December 19, 2016
10 min read

Prolonged opioid therapy elevates risk for endocrine dysfunction, bone fractures

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The long-term use of prescribed opioid therapy has continued to rise in the United States. According to the CDC, an estimated 20% of patients with noncancer pain or pain-related diagnoses are prescribed opioids in office-based settings. Approximately 200 million prescriptions for opioids were dispensed in 2013, according to the NIH, a trend that has grown by more than 50% in the past decade.

For patients with diabetic neuropathy treated with opioid therapy, comorbidities already associated with diabetes, such as depression, anxiety and fatigue, can be further exacerbated by opioid use, according to Aaron Vinik, MD, PhD, FCP, MACP, FACE.

Photo courtesy of EVMS Marketing and Communications.

The rise in opioid therapy brings with it an increase in opioid-related endocrinopathy, often manifesting as androgen deficiency or hypogonadism. But the symptoms, which range from decreased libido, fatigue and loss of muscle mass to erectile dysfunction in men and amenorrhea in women, are often not clinically recognized as opioid-related, according to experts.

“Sedation, nausea, vomiting and constipation are commonly recognized as classic opioid side effects, with constipation often regarded as the most frequent complication of opioids,” Michael J. Brennan, MD, of The Pain Center of Fairfield, Connecticut, wrote in the March 2013 issue of The American Journal of Medicine. “In actuality, hypogonadism may be the most common toxicity associated with long-term opioid treatment.”

Left untreated, experts caution, opioid-induced androgen deficiency can dramatically affect patients’ quality of life and increase their risk for osteopenia and osteoporosis, potentially leading to fractures.

“Clinicians should be aware that there could be problems with opioid therapy that are not as well recognized,” Vin Tangpricha, MD, PhD, FACE, associate professor of medicine at Emory University, told Endocrine Today. “There could be issues with sex hormones and bone health. I’m sure endocrinologists see this a lot and say, ‘Oh, well this is obvious.’ But the referring physician is not thinking about it.”

Endocrine effects of opioid use

Vin Tangpricha

Opioids have a well-documented effect on two endocrine systems, according to Brennan. In the hypothalamic-pituitary-gonadal axis, opioids act as an inhibitor of gonadotropin-releasing hormone secretion in the hypothalamus, typically resulting in reduced testosterone levels. In men, effects can include decreased sperm production and intratesticular testosterone. In women, opioid therapy can limit the production of luteinizing hormone by binding to receptors in the pituitary gland, affecting the menstrual cycle and fertility.

Opioid therapy also has been shown to affect the hypothalamic-pituitary-adrenal axis, Brennan wrote, reducing the capacity of the pituitary to respond to corticotrophin-releasing hormone and interfering with the production of cortisol and dehydroepiandrosterone, also affecting sexual function in men and women.

“What you encounter as a clinician is that people are who are chronically habituated to opioids present with sexual dysfunction, erectile dysfunction, hypogonadism and loss of sex drive,” Aaron Vinik, MD, PhD, FCP, MACP, FACE, professor of medicine, pathology and neurobiology and director of the research and neuroendocrine unit at Eastern Virginia Medical School, told Endocrine Today. “[Symptoms] can be clinically difficult to elicit, and the endocrine workup is often extensive before you actually realize that this is all an effect of opioid abuse.

“We have a big gap in understanding of the use of pain-relieving drugs when it comes to neuropathic and cancer-related pain,” Vinik said. “That’s different from people who are addicted.”

Overlooked conditions

For many patients, the sexual side effects of opioid therapy are left untreated because they are not talked about, Koddus Ali, BMedSci, a researcher in the department of health, education and life sciences at Birmingham City University, United Kingdom, told Endocrine Today.

“The main reason for the lack of recognition of side effects of opioids on reduced sex hormones is due to the nature of the side effect itself,” Ali said. “A patient may be too embarrassed to come forward with symptoms associated with the opioid therapy. Keep in mind that the patient may not be aware that the opioid is responsible for side effects. Due to the lack of the patient coming forward with these symptoms, the clinician is not able to justify measuring the parameters of sex hormones.”


Tangpricha agreed.

“The pain is the issue that is bringing the patient to the doctor, and the endocrine issues tend to be secondary,” Tangpricha said. “The pain is the chief complaint of the patient.”

