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15 Articles in Volume 19, Issue #3
Analgesics of the Future: The Potential of the Endocannabinoid System
Buprenorphine: A Promising Yet Overlooked Tool
Chronic Pain and the Psychological Stages of Grief
Could a Personalized Approach to Therapy End the War on Pain?
Finally, A Systematic Classification of Pain
Hormone Therapy for Chronic Pain
How to Communicate with a Medical Marijuana Dispensary
Letters: Opioid Conversions; Scrambler Therapy for CRPS
MSK Pain: Time for an Enhanced Assessment Model
National Drug Use & Abuse Trends: Prescribed and Illicit
Neuroplasticity and the Potential to Change Pain Response
Should Emergency Naloxone Be in Schools?
Talking to Patients about Medical Cannabis
Utility of Pulsed Radiofrequency Ablation in Xiphodynia
When Opioid Prescriptions Are Denied

Hormone Therapy for Chronic Pain

Emerging and potential uses for neurosteroids, human chorionic gonadotropin, corticosteroids, oxytocin, and nandrolone in the management of complicated neuro-inflammatory diseases.
Pages 39-70

Just a few years ago, lead author Forest Tennant, MD, DrPH, hypothesized in Practical Pain Management that hormone therapies would become a major component of pain care simply due to the fact that their natural function in the human body is one of healing. Scientific findings that the central nervous system (CNS) actually manufactures hormones, now known as neurosteroids (NS), for neuroprotection and neuroregeneration underscores this notion.1-4 The purpose of this article is to provide the latest information supporting the emerging clinical role of hormone therapy as a key treatment for the underlying causes of chronic pain. The demand by both patients and practitioners for treatments designed to attack the root cause of pain is a driving force behind the growing use of hormonal therapies. Neither patients nor the public view temporary symptomatic relief, with no prospect for a cure, as an adequate response to the problems posed by chronic pain.

A Brief History of Hormones in Pain Management

In 2015, there were essentially two significant uses of hormones in pain care that remain in use today. One was the continuation of the long-time use of localized corticosteroid injections into joints, trigger points, and the epidural space (non-FDA indicated) to reduce inflammation and provide pain relief. Short-term corticosteroid use was also prevalent in treating acute, severely painful conditions such as post-herpetic neuralgia and arthritic flares. The second hormonal therapy commonly used was testosterone supplementation or replenishment for pain patients on long-term opioid therapy. Hormone testing was just beginning to come into prominence in 2015 as it became more commonly known that opioids could suppress pituitary-gonadal-adrenal function and lower serum hormone concentration, thus potentially reducing chronic pain therapeutic effectiveness.5,6 The recognition of the therapeutic utility of hormones in treating pain has grown since then, and the role of hormonal therapies in pain care continues to expand. Many, but not all, of these emerging hormonal therapies are described herein. Several are in the early stages of clinical use and only time will tell which approaches have enduring curative properties.

An increasing number of HCPs are identifying serum blood levels of neurosteroids in patients and supplementing or replenishing any that are low. (Source: 123RF)

Neurosteroids – What Are They?

Neurosteroids are neuroactive steroids born of the CNS.7 They are produced by and act on glial cells and neurons in the brain and spinal cord. Their intrinsic ability to produce analgesia is primarily indirect by acting through various membrane receptors, such as gamma amino butyric acid (GABA) and N-methyl-D-asparate (NMDA). They also suppress neuroinflammation and promote neuroregeneration. The major CNS neurosteroids are: pregnenolone (PREG), dehydroepiandrosterone (DHEA), allopregnanolone, estradiol, progesterone, and testosterone.1-4, 7-17

PREG, DHEA, and allopregnanolone metabolize to the other steroids. Neurosteroids are also produced in the adrenals and gonads. Cortisol is not considered a neurosteroid because it is apparently not produced in the CNS. It is, however, very active on neural structures as it freely crosses the blood-brain barrier to act on a large number of receptors, including those on glial cells.18-20

Major Physiologic Effects

There is now a plethora of basic science, including animal and in-vitro studies, that demonstrate the many physiologic effects of neurosteroids. While some references to these studies are included herein, the key takeaway is that the basic science relative to neurosteroids and pain care is so voluminous and consistent relative to the basic physiologic functions of neurosteroids, that their use in clinical pain practice is overdue. Neurosteroids have three major physiologic functions related to pain management:

  • Suppression of overactive glial cells and neuroinflammation: Research has clearly shown that glial cells, particularly the microglia, become activated when severe pain persists, causing neuroinflammation. This glial activation process is the apparent cause of pain centralization and central sensitivity. The most serious clinical ramification of centralization is that pain may transcend from an intermittent mild or moderate state to one of severe constant pain.11-17
  • Protection of both glia and neurons from cell death (ie, neuroprotection).21-25
  • Neuroregeneration/Neurogenesis: Studies in rats with PREG, DHEA, progesterone, and human chorionic gonadotropin (HCG) have demonstrated healing effects in severed or damaged spinal cords.21-23,26-33

Given the clinical need to suppress neuroinflammation, protect nerve cells, and promote neuroregeneration, it is most understandable that pain practitioners are beginning to investigate the utility of neurosteroids and perform therapeutic trials with their agents.

