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11 Articles in Volume 14, Issue #4
Recognizing and Treating Concussions Related to Sports Injuries
CDC Initiative: Concussion in Sports and Play
Pain Management After ACL Surgery
Risk Assessment in the Digital Age: Developing Meaningful Screening Tools for Opioid Prescribers
Testosterone Replacement: Essential in Pain Management
Why Is There Hydromorphone In My Patient’s Urine?
Benzodiazepines in Pain Practice: Necessary But Troubling
Commentary: Risk Assessment in the Digital Age
Zohydro Debate: Drug Hysteria or True Concern
Benefit of Long-acting Versus Short-acting Opioids?
Epidural Steroid Injections, Coping Skills, Medical Marijuana

Testosterone Replacement: Essential in Pain Management

Recent articles about increased cardiovascular risk have raised concerns about the safe use of testosterone replacement. Chronic pain patients often have low serum testosterone levels caused by both the underlying disease and treatments. Therefore, testosterone replacement remains an essential element of chronic pain management in both men and women. Pain patients with known cardiovascular disease, especially, need to be informed of a possible increased risk and must weigh the risks of hormone therapy versus its benefits.

Testosterone replacement has been around since the 1970s. However, there has been a sharp increase in the number of prescriptions for testosterone in the past decade. Between 2000 and 2011, for example, the United States saw a 4-fold increase in testosterone use among men, many of whom had normal levels of testosterone.1

To review, testosterone helps support body composition, bone and muscle strength, and quality of life.2-6 In older men, testosterone replacement has been shown to increase lean body mass and improve strength,2,3 whereas testosterone deficiency has been associated with an increase mortality risk.6

Recent studies, however, have suggested that there is a link between testosterone replacement and an increased risk for heart disease and stroke.7,8 This has led the FDA to announce that they are going to investigate the safety of FDA-approved testosterone products.9 This has raised some concern among pain practitioners who want to know whether testosterone replacement is safe.

Despite these reports, testosterone replacement remains an essential element of chronic pain management in both males and females. Why? Chronic pain patients often have low serum testosterone levels. This is caused by both the condition and the treatments. Pain itself can cause hyperarousal of the hypothalamic-pituitary-adrenal axis, depleting patients of hormones such as cortisol and testosterone.10-15 In addition, chronic opioid therapy causes hypogonadism. For both these conditions, testosterone replacement is a needed remedy. The only cases in which this would be contraindicated are patients with active cancer of the prostate, ovaries, and/or breast. This article will review the role of testosterone replacement in pain patients in light of recent controversies.

The Cardiovascular Controversy

The first publication that prompted the FDA to reassess the cardiovascular safety of testosterone therapy was an observational study of older men in the US Veteran Affairs health system by Vigen et al.7 The veterans included in this study had low serum testosterone (<300 ng/dL), were over 60 years of age, and were undergoing coronary angiography to assess for the presence of coronary artery disease. According to the authors, those who were placed on testosterone therapy had a 30% increased risk of stroke, heart attack, and death compared to those not prescribed testosterone therapy.

However, there were some limitations to the Vigen et al study and there have been many published criticisms, including letters from leading endocrinologists and urologists.16-21 Table 1 lists some of the major criticisms of the study, which was an observational study rather than the more rigorous randomized control study. Many of the critics of the study reject its veracity and continue to support testosterone replacement in males who are middle age and older and have low testosterone levels.

The second study reported an increased risk of heart attack in older men, as well as in younger men with pre-existing heart disease, who filled a prescription for testosterone therapy.8 The study reported a 2-fold increase in the risk for heart attack among men aged 65 years and older in the first 90 days following the first prescription. Among younger men <65 years old with a pre-existing history of heart disease, the study reported a 2- to 3-fold increased risk for heart attack in the first 90 days following a first prescription. Younger men without a history of heart disease who filled a prescription for testosterone, however, did not have an increased risk for heart attack.

Since over a million men take testosterone replacement,1 these studies caused predictable reactions. In addition to the FDA announcement, there was immediate and widespread media coverage in the lay press. Indeed, even before the print was dry, lawyers were advertising for plaintiffs to sue the makers of testosterone products.