For some patients, the side effects are harder to recognize, Oliver Seyfried, MBBS, FRCA, FFPMRCA, a consultant in pain medicine and anesthesia with St George’s University Hospital NHS Trust in London, told Endocrine Today.

“It has been known for many years that opioids affected a man’s physiognomy, but the people this was noted in were largely on the periphery of society as much as they may be today — addicts, the elderly, the chronically unwell,” Seyfried said. “Patients and their primary physicians are often unaware of these serious but more silent side effects, as their onset is often insidious and non-binary.

Oliver Seyfried

“You either have an itch, or constipation, or you don’t,” Seyfried said. “Loss of libido is harder to recognize and follows more of a normal distribution, and there may be many other potential reasons for failure to conceive that are considered first.”

In older patients taking long-term opioid therapy, impaired sexual function may also mistakenly be considered an expected part of the aging process, Seyfried said.

In an overview of studies examining hypogonadism in patients taking opioids, published in the September issue of Postgraduate Medicine, Ali and colleagues noted that other clinical issues also complicate a diagnosis of hypogonadism in opioid users.

“Clinical diagnosis in men is hampered by the lack of specificity of assessment tools and the lack of consensus on the threshold of serum testosterone to diagnose hypogonadism,” the researchers wrote. “In women, symptoms of hypogonadism may go unrecognized or may be attributed to other conditions, such as depression.”

“Leaving such side effects untreated could lead to a cascade of physiological abnormalities because of the weakening and diminishing of muscle mass,” Ali said. “As opioid therapy reduces the sex hormone levels, you have an increased risk for fracture, including hip fracture. With this, a patient’s quality of life is majorly affected as well.”

Worsening diabetes symptoms

For patients with chronic pain conditions, such as diabetic neuropathy treated with opioid therapy, comorbidities already associated with diabetes, such as depression, anxiety and fatigue, can be further exacerbated by opioid use, Vinik said.

“When we look at patients with complications of diabetes, like neuropathy, we find that about 90% of them have sleep disturbances, about three-quarters have depression and about half have anxiety syndrome,” Vinik said. “So here, you’re using a drug to treat pain, and you end up exacerbating the comorbidities that you encounter with the disease. Even treating people with diabetes, in general, you find that, using opioids, you’re also confronted with the comorbidities.”

Chronic opioid use also is associated with weight gain, hyperglycemia and worsening diabetes, likely a central action via the sympathetic nervous system and impaired insulin secretion, Seyfried and Joan Hester, MBBS, FRCA, MSc, FFPMRCA, a consultant in pain medicine at King’s College Hospital, wrote in the February 2012 issue of The British Journal of Pain. Data also suggest that opioids play a role in regulating food intake and food choice as well as the reward system associated with good-tasting foods, the researchers wrote. Hypogonadism, too, is associated with an increase in insulin resistance and risk for incident diabetes.

“Opioids affect many systems within the body,” Seyfried told Endocrine Today. “Opioids are associated with weight gain and the metabolism of catecholamines, both contributing to hypertension. Poor nutrition and health status and the potential for cortical bone weakening make fractures more likely in this group.”

Research suggests that opioids may also be an immunosuppressant as well as carcinogenic, Seyfried said; however, evidence is weak and further study is warranted.


“Opioids have receptors not only in the central nervous system and peripheral nervous system, but also in small blood vessels in the muscles in the peripheral nervous system,” Vinik said. “So, you begin to see other components that emerge with opioids. Some of the features are related to increased sensitivity to sensory stimuli, blood vessel constriction ... a rise in the blood pressure, and then you get the paradoxical effects that come from the long-term use of opioids, like the anorexia, the physical agitation, the difficulty sleeping, hypervigilance. It’s like a bell-shaped curve. Up the one side, down the other side.”

Bone health risks

Patients on long-term opioids may be at an increased risk for developing osteopenia and osteoporosis vs. patients not on long-term opioid therapy. In a June 2013 study published in BMJ Open, Rui V. Duarte, PhD, of the department of pain management at Russells Hall Hospital in Dudley, United Kingdom, and colleagues analyzed data from 20 men attending follow-up clinics for intrathecal opioid therapy for chronic noncancer pain; 14 men underwent DXA scans for bone mineral density measurements. Within the cohort, three men had osteoporosis, seven had osteopenia and five were at or above the intervention threshold for hip fracture.

