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Ketamine with Oxytocin for pain , fibromyalgia, addiction, social anxiety , and other disorders.

I compiled a few snippets of articles regarding Ketamine combined with Oxytocin for treating various ailments, in particular pain. There are a number of articles discussing pain management with Oxytocin intranasally and in other formulations. The articles are scavenged with links as well.

Dr. Sendi uses Oxytocin for anxiety, social phobia, and chronic pain in the office setting. Call for an evaluation! 703-844-0184

Unique Drug Combo Promising for Severe, Intractable Pain

SAN DIEGO — Low doses of the hormone oxytocin along with the anesthetic ketamine may provide a unique and effective therapeutic approach to some patients with severe, intractable pain

This therapeutic approach is “incredibly unique” and is safe and effective in some patients with intractable pain. “If you put these two together, you could replace any short-acting opiate,” Caron Pedersen, FNP-C, DC, BSN, BS-PT, a nurse practitioner, chiropractor, and physical therapist specializing in patients with spinal pain, told Medscape Medical News.

Dr Caron Pedersen

Dr Pedersen has been working with pain management expert, Forest Tennant, MD, DPH, Veract Intractable Pain Clinic, West Covina, California, to find better ways to treat patients with very severe pain.

Such patients, said Dr Pedersen, “are pretty much opioid-dependent and have been for long time, and are not getting relief.”

Dr Pedersen presented some of her research here at the Academy of Integrative Pain Management (AIPM) 28th Annual Meeting.

Alternative to Opioids?

A variety of antiseizure, antidepressant, and anti-inflammatory agents, as well as muscle relaxants and adrenergic blocking agents, provide mild to moderate pain relief. But these approaches are not always a substitute for opioids in patients with severe pain.

Both oxytocin and ketamine provide analgesia by mechanisms other than stimulating opioid receptors.

Produced in the hypothalamus, oxytocin is a potent natural pain reliever. The hormone is released in pregnant women during labor and also in other painful conditions or stressful events.

It has been reported to relieve pain in patients with headache, chronic back pain, and fibromyalgia, and there is “a mountain of research” on oxytocin’s complex production, release, and receptor system, said Dr Pedersen.

Dr Tennant explained that some of the hormone is released into the peripheral circulation via the posterior pituitary and some into the central nervous system, including the spinal fluid.

Oxytocin receptors are found at multiple sites in the brain and throughout the spinal cord, said Dr Tennant. In addition to activating its own receptors and decreasing pain signals, oxytocin binds to opioid receptors and stimulates endogenous opioid release in the brain.

In addition to relieving pain, oxytocin lowers serum cortisol and can produce a calming effect and improve mood.

“It has the effect of making people happy, making them feel a little less anxious,” said Dr Pedersen. “It changes the central nervous system; it makes the hypothalamus pump out chemicals that are telling the body it’s okay, calm down.”

Oxytocin can block “anticipatory pain,” added Dr Pedersen. Patients with intractable pain are constantly waiting for “the next burse of pain” so are “in constant stress,” she said.

However, when they take oxytocin, “they may actually get a lot of relief based on the fact that they are no longer having that anticipation.”

Pain Free, No Side Effects

The investigators are working to determine optimal doses and routes of administration for oxytocin. They have experimented with combining oxytocin with low-dose naltrexone, benzodiazepines, neuropathic agents, opioids, and now ketamine, an N-methyl-D-aspartic acid receptor antagonist.

There has been a resurgence of interest in ketamine as a possible therapy for chronic pain conditions, including neuropathic pain, complex regional pain syndrome, fibromyalgia, postherpetic neuralgia, migraines, and spinal cord injury.

At relatively high doses, ketamine has significant psychomimetic and euphoric properties that have led to abuse. Oral ketamine, sometimes called Special K, has become a popular nightclub drug.

Dr Tennant and Dr Pedersen have been experimenting with low-dose ketamine added to oxytocin in patients with the most severe intractable pain.

The study they presented at the AIPM meeting included five such patients (mean age, about 40 years) who had used oxycodone, morphine, hydrocodone, or hydromorphone for over a year.

Patients had not taken their short-acting opiate for several hours when they received 0.5 mL (2 mg — half of a syringe, or 20 units) of liquid oxytocin sublingually. Within 10 minutes, all five patients reported varying degrees of pain relief.

About 15 minutes after receiving the oxytocin, patients then received 0.25 to 0.50 mL (12.5 to 25 mg) of liquid ketamine, also sublingually.

The ketamine enhanced the pain relief. With the combination, two patients became completely pain free. These patients would “positively not” have been pain free with opioids, said Dr Pedersen.

The pain relief lasted about 4 hours with no side effects.

The Worst of the Worst

Dr Pedersen said the study patients were “the very worst” of pain patients. In her clinic, many patients suffer intractable pain — pain that never completely goes away with surgery or with drugs. “Some have had, say, seven or eight back surgeries and they have so much inflammation in their spine.”

Some are battling an autoimmune disease, such as lupus. Others have arachnoiditis, an incurable inflammatory condition of the arachnoid mater, the middle layer of the meninges.

Because oxytocin is a hormone, its pain-relieving ability varies from patient to patient and its effectiveness is related, among other things, to blood levels, pain severity, and sex.

In her experience, Dr Pedersen has found that men tend to have a better response to the combination of oxytocin and ketamine than women.

But women also respond “fabulously,” she said. She described one 38-year-old female patient in her practice with a disc herniation who had been taking opioids, which were not helping her much. “She stopped taking them when she started using this combination therapy.”

Other patients have been able to cut back on opioids “significantly enough that if they had to stop taking them, they would be okay,” said Dr Pedersen.

The combination therapy may also address the issue of addiction, said Dr Pedersen. Some of her patients had become addicted to opioids, but after using the oxytocin-ketamine regimen, they’re not craving or abusing opioids.

The liquid form taken sublingually provides “the best delivery system” and is much more effective than pills, said Dr Pedersen.

Although liquid oxytocin typically has a shelf life of only about 10 days, Dr Pedersen has found pharmacies that put the hormone in a suspension that lasts for 3 months.

Intriguing Results

Commenting on the research for Medscape Medical News, Charles E. Argoff, MD, professor of neurology, and director, Comprehensive Pain Center, Albany Medical College, New York, said it “provides intriguing results.”

However, he said, a single-center open-label study of only five patients “is insufficient to draw any conclusions.”

While the use of oxytocin as an analgesic is supported by basic science, “this study does not add significantly to the human studies already completed, given its size and design,” said Dr Argoff.

Adding ketamine “dampens enthusiasm” for this therapeutic approach because of concerns about dependency and side effects, said Dr Argoff.

Adverse effects of ketamine can include nausea, headaches, fatigue, and dysphoria.

The authors have disclosed no relevant financial relationships.

Academy of Integrative Pain Management (AIPM) 28th Annual Meeting. Abstract 24. Presented October 21, 2017.

Oxytocin is a hormone that is produced in the hypothalamus and released by the posterior pituitary gland. It is well known as a “feel good hormone” with important roles in social bonding. There have been studies that show that giving a loved one a hug can increase oxytocin.

Its most well-known role, however, is how it helps with reproduction and childbirth. Specifically, oxytocin stimulates the uterus to contract during childbirth.

