Opioid-Induced Endocrinopathy

Etiology

There is mounting evidence that a disruption of the hypothalamic-pituitary-gonadal (HPG) axis, as well as the hypothalamic-pituitary-adrenal (HPA) axis, are responsible for the plethora of endocrine dysfunctions and clinical findings that occur with long-term opioid use.[1]

Epidemiology

It was estimated that up to 5 million men suffer from Opioid-induced androgen deficiency in the United States as of 2011. With the high number of opioid prescriptions and prevalence of chronic opioid therapy, it is logical to state that OIE is a very common and prevalent condition.[2] Unfortunately, there is limited awareness of OIE as a common side effect of chronic opioid therapy, and it is often not considered nor tested for. Limited data on this often unrecognized phenomenon impedes understanding of the true scope of the condition and the number of cases affecting both men and women. Given that opioids affect both the HPA axis as well as the HPG axis, this only underscores the importance of increasing awareness of OIE and indicates that OIE is a common and important type of endocrinopathy.

Pathophysiology

The secretion of gonadal hormones such as testosterone via testes in males and estrogen via ovaries in females is mainly regulated by the HPG axis. The hypothalamus initially secretes gonadotropic releasing hormone (GnRH), which stimulates the anterior pituitary release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH and LH go on to directly stimulate the testes and ovaries. The stimulation of the testes increases plasma levels of testosterone, while the stimulation of the ovaries increases plasma estrogen levels. Increasing testosterone and estrogen levels both have feedback inhibitory effects on the GnRH release from the hypothalamus. The inhibition of GnRH essentially causes a downward cascade of inhibition on the HPG axis, thus decreasing all associated downstream hormones such as LH, FSH, testosterone, estrogen, dehydroepiandrosterone (DHEAS), and growth hormone. Opioid agonists have been shown to act via this same feedback inhibitory fashion on the hypothalamus, while opioid antagonists have been shown to stimulate GnRH release. It is important to note that the origin of androgen production in females is primarily via the adrenal glands. This may explain why DHEAS, secreted by the adrenal glands, is a better measure of female adrenal androgen function. It is well known that just 1 month of sustained opioid therapy, regardless of opioid class, may be sufficient to reduce DHEAS levels in a significant fashion. As stated above, the reduced production of adrenally synthesized DHEAS signifies decreased cellular activity or atrophy of adrenal origin. Many case reports have documented the suppression of the HPA axis. Adrenal glands may have a blunted response to corticotrophin hormone, which may not allow the body to synthesize appropriate levels of cortisol when necessary. Thus, this patient population is at increased risk of adrenal crisis or adrenal insufficiency at times of increased physiological stress, such as surgery and sickness.

History and Physical

Duration of opioid use is a better predictor for developing OIE than age or gender. Patients with OIE typically present with generalized complaints of fatigue, depression, sleep disturbance, immune suppression, hyperalgesia, weight gain, decreased libido, infertility, erectile dysfunction, amenorrhea, anemia, osteoporosis, and other related symptoms.[3][4][5] Often, a patient is assessed and diagnosed with OIE as a secondary or incidental finding in addition to their chief complaint. Obtaining a detailed drug history is essential, as polypharmacy may contribute to or mask a patient's symptoms. It is important to accurately understand a patient's medical history and detailed symptomology to help rule out other medical conditions and diseases on the differential diagnosis. Illicit substance use, depression, anxiety disorders, alcohol use disorder, over-the-counter and herbal medication use, domestic abuse, nutrition and dietary habits, possible causes of anemia, and possible causes of osteoporosis should be considered when developing a differential diagnosis in patients presenting with symptoms possibly related to OIE. On examination, possible findings may include depressed psychomotor tone, mood lability, pallor, and primary hypogonadism.[5]

Evaluation

A thorough panel of endocrinologic assays should be attained to assess for HPA and HPG axis dysfunction. These assays may include gonadotropic releasing hormone (GnRH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), free testosterone, estradiol, and growth hormone, among other laboratory tests.[6] When considering your differential diagnosis, it is prudent to appreciate both pertinent positive and negative findings in the venture to narrow down a final diagnosis of OIE.

