There are many people who have advanced and degenerative osteoarthritis but who are too young for joint replacement. These patients tend to be “pain managed” until they are told they are old enough now for a hip or knee replacement. But while they wait to get older, many are losing hormones, gaining weight, and losing mobility. Typically, these people will have lower levels of activity, chronic pain, leading to weight gain and obesity and are on pain medications. They are, clearly, in a poor healing milieu. Many doctors see men who had a long history of opioid usage and display signs of low testosterone levels including, but not limited to, loss of muscle, fatigue, obesity and metabolic syndrome disorders such as type 2 diabetes, high cholesterol, and high blood pressure. Men who have a history of opioid use from chronic pain are at higher risk for testosterone or androgen deficiency. This is not an opinion, this is the cumulative research of the medical community who started to assess the collateral damage of the opioid epidemic and found a clear connection between opioid use and low testosterone levels in opioid users.
If you have long-term opioid use history,
you can be at greater risk for testosterone deficiency.
A typical patient will be a man in his 50s or 60s or 70s who will describe that he was very active, then he had a minor knee injury. Over the course of a few months it became more difficult to work or do his activities without pain. A trip to the orthopedist revealed that he had torn his meniscus, his knee MRI showed some osteoarthritis, but there was not enough damage to go to immediate surgery so he went to physical therapy and was prescribed medications to use on an as need basis. A few months turned into a few years and finally the knee was bad enough that a surgery could be authorized. Following the knee surgery, more painkillers.
Eventually the man would display symptoms typical of low testosterone.
- Loss of muscle mass,
- lethargy or fatigue,
- weight gain,
- loss of sex drive.
Symptoms that were more than the knee damage and resulting inactivity should have caused.
Individuals with opioid use disorder are at increased risk of testosterone deficiency than the general population, but nearly 90% are not evaluated for this condition even after development symptoms.
An April 2024 study (1) from researchers at Penn State Hershey Medical Center, University of Maryland Medical Center, Idaho College of Osteopathic Medicine and the University of Texas Health Science Center at San Antonio write: “Individuals with opioid use disorder have reduced life expectancy and inferior outcomes when treated for depression, diabetes, and fractures. Their elevated risk of testosterone deficiency may contribute to all of these relationships, however few individuals prescribed opioids are evaluated with testosterone assays. . . .Testosterone testing was (uncommonly done) for all patients with erectile dysfunction (commonly attributed as a symptom of low testosterone levels).”
- Among 20,658 patients, it was assessed in 11.2% with opioid use disorder and 15.1% without opioid use disorder. Among those screened, 40% individuals with opioid use disorder and erectile dysfunction had testosterone deficiency.
- Individuals with opioid use disorder are at increased risk of testosterone deficiency than the general population, but nearly 90% are not evaluated for this condition even after development symptoms.
- That 40% of individuals assessed were classified as testosterone deficient suggests endocrine disorders may be contributing to increased fracture risk, chronic pain, and severe depression commonly encountered in patients with opioid use disorder. Addressing this care gap may reduce morbidity and mortality associated with opioid use disorder.
Opioids act on the hypothalamus, pituitary, and directly on the gonads affecting serum testosterone levels
The hypothalamus is that portion of your brain that helps keep the body in balance. One way the hypothalamus keeps the body in balance is by regulating hormone levels. An October 2020 study (2) states that “. . . Opioids act on the hypothalamus, pituitary, and directly on the gonads affecting serum testosterone levels. Narcotic-induced androgen insufficiency contributes to sexual dysfunction, infertility, hyperalgesia (hypersensitivity to pain) , and involving various body functions overall, affecting the quality of life. . . ” Further along this line is an August 2022 study (3) which says: “Androgen insufficiency under treatment with opioids, antidepressants and anticonvulsants in chronic pain diseases is a side effect with a high prevalence. It can lead to clinical metabolic alterations, adynamia, stress intolerance, anemia or osteoporosis and has a significant impact on the quality of life.”
A December 2019 study in the Journal of the American Medical Association (4) comes from the Veterans Health Administration. Here researchers acknowledged that androgen (testosterone) deficiency is common among male opioid users, and opioid use has emerged as a common antecedent (the cause of) testosterone treatment. (If you have long-term opioid use history, you will be at greater risk for testosterone deficiency.)
- The study included 21,272 long-term opioid users (average age 53 years old) with low total or free testosterone levels. 14,121 (66.4%) received testosterone supplementation and 7151 (33.6%) did not.
This study found that, in the VHA system, “male long-term opioid users with testosterone deficiency who were treated with opioid and testosterone medications had significantly lower all-cause mortality and significantly lower incidence of major adverse cardiovascular events (MACE) , femoral or hip fractures, and anemia after a multiyear follow-up.”
- In musculoskeletal health, the reduction in this study of femoral or hip fractures demonstrates that testosterone was able to positively impact bone weakening or bone mineral density loss. An important factor in helping older men especially the master athlete heal well. Bone remodeling and collagen production are key factors to joint regeneration.