Interestingly, a small study out of San Diego found that combining low doses of oxytocin with ketamine therapy, may provide more effective pain relief to people living with severe and treatment-resistant pain.

Oxytocin’s role in analgesia is two-fold. There are oxytocin receptors throughout the central nervous system in the brain and also along the spinal cord. When oxytocin binds to these receptors, it decreases pain signals. Additionally, oxytocin can bind to opioid receptors which causes a release of the body’s own endogenous opioids in the brain. These two effects together result in analgesia.

Oxytocin may also have a role in depression treatment. Oxytocin decreases the levels of cortisol (a stress hormone) in the blood stream. This can result in improvement of mood and increased relaxation.

Oxytocin, an Opioid Alternative, Ready for Regular Clinical Use to Manage Chronic Pain

There are few concerning adverse events associated with exogenous oxytocin, and any side effects are mostly subjective and transient, with reports consisting of dizziness, nausea, and dysphoria.26 Also, no known drug interactions have been observed or reported by patients in my clinic.4,5 We have administered oxytocin to patients who also were taking ketamine, low dose naltrexone, benzodiazepines, neuropathic agents, and opioids, with no observed or reported adverse reactions.

In fact, the apparent and relative non-interaction of oxytocin with common pain-relieving medications supports its favorable safety profile. We have prescribed it both as a regular pain lowering, maintenance agent and for pain flares in lieu of an opioid. My patients with chronic pain conditions have received instructions to take oxytocin two to three times a day.5,20 The potency of oxytocin is the equivalent of about 30 mg of oxycodone or morphine.

Not a Magic Bullet, But a Great Option

It is important to acknowledge that oxytocin, as is the case with any pain reliever, will not produce pain relief in every patient. The pain-relieving ability of this hormone will likely vary from patient to patient, and its effectiveness undoubtedly will be related to intrinsic blood levels, sex, and pain severity, among others factors known and unknown.

In summary, oxytocin is a hormone with a strong, pain-reducing potential that represents a relatively safe alternative to opioids for some patients. Oxytocin appears to offer pain practitioners a potent, intrinsic analgesic that has a complex and formidable production, release, and receptor system that clearly supports its pain-relieving properties.

Admittedly, there is an urgent need to offer patients with chronic, intractable, severe pain conditions an array of alternatives so they are able to medically manage their pain and effectively maintain their function. At the same time, we are challenged to lessening any opportunity for misuse or abuse of opioids, allowing that opioids may be a necessary pain reliever of last resort. As such, it is timely to herald the possible introduction of oxytocin, as an opioid alternative, for new patients who will present with a chronic pain condition so they are not compelled to turn to a potent opioid as the only answer to their unrelenting pain.

Oxytocin – a multifunctional analgesic for chronic deep tissue pain.

  1. Masters NJ. Brompton cocktail. Lancet. 1979;7;2(8132):47.
  2. Bayer. Aspirin—Surprisingly versatile. Available at: “http://www.bayer.com/en/aspirin.aspx” www.bayer.com/en/aspirin.aspx. Accessed Oct. 25, 2017.
  3. Goodin BR, Ness TJ, Robbins MT. Oxytocin— A multifunctional analgesic for chronic deep tissue pain. Curr Pharm Des. 2015;21(7):906-913.
  4. Tennant F. Oxytocin in intractable pain patient unresponsive to standard treatments. Poster presented at the 33rd annual meeting of the American Pain Society. April 30-May 3, 2014. Tampa, Florida.
  5. Tennant F, Pedersen C. Sublingual oxytocin and ketamine for pain relief. Poster presented at PAINWeek.  September 5 – 9, 2017. Las Vegas, Nevada.
  6. Rash JA, Aguirre-Camacho A, Campbell TS. Oxytocin and pain: a systemic review and synthesis of findings. Clin J Pain 2014;30(5):453-462.
  7. Lee HJ, Macbeth AH, Pagani JH, Young WS. Oxytocin: the great facilitator of life. Prog Neurobiol. 2009;88(2):127-151.
  8. Rash JA, Campbell TS. The effect of intranasal oxytocin administration on acute cold pressor pain: a placebo-controlled, double-blind, within-subjects crossover trial. Psychosom Med. 2014;76(6):422-429.
  9. Yang J, Yang Y, Chen JM, et al. Central oxytocin enhances antinociception in the rat. Peptides. 2007;28:1113-1119.
  10. Paloyelis Y, Krahe C, Maltezos S, Williams SC, Howard MA, Fotopoulou A. The analgesic effect of oxytocin in humans: a double-blind placebo controlled cross-over study using laser-evoked potentials. J Neuroendocrinol. 2016;28(4):10.111.
  11. Jo YH, Stocekel ME, Freund-Mercier MJ, et al. Oxytocin modulates glutamalergic synaptic transmission between cultured neonatal spinal cord dorsal horn neurons. J Neurosci. 1998;18:2377-2386.
  12. Reiter MK, Kremarik P, Freund-Mercier MJ, et al. Localization of oxytocin binding sites in the thoracic and upper lumbar spinal cord of the adult and postnatal rat: a histoautoradiographic study. Eur J Neurosci. 1994;6:98-104.
  13. Reeta KH, Mediratta PK, Rathi N, Jain H, Chugh C, Sharma KK. Role of kappa-and delta opioid receptors in the antinociceptive effect of oxytocin in formalin-induced pain response in mice. Regulatory Peptides. 2006;135(1-2):85-90.
  14. Breton JD, Veinante P, Uhl-Bronner S, et al. Oxytocin-induced antinociception in the spinal cord is mediated by a subpopulation of glutamatergic neurons in lamina I-II which amplify GABAergic inhibition. Mol Pain. 2008;4:19.
  15. Gimpi G, Fahranholz F. The oxytocin receptor system: structure, function, and regulation. Physiol Rev. 2001;81:629-683.
  16. Wei D, Lee D, Cox CD, et al. Endocannabinoid signaling mediates oxytocin-driven social reward. PNAS. 2015;112(45):14084-14089.
  17. Windle R, Shanks N, Lightman SL, Ingram CD. Central oxytocin administration reduces stress-induced corticosterone release and anxiety behavior in rats. Endocrinol.1997;138(7):2829-2834.
  18. Douglas AJ, Neumann I, Meeren HKM, et al. Central endogenous opioid inhibition of supraoptic oxytocin neurons in pregnant rats. J Neurosci. 1995;15(7):5049-5057.
  19. Wang YL, Yuan Y, Yang J, et al. The interaction between the oxytocin and pain modulation in headache patients. Neuropeptides. 2003;47(2):93-97.
  20. Goodin BR, Ness TJ, Robbins MT. Oxytocin—A multifunctional analgesic for chronic deep tissue pain. Curr Pharm Res. 2015;21:906-913.
  21. Yang J, Intrathecal administration of oxytocin induces analgesia in low back pain involving the endogenous opiate peptide system. Spine. 1994;19:867-871.
  22. Louvel D, Delvaux M, Felez A, et al. Oxytocin increases thresholds of colonic visceral perception in patients with irritable bowel syndrome. Gut 1996;39:741-747.
  23. Ohlsson B, Truedsson M, Bengtsson M, et al. Effects of long-term treatment with oxytocin in chronic constipation; a double-blind, placebo-controlled pilot trial.Neurogastroenterol Motil. 2005;17:697-704.
  24. Striepens N, Kendrick KM, Hanking V, et al. Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal administration in humans. Sci Rep. 2013;3:3440.
  25. Modi ME, Connor-Stoud F, Landgraf R, et al. Aerosolized oxytocin increases cerebrospinal fluid oxytocin in rhesus macaques. Psychoneuroendocrinology. 2014;45:49-57.
  26. Dal Monte O, NOble PL, Turchi J, et al. CSF and blood oxytocin concentration changes following intranasal delivery in macaque. PLoS One. 2014;9:e10367.
  27. RxList. Pitocin (oxytocin). Available at:  “https://www.rxlist.com/pitocin-side-effects-drug-center.htm”>https://www.rxlist.com/pitocin-side-effects-drug-center.htm. Accessed Oct. 25, 2017.

