What are the health effects of long-term use of Tussionex (hydrocodone) in patients, particularly those with a history of substance abuse or pre-existing respiratory, kidney, or liver disease?

Long-Term Health Effects of Tussionex (Hydrocodone)

Long-term use of Tussionex (hydrocodone) carries substantial risks including dose-dependent addiction (adjusted OR up to 122.5), serious overdose (adjusted HR 8.4), cardiovascular events, fractures, endocrine dysfunction, and death—risks that escalate dramatically with higher doses and concurrent benzodiazepine use. 1

Critical Mortality and Morbidity Risks

Addiction and Substance Use Disorder

• Long-term opioid use is associated with dramatically increased risk of abuse or dependence, with adjusted odds ratios ranging from 14.9 to 122.5 depending on dose. 1
• In primary care settings, prevalence of opioid abuse ranges from 0.6% to 8% and dependence from 3% to 26%. 1
• In pain clinic settings, prevalence of misuse ranges from 8% to 16% and addiction from 2% to 14%. 1
• Patients with active or previous substance abuse (including alcoholism) and family history of substance abuse are at significantly higher risk for misuse and abuse. 1

Overdose and Death

• Current opioid use is associated with a 5.2-fold increased risk of any overdose events (adjusted HR 5.2,95% CI = 2.1–12) and an 8.4-fold increased risk of serious overdose events (adjusted HR 8.4,95% CI = 2.5–28) versus nonuse. 1
• The risk escalates dramatically with dose: at ≥100 MME/day, the adjusted HR for overdose reaches 8.87 (95% CI = 3.99–19.72), and at ≥200 MME/day, the adjusted OR for opioid-related death is 2.88 (95% CI = 1.79–4.63). 1
• Fatal overdose deaths show concurrent benzodiazepine use in 31-61% of cases, with the combination producing synergistic respiratory depression. 1, 2

Cardiovascular Complications

• Long-term opioid use is associated with increased risk of myocardial infarction versus nonuse (adjusted OR 1.28,95% CI = 1.19–1.37 and incidence rate ratio 2.66,95% CI = 2.30–3.08). 1
• The risk increases in a dose-dependent manner: for cumulative doses of 8,100 to <18,000 MME during a 90-day period, the incidence rate ratio for myocardial infarction is 1.89 (95% CI = 1.54–2.33). 1

Fractures and Falls

• Opioid use is associated with increased risk of fracture (adjusted HR 1.28,95% CI = 0.99–1.64 in cohort studies and adjusted OR 1.27,95% CI = 1.21–1.33 in case-control studies). 1
• Risk increases with dose from an adjusted HR of 1.20 at 1 to <20 MME/day to 2.00 at ≥50 MME/day. 1
• Long-term opioid use is associated with dose-dependent increases in falls risk. 3

Endocrine Dysfunction

• Long-term opioid use is associated with increased risk for use of medications for erectile dysfunction or testosterone replacement versus nonuse (adjusted OR 1.5,95% CI = 1.1–1.9). 1
• At ≥120 MME/day, the adjusted OR for use of medications for erectile dysfunction or testosterone replacement is 1.6 (95% CI = 1.0–2.4). 1
• Higher-dose long-term opioid therapy is associated with increased risk of androgen deficiency among men receiving immediate-release opioids (adjusted OR per 10 MME/day 1.16,95% CI = 1.09–1.23). 1

High-Risk Populations Requiring Special Caution

Patients with Respiratory Disease

• Risk is substantially greater for patients with sleep apnea or other causes of sleep-disordered breathing. 1
• Opioid therapy can decrease respiratory drive, worsen central sleep apnea in obstructive sleep apnea patients, and cause further desaturation in obstructive sleep apnea patients not on continuous positive airway pressure (CPAP). 1
• Long-term opioid therapy can result in an abnormal apnea-hypopnea index in a high percentage of patients. 1

