Is low testosterone expected in a 68‑year‑old man receiving long‑term Sublocade (extended‑release buprenorphine)?

Low Testosterone in a 68-Year-Old Man on Long-Term Sublocade

Yes, low testosterone is expected and common in men receiving long-term buprenorphine (Sublocade), though the degree of suppression is significantly less severe than with methadone. 1, 2

Understanding Opioid-Induced Hypogonadism

Buprenorphine vs. Methadone Effects

• Buprenorphine causes hypogonadotropic hypogonadism in approximately 28% of men, compared to 65% with methadone, making it substantially less suppressive but still clinically significant. 2
• Men on buprenorphine maintenance have significantly higher testosterone levels (mean 5.1 ng/mL or 17.7 nmol/L) compared to methadone users (2.8 ng/mL or 9.7 nmol/L), though still lower than age-matched controls. 1
• The mechanism is central suppression of LH and FSH secretion (hypogonadotropic hypogonadism), not primary testicular failure. 2
• Prolactin levels typically remain normal with buprenorphine, distinguishing this from prolactinoma-related hypogonadism. 2

Age-Related Contribution

• At 68 years old, approximately 30% of men have age-related low testosterone independent of medication effects, making this patient's risk cumulative. 3
• Testosterone declines at 1.6% per year starting in the mid-30s, so age alone contributes substantially to this patient's hormonal status. 3
• The combination of age-related decline plus opioid-induced suppression creates a "double hit" scenario that significantly increases the likelihood of symptomatic hypogonadism. 3, 2

Diagnostic Confirmation Required

Do not assume hypogonadism based on medication history alone—biochemical confirmation with two morning testosterone measurements is mandatory. 3, 4

Essential Laboratory Testing

• Measure morning total testosterone (8-10 AM) on two separate occasions, as single measurements are insufficient due to diurnal variation and assay variability. 3, 4
• Measure free testosterone by equilibrium dialysis (or calculate using validated formulas), especially given likely obesity or metabolic syndrome in this population. 3, 4
• Obtain LH and FSH levels to confirm hypogonadotropic (secondary) hypogonadism, which is the expected pattern with opioid use. 4, 2
• Check prolactin to exclude hyperprolactinemia as a contributing factor, though this is typically normal with buprenorphine. 2

Diagnostic Thresholds

• Hypogonadism is defined as total testosterone <300 ng/dL on two separate morning measurements plus specific symptoms. 3, 4
• Free testosterone should be assessed when total testosterone is borderline or when SHBG is abnormal. 3, 4

Clinical Symptom Assessment

Treatment decisions must be based on specific symptoms, not testosterone levels alone. 3, 5

Symptoms That Justify Treatment

• Diminished libido (decreased sexual desire) is the most specific symptom warranting testosterone therapy consideration. 3, 5
• Erectile dysfunction, particularly if PDE5 inhibitors have failed, strongly suggests testosterone deficiency. 3, 5
• Decreased spontaneous or morning erections are "more specific" for hypogonadism compared to other symptom categories. 3

Symptoms With Minimal or No Proven Benefit

• Fatigue, low energy, and decreased vitality show minimal improvement with testosterone therapy (standardized mean difference only 0.17), even in confirmed hypogonadism. 5
• Cognitive symptoms, depression, and physical function show little to no benefit from testosterone replacement. 5
• The American College of Physicians explicitly recommends against testosterone therapy for energy, vitality, physical function, or cognition alone. 3, 5

Treatment Considerations

When to Treat

If this patient has confirmed biochemical hypogonadism (testosterone <300 ng/dL on two occasions) AND sexual symptoms (diminished libido or erectile dysfunction), testosterone therapy is appropriate. 5, 4

• Expected benefits are modest: small but significant improvements in sexual function (standardized mean difference 0.35) and quality of life, primarily in sexual domains. 5, 4
• Set realistic expectations: testosterone will not meaningfully improve energy, mood, or cognitive function. 5
• Reevaluate at 12 months and discontinue if no improvement in sexual function, to avoid unnecessary long-term exposure to potential risks. 5, 4