Oxytocin is being studied as well for drug addiction:

Breaking the loop: Oxytocin as a potential treatment for drug addiction

Breaking the loop Oxytocin as a potential treatment for drug addiction

Drug use typically occurs within a social context, and social factors play an important role in the initiation, maintenance and recovery from addictions. There is now accumulating evidence of an interaction between the neural substrates of affiliative behavior and those of drug reward, with a role for brain oxytocin systems in modulating acute and long-term drug effects. Early research in this field indicated that exogenous oxytocin administration can prevent development of tolerance to ethanol and opiates, the induction of stereotyped, hyperactive behavior by stimulants, and the withdrawal symptoms associated with sudden abstinence from drugs and alcohol. Additionally, stimulation of endogenous oxytocin systems is a key neurochemical substrate underlying the prosocial and empathogeniceffects of party drugs such as MDMA (Ecstasy) and GHB (Fantasy). Brain oxytocin systems exhibit profound neuroplasticity and undergo major neuroadaptations as a result of drug exposure. Many drugs, including cocaine, opiates, alcohol, cannabis, MDMA and GHB cause long-term changes in markers of oxytocin function and this may be linked to enduring deficits in social behavior that are commonly observed in laboratory animals repeatedly exposed to these drugs. Very recent preclinical studies have illustrated a remarkable ability of exogenously delivered oxytocin to inhibit stimulant and alcohol self-administration, to alter associated drug-induced changes in dopamineglutamate and Fos expression in cortical and basal ganglia sites, and to prevent stress and priming-induced relapse to drug seeking. Oxytocin therefore has fascinating potential to reverse the corrosive effects of long-term drugs abuse on social behavior and to perhaps inoculate against future vulnerability to addictive disorders. The results of clinical studies examining intranasal oxytocin effects in humans with drug use disorders are eagerly awaited. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.

Modulating-social-behavior-with-oxytocin–How-does-it-wo_2012_Hormones-and-B

Oxytocin-and-social-affiliation-in-humans_2012_Hormones-and-Behavior

The-contributions-of-oxytocin-and-vasopressin-pathway-g_2012_Hormones-and-Be

 

The Analgesic Effect of Oxytocin in Humans A Double-Blind, Placebo-Controlled Cross-Over Study Using Laser-Evoked Potentials.::

Abstract

Oxytocin is a neuropeptide regulating social-affiliative and reproductive behaviour in mammals. Despite robust preclinical evidence for the antinociceptive effects and mechanisms of action of exogenous oxytocin, human studies have produced mixed results regarding the analgesic role of oxytocin and are yet to show a specific modulation of neural processes involved in pain perception. In the present study, we investigated the analgesic effects of 40 IU of intranasal oxytocin in 13 healthy male volunteers using a double-blind, placebo-controlled, cross-over design and brief radiant heat pulses generated by an infrared laser that selectively activate Aδ- and C-fibre nerve endings in the epidermis, at the same time as recording the ensuing laser-evoked potentials (LEPs). We predicted that oxytocin would reduce subjective pain ratings and attenuate the amplitude of the N1, N2 and P2 components. We observed that oxytocin attenuated perceived pain intensity and the local peak amplitude of the N1 and N2 (but not of P2) LEPs, and increased the latency of the N2 component. Importantly, for the first time, the present study reports an association between the analgesic effect of oxytocin (reduction in subjective pain ratings) and the oxytocin-induced modulation of cortical activity after noxious stimulation (attenuation of the N2 LEP). These effects indicate that oxytocin modulates neural processes contributing to pain perception. The present study reports preliminary evidence that is consistent with electrophysiological studies in rodents showing that oxytocin specifically modulates Aδ/C-fibre nociceptive afferent signalling at the spinal level and provides further specificity to evidence obtained in humans indicating that oxytocin may be modulating pain experience by modulating activity in the cortical areas involved in pain processing.

Intranasal oxytocin enhances intrinsic corticostriatal functional connectivity in women.

Oxytocin increased connectivity between corticostriatal circuitry typically involved in reward, emotion, social communication, language and pain processing. This effect was 1.39 standard deviations above the null effect of no difference between oxytocin and placebo. This oxytocin-related effect on corticostriatal connectivity covaried with autistic traits, such that oxytocin-related increase in connectivity was stronger in individuals with higher autistic traits. In sum, oxytocin strengthened corticostriatal connectivity in women, particularly with cortical networks that are involved in social-communicative, motivational and affective processes. This effect may be important for future work on neurological and psychiatric conditions (for example, autism), particularly through highlighting how oxytocin may operate differently for subsets of individuals.

Role of oxytocin in the ventral tegmental area in social reinforcement.

r, these data support the hypothesis that activation of OT receptors in
the VTA are critical for the reinforcing properties of social interactions. Furthermore, social interactions may
exhibit duration and cost dependent reinforcing effects on behavior similar to those observed with food and
drugs of abuse.

Neuroinflammation: Treating the Underlying Cause of Chronic, Severe Pain

 

“Neuroinflammation due to microglial activation is the underlying cause of severe persistent or constant pain,” pointed Dr Tennant.“Neuroinflammation due to microglial activation is the underlying cause of severe persistent or constant pain,” pointed Dr Tennant.
The following article features coverage from PAINWeek 2017 in Las Vegas, Nevada. Click hereto read more of Clinical Pain Advisor‘s conference coverage.

LAS VEGAS – At Pain Week 2017, held September 5-9, Forest Tennant, MD, DrPH, an internist, addictionologist, and researcher at the Veract Intractable Pain Clinics in West Covina, California, sought to highlight the role of neuroinflammation in severe chronic pain.1

Dr Tennant aimed to help attendees identify patients with neuroinflammation, the diseases most commonly implicated in severe neuroinflammation, complications and outcomes associated with the condition, and optimal treatment options. “Neuroinflammation due to microglial activation is the underlying cause of severe persistent or constant pain, and unless it is suppressed, no real treatment of the cause of pain can be realized,” Dr Tennant told Clinical Pain Advisor.2,3

 

“Time has taught us that there is a relatively short list of pathologic conditions that cause the most severe, chronic pain — every pain practitioner should have awareness of these,” he added. These conditions include Ehlers-Danlos syndrome, sickle cell disease, Lyme disease, and severe peripheral neuropathies. Dr Tennant also gave examples of pathologic consequences and symptoms of neuroinflammation, including constant pain, insomnia, depression, central sensitization with allodynia and hyperalgesia, and febrile heat episodes.

