can now be obtained from laboratories throughout the country. Uncontrolled, severe pain has a profound impact on the endocrine system. Because pain is a potent stressor, it initially causes pituitary, adrenal, and gonadal hormones to be elevated in the serum. If severe pain goes uncontrolled for too long, hormone levels may drop in the serum. The finding of abnormal (too high or low) serum hormone levels serves as a biomarker of uncontrolled pain, and enhanced analgesia as well as hormone replacement may be necessary. Adequate physiologic levels of certain hormones are necessary for analgesia, neuroprotection, and neurogenesis. Pain patients almost always report some positive, symptomatic benefit when their deficient hormones are normalized. Although not a substitute for opioids, some hormone replacement may minimize their use. We know that the CNS produces a group of hormones called neurohormones. Part of their natural function is neuroprotection and neurogenesis. Their clinical use in centralized
pain states is new, but early anecdotal reports indicate that they may have benefit for the suffering pain patient.
Conflict of Interest Statement
Forest Tennant, MD, DrPH, has no conflicts of interest to declare.
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Hormone Testing and Treatment Enters Pain Care 69. Tennant F. Clinical trial of progesterone for intractable, central pain. Presented at the meeting of the American Academy of Pain Medicine, Palm Springs, CA, 2012. 70. Policoloa C, Stokes V, Karavitski N, et al. Adrenal insufficiency in acute oral opiate therapy. Endocrinol Diabetes Metab Case Rep. 2014;2014:130071. 71. Oltmanns KM, Fehm HL, Peters A. Chronic Fentanyl application induces adrenocortical insufficiency. J Intern Med. 2005;257(5):478–480. 72. DeBono M, Chan S, Rolfe C, et al. Tramadol-induced adrenal insufficiency. Eur J Clin Pharmacol. 2011;67(8):865–867. 73. Lee C, Ludwig S, Duerbsan DR. Low serum cortisol associated with opioid use: case report and review of literature. Endocrinology. 2002;12:5–8. 74. Rabi J. Chronic opioid use causing adrenal insufficiency. Pract Pain Manag. 2014;14(6):31–34. 75. Rubinstein AL, Carpenter DM, Minkoff JR. Hypogonadism in men with chronic pain linked to the use of long-acting rather than short-acting opioids. Clin J Pain. 2014;29(10):840–845. 76. Rubinstein AL, Carpenter DM. Elucidating risk factors for androgen deficiency associated with daily opioid use. Am J Med. 2014. dol:10.1016/j.amjmed.2014.07.015.
77. Mendelson JH, Ellingboe J, Kuehnie JC, et al. Heroin and naltrexone effects on pituitary-gonadal hormones in man: interaction of steroid feedback effects, tolerance and supersensitivity. J Pharmacol Exp Ther. 1980;214:503–505. 78. Khorami S, Muniyappa R, Nackers L, et al. Effect of chronic osteoarthritis pain on neuroendocrine function in men. J Clin Endocrinol Metab. 2006;11:4313–4318. 79. Urban RJ, Harris P, Masel B. Anterior hypopituitarism following traumatic brain injury. Brain Inj. 2005;19(5):349–358. 80. Wilkinson CW, Pogulayan KF, Petrie EC, et al. High prevalence of chronic pituitary and target-organ hormone abnormalities after blastrelated mild traumatic brain injury. Front Neurol. 2012;3:1–12. 81. Agha A, Phillips J, O’Kelly P, et al. The natural history of post-traumatic hypopituitarism: implications for assessment and treatment. Am J Med. 2005;118(12):1416–1420. 82. Caturegli P, Newschaffer C, Olivi A, et al. Autoimmune hypophysitis. Endocr Rev. 2005;26:599–614.