Serum Testing for Neurosteroids

The total amount of neurosteroids found in blood is a combination of production by the peripheral glands and the CNS, however, the exact contribution of each producer is unknown. What is known is that patients with chronic pain may demonstrate reduced levels of serum hormones, including PREG, DHEA, testosterone, and allopregnanolone.5,6,34-36 American soldiers who have returned from conflict zones and who have pain, for example, have been shown to have low serum levels of allopregnanolone and progesterone.34,35  Some patients with systemic lupus erythematosus (SLE) have demonstrated low serum levels of DHEA.37,38 Patients with rheumatoid arthritis and adhesive arachnoiditis have demonstrated lowered levels of multiple hormones, including serum cortisol.39,40 The cause of these reduced serum hormone levels is likely due to the inability of hormone-producing tissue to meet the stresses of chronic pain.5

Based on this growing evidence, an increasing number of clinicians are determining serum blood levels of neurosteroids in patients and supplementing or replenishing any that are low. Although testosterone has been the hormone most supplemented or replenished, some practitioners are replenishing other hormones, such as PREG and DHEA, when testing demonstrates reduced serum levels. Hormone testing is now largely available in every community from a licensed clinical laboratory. The authors recommend that a hormone test panel include these six hormones: pregnenolone, DHEA, progesterone, estradiol, testosterone, and cortisol.

The Two Types of Neurosteroid Therapy: Replenishment and Supraphysiological Dosing

Pure hormones are authorized by the FDA. Some require a physician’s prescription (eg, estradiol, progesterone, testosterone) while others are sold over the counter (OTC) without a prescription (eg, PREG and DHEA). The manufacturers of pure prescription and non-prescription hormones provide directions for use on their label.

Neurosteroids may be administered to simply raise low serum levels or they may be given in supraphysiological dosage in an effort to create a physiologic state medically designed to reduce neuroinflammation and promote neuroregeneration. Supplementation or replenishment of reduced hormones, as noted in blood laboratory testing, to normalize serum levels may be considered prudent as there is little, if any, risk of permanent hormonal suppression or cancer. Although we know of no studies associating hormone blood levels with cancer or other serious disease, it is prudent in our opinion to keep blood levels within normal range. As an extra cautionary measure, we recommend low, intermittent dosages and favor skipped days over everyday dosing.

In relationship to pain management, treatment with simple hormone replenishment has not been shown to reduce pain in controlled human studies. Clinically, however, public demand for hormone replacement therapy has increased as anecdotal reports, including those to the authors, have emerged on how patients receiving hormone replenishment experience less pain, reduced fatigue, and reduced depression. The most studied and clinically reported hormone is testosterone, which acts as a type of co-factor or co-analgesic agent with opioids and possibly other analgesics.41-44

Both historical and clinical data support the use of supraphysiologic dosages of other neurosteroids besides testosterone. The normal supplemental dose of both PREG and DHEA is 25 to 100 mg a day. A supraphysiologic dosage in the 100 to 300 mg a day range may provide pain relief in some patients.45,46 There are also reports that DHEA in dosages over 200 mg a day may provide significant therapeutic benefits in patients with SLE.37,38 In the 1940s, PREG was destined to be the primary treatment for rheumatoid arthritis and other rheumatoid diseases.45,46 Dosages in the 400- to 600-mg a day range were often used prior to the discovery of prednisone in about 1950, which put PREG on the shelf. At dosages over 100 to 200 mg, PREG and DHEA may metabolize to estradiol, progesterone, and testosterone in sufficient quantities to produce the desired therapeutic effect of these hormones without the addition of any other hormones. Pain practitioners may wish to administer one or more neurosteroids as a therapeutic trail. The authors recommend a period no longer than 1 to 2 months to determine if a given neurosteroid may be beneficial to a pain patient.