Physical examination findings may include elevated pulse rate, respiratory rate, blood pressure, and reflex activity; cold extremities; mydriasis; and diaphoresis. Diagnostic tests may reveal elevated serum levels of inflammatory markers such as high-sensitivity C-reactive protein, interleukins, and tumor necrosis factor, as well as abnormal levels of hormones such as dehydroepiandrosterone, testosterone, and progesterone.

Here are the 4 components of treatment for centralized pain and neuroinflammation:

  • Pain relief using standard nonpharmacologic and pharmacologic approaches
  • Neuroinflammation control with varying combinations of low-dose corticosteroids, anti-inflammatories, microglial suppressors, and nutritional supplements
  • Spinal fluid flow exercises including walking arm swings, upper body gyration, and deep breathing
  • Neuroregeneration with B12, replenishment of hormones showing low serum levels, and the administration of neurohormones that have been found to produce neuroregeneration in animal studies — for example, oxytocin, human growth hormone, and human chorionic gonadotropin4

According to Dr Tennant, there is a large body of animal and in vitro research on neuroregeneration and hormonal suppression of neuroinflammation, and results have been positive among the few clinical researchers who have applied the basic science findings to real patients. He recommends clinical trials with neurohormones in motivated patients whose pain is reasonably under control. “It is too early to recommend a specific clinical indication, but the neurohormones appear quite safeand I believe astute practitioners should begin using neurohormones,” he added.

 

He stated that neither FDA approval of these agents nor a consensus on evidence-based practice in this area is likely, as pharmaceutical companies will not spend money on large trials since hormones cannot be patented, and they have not been in use long enough to accumulate much evidence-based data. He distributed references to give practitioners confidence that prescribing neurohormones is not a “pie-in-the-sky” concept.

“Overall, hormone treatment of both types should begin to be a new paradigm in pain treatment,” Dr Tennant said. “To date, we’ve been simply throwing symptomatic pharmaceuticals at pain patients because that is all we have had — now we can begin to treat the underlying cause of pain as opposed to just symptomatic care.”

 

References

  1. Tennant F. Neuroinflammation: treating the underlying cause of chronic, severe pain. Presented at Pain Week 2017; September 5-9, 2017; Las Vegas, NV.
  2. Graeber MB, Christei MJ. Multiple mechanisms of microglia: a gatekeeper’s contribution to pain states. Exp Neurol. 2012; 234(2):255-61. doi:10.1016/j.expneurol.2012.01.007
  3. Gwak YS, Hulsebosch CE. Remote astrocytic and microglial activation modulates neuronal hyperexcitability and below-level neuropathic pain after spinal injury in rat.Neuroscience. 2009;161(3):895-903. doi:10.1016/j.neuroscience.2009.03.055
  4. Lei ZM, Rao CV. Neural actions of luteinizing hormone and human chorionic gonadotropinSemin Reprod Med. 2001;19(1):103-9. doi:10.1055/s-2001-13917

 

Neurohormones in Pain and Headache Management: New and Emerging Concepts

The recent discovery and awareness that the central nervous system (CNS) makes specific hormones for intrinsic use in addition to those for peripheral use is a profound finding that is critical to clinical pain and headache management. Some neurohormones provide the physiologic effects of neuroprotection and neurogenesis that are essential for pain reduction, prevention, and treatment.

Following is an attempt to provide an early status report on what we do (and don’t) know about the function of neurohormones relative to pain management. Be clearly advised that this report is elementary and, undoubtedly, will be subject to expansion and revision as more basic science and clinical experience are accumulated. This review looks at 8 neurohormones that are in early clinical use.

Definition of Neurohormones

The CNS, including the pituitary gland, produces numerous hormones, but relatively few are known to have pain-related functions within the CNS.1-22 For the purposes of this article, we define a neurohormone as a hormone that is produced, retained, and has functions within the CNS that promote pain control. Additional hormones surely will be found.

We did not include hormones that are produced in the peripheral endocrine system and then transported by arterial blood into the CNS for biologic actions, such as cortisol, epinephrine, thyroid hormones, or insulin.11-13 Also excluded from discussion are endorphins, prolactin, melatonin, vitamins (ie, D2 and D3), dopamine, cytokines, and various releasing hormones because, although they may have a pain modulatory function, they are generally considered neurotransmitters or neuromodulators. At this time, many of these hormones cannot be readily measured in serum or formulated into compounds.

Neurohormones appear to have 3 basic pain control functions: analgesia or pain modulation; neuroprotection of CNS cells; and neurogenesis, defined as re-growth of damaged tissue.14-21 Table 2 outlines the biologic actions of neurohormones. Neurohormones likely exert some neuromodulatory and transmission effects, and some appear to have direct analgesic properties. For example, oxytocin is known to surge during childbirth as a component of natural anesthesia.

Serum Testing: Why, When, and How

One of the best uses of hormone profiles is for chronic pain patients who have not responded to a standard treatment regimen and continue to have uncontrolled pain.22 A hormone profile can measure all 5 neurosteroids; HCG, HGH, and oxytocin testing usually are only available through specialty labs that use early-phase testing protocols with non-standard assays.

A serum concentration of a hormone, such as pregnenolone, progesterone, or DHEA, has adrenal and gonadal sources, as well as CNS sources. Thus, it is unknown how much of a serum neurohormone concentration is from CNS versus peripheral sources. However, pain control requires hormone homeostasis in both the CNS and periphery, so a low serum level can be treated without concern as to which sources are not producing enough. Results from a hormone profile will give the practitioner some clues as to why a treatment regimen is not effective and provide enough information so the clinician can take measures to help the patient adjust, or modify, his or her regimen to attain better pain control.22 For example, serum testing is recommended before starting DHEA, pregnenolone, progesterone, testosterone, and estradiol.

Our recommendation is that hormone administration be restricted to patients who show serum deficiencies. A goal of hormone administration should be to bring serum concentrations into the normal or optimal range.

Neurohormones

Progesterone and Allopregnanolone

Although a great deal of basic science and animal research has been conducted on neurohormones,23-53 prior to 2010 there was little interest in neurohormones other than testosterone for pain management. In 2010, Kilts et al observed that nearly half of veterans returning from the Middle East who experienced persistent pain had low serum levels of allopregnanolone,23 a metabolite of progesterone.25,29,43 It was theorized that the pain experienced by the veterans was due to a lack of progesterone, which has been shown in multiple studies to reduce neuroinflammation, oxidative stress, and brain damage in animals.24,27,33,39 Progesterone also may be a precursor of cortisol, the central hormone in the stress response.

Progesterone is being studied in cerebral vascular accidents and traumatic brain injury (TBI).39-42 Our preliminary open-label investigation of progesterone is encouraging, but no specific recommendations on its clinical use can be made yet.27 However, it is important to take a broader look at the pain patient’s hormonal status and measure it, even in young men and women. Progesterone cannot be considered ONLY the “baby” hormone anymore!

Dehydroepiandrosterone

DHEA is, on a quantitative basis, the most plentiful hormone in the human body. It circulates in abundance in the form of a sulfated reserve (DHEA-S).54-73 DHEA, the levels of which decline with age,59 has been well studied and used as a dietary and hormonal supplement for hyperlipidemia and cardiovascular disorders.68-73 It also has been a favorite anti-aging and stress-relieving dietary supplement.