“One of the main comorbidities associated with hypogonadism is osteoporosis,” Ali said. “The mechanism underlying this appears to be both direct and indirect on bone metabolism. The direct presence of opioid receptors on the osteoblast-like cells have been speculated to inhibit osteoblasts through the binding of opioids to mu receptors of the bone.”

The inhibition of the osteoblasts can cause a decrease in bone synthesis, leading to a decrease in bone density itself, Ali said. Opioid therapy can also decrease levels of osteocalcin, a protein and biomarker for osteoblast activity.

However, it remains unclear whether opioid therapy is directly linked to the risk for fracture, according to Michael S. Irwig, MD, FACE, associate professor of medicine and director of the Andrology Center at George Washington University School of Medicine and Health Sciences.

“The fracture issue is actually controversial,” Irwig told Endocrine Today. “If you look at men who have been on opiates, some men have a lower BMD, but some do not. It’s unclear whether opiates are associated with an increased risk for fracture due to bone density. One study found that opiate users do have a higher risk for fracture, but that this is due to the acute central nervous system side effects — the sedation, the dizziness causing falling, rather than the hypogonadism or the androgen deficiency.

Michael S. Irwig

“We don’t have a lot of great studies in this area, and it’s unclear whether treatment with testosterone therapy for men with androgen deficiency could change the incidence of the rate of fracture,” Irwig said.

Managing symptoms

Currently, there are no accepted standards for monitoring or treating opioid-induced hypogonadism or hypoadrenalism. Experts recommend checking testosterone and estradiol levels, asking patients about their symptoms, and considering several options on a case-by-case basis.

“When I see a man who has low testosterone who is on opiates, there are a few things to consider,” Irwig said. “One, is he going to come off the opioid or will they be tapered? If the patient plans to taper, then you don’t need to do anything. Whereas, if it is a patient who’s been on opioid therapy for a long time and doesn’t plan to come off, or doesn’t think that he’ll be able to come off, I’m much more likely to prescribe androgen replacement therapy.

“Now, having said that, opiates can cause low libido independent of the testosterone levels,” Irwig said. “What is frustrating to these men is that you can treat them for low testosterone and they continue to have low libido. There is something else in the central nervous system lowering their libido.”


Opioid rotation, too, is an option for patients with sexual side effects, Ali said, although this route can be difficult due to differing effects from different drugs.

“Take levorphanol, which has affinity for all three receptors — delta, kappa and mu — in comparison to morphine, which has an affinity for mu receptors,” Ali said. “This suggests that the patient on levorphanol may not be able to rotate to other opioids successfully. Therefore, this highlights the importance of the type of opioids prescribed, and in which sequence each of the drugs are prescribed.”

A thorough history and examination remain the most efficacious and economical approach to managing patients on long-term opioid therapies, while keeping in mind that both sexes may struggle with infertility, fatigue and night sweats, among other symptoms, Seyfried said.

“It is wise to measure testosterone levels, sex hormone-binding globulin, luteinizing hormone, follicle stimulating hormone and estradiol levels in those whom this may be a diagnosis,” Seyfried said.

The key, Vinik said, is for clinicians to talk to patients on opioid therapy early and openly about any symptoms they may have, including sexual side effects, before symptoms are ignored for too long and complications worsen.

“It is a tragedy because, in the beginning, when you have impairment of sexual function, or erectile dysfunction ... that’s the time when you need to try and reduce the opioids so you don’t further compromise this activity,” Vinik said. “You want to get in [and intervene] as early as possible.” – by Regina Schaffer

Disclosures: Vinik reports financial ties with Impeto Medical Research, Intarcia, Ionis, NeuroMetrix, Novo Nordisk, Pamlab Pharmaceuticals, Pfizer, Sanofi-Aventis, VeroScience and ViroMed. Ali, Irwig, Seyfried and Tangpricha report no relevant financial disclosures.

Click here to read the POINTCOUNTER, "What is the best way to manage opioid-induced hypogonadism without disregard for pain relief?"