Testosterone suppression is well known to occur in chronic pain

patients who must regularly take opioids.  (1,2)  Replacement of testosterone in

male chronic pain patients is now commonplace.

To date, however, testosterone replacement in female chronic pan patients is not routine and practitioners are just beginning to recognize the needs

and merits of doing so. (3,4)  Reported here is the female testosterone replacement procedure used by the author. A patient education handout and an off-label consent form is included which practitioners may adopt if desired. Since there is no commercial FDA approved testosterone product for females, physicians should systematically prescribe testosterone to female patients by diligently providing information about risk-benefit and carefully documenting a need for testosterone replacement.

Symptoms Of  Testosterone Deficiency

Pain patients who are being routinely followed may slowly but progressively develop testosterone deficient symptoms (see Table 1). While loss of libido is the best known of testosterone deficiency symptoms, there are many others. (5) Testosterone has some critical biologic functions very relevant to pain treatment. (6-8) Testosterone is a major anabolic compound both in females and males and, therefore, has a major healing and pain reduction function in long-term pain care. (4) Testosterone levels are apparently necessary for proper transport of opioids across the blood brain barrier and for opioid receptor-site binding. (6-8) Consequently, adequate levels of serum testosterone are necessary for maximal opioid effectiveness. Other central effects are more subjective, but testosterone deficiency is associated with depression, fatigue, apathy, and loss of motivation.

 

 

 

Patient Education

 

Females, as well as males, need to be educated about the need for adequate

serum levels of testosterone. Since testosterone replacement in females is a new procedure and obviously controversial, it is deemed important that practitioners educate all parties on the benefits and necessity of testosterone replacement. Many parties are not even aware that females normally carry a serum concentration of testosterone that is about 15 to 25 % of that in the male. Furthermore, adequate serum testosterone levels in female pain patients is critical for maximal pain control.

 

Stepwise Guidlines For Replacement

 

If symptoms of testosterone deficiency are present in a female chronic pain patient, obtain a serum testosterone concentration. Laboratories now report normal ranges for serum testosterone in females as well as males. If the female patient demonstrates a low or borderline low level, I give a test dose of intramuscular testosterone ranging from 25 to 50 mg. This test dose is usually therapeutic within 24 hours, as female patients with testosterone

deficiency rapidly experience a number of positive benefits as symptoms

of testosterone deficiency are ameliorated. Once testosterone deficiency is documented, the patient is asked to sign an informed consent form for off-label

use of testosterone (see Table 3). I use a testosterone gel (Testim® or Androgel®) at 1/3 to 1/2 the male dosage. Initially, the patient rubs on the gel every other day. This dose can be titrated upward over time. At the end of about 90 days, I repeat the serum testosterone test and require a one week break. If symptoms recur and the serum level is still low, I continue the testosterone.

The reduction and amelioration of testosterone deficiency symptoms is often

remarkable. At this early phase of female testosterone treatment, I have not

witnessed complications or long-term side-effects.

 

Laboratory Testing and Interpretation

 

All major clinical laboratories now test for total and free serum testosterone. They will report their normal values for sex and age which makes it easy to diagnose hypotestosteronemia.

At this time there is a raging debate among some endocrinologists and urologists as to the meaning of serum free and total testosterone and sex hormone binding globulin. The issue stems from the fact that most (over 80%) of serum testosterone, is bound to serum proteins including sex hormone binding globulin.Some experts believe that only about 1% of serum testosterone is “active,” due to the protein/globulin binding nature of testosterone. They even argue that the remaining protein-bound testosterone is irrelevant and apparently some sort of biologic waste product. At this time, it is recommended that pain practitioners let the testosterone debates rage on and simply use laboratory-reported serum levels of free or total testosterone in combination with clinical symptoms as the reason to initiate a low dose clinical trial.

The author does not believe that serum testosterone, which is protein bound, is

simply biologic waste and irrelevant to pain treatment. Endocrinologists and urologists are primarily interested in the sexual effects of testosterone and, indeed, the small serum fraction of testosterone that is unbound may be the essential, active component that raises libido. Pain practitioners, however, must know that we need testosterone to assist opioids cross the blood brain barrier and help activate a number of central receptors and neurochemicals systems. (6-8) Also, testosterone may enter pain sites and other tissue compartments in the periphery to help healing. Rather than biologic waste, the serum proteins that bind to testosterone may be required to transport or store testosterone in select anatomic sites and even release testosterone in these sites. The academic question of the eventual fate of protein-bound testosterone is intriguing and may have great relevance to the anabolic, immunologic, and neurochemical properties of testosterone in pain treatment.

