Case Reports

Opioid-Induced Androgen Deficiency in Veterans With Chronic Nonmalignant Pain

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

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.

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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.

In February 2014, a VA National Pharmacy Benefits Management (PBM) bulletin addressed 2 recent studies that had identified a possible risk of increased CV events in men receiving TRT. The bulletin noted that these studies had prompted the FDA to reassess the CV safety of TRT.¹⁹ The TRT CFU was updated by VISN 8 to ensure that the patients receive appropriate treatment and are monitored accordingly.

One of the major changes to the CFU was defining the reference ranges for TRT (interpretation based on a local laboratory’s reference range for total testosterone): serum TT < 200 ng/dL be “treated as  hypogonadal, those with TT  > 400 ng/dL be considered normal and those with TT 200-400 ng/dL be treated based on their clinical presentation if symptomatic; TT levels  > 350 ng/dL do not require treatment, and levels below 230 ng/dL (with symptoms) may require testosterone replacement therapy.”¹⁶ Other important updates included revision of the exclusion criteria as well as  highlighting special considerations related to TRT, including the use of free testosterone levels rather than TT levels in patients with suspected protein-binding issues, role in fertility treatments, limited use in patients on spironolactone therapy (due to spironolactone’s anti-androgen effects), and potential association with mood and behavior.¹⁶

As chronic opioid therapy is associated with OPIAD, the renewed interest in TRT and its potential AEs provides yet another reason to reconsider opioid therapy. This is especially valid when opioids are the potential cause of hypogonadism and the reaction is treating the AEs of opioids (as opposed to considering elimination of the causative agent) with a therapy that can potentially increase the risk for CV events so that opioids can be continued. Outside the potential CV risk with TRT, opioids carry the innate risk for substance abuse and addiction.

The Opioid Safety Initiative Requirements was released as a memorandum in April 2014 and is the VHA’s effort to “reduce harm from unsafe medications and/or excessive doses while adequately controlling pain in Veterans.”²⁰ Although it does not discuss the risk of OPIAD, it does highlight the need to identify and mitigate high-risk patients as well as high-risk opioid regimens. All these factors, including the possibility of hypogonadism, should be considered before starting opioid therapy and at the time of opioid renewal, as it is known that opioid therapy is not without risks.

At the West Palm Beach VAMC, the primary care providers (PCPs) are responsible for the management of TRT, including the workup, renewal, and monitoring. The Chronic Nonmalignant Pain Management Clinic (CNMPMC) orders testosterone levels on patients who report symptoms of low testosterone, such as hot flashes, depression, and low energy level and refers them to their PCP as indicated. The authors believe that this is most appropriate for a number of reasons: (1) the CNMPMC is a consult service, and patients are not followed indefinitely; (2) patients should be fully evaluated for appropriateness of TRT (including assessment of CV risk) before starting therapy; and (3) the necessary monitoring parameters (laboratory testing, digital rectal exam, and osteoporosis screening) are not typically within the VA pain clinic provider’s scope of practice or expertise. A consideration for future practice would be to incorporate the use of a standardized questionnaire for OPIAD monitoring in patients receiving ≥ 100 mg of morphine daily (eg, the Aging Males’ Symptoms scale).²¹ It should, however, be at the forefront of the pain specialist’s and PCP’s minds that all patients on chronic opioid therapy or considering chronic opioid therapy should be counseled on the risk for OPIAD. If OPIAD is identified, the patient should be carefully considered for an opioid dose reduction as an initial management strategy.

Limitations

A limitation of this review is the lack of consistency or adequacy of serum testosterone sampling, noting that valid testosterone levels need to be drawn in the morning and not obtained during a time of acute illness. In addition, testosterone levels need to be drawn at an appropriate interval while on TRT (eg, at the midpoint between testosterone injections).¹⁶Although the time of the sample collection is documented in the Computerized Patient Record System (CPRS), it is unknown whether the patient was acutely ill on the day of the sampling unless a progress note is entered, and it is difficult to determine whether the level timing was accurate based on the testosterone replacement formulation. Another limitation is that the average decline in serum testosterone levels with aging in men is 1% to 2% per year. A significant fraction of older men have levels below the lower limit of the normal range for healthy young men, so in older men it can be more difficult to determine whether low testosterone is related to chronic opioid use or to older age.^5,16