Patients with Renal or Hepatic Disease

• Reduced renal or hepatic function results in greater peak effect and longer duration of action, reducing the dose at which respiratory depression and overdose occurs. 1, 4
• Patients with renal impairment may have up to 70% higher systemic exposure to hydrocodone, with mean AUC0-∞ increasing from 565 ng·h/mL in normal function to 973-983 ng·h/mL in moderate to severe impairment. 5
• Patients with moderate hepatic impairment show mean AUC0-∞ of 269 ng·h/mL versus 155 ng·h/mL in those with normal function. 5
• Use a low initial dose in patients with hepatic or renal impairment and follow closely for adverse events such as respiratory depression and sedation. 4

Elderly Patients

• Elderly patients (aged 65 years or older) have increased sensitivity to hydrocodone due to age-related changes including reduced renal function and medication clearance, even in the absence of renal disease. 1, 4
• This results in a smaller therapeutic window between safe dosages and dosages associated with respiratory depression and overdose. 1
• Respiratory depression is the chief risk for elderly patients treated with opioids, particularly after large initial doses or when co-administered with other agents that depress respiration. 4
• Titrate dosage slowly in geriatric patients and follow closely for signs of central nervous system and respiratory depression. 4

Patients with Substance Abuse History

• Patients with active or previous substance abuse (including alcoholism) and family history of substance abuse are more likely to misuse and abuse opioids. 1
• This risk must be considered before treatment with an opioid analgesic is initiated. 1

Pregnant Women

• Opioid use in pregnancy is associated with birth defects including neural tube defects, congenital heart defects, and gastroschisis; preterm delivery; poor fetal growth; and stillbirth. 1
• Opioid use during pregnancy can lead to neonatal opioid withdrawal syndrome. 1, 4
• Hydrocodone crosses the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. 4
• Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. 4

Patients with Mental Health Conditions

• Patients with mental health comorbidities might be at higher risk than other patients for opioid use disorder. 1
• Patients with depression or other mental health conditions are at increased risk for harm. 1

Additional Serious Adverse Effects

Gastrointestinal Complications

• Long-term opioid use is associated with dose-dependent increases in gastrointestinal pathology and bleeding. 3
• Constipation tends to be a chronic problem for patients taking opioids and should be monitored closely and treated with a bowel regimen. 1

Hematologic Effects

• Long-term opioid use is associated with dose-dependent increases in iron deficiency anemia. 3

Immune System Effects

• Growing evidence indicates that long-term opioid use may have significant effects on the immune system, potentially increasing the risk of infections. 6

Accidental Poisoning

• Long-term opioid use is associated with dose-dependent increases in the risk of accidental poisoning. 3

Intentional Self-Harm

• Long-term opioid use is associated with dose-dependent increases in the risk of intentional overdose, attempted suicide, and self-harm. 3

Critical Drug Interactions

Benzodiazepines: The Most Dangerous Combination

• Concurrent use of benzodiazepines and opioids produces synergistic respiratory depression, with death rates 3- to 10-fold higher compared to opioids alone. 2
• Epidemiologic studies found evidence of concurrent benzodiazepine use in 31-61% of fatal overdose deaths. 1, 2
• The combination of opioid and benzodiazepine is the most dangerous combination with synergistic respiratory depression. 2
• Patients receiving combined opioid and sedative therapy require increased intensity and duration of monitoring. 2

Other Sedating Medications

• Adding parenteral opioids or hypnotics to neuraxial opioids increases respiratory depression occurrence. 2

Prevalence of Long-Term Use

• Although only 1.7% of immediate-release hydrocodone/acetaminophen patients continue treatment long-term (>90 days), this represents 104,839 patients—nearly 5 times the number receiving extended-release morphine and nearly 4 times the number receiving extended-release oxycodone long-term. 7
• Approximately 15% of IR hydrocodone/acetaminophen patients (n > 900,000) were prescribed total daily acetaminophen doses exceeding 4 g (the FDA-recommended limit) at their initial prescription or any time during therapy. 7

Clinical Implications for Monitoring

• Opioid prescribing should be reviewed before long-term use becomes established, and periodically thereafter to ensure that patients are not being exposed to increased risk of harm which is not balanced by therapeutic benefit. 3
• Patients who do not experience clinically meaningful pain relief early in treatment (within 1 month) are unlikely to experience pain relief with longer-term use. 1
• All patients treated with long-term opioid therapy develop physical dependence; therefore, it is important to taper dosages gradually when treatment is being discontinued. 1