Treatment / Management

The use of opioids and chronic opioid therapy in the treatment of chronic pain is always a risk versus benefit consideration that must be reassessed continuously to help ensure that the benefits outweigh the risks as well as to minimize the potential long-term risks and side effects of opioid medications such as dependence addiction constipation as well as OIE. Opioid medications may have an important role in treating and managing a patient's chronic pain and when opioid cessation is not possible, and chronic opioid therapy is indicated, treating the potential side effects of opioid medications such as OIE should be addressed accordingly. In men, there appears to be widespread consensus that revolves around testosterone replacement therapy. To maintain stable testosterone levels, stable modes of release testosterone treatment may include buccal, gel, cream, and transdermal patch release formulations. IV route administration of testosterone therapy may be attributed to unstable serum levels over the aforementioned forms. Hormone replacement therapy should include follow-up laboratory assessments at approximately 2- to 3-week intervals to titrate dosages appropriately.[4] Although testosterone replacement therapy in males is well-supported and common, there appears to be relatively little evidence supporting this treatment in women. This may be due to, in part, the constantly fluctuating baseline hormone levels, which can complicate and impede the ability to verify the successful restoration of the HPG and HPA axes. For this reason, guidelines on hormone replacement in females are not well-established or documented. In females, hormone replacement in the form of estrogen-methyltestosterone is only approved for the treatment of postmenopausal vasomotor symptoms. DHEAS supplementation has shown promise in the female patient pool, with reports of increased energy, increased libido, and weight loss having been found. This treatment, however, remains less well-established and controversial.

Opioid rotation may be a viable option, as many patients may not tolerate the adverse effects associated with hormone replacement. This may be fruitful in the female patient population as a treatment choice before hormone supplementation is considered. Opioid rotation is a concept of switching the current opioid class for an equipotent opioid dosage since different opioids bind to different receptor subtypes (mu, delta, kappa) with varying affinities (differential binding), hence potentially mitigating their inhibitory effect on the HPG and HPA axis. It is important to realize that certain classes of opioids may inherently possess more sedative effects than others for certain patients, thereby impacting a patient's perception of fatigue or decreased libido as being brought on by the OIE disease process or as being a direct side effect from the opioid regimen itself. Opioids with sedative effects include morphine and methadone, while potentially less-sedative opioids include oxycodone and Suboxone. Other potential benefits of opioid rotation include the fact that there is incomplete cross-tolerance between various opioids, which therefore allows an overall dose reduction and lowering of the overall milligram morphine equivalent.

Differential Diagnosis

The clinical presentation of generalized endocrinopathy can be exhaustive. Fatigue, decreased libido, and erectile dysfunction may be the only findings in a patient, which may lead to a misdiagnosis of depression or a physician attributing these findings as a psychosocial consequence of a patient's chronic pain status.[7] For this reason, a high degree of suspicion and proper laboratory findings may be needed to rule out a diagnosis of OIE.

A differential diagnosis for OIE includes but is not limited to the following:

• Depression
• Hypothyroidism
• Adrenal insufficiency
• Primary erectile dysfunction
• Anemia

Prognosis

The prognosis is positive, as the majority of patients witness a reversal of endocrine abnormalities upon cessation of opioid use. For those less fortunate to recover incompletely or for those who are unable to wean from opioid therapy completely, hormone supplementation remains a viable option.[8]

Complications

Although the majority of sequelae associated with this disease are not immediately life-threatening, the quality of life in a patient suffering from chronic pain compounded by the insidious effects of OIE may be substantial. Of note, several case reports illustrate episodes of adrenal crisis as a possible complication in this patient population. The exact effect and role of glucocorticoid replacement in patients with OIE remain not fully understood.[9]