Marc Darrow, MD, JD.
I see a number of patients who have advancing osteoarthritis but who are too young for joint replacement and are being managed for their joint pain until they are old enough for joint replacement. At the same time, they are losing hormones, gaining weight, and losing mobility. Typically, they have lower levels of activity, chronic pain, are becoming obese, and are on pain medications. They are, clearly, in a poor healing milieu. In our office we have seen many 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 will be at greater risk for testosterone deficiency.
I will get an email from a man in his 50s or 60s or 70s and he will describe to me a story I hear very often. He was very active, then he kind of tweaked his knee. 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
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 (1) 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 (2) 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 (3) 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 (4) “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 (5) 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 (6) 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 (7) 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 (8) 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 (9) 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, (10) 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 (11) 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.(12)
It is unclear what impact testosterone supplementation will have on restoring correct body composition, pain perception, and adrenal function
A June 2020 study (13) 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.
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.(14) 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.
With over 25 years experience in regenerative medicine techniques and the treatment of thousands of patients, Dr. Darrow is considered a leading pioneer in the non-surgical treatment of degenerative Musculoskeletal Disorders and sports related injuries. He is one of the busiest Regenerative Medicine doctors in the world. Dr. Darrow has co-authored and continues to co-author leading edge medical research including research on bone marrow derived stem cells. He also comments and writes on research surrounding the treatment of chronic tendon injury, ankle and foot pain, elbow, hand and finger pain.
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1 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).
2 Wirz S, Schenk M, Kieselbach K. Adverse effects of opioids, antidepressants and anticonvulsants on sex hormones: Often unnoticed but clinically relevant. Schmerz (Berlin, Germany). 2022 Aug;36(4):293-307.
3 Jasuja GK, Ameli O, Reisman JI, Rose AJ, Miller DR, Berlowitz DR, Bhasin S. Health Outcomes Among Long-term Opioid Users With Testosterone Prescription in the Veterans Health Administration. JAMA Network Open. 2019 Dec 2;2(12):e1917141-.
4 Janke E, Groh A, Mühle C, Dürsteler-MacFarland KM, Wiesbeck GA, Kornhuber J, Jahn K, Groeschl M, Lichtinghagen R, Frieling H, Bleich S. Association of Testosterone Levels and Steroid 5-Alpha-Reductase 2 Polymorphisms with Opioid Craving. Neuropsychobiology. 2021;80(1):64-73.
5 Hsieh A, DiGiorgio L, Fakunle M, Sadeghi-Nejad H. Management Strategies in Opioid Abuse and Sexual Dysfunction: A Review of Opioid-Induced Androgen Deficiency. Sexual medicine reviews. 2018 Oct 1;6(4):618-23.
6 Coluzzi F, Billeci D, Maggi M, Corona G. Testosterone deficiency in non-cancer opioid-treated patients. J Endocrinol Invest. 2018 Dec;41(12):1377-1388. doi: 10.1007/s40618-018-0964-3. Epub 2018 Oct 20. PMID: 30343356; PMCID: PMC6244554.
7 Baillargeon J, Raji MA, Urban RJ, Lopez DS, Williams SB, Westra JR, Kuo YF. Opioid-Induced Hypogonadism in the United States. Mayo Clinic Proceedings: Innovations, Quality & Outcomes. 2019 Sep 1;3(3):276-84.
8 Diasso PD, Abou‐Kassem D, Nielsen SD, Main KM, Sjøgren P, Kurita GP. Long‐term opioid treatment and endocrine measures in chronic non‐cancer pain patients. European Journal of Pain. 2023 May 26.
9 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.
10 Hussain SM, Cicuttini FM, Giles GG, Graves SE, Wang Y. Relationship between circulating sex steroid hormone concentrations and incidence of total knee and hip arthroplasty due to osteoarthritis in men. Osteoarthritis Cartilage. 2016 Apr 12. pii: S1063-4584(16)30024-3. doi: 10.1016/j.joca.2016.04.008.
11 Almehmadi Y, Yassin AA, Nettleship JE, Saad F. Testosterone replacement therapy improves the health-related quality of life of men diagnosed with late-onset hypogonadism. Arab J Urol. 2016 Mar;14(1):31-6. doi: 10.1016/j.aju.2015.10.002.
12 Cepeda MS, Zhu V, Vorsanger G, Eichenbaum G. Effect of Opioids on Testosterone Levels: Cross-Sectional Study using NHANES. Pain Med. 2015 Jul 14. doi: 10.1111/pme.12843.
13 Glintborg D, Vaegter HB, Christensen LL, et al. Testosterone replacement therapy of opioid-induced male hypogonadism improved body composition but not pain perception: a double-blind, randomized, and placebo-controlled trial. Eur J Endocrinol. 2020;182(6):539‐548. doi:10.1530/EJE-19-0979
14 Tennant F. Hormone abnormalities in patients with severe and chronic pain who fail standard treatments. Postgrad Med. 2015 Jan;127(1):1-4. Epub 2014 Dec 15.