Enthusiasm for use of DHEA in pain management began in 1994, when it was found to suppress pain and pain flares in patients with systemic lupus erythematosus (SLE).68 Since that time, a number of studies have confirmed its effectiveness in SLE. It clearly possesses anti-inflammatory properties and suppresses interleukin 10 synthesis in women with SLE.

In addition to having peripheral anti-inflammatory actions, DHEA also has been shown to be produced in the CNS and have additional critical properties related to pain management.56 It is neuroprotective and inhibits tumor necrosis factor alpha (TNF-a) and CNS inflammatory markers by inhibiting production of monocytes, astrocytes, and microglial cells. Its neuroprotective action in the CNS is at least partially attributed to conversion to estrogen and estradiol.54

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16_Hormone_Thearpy_Tennant_F  << Lecture notes re Oxytocin

Neurohormones in Pain and Headache Management: New and Emerging Concepts

The recent discovery and awareness that the central nervous system (CNS) makes specific hormones for intrinsic use in addition to those for peripheral use is a profound finding that is critical to clinical pain and headache management. Some neurohormones provide the physiologic effects of neuroprotection and neurogenesis that are essential for pain reduction, prevention, and treatment.

Following is an attempt to provide an early status report on what we do (and don’t) know about the function of neurohormones relative to pain management. Be clearly advised that this report is elementary and, undoubtedly, will be subject to expansion and revision as more basic science and clinical experience are accumulated. This review looks at 8 neurohormones that are in early clinical use.

Definition of Neurohormones

The CNS, including the pituitary gland, produces numerous hormones, but relatively few are known to have pain-related functions within the CNS.1-22 For the purposes of this article, we define a neurohormone as a hormone that is produced, retained, and has functions within the CNS that promote pain control. Additional hormones surely will be found.

Table 1 lists the 8 neurohormones that have been identified as affecting pain. Five of these are called neurosteroids because they have the steroid moiety (4 carbon rings) as part of their chemical structure.9-10 These are dehydroepiandrosterone (DHEA), estradiol, pregnenolone, progesterone, and testosterone. The 3 remaining neurohormones are human chorionic gonadotropin (HCG), human growth hormone (HGH), and oxytocin.

We did not include hormones that are produced in the peripheral endocrine system and then transported by arterial blood into the CNS for biologic actions, such as cortisol, epinephrine, thyroid hormones, or insulin.11-13 Also excluded from discussion are endorphins, prolactin, melatonin, vitamins (ie, D2 and D3), dopamine, cytokines, and various releasing hormones because, although they may have a pain modulatory function, they are generally considered neurotransmitters or neuromodulators. At this time, many of these hormones cannot be readily measured in serum or formulated into compounds.

Neurohormones appear to have 3 basic pain control functions: analgesia or pain modulation; neuroprotection of CNS cells; and neurogenesis, defined as re-growth of damaged tissue.14-21 Table 2 outlines the biologic actions of neurohormones. Neurohormones likely exert some neuromodulatory and transmission effects, and some appear to have direct analgesic properties. For example, oxytocin is known to surge during childbirth as a component of natural anesthesia.

Serum Testing: Why, When, and How

One of the best uses of hormone profiles is for chronic pain patients who have not responded to a standard treatment regimen and continue to have uncontrolled pain.22 A hormone profile can measure all 5 neurosteroids; HCG, HGH, and oxytocin testing usually are only available through specialty labs that use early-phase testing protocols with non-standard assays.

A serum concentration of a hormone, such as pregnenolone, progesterone, or DHEA, has adrenal and gonadal sources, as well as CNS sources. Thus, it is unknown how much of a serum neurohormone concentration is from CNS versus peripheral sources. However, pain control requires hormone homeostasis in both the CNS and periphery, so a low serum level can be treated without concern as to which sources are not producing enough. Results from a hormone profile will give the practitioner some clues as to why a treatment regimen is not effective and provide enough information so the clinician can take measures to help the patient adjust, or modify, his or her regimen to attain better pain control.22 For example, serum testing is recommended before starting DHEA, pregnenolone, progesterone, testosterone, and estradiol.

Our recommendation is that hormone administration be restricted to patients who show serum deficiencies. A goal of hormone administration should be to bring serum concentrations into the normal or optimal range.

Neurohormones

Progesterone and Allopregnanolone
Although a great deal of basic science and animal research has been conducted on neurohormones,23-53 prior to 2010 there was little interest in neurohormones other than testosterone for pain management. In 2010, Kilts et al observed that nearly half of veterans returning from the Middle East who experienced persistent pain had low serum levels of allopregnanolone,23 a metabolite of progesterone.25,29,43 It was theorized that the pain experienced by the veterans was due to a lack of progesterone, which has been shown in multiple studies to reduce neuroinflammation, oxidative stress, and brain damage in animals.24,27,33,39 Progesterone also may be a precursor of cortisol, the central hormone in the stress response.

Progesterone is being studied in cerebral vascular accidents and traumatic brain injury (TBI).39-42 Our preliminary open-label investigation of progesterone is encouraging, but no specific recommendations on its clinical use can be made yet.27 However, it is important to take a broader look at the pain patient’s hormonal status and measure it, even in young men and women. Progesterone cannot be considered ONLY the “baby” hormone anymore!

Dehydroepiandrosterone

DHEA is, on a quantitative basis, the most plentiful hormone in the human body. It circulates in abundance in the form of a sulfated reserve (DHEA-S).54-73 DHEA, the levels of which decline with age,59 has been well studied and used as a dietary and hormonal supplement for hyperlipidemia and cardiovascular disorders.68-73 It also has been a favorite anti-aging and stress-relieving dietary supplement.

Enthusiasm for use of DHEA in pain management began in 1994, when it was found to suppress pain and pain flares in patients with systemic lupus erythematosus (SLE).68 Since that time, a number of studies have confirmed its effectiveness in SLE. It clearly possesses anti-inflammatory properties and suppresses interleukin 10 synthesis in women with SLE.

In addition to having peripheral anti-inflammatory actions, DHEA also has been shown to be produced in the CNS and have additional critical properties related to pain management.56 It is neuroprotective and inhibits tumor necrosis factor alpha (TNF-a) and CNS inflammatory markers by inhibiting production of monocytes, astrocytes, and microglial cells. Its neuroprotective action in the CNS is at least partially attributed to conversion to estrogen and estradiol.5

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Hormone Testing and Replacement in Pain Patients Made Simple

A progression of clinical studies over the past four decades provides a sound scientific basis to test and administer specific adrenal and gonadal hormones in patients with chronic pain.1-12 Therefore, I believe that testing and replacement of some hormones are essential elements of pain management. Testing can tell the practitioner whether a treatment regimen is providing adequate pain control, and if not, which hormone replacements are necessary to maximize physical and mental function. This article will review a four-hormone panel screen, which I recommend, as well as a simple replacement guideline (Table 1).