Human Chorionic Gonadotropin

Human chorionic gonadotropin (HCG) raises biologic levels of progesterone, estradiol, and testosterone.47,48 It also has a purely anabolic component and is known to be the responsible agent for the growth of ectoderm (ie, skin, hair, nail, and CNS) in the embryo.48 HCG also has a CNS receptor.49 Of great interest is the observation that HCG has been shown to promote functional recovery in spinal-cord sectioned rats in two different studies.32,33

Open-label clinical trials have further shown HCG to be of considerable therapeutic benefit.50 When considering rat studies that have demonstrated a profound effect on spinal-cord recovery in combination with anecdotal clinic reports of patient benefit, a trial of HCG, by itself, may be justified as an adjunct to standard symptomatic treatment for pain.32,33,50 A clinical trial of 1 to 2 months may be long enough to determine whether an anabolic effect from HCG is occurring. HCG may be administered by injection, troche, or sublingual preparation. The authors recommend a starting dosage of 250 to 500 units, two to three times a week.

Corticosteroids and Neuroinflammation

Corticosteroids have long been a mainstay in treating select, painful conditions. The most common use is to inject a corticosteroid into joints, soft tissue, or the epidural space (non-FDA indicated), to control a localized, very painful inflammatory site. Corticosteroids are also commonly used to help manage acute painful conditions, such as post-herpetic neuralgia and arthritic flares.

Recently, there has been a renewed interest in the potential new uses of corticosteroids as therapeutic agents. This re-evaluation of corticosteroids may be traced to the observation that some corticosteroids function as potent suppressors of activated glial cells and neuroinflammation.19,20,51-55 In fact, some corticosteroids may be, on a short-term basis, the most potent suppressors of neuroinflammation. Although the reason is unclear, methylprednisolone and dexamethasone are the two corticosteroids that best suppress glial cell activation and neuroinflammation.52,54 Other corticosteroids such as prednisone, hydrocortisone, and triamcinolone have not proven to be very effective in controlling neuroinflammation in contrast to their effectiveness in the periphery. It is postulated that corticosteroids lacking effectiveness in the CNS are either unable to cross the blood-brain barrier in sufficient concentrations to successfully enter the spinal fluid or they may not act on the specific receptors that are related to glial cell suppression.51

In addition to suppression of neuroinflammation, corticosteroids have multiple other CNS functions that may contribute to pain relief.19 These include physiologic maintenance of the blood-brain barrier and opioid receptors.18

New Potential Uses of Corticosteroids

Since methylprednisolone and dexamethasone are potent suppressors of neuroinflammation, they appear to be the most useful among the corticosteroids for pain care. When used for severe pain flares or breakthrough episodes, low oral or injectable dosages of either of these two corticosteroids may be given alone or as an adjunct treatment with ketorolac, antihistamines, or opioid. For example, the combined use of injectable ketorolac and methylprednisolone will usually spare opioid use when given for an acute pain flare.

A short therapeutic trial of methylprednisolone or dexamethasone may be useful as both diagnostic and therapeutic tools in select clinical situations. Patients with chronic pain who experience severe flares are prime candidates for a therapeutic trial of one of these two, powerful potential suppressors of neuroinflammation. In addition, patients who develop back pain following a spinal tap or an epidural corticosteroid injection may be developing neuroinflammation of nerve roots in the cauda equina.56 A short-term trial of methylprednisolone or dexamethasone may prevent the development of arachnoiditis for these at-risk patients. A commercial six-day dose pack of oral methylprednisolone (Medrol) offers one simple and convenient way to perform a therapeutic trial. As an alternative, injections administered over two to three days may provide an effective test. If pain is reduced and physical functions improve following a corticosteroid trial, neuroinflammation may be assumed to be present and contributory to a patient’s pain.

Intermittent, low-dose corticosteroid treatment appears beneficial in some patients with severe chronic pain. Candidates for this treatment may include those who demonstrate a low serum cortisol or who respond to a therapeutic trial of methylprednisolone or dexamethasone. Intermittent, low dose corticosteroid treatment appears beneficial to us in some severe chronic pain patients. The reason for this observation may be that some corticoids suppress glial cell activation and the resulting neuroinflammation.51-55 Low intermittent dosages of corticosteroids may be helpful in some severe chronic pain patients who have such neuroinflammatory conditions, such as adhesive arachnoiditis, or complex regional pain syndrome (CRPS). These conditions may overstress the ability of the adrenal glands to produce adequate cortisol.5 Examples of low-dose, intermittent corticosteroid treatments are methylprednisolone 4 mg, or dexamethasone 0.5 to 0.75 mg, given 2 to 4 days per week.

Other Hormone Therapeutics

Oxytocin as an Analgesic

Oxytocin has been a most welcome surprise in hormone therapeutics. While the other hormones discussed in this review act indirectly on CNS mechanisms to reduce pain, oxytocin acts as a direct analgesic substance.57-60 This effect should come as no surprise as the medication is classically known to produce analgesia during childbirth.