Formulation Selection

• Transdermal testosterone gel (1.62% at 40.5 mg daily) is preferred first-line due to more stable day-to-day levels and lower erythrocytosis risk compared to injectable preparations. 4
• Intramuscular testosterone cypionate or enanthate (100-200 mg every 2 weeks) is a more economical alternative if cost is a concern. 4
• Target mid-normal testosterone levels (450-600 ng/dL) rather than upper-normal range, especially given this patient's age and likely cardiovascular risk factors. 4

Critical Monitoring Requirements

• Monitor hematocrit at baseline and periodically—withhold treatment if >54% and consider phlebotomy in high-risk cases. 4
• Injectable testosterone carries higher erythrocytosis risk (up to 44%) compared to transdermal preparations. 5, 4
• Monitor PSA levels in men over 40 years before initiating therapy and periodically during treatment. 4
• Check testosterone levels at 2-3 months after initiation, then every 6-12 months once stable. 4

Absolute Contraindications

• Active desire for fertility preservation (testosterone causes azoospermia; gonadotropin therapy would be required instead). 4
• Active or treated male breast cancer. 4
• Hematocrit >54%. 4
• Recent cardiovascular events within the past 3-6 months. 4

Alternative and Adjunctive Approaches

Lifestyle Modifications

• Weight loss through calorie restriction can improve testosterone levels in men with obesity-associated secondary hypogonadism, which is common in this population. 5, 4
• Regular physical activity (minimum 150 minutes/week of moderate-intensity aerobic exercise plus resistance training 2-3 times weekly) should be encouraged. 4
• These interventions may partially reverse opioid-induced hypogonadism and should be implemented regardless of whether testosterone therapy is initiated. 4

Addressing Sexual Dysfunction

• PDE5 inhibitors (sildenafil, tadalafil) should be first-line treatment for erectile dysfunction, and can be combined with testosterone therapy for optimal results. 4
• A minimal level of testosterone is required for complete effect of PDE5 inhibitor therapy, explaining why some men fail these medications when testosterone is low. 4
• Combining PDE5 inhibitors with testosterone therapy improves outcomes in men with low testosterone (standardized mean difference 0.35 for sexual function). 4

Evaluating Alternative Causes

• Screen for sleep disorders, thyroid dysfunction, anemia, vitamin D deficiency, and metabolic syndrome, as these commonly cause fatigue and may be mistaken for testosterone deficiency. 5
• Assess for depression using validated instruments, as depression is common in this population and contributes to sexual dysfunction independent of testosterone levels. 6

Common Pitfalls to Avoid

• Do not diagnose hypogonadism based on symptoms or medication history alone—always confirm with two morning testosterone measurements. 3, 4
• Do not initiate testosterone therapy for nonspecific symptoms (fatigue, low energy, mood changes) without sexual dysfunction, as evidence shows minimal to no benefit. 5
• Do not assume the patient desires fertility preservation without asking directly—testosterone therapy causes prolonged, potentially irreversible azoospermia. 4
• Do not ignore the cumulative cardiovascular risk in this age group—monitor closely for fluid retention, worsening heart failure, and erythrocytosis. 5, 4
• Do not continue testosterone indefinitely without reassessing benefit—if sexual function does not improve within 12 months, discontinue therapy. 5, 4

Clinical Bottom Line

Low testosterone is expected in men on long-term Sublocade, with approximately 28% developing biochemical hypogonadism, though this is substantially less common than with methadone (65%). 2 At age 68, the combination of age-related decline and opioid-induced suppression creates high risk for symptomatic hypogonadism. 3, 2 Confirm the diagnosis with two morning testosterone measurements and assess for sexual symptoms (diminished libido, erectile dysfunction) before considering treatment. 3, 5, 4 If treatment is indicated, set realistic expectations: testosterone improves sexual function modestly but has little to no effect on energy, mood, or cognition. 5