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Hormone Testing and Treatment Enters Pain Care Forest Tennant MD, DrPH To cite this article: Forest Tennant MD, DrPH (2014) Hormone Testing and Treatment Enters Pain Care, Hospital Practice, 42:5, 7-13 To link to this article: http://dx.doi.org/10.3810/hp.2014.12.1154
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CLINICAL FOCUS: ONCOLOGY
Hormone Testing and Treatment Enters Pain Care
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DOI: 10.3810/hp.2014.12.1154
Forest Tennant, MD, DrPH Veract Intractable Pain Clinic, West Covina, CA
Abstract: A number of factors have recently coalesced to bring hormone testing and treatment to the field of pain care. Uncontrolled, severe pain as well as opioid drugs have a profound impact on the endocrine system. Because pain is a potent stressor, it initially causes pituitary, adrenal, and gonadal hormones to elevate in the serum. If severe pain goes uncontrolled for too long, however, hormone levels deplete in the serum. The finding of abnormal (too high or low) serum hormone levels serve as biomarker of endocrinopathies, which helps inform the clinician that enhanced analgesia as well as hormone replacement may be necessary. Adequate, physiologic levels of some specific hormones are necessary for optimal analgesia, neuroprotection, and neurogenesis. Although not a substitute for opioids, some hormone replacements may minimize their use. We know that the central nervous system produces a group of hormones called neurohormones whose natural function is neuroprotection and neurogenesis. Their clinical use in centralized pain states is new, and early reports indicate that they may have considerable benefit for treatment. Keywords: hormone; endocrine; adrenal; pain
Introduction
A new dimension in pain care is the entry of hormone testing and treatment.1,2 This recent development is underpinned by the urgent need to enhance our current therapies and reexamine the need for opioid drugs. A key factor that has allowed the emergence of hormone testing and treatment in pain care is advances in laboratory technology. Today, panels or profiles of several serum hormone concentrations can be rapidly obtained at relatively modest cost.3 This article reviews the current status of hormone testing and treatment in pain care.
Materials and Methods
A literature search was conducted in September 2014 of PubMed, the Cochrane Central Register of Controlled Trials, the National Library of Medicine, and Bing. The search terms were pain, hormones, endocrine, and adrenal. The applicable articles are discussed here.
Why Hormones are Essential to Pain Care
Correspondence: Forest Tennant, MD, PhD, Veract Intractable Pain Clinic, 338 S Glendora Avenue, West Covina, CA 91790-3043. Tel: 626-919-7476 E-mail: [email protected]
Research during the last 5 decades has progressively shown that pain control is interdependent on adequate hormone body levels or homeostasis of certain hormones.4–14 Immune function, inflammation control, and tissue healing have long been known to be critical physiologic functions of cortisol and other hormones15,16 (Table 1). Above and beyond these basic hormonal functions are some specific central nervous system (CNS) functions that are essential for adequate pain control. Some hormones facilitate,
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Forest Tennant
Table 1. Major Pain Control Mechanisms of Hormones
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• Immune facilitation • Anti-inflammatory action • Tissue regeneration • Glucose control • Central nervous system pain functions • Receptor binding • Nerve conduction • Neuroprotection • Neurogenesis • Maintenance of blood–brain barrier
within the CNS, receptor site binding, nerve conduction, and maintenance of the blood–brain barrier.17–20 For example, opioids may not exert their maximal effect on opioid receptors if there is a hormone deficiency.18 Some hormones are now known to have neuroprotective and neurogenic properties.21–31 For example, they keep nerve cells from disintegrating due to an insult such as severe pain, and they stimulate cell regrowth in the CNS. This is often referred to as neuroplasticity.
Why the Recent Emergence of Testing and Treatment?
Hormone testing and treatment have recently come to the forefront due to a number of reasons. The use of contemporary pharmaceuticals including opioids may entail hormone replacement to achieve endocrine homeostasis.30–35 Numerous studies dating back 5 decades show that severe pain, acute and chronic, has a profound effect on the endocrine system.8,36–48 The seminal study was done in 1964 when Shenkin, 36 a Philadelphia neurologist, found that 87% of hospitalized patients with pain compared with 16% of those without pain demonstrated elevated cortisol levels. Similarly, Lascelles et al49 in 1974 found that psychiatric patients with chronic pain had elevated cortisol levels. Several studies since then have shown that only patients with severe pain compared to those with mild or moderate pain demonstrate abnormal hormone levels.45,50–54 Another factor that has driven the interest in hormone testing and treatment is that opioids may commonly suppress some hormones, particularly testosterone and estrogen.55–59 Pain patients who are being treated with opioids and who alter their hormone levels may develop comorbidities including low libido, impaired sexual performance, depression, amenorrhea, lethargy, hyperalgesia, and hypoalgesia.58,59 A recent development that has boosted hormone testing and treatment in pain care is laboratory technology. Hormone panels of profiles consisting of 6 to 10 hormones can now 8
be obtained rapidly.3 This rapid access makes it possible not only to screen patients, but also to assess treatment effectiveness over time. The author’s experience, to date, indicates that third-party payer approval is usually granted when the payer is informed that test results frequently result in a change in pain treatment that may be more effective clinically and possibly less expensive.