Does low testosterone make opioid craving worse?
A 2021 study suggested (5) “Opioid dependence is a severe disease which is associated with a high risk of relapse, even in cases of successful withdrawal therapy. Studies have shown alterations of the hypothalamic-pituitary-gonadal axis in opioid-dependent patients, such as decreased testosterone serum levels in affected males.”
Research: Screening (blood tests) for low testosterone levels is surprisingly low among prolonged opioid users
An October 2018 study (6) suggests the opioid epidemic put a lot of men in the low testosterone category: “Over the last several decades, the opioid epidemic has become a national crisis, largely spurred by the spike in the use of prescription painkillers. With the epidemic came a concomitant rise in the incidence of opioid-induced androgen deficiency (OPIAD). Although OPIAD can significantly impact male sexual function and quality of life, it is an overlooked and poorly understood clinical entity that requires more attention from healthcare providers. Because OPIAD is an underappreciated and underdiagnosed consequence of chronic opioid abuse, healthcare providers should be particularly vigilant for signs of hypogonadism in this patient population. It is reasonable for pain specialists, urologists, and primary care physicians to closely monitor patients on prescription opioids and discuss available options for treatment of hypogonadism.
Opioids lower the testosterone in both male and female patients which in turn prevents healing among other health concerns.
A 2018 study published in the Journal of endocrinological investigation (7) wrote: (testosterone deficiency) is a common adverse effect of opioid treatment and contributes to sexual dysfunction, impairs pain relief and reduces overall quality of life. The evaluation of serum testosterone levels should be considered in male chronic opioid users and the decision to initiate testosterone treatment should be based on the clinical profile of individuals, in consultation with the patient.”
Research has shown us opioids have a number of adverse effects including hormonal imbalances. These imbalances have been reported to primarily involve testosterone and affect both males and females to the point of interfering with successful treatment of pain management.
There is a growing body of evidence which makes it clear that the long-term treatment of chronic pain with opioid pain-killer medications puts the patient at great risk for hormonal abnormalities including lowering the testosterone in both male and female patients which in turn prevents healing among other health concerns.
In September 2019, researchers writing in the journal Mayo Clinic proceedings. Innovations, quality & outcomes (8) suggested surprise that despite the number of men on opioids, few were screened or treated for low testosterone levels. Here is what they wrote:
“Screening for hypogonadism was surprisingly low among prolonged opioid users in our study—(within the first year only about 6% of men were tested and 17.15% of men were tested at 5 years) —given prior studies’ estimates of opioid-induced hypogonadism, ranging as high as 90%. . . This finding suggests a widespread underscreening of opioid-induced hypogonadism during critical years of the opioid epidemic in the United States.
It is not clear what factors drove this exceedingly low rate of serum testosterone screening.
It may reflect a lack of awareness by some clinicians of the association between long-term opioid use and hypogonadism. Additionally, many clinicians—when treating patients with multimorbid disease and complex drug regimens—may be reluctant to screen for conditions that would require additional pharmacotherapy. From a patient’s perspective, it is possible that men who are struggling with chronic pain and associated conditions are less concerned than their peers about early hypogonadal symptoms, such as low libido, sexual dysfunction, increased adiposity, and decreased muscle mass. They may, therefore, be less likely to bring these symptoms to the attention of their physician or to request a hypogonadism screening test.
Finally, our observation that only 5.76% of prolonged opioid users received testosterone therapy at 5 years and only 1.50% at 1 year suggests that this condition is undertreated in the United States.”
Opioids impacts many hormones beyond testosterone.
Opioids impact growth hormones too.
A May 2023 clinical study (9) found associations between long-term opioid treatment, androgens, growth hormone and prolactin (in men, higher levels of prolactin are linked to reduced testosterone and sperm production) in patients with chronic non-cancer related pain compared to controls. The results of this study support previous and older studies as well as add new knowledge to the field, including an association between high opioid dose and low growth hormone levels.
Ibuprofen Affects the Hormonal Balance in Adult Men
A 2018 study (10) published in the “Proceedings of the National Academy of Sciences of the United States of America” wrote: “Ibuprofen Affects the Hormonal Balance in Adult Men.” Here is the researchers statement: “Concern has been raised over declining male reproductive health in humans. Our study addresses this issue by extending data showing antiandrogen effects of analgesics and suggests that such compounds may be involved in adult male reproductive problems. Using a unique combination of a randomized, controlled clinical trial and ex vivo and in vitro approaches, we report a univocal depression of important aspects of testicular function, including testosterone production, after use of over-the-counter ibuprofen. The study shows that ibuprofen use results in selective transcriptional repression of endocrine cells in the human testis. This repression results in the elevation of the stimulatory pituitary hormones, resulting in a state of compensated hypogonadism, a disorder associated with adverse reproductive and physical health disorders.”