Oxytocin appears to produce nociception by more than one mechanism.57,59 Produced in the hypothalamus, oxytocin is released by the posterior pituitary into the peripheral circulation and spinal fluid. At times of stress or pain, surges of oxytocin are released. There are neuronal projections from the hypothalamus to receptors in the dorsal horn of the spinal cord that function to prevent pain signals from reaching the brain. Oxytocin activates this anatomic system as well as the endogenous endorphin compounds that bind and activate CNS opioid receptors. Much like exogenous opioids, it may be blocked by naloxone.57

Oxytocin may be a very useful non-opioid pain reliever. It does, however, have some limitations. First, it is relatively short-acting with a maximal duration of action about 4 to 6 hours. Since it provides some of its analgesic action by binding to opioid receptors, oxytocin is not very effective if the patient is already taking opioids. Although oxytocin has shown beneficial effects with mood and depression, opioid-naiive patients may notice the pain-relieving effects most dramatically.57,59,60 For example, oxytocin may not be very useful as a breakthrough remedy in patients who maintain on a long-acting opioid, however, it may be beneficial to an opioid-naiive patient who needs short-term, intermittent pain relief or as an opioid-sparing option to a patient with mild to moderate pain. Oxytocin may be simultaneously used with other non-opioid agents, such OTC anti-inflammatory agents or ketamine.61 Single dosages range from about 40 to 80 units given in a sublingual liquid formulation, troche, or nasal formulation.

Nandrolone for Catabolic Pain States

Nandrolone, also known as 19-nortestosterone, is a synthetic derivative of testosterone and classified as an anabolic steroid. Unfortunately, its abuse for tissue building and weight gain by athletes has given it a pejorative reputation and obscured its labeled medical use. It is labeled for medical use in degenerative, wasting, and catabolic disease states. It has been found to be useful in anemia, osteoporosis, muscle tears, breast cancer, protein-wasting of old age, burns, and infections, particularly HIV. Some severe, intractable pain states may progress to the point that the patients enters a catabolic state with muscle wasting, anorexia, weakness, and weight loss. A catabolic pain state may occur in not only metastatic carcinoma and HIV, but also with adhesive arachnoiditis, CRPS, and some autoimmune disorders.62-67

OTC Hormone Products

Chronic pain patients increasingly are reporting to the authors that they are acquiring and using OTC hormone preparations. Pain practitioners should be aware of the growing popularity of OTC hormonal products among chronic pain patients. Both PREG and DHEA are commercially available in oral capsules that range in strength from 25 to 100 mg.

In addition, the dietary supplements colostrum, which contains small quantities of human growth hormone, and gonadal extracts (bovine) may be considered for anabolic effect in chronic pain patients. Gonadal extracts contain a number of hormones with anabolic properties including DHEA and testosterone (eg, Orchex and others). There are no reported complications from bovine gonadal extracts or colostrum. Herbal products that contain estrogens or progestins are also popular. The authors recommend periodic hormone blood levels be determined in patients who take OTC hormones as they can cascade to unintended hormone imbalances that may interfere with pain care.

Conclusion

Neuroinflammation poses a major challenge for pain treatment as the occurrence may accentuate and prolong a pain state. To date, pain management has largely been symptomatic with the use of neuropathic and analgesic drugs, particularly opioids. Yet, as discussed, basic science and animal studies have shown that at least six neurosteroids are produced by cellular synthesis or metabolism in the CNS. These neurosteroids may provide neuroprotection and promote plasticity or neuroregeneration. Based on the animal studies and open-label reports noted herein, clinical trials of one to two months with a neurosteroid or HCG may be warranted.

In addition, corticosteroids, which have long been used in pain care for local tissue injections and some acute, painful conditions, are growing in interest. A therapeutic trial of methylprednisolone or dexamethasone, in particular, may not only prove to be therapeutic but also diagnostic. Clinicians may also consider the use of intermittent, low-dose corticosteroids to help manage pain in such conditions as rheumatoid arthritis, psoriatic arthritis, and SLE. A similar approach may be suitable in severe chronic pain patients who have significant neuroinflammation from a disease such as adhesive arachnoiditis, EDS, or CRPS.

When examining other potential hormone therapeutics, nandrolone may produce soft tissue and nerve regeneration to provide long-term pain reduction in severe degenerative cases of EDS and other painful connective tissue disorders. As an opioid alternative, oxytocin may be simultaneously used with low dose ketamine or other non-opioid agents.

Overall, more patients are becoming aware of the benefits of hormone therapies for chronic pain. The non-prescription hormones PREG and DHEA, adrenal and gonadal extracts, and colostrum, in particular, are increasingly being used by this population and practitioners need to help monitor safety. Clinicians may also more readily consider trialing the hormonal therapies reviewed herein for the management of certain painful neuro-inflammatory conditions.

Last updated on: May 3, 2019
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