Why Test?
First of all, why test hormone levels in patients with chronic pain? As noted, hormones are essential to the body’s function. When the body becomes stressed, as through injury, the body’s mechanism sets off a chain reaction (flight or fight response) that releases hormones from the hypothalamus, pituitary, and adrenal glands (HPA axis). Initially, the body is flooded with hormones, but if that stress response persists over a long period of time, the body’s organs become depleted of hormones. Because natural pain control and healing is mediated through the endocrine system, if any adrenal or gonadal hormone is deficient, optimal pain control will not be achieved.6,13-15

Essentially all pain is accompanied by inflammation, including neuroinflammation.14,16-20 Pain increases the release of cortisol and pregnenolone, the two major glucocorticoids that control inflammation.16,19,21 Pregnenolone also controls γ-aminobutyric acid (GABA) receptors in the central nervous system (CNS), which regulate pain signals in nerves.21 Adrenal hormones, such as cortisol, are critical for multiple CNS functions including nerve conduction, memory storage, and receptor binding.22-29 Corticotropin-releasing hormone (CRH) is the major pituitary hormone that stimulates production of all adrenal hormones (ie, glucocorticoids), so a deficiency of this hormone can produce profound symptomatology and uncontrolled pain.9,11,30,31 Testosterone is critical for tissue growth including bone.32-34 Pain decreases the amount of testosterone in the body. A deficiency in testosterone actually leads to a catabolic or degenerative state. The four basic mechanisms by which adrenal and gonadal hormones control pain are outlined in Table 2.

Besides identifying which hormones need to be replaced, hormone testing has other merits. First, it will tell you if a severe stress state is present; if so, the clinician may need to institute—or increase dosages of—neuropathic agents, antidepressants, opioids, or other medication used in pain management.12,35,36 Opioids and antidepressants, among the other treatment agents, will not properly bind to CNS receptors if hormone levels are not adequate.7,22Hormones maintain the blood–brain barrier by which hormones and medications flow.8

Another critical reason to conduct hormone testing is to identify a hormone abnormality that may cause long-term complications. This is especially a risk factor when a patient has either too high or too low serum cortisol levels.37-39Many clinical symptoms such as depression, insomnia, hyperalgesia, allodynia, and opioid tolerance and ineffectiveness are often, erroneously, blamed on factors other than the true cause—hormone deficiency. Identification of a hormone deficiency and subsequent hormone replacement may eliminate these symptoms. Simply put, optimal treatment of a chronic pain patient can only be achieved if all adrenal and gonadal hormones are maintained at adequate levels.

Table 3 outlines which pain patients benefit from hormone testing.35,36,40 In my opinion, patients with intractable pain that causes relentless stress to the hypothalamus and pituitary, thus causing the presence of abnormal serum hormone levels, should be tested.40 In all likelihood, patients with constant pain (present 24/7) have centralized their pain. Chronic pain patients who only have intermittent or episodic pain need not be tested.36,40 For example, the average osteoarthritic or neuropathy patient with mild or moderate fluctuating pain on some days or during some hours, but no pain on other days, will not likely show any hormonal abnormality that would require hormone replacement.40

Which Hormones to Test?
Although many hormones can be tested and replaced, the four-hormone screen described here has been deemed the most critical to the evaluation and treatment of a pain patient. All four can be tested on a single early morning blood specimen. These four screens will give you enough information to evaluate the patient’s pain effect on the hormonal system, tell you whether the patient needs more aggressive pain treatment, and identify which hormones must be replaced to prevent complications from hormone abnormalities (Table 4).

A brief description of each of these four hormones is given here. Also, you should know enough about each hormone to educate patients, family, and other concerned parties.

Adrenocorticotropin (ACTH)
The pituitary gland produces ACTH. This hormone is your best, simplest screen as to whether pain is over-stimulating or suppressing hypothalamic and pituitary function. Severe, uncontrolled pain will cause ACTH to rise above normal serum levels.6,13-15 If severe pain goes unabated for a considerable time period, it will depress pituitary function, which results in low serum ACTH levels.

A low serum ACTH level almost always means that pain control has been inadequate for a considerable period of time. An abnormal ACTH, high or low, also likely means that the patient has centralized their pain and is causing excess stimulation of the hypothalamus and pituitary.

Table: Why test for hormone abnormalities?

Pregnenolone
Pregnenolone is the precursor of all hormones produced in the adrenal and gonad glands (Figure 1). It is also produced in the CNS where it acts as a neurosteroid. The functions of pregnenolone include anti-inflammation, neurogenic growth, and regulation of GABA receptors.1,2,21 In the author’s experience, a low serum pregnenolone level is the most common hormone abnormality observed in patients with uncontrolled pain. When corrected, patients usually report improved pain control, energy, and sleep. Allodynia (pain to light touch) and hyperalgesia (excess pain on pressure), if present, often resolve. Just why serum pregnenolone abnormalities occur is somewhat unclear. High levels may be due to pain’s initial over-stimulation of the pituitary–adrenal–gonadal axis, whereas low levels are most likely due to long-term pain’s depressive effect on the system. In fact, uncontrolled pain suppresses or depletes production of pregnenolone in the CNS.21 Regardless, replacement is most welcome by pain patients as pregnenolone is needed to produce other adrenal-gonadal hormones such as progesterone, estrogen, and dehydroepiandrosterone (DHEA).

Testosterone
This end product of adrenal and gonadal production is now recognized, in males and females, to be critical for pain control, mood, energy, tissue healing, and libido.32-34,41 Most of the publicity about testosterone in pain treatment is related to the fact that opioids exert a preferential suppressive effect on the hypothalamic and pituitary hormones, which produce testosterone.42-45

A key point to be made is that low levels of serum testosterone may occur due to long-standing severe pain in patients who have never been treated with opioids. A major point in pain treatment is that testosterone is an anabolic compound that provides critical tissue growth and healing.

Cortisol
Cortisol is an end product of adrenal metabolism. Normal levels tell the practitioner that pituitary-adrenal homeostasis is at least relatively intact and stable.36 High serum levels mean there is overstimulation of the hypothalamus and pituitary by uncontrolled pain. Low serum levels mean the pain has been so unrelenting that it has suppressed the hormone system. Normal serum levels are critical for pain management. Cortisol is known to be essential for opioid effectiveness in the CNS.7,8 Resolution of inflammation relies on cortisol.16-19 Simply put, any inflammatory condition involving the spine, peripheral nerves, or joints can hardly resolve without adequate cortisol.46-48

Chronic low (Addison’s disease) or high (Cushing’s syndrome) serum cortisol levels have long-term devastating effects.29 Chronic low serum cortisol levels produce a catabolic state with weakness, muscle wasting, depression, weight loss, mental confusion, and lack of desire to physically move or ambulate.41 High chronic cortisol levels produce hypertension, hyperlipidemia, diabetes, upper trunk obesity, and most critically, osteopenia and osteoporosis.37-39 The latter, in chronic pain patients, occurs over time and may not be recognized until there is sudden spine collapse or knee degeneration (see case photographs below).

Case photograph: Severe progressive osteopporosis and vertebral collapseCase photograph: Severe progressive osteoporosis and vertebral collapse

Additional Hormones for Testing Consideration
A pain practitioner may wish to test other hormones in addition to the four-panel profile recommended here. Additional hormone screens can provide, in some patients, further information. Hormones you may wish to add to the basic panel are listed here, as well as their limitations and benefits to testing and replacement.

DHEA
DHEA is an intermediary compound in the hormone pathway of the adrenals and gonads. It has both precursor and direct functions.42 DHEA is sold over the counter. Serum testing is readily available and laboratories can report low, normal, or high serum concentrations. Occasionally, a low level of DHEA is found in patients on long-term opioids when pregnenolone, cortisol, and testosterone are normal. Replacement dosage is usually 100 to 200 mg per day.