Low testosterone is associated with an increased risk of both
knee and hip replacement in overweight and obese men
In a study published in the journal Osteoarthritis Cartilage, (11) doctors in Australia confirmed that low testosterone is associated with an increased risk of both knee replacement and hip replacement in overweight and obese men. The findings suggest that circulating sex steroids may play a role in the origins and acceleration of osteoarthritis in men. Supporting this idea, another study lead by an international team of doctors and published by the Arab Association of Urology (12) found that restoring testosterone levels helped aging men with their joint problems, physical activity, and quality of life.
Of course these are not the only two studies to suggest that low levels of testosterone negatively impact joint pain and that providing testosterone replacement therapy may help the situation. They are however among the most recent to specifically test the theory that low testosterone levels do cause joint pain and joint pain causes low testosterone levels.
Even after only 30 days, patients on opioid medication for pain management
suffer from reduced levels of testosterone
Often we will see people who are trying to balance hormonal levels and the need to function with knee or hip pain. Many times these people have to resort to painkillers to help them get through their day. These people are in our office because they are seeking a more long-term solution to their pain issues than the daily management of pain and eventual succumbing to joint replacement surgery.
A recent study in the medical journal Pain Management suggests that even after only 30 days, patients on opioid (narcotic) medication for pain management suffer from reduced levels of testosterone.(13)
It is unclear what impact testosterone supplementation will have on
restoring correct body composition, pain perception, and adrenal function
A June 2020 study (14) from Odense University Hospital in Denmark updated this research. In this study it is acknowledged that men suffer from low testosterone levels during opioid treatment, but it is unclear what impact testosterone supplementation will have on restoring correct body composition, pain perception, and adrenal function.
- This study examined 41 men with an age range of 46 to to 59 years old.
- Scores and measurements were taken for body composition (lean body mass and fat mass assessed), clinical pain intensity (numerical rating scale), and experimental pain perception (quantitative sensory assessment), quality of life, and adrenocorticotrophic hormone (ACTH) test (adrenal function).
When testosterone replacement therapy was introduced the following results were noted:
- Increased lean body mass
- Decreased total fat mass.
However, testosterone alone could not fix chronic pain problems.
- The men still had the same pains
- Quality of life did not dramatically improve
- Cortisol levels did not improve. (In cases of low cortisol levels, increase in blood sugar, weight gain and greater risk for Type 2 Diabetes are seen.
Conclusions: “Six months of testosterone replacement therapy improved body composition in men with opioid-induced hypogonadism without significant changes in outcomes of pain perception, quality of life, or adrenal function.”
This is where regenerative medicine treatments come in. Testosterone supplementation can help with symptoms but for many, it cannot take you all the way to joint repair, you need regenerative medicine recommendations to rebuild a damaged joint without surgery.
It is unclear what impact testosterone supplementation will have on restoring correct body composition, pain perception, and adrenal function
Abnormal Hormone Levels Show Painkillers Not Working
Study: 80.3% of patients demonstrated hormone abnormality and pain dysfunction.
Investigators researching opioids say some patients with severe and chronic pain fail to obtain adequate pain relief with standard pharmacologic treatment agents, including low to moderate dosages of opioid. Understandably, physicians might not believe patients who claim that a standard opioid dosage is an ineffective treatment. These patients may be severely impaired, nonfunctional, and bedridden or housebound.
To help characterize these individuals and develop treatment strategies for them, a serum hormone profile consisting of adrenocorticotropin, cortisol, pregnenolone, progesterone, dehydroepiandrosterone, and testosterone was obtained on 61 chronic pain patients who failed standard treatments; 49 patients (80.3%) demonstrated hormone abnormality.(15) To manage this problem the researchers suggested enhanced analgesia (more painkillers) is required and that hormone replacement may be indicated.
Years of chronic pain require a broad understanding that in many patients, pain and function problems are more than a hole in the cartilage. Hormones can be involved, weight can be an issue, lifestyle choices can be an issue. The path to healing crosses many roads.
The unending cycle:
A November 2023 study (16) suggests strong ties between the development and advancement of arthritis symptoms in adults with low testosterone levels. In this study of 10,439 adults, researchers found those with low testosterone levels, (especially women and obese patients) were at greater risk for development and worsening of arthritis symptoms than those in the study who were considered to have normal testosterone levels.
References
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2 Marudhai S, Patel M, Subas SV, Ghani MR, Busa V, Dardeir A, Cancarevic I. Long-term Opioids Linked to Hypogonadism and the Role of Testosterone Supplementation Therapy. Cureus. 2020 Oct;12(10).
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10 Kristensen DM, Desdoits-Lethimonier C, Mackey AL, Dalgaard MD, De Masi F, Munkbøl CH, Styrishave B, Antignac JP, Le Bizec B, Platel C, Hay-Schmidt A. Ibuprofen alters human testicular physiology to produce a state of compensated hypogonadism. Proceedings of the National Academy of Sciences. 2018 Jan 23;115(4):E715-24.
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