Editor's Memo: Neurosteroids—Gaining Ground In Pain Management Research
For more than a decade, researchers have been studying the neuroprotective effects of "neurosteroids."1,2 The term neurosteroid designates bioactive steroids that are endogenously synthesized in neurons and/or glial cells in the central nervous system (CNS) and peripheral nervous system (PNS) (Table 1). For the pain practitioner, this is a new and exciting frontier. These agents offer great hope as possible adjuncts to our current pain treatment armamentarium.
The chemical structures of neurosteroids are identical to hormones produced in the adrenal and gonad (ovaries and testes) glands. Table 2 lists the three neurosteroids that are of critical importance to the control and even the cure of pain: pregnenolone, progesterone, and dehydroepiandrosterone (DHEA). The main difference between neurosteroids and other hormones is that neurosteroids are produced in the CNS or PNS independent of the activity of the adrenal and gonad glands, as well as the hypothalamic-releasing hormones and the stimulatory hormones of the pituitary, adrenocorticotropin (ACTH), follicle-stimulating hormone, and luteinizing hormone.
Multiple animal studies have demonstrated quite clearly that neurosteroids provide neuroprotection and neurogenesis when there is experimental, intentional injury.3-9 Neurosteroids modulate nervous system activity and pain control by acting through various membrane receptors including γ-aminobutyric acid-A, N-methyl-D-aspartate, and Σ.10-13 In addition, the neurosteroids have anti-fatigue and memory enhancing properties.1-3,14 To date, a limited number of studies have shown that neurosteroids may reduce nociceptive and neuropathic pain, including allodynia.5
In a clinical study of veterans of the Iraq war, neurosteroids were found to be relevant to the pathophysiology of self-reported pain symptoms.14 A close relative of progesterone, allopregnanolone, is synthesized in the CNS but apparently not in adrenal or gonadal tissue. In the study, allopregnanolone levels were inversely associated with low back pain (P=0.044) and chest pain (P=0.013), and DHEA levels were inversely associated with muscle soreness (P=0.024). DHEA levels were positively associated with chest pain (P=0.001). Additionally, there was a positive association between traumatic brain injury and muscle soreness (P=0.002).14
As I have noted before, I have begun to routinely test for these three neurosteroids and administering them in patients who have low serum levels. In my open-label trial, 34 patients with severe, intractable pain were given oral (10 mg bid) or topical (20 mg in 1 oz cream) medroxyprogesterone. All the patients had been maintained on opioids for periods ranging from 3 to 25 years. At the end of 60 days, 22 of the 34 (65%) subjects generally reported clinical improvement in symptoms, including less baseline pain, fewer pain flares, less allodynia, less fatigue, and better mental functions.15 In addition, I have been able to reduce opioid doses in most patients. DHEA has been particularly useful in women who take opioids and have low testosterone levels, as it is known to raise these levels.
The proportional contribution of CNS, PNS, and adrenal–gonadal production to serum levels of pregnenolone, progesterone, and DHEA is unknown. I have observed severe pain patients who have low serum levels of ACTH and cortisol but have normal levels of pregnenolone and DHEA, which should not occur unless there is a serum contribution from other than the adrenals. I also have observed the reverse, which suggests there may be CNS and PNS suppression of neurosteroids in the face of normal adrenal production. Given the critical pain control functions of these three neurosteroids, it appears to be common sense and logical to maintain serum homeostasis of these neurosteroids by simple, systemic administration.
To me the basic science studies and my clinical experience, to date, are very encouraging and provide new hope in pain therapeutics. It should be noted, however, that none of these agents are FDA approved for pain relief. The purpose of this note is to encourage interest in neurosteroids. Keep in mind the profoundness of the discovery that the brain itself produces its own pregnenolone, progesterone, and DHEA for neuroprotection, neurogenesis, and other pain-related functions.1,2 I encourage the further study of these agents in clinical trials.