Case Reports

Opioid-Induced Androgen Deficiency in Veterans With Chronic Nonmalignant Pain

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

References

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The average age of the male patients with a testosterone level drawn was 58.3 years, which was not significantly different from the calculated median age of 60 years. No female patients had a testosterone level drawn. On average, the TT level was normal before starting opioids (reference range per local laboratory: 175-781 ng/dL). Once opioids were initiated, patients were treated for an average duration of 52.5 months (calculated through December 2013) with an average daily dose of 126.8 MED (Table). Fifty of the 70 patients (71.4%) with testosterone levels drawn in 2013 received TRT. The most common symptoms reported by patients related to low testosterone included ED, decreased libido, depression, chronic fatigue, generalized weakness, and hot flashes or night sweats.

The average TT level prior to TRT was 145.3, and the average  testosterone level after initiation of or  during treatment with TRT was 292.4, which is within the normal TT level range. Most patients receiving TRT were treated with testosterone cypionate injections, and this was also the formulation used for the longest periods, likely due to the local CFU. In addition to testosterone cypionate injections, patients were also treated with testosterone enanthate injections, testosterone patches, and testosterone gel.

Figure 1 compares current testosterone level and testosterone level before TRT with total daily MEDs. Figure 2 compares current testosterone level and testosterone level before TRT with length of opioid therapy. The 2 figures use data from all patients included in the analysis and indicate a potential inverse relationship between the total daily MED and duration of therapy with the testosterone level, although none of the calculated correlation coefficients indicate that a strong relationship was present.

Figures 3 and 4 include data only for patients who had both a testosterone level collected before opioids (baseline testosterone level) and a current testosterone level. Figure 3 trends the data using total daily MED, and Figure 4 uses the duration of opioid therapy. The correlation for Figure 4 is slightly stronger; the strongest negative correlations were identified between total daily MED and testosterone level before opioid therapy (r = -0.273) and duration of opioid therapy and testosterone level prior to opioid therapy (r = -0.396). The trends indicate that most patients had a normal TT level before opioid treatment and that patients treated with higher MEDs and for longer durations of time were more likely to have lower total testosterone levels.

Discussion

Low testosterone levels can adversely affect patients’ quality of life (QOL) and add to patients’ medication burden with the initiation of TRT. Given new data analyzing the potential effects of TRT on CV event risk, the use of TRT should be carefully considered, as it may carry significant risks and may not be suitable for all patients.

In November 2013, a study was published regarding TRT and  increased CV risk.¹⁷ This was a retrospective cohort study of men with low testosterone levels (< 300 ng/dL) who had undergone coronary angiography in the VA system between 2005 and 2011 (average age in testosterone group was 60.6 years). The results were significant for an absolute rate of events (all-cause mortality, myocardial infarction [MI], and ischemic stroke) of 19.9% in the no testosterone group and 25.7% in the TRT group, an absolute risk difference of 5.8% at 3 years after coronary angiography. Kaplan-Meier survival curves demonstrated that testosterone use was associated with increased risk of death, MI, and stroke. This result was unchanged when adjusted for the presence of coronary artery disease (CAD). In  addition, no significant difference was found between the groups in terms of systolic blood pressure, low- density lipoprotein cholesterol level, or in the use of beta-blocker and statin medications. What is important to note is that in this cohort, 20% had a prior history of MI and heart failure, and more than 50% had confirmed obstructive CAD on angiography. In addition, as this was an observational study, confounding or bias may exist, and given the study population,  generalizability may be limited to a veteran population.

Another retrospective cohort study assessed the risk of acute nonfatal MI following an initial TRT prescription in a large health care database (average age based on TRT prescription was 54.4 years).¹⁸ In men aged ≥ 65 years, a 2-fold increase in the risk of MI in the immediate 90 days after filling an initial TRT prescription declined to baseline after 91 to 180 days among those who did not refill their prescription. Younger men with a history of heart disease had a 2- to 3-fold increased risk of MI in the 90 days following initial TRT prescription. No excess risk was observed in the younger men without such a history. Again, this study has its limitations related to the retrospective design and use of a health care database as opposed to a randomized controlled trial.