The 2-Phase Physiologic Effects of Pain
Severe, chronic pain is a major stressor that has a profound effect on the endocrine system.1,3 Initially, pain causes the hypothalamus and pituitary to secrete hormones into the serum including thyroid-stimulating hormone, adrenocorticotropin, and follicle-stimulating hormone, and to induce the pineal gland to secrete melatonin.36,37,48–57 Pain produces an increase of serum hormones including cortisol, pregnenolone, and testosterone, among others. The elevation of serum hormones is phase 1. If severe pain goes uncontrolled and disabling for a considerable period of time, the hypothalamicpituitary-adrenal-gonadal system cannot keep up, and serum hormones may drop below their normal range.48,53,60,61 The depletion of serum hormones is phase 2 (Figure 1). Because severe chronic pain may produce either serum hormone concentrations that are too high or too low, a finding of a hormone level outside the normal physiologic range should prompt an assessment about whether enhanced analgesia is advisable.
Hormones Most Critical in Pain Care
It has long been known that cortisol is essential for the control of inflammation, healing, and immunosuppression.15,16 Hydrocortisone and its various analogues have been a mainstay in pain treatment for decades, as the corticosteroids have been and continue to be used topically, systemically, intralesionally, and for epidural injection. Numerous studies have found, however, that a number of other hormones are critical for pain care,2,7,11–13 such as thyroid-stimulating hormone, pregnenolone, progesterone, estrogen, dehydroepiandrosterone (DHEA), and testosterone. Vitamin D, whose chemical structure closely resembles that of progesterone and pregnenolone, is considered a hormone by many observers.62 It has been the realization that multiple hormones contribute to pain control that has driven the need for pain practitioners to obtain panels or profiles of multiple hormones. Some hormones that are not listed here may contribute to pain control, but limited knowledge about them, the lack of laboratory
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Hormone Testing and Treatment Enters Pain Care Figure 1. Uncontrolled pain initially elevates but may later cause serum levels to drop.1 36–38 44–50
oxytocin and human chorionic gonadotropin are currently being tested in clinical trials of chronic pain patients who have likely centralized their pain65–69 (which is often called central sensitization). Early trials and anecdotal reports suggest that neurohormones may reduce certain aspects of chronic pain such as intensity, length, or severity of flares as well as prevent opioid hyperalgesia and allodynia.23,27 Also, they appear to help maintain opioid effectiveness.11,18,30,31
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Hormone Suppression by Opioids
testing availability, or clinical nonavailability make them currently impractical to test and administer in pain care.63,64
Neurohormones
One of the more amazing discoveries of the past decade is that the CNS is an endocrine organ2,11,12 (Table 2). It produces $ 6 hormones that are active within the CNS for neuroprotection and neurogenesis. They are pregnenolone, progesterone, DHEA, estrogen, oxytocin, and human chorionic gonadotropin. These hormones are produced independently of hypothalamic-pituitary control.3,7,13 At this time little is known or understood about production levels, reserve storage, or diurnal variation. Also, it is unknown how much they contribute to serum levels. Two things are, however, clear and important for pain control: (1) a deficient serum level of 1 of these hormones probably represents low production by the CNS as well as in adrenals and gonads, and (2) the CNS requires these hormones for neurogenesis and neuroplasticity. Given the critical importance of neurohormones in neuroprotection and neurogenesis, consideration should be given to replacement when any neurohormone is found to be deficient on serum testing. All the neurohormones including Table 2. Neurohormones Produced in the Central Nervous Systema • Pregnenolone • Progesterone • DHEA • Estrogen • Human chorionic gonadotropin • Oxytocin a The hormones listed here have neuroprotective and neuroregenerative properties.2 4–7 12 13 20–29 Abbreviation: DHEA, dehydroepiandrosterone.
