Continuing Education Activity

Hormone replacement therapy is a mainstay of treatment for those suffering from opioid-induced endocrinopathy (OIE) which can have a significant impact on a patient's health and quality of life. This activity reviews the role of the inter-professional team in the evaluation and management of OIE.

Objectives:

• Describe the pathophysiology of opioid-induced endocrinopathy.

• Outline the typical presentation of a patient with opioid-induced endocrinopathy.

• Summarize the treatment of a patient with opioid-induced endocrinopathy.

• Identify the role of the interprofessional team in the evaluation and management of the opioid-induced endocrinopathy.

Introduction

Opioid-induced endocrinopathy (OIE) is a condition which is estimated to affect more Americans than other common comorbid conditions such as heart disease and diabetes combined.[1] It is an important and often unrecognized cause of endocrinopathy, and can result in various clinical manifestations such as sexual dysfunction, amenorrhea, osteoporosis, fatigue, decreased muscle mass, gynecomastia, anemia, and depression. It is essential to increase awareness of the OIE and the adverse effects of the long-term opioid therapy as they should not be overlooked in the treatment of chronic pain, so there is an expectation that the medical benefits of the chronic opioid therapy, in fact, outweigh its potential risks and side effects.

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 s a very common and prevalent condition.[2]

Unfortunately, there is limited awareness of OIE as a common side effect of chronic opioid therapy and often is 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 that are 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 opioid-induced endocrinopathy 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 hypothalamic-pituitary-gonadal axis (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 levels of estrogen. Increasing levels of testosterone and estrogen 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), growth hormone (GH). 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 the origin of androgen production in females as primarily via the adrenal glands. This may explain why DHEAS, secreted by the adrenal glands, is a better measure for adrenal androgen function in females. It is well known that just one 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 perhaps atrophy of adrenal origin. Many case reports have documented the suppression of the hypothalamic-pituitary-adrenal axis (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 placing this patient population at increased risk of adrenal crisis and/or adrenal insufficiency at times of increased physiological stress such as surgery and sickness.

History and Physical

Age and gender do not predict who will suffer from opioid-induced endocrinopathy, as much as the duration of opioid use itself will. Patients with OIE will 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] Many times a patient will usually be assessed and diagnosed with opioid-induced endocrinopathy as a secondary or incidental finding in addition to their chief complaint. 

Obtaining a detailed drug history is essential as polypharmacy may contribute or mask a patient's symptoms. It is important to obtain an accurate understanding of a patient's medical history and detailed symptomology in order 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, 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, growth hormone (GH) among other laboratory tests.[6] When considering your differential diagnosis, it is prudent to appreciate both pertinent positive, as well as pertinent negative findings in the venture to narrow down a final diagnosis of opioid-induced endocrinopathy.

Treatment / Management

The use of opioids and chronic opioid therapy in the treatment of chronic pain is always a risk versus benefit consideration which must be reassessed on a continuing basis in order to help assure that the benefits outweigh the risks as well as in order 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 opioid-induced endocrinopathy should be addressed accordingly.

In men, there appears to be widespread consensus that revolves around testosterone replacement therapy. In order 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 attribute to unstable serum levels over the aforementioned forms. Hormone replacement therapy should include follow-up laboratory assessments at approximately 2 to 3-week intervals so that dosages are titrated 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 will bind 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 (MME).

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 patients' chronic pain status.[7] For this reason, a high degree of suspicion, in addition to proper laboratory findings, may be needed to rule in a diagnosis of opioid-induced endocrinopathy.

A differential diagnosis for opioid-induced endocrinopathy includes but are not limited to the following;

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

Prognosis

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 completely wean from opioid therapy, 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 opioid-induced endocrinopathy may be substantial.

Of note, there are several case reports that illustrate episodes of adrenal crisis as a possible complication in this patient population. The exact effect and role of glucocorticoid replacement in patients with opioid-induced endocrinopathy remain not fully understood.[9]

Consultations

The potential adverse clinical effects of chronic opioid use are associated with a large differential diagnosis. Also, the exact etiology of endocrine dysfunction can be complex and challenging, as the root cause may stem from many factors such as a patient's age, polypharmacy, psychological conditions, and various medical conditions and underlying comorbidities. Proper consultation of a chronic pain specialist and especially an endocrinologist may be fruitful.[5] The fact that opioid-induced endocrinopathy can mirror the clinical findings of many common comorbidities illustrates how it may be overlooked or go unrecognized by healthcare professionals. It is for this reason that providers not familiar with OIE be further educated on this condition such that these cases do not go unnoticed.[10]

Deterrence and Patient Education

It is imperative to form a patient-centered plan, as possibilities for weaning patients off of long term opioid therapy will require a high degree of patient motivation and understanding. Patients should be educated on alternatives to chronic opioid therapy, the value of a multimodal treatment plan, the logic behind the downward titration of opioid dosage, as well as possibly changing opioid class if chronic opioid therapy remains indicated.

Patients with chronic pain who continue to require opioids as part of their treatment plan tend to get accustomed to their opioid regimen and maybe psychologically dependent, thus changing the status quo may be alarming to them. It may be useful to discuss alternatives to chronic opioid therapy, the value of a multimodal treatment plan, and the logic behind the downward titration of their opioid dosage. It is also important to discuss the various factors that go into the selection of a specific opioid regimen such that the patient can understand to a reasonable level, the extent of the complexity that goes into choosing the correct opioid regimen.[11]

Enhancing Healthcare Team Outcomes

Due to a generalized and commonly non-acute clinical presentation, due to a limited understanding and testing for OIE, the data pertaining to its prevalence and pervasiveness remains unclear. The current evidence indicates that OIE is very common with significant clinical consequences. Patients suffering from chronic pain being treated with chronic opioid therapy are likely to be suffering from OIE. Increasing the awareness of this condition as well as more routinely testing for, diagnosing, and treating OIE is necessary as this will likely have a significant improvement in these patients' quality of life. 

When considering the continuation of chronic opioid therapy, as part of the informed consent process, patients should be counseled on the common risks and side effects of long-term opioids to include OIE, and with its many clinical manifestations which may include low energy, decreased libido, impotence, amenorrhea, osteoporosis, anemia, depression, and decreased muscle mass.

Recognizing, testing for and diagnosing as well as treating OIE while ruling out as well as addressing and treating other possible contributing factors and conditions common in patients with chronic pain being treated with opioids require a multi-disciplinary approach to patient care and management.

The involvement of and routine follow-up and communication with chronic pain specialists, as well as endocrinologists, may be a promising approach to optimal patient care and outcomes. Unless clinically indicated, the majority of the disease course may be managed on an outpatient basis.