 

Off-Label Use

 

 

At this time, there is no commercial, female testosterone product that has

United States Food and Drug Administration (FDA) approval . Consequently, testosterone replacement in females is an off-label use. A great deal of lay and professional publicity has been recently published on off-label use of drugs by physicians. It is not only legal but ethically desirable that physicians judiciously utilize select drugs off-label. (9) Testosterone replacement in female chronic pain patients who require opioids is a judicious, ethical, and clinically necessary practice as long as the patient is clearly educated on the risks and benefits and gives informed consent.

 

Summary

 

 

While testosterone replacement has emerged as a rather standard practice for male chronic pain patients who require long-term opioid therapy, it is now clear

that many females with chronic pain who require opioid therapy also need testosterone replacement. Although it is universally known that testosterone enhances libido, it is less well appreciated that testosterone is required for energy, mental concentration, mood, anabolic healing, and even proper opioid pain relief. These necessities for pain treatment are forcing pain practitioners to

embark upon female testosterone replacement before other medical fields

have begun this practice in earnest. Although clinical trials for female testosterone commercial products are in the pipeline for future FDA approval, females who now need treatment can be effectively and safely given testosterone.

Forest Tennant, MD, DrPH is an internist and

addictionologist who specializes in the research

and treatment of intractable pain at the Veract

Intractable Pain Clinics he founded in West

Covina, California. Dr. Tennant is Editor-in-

Chief Emeritus of Practical Pain Management

journal and continues to be active on its Editorial

Board. Address any correspondence to Dr.

Forest Tennant, 338 S. Glendora Ave, West

Covina, CA 91790-3043. 888-919-7496; fax

626-919-7497. E-mail: veractinc@msn.com.

References

 

 

1. Daniel HW. The association of endogenous

hormone levels and exogenously administered

opiates in Males. Amer J Pain Management. 2001.

11: 8-10.

2. Abs R, Verheist J, Maeyaert J, et al. Endocrine

consequences of long-term intrathecal administration

known that testosterone enhances

of opioids. J Clin Endocrinal Metab. 2000. 85: 2215-

2222.

3. Tennant FS. Hypotestosteronemia and testosterone

replacement in females with severe persistent

pain. Presented before the American Academy of

Pain Medicine. 2004.

4. Dolon S, Wilke S, Aliabodi N, et al. Effects of

testosterone administration in human immunodeficiency

virus-infected women with low-weight. Arch

Intern Med. 2004.164: 897-904.

5. Ambler N, Williams AC, Hill P, et al. Sexual difficulties

of chronic pain patients. Clin J Pain. 2001. 17:

138-145.

6. Fednekar N and Mulgaomker V. Role of testosterone

on pain threshold in rats. Indian J Physiol

Pharmacol. 1995. 39: 423-424.

7. Forman IJ, Tingle V, Estilow S, and Cater J. The

response to analgesia testing is affected by gonadal

steroids in the rat. Life Sciences. 1989. 45: 447-454.

8. Stafford EC, Ulibarri CM, Folk JE, et al. Gonadal

hormone modulation of mu, kappa, an, delta opioid

antinociception in male and female rats. J of Pain.

2005. 6: 261-274.

9. Largent EA, Miller FG, and Pearson SD. Going offlabel

without venturing off-course. Arch Intern Med.

2009. 169: 1745-1747.

*** This article is made available courtesy of PPM Communications, Inc. Practice Pain Management. 2009. Volume 9, Issue 9.  Pp. 25 - 27.

 

Addendum by Irene Turner:

A randomized, double-blind Phase III clinical trial, involving approximately 1,140 patients over a three-to-six year period using the hormone progesterone to treat traumatic brain injury (TBI) will start in March 2010 at 17 medical centers across the USA. The National Institutes of Health (NIH) is funding the grant, which was awarded to Emory University.

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