April 30, 2020

Long-Term Risks of Opioids – The Science, the Stories, and the Oath

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Long-Term Risks of Opioids – The Science, the Stories, and the Oath

Lee A. Kral, Pharm.D., CPE

Clinical Assistant Professor, The University of Iowa Carver College of Medicine, Clinical Pharmacy Specialist, Pain Management, University of Iowa Hospitals & Clinics, Iowa City, Iowa

Lee A. Kral is Clinical Assistant Professor at The University of Iowa Carver College of Medicine and a faculty member of the Pain Medicine Fellowship. She received Bachelor of Science and Doctor of Pharmacy degrees from The University of Iowa College of Pharmacy, completed residency at The University of Iowa Hospitals & Clinics (UIHC), and is a certified pain educator.

Dr. Kral runs a chronic pain medication management clinic within the Pain Management Clinic at UIHC working with chronic pain patients. She also works with the Acute Pain Service, engaged in pre-operative pain assessments for the surgical teams and perioperative interdisciplinary pain management.


Which of the following would you consider using in your patients taking long-term opioids?

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Historically, opioids were only used for short-term severe acute pain and in the palliative care and hospice settings. That’s what we learned in pharmacy school when we learned about treating cancer pain. Of course, opioid therapy has now expanded to long-term use for patients who suffer from chronic pain and do not have life-limiting illness. There are STILL practice leaders that state that these analgesics are well-tolerated and pose low risk when used long-term, especially if you screen for risk of abuse/misuse. Unfortunately, this is a misleading message that has led to many of the problems we see today. I am not referring to respiratory depression or overdose, or even constipation, itching, nausea, sedation, or even sleep-disordered breathing. I am referring to the sneaky long-term consequences of long-term opioid therapy. In the past 20 years of escalating and long-term use, we have had the opportunity to identify and study these risks. We have also had the responsibility of caring for patients who experience the long-term adverse effects of chronic opioid therapy.

Hypoadrenalism and Hypogonadism

It is well known now that opioids cause many of the same long-term adverse effects as corticosteroids. One of these is central suppression of the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonadal axis.1-3 We have seen adrenal suppression in both the inpatient and outpatient settings with an incidence ranging from 9-29%.1 For inpatients, we have difficulty maintaining blood pressure after surgery, needing vasopressor therapy. Cortrosyn testing typically reveals that we need to add stress-dose hydrocortisone. For outpatients, we have seen persistent hypotension requiring fludrocortisone to maintain pressures. This is one of the reasons that we prioritize opioid tapering before surgery at our institution.

Gonadotropin suppression was described decades ago but mostly ignored until recently. For years we have seen the clinical consequences of reduced sexual function, reduced libido, and infertility in both genders. This is starting to be a better-known consequence in the fertility and gender health fields. This seems to be most commonly seen with long-acting opioid formulations compared with short-acting opioids.4,5

Of course, the long-term effects of hypogonadism also include osteoporosis. Patients over the age of 60 taking at least 50 MME (morphine milligram equivalents) have a 10% rate of fracture per year. These patients, after controlling for other confounding variables, were noted to have a 2-fold higher risk of fracture than if they did not take opioids.6 This is another reason that we taper opioids (and check bone density) before surgery, particularly spine surgery, at our institution.


Opioids are also well-known immunosuppressants, and several published studies show increased rates and severity of infection in patients taking chronic opioid therapy. Types of infections have included pneumonia (including invasive pneumococcal disease), bacteremia, CNS infections, septic arthritis, osteomyelitis, endocarditis, pyelonephritis, and cellulitis. The risk has been estimated in various studies from 38% up to 62%. This has typically been seen in patients taking long-acting, high-potency, and high dose opioids, most commonly morphine, codeine, fentanyl, and methadone, as well as those recently initiating use.7

Central Sensitization

For me, the most devastating long-term adverse effect and the most difficult to manage is central sensitization.8 It is now known that stimulation of glial cells occurs in the central, peripheral, and enteric nervous systems. Just as central sensitization appears to be the cause of the “chronic” part of chronic pain, it is also the result of therapies that we use to treat the chronic pain, like opioids.9 Some have called this “opioid-induced hyperalgesia” but it is much more than that. The consequences of central sensitization are, most notably, more diffuse and intense pain. The management involves either reducing the stimulus (e.g., tapering opioid) or managing the response (e.g., ketamine).10

We have seen tapering to be more effective in the chronic pain population and adjuvants to be effective in patients who are not able to taper (e.g., palliative and acute post-surgical settings). This is another reason why we taper opioids before surgery at our institution. You can imagine that this is not a popular patch for patients who have used opioids for years. Compassion along with education is necessary. Avoid fast tapers and sudden changes and have conversations about risk and benefit.

Do No Harm

What does all this mean for pharmacists? It means we need to take long-term monitoring seriously and be willing to have some difficult conversations with patients. Standards have not been established for monitoring and treating opioid-induced hypogonadism or hypoadrenalism. Consider lab and bone mineral density monitoring in patients taking opioid therapy equivalent to 100 mg of morphine daily. Bone mineral density testing is recommended every 2 years for patients with hypogonadism.11 Consider pre-operative opioid tapering, or at the least, monitoring for adverse effects postoperatively. There is no set formula developed yet, but this is currently being studied. Be especially mindful of infectious complications in patients prone to them.

Patients may not report any of these adverse effects, or they may say that they do not care about the risks as long as they continue to receive their opioid. You have probably also seen patients taking chronic prednisone be very reluctant to taper or stop this, despite no elevation in inflammatory markers and despite the long-term risks. However, our oath requires that we do no harm, and at the very least we need to embark on a journey with patients to find the lowest effective dose of their opioid (and steroid!) and monitor for long-term adverse effects.

More Information


  1. Donegan D, Bancos I. Opioid-induced adrenal insufficiency. Mayo Clin Proc. 2018; 93:937-44.
  2. Colameco S, Coren JS. Opioid-induced endocrinopathy. J Am Osteopath Assoc. 2009; 109:20-5.
  3. Brennan MJ. The effect of opioid therapy on endocrine function. Am J Med. 2013; 126:S12-S18.
  4. Rubinstein AL, Carpenter DM, Minkoff JR. Hypogonadism in men with chronic pain linked to the use of long-acting rather than short-acting opioids. Clin J Pain. 2013; 29:840-5.
  5. Daniell HW. Opioid endocrinopathy in women consuming prescribed sustained-action opioids for the control of nonmalignant pain. J Pain. 2008; 9:28-36.
  6. Saunders KW, Dunn KM, Merrill JO et al. Relationship of opioid use and dosage levels to fractures in older chronic pain patients. J Gen Intern Med. 2010; 25:310-5.
  7. Wiese AD, Grijalva CG. The use of prescribed opioid analgesics & the risk of serious infections. Future Microbiol. 2018; 13:849-52.
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  9. Grace PM, Maier SF, Watkins LR. Opioid-induced central immune signaling: implications for opioid analgesia. Headache. 2015; 55:475-89.
  10. Nijs J, Meeus M, Van Oosterwijck J et al. Treatment of central sensitization in patients with ‘unexplained’ chronic pain: what options do we have? Expert Opin Pharmacother. 2011; 12:1087-98.
  11. Wang C, Nieschlag E, Swerdloff R et al; International Society of Andrology (ISA); International Society for the Study of Aging Male (ISSAM); European Association of Urology (EAU); European Academy of Andrology (EAA); American Society of Andrology (ASA). Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. J Androl. 2009; 30:1-9.