Progesterone and Estrogen
The major limitation to testing for these hormones is that normal levels vary considerably between male and female patients and, in women, vary according to age, menstrual cycles, and menopause status. Laboratories commonly report serum concentrations down to zero, making it difficult to know whether there is a deficiency. Both of these compounds may affect pain levels, so replacement may be in order. As an option to blood testing, short-term clinical trials of either hormone can be done to determine whether a patient may benefit.

Follicle-stimulating and Luteinizing Hormone
Testing for these pituitary hormones is usually done to determine whether opioids are the cause of low testosterone or estrogen levels, as opioids will suppress these sex hormones by suppressing these pituitary hormones.42-45

Free Testosterone and Sex Hormone Binding Globulin (SHBG)
In addition to total testosterone, these measurements may help to determine whether testosterone therapy is needed for libido and sexual function. A total testosterone serum level is one of the basic four-hormone panel because testosterone has many nonsexual functions including affecting energy, depression, tissue growth, and opioid-binding capacity, which are unrelated to libido and sexual function.32,33,41

CRH or Corticotropin-releasing Factor
CRH is produced in the hypothalamus. Investigations have found that pain primarily stimulates or suppresses this hormone, which in turn causes ACTH release.11,13,35 Unfortunately, the lower serum level is usually reported as zero by most laboratories, so a deficiency can be difficult to identify. A high serum level, however, should be interpreted as the presence of centralized pain that is severely out of control.

Figure: Hormone metabolic pathway in adrenal and gonad glands.

When to Test?
The time of day should be morning between about 6:00 and 9:00 am. This is because the circadian rhythm of most hormone production in the body hits its peak in early morning. The patient should not fast, but consume their normal food and drink.

The other aspect of “when” relates to follow-up testing. Once hormone abnormalities are detected, quarterly retesting is generally recommended. Monthly, or even more often, follow-up may be needed with emergency replacement of cortisol, pregnenolone, or testosterone. An emergency situation is defined here as a hormone serum level of cortisol, pregnenolone, or testosterone that is near zero.

Guidelines for Management Of New Pain Patients
Each new patient who enters pain treatment and who has constant pain that interferes with activities of daily living such as sleep, eating, dressing, ambulation, socializing, and toiletry should be evaluated by the four-hormone screen. Hormone abnormalities tell the practitioner whether the pain patient is in a severe stress state and requires more aggressive pain management.10,12 On the contrary, a pain patient with a normal hormone profile indicates there is no unusual stress on the pituitary–adrenal–gonadal axis, so not much more, if any, additional pain treatment is required unless the patient demands additional pain relief. Hormone levels should never override a patient’s stated need for additional medication. Here are case examples.

When to Test?
The time of day should be morning between about 6:00 and 9:00 am. This is because the circadian rhythm of most hormone production in the body hits its peak in early morning. The patient should not fast, but consume their normal food and drink.

The other aspect of “when” relates to follow-up testing. Once hormone abnormalities are detected, quarterly retesting is generally recommended. Monthly, or even more often, follow-up may be needed with emergency replacement of cortisol, pregnenolone, or testosterone. An emergency situation is defined here as a hormone serum level of cortisol, pregnenolone, or testosterone that is near zero.

Guidelines for Management Of New Pain Patients
Each new patient who enters pain treatment and who has constant pain that interferes with activities of daily living such as sleep, eating, dressing, ambulation, socializing, and toiletry should be evaluated by the four-hormone screen. Hormone abnormalities tell the practitioner whether the pain patient is in a severe stress state and requires more aggressive pain management.10,12 On the contrary, a pain patient with a normal hormone profile indicates there is no unusual stress on the pituitary–adrenal–gonadal axis, so not much more, if any, additional pain treatment is required unless the patient demands additional pain relief. Hormone levels should never override a patient’s stated need for additional medication. Here are case examples.

Case Example: More Treatment Needed
A 45-year-old woman developed severe cervical spine degeneration and stenosis following an automobile accident. Her morphine equivalent dose of opioids was about 350 to 400 mg per day. She complained of poor pain control, arm weakness, severe insomnia, fatigue, and a need to be in bed about 4 hours each day. Her early morning serum cortisol concentration was 31.0 mcg/dL (normal is 5 to 20 mcg/dL) and pregnenolone serum concentration was 10 pg/mL (normal above 15 pg/mL). Her morphine daily equivalent dose was raised to 600 mg per day, and she was concomitantly started on a topical analgesic, muscle relaxant, and stretching exercises. Within eight weeks she was no longer bed-bound; slept reasonably well; and claimed much better pain control, energy, and arm movement. A repeat serum cortisol and pregnenolone screen conducted after 12 weeks on a higher opioid dosage showed normal values. In this case, high serum levels of hormones showed that the patient’s pain was not well controlled, indicating a need for increased pain medications.

Case Example: Treatment Regimen Satisfactory
A 50-year-old man with facial neuropathies due to a traumatic injury was referred to my clinic. The patient was taking an oral dose of 10 mg hydrocodone combined with 325 mg acetaminophen 6 to 8 times per day. He also was prescribed zolpidem 10 mg per day and diazepam 10 mg twice per day. The patient stated he had a full-time job and was happy with his pain treatment, but his primary care doctor was uncomfortable with his “high” opioid dosage and referred him for evaluation. The four-hormone panel screen showed normal serum concentrations of ACTH, testosterone, cortisol, and pregnenolone. Other than prescribing some dietary supplements, a topical analgesic, and stretching exercises, no change in his regimen was recommended. Interestingly, insurance companies rarely turn down hormone testing requests, probably because they recognize that serious outcomes can result from abnormal levels.

Guidelines for Patients Already on Opioids
Opioids are now well known to suppress hormone production, and the phrase “opioid endocrinopathy” is often applied to this situation.44,49,50 Clinically, testosterone is the only hormone that is commonly suppressed, and this only occurs in pain patients who have constant pain and take opioids in a dosage of ≥100 mg equivalent of morphine per day. Testosterone suppression is most common with long-acting opioids and around-the-clock dosing.43,44 The hormone system is least suppressed when there are hours in the 24-hour-day cycle in which no opioids are in the blood stream. In addition to testosterone, opioids may occasionally suppress ACTH, cortisol, or pregnenolone in severe pain patients who take high-dose opioids.44,50 In these cases, hormone replacement will be necessary.

A challenge to the practitioner with a severe chronic pain patient who requires high-dose opioids is to know whether the pain, the opioids, or both are causing low serum levels of testosterone and/or other hormones. Sometimes it is difficult to tell but, nevertheless, replacement must be done.

A common clinical mistake is to automatically assume that such symptoms as hyperalgesia, allodynia, depression, insomnia, or poor pain control are caused by opioids when, in reality, hormone deficiencies and/or too low a dose of an opioid (uncontrolled pain causing depletion of stress hormones) may be the culprit. Keep in mind that patients who must take high-dose or long-acting opioids have probably centralized their pain and have ongoing neuroinflammation with progressive tissue destruction, loss of opioid receptors in the CNS, and reorganization of cells (eg, neuroplasticity).46-48 This process causes severe symptoms, and adequate opioid dosages and hormone levels are mandatory to control the neurodestructive process of centralized pain.