The major complication of opioids is hormone suppression, which is sometimes called “opioid-endocrinopathy.”34,59 Opioids suppress releasing hormones in the hypothalamus. For unknown reasons they preferentially suppress gonadotropin-releasing hormone but may sometimes suppress corticotropin-releasing hormone.35,39 The usual result is lowering the serum levels of testosterone, DHEA, and estrogen, which may occur following a brief period of elevation.35 Low levels of serum testosterone and DHEA, in both males and females, result in typical symptomatology including depression, lethargy, immobility, loss of libido, poor analgesic response, and elevated pain, as well as erectile dysfunction in males.32,34 The suppression of estrogen in females may result in amenorrhea or oligomenorrhea.59 Males may develop gynecomastia. Fortunately, opioids do not often lower cortisol or pregnenolone to dangerous levels, but there are reported cases of pituitary-adrenal failure with opioids.70–74 Long-acting and intrathecal opioids suppress hormones more than short-acting opioids.32,58,59,75 The apparent, but unproven, rationale for this observation is that long-acting and intrathecal opioids continuously suppress the releasing hormone centers in the hypothalamus, whereas short-acting opioids may allow periods of nonsuppression. Rubenstein and Carpenter76 of the Kaiser Permanente Group recently surveyed 1585 men for androgen deficiency as it related to the intake of 7 opioids: codeine, hydrocodone, hydromorphone, fentanyl, methadone, morphine, and oxycodone. They found, as have others, that the long-acting opioids were more suppressive of testosterone than were the short-acting opioids. Interestingly, higher dosages of the short-acting opioids but not the longacting opioids were more suppressive. The opioids fentanyl, methadone, and oxycodone were more suppressive than were hydrocodone or morphine. Although 60% to 85% of opioidtreated pain patients may initially develop some hormone suppression, some patients apparently develop a tolerance to hormone suppression as serum levels of hormones may normalize after a few months of opioid administration.77
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Forest Tennant
Due to the high incidence and prevalence of hormone suppression in opioid-maintained pain patients, some practitioners recommend that these patients be periodically screened for hormone deficiencies. Under select circumstances, such as the presence of impotence and depression, hormone screening may be an alternative to explore replacement therapy.
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Hormone Abnormalities as Biomarkers
Pain, per se, may not be objectively measurable, but its effect on the endocrine system may reflect pain as an indicator. Hormonal serum abnormalities indicate to the physician that a patient’s pain is severe and that more aggressive analgesia may be needed. Although the patient’s verbal complaint of pain and need for analgesia must always be paramount in pain care, a finding of abnormal adrenocorticotropin, cortisol, or pregnenolone, for example, is a biomarker of pain severity. Foremost, however, it is an indicator that more analgesia, including neuropathic (antiseizure and antidepressant) agents or opioids is needed (Table 3).
Who Should be Tested?
Not every chronic pain patient needs to be tested. For example, patients who have mild to moderate painful conditions such as osteoarthritis, fibromyalgia, headaches, and carpal tunnel syndrome usually have normal hormone levels.50,51,78 The chronic pain patients who complain of severe pain on most days may be a candidate for hormone testing in defined circumstances.3 Those patients who claim their pain is constant and require a sleep aid are most likely to have serum hormone abnormalities. Those pain patients whose pain is severe enough to require daily opioids are candidates for hormone testing. It is highly recommended that patients who currently take opioids and complain that their pain is still not controlled be tested for hormonal deficiencies, which may be the reason that their treatment regimen is unsatisfactory.
Minimization of Opioids
The administration of hormones ideally may minimize the use of opioids (Table 4). For example, if a chronic pain patient is not responding well to nonopioid measures, a hormone profile that shows deficiencies signals that a clinical trial of hormone replacement is preferable rather than simply turning to opioids (situation 1 on Table 4). If a patient is on short-acting opioids such as tramadol or hydrocodone, a hormone profile that shows deficiencies may lead to a hormone replacement trial that, it is hoped, may obviate the 10
Table 3. Benefits of Serum Hormone Testing • Biomarker of uncontrolled pain • Need to replace hormones • Monitor treatment success • Suspect complications of hormone deficiency or excess
need for additional opioid therapy (situation 2 on Table 4). Patients who are taking opioids on a daily basis frequently show hormonal deficiencies, although the precise dosages required to produce them are unknown.75,76 It is hoped that if hormones are replaced, the patient may be able to reduce the opioids or at least stop an escalation of the daily dosage. Although hormone replacement may minimize or reduce the need for opioids, there are currently only anecdotal reports that this may be possible.