In summary, these studies contradict the literature on the safety of testosterone replacement that spans more than 20 years.2-6,22-28 Pain practitioners must now, in light of these studies, factor in the possibility of an adverse cardiovascular event (myocardial infarction or stroke) when prescribing testosterone replacement. Pain patients with known cardiovascular disease, especially, need to be informed of a possible increased risk and must weigh the risks of hormone therapy versus its benefits.

The Prostate Specific Antigen Controversy

Prostate-specific antigen, or PSA, is a protein produced by cells of the prostate gland. According to the National Cancer Institute (NCI), the PSA test originally was approved by the FDA in 1986 to monitor the progression of prostate cancer in men who already had been diagnosed with the disease. In 1994, the FDA expanded the use of the PSA test, in conjunction with a digital rectal exam, to test asymptomatic men for prostate cancer. Most recently, however, a number of leading organizations have questioned the need for aggressive screening and have issued new guidelines for PSA testing in men that further define appropriate candidates for screening (Table 2). Routine testing no longer is recommended by the American Academy of Family Physicians. The American Society of Clinical Oncology recommends against PSA testing in males unless they have obstructive urinary symptoms, such as hesitancy, frequency, and nocturia. Also, the American Urological Association recommends that PSA testing should be considered primarily for men between the ages of 55 to 69.

So why is PSA testing an issue in pain patients with low testosterone levels? Testosterone replacement therapy may increase prostate size and elevate PSA levels in men with low testosterone levels, raising their risk of developing prostate cancer. As noted, in normal aging, testosterone levels drop and prostate cancer rates increase. However, there is no evidence that testosterone replacement therapy increases the risk for prostate cancer in hypogonadal men.29

The debate over PSA testing has been fueled by the number of false-positive results that occur, leading to unnecessary and expensive tests, surgery, and radiation that have been harmful in many cases. Two recent publications have added to the argument against PSA testing. The first is the book The Great Prostate Hoax: How Big Medicine Hijacked the PSA Test and Caused a Public Health Disaster by Richard Albin and Ronald Piana. In it, the authors argue that some health care providers have conspired to oversell the PSA test and the procedures that follow. The second was an article from the politically powerful American Association of Retired Persons (AARP). In the article, entitled “10 Tests to Avoid,” they recommend that PSA testing not be done (AARP Bulletin, March 2014).

(Currently, Medicare provides coverage for an annual PSA test for all Medicare-eligible men age 50 and older, according to the NCI. Many private insurers cover PSA screening as well.)

In pain medicine, it has been common practice to obtain a baseline PSA level before starting hormone therapy in men with low testosterone levels. The recent controversy over the value of PSA screening suggests, however, that PSA screening should be done on only a few select males, if at all. The correct level of testosterone in normal aging is unclear, and low testosterone from dysfunction in the hypothalamic-pituitary-testicular axis, as seen in pain patients, may have different effects than declining levels in healthy aging men. The presence of severe pain puts the patient in a separate category from middle age and older men who are routinely screened with PSA.

In summary, although fear of giving testosterone to a male pain patient with a high PSA naturally exists, there are no reports that show that this causes any harm. Until that is shown to be the case, we do not recommend routine PSA screening before testosterone is prescribed for a male pain patient with low serum testosterone. A prudent, middle ground approach is to order a PSA test in pain patients between the ages of 55 and 69 and/or those who have urinary symptoms of obstruction. If a pain patient has an elevated PSA, it is prudent to refer the patient to an urologist before starting testosterone.

The Special Needs of Pain Patients

What is lost in the recent controversies, however, is that the vast majority of testosterone is not prescribed to pain patients—but rather to middle age and older males for maintenance of libido, muscle mass, mood, and energy.2,23 These issues also may be of considerable importance to pain patients, but testosterone has 3 additional, critical properties in pain patients:

  • Protection and regeneration of damaged neural tissue (peripheral and central)10,24
  • Maintenance of opioid effectiveness, so dosage can be minimized10-15
  • Prevention of opioid complications, including osteoporosis 15,30-33

Testosterone is well known to have analgesic properties.10-15 In my own clinical experience and anecdotal reports, pain patients who start testosterone reduce their opioid requirements. Testosterone is known to assist opioid binding on receptors.15 Opioids have a suppressive effect on the endocrine system and on bone formation.30-41 Osteoporosis frequently occurs in opioid-maintained patients.30-33,39,40

It is essential in the debate about testosterone that clinicians acknowledge that chronic severe pain is itself a major cardiovascular risk factor (Table 3). This often is overlooked, but it must be a part of practitioner’s decision making when it comes to choosing pain control therapeutics. Severe pain, acute or chronic, peripheral or central, causes hyperarousal of the autonomic nervous system and the hypothalamic-pituitary-adrenal axis. Chronic hyperarousal of these 2 systems causes several physiologic dysfunctions that are associated with cardiovascular risk factors such as hypertension, tachycardia, vasoconstriction, and hypercortisolemia with its attendant effects of hyperlipidemia and hyperglycemia.