The key recommendation is to test for hormone serum levels and replace the hormones that are deficient rather than rely on raising or lowering opioid dosages (Table 5). The finding of high hormone levels means the opioid dosage may be inadequate. However, I do not recommend raising opioid dosages solely on a high-hormone level if a patient states they have good pain relief on their current regimen. If some hormones are high and others low, replace the low ones and adjust the opioid dosage by patient report or attempt some non-opioid measures—but follow-up with additional testing. Low hormone levels, but no high levels, call for replacement and some lowering of opioid dosages, if possible. Here are instructive case illustrations.

Case Example: Elevated Hormone Levels
A 48-year-old woman with severe lumbar spine disease was being treated with a regimen of oxycodone 30 mg four times per day (qid), oxycodone ER 40 mg three times per day, fentanyl lozenges 1,600 mcg qid, carisoprodol 350 mg qid, and an anti-inflammatory agent (ibuprofen 400 mg qid). Her daily morphine equivalent dose ranged from about 350 to 400 mg per day. She claimed to function reasonably well but suffered severe insomnia, and on some days had severe breakthrough pain. Her early morning cortisol level was 32 mcg/dL (normal is 5 to 20 mcg/dL), and ACTH level was 60 g/mL (normal is 6 to 56 g/mL). Adjustments were made to her treatment regimen, including increasing her opioid doses by 10% and adding temazepam 30 mg at bedtime to help with sleep. These adjustments brought her cortisol and corticotropin levels into normal range, and decreased her breakthrough pain and severe insomnia within one month.

Table: Replacement guidelines

Case Example: Cortisol Replacement Needed
The wife of a 51-year-old retired air force officer with severe lumbar spine disease called about her husband. The man has a history of three spinal surgeries and has a documented cytochrome P450 defect, which likely will limit which opioid he can take and/or require a higher-than-normal dosage. The patient’s wife called because her husband had developed a severe pain flare and had suddenly taken to bed, despite a daily morphine equivalent dose of about 700 mg per day, in addition to a regimen of lorazepam (Ativan) 0.5 mg three times per day, celecoxib (Celebrex) 100 mg twice per day, and dextroamphetamine 5 mg twice per day. An early morning serum cortisol concentration was 1.4 mcg/dL (normal is 5 to 20 mcg/dL). He was immediately started on hydrocortisone 20 mg per day to address low cortisol levels and within two days his pain began to return to normal and he was able to leave his bed. No change was made to his opioid dosage. He remained on hydrocortisone for 30 days.

 

Case Example: Pregnenolone Replacement Needed
A 45-year-old community college instructor weighs 250 pounds and stands 6′ 4″. He has severe hip dysplasia and lumbar spine degeneration, but he was able to work daily with the use of a fentanyl transdermal patch and oral opioids for breakthrough pain. He has a documented cytochrome P450 defect. His daily morphine equivalent dosage is about 800 mg per day. Without apparent reason, his pain abruptly worsened, and he was unable to walk or work. Simple touch of his painful areas showed hyperalgesia and allodynia. His early morning serum pregnenolone concentration was almost undetectable with a level under 5 pg/mL (normal is more than 15 pg/mL). He was started on 300 mg of chewable sublingual pregnenolone tablets per day, which provided relief within 48 hours. The daily maintenance dosage of pregnenolone was progressively increased over two weeks to 500 mg per day. No change was made to his opioid dosage. He returned to his full-time job and reports he hasn’t missed a workday in three months. He has been maintained on 300 to 400 mg of pregnenolone per day.

Replacement Therapy Guidelines
Pregnenolone, cortisol, and testosterone can be replaced simply. Table 6 gives recommended starting dosages. Pregnenolone and cortisol replacement may not need to be long term, and can usually be stopped when good pain control is achieved. Patients should be retested after 60 to 90 days, and if normal hormone levels are present, attempt to withdraw or lower the hormone dosage. Testosterone replacement is usually only necessary long term in patients whose testosterone level is suppressed by long-acting opioids.42,44 In patients who have hypotestosteronemia due to uncontrolled pain, serum levels usually return to normal with enhanced pain control.

Two adrenal-gonadal hormones that are precursors of other hormones are DHEA and progesterone.51,52 I use DHEA liberally in a dosage of 50 to 100 mg per day and progesterone in topical form. Both are non-prescription and can be purchased over the counter in health food stores. I’ve never had a patient complain of side effects with either agent, and they often seem to aid in the replacement and effectiveness of other hormones.

Can You Hurt Someone By Replacing Hormones?
In a chronic pain patient with constant pain, the value of hormone replacement far outweighs the risks of inadequate hormone levels. Pregnenolone replacement that is too high will produce the nuisance symptoms of headache, dizziness, mental confusion, and acne. These symptoms are well recognized, and when communicated to the patients, the hormone replacement can be stopped or reduced.

The only risk of long-term testosterone replacement is that the serum testosterone levels can rise too high to produce prostate enlargement or cancer of the prostate, breast, or ovary.53 Long before this could happen the androgenic side effects of acne, hirsutism, and hypertension would likely be obvious, particularly in women, at which time the dosage of testosterone could be cut back or testosterone temporarily stopped.

Cortisol serum levels that remain too high for too long can produce Cushing’s syndrome, characterized by hypertension, hyperlipidemia, diabetes, obesity, and osteoporosis.37-39 Adrenal suppression can occur, and it can be permanent. Periodic testing of cortisol and testosterone, which should be done every 60 to 90 days, however, can eliminate these risks. If a serum cortisol level is above normal, simply cut back the dosage. The same applies to pregnenolone and testosterone.

Opioid Dosage Minimization: A Goal of Hormone Treatment
Initiation of opioids or increases in opioid dosage is implemented frequently though, in reality, hormone replacement may obviate the need to do this. For example, in a new patient, a low pregnenolone, cortisol, or testosterone serum level may be preventing a resolution of an inflammatory process.14,16,41 Hormone replacement may obviate the need for starting or increasing opioids. The author sometimes gives an injection of methylprednisolone, testosterone, or estrogen as a challenge test to know whether temporary hormone replacement may be indicated. If the patient gets considerable pain relief within 48 hours, hormone replacement rather than opioids may be possible. This same scenario can be applied to established patients. Before the doses of opioids are increased due to complaints of allodynia, hyperalgesia, depression, or poor pain control, hormones should be tested and replaced.

Summary
Hormone testing and replacement should be a routine procedure in the medical management of intractable, chronic pain. Hormones control inflammation, nerve conduction, tissue growth, and receptor binding—all essential for pain control. It is the “constancy factor” that excessively stimulates or suppresses the hypothalamic–pituitary–adrenal–gonadal system and produces serum hormone abnormalities.

Only those patients who have constant pain and require daily opioid therapy for the management of their pain need to have their hormone levels tested. A basic panel of four hormones is recommended for screening: cortisol, pregnenolone, ACTH, and testosterone. A majority of patients who have hormone abnormalities likely have centralized their pain. When these four hormones are normalized, other adrenal and gonadal hormones will, in the author’s experience, almost always normalize. Long-term hormone replacement may not be needed if good pain control is achieved. Also, a short course of hormones may resolve an inflammatory process and obviate the need for opioids.

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