Case Reports

Opioid-Induced Androgen Deficiency in Veterans With Chronic Nonmalignant Pain

Patients on chronic opioid therapy or considering it should be counseled about the risks  associated with opioid-induced androgen deficiency.

Fed Pract. 2015 October;32(10):26-31

Author(s):

Abigail Brooks, PharmD, BCPS

Mitchell Nazario, CPE

Sandra DiScala, BCPS

Ramon Cuevas-Trisán, MD

John Meléndez-Benabe, MD

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References

1. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control. Unintentional drug poisoning in the United States, 2010. Atlanta, GA: Centers for Disease Control and Prevention Website. http://www.cdc.gov /HomeandRecreationalSafety/pdf/poison-issue-brief .pdf. Published July 2010. Accessed August 28, 2015.

2. American Academy of Family Physicians. Using opioids in the management of chronic pain patients: challenges and future options. University of Kentucky Medical Center Website. http://www .mc.uky.edu/equip-4-pcps/documents/CRx%20Literature/Opioids%20for%20chronic%20pain.pdf. Published 2010. Accessed August 28, 2015.

3. Duarte RV, Raphael JH, Labib M, Southall JL, Ashford RL. Prevalence and influence of diagnostic criteria in the assessment of hypogonadism in intrathecal opioid therapy patients. Pain Physician. 2013;16(1):9-14.

4. Smith HS, Elliott JA. Opioid-induced androgen deficiency (OPIAD). Pain Physician. 2012;15(suppl 3):ES145-ES156.

5. De Maddalena C, Bellini M, Berra M, Meriggiola MC, Aloisi AM. Opioid-induced hypogonadism: why and how to treat it. Pain Physician. 2012;15(suppl 3):ES111-ES118.

6. Bhasin S, Cunningham GR, Hayes FJ, et al; VM Endocrine Society Task Force. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536-2559.

7. Petak SM, Nankin HR, Spark RF, Swerdloff RS, Rodriguez-Rigau LJ; American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists Medical Guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients–2002 update. Endocr Pract. 2002;8(6):440-456.

8. Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. J Androl. 2009;30(1):1-9.

9. Reddy RG, Aung T, Karavitaki N, Wass JA. Opioid induced hypogonadism. BMJ. 2010;341:c4462.

10. U.S. Department of Veterans Affairs, Veterans Health Administration. VHA Handbook 1058.05: VHA operations activities that may constitute research. U.S. Department of Veterans Affairs Website. http://www.va.gov/vhapublications /ViewPublication.asp?pub_ID=2456. Published October 28, 2011. Accessed August 28, 2015.

11. AndroGel [package insert]. North Chicago, IL: AbbVie Inc; 2013.

12. Axiron [package insert]. Indianapolis, IL: Lilly USA, LLC; 2011.

13. U.S. Department of Veterans Affairs. Opioid therapy for chronic pain pocket guide. U.S. Department of Veterans Affairs. http://www.healthquality .va.gov/guidelines/pain/cot/opioidpocketguide23may2013v1.pdf. Published May 2013 Accessed August 28, 2015.

14. McPherson ML. Demystifying Opioid Conversion Calculations: A Guide for Effective Dosing. Bethesda, MD: American Society of Health-System Pharmacists; 2009.

15. Butrans [package insert]. Stamford, CT: Purdue Pharma LP; 2014.

16. Testosterone Replacement Therapy Criteria for Use. VISN 8: VISN Pharmacist Executives, Veterans Health Administration, Department of Veterans Affairs; 2014. [Internal document.]

17. Vigen R, O’Donnell CI, Barón AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17):1829-1836.

18. Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One. 2014;9(1):e85805.

19. U.S. Department of Veterans Affairs. Testosterone products and cardiovascular safety. U.S. Department of Veterans Affairs Website. http://www.pbm .va.gov/PBM/vacenterformedicationsafety /nationalpbmbulletin/Testosterone_Products_and _Cardiovascular_Safety_NATIONAL_PBM _BULLETIN_02.pdf. Published February 7, 2014. Accessed August 28, 2015.

20. U.S. Department of Veterans Affairs Veterans Health Administration (VHA) Pharmacy Benefits Management Services (PBM), Medical Advisory Panel (MAP) and Center for Medication Safety (VA MEDSAFE). Memorandum: Opioid Safety Initiative Requirements. U.S. Department of Veterans Affairs Website. http://www.veterans.senate.gov/imo /media/doc/VA%20Testimony%20-%20April%2030%20SVAC%20Overmedication%20hearing.pdf. Published April 30, 2014. Accessed August 28, 2015.

21. Brennan MJ. The effect of opioid therapy on endocrine function. Am J Med. 2013;126(3)(suppl 1):S12-S18.

22. 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(10):840-845.

23. Rubinstein A, Carpenter DM. Elucidating risk factors for androgen deficiency associated with daily opioid use. Am J Med. 2014;127(12):1195-1201.