Replacement of Hormones
The majority of chronic pain patients have normal, nondiseased glands, including pituitary, thyroid, adrenals, and gonads. Their deficiencies with severe chronic pain are physiologic, and they usually resolve with increased analgesia or sub-replacement of deficient hormones. Seldom does a pain patient require a full replacement dosage of cortisol, pregnenolone, or other hormone. The exception is a pain patient with autoimmune disease or traumatic brain injury with pituitary insufficiency.79–82 It is recommended that hormones be administered only to pain patients who demonstrate deficient serum levels. At this time it is unknown if bioidentical or synthetic analogues will be the most beneficial. The starting dosages should be low and titrated upward. The author recommends that a patient’s serum level should be monitored every 3 to 4 months to ensure that the hormone levels stay in the physiologic range. If, after a few weeks, better analgesia is attained, hormone replacement may no longer be necessary. By these simple measures, any risk of negative feedback on the glands or the induction of cancer or prostatic hypertrophy is extremely low. Table 4. Case Illustrations of Minimizing Opioids Situation 1: Avoid starting an opioid A 34-year-old woman with fibromyalgia; on duloxetine (Cymbalta) and celecoxib (Celebrex); had low pregnenolone and DHEA; replacement avoided opioids Situation 2: Avoid a long-acting opioid A 44-year-old man with lumbar spine degeneration; on hydrocodone/ acetaminophen (Vicodin) and gabapentin (Neurontin); had low testosterone and pregnenolone; replacement avoided a long-acting opioid
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Hormone Testing and Treatment Enters Pain Care
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Hormones are administered to ambulatory patients by oral, topical, sublingual, or intramuscular routes. Practitioners and their compounding pharmacists are currently developing novel and innovative ways to administer hormones to patients. The recommendation here is that each practitioner tailor the hormones to the individual patient, based on the resources available and the patient’s and practitioner’s personal preferences. Some hormones, including testosterone, have poor oral bioavailability, and are therefore usually given by intramuscular or topical routes. At this time there is not sufficient data on bioavailability with most hormones to recommend a specific route of administration over the others.
Major Hormone Complications
Severe pain that is uncontrolled and goes on for a long period of time may cause 2 serious complications: (1) pituitary-adrenal insufficiency, and (2) osteoporosis. In the former, cortisol serum levels may drop to , 1.0 µg/dL.70–74 This level should be considered an urgency in pain patients, and replacement with hydrocortisone or cortisol should be immediately started. Patients who are symptomatic with great weakness, fatigue, and immobility and have cortisol levels , 1.0 µg/dL may need an immediate injection or infusion of methylprednisolone or other potent corticosteroid as well as aggressive analgesia.74
Conclusion
A number of factors have recently coalesced to bring hormone testing and treatment into the field of pain care. A major factor is the availability of hormone panels or profiles that can now be obtained from laboratories throughout the country. Uncontrolled, severe pain has a profound impact on the endocrine system. Because pain is a potent stressor, it initially causes pituitary, adrenal, and gonadal hormones to be elevated in the serum. If severe pain goes uncontrolled for too long, hormone levels may drop in the serum. The finding of abnormal (too high or low) serum hormone levels serves as a biomarker of uncontrolled pain, and enhanced analgesia as well as hormone replacement may be necessary. Adequate physiologic levels of certain hormones are necessary for analgesia, neuroprotection, and neurogenesis. Pain patients almost always report some positive, symptomatic benefit when their deficient hormones are normalized. Although not a substitute for opioids, some hormone replacement may minimize their use. We know that the CNS produces a group of hormones called neurohormones. Part of their natural function is neuroprotection and neurogenesis. Their clinical use in centralized
pain states is new, but early anecdotal reports indicate that they may have benefit for the suffering pain patient.
Conflict of Interest Statement
Forest Tennant, MD, DrPH, has no conflicts of interest to declare.
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