Long-Term Cancer Pain and Endocrinopathy

Cancer causes a specific type of pain. As cancer progresses, it can expand and put pressure on sensitive body structures and invade nerves and bones.¹ Ninety percent of cancer patients experience pain, and opioids remain the foundation of long-term cancer pain control. The World Health Organization analgesic ladder is a three-step guide for treating cancer pain, based on a numerical pain rating from 1 to 10.²  WHO advocates using opioids to treat moderate-to-severe pain (5 to 10). ^1,2

“Opioids are a very large part of pain treatment for cancer. But you need to consider and treat total pain. Long-term pain requires a holistic approach that includes nonpharmacologic measures along with opioids,” said Jennifer S. Scherer, MD, assistant professor of medicine and palliative care at NYU Langone Medical Center in New York City. 

Side Effects of Opioids

There is a wide array of choices when it comes to opioids. Strength, duration, and route of administration should all be considered when individualizing treatment.⁴ Future research may offer more opioid choices that selectively bind opioid receptor sites for analgesia. 

Endogenous opioids may be antinociceptive agents that are as effective as opioids without adverse effects.¹ But for now, the best opioid choice is the one that controls pain with the fewest side effects. The most commonly recognized side effects are nausea, sleepiness, and constipation.³

“The side effect that seems to cause the most problems is constipation because people do not develop a tolerance for it. We can reduce this risk with an aggressive bowel regimen including liberal use of stool softeners. Other risks we worry about are urinary retention and respiratory depression,” said Scherer. ³

Among many management strategies for decreasing side effects while still controlling pain are lowering the dose, changing to a longer-acting opioid, changing routes of administration, adding nonpharmacologic therapies, and using adjuvant medications.³ The National Cancer Institute includes acupuncture, biofeedback, massage, meditation, guided relaxation, hypnosis, and cognitive behavioral therapy as therapies that may help. ³

“The most important thing is to maintain constant communication with the patient. Keeping a pain diary is helpful for evaluating breakthrough pain. You don’t want to make too many changes too fast. Start with a stable dose of short-acting opioid before switching to a long-acting [one]. Adjuvant meds that may help include antidepressants and anticonvulsants,” said Scherer.  Other adjuvant drugs may include NSAIDs, acetaminophen, local anesthetics, corticosteroids, stimulants, and bisphosphonates for bone pain.³

Opioid Endocrinopathy

A growing body of research suggests that long-term opioids may have a significant impact on endocrine function. A 2014 systematic review of opioid effects on the hypogonadal axis of cancer patients was published in Supportive Care in Cancer. The review included four studies and concluded that the association between opioids and hypogonadism warrants further investigation. ²

A 2013 review of this topic was published in The American Journal of Medicine. The review stated that opioid-induced endocrine dysfunction is underappreciated and suggested that hypogonadism may be the most common toxicity of long-term opioid treatment. The effect is most prominent on the hypothalamic-pituitary-gonadal axis. Research indicates that opioids inhibit the entire axis by binding to receptors in the hypothalamus and decreasing secretion of gonadotropin-releasing hormone. ⁴

Andrea Rubinstein, MD, is an anesthesiologist and pain management specialist at Kaiser Permanente in Santa Rosa, California. She and her colleagues in the endocrinology division have studied the effects of long-acting opioids on hypogonadism in men. Their 2013 study, published in The Clinical Journal of Pain, looked at 81 men receiving a stable dose of opioid at a chronic pain clinic. None of the men had a previous history of hypogonadism. Seventy-four percent of men on long-acting opioids became hypogonadal compared to 34% of men on short-acting opioids. ⁵

“We have now done two studies on the effects of long-acting opioids on hypogonadism in men. Even after controlling for everything we could throw at them, we still get low testosterone in 70 percent of men. Men make testosterone every 90 minutes. If you suppress production with opioids all the time, you get hypogonadism. With short-acting opioids, you may get suppression for three to four hours, but testosterone can still be made,” explained Dr. Rubinstein. 

Opioids may also suppress the hypothalamic-pituitary-adrenal axis resulting in low levels of cortisone, and opioid endocrinopathy may also affect women, but the best evidence is for hypogonadism in men.⁴ “We don’t really have much evidence for the effects of long-term opioids on cortisol. Hypogonadism in women may occur but the symptoms are not as obvious. Amenorrhea would be expected, but many women with cancer pain are already past menopause. At this point, we don’t have any good data on opioid-induced hypogonadism in women,” said Rubinstein. 

Evaluating and Treating Opioid Endocrinopathy

Opioid endocrinopathy may occur in men or women with or without cancer. But a 2014 study published in Cancer suggests that hypogonadism in men with cancer may be particularly dangerous. The study looked at 131 men with cancer and concluded that low testosterone was associated with more inflammation, more weight loss, greater symptom burden, and poor survival. Opioid use was one factor that contributed to low testosterone. ⁶

“All men on long-term opioids should have a total testosterone taken in the morning. They should have the test while taking their opioid as usual. If low testosterone is found, they should have a full endocrine panel drawn,” said Rubinstein. 

Health care providers should ask men about symptoms of hypogonadism. Standardized hypogonadism questionnaires have been shown to be sensitive for diagnosis. If male hypogonadism has been established with a blood sample, options for treatment may include opioid rotation to see if another opioid may have less effect on the gonadal axis.One opioid that may have fewer effects is buprenorphine. ⁴

As of now, there is no evidence to support or direct treatment of women with opioid-induced hypogonadism. Hormone replacement therapy in women has been linked to breast cancer and cardiovascular disease. Treatment may be an option but needs to be evaluated individually. ⁴

“Switching to a short-acting opioid makes sense. There is no evidence that a long-acting opioid is safer or has less risk of abuse. Testosterone replacement should be considered for men who meet all the criteria. All men on long-term opioids should be checked for low testosterone. Low testosterone is easy to treat and a shame to miss. It adds to the stress of living with cancer,” said Rubinstein. 

Medically reviewed by: Pat F. Bass III, MD, MS, MPH

References

1. Plante GE et al. Metabolism. 2010; 59(S1): S47-52.

2. McWilliams K et al. “A systemic review of opioid effects on the hypogonadal axis of cancer patients.” Support Care Cancer. 2014; 22(6):1699-1704.

3. Pain (PDQ), National Cancer Institute,

4. Brennan MJ.  Amer J  Med. 2013; 126(3A): S12-S18.

5. Rubinstein AL.  Clin J Pain. 2013;10:840-5. 

6. Dev R et al. Cancer. 2014; 120(10):1586-1593.