According to the CDC, the medical use of opioid painkillers has increased at least 10-fold during the past  20 years, “because of a movement toward more aggressive management of pain.”¹ Although opioid therapy is generally considered effective for the treatment of pain, long-term use (both orally and intrathecally) is associated with adverse effects (AEs) such as constipation, fatigue, nausea, sleep disturbances, depression, sexual dysfunction, and hypogonadism.^2,3Opioid-induced androgen deficiency (OPIAD), as defined by Smith and Elliot, is a clinical syndrome characterized by inappropriately low concentrations of gonadotropins (specifically, follicle-stimulating hormone [FSH] and luteinizing hormone [LH]), which leads to inadequate production of sex hormones, including estradiol and testosterone.⁴

The mechanism behind this phenomenon is initiated by either endogenous or exogenous opioids acting on opioid receptors in the hypothalamus, which causes a decrease in the release of gonadotropin- releasing hormone (GnRH). This decrease in GnRH causes a reduction in the release of LH and FSH from the pituitary gland as well as testosterone or estradiol from the gonads.^4,5 Various guidelines report different cutoffs for the lower limit of normal total testosterone: The Endocrine Society recommends 300 ng/dL, the American Association of Clinical Endocrinologists suggests 200 ng/dL, and various other organizations suggest 230 ng/dL.^6-8 Hypotestosteronism can result in patients presenting with a broad spectrum of clinical symptoms, including reduced libido, erectile dysfunction (ED), fatigue, hot flashes, depression, anemia, decreased muscle mass, weight gain, and osteopenia or osteoporosis.⁴ Women with low testosterone levels can experience irregular menstrual periods, oligomenorrhea, or amenorrhea.⁹ Opioid-induced androgen deficiency often goes unrecognized and untreated. The reported prevalence of opioid-induced hypogonadism ranges from 21% to 86%.^4,9 Given the growing number of patients on chronic opioid therapy, OPIAD warrants further investigation to identify the prevalence in the veteran population to appropriately monitor and manage this deficiency.

The objective of this retrospective review was to identify the presence of secondary hypogonadism in chronic opioid users among a cohort of veterans receiving chronic opioids for nonmalignant pain. In addition to identifying the presence of secondary hypogonadism, the relationship between testosterone concentrations and total daily morphine equivalent doses (MEDs) was reviewed. These data along with the new information recently published on testosterone replacement therapy (TRT) and cardiovascular (CV) risk were then used to evaluate current practices at the West Palm Beach VAMC for OPIAD monitoring and management and to modify and update the local Criteria for Use (CFU) for TRT.

Methods

Patient data from the West Palm Beach VAMC in Florida from January 2013 to December 2013 were reviewed to identify patients who had a total testosterone (TT) level measured. All patient appointments for evaluation and treatment by the clinical pharmacy specialist in pain management were reviewed for data collection. This retrospective review was approved by the scientific advisory committee as part of the facility’s ongoing performance improvement efforts as defined by VHA Handbook 1058.05 and did not require written patient consent.¹⁰

Several distinct TT level data were collected. The descriptive data included patient age; gender; type of treated pain; testosterone level(s) drawn, including TT level before opioid therapy, TT level before/during/after TRT, and current total testosterone level; total daily MED of opioid therapy; duration of chronic opioid therapy; symptoms of exhibited hypogonadism; TRT formulation, dose, and duration; TRT prescriber; symptom change (if any); and laboratory tests ordered for TRT monitoring (lipid profile, liver profile, complete blood count, LH/FSH, and prostate specific antigen [PSA] panel).^5,11,12

Daily MED of opioid therapy was calculated using the VA/DoD opioid conversion table for patients on oxycodone, hydromorphone, or hydrocodone.¹³ For those on the fentanyl patch or methadone, conversion factors of 1:2 (fentanyl [µg/h]:morphine [mg/d]) and 1:3 (methadone:morphine) were used to convert to the MED.¹⁴ For patients on the buprenorphine patch, the package insert was used to convert to the corresponding MED.¹⁵ Combination therapies used the applicable conversions to calculate the total daily MED.

Once the data were collected, descriptive statistics were used to analyze the data. In addition, 4 graphs were generated to review potential relationships. The correlation coefficient was calculated using the Alcula Online Statistics Calculator (http://www.alcula.com; Correlation Coefficient Calculator).

Results

A total of 316 unique veteran patients were seen by the clinical pharmacy specialist in pain management from January 1, 2013, through December 31, 2013. Of these, 73 patients (23.1%) had at least 1 TT level drawn in 2013. Three patients with testosterone levels drawn (4.1%) were excluded from the data analysis for the following reasons: 1 patient did not have testosterone levels on file before receiving testosterone replacement from a non-VA source,  1 patient received opioids from a non-VA source (MED and duration of opioid therapy could not be calculated), and 1 patient inconsistently received opioids and MED used at the time of testosterone level draw. Per the local TRT CFU, a TT level > 350 ng/dL does not require treatment, whereas levels < 230 ng/dL (with symptoms) may require TRT, and  < 200 ng/dL should be treated as  hypogonadal (interpretation based on local laboratory’s reference range for TT).16 Of the 70 patients included in the analysis, 34 (48.6%) had a TT level < 230 ng/dL and would be considered eligible for TRT if they presented with symptoms  of low testosterone. Of these 34 patients with a low testosterone level, 28 (40%) were being treated or had been treated with TRT (Figure 1).