Older males have low testosterone because of physiologic gonadal decline,3,4 whereas chronic pain patients have low testosterone due to hypothalamic-pituitary suppression from pain and/or opioids.34-41 It may be that testosterone administration in older males (without pain-induced hypogonodism), produces abnormal physiologic effects not seen in younger pain patients with normal physiologic function, but to date, there have been no reports of testosterone administration causing any severe adverse events in pain patients.

Safety Precautions

Despite what appears to be a flawed cardiovascular study and rejections of PSA testing by many authorities, some extra cautions and recommendations are advised when prescribing testosterone replacement therapy (Table 4). The first is discussing and obtaining informed consent (sample of form below table), after a written summary of the risks and benefits of testosterone therapy has been presented to the patient. Pain patients, particularly, need to know about testosterone’s neurogenic and neuroprotective properties and its positive analgesic effects.14,15 They also need to know that pain itself carries significant cardiovascular risks. They should know that there are no reported cases of testosterone causing cardiovascular events, cancer, benign prostatic hypertrophy, or elevations of PSA in pain patients. Testosterone only should be administered if the blood level is below normal. Serum testosterone levels should be periodically monitored in these patients to make sure that serum levels remain within normal range.

Testosterone Replacement In Women

Adequate serum levels of testosterone are as necessary in women as in men.19,14,39 Since the normal serum level of testosterone in women is much lower than that in men, it has been my experience that the percentage drop in serum level and symptoms may be greater in women, sometimes with catastrophic effect. When the testosterone level drops below detectable levels, women suffer significant mental and physical handicaps, which are only reversed with testosterone administration.

There are no commercially available products that are labeled specifically for women. When used off-label, the starting testosterone dosage in females is no more than one-fourth to one-third of the starting male dosage. It is critical to regularly monitor blood levels of testosterone to maintain a normal serum range based on the laboratory tests used. Many national laboratories are now publishing their normal testosterone ranges for physicians who want to treat women.

Human chorionic gonadotropin (HCG) is FDA-approved for the treatment of select cases of female infertility and male hypogonadism. FDA-approved HCG products only are available in injection form and they contain follicle-stimulating hormone (FSH) and luteinizing hormone (LH). HCG products can sometimes be a substitute for testosterone, particularly in females. Dehydroepiandrosterone (DHEA), a precursor of testosterone, is not-FDA approved, but it is a dietary supplement available in health food stores. It may be possible to elevate testosterone serum levels in some patients with DHEA. 

Summary

When testosterone therapy has been used with licensed products at the recommended initiation dose and adjusted to achieve a normal serum range, long-term studies over 3 years have not identified any adverse cardiovascular effects.42 Moreover, there are convincing data that overall mortality is lower in patients with hypogonadism who are treated.22 A recent retrospective study demonstrated that testosterone therapy in men with type 2 diabetes reduced mortality by 56%.6 Testosterone usually is prescribed to men of middle age or older to maintain libido, muscle mass, mood, and energy. Pain patients with low serum testosterone levels need therapy for not only these standard reasons, but also for testosterone’s neuroprotective, neurogenic, and analgesic properties.10-15 It also tends to neutralize the side-effects of opioids, particularly hypogonodism, hyperalgesia, and osteoporosis, as well as to allow the use of reduced dosages of opioid.24,30,40

Although sometimes overlooked, chronic severe pain is a cardiovascular risk factor in that it raises blood pressure, pulse rate, serum cortisol, and lipids. Rather than totally reject PSA screening before testosterone administration, I recommend testing for males between the ages of 55 to 69, as well as men of any age who report symptoms of urinary obstruction.

The current controversies about PSA testing and cardiovascular risk with testosterone are not cause to withhold testosterone treatment in pain patients who have low testosterone levels. Testosterone therapy has benefits for pain patients with low serum levels that greatly outweigh any known risks.

Last updated on